Complications in the adult spinal deformity patient having combined surgery. Does revision increase the risk?
A comparison of short-term complications (within 6 months after surgery) between primary combined adult spinal deformity (multilevel scoliosis, kyphosis, fixed coronal-sagittal imbalance) surgeries (n = 18) and combined adult spinal deformity revision surgeries (n = 26). To analyze the short-term complications and to determine whether revision status increases the risks of short-term complications in this group of patients. There is no peer-reviewed article comparing complications of revision to those in primary patients in a group of patients undergoing combined surgery for adult spinal deformity. Major and minor complications were analyzed for both patient groups, and demographic data were collected. The demographic data of the two groups were very similar. The major (11.1% vs. 7.8%) and minor (11.1% vs. 11.5%) complications for the two groups (primary vs. revision) were very similar. All patients had combined procedures and all were patients with adult spinal deformity. The wound complications were less in those receiving total parenteral nutrition (2 of 31) than in those without (2 of 13). The group receiving parenteral nutrition was thought to be at higher risk for wound complications. The risk of major and minor complications within the first 6 months after surgery is not necessarily greater in the revision group than in the primary group of patients with adult spinal deformity who have combined surgeries. Total parenteral nutrition does appear to have a role in many of these patients.


[Effect of adrenocortical insufficiency on the motor activity of the gall bladder].
In chronical experiments on dogs, blocking of glococorticoidal function of adrenal cortex O, pI -- DDD decreases the gall bladder motility. Disorders of mineralcorticoid activity of adrenal cortex leads to an increase of the motility. Administration of hydrocortisone and 1% solution of sodium chloride aids to normalize the gall bladder motility in animals with adrenal insufficiency.


Influence of age and duration of follow-up on lung function after combined chemotherapy for Hodgkin's disease.
Pulmonary function was studied in 48 patients 4-13 yrs after treatment for Hodgkin's disease with mantle-field irradiation followed by standard mechlorethamine, Oncovin, procarbazine and prednisone (MOPP) chemotherapy. The patients were found to have a restrictive lung disease suggestive of pulmonary fibrosis. Low age at therapy (less than or equal to 30 yrs, median 24 yrs) was associated with a significantly more pronounced restrictive lung function impairment than older age (greater than 30 yrs, median 40 yrs) suggesting a higher susceptibility to the pulmonary side-effects of therapy. In addition younger smokers had a significantly greater reduction in diffusion capacity and forced expiratory volume in one second than older smokers, suggesting a higher susceptibility to the additional adverse effect of smoking. With longer follow-up nonsmokers had an increase in static lung volumes. It is suggested that this may be the result of more frequent pulmonary infections in such patients as compared with the general population. However, the duration of follow-up was not associated with changes in other indices of lung function.


A taxonomy for brainstem cavernous malformations: subtypes of midbrain lesions.
Anatomical taxonomy is a practical tool that has successfully guided clinical decision-making for patients with brain arteriovenous malformations. Brainstem cavernous malformations (BSCMs) are similarly complex lesions that are difficult to access and highly variable in size, shape, and position. The authors propose a novel taxonomy for midbrain cavernous malformations based on clinical presentation (syndromes) and anatomical location (identified with MRI). The taxonomy system was developed and applied to an extensive 2-surgeon experience over a 30-year period (1990-2019). Of 551 patients with appropriate data who underwent microsurgical resection of BSCMs, 151 (27.4%) had midbrain lesions. These lesions were further subtyped on the basis of predominant surface presentation identified on preoperative MRI. Five distinct subtypes of midbrain BSCMs were defined: interpeduncular (7 lesions [4.6%]), peduncular (37 [24.5%]), tegmental (73 [48.3%]), quadrigeminal (27 [17.9%]), and periaqueductal (7 [4.6%]). Neurological outcomes were assessed using modified Rankin Scale (mRS) scores. A postoperative score ≤ 2 was defined as a favorable outcome; a score > 2 was defined as a poor outcome. Clinical and surgical characteristics and neurological outcomes were compared among subtypes. Each midbrain BSCM subtype was associated with a recognizable constellation of neurological symptoms. Patients with interpeduncular lesions commonly presented with ipsilateral oculomotor nerve palsy and contralateral cerebellar ataxia or dyscoordination. Peduncular lesions were associated with contralateral hemiparesis and ipsilateral oculomotor nerve palsy. Patients with tegmental lesions were the most likely to present with contralateral sensory deficits, whereas those with quadrigeminal lesions commonly presented with the features of Parinaud syndrome. Periaqueductal lesions were the most likely to cause obstructive hydrocephalus. A single surgical approach was preferred (> 90% of cases) for each midbrain subtype: interpeduncular (transsylvian-interpeduncular approach [7/7 lesions]), peduncular (transsylvian-transpeduncular [24/37]), tegmental (lateral supracerebellar-infratentorial [73/73]), quadrigeminal (midline or paramedian supracerebellar-infratentorial [27/27]), and periaqueductal (transcallosal-transchoroidal fissure [6/7]). Favorable outcomes (mRS score ≤ 2) were observed in most patients (110/136 [80.9%]) with follow-up data. No significant differences in outcomes were observed between subtypes (p = 0.92). The study confirmed the authors' hypothesis that taxonomy for midbrain BSCMs can meaningfully guide the selection of surgical approach and resection strategy. The proposed taxonomy can increase diagnostic acumen at the patient bedside, help identify optimal surgical approaches, enhance the consistency of clinical communications and publications, and improve patient outcomes.


Persistence of N7-(2,3,4-trihydroxybutyl)guanine adducts in the livers of mice and rats exposed to 1,3-butadiene.
Liquid chromatography (LC) in combination with tandem mass spectrometry (MS/MS) and stable isotope methodology was employed for the analysis of the N7-guanine (Gua) adducts derived from 1,2:3, 4-diepoxybutane (BDO2) a reactive metabolite of 1,3-butadiene (BD). Two diastereomeric forms of N7-(2,3,4-trihydroxybutyl)guanine (THBG) were identified in the livers of both mice and rats. One of the diastereomers [(+/-)-THBG] was formed by reaction of DNA with (+/-)-BDO2, and the other diastereomer (meso-THBG) was formed by reaction of DNA with meso-BDO2. There was significantly more (+/-)-THBG and meso-THBG in the liver DNA of the mice when compared with those of the rats during the 10 days of exposure to BD and the 6 days of postexposure that were monitored. There was a 2-fold excess of (+/-)-THBG over meso-THBG in the rat liver at all the time points. In the mouse liver after 10 days of exposure to BD, the (+/-)-THBG (3.9 adducts/10(6) normal bases) was also present in an almost 2-fold excess over meso-THBG (2.2 adducts/10(6) normal bases). However, 6-days after exposure to BD, (+/-)-THBG (1.2 adducts/10(6) normal bases) and meso-THBG (1.0 adduct/10(6) normal bases) were present in almost equal amounts in the mouse liver. Furthermore, there was an almost 5-fold excess of the two THBG diastereomers in the mouse liver DNA 6 days after exposure to BD when compared with rat liver DNA. The half-lives of (+/-)-THBG and meso-THBG appeared to be slightly longer in mouse liver (4.1 and 5.5 days, respectively) than in rat liver (3.6 and 4.0 days, respectively). The apparent persistence of these adducts in the mouse may contribute to the increased susceptibility of this species to BD-induced carcinogenesis. It is possible that (+/-)-THBG and meso-THBG could have also been derived from the reaction of DNA with the hydrolysis product of BDO2, 1,2-dihydroxy-3,4-epoxybutane (DHEB). Surprisingly, a vast majority of the studies in which the mutagenic and carcinogenic potential of BDO2 have been examined have only employed the commercially available (+/-)-BDO2. In light of the present findings, additional studies will be required to determine the potency of meso-BDO2 and the DHEB that is the precursor to meso-THBG as mutagens and carcinogens.


Irreversible electroporation of the lumbar vertebrae in a porcine model: is there clinical-pathologic evidence of neural toxicity?
To evaluate the effects of irreversible electroporation (IRE) in the porcine spine. This study was approved by the institutional animal care and use committee. Twenty computed tomographically guided IRE ablations in either a transpedicular location or directly over the posterior cortex were performed in the lumbar vertebrae of 10 pigs by a single operator. T1- and T2-weighted magnetic resonance (MR) imaging was performed with and without contrast material 2 or 7 days after ablation. Mathematical modeling was performed to estimate the extent of ablation. Clinical, radiologic, pathologic, and simulation findings were analyzed. The Miller low-bias back transformation was used to construct 95% confidence intervals for the mean absolute percentage difference between the maximum length and width of the ablation zone on MR images and pathologic measurements by using square-root-transformed data. Bipolar IRE electrode placement and ablation were successful in all cases. The mean distances from the IRE electrode to the posterior wall of the vertebral body or the exiting nerve root were 2.93 mm ± 0.77 (standard deviation) and 7.87 mm ± 1.99, respectively. None of the animals had neurologic deficits. Well-delineated areas of necrosis of bone, bone marrow, and skeletal muscle adjacent to the vertebral body were present. Histopathologic changes showed outcomes that matched with simulation-estimated ablation zones. The percentage absolute differences in the ablation measurements between MR imaging and histopathologic examination showed the following average errors: 24.2% for length and 28.8% for width measurements on T2-weighted images, and 26.1% for length and 33.3% for width measurements on T1-weighted contrast material-enhanced images. IRE ablation in the porcine spine is feasible and safe and produces localized necrosis with minimal neural toxicity. Signal intensity changes on images acquired with standard MR imaging sequences demonstrate the ablation zone to be larger than that at histopathologic examination.


Development and Validation of HIV-ASSIST, an Online, Educational, Clinical Decision Support Tool to Guide Patient-Centered ARV Regimen Selection.
Multiple antiretroviral (ARV) regimens are effective at achieving HIV viral suppression, but differ in pill burden, side effects, barriers to resistance, and impact on comorbidities. Current guidelines advocate for an individualized approach to ARV regimen selection, but synthesizing these modifying factors is complex and time-consuming. We describe the development of HIV-ASSIST (https://www.hivassist.com), a free, online decision support tool for ARV selection and HIV education. HIV-ASSIST ranks potential ARV options for any given patient scenario using a composite objective of achieving viral suppression while maximizing tolerability and adherence. We used a multiple-criteria decision analysis framework to construct mathematical algorithms and synthesize various patient-specific (eg, comorbidities and treatment history) and virus-specific (eg, HIV mutations) attributes. We then conducted a validation study to evaluate HIV-ASSIST with prescribing practices of experienced HIV providers at 4 large academic centers. We report on concordance of provider ARV selections with the 5 top-ranked HIV-ASSIST regimens for 10 diverse hypothetical patient-case scenarios. In the validation cohort of 17 experienced HIV providers, we found 99% concordance between HIV-ASSIST recommendations and provider ARV selections for 4 case-scenarios of ARV-naive patients. Among 6 cases of ARV-experienced patients (3 with and 3 without viremia), there was 84% and 88% concordance, respectively. Among 3 cases of ARV-experienced patients with viremia, providers reported 20 different ARV selections, suggesting substantial heterogeneity in ARV preferences in clinical practice. HIV-ASSIST is a novel patient-centric educational decision support tool that provides ARV recommendations concordant with experienced HIV providers for a diverse set of patient scenarios.


Indications for and short- and long-term outcome of permanent tracheostomy performed in standing horses: 82 cases (1995-2005).
To identify indications for and short- and long-term outcome of permanent tracheostomy performed in standing horses. Retrospective case series. 82 horses undergoing permanent tracheostomy. Data obtained from medical records included signalment, diagnosis, surgical technique, complications, use of the horse before and after surgery, and owner satisfaction. Follow-up information was obtained through a telephone questionnaire administered to owners. Indications for permanent tracheostomy included nasopharyngeal cicatrix (n = 59), arytenoid chondropathy (55), and laryngeal hemiplegia (20); 54 horses had multiple indications for tracheostomy. Complications identified prior to discharge included partial dehiscence (n = 8), transient fever (10), and excessive swelling (13). Complications identified after discharge included partial dehiscence (n = 3), inversion of skin (2), and stenosis of the tracheostomy requiring repair (1). Long-term follow-up information was available for 64 horses. Fifty-seven of the 64 (89%) horses returned to their previous use, and owners of 63 (98%) horses reported being very satisfied with the results. The owner of 1 (2%) horse was unsatisfied with the results. The 1-year survival rate was 97% (95% confidence interval, 95% to 100%). Mean estimated truncated survival time (ie, failure-free period) was 9.7 years (95% confidence interval, 9.3 to 10.1 years). Results suggested that permanent tracheostomy can be safely performed in standing horses and was a viable treatment for horses with obstructive disease of the upper respiratory tract that was unresponsive to medical treatment or other surgical treatments.


Correlation between myocardial deformation on three-dimensional speckle tracking echocardiography and cardiopulmonary exercise testing.
Heart failure (HF) is a multifactorial entity that combines derangements in both systolic and diastolic function. The relationship between systolic and diastolic function and exercise capacity is not fully understood. We sought to determine the mechanisms linking cardiac function and exercise tolerance in patients with HF. One hundred fifty-six subjects with different cardiac function levels were included in the study. Subjects' 2D echocardiographic, 3D speckle tracking echocardiographic, and cardiopulmonary exercise testing (CPET) data were collected. The amount of untwisting at 25% of the untwist duration (25%Untwist) and global longitudinal peak systolic strain (GLS) showed the best positive correlations with peak oxygen uptake (peakVO2 ) (r = .41; P < .001 and r = .32; P < .001, respectively), while the left ventricular ejection fraction (EF) was weakly correlated with peakVO2 . The 25%Untwist value was negatively correlated with the carbon dioxide equivalent slope (VE/VCO2 ) (r = -.49; P < .001). Both E/e and the left atrium volume index (LA index) exhibited good positive correlations with VE/VCO2 (r = .39; P < .01 and r = .32; P < .001). In the multiple regression analysis, the best predictive model for the peakVO2 included the 25%Untwist, GLS, and E/e, explained 64% of the variation in peakVO2 , with 25%Untwist explaining 17.6% of the variation. Including EF in the model explained only 3.1% of the variation in peakVO2 . In a multivariable model for VE/VCO2 , 25%Untwist was the strongest independent predictor, explaining 23% of the variance in VE/VCO2 . Left ventricular early diastolic function is a modest independent predictor of aerobic exercise capacity. The 25%Untwist value is a good indicator of cardiac diastolic function.


Inflow Jet Patterns of Unruptured Cerebral Aneurysms Based on the Flow Velocity in the Parent Artery: Evaluation Using 4D Flow MRI.
Inflow jet characteristics may be related to aneurysmal bleb formation and rupture. We investigated the visualization threshold on the basis of the flow velocity in the parent artery to classify the inflow jet patterns observed on 4D flow MR imaging. Fifty-seven unruptured aneurysms (24 bifurcation and 33 sidewall aneurysms) were subjected to 4D flow MR imaging to visualize inflow streamline bundles whose velocity exceeded visualization thresholds corresponding to 60%, 75%, and 90% of the maximum flow velocity in the parent artery. The shape of the streamline bundle was determined visually, and the inflow jet patterns were classified as concentrated, diffuse, neck-limited, and unvisualized. At the 75% threshold, bifurcation aneurysms exhibited a concentrated inflow jet pattern at the highest rate. At this threshold, the inflow jets were concentrated in 13 aneurysms (group C, 22.8%), diffuse in 18 (group D, 31.6%), neck-limited in 11 (group N, 19.3%), and unvisualized in 15 (group U, 26.3%). In 16 (28.1%) of the 57 aneurysms, the inflow jet pattern was different at various thresholds. Most inflow parameters, including the maximum inflow velocity and rate, the inflow velocity ratio, and the inflow rate ratio, were significantly higher in groups C and D than in groups N and U. The inflow jet pattern may depend on the threshold applied to visualize the inflow streamlines on 4D flow MR imaging. For the classification of the inflow jet patterns on 4D flow MR imaging, the 75% threshold may be optimal among the 3 thresholds corresponding to 60%, 75%, and 90% of the maximum flow velocity in the parent artery.


Why patients with congestive heart failure die: arrhythmias and sudden cardiac death.
Patients with congestive heart failure have a high incidence of sudden cardiac death that is attributed to ventricular arrhythmias. The mortality rate in a group of patients with class III and IV heart failure is about 40% per year, and half of the deaths are sudden. Half of the patients with New York Heart Association class III or IV heart failure have unsustained ventricular tachycardia detected on a 24 hr continuous electrocardiographic recording. The presence of ventricular tachycardia in patients with congestive heart failure increases the probability of dying; in class III or IV heart failure, the presence of unsustained ventricular tachycardia on a 24 hr continuous ECG recording increases the odds of dying about threefold over a 1 to 2 year follow-up period. Many electrical, mechanical, humoral, and electrolyte abnormalities may promote ventricular arrhythmias in patients with heart failure. Correction of these predisposing factors could reduce the risk of lethal ventricular arrhythmias and therefore every effort should be made to do so. Because there has been no definitive study of the impact of antiarrhythmic drug treatment on the survival of patients with heart failure and ventricular arrhythmias, the role of therapy with antiarrhythmic drugs remains uncertain at the present time.


Cytokine-induced beta-cell death is independent of endoplasmic reticulum stress signaling.
Cytokines contribute to beta-cell destruction in type 1 diabetes. Endoplasmic reticulum (ER) stress-mediated apoptosis has been proposed as a mechanism for beta-cell death. We tested whether ER stress was necessary for cytokine-induced beta-cell death and also whether ER stress gene activation was present in beta-cells of the NOD mouse model of type 1 diabetes. INS-1 beta-cells or rat islets were treated with the chemical chaperone phenyl butyric acid (PBA) and exposed or not to interleukin (IL)-1beta and gamma-interferon (IFN-gamma). Small interfering RNA (siRNA) was used to silence C/EBP homologous protein (CHOP) expression in INS-1 beta-cells. Additionally, the role of ER stress in lipid-induced cell death was assessed. Cytokines and palmitate triggered ER stress in beta-cells as evidenced by increased phosphorylation of PKR-like ER kinase (PERK), eukaryotic initiation factor (EIF)2alpha, and Jun NH(2)-terminal kinase (JNK) and increased expression of activating transcription factor (ATF)4 and CHOP. PBA treatment attenuated ER stress, but JNK phosphorylation was reduced only in response to palmitate, not in response to cytokines. PBA had no effect on cytokine-induced cell death but was associated with protection against palmitate-induced cell death. Similarly, siRNA-mediated reduction in CHOP expression protected against palmitate- but not against cytokine-induced cell death. In NOD islets, mRNA levels of several ER stress genes were reduced (ATF4, BiP [binding protein], GRP94 [glucose regulated protein 94], p58, and XBP-1 [X-box binding protein 1] splicing) or unchanged (CHOP and Edem1 [ER degradation enhancer, mannosidase alpha-like 1]). While both cytokines and palmitate can induce ER stress, our results suggest that, in contrast to lipoapoptosis, the PERK-ATF4-CHOP ER stress-signaling pathway is not necessary for cytokine-induced beta-cell death.


The prognostic effect of smoking status on intensively treated acute myeloid leukaemia - A Danish nationwide cohort study.
With rising life expectancy, the importance of patient-related prognostic factors and how to integrate such data into clinical decision-making becomes increasingly important. The aim of this study was to evaluate the prognostic impact of smoking status in patients with acute myeloid leukaemia (AML) treated with intensive chemotherapy. We conducted a nationwide cohort study based on data obtained from the Danish National Leukaemia Registry (DNLR). The study comprised Danish patients aged 18-75 years, diagnosed with AML between 1 January 2000 and 31 December 2012. Medical records were reviewed and data on smoking status were collected. A total of 1040 patients (median age 59 years) were included, and 602 patients (58·9%) were categorised as ever-smokers and the remaining as never-smokers. Kaplan-Meier survival estimates revealed that ever-smokers had a significant shorter median overall survival (OS) at 17·2 months [95% CI (14·9;19·1)] compared to never-smokers at 24·5 months (95% CI [19·2;30·7]). Multivariate analysis revealed smoking status as a significant prognostic factor for inferior OS with a hazard ratio (HR) of 1·22 [95% CI (1·04;1·44)]. In conclusion, smoking status was found to be associated with inferior OS in intensively treated AML patients.


Nurses' experiences of busyness in their daily work.
The purpose of this study is to explore and illuminate the phenomenon of busyness as experienced by nurses. The daily work of nursing practice is often characterized by a hectic pace in the execution of tasks. Previous research shows that busyness can potentially lead to a reduction in the quality of nursing. Little has been explored about nurses' own experiences of busyness. This study has a qualitative design. The method chosen is a phenomenological hermeneutical exploration of personal experiences. Results reveal that busyness is experienced as a disparity between perceived necessary tasks and time available to accomplish them. Busyness has an outer dimension of events and a dimension of internal processes. Busyness is experienced as acceptable to some extent, but feels strongly uncomfortable if important tasks remain undone. The intolerable busyness raises negative emotions, steals energy and weakens health. Coping with busyness seems to be a personal and individual struggle, even though health service enterprises are a collective matter.


Whitnall's sling for poor function ptosis.
Severe unilateral ptosis with poor levator function has previously been treated with maximal levator muscle resection or bilateral or unilateral frontalis suspension. One of us (R.L.A.) has developed a technique called "Whitnall's sling," where only the levator aponeurosis is resected, preserving Whitnall's ligament and its attachments. Whitnall's ligament and the underlying resected levator muscle are sutured to the superior portion of the tarsal plate. This surgery preserves levator muscle, Müller's muscle, and Whitnall's ligament without altering the structures that produce the three-layer tear film. In 69 eyelids operated on between July 1976 and July 1986, in which a minimum of 1 year of follow-up by one of use was obtained, results have been satisfactory and directly related to levator function. We believe this technique to be anatomically and physiologically superior to "maximal levator resection" with similar long-term results. More recent results have shown that the addition of a 5-mm superior tarsectomy provides an additional elevation of 1 to 1.5 mm. Whitnall's sling is best suited for cases where the opposite fissure height is 9 mm or less and levator function of the ptotic eyelid is 3 to 5 mm.


[Participation of thalamic relay nuclei in the genesis of barbiturate spindle-like activity].
The specific relay ventro-postero-lateral nucleus (VPL) of the thalamus was electrocoagulated in cats with the view of studying its role in the genesis of the barbituric spindle activity in the cortical projection zone on the side of ablation. It was shown that the specific nuclei, although of considerable importance to the spindle modulation of the potentials, are not its only source. Involved in modulation is also the nonspecific thalamo-cortical system acting along the pathways independent of the specific system. The leading role in the genesis of reaction of rhythmic slow after-effect, which is a variety of spindles, belongs to the specific thalamo-cortical system.


Long-term enzyme replacement therapy in a severe case of mucopolysaccharidosis type II (Hunter syndrome).
Hunter syndrome or mucopolysaccharidosis II (MPS II) is a rare X-linked disease caused by a deficiency of the iduronate-2-sulphatase (12S) lysosomal enzyme, resulting in a progressive accumulation of glycosaminoglycans (GAGs). Enzyme replacement therapy (ERT) with recombinant human 12S idursulfase has been used infrequently in children < 5 years. We present the case of a 7 years and 10 months-old child, who was diagnosed with a severe form of MPS II at the age of 3 years, and who began a 36 months' treatment with idursulfase at 4 years 10 months. After 10 months, GAG urinary excretion was normal, but after just 4 months the liver and spleen had decreased in size, returning to normal limits by 36 months. Significant bone remodeling was noted after 16 months. Cardiac and neurological development, however, progressively deteriorated. The only adverse reactions were episodic inflammations of the upper and/or lower respiratory tract, but there was no otitis. Early use of ERT, presuming good treatment adherence, can significantly improve bone abnormalities.


Mechanisms of pHi recovery from NH4Cl-induced acidosis in anoxic isolated turtle heart: a 31P-NMR study.
Mechanisms of intracellular pH (pHi) recovery from NH4Cl-induced acidosis were investigated on isolated perfused hearts of the turtle, Chrysemys picta bellii, using 31P nuclear magnetic resonance (NMR) spectroscopy at 20 degrees C. A major goal was to assess the activity of these mechanisms under anoxic conditions. Based on calculated buffer capacity and a pHi recovery range at 20 degrees C of 6.75-6.95 (normal pHi 7.2-7.4), mean H' efflux rate during perfusion with CO2-free N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES)-buffered Ringer was only 15% (normoxia) and 25% (anoxia) of that with HCO3-buffered Ringer. With HCO3 solution, anoxic H1 efflux rate was approximately 50% of normoxia (0.333 vs. 0.645 mmol.l-1.min-1), but in TES solution, H1 efflux rate was unaffected by anoxia. To further characterize the transporters, we used blockers [the Na(+)-H+ antiport inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) and the anion exchanger inhibitor 4,4'diisothiocyanostilbene-2, 2'-disulfonic acid (DIDS)], ion substitution, and temperature change. EIPA (10 microM) inhibited H+ efflux rate by 40% in anoxic TES solution; DIDS (0.5 mM) blocked H+ efflux rate by 85% in anoxic HCO3 solution. No pHi recovery was observed in either normoxic or anoxic Na(+)-free solutions, but normal recovery was observed in the absence of extracellular Cl-. Recovery of pHi occurred 2-3 times faster at 30 degrees C than at 20 degrees C. ATP was unaffected by any manipulation in this study, whereas creatine phosphate (CP) fell during anoxia, and both CP and mechanical performance changed in parallel to pHi. We conclude that pHi regulation functions during anoxia, although at a reduced rate, and that recovery from acidosis is dominated, during both normoxia and anoxia, by a DIDS-sensitive Na+ and HCO3(-)-dependent mechanism, whereas EIPA-sensitive Na(+)-H+ antiport plays a less important role.


Physiotherapy: At what cost? Parents experience of performing chest physiotherapy for infants with cystic fibrosis.
Physiotherapy is one of the most burdensome aspects of cystic fibrosis (CF) care. Healthcare requirements for older children with CF are reported to impact parental quality of life and physiotherapy adherence. How parents of infants experience performing chest physiotherapy as a part of CF care is unknown. This study aimed to explore the experience of performing chest physiotherapy for parents of infants with CF. In this study, 13 parents of infants (aged 1-2 years) with CF participated in one in-depth semi-structured interview and completed a daily diary for five days. Principles of hermeneutic phenomenology guided interpretation of interview transcripts, diary entries, and field notes. For these parents, being responsible for performing chest physiotherapy was an ever-present experience of pressure, doubt, and guilt. Managing chest physiotherapy resulted in sacrifices that were perceived by parents as an expected and necessary part of meeting the healthcare needs of their child. Despite perceived sacrifices, performing chest physiotherapy was also experienced by parents as an opportunity to positively impact the health of their child. Awareness of parental perceptions and experiences of chest physiotherapy in CF may enhance the personalization of physiotherapy and minimize burden.


Trapping wave fields in an expulsive potential by means of linear coupling.
We demonstrate the existence of confined states in one- and two-dimensional (1D and 2D) systems of two linearly coupled components, with the confining harmonic-oscillator (HO) potential acting upon one component and an expulsive anti-HO potential acting upon the other. The systems can be implemented in optical and BEC dual-core waveguides. In the 1D linear system, codimension-one solutions are found in an exact form for the ground state (GS) and dipole mode (the first excited state). Generic solutions are produced by means of the variational approximation and are found in a numerical form. Exact codimension-one solutions and generic numerical ones are also obtained for the GS and vortex states in the 2D system (the exact solutions are found for all values of the vorticity). Both the trapped and antitrapped components of the bound states may be dominant ones, in terms of the norm. The localized modes may be categorized as bound states in continuum, as they coexist with delocalized ones. The 1D states, as well as the GS in 2D, are weakly affected and remain stable if the self-attractive or repulsive nonlinearity is added to the system. The self-attraction makes the vortex states unstable against splitting, while they remain stable under the action of the self-repulsion.


Rapid signaling at inhibitory synapses in a dentate gyrus interneuron network.
Mutual synaptic interactions between GABAergic interneurons are thought to be of critical importance for the generation of network oscillations and for temporal encoding of information in the hippocampus. However, the functional properties of synaptic transmission between hippocampal interneurons are largely unknown. We have made paired recordings from basket cells (BCs) in the dentate gyrus of rat hippocampal slices, followed by correlated light and electron microscopical analysis. Unitary GABA(A) receptor-mediated IPSCs at BC-BC synapses recorded at the soma showed a fast rise and decay, with a mean decay time constant of 2.5 +/- 0.2 msec (32 degrees C). Synaptic transmission at BC-BC synapses showed paired-pulse depression (PPD) (32 +/- 5% for 10 msec interpulse intervals) and multiple-pulse depression during repetitive stimulation. Detailed passive cable model simulations based on somatodendritic morphology and localization of synaptic contacts further indicated that the conductance change at the postsynaptic site was even faster, decaying with a mean time constant of 1.8 +/- 0.6 msec. Sequential triple recordings revealed that the decay time course of IPSCs at BC-BC synapses was approximately twofold faster than that at BC-granule cell synapses, whereas the extent of PPD was comparable. To examine the consequences of the fast postsynaptic conductance change for the generation of oscillatory activity, we developed a computational model of an interneuron network. The model showed robust oscillations at frequencies >60 Hz if the excitatory drive was sufficiently large. Thus the fast conductance change at interneuron-interneuron synapses may promote the generation of high-frequency oscillations observed in the dentate gyrus in vivo.


De Ritis Ratio: a Potent Marker in Cancer.
The role of conventional liver function clinical laboratory marker De Ritis Ratio in evaluating the prognosis, assisting diagnosis, and monitoring therapeutic efficacy of cancer is gaining increasing attention, especially in the last decade. According to the most recent articles, the De Ritis Ratio functions have progressed, which indicates that the De Ritis Ratio appears to be a promising tumor marker. The aim of this review was to evaluate the clinical importance from studies made on this subject. Using the search words "De Ritis Ratio", "aspartate transaminase/alanine transaminase", "aspartate transaminase", "alanine transaminase", "cancer", "prognostic significance", "diagnostic significance", and "predictive significance", a search was carried out on PubMed. Exclusion criteria were articles never published in English and articles evaluating tumor markers in cancer not involving the De Ritis Ratio. As a predictor of prognosis, the De Ritis Ratio is strongly associated with prognostic risk factors and can be used to assess therapeutic efficacy. As a predictor of incidence, the De Ritis Ratio could promote the prediction of the disease progression. As a biomarker, the De Ritis Ratio is more likely to improve diagnostics by being combined with other biomarkers. Therefore, since it is easily accessible, involves no additional laborious efforts, and is a relatively inexpensive marker, the De Ritis Ratio is emerging as an attractive and clinically valuable marker in cancer. In the review, we explore the possible mechanisms of the De Ritis Ratio related to cancer and summarize the clinical importance of the De Ritis Ratio as a promising marker for cancer.


[Osteogenetic induction (critical comments to the concept "bone graft") (author's transl)].
The author makes an attempt to prove the following facts on the basis of his histological studies: 1. The mechanical process of cutting out small bone fragments from the outer cortex of the long bones of fragments from the outer cortex of the long bones of living humans results in an immediate devitalisation or emptying of the lacunae. 2. In almost 74% of the cases, there is an emptying of the lacunae or absence of the mature osteocytes, as well as degeneration--albeit to a varying degree--in almost 95% of the remaining osteocytes. 3. These facts, i.e. immediate devitalisation of these small fragments of living bones, prompted the author to question the expression "bone graft", even with free or floating bone fragments taken from the same patient, i.e. also with the socalled autogenic or autologus bone grafts. 4. Transplanting or grafting a living bone fragment from the donor area to a recipient area will stimulate the recipient area to form new bones. In this manner, it is possible to achieve osteogenetic induction, and expression which respresents the course of facts with biological accuracy. 5. The mature osteocyte does not participate as a living cell in the osteogenetic process of rehabilitation, does not multiply, and dies. 6. The new bone is shaped by the recipient and not by the grafted bone of the donor.


Altered Osteogenic Differentiation in Mesenchymal Stem Cells Isolated from Compact Bone of Chicken Treated with Varying Doses of Lipopolysaccharides.
Persistent inflammation biologically alters signaling molecules and ultimately affects osteogenic differentiation, including in modern-day broilers with unique physiology. Lipopolysaccharides (LPS) are Gram-negative bacterial components that activate cells via transmembrane receptor activation and other molecules. Previous studies have shown several pathways associated with osteogenic inductive ability, but the pathway has yet to be deciphered, and data related to its dose-dependent effect are limited. Primary mesenchymal stem cells (MSCs) were isolated from the bones of day-old broiler chickens, and the current study focused on the dose-dependent variation (3.125 micrograms/mL to 50 micrograms/mL) in osteogenic differentiation and the associated biomarkers in primary MSCs. The doses in this study were determined using a cell viability (MTT) assay. The study revealed that osteogenic differentiation varied with dose, and the cells exposed to higher doses of LPS were viable but lacked differentiating ability. However, this effect became transient with lower doses, and this phenotypic character was observed with differential staining methods like Alizarin Red, Von Kossa, and alkaline phosphatase. The data from this study revealed that LPS at varying doses had a varying effect on osteogenic differentiation via several pathways acting simultaneously during bone development.


[Diagnosis of protozoa by loop-mediated isothermal amplification: (LAMP)].
Plasmodium, Isospora, Toxoplasma, Babesia and Cryptosporidium are parasites which have a significant role in human health. The location in which the protozoon settles in the body, the way that it leaves the host, and the sample which is send from the clinic are the elements of the general methods used in the diagnosis of the ailments caused from protozoan. Classical methods are not adequate for the identification of some protozoon; also, molecular methods have to be used in designating the distinctions between the species. In recent years, one of the molecular methods which has been used frequently in the identification of protozoon is the technique of LAMP. With the aid of the LAMP technique, from which it is possible to obtain reliable outcomes without the contribution of technical skills and professional equipment, in constant temperature it is possible to have a great number of copies from the targeted DNA in a short period. The aim of this collation is to give information about the usage of the technique of LAMP in the identification of the protozoa which are important for human health and the comparison between the technique of LAMP and other molecular methods.


Guanine-Rich Sequences Are a Dominant Feature of Exosomal microRNAs across the Mammalian Species and Cell Types.
Exosome is an extracellular vesicle released from multivesicular endosomes and contains micro (mi) RNAs and functional proteins derived from the donor cells. Exosomal miRNAs act as an effector during communication with appropriate recipient cells, this can aid in the utilization of the exosomes in a drug delivery system for various disorders including malignancies. Differences in the miRNA distribution pattern between exosomes and donor cells indicate the active translocation of miRNAs into the exosome cargos in a miRNA sequence-dependent manner, although the molecular mechanism is little known. In this study, we statistically analyzed the miRNA microarray data and revealed that the guanine (G)-rich sequence is a dominant feature of exosome-dominant miRNAs, across the mammalian species-specificity and the cell types. Our results provide important information regarding the potential use of exosome cargos to develop miRNA-based drugs for the treatment of human diseases.


Comparison of Protein and Peptide Targeting for the Development of a CD169-Based Vaccination Strategy Against Melanoma.
CD169+ macrophages are part of the innate immune system and capture pathogens that enter secondary lymphoid organs such as the spleen and the lymph nodes. Their strategic location in the marginal zone of the spleen and the subcapsular sinus in the lymph node enables them to capture antigens from the blood and the lymph respectively. Interestingly, these specific CD169+ macrophages do not destroy the antigens they obtain, but instead, transfer it to B cells and dendritic cells (DCs) which facilitates the induction of strong adaptive immune responses. This latter characteristic of the CD169+ macrophages can be exploited by specifically targeting tumor antigens to CD169+ macrophages for the induction of specific T cell immunity. In the current study we target protein and peptide antigen as antibody-antigen conjugates to CD169+ macrophages. We monitored the primary, memory, and recall T cell responses and evaluated the anti-tumor immune responses after immunization. In conclusion, both protein and peptide targeting to CD169 resulted in strong primary, memory, and recall T cell responses and protective immunity against melanoma, which indicates that both forms of antigen can be further explored as anti-cancer vaccination strategy.


Can Inter-Subject Associativity Predict Data-Driven BCI Performance?
Intra- and inter-subject variability causes covariate shifts in training and testing feature spaces, resulting in low sensorimotor (SMR) brain-computer interface (BCI) performance for practical implementation. Studies involving data-driven transfer learning strategies demonstrated improving BCI performance by covariate shift adaptation. In this study, we aim to illustrate if inter-subject associativity (e.g., subjects having similar SMR brain dynamics) can predict data-driven inter-subject BCI performance. We implemented a BCI classification pipeline with a common spatial pattern, principal component analysis and linear discriminant analysis for performance evaluation. Both intra- and inter-subject BCI were evaluated in 5-Fold Validation settings. We further proposed a Bhattacharyya distance-based covariate shift score (CSS) for assessing the difference between training and testing feature domains. We performed Pearson correlation analysis to draw the relation-ship between BCI performance and CSS. Intra-subject BCI performances were significantly and negatively correlated with CSS (r = -0.94, p < 0.05). For the inter-subject experiment, BCI performances were also highly and negatively associated with CSS (r = -0.61, p < 0.05). However, this data-driven BCI evaluation framework does not necessarily manifest inter-subject associativity in BCI performance, requiring further investigations for a conclusion.Clinical relevance- If it predicts BCI performance successfully, inter-subject associativity could reduce time-consuming and annoying subject-specific calibration for the users.


An exchange of ophthalmologists with the People's Republic of China.
From 1978 through 1981, three teams of ophthalmologists from the United States have traveled to the People's Republic of China under the auspices of the World Eye Foundation. The purpose of these visits has been to open an avenue of exchange between American and Chinese ophthalmologists. The US ophthalmologists delivered lectures and participated in discussion groups with the Chinese ophthalmologists. They had the opportunity to participate in surgical teaching cases, including some using acupuncture anesthesia. They also had the opportunity to develop ongoing working and research relationships with many Chinese ophthalmologists. As a result of these working relationships, some of these Chinese ophthalmologists have had the opportunity to visit and study in the United States.


Training Otolaryngologists in Palliative Care Delivery: An Underutilized Opportunity.
Palliative care is an underutilized and often misunderstood discipline in the treatment of patients with head and neck cancer. The key components of palliative care include symptoms management, psychosocial support, and enhanced communications. Abundant evidence has demonstrated the beneficial effect for the early incorporation of palliative care in the treatment paradigm for patients with chronic diseases and malignancies, with findings supporting its positive effect on patients' quality of life as well their survival. Particularly for otolaryngologists, the unique morbidities of head and neck cancer make our patients especially vulnerable and even more in need of the support and benefits that can come from palliative care. While increased consultation with palliative care providers for patients with head and neck cancer is a good first step, training otolaryngologists to develop their own "primary palliative care competencies" is key for improving our patients' outcomes.


Substitution of ethambutol with linezolid during the intensive phase of treatment of pulmonary tuberculosis: a prospective, multicentre, randomised, open-label, phase 2 trial.
Linezolid improves the treatment outcomes of multidrug-resistant tuberculosis substantially. We investigated whether use of linezolid instead of ethambutol increases the proportion of sputum culture conversion at 8 weeks of treatment in patients with pulmonary tuberculosis. We did a phase 2, multicentre, randomised, open-label trial for patients with pulmonary tuberculosis at the three affiliated hospitals to Seoul National University and National Medical Center (Seoul-Seongnam, South Korea). Patients, aged 20-80 years, with a positive sputum for pulmonary tuberculosis, but without resistance to rifampicin, and current treatment administered for 7 days or fewer, were randomly assigned at a 1:1:1 ratio into three groups. The control group received ethambutol (2 months) with isoniazid, rifampicin, and pyrazinamide. The second group used linezolid (600 mg/day) for 2 weeks and the third group for 4 weeks instead of ethambutol for 2 months. We used a minimisation method to randomise, and stratified according to institution, cavitation on chest radiographs, and diabetes. The primary endpoint was the proportion of patients with negative culture conversion of sputum in liquid media after 8 weeks of treatment. The results of this trial were analysed primarily in the modified intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT01994460. Between Feb 19, 2014, and Jan 13, 2017, a total of 429 patients were enrolled and 428 were randomly assigned into either the control group (142 patients), the linezolid 2 weeks group (143 patients), or the linezolid 4 weeks group (143 patients). Among them, 401 were eligible for primary efficacy analyses. In the modified intention-to-treat analyses, negative cultures in liquid media at 8 weeks of treatment were observed in 103 (76·9%) of 134 control patients, 111 (82·2%) of 135 in the linezolid 2 weeks group, and 100 (75·8%) of 132 in the linezolid 4 weeks groups. The difference from the control group was 5.4% (95% CI -4·3 to 15·0, p=0·28) for the linezolid 2 weeks group and -1·1% (-11·3 to 9·1, p=0·83) for the linezolid 4 weeks group. Numbers of patients who experienced at least one adverse event were similar across the groups (86 [62·8%] of 137 in control, 79 [57·2%] of 138 in the linezolid 2 weeks group, and 75 [62·0%] of 121 in the linezolid 4 weeks group). Resistance to linezolid was not identified in any patient. Higher rates of culture conversion at 8 weeks of treatment with short-term use of linezolid were not observed. However, safety analyses and the resistance profile suggested the potential role of linezolid in shortening of treatment for drug-susceptible tuberculosis. Ministry of Health and Welfare, South Korea.


WRKY41 controls Arabidopsis seed dormancy via direct regulation of ABI3 transcript levels not downstream of ABA.
Although seed dormancy is an important agronomic trait, its molecular basis is poorly understood. ABSCISIC ACID INSENSITIVE 3 (ABI3) plays an essential role in the establishment of seed dormancy. Here, we show that the lack of a seed-expressed WRKY transcription factor, WRKY41, confers reduced primary seed dormancy and thermoinhibition, phenotypes resembling those for a lack of ABI3. Loss-of-function abi3-17 and wrky41 alleles also both confer reduced sensitivity to ABA during germination and early seedling growth. Absence of WRKY41 decreases ABI3 transcript abundance in maturing and imbibed seeds, whereas transgenically overexpressing WRKY41 increases ABI3 expression. Moreover, transgenic overexpression of ABI3 completely restores seed dormancy phenotypes on wrky41. ChIP-qPCR and EMSA reveal that WRKY41 binds directly to the ABI3 promoter through three adjacent W-boxes, and a transactivation assay indicates that these W-boxes are essential for ABI3 expression. Whilst RT-qPCR analysis shows that the regulation of ABI3 by WRKY41 is not through ABA and other factors known to promote ABI3 transcription during seed maturation and germination, we also show that high concentrations of ABA might promote negative feedback regulation of WRKY41 expression. Finally, analysis of the wrky41 aba2 double mutant confirms that WRKY41 and ABA collaboratively regulate ABI3 expression and seed dormancy. In summary, our results demonstrate that WRKY41 is an important regulator of ABI3 expression, and hence of seed dormancy.


Apigenin inhibits TGF-β-induced VEGF expression in human prostate carcinoma cells via a Smad2/3- and Src-dependent mechanism.
Cancer progression relies on establishment of the blood supply necessary for tumor growth and ultimately metastasis. Prostate cancer mortality is primarily attributed to development of metastases rather than primary, organ-confined disease. Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis in prostate tissue. Our previous studies have demonstrated that the chemopreventive bioflavonoid apigenin inhibited hypoxia-induced elevation of VEGF production at low oxygen conditions characteristic for solid tumors. Low oxygen (hypoxia) and transforming growth factor-β (TGF-β) are two major factors responsible for increased VEGF secretion. In the present study, experiments were performed to investigate the inhibitory effect of apigenin on TGF-β-induced VEGF production and the mechanisms underlying this action. Our results demonstrate that VEGF expression is induced by TGF-β1 in human prostate cancer PC3-M and LNCaP C4-2B cells, and treatment with apigenin markedly decreased VEGF production. Additionally, apigenin inhibited TGF-β1-induced phosphorylation and nuclear translocation of Smad2 and Smad3. Further experiments demonstrated that specific transient knockdown of Smad2 or Smad3 blunted apigenin's effect on VEGF expression. We also found that apigenin inhibited Src, FAK, and Akt phosphorylation in PC3-M and LNCaP C4-2B cells. Furthermore, constitutively active Src reversed the inhibitory effect of apigenin on VEGF expression and Smad2/3 phosphorylation. Taken together, our results suggest that apigenin inhibits prostate carcinogenesis by modulating TGF-β-activated pathways linked to cancer progression and metastases, in particular the Smad2/3 and Src/FAK/Akt pathways. These findings provide new insights into molecular pathways targeted by apigenin, and reveal a novel molecular mechanism underlying the antiangiogenic potential of apigenin.


The changing landscape of advanced and castration resistant prostate cancer: latest science and revised definitions.
One fifth of men with newly diagnosed prostate cancer present with locally advanced or metastatic disease. Androgen deprivation therapy (ADT) is the standard systemic therapy in these patients. Despite initial response, essentially all patients will develop castration resistant prostate cancer (CRPC). In this review, we will discuss the revised definitions of CRPC and the latest understanding of the biology of the androgen/androgen receptor axis in the development of advanced prostate cancer. A systematic literature review was conducted via electronic database articles based on title, abstract, study format, and content. The majority of selected articles were published between 1992 and 2013. Older studies were included selectively if historically relevant. Prostate cancer becomes castration resistant through numerous pathways, including androgen and androgen receptor (AR) dependent mechanisms as well as ligand and AR independent pathways. Therefore the terms androgen-insensitive and hormone-refractory should be avoided and replaced by the term castration resistant. Recent advances in understanding molecular mechanisms of castration resistance have led to development of novel CRPC therapeutics. CRPC remains an incurable disease. Further understanding of the pathways involved in castration resistance will set the basis for development of therapies to increase survival in these patients.


Absence of SOCS3 in the cardiomyocyte increases mortality in a gp130-dependent manner accompanied by contractile dysfunction and ventricular arrhythmias.
Suppressor of cytokine signaling-3 (SOCS3) is a key negative-feedback regulator of the gp130 receptor that provides crucial signaling for cardiac hypertrophy and survival; however, an in vivo role of SOCS3 regulation on cardiac gp130 signaling remains obscure. We generated cardiac-specific SOCS3 knockout (SOCS3 cKO) mice. These mice showed increased activation of gp130 downstream signaling targets (STAT3, ERK1/2, AKT, and p38) from 15 weeks of age and developed cardiac dysfunction from approximately 25 weeks of age with signs of heart failure. Surprisingly, SOCS3 cKO failing hearts had minimal histological abnormalities with intact myofibril ultrastructure. In addition, Ca(2+) transients were significantly increased in SOCS3 cKO failing hearts compared with wild-type hearts. We also found that Ser23/24 residues of troponin I were hypophosphorylated in SOCS3 cKO hearts before the manifestation of cardiac dysfunction. These data suggested the presence of abnormalities in myofilament Ca(2+) sensitivity in SOCS3 cKO mice. In addition to the contractile dysfunction, we found various ventricular arrhythmias in SOCS3 cKO nonfailing hearts accompanied by a sarcoplasmic reticulum Ca(2+) overload. To determine the contribution of gp130 signaling to the cardiac phenotype that occurs with SOCS3 deficiency, we generated cardiac-specific gp130 and SOCS3 double KO mice. Double KO mice lived significantly longer and had different histological abnormalities when compared with SOCS3 cKO mice, thus demonstrating the importance of gp130 signaling in the SOCS3 cKO cardiac phenotype. Our results demonstrate an important role of SOCS3 regulation on cardiac gp130 signaling in the pathogenesis of contractile dysfunction and ventricular arrhythmias.


[Cancer-related lymphedema in Israel].
Lymphedema, the accumulation of protein-rich fluid in an involved extremity or other body part, is a chronic life-long condition following many types of surgical procedures, most often breast cancer surgical therapy. The patient suffering from lymphedema faces difficult medical, social, psychological and aesthetic issues. The incidence of lymphedema after modern breast cancer surgical treatment has been reported for between 5 to 56% of patients. Taking into account the incidence of breast cancer in Israel, there could be a yearly incidence of over 1000 new patients per year in Israel suffering from arm lymphedema. The authors reviewed the literature concerning epidemiology, pathophysiology, risk factors, diagnosis and treatment strategy. In addition, some insights were provided regarding lymphedema treatment in Israel. This review aims to improve the awareness and knowledge of physicians and other health care professionals on this treatable but often forgotten condition.


Piconewton Mechanical Forces Promote Neurite Growth.
Investigations over half a century have indicated that mechanical forces induce neurite growth, with neurites elongating at a rate of 0.1-0.3 μm h-1 pN-1 when mechanical force exceeds a threshold, with this being identified as 400-1000 pN for neurites of PC12 cells. In this article, we demonstrate that neurite elongation of PC12 cells proceeds at the same previously identified rate on application of mechanical tension of ∼1 pN, which is significantly lower than the force generated in vivo by axons and growth cones. This observation raises the possibility that mechanical tension may act as an endogenous signal used by neurons for promoting neurite elongation.


Naming very familiar people: when retrieving names is faster than retrieving semantic biographical information.
One of the most reliable findings in the literature on person indentification is that semantic categorization of a face occurs more quickly than naming a face. Here we present two experiments in which participants are shown the faces of their colleagues, i.e., personally familiar people, encountered with high frequency. In each experiment, naming was faster than making a semantic classification, despite the fact that the semantic classifications were highly salient to the participants (Experiment 1: highest degree obtained; Experiment 2: nationality). The finding is consistent with models that allow or parallel access from faces to semantic information and to names, and demonstrates the need for the frequency of exposure to names to be taken into account in models of proper name processing e.g. Burke, Mackay, Worthley and Wade (1991).


Designing and interpreting 4D tumour spheroid experiments.
Tumour spheroid experiments are routinely used to study cancer progression and treatment. Various and inconsistent experimental designs are used, leading to challenges in interpretation and reproducibility. Using multiple experimental designs, live-dead cell staining, and real-time cell cycle imaging, we measure necrotic and proliferation-inhibited regions in over 1000 4D tumour spheroids (3D space plus cell cycle status). By intentionally varying the initial spheroid size and temporal sampling frequencies across multiple cell lines, we collect an abundance of measurements of internal spheroid structure. These data are difficult to compare and interpret. However, using an objective mathematical modelling framework and statistical identifiability analysis we quantitatively compare experimental designs and identify design choices that produce reliable biological insight. Measurements of internal spheroid structure provide the most insight, whereas varying initial spheroid size and temporal measurement frequency is less important. Our general framework applies to spheroids grown in different conditions and with different cell types.


Mitochondrial and pedigree analysis in Przewalski's horse populations: implications for genetic management and reintroductions.
Przewalski's horses have been imported from the western zoos to China since 1985. Yet the genetic diversity in China's populations has not been studied, thus lacking of such knowledge inevitably affects this population's management. The aim of this study was to assess genetic diversity in Chinese population of Przewalski's horses via mitochondrial DNA (mtDNA) control region and pedigree analysis. Two captive and one reintroduced populations were examined based on mitochondrial DNA control region variation via fecal sampling from 2010 to 2012, together with pedigree analysis. Amplification success rates of fecal mtDNA were as high as 96.2% (93.8%-100%), and were higher for sample in winter than in summer and autumn. Two haplotypes were identified and shared among three populations, but the proportion of individuals with each haplotype varied among the three populations (F(ST) = 0.10874, p = 0.00978). Haplotype diversity in the released population (0.153) was much lower than that in the two captive populations (0.4011 and 0.4966), in accordance with the direction of increase in probability of identity at the dam lines. Future concerns in Przewalski's horse population management should emphasize on strict reproduction control to minimize inbreeding in captivity, followed by long-term genetic diversity guidelines and non-invasive monitoring in the reintroduction programmes.


Educational paper: decreasing the burden of cardiovascular disease in childhood cancer survivors: an update for the pediatrician.
The cardiovascular impact of cancer therapies on the heart is one of the major concerns in the long-term follow-up of childhood cancer survivors (CCSs). Long-term cardiovascular effects include the development of left ventricular dysfunction resulting in congestive heart failure and ischemic heart disease, as well as valvular and pericardial disease. This is mainly ascribed to the cardiotoxic side effects of chemotherapeutic agents (especially anthracyclines) and radiotherapy, but other factors such as radiation and inflammation play a role in the effect of childhood cancer on the cardiovascular health. The most concerning effect is the high incidence of symptomatic heart failure in CCS patients treated with anthracyclines. More than 50 % of CCSs treated with anthracyclines develop asymptomatic left ventricular dysfunction after cancer therapy, with approximately 5 % developing clinical signs of heart failure during long-term follow-up. Once CCS patients develop congestive heart failure, prognosis is poor and is not influenced by current medical treatment strategies. To reduce the long-term burden of cardiovascular disease in pediatric cancer patients, a diversified approach will be necessary. In the acute phase, prevention of cardiac damage through the use of cardioprotective agents (e.g., dexrazoxane) or by administering less cardiotoxic chemotherapeutic agents is to be considered. A recent randomized trial suggested that the use of dexrazoxane reduced cardiac toxicity without affecting cancer outcomes. Especially patients requiring high doses of chemotherapeutic agents could benefit from this approach. Recent data suggest that genetic testing might identify patients at higher risk for cardiotoxicity. This seems mainly related to genes involved in drug metabolism. This would allow personalized approach adjusting chemotherapy based on cardiovascular risk profiling. This could be combined with newer monitoring strategies in the acute phase using newer echocardiographic techniques and biomarker screening to identify patients with early damage to the myocardium. For the long-term CCS cohort, early detection and treatment of early dysfunction prior to the development of congestive heart failure could potentially improve long-term outcomes. Promoting healthy lifestyles and controlling additional cardiovascular risk factors (e.g., obesity, diabetes, arterial hypertension) is an important task for every physician involved in the care of this growing cohort.


The Arabidopsis UVH1 gene is a homolog of the yeast repair endonuclease RAD1.
Ultraviolet radiation induces DNA damage products, largely in the form of pyrimidine dimers, that are both toxic and mutagenic. In most organisms, including Arabidopsis, these lesions are repaired both through a dimer-specific photoreactivation mechanism and through a less efficient light-independent mechanism. Several mutants defective in this "dark repair" pathway have been previously described. The mechanism of this repair has not been elucidated, but is thought to be homologous to the nucleotide excision repair mechanisms found in other eukaryotes. Here we report the complementation of the Arabidopsis uvh1 dark repair mutant with the Arabidopsis homolog of the yeast nucleotide excision repair gene RAD1, which encodes one of the subunits of the 5'-repair endonuclease. The uvh1-2 mutant allele carries a glycine-->aspartate amino acid change that has been previously identified to produce a null allele of RAD1 in yeast. Although Arabidopsis homologs of genes involved in nucleotide excision repair are readily identified by searching the genomic database, it has not been established that these homologs are actually required for dark repair in plants. The complementation of the Arabidopsis uvh1 mutation with the Arabidopsis RAD1 homolog clearly demonstrates that the mechanism of nucleotide excision repair is conserved among the plant, animal, and fungal kingdoms.


Friend or foe: Risso's dolphins eavesdrop on conspecific sounds to induce or avoid intra-specific interaction.
The detection and use of emitters' signals by unintended receivers, i.e., eavesdropping, represents an important and often low-cost way for animals to gather information from their environment. Acoustic eavesdropping can be a key driver in mediating intra- and interspecific interactions (e.g., cooperation, predator-prey systems), specifically in species such as cetaceans that use sound as a primary sensory modality. While most cetacean species produce context-specific sounds, little is known about the use of those sounds by potential conspecific eavesdroppers. We experimentally tested the hypothesis that a social cetacean, Risso's dolphin (Grampus griseus), is able to gather biologically relevant information by eavesdropping on conspecific sounds. We conducted playback experiments on free-ranging dolphins using three context-specific sounds stimuli and monitored their horizontal movement using visual or airborne focal follow observations. We broadcasted natural sequences of conspecific foraging sounds potentially providing an attractive dinner bell signal (n = 7), male social sounds simulating a risk of forthcoming agonistic interaction (n = 7) and female-calf social sounds representing no particularly threatening context (n = 7). We developed a quantitative movement response score and tested whether animals changed their direction of horizontal movement towards or away from the playback source. Dolphins approached the foraging and the social female-calf sounds whereas they avoided the social male sounds. Hence, by acoustically eavesdropping on conspecifics, dolphins can discriminate between social and behavioural contexts and anticipate potential threatening or beneficial situations. Eavesdropping and the ensuing classification of 'friend or foe' can thus shape intra-specific social interactions in cetaceans.


Stem cell therapy for heart failure: Medical breakthrough, or dead end?
Heart failure continues to be one of the leading causes of morbidity and mortality worldwide. Myocardial infarction is the primary causative agent of chronic heart failure resulting in cardiomyocyte necrosis and the subsequent formation of fibrotic scar tissue. Current pharmacological and non-pharmacological therapies focus on managing symptoms of heart failure yet remain unable to reverse the underlying pathology. Heart transplantation usually cannot be relied on, as there is a major discrepancy between the availability of donors and recipients. As a result, heart failure carries a poor prognosis and high mortality rate. As the heart lacks significant endogenous regeneration potential, novel therapeutic approaches have incorporated the use of stem cells as a vehicle to treat heart failure as they possess the ability to self-renew and differentiate into multiple cell lineages and tissues. This review will discuss past, present, and future clinical trials, factors that influence stem cell therapy outcomes as well as ethical and safety considerations. Preclinical and clinical studies have shown a wide spectrum of outcomes when applying stem cells to improve cardiac function. This may reflect the infancy of clinical trials and the limited knowledge on the optimal cell type, dosing, route of administration, patient parameters and other important variables that contribute to successful stem cell therapy. Nonetheless, the field of stem cell therapeutics continues to advance at an unprecedented pace. We remain cautiously optimistic that stem cells will play a role in heart failure management in years to come.


Inhibition of lysosomal degradative functions in RPE cells by a retinoid component of lipofuscin.
To investigate the effect of the lipofuscin component N-retinylidene-N-retinylethanolamine (A2-E) on degradative functions of lysosomes in human retinal pigment epithelial (RPE) cells and to evaluate its mechanism of action. A2-E was coupled to low-density lipoprotein (LDL). Human RPE cell cultures were loaded with the A2-E/LDL complex, and controls were run with medium containing LDL alone. To determine whether A2-E accumulated in lysosomes, cells were fractionated in a Percoll gradient, and protein degradation was determined by metabolic labeling and measurement of the release of low-molecular-weight radioactivity. Lysosomal degradation was distinguished from nonlysosomal degradation by inclusion of NH4Cl in the medium. The metabolism of sulfated glycosaminoglycans was studied by radiosulfate incorporation in pulse-chase experiments. Intralysosomal pH was determined using a fluorescent lysosomotropic pH indicator. A2-E accumulated almost exclusively in the lysosomal compartment. Lysosomal protein degradation was reduced in a dose-dependent fashion in A2-E-treated cells. The selectivity of A2-E on lysosomal function was demonstrated by its lack of effect on degradation of extralysosomal protein. Lysosomal glycosaminoglycan catabolism of RPE cells was also strongly inhibited by A2-E. Lysosomal pH was increased by A2-E. The findings indicate that accumulation of A2-E in RPE cells interferes with lysosomal functions as exemplified by its inhibitory effect on protein and glycosaminoglycan catabolic pathways. The quaternary amine character of the A2-E apparently causes a perturbation of the acidic intralysosomal milieu, resulting in diminished hydrolase action and consequent accumulation of undegraded material. Such mechanism could be operative in retinal diseases associated with excessive lipofuscin accumulation including age-related macular degeneration.


Pathogenesis of Eimeria praecox in chickens: virulence of field strains compared with laboratory strains of E. praecox and Eimeria acervulina.
The pathogenesis in chickens of the apicomplexan Eimeria praecox was compared with that of Eimeria acervulina, using intestinal lesions, mucosal integrity, body weight gain (BWG) and the feed conversion ratio (FCR) as criteria. Characteristics of each species were described by combinations of polymerase chain reaction assays and classic parasitological signs. There were considerable overlaps in lengths, breadths, shape indices and volumes of the oocysts of each species. Both species caused statistically significant reductions in BWG at the lowest inocula tested (500,000 sporulated oocysts per bird of E. praecox and 250,000 of E. acervulina). E. praecox was observed for the first time to cause actual body weight loss and marked increases in FCR, as did E. acervulina. E. acervulina caused gross, white pathognomonic lesions, but E. praecox caused micro-lesions, visible in fresh tissue only with a dissecting microscope. Occasionally, lesions of the Houghton strain of E. acervulina were observed to be rounded, rather than typically "ladder-like". Both species caused villous erosion and atrophy. No mortality occurred in birds receiving up to 1 million sporulated oocysts of either species. Using BWG and FCR as criteria, the virulence of recent field strains of E. praecox from Wales (Tynygongl) and the USA (Raleigh) was compared with English laboratory strains of E. praecox (Houghton) and E. acervulina (Houghton). E. praecox (Tynygongl) was markedly more virulent than E. acervulina (Houghton), which was more virulent than E. praecox (Raleigh) and E. praecox (Houghton).


Retinoic acid receptor-related orphan receptor α-induced activation of adenosine monophosphate-activated protein kinase results in attenuation of hepatic steatosis.
There is increasing evidence that the retinoic acid receptor-related orphan receptor α (RORα) plays an important role in the regulation of metabolic pathways, particularly of fatty acid and cholesterol metabolism; however, the role of RORα in the regulation of hepatic lipogenesis has not been studied. Here, we report that RORα attenuates hepatic steatosis, probably via activation of the adenosine monophosphate (AMP)-activated protein kinase (AMPK) and repression of the liver X receptor α (LXRα). First, RORα and its activator, cholesterol sulfate (CS), induced phosphorylation of AMPK, which was accompanied by the activation of serine-threonine kinase liver kinase B1 (LKB1). Second, the activation of RORα, either by transient transfection or CS treatment, decreased the TO901317-induced transcriptional expression of LXRα and its downstream target genes, such as the sterol regulatory element binding protein-1 (SREBP-1) and fatty acid synthase. RORα interacted physically with LXRα and inhibited the LXRα response element in the promoter of LXRα, indicating that RORα interrupts the autoregulatory activation loop of LXRα. Third, infection with adenovirus encoding RORα suppressed the lipid accumulation that had been induced by a free-fatty-acid mixture in cultured cells. Furthermore, we observed that the level of expression of the RORα protein was decreased in the liver of mice that were fed a high-fat diet. Restoration of RORα via tail-vein injection of adenovirus (Ad)-RORα decreased the high-fat-diet-induced hepatic steatosis. Finally, we synthesized thiourea derivatives that activated RORα, thereby inducing activation of AMPK and repression of LXRα. These compounds decreased hepatic triglyceride levels and lipid droplets in the high-fat-diet-fed mice. We found that RORα induced activation of AMPK and inhibition of the lipogenic function of LXRα, which may be key phenomena that provide the beneficial effects of RORα against hepatic steatosis.


CCK-independent mTORC1 activation during dietary protein-induced exocrine pancreas growth.
Dietary protein can stimulate pancreatic growth in the absence of CCK release, but there is little data on the regulation of CCK-independent growth. To identify mechanisms whereby protein stimulates pancreatic growth in the absence of CCK release, C57BL/6 control and CCK-null male mice were fed normal-protein (14% casein) or high-protein (75% casein) chow for 7 days. The weight of the pancreas increased by 32% in C57BL/6 mice and 26% in CCK-null mice fed high-protein chow. Changes in pancreatic weight in control mice were due to both cell hypertrophy and hyperplasia since there was an increase in protein-to-DNA ratio, total DNA content, and DNA synthesis. In CCK-null mice pancreatic growth was almost entirely due to hypertrophy with both protein-to-DNA ratio and cell size increasing without significant increases in DNA content or DNA synthesis. ERK, calcineurin, and mammalian target of rapamycin complex 1 (mTORC1) are activated in models of CCK-induced growth, but there were no differences in ERK or calcineurin activation between fasted and fed CCK-null mice. In contrast, mTORC1 activation was increased after feeding and the duration of activation was prolonged in mice fed high-protein chow compared with normal-protein chow. Changes in pancreatic weight and RNA content were completely inhibited, and changes in protein content were partially abated, when the mTORC1 inhibitor rapamycin was administered during high-protein chow feeding. Prolonged mTORC1 activation is thus required for dietary protein-induced pancreatic growth in the absence of CCK.


A neuroprotective role of the NMDA receptor subunit GluN3A (NR3A) in ischemic stroke of the adult mouse.
GluN3A or NR3A is a developmentally regulated N-methyl-d-aspartate receptor (NMDAR) subunit, showing a unique inhibitory role that decreases NMDAR current and the receptor-mediated Ca(2+) influx. In the neonatal brain, GluN3A is shown to associate with synaptic maturation and spine formation and plays a neuroprotective role. Its functional role in the adult brain, however, is largely unknown. We tested the hypothesis that, disrespecting the relatively lower expression level of GluN3A in the adult brain, this inhibitory NMDAR subunit shows a protective action against ischemia-induced brain injury. In littermate wild-type (WT) and GluN3A knockout (KO) mice, focal cerebral ischemia was induced by permanent occlusion of right distal branches of the middle cerebral artery (MCA) plus 10-min ligation of both common carotid arteries (CCAs). Twenty-four hours after focal cerebral ischemia, the infarction volume assessed using 2,3,5-triphenyltetrazolium chloride (TTC) staining was significantly larger in GluN3A KO mice compared with WT mice. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining demonstrated enhanced cell death in GluN3A KO mice. Moreover, the deletion of GluN3A hindered sensorimotor functional recovery after stroke. It is suggested that, although the expression level is relatively lower in the adult brain, GluN3A is still a noteworthy regulator in ischemia-induced excitotoxicity and brain injury.


Assessment of Contact Toxicity and Repellent Effects of Essential Oils from Piper Plants Piper yunnanense and Piper boehmeriifolium against Three Stored-Product Insects.
Storage is a crucial part during grain production for the massive spoilage caused by stored product insects. Essential oils (EOs) of plant origin have been highly recommended to combating insects which are biodegradable and safe mode of action. Hence, to make the fullest use of natural resources, essential oils of different parts from Piper yunnanense (the whole part, PYW; fruits, PYF; leaves, PYL) and Piper boehmeriifolium (leaves, PBL) were extracted by steam distillation method in the present study. Gas chromatography-mass spectrometry (GC-MS) characterization revealed bicyclogermacrene (PYW), γ-muurolene (PYF), δ-cadinene (PYL) and methyl 4,7,10,13,16,19-docosahexaenoate (PBL) as the principal compound of each essential oil. Sesquiterpene hydrocarbons were also recognized as the richest class accounting for 56.3 %-94.9 % of the total oil. Three storage pests, Tribolium castaneum, Lasioderma serricorne and Liposceis bostrychophila, were exposed to different concentrations of EOs to determine their insecticidal effects. All tested samples performed modest contact toxicity in contrast to a bioactive ingredient pyrethrin, among which the most substantial effects were observed in PYF EOs against T. castaneum (35.84 μg/adult), PBL EOs against L. serricorne (15.76 μg/adult) and PYW EOs against L. bostrychophila (57.70 μg/cm2 ). In terms of repellency tests, essential oils of PYF at 78.63 nL/cm2 demonstrated to have a remarkable repellence against T. castaneum at 2h and 4h post-exposure. The investigations indicate diverse variations in the chemical profiles and insecticidal efficacies of P. yunnanense and P. boehmeriifolium EOs, providing more experimental evidence for the use of the Piper plants.


Working memory training to improve speech perception in noise across languages.
Working memory capacity has been linked to performance on many higher cognitive tasks, including the ability to perceive speech in noise. Current efforts to train working memory have demonstrated that working memory performance can be improved, suggesting that working memory training may lead to improved speech perception in noise. A further advantage of working memory training to improve speech perception in noise is that working memory training materials are often simple, such as letters or digits, making them easily translatable across languages. The current effort tested the hypothesis that working memory training would be associated with improved speech perception in noise and that materials would easily translate across languages. Native Mandarin Chinese and native English speakers completed ten days of reversed digit span training. Reading span and speech perception in noise both significantly improved following training, whereas untrained controls showed no gains. These data suggest that working memory training may be used to improve listeners' speech perception in noise and that the materials may be quickly adapted to a wide variety of listeners.


Quantitative changes associated with calving in the levels of bovine immunoglobulins in selected body fluids. I. Changes in the levels of IgA, IgGl and total protein.
Levels of bovine IgA, IgG1 and total protein (TP) were determined in serum, saliva, tears and individual quarter lacteal secretions of six Holstein-Friesian cows sampled from six weeks before to four weeks after parturition. Hierarchal analyses of variance indicated significant variations among weeks, cows and quarters of the udder. A precipitous but non proportional drop in the levels of IgA and IgA1 in lacteal secretions occurred at calving. There was a concomitant increase in IgG1, and decrease in IgA, in serum. Correlation studies supported the concept of selective transport of IgG1 from serum to lacteal secretions in regulated amounts independent of serum IgG1 levels. Changes in the IgG1/TP ratio of serum and lacteal secretions supported the idea of a decrease in the selective transport mechanism. Correlation studies and estimations of secretory IgA (SIgA) in serum suggest that serum IgA is derived from IgA synthesized in secretory tissues. Highly significant correlations between IgA and IgG1 levels in all secretions postpartum suggest that local IgA synthesis and either IgG1 transport or local IgG1 synthesis are initiated by the same stimuli. Although some of the variation in the level reported for IgA and IgG1 in secretions resulted from protein dilution, much of the variation represents physiological differences between individual animals and tissues in the same animal. An IgG2/IgG1 ratio approaching that of serum occurred in a mastitic quarter of one cow. IgA was the principal immunoglobulin in saliva and tears, comprised a greater proportion of the immunoglobulin in milk whey than in prepartum lacteal secretions and was a minor immunoglobulin in bovine serum.


Progress in the development of ultra-long-acting local anesthetics.
Local anesthetic agents with a duration of action longer than the currently available local anesthetics could have widespread clinical application for the treatment of both chronic and acute pain. Over the last several decades, several different approaches have been used in the development of ultra-long-acting agents. There are currently promising preparations in development which may prove clinically useful in the near future. A Medline search was conducted for relevant articles published in peer-reviewed journals between 1971 and 1996. Investigations related to prolongation of the effect of local anesthetics either by alterations in the local anesthetic molecule, use of new or novel agents, or use of new delivery systems were reviewed. In addition, bibliographies of relevant articles were searched to capture any articles that were missed by the Medline search. Over the last several decades, numerous attempts have been made to prolong the duration of action of local anesthetics. Initially, research focused on alterations in the local anesthetic molecule or the identification of new agents with local anesthetic action. Recently, the focus of much of the work has shifted to new drug-delivery systems such as polymers and liposomes. Although encouraging results have been reported in the literature, there is currently no agent or delivery system that has shown reliable and practical prolongation of local anesthetic effect in humans. There have been several encouraging reports in animals that have shown local anesthetic effects lasting up to several days, but these results must be validated and then performed in human studies before a clinically useful agent is found. Further research is warranted.


[Effect of anti-inflammatory preparations on the process of thermogenesis in blood erythrocytes].
The authors studied the influence of the main antiphlogistic agents (prednisolone, acetylsalicylic acid, rheopyrine, chloroquine and indomethacine) on the thermal effect of the peripheral blood erythrocytes in man. It was found that only chloroquine possessed a significant inhibitory effect. This fact pointed to the inhibition by chloroquine of energy production in the process of glycolysis, which could be regarded as one of the factors of the therapeutic action of this preparation.


Long-term Outcomes of Autologous Chondrocyte Implantation in Adolescent Patients.
Treating symptomatic articular cartilage lesions is challenging, especially in adolescent patients, because of longer life expectancies and higher levels of functional activity. For this population, long-term outcomes after autologous chondrocyte implantation (ACI) remain to be determined. To evaluate long-term outcomes in adolescents after ACI using survival analyses, validated outcome questionnaires, and standard radiographs. Case series; Level of evidence, 4. We performed a review of prospectively collected data from patients who underwent ACI between 1996 and 2013. We evaluated 27 patients aged <18 years old (29 knees; mean age, 15.9 years) who were treated by a single surgeon for symptomatic, full-thickness articular cartilage lesions over a mean 9.6-year follow-up (median, 13 years; range, 2-19 years). A mean of 1.5 lesions per knee were treated over a mean total surface area of 6.2 cm2 (range, 2.0-23.4 cm2) per knee. Survival analysis was performed using the Kaplan-Meier method, with graft failure as the end point. The modified Cincinnati Knee Rating Scale, Western Ontario and McMaster Universities Osteoarthritis Index, visual analog scale, and Short Form 36 scores were used to evaluate clinical outcomes. Patients also self-reported knee function and satisfaction. Standard radiographs were evaluated using Kellgren-Lawrence grades. Both 5- and 10-year survival rates were 89%. All clinical scores improved significantly postoperatively. A total of 96% of patients rated knee function as better after surgery, and all patients indicated that they would undergo the same surgery again. Approximately 90% rated knee-specific outcomes as good or excellent and were satisfied with the procedure. At last follow-up, 12 of 26 successful knees were radiographically assessed (mean, 5.6 years postoperatively), with no significant osteoarthritis progression. Three knees were considered failures, which were managed by autologous bone grafting or osteochondral autologous transplantation. Twenty knees required subsequent surgical procedures. These were primarily associated with periosteum and were arthroscopically performed. ACI resulted in satisfactory survival rates and significant improvements in function, pain, and mental health for adolescent patients over a long-term follow-up. ACI was associated with very high satisfaction postoperatively, despite the subsequent procedure rate being relatively high primarily because of the use of periosteum. If periosteum is used, this rate should be a consideration when discussing ACI with patients and their parents.


[Complicated form of A/HINI (2009) influenza in pregnant women].
We undertook prospective and retrospective analysis of 120 cases of A/HINI (2009) influenza complicated by pneumonia in pregnant women with the purpose of comprehensive assessment of these conditions taking into account relevant risk factors and preventive measures. Control groups were comprised of 100 pregnant women with uncomplicated influenza and 100 ones who did not fall ill during flu pandemic. The risk of severe disease and probability of its fatal outcome in pregnant women were 2.5 and 2.4 times those in the general population. Most women developed pneumonia in the 3d trimester Risk factors offlu complications included smoking, obesity, underlying respiratory and cardiovascular diseases, sexually transmitted infections. Combined prophylaxis reduced probability of pandemic influenza in pregnant women by 5.6-7 times. Severe forms of the disease were due to manifest symptoms of intoxication and concomitant pneumonia. The clinical picture of lethal cases was characterized by severe pneumonia with subtotal lung involvement, rapid progress of acute respiratory distress syndrome, and development of polyorgan insufficiency.


Transcriptional response to the host cell environment of a multidrug-resistant Mycobacterium tuberculosis clonal outbreak Beijing strain reveals its pathogenic features.
Tuberculosis is a global public health problem with emergence of multidrug-resistant infections. Previous epidemiological studies of tuberculosis in Thailand have identified a clonal outbreak multidrug-resistant strain of Mycobacterium tuberculosis in the Kanchanaburi province, designated "MKR superspreader", and this particular strain later was found to also spread to other regions. In this study, we elucidated its biology through RNA-Seq analyses and identified a set of genes involved in cholesterol degradation to be up-regulated in the MKR during the macrophage cell infection, but not in the H37Rv reference strain. We also found that the bacterium up-regulated genes associated with the ESX-1 secretion system during its intracellular growth phase, while the H37Rv did not. All results were confirmed by qRT-PCR. Moreover, we showed that compounds previously shown to inhibit the mycobacterial ESX-1 secretion system and cholesterol utilisation, and FDA-approved drugs known to interfere with the host cholesterol transportation were able to decrease the intracellular survival of the MKR when compared to the untreated control, while not that of the H37Rv. Altogether, our findings suggested that such pathways are important for the MKR's intracellular growth, and potentially could be targets for the discovery of new drugs against this emerging multidrug-resistant strain of M. tuberculosis.


Scanning electron microscopy of alcohol-fixed cytopathology specimens.
Cells in specimens fixed in alcohol and stained by the Papanicolaou method for routine cytodiagnosis were subsequently studied by scanning electron microscopy (SEM) to determine if they manifested topologic features described in specimens prepared for optimal SEM observation. In normal bronchial washings, ciliated columnar cells were obvious, and microridges were detected in several squamous cells. Microvilli, although sometimes coarse and blunted, were present in cells of adenocarcinoma, squamous carcinoma and malignant mesothelioma in fluid specimens. Benign histiocytes in bronchial washings, neuroblastoma cells in a smear of bone marrow aspirate and lymphocytic lymphoma cells in spinal fluid had ruffled surfaces. Should topologic features prove to be diagnostically significant, SEM may be of value in further studying equivocal specimens even though they were previously prepared for routine light microscopic observation.


Overcoming Radical Stability Order via DABCO-Triggered Desulfurization: Visible-Light-Promoted 1,2,4-Trifunctionalization of Butenyl Benzothiazole Sulfone with Thiosulfonate.
A radical 1,2,4-trifunctional reaction of thiosulfonate to unactivated olefin is achieved by a migration strategy under mild conditions. In this reaction, the more unstable primary free radicals are in situ generated after the migration of heteroaryl groups in the presence of DABCO. This trifunctionalization of unactivated olefins involves two C-S bond formations and one C-C bond formation.


A mixture model for population codes of Gabor filters.
Population coding is a coding scheme which is ubiquitous in neural systems, and is also of more general use in coding stimuli, for example in vision problems. A population of responses to a stimulus can be used to represent not only the value of some variable in the environment, but a full probability distribution for that variable. The information is held in a distributed and encoded form, which may in some situations be more robust to noise and failures than conventional representations. Gabor filters are a popular choice for detecting edges in the visual field for several reasons. They are easily tuned for a variety of edge widths and orientations, and are considered a close model of the edge filters in the human visual system. In this paper, we consider population codes of Gabor filters with different orientations. A probabilistic model of Gabor filter responses is presented. Based on the analytically derived orientation tuning function and a parametric mixture model of the filter responses in the presence of local edge structure with single or multiple orientations a probability density function (pdf) of the local orientation in any point (x, y) can be extracted through a parameter estimation procedure. The resulting pdf of the local contour orientation captures not only angular information at edges, corners or T-junctions but also describes the certainty of the measurement which can be characterized in terms of the entropy of the individual mixture components.


TrkC-Targeted Kinase Inhibitors And PROTACs.
A small molecule motif (IY-IY), which binds the tropomyosin receptor kinase C (TrkC), was used to deliver the promiscuous kinase inhibitor (KI) dasatinib into breast cancer. Conjugates with noncleavable (1) and cleavable (2) linkers were compared in cellular assays and shown to have more impact on the cell viabilities of TrkC+ breast cancer cells over TrkC- epithelial cells. The IY-IY fragment was also used to recruit the E3 ligase cereblon, giving a potent proteolysis targeting chimeric (PROTAC) for TrkC degradation in metastatic breast cancer cells.


Hypoxic vascular response and ventilation/perfusion matching in end-stage COPD may depend on p22phox.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease in which the amount of emphysema and airway disease may be very different between individuals, even in end-stage disease. Emphysema formation may be linked to the involvement of the small pulmonary vessels. The NAPDH oxidase (Nox) family is emerging as a key disease-related factor in vascular diseases, but currently its role in hypoxia-induced pulmonary remodelling in COPD remains unclear.Here we investigate the role of p22phox, a regulatory subunit of Nox, in COPD lungs, hypoxic pulmonary vasoconstriction (HPV), hypoxia-induced pulmonary vascular remodelling and pulmonary hypertension.In COPD, compared to control lungs, p22phox expression was significantly reduced. The expression was correlated positively with mean pulmonary arterial pressure and oxygenation index and negatively with the diffusing capacity of the lung for carbon monoxide (p<0.02). This suggests a role of p22phox in ventilation/perfusion ratio matching, vascular remodelling and loss of perfused lung area. In p22phox-/- mice, HPV was significantly impaired. In the chronic hypoxic setting, lack of p22phox was associated with improved right ventricular function and decreased pulmonary vascular remodelling.p22phox-dependent Nox plays an important role in the COPD phenotype, by its action on phase II HPV and chronic vascular remodelling.


Testing claimed minimal detectable concentrations of in vitro medical diagnostic devices.
Manufacturers and users of medical diagnostic devices are provided a statistical decision tool for investigating a claimed minimal detectable concentration (MDC). The MDC is defined by setting two respective probabilities: that the blank sample being analyzed is determined to have analyte and that the device fails to determine a low concentration of analyte at the MDC. The statistical procedure for simultaneously testing the two aforementioned analytical decision errors assumes that signal responses follow a gaussian distribution but does not require a fitted calibration curve, knowledge of distribution parameters, or the assumption of constant variance in the low assay range. Evaluation of the operating characteristics of the procedure requires knowledge only of the variance ratio between the MDC and zero-dose signal distributions, which usually is well known.


[Prevalence and clinical-urodynamic characteristics of vesical voiding dysfunction in two urodynamic centres].
It has been estimated in English medical reports, that the frequency of vesical voiding dysfunction in urogynecological patients is around of 22-24%; however in our country it does not have any published epidemiological study about this problem. To detect the prevalence of vesical voiding dysfunction in our urodynamic unities and describe the clinical and urodynamic findings. This is a descriptive and retrospective study in which were revised the clinical reports of 300 female patients, that were sent to some of our urodynamic units because they were suffering of lower urinary tract symptoms. Assessment variables included: Patient clinical history, physical examination, urinalysis, urine culture, urethral calibration, Q tip test, urethrocistoscopy, uroflowmetry, multichannel cystometry, electromyography and pressure voiding study. The diagnosis criterion was based in the concept that Blaivas established for vesical voiding dysfunction in women. The diagnosis of vesical voiding dysfunction was established in 72 cases of the total 300 patients analyzed. The most frequent symptom was the irritative vesical type (frequency/urgency), following of weak stream. Some grade of pelvic organ prolapse was detected in 84.8% of cases. Uroflowmetry was normal in 50% of the cases; nevertheless in the morphologic aspect were observed profile signs suggestive of distal vesical obstruction in 75%, and detrusor hypoactivity in 25% of the total of the cases. The frequency of obstruction in our casuistic was similar to the other authors. The obtained results permit us to confirm that the vesical voiding dysfunction in the urogynecological Mexican patients is a frequent problem in the urogynecological patient; however the diagnostic is complex and require a carefully correlation as clinical as urodynamical aspects in addition to endoscopic and image studies.