CLEFT PALATE IN THE MOUSE: A TERATOGENIC INDEX OF GLUCOCORTICOID POTENCY.
Clinically equivalent doses of hydrocortisone, prednisolone, and dexamethasone have progressively increasing teratogenic activity as judged by their ability to induce cleft palate in the offspring of pregnant mice treated with these drugs during the middle period of gestation. Mole for mole, dexamethasone is at least 300 times more teratogenic than hydrocortisone. The enhanced teratogenicity of dexamethasone probably does not result from its relatively decreased mineralocorticoid activity.


Therapeutic thoracentesis symptoms and activity: a qualitative study.
Malignant pleural effusions (MPEs) commonly occur in patients with advanced cancer. Drainage of fluid is used to relieve symptoms and improve quality of life. To improve our understanding of how therapeutic aspiration affects symptoms and activities in patients with MPE. Patients presenting to the Pleural Clinic at Norfolk and Norwich University Hospital with a confirmed or suspected MPE participated in up to three semistructured interviews during their diagnostic/therapeutic pathway. Interviews were analysed using framework analysis by two researchers independently. Sixteen patients participated. Symptoms reported before drainage included breathlessness, cough, chest pain, fatigue and anorexia. Symptoms affected their activities, including walking, bending over and socialisation. Patients described anxiety about the underlying diagnosis and fear of over-reliance on others. Expectations of drainage outcome varied, with some hoping for a cure and others hoping for any improvement. After drainage, breathlessness, chest pain and cough improved in some patients. They reported feeling and sleeping better, but fatigue and poor appetite remained. Participants were more active after aspiration, but the duration of improvement was a few days only. Despite this, patients still felt the procedure worthwhile. Overall health and respiratory symptoms improved following drainage, but constitutional symptoms did not improve. This may be because constitutional symptoms are caused by the underlying cancer. This study suggests that clinicians should consider a range of symptoms, rather than just breathlessness, in planning outcomes for clinical trials. These results are important to inform patients about the potential benefits and duration of symptom improvement after therapeutic aspiration.


Alteration of serotonin transporter density and activity in fibromyalgia.
The aim of the study was to evaluate the kinetic parameters of a specific serotonin transporter (SERT) and serotonin uptake in a mentally healthy subset of patients with fibromyalgia. Platelets were obtained from 40 patients and 38 healthy controls. SERT expression and functionality were evaluated through the measurement of [3H]paroxetine binding and the [3H]serotonin uptake itself. The values of maximal membrane binding capacity (Bmax) were statistically lower in the patients than in the healthy volunteers, whereas the dissociation constant (Kd) did not show any statistically significant variations. Moreover, a decrease in the maximal uptake rate of SERT (Vmax) was demonstrated in the platelets of patients, whereas the Michaelis constant (Km) did not show any statistically significant variations. Symptom severity score (tiredness, tender points index and Fibromyalgia Impact Questionnaire) were negatively correlated with Bmax and with Vmax, and positively correlated with Km. A change in SERT seems to occur in fibromyalgic patients, and it seems to be related to the severity of fibromyalgic symptoms.


Virological Characterization of Critically Ill Patients With COVID-19 in the United Kingdom: Interactions of Viral Load, Antibody Status, and B.1.1.7 Infection.
Convalescent plasma containing neutralizing antibody to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is under investigation for coronavirus disease 2019 (COVID-19) treatment. We report diverse virological characteristics of UK intensive care patients enrolled in the Immunoglobulin Domain of the REMAP-CAP randomized controlled trial that potentially influence treatment outcomes. SARS-CoV-2 RNA in nasopharyngeal swabs collected pretreatment was quantified by PCR. Antibody status was determined by spike-protein ELISA. B.1.1.7 was differentiated from other SARS-CoV-2 strains using allele-specific probes or restriction site polymorphism (SfcI) targeting D1118H. Of 1274 subjects, 90% were PCR positive with viral loads 118-1.7 × 1011IU/mL. Median viral loads were 40-fold higher in those IgG seronegative (n = 354; 28%) compared to seropositives (n = 939; 72%). Frequencies of B.1.1.7 increased from <1% in November 2020 to 82% of subjects in January 2021. Seronegative individuals with wild-type SARS-CoV-2 had significantly higher viral loads than seropositives (medians 5.8 × 106 and 2.0 × 105 IU/mL, respectively; P = 2 × 10-15). High viral loads in seropositive B.1.1.7-infected subjects and resistance to seroconversion indicate less effective clearance by innate and adaptive immune responses. SARS-CoV-2 strain, viral loads, and antibody status define subgroups for analysis of treatment efficacy.


Effects of systemic beta-blocker therapy on the efficacy and safety of topical brimonidine and timolol. Brimonidine Study Groups 1 and 2.
To determine the impact of coadminstration of systemic beta-blockers on the ocular hypotensive efficacy and safety of topical timolol, a nonselective, beta-blocker, and that of brimonidine, an alpha2-selective adrenergic agonist, in patients with glaucoma or ocular hypertension. Post hoc evaluation of data collected from two prospective, multicenter, randomized, double-masked, parallel-group, actively-controlled, 12-month clinical trials. Of the 926 subjects with ocular hypertension or glaucoma that were enrolled in the two prospective trials, 66 (7.1%) were concurrently maintained on systemic beta-blocker therapy. Of these patients, 34 had been assigned to the brimonidine group and 32 to the timolol group. Subjects instilled into each eye either 1 drop of brimonidine 0.2% or timolol 0.5% twice daily for 1 year. Study subjects within medication treatment groups were classified as to their use or nonuse of concurrent systemic beta-blockers, and mean intraocular pressure (IOP) reduction, adverse events, heart rate, and blood pressure were compared. Mean IOP reduction from baseline was the primary efficacy variable. Adverse events and mean changes in heart rate and blood pressure from baseline were the primary safety variables. Timolol-treated subjects concurrently taking systemic beta-blockers had smaller decreases in IOP, a greater mean change in systolic (at week 2, months 1, 2, 6, and 9; P < or = 0.001) and diastolic blood pressure (months 2 and 6; P < or = 0.02), and a significantly greater mean decrease in heart rate (month 6; P = 0.004) compared with timolol subjects not taking systemic beta-blockers. By contrast, there was a modest enhancement of IOP-lowering efficacy at trough and no effect on blood pressure or heart rate in brimonidine-treated subjects who were concurrently receiving systemic beta-blocker therapy compared with brimonidine subjects not receiving systemic beta-blockers. Concurrent systemic beta-blocker therapy had no deleterious effect on ocular hypotensive efficacy and no impact on systemic safety parameters with topical brimonidine, whereas efficacy was reduced and systemic safety parameters were impacted with topical timolol. Ocular hypotensive agents other than beta-blockers, such as the alpha2 agonist brimonidine, may be a more appropriate first-line therapy for ocular hypertension and glaucoma patients concurrently taking systemic beta-blockers.


Renin-Angiotensin Activation and Oxidative Stress in Early Heart Failure with Preserved Ejection Fraction.
Animal models have suggested a role of renin-angiotensin system (RAS) activation and subsequent cardiac oxidation in heart failure with preserved ejection fraction (HFpEF). Nevertheless, RAS blockade has failed to show efficacy in treatment of HFpEF. We evaluated the role of RAS activation and subsequent systemic oxidation in HFpEF. Oxidative stress markers were compared in 50 subjects with and without early HFpEF. Derivatives of reactive oxidative metabolites (DROMs), F2-isoprostanes (IsoPs), and ratios of oxidized to reduced glutathione (E h GSH) and cysteine (E h CyS) were measured. Angiotensin converting enzyme (ACE) levels and activity were measured. On univariate analysis, HFpEF was associated with male sex (p = 0.04), higher body mass index (BMI) (p = 0.003), less oxidized E h CyS (p = 0.001), lower DROMs (p = 0.02), and lower IsoP (p = 0.03). Higher BMI (OR: 1.3; 95% CI: 1.1-1.6) and less oxidized E h CyS (OR: 1.2; 95% CI: 1.1-1.4) maintained associations with HFpEF on multivariate analysis. Though ACE levels were higher in early HFpEF (OR: 1.09; 95% CI: 1.01-1.05), ACE activity was similar to that in controls. HFpEF is not associated with significant systemic RAS activation or oxidative stress. This may explain the failure of RAS inhibitors to alter outcomes in HFpEF.


How the social ecology and social situation shape individuals' affect valence and arousal.
Many theories highlight the role social contexts play in shaping affective experience. However, little is known about how individuals' social environments influence core affect on short time-scales (e.g., hours). Using experience sampling data from the iSAHIB, wherein 150 adults aged 18 to 89 years reported on 64,213 social interactions (average 6.92 per day, SD = 2.85) across 9 weeks of daily life, we examined how 4 features of individuals' social ecology (between-person differences) and immediate social situations (within-person changes) were associated with core affect-valence and arousal-and how those associations differ with age. Results from multilevel models revealed that familiarity, importance, type of social partner, and gender composition of the social context were associated with affect valence and/or affect arousal. Higher familiarity, higher importance, and same-gender composition were associated with more positive affect valence and higher arousal. Interactions with family and friends were linked to more positive valence whereas nonfamily social partners were linked to higher arousal. Age moderated the associations between importance and affect arousal, and between type of social partner and both dimensions of core affect. Findings align with theoretical propositions, contributing to but also suggesting need for further precision regarding how development shapes the interplay between social context and moment-to-moment affective experience. (PsycINFO Database Record


From personal fear to mass panic: The neurological basis of crowd perception.
Recent studies have investigated the neural correlates of how we perceive emotions of individuals or a group of individuals using images of individual bodily expressions. However, it is still largely unknown how we perceive the emotion of a dynamic crowd. This fMRI study used realistic videos of a large group of people expressing fearful, happy or neutral emotions. Furthermore, the emotions were expressed by either unrelated individuals in the group or by an interacting group. It was hypothesized that the dynamics between the people in a crowd is a more salient signal than merely the emotion of the crowd. Second, it was expected that the group interaction is of special importance in a fearful or "panic" situation, as opposed to a happy or neutral situation. Using a fast-event related design, it was revealed that observing interactive individuals, more so than independently expressive individuals, activated networks related to the perception, execution and integration of action and emotion. Most importantly, the interactive or panicked crowds, as opposed to the individually fearful crowds, triggered more anticipatory and action preparation activity, whereas the brain was less sensitive to the dynamics of individuals in a happy or neutral crowd. This is the first study to assess the effect of the dynamics between people and the collectively displayed emotion as an important aspect of emotional crowd perception.


Chemotherapy follow-up in older adults: results of a quality-improvement project.
Caring for older adults with cancer receiving chemotherapy may present a number of challenges. Complications from chemotherapy are more common among older patients, and prevention and early detection of toxicities can improve treatment adherence, decrease costs, and improve treatment outcomes in this population. Over 12 months, 18 older adults with cancer (aged 65 years or older) participated in a quality-improvement project that provided telephone follow-up and intervention after chemotherapy administration; first-time chemotherapy recipients received telephone calls that followed assessment and referral guidelines over 10 days. Several characteristics of patients with increased toxicity were noted, including poor functional status, limited support at home, and significant comorbid disease. Recommendations for identifying patients at high risk are included so that services may be targeted for the most appropriate use of resources.


Analyzing the impact of ambient temperature indicators on transformer life in different regions of Chinese mainland.
Regression analysis is applied to quantitatively analyze the impact of different ambient temperature characteristics on the transformer life at different locations of Chinese mainland. 200 typical locations in Chinese mainland are selected for the study. They are specially divided into six regions so that the subsequent analysis can be done in a regional context. For each region, the local historical ambient temperature and load data are provided as inputs variables of the life consumption model in IEEE Std. C57.91-1995 to estimate the transformer life at every location. Five ambient temperature indicators related to the transformer life are involved into the partial least squares regression to describe their impact on the transformer life. According to a contribution measurement criterion of partial least squares regression, three indicators are conclusively found to be the most important factors influencing the transformer life, and an explicit expression is provided to describe the relationship between the indicators and the transformer life for every region. The analysis result is applicable to the area where the temperature characteristics are similar to Chinese mainland, and the expressions obtained can be applied to the other locations that are not included in this paper if these three indicators are known.


Neuroinflammation During RNA Viral Infections.
Neurotropic RNA viruses continue to emerge and are increasingly linked to diseases of the central nervous system (CNS) despite viral clearance. Indeed, the overall mortality of viral encephalitis in immunocompetent individuals is low, suggesting efficient mechanisms of virologic control within the CNS. Both immune and neural cells participate in this process, which requires extensive innate immune signaling between resident and infiltrating cells, including microglia and monocytes, that regulate the effector functions of antiviral T and B cells as they gain access to CNS compartments. While these interactions promote viral clearance via mainly neuroprotective mechanisms, they may also promote neuropathology and, in some cases, induce persistent alterations in CNS physiology and function that manifest as neurologic and psychiatric diseases. This review discusses mechanisms of RNA virus clearance and neurotoxicity during viral encephalitis with a focus on the cytokines essential for immune and neural cell inflammatory responses and interactions. Understanding neuroimmune communications in the setting of viral infections is essential for the development of treatments that augment neuroprotective processes while limiting ongoing immunopathological processes that cause ongoing CNS disease.


The rise of carbapenem-resistant Acinetobacter baumannii.
Acinetobacter spp. are Gram-negative bacteria that have become one of the most difficult pathogens to treat. The species A. baumannii, largely unknown 30 years ago, has risen to prominence particularly because of its ability to cause infections in immunocompromised patients. It is now a predominant pathogen in many hospitals as it has acquired resistance genes to virtually all antibiotics capable of treating Gram-negative bacteria, including the fluoroquinolones and the cephalosporins. Some members of the species have accumulated these resistance genes in large resistance islands, located in a "hot-spot" within the bacterial chromosome. The only conventional remaining treatment options were the carbapenems. However, A. baumannii possesses an inherent class D β-lactamase gene (blaOXA-51-like) that can have the ability to confer carbapenem resistance. Additionally, mechanisms of carbapenem resistance have emerged that derive from the importation of the distantly related class D β-lactamase genes blaOXA-23 and blaOXA-58. Although not inducible, the expression of these genes is controlled by mobile promoters carried on ISAba elements. It has also been found that other resistance genes including the chromosomal class C β-lactamase genes conferring cephalosporin resistance are controlled in the same manner. Colistin is now considered to be the final drug capable of treating infections caused by carbapenem-resistant A. baumannii; however, strains are now being isolated that are resistant to this antibiotic as well. The increasing inability to treat infections caused by A. baumannii ensures that this pathogen more than ranks with MRSA or Clostridium difficile as a threat to modern medicine.


The importance of migratory connectivity for global ocean policy.
The distributions of migratory species in the ocean span local, national and international jurisdictions. Across these ecologically interconnected regions, migratory marine species interact with anthropogenic stressors throughout their lives. Migratory connectivity, the geographical linking of individuals and populations throughout their migratory cycles, influences how spatial and temporal dynamics of stressors affect migratory animals and scale up to influence population abundance, distribution and species persistence. Population declines of many migratory marine species have led to calls for connectivity knowledge, especially insights from animal tracking studies, to be more systematically and synthetically incorporated into decision-making. Inclusion of migratory connectivity in the design of conservation and management measures is critical to ensure they are appropriate for the level of risk associated with various degrees of connectivity. Three mechanisms exist to incorporate migratory connectivity into international marine policy which guides conservation implementation: site-selection criteria, network design criteria and policy recommendations. Here, we review the concept of migratory connectivity and its use in international policy, and describe the Migratory Connectivity in the Ocean system, a migratory connectivity evidence-base for the ocean. We propose that without such collaboration focused on migratory connectivity, efforts to effectively conserve these critical species across jurisdictions will have limited effect.


Genomic insights into multidrug-resistance, mating and virulence in Candida auris and related emerging species.
Candida auris is an emergent multidrug-resistant fungal pathogen causing increasing reports of outbreaks. While distantly related to C. albicans and C. glabrata, C. auris is closely related to rarely observed and often multidrug-resistant species from the C. haemulonii clade. Here, we analyze near complete genome assemblies for the four C. auris clades and three related species, and map intra- and inter-species rearrangements across the seven chromosomes. Using RNA-Seq-guided gene predictions, we find that most mating and meiosis genes are conserved and that clades contain either the MTLa or MTLα mating loci. Comparing the genomes of these emerging species to those of other Candida species identifies genes linked to drug resistance and virulence, including expanded families of transporters and lipases, as well as mutations and copy number variants in ERG11. Gene expression analysis identifies transporters and metabolic regulators specific to C. auris and those conserved with related species which may contribute to differences in drug response in this emerging fungal clade.


Effect of UVA/Riboflavin Collagen Crosslinking on Biomechanics of Artificially Swollen Corneas.
The purpose of this study was to characterize the relation between corneal hydration and stiffening effects of the UVA/riboflavin collagen crosslinking treatment and to investigate how artificially swelling the cornea prior to this treatment procedure affects tensile property improvement. Porcine corneas were collagen crosslinked in vitro at different hydration levels using a number of hypoosmolar and isoosmolar riboflavin solutions. Thickness of the specimens prior to crosslinking was taken as a proxy for their hydration and was used to divide them into different thickness groups. A Dynamic Mechanical Analysis (DMA) machine was used to perform mechanical tensile tests. The hydration of specimens during the mechanical tests was kept similar to the hydration at which they were crosslinked. The recorded force was used to calculate the maximum tensile stress and tangent modulus as a function of thickness (hydration) prior to collagen crosslinking treatment. Collagen crosslinking with either a hypoosmolar or isoosmolar solution significantly increased corneal tensile modulus (P < 0.05). Corneas that were swollen prior to crosslinking showed significantly softer tensile properties compared with those that were crosslinked at lower hydration (P < 0.05). Although the degree of tensile property improvement was hydration dependent, the stiffness of samples crosslinked at higher hydration was not significantly different than the stiffness of those crosslinked at lower hydration when the hydration was kept similar in the mechanical experiments. Swelling porcine corneas to the different extents prior to collagen crosslinking treatment does not significantly change the amount of biomechanical improvement if tensile properties are measured at similar hydration.


Concussion Education in U.S. Collegiate Sport: What Is Happening and What Do Athletes Want?
Concussion education for athletes has the potential to play a role in reducing the health burden of concussions from sport by modifying individual risk-related behaviors. In U.S. collegiate sport, decisions about content and delivery of concussion education are left up to the individual institution. This may result in a high degree of variability in what educational materials athletes receive and is particularly problematic as few concussion education programs have demonstrated efficacy. Health educators can play an important role in working collaboratively with sports medicine clinicians to design and evaluate evidence-based concussion education materials for athletes that meet their learning needs. As a first step in this process, the present study characterizes the content, source, and delivery modalities of concussion currently being provided to U.S. collegiate athletes. It also describes the reported concussion education preferences of a sample of U.S. collegiate athletes. Participants were 789 athletic trainers from 276 schools and 325 athletes from four schools. Results indicated that education is most frequently provided by athletic trainers but that many athletes would also like coaches and physicians to be involved in this process. Athletes also indicated a preference for content provision across a range of topics, including athletic and academic consequences of continued play with a concussion. Implications for the design and delivery of concussion education for athletes are discussed.


CHIP/Stub1 regulates the Warburg effect by promoting degradation of PKM2 in ovarian carcinoma.
Tumor cells preferentially adopt aerobic glycolysis for their energy supply, a phenomenon known as the Warburg effect. It remains a matter of debate as to how the Warburg effect is regulated during tumor progression. Here, we show that CHIP (carboxyl terminus of Hsc70-interacting protein), a U-box E3 ligase, suppresses tumor progression in ovarian carcinomas by inhibiting aerobic glycolysis. While CHIP is downregulated in ovarian carcinoma, induced expression of CHIP results in significant inhibition of the tumor growth examined by in vitro and in vivo experiments. Reciprocally, depletion of CHIP leads to promotion of tumor growth. By a SiLAD proteomics analysis, we identified pyruvate kinase isoenzyme M2 (PKM2), a critical regulator of glycolysis in tumors, as a target that CHIP mediated for degradation. Accordingly, we show that CHIP regulates PKM2 protein stability and thereafter the energy metabolic processes. Depletion or knockout of CHIP increased the glycolytic products in both tumor and mouse embryonic fibroblast cells. Simultaneously, we observed that CHIP expression inversely correlated with PKM2 levels in human ovarian carcinomas. This study reveals a mechanism that the Warburg effect is regulated by CHIP through its function as an E3 ligase, which mediates the degradation of PKM2 during tumor progression. Our findings shed new light into understanding of ovarian carcinomas and may provide a new therapeutic strategy for ovarian cancer.


Deep Learning for Electromyographic Hand Gesture Signal Classification Using Transfer Learning.
In recent years, deep learning algorithms have become increasingly more prominent for their unparalleled ability to automatically learn discriminant features from large amounts of data. However, within the field of electromyography-based gesture recognition, deep learning algorithms are seldom employed as they require an unreasonable amount of effort from a single person, to generate tens of thousands of examples. This paper's hypothesis is that general, informative features can be learned from the large amounts of data generated by aggregating the signals of multiple users, thus reducing the recording burden while enhancing gesture recognition. Consequently, this paper proposes applying transfer learning on aggregated data from multiple users while leveraging the capacity of deep learning algorithms to learn discriminant features from large datasets. Two datasets comprised 19 and 17 able-bodied participants, respectively (the first one is employed for pre-training), were recorded for this work, using the Myo armband. A third Myo armband dataset was taken from the NinaPro database and is comprised ten able-bodied participants. Three different deep learning networks employing three different modalities as input (raw EMG, spectrograms, and continuous wavelet transform (CWT)) are tested on the second and third dataset. The proposed transfer learning scheme is shown to systematically and significantly enhance the performance for all three networks on the two datasets, achieving an offline accuracy of 98.31% for 7 gestures over 17 participants for the CWT-based ConvNet and 68.98% for 18 gestures over 10 participants for the raw EMG-based ConvNet. Finally, a use-case study employing eight able-bodied participants suggests that real-time feedback allows users to adapt their muscle activation strategy which reduces the degradation in accuracy normally experienced over time.


Role of cellular bioenergetics in smooth muscle cell proliferation induced by platelet-derived growth factor.
Abnormal smooth muscle cell proliferation is a hallmark of vascular disease. Although growth factors are known to contribute to cell hyperplasia, the changes in metabolism associated with this response, particularly mitochondrial respiration, remain unclear. Given the increased energy requirements for proliferation, we hypothesized that PDGF (platelet-derived growth factor) would stimulate glycolysis and mitochondrial respiration and that this elevated bioenergetic capacity is required for smooth muscle cell hyperplasia. To test this hypothesis, cell proliferation, glycolytic flux and mitochondrial oxygen consumption were measured after treatment of primary rat aortic VSMCs (vascular smooth muscle cells) with PDGF. PDGF increased basal and maximal rates of glycolytic flux and mitochondrial oxygen consumption; enhancement of these bioenergetic pathways led to a substantial increase in the mitochondrial reserve capacity. Interventions with the PI3K (phosphoinositide 3-kinase) inhibitor LY-294002 or the glycolysis inhibitor 2-deoxy-D-glucose abrogated PDGF-stimulated proliferation and prevented augmentation of glycolysis and mitochondrial reserve capacity. Similarly, when L-glucose was substituted for D-glucose, PDGF-dependent proliferation was abolished, as were changes in glycolysis and mitochondrial respiration. Interestingly, LDH (lactate dehydrogenase) protein levels and activity were significantly increased after PDGF treatment. Moreover, substitution of L-lactate for D-glucose was sufficient to increase mitochondrial reserve capacity and cell proliferation after treatment with PDGF; these effects were inhibited by the LDH inhibitor oxamate. These results suggest that glycolysis, by providing substrates that enhance the mitochondrial reserve capacity, plays an essential role in PDGF-induced cell proliferation, underscoring the integrated metabolic response required for proliferation of VSMCs in the diseased vasculature.


JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy.
As the incidence of COVID-19 increases with time, more and more efforts are made to pave a way out for the therapeutic strategies to deal with the disease progression. Inflammation being a significant influencer in COVID-19 patients, it drives our focus onto the signaling cascades of the JAK/STAT pathway. JAK phosphorylation mediated by cytokine receptor activation leads to phosphorylation of STATs that translocate into the nucleus to translate for inflammatory mediators. The SARS-CoV-2 structural proteins like spike, nucleocapsid, membrane and envelope proteins along with the non- structural proteins 1-16 including proteases like 3CL pro and PLpro promote its entry and survival in hosts. The SARS-CoV-2 infection triggers inflammation via the JAK/STAT pathway leading to recruitment of pneumocytes, endothelial cells, macrophages, monocytes, lymphocytes, natural killer cells and dendritic cells progressing towards cytokine storm. This produces various inflammatory markers in the host that determine the disease severity. The JAK/STAT signaling also mediates immune responses via B cell and T cell differentiation.With an attempt to reduce excessive inflammation, JAK/STAT inhibitors like Ruxolitinib, Baricitinib, Tofacitinib have been employed that mediate its actions via suppressors of cytokine signaling, cytokine inducible SH2 containing protein, Protein inhibitor of activated STAT and protein tyrosine phosphatases. Even though they are implicated with multiple adverse effects, the regulatory authorities have supported its use, and numerous clinical trials are in progress to prove their safety and efficacy. On the contrary, the exact mechanism of JAK/STAT inhibition at molecular levels remains speculative for which further investigations are required.


Diffraction inhibition in two-dimensional photonic crystals.
We show the existence of flat equal-frequency contour across the entire first Brillouin zone in two-dimensional photonic crystals. Under this condition, light diffraction can be inhibited. Moreover, the beam can be highly localized between two neighboring rows of the defect-free photonic crystal. Such a finding may have novel applications in light beam manipulations and on-chip integrated photonic devices.


Increased adrenergic signaling is responsible for decreased glucose-stimulated insulin secretion in the chronically hyperinsulinemic ovine fetus.
Insulin may stimulate its own insulin secretion and is a potent growth factor for the pancreatic β-cell. Complications of pregnancy, such as diabetes and intrauterine growth restriction, are associated with changes in fetal insulin concentrations, secretion, and β-cell mass. However, glucose concentrations are also abnormal in these conditions. The direct effect of chronic fetal hyperinsulinemia with euglycemia on fetal insulin secretion and β-cell mass has not been tested. We hypothesized that chronic fetal hyperinsulinemia with euglycemia would increase glucose-stimulated insulin secretion (GSIS) and β-cell mass in the ovine fetus. Singleton ovine fetuses were infused with iv insulin to produce high physiological insulin concentrations, or saline for 7-10 days. The hyperinsulinemic animals also received a direct glucose infusion to maintain euglycemia. GSIS, measured at 133 ± 1 days of gestation, was significantly attenuated in the hyperinsulinemic fetuses (P < .05). There was no change in β-cell mass. The hyperinsulinemic fetuses also had decreased oxygen (P < .05) and higher norepinephrine (1160 ± 438 vs 522 ± 106 pg/mL; P < .005). Acute pharmacologic adrenergic blockade restored GSIS in the hyperinsulinemic-euglycemic fetuses, demonstrating that increased adrenergic signaling mediates decreased GSIS in these fetuses.


Confined water radiolysis in aluminosilicate nanotubes: the importance of charge separation effects.
Imogolite nanotubes are potentially promising co-photocatalysts because they are predicted to have curvature-induced, efficient electron-hole pair separation. This prediction has however not yet been experimentally proven. Here, we investigated the behavior upon irradiation of these inorganic nanotubes as a function of their water content to understand the fate of the generated electrons and holes. Two types of aluminosilicate nanotubes were studied: one was hydrophilic on its external and internal surfaces (IMO-OH) and the other had a hydrophobic internal cavity due to Si-CH3 bonds (IMO-CH3), with the external surface remaining hydrophilic. Picosecond pulse radiolysis experiments demonstrated that the electrons are efficiently driven outward. For imogolite samples with very few external water molecules (around 1% of the total mass), quasi-free electrons were formed. They were able to attach to a water molecule, generating a water radical anion, which ultimately led to dihydrogen. When more external water molecules were present, solvated electrons, precursors of dihydrogen, were formed. In contrast, holes moved towards the internal surface of the tubes. They mainly led to the formation of dihydrogen and of methane in irradiated IMO-CH3. The attachment of the quasi-free electron to water was a very efficient process and accounted for the high dihydrogen production at low relative humidity values. When the water content increased, electron solvation dominated over attachment to water molecules. Electron solvation led to dihydrogen production, albeit to a lesser extent than quasi-free electrons. Our experiments demonstrated the spontaneous curvature-induced charge separation in these inorganic nanotubes, making them very interesting potential co-photocatalysts.


Optoacoustic image formation approaches-a clinical perspective.
Clinical translation of optoacoustic imaging is fostered by the rapid technical advances in imaging performance as well as the growing number of clinicians recognizing the immense diagnostic potential of this technology. Clinical optoacoustic systems are available in multiple configurations, including hand-held and endoscopic probes as well as raster-scan approaches. The hardware design must be adapted to the accessible portion of the imaged region and other application-specific requirements pertaining the achievable depth, field of view or spatio-temporal resolution. Equally important is the adequate choice of the signal and image processing approach, which is largely responsible for the resulting imaging performance. Thus, new image reconstruction algorithms are constantly evolving in parallel to the newly-developed set-ups. This review focuses on recent progress on optoacoustic image formation algorithms and processing methods in the clinical setting. Major reconstruction challenges include real-time image rendering in two and three dimensions, efficient hybridization with other imaging modalitites as well as accurate interpretation and quantification of bio-markers, herein discussed in the context of ongoing progress in clinical translation.


CD28-CD80 interactions control regulatory T cell motility and immunological synapse formation.
Regulatory T cells (Tregs) are essential for tolerance to self and environmental Ags, acting in part by downmodulating costimulatory molecules on the surface of dendritic cells (DCs) and altering naive CD4 T cell-DC interactions. In this study, we show that Tregs form stable conjugates with DCs before, but not after, they decrease surface expression of the costimulatory molecule CD80 on the DCs. We use supported planar bilayers to show that Tregs dramatically slow down but maintain a highly polarized and motile phenotype after recognizing Ag in the absence of costimulation. These motile cells are characterized by distinct accumulations of LFA-1-ICAM-1 in the lamella and TCR-MHC in the uropod, consistent with a motile immunological synapse or "kinapse." However, in the presence of high, but not low, concentrations of CD80, Tregs form stationary, symmetrical synapses. Using blocking Abs, we show that, whereas CTLA-4 is required for CD80 downmodulation, CD28-CD80 interactions are critical for modulating Treg motility in the presence of Ag. Taken together, these results support the hypothesis that Tregs are tuned to alter their motility depending on costimulatory signals.


Bone morphogenetic protein receptor II regulates pulmonary artery endothelial cell barrier function.
Mutations in bone morphogenetic protein receptor II (BMPR-II) underlie most heritable cases of pulmonary arterial hypertension (PAH). However, less than half the individuals who harbor mutations develop the disease. Interestingly, heterozygous null BMPR-II mice fail to develop PAH unless an additional inflammatory insult is applied, suggesting that BMPR-II plays a fundamental role in dampening inflammatory signals in the pulmonary vasculature. Using static- and flow-based in vitro systems, we demonstrate that BMPR-II maintains the barrier function of the pulmonary artery endothelial monolayer suppressing leukocyte transmigration. Similar findings were also observed in vivo using a murine model with loss of endothelial BMPR-II expression. In vitro, the enhanced transmigration of leukocytes after tumor necrosis factor α or transforming growth factor β1 stimulation was CXCR2 dependent. Our data define how loss of BMPR-II in the endothelial layer of the pulmonary vasculature could lead to a heightened susceptibility to inflammation by promoting the extravasation of leukocytes into the pulmonary artery wall. We speculate that this may be a key mechanism involved in the initiation of the disease in heritable PAH that results from defects in BMPR-II expression.


A study on delay in treatment of kala-azar patients in Bangladesh.
Visceral leishmaniasis (kala-azar) continues to be a major rural public health problem in Bangladesh. A cross-sectional study was carried out in two subdistricts of Mymensingh district from January 2006 to June 2007 to evaluate the delay kala-azar treatment. Suspected patients who attended to out patient department (OPD) were subjected to a dipstick test (RK39) for kala-azar. Sixty five from Bhaluka and 60 positive patients from Gafargaon subdistrict were enrolled. Most of the patients (80%) first visited nonqualified private practitioners, while only 15.2% consulted registered doctors. Fifty per cent were referred to the Upazilla health complex (UZHC) by the family members or relatives. About 49% and 43% patients required third and second health-care providers for kala-azar treatment, respectively. Patient delay ranged from 2 to 30 days; median 4 (IQR 3 to 7 days), the system delay ranged from 0 days to 225 days; median 54 (IQR 40-66 days). Residential status (p value <0.05) had impact on patient delay. Educational status and number of treatment providers had impact on system delay (p<0.05). System delay rather than patient delay is the important weakness of the kala-azar control programme in Bangladesh. Residence in rural areas, low educational background and treatment providers are associated with these delays. A proper educational programme may reduce the delay.


The retention of health human resources in primary healthcare centers in Lebanon: a national survey.
Critical shortages of health human resources (HHR), associated with high turnover rates, have been a concern in many countries around the globe. Of particular interest is the effect of such a trend on the primary healthcare (PHC) sector; considered a cornerstone in any effective healthcare system. This study is a rare attempt to investigate PHC HHR work characteristics, level of burnout and likelihood to quit as well as the factors significantly associated with staff retention at PHC centers in Lebanon. A cross-sectional design was utilized to survey all health providers at 81 PHC centers dispersed in all districts of Lebanon. The questionnaire consisted of four sections: socio-demographic/ professional background, organizational/institutional characteristics, likelihood to quit and level of professional burnout (using the Maslach-Burnout Inventory). A total of 755 providers completed the questionnaire (60.5% response rate). Bivariate analyses and multinomial logistic regression were used to determine factors associated with likelihood to quit. Two out of five respondents indicated likelihood to quit their jobs within the next 1-3 years and an additional 13.4% were not sure about quitting. The top three reasons behind likelihood to quit were poor salary (54.4%), better job opportunities outside the country (35.1%) and lack of professional development (33.7%). A U-shaped relationship was observed between age and likelihood to quit. Regression analysis revealed that high levels of burnout, lower level of education and low tenure were all associated with increased likelihood to quit. The study findings reflect an unstable workforce and are not conducive to supporting an expanded role for PHC in the Lebanese healthcare system. While strategies aiming at improving staff retention would be important to develop and implement for all PHC HHR; targeted retention initiatives should focus on the young-new recruits and allied health professionals. Particular attention should be dedicated to enhancing providers' role satisfaction and sense of job security. Such initiatives are of pivotal importance to stabilize the workforce and ensure its longevity.


Intersecting Worlds of Transfusion and Transplantation Medicine: An International Symposium Organized by the Canadian Blood Services Centre for Innovation.
The principal theme of the symposium was centered on how the world of regenerative medicine intersects with that of transfusion medicine, with a particular focus on hematopoietic stem cells (HSCs) and stem cell therapies. The symposium highlighted several exciting developments and identified areas where additional research is needed. A revised map of human hematopoietic hierarchy was presented based on the functional and phenotypic analysis of thousands of single stem and progenitor cells from adult bone marrow and fetal liver. These analyses revealed that multipotency is largely restricted to the HSC and multipotent progenitor compartments in adult bone marrow where most progenitors are unipotent, whereas fetal liver contains a large number of distinct oligopotent progenitors. Furthermore, unlike adult bone marrow, multipotency is extended in the downstream progenitors in the hierarchy in the fetal liver stage. Production of platelets ex vivo from HSCs is emerging as a potentially viable option because of advances in culture techniques that combine cytokine mixtures, small molecules, and shear stress. However, limited HSC expansion and low platelet yield from culture-derived megakaryocytes remain problematic. Evidence was presented to support stricter guidelines for transfusion of platelets and red blood cells practices in allogeneic HSC transplant patients, although evidence is often extrapolated from general indications. Basic principles of human leukocyte antigen testing in HSC transplant were described, emphasizing the need for a national (and global) stem cell donor registry. Ongoing research is aimed at improving cellular cryopreservation including the establishment of a new thawing protocol that improves viability of umbilical cord blood CD34+ cells. Umbilical cord blood transplantation practices have also been improved; recent studies suggest noninferior outcomes when patients are transplanted with umbilical cord blood vs a matched adult donor. Finally, mesenchymal stem cell infusion is an example of a cellular therapy useful for immunomodulation. Preclinical trials suggest that mesenchymal stem cells may be effective in managing sepsis. In conclusion, practices and research surrounding HSCs are continuing to evolve rapidly as new information is obtained.


Differential flight muscle development in workers, queens and males of the eusocial bees, Apis mellifera and Scaptotrigona postica.
The flight capability of the adult eusocial bees, Apis mellifera L. and Scaptotrigona postica Latreille (Hymenoptera: Apidae), is intrinsically linked to their colonial functions, such as the nuptial flight for mating in the case of queens and males, and the exploration of new habitats for nesting and food sources in the case of workers. Flight is achieved by the contraction of indirect flight muscles that produce changes in thoracic volume and, therefore, wing movement. The purpose of this work is to examine possible differences in muscle development that may be associated with the flying activity of individuals in a given life stage considering the behavioral and physiological differences among the stages and between the two species studied. Measurements of the muscle fibers obtained from light microscopy preparations of muscle were submitted to statistical analysis in order to detect the differences at a given time, or throughout the life of the individual. The results show that muscle morphology is similar in both species, but in A. mellifera the muscle fibers are thicker and more numerous than in S. postica. Differences in the fiber thickness according to life stage in all classes of individuals of both species were detected. These results are discussed in relation to the need for flying in each life stage.


Uncorrected refractive errors and spectacle utilisation rate in Tehran: the unmet need.
To determine the prevalence of the met and unmet need for spectacles and their associated factors in the population of Tehran. 6497 Tehran citizens were enrolled through random cluster sampling and were invited to a clinic for an interview and ophthalmic examination. 4354 (70.3%) participated in the survey, and refraction measurement results of 4353 people aged 5 years and over are presented. The unmet need for spectacles was defined as the proportion of people who did not use spectacles despite a correctable visual acuity of worse than 20/40 in the better eye. The need for spectacles in the studied population, standardised for age and sex, was 14.1% (95% confidence interval (CI), 12.8% to 15.4%). This need was met with appropriate spectacles in 416 people (9.3% of the total sample), while it was unmet in 230 people, representing 4.8% of the total sample population (95% CI, 4.1% to 5.4%). The spectacle coverage rate (met need/(met need + unmet need)) was 66.0%. Multivariate logistic regression showed that variables of age, education, and type of refractive error were associated with lack of spectacle correction. There was an increase in the unmet need with older age, lesser education, and myopia. This survey determined the met and unmet need for spectacles in a Tehran population. It also identified high risk groups with uncorrected refractive errors to guide intervention programmes for the society. While the study showed the unmet need for spectacles and its determinants, more extensive studies towards the causes of unmet need are recommended.


Improved outcome of pediatric kidney transplantations in the Netherlands -- effect of the introduction of mycophenolate mofetil?
Collaboration of the Dutch centers for kidney transplantation in children started in 1997 with a shared immunosuppressive protocol, aimed at improving graft survival by diminishing the incidence of acute rejections. This study compares the results of transplantations in these patients to those in a historical reference group. Ninety-six consecutive patients receiving a first kidney transplant were treated with an immunosuppressive regimen consisting of mycophenolate mofetil, cyclosporine and corticosteroids. The results were compared with those of historic controls (first transplants between 1985 and 1995, n = 207), treated with different combinations of corticosteroids, cyclosporine A and/or azathioprine. Cytomegalovirus (CMV) prophylaxis was prescribed to high-risk patients in the study group, and only a small proportion of the reference group. The graft survival at 1 yr improved significantly: 92% in the study group, vs. 73% in the reference group (p < 0.001). In the study group 63% of patients remained rejection-free during the first year; in the reference group 28% (p < 0.001). After statistical adjustment of differences in baseline data, as cold ischemia time, the proportion of LRD, preemptive transplantation, and young donors, the difference between study and reference group in graft survival (RR 0.33, p = 0.003) and incidence of acute rejection (RR 0.37, p < 0.001), as the only factor, remained statistically significant, indicating the effect of the immunosuppressive therapy. In the first year one case of malignancy occurred in each group. CMV disease occurred less frequently in the study group (11%) than in the reference group (26%, p = 0.02). As a new complication in 4 patients bronchiectasis was diagnosed. A new consensus protocol, including the introduction of mycophenolate mofetil, considerably improved the outcome of pediatric kidney transplantation in the Netherlands, measured as reduction of the incidence of acute rejection and improved graft survival.


ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism.
Congenital hyperinsulinism (CHI) is characterised by an over secretion of insulin by the pancreatic β-cells. This condition is mostly caused by mutations in ABCC8 or KCNJ11 genes encoding the SUR1 and KIR6.2 subunits of the ATP-sensitive potassium (K(ATP)) channel. CHI patients are classified according to their responsiveness to diazoxide and to their histopathological diagnosis (either focal, diffuse or atypical forms). Here, we raise the benefits/limits of the genetic diagnosis in the clinical management of CHI patients. ABCC8/KCNJ11 mutational spectrum was established in 109 diazoxide-unresponsive CHI patients for whom an appropriate clinical management is essential to prevent brain damage. Relationships between genotype and radiopathological diagnosis were analysed. ABCC8 or KCNJ11 defects were found in 82% of the CHI cases. All patients with a focal form were associated with a single K(ATP) channel molecular event. In contrast, patients with diffuse forms were genetically more heterogeneous: 47% were associated with recessively inherited mutations, 34% carried a single heterozygous mutation and 19% had no mutation. There appeared to be a predominance of paternally inherited mutations in patients diagnosed with a diffuse form and carrying a sole K(ATP) channel mutation. The identification of recessively inherited mutations related to severe and diffuse forms of CHI provides an informative genetic diagnosis and allows prenatal diagnosis. In contrast, in patients carrying a single K(ATP) channel mutation, genetic analysis should be confronted with the PET imaging to categorise patients as focal or diffuse forms in order to get the appropriate therapeutic management.


ElNemo: a normal mode web server for protein movement analysis and the generation of templates for molecular replacement.
Normal mode analysis (NMA) is a powerful tool for predicting the possible movements of a given macromolecule. It has been shown recently that half of the known protein movements can be modelled by using at most two low-frequency normal modes. Applications of NMA cover wide areas of structural biology, such as the study of protein conformational changes upon ligand binding, membrane channel opening and closure, potential movements of the ribosome, and viral capsid maturation. Another, newly emerging field of NMA is related to protein structure determination by X-ray crystallography, where normal mode perturbed models are used as templates for diffraction data phasing through molecular replacement (MR). Here we present ElNémo, a web interface to the Elastic Network Model that provides a fast and simple tool to compute, visualize and analyse low-frequency normal modes of large macro-molecules and to generate a large number of different starting models for use in MR. Due to the 'rotation-translation-block' (RTB) approximation implemented in ElNémo, there is virtually no upper limit to the size of the proteins that can be treated. Upon input of a protein structure in Protein Data Bank (PDB) format, ElNémo computes its 100 lowest-frequency modes and produces a comprehensive set of descriptive parameters and visualizations, such as the degree of collectivity of movement, residue mean square displacements, distance fluctuation maps, and the correlation between observed and normal-mode-derived atomic displacement parameters (B-factors). Any number of normal mode perturbed models for MR can be generated for download. If two conformations of the same (or a homologous) protein are available, ElNémo identifies the normal modes that contribute most to the corresponding protein movement. The web server can be freely accessed at http://igs-server.cnrs-mrs.fr/elnemo/index.html.


From L-dopa to dihydroxyphenylacetaldehyde: a toxic biochemical pathway plays a vital physiological function in insects.
One protein in Aedes aegypti, classified into the aromatic amino acid decarboxylase (AAAD) family based on extremely high sequence homology (∼70%) with dopa decarboxylase (Ddc), was biochemically investigated. Our data revealed that this predicted AAAD protein use L-dopa as a substrate, as does Ddc, but it catalyzes the production of 3,4-dihydroxylphenylacetaldehyde (DHPAA) directly from L-dopa and apparently has nothing to do with the production of any aromatic amine. The protein is therefore named DHPAA synthase. This subsequently led to the identification of the same enzyme in Drosophila melanogaster, Anopheles gambiae and Culex quinquefasciatus by an initial prediction of putative DHPAA synthase based on sequence homology and subsequent verification of DHPAA synthase identity through protein expression and activity assays. DHPAA is highly toxic because its aldehyde group readily reacts with the primary amino groups of proteins, leading to protein crosslinking and inactivation. It has previously been demonstrated by several research groups that Drosophila DHPAA synthase was expressed in tissues that produce cuticle materials and apparent defects in regions of colorless, flexible cuticular structures have been observed in its gene mutants. The presence of free amino groups in proteins, the high reactivity of DHPAA with the free amino groups, and the genetically ascertained function of the Drosophila DHPAA synthase in the formation of colorless, flexible cuticle, when taken together, suggest that mosquito and Drosophila DHPAA synthases are involved in the formation of flexible cuticle through their reactive DHPAA-mediated protein crosslinking reactions. Our data illustrate how a seemingly highly toxic pathway can serve for an important physiological function in insects.


Enhancement of angiogenic potential of endothelial cells by contact with retinal pigment epithelial cells in a model simulating pathological conditions.
Choroidal neovascularization (CNV) is the leading cause of vision loss in chorioretinal diseases involving contact between retinal pigment epithelial (RPE) and endothelial cells (ECs). The aim of this study was to investigate changes in the angiogenic potential of ECs induced by RPE-EC interaction in two models of RPE-EC coculture. RPE and ECs were grown in contact or noncontact coculture. Selection of ECs was achieved using magnetic beads coated with antibodies specific for EC surface proteins. Angiogenesis was assessed by analyzing the expression of EC genes involved in angiogenesis by RT-PCR. Tube formation on Matrigel was used as a functional angiogenesis assay. Expression and activity of matrix metalloproteases (MMPs) were examined by RT-PCR and zymography, respectively. Coculture of ECs with RPE in the contact model under normoxic conditions induced markedly upregulated EC mRNA expression of 16 genes involved in positive regulation of angiogenesis. Solo ECs subjected to hypoxia demonstrated upregulated expression of the same 16 genes, including VEGF and HIF1. The EC VEGF level was not affected by coculture with RPE in the noncontact model. ECs demonstrated enhanced tube formation on Matrigel after contact coculture with RPE. EC MMP2 mRNA and activity levels were elevated in contact, but not in noncontact, coculture. Coculture of ECs with RPE under conditions enabling direct EC-RPE contact enhances the proangiogenic potential of ECs under normoxia, to an extent similar to that induced by hypoxia, suggesting that ECs in direct contact with RPE cells might be more prone to pathologic angiogenesis involved in CNV formation.


Identification of Edc3p as an enhancer of mRNA decapping in Saccharomyces cerevisiae.
The major pathway of mRNA decay in yeast initiates with deadenylation, followed by mRNA decapping and 5'-3' exonuclease digestion. An in silico approach was used to identify new proteins involved in the mRNA decay pathway. One such protein, Edc3p, was identified as a conserved protein of unknown function having extensive two-hybrid interactions with several proteins involved in mRNA decapping and 5'-3' degradation including Dcp1p, Dcp2p, Dhh1p, Lsm1p, and the 5'-3' exonuclease, Xrn1p. We show that Edc3p can stimulate mRNA decapping of both unstable and stable mRNAs in yeast when the decapping enzyme is compromised by temperature-sensitive alleles of either the DCP1 or the DCP2 genes. In these cases, deletion of EDC3 caused a synergistic mRNA-decapping defect at the permissive temperatures. The edc3Delta had no effect when combined with the lsm1Delta, dhh1Delta, or pat1Delta mutations, which appear to affect an early step in the decapping pathway. This suggests that Edc3p specifically affects the function of the decapping enzyme per se. Consistent with a functional role in decapping, GFP-tagged Edc3p localizes to cytoplasmic foci involved in mRNA decapping referred to as P-bodies. These results identify Edc3p as a new protein involved in the decapping reaction.


Neurophysiological effects of chronic indoor environmental toxic mold exposure on children.
The phenomenon of building-related diseases is attracting much research interest in recent years because of the extent to which it affects people with compromised immune systems, especially children. In this study, we reported the neurological findings in children who attended our Center because of chronic exposure to toxic molds. Clinical neurological and neurobehavioral questionnaires were administered with the cooperation of the children's parents. The children then underwent a series of neurophysiological tests including electroencephalogram (EEG), brainstem evoked potential (BAEP), visual evoked potential (VEP), and somatosensory evoked potential (SSEP). The results showed high levels of abnormalities in the analysis of the subjective responses derived from the questionnaires. The EEG examination was abnormal in seven out of ten of the patients compared to the controls with only one in ten with episodes of bihemispheric sharp activity. In all the patients, there was frontotemporal theta wave activity that seemed to indicate diffuse changes characteristic of metabolic encephalopathies. Also, there was highly marked 1 to 3 Hz delta activity that was asymmetrical in the right hemisphere of the brain in three out of ten patients. The waveforms of BAEP showed abnormalities in 90% of the patients with both 15' and 31' check sizes compared to none in the controls. There were significant delays in waveform V in a majority of the patients representing dysfunctional cognitive process and conductive hearing loss in both ears. VEP showed clear abnormalities in four in ten of the patients with P100 amplitudes and latencies decreased bilaterally. In all the patients, there was slowing of conduction in the right tibial at an average of 36.9 ms and there was significant decrease in amplitude of response at the proximal stimulation site. Sensory latencies obtained in the median, ulnar, and sural nerves bilaterally showed abnormalities in five out of ten compared to none in the controls. The median, ulnar, and sural sensory potentials were abnormal in six out of ten patients. There was prolongation of the median distal sensory latencies bilaterally at an average of 4.55 ms on the right and an average of 6.10 ms on the left as compared to the ulnars of 2.55 ms bilaterally. There was no abnormality in the controls. These findings represent evidence of diffuse polyneuropathy to which three patients demonstrated borderline slow motor conduction at an average of 41.1 ms. Overall, the objective neurophysiological measurements (EEG, BAEP, VEP, and SSEP) were abnormal, indicating significant neurological deficits in all the patients. Our findings revealed the extent to which toxic molds can affect the neurological and behavioral status of children. Further work should be encouraged in this regard.


Restoration of functional defects in peripheral blood mononuclear cells isolated from cancer patients by thiol antioxidants alpha-lipoic acid and N-acetyl cysteine.
The ability of Alpha-Lipoic Acid (ALA) and N-Acetyl Cysteine (NAC), two active antioxidant agents, to correct in vitro the most significant functional defects of peripheral blood mononuclear cells (PBMC) isolated from advanced stage cancer patients was studied. The proliferative response of PBMC isolated from cancer patients to anti-CD3 monoclonal antibody (MAb) and the expression of CD25 (IL-2R) and CD95 (Fas) on unstimulated and anti-CD3 MAb-stimulated PBMC were studied, and the serum levels of proinflammatory cytokines IL-1, IL-6, TNFalpha as markers of pro-cachectic activity in cancer patients, and the serum levels of IL-2 and sIL-2R were assessed. Twenty patients (mean age 64.6 years) with cancer of lung, ovary, endometrium, and head and neck, all in advanced (III, IV) stage of disease, were studied. The serum levels of IL-1beta, IL-2, IL-6, TNFalpha, and sIL-2R were significantly higher in cancer patients than in normal subjects. The response of PBMC isolated from cancer patients to anti-CD3 MAb was significantly lower than that of controls. The addition of either ALA 0.001 mM or NAC 0.004 mM in the PBMC cultures stimulated with anti-CD3 MAb significantly increased the response of PBMC isolated from cancer patients and normal subjects. After 24 and 72 hr of culture with anti-CD3 MAb, the expression of CD25 and CD95 on PBMC isolated from cancer patients was significantly lower than that of PBMC isolated from normal subjects. The addition of either ALA or NAC into cultures of PBMC isolated from cancer patients significantly increased the percentage of cells expressing CD25 as well as those expressing CD95. The results of the present study show a favorable effect of antioxidant agents ALA and NAC on several important T-cell functions in vitro in advanced-stage cancer patients.


Complete genome sequence provides insights into the quorum sensing-related spoilage potential of Shewanella baltica 128 isolated from spoiled shrimp.
Shewanella baltica 128 is a specific spoilage organism (SSO) isolated from the refrigerated shrimp that results in shrimp spoilage. This study reported the complete genome sequencing of this strain, with the primary annotations associated with amino acid transport and metabolism (8.66%), indicating that S. baltica 128 has good potential for degrading proteins. In vitro experiments revealed Shewanella baltica 128 could adapt to the stress conditions by regulating its growth and biofilm formation. Genes that related to the spoilage-related metabolic pathways, including trimethylamine metabolism (torT), sulfur metabolism (cysM), putrescine metabolism (speC), biofilm formation (rpoS) and serine protease production (degS), were identified. Genes (LuxS, pfs, LuxR and qseC) that related to the specific QS system were also identified. Complete genome sequence of S. baltica 128 provide insights into the QS-related spoilage potential, which might provide novel information for the development of new approaches for spoilage detection and prevention based on QS target.


Decreased directed functional connectivity in the psychedelic state.
Neuroimaging studies of the psychedelic state offer a unique window onto the neural basis of conscious perception and selfhood. Despite well understood pharmacological mechanisms of action, the large-scale changes in neural dynamics induced by psychedelic compounds remain poorly understood. Using source-localised, steady-state MEG recordings, we describe changes in functional connectivity following the controlled administration of LSD, psilocybin and low-dose ketamine, as well as, for comparison, the (non-psychedelic) anticonvulsant drug tiagabine. We compare both undirected and directed measures of functional connectivity between placebo and drug conditions. We observe a general decrease in directed functional connectivity for all three psychedelics, as measured by Granger causality, throughout the brain. These data support the view that the psychedelic state involves a breakdown in patterns of functional organisation or information flow in the brain. In the case of LSD, the decrease in directed functional connectivity is coupled with an increase in undirected functional connectivity, which we measure using correlation and coherence. This surprising opposite movement of directed and undirected measures is of more general interest for functional connectivity analyses, which we interpret using analytical modelling. Overall, our results uncover the neural dynamics of information flow in the psychedelic state, and highlight the importance of comparing multiple measures of functional connectivity when analysing time-resolved neuroimaging data.


Meta-analysis of linkage data under worst-case conditions: a demonstration using the human OB region.
To date, few methods have been developed explicitly for meta-analysis of linkage analyses. Moreover, the methods that have been developed or suggested generally depend on certain ideal situations and have not been widely applied. In this article, we apply standard statistical theory and meta-analytic techniques in novel ways to five published papers discussing the evidence of linkage of body mass index (BMI) to the region of the human genome containing the OB gene. These methods are "inference based," meaning that they allow one to make statements about the statistical significance of the entire body of evidence. As currently developed, they do not allow specific statements to be made about the amount of variance explained by any putative locus or allow precise confidence intervals to be placed around the putative location of a linked locus. By applying these techniques to the literature on linkage in the human OB gene region, we are able to show that the evidence for linkage somewhere in the region is extremely strong (P = 1.5 x 10[-5]).


Digital clocks: simple Boolean models can quantitatively describe circadian systems.
The gene networks that comprise the circadian clock modulate biological function across a range of scales, from gene expression to performance and adaptive behaviour. The clock functions by generating endogenous rhythms that can be entrained to the external 24-h day-night cycle, enabling organisms to optimally time biochemical processes relative to dawn and dusk. In recent years, computational models based on differential equations have become useful tools for dissecting and quantifying the complex regulatory relationships underlying the clock's oscillatory dynamics. However, optimizing the large parameter sets characteristic of these models places intense demands on both computational and experimental resources, limiting the scope of in silico studies. Here, we develop an approach based on Boolean logic that dramatically reduces the parametrization, making the state and parameter spaces finite and tractable. We introduce efficient methods for fitting Boolean models to molecular data, successfully demonstrating their application to synthetic time courses generated by a number of established clock models, as well as experimental expression levels measured using luciferase imaging. Our results indicate that despite their relative simplicity, logic models can (i) simulate circadian oscillations with the correct, experimentally observed phase relationships among genes and (ii) flexibly entrain to light stimuli, reproducing the complex responses to variations in daylength generated by more detailed differential equation formulations. Our work also demonstrates that logic models have sufficient predictive power to identify optimal regulatory structures from experimental data. By presenting the first Boolean models of circadian circuits together with general techniques for their optimization, we hope to establish a new framework for the systematic modelling of more complex clocks, as well as other circuits with different qualitative dynamics. In particular, we anticipate that the ability of logic models to provide a computationally efficient representation of system behaviour could greatly facilitate the reverse-engineering of large-scale biochemical networks.


MSblender: A probabilistic approach for integrating peptide identifications from multiple database search engines.
Shotgun proteomics using mass spectrometry is a powerful method for protein identification but suffers limited sensitivity in complex samples. Integrating peptide identifications from multiple database search engines is a promising strategy to increase the number of peptide identifications and reduce the volume of unassigned tandem mass spectra. Existing methods pool statistical significance scores such as p-values or posterior probabilities of peptide-spectrum matches (PSMs) from multiple search engines after high scoring peptides have been assigned to spectra, but these methods lack reliable control of identification error rates as data are integrated from different search engines. We developed a statistically coherent method for integrative analysis, termed MSblender. MSblender converts raw search scores from search engines into a probability score for every possible PSM and properly accounts for the correlation between search scores. The method reliably estimates false discovery rates and identifies more PSMs than any single search engine at the same false discovery rate. Increased identifications increment spectral counts for most proteins and allow quantification of proteins that would not have been quantified by individual search engines. We also demonstrate that enhanced quantification contributes to improve sensitivity in differential expression analyses.


Aluminum-26 and beryllium-10 in marine sediment.
Activities of aluminum-26 and beryllium-10 in marine sediment were measured at 0.01 +/- 0.13 and 4.4 +/- 0.9 disintegrations per minute, per kilogram dry weight, respectively. Only an upper limit of 0.03 could be determined for the ratio of aluminum-26 to beryllium-10 in the sediment. The ratio is probably explained by production by cosmic rays in the atmosphere.


Mosquito bite-avoidance attitudes and behaviors in travelers at risk of malaria.
Mosquito bite prevention is an important strategy to reduce the risk of contracting malaria and advice on the methods available should be offered in pre-travel consultations. This study examines the attitudes of a cohort of UK travelers to the various bite-avoidance strategies and the extent to which they are practiced when visiting malaria-endemic areas. This was a retrospective cohort study of UK travelers above 18 years of age returning from malaria-endemic areas. Those who agreed to participate were emailed a Web-based questionnaire on their return to the UK. The questionnaire consisted of items relating to attitudes to bite-avoidance measures and malaria and the use of bite-avoidance measures while away. One hundred and thirty-two travelers completed the questionnaire representing a 51% response rate. Frequent use of repellents (69%) was higher than covering the arms (49%) and legs (56%), or using insecticide vaporizers (16%), sprays (24%), and bed nets (32%). Those under the age of 30 tended to use bite avoidance less frequently. Gender, purpose, and duration of travel were also found to influence the use of particular measures. A reliable 17-point attitude to the bite-avoidance questionnaire (Cronbach's alpha = 0.70) was constructed and a subscale score indicated that attitudes influenced the use of repellents. The use of measures to avoid mosquito bites on retiring and covering arms and legs needs to be further emphasized to travelers. The attitude scales described could be a useful tool in practice and research into this area.


Bioinformatics issues for automating the annotation of genomic sequences.
The rapid explosion in the amount of biological data being generated worldwide is surpassing efforts to manage analysis of the data. As part of an ongoing project to automate and manage bioinformatics analysis, the authors have designed and implemented a simple automated annotation system, which is described in this paper. The system is applied to existing GenBank/DDBJ/EMBL entries and compared with existing annotations to illustrate not only potential errors but also that they are generally not up-to-date, as a result of new versions of analysis tools and updates of genomic repositories. We highlight the important Bioinformatics issues of storage and management of information to ensure data and results are kept up-to-date in light of new information becoming available. Surprisingly, from just four database entries, a significant number of new features were found. We describe the results as well as identify important issues that need to be addressed in order to automate the re-analysis/re-annotation of genomic sequences within a reasonable timeframe.


Comparison of cervical volume and cervical length to predict preterm delivery by transvaginal ultrasound.
The objective of this study was to evaluate predictive value of cervical volume and length measurement for preterm delivery in low-risk pregnancies by transvaginal ultrasound. Two hundred fifty pregnant women were underwent ultrasound examination at 22 weeks of gestation by transvaginal route. Cervical length, width, and anteroposterior diameters were measured and cervical volume was calculated. All subjects were observed until term. Predictive values of cervical length and cervical volume were calculated and compared with predict preterm delivery. Preterm delivery occurred in 18 patients (7.2%). Mean cervical length and volume were statistically different between term and preterm delivered patients ( P = 0.001). Areas under curves were 0.913 for cervical volume and 0.923 for cervical length; this difference was not statistically significant ( P = 0.289). Sensitivity of cervical volume was 73.3% for 32-mL cut-off value with 12.85% false-positive rate and cervical length had 80% sensitivity at the 33.15-mm cut-off value with 12.7% false-positive rate. Cervical volume measurement by two-dimensional ultrasound did not add any benefit compared with the cervical length measurement for prediction of preterm delivery.


Differences in willingness to pay for artemisinin-based combinations or monotherapy: experiences from the United Republic of Tanzania.
The cost of combination treatment is thought to be one of the greatest barriers to their deployment, but this has not been tested directly. Estimates of willingness to pay were compared across four drug combinations used to treat Tanzanian children with uncomplicated malaria. The reasons behind respondents' valuations and the effect of socioeconomic status on willingness to pay were explored. One hundred and eighty mothers whose children had been recruited into a recently completed randomized effectiveness trial of amodiaquine + artesunate (AQ+AS), amodiaquine + sulfadoxine-pyrimethamine (AQ+SP), artemether-lumefantrine (coartemether) and amodiaquine monotherapy (AQ) were interviewed about their willingness to pay for these drugs two weeks after treatment. Estimates of willingness to pay were elicited with the bidding game technique. A significant difference was detected in the mean amounts respondents were willing to pay, with those who received AQ+AS willing to pay the most, followed by co-artemether, AQ+SP and finally AQ. The amounts patients' mothers were willing to pay for the artemisinin-based combinations, however, fell well short of the market costs. Socioeconomic status was not found to have a statistically significant effect on mean willingness to pay scores for any treatment group. This study shows that families who live in an area in which drug resistance to monotherapy is very high are willing to pay more for more effective artemisinin-based combination therapies. These amounts, however, are nowhere near the real costs of delivering the new drugs. Only with subsidies will artemisinin-based combination therapies realistically have any impact.


Primary cardiac angiosarcoma diagnosed in the first trimester of pregnancy.
Primary cardiac angiosarcoma (PCAS) is a malignancy seldom seen in pregnancy. A 23-year-old G1P0 Chinese female was found to have PCAS during her first trimester when she presented with tamponade physiology. The transthoracic echocardiography (TTE) results did not indicate the presence of an intracardiac lesion, and pericardial fluid cytology analysis showed no evidence of malignancy. Cardiac magnetic resonance imaging (CMRI) exhibited a right atrial mass, and tissue biopsy indicated a high-grade angiosarcoma. MRI of the abdomen was suggestive of liver metastasis. She underwent an abortion and was started on combination chemotherapy, with a reduction in both the cardiac and liver masses. In cardiac angiosarcomas, advanced imaging modalities such as MRI should be utilised when there is high clinical suspicion or in the case of pregnancy when trying to minimise foetal harm. Prognosis is poor, and a standardised treatment protocol regardless of pregnancy continues to elude the medical community.


Impairment of actions chains in autism and its possible role in intention understanding.
Experiments in monkeys demonstrated that many parietal and premotor neurons coding a specific motor act (e.g., grasping) show a markedly different activation when this act is part of actions that have different goals (e.g., grasping for eating vs. grasping for placing). Many of these "action-constrained" neurons have mirror properties firing selectively to the observation of the initial motor act of the actions to which they belong motorically. By activating a specific action chain from its very outset, this mechanism allows the observers to have an internal copy of the whole action before its execution, thus enabling them to understand directly the agent's intention. Using electromyographic recordings, we show that a similar chained organization exists in typically developing children, whereas it is impaired in children with autism. We propose that, as a consequence of this functional impairment, high-functioning autistic children may understand the intentions of others cognitively but lack the mechanism for understanding them experientially.


The effect of inhibitors on the oxygen kinetics of terminal oxidases of Acanthamoeba castellanii.
1. Respiration of growing cultures of Acanthamoeba castellanii is inhibited less than 60% by azide (35 mM); the respiration of early-exponential-phase cultures differs from that of late-exponential-phase cultures in being stimulated by up to 120% by low concentrations (less than 1 mM) of this inhibitor. Azide (0.5 mM) plus 1 mM-salicylhydroxamic acid gives 80% inhibition of respiration in early- or late-exponential-phase cultures. 2. Lineweaver-Burk plots of 1/v against 1/[O2] for growing and stationary-phase cultures give values of less than 1 muM for the apparent Km for oxygen. 3. These values are not significantly altered when determined in the presence of 1 mM-salicylhydroxamic acid. 4. Higher values (greater than 7 muM) for apparent Km values for oxygen were obtained in the presence of azide, which gives non-linear Lineweaver-Burk plots. 5. Competitive inhibition of respiration by CO occurs with Ki 2.4 muM. 6. The results are discussed in terms of the presence of three terminal oxidases in this organism, namely two oxidases with high affinities for oxygen (cytochrome c oxidase of the main phosphorylating electron-transport chain and the salicylhydroxamic acid-sensitive oxidase) and a third oxidase with a low affinity for oxygen, sensitive to inhibition by cyanide but not by azide or salicylhydroxamic acid. The relative contributions to oxygen utilization by these oxidases change during the growth of a batch culture.


Pest categorisation of Tetraleurodes perseae.
The EFSA Panel on Plant Health performed a pest categorisation of Tetraleurodes perseae (Hemiptera: Aleyrodidae), the red-banded whitefly, for the territory of the EU. T. perseae is a tropical and subtropical species that originated in the Neotropical region and has now spread and established in the USA (California and Florida), Israel and Lebanon. T. perseae is not listed in Commission Implementing Regulation (EU) 2019/2072. It is oligophagous on Lauraceae and most frequently reported on avocado (Persea americana), on which it is considered a minor or secondary pest. No evidence was found indicating damage to other plants. T. perseae larvae develop on the foliage and don't attack the fruit. The number of generations per year varies between one and ten. High populations may promote the growth of black sooty moulds on the foliage and fruit, and adults feeding on the buds can lead to deformed immature leaves and premature leaf drop. However, T. perseae populations are usually effectively controlled by hymenopteran parasitoids, at least one of which (Cales noacki) is widespread in the EU. The producers of organic avocados in the EU could encourage the use of C. noacki, although occasional outbreaks of T. perseae could temporarily impact the fruit quality. Adults disperse naturally by flying and all stages can be moved over long distances by the trade of infested plant material. Plants for planting provide potential pathways for entry and spread in the EU. Climatic conditions and availability of host plants in southern EU countries are conducive for establishment. Phytosanitary measures are available to reduce the risk. T. perseae satisfies all of the criteria that are within the remit of EFSA to assess for it to be regarded as a potential Union quarantine pest. However, this conclusion has a high uncertainty regarding magnitude of potential impact as the insect is a minor and sporadic pest in its current area of distribution.


Palliative Care Evidence Review Service (PaCERS): a knowledge transfer partnership.
The importance of linking evidence into practice and policy is recognised as a key pillar of a prudent approach to healthcare; it is of importance to healthcare professionals and decision-makers across the world in every speciality. However, rapid access to evidence to support service redesign, or to change practice at pace, is challenging. This is particularly so in smaller specialties such as Palliative Care, where pressured multidisciplinary clinicians lack time and skill sets to locate and appraise the literature relevant to a particular area. Therefore, we have initiated the Palliative Care Evidence Review Service (PaCERS), a knowledge transfer partnership through which we have developed a clear methodology to conduct evidence reviews to support professionals and other decision-makers working in palliative care.PaCERS methodology utilises modified systematic review methods as there is no agreed definition or an accepted methodology for conducting rapid reviews. This paper describes the stages involved based on our iterative recent experiences and engagement with stakeholders, who are the potential beneficiaries of the research. Uniquely, we emphasise the process and opportunities of engagement with the clinical workforce and policy-makers throughout the review, from developing and refining the review question at the start through to the importance of demonstrating impact. We are faced with the challenge of the trade-off between the timely transfer of evidence against the risk of impacting on rigour. To address this issue, we try to ensure transparency throughout the review process. Our methodology aligns with key principles of knowledge synthesis in defining a process that is transparent, robust and improving the efficiency and timeliness of the review.Our reviews are clinically or policy driven and, although we use modified systematic review methods, one of the key differences between published review processes and our review process is in our relationship with the requester. This streamlining approach to synthesising evidence in a timely manner helps to inform decisions faced by clinicians and decision-makers in healthcare settings, supporting, at pace, knowledge transfer and mobilisation.


Mammographic interpretive volume and diagnostic mammogram interpretation performance in community practice.
To investigate the association between radiologist interpretive volume and diagnostic mammography performance in community-based settings. This study received institutional review board approval and was HIPAA compliant. A total of 117,136 diagnostic mammograms that were interpreted by 107 radiologists between 2002 and 2006 in the Breast Cancer Surveillance Consortium were included. Logistic regression analysis was used to estimate the adjusted effect on sensitivity and the rates of false-positive findings and cancer detection of four volume measures: annual diagnostic volume, screening volume, total volume, and diagnostic focus (percentage of total volume that is diagnostic). Analyses were stratified by the indication for imaging: additional imaging after screening mammography or evaluation of a breast concern or problem. Diagnostic volume was associated with sensitivity; the odds of a true-positive finding rose until a diagnostic volume of 1000 mammograms was reached; thereafter, they either leveled off (P < .001 for additional imaging) or decreased (P = .049 for breast concerns or problems) with further volume increases. Diagnostic focus was associated with false-positive rate; the odds of a false-positive finding increased until a diagnostic focus of 20% was reached and decreased thereafter (P < .024 for additional imaging and P < .001 for breast concerns or problems with no self-reported lump). Neither total volume nor screening volume was consistently associated with diagnostic performance. Interpretive volume and diagnostic performance have complex multifaceted relationships. Our results suggest that diagnostic interpretive volume is a key determinant in the development of thresholds for considering a diagnostic mammogram to be abnormal. Current volume regulations do not distinguish between screening and diagnostic mammography, and doing so would likely be challenging.


Cloning of a 67-kD neutrophil oxidase factor with similarity to a noncatalytic region of p60c-src.
Chronic granulomatous diseases (CGDs) are characterized by recurrent infections resulting from impaired superoxide production by a phagocytic cell, nicotinamide adenine dinucleotide phosphate (reduced) (NADPH) oxidase. Complementary DNAs were cloned that encode the 67-kilodalton (kD) cytosolic oxidase factor (p67), which is deficient in 5% of CGD patients. Recombinant p67 (r-p67) partially restored NADPH oxidase activity to p67-deficient neutrophil cytosol from these patients. The p67 cDNA encodes a 526-amino acid protein with acidic middle and carboxyl-terminal domains that are similar to a sequence motif found in the noncatalytic domain of src-related tyrosine kinases. This motif was recently noted in phospholipase C-gamma, nonerythroid alpha-spectrin (fodrin), p21ras-guanosine triphophatase-activating protein (GAP), myosin-1 isoforms, yeast proteins cdc-25 and fus-1, and the 47-kD phagocyte oxidase factor (p47), which suggests the possibility of common regulatory features.


Mycobacterium marseillense sp. nov., Mycobacterium timonense sp. nov. and Mycobacterium bouchedurhonense sp. nov., members of the Mycobacterium avium complex.
An rpoB sequence-based evaluation of 100 Mycobacterium avium complex (MAC) clinical isolates led to the identification of five respiratory tract isolates that were potential representatives of three novel MAC species. Distinctive phenotypic features of isolates 62863 and 5356591(T) included a pseudomycelium morphology and both esterase and acid phosphatase activities. These two isolates exhibited sequence similarities of 99.8 % for the 16S rRNA gene, 86.3 and 86.1 % for 16S-23S rRNA gene internal transcribed spacer (ITS-1) sequence, 96.7 and 97.8 % for rpoB and 97.6 and 97.4 % for hsp65, respectively, with the type strain of Mycobacterium chimaera, the most closely related species. Isolates 3256799 and 5351974(T) lacked alpha-mannosidase and beta-glucosidase activities. They exhibited sequence similarities of 99.6 % for the 16S rRNA gene, 90.1 and 90.4 % for ITS-1, 97.8 % for rpoB and 98.0 and 98.1 % for hsp65, respectively, with the type strain of M. chimaera, the most closely related species. Isolate 4355387(T) lacked urease and alpha-glucosidase activities, but it exhibited valine arylamidase, cystine arylamidase and acid phosphatase activities. It had sequence similarities of 99.3 % for the 16S rRNA gene, 51.8 % for ITS-1, 97.1 % for rpoB and 97.8 % for hsp65 with the type strain of Mycobacterium colombiense, the most closely related species. A phylogenetic tree based on concatenated 16S rRNA gene, ITS-1, rpoB and hsp65 sequences showed the uniqueness of these five isolates as representatives of three novel species, with bootstrap values >/=95 % in all nodes. On the basis of these phenotypic and genetic characteristics, these five isolates are proposed as representatives of three novel MAC species: Mycobacterium marseillense sp. nov., with strain 5356591(T) (=CCUG 56325(T) =CIP 109828(T) =CSUR P30(T)) as the type strain; Mycobacterium timonense sp. nov., with strain 5351974(T) (=CCUG 56329(T) =CIP 109830(T) =CSUR P32(T)) as the type strain; and Mycobacterium bouchedurhonense sp. nov., with strain 4355387(T) (=CCUG 56331(T) =CIP 109827(T) =CSUR P34(T)) as the type strain.


Step length adaptation on ridge functions.
Step length adaptation is central to evolutionary algorithms in real-valued search spaces. This paper contrasts several step length adaptation algorithms for evolution strategies on a family of ridge functions. The algorithms considered are cumulative step length adaptation, a variant of mutative self-adaptation, two-point adaptation, and hierarchically organized strategies. In all cases, analytical results are derived that yield insights into scaling properties of the algorithms. The influence of noise on adaptation behavior is investigated. Similarities and differences between the adaptation strategies are discussed.


Loss of cytoskeletal support is not sufficient for anoxic plasma membrane disruption in renal cells.
The goal of this study was to determine whether anoxic membrane disruption is initiated by loss of cytoskeletal support in rabbit renal proximal tubules (PT). We specifically tested 1) whether cytoskeletal perturbation affects membrane integrity under normoxia, 2) whether cytoskeletal perturbation potentiates anoxic membrane damage, and 3) whether the membrane protection by glycine depends on cytoskeletal integrity. Cytoskeletal perturbation was achieved with 10 microM cytochalasin D (CD) because it selectively disturbs F-actin organization and has similar effects as anoxia on the cytoskeleton of PT. During normoxia, CD caused decreased basal F-actin content, microvillar breakdown, and membrane-cytoskeleton dissociation, as revealed by the use of laser tweezers. However, membrane integrity was not altered by CD, as monitored by lactate dehydrogenase release. CD pretreatment of PT did not potentiate anoxic membrane damage. Finally, plasma membrane protection by glycine during anoxia remained in CD-pretreated PT despite loss of cytoskeletal support. These results demonstrate that loss of cytoskeletal support is not sufficient for anoxic plasma membrane disruption.


Mapping of a non-spatial dimension by the hippocampal-entorhinal circuit.
During spatial navigation, neural activity in the hippocampus and the medial entorhinal cortex (MEC) is correlated to navigational variables such as location, head direction, speed, and proximity to boundaries. These activity patterns are thought to provide a map-like representation of physical space. However, the hippocampal-entorhinal circuit is involved not only in spatial navigation, but also in a variety of memory-guided behaviours. The relationship between this general function and the specialized spatial activity patterns is unclear. A conceptual framework reconciling these views is that spatial representation is just one example of a more general mechanism for encoding continuous, task-relevant variables. Here we tested this idea by recording from hippocampal and entorhinal neurons during a task that required rats to use a joystick to manipulate sound along a continuous frequency axis. We found neural representation of the entire behavioural task, including activity that formed discrete firing fields at particular sound frequencies. Neurons involved in this representation overlapped with the known spatial cell types in the circuit, such as place cells and grid cells. These results suggest that common circuit mechanisms in the hippocampal-entorhinal system are used to represent diverse behavioural tasks, possibly supporting cognitive processes beyond spatial navigation.


Co-ordinate but disproportionate activation of apoptotic, regenerative and inflammatory pathways characterizes the liver response to acute amebic infection.
The liver has the remarkable ability to respond to injury with repair and regeneration. The protozoan parasite Entamoeba histolytica is the major cause of liver abscess worldwide. We report a transcriptional analysis of the response of mouse liver to E. histolytica infection, the first study looking at acute liver infection by a non-viral pathogen. Focusing on early time points, we identified 764 genes with altered transcriptional levels in amebic liver abscess. The response to infection is rapid and complex, with concurrent increased expression of genes linked to host defence through IL-1, TLR2, or interferon-induced pathways, liver regeneration via activation of IL-6 pathways, and genes associated with programmed cell death possibly through TNFalpha or Fas pathways. A comparison of amebic liver infection with the liver response to partial hepatectomy or toxins reveals striking similarities between amebic liver abscess and non-infectious injury in key components of the liver regeneration pathways. However, the response in amebic liver abscess is biased towards apoptosis when compared with acute liver injury from hepatectomy, toxins, or other forms of liver infection. E. histolytica infection of the liver simultaneously activates inflammatory, regenerative and apoptotic pathways, but the sum of these early responses is biased towards programmed cell death.


Mixing It Up: Coadministration of tPA/DNase in Complicated Parapneumonic Pleural Effusions and Empyema.
A recent randomized controlled trial showed 12 serial doses of tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) is safe and effective in managing complicated parapneumonic pleural effusions and empyema (CPEE). However, this regimen is laborious, requiring trained personnel to open/close the chest tube 8 times daily for 3 days. We present our observational data using a simplified regimen of coadministered tPA/DNase. This is a retrospective observational study of patients who received coadministered tPA/DNase for CPEE from January 2012 to April 2015 at the University of Texas Medical Branch. Patient demographics, pleural fluid, radiologic and treatment characteristics, and outcomes were collected. Data are presented as proportions and percentages. Our primary outcome was successful treatment without need of surgery and discharge home alive. Secondary outcomes were dose and length of treatment and hospital stay, treatment complications, and 90-day mortality. The study included 39 patients. All pleural effusions were loculated, 59% macroscopically purulent, 50% had a positive organism in Gram stain, and 40% were culture positive. A median of 6 (interquartile range, 3.5 to 6) doses were coadministered mainly via small bore chest tube (≤14 Fr in 79%) with a median of 14.5 (interquartile range, 9.5 to 21.5) hospital days. Overall, 85% were successfully treated without need for surgery. Treatment failures occurred in 15%: 3/39 (7%) received surgery; 3/39 (7%) died. Only 1 (2.5%) complication of hemorrhagic pleural effusion resolved after discontinuation of intrapleural treatment. Our study shows intrapleural coadministration of tPA/DNase was effective and safe in management of CPEE.