Sugary interfaces mitigate contact damage where stiff meets soft.
The byssal threads of the fan shell Atrina pectinata are non-living functional materials intimately associated with living tissue, which provide an intriguing paradigm of bionic interface for robust load-bearing device. An interfacial load-bearing protein (A. pectinata foot protein-1, apfp-1) with L-3,4-dihydroxyphenylalanine (DOPA)-containing and mannose-binding domains has been characterized from Atrina's foot. apfp-1 was localized at the interface between stiff byssus and the soft tissue by immunochemical staining and confocal Raman imaging, implying that apfp-1 is an interfacial linker between the byssus and soft tissue, that is, the DOPA-containing domain interacts with itself and other byssal proteins via Fe3(+)-DOPA complexes, and the mannose-binding domain interacts with the soft tissue and cell membranes. Both DOPA- and sugar-mediated bindings are reversible and robust under wet conditions. This work shows the combination of DOPA and sugar chemistry at asymmetric interfaces is unprecedented and highly relevant to bionic interface design for tissue engineering and bionic devices.


Escherichia coli producing CNF1 toxin hijacks Tollip to trigger Rac1-dependent cell invasion.
Rho GTPases, which are master regulators of both the actin cytoskeleton and membrane trafficking, are often hijacked by pathogens to enable their invasion of host cells. Here we report that the cytotoxic necrotizing factor-1 (CNF1) toxin of uropathogenic Escherichia coli (UPEC) promotes Rac1-dependent entry of bacteria into host cells. Our screen for proteins involved in Rac1-dependent UPEC entry identifies the Toll-interacting protein (Tollip) as a new interacting protein of Rac1 and its ubiquitinated forms. We show that knockdown of Tollip reduces CNF1-induced Rac1-dependent UPEC entry. Tollip depletion also reduces the Rac1-dependent entry of Listeria monocytogenes expressing InlB invasion protein. Moreover, knockdown of Tollip, Tom1 and clathrin, decreases CNF1 and Rac1-dependent internalization of UPEC. Finally, we show that Tollip, Tom1 and clathrin associate with Rac1 and localize at the site of bacterial entry. Collectively, these findings reveal a new link between Rac1 and Tollip, Tom1 and clathrin membrane trafficking components hijacked by pathogenic bacteria to allow their efficient invasion of host cells.


Ecological control of fecal indicator bacteria in an urban stream.
Fecal indicator bacteria (FIB) have long been used as a marker of fecal pollution in surface waters subject to point source and non-point source discharges of treated or untreated human waste. In this paper, we set out to determine the source(s) of elevated FIB concentrations in Cucamonga Creek, a concrete-lined urban stream in southern California. Flow in the creek consists primarily of treated and disinfected wastewater effluent, mixed with relatively smaller but variable flow of runoff from the surrounding urban landscape. Dry and wet weather runoff contributes nearly 100% of FIB loading to Cucamonga Creek, while treated wastewater contributes significant loading of nutrients, including dissolved organic carbon (DOC), phosphorus, nitrate, and ammonium. FIB concentrations are strongly positively correlated with DOC concentration in runoff (Spearman's rho >or= 0.66, P <or= 0.037), and microcosm studies reveal that the survival of Escherichia coli and enterococci bacteria in runoff is strongly dependent on the concentration of both DOC and phosphorus. Below threshold concentrations of 7 and 0.07 mg/L, respectively, FIB die off exponentially (die-off rate 0.09 h(-1)). Above these thresholds, FIB either grow exponentially (growth rate 0.3 h(-1)) or exhibit a periodic steady-state in which bacterial concentrations fluctuate around some mean value. The periodic steady-state pattern is consistent with a Lotka-Volterra predator-prey oscillation model, and the clearance rate (20 microL predator(-1) h(-1)) obtained by fitting the model to our data is consistent with the hypothesis that predacious protozoa regulate FIB concentrations in runoff at high DOC concentrations. Collectively, these results indicate that FIB impairment of Cucamonga Creek is best viewed as an ecological phenomenon characterized by both bottom-up and top-down control.


Predation by mammalian carnivores on nocturnal primates: is the lack of evidence support for the effectiveness of nocturnality as an antipredator strategy?
The apparent paucity of accounts of predation, particularly by felids, on nocturnal primates is confirmed by a quasi-systematic review of 1,939 publications which revealed just 1 case of a felid eating a nocturnal primate. This instance was amongst only 51 direct reports of predation by vertebrates on nocturnal primates (90% were on Madagascar, where 56% of approx. 110 nocturnal primate species occur), of which 41% were by birds of prey. These findings prompt discussion of two possibilities: (a) nocturnality is, in part, an effective antipredator adaptation, and (b) knowledge of nocturnal primates is so biased by their elusiveness and, for predation, underreporting (e.g. inadequate mechanisms to publish opportunistic observations) that understanding of their biology urgently necessitates both the collation of field observations and innovative research. Interspecific comparisons facilitate deductions about the role of predation in the evolution of primate nocturnality and associated traits, but intraspecific comparisons of changing activity rhythms in response to different levels of predation risk offer the most compelling insights into the functional significance of these adaptations.


What matters most: an investigation of predictors of perceived stress among young mothers in Khayelitsha.
Our purpose in the present study was to examine how two different sets of stressors, one representing the physical environment and the other representing the social environment, related to perceived stress among new mothers served by a health clinic in Khayelitsha, South Africa. We found that among the chronic urban poverty-environmental stressors related to water, housing, transportation, toileting, and lack of food, that lack of drinkable water in the home had the strongest correlation with perceived stress. In terms of social stressors we found that 60% of new mothers had no partner, and 43% of those with a partner reported that they currently were not coresiding. In terms of the social stressors, the inability to depend on a partner in times of trouble had the strongest relationship to perceived stress. Other findings relating to partner support are discussed as well as sample and community characteristics. Given the importance of partner support, it is argued that the conditions of poverty itself serve to destabilize relationships, which in turn contributes to the cycle of poverty experienced by many residents of periurban settlements like Khayelitsha.


Acupuncture for infertile women without undergoing assisted reproductive techniques (ART): A systematic review and meta-analysis.
Acupuncture is widely used for infertile women without undergoing assisted reproductive techniques (ART) in China but its effect is unclear. We aim to assess whether acupuncture and its combined therapy exert a positive influence on the outcome of female fertility. We searched 6 databases, including Medline, EMBASE, the Cochrane Central Register of Controlled Trials, the China National Knowledge Infrastructure (CNKI), the China Science and Technology Journal Database (VIP), and Wan-Fang Data, from inception to June 2018. Studies of randomized controlled trials (RCTs) on women with infertility treated by acupuncture or its combined therapy were included. A meta-analysis was performed using Revman 5.3. The methodological quality of the studies was assessed through the risk of bias assessment tool by the Cochrane Collaboration. The pregnancy rate was significantly improved with treatment (RR = 1.84, 95% CI 1.62 to 2.10, P < .00001), compared to that in the control group. Subgroup analysis showed that comparing with pure western medicine intervention, no matter intervention with acupuncture alone, with acupuncture plus western medicine, with acupuncture plus Chinese medicine, or acupuncture plus Chinese medicine and western medicine, all of these subgroups exhibited significant improvement. The subgroup according to different types of infertility showed a significant improvement in infertility caused by polycystic ovary syndrome, tubal infertility, ovulatory disorder, and other factors. In addition, the ovulation rate and endometrial thickness were significantly increased. The level of LH was obviously decreased. Moreover, with acupuncture, less adverse effects occurred. The funnel plot revealed that publication bias might exist. All trials included had unclear risks in the aspects of allocation concealment, blinding of participants and personnel, blinding of outcome assessment, selective reporting, and other bias. Only 1 study was assessed as unclear risk in random sequence generation. In the incomplete outcome data, all studies were low risk, except 1. Acupuncture and its combined therapy may be effective for treating female infertility. However, the included studies are not robust enough to draw a firm conclusion due to the not robustly sampled quality of the included studies. Future high-quality RCTs are needed to confirm our findings.


Patterns of nurse-physician communication and agreement on the plan of care.
Interdisciplinary communication is critically important to provide safe and effective care, yet it has been inadequately studied for hospitalised medical patients. Our objective was to characterise nurse-physician communication and their agreement on patients' plan of care. During a one-month period, randomly selected hospitalised patients, their nurses and their physicians were interviewed. Nurses and physicians were asked to identify one another, whether communication had occurred, and about six aspects of the plan of care. Two internists rated nurse-physician agreement on aspects of the plan of care as none, partial or complete agreement. Measures included the percentage of nurses and physicians able to identify one another and reporting communication and the percentage of nurse-physician pairs in agreement on aspects of the plan of care. 310 (91%) and 301 (88%) of 342 eligible nurses and physicians completed interviews. Nurses correctly identified patients' physicians 71% of the time and reported communicating with them 50% of the time. Physicians correctly identified the patients' nurses 36% of the time and reported communicating with them 62% of the time. Physicians and nurses showed no agreement on aspects of the plan of care ranging from 11% for planned procedures to 42% for medication changes. Nurses and physicians did not reliably communicate with one another and were often not in agreement on the plan of care for hospitalised medical patients.


Micro-computed tomography evaluation of human fat grafts in nude mice.
Although autologous fat grafting has revolutionized the field of soft tissue reconstruction and augmentation, long-term maintenance of fat grafts is unpredictable. Recent studies have reported survival rates of fat grafts to vary anywhere between 10% and 80% over time. The present study evaluated the long-term viability of human fat grafts in a murine model using a novel imaging technique allowing for in vivo volumetric analysis. Human fat grafts were prepared from lipoaspirate samples using the Coleman technique. Fat was injected subcutaneously into the scalp of 10 adult Crl:NU-Foxn1(nu) CD-1 male mice. Micro-computed tomography (CT) was performed immediately following injection and then weekly thereafter. Fat volume was rendered by reconstructing a three-dimensional (3D) surface through cubic-spline interpolation. Specimens were also harvested at various time points and sections were prepared and stained with hematoxylin and eosin (H&E), for macrophages using CD68 and for the cannabinoid receptor 1 (CB1). Finally, samples were explanted at 8- and 12-week time points to validate calculated micro-CT volumes. Weekly CT scanning demonstrated progressive volume loss over the time course. However, volumetric analysis at the 8- and 12-week time points stabilized, showing an average of 62.2% and 60.9% survival, respectively. Gross analysis showed the fat graft to be healthy and vascularized. H&E analysis and staining for CD68 showed minimal inflammatory reaction with viable adipocytes. Immunohistochemical staining with anti-human CB1 antibodies confirmed human origin of the adipocytes. Studies assessing the fate of autologous fat grafts in animals have focused on nonimaging modalities, including histological and biochemical analyses, which require euthanasia of the animals. In this study, we have demonstrated the ability to employ micro-CT for 3D reconstruction and volumetric analysis of human fat grafts in a mouse model. Importantly, this model provides a platform for subsequent study of fat manipulation and soft tissue engineering.


Endoscopic versus rear-entry ACL reconstruction: a systematic review.
Anterior cruciate ligament reconstruction is commonly performed using the all-endoscopic (also known as all-inside or single-incision) method or the rear-entry (also known as outside-in or two-incision) method. We report a systematic review of four prospective, randomized clinical trials comparing these two operative techniques. Operative time was shorter in the all-endoscopic groups in two studies. A higher percentage of patients in the rear-entry group had a difference of 3 mm or less on the KT-2000 arthrometer, although the two surgical techniques were similar in the other studies. A higher rate of return to full activity was achieved in patients undergoing the rear-entry technique in one study. All four studies were similar in pain medication used, progression of rehabilitation, range of motion, quadriceps or hamstring strength, patellofemoral pain, one-leg hop test, Lysholm, Tegner, and International Knee Documentation Committee scores. Overall, these studies show similar outcomes comparing the all-endoscopic and rear-entry anterior cruciate ligament reconstruction techniques.


Antibody Targets on the Surface of Plasmodium falciparum-Infected Erythrocytes That Are Associated With Immunity to Severe Malaria in Young Children.
Sequestration of Plasmodium falciparum-infected erythrocytes (IEs) in the microvasculature contributes to pathogenesis of severe malaria in children. This mechanism is mediated by antigens expressed on the IE surface. However, knowledge of specific targets and functions of antibodies to IE surface antigens that protect against severe malaria is limited. Antibodies to IE surface antigens were examined in a case-control study of young children in Papua New Guinea presenting with severe or uncomplicated malaria (n = 448), using isolates with a virulent phenotype associated with severe malaria, and functional opsonic phagocytosis assays. We used genetically modified isolates and recombinant P. falciparum erythrocyte membrane protein 1 (PfEMP1) domains to quantify PfEMP1 as a target of antibodies associated with disease severity. Antibodies to the IE surface and recombinant PfEMP1 domains were significantly higher in uncomplicated vs severe malaria and were boosted following infection. The use of genetically modified P. falciparum revealed that PfEMP1 was a major target of antibodies and that PfEMP1-specific antibodies were associated with reduced odds of severe malaria. Furthermore, antibodies promoting the opsonic phagocytosis of IEs by monocytes were lower in those with severe malaria. Findings suggest that PfEMP1 is a dominant target of antibodies associated with reduced risk of severe malaria, and function in part by promoting opsonic phagocytosis.


Health-Care-Associated Infections Management, sow the seed of good habits: a grounded theory study.
The reasons that condition and motivate adherence to good practices have a multifactorial nature. From the literature review, emerged different elements that interact within the operating context and represent a part of the variables that condition the "Best Practice". The aim of this research was to investigate the variables that influence adherence to operators' good practices. A qualitative study with Grounded Theory (GT) methodology was carried out, which leads to the establishment of a theory about basic social processes. This theory is based on the observation and perception of the social scene and evolves during data collection. Data collection took place through interviews with the participants, through an ad hoc semi-structured interview grid. The initial sampling consisted of 12 health workers, while the theoretical sample was made up of 6 health workers. The analysis organization through the creation of schemes and diagrams has allowed to formulate different concepts including: false beliefs, knowledge and emotions experienced, that connect with the initial condition of Unconsciousness unaware; awareness of the consequences, team, welcome the new, which are connected to the intermediate phase of Revolution of the professional oneself; awareness of the limits, culture, responsibility, context, rigor and control that connects to the final state of Attentive Habit. The theoretical model develops through a path of growth and revolution that starts from the roots of an Unconsciousness unaware and brings with it the seed of a model.


Effects of nanocrystalline silver (NPI 32101) in a rat model of ulcerative colitis.
Nanocrystalline silver (NPI 32101) has been demonstrated to have antimicrobial and anti-inflammatory properties. The purpose of this study was to assess the effect of NPI 32101 in a rat model of ulcerative colitis and the possible mechanisms of action of the effects observed. NPI 32101, 4 mg/kg intracolonically or 40 mg/kg orally, significantly reduced colonic inflammation compared to the placebo and no-treatment groups. Sulfasalazine (100 mg/kg), either intracolonically or orally, also reduced colonic inflammation. NPI 32101 significantly suppressed the expression of matrix metalloproteinase (MMP)-9, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-12, whereas sulfasalazine suppressed MMP-9, IL-1beta, and TNF-alpha, but not IL-12, compared to placebo. MMP-9 activity was reduced by NPI 32101 and sulfasalazine. NPI 32101 administered intracolonically or orally decreases ulcerative colitis in a rat model and is as effective as sulfasalazine. NPI 32101 treatment suppresses the expression and activity of MMP-9 and the expression of TNF-alpha, IL-1beta, and IL-12, mechanisms by which NPI 32101 may exert its anti-inflammatory effects. NPI 32101 may have therapeutic potential for treatment of ulcerative colitis.


Transparent, conductive, and SERS-active Au nanofiber films assembled on an amphiphilic peptide template.
The use of biological materials as templates for functional molecular assemblies is an active research field at the interface between chemistry, biology, and materials science. We demonstrate the formation of gold nanofiber films on β-sheet peptide domains assembled at the air/water interface. The gold deposition scheme employed a recently discovered chemical process involving spontaneous crystallization and reduction of water-soluble Au(SCN)4(1-) upon anchoring to surface-displayed amine moieties. Here we show that an interlinked network of crystalline Au nanofibers is readily formed upon incubation of the Au(iii) thiocyanate complex with the peptide monolayers. Intriguingly, the resultant films were optically transparent, enabled electrical conductivity, and displayed pronounced surface enhanced Raman spectroscopy (SERS) activity, making the approach a promising avenue for construction of nano-structured films exhibiting practical applications.


Performance of cystatin C- and creatinine-based estimated glomerular filtration rate equations depends on patient characteristics.
The Kidney Disease Improving Global Outcomes (KDIGO) guideline recommends use of a cystatin C-based estimated glomerular filtration rate (eGFR) to confirm creatinine-based eGFR between 45 and 59 mL · min(-1) · (1.73 m(2))(-1). Prior studies have demonstrated that comorbidities such as solid-organ transplant strongly influence the relationship between measured GFR, creatinine, and cystatin C. Our objective was to evaluate the performance of cystatin C-based eGFR equations compared with creatinine-based eGFR and measured GFR across different clinical presentations. We compared the performance of the CKD-EPI 2009 creatinine-based estimated GFR equation (eGFRCr) and the newer CKD-EPI 2012 cystatin C-based equations (eGFRCys and eGFRCr-Cys) with measured GFR (iothalamate renal clearance) across defined patient populations. Patients (n = 1652) were categorized as transplant recipients (n = 568 kidney; n = 319 other organ), known chronic kidney disease (CKD) patients (n = 618), or potential kidney donors (n = 147). eGFRCr-Cys showed the most consistent performance across different clinical populations. Among potential kidney donors without CKD [stage 2 or higher; eGFR >60 mL · min(-1) · (1.73 m(2))(-1)], eGFRCys and eGFRCr-Cys demonstrated significantly less bias than eGFRCr; however, all 3 equations substantially underestimated GFR when eGFR was <60 mL · min(-1) · (1.73 m(2))(-1). Among transplant recipients with CKD stage 3B or greater [eGFR <45 mL · min(-1) · (1.73 m(2))(-1)], eGFRCys was significantly more biased than eGFRCr. No clear differences in eGFR bias between equations were observed among known CKD patients regardless of eGFR range or in any patient group with a GFR between 45 and 59 mL · min(-1) · (1.73 m(2))(-1). The performance of eGFR equations depends on patient characteristics that are readily apparent on presentation. Among the 3 CKD-EPI equations, eGFRCr-Cys performed most consistently across the studied patient populations.


The temporal dynamics of insula activity to disgust and happy facial expressions: a magnetoencephalography study.
The insula has consistently been shown to be involved in processing stimuli that evoke the emotional response of disgust. Recently, its specificity for processing disgust has been challenged and a broader role of the insula in the representation of interoceptive information has been suggested. Studying the temporal dynamics of insula activation during emotional processing can contribute valuable information pertaining to this issue. Few studies have addressed the insula's putative specificity to disgust and the dynamics of its underlying neural processes. In the present study, neuromagnetic responses of 13 subjects performing an emotional continuous performance task (CPT) to faces with disgust, happy, and neutral expressions were obtained. Magnetic field tomography extracted the time course of bilateral insula activities. Right insula activation was stronger to disgust and happy than neutral facial expressions at about 200 ms after stimulus onset. Later only at about 350 ms after stimulus onset the right insula was activated stronger to disgust than happy facial expressions. Thus, the early right insula response reflects activation to emotionally arousing stimuli regardless of valence, and the later right insula response differentiates disgust from happy facial expressions. Behavioral performance but not the insula activity differed between 100 ms and 1000 ms presentation conditions. Present findings support the notion that the insula is involved in the representation of interoceptive information.


NMRShiftDB-constructing a free chemical information system with open-source components.
The process of designing and implementing NMRShiftDB, an open-source, open-content database for chemical structures and their NMR data based solely on free software is described. NMRShiftDB is available to the community on http://www.nmrshiftdb.org. It allows for open submission and retrieval of data sets by its user community. The software and the content itself is freely distributable, allowing for the establishment of a highly available mirror system of databases in collaborating laboratories.


Real time assessment of RF cardiac tissue ablation with optical spectroscopy.
An optical spectroscopy approach is demonstrated allowing for critical parameters during RF ablation of cardiac tissue to be evaluated in real time. The method is based on incorporating in a typical ablation catheter transmitting and receiving fibers that terminate at the tip of the catheter. By analyzing the spectral characteristics of the NIR diffusely reflected light, information is obtained on such parameters as, contact of catheter with the tissue, lesion formation, depth of penetration of the lesion, formation of char and coagulum during the ablation.


Guilt, fear, stigma and knowledge gaps: ethical issues in public health communication interventions.
Public health communication campaigns have been credited with helping raise awareness of risk from chronic illness and new infectious diseases and with helping promote the adoption of recommended treatment regimens. Yet many aspects of public health communication interventions have escaped the scrutiny of ethical discussions. With the transference of successful commercial marketing communication tactics to the realm of public health, consideration of ethical issues becomes an essential component in the development and application of public health strategies. Ethical issues in public health communication are explored as they relate to eight topics: 'targeting' and 'tailoring' public health messages to particular population segments; obtaining the equivalence of informed consent; the use of persuasive communication tactics; messages on responsibility and culpability; messages that apply to harm reduction; and three types of unintended adverse effects associated with public health communication activities that may label and stigmatise, expand social gaps, and promote health as a value. We suggest that an ethical analysis should be applied to each phase of the public health communication process in order to identify ethical dilemmas that may appear subtle, yet reflect important concerns regarding potential effects of public health communication interventions on individuals and society as a whole.


Glass-liquid transition of water at high pressure.
The knowledge of the existence of liquid water under extreme conditions and its concomitant properties are important in many fields of science. Glassy water has previously been prepared by hyperquenching micron-sized droplets of liquid water and vapor deposition on a cold substrate (ASW), and its transformation to an ultraviscous liquid form has been reported on heating. A densified amorphous solid form of water, high-density amorphous ice (HDA), has also been made by collapsing the structure of ice at pressures above 1 GPa and temperatures below approximately 140 K, but a corresponding liquid phase has not been detected. Here we report results of heat capacity C(p) and thermal conductivity, in situ, measurements, which are consistent with a reversible transition from annealed HDA to ultraviscous high-density liquid water at 1 GPa and 140 K. On heating of HDA, the C(p) increases abruptly by (3.4 ± 0.2) J mol(-1) K(-1) before crystallization starts at (153 ± 1) K. This is larger than the C(p) rise at the glass to liquid transition of annealed ASW at 1 atm, which suggests the existence of liquid water under these extreme conditions.


Effects of 2,4-dinitrophenol or low [ATP]i on cell excitability and action potential propagation in guinea pig ventricular myocytes.
Inhibition of aerobic metabolism leads to a major disruption of cardiac cell homeostasis. The purpose of the present study was twofold: 1) We determined the relative importance of junctional and nonjunctional membrane resistance (Rj and Rm, respectively) in the development of propagation failure during inhibition of aerobic metabolism in guinea pig ventricular cell pairs. 2) We used the patch-action potential clamp technique in single ventricular myocytes to study some of the properties of the membrane channels that are responsible for shortening of action potential duration and eventual failure of cell excitation after metabolic blockade. In most experiments, whole-cell patch pipettes were filled with a solution containing 1 mM EGTA, 5 mM HEPES, and 5 mM ATP. Our results in cell pairs showed that pharmacological inhibition of aerobic metabolism with the mitochondrial uncoupler 2,4-dinitrophenol (DNP) led to a drop in Rm followed by an increase in Rj. The increase in Rj was not sufficient to cause a measurable delay in cell-to-cell propagation, whereas the drop in Rm consistently led to failure of cell excitation. Similar results were obtained in additional experiments in which the EGTA concentration in the pipette was reduced to 50 microM. Similar results were also obtained by loading the recording patch pipettes with a solution containing only 0.1 mM ATP. Our patch-action potential clamp experiments, on the other hand, revealed that DNP induced the opening of time- and voltage-independent membrane channels, with a unitary conductance of 23 pS. The channels allowed for the passage of outward current in the voltage range of the action potential, and the increase in membrane patch conductance correlated with the observed shortening of action potential duration during DNP superfusion. Our experiments provide the first simultaneous recordings of action potentials and DNP-induced channel currents in guinea pig ventricular myocytes. Overall, the data provide new evidence for the understanding of the cellular and subcellular mechanisms involved in the development of slow conduction velocity and propagation block after metabolic blockade.


Prognostic factors and clinical outcome in acute lower respiratory tract infections: a prospective study in general practice.
Unrealistic expectations about illness duration are likely to result in reconsultations and associated unnecessary antibiotic prescriptions. An evidence-based account of clinical outcomes in patients with lower respiratory tract infection (LRTI) may help avoid unnecessary antibiotic prescriptions and reconsultations. We aimed to identify clinical factors that may predict a prolonged clinical course or poor outcome for patients with LRTI and to provide an evidence-based account of duration of an LRTI and the impact of the illness on daily activities in patients consulting in general practice. A prospective cohort study of 247 adult patients with a clinical diagnosis of LRTI presenting to 25 GPs in The Netherlands was carried out. Multivariable Cox regression analysis was used to identify baseline clinical and infection parameters that predicted the time taken for symptoms to resolve. A Kaplan-Meier curve was used to analyse time-to-symptom resolution. Clinical cure was recorded by the GPs at 28 days after the initial consultation and by the patients at 27 days. Co-morbidity of asthma was a statistically significant predictor of delayed symptom resolution, whereas the presence of fever, perspiring and the prescription of an antibiotic weakly predicted enhanced symptom resolution. The GPs considered 89% of the patients clinically cured at 28 days, but 43% of these nevertheless reported ongoing symptoms. Patient-reported cure was much lower (51%), and usual daily activities were limited in 73% of the patients at baseline, and 19% at final follow-up. The course of LRTI was generally uncomplicated, but the morbidity of this illness was considerable with a longer duration than generally reported, especially for patients with co-existent asthma. These results underline once again the importance of providing GPs with an evidence-based account of outcomes to share with patients in order to set realistic expectations and of enhancing their communication skills within the consultation.


Impact of abnormal diffusion-weighted imaging results on short-term outcome following transient ischemic attack.
To characterize short-term prognoses among patients with transient ischemic attack (TIA) and normal diffusion-weighted imaging (DWI) results, TIA patients with abnormal DWI results (transient symptoms associated with infarction [TSI]), and patients with completed ischemic stroke (IS). Retrospective study. University hospital. We reviewed patient medical records between January 2003 and December 2004 with International Classification of Diseases, Ninth Revision codes for TIA at admission, resolution of neurological symptoms within 24 hours, magnetic resonance imaging within 48 hours, and a discharge diagnosis of TIA or IS. A random sample of 50 IS patients was selected from all IS admissions and discharges by International Classification of Diseases, Ninth Revision codes. Demographic, clinical, radiographic, and in-hospital outcome data were recorded. Three diagnostic categories were created: TIA with normal DWI results, TSI, and IS. Multivariate logistic regression was used to estimate the association between diagnostic category and rate of in-hospital stroke or recurrent TIA among the 3 groups. We identified 146 classic TIA (25% with TSI) and 50 IS cases. There were 4 recurrent TIAs and 6 strokes among patients with TSI (27.0%); 3 recurrent TIAs and no strokes among patients with normal DWI results (2.8%); and 1 recurrent stroke and no TIAs among IS patients (2.0%). Transient symptoms associated with infarction was independently associated with in-hospital recurrent TIA or stroke (adjusted odds ratio, 11.2; P < .01). Transient symptoms associated with infarction is associated with a greater rate of early recurrent TIA and stroke than both IS and TIA with normal DWI results. These data suggest that TSI may be a separate clinical entity with unique prognostic implications.


Prevalence of pulmonary arteriovenous malformations as estimated by low-dose thoracic CT screening.
Pulmonary arteriovenous malformations (PAVMs) are rarely encountered in clinical practice. The prevalence of PAVMs associated with hereditary hemorrhagic telangiectasia (HHT) has been estimated based on the rate in the family members of HHT patients, but the prevalence of PAVMs in the general population remains unknown. We retrospectively examined the prevalence and clinical characteristics of PAVMs as detected by a low-dose thoracic CT screening program for lung cancer at the Hitachi Medical Center and the Hitachi General Health Care Center in the northern part of Ibaraki Prefecture, Japan. From 2001 to 2007, we identified eight patients (seven females and one male) with PAVMs among 21,235 initial screening participants (the mean age of the patients with PAVMs and that of the screening participants was 60.6 years). The prevalence of PAVMs was estimated at 38 per 100,000 individuals [95% confidence interval (CI)=18-76]. The diameter of the PAVMs was a mean of 6.6 mm, and none of the lesions could be detected by chest X-ray. Females older than 60 years tended to have larger PAVMs than younger women did (p=0.06). Two patients (25%) were diagnosed with HHT. One patient had previously undergone surgery for a brain abscess. PAVMs are more prevalent than previously reported, especially among females.


Effects of X‑ray irradiation in combination with ascorbic acid on tumor control.
Our previous studies demonstrated that the combination of treatment with ascorbic acid (AsA) and X‑ray irradiation results in increased apoptosis in HL60 cells. The present study was performed to investigate the effects of the combined use of AsA and X‑ray irradiation on epithelial cancer and sarcoma cells, and its potential use in future clinical treatment. X‑ray irradiation combined with AsA treatment resulted in increased suppression of cell growth of HT1080, SAS and A549 cells in vitro compared with X‑ray irradiation alone. The combined treatment also suppressed tumor growth in implanted HT‑1080 cells in vivo. Using annexin V/propidium iodide staining and the detection of activated caspase 3, it was found that X‑ray irradiation increased the apoptotic rate of HT1080 cells and resulted in G2/M arrest. However, apoptosis in the HT1080 cells treated with 5 mM AsA remained unchanged, and no changes were observed in the G2/M fraction. By contrast, AsA treatment caused increased suppression of proliferation compared with X‑ray irradiation. These results suggested that 5 mM AsA slowed the cell cycle and reduced tumor growth. Therefore, X‑ray irradiation combined with AsA treatment may be effective against epithelial cancer and sarcoma cells.


Do the pleiotropic effects of statins in the vasculature predict a role in inflammatory diseases?
Pleiotropic effects are now described for the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (or statins) that might have utility in the context of chronic inflammatory autoimmune disease. Here we discuss the pharmacology and established uses of statins and in this context describe potential anti-inflammatory and immune-modulatory effects. An extensive in vitro data set defines roles for statins in modifying endothelial function, particularly with respect to adhesion molecule expression and apoptosis. Broader effects on leukocyte function have now emerged including altered adhesion molecule expression, cytokine and chemokine release and modulation of development of adaptive immune responses via altered MHC class II upregulation. In vivo data in several inflammatory models, including collagen-induced inflammatory arthritis and experimental autoimmune encephalomyelitis, suggest that such effects might have immune-modulatory potential. Finally, a recent clinical trial has demonstrated immunomodulatory effects for statins in patients with rheumatoid arthritis. Together with their known vasculoprotective effects, this growing body of evidence provides compelling support for longer-term trials of statin therapy in human disease such as rheumatoid arthritis.


Patients' experiences with at-home preoperative skin disinfection before elective hip replacement surgery.
The aim of the study was to describe patients' experiences with preoperative skin disinfection carried out in their home before elective hip replacement surgery with the aim of lowering the microbial burden and avoiding surgical site infections. The literature was reviewed for relevant studies. Optimal preparations before surgery depend on patients being able to assimilate preoperative information and instructions. The study was based on 14 interviews with patients who had undergone elective hip replacement surgery. Data were analysed with qualitative manifest content analysis according to Graneheim and Lundman (2004). The main categories of findings were: patients' experience of obstacles and limitations, the importance of supportive surroundings, and personal resources as strength when performing preoperative skin disinfection. The findings of this study agree with earlier studies showing a lack of compliance to preoperative skin disinfection. The findings also suggest reasons for non-compliance. Preoperative skin disinfection involves many important steps that need to be accomplished to ensure the maximum effect on microbial burden on skin surface. These steps can be difficult for some patient groups. Perioperative dialogue is one way to identify patients' individual needs and to help patients participate in the process. The study concludes that patients who carried out skin disinfection at home before surgery have a great responsibility to prepare themselves. The challenge for perioperative nurses who work with preoperative information is to identify and individually guide those patients who need extended support so that all patients with elective hip replacement surgery receive the same quality of care. Further research should focus on how caregivers discover individuals with extended needs and on identifying the kind of support that is effective to achieve optimal conditions for hip replacement surgery.


A multicenter study of recombinant human interleukin 12 for the treatment of chronic hepatitis C virus infection in patients nonresponsive to previous therapy.
Recombinant human interleukin 12 (IL-12) is an immunomodulatory cytokine that is active against several viruses. Treatment options in patients with chronic hepatitis C with nonresponse to interferon (IFN)-based therapy are limited. Prior dose-ranging studies have indicated drug tolerability and transient suppression of hepatitis C virus (HCV) RNA by IL-12. The aim of this study was to determine the safety and efficacy of prolonged IL-12 therapy in patients who have failed treatment with IFN-alpha +/- ribavirin. A total of 225 patients at 21 U.S. sites who had a history of nonresponse to IFN-alpha or combination IFN-alpha plus ribavirin for treatment of HCV were randomized to 500 ng/kg IL-12 or placebo subcutaneously twice weekly for 12 weeks. The groups were then unblinded; patients receiving IL-12 continued for another 36 weeks, and the placebo group received 48 weeks of treatment with IL-12 in an open-label fashion. HCV RNA, serum alanine aminotransferase (ALT) level, and a repeat liver biopsy were assessed at 24 weeks following therapy. Approximately 1% (2 of 160) of nonresponsive patients enrolled for treatment had a sustained virologic response to IL-12 therapy, but 3% (7 of 225) developed severe adverse events probably related to treatment, resulting in early termination of the trial. Common adverse effects reported by most patients included chills, fever, fatigue, headache, and arthralgia. At termination of the study, 160 patients had received at least 8 weeks of treatment with IL-12. Paired liver biopsy specimens were available for evaluation in 54 patients, but there were no significant changes in Knodell fibrosis or histologic activity index (HAI) scores. In conclusion, IL-12 as monotherapy at the doses used in this trial for chronic hepatitis C has low efficacy, was poorly tolerated, and is unlikely to provide an alternative to conventional IFN-based therapy.


Dry needling versus acupuncture: the ongoing debate.
Although Western medical acupuncture (WMA) is commonly practised in the UK, a particular approach called dry needling (DN) is becoming increasingly popular in other countries. The legitimacy of the use of DN by conventional non-physician healthcare professionals is questioned by acupuncturists. This article describes the ongoing debate over the practice of DN between physical therapists and acupuncturists, with a particular emphasis on the USA. DN and acupuncture share many similarities but may differ in certain aspects. Currently, little information is available from the literature regarding the relationship between the two needling techniques. Through reviewing their origins, theory, and practice, we found that DN and acupuncture overlap in terms of needling technique with solid filiform needles as well as some fundamental theories. Both WMA and DN are based on modern biomedical understandings of the human body, although DN arguably represents only one subcategory of WMA. The increasing volume of research into needling therapy explains its growing popularity in the musculoskeletal field including sports medicine. To resolve the debate over DN practice, we call for the establishment of a regulatory body to accredit DN courses and a formal, comprehensive educational component and training for healthcare professionals who are not physicians or acupuncturists. Because of the close relationship between DN and acupuncture, collaboration rather than dispute between acupuncturists and other healthcare professionals should be encouraged with respect to education, research, and practice for the benefit of patients with musculoskeletal conditions who require needling therapy.


Effect of dilution rate and methanol-glycerol mixed feeding on heterologous Rhizopus oryzae lipase production with Pichia pastoris Mut(+) phenotype in continuous culture.
The induction using substrate mixtures is an operational strategy for improving the productivity of heterologous protein production with Pichia pastoris. Glycerol as a cosubstrate allows for growth at a higher specific growth rate, but also has been reported to be repressor of the expression from the AOX1 promoter. Thus, further insights about the effects of glycerol are required for designing the induction stage with mixed substrates. The production of Rhizopus oryzae lipase (ROL) was used as a model system to investigate the application of methanol-glycerol feeding mixtures in fast metabolizing methanol phenotype. Cultures were performed in a simple chemostat system and the response surface methodology was used for the evaluation of both dilution rate and methanol-glycerol feeding composition as experimental factors. Our results indicate that productivity and yield of ROL are strongly affected by dilution rate, with no interaction effect between the involved factors. Productivity showed the highest value around 0.04-0.06 h(-1) , while ROL yield decreased along the whole dilution rate range evaluated (0.03-0.1 h(-1) ). Compared to production level achieved with methanol-only feeding, the highest specific productivity was similar in mixed feeding (0.9 UA g-biomass(-1) h(-1) ), but volumetric productivity was 70% higher. Kinetic analysis showed that these results are explained by the effects of dilution rate on specific methanol uptake rate, instead of a repressor effect caused by glycerol feeding. It is concluded that despite the effect of dilution rate on ROL yield, mixed feeding strategy is a proper process option to be applied to P. pastoris Mut(+) phenotype for heterologous protein production.


Importance of MAP kinases during protoperithecial morphogenesis in Neurospora crassa.
In order to produce multicellular structures filamentous fungi combine various morphogenetic programs that are fundamentally different from those used by plants and animals. The perithecium, the female sexual fruitbody of Neurospora crassa, differentiates from the vegetative mycelium in distinct morphological stages, and represents one of the more complex multicellular structures produced by fungi. In this study we defined the stages of protoperithecial morphogenesis in the N. crassa wild type in greater detail than has previously been described; compared protoperithecial morphogenesis in gene-deletion mutants of all nine mitogen-activated protein (MAP) kinases conserved in N. crassa; confirmed that all three MAP kinase cascades are required for sexual development; and showed that the three different cascades each have distinctly different functions during this process. However, only MAP kinases equivalent to the budding yeast pheromone response and cell wall integrity pathways, but not the osmoregulatory pathway, were essential for vegetative cell fusion. Evidence was obtained for MAP kinase signaling cascades performing roles in extracellular matrix deposition, hyphal adhesion, and envelopment during the construction of fertilizable protoperithecia.


Alteration of -656(G/T) and -607(C/A) polymorphisms in interleukin-18 (IL-18) gene in house dust mite-sensitive allergic rhinitis patients in Thailand.
Allergic rhinitis (AR) is an IgE-mediated inflammation of the nasal membranes, which is naturally triggered by aeroallergens. House dust mites (HDM) are the most common inhalant allergens. Interleukin-18 (IL-18) has been established as an essential cytokine that can activate the generation of IgE. This randomized controlled study aimed to identify the possible relationship of the genetic variations in the IL-18 gene with AR in mite-sensitive Thai patients. Study subjects consisted of 150 AR patients and 50 normal participants. Genomic DNA of 30 randomized AR patients and 30 randomized controls were screened by sequencing for the selection of candidate single nucleotide polymorphisms (SNPs), and further analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay for all subjects. The following five SNPs were detected in the IL-18 gene: -656 G/T, -607 C/A, and -137 G/C in promoter 1 and -920 C/T and -373 C/G in promoter 2. The results showed that -656 G/T and -607 C/A SNPs were significantly correlated with IgE levels specific to Dermatophagoides pteronyssinus (Der p) allergen (P = 0.045 and P = 0.045, respectively), and significant differences were observed in the genotype distribution of AR patients when compared with controls [P = 0.044 and P = 0.044, respectively; odds ratios (ORs): 1.941 (95%CI, 1.014-3.715) and 1.941 (95%CI, 1.014-3.715), respectively]. Our findings indicate that the IL-18 alleles, -656T (rs1946519) and -607A (rs1946518), might be associated with the higher production of Der p allergen-specific IgE in mite-sensitive AR patients.


Successful palliation of malignant ascites from peritoneal mesothelioma by laparoscopic intraperitoneal hyperthermic chemotherapy.
A variety of options have been proposed to treat malignant ascites but most of them have failed to reach a significant impact in terms of palliation. Laparoscopic hyperthermic intraperitoneal chemotherapy (LHIPEC) could represent a good therapeutic tool for patients in whom medical therapies have failed and peritoneovenous shunting is contraindicated. Here we present a case of a 49-year-old woman with malignant ascites secondary to peritoneal spreading of a right pleural mesothelioma. After failure of medical therapy, the patient underwent LHIPEC with Cisplatin 25 mg/m/L and Doxorubicin 7 mg/m/L. A dramatic reduction of ascites was documented in the postoperative period and the patient experienced complete abdominal symptom relief. Ascites did not recur during a follow-up period of 6 months. LHIPEC could be a good therapeutic option to palliate malignant ascites from mesothelioma in cases not eligible for a radical treatment. Further studies are needed to standardize dosage and perfusion parameters.


Direct in Vitro Selection of Trans-Acting Ribozymes for Posttranscriptional, Site-Specific, and Covalent Fluorescent Labeling of RNA.
General and efficient tools for site-specific fluorescent or bioorthogonal labeling of RNA are in high demand. Here, we report direct in vitro selection, characterization, and application of versatile trans-acting 2'-5' adenylyl transferase ribozymes for covalent and site-specific RNA labeling. The design of our partially structured RNA pool allowed for in vitro evolution of ribozymes that modify a predetermined nucleotide in cis (i.e., intramolecular reaction) and can then be easily engineered for applications in trans (i.e., in an intermolecular setup). The resulting ribozymes are readily designed for specific target sites in small and large RNAs and accept a wide variety of N6-modified ATP analogues as small-molecule substrates. The most efficient new ribozyme (FH14) shows excellent specificity toward its target sequence also in the context of total cellular RNA.


Genetic architecture of quantitative flower and leaf traits in a pair of sympatric sister species of Primulina.
Flowers and leaves each represent suites of functionally interrelated traits that are often involved in species divergence and local adaptation. However, a major unresolved issue is how the individual component traits that make up a complex trait such as a flower evolve in a coordinated fashion to retain a high degree of functionality. We use a quantitative trait loci (QTL) approach to elucidate the genetic architecture of divergence in flower and leaf traits between the sister species Primulina depressa and Primulina danxiaensis, which grow sympatrically but in contrasting microhabitats. We found that flower traits were controlled by multiple QTL of small effect, while leaf physiological and morphological traits tended to be controlled by QTL of larger effect. The observed floral integration, manifested by a high degree overlap in both individual trait QTL and QTL for principal component scores (PCA QTL), may have been critical for evolutionary divergence of floral morphology in relation to their pollinators. This overlap suggests that direct selection on only one or a few of the component traits could have caused substantial divergence in other floral traits due to genetic correlations, while the low QTL overlap between floral and vegetative traits suggests that these trait suites are genetically unlinked and can evolve independently in response to different selective pressures corresponding to their distinct functions.


European health systems and the internal market: reshaping ideology?
Departing from theories of distributive justice and their relation with the distribution of health care within society, especially egalitarianism and libertarianism, this paper aims at demonstrating that the approach taken by the European Court of Justice regarding the application of the Internal Market principles (or the market freedoms) to the field of health care services has introduced new values which are more concerned with a libertarian view of health care. Moreover, the paper also addresses the question of how these new values introduced by the Court may affect common principles of European health systems, such as equity and accessibility.


Exploring the association between cannabis use and depression.
To examine the evidence on the association between cannabis and depression and evaluate competing explanations of the association. A search of Medline, Psychinfo and EMBASE databases was conducted. All references in which the terms 'cannabis', 'marijuana' or 'cannabinoid', and in which the words 'depression/depressive disorder/depressed', 'mood', 'mood disorder' or 'dysthymia' were collected. Only research studies were reviewed. Case reports are not discussed. There was a modest association between heavy or problematic cannabis use and depression in cohort studies and well-designed cross-sectional studies in the general population. Little evidence was found for an association between depression and infrequent cannabis use. A number of studies found a modest association between early-onset, regular cannabis use and later depression, which persisted after controlling for potential confounding variables. There was little evidence of an increased risk of later cannabis use among people with depression and hence little support for the self-medication hypothesis. There have been a limited number of studies that have controlled for potential confounding variables in the association between heavy cannabis use and depression. These have found that the risk is much reduced by statistical control but a modest relationship remains. Heavy cannabis use and depression are associated and evidence from longitudinal studies suggests that heavy cannabis use may increase depressive symptoms among some users. It is still too early, however, to rule out the hypothesis that the association is due to common social, family and contextual factors that increase risks of both heavy cannabis use and depression. Longitudinal studies and studies of twins discordant for heavy cannabis use and depression are needed to rule out common causes. If the relationship is causal, then on current patterns of cannabis use in the most developed societies cannabis use makes, at most, a modest contribution to the population prevalence of depression.


Glossiness and perishable food quality: visual freshness judgment of fish eyes based on luminance distribution.
Previous studies have reported the effects of statistics of luminance distribution on visual freshness perception using pictures which included the degradation process of food samples. However, these studies did not examine the effect of individual differences between the same kinds of food. Here we elucidate whether luminance distribution would continue to have a significant effect on visual freshness perception even if visual stimuli included individual differences in addition to the degradation process of foods. We took pictures of the degradation of three fishes over 3.29 hours in a controlled environment, then cropped square patches of their eyes from the original images as visual stimuli. Eleven participants performed paired comparison tests judging the visual freshness of the fish eyes at three points of degradation. Perceived freshness scores (PFS) were calculated using the Bradley-Terry Model for each image. The ANOVA revealed that the PFS for each fish decreased as the degradation time increased; however, the differences in the PFS between individual fish was larger for the shorter degradation time, and smaller for the longer degradation time. A multiple linear regression analysis was conducted in order to determine the relative importance of the statistics of luminance distribution of the stimulus images in predicting PFS. The results show that standard deviation and skewness in luminance distribution have a significant influence on PFS. These results show that even if foodstuffs contain individual differences, visual freshness perception and changes in luminance distribution correlate with degradation time.


Molecular biology of human immunodeficiency virus type 1.
Since the discovery of human immunodeficiency virus (HIV) as the etiologic agent of acquired immune deficiency syndrome (AIDS) more than a decade ago, tremendous progress has been made in various aspects of this virus and its interplay with the host immune system. The advent of potent combination therapy has made it possible to achieve effective and durable control of HIV-1 replication in vivo, yet the persistence of the latent reservoirs pose a new challenge. The recent identifications of several cellular proteins interacting with different viral gene products have not only shed new insights into our understanding of the HIV-1 and the host cell biology, but also provided the bases for developing novel strategies to block HIV-1 replication. It is from this perspective that we review the current understanding of the molecular mechanisms governing the HIV-1 life cycle.


Barriers to the delivery of the hepatitis B birth dose: a study of five Papua New Guinean hospitals in 2007.
Hepatitis B is highly endemic in Papua New Guinea (PNG). Vaccination at birth is a key mother-to-child transmission prevention strategy. Despite recommendations for newborns to be vaccinated within 24 hours of delivery, a 2005 survey showed 23% coverage among children born in health facilities. Our study examined hepatitis B birth-dose coverage and knowledge, practices and barriers to vaccine delivery in five major PNG hospitals. Data on births and vaccines administered were sourced from the National Department of Health (NDoH) and directly from the five hospitals. A maternity unit audit and staff survey were undertaken. Across the five hospitals, the hospital-level data of hepatitis B birth-dose coverage was 79% (range: 40-96%) compared to 19% from national data (range: 0-106%). Despite hospitals having adequate vaccine supply, access to appropriately stored vaccine in maternity units was compromised with only one unit having a vaccine-specific temperature-monitored refrigerator. In interviews of 25 staff, incorrect reasons given for delaying vaccination were prematurity (60%), low birthweight (48%) and difficult birth (36%). This study found encouraging birth-dose coverage rates in five major hospitals but 20% of babies still missed receiving the recommended vaccine. The NDoH Immunization Unit will use the results of this study to inform strategies to improve hepatitis B birth-dose coverage in hospitals.


[5-fluorouracil therapeutic drug monitoring: Update and recommendations of the STP-PT group of the SFPT and the GPCO-Unicancer].
Despite being 60-years old now, 5-FU remains the backbone of numerous regimen to treat a variety of solid tumors such as breast, head-and-neck and digestive cancers either in neo-adjuvant, adjuvant or metastatic settings. Standard 5-FU usually claims 15-40% of severe toxicities and up to 1% of toxic-death. Numerous studies show a stiff relationship between 5-FU exposure and toxicity or efficacy. In addition, 5-FU pharmacokinetics is highly variable between patients. Indeed, 80% of the 5-FU dose is catabolized in the liver by dihydropyrimidine dehydrogenase (DPD) into inactive compounds. It is now well established that DPD deficiency could lead to severe toxicities and, thus, require dose reduction in deficient patients. However, despite dosage adaptation based on DPD status, some patients may still experience under- or over-exposure, leading to inefficacy or major toxicity. The "Suivi thérapeutique pharmacologique et personnalisation des traitements" (STP-PT) group of the "Société française de pharmacologie et de thérapeutique" (SFPT) and the "Groupe de pharmacologie clinique oncologique" (GPCO)-Unicancer, based on the latest and most up-to-date literature data, recommend the implementation of 5-FU Therapeutic Drug Monitoring in order to ensure an adequate 5-FU exposure.


Effects of simulated crouch gait on foot kinematics and kinetics in healthy children.
Identification of secondary and tertiary impairments in neurologically induced gait deviations, such as crouch gait, is not always straightforward, but essential in order to decide upon the most efficient medical treatment in patients with cerebral palsy (CP). Until now, exact intersegmental dependency of the development of foot deformities has not been investigated. Therefore, the aim of this study was to explore if an artificially induced bilateral knee flexion contracture causes compensatory mechanisms in foot motion during gait in healthy children. Three-dimensional kinematic and kinetic data from 30 healthy children (mean age 10.6 years) were derived from the Oxford Foot model (OFM). Participants walked first in an artificially induced crouch gait (limitation of knee extension to 40°) and then normally. Walking speed was kept the same in both conditions. Analysis revealed small but significant (p<0.05) differences between the two conditions in hindfoot and forefoot kinematics in all three planes during the stance phase as well as for all peak internal moments within the foot. In general the foot tended to compensate for an artificial knee flexion contracture with an increase in maximal dorsiflexion, eversion and external rotation of the hindfoot, which also allowed increased foot motion in other foot segments. The results of this study showed that an isolated proximal joint contracture had an influence on foot position during stance in healthy children. Further interpretation of the data in relation to CP children will be possible as soon as comparable OFM data of pathological crouch gait is available.


A Deep Blue B,N-Doped Heptacene Emitter That Shows Both Thermally Activated Delayed Fluorescence and Delayed Fluorescence by Triplet-Triplet Annihilation.
An easy-to-access, near-UV-emitting linearly extended B,N-doped heptacene with high thermal stability is designed and synthesized in good yields. This compound exhibits thermally activated delayed fluorescence (TADF) at ambient temperature from a multiresonant (MR) state and represents a rare example of a non-triangulene-based MR-TADF emitter. At lower temperatures triplet-triplet annihilation dominates. The compound simultaneously possesses narrow, deep-blue emission with CIE coordinates of (0.17, 0.01). While delayed fluorescence results mainly from triplet-triplet annihilation at lower temperatures in THF solution, where aggregates form upon cooling, the TADF mechanism takes over around room temperature in solution when the aggregates dissolve or when the compound is well dispersed in a solid matrix. The potential of our molecular design to trigger TADF in larger acenes is demonstrated through the accurate prediction of ΔEST using correlated wave-function-based calculations. On the basis of these calculations, we predicted dramatically different optoelectronic behavior in terms of both ΔEST and the optical energy gap of two constitutional isomers where only the boron and nitrogen positions change. A comprehensive structural, optoelectronic, and theoretical investigation is presented. In addition, the ability of the achiral molecule to assemble on a Au(111) surface to a highly ordered layer composed of enantiomorphic domains of racemic entities is demonstrated by scanning tunneling microscopy.


Role of carbohydrate in exercise.
Carbohydrate is an important energy source during exercise. During short, heavy exercise it may be the only energy source for the working muscle and may be derived exclusively from the glycogen stores within the muscle fibers themselves. During prolonged, submaximal exercise the magnitude of the contribution that carbohydrate makes to the total fuel consumed depends upon a number of factors, including (1) the intensity of the exercise, (2) the duration of the exercise, (3) the state or type of training that the individual has engaged in, or both, and (4) the diet previously consumed. Due to their limited storage in the body and the relative ease with which these stores can be manipulated by combinations of diet and/or training, a knowledge of the dynamics of carbohydrate metabolism is an important component in the arsenal of knowledge for coaches and athletes.


Protoporphyrin IX enhancement by 5-aminolaevulinic acid peptide derivatives and the effect of RNA silencing on intracellular metabolism.
Intracellular generation of the photosensitiser, protoporphyrin IX, from a series of dipeptide derivatives of the haem precursor, 5-aminolaevulinic acid (ALA), was investigated in transformed PAM212 murine keratinocytes, together with studies of their intracellular metabolism. Porphyrin production was substantially increased compared with equimolar ALA using N-acetyl terminated phenylalanyl, leucinyl and methionyl ALA methyl ester derivatives in the following order: Ac-L-phenylalanyl-ALA-Me, Ac-L-methionyl-ALA-Me and Ac-L-leucinyl-ALA-Me. The enhanced porphyrin production was in good correlation with improved photocytotoxicity, with no intrinsic dark toxicity apparent. However, phenylalanyl derivatives without the acetyl/acyl group at the N terminus induced significantly less porphyrin, and the replacement of the acetyl group by a benzyloxycarbonyl group resulted in no porphyrin production. Porphyrin production was reduced in the presence of class-specific protease inhibitors, namely serine protease inhibitors. Using siRNA knockdown of acylpeptide hydrolase (ACPH) protein expression, we showed the involvement of ACPH, a member of the prolyl oligopeptidase family of serine peptidases, in the hydrolytic cleavage of ALA from the peptide derivatives. In conclusion, ALA peptide derivatives are capable of delivering ALA efficiently to cells and enhancing porphyrin synthesis and photocytotoxicity; however, the N-terminus state, whether free or substituted, plays an important role in determining the biological efficacy of ALA peptide derivatives.


Genomic heterozygosity and hybrid breakdown in cotton (Gossypium): different traits, different effects.
Hybrid breakdown has been well documented in various species. Relationships between genomic heterozygosity and traits-fitness have been extensively explored especially in the natural populations. But correlations between genomic heterozygosity and vegetative and reproductive traits in cotton interspecific populations have not been studied. In the current study, two reciprocal F2 populations were developed using Gossypium hirsutum cv. Emian 22 and G. barbadense acc. 3-79 as parents to study hybrid breakdown in cotton. A total of 125 simple sequence repeat (SSR) markers were used to genotype the two F2 interspecific populations. To guarantee mutual independence among the genotyped markers, the 125 SSR markers were checked by the linkage disequilibrium analysis. To our knowledge, this is a novel approach to evaluate the individual genomic heterozygosity. After marker checking, 83 common loci were used to assess the extent of genomic heterozygosity. Hybrid breakdown was found extensively in the two interspecific F2 populations particularly on the reproductive traits because of the infertility and the bare seeds. And then, the relationships between the genomic heterozygosity and the vegetative reproductive traits were investigated. The only relationships between hybrid breakdown and heterozygosity were observed in the (Emian22 × 3-79) F2 population for seed index (SI) and boll number per plant (BN). The maternal cytoplasmic environment may have a significant effect on genomic heterozygosity and on correlations between heterozygosity and reproductive traits. A novel approach was used to evaluate genomic heterozygosity in cotton; and hybrid breakdown was observed in reproductive traits in cotton. These findings may offer new insight into hybrid breakdown in allotetraploid cotton interspecific hybrids, and may be useful for the development of interspecific hybrids for cotton genetic improvement.


The thinner the better: self-esteem and low body weight in anorexia nervosa.
The aim of the present study was to examine the associations between self-esteem, motive satisfaction, and body weight in acute (acAN) and recovered (recAN) inpatients with anorexia nervosa (AN) and in healthy controls. Both acAN and recAN showed lower levels of self-esteem as compared with healthy controls but did not differ from each other. In acAN, decreased body weight was associated with increased self-esteem. Satisfaction of an achievement motive but not satisfaction of a superiority motive mediated this association. No such correlations could be observed in the other groups. This is the first study to show an often assumed association between decreased body weight and increased self-esteem in AN patients. These preliminary results strengthen the assumption that low body weight may foster self-esteem in patients with acAN, mainly through the satisfaction of an achievement motive. Self-esteem should be focused very early in the treatment of AN since weight gain may deprive the patient of an important source of self-esteem. Treatment interventions should be attuned to underlying motives of threatened self-esteem; in AN patients, the enhancement of self-esteem via weight loss seems to be rather fuelled by the satisfaction of an achievement motive than by the satisfaction of a superiority motive. Specific trainings to improve self-esteem in AN patients seem to be promising as an add-on to regular treatment.


Identification of hsa-miR-335 as a prognostic signature in gastric cancer.
Gastric cancer (GC) is one of the most common malignancy and primary cause of death in Chinese cancer patients. Recurrence is a major factor leading to treatment failure and low level of 5-year survival rate in GC patients following surgical resection. Therefore, identification of biomarkers with potential in predicting recurrence risk is the key problem of the prognosis in GC patients. A total of 74 GC patients were selected for systematic analysis, consisting of 31 patients with recurrence and 43 patients without recurrence. Firstly, miRNAs microarray and bioinformatics methods were used to characterize differential expressed miRNAs from primary tumor samples. Following, we used a ROC method to select signature with best sensitivity and specificity. Finally, we validated the signature in GC samples (frozen fresh and blood samples) using quantitative PCR. We have identified 12 differential miRNAs including 7 up-regulated and 5 down-regulated miRNAs in recurrence group. Using ROC method, we further ascertained hsa-miR-335 as a signature to recognize recurrence and non-recurrence cases in the training samples. Moreover, we validated this signature using quantitative PCR method in 64 test samples with consistent result with training set. A high frequency recurrence and poor survival were observed in GC cases with high level of hsa-miR-335 (P<0.001). In addition, we evaluated that hsa-miR-335 were involved in regulating target genes in several oncogenic signal-pathways, such as p53, MAPK, TGF-β, Wnt, ERbB, mTOR, Toll-like receptor and focal adhesion. Our results indicate that the hsa-miR-335 has the potential to recognize the recurrence risk and relate to the prognosis of GC patients.


Impaired executive control is associated with a variation in the promoter region of the tryptophan hydroxylase 2 gene.
Current models of attention describe attention not as a homogenous entity but as a set of neural networks whose measurement yields a set of three endophenotypes-alerting, orienting, and executive control. Previous findings revealed different neuroanatomical regions for these subsystems, and data from twin studies indicate differences in their heritability. The present study investigated the molecular genetic basis of attention in a sample of 100 healthy subjects. Attention performance was assessed with the attention network test that distinguishes alerting, orienting, and executive control (conflict) using a simple reaction time paradigm with different cues and congruent and incongruent flankers. Two gene loci on candidate genes for cognitive functioning, the functional catechol-O-methyltransferase (COMT) VAL158MET and the tryptophan hydroxylase 2 (TPH2) -703 G/T promoter polymorphism, were tested for possible associations with attention. COMT is involved in the catabolism of dopamine, and TPH is the rate-limiting enzyme for serotonin synthesis. Results showed no effect of the COMT polymorphism on attention performance. However, the TT genotype of TPH2 -03 G/T was significantly associated with more errors (a possible indicator of impaired impulse control; p = .001) and with decreased performance in executive control (p = .001). This single-nucleotide polymorphism on the TPH2 gene explained more than 10% of the variance in both indicators of attention stressing the role of the serotonergic system for cognitive functions.


Disseminating alcohol screening and brief intervention at trauma centers: a policy-relevant cluster randomized effectiveness trial.
In 2005 the American College of Surgeons passed a mandate requiring that level I trauma centers have mechanisms to identify and intervene with problem drinkers. The aim of this investigation was to determine if a multi-level trauma center intervention targeting both providers and patients would lead to higher-quality alcohol screening and brief intervention (SBI) when compared with trauma center mandate compliance without implementation enhancements. Cluster randomized trial in which intervention site (site n = 10, patient n = 409) providers received 1-day workshop training on evidence-based motivational interviewing (MI) alcohol interventions and four 30-minute feedback and coaching sessions; control sites (site n = 10, patient n = 469) implemented the mandate without study team training enhancements. Trauma centers in the United States of America. A total of 878 blood alcohol-positive in-patients with and without traumatic brain injury (TBI). MI skills of providers were assessed with fidelity coded standardized patient interviews. All patients were interviewed at baseline and 6- and 12-months post-injury with the Alcohol Use Disorders Identification Test (AUDIT). Intervention site providers consistently demonstrated enhanced MI skills compared with control providers. Intervention patients demonstrated an 8% reduction in AUDIT hazardous drinking relative to controls over the course of the year after injury (relative risk = 0.88, 95%, confidence interval = 0.79, 0.98). Intervention patients were more likely to demonstrate improvements in alcohol use problems in the absence of traumatic brain injury (TBI) (P = 0.002). Trauma center providers can be trained to deliver higher-quality alcohol screening and brief intervention (SBI) than untrained providers, which is associated with modest reductions in alcohol use problems, particularly among patients without TBI.


Intravenous amodiaquine and oral amodiaquine/erythromycin in the treatment of chloroquine-resistant falciparum malaria.
In eastern Thailand, 14 adults with moderately severe falciparum malaria were treated with intravenous amodiaquine dihydrochloride, loading dose 10 mg base/kg infused over 4 h followed by three further intravenous infusions of 5 mg base/kg at 24, 48, and 72 h. All patients were clinically cured--mean fever clearance time 37.8 h (range 24-60), mean parasite clearance time 64.9 h (18-164). There were no serious toxic effects. 33 patients aged over 5 years with uncomplicated falciparum malaria were given oral amodiaquine dihydrochloride (mean total dose 41 mg base/kg over 3 days) combined with erythromycin estolate (mean dose 48 mg base/kg daily for 5 days). 2 patients failed to respond. In the other 31 patients mean fever clearance time was 55.9 h (range 10-104) and mean parasite clearance time was 65.4 h (40-120). In both studies, more than half the patients followed-up had recurrent parasitaemia but reinfection could not be excluded. Parasites isolated from 18 patients were highly resistant to chloroquine in vitro.


Assessment of fish health status in the Upper Danube River by investigation of ultrastructural alterations in the liver of barbel Barbus barbus.
Despite intensive efforts and tightened guidelines for improvement of water quality over the last 2 decades, declines of fish populations have been reported for several rivers around the world. The present study forms part of a comprehensive weight-of-evidence approach, which aims to identify potential causes for the decline in fish catches observed in the Upper Danube River. The major focus of the present study is the investigation of the health status of wild barbel Barbus barbus L. collected from 3 locations along the Danube River, which experienced different levels of contamination. Whereas the comparison of the condition factor (CF) of field fish with that of control fish revealed no differences, ultrastructural investigations indicated severe disturbance of hepatic cell metabolism in field fish from the more contaminated sites Rottenacker and Ehingen, compared to both control fish and field fish from the less contaminated site Riedlingen. The ultrastructural analysis provided information about reactions of e.g. the rough endoplasmic reticulum, peroxisomes, and mitochondria, indicating an impaired health status of barbel at the sampling sites Rottenacker and Ehingen. Even though a straightforward cause-effect relationship between sediment contamination and ultrastructural alterations could not be established, based on a meta-analysis and toxicity assays it may be suggested that sediment-bound xenobiotics at least partly account for the hepatocellular changes. A relationship between impaired fish health status and the decline of fish catches along the Upper Danube River cannot be excluded.


Use of Graph Theory to Characterize Human and Arthropod Vector Cell Protein Response to Infection With Anaplasma phagocytophilum.
One of the major challenges in modern biology is the use of large omics datasets for the characterization of complex processes such as cell response to infection. These challenges are even bigger when analyses need to be performed for comparison of different species including model and non-model organisms. To address these challenges, the graph theory was applied to characterize the tick vector and human cell protein response to infection with Anaplasma phagocytophilum, the causative agent of human granulocytic anaplasmosis. A network of interacting proteins and cell processes clustered in biological pathways, and ranked with indexes representing the topology of the proteome was prepared. The results demonstrated that networks of functionally interacting proteins represented in both infected and uninfected cells can describe the complete set of host cell processes and metabolic pathways, providing a deeper view of the comparative host cell response to pathogen infection. The results demonstrated that changes in the tick proteome were driven by modifications in protein representation in response to A. phagocytophilum infection. Pathogen infection had a higher impact on tick than human proteome. Since most proteins were linked to several cell processes, the changes in protein representation affected simultaneously different biological pathways. The method allowed discerning cell processes that were affected by pathogen infection from those that remained unaffected. The results supported that human neutrophils but not tick cells limit pathogen infection through differential representation of ras-related proteins. This methodological approach could be applied to other host-pathogen models to identify host derived key proteins in response to infection that may be used to develop novel control strategies for arthropod-borne pathogens.


Attenuation of metabolic heat production and cold-escape/warm-seeking behaviour during a cold exposure following systemic salt loading in rats.
The reduction of body core temperature (Tcore) after salt loading has been reported. In this study, we tested the hypothesis that, during a cold exposure in rats, (1) salt loading would decrease metabolic rate (MR), reducing Tcore, but (2) Tcore would be maintained when cold-escape/warm-seeking behaviour is available. In the first experiment (n = 7), MR and Tcore were measured by indirect calorimetry and telemetry, respectively, during 26, 20 and 10 degrees C exposure for 1 h each, in that order. In the second experiment (n = 7), each rat was placed in an operant system during the same exposure protocol as in the first experiment, where it could trigger a 40 degrees C air reward for 30 s at 20 and 10 degrees C by moving into specific areas (operant behaviour). In each experiment, rats repeated the same protocol twice with a subcutaneous injection (10 ml kg-1) of either isotonic saline (154 mM) or hypertonic saline (2500 mM). In the first experiment, MR in the isotonic-saline trial increased (P < 0.05) at 20 and 10 degrees C compared with that at 26 degrees C by 21 +/- 5 and 48 +/- 6 %, respectively (means +/- S.E.M.), with Tcore unchanged. However, values for MR and Tcore in the hypertonic-saline trial were lower (P < 0.05) than those in the isotonic-saline trial in any ambient temperature. In the second experiment, Tcore was also lower (P < 0.05) in the hypertonic-saline trial than in the isotonic-saline trial. The counts of the operant behaviour in the hypertonic-saline trial remained unchanged in each exposure period, but those in the isotonic-saline trial increased (P < 0.05) at 10 degrees C. These results may suggest that salt loading attenuates both metabolic and behavioural thermoregulatory responses to the cold.


Thirty year trends in the prevalence and distribution of dental caries in Swedish adults (1973-2003).
The aim of the present investigation is to report on the trends in the prevalence and severity of dental caries and dental status in an adult Swedish population over a 30-year period (1973-2003). Four cross-sectional epidemiological studies in 1973, 1983, 1993, and 2003 were performed in Jönköping, Sweden.A random sample of individuals aged 20, 30, 40, 50, 60, 70, and 80 years were examined clinically and radiographically, a total of 2521 individals. Diagnostic variables were edentulousness, number of teeth, initial and manifest caries lesions, restorations, fissure sealants, and quality of restorations (secondary caries and overhangs). The percentage of edentulous 40- to 70-year-old individuals decreased during the 30-year period from 16% to 1%. The distribution of individuals by DFS in the age groups 20-50 years showed a gradual shift towards a positively skewed distribution between the years 1973 to 2003. There was a steady decrease in mean number of DFS in the age groups 20-50 years. In the 20-year-olds the mean number of DFS decreased by 72% and for 50-year-olds, by 37%. In conclusion there has been a marked decrease in DFS in adults up to middle age and a marked reduction in edentulousness over a thirty year period. This shows that the decrease in caries levels in children and adolescents is also occurring among adults.


From sequence analysis of three novel ascorbate peroxidases from Arabidopsis thaliana to structure, function and evolution of seven types of ascorbate peroxidase.
Ascorbate peroxidases are haem proteins that efficiently scavenge H2O2 in the cytosol and chloroplasts of plants. Database analyses retrieved 52 expressed sequence tags coding for Arabidopsis thaliana ascorbate peroxidases. Complete sequencing of non-redundant clones revealed three novel types in addition to the two cytosol types described previously in Arabidopsis. Analysis of sequence data available for all plant ascorbate peroxidases resulted in the following classification: two types of cytosol soluble ascorbate peroxidase designated cs1 and cs2; three types of cytosol membrane-bound ascorbate peroxidase, namely cm1, bound to microbodies via a C-terminal membrane-spanning segment, and cm2 and cm3, both of unknown location; two types of chloroplast ascorbate peroxidase with N-terminal transit sequences, the stromal ascorbate peroxidase (chs), and the thylakoid-bound ascorbate peroxidase showing a C-terminal transmembrane segment and designated cht. Further comparison of the patterns of conserved residues and the crystal structure of pea ascorbate peroxidase showed that active site residues are conserved, and three peptide segments implicated in interaction with reducing substrate are similar, excepting cm2 and cm3 types. A change of Phe-175 in cytosol types to Trp-175 in chloroplast types might explain the greater ascorbate specificity of chloroplast compared with cytosol ascorbate peroxidases. Residues involved in homodimeric subunit interaction are conserved only in cs1, cs2 and cm1 types. The proximal cation (K+)-binding site observed in pea ascorbate peroxidase seems to be conserved. In addition, cm1, cm2, cm3, chs and cht ascorbate peroxidases contain Asp-43, Asn-57 and Ser-59, indicative of a distal monovalent cation site. The data support the hypothesis that present-day peroxidases evolved by an early gene duplication event.


A mixed boundary condition for accounting energy absorption and transmission in a diffusion equation model.
The acoustic diffusion equation model has shown to be a versatile alternative model for certain types of scenarios where the classical geometrical methods have been demonstrated to be inefficient or even inaccurate. In certain scenarios, the transmission loss plays a fundamental role for accounting, i.e., noise levels and sound propagation between rooms. This paper presents an extension of the absorption boundary conditions known as modified that unifies previously proposed boundary conditions in one equation, including transmission of energy between coupled rooms by both openings and enclosures.


Trust in the Medical Profession Among Adolescents in an Emergency Department.
The aims of this study were to assess trust in the medical profession among adolescents in an urban pediatric emergency department (ED) and explore factors associated with trust. We used a computerized survey to assess personal trust, perceived trust among family/friends, health care use, general and genital examination preferences, health behaviors, and demographics among youth aged 14 to 19 years. The primary outcome was the mean composite score of a validated 5-item scale. Responses were summed (range, 5-25); higher scores indicated greater trust. We compared trust between subgroups using the t test for independent samples. We enrolled 150 adolescents (80% of approached); 146 completed the survey (mean age, 15.6 y; 40% male; 36% African American, 40% white, 17% Hispanic; 29% commercial insurance). The mean trust score was 19.51 ± 3.1 (range, 7-25), indicating a fairly high level of trust. Trust was not associated with race, ethnicity, sex, type of insurance, or health care use. The mean score for those with high paternal trust was higher than those reporting low paternal trust (19.8 ± 2.2 vs 15.3 ± 5.7, P = 0.02); there was no association with perceived trust among mothers or friends. Preference for a chaperoned genital examination was associated with lower trust and female sex. Adolescents in this ED reported high levels of trust in the medical profession, and trust was not associated with race, ethnicity, sex, insurance, or health care use. Youth with lower trust preferred chaperoned genital examinations. Adolescent trust may be influenced by perceived trust among important adults. Exploration of these associations seems warranted to facilitate optimal sexual health outcomes.


Negative life stress and longitudinal hippocampal volume changes in older adults with and without depression.
Major depressive disorder is associated with smaller hippocampal volumes but the mechanisms underlying this relationship are unclear. To examine the effect of environmental influences, we examined the relationship between self-reported stressors and two-year change in hippocampal volume. Seventy elderly nondepressed subjects and eighty-nine elderly depressed subjects were followed for two years. The number of negative stressful life events (nSLE), perceived stress levels, and cranial MRI were obtained at baseline and at the two-year assessment. For secondary analyses, subjects provided blood for 5-HTTLPR polymorphism genotyping. After controlling for covariates including presence or absence of depression, greater numbers of baseline nSLEs were significantly associated with greater baseline hippocampal volumes bilaterally. Greater numbers of baseline nSLEs were also associated with reduction in hippocampal volume over two years in the right but not the left hemisphere. Neither perceived stress levels nor changes in stress measures were significantly associated with hippocampal volume measures. However, in secondary analyses, we found that increases in perceived stress over time was associated with volume reduction of the left hippocampus, but only in 5-HTTLPR L/L homozygotes. Our findings suggest different short- and long-term effects of negative life stressors on hippocampal volumes in older adults. These effects appear independent on the presence or absence of depression. Furthermore, these effects may be moderated by genetic polymorphisms in key neurotransmitter systems. These novel findings have important implications for understanding environmental influences on brain aging.


Connective tissue growth factor induces collagen I expression in human lung fibroblasts through the Rac1/MLK3/JNK/AP-1 pathway.
Connective tissue growth factor (CTGF) plays an important role in lung fibrosis. In this study, we investigated the role of Rac1, mixed-lineage kinase 3 (MLK3), c-Jun N-terminal kinase (JNK), and activator protein-1 (AP-1) in CTGF-induced collagen I expression in human lung fibroblasts. CTGF caused concentration- and time-dependent increases in collagen I expression. CTGF-induced collagen I expression was inhibited by the dominant negative mutant (DN) of Rac1 (RacN17), MLK3DN, MLK3 inhibitor (K252a), JNK1DN, JNK2DN, a JNK inhibitor (SP600125), and an AP-1 inhibitor (curcumin). Treatment of cells with CTGF caused activation of Rac1, MLK3, JNK, and AP-1. The CTGF-induced increase in MLK3 phosphorylation was inhibited by RacN17. Treatment with RacN17 and the MLK3DN inhibited CTGF-induced JNK phosphorylation. CTGF caused increases in c-Jun phosphorylation and the recruitment of c-Jun and c-Fos to the collagen I promoter. Furthermore, stimulation of cells with the CTGF resulted in increases in AP-1-luciferase activity; this effect was inhibited by Rac1N17, MLK3DN, JNK1DN, and JNK2DN. Moreover, CTGF-induced α-smooth muscle actin (α-SMA) expression was inhibited by the procollagen I small interfering RNA (siRNA). These results suggest for the first time that CTGF acting through Rac1 activates the MLK3/JNK signaling pathway, which in turn initiates AP-1 activation and recruitment of c-Jun and c-Fos to the collagen I promoter and ultimately induces collagen I expression in human lung fibroblasts.


Validation of the Critical Care Pain Observation Tool in Critically Ill Patients With Delirium: A Prospective Cohort Study.
The 2013 clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the ICU suggest that pain be routinely assessed using a validated pain assessment tool. Currently available tools have only been evaluated in nondelirious critically ill patients, yet delirium can affect as many as 80% of ICU patients. The validated pain assessment tool adopted by our institution is the Critical Care Pain Observation Tool, and the objective of this study was to investigate the validity of this tool in patients with evidence of delirium. Prospective cohort study. Two ICUs within a Canadian tertiary healthcare center. Forty consecutive adult patients deemed delirious on the day of enrollment using the Confusion Assessment Method for ICU. Serial Critical Care Pain Observation Tool assessments were conducted simultaneously by study personnel and objective nurses at baseline and after nonpainful and painful stimuli. Subjective opinions about pain and objective physical variables (including mean arterial pressure, heart rate, respiratory rate, and oxygen saturation) were collected at the same time points. Discriminant validity was described using paired t tests, whereas internal consistency was described using the Cronbach α statistic. Responsiveness of the Critical Care Pain Observation Tool was measured by effect size, and reliability was described as the agreement between raters. Comparisons between the Critical Care Pain Observation Tool and the subjective assessments and objective measurements were based on positive and negative percent agreement. Critical Care Pain Observation Tool demonstrated excellent discriminant validity as evidenced by a highly statistically and clinically significant change in mean Critical Care Pain Observation Tool scores between baseline and painful procedures (mean difference, 3.13 ± 1.56; p < 0.001; Cohen D, 2.0). Interrater agreement was also excellent (κ > 0.6), and scores between raters were highly correlated (r = 0.957). The Critical Care Pain Observation Tool possessed a high level of internal consistency (overall Cronbach α, 0.778). Percent agreement was found to be greater between the Critical Care Pain Observation Tool and the nurse's subjective opinion of the presence or absence of pain when compared with that between the Critical Care Pain Observation Tool and physiologic variables (80.5% vs 67.5%, respectively). The Critical Care Pain Observation Tool is a valid pain assessment tool in noncomatose, delirious adult ICU patients who are unable to reliably self-report the presence or absence of pain.


Increased expression of mitochondrial glycerophosphate dehydrogenase and antioxidant enzymes in prostate cancer cell lines/cancer.
The involvement of mitochondrial glycerophosphate dehydrogenase (mGPDH) has previously been established in the production of ROS in prostate cancer cell lines (LNCaP, DU145, PC3 and CL1). The current study demonstrates that the mRNA level of mGPDH in prostate cancer cells is 3.3-8.9-fold higher compared to the normal prostate epithelial cell line, PNT1A. This is consistent with the enzymatic activity and protein level of mGPDH. However, cytochrome c oxidase (COX) activity is 2.9-3.2-fold down-regulated in androgen-independent prostate cancer cell lines. The level of antioxidant enzymes, catalase, MnSOD and CuZnSOD are up-regulated in prostate cancer cell lines. Furthermore, it was observed that the activity of mGPDH is significantly higher in liver tissues from all mice with cancer compared to liver tissues from control mice. These data suggest that the up-regulation of mGPDH, due to a highly glycolytic environment, contributes to the overall increase in ROS generation and may result in the progression of the cancer.


Palmitoylethanolamide as adjunctive therapy for autism: Efficacy and safety results from a randomized controlled trial.
Inflammation as well as glutamate excitotoxicity have been proposed to participate in the propagation of autism. Palmitoylethanolamide (PEA) is an endocannabinoid proven to prevent glutamatergic toxicity and inhibit inflammatory responses simultaneously. The present randomized, parallel group, double-blind placebo-controlled trial is the first study depicted to probe the efficacy of co-treatment with risperidone and PEA over 10 weeks in children with autism. Seventy children (aged 4-12 years) with autism and moderate to severe symptoms of irritability were randomly assigned to two treatment regimens. The study outcomes were measured using the Aberrant Behavior Checklist-Community Edition (ABC-C). At trial endpoint (week 10), combination of PEA and risperidone had superior efficacy in ameliorating the ABC-irritability and hyperactivity/noncompliance symptoms (Cohen's d, 95% confidence interval (CI) = 0.94, 0.41 to 1.46, p = 0.001) compared with a risperidone plus placebo regimen. Interestingly, effect of combination treatment on hyperactivity symptoms was also observed at trial midpoint (week 5) but with a smaller effect size (d = 0.53, p = 0.04) than that at the endpoint (d = 0.94, p = 0.001). Meanwhile, there was a trend toward significance for superior effect of risperidone plus PEA over risperidone plus placebo on inappropriate speech at trial endpoint (d = 0.51, p = 0.051). No significant differences existed between the two treatment groups for the other two ABC-C subscales (lethargy/social withdrawal and stereotypic behavior). The findings suggest that PEA may augment therapeutic effects of risperidone on autism-related irritability and hyperactivity. Future studies are warranted to investigate whether PEA can serve as a stand-alone treatment for autism.


MixInYeast: A Multicenter Study on Mixed Yeast Infections.
Invasive candidiasis remains one of the most prevalent systemic mycoses, and several studies have documented the presence of mixed yeast (MY) infections. Here, we describe the epidemiology, clinical, and microbiological characteristics of MY infections causing invasive candidiasis in a multicenter prospective study. Thirty-four centers from 14 countries participated. Samples were collected in each center between April to September 2018, and they were sent to a reference center to confirm identification by sequencing methods and to perform antifungal susceptibility testing, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST). A total of 6895 yeast cultures were identified and MY occurred in 150 cases (2.2%). Europe accounted for the highest number of centers, with an overall MY rate of 4.2% (118 out of 2840 yeast cultures). Of 122 MY cases, the most frequent combinations were Candida albicans/C. glabrata (42, 34.4%), C. albicans/C. parapsilosis (17, 14%), and C. glabrata/C. tropicalis (8, 6.5%). All Candida isolates were susceptible to amphotericin B, 6.4% were fluconazole-resistant, and two isolates (1.6%) were echinocandin-resistant. Accurate identification of the species involved in MY infections is essential to guide treatment decisions.