Effects of Ginkgo biloba on dementia: An overview of systematic reviews.
To assess the cumulative evidence on the efficacy and effectiveness of Ginkgo biloba extract (GbE) in the treatment of dementia. Overview of systematic reviews. PubMed/MEDLINE, EMBASE, Cochrane, and Google Scholar were searched in June 2016. Systematic reviews (SRs) of randomized controlled trials (RCTs) evaluating the effects of GbE on different outcomes in people with dementia or cognitive impairment were included. Methodological quality of the included SRs was assessed using the AMSTAR tool. The quality of evidence of the primary studies was assessed using GRADE. Twelve SRs with meta-analyses met the eligibility criteria. The quality of the evidence reported in these SRs varies ranging from low to moderate level. Overall, the available evidence suggests that GbE has potentially beneficial effects over placebo on cognitive performance, activities of daily living, and clinical global impression in the treatment of dementia at doses greater than 200mg/day (usually 240mg/day) administrated for 22 weeks or longer, and that GbE appears to be safe for human consumption. No sufficient evidence supports the favorable effects of GbE administrated for less than 22 weeks. The available evidence consistently indicates that a dose less than 200mg/day of GbE may not be adequate to yield clinical relevant effects in the treatment of dementia. GbE has potentially beneficial effects for people with dementia when it is administered at doses greater than 200mg/day for at least 5 months. Given the lower quality of the evidence, further rigorously-designed, multicenter-based, large-scale RCTs are warranted.


Cyclic 3',5'-AMP relay in Dictyostelium discoideum III. The relationship of cAMP synthesis and secretion during the cAMP signaling response.
Refinement of a perfusion technique permitted the simultaneous measurement of cAMP-elicited [3H]cAMP secretion and intracellular [3H]cAMP levels in sensitive D. discoideum amoebae. These data were compared with measurements of the rate of [32P]cAMP synthesis by extracts of amoebae sonicated at different times during the cAMP signaling response. cAMP stimulation of intact cells led to a transient activation of adenylate cyclase, which was blocked if 10(-4) M NaN3 was added with the stimulus. During responses elicited by 10(-6) M cAMP, 10(-8) M cAMP, and an increment in cAMP from 10(-8) M to 10(-7) M, the rate of cAMP secretion was proportional to the intracellular cAMP concentration. Removal of a 10(-6) M cAMP stimulus 2 min after the initiation of the response led to a precipitous decline in intracellular cAMP. This decline was more rapid than could be accounted for by secretion alone, suggesting intracellular phosphodiesterase destruction of newly synthesized cAMP. Employing these data and a simple rate equation, estimates of the time-course of the transient activation of adenylate cyclase and the rate constants for cAMP secretion and intracellular phosphodiesterase activity were obtained. The calculated rate of cAMP synthesis rose for approximately 1 to 2 min, peaked, and declined to approach prestimulus levels after 3 to 4 min. This time-course agreed qualitatively with direct measurements of the time-course of activation, indicating that the activation of adenylate cyclase is a major in determining the time-course of the cAMP secretion response.


A Francisella tularensis Schu S4 purine auxotroph is highly attenuated in mice but offers limited protection against homologous intranasal challenge.
Francisella tularensis is a gram-negative coccobacillus that causes the febrile illness tularemia. Subspecies that are pathogenic for humans include those comprising the type A (subspecies tularensis) or type B (subspecies holarctica) biovars. An attenuated live vaccine strain (LVS) developed from a type B isolate has previously been used to vaccinate at-risk individuals, but offers limited protection against high dose (>1000 CFUs) challenge with type A strains delivered by the respiratory route. Due to differences between type A and type B F. tularensis strains at the genetic level, it has been speculated that utilization of an attenuated type A strain as a live vaccine might offer better protection against homologous respiratory challenge compared with LVS. Here, we report the construction and characterization of an unmarked Delta purMCD mutant in the highly virulent type A strain Schu S4. Growth of Schu S4 Delta purMCD was severely attenuated in primary human peripheral blood monocyte-derived macrophages and in the A549 human lung epithelial cell line. The Schu S4 Delta purMCD mutant was also highly attenuated in mice when delivered via either the intranasal or intradermal infection route. Mice vaccinated intranasally with Schu S4 Delta purMCD were well protected against high dose intradermal challenge with virulent type A or type B strains of F. tularensis. However, intranasal vaccination with Schu S4 Delta purMCD induced tissue damage in the lungs, and conferred only limited protection against high dose Schu S4 challenge delivered by the same route. The level of protection observed was similar to that conferred following vaccination with wild-type LVS or the analogous LVS Delta purMCD mutant. Collectively, these results argue that development of the next generation live attenuated vaccine for Francisella should be based on use of the less pathogenic type B biovar rather than the more reactogenic type A biovar.


Operational dynamic modeling transcending quantum and classical mechanics.
We introduce a general and systematic theoretical framework for operational dynamic modeling (ODM) by combining a kinematic description of a model with the evolution of the dynamical average values. The kinematics includes the algebra of the observables and their defined averages. The evolution of the average values is drawn in the form of Ehrenfest-like theorems. We show that ODM is capable of encompassing wide-ranging dynamics from classical non-relativistic mechanics to quantum field theory. The generality of ODM should provide a basis for formulating novel theories.


Acute Changes in Peripheral Vascular Tonus and Systemic Circulation during Static Stretching.
This study aimed to investigate the acute effect of static stretching (SS) on peripheral vascular tonus and to clarify the effect of SS on systemic circulation. Twenty healthy young male volunteers performed a 1-min SS motion of the right triceps surae muscle, repeated five times. The peripheral vascular tonus (|d/a| ratio) was obtained using second derivatives of the photoplethysmogram readings before, during, and after SS. Heart rate and blood pressure (BP) were also measured. The |d/a| ratio and BP were transiently, but significantly, elevated during SS and returned to baseline immediately after SS. Furthermore, we observed a significant correlation between the amount of change in the |d/a| ratio and the ankle range of motion during SS (r = 0.793 to 0.832, P = 0.01). These responses may be caused by mechanical stress during SS.


Prevalence of uncontrolled hypertension in primary care settings in Al seeb wilayat, oman.
This study aimed to estimate the prevalence of uncontrolled hypertension (HTN) among Omani hypertensive patients, on treatment and under primary health care (PHC) follow-up in Al Seeb Wilayat, Oman. Socio-demographic and clinical factors were explored for possible influence on blood pressure (BP) control. Based on an assumption of 50% prevalence of uncontrolled HTN, a retrospective data collection was conducted on the last three follow-up visits of 411 randomly selected Omani adults (≥18 years) from 3,459 hypertensive patients. Adequate BP control was defined using criteria from 7(th) Report of the Joint National Committee on Prevention Detection Evaluation & Treatment of High Blood Pressure (JNC-7). A P value of <0.05 and odds ratios with 95% confidence interval were used to assess for association. The targets for adequate BP control were achieved in 39% of the studied patients (95% confidence interval [CI]: 34-44%). Lower BP control was found among hypertensives with diabetes (6.4%, P = <0.001) and renal disease (18.5%, P = 0.02); those with cardiovascular disease (CVD) showed relatively better control (58%). Age and gender had no impact on BP control. Most patients were only on one (24%) or two (47%) antihypertensive medications, the most frequently used being β-blockers (58.2%) and diuretics (56.3%). HTN is not adequately controlled in over 60% of treated patients; the presence of co-morbidity and less than aggressive treatment are significant contributors. Improving the quality of HTN care is a priority; effective efforts should be undertaken to improve BP control.


Incorporating a Spatial Prior into Nonlinear D-Bar EIT Imaging for Complex Admittivities.
Electrical Impedance Tomography (EIT) aims to recover the internal conductivity and permittivity distributions of a body from electrical measurements taken on electrodes on the surface of the body. The reconstruction task is a severely ill-posed nonlinear inverse problem that is highly sensitive to measurement noise and modeling errors. Regularized D-bar methods have shown great promise in producing noise-robust algorithms by employing a low-pass filtering of nonlinear (nonphysical) Fourier transform data specific to the EIT problem. Including prior data with the approximate locations of major organ boundaries in the scattering transform provides a means of extending the radius of the low-pass filter to include higher frequency components in the reconstruction, in particular, features that are known with high confidence. This information is additionally included in the system of D-bar equations with an independent regularization parameter from that of the extended scattering transform. In this paper, this approach is used in the 2-D D-bar method for admittivity (conductivity as well as permittivity) EIT imaging. Noise-robust reconstructions are presented for simulated EIT data on chest-shaped phantoms with a simulated pneumothorax and pleural effusion. No assumption of the pathology is used in the construction of the prior, yet the method still produces significant enhancements of the underlying pathology (pneumothorax or pleural effusion) even in the presence of strong noise.


Lipid-based nanovesicles for nanomedicine.
Molecular self-assembly has enabled the fabrication of biologically inspired, advanced nanostructures as lipid-based nanovesicles (L-NVs). The oldest L-NVs, liposomes, have been widely proposed as potential candidates for drug delivery, diagnostic and/or theranostic applications and some liposome-based drug products have already stepped from the lab-bench to the market. This success is attributed to their ability to encapsulate both hydrophobic and/or hydrophilic molecules, efficiently carry and protect them within the body and finally deliver them at the target site. These positive features are also coupled with high biocompatibility. However, liposomes still present some unsolved drawbacks, such as poor colloidal stability, short shelf-life, restricted and expensive conditions of preparation because of the inherent nature of their fundamental constituents (phospholipids). The new tools available in the self-assembly of controlled molecules have significantly advanced the field of L-NV design and synthesis, and non-liposomal L-NVs have been recently developed; this new generation of nanovesicles can represent a paradigm shift in nanomedicine: they may complement liposomes, showing their advantages and overcoming most of their drawbacks. Clearly, being still young, their rocky way to the clinic first and then to the market has just started and it is still long, but they have all the potentialities to reach their objective target. The purpose of this review is to first present the large plethora of L-NVs available, focusing on this new generation of non-liposomal L-NVs and showing their similarities and differences with respect to their ancestors (liposomes). Since the overspread of a nanomaterial to the market is also strongly dependent on the availability of technological-scale preparation methods, we will also extensively review the current approaches exploited for L-NV production. The most cutting-edge approaches based on compressed fluid (CF) technologies will be highlighted here since they show the potential to represent a game-change in the production of L-NVs, favouring their step from the bench to the market. Finally, we will briefly discuss L-NV applications in nanomedicine, looking also for their future perspectives.


Behavioral, computational, and neuroimaging studies of acquired apraxia of speech.
A critical examination of speech motor control depends on an in-depth understanding of network connectivity associated with Brodmann areas 44 and 45 and surrounding cortices. Damage to these areas has been associated with two conditions-the speech motor programming disorder apraxia of speech (AOS) and the linguistic/grammatical disorder of Broca's aphasia. Here we focus on AOS, which is most commonly associated with damage to posterior Broca's area (BA) and adjacent cortex. We provide an overview of our own studies into the nature of AOS, including behavioral and neuroimaging methods, to explore components of the speech motor network that are associated with normal and disordered speech motor programming in AOS. Behavioral, neuroimaging, and computational modeling studies are indicating that AOS is associated with impairment in learning feedforward models and/or implementing feedback mechanisms and with the functional contribution of BA6. While functional connectivity methods are not yet routinely applied to the study of AOS, we highlight the need for focusing on the functional impact of localized lesions throughout the speech network, as well as larger scale comparative studies to distinguish the unique behavioral and neurological signature of AOS. By coupling these methods with neural network models, we have a powerful set of tools to improve our understanding of the neural mechanisms that underlie AOS, and speech production generally.


Evidence insufficient to confirm the value of population screening for diabetes and hypertension in low- and-middle-income settings.
To assess the evidence from systematic reviews on the effect on morbidity and mortality of blanket screening for hypertension or diabetes mellitus compared with targeted, opportunistic or no screening, we searched for relevant systematic reviews and conducted duplicate study selection, data extraction and quality appraisal. Results were summarised narratively. We included two completed reviews of moderate quality and one ongoing Cochrane review. In one completed review, general health checks had no effect on total morbidity or mortality or on healthcare services compared with no health checks. In the other, intensive hypertension screening methods were ineffective in increasing screening uptake or detecting new cases compared with less intensive methods. Both reviews included studies in high-income settings. There is insufficient evidence from currently available systematic reviews to confirm a beneficial effect of blanket screening for hypertension and/or diabetes compared with other types of screening methods in low- and middle-income settings. Scarce resources are being mobilised to implement mass screening intervention for diabetes and hypertension without adequate evidence of its effects. A systematic review is needed to assess clinical effectiveness, cost-effectiveness and overall impact on the health system of screening strategies, especially in low- and middle-income settings such as exist in South Africa. Robust evaluation of these outcomes would then be necessary to inform secondary prevention strategies.


Paget disease of bone.
Paget disease of bone (PD) is characterized by excessive bone resorption in focal areas followed by abundant new bone formation, with eventual replacement of the normal bone marrow by vascular and fibrous tissue. The etiology of PD is not well understood, but one PD-linked gene and several other susceptibility loci have been identified, and paramyxoviral gene products have been detected in pagetic osteoclasts. In this review, the pathophysiology of PD and evidence for both a genetic and a viral etiology for PD will be discussed.


Substrate utilization by the failing human heart by direct quantification using arterio-venous blood sampling.
Metabolic substrate utilization of the human failing heart is an area of controversy. The purpose of this study is to directly quantify myocardial substrate utilization in moderately severe heart failure, type 2 diabetes and healthy controls using simultaneous coronary sinus and arterial blood sampling. Patients with heart failure (n = 9, mean NYHA 2.7+/-0.5), with type 2 diabetes (n = 5) and with normal heart function (n = 10) were studied after an overnight fast in connection with electrophysiological investigations/treatments.A systemic infusion of [(2)H(2)]palmitate allowed for the calculation of absolute palmitate extraction across the heart. Blood samples were analysed for non-esterified fatty acids, triacylglycerol, glycerol, glucose, pyruvate, lactate, 3-hydroxybutyrate, and blood gases after simultaneous sampling of arterial and coronary sinus blood. Arterio-coronary sinus metabolite concentration differences and fractional extractions for all substrates were similar between the groups. The absolute NEFA uptakes assessed by [(2)H(2)]palmitate extraction were also similar between the groups. Using direct measurements of metabolic substrate uptake by arterio-venous difference technique, the compensated human failing heart does not appear to have reduced myocardial fatty acid uptake.


Single-cell RNA-seq reveals a concomitant delay in differentiation and cell cycle of aged hematopoietic stem cells.
Hematopoietic stem cells (HSCs) are the guarantor of the proper functioning of hematopoiesis due to their incredible diversity of potential. During aging, heterogeneity of HSCs changes, contributing to the deterioration of the immune system. In this study, we revisited mouse HSC compartment and its transcriptional plasticity during aging at unicellular scale. Through the analysis of 15,000 young and aged transcriptomes, we identified 15 groups of HSCs revealing rare and new specific HSC abilities that change with age. The implantation of new trajectories complemented with the analysis of transcription factor activities pointed consecutive states of HSC differentiation that were delayed by aging and explained the bias in differentiation of older HSCs. Moreover, reassigning cell cycle phases for each HSC clearly highlighted an imbalance of the cell cycle regulators of very immature aged HSCs that may contribute to their accumulation in an undifferentiated state. Our results establish a new reference map of HSC differentiation in young and aged mice and reveal a potential mechanism that delays the differentiation of aged HSCs and could promote the emergence of age-related hematologic diseases.


Self-reported Sleep Quality and Bone Outcomes in Older Adults: Findings from the Hertfordshire Cohort Study.
Sleep duration may be associated with risk of osteoporosis, with suggestions that too little or indeed too much sleep may be detrimental to bone health. In this study, we considered whether perceived sleep quality is also associated with bone health in older adults. We explored this association in a cohort of 443 older community-dwelling UK adults. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI); poor sleep quality was defined as > 5 on this score system. Bone density, shape and microarchitecture were assessed using dual energy X-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT) and high-resolution pQCT (HRpQCT). Thirty-seven percent of men and 43% of women had a PSQI score greater than 5, indicative of poor perceived sleep. We found that quality of sleep was associated with altered bone microarchitecture. In men, poor sleep quality was associated with lower radial trabecular (4% slice, p < 0.04) and cortical (66% slice, p = 0.02) bone mineral density, as well as decreased tibial cortical density (p < 0.02) and increased porosity (p < 0.04), but increased size of the tibia (p < 0.04). In women, poor perceived sleep quality was associated with thinner (p < 0.03) and less dense (p < 0.04) cortices of the radius, but greater tibial trabecular number (p < 0.02) and lower separation (p < 0.04). Relationships with DXA parameters were non-significant after adjustment for confounders. Taking sleep medications was associated with decreased tibial size (38% and 66% slices) and strength in women (all p < 0.05), but not in men. Perceived sleep quality was associated with altered bone density and microarchitecture in older adults, and these differences varied according to biological sex and site. Further work is indicated to investigate possible mechanisms underlying these observations.


Developing role models in clinical settings: A qualitative study of medical students, residents and clinical teachers.
To explore how positive role modelling attributes can be developed in students, residents and clinical teachers. The qualitative study using focus group discussions was held at Aga Khan University, Karachi from March to May 2018, and comprised medical students, residents and clinical teachers. Overall 11 focus group discussions were conducted till data saturation was achieved. Content analysis was used to analyse the data which was transcribed verbatim. Of the 116 subjects, 60(51.7%) were medical students, 35(30.2%) were residents and 21(18%) were clinical teachers. Of the 11 focus group discussions, 4(36.5%) each were held with the students and the residents, while 3(27%) were held with the teachers. Five major themes that emerged from the study included definition of role models, attributes of role models, role modelling as a learnt behaviour, challenges in developing role models, and recommendations for developing positive role models. A number of attributes of positive and negative role models were identified by the participants. All the participants including students, residents and teachers appreciated the importance of role modelling in developing professionalism among health professionals and medical students. Factors hindering development and demonstration of positive role modelling were also identified and possible solutions were suggested. Clinical teachers needed to be made cognizant of their role as positive role models in developing professionally competent physicians. The medical institutions needed to develop and implement policies that would enhance positive role modelling by the teachers and facilitate learning of positive attributes at all levels.


Geometrical renormalization approach to calculating optical properties of fractal carbonaceous soot.
We develop a theoretical approach to calculating optical properties of carbonaceous soot in the long-wavelength limit. Our method is based on geometrical renormalization of clusters; it avoids both the inaccuracy of the dipole approximation in its pure form and the numerical complexity of rigorous direct methods of solving the EM boundary problem. The results are verified by comparison with the experimental measurements for specific extinction of diesel soot in the spectral region from 0.488 microm to 0.857 cm that were performed by Bruce et al. [Appl. Opt. 30, 1537 (1991)]. The theory leads to analytical expressions that are applicable to different soots, with various geometrical properties and optical constants. We show that the functional form of the long-wavelength asymptote of the specific extinction can depend critically on a parameter characterizing the sample geometry, and we identify the critical value of this parameter.


Physician-patient communication following invasive procedures: an analysis of post-angiogram consultations.
Although rarely studied, physician-patient interactions immediately following diagnostic tests are significant medical events because during these encounters the physician and patient often make decisions about major and sometimes invasive treatment. This investigation analyzed patterns of physician-patient communication following coronary angiography with particular attention to behaviors important to decision-making: physician information-giving, physician use of partnership-building, and active forms of patient participation (e.g., asking questions, being assertive, expressing concerns). We were particularly interested in effects related to the patient's race in light of documented evidence of racial disparities in cardiac care and outcomes. From audiotape recordings, 93 physician-patient interactions after coronary angiogram in a catheterization laboratory in a large US Veterans Affairs Medical Center were coded to measure the frequency of physicians' information-giving and partnership-building and the frequency of active patient participation. We also stratified these behaviors according to whether the behavior was prompted (e.g., physician information in response to a patient's question; a patient's opinion solicited by the doctor) or self-initiated. Several findings were noteworthy. First, these interactions were very brief and dominated by the physician. Second, although physician information-giving increased with more active patient participation, which in turn was correlated with physicians' use of partnership-building, proportionally little of the physicians' information (8%) and active patient participation (9%) was directly prompted by the other interactant. Finally, there was a tendency for physicians to self-initiate less information giving to black patients and for black patients to self-initiate less active participation than white patients. Although these differences were attenuated when other variables (e.g., the physician's training, disease severity) were included in the analysis, the pattern suggests a potential cycle of passivity where certain patients tend to receive fewer informational resources and these patients in turn do less to prompt the doctor for more.


Further evidence for the impact of a genome-wide-supported psychosis risk variant in ZNF804A on the Theory of Mind Network.
The single-nucleotide polymorphism (SNP) rs1344706 in ZNF804A is one of the best-supported risk variants for psychosis. We hypothesized that this SNP contributes to the development of schizophrenia by affecting the ability to understand other people's mental states. This skill, commonly referred to as Theory of Mind (ToM), has consistently been found to be impaired in schizophrenia. Using functional magnetic resonance imaging, we previously showed that in healthy individuals rs1344706 impacted on activity and connectivity of key areas of the ToM network, including the dorsomedial prefrontal cortex, temporo-parietal junction, and the posterior cingulate cortex, which show aberrant activity in schizophrenia patients, too. We aimed to replicate these results in an independent sample of 188 healthy German volunteers. In order to assess the reliability of brain activity elicited by the ToM task, 25 participants performed the task twice with an interval of 14 days showing excellent accordance in recruitment of key ToM areas. Confirming our previous results, we observed decreasing activity of the left temporo-parietal junction, dorsomedial prefrontal cortex, and the posterior cingulate cortex with increasing number of risk alleles during ToM. Complementing our replication sample with the discovery sample, analyzed in a previous report (total N=297), further revealed negative genotype effects in the left dorsomedial prefrontal cortex as well as in the temporal and parietal regions. In addition, as shown previously, rs1344706 risk allele dose positively predicted increased frontal-temporo-parietal connectivity. These findings confirm the effects of the psychosis risk variant in ZNF804A on the dysfunction of the ToM network.


Temperature rises during application of Er:YAG laser under different primary dentin thicknesses.
The present study investigated the effects of the Er:YAG laser's different pulse repetition rates on temperature rise under various primary dentin thicknesses. The Er:YAG laser can be used for restorative approaches in clinics and is used to treat dental caries. There are some reports that explain the temperature rise effect of the Er:YAG laser. Recently, the Er:YAG laser has been found to play an important role in temperature rises during the application on dentin. Caries-free primary mandibular molars were prepared to obtain dentin discs with 0.5, 1, 1.5, and 2 mm thicknesses (n=10). These discs were placed between the Teflon mold cylinders of a temperature test apparatus. We preferred three pulse repetition rates of 10, 15, and 20 Hz with an energy density of 12.7 J/cm2 and a 230 μs pulse duration. All dentin discs were irradiated for 30 sec by the Er:YAG laser. Temperature rises were recorded using an L-type thermocouple and universal data loggers/scanners (E-680, Elimko Co., Turkey). Data were analyzed by two-way ANOVA and Tukey tests. Whereas the lowest temperature rise (0.44±0.09 °C) was measured from a 10 Hz pulse repetition rate at a dentin thickness of 2 mm, the highest temperature rise (3.86±0.43 °C) was measured from a 20 Hz pulse repetition rate at a 0.5 mm dentin thickness. Temperature rise did not reach critical value for pulpal injury in any primary dentin thicknesses irradiated by a high repetition rate of the Er:YAG laser.


Effect of Initial Bedside Ultrasonography on Emergency Department Skin and Soft Tissue Infection Management.
We examine the utility of emergency department (ED) ultrasonography in treatment of skin and soft tissue infections. We enrolled ED patients with skin and soft tissue infections and surveyed clinicians in regard to their pre-ultrasonography certainty about the presence or absence of an abscess, their planned management, post-ultrasonography findings, and actual management. We determined sensitivity and specificity of ultrasonography and clinical evaluation, and assessed appropriateness of management changes based on initial clinical assessment and outcomes through 1-week follow-up. Among 1,216 patients, clinicians were uncertain of abscess presence in 105 cases (8.6%) and certain for 1,111 cases (91.4%). Based on surgical exploration and follow-up through 1 week, sensitivity and specificity for abscess detection by clinical evaluation were 90.3% and 97.7%, and by ultrasonography were 94.0% and 94.1%, respectively. Among 1,111 cases for which the clinician was certain, sensitivity and specificity of clinical evaluation were 96.6% and 97.3% compared with ultrasonographic evaluation sensitivity and specificity of 95.7% and 96.2%, respectively. Of 105 uncertain cases, sensitivity and specificity of ultrasonography were 68.5% and 80.4%. Ultrasonography changed management in 13 of 1,111 certain cases (1.2%), appropriately in 10 of 13 (76.9%) and inappropriately in 3 of 13 (23.1%). Of 105 uncertain cases, ultrasonography changed management in 25 (23.8%), appropriately in 21 of 25 (84.0%) and inappropriately in 4 of 25 (16.0%). Ultrasonography rarely changed management when clinicians were certain about the presence or absence of an abscess. When they were uncertain, ultrasonography changed drainage decisions in approximately one quarter of cases, of which most (84%) were appropriate.


Occupational exposure and amyotrophic lateral sclerosis in a prospective cohort.
To prospectively study suspected occupational risk factors for amyotrophic lateral sclerosis (ALS). For this case-cohort analysis within the prospective Netherlands Cohort Study, 58 279 men and 62 573 women aged 55-69 years at enrolment in 1986 were followed up for 17.3 years on ALS mortality. Information on occupational history and potential confounders were collected at baseline through a self-administered questionnaire and entered for a random subcohort (2092 men and 2074 women) and ALS deaths (76 men and 60 women). Occupational exposure to solvents, pesticides, metals, extremely low frequency magnetic fields (ELF-MFs) and electrical shocks was estimated by means of job exposure matrices (JEMs). Associations between ever/never occupationally exposed and cumulative exposure and ALS mortality were analysed by gender using Cox regression. Occupational exposure to ELF-MF showed a possible association with ALS mortality among men: HR for ever holding a job with high exposure versus background 2.19 (95% (CI): 1.02 to 4.73) and HR for the highest tertile of cumulative exposure versus background 1.93 (95% CI 1.05 to 3.55). These results strengthen the evidence suggesting a positive association between ELF-MF exposure and ALS. We did not replicate earlier positive findings for other occupational exposures.


Recurrent spontaneous Escherichia coli meningitis in an adult: a case report.
The aim of this study was to characterize an unusual case of spontaneous, community-acquired Escherichia coli meningitis in an adult presenting to a general hospital in Kenya, where initial clinical recovery was followed by reinfection with an MDR, hospital-acquired strain. An adult presented to a hospital in Kenya with meningitis symptoms. E. coli was cultured from CSF. Treatment with ceftriaxone was successful; however, the patient relapsed a few days later. E. coli was cultured from CSF and blood during the reinfection episode, though the patient died during admission. We sequenced the isolates using Illumina MiSeq and performed antimicrobial susceptibility testing, fitness and virulence assays on the bacteria. The E. coli isolates from the two episodes were found to be distinct: the initial strain was ST88, serotype O8 H17 while the subsequent episode was caused by an ST167, serotype O101 H5 MDR strain. The ST88 strain was susceptible to all drugs except ampicillin and amoxicillin/clavulanate while the ST167 strain was MDR, including to all β-lactam drugs due to the presence of the carbapenemase gene bla NDM-5. The hospital-acquired ST167 strain was also resistant to newer drugs such as cefiderocol and eravacycline, which are currently not available locally, and had overall lower fitness and virulence in vitro compared with the initial infecting strain. Though less fit and virulent in vitro, the MDR strain was fatal, suggesting that host factors, rather than bacterial virulence, may have been of greater importance in this patient's outcome.


Combining chemodescriptors and biodescriptors in quantitative structure-activity relationship modeling.
In view of the wide distribution of halocarbons in our world, their toxicity is a public health concern. Previous work has shown that various measures of toxicity can be predicted with standard molecular descriptors. In our work, biodescriptors of the effect of halocarbons on the liver were obtained by exposing hepatocytes to 14 halocarbons and a control and by producing two-dimensional electrophoresis gels to assess the expressed proteome. The resulting spot abundances provide additional biological information that might be used in toxicity prediction. QSAR models were fitted via ridge regression to predict eight dependent toxicity measures: d37, arr, EC50MTT, EC50LDH, EC20SH, LECLP, LECROS, and LECCAT. Three predictor sets were used for each-the chemodescriptors alone, the biodescriptors alone, and the combined set of both chemo- and biodescriptors. The results differed somewhat from one dependent to another, but overall it was shown that better results could be obtained by using both chemo- and biodescriptors in the model than by using either chemo- or biodescriptors alone. The library of compounds used was small and quite homogeneous, so our immediate conclusions are correspondingly limited in scope, but we believe the underlying methodologies have broad applicability at the interface of chemical and biological descriptors.


Bovine calves as ideal bio-indicators for fluoridated drinking water and endemic osteo-dental fluorosis.
Relative susceptibility to fluoride (F) toxicosis in the form of osteo-dental fluorosis was observed in an observational survey of 2,747 mature and 887 immature domestic animals of diverse species living in areas with naturally fluoridated (>1.5 ppm F) drinking water. These animals included buffaloes (Bubalus bubalis), cattle (Bos taurus), camels (Camelus dromedarius), donkeys (Equus asinus), horses (Equus caballus), goats (Capra hircus), and sheep (Ovis aries). Of these mature and immature animals, 899 (32.7 %) and 322 (36.3 %) showed evidence of dental fluorosis with varying grades, respectively. Their incisor teeth were stained with light to deep brownish color. On clinical examination, 31.2 % mature and 10.7 % immature animals revealed periosteal exostoses, intermittent lameness, and stiffness of tendons in the legs as signs of skeletal fluorosis. The maximum susceptibility to fluoride toxicosis was found in bovines (buffaloes and cattle) followed by equines (donkeys and horses), flocks (goats and sheep), and camelids (camels). The bovine calves were found to be more sensitive and highly susceptible to F toxicosis and revealed the maximum prevalence (92.2 %) of dental fluorosis. This indicates that bovine calves are less tolerant and give early sign of F poisoning (dental fluorosis) and therefore, they can be considered as bio-indicators for fluoridated water as well as for endemicity of osteo-dental fluorosis. Causes for variation in susceptibility to F toxicosis (fluorosis) in various species of domestic animal are also discussed.


Blood α-tocopherol, γ-tocopherol levels and risk of prostate cancer: a meta-analysis of prospective studies.
Epidemiological studies that have examined the association of blood α-tocopherol and γ-tocopherol (the principal bioactive form of vitamin E) levels with the risk of prostate cancer have yielded inconsistent results. In addition, a quantitative assessment of published studies is not available. In this meta-analysis, relevant studies were sought by a search of the PubMed and Embase databases for articles published up to October 2013, with no restrictions. Bibliographies from retrieved articles also were scoured to find further eligible studies. Prospective studies that reported adjusted relative risk (RR) estimates with 95% confidence intervals (CIs) for the association between blood tocopherol levels and the risk of prostate cancer were included. Nine nested case-control studies involving approximately 370,000 participants from several countries were eligible. The pooled RRs of prostate cancer for the highest versus lowest category of blood α-tocopherol levels were 0.79 (95% CI: 0.68-0.91), and those for γ-tocopherol levels were 0.89 (95% CI: 0.71-1.12), respectively. Significant heterogeneity was present among the studies in terms of blood γ-tocopherol levels (p = 0.008) but not in terms of blood α-tocopherol levels (p = 0.33). The risk of prostate cancer decreased by 21% for every 25-mg/L increase in blood α-tocopherol levels (RR: 0.79; 95% CI: 0.69-0.91). Blood α-tocopherol levels, but not γ-tocopherol levels, were inversely associated with the risk of prostate cancer in this meta-analysis.


Low vitamin D levels predict clinical features of schizophrenia.
Vitamin D plays crucial roles in neuroprotection and neurodevelopment, and low levels are commonly associated with schizophrenia. We considered if the association was spurious or causal by examining the association of Vitamin D with Leukocyte Telomere Length (LTL), a marker of cellular aging. Vitamin D levels in 22 well-characterized schizophrenia cases were examined with respect to symptoms, cognition, and functioning. LTL was assessed using quantitative polymerase chain reaction (qPCR). The results showed that 91% (20) had deficient or insufficient Vitamin D levels, which were associated with excitement and grandiosity, social anhedonia, and poverty of speech. Sex-specific analyses showed strong associations of hypovitamintosis D to negative symptoms and decreased premorbid adjustment in males, and to lesser hallucinations and emotional withdrawal, but increased anti-social aggression in females. In females LTL was furthermore associated with Vitamin D levels. This study demonstrates a relationship of low vitamin D levels with increased cellular aging in females. It is also the first study to demonstrate potential sex-specific profiles among schizophrenia cases with hypovitaminosis.


Up-regulation of serum miR-4262 predicts clinical outcome of patients with acute myeloid leukemia.
The aim of this study was to investigate whether miR-4262 was associated with the prognosis of acute myeloid leukemia (AML) patients. Serum and bone marrow miR-4262 expression were investigated in 186 AML patients and 115 healthy normal controls by using Real-time PCR. Associations between miR-4262 expressions and various clinicopathological characteristics were analyzed. Overall survival and relapse-free survival were evaluated using the Kaplan-Meier method. Univariate and multivariate analysis were performed using the Cox proportional hazard analysis. Expression levels of miR-4262 in the bone marrow and serum of AML patients were both significantly higher than those in healthy controls (both p<0.01). Moreover, increased miR-4262 expression was significantly associated with FAB classification (p=0.001) and cytogenetics (p=0.001). Patients with high miR-4262 expression had poorer overall survival time and relapse-free survival time than those with low miR-4262 expression. Finally, multivariate analysis identified high miR-4262 expression as an independent prognostic factor for AML (p<0.001). Our data revealed that the evaluation of miR-4262 expression in the bone marrow and serum was an ideal tool for predicting the progression of AML and prognosis.


Prion protein codon 129 polymorphism in mild cognitive impairment and dementia: the Rotterdam Study.
Creutzfeldt-Jakob disease is a rare, fatal, neurodegenerative disease caused by the accumulation of abnormally folded prion proteins. The common polymorphism at codon 129 (methionine/valine) in the prion protein (PRNP) gene is the most important determinant of genetic susceptibility. Homozygotes of either allele have a higher risk of sporadic Creutzfeldt-Jakob disease. Various studies suggest that this polymorphism is also involved in other forms of dementia. We studied the association between the codon 129 polymorphism of the PRNP gene and mild cognitive impairment in 3605 participants from the Rotterdam Study using logistic regression analyses. Subsequently, we studied the association between this polymorphism and incident dementia, including Alzheimer's disease, in 11 070 participants using Cox proportional hazard models. Analyses were adjusted for age and sex. We found the prevalence of mild cognitive impairment to be higher for carriers of the methionine/methionine genotype (odds ratio, 1.40; 95% confidence interval, 1.11-1.78; P = 0.005) as well as for carriers of the valine/valine genotype (odds ratio, 1.37; 95% confidence interval, 0.96-1.97; P = 0.08). The codon 129 polymorphism was not associated with the risk of incident dementia or Alzheimer's disease. In conclusion, we found a statistically significant higher prevalence of mild cognitive impairment in carriers of the methionine/methionine genotype in the codon 129 polymorphism of the PRNP gene within this population-based study. No associations were found between the codon 129 polymorphism and dementia or Alzheimer's disease in the general population.


Simultaneous observation of surface- and edge-states of a 2D topological insulator through scanning tunneling spectroscopy and differential conductance imaging.
A 2D form of Bi2Se3 which acts as a topological insulator was grown through colloidal synthesis method. The surface-states and edge-states of the nanoplates were simultaneously probed through scanning tunneling spectroscopy (STS). At the interior, density of states (DOS) revealed the location of conduction and valence band edges. The DOS at the edges, on the other hand, brought out gapless conducting states along with a Dirac point at a non-zero value below the Fermi energy representing the Dirac cone of a 2D topological insulator. In differential tunnel conductance (dI/dV), images are recorded at different voltages and the two sections of the topological insulator can be viewed selectively or simultaneously with a clear contrast in illumination. Upon increasing the 2D-nanoplates thickness, the material turned into a 3D topological insulator with gapless surface states.


Efficacy and safety of abatacept in routine care of patients with rheumatoid arthritis: Orencia(®) as Biological Intensive Treatment for RA (ORBIT) study.
To investigate the efficacy and safety of abatacept for treating patients with rheumatoid arthritis (RA) in routine clinical practice. We performed a retrospective study of 137 RA patients who were treated with abatacept for 24 weeks between October 2010 and June 2011 at four rheumatology centers in Japan. Outcomes were compared between biologic-naïve and biologic-experienced patients. Disease activity was assessed using the Simplified Disease Activity Index (SDAI) and the 28-joint Disease Activity Score based on the erythrocyte sedimentation rate (DAS28-ESR). The retention rate of abatacept at 24 weeks was 79.6%. SDAI (from 24.6 ± 12.5 to 12.9 ± 11.6) and DAS28-ESR (from 5.2 ± 1.4 to 3.9 ± 1.4) decreased significantly from baseline to Week 24 (both P < 0.001). Remission/low disease activity were achieved in 2.2%/11.2% (SDAI) and in 5.3%/2.3% (DAS28-ESR). The change in SDAI and the remission/low disease activity rates at Week 24 was greater in biologic-naïve patients than in biologic-experienced patients. Structural remission (van der Heijde-modified total Sharp score ≤ 0.5) was achieved by 63.4% of patients. The present results confirm that abatacept is effective in routine clinical practice and support its use as the first-line biologic agent in patients.


Thermodynamic cycles of the alkali metal-ligand complexes central to electride formation.
Alkali metal-ligand complexes are the building blocks of the exotic organic alkalide and electride materials. In this work, density-functional theory is used to construct thermodynamic cycles for the alkali metal-ligand complexes, highlighting the energy changes that enable alkalide and electride formation. Strong alkali metal- and cation-to-ligand binding energies are predicted and Rydberg-like ground states of the alkali metal-ligand complexes are identified, consistent with previous work. Calculations on molecular electride species do not reveal consistency with the identified trends, suggesting that the molecular electrides are a class of material unto themselves. The ionisation potentials of the alkali metal-ligand complexes are calculated to be consistently between 1 and 2 eV, suggesting that a specific ionisation potential (IP) is central to electride formation. Further, the thermodynamic cycle for the simplest electride, Cs+(15C5)2e-, shows stabilisation of the solid crystal due to electride formation that is consistent in magnitude with the IP of the equivalent alkali metal-ligand complex. In light of this, computational screening of the alkali metal-ligand complexes' IP presents a new design criterion for alkalide and electride materials.


Evolution of a modular software network.
"Evolution behaves like a tinkerer" (François Jacob, Science, 1977). Software systems provide a singular opportunity to understand biological processes using concepts from network theory. The Debian GNU/Linux operating system allows us to explore the evolution of a complex network in a unique way. The modular design detected during its growth is based on the reuse of existing code in order to minimize costs during programming. The increase of modularity experienced by the system over time has not counterbalanced the increase in incompatibilities between software packages within modules. This negative effect is far from being a failure of design. A random process of package installation shows that the higher the modularity, the larger the fraction of packages working properly in a local computer. The decrease in the relative number of conflicts between packages from different modules avoids a failure in the functionality of one package spreading throughout the entire system. Some potential analogies with the evolutionary and ecological processes determining the structure of ecological networks of interacting species are discussed.


Sexually transmitted infections and risk behaviours in women who have sex with women.
To assess the prevalence of sexually transmitted infections (STIs) and blood borne viruses, risk behaviours, and demographics in women who have sex with women (WSW). Retrospective cross sectional study using a multivariate model. Demographic, behavioural, and morbidity data were analysed from standardised medical records of patients attending a public STI and HIV service in Sydney between March 1991 and December 1998. All women with any history of sex with a woman were compared with women who denied ever having sex with another woman (controls). 1408 WSW and 1423 controls were included in the study. Bacterial vaginosis (BV) was significantly more common among WSW (OR 1.7, p < 0.001). Abnormalities on cervical cytology were equally prevalent in both groups, except for the higher cytological BV detection rate in WSW (OR 5.3, p = 0.003). Genital herpes and genital warts were common in both groups, although warts were significantly less common in WSW (OR 0.7, p = 0.001). Prevalence of gonorrhoea and chlamydia were low and there were no differences between the groups. The prevalence of hepatitis C was significantly greater in WSW (OR 7.7, p < 0.001), consistent with the more frequent history of injecting drug use in this group (OR 8.0, p < 0.001). WSW were more likely to report previous sexual contact with a homo/bisexual man (OR 3.4, p < 0.001), or with an injecting drug user (OR 4.2, p < 0.001). Only 7% of the WSW reported never having had sexual contact with a male. We demonstrated a higher prevalence of BV, hepatitis C, and HIV risk behaviours in WSW compared with controls. A similar prevalence of cervical cytology abnormalities was found in both groups. Measures are required to improve our understanding of STI/HIV transmission dynamics in WSW, to facilitate better health service provision and targeted education initiatives.


No superoxide dismutase activity of cellular prion protein in vivo.
Prion diseases are characterized by the deposition of PrP(Sc), an abnormal form of the cellular prion protein PrP(C), which is encoded by the Prnp gene. PrP(C) is highly expressed on neurons and its function is unknown. Recombinant PrP(C) was claimed to possess superoxide dismutase (SOD) activity, and it was hypothesized that abrogation of this function may contribute to neurodegeneration in prion diseases. We tested this hypothesis in vivo by studying copper/zinc and manganese SOD activity in genetically defined crosses of mice lacking the Sod1 gene with mice lacking PrP(C), and with hemizygous or homozygous tga20 transgenic mice overexpressing various levels of PrP(C). We failed to detect any influence of the Prnp genotype and gene dosage on SOD1 or SOD2 activity in heart, spleen, brain, and synaptosome-enriched brain fractions. Control experiments included crosses of mice lacking or overexpressing PrPc with mice overexpressing human Cu2+/Zn2+-superoxide dismutase, and confirmed that SOD enzymatic activity correlated exclusively with the gene dosage of bona fide human or murine SOD. We conclude that PrP(C) in vivo does not discernibly contribute to total SOD activity and does not possess an intrinsic dismutase activity.


[Environmental primary care for the 21st century].
Primary environmental care combines the original strategy proclaimed at Alma-Ata as primary health care and the conception of integral rural development that emerged from the agrarian policies of Third World countries during the seventies. Within the renewed goal of health for all in the 21st century, the primary environmental care strategy may be considered as all those actions necessary to improve and protect the local surroundings through foresight and prevention of possible problems, with tasks institutionalized at the local level. Analysis and practice of this strategy are based on a model focused on the promotion of human beings, the environment, and social development. Furthermore, it is founded on critical theory and has a holistic perspective. This operational frame encourages participation and action, thus endowing individuals, communities, and societies with the power to make decisions. In this way, leadership is created for the sustainable development of nations.


Induction of epitope-specific neutralizing antibodies against West Nile virus.
Previous studies have established that an epitope on the lateral ridge of domain III (DIII-lr) of West Nile virus (WNV) envelope (E) protein is recognized by strongly neutralizing type-specific antibodies. In contrast, an epitope against the fusion loop in domain II (DII-fl) is recognized by flavivirus cross-reactive antibodies with less neutralizing potential. Using gain- and loss-of-function E proteins and wild-type and variant WNV reporter virus particles, we evaluated the expression pattern and activity of antibodies against the DIII-lr and DII-fl epitopes in mouse and human serum after WNV infection. In mice, immunoglobulin M (IgM) antibodies to the DIII-lr epitope were detected at low levels at day 6 after infection. However, compared to IgG responses against other epitopes in DI and DII, which were readily detected at day 8, the development of IgG against DIII-lr epitope was delayed and did not appear consistently until day 15. This late time point is notable since almost all death after WNV infection in mice occurs by day 12. Nonetheless, at later time points, DIII-lr antibodies accumulated and comprised a significant fraction of the DIII-specific IgG response. In sera from infected humans, DIII-lr antibodies were detected at low levels and did not correlate with clinical outcome. In contrast, antibodies to the DII-fl were detected in all human serum samples and encompassed a significant percentage of the anti-E protein response. Our experiments suggest that the highly neutralizing DIII-lr IgG antibodies have little significant role in primary infection and that the antibody response of humans may be skewed toward the induction of cross-reactive, less-neutralizing antibodies.


Overcoming Challenges In Codifying And Replicating Complex Health Care Interventions.
The complex nature of many health care interventions poses challenges for successful replication. This article presents insights on tackling these challenges primarily drawn from recent research and programs in the UK. These insights include the need to codify complex interventions in ways that reflect their social, context-sensitive, and dynamic nature; to capture learning as the intervention is implemented in new contexts; and to design programs in ways that respect adopters' role in the spread process. We argue that program leaders should have familiarity with theoretical approaches for conceptualizing complex interventions, that a discrete testing-and-revision phase should be recognized as part of the spread process, and that programs should be designed in ways that build and sustain adopter commitment. These perspectives complement the traditional focus on the innovator in models of spread by highlighting the role adopters play in adapting interventions and generating learning, and they have implications for the design of programs to spread innovation.


Salvage liver transplantation for recurrent hepatocellular carcinoma within UCSF criteria after liver resection.
Salvage liver transplantation (SLT) is restricted to patients who develop hepatocellular carcinoma (HCC) recurrence within Milan criteria (MC). Little is known about outcomes for SLT in patients with recurrent HCC within University of California San Francisco (UCSF) criteria after liver resection (LR). Between January 2001 and December 2011, 380 patients with HCC meeting UCSF criteria, 200 of which were resected (LR group) from a perspective of SLT in case of recurrence, and 180 directly underwent LT (PLT). We compared patient characteristics, perioperative and long-term outcomes between SLT and PLT groups. We also assessed the outcome of LR and PLT groups. Among the 200 patients in LR group, 86 (43%) developed HCC recurrence and 15/86 (17%) of these patients presented HCC recurrence outside UCSF criteria. Only 39 of the 86 patients underwent SLT, a transplantation rate of 45% of patients with HCC recurrence. Compared with PLT group, LR group showed lower overall survival rate (P = 0.005) and higher recurrence rate (P = 0.006). Although intraoperative blood loss and required blood transfusion were more frequent in SLT group, the perioperative mortality and posttransplant complications were similar in SLT and PLT groups. The overall survival and recurrence rates did not significantly differ between the two groups. When stratifying by graft type in the SLT group, overall survival and recurrence rates did not significantly differ between deceased donor LT (DDLT) and living donor LT (LDLT) groups. In the subgroup analysis by MC, similar results were observed between patients with recurrent HCC meeting MC and patients with recurrent HCC beyond MC but within UCSF criteria. Our single institution experience demonstrated that prior hepatectomy and SLT for recurrent HCC within UCSF criteria was feasible and SLT could achieve the same outcome as PLT.


Hyperpolarized singlet lifetimes of pyruvate in human blood and in the mouse.
Hyperpolarized NMR is a promising technique for non-invasive imaging of tissue metabolism in vivo. However, the pathways that can be studied are limited by the fast T1 decay of the nuclear spin order. In metabolites containing pairs of coupled nuclear spins-1/2, the spin order may be maintained by exploiting the non-magnetic singlet (spin-0) state of the pair. This may allow preservation of the hyperpolarization in vivo during transport to tissues of interest, such as tumors, or to detect slower metabolic reactions. We show here that in human blood and in a mouse in vivo at millitesla fields the (13)C singlet lifetime of [1,2-(13)C2]pyruvate was significantly longer than the (13)C T1, although it was shorter than the T1 at field strengths of several tesla. We also examine the singlet-derived NMR spectrum observed for hyperpolarized [1,2-(13)C2]lactate, originating from the metabolism of [1,2-(13)C2]pyruvate.


Stereotactic Radiosurgery for the Treatment of Primary and Metastatic Spinal Sarcomas.
Despite advancements in local and systemic therapy, metastasis remains common in the natural history of sarcomas. Unfortunately, such metastases are the most significant source of morbidity and mortality in this heterogeneous disease. As a classically radioresistant histology, stereotactic radiosurgery has emerged to control spinal sarcomas and provide palliation. However, there is a lack of data regarding pain relief and relapse following stereotactic radiosurgery. We queried a retrospective institutional database of patients who underwent spine stereotactic radiosurgery for primary and metastatic sarcomas. The primary outcome was pain relief following stereotactic radiosurgery. Secondary outcomes included progression of pain, radiographic failure, and development of toxicities following treatment. Forty treatment sites were eligible for inclusion; the median prescription dose was 16 Gy in a single fraction. Median time to radiographic failure was 14 months. At 6 and 12 months, radiographic control was 63% and 51%, respectively. Among patients presenting with pain, median time to pain relief was 1 month. Actuarial pain relief at 6 months was 82%. Median time to pain progression was 10 months; at 12 months, actuarial pain progression was 51%. Following multivariate analysis, presence of neurologic deficit at consult (hazard ratio: 2.48, P < .01) and presence of extraspinal bone metastases (hazard ratio: 2.83, P < .01) were associated with pain relief. Greater pain at consult (hazard ratio: 1.92, P < .01), prior radiotherapy (hazard ratio: 4.65, P = .02), and greater number of irradiated vertebral levels were associated with pain progression. Local treatment of spinal sarcomas has remained a challenge for decades, with poor rates of local control and limited pain relief following conventional radiotherapy. In this series, pain relief was achieved in 82% of treatments at 6 months, with half of patients experiencing pain progression by 12 months. Given minimal toxicity and suboptimal pain control at 12 months, dose escalation beyond 16 Gy is warranted.


Differences in micronucleus frequency and acrylamide adduct levels with hemoglobin between vegetarians and non-vegetarians.
Nutrients and food constituents can prevent or contribute to genotoxicity. In this study, the possible influence of a vegetarian/non-vegetarian diet on genotoxic effects was investigated in 58 non-smoking healthy vegetarians (V) and non-vegetarians (NV), age 21-37 years from the Stockholm area in Sweden. Physical activity and dietary habits were similar in both groups, with the exception of the intake of meat and fish. Using flow cytometry, we determined the formation of micronuclei (MN) in transferrin-positive immature peripheral blood reticulocytes (Trf-Ret) (Total: n = 53; V: n = 27; NV: n = 26). Dietary exposure to acrylamide was measured through hemoglobin (Hb) adducts in peripheral erythrocytes (Total: n = 53; V: n = 29; NV: n = 24). Hb adducts of both acrylamide and its genotoxic metabolite glycidamide were monitored as a measure of the corresponding in vivo doses. Our data demonstrated that compared with the non-vegetarians, the vegetarians exhibited lower frequencies of MN (fMN) in the Trf-Ret (p < 0.01, Student's t test). A multivariate analysis demonstrated that there was no association between the fMN and factors such as age, sex, intake of vitamins/minerals, serum folic acid and vitamin B12 levels, physical activity, and body mass index. The mean Hb adduct levels of acrylamide and glycidamide showed no significant differences between vegetarians and non-vegetarians. Furthermore, there were no significant relationships between the adduct levels and fMN in the individuals. The ratio of the Hb adduct levels from glycidamide and acrylamide, however, showed a significant difference (p < 0.04) between the two groups. These data suggest that the vegetarian diet might be beneficial in lowering genomic instability in healthy individuals. The measured Hb adduct levels indicate that the total intake of acrylamide does not differ between the two studied groups and does not contribute to the observed difference in fMN, although an influence of the diet on the metabolic rates of acrylamide was indicated. In addition, the observed significant difference in the background fMN in the two groups demonstrated that the MN analysis method has a sensitivity applicable to the biomonitoring of human lifestyle factors.


Prion disease diagnosis using subject-specific imaging biomarkers within a multi-kernel Gaussian process.
Prion diseases are a group of rare neurodegenerative conditions characterised by a high rate of progression and highly heterogeneous phenotypes. Whilst the most common form of prion disease occurs sporadically (sporadic Creutzfeldt-Jakob disease, sCJD), other forms are caused by prion protein gene mutations, or exposure to prions in the diet or by medical procedures, such us surgeries. To date, there are no accurate quantitative imaging biomarkers that can be used to predict the future clinical diagnosis of a healthy subject, or to quantify the progression of symptoms over time. Besides, CJD is commonly mistaken for other forms of dementia. Due to the heterogeneity of phenotypes and the lack of a consistent geometrical pattern of disease progression, the approaches used to study other types of neurodegenerative diseases are not satisfactory to capture the progression of human form of prion disease. In this paper, using a tailored framework, we aim to classify and stratify patients with prion disease, according to the severity of their illness. The framework is initialised with the extraction of subject-specific imaging biomarkers. The extracted biomakers are then combined with genetic and demographic information within a Gaussian Process classifier, used to calculate the probability of a subject to be diagnosed with prion disease in the next year. We evaluate the effectiveness of the proposed method in a cohort of patients with inherited and sporadic forms of prion disease. The model has shown to be effective in the prediction of both inherited CJD (92% of accuracy) and sporadic CJD (95% of accuracy). However the model has shown to be less effective when used to stratify the different stages of the disease, in which the average accuracy is 85%, whilst the recall is 59%. Finally, our framework was extended as a differential diagnosis tool to identify both forms of CJD among another neurodegenerative disease. In summary we have developed a novel method for prion disease diagnosis and prediction of clinical onset using multiple sources of features, which may have use in other disorders with heterogeneous imaging features.


Broad- to fine-scale population genetic patterning in the smallmouth bass Micropterus dolomieu across the Laurentian Great Lakes and beyond: an interplay of behaviour and geography.
Analysis of population genetic relationships reveals the signatures of current processes such as spawning behaviour and migration, as well as those of historical events including vicariance and climate change. This study examines these signatures through testing broad- to fine-scale genetic patterns among smallmouth bass Micropterus dolomieu spawning populations across their native Great Lakes range and outgroup areas, with fine-scale concentration in Lake Erie. Our primary hypotheses include whether genetic patterns result from behavioural and/or geographical isolation, specifically: (i) Are spawning groups in interconnected waterways genetically separable? (ii) What is the degree of isolation across and among lakes, basins, and tributaries? (iii) Do genetic divergences correspond to geographical distances? and (iv) Are historical colonization patterns from glacial refugia retained? Variation at eight nuclear microsatellite DNA loci are analysed for 666 smallmouth bass from 28 locations, including 425 individuals in Lake Erie; as well as Lakes Superior, Huron, and Ontario, and outgroups from the Mississippi, Ohio, St. Lawrence, and Hudson River drainages. Results reveal marked genetic differences among lake and river populations, as well as surprisingly high divergences among closely spaced riverine sites. Results do not fit an isolation-by-geographical-distance prediction for fine-scale genetic patterns, but show weak correspondence across large geographical scales. Genetic relationships thus are consistent with hypotheses regarding divergent origins through vicariance in glacial refugia, followed by colonization pathways establishing modern-day Great Lakes populations, and maintenance through behavioural site fidelity. Conservation management practices thus should preserve genetic identity and unique characters among smallmouth bass populations.


Too far to walk: maternal mortality in context.
The Prevention of Maternal Mortality Program is a collaborative effort of Columbia University's Center for Population and Family Health and multidisciplinary teams of researchers from Ghana, Nigeria and Sierra Leone. Program goals include dissemination of information to those concerned with preventing maternal deaths. This review, which presents findings from a broad body of research, is part of that activity. While there are numerous factors that contribute to maternal mortality, we focus on those that affect the interval between the onset of obstetric complication and its outcome. If prompt, adequate treatment is provided, the outcome will usually be satisfactory; therefore, the outcome is most adversely affected by delayed treatment. We examine research on the factors that: (1) delay the decision to seek care; (2) delay arrival at a health facility; and (3) delay the provision of adequate care. The literature clearly indicates that while distance and cost are major obstacles in the decision to seek care, the relationships are not simple. There is evidence that people often consider the quality of care more important than cost. These three factors--distance, cost and quality--alone do not give a full understanding of decision-making process. Their salience as obstacles is ultimately defined by illness-related factors, such as severity. Differential use of health services is also shaped by such variables as gender and socioeconomic status. Patients who make a timely decision to seek care can still experience delay, because the accessibility of health services is an acute problem in the developing world. In rural areas, a woman with an obstetric emergency may find the closest facility equipped only for basic treatments and education, and she may have no way to reach a regional center where resources exist. Finally, arriving at the facility may not lead to the immediate commencement of treatment. Shortages of qualified staff, essential drugs and supplies, coupled with administrative delays and clinical mismanagement, become documentable contributors to maternal deaths. Findings from the literature review are discussed in light of their implications for programs. Options for health programs are offered and examples of efforts to reduce maternal deaths are presented, with an emphasis on strategies to mobilize and adapt existing resources.


The atypical homeodomain transcription factor Mohawk controls tendon morphogenesis.
The Mohawk homeobox (Mkx) gene encodes a new atypical homeodomain-containing protein with transcriptional repressor activity. Mkx mRNA exhibited dynamic expression patterns during development of the palate, somite, kidney, and testis, suggesting that it may be an important regulator of multiple developmental processes. To investigate the roles of Mkx in organogenesis, we generated mice carrying a null mutation in this gene. Mkx(-/-) mice survive postnatally and exhibit a unique wavy-tail phenotype. Close examination revealed that the mutant mice had smaller tendons than wild-type littermates and that the rapid postnatal growth of collagen fibrils in tendons was disrupted in Mkx(-/-) mice. Defects in tendon development were detected in the mutant mouse embryos as early as embryonic day 16.5 (E16.5). Although collagen fibril assembly initially appeared normal, the tendons of Mkx(-/-) embryos expressed significantly reduced amounts of collagen I, fibromodulin, and tenomodulin in comparison with control littermates. We found that Mkx mRNA was strongly expressed in differentiating tendon cells during embryogenesis and in the tendon sheath cells in postnatal stages. In addition to defects in tendon collagen fibrillogenesis, Mkx(-/-) mutant mice exhibited abnormal tendon sheaths. These results identify Mkx as an important regulator of tendon development.


Improving infant outcome with a 10 min Apgar of 0.
Asystole at birth and extending through 10 min is rare, with current international recommendations stating it may be appropriate to consider discontinuation of resuscitation in this clinical scenario. These recommendations are based on small case series of both term and preterm infants, where death or abnormal outcome was nearly universal. Study objective was to determine recent outcome of infants with an Apgar score of 0 at 10 min despite cardiopulmonary resuscitation, treated with therapeutic hypothermia or standard treatment, in randomised cooling studies. Outcome studies of infants with an Apgar of 0 at 10 min subsequently resuscitated and treated with hypothermia or standard treatment were reviewed and combined with local outcome data of infants treated with hypothermia. Four recent studies (n=81) and local data (n=9) yielded a total of 90 infants with an Apgar of 0 at 10 min, with 56 treated with hypothermia and 34 controls. Primary outcome of death or abnormal neurodevelopmental outcome (18-24 months) occurred in 73% cooled and 79.5% normothermic infants (p=0.61). Although poor, the outcome for infants with an Apgar of 0 at 10 min of life has improved substantially in recent years. This may be related to treatment with hypothermia, enhanced resuscitation techniques and/or other supportive management. Current recommendations to consider discontinuation of resuscitation without a detectable heart rate at 10 min should consider these findings.


Dual inhibition of monoamine oxidase B and antagonism of the adenosine A(2A) receptor by (E,E)-8-(4-phenylbutadien-1-yl)caffeine analogues.
The adenosine A(2A) receptor has emerged as an attractive target for the treatment of Parkinson's disease (PD). Evidence suggests that antagonists of the A(2A) receptor (A(2A) antagonists) may be neuroprotective and may help to alleviate the symptoms of PD. We have reported recently that several members of the (E)-8-styrylcaffeine class of A(2A) antagonists also are potent inhibitors of monoamine oxidase B (MAO-B). Since MAO-B inhibitors are known to possess anti-parkinsonian properties, dual-target-directed drugs that block both MAO-B and A(2A) receptors may have enhanced value in the management of PD. In an attempt to explore this concept further we have prepared three additional classes of C-8 substituted caffeinyl analogues. The 8-phenyl- and 8-benzylcaffeinyl analogues exhibited relatively weak MAO-B inhibition potencies while selected (E,E)-8-(4-phenylbutadien-1-yl)caffeinyl analogues were found to be exceptionally potent reversible MAO-B inhibitors with enzyme-inhibitor dissociation constants (K(i) values) ranging from 17 to 149 nM. Furthermore, these (E,E)-8-(4-phenylbutadien-1-yl)caffeines acted as potent A(2A) antagonists with K(i) values ranging from 59 to 153 nM. We conclude that the (E,E)-8-(4-phenylbutadien-1-yl)caffeines are a promising candidate class of dual-acting compounds.


Fish possess multiple copies of fgfrl1, the gene for a novel FGF receptor.
FGFRL1 is a novel FGF receptor that lacks the intracellular tyrosine kinase domain. While mammals, including man and mouse, possess a single copy of the FGFRL1 gene, fish have at least two copies, fgfrl1a and fgfrl1b. In zebrafish, both genes are located on chromosome 14, separated by about 10 cM. The two genes show a similar expression pattern in several zebrafish tissues, although the expression of fgfrl1b appears to be weaker than that of fgfrl1a. A clear difference is observed in the ovary of Fugu rubripes, which expresses fgfrl1a but not fgfrl1b. It is therefore possible that subfunctionalization has played a role in maintaining the two fgfrl1 genes during the evolution of fish. In human beings, the FGFRL1 gene is located on chromosome 4, adjacent to the SPON2, CTBP1 and MEAEA genes. These genes are also found adjacent to the fgfrl1a gene of Fugu, suggesting that FGFRL1, SPON2, CTBP1 and MEAEA were preserved as a coherent block during the evolution of Fugu and man.


Better Epitope Discovery, Precision Immune Engineering, and Accelerated Vaccine Design Using Immunoinformatics Tools.
Computational vaccinology includes epitope mapping, antigen selection, and immunogen design using computational tools. Tools that facilitate the in silico prediction of immune response to biothreats, emerging infectious diseases, and cancers can accelerate the design of novel and next generation vaccines and their delivery to the clinic. Over the past 20 years, vaccinologists, bioinformatics experts, and advanced programmers based in Providence, Rhode Island, USA have advanced the development of an integrated toolkit for vaccine design called iVAX, that is secure and user-accessible by internet. This integrated set of immunoinformatic tools comprises algorithms for scoring and triaging candidate antigens, selecting immunogenic and conserved T cell epitopes, re-engineering or eliminating regulatory T cell epitopes, and re-designing antigens to induce immunogenicity and protection against disease for humans and livestock. Commercial and academic applications of iVAX have included identifying immunogenic T cell epitopes in the development of a T-cell based human multi-epitope Q fever vaccine, designing novel influenza vaccines, identifying cross-conserved T cell epitopes for a malaria vaccine, and analyzing immune responses in clinical vaccine studies. Animal vaccine applications to date have included viral infections of pigs such as swine influenza A, PCV2, and African Swine Fever. "Rapid-Fire" applications for biodefense have included a demonstration project for Lassa Fever and Q fever. As recent infectious disease outbreaks underscore the significance of vaccine-driven preparedness, the integrated set of tools available on the iVAX toolkit stand ready to help vaccine developers deliver genome-derived, epitope-driven vaccines.


Designing refoldable model molecules.
We report a numerical study of the design of lattice heteropolymers that can refold when the properties of only a few monomers are changed. If we assume that the effect of an external agent on a heteropolymer is to alter the interactions between its constituent monomers, our simulations provide a description of a simple allosteric transition. We characterize the free energy surfaces of the initial and the modified chain molecule. We find that there is a region of conformation space where molecules can be made to refold with minimal free energy cost. This region is accessible by thermal fluctuations. The efficiency of a motor based on such an allosteric transition would be enhanced by "borrowing" heat from the environment in the initial stages of the refolding, and "paying back" later. In fact, the power cycle of many real molecular motors does involve such a borrowing activation step.


Licensure of a 13-valent pneumococcal conjugate vaccine (PCV13) and recommendations for use among children - Advisory Committee on Immunization Practices (ACIP), 2010.
On February 24, 2010, a 13-valent pneumococcal conjugate vaccine (PCV13 [Prevnar 13, Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.]) was licensed by the Food and Drug Administration (FDA) for prevention of invasive pneumococcal disease (IPD) caused by the 13 pneumococcal serotypes covered by the vaccine and for prevention of otitis media caused by serotypes in the 7-valent pneumococcal conjugate vaccine formulation (PCV7 [Prevnar, Wyeth]). PCV13 is approved for use among children aged 6 weeks-71 months and succeeds PCV7, which was licensed by FDA in 2000. The Pneumococcal Vaccines Work Group of the Advisory Committee on Immunization Practices (ACIP) reviewed available data on the immunogenicity, safety, and cost-effectiveness of PCV13, and on estimates of the vaccine-preventable pneumococcal disease burden. The working group then presented policy options for consideration of the full ACIP. This report summarizes recommendations approved by ACIP on February 24, 2010, for 1) routine vaccination of all children aged 2-59 months with PCV13, 2) vaccination with PCV13 of children aged 60-71 months with underlying medical conditions that increase their risk for pneumococcal disease or complications, and 3) PCV13 vaccination of children who previously received 1 or more doses of PCV7. CDC guidance for vaccination providers regarding transition from PCV7 to the PCV13 immunization program also is included.


Prediction of Opioid-Induced Respiratory Depression on Inpatient Wards Using Continuous Capnography and Oximetry: An International Prospective, Observational Trial.
Opioid-related adverse events are a serious problem in hospitalized patients. Little is known about patients who are likely to experience opioid-induced respiratory depression events on the general care floor and may benefit from improved monitoring and early intervention. The trial objective was to derive and validate a risk prediction tool for respiratory depression in patients receiving opioids, as detected by continuous pulse oximetry and capnography monitoring. PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) was a prospective, observational trial of blinded continuous capnography and oximetry conducted at 16 sites in the United States, Europe, and Asia. Vital signs were intermittently monitored per standard of care. A total of 1335 patients receiving parenteral opioids and continuously monitored on the general care floor were included in the analysis. A respiratory depression episode was defined as respiratory rate ≤5 breaths/min (bpm), oxygen saturation ≤85%, or end-tidal carbon dioxide ≤15 or ≥60 mm Hg for ≥3 minutes; apnea episode lasting >30 seconds; or any respiratory opioid-related adverse event. A risk prediction tool was derived using a multivariable logistic regression model of 46 a priori defined risk factors with stepwise selection and was internally validated by bootstrapping. One or more respiratory depression episodes were detected in 614 (46%) of 1335 general care floor patients (43% male; mean age, 58 ± 14 years) continuously monitored for a median of 24 hours (interquartile range [IQR], 17-26). A multivariable respiratory depression prediction model with area under the curve of 0.740 was developed using 5 independent variables: age ≥60 (in decades), sex, opioid naivety, sleep disorders, and chronic heart failure. The PRODIGY risk prediction tool showed significant separation between patients with and without respiratory depression (P < .001) and an odds ratio of 6.07 (95% confidence interval [CI], 4.44-8.30; P < .001) between the high- and low-risk groups. Compared to patients without respiratory depression episodes, mean hospital length of stay was 3 days longer in patients with ≥1 respiratory depression episode (10.5 ± 10.8 vs 7.7 ± 7.8 days; P < .0001) identified using continuous oximetry and capnography monitoring. A PRODIGY risk prediction model, derived from continuous oximetry and capnography, accurately predicts respiratory depression episodes in patients receiving opioids on the general care floor. Implementation of the PRODIGY score to determine the need for continuous monitoring may be a first step to reduce the incidence and consequences of respiratory compromise in patients receiving opioids on the general care floor.


Probing dynamics at interfaces: resonance enhanced dynamic light scattering.
Experiments addressing supramolecular dynamics at interfaces are of paramount importance for the understanding of the dynamic behaviour of polymers, particles, or cells at interfaces, transport phenomena to and from surfaces, thin films or membranes. However, there are only few reports in the literature due to the paucity of experimental methods that offer the required spatial and time resolution. Evanescent wave dynamic light scattering originally developed to meet these needs has limited sensitivity and is restricted to glass substrates. Here we report the first experimental realization of a dynamic light scattering experiment close to an interface using surface plasmon polaritons as light source offering a strong increase in the signal to noise ratio and allowing for the use of metallic interfaces. As a proof of concept, we consider the diffusion of particles with radii down to 10nm in dilute dispersions close to a gold surface.


Increased expression of heat shock protein-binding protein 1 and heat shock protein 70 in human hepatocellular carcinoma tissues.
Heat shock protein-binding protein 1 (HspBP1) is a co-chaperone that inhibits heat shock 70-kDa protein (Hsp70) activity. In mouse neuroblastomas and lung tumors, the protein levels of HspBP1 and Hsp70 are elevated by a similar amount compared to non-tumor tissues. However, no studies have been reported regarding the levels of HspBP1 in human cancer tissues. Our previous proteomic study demonstrated that the expression of Hsp70 was increased in human hepatitis C virus-related hepatocellular carcinoma (HCV-HCC) tissues. Here, we investigated the expression of HspBP1 in human HCV-HCC. Immunoblotting analysis of HspBP1 and Hsp70 was performed in human HCV-HCC tissues from 20 patients. In 80% of the patients, Hsp70 increased an average of 3.55-fold, and in 50% of the patients, HspBP1 increased an average of 2.02-fold. Comparison and analysis of expression and clinical data revealed a significant difference between moderately-differentiated HCC and non-tumor tissues. In addition, there was a significant difference between the ratio of HspBP1 to Hsp70 levels and tumor size (<3 cm vs. ≥ 3cm) with larger tumors having a lower ratio. This ratio was significantly lower in moderately-differentiated HCC tissues than in non-tumor HCC tissues. In conclusion, HspBP1 was up-regulated in human HCV-HCC, an increase which correlated with the increase of Hsp70 levels. The ratio of HspBP1 to Hsp70 in HCC may provide novel information concerning the characterization of tumors, tumor progression and resistance to treatment.


The effect of good continuation on the contact order judgment of causal events.
When a ball on a pool table moves to hit another ball, people feel the causal impression between the two balls: The first ball causes the second ball's motion, which is known as the launching effect. Previous research has shown that the causal impression becomes stronger when the two balls have a similar direction of movement. Here, we tested whether this good continuation influenced perception of the contact time between the causal object and the effect object. A variant of Michotte's visual collision event was used as a stimulus, consisting of two competing cause objects and one effect object. In the display, the two cause objects on the left begin to move and contact the effect object in the center, causing it to move. In Experiments 1 to 4, the contact order of the cause objects and the motion direction of the effect object were systematically varied. The observers were asked to judge which of the cause objects had a more causal relationship and made contact first. The results showed that the observers were more likely to judge a cause object as having a more causal relationship with the effect object when there was good continuation, and they often erroneously judged the cause object as having first contacted the effect object; this effect was maintained with up to approximately 100 ms of delay after contact. These results suggest that good continuation is an important cue that postdictively determines perception of the contact time of a cause object in a short time window.


Neuroscientific Implications in Assessment and Intervention for Aphasia.
Within an overarching theme of generational change in aphasiology, the aims of this paper are to (a) unify the neuroscience of the language impairment of aphasia with the psychosocial science of aphasia, (b) consider the implications of technology and (c) address the global challenge of translational research in this field. To achieve the first two aims, 10 principles of neuroplasticity will be interpreted within the World Health Organization's International Classification of Functioning, Disability and Health (ICF). Two novel treatment approaches to aphasia (UQ Aphasia LIFT and CommFit™) will be described that illustrate how the neuroplasticity principles can be interpreted more broadly within the ICF. The global challenge of translational research will bring the perspective of clinicians and consumers through to aphasia research via 3 recent sets of best practice statements for aphasia. Each demonstrates how the field of aphasiology is undertaking a knowledge synthesis within its broader remit of knowledge transfer and exchange. The Australian Aphasia Rehabilitation Pathway is described as a way of creating living clinical guidelines that are helpful to all stakeholders in aphasia research.


Pushing the envelope of retinal ganglion cell genesis: context dependent function of Math5 (Atoh7).
The basic-helix-loop helix factor Math5 (Atoh7) is required for retinal ganglion cell (RGC) development. However, only 10% of Math5-expressing cells adopt the RGC fate, and most become photoreceptors. In principle, Math5 may actively bias progenitors towards RGC fate or passively confer competence to respond to instructive factors. To distinguish these mechanisms, we misexpressed Math5 in a wide population of precursors using a Crx BAC or 2.4 kb promoter, and followed cell fates with Cre recombinase. In mice, the Crx cone-rod homeobox gene and Math5 are expressed shortly after cell cycle exit, in temporally distinct, but overlapping populations of neurogenic cells that give rise to 85% and 3% of the adult retina, respectively. The Crx>Math5 transgenes did not stimulate RGC fate or alter the timing of RGC births. Likewise, retroviral Math5 overexpression in retinal explants did not bias progenitors towards the RGC fate or induce cell cycle exit. The Crx>Math5 transgene did reduce the abundance of early-born (E15.5) photoreceptors two-fold, suggesting a limited cell fate shift. Nonetheless, retinal histology was grossly normal, despite widespread persistent Math5 expression. In an RGC-deficient (Math5 knockout) environment, Crx>Math5 partially rescued RGC and optic nerve development, but the temporal envelope of RGC births was not extended. The number of early-born RGCs (before E13) remained very low, and this was correlated with axon pathfinding defects and cell death. Together, these results suggest that Math5 is not sufficient to stimulate RGC fate. Our findings highlight the robust homeostatic mechanisms, and role of pioneering neurons in RGC development.


AME evidence series 001-The Society for Translational Medicine: clinical practice guidelines for diagnosis and early identification of sepsis in the hospital.
Sepsis is a heterogeneous disease caused by an infection stimulus that triggers several complex local and systemic immuno-inflammatory reactions, which results in multiple organ dysfunction and significant morbidity and mortality. The diagnosis of sepsis is challenging because there is no gold standard for diagnosis. As a result, the clinical diagnosis of sepsis is ever changing to meet the clinical and research requirements. Moreover, although there are many novel biomarkers and screening tools for predicting the risk of sepsis, the diagnostic performance and effectiveness of these measures are less than satisfactory, and there is insufficient evidence to recommend clinical use of these new techniques. As a consequence, diagnostic criteria for sepsis need regular revision to cope with emerging evidence. This review aims to present the most updated information on diagnosis and early recognition of sepsis. Recommendations for clinical use of different diagnostic tools rely on the Grades of Recommendation Assessment, Development and Evaluation (GRADE) framework. Because most of the studies were observational and did not allow a reliable assessment of these tools, a two-step inference approach was employed. Future trials need to confirm or refute a particular index test and should directly explore relevant patient outcome parameters.


SOCS1 and regulation of regulatory T cells plasticity.
Several reports have suggested that natural regulatory T cells (Tregs) lose Forkhead box P3 (Foxp3) expression and suppression activity under certain inflammatory conditions. Treg plasticity has been studied because it may be associated with the pathogenesis of autoimmunity. Some studies showed that a minor uncommitted Foxp3(+) T cell population, which lacks hypomethylation at Treg-specific demethylation regions (TSDRs), may convert to effector/helper T cells. Suppressor of cytokine signaling 1 (SOCS1), a negative regulator of cytokine signaling, has been reported to play an important role in Treg cell integrity and function by protecting the cells from excessive inflammatory cytokines. In this review, we discuss Treg plasticity and maintenance of suppression functions in both physiological and pathological settings. In addition, we discuss molecular mechanisms of maintaining Treg plasticity by SOCS1 and other molecules. Such information will be useful for therapy of autoimmune diseases and reinforcement of antitumor immunity.


Recombinant human thyrotropin is a potent stimulator of thyroid function in normal subjects.
Recombinant human TSH (rhTSH) is known to stimulate 131I uptake and thyroglobulin (Tg) release from the postoperative remnant and metastases in thyroid cancer patients, but its effects on serum thyroid hormone and Tg concentrations in normal subjects have not been reported. Before using rhTSH in the management of thyroid disorders other than cancer, the thyroid response to rhTSH in normal subjects must be assessed. Six subjects, two men and four women, without evidence of thyroid disease, including normal serum free T4 index and TSH concentrations and negative tests for antithyroid peroxidase and Tg, were studied. Each received 0.1 mg rhTSH, im, 11% of the lowest dose that has been administered to thyroid cancer patients. Blood was obtained before; 2, 4, and 8 h after; and 1, 2, 3, 4, 7, and about 3 weeks after rhTSH administration. Serum TSH significantly increased at 2 h (mean +/- SE, 2.4 +/- 0.9 to 40.7 +/- 7.4 mU/mL), peaked at 4 h (50.9 +/- 9.3), remained significantly elevated for 1 day, and was significantly below baseline (0.8 +/- 0.5) 7 days after rhTSH administration. Serum T3 increased significantly at 4 h (115 +/- 4 to 190 +/- 14 ng/dL), peaked at 24 h (217 +/- 23 ng/dL), and remained significantly elevated for 3 days (151 +/- 12 ng/dL). Serum T4 increased significantly at 8 h (7.3 +/- 0.2 to 9.8 +/- 0.4 micrograms/dL), peaked at 24 h (11.2 +/- 0.5 micrograms/dL), and remained significantly elevated for 4 days (9.4 +/- 0.5 micrograms/dL). Serum Tg did not change for the first 8 h, increased significantly at 1 day (15.9 +/- 3.9 to 34.7 +/- 6.0 ng/mL), peaked at 2 days (44.2 +/- 7.0 ng/mL), and remained significantly elevated for 4 days (37.7 +/- 13.7 ng/mL). All values returned to baseline at 3 weeks. TSH antibodies were not detected at 3 weeks. A single dose of 0.1 mg rhTSH is a potent stimulator of thyroid function in normal subjects. rhTSH may be a useful agent to test thyroid reserve and for use in clinical settings that require direct thyroid stimulation.


Extent of structurally reduced venous distensibility in rats.
1. Venous pressure--volume relations were studied in maximally vasodilated whole-body preparations after cardiac arrest, as well as in fully vasodilated, perfused hindquarter preparations of spontaneously hypertensive rats (SHR) and normotensive controls. Central venous pressures were measured also in the anaesthetized animals before cardiac arrest. 2. Central venous pressure in intact, anaesthetized SHR was 1.9 +/- 0.20 mmHg compared with 0.75 +/- 0.25 in controls (P less than 0.001). 3. In both preparations SHR showed a nearly 20% reduction in venous compliance, whereas calculated 'unstressed' volumes (volumes at zero transmural pressure) were largely equal in SHR and controls. 4. SHR capacitance vessels thus appear to have a structurally reduced wall distensibility of about 10% with no change in overall size. It probably reflects a structural adaptation to a modest increase of average transmural pressure that also affects the low-pressure side.


Boundaries to grounding abstract concepts.
Grounded theories of cognition claim that concept representation relies on the systems for perception and action. The sensory-motor grounding of abstract concepts presents a challenge for these theories. Some accounts propose that abstract concepts are indirectly grounded via image schemas or situations. Recent research, however, indicates that the role of sensory-motor processing for concrete concepts may be limited, providing evidence against the idea that abstract concepts are grounded via concrete concepts. Hybrid models that combine language and sensory-motor experience may provide a more viable account of abstract and concrete representations. We propose that sensory-motor grounding is important during acquisition and provides structure to concepts. Later activation of concepts relies on this structure but does not necessarily involve sensory-motor processing. Language is needed to create coherent concepts from diverse sensory-motor experiences.This article is part of the theme issue 'Varieties of abstract concepts: development, use and representation in the brain'.


In vitro activity of a novel antibacterial agent, levonadifloxacin, against clinical isolates collected in a prospective, multicentre surveillance study in India during 2016-18.
Levonadifloxacin is a novel antibiotic belonging to the benzoquinolizine subclass of fluoroquinolones with potent activity against MRSA and quinolone-resistant Staphylococcus aureus. IV levonadifloxacin and its oral prodrug alalevonadifloxacin have recently been approved in India for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) including diabetic foot infections. To investigate the in vitro activity of levonadifloxacin against contemporary clinical isolates collected from multiple tertiary care hospitals across India in the Antimicrobial Susceptibility Profiling of Indian Resistotypes (ASPIRE) surveillance study. A total of 1376 clinical isolates, consisting of staphylococci (n = 677), streptococci (n = 178), Enterobacterales (n = 320), Pseudomonas aeruginosa (n = 140) and Acinetobacter baumannii (n = 61), collected (2016-18) from 16 tertiary hospitals located across 12 states in India, were included in the study. The MICs of levonadifloxacin and comparator antibiotics were determined using the reference agar dilution method and broth microdilution method. Levonadifloxacin exhibited potent activity against MSSA (MIC50/90: 0.5/1 mg/L), MRSA (MIC50/90: 0.5/1 mg/L) and levofloxacin-resistant S. aureus (MIC50/90: 1/1 mg/L) isolates. Similarly, potent activity of levonadifloxacin was also observed against CoNS including MDR isolates (MIC50/90: 1/2 mg/L). Against Streptococcus pneumoniae, levonadifloxacin (MIC50/90: 0.5/0.5 mg/L) showed superior activity compared with levofloxacin (MIC50/90: 1/2 mg/L). Among levofloxacin-susceptible Enterobacterales, 80.6% of isolates were inhibited at ≤2 mg/L levonadifloxacin. Levonadifloxacin displayed potent activity against contemporary MRSA and fluoroquinolone-resistant staphylococcal isolates, thus offering a valuable IV as well as an oral therapeutic option for the treatment of ABSSSIs. Furthermore, levonadifloxacin exhibited a broad-spectrum activity profile as evident from its activity against streptococci and levofloxacin-susceptible Gram-negative isolates.