The genealogy of samples in models with selection.
We introduce the genealogy of a random sample of genes taken from a large haploid population that evolves according to random reproduction with selection and mutation. Without selection, the genealogy is described by Kingman's well-known coalescent process. In the selective case, the genealogy of the sample is embedded in a graph with a coalescing and branching structure. We describe this graph, called the ancestral selection graph, and point out differences and similarities with Kingman's coalescent. We present simulations for a two-allele model with symmetric mutation in which one of the alleles has a selective advantage over the other. We find that when the allele frequencies in the population are already in equilibrium, then the genealogy does not differ much from the neutral case. This is supported by rigorous results. Furthermore, we describe the ancestral selection graph for other selective models with finitely many selection classes, such as the K-allele models, infinitely-many-alleles models. DNA sequence models, and infinitely-many-sites models, and briefly discuss the diploid case.


Poly (N-isopropylacrylamide)-co-(acrylic acid) microgel/Ag nanoparticle hybrids for the colorimetric sensing of H2O2.
Poly (N-isopropylacrylamide)-co-(acrylic acid) (pNIPAm-co-AAc) microgels composed of Ag nanoparticles (Ag NPs) have been synthesized and employed for the colorimetric sensing of H2O2. Each pNIPAm-co-AAc microgel, which exhibited a diameter of ∼800 nm, contained multiple Ag NPs (diameter of ∼5 nm), and solutions of these hybrid materials showed a UV-vis absorption band at ∼400 nm. This is due to the excitation of the Ag NP surface plasmon. We go on to show that the intensity of this absorption band is dependent on the concentration of H2O2 in solution. Specifically, in the presence of H2O2 the magnitude of the absorption peak dramatically decreases in a linear fashion over the concentration range of 0.30 to 3.00 μM H2O2 (r(2) = 0.9918). We go on to show that the response is selective for H2O2 and can still function in complex mixtures, e.g., we showed that the response is still robust in milk samples. While Ag NPs themselves can exhibit similar responses, this system has many benefits including sample processing and long term stability - i.e., Ag NPs are destabilized in solutions of a certain pH, and aggregate readily. Our microgel/Ag NP hybrids have been shown to be extremely stable and are easily purified prior to use by simple centrifugation/washing protocols. This system is simple and straightforward to use, is low cost, and can be used in complex media, which makes it practical for analyzing complex biological and environmental samples.


Diagnosis and management of moderate to severe adult atopic dermatitis: a Consensus by the Italian Society of Dermatology and Venereology (SIDeMaST), the Italian Association of Hospital Dermatologists (ADOI), the Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC), and the Italian Society of Allergological, Environmental and Occupational Dermatology (SIDAPA).
Atopic dermatitis (AD) is a chronic immune-mediated inflammatory skin disease, currently recognized as a systemic disease possibly burdened by various comorbidities, including, but not limited to, other allergic conditions. Management guidelines issued by American and European dermatology and allergy scientific societies are available. However, some discrepancies exist in these guidelines, and some aspects of the management process, including diagnosis and severity assessment, as well as therapy duration and switch criteria, are not fully clarified by existing guidelines. Moreover, biologics such as dupilumab have now entered the therapeutic scenario of moderate-to-severe AD, offering a great opportunity to treat effectively and safely in need AD patients. For all these reasons, four Italian dermatology and allergy scientific societies joined to provide practical guidance for the management of moderate-to-severe adult AD suitable for the Italian clinical practice. Through a modified Delphi procedure, consensus was reached by 63 Italian dermatologists and allergists experienced in the management of adult AD on 14 statements covering five AD areas of interest, i.e. diagnosis, severity definition, current systemic therapies, eligibility criteria to biologic treatments, and comorbidities, with the aim to define treatment goals and improve adult AD management. The potential usefulness of a multidisciplinary approach is also underlined, given the complexity of AD and its comorbidities.


401(k) plan asset allocation, account balances, and loan activity in 2009.
CONSISTENT SAMPLE: Because 401(k) balances can fluctuate with market returns from year to year, meaningful analysis of 401(k) plans must examine how participants' accounts have performed over the long term. Looking at consistent participants in the EBRI/ICI 401(k) database over the six-year period from 2003 to 2009 (which included one of the worst bear markets for stocks since the Great Depression), the study found: After rising in 2003 and for the next four consecutive years, the average 401(k) retirement account fell 27.8 percent in 2008, before rising 31.9 percent in 2009. The average 401(k) account balance moved up and down with stock market performance, but over the entire six-year time period increased at an average annual growth rate of 10.5 percent, attaining $109,723 at year-end 2009. The median (or midpoint, half above and half below) 401(k) account balance increased at an average annual growth rate of 14.7 percent over the 2003-2009 period to $59,381 at year-end 2009. THE BULK OF 401(K) ASSETS CONTINUED TO BE INVESTED IN STOCKS: On average, at year-end 2009, 60 percent of 401(k) participants' assets were invested in equity securities through equity funds, the equity portion of balanced funds, and company stock. Thirty-six percent was in fixed-income securities such as stable-value investments and bond and money funds. MORE THAN THREE-QUARTERS OF 401(K) PLANS INCLUDED TARGET-DATE FUNDS IN THEIR INVESTMENT LINEUP AT YEAR-END 2009: At year-end 2009, nearly 10 percent of the assets in the EBRI/ICI 401(k) database was invested in target-date funds and 33 percent of 401(k) participants held target-date funds. Also known as lifecycle funds, they are designed to simplify investing and to automate account rebalancing. NEW EMPLOYEES CONTINUED TO USE BALANCED FUNDS, INCLUDING TARGET-DATE FUNDS: Across all but the oldest age group, more new or recent hires invested their 401(k) assets in balanced funds, including target-date funds. At year-end 2009, about 42 percent of the account balances of recently hired participants in their 20s were invested in balanced funds, compared with 36 percent in 2008, and about 7 percent in 1998. At year-end 2009, 31 percent of the account balances of recently hired participants in their 20s was invested in lifecycle funds, compared with almost 23 percent at year-end 2008. 401(K) PARTICIPANTS CONTINUED TO SEEK DIVERSIFICATION OF THEIR INVESTMENTS: The share of 401(k) accounts invested in company stock continued to shrink, falling by half of a percentage point (to 9.2 percent) in 2009. That continued a steady decline that started in 1999. Recently hired 401(k) participants contributed to this trend: They tended to be less likely to hold employer stock. PARTICIPANTS' 401(K) LOAN ACTIVITY ROSE IN 2009: In 2009, 21 percent of all 401(k) participants eligible for loans had a loan outstanding against their 401(k) account, compared with 18 percent at year-end 2008 and year-end 2007. Loans outstanding amounted to 15 percent of the remaining account balance, on average, at year-end 2009, compared with 16 percent at year-end 2008. Loan amounts remained in line with the past few years in terms of typical dollar amounts.


Role for O-glycosylation of RFP in the interaction with enhancer of polycomb.
We recently demonstrated that RFP, which belongs to the large B-box RING finger protein family, interacts with Enhancer of Polycomb 1 (EPC1) and functions as a transcriptional repressor in human cultured cells. In this study, we examined the expression of RFP and EPC1 in mouse tissues by immunoblotting as well as their interaction by a pull-down assay. Both RFP and EPC1 proteins are expressed in several mouse tissues including testis, spleen, thymus, adrenal gland, cerebrum, and cerebellum. In addition, they were coprecipitated from the lysate of mouse testis. Pull-down assays using glutathione S-transferase (GST)-fused EPC1 proteins revealed that RFP is associated with the EPcA, EPcB, and carboxy-terminal (CT) regions of EPC1. Although RFP is highly expressed as 58- and 68-kDa proteins in mouse testis, the EPC1 CT region more strongly interacted with the 68-kDa form than the EPcA or EPcB region. Interaction of the 58-kDa form of RFP with each region was weak compared with that of the 68-kDa form with the EPC1 CT region. Because the 68-kDa form of RFP was almost completely digested with O-glycosidase but not with N-glycosidase, this suggested that O-glycosylation of RFP plays a role in its interaction with the EPC1 CT region that may be responsible for transcriptional repression. In addition, the luciferase reporter gene assay showed that expression of the EPcA region strongly impairs the transcriptional repressive activity of RFP.


Anthropometry and blood pressure changes in a Caribbean adolescent population of African ancestry: an evaluation of longitudinal data using a multilevel mixed regression approach.
The aim of this study was to determine the effect of growth pattern on blood pressure changes in an adolescent population of African ancestry based on longitudinal data and to compare this with estimates derived from cross-sectional data. Participants had measurements of weight, height, blood pressure and percentage body fat taken annually using standardized procedures. Annual blood pressure and anthropometry velocities as well as one- and three-year interval gender specific tracking coefficients were computed. We investigated whether changes in blood pressure could be explained by measures of growth using a multilevel mixed regression approach. The results showed that systolic blood pressure (SBP) increased by 1.27 and 3.09 mmHg per year among females and males, respectively. Similarly, diastolic blood pressure (DBP) increased by 1.16 and 1.92 mmHg per year among females and males, respectively. Multilevel analyses suggested that weight, body mass index, percentage body fat and height were the strongest anthropometric determinants of blood pressure change in this population. The results also suggest that there are gender differences in the relative importance of these anthropometric measures with height playing a minor role in predicting blood pressure changes among adolescent females. With the exception of DBP at 18 years among females, there were no significant differences between mean blood pressure generated from cross-sectional and longitudinal data by age in both males and females. Anthropometric measures are important covariates of age-related blood pressure changes and cross-sectional data may provide a more cost-effective and useful proxy for generating age-related blood pressure estimates in this population.


Acute clinical adverse radiation effects after Gamma Knife surgery for vestibular schwannomas.
OBJECTIVE Vestibular schwannomas (VSs) represent a common indication of Gamma Knife surgery (GKS). While most studies focus on the long-term morbidity and adverse radiation effects (AREs), none describe the acute clinical AREs that might appear on a short-term basis. These types of events are investigated, and their incidence, type, and outcomes are reported in the present paper. METHODS The included patients were treated between July 2010 and March 2016, underwent at least 6 months of follow-up, and presented with a disabling symptom during the first 6 months after GKS that affected their quality of life. The timing of appearance, as well as the type of main symptom and outcome, were noted. The prescribed dose was 12 Gy at the margin. RESULTS Thirty-five (22%) of 159 patients who fulfilled the inclusion criteria had acute clinical AREs. The mean followup period was 30 months (range 6-49.2 months). The mean time of appearance was 37.9 days (median 31 days; range 3-110 days). In patients with de novo symptoms, the more frequent symptoms were vertigo (n = 4; 11.4%) and gait disturbance (n = 3; 8.6%). The exacerbation of a preexisting symptom was more frequently related to hearing loss (n = 10; 28.6%), followed by gait disturbance (n = 7; 20%) and vertigo (n = 3, 8.6%). In the univariate logistic regression analysis, the following factors were statistically significant: age (p = 0.002; odds ratio [OR] 0.96), hearing at baseline by Gardner-Robertson (GR) class (p = 0.006; OR 0.21), pure tone average at baseline (p = 0.006; OR 0.97), and Koos grade at baseline (with Koos Grade I used as a reference) (for Koos Grade II, OR 0.17 and p = 0.002; for Koos Grade III, OR 0.42 and p = 0.05). The following were not statistically significant but showed a tendency toward significance: the number of isocenters (p = 0.06; OR 0.94) and the maximal dose received by the cochlea (p = 0.07; OR 0.74). Fractional polynomial regression analysis showed a nonlinear relationship between the outcome and the radiation dose rate (minimum reached at a cutoff of 2.5 Gy/minute) and the maximal vestibular dose (maximum reached at a cutoff of 8 Gy), but the small sample size precludes a detailed analysis of the former. The clinical acute AREs disappeared in 32 (91.4%) patients during the first 6 months after appearance. Permanent and somewhat disabling morbidity was found in 3 cases (1.9% from the whole series): 1 each with complete hearing loss (GR Class I before and V after), hemifacial spasm (persistent but alleviated), and dysgeusia. CONCLUSIONS Acute effects after radiosurgery for VS are not rare. They concern predominantly de novo vertigo and gait disturbance and the exacerbation of preexistent hearing loss. In de novo vestibular symptoms, a vestibular dose of more than 8 Gy is thought to play a role. In most cases, none of these effects are permanent, and they will ultimately improve or disappear with steroid therapy. Permanent AREs remain very rare.


Haemophilus influenzae type B meningitis among children in Hanoi, Vietnam: epidemiologic patterns and estimates of H. Influenzae type B disease burden.
From March 2000 to February 2002, a population-based study of Haemophilus influenzae type b (Hib) meningitis was conducted among children less than five years of age in Hanoi, Vietnam. Children with suspected bacterial meningitis were referred to hospitals and each patient underwent standardized clinical examination and microbiologic testing. In Hanoi, 580 children were evaluated for bacterial meningitis and 23 (4%) had confirmed or probable Hib meningitis. The incidence of all Hib meningitis was 12/100,000 child-years less than five years of age and 26/100,000 child-years less than two years of age. Nationally, an estimated 1,005 children less than five years of age are hospitalized for Hib meningitis and 5,107 are hospitalized for Hib pneumonia. Among children with Hib meningitis, at least 100 will develop severe neurologic sequelae and 40 will die. These data suggest there is a substantial burden of Hib disease in Vietnam. National leaders will be provided with these data to facilitate development of national vaccination policies for children in Vietnam.


Soluble rhesus lymphocryptovirus gp350 protects against infection and reduces viral loads in animals that become infected with virus after challenge.
Epstein-Barr virus (EBV) is a human lymphocryptovirus that is associated with several malignancies. Elevated EBV DNA in the blood is observed in transplant recipients prior to, and at the time of post-transplant lymphoproliferative disease; thus, a vaccine that either prevents EBV infection or lowers the viral load might reduce certain EBV malignancies. Two major approaches have been suggested for an EBV vaccine- immunization with either EBV glycoprotein 350 (gp350) or EBV latency proteins (e.g. EBV nuclear antigens [EBNAs]). No comparative trials, however, have been performed. Rhesus lymphocryptovirus (LCV) encodes a homolog for each gene in EBV and infection of monkeys reproduces the clinical, immunologic, and virologic features of both acute and latent EBV infection. We vaccinated rhesus monkeys at 0, 4 and 12 weeks with (a) soluble rhesus LCV gp350, (b) virus-like replicon particles (VRPs) expressing rhesus LCV gp350, (c) VRPs expressing rhesus LCV gp350, EBNA-3A, and EBNA-3B, or (d) PBS. Animals vaccinated with soluble gp350 produced higher levels of antibody to the glycoprotein than those vaccinated with VRPs expressing gp350. Animals vaccinated with VRPs expressing EBNA-3A and EBNA-3B developed LCV-specific CD4 and CD8 T cell immunity to these proteins, while VRPs expressing gp350 did not induce detectable T cell immunity to gp350. After challenge with rhesus LCV, animals vaccinated with soluble rhesus LCV gp350 had the best level of protection against infection based on seroconversion, viral DNA, and viral RNA in the blood after challenge. Surprisingly, animals vaccinated with gp350 that became infected had the lowest LCV DNA loads in the blood at 23 months after challenge. These studies indicate that gp350 is critical for both protection against infection with rhesus LCV and for reducing the viral load in animals that become infected after challenge. Our results suggest that additional trials with soluble EBV gp350 alone, or in combination with other EBV proteins, should be considered to reduce EBV infection or virus-associated malignancies in humans.


Femtosecond digital lensless holographic microscopy to image biological samples.
The use of femtosecond laser radiation in digital lensless holographic microscopy (DLHM) to image biological samples is presented. A mode-locked Ti:Sa laser that emits ultrashort pulses of 12 fs intensity FWHM, with 800 nm mean wavelength, at 75 MHz repetition rate is used as a light source. For comparison purposes, the light from a light-emitting diode is also used. A section of the head of a drosophila melanogaster fly is studied with both light sources. The experimental results show very different effects of the pinhole size on the spatial resolution with DLHM. Unaware phenomena on the field of the DLHM are analyzed.


Tradeoffs in bacterial physiology determine the efficiency of antibiotic killing.
Antibiotic effectiveness depends on a variety of factors. While many mechanistic details of antibiotic action are known, the connection between death rate and bacterial physiology is poorly understood. A common observation is that death rate in antibiotics rises linearly with growth rate; however, it remains unclear how other factors, such as environmental conditions and whole-cell physiological properties, affect bactericidal activity. To address this, we developed a high-throughput assay to precisely measure antibiotic-mediated death. We found that death rate is linear in growth rate, but the slope depends on environmental conditions. Growth under stress lowers death rate compared to nonstressed environments with similar growth rate. To understand stress's role, we developed a mathematical model of bacterial death based on resource allocation that includes a stress-response sector; we identify this sector using RNA-seq. Our model accurately predicts the minimal inhibitory concentration (MIC) with zero free parameters across a wide range of growth conditions. The model also quantitatively predicts death and MIC when sectors are experimentally modulated using cyclic adenosine monophosphate (cAMP), including protection from death at very low cAMP levels. The present study shows that different conditions with equal growth rate can have different death rates and establishes a quantitative relation between growth, death, and MIC that suggests approaches to improve antibiotic efficacy.


Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management.
While congenital malformations and genetic diseases are a leading cause of early infant death, to our knowledge, the contribution of single-gene disorders in this group is undetermined. To determine the diagnostic yield and use of clinical exome sequencing in critically ill infants. Clinical exome sequencing was performed for 278 unrelated infants within the first 100 days of life who were admitted to Texas Children's Hospital in Houston, Texas, during a 5-year period between December 2011 and January 2017. Exome sequencing types included proband exome, trio exome, and critical trio exome, a rapid genomic assay for seriously ill infants. Indications for testing, diagnostic yield of clinical exome sequencing, turnaround time, molecular findings, patient age at diagnosis, and effect on medical management among a group of critically ill infants who were suspected to have genetic disorders. The mean (SEM) age for infants participating in the study was 28.5 (1.7) days; of these, the mean (SEM) age was 29.0 (2.2) days for infants undergoing proband exome sequencing, 31.5 (3.9) days for trio exome, and 22.7 (3.9) days for critical trio exome. Clinical indications for exome sequencing included a range of medical concerns. Overall, a molecular diagnosis was achieved in 102 infants (36.7%) by clinical exome sequencing, with relatively low yield for cardiovascular abnormalities. The diagnosis affected medical management for 53 infants (52.0%) and had a substantial effect on informed redirection of care, initiation of new subspecialist care, medication/dietary modifications, and furthering life-saving procedures in select patients. Critical trio exome sequencing revealed a molecular diagnosis in 32 of 63 infants (50.8%) at a mean (SEM) of 33.1 (5.6) days of life with a mean (SEM) turnaround time of 13.0 (0.4) days. Clinical care was altered by the diagnosis in 23 of 32 patients (71.9%). The diagnostic yield, patient age at diagnosis, and medical effect in the group that underwent critical trio exome sequencing were significantly different compared with the group who underwent regular exome testing. For deceased infants (n = 81), genetic disorders were molecularly diagnosed in 39 (48.1%) by exome sequencing, with implications for recurrence risk counseling. Exome sequencing is a powerful tool for the diagnostic evaluation of critically ill infants with suspected monogenic disorders in the neonatal and pediatric intensive care units and its use has a notable effect on clinical decision making.


Pragmatic Study of Clinician Use of a Personalized Patient Decision Aid Integrated into the Electronic Health Record: An 8-Year Experience.
Background: Patient decision aids (PDAs) facilitate shared decision-making (SDM) and are delivered in a variety of formats, including printed material or instructional videos, and, more recently, web-based tools. Barriers such as time constraints and disruption to clinical workflow are reported to impede usage in routine practice. Introduction: This pragmatic study examines use of PDAs integrated (iPDAs) into the electronic health record (EHR) over an 8-year period. Methods: A suite of iPDAs that personalize decision-making was integrated into an academic health system EHR. Clinician use was tracked using patient and clinician encrypted information, enabling identification of clinician types and unique uses for an 8-year period. Clinician feedback was obtained through survey. Results: Over 8 years, 1,209 identifiable clinicians used the iPDAs at least once ("aware"). Use increased over time, with 2,415 unique uses in 2010, and 23,456 in 2017. Clinicians who used an iPDA with at least 5 patients ("adopters"), increased by 82 clinicians each year (range 56-108); of clinicians who used the tool once, 54.3% became adopters. Of 261 primary care clinicians, 93.5% were aware, 86.2% were adopters, and 80.5% used the tools in the last 90 days. Clinicians perceived the iPDAs to be convenient, efficient, and encouraging of SDM. Discussion: We demonstrate that use of decision aids integrated into the EHR result in repeated use among clinicians over time and have the potential to overcome barriers to implementation. We noted a high degree of clinician satisfaction, without a sense of increase in visit time. Conclusion: Integration of PDAs into the EHR results in sustained use. Further research is needed to assess the impact of iPDAs on decisional quality.


Comparative analysis of the root transcriptomes of cultivated and wild rice varieties in response to Magnaporthe oryzae infection revealed both common and species-specific pathogen responses.
Magnaporthe oryzae, the causal fungus of rice blast disease, negatively impacts global rice production. Wild rice (Oryza rufipogon), a relative of cultivated rice (O. sativa), possesses unique attributes that enable it to resist pathogen invasion. Although wild rice represents a major resource for disease resistance, relative to current cultivated rice varieties, no prior studies have compared the immune and transcriptional responses in the roots of wild and cultivated rice to M. oryzae. In this study, we showed that M. oryzae could act as a typical root-infecting pathogen in rice, in addition to its common infection of leaves, and wild rice roots were more resistant to M. oryzae than cultivated rice roots. Next, we compared the differential responses of wild and cultivated rice roots to M. oryzae using RNA-sequencing (RNA-seq) to unravel the molecular mechanisms underlying the enhanced resistance of the wild rice roots. Results indicated that both common and genotype-specific mechanisms exist in both wild and cultivated rice that are associated with resistance to M. oryzae. In wild rice, resistance mechanisms were associated with lipid metabolism, WRKY transcription factors, chitinase activities, jasmonic acid, ethylene, lignin, and phenylpropanoid and diterpenoid metabolism; while the pathogen responses in cultivated rice were mainly associated with phenylpropanoid, flavone and wax metabolism. Although modulations in primary metabolism and phenylpropanoid synthesis were common to both cultivated and wild rice, the modulation of secondary metabolism related to phenylpropanoid synthesis was associated with lignin synthesis in wild rice and flavone synthesis in cultivated rice. Interestingly, while the expression of fatty acid and starch metabolism-related genes was altered in both wild and cultivated rice in response to the pathogen, changes in lipid acid synthesis and lipid acid degradation were dominant in cultivated and wild rice, respectively. The response mechanisms to M. oryzae were more complex in wild rice than what was observed in cultivated rice. Therefore, this study may have practical implications for controlling M. oryzae in rice plantings and will provide useful information for incorporating and assessing disease resistance to M. oryzae in rice breeding programs.


Predictors of Six-month Change in the Voice Handicap Index in a Treatment-seeking Population.
To evaluate predictors of longitudinal change in patient-perceived voice impact as determined by the Voice Handicap Index (VHI). Prospective, survey study. Patients consented to the University of Wisconsin Voice and Swallow Clinics Outcomes Database with voice, concerns with a baseline clinic visit from November 2012 to January 2014 were eligible for the study. The VHI was sent to patients 6 months post clinic visit to determine change in voice handicap from baseline. General health was screened using the 12-item Short Form Health Survey, using physical component summary and mental component summary scores. Predictor variables included treatment (medical and/or behavioral); dysphonia sub-diagnosis; grade, roughness, breathiness, asthenia, and strain rating; age; sex; socioeconomic factors; smoking history; and comorbidity score. Two hundred thirty-seven patients met study criteria and were followed longitudinally. Eighty-two patients returned 6-month surveys. The VHI was significantly correlated with mental component summary scores. Patients with a higher grade in baseline grade, roughness, breathiness, asthenia, and strain score were more likely to receive voice intervention (P = 0.04). Six-month improvement in VHI score was associated with both higher initial VHI score and higher educational level in both univariate (P < 0.01, P = 0.04) and multivariate analyses (P < 0.01, P = 0.02). Voice treatment (medical and/or behavioral) was not a significant factor for improvement in VHI score. Our results suggest that it is important to consider baseline self-perceived voice impact measures and educational level in setting expectations for voice treatment. Future studies examining the relationship between treatment patterns and voice-related patient outcomes are warranted.


Spinal motion palpation: a comparison of studies that assessed intersegmental end feel vs excursion.
Spinal motion palpation (MP) is a procedure used to detect intersegmental hypomobility/hypermobility. Different means of assessing intersegmental mobility are described, assessing either excursion of the segments (quantity of movement) or end feel (quality of motion when stressed against the paraphysiological space). The objective of this review was to classify and compare studies based on method of MP used, considering that some studies may have used both methods. Four databases were searched: MEDLINE-PubMed, Manual Alternative and Natural Therapy System, Index to Chiropractic Literature, and Cumulative Index to Nursing and Allied Health Literature databases for the years 1965 through January 2007. Retrieved citations were independently screened for inclusion by 2 of the authors consistent with the inclusion and exclusion criteria. Included studies were appraised for quality, and data were extracted and recorded in tables. The search strategy generated 415 citations, and 29 were harvested from reference lists. After removing articles that did not meet the inclusion criteria, 44 were considered relevant and appraised for quality. Fifteen studies focused on MP excursion, 24 focused on end feel, and 5 used both. Eight studies reported high levels of reproducibility (kappa = >or=0.4), although 4 were not of acceptable quality, and 2 were only marginally acceptable. When only high-quality studies were considered, 3 of 24 end-feel studies reported good reliability compared with 1 of 15 excursion studies. There was no statistical support for a difference between the 2 groupings. A difference in reported reliability was observed when the method of MP varied, although it was not statistically significant. There was no support in the literature for the advantage of one MP method over the other.


Impact of resident participation on morbidity and mortality in neurosurgical procedures: an analysis of 16,098 patients.
The authors sought to determine the impact of resident participation on overall 30-day morbidity and mortality following neurosurgical procedures. The American College of Surgeons National Surgical Quality Improvement Program database was queried for all patients who had undergone neurosurgical procedures between 2006 and 2012. The operating surgeon(s), whether an attending only or attending plus resident, was assessed for his or her influence on morbidity and mortality. Multivariate logistic regression, was used to estimate odds ratios for 30-day postoperative morbidity and mortality outcomes for the attending-only compared with the attending plus resident cohorts (attending group and attending+resident group, respectively). The study population consisted of 16,098 patients who had undergone elective or emergent neurosurgical procedures. The mean patient age was 56.8 ± 15.0 years, and 49.8% of patients were women. Overall, 15.8% of all patients had at least one postoperative complication. The attending+resident group demonstrated a complication rate of 20.12%, while patients with an attending-only surgeon had a statistically significantly lower complication rate at 11.70% (p < 0.001). In the total population, 263 patients (1.63%) died within 30 days of surgery. Stratified by operating surgeon status, 162 patients (2.07%) in the attending+resident group died versus 101 (1.22%) in the attending group, which was statistically significant (p < 0.001). Regression analyses compared patients who had resident participation to those with only attending surgeons, the referent group. Following adjustment for preoperative patient characteristics and comorbidities, multivariate regression analysis demonstrated that patients with resident participation in their surgery had the same odds of 30-day morbidity (OR = 1.05, 95% CI 0.94-1.17) and mortality (OR = 0.92, 95% CI 0.66-1.28) as their attending only counterparts. Cases with resident participation had higher rates of mortality and morbidity; however, these cases also involved patients with more comorbidities initially. On multivariate analysis, resident participation was not an independent risk factor for postoperative 30-day morbidity or mortality following elective or emergent neurosurgical procedures.


Generating optimal control simulations of musculoskeletal movement using OpenSim and MATLAB.
Computer modeling, simulation and optimization are powerful tools that have seen increased use in biomechanics research. Dynamic optimizations can be categorized as either data-tracking or predictive problems. The data-tracking approach has been used extensively to address human movement problems of clinical relevance. The predictive approach also holds great promise, but has seen limited use in clinical applications. Enhanced software tools would facilitate the application of predictive musculoskeletal simulations to clinically-relevant research. The open-source software OpenSim provides tools for generating tracking simulations but not predictive simulations. However, OpenSim includes an extensive application programming interface that permits extending its capabilities with scripting languages such as MATLAB. In the work presented here, we combine the computational tools provided by MATLAB with the musculoskeletal modeling capabilities of OpenSim to create a framework for generating predictive simulations of musculoskeletal movement based on direct collocation optimal control techniques. In many cases, the direct collocation approach can be used to solve optimal control problems considerably faster than traditional shooting methods. Cyclical and discrete movement problems were solved using a simple 1 degree of freedom musculoskeletal model and a model of the human lower limb, respectively. The problems could be solved in reasonable amounts of time (several seconds to 1-2 hours) using the open-source IPOPT solver. The problems could also be solved using the fmincon solver that is included with MATLAB, but the computation times were excessively long for all but the smallest of problems. The performance advantage for IPOPT was derived primarily by exploiting sparsity in the constraints Jacobian. The framework presented here provides a powerful and flexible approach for generating optimal control simulations of musculoskeletal movement using OpenSim and MATLAB. This should allow researchers to more readily use predictive simulation as a tool to address clinical conditions that limit human mobility.


Use of space and behavior of weaned piglets kept in enriched two-level housing system.
In this study, the possibility of introducing an elevated platform to a piglet pen was explored as a way of increasing available space and creating functional areas. On the platform, nine different manipulable materials were offered. In four batches, 40 weaned piglets were kept for five weeks in the two-level pen. Video recordings were taken two days per week. In the afternoon, more piglets were on the platform than in the morning or at night (7.2 ± 0.1 vs. 4.9 ± 0.1 vs. 0.6 ± 0.1 piglets/5 minutes; p < .05). The area under the platform was preferred more in the morning and at night than in the afternoon (18.5 ± 0.1 vs. 21.6 ± 0.2 vs. 12.5 ± 0.1 piglets/5 minutes; p < .05). Up to 36 piglets were counted there simultaneously, mainly in the recumbent position. On and under the platform, air velocity and ammonia concentration were within the recommended ranges. The study concluded that a two-level pen is a feasible option to increase space allowance and to create functional areas in a piglet pen.


Using co-variations in the Hb signal to detect visual activation: a near infrared spectroscopic imaging study.
The premise of this report is that functional Near Infrared Spectroscopy (fNIRS) imaging data contain valuable physiological information that can be extracted by using analysis techniques that simultaneously consider the components of the measured hemodynamic response [i.e., levels of oxygenated, deoxygenated and total hemoglobin (oxyHb, deoxyHb and totalHb, respectively)]. We present an algorithm for examining the spatiotemporal co-variations among the Hb components, and apply it to the data obtained from a demonstrational study that employed a well-established visual stimulation paradigm: a contrast-reversing checkerboard. Our results indicate that the proposed method can identify regions of tissue that participate in the hemodynamic response to neuronal activation, but are distinct from the areas identified by conventional analyses of the oxyHb, deoxyHb and totalHb data. A discussion is provided that compares these findings to other recent studies using fNIRS techniques.


Synthesis of Zwitterionic Pluronic Analogs.
Novel polymer amphiphiles with chemical structures designed as zwitterionic analogs of Pluronic block copolymers were prepared by controlled free radical polymerization of phosphorylcholine (PC) or choline phosphate (CP) methacrylate monomers from a difunctional poly(propylene oxide) (PPO) macroinitiator. Well-defined, water-dispersible zwitterionic triblock copolymers, or "zwitteronics", were prepared with PC content ranging from 5 to 47 mol percent and composition-independent surfactant characteristics in water, which deviate from the properties of conventional Pluronic amphiphiles. These PC-zwitteronics assembled into nanoparticles in water, with tunable sizes and critical aggregation concentrations (CACs) based on their hydrophilic-lipophilic balance (HLB). Owing to the lower critical solution temperature (LCST) miscibility of the hydrophobic PPO block in water, PC-zwitteronics exhibited thermoreversible aqueous solubility tuned by block copolymer composition. The chemical versatility of this approach was demonstrated by embedding functionality, in the form of alkyne groups, directly into the zwitterion moieties. These alkynes proved ideal for cross-linking the zwitteronic nanoparticles and for generating nanoparticle-cross-linked hydrogels using UV-initiated thiol-yne "click" chemistry.


A magnetic resonance imaging study of regional cortical volumes following stereotactic anterior cingulotomy.
The purpose of this study was to test the hypothesis that orbitofrontal cortical volume would be reduced following anterior cingulotomy for obsessive-compulsive disorder (OCD). Whole brain cortical parcellation was performed on magnetic resonance imaging (MRI) data from nine patients, before and 9 (+/-6) months following anterior cingulotomy. No significant volumetric reductions were found in the orbitofrontal cortex. Exploratory findings of reduced volume in ventral temporo-fusiform and posterior cingulate regions were consistent with chance differences, in the face of multiple comparisons. Therefore, though the circumscribed lesions of anterior cingulotomy have recently been associated with corresponding volumetric reductions in the caudate nucleus, no comparable volumetric reductions are evident in cortical territories. Taken together, these results are most consistent with a model of cingulo-striatal perturbation as a putative mechanism for the efficacy of this procedure. While limitations in sensitivity may have also contributed to these negative findings, the methods employed have previously proven sufficient to detect cortical volumetric abnormalities in OCD. The current results may reflect a relatively diffuse pattern of cortico-cortical connections involving the neurons at the site of cingulotomy lesions. Future functional neuroimaging studies are warranted to assess possible cortical or subcortical metabolic changes associated with anterior cingulotomy, as well as predictors of treatment response.


Intensity of Medical Interventions between Diagnosis and Death in Patients with Advanced Lung and Colorectal Cancer: A CanCORS Analysis.
Medical interventions are an important component of the illness experience in advanced cancer. To describe the use of medical interventions between diagnosis and death in decedents with metastatic lung and colorectal cancer. Retrospective analysis of a prospective cohort study. We studied 1,840 decedents from the Cancer Care Outcomes Research and Surveillance (CanCORS) study. Subjects had been diagnosed with stage IV lung or colorectal cancer between 2003 and 2005. Hospitalizations, surgeries, radiation therapy treatments, chemotherapy treatments, and end-of-life care, reported by tertile of overall survival time. Median survival in the bottom, middle, and top tertiles of survival was 1.2, 5.3, and 15.3 months for lung cancer, and 3.0, 18.0, and 44.4 months for colorectal cancer. Hospitalizations, chemotherapy receipt, and hospice enrollment increased with increasing survival. The median duration of chemotherapy in the top survival tertile was 149 days for lung cancer and 498 days for colorectal cancer. A minority of decedents used any hospice services, and the median duration of hospice enrollment exceeded 30 days only for enrollees in the top survival tertile (lung cancer, 35 days; colorectal cancer, 66 days). For patients with metastatic lung and colorectal cancer, longer survival is associated with increased intensity of medical care, characterized by greater use of chemotherapy and acute hospital care. Hospice utilization was uniformly low, and most hospice enrollees were referred to hospice in the last 30 days of life.


Differential inhibitory effects of three nitric oxide donors on ornithine decarboxylase activity in human colon carcinoma cells.
Ornithine decarboxylase (ODC, EC 126.96.36.199) is the enzyme responsible for the synthesis of polyamines, which are absolutely necessary for cell proliferation. In the present work, we tested the effects of 3 nitric oxide (NO) donors, namely, sodium nitroprusside (SNP), (Z)-1-(N-methyl-N-[6-(N-methylammoniohexyl)amino] diazen-1-ium-1,2-diolate (MAHMA/NO) and 1,1-diethyl-2-hydroxy-2-nitroso-hydrazine sodium (DEA/NO), on ODC activity in human-colon carcinoma cells (HT-29). SNP was the most effective inhibitor of ODC activity with a concentration of 8 micromol/L inducing 50% inhibition of basal activity. The effect of SNP was reversed by haemoglobin (Hb), but not by GSH or L-cysteine (CYS). Very little of the SNP in solution was degraded into nitrite, but the presence of cellular homogenate increased the production of nitrite. MAHMA/NO and DEA/NO were much less effective than SNP as ODC inhibitors, since the concentrations of these agents which induce 50% inhibition of basal activity were 20- to 60-fold higher than that of SNP. The effects of MAHMA/NO and DEA/NO were not reversed by haemoglobin. In solution, these latter 2 agents were totally degraded into nitrites. In conclusion, SNP on the one hand and MAHMA/NO and DEA/NO on the other appeared to release different NOx species with different efficiency on ODC activity.


Operational criteria for the classification of chronic alcoholics: identification of Wernicke's encephalopathy.
To establish better operational criteria for the diagnosis of Wernicke's encephalopathy. Current criteria for diagnosing Wernicke's encephalopathy require the presence of three clinical signs (oculomotor abnormalities, cerebellar dysfunction, and an altered mental state), although it has often been reported that most patients do not fulfil all these criteria. The clinical histories of 28 alcoholics with neurological and neuropsychological assessments and definitive neuropathological diagnoses were examined to determine clinical signs for use in a screening schedule. Operational criteria were then proposed for differentiating patients with Wernicke's encephalopathy alone or in combination with Korsakoff's psychosis or hepatic encephalopathy. The new criteria for Wernicke's encephalopathy require two of the following four signs; (1) dietary deficiencies, (2) oculomotor abnormalities, (3) cerebellar dysfunction, and (4) either an altered mental state or mild memory impairment. Reproducibility and validity testing of these criteria were performed on 106 alcoholics screened from a large necropsy sample. Despite rater variability with regard to specific symptoms, within and between rater reliability for diagnostic classification using the criteria retrospectively on patient records was 100% for three independent raters. Validity testing showed that Wernicke's encephalopathy was underrecognized only when occurring with hepatic encephalopathy (50% sensitivity). By contrast with current criteria, the proposed operational criteria show that the antemortem identification of Wernicke's encephalopathy can be achieved with a high degree of specificity.


In vitro drug release characteristic and cytotoxic activity of silibinin-loaded single walled carbon nanotubes functionalized with biocompatible polymers.
In this paper, we demonstrate the preparation of silibinin-loaded carbon nanotubes (SWSB) with surface coating agents via non-covalent approach as an effective drug delivery system. The resulting surface-coated SWSB nanocomposites are extensively characterized by Fourier transform infrared (FTIR) and Raman spectroscopies, ultraviolet-visible (UV-Vis) spectrometry and field emission scanning electron microscopy (FESEM). The FTIR and Raman studies show that an additional layer is formed by these coating agents in the prepared nanocomposites during the coating treatment and these results are confirmed by FESEM. Drug loading and release profiles of the coated SWSB nanocomposites in phosphate buffered saline solution at pH 7.4 is evaluated by UV-Vis spectrometry. The in vitro results indicate that the surface-modified nanocomposites, with SB loading of 45 wt%, altered the initial burst and thus, resulted in a more prolonged and sustained release of SB. In addition, these nanocomposites exhibit a pseudo-second-order release kinetic which was driven by the ion exchange between the ionized SWSB and the anions in the release medium. The cytotoxicity effect of the resulting nanocomposites on normal mouse fibroblast cells is evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. It is observed that the surfactant and polymer coating improved the biocompatibility of the SWSB nanocomposites significantly, which deem further exploitation for their application as potential anticancer drug delivery system.


Endotoxin induces parathyroid hormone-related protein gene expression in splenic stromal and smooth muscle cells, not in splenic lymphocytes.
PTH-related protein (PTHrP), the peptide that is responsible for most cases of hypercalcemia of malignancy, is also produced under normal circumstances by a variety of tissues. Its role and regulation at these sites are not well understood. Recently, we have shown that PTHrP is induced in the spleen during the host response to endotoxin (LPS) and that tumor necrosis factor (TNF) is a major mediator of this effect. Given the large body of in vitro evidence suggesting that PTHrP can be produced by lymphocytes and act in an autocrine loop to alter their function, studies were undertaken to determine whether lymphocytes were the cells responsible for PTHrP production in the spleen. Both constitutive and LPS-induced PTHrP messenger RNA (mRNA) levels were the same in mice lacking mature T cells (nude mice) and in mice lacking natural killer (NK) cells (due to pretreatment with antibody against NK 1.1) compared to levels in normal mice, suggesting that neither mature T cells nor NK cells were the splenic source of PTHrP. Even scid mice that lack functioning T and B cells responded to TNF with the induction of splenic PTHrP mRNA levels comparable to those in control mice. Localization of PTHrP mRNA in subfractions of rat spleens after in vivo treatment with LPS confirmed the results of the murine studies; PTHrP mRNA was barely detectable in the lymphocyte-rich single cell fraction of the spleen. In contrast, the stromal fraction of the spleen was enriched with PTHrP mRNA both in the basal state and in response to LPS. A similar pattern of distribution was seen for interleukin-6; LPS only increased mRNA levels of this TNF-inducible cytokine in the splenic stroma. In addition, mRNA for the PTH/PTHrP receptor, which decreased in response to LPS, colocalized with PTHrP mRNA in the stromal fraction of the spleen. Immunohistochemical studies identified PTHrP in two populations of splenic cells: 1) smooth muscle cells located in the splenic capsule and trabeculae and 2) a subpopulation of stromal cells located in the red pulp of the spleen, primarily in a subcapsular distribution. Consistent with the localization of PTHrP mRNA, lymphocytes in the white pulp of the spleen did not stain for PTHrP.


Instrument line-shape modeling and correction for off-axis detectors in fourier-transform spectrometry.
Spectra measured by off-axis detectors in a high-resolution Fourier-transform spectrometer are characterized by frequency scaling, asymmetry and broadening of their line shape, and self-apodization in the corresponding interferogram. For a narrow-band input spectrum and a specified detector geometry, a formalism is presented that accounts for these effects with separate terms. Some of the terms are used to correct the larger off-axis effects as part of the calibration. The remaining terms are used to model the residual effects with the on-axis instrument line shape. We extend this approach to the broadband case using filter banks. The technique is applied to simulated spectra for the Tropospheric Emissions Spectrometer. This approach is shown to maintain a radiometric accuracy to less than 0.1%.


Observable Two-Step Nucleation Mechanism in Solid-State Formation of Tungsten Carbide.
The nucleation of crystals from ubiquitous solid-state reactions impacts a wide range of natural and synthetic processes and is fundamental to physical and chemical synthesis. However, the microscopic organization mechanism of amorphous precursors to nanoscale clusters of ordered atoms (nucleus) in an all-solid environment is inaccessible by common experimental probes. Here, by using in situ transmission electron microscopy in combination with theoretical simulations, we show in the reactive formation of a metal carbide that nucleation actually occurs via a two-step mechanism, in which a spinodal-structured amorphous intermediate reorganizes from an amorphous precursor and precedes the emergence of a crystalline nucleus, rather than direct one-step nucleation from classical consideration. We further isolated a series of sophisticated dynamics during formation and development of the nucleus in real-space and interpreted them by thermodynamic favorability. We anticipate that such an indirect organization mechanism which contains a metastable intermedium among the free energy gap between precursors and nanocrystals has its chance in underlying most solid-state crystallizations, whereas the as-established experimental method represents a step forward in exploring fundamentals in chemical reaction, material engineering, etc.


Phase II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in combination with rituximab in patients with recurrent B-cell non-Hodgkin lymphoma.
Oblimersen sodium plus rituximab was evaluated in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) patients. Oblimersen was administered as a continuous intravenous infusion at a daily dose of 3 mg/kg/d for 7 d on alternate weeks for 3 weeks. Rituximab was given at a weekly dose of 375 mg/m(2) for six doses. Patients with stable disease or objective response were allowed to receive a second course of treatment. The overall response rate (ORR) was 42% with 10 complete responses (CR) and eight partial responses (PR). Twelve (28%) patients achieved a minimal response or stable disease. Among the 20 patients with follicular lymphoma the ORR was 60% (eight CR, four PR). Three of the responders were refractory to prior treatment with rituximab, and two of the responses occurred in patients who had failed an autologous stem cell transplant. Median duration of response was 12 months. Most toxicities were low grade and reversible. In conclusion, oblimersen sodium can be safely combined with rituximab. The combination appears to be most beneficial in patients with indolent NHL and warrants further investigation in a large randomized trial.


Voices from the bush: remote area nurses prioritise hazards that contribute to violence in their workplace.
Remote Area Nurses (RANs) in Australia frequently encounter hazards that contribute to violence in the work place. Resources to deal with this problem are limited. Adopting a risk management approach and using the Delphi method, a panel of expert RANs (n=10) from geographically diverse communities across Australia, identified and prioritised hazards that increase the risk of violence to nurses. This descriptive study found that RANs encounter a wide variety of hazards from a variety of sources. Environmental hazards are complicated by living in remote areas and practicing in different locations. Relationships between the nurse and the community can be complex and lack of experience and organisational support may contribute to an increased risk of violence. Hazards prioritised as 'major' or 'extreme' risks included: clinic maintenance and security features, attending to patients at staff residences, RAN inexperience and lack of knowledge about the community, as well as intoxicated clients with mental health issues. A work culture that accepts verbal abuse as 'part of the job' was identified as a significant organisational risk to RANs. A lack of action from management when hazards are identified by clinic staff and insufficient recognition of the risk of violence by employers were also significant hazards. Further consideration of the hazards described in this study following the risk management process, may provide opportunities to reduce the risk of violence towards RANs. Proposed control measures should be developed in consultation with RANs and the remote communities they work in.


Cerebellar infarction. Clinical and anatomic observations in 66 cases.
Cerebellar infarction displays different clinical features, depending on the vascular territory involved. We studied patients with infarcts in the territories of the posterior inferior cerebellar artery or the superior cerebellar artery to compare their clinical presentation, course, and prognosis. We retrospectively analyzed the clinical features, laboratory data, and imaging studies of 66 patients with cerebellar infarction collected consecutively at five institutions. All the cerebellar infarcts were documented on computed tomographic scan or magnetic resonance imaging. Two distinct profiles emerged, depending on the vascular territory involved. In 36 patients with posterior inferior cerebellar artery territory infarcts, a triad of vertigo, headache, and gait imbalance predominated at stroke onset. Computed tomography showed severe cerebellar mass effect in 11 cases (30%), with associated hydrocephalus in seven. In these seven patients (19%), postinfarct swelling led to brain stem compression that resulted in four deaths. In 30 patients with superior cerebellar artery infarcts, gait disturbance predominated at onset; vertigo and headache were significantly less common. The clinical course was usually benign. Computed tomography showed marked cerebellar mass effect, hydrocephalus, and brain stem compression in only two instances (7%). Presumed cerebral embolism was the predominant stroke mechanism in patients with superior cerebellar artery distribution infarcts, whereas in those with posterior inferior cerebellar artery distribution infarcts, the stroke mechanism was equally divided between cardiogenic embolism and posterior circulation arterial disease. Cerebellar infarcts in the posterior inferior cerebellar artery and superior cerebellar artery distribution have distinct differences in clinical presentation, course, and prognosis. These differences should help in the selection of appropriate monitoring and treatment strategies.


Controlling the mode of operation of organic transistors through side-chain engineering.
Electrolyte-gated organic transistors offer low bias operation facilitated by direct contact of the transistor channel with an electrolyte. Their operation mode is generally defined by the dimensionality of charge transport, where a field-effect transistor allows for electrostatic charge accumulation at the electrolyte/semiconductor interface, whereas an organic electrochemical transistor (OECT) facilitates penetration of ions into the bulk of the channel, considered a slow process, leading to volumetric doping and electronic transport. Conducting polymer OECTs allow for fast switching and high currents through incorporation of excess, hygroscopic ionic phases, but operate in depletion mode. Here, we show that the use of glycolated side chains on a thiophene backbone can result in accumulation mode OECTs with high currents, transconductance, and sharp subthreshold switching, while maintaining fast switching speeds. Compared with alkylated analogs of the same backbone, the triethylene glycol side chains shift the mode of operation of aqueous electrolyte-gated transistors from interfacial to bulk doping/transport and show complete and reversible electrochromism and high volumetric capacitance at low operating biases. We propose that the glycol side chains facilitate hydration and ion penetration, without compromising electronic mobility, and suggest that this synthetic approach can be used to guide the design of organic mixed conductors.


Comparison of a new self developing photopolymer with AA/PVA based photopolymer utilizing the NPDD model.
The development of suitable recording media for applications such as holographic optical elements and holographic data storage are of significant research and commercial interest. In this paper, a photopolymer material developed by Bayer MaterialScience is examined using various optical techniques and then characterised using the Non-local Photo-polymerization Driven Diffusion model. This material demonstrates the capabilities of a new class of photopolymer offering high index modulation, full colour recording, high light sensitivity and environmental stability. One key result of this study is the material's high spatial frequency resolution, indicating a very low non-local effect, thus qualifying it as a very good storage medium.


The association of CYP2D6 genotype and postoperative nausea and vomiting in orthopedic trauma patients.
The CYP2D6 gene encodes for an enzyme that is involved in the metabolism of more than 25% of all medications, including many opioids and antiemetics. It may contribute to the risk of postoperative nausea and vomiting (PONV), a common surgical complication. However, little research has been conducted in this area. The purpose of this study was to explore the association of CYP2D6 genotypes with PONV in adult surgical trauma patients. Data from 112 patients (28% female) with single extremity fractures, aged 18-70 years, were analyzed. PONV was defined as present if patients reported nausea, were observed vomiting, or received medication for PONV. Saliva samples collected for DNA extraction and Taqman(®) allele discrimination and quantitative real time polymerase chain reaction (qRT-PCR) were used to collect genotype data that were then used to assign CYP2D6 phenotype classification. The incidence of PONV was 38% in the postanesthesia care unit and increased to 50% when assessed at 48 hr. CYP2D6 classification results were 7 (6%) poor metabolizers, 34 (30%) intermediate metabolizers, and 71 (63%) extensive metabolizers. No ultrarapid metabolizers were identified. Patients who were classified as poor metabolizers had less PONV and higher pain scores. Gender and history of PONV, but not smoking, were also significant risk factors. Findings suggest variability in CYP2D6 impacts susceptibility to PONV.


Cell Culture in Microfluidic Droplets.
Cell manipulation in droplets has emerged as one of the great successes of microfluidic technologies, with the development of single-cell screening. However, the droplet format has also served to go beyond single-cell studies, namely by considering the interactions between different cells or between cells and their physical or chemical environment. These studies pose specific challenges linked to the need for long-term culture of adherent cells or the diverse types of measurements associated with complex biological phenomena. Here we review the emergence of droplet microfluidic methods for culturing cells and studying their interactions. We begin by characterizing the quantitative aspects that determine the ability to encapsulate cells, transport molecules, and provide sufficient nutrients within the droplets. This is followed by an evaluation of the biological constraints such as the control of the biochemical environment and promoting the anchorage of adherent cells. This first part ends with a description of measurement methods that have been developed. The second part of the manuscript focuses on applications of these technologies for cancer studies, immunology, and stem cells while paying special attention to the biological relevance of the cellular assays and providing guidelines on improving this relevance.


Gender Differences in Fear and Risk Perception During the COVID-19 Pandemic.
The COVID-19 pandemic has led many people to suffer from emotional distress. Previous studies suggest that women process and express affective experiences, such as fear, with a greater intensity compared to men. We administered an online survey to a sample of participants in the United States that measures fear of COVID-19, perceptions about health and financial risks, and preventative measures taken. Despite the empirical fact that men are more likely to experience adverse health consequences from COVID-19, women report greater fear and more negative expectations about health-related consequences of COVID-19 than men. However, women are more optimistic than men regarding the financial consequences of the pandemic. Women also report more negative emotional experiences generally during the pandemic, particularly in situations where other people or the government take actions that make matters worse. Though women report taking more preventative measures than men in response to the pandemic, gender differences in behavior are reduced after controlling for fear. These results shed light on how differences in emotional experiences of the pandemic may inform policy interventions.


Functional interactions between coexisting toxin-antitoxin systems of the ccd family in Escherichia coli O157:H7.
Toxin-antitoxin (TA) systems are widely represented on mobile genetic elements as well as in bacterial chromosomes. TA systems encode a toxin and an antitoxin neutralizing it. We have characterized a homolog of the ccd TA system of the F plasmid (ccd(F)) located in the chromosomal backbone of the pathogenic O157:H7 Escherichia coli strain (ccd(O157)). The ccd(F) and the ccd(O157) systems coexist in O157:H7 isolates, as these pathogenic strains contain an F-related virulence plasmid carrying the ccd(F) system. We have shown that the chromosomal ccd(O157) system encodes functional toxin and antitoxin proteins that share properties with their plasmidic homologs: the CcdB(O157) toxin targets the DNA gyrase, and the CcdA(O157) antitoxin is degraded by the Lon protease. The ccd(O157) chromosomal system is expressed in its natural context, although promoter activity analyses revealed that its expression is weaker than that of ccd(F). ccd(O157) is unable to mediate postsegregational killing when cloned in an unstable plasmid, supporting the idea that chromosomal TA systems play a role(s) other than stabilization in bacterial physiology. Our cross-interaction experiments revealed that the chromosomal toxin is neutralized by the plasmidic antitoxin while the plasmidic toxin is not neutralized by the chromosomal antitoxin, whether expressed ectopically or from its natural context. Moreover, the ccd(F) system is able to mediate postsegregational killing in an E. coli strain harboring the ccd(O157) system in its chromosome. This shows that the plasmidic ccd(F) system is functional in the presence of its chromosomal counterpart.


Bioinspired phase-separated disordered nanostructures for thin photovoltaic absorbers.
The wings of the black butterfly, Pachliopta aristolochiae, are covered by micro- and nanostructured scales that harvest sunlight over a wide spectral and angular range. Considering that these properties are particularly attractive for photovoltaic applications, we analyze the contribution of these micro- and nanostructures, focusing on the structural disorder observed in the wing scales. In addition to microspectroscopy experiments, we conduct three-dimensional optical simulations of the exact scale structure. On the basis of these results, we design nanostructured thin photovoltaic absorbers of disordered nanoholes, which combine efficient light in-coupling and light-trapping properties together with a high angular robustness. Finally, inspired by the phase separation mechanism of self-assembled biophotonic nanostructures, we fabricate these bioinspired absorbers using a scalable, self-assembly patterning technique based on the phase separation of binary polymer mixture. The nanopatterned absorbers achieve a relative integrated absorption increase of 90% at a normal incident angle of light to as high as 200% at large incident angles, demonstrating the potential of black butterfly structures for light-harvesting purposes in thin-film solar cells.


Differential expression of the intermediate filament peripherin in cutaneous neural lesions and neurotized melanocytic nevi.
Peripherin is an intermediate filament involved in growth and development of the peripheral nervous system, and is produced by neurons and the beta cells of the islets of Langerhans. Recently, malignant melanomas and some melanocytic nevi have been shown to express peripherin. It is unknown if Schwann cells, also derived from the neural crest, express peripherin. Expression of peripherin was evaluated by immunohistochemistry in cutaneous lesions characterized by a prominent Schwann cell component including 26 neurofibromas (NF), 10 schwannomas (SCH), seven granular cell tumors, and five palisaded encapsulated neuromas (PEN); 13 neurotized melanocytic nevi (NMN) also were evaluated because these lesions contain Wagner-Meissnerlike structures and type C nevus cells, which exhibit a "schwannian" phenotype. Peripherin was detected in the axons of normal peripheral nerves. NF and PEN contained numerous axons dispersed throughout the lesions, whereas only scattered small nerves were seen in GCT. In SCH, only rare axons were labeled, mostly at the periphery of the lesions. All other cells in these four types of lesions, therefore including Schwann cells, were not labeled. In most NMN, labeled axons were identified within the lesions. In a few cases, rare epithelioid melanocytes within the superficial portions of the nevi were labeled. The Wagner-Meissnerlike structures and type C nevus cells (schwannian) were not labeled in any lesion; however, numerous labeled axons invested these areas. Because there are different relative numbers of peripherin-labeled axons throughout NF, PEN, some nevi, and SCH, analysis of peripherin expression may be helpful in the diagnosis of these lesions. Neurons and some epithelioid melanocytes, in contrast to type C nevus cells and Schwann cells of NF and SCH, express peripherin, providing further evidence for a transition from a more neuronal to a more schwannian phenotype during the normal maturation sequence of melanocytes in nevi.


The Impact of Selection, Gene Conversion, and Biased Sampling on the Assessment of Microbial Demography.
Recent studies have linked demographic changes and epidemiological patterns in bacterial populations using coalescent-based approaches. We identified 26 studies using skyline plots and found that 21 inferred overall population expansion. This surprising result led us to analyze the impact of natural selection, recombination (gene conversion), and sampling biases on demographic inference using skyline plots and site frequency spectra (SFS). Forward simulations based on biologically relevant parameters from Escherichia coli populations showed that theoretical arguments on the detrimental impact of recombination and especially natural selection on the reconstructed genealogies cannot be ignored in practice. In fact, both processes systematically lead to spurious interpretations of population expansion in skyline plots (and in SFS for selection). Weak purifying selection, and especially positive selection, had important effects on skyline plots, showing patterns akin to those of population expansions. State-of-the-art techniques to remove recombination further amplified these biases. We simulated three common sampling biases in microbiological research: uniform, clustered, and mixed sampling. Alone, or together with recombination and selection, they further mislead demographic inferences producing almost any possible skyline shape or SFS. Interestingly, sampling sub-populations also affected skyline plots and SFS, because the coalescent rates of populations and their sub-populations had different distributions. This study suggests that extreme caution is needed to infer demographic changes solely based on reconstructed genealogies. We suggest that the development of novel sampling strategies and the joint analyzes of diverse population genetic methods are strictly necessary to estimate demographic changes in populations where selection, recombination, and biased sampling are present.


Diet quality in a wild grazer declines under the threat of an ambush predator.
Predators influence prey populations not only through predation itself, but also indirectly through prompting changes in prey behaviour. The behavioural adjustments of prey to predation risk may carry nutritional costs, but this has seldom been studied in the wild in large mammals. Here, we studied the effects of an ambush predator, the African lion (Panthera leo), on the diet quality of plains zebras (Equus quagga) in Hwange National Park, Zimbabwe. We combined information on movements of both prey and predators, using GPS data, and measurements of faecal crude protein, an index of diet quality in the prey. Zebras which had been in close proximity to lions had a lower quality diet, showing that adjustments in behaviour when lions are within short distance carry nutritional costs. The ultimate fitness cost will depend on the frequency of predator-prey encounters and on whether bottom-up or top-down forces are more important in the prey population. Our finding is the first attempt to our knowledge to assess nutritionally mediated risk effects in a large mammalian prey species under the threat of an ambush predator, and brings support to the hypothesis that the behavioural effects of predation induce important risk effects on prey populations.


Quadrivalent inactivated influenza vaccine (VaxigripTetra™).
VaxigripTetra™ (IIV4; Sanofi Pasteur) is a quadrivalent split-virion influenza vaccine approved in Europe in 2016 for individuals ≥ 3 years of age. IIV4 builds on the well-established record of the trivalent split-virion influenza vaccine (Vaxigrip®). Areas covered: This literature review summarizes the rationale for developing quadrivalent influenza vaccines and discusses the phase III clinical trial results supporting the immunogenicity, safety, and tolerability of IIV4. Expert commentary: IIV4 is immunogenic and well tolerated. Adding a second B strain to the trivalent split-virion influenza vaccine provides a superior immune response for the additional strain but does not reduce the immune response for the three other strains or negatively affect the safety profile. By offering broader protection against co-circulating influenza B lineages, IIV4 has the potential to further reduce influenza-related morbidity and mortality beyond that achieved with trivalent vaccines.


Impact of direct-acting antiviral agents on the development of hepatocellular carcinoma: evidence and pathophysiological issues.
Hepatitis C virus (HCV) infection is currently one of the main causes of cirrhosis and hepatocellular carcinoma (HCC) at a global level. Recently, a new generation of direct-acting antiviral agents (DAAs) has entered the HCV treatment landscape, providing impressively high rates of sustained virological response (SVR), and is expected to lead to an eventual decrease in HCV-related cirrhosis, liver transplantation and mortality. However, during the first years of their use, several studies reported a possible correlation between DAA treatment and an increased risk of HCC. Following the publication of larger prospective studies, the risk of de novo HCC occurrence has clearly been proven to be lower after the achievement of SVR, regardless of antiviral treatment. On the other hand, the risk of HCC recurrence following treatment with DAAs is debatable; existing data remain controversial, possibly because of the lack of large, well designed cohorts with more homogeneous patient populations. With regard to the pathophysiology behind the above observations, especially in patients with previous HCC history, HCC development could possibly be favored by the changes in the immunological milieu and the different cellular behavior after eradication of HCV infection with DAA treatment.


A tool box strategy using Bacteroides genetic markers to differentiate human from non-human sources of fecal contamination in natural water.
Bacteroides genetic markers have been widely used to identify fecal pollution of water originating from human and animal sources. Many of the assays currently used for detecting human-specific Bacteroides produce false positive results. The focus of this study was to develop a microbial source tracking (MST) tool box strategy for differentiating Bacteroides from human and animal sources. Bacteroides 16S rRNA gene sequences from fish and selected animals were aligned against human fecal Bacteroides isolates to compare and characterize the variable regions within the 16S rRNA gene sequence. Conserved sequences between 4 variable regions were deleted and the truncated sequences were combined to develop a hyper-variable genomic segment (HVGS). The cladogram created from truncated sequences show a clear separation of Bacteroides from human feces and those from animal sources. The proposed strategy was field tested by collecting water samples from central Arizona source waters and three different recreational ponds. PCR using HF134 and HF183 primer sets was performed and sequences from positive reactions were aligned against human Bacteroides sequences to identify the source of contamination. Based on PCR results, the source of fecal contamination was presumptively identified as either human or from another source. For samples testing positive using the HF183 primer set (8/13), fecal contamination was presumed to be from human sources, but to confirm the results, PCR products were sequenced and aligned against the four variable regions and then incorporated within the truncated cladogram. As expected, the sequences from water samples with human fecal contamination grouped in a separate clade. A variability matrix, developed after exclusion of conserved sequences among the four regions, was utilized to establish discrete groupings for sequences within the truncated cladogram, generally differentiating Bacteroides isolates from varying host animals, but most importantly, separating Bacteroides from human feces from Bacteroides from other animals. The proposed strategy offers a new tool box method for MST and a step-wise methodology essential for identifying human sources of fecal pollution.


Virtual reality, augmented reality…I call it i-Reality.
The new term improved reality (i-Reality) is suggested to include virtual reality (VR) and augmented reality (AR). It refers to a real world that includes improved, enhanced and digitally created features that would offer an advantage on a particular occasion (i.e., a medical act). I-Reality may help us bridge the gap between the high demand for medical providers and the low supply of them by improving the interaction between providers and patients.


High Grazing Pressure of Geese Threatens Conservation and Restoration of Reed Belts.
Reed (Phragmites australis (Cav.) Trin. ex Steud.) beds are important habitat for marsh birds, but are declining throughout Europe. Increasing numbers of the native marsh bird, the Greylag goose (Anser anser L.), are hypothesized to cause reed bed decline and inhibit restoration of reed beds, but data are largely lacking. In this study, we experimentally tested the effect of grazing by Greylag geese on the growth and expansion of reed growing in belts along lake shorelines. After 5 years of protecting reed from grazing with exclosures, reed stems were over 4-fold denser and taller than in the grazed plots. Grazing pressure was intense with 50-100% of the stems being grazed among years in the control plots open to grazing. After 5 years of protection we opened half of the exclosures and the geese immediately grazed almost 100% of the reed stems. Whereas this did not affect the reed stem density, the stem height was strongly reduced and similar to permanently grazed reed. The next year geese were actively chased away by management from mid-March to mid-June, which changed the maximum amount of geese from over 2300 to less than 50. As a result, reed stem density and height increased and the reed belt had recovered over the full 6 m length of the experimental plots. Lastly, we introduced reed plants in an adjacent lake where no reed was growing and geese did visit this area. After two years, the density of the planted reed was six to nine-fold higher and significantly taller in exclosures compared to control plots where geese had access to the reed plants. We conclude that there is a conservation dilemma regarding how to preserve and restore reed belts in the presence of high densities of Greylag geese as conservation of both reed belts and high goose numbers seems infeasible. We suggest that there are three possible solutions for this dilemma: (1) effects of the geese can be mediated by goose population management, (2) the robustness of the reed marshes can be increased, and (3) at the landscape level, spatial planning can be used to configure landscapes with large reed bed reserves surrounded by unmown, unfertilized meadows.


Diagnostic Performance of Risk of Ovarian Malignancy Algorithm Against CA125 and HE4 in Connection With Ovarian Cancer: A Meta-analysis.
The aim of this study was to determine whether the Risk of Ovarian Malignancy Algorithm (ROMA) is more accurate than the human epididymis 4 (HE4) or carbohydrate antigen 125 (CA125) biomarkers with respect to the differential diagnosis of women with a pelvic mass. The secondary objective is to assess the performance of ROMA in early-stage ovarian cancer (OC) and late-stage OC, as well as premenopausal and postmenopausal patient populations. The PubMed and Google Scholar databases were searched for relevant clinical studies. Eligibility criteria included comparison of ROMA with both HE4 and CA125 levels in OC (unspecified, epithelial, and borderline ovarian tumors), use of only validated ROMA assays, presentation of area under the curve and sensitivity/specificity data, and results from early-stage OC, late-stage OC and premenopausal and postmenopausal women. Area under the curve (AUC), sensitivity/specificity, and the diagnostic odds ratio (DOR) results were summarized. Five studies were selected comprising 1975 patients (premenopausal, n = 1033; postmenopausal, n = 925; benign, n = 1387; early stage, n = 192; and late stage, n = 313). On the basis of the AUC (95% confidence interval) data for all patients, ROMA (0.921 [0.855-0.960]) had a numerically greater diagnostic performance than CA125 (0.883 [0.771-0.950]) and HE4 (0.899 [0.835-0.943]). This was also observed in each of the subgroup populations, in particular, the postmenopausal patients and patients with early OC. The sensitivity and specificity (95% confidence interval) results showed ROMA (sensitivity, 0.873 [0.752-0.940]; specificity, 0.855 [0.719-0.932]) to be numerically superior to CA125 (sensitivity, 0.796 [0.663-0.885]; specificity, 0.825 [0.662-0.919]) and HE4 (sensitivity, 0.817 [0.683-0.902]; specificity, 0.851 [0.716-0.928]) in all patients and for the early- and late-stage OC subgroups. Finally, the ROMA log DOR results were better than HE4 and CA125 log DOR results especially for the early-stage patient group. The results presented support the use of ROMA to improve clinical decision making, most notably in patients with early OC.


An adaptive semantic based mediation system for data interoperability among Health Information Systems.
Heterogeneity in the management of the complex medical data, obstructs the attainment of data level interoperability among Health Information Systems (HIS). This diversity is dependent on the compliance of HISs with different healthcare standards. Its solution demands a mediation system for the accurate interpretation of data in different heterogeneous formats for achieving data interoperability. We propose an adaptive AdapteR Interoperability ENgine mediation system called ARIEN, that arbitrates between HISs compliant to different healthcare standards for accurate and seamless information exchange to achieve data interoperability. ARIEN stores the semantic mapping information between different standards in the Mediation Bridge Ontology (MBO) using ontology matching techniques. These mappings are provided by our System for Parallel Heterogeneity (SPHeRe) matching system and Personalized-Detailed Clinical Model (P-DCM) approach to guarantee accuracy of mappings. The realization of the effectiveness of the mappings stored in the MBO is evaluation of the accuracy in transformation process among different standard formats. We evaluated our proposed system with the transformation process of medical records between Clinical Document Architecture (CDA) and Virtual Medical Record (vMR) standards. The transformation process achieved over 90 % of accuracy level in conversion process between CDA and vMR standards using pattern oriented approach from the MBO. The proposed mediation system improves the overall communication process between HISs. It provides an accurate and seamless medical information exchange to ensure data interoperability and timely healthcare services to patients.


Detergents destabilize the cubic phase of monoolein: implications for membrane protein crystallization.
The in meso method for membrane protein crystallization uses a lipidic cubic phase as the hosting medium. The cubic phase provides a lipid bilayer into which the protein presumably reconstitutes and from which protein crystals nucleate and grow. The solutions used to spontaneously form the protein-enriched cubic phase often contain significant amounts of detergents that were employed initially to purify and to solubilize the membrane protein. By virtue of their surface activity, detergents have the potential to impact on the phase properties of the in meso system and, by extension, the outcome of the crystallization process. The purpose of this study was to quantify the effects that a popular series of nonionic detergents, the n-alkyl-beta-D-glucopyranosides, have on the phase behavior of hydrated monoolein, the lipid upon which the in meso method is based. Phase identity and phase microstructure were characterized by small-angle x-ray diffraction on samples prepared to mimic in meso crystallization conditions. Measurements were made in the 0-40 degrees C range. Samples prepared in the cooling direction allow for the expression of metastability, a feature of liquid crystalline phases that might be exploited in low-temperature crystallization. The results show that the cubic phase is relatively insensitive to small amounts of alkyl glucosides. However, at higher levels the detergents trigger a transition to the lamellar phase in a temperature- and salt concentration-dependent manner. These effects have important implications for in meso crystallization. A diffraction-based method for assaying detergents is presented.


Protostane and fusidane triterpenes: a mini-review.
Protostane triterpenes belong to a group of tetracyclic triterpene that exhibit unique structural characteristics. Their natural distribution is primarily limited to the genus Alisma of the Alismataceae family, but they have also been occasionally found in other plant genera such as Lobelia, Garcinia, and Leucas. To date, there are 59 known protostane structures. Many of them have been reported to possess biological properties such as improving lipotropism, hepatoprotection, anti-viral activity against hepatitis B and HIV-I virus, anti-cancer activity, as well as reversal of multidrug resistance in cancer cells. On the other hand, fusidanes are fungal products characterized by 29-nor protostane structures. They possess antibiotic properties against staphylococci, including the methicillin-resistant Staphylococcus aureus (MRSA). Fusidic acid is a representative member which has found clinical applications. This review covers plant sources of the protostanes, their structure elucidation, characteristic structural and spectral properties, as well as biological activities. The fungal sources, structural features, biological activities of fusidanes are also covered in this review. Additionally, the biogenesis of these two types of triterpenes is discussed and a refined pathway is proposed.


Spindle checkpoint-independent inhibition of mitotic chromosome segregation by Drosophila Mps1.
Monopolar spindle 1 (Mps1) is essential for the spindle assembly checkpoint (SAC), which prevents anaphase onset in the presence of misaligned chromosomes. Moreover, Mps1 kinase contributes in a SAC-independent manner to the correction of erroneous initial attachments of chromosomes to the spindle. Our characterization of the Drosophila homologue reveals yet another SAC-independent role. As in yeast, modest overexpression of Drosophila Mps1 is sufficient to delay progression through mitosis during metaphase, even though chromosome congression and metaphase alignment do not appear to be affected. This delay in metaphase depends on the SAC component Mad2. Although Mps1 overexpression in mad2 mutants no longer causes a metaphase delay, it perturbs anaphase. Sister kinetochores barely move apart toward spindle poles. However, kinetochore movements can be restored experimentally by separase-independent resolution of sister chromatid cohesion. We propose therefore that Mps1 inhibits sister chromatid separation in a SAC-independent manner. Moreover, we report unexpected results concerning the requirement of Mps1 dimerization and kinase activity for its kinetochore localization in Drosophila. These findings further expand Mps1's significance for faithful mitotic chromosome segregation and emphasize the importance of its careful regulation.


Natural variation in Pristionchus pacificus dauer formation reveals cross-preference rather than self-preference of nematode dauer pheromones.
Many free-living nematodes, including the laboratory model organisms Caenorhabditis elegans and Pristionchus pacificus, have a choice between direct and indirect development, representing an important case of phenotypic plasticity. Under harsh environmental conditions, these nematodes form dauer larvae, which arrest development, show high resistance to environmental stress and constitute a dispersal stage. Pristionchus pacificus occurs in a strong association with scarab beetles in the wild and remains in the dauer stage on the living beetle. Here, we explored the circumstances under which P. pacificus enters and exits the dauer stage by using a natural variation approach. The analysis of survival, recovery and fitness after dauer exit of eight P. pacificus strains revealed that dauer larvae can survive for up to 1 year under experimental conditions. In a second experiment, we isolated dauer pheromones from 16 P. pacificus strains, and tested for natural variation in pheromone production and sensitivity in cross-reactivity assays. Surprisingly, 13 of the 16 strains produce a pheromone that induces the highest dauer formation in individuals of other genotypes. These results argue against a simple adaptation model for natural variation in dauer formation and suggest that strains may have evolved to induce dauer formation precociously in other strains in order to reduce the fitness of these strains. We therefore discuss intraspecific competition among genotypes as a previously unconsidered aspect of dauer formation.


A putative sensor kinase, Hik31, is involved in the response of Synechocystis sp. strain PCC 6803 to the presence of glucose.
The reason(s) for glucose sensitivity in certain cyanobacterial strains is poorly understood. Inactivation of genes encoding the putative sensor kinase Hik31 in Synechocystis sp. strain PCC 6803 resulted in a mutant unable to grow in the presence of D-glucose. Sensitivities to D-glucose, its analogue 2-deoxy-D-glucose, and fructose, were alleviated in mutants in which glcP, encoding the glucose transporter, was inactivated. These data indicate that permeation of these substrates is required to inflict cell death. The mutant Deltahik31, and the glucose-sensitive strain of Synechocystis, do not possess glucokinase activity, although a transcript originating from glk, encoding glucokinase, is present. Inactivation of glk led to severe sensitivity to glucose, indicating that the presence of glucose itself, within the cells, inflicted this sensitivity. On the other hand, sensitivity to 2-deoxy-D-glucose was lower in Deltaglk, thus distinguishing between the effect of glucose itself and that of its analogue, which, in the absence of glucokinase activity, may not be phosphorylated. Addition of glucose led to a small rise in glucose-6-phosphate dehydrogenase activity in the wild type, but constitutive activity was observed in the Deltahik31 mutant regardless of the presence of glucose. Microarray analyses showed only small changes in the abundance of global transcripts in Synechocystis following glucose addition, but the transcription levels of several genes, including icfG, but not glk, were strongly affected by inactivation of hik31. The mechanism(s) whereby Hik31 is involved in glucose sensing and response is discussed.


Parametric fuzzy sets for automatic color naming.
In this paper we present a parametric model for automatic color naming where each color category is modeled as a fuzzy set with a parametric membership function. The parameters of the functions are estimated in a fitting process using data derived from psychophysical experiments. The name assignments obtained by the model agree with previous psychophysical experiments, and therefore the high-level color-naming information provided can be useful for different computer vision applications where the use of a parametric model will introduce interesting advantages in terms of implementation costs, data representation, model analysis, and model updating.


The role of phytochemicals in the treatment and prevention of dementia.
Dementia pathologies such as Alzheimer's disease (AD) are reaching epidemic proportions, yet they are not successfully managed by effective symptomatic treatments. Only five drugs have been developed to alleviate cognitive symptoms, and more effective and safe treatments are needed for both the cognitive symptoms and behavioural and psychological symptoms of dementia (BPSD). As two of these licensed drugs (cholinesterase inhibitors [ChEIs]) are naturally derived (galantamine and rivastigmine), the potential for plants to yield new therapeutic agents has stimulated extensive research to discover new ChEIs together with plant extracts, phytochemicals and their derivatives with other mechanistic effects relevant to dementia treatment. This review presents the potential and actual therapeutic strategies for dementia in relation to the known mechanisms of dementia pathology. Phytochemicals that have shown mechanistic effects relevant to the pathological targets in dementia are discussed, with an emphasis on those showing positive clinical trial evidence. Those phytochemicals discussed include the alkaloid physostigmine, a ChEI from the calabar bean (Physostigma venenosum), which has been used as a template for the development of synthetic derivatives that inhibit acetylcholinesterase, including the drug rivastigmine. Also discussed are other ChEI alkaloids including huperzine A, from Huperzia serrata, and galantamine, originally from the snowdrop (Galanthus woronowii); both alkaloids improve cognitive functions in AD patients. Other phytochemicals discussed include cannabinoids (e.g. cannabidiol) from Cannabis sativa, which are emerging as potential therapeutic agents for BPSD, and resveratrol (occurs in various plants) and curcumin (from turmeric [Curcuma longa]), which have been investigated for their pharmacological activities relevant to dementia and their potential effects on delaying dementia progression. The review also discusses plant extracts, and their known constituents, that have shown relevant mechanistic effects for dementia and promising clinical data, but require more evidence for their clinical efficacy and safety. Such plants include Ginkgo biloba, which has been extensively studied in numerous clinical trials, with most outcomes showing positive effects on cognitive functions in dementia patients; however, more reliable and consistent clinical data are needed to confirm efficacy. Other plants and their extracts that have produced promising clinical data in dementia patients, with respect to cognition, include saffron (Crocus sativus), ginseng (Panax species), sage (Salvia species) and lemon balm (Melissa officinalis), although more extensive and reliable clinical data are required. Other plants that are used in traditional practices of medicine have been suggested to improve cognitive functions (e.g. Polygala tenuifolia) or have been associated with alleviation of BPSD (e.g. the traditional prescription yokukansan); such remedies are often prescribed as complex mixtures of different plants, which complicates interpretation of pharmacological and clinical data and introduces additional challenges for quality control. Evidence for the role of natural products in disease prevention, the primary but considerably challenging aim with respect to dementia, is limited, but the available epidemiological and clinical evidence is discussed, with most studies focused on ChEIs, nicotine (from Nicotiana species), curcumin, wine polyphenols such as resveratrol and G. biloba. Challenges for the development of phytochemicals as drugs and for quality control of standardized plant extracts are also considered.


A comparison of palliative stenting or emergent surgery for obstructing incurable colon cancer.
Acute colonic obstruction because of advanced colonic malignancy is a surgical emergency. Our aim was to review our experience with self-expanding metal stents (SEMS) compared to emergent surgery as the initial therapy for the management of patients with incurable obstructing colon cancer. A retrospective review of patients with obstructing colon cancer who underwent insertion of a SEMS (n = 53) or surgery (n = 70) from 2002 to 2008 was performed. The primary endpoint was relief of obstruction. Secondary endpoints include technical success of the procedure, duration of hospital stay, early and long-term complications, and overall survival. Both groups were similar in age, sex, and tumor distribution. Placement of SEMS was successful in 50/53 (94%) patients. Surgery was effective in relieving obstruction in 70/70 (100%) patients. Patients in the SEMS group have a significantly shorter median hospital stay (2 days) as compared to the surgery group (8 days) (P < 0.001). Patients with SEMS also had significantly less acute complications compared to the surgery group (8 vs. 30%, P = 0.03). The hospital mortality for the SEMS group was 0% compared to 8.5% in patients that underwent surgical decompression (P = 0.04). There was no difference in survival between the two groups (P = 0.76). In patients with colorectal cancer and obstructive symptoms, SEMS provide a highly effective and safe therapy when compared to surgery. In most patients with metastatic colorectal cancer and obstruction, SEMS provide a minimally invasive alternative to surgical intervention.