A New Phytophthora sp. Causing Root and Collar Rot on Pistacia lentiscus in Italy.
Lentisk (Pistacia lentiscus L., Anacardiaceae) is an evergreen shrub that is widespread over the Mediterranean Region. The species is also cultivated as an ornamental plant in Italy. In August 2008, a survey carried out in a forest nursery in Sardinia (39°57'N, 9°13'E) revealed the presence of symptoms such as wilting and desiccation of foliage associated with root and collar rot on 1- to 3-year-old potted seedlings of lentisk. Approximately 30% of 1,500 potted plants were affected. A Phytophthora sp. was consistently isolated from infected roots on synthetic mucor agar medium. Colonies on carrot agar (CA) were stellate to slightly radiate with low aerial mycelium. Growth occurred from 6 to 38°C, with an optimum around 30°C (mean radial growth rate was 11.8 mm per day). Sporangia were produced abundantly in unsterile pond water; they were nonpapillate, persistent, ellipsoid to obpyriform, (57.8-) 80.5 (-100.5) × (30.2-) 39.3 (-51.5) μm, with a length/breadth ratio of 2.0:1, proliferating internally or externally. Hyphal swellings were spherical to irregular and frequently produced in chains. Chlamydospores were not observed. Isolates were heterothallic and produced oogonia with amphigynous antheridia when paired with A2 mating type of Phytophthora drechsleri and P. cryptogea. Cultural and morphological features were in close agreement with those recently published for Phytophthora sp. "niederhauserii" (4). The rDNA internal transcribed spacer (ITS) sequence (ITS1-5.8S-ITS2) of a representative isolate (LEN1) was submitted to GenBank (Accession No. GU119914) and BLAST searches showed 100% similarity with sequences of P. sp. "niederhauserii" deposited in GenBank (Accession Nos. GQ848201 and EU244850). The strain LEN1 was stored in the culture collection of the Department of Plant Protection at the University of Sassari. Its pathogenicity was verified by inoculating 10 1-year-old lentisk seedlings grown in pots. A mycelial plug (3 to 4 mm2) taken from the margin of a 4-day-old culture grown on CA was put in a shallow wound (~3 mm) made by a sterile scalpel at the root collar of each seedling. All plants were kept in a greenhouse at 25°C in natural daylight. After 20 days, inoculated plants began to show symptoms similar to those observed on naturally infected plants. Five control plants inoculated with sterile CA plugs did not develop any disease symptoms. The pathogen was reisolated from infected tissues, thus fulfilling Koch's postulates. P. sp. "niederhauserii" has not been formally described, however, so far there have been several reports of this species in Europe (1,3). Previously, other Phytophthora spp. were reported associated with lentisk root rot in Italy (2). To our knowledge, this is the first report of P. sp. "niederhauserii" on Pistacia lentiscus and it emphasizes the susceptibility of the Mediterranean species to this new pathogen. References: (1) A. Józsa et al. Plant Pathol. 59:1166, 2010. (2) G. Magnano Di San Lio et al. Micol. Ital. 21:3, 1992. (3) E. Moralejo et al. Plant Pathol. 58:100, 2009. (4) A. Pérez-Sierra et al. Plant Dis. 94:534, 2010.


Social Management Training in Males With 47,XXY (Klinefelter Syndrome): A Pilot Study of a Neurocognitive-Behavioral Treatment Targeting Social, Emotional, and Behavioral Problems.
Klinefelter syndrome (47,XXY) is associated with problems in social interaction and behavioral adaptation. Sixteen adolescents and adult men with 47,XXY enrolled in a pilot-study evaluating the effectiveness of Social Management Training (SMT), a novel neurocognitive-behavioral treatment program targeted at improving social, emotional, and behavioral functioning. Participants reported improved emotional stability from pre- to post-test (5 months). Informants reported reductions in internalizing and externalizing symptoms, including improvement in self-regulation. Although informants did not report changes in autism-like symptoms, increased awareness of social challenges was found. SMT may improve emotional stability, self-regulation, and self-reflection in people males with Klinefelter syndrome. This potentially efficacious treatment approach may prove to be a promising psychosocial therapeutic intervention for this population.


Modeling the toxicity of copper and zinc salts to wheat in 14 soils.
Interest is mounting in developing and utilizing soil-specific soil quality guidelines. This requires quantifying the effects that soil physicochemical properties have on various ecotoxicological endpoints, including phytotoxicity. To this end, 14 agricultural soils from Australia with differing soil properties were spiked with copper (Cu) and zinc (Zn) salts and used to conduct 21-d plant growth inhibition tests using wheat (Triticum aestivum L.) in pot trials. The toxicity of Cu and Zn was similar with 10% effect concentration (EC10) values ranging from 110 to 945 and from 235 to 965 mg/kg, respectively, while the corresponding median effect concentration (EC50) values ranged from 240 to 1,405 and 470 to 1,745 mg/kg, respectively. Copper toxicity values (EC10, EC20, and EC50) were best modeled by the logarithm of cation exchange capacity (CEC) and either soil pH or electrical conductivity. Zinc EC50 and EC20 values were best modeled using the logarithm of CEC, while the EC10 data were best modeled using soil pH and the logarithm of organic carbon. These models generally estimated toxicity within a factor of two of the measured values.


Comparing treatment effects after adjustment with multivariable Cox proportional hazards regression and propensity score methods.
To compare adjusted effects of drug treatment for hypertension on the risk of stroke from propensity score (PS) methods with a multivariable Cox proportional hazards (Cox PH) regression in an observational study with censored data. From two prospective population-based cohort studies in The Netherlands a selection of subjects was used who either received drug treatment for hypertension (n = 1293) or were untreated 'candidates' for treatment (n = 954). A multivariable Cox PH was performed on the risk of stroke using eight covariates along with three PS methods. In multivariable Cox PH regression the adjusted hazard ratio (HR) for treatment was 0.64 (CI(95%): 0.42, 0.98). After stratification on the PS the HR was 0.58 (CI(95%): 0.38, 0.89). Matching on the PS yielded a HR of 0.49 (CI(95%): 0.27, 0.88), whereas adjustment with a continuous PS gave similar results as Cox regression. When more covariates were added (not possible in multivariable Cox model) a similar reduction in HR was reached by all PS methods. The inclusion of a simulated balanced covariate gave largest changes in HR using the multivariable Cox model and matching on the PS. In PS methods in general a larger number of confounders can be used. In this data set matching on the PS is sensitive to small changes in the model, probably because of the small number of events. Stratification, and covariate adjustment, were less sensitive to the inclusion of a non-confounder than multivariable Cox PH regression. Attention should be paid to PS model building and balance checking.


A comparative analysis of survival outcomes between pancreatectomy and chemotherapy for elderly patients with adenocarcinoma of the pancreas.
The survival rates after pancreatectomy for elderly patients with adenocarcinoma of the pancreas remain poor. Elderly patients have increased perioperative mortality rates, higher morbidity rates, and higher rates of continued inpatient nursing care after pancreatectomy. The objective of the current study was to evaluate the outcomes of surgical resection versus chemotherapy (with or without radiotherapy) for elderly patients with potentially resectable adenocarcinoma of the pancreas. Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data for 2000 through 2010, the authors examined the relationship between patient characteristics and receipt of surgery using multivariate logistic regression. The patient cohort was restricted to patients with American Joint Committee on Cancer stage I and stage II disease and Charlson Comorbidity index of ≤2. The association between treatment (surgery or chemotherapy without surgery) and hazard of death was evaluated using Kaplan-Meier Cox proportional hazards modeling. The authors identified 2629 patients with pancreatic adenocarcinoma who underwent either surgery (pancreatectomy) or chemotherapy without surgery. Younger patient age and smaller tumor size were found to be significantly associated with receipt of surgery. For the overall cohort, the median survival rate was significantly longer for those patients treated with surgery compared with those who received chemotherapy (15 months vs 10 months). However, the absolute survival benefit attenuated as the cohort became older. The survival benefit associated with surgical resection compared with chemotherapy was very small for certain subgroups of patients (those aged ≥80 years and those with lymph node metastases). The results of the current study indicate that although surgery is associated with a survival benefit in the elderly, chemotherapy should be considered as a legitimate therapeutic alternative. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:3378-3385. © 2016 American Cancer Society.


Gated Transformer for Decoding Human Brain EEG Signals.
In this work, we propose to use a deep learning framework for decoding the electroencephalogram (EEG) signals of human brain activities. More specifically, we learn an end-to-end model that recognizes natural images or motor imagery by the EEG data that is collected from the corresponding human neural activities. In order to capture the temporal information encoded in the long EEG sequences, we first employ an enhanced version of Transformer, i.e., gated Transformer, on EEG signals to learn the feature representation along a sequence of embeddings. Then a fully-connected Softmax layer is used to predict the classification results of the decoded representations. To demonstrate the effectiveness of the gated Transformer approach, we conduct experiments on the image classification task for a human brain-visual dataset and the classification task for a motor imagery dataset. The experimental results show that our method achieves new state-of-the-art performance compared to multiple existing methods that are widely used for EEG classification.


Re-description of Cryptosporidium cuniculus Inman and Takeuchi, 1979 (Apicomplexa: Cryptosporidiidae): morphology, biology and phylogeny.
To provide re-description of Cryptosporidium cuniculus Inman and Takeuchi, 1979 (synonymous with rabbit genotype), a species closely related to Cryptosporidium hominis, the morphology, natural and experimental host specificity, and genetic characterisation were investigated. The morphology and diagnostic characteristics are typical of other intestinal species of Cryptosporidium, albeit with slightly larger oocysts (5.55-6.40×5.02-5.92 μm; mean 5.98×5.38 μm; length:width=1.1; n=50). Natural hosts appear to be European rabbits (Oryctolagus cuniculus) and humans (Homo sapiens). Experimental infections have been established in weanling rabbits (O. cuniculus), immunosuppressed Mongolian gerbils (Meriones unguiculatus) and immunosuppressed adult Porton strain mice (Mus musculus), but not in neonatal mice. Patterns of infection measured by oocyst shedding are significantly different compared with C. hominis, particularly in rabbits. Histological examination reveals endogenous stages in the brush border of the epithelium of the small intestinal villi, but clinical signs are absent. Inoculation of human HCT-8 cells results in discrete clusters of endogenous stages. A close relationship with C. hominis is inferred from molecular analyses at the ssrRNA, 70 kDa heat shock protein (HSP70), actin, Cryptosporidium oocyst wall protein (COWP), 60 kDa glycoprotein (GP60) genes and a region encoding a product of unknown function (LIB13). Sequences contained limited, consistent polymorphisms at the ssrRNA, HSP70 and actin genes, were identical at the COWP and LIB13 genes and demonstrated two unique families at the GP60 gene. Although genetically closely related, there are significant biological differences between C. cuniculus and C. hominis that support these protozoa being separate species. This is based on the current understanding of these organisms and relies on the assumption that mating between these species would not normally occur. If this is subsequently demonstrated their categorisation may need to be re-addressed.


Self-efficacy regarding physical activity is superior to self-assessed activity level, in long-term prediction of cardiovascular events in middle-aged men.
Self-efficacy has been determined to be a strong predictor of who will engage in physical activity. We aimed to evaluate the associations between self-efficacy to perform physical activity, self-reported leisure-time physical activity and cardiovascular events in a population-based cohort of middle-aged Swedish men with no previous cardiovascular disease, or treatment with cardiovascular drugs. Analyses are based on 377 men randomly selected and stratified for weight and insulin sensitivity from a population sample of 58-year-old men (n = 1728) and who had answered a question about their competence to perform exercise (as an assessment of physical self-efficacy). The Saltin-Grimby Physical Activity Level Scale was used to assess self-reported levels of leisure-time physical activity. Cardiovascular events were recorded during 13-years of follow-up. The group with poor self-efficacy to perform physical activity had a significantly higher incidence of cardiovascular events compared with the group with good physical self-efficacy (32.1% vs 17.1%, p < 0.01). Multivariate analyses showed that poor physical self-efficacy was associated with an increased relative risk of 2.0 (95% CI 1.2 to 3.0), of having a cardiovascular event during follow-up also after adjustments for co-variates such as waist to hip ratio, heart rate, fasting plasma glucose, serum triglycerides, systolic blood pressure, apoB/apoA-I ratio and leisure-time physical activity. Self-efficacy to perform physical activity was strongly and independently associated with cardiovascular events and was superior to self-assessed physical activity in predicting cardiovascular events during 13-years of follow-up in a group of middle-aged men, without known CVD or treatment with cardiovascular drugs.


DARPins recognizing the tumor-associated antigen EpCAM selected by phage and ribosome display and engineered for multivalency.
Designed Ankyrin Repeat Proteins (DARPins) represent a novel class of binding molecules. Their favorable biophysical properties such as high affinity, stability and expression yields make them ideal candidates for tumor targeting. Here, we describe the selection of DARPins specific for the tumor-associated antigen epithelial cell adhesion molecule (EpCAM), an approved therapeutic target on solid tumors. We selected DARPins from combinatorial libraries by both phage display and ribosome display and compared their binding on tumor cells. By further rounds of random mutagenesis and ribosome display selection, binders with picomolar affinity were obtained that were entirely monomeric and could be expressed at high yields in the cytoplasm of Escherichia coli. One of the binders, denoted Ec1, bound to EpCAM with picomolar affinity (K(d)=68 pM), and another selected DARPin (Ac2) recognized a different epitope on EpCAM. Through the use of a variety of bivalent and tetravalent arrangements with these DARPins, the off-rate on cells was further improved by up to 47-fold. All EpCAM-specific DARPins were efficiently internalized by receptor-mediated endocytosis, which is essential for intracellular delivery of anticancer agents to tumor cells. Thus, using EpCAM as a target, we provide evidence that DARPins can be conveniently selected and rationally engineered to high-affinity binders of various formats for tumor targeting.


Japan Society of Hepatology guidelines for the management of hepatitis C virus infection: 2019 update.
The Drafting Committee for Hepatitis Management Guidelines established by the Japan Society of Hepatology (JSH) drafted the first version of the clinical practice guidelines for the management of hepatitis C virus (HCV) infection in 2012. Since then, we have been publishing updates as new drugs for hepatitis C become available and new indications for existing drugs are added. The new approval of sofosbuvir/velpatasvir prompted us to publish the seventh version of the guidelines in Japanese in March 2019. We also published the first English-language version of the JSH guidelines in 2013 and English versions of updates made to the Japanese-language guidelines in 2014 and 2016. In 2020, the Committee has decided to publish a new English version, covering general information about treatment for hepatitis C, drugs used, recommended treatments for chronic hepatitis and cirrhosis, and special populations, such as patients who have renal impairment, are on dialysis, or have developed recurrence of hepatitis C after liver transplantation. Furthermore, the Committee has released a separate publication covering the protective effect of antiviral therapy against hepatocarcinogenesis.


Graft failure due to noncompliance among 628 kidney transplant recipients with long-term follow-up: a single-center observational study.
In adult kidney transplantation, there is no clear consensus on the incidence of graft failure-due-to noncompliance (GFNC), with some reporting it as relatively uncommon and others as a major cause of late graft failure. We suspected that GFNC was a major cause of late graft loss at our center but did not know the extent of this problem. In our prospectively followed cohort of 628 adult, primary kidney-alone transplant recipients with long-term follow-up, GFNC and other graft loss causes were determined from our ongoing clinical evaluations. Using competing risks methodology, we determined the overall percentage of patients developing GFNC and the significant prognostic factors for its hazard rate and cumulative incidence (via Cox regression). Cumulative incidence estimates (± standard error) of GFNC (n=29), GF-with-compliance (n=46), receiving a never-functioning graft (n=7), and death-with-a-functioning-graft (n=53) at 101 months after transplant (last-observed-graft loss) were as follows: 9.8%± 2.4%, 10.9%± 1.7%, 1.1%± 0.4%, and 13.0%± 1.9%, respectively. Only three patients experienced GFNC during the first 24 months; GFNC represented 48.1% (26/54) of death-censored GFs beyond 24 months. Two baseline variables were jointly associated with a significantly higher GFNC hazard and cumulative incidence: younger recipient age (P<0.000001 each) and non-white recipient (P=0.004 and P=0.02). Estimated percentages of ever developing GFNC were 28.4%± 6.5% among 79 non-whites younger than 35 years versus 0.0% (0/144) among whites 50 years or older. Among 302 recipients younger than 50 years, 18.1%± 4.1% developed GFNC, representing 67.6% (25/37) of its death-censored graft failures observed beyond 24 months after transplant. GFNC is a major cause of late GF at our center, with younger and non-white recipients at a significantly greater GFNC risk. Interventional approaches to eliminate GFNC could dramatically improve long-term kidney graft survival.


Perceived realism and Twitter use are associated with increased acceptance of cosmetic surgery among those watching reality television cosmetic surgery programs.
Reality television programming is a popular type of television programming, and features shows about cosmetic surgery. Social media such as Facebook and Twitter are increasingly popular methods of sharing information. The authors surveyed college students to determine among those watching reality television cosmetic surgery programs whether perceived realism or social media use was associated with attitudes toward cosmetic surgery. Participants (n=126) were surveyed about their reality television cosmetic surgery program viewing habits, their perception of the realism of reality television programming, and social media topics of Twitter and Facebook. Outcome variables were the Acceptance of Cosmetic Surgery Scales of social, intrapersonal, and consider. Perceived realism was significantly associated with increased scores on the Acceptance of Cosmetic Surgery Scale subscales of social (p=0.004), intrapersonal (p=0.03), and consider (p=0.03). Following a character from a reality television program on Twitter was significantly associated with increased social scores (p=0.04). There was no significant association of Facebook behavior with attitudes toward cosmetic surgery. Cosmetic plastic surgeons may benefit by advertising their services on cosmetic surgery reality television programs. These reality television programs portray cosmetic surgery in a positive manner, and viewers with increased perceived realism will be a potential receptive audience toward such advertising. Also, advertising cosmetic surgery services on Twitter feeds that discuss cosmetic surgery reality television programs would be potentially beneficial.


The use of the dimensionless Womersley number to characterize the unsteady nature of internal flow.
Dimensionless numbers are very useful in characterizing mechanical behavior because their magnitude can often be interpreted as the relative importance of competing forces that will influence mechanical behavior in different ways. One dimensionless number, the Womersley number (Wo), is sometimes used to describe the unsteady nature of fluid flow in response to an unsteady pressure gradient; i. e., whether the resulting fluid flow is quasi-steady or not. Fluids surround organisms which themselves contain fluid compartments; the behaviors exhibited by these biologically-important fluids (e.g. air, water, or blood) are physiologically significant because they will determine to a large extent the rates of mass and heat exchange and the force production between an organism and its environment or between different parts of an organism. In the biological literature, the use of the Womersley number is usually confined to a single geometry: the case of flow inside a circular cylinder. We summarize the evidence for a broader role of the Womersley number in characterizing unsteady flow than indicated by this geometrical restriction. For the specific category of internal flow, we show that the exact analytical solution for unsteady flow between two parallel walls predicts the same pattern of fluid behavior identified earlier for flow inside cylinders; i.e., a dichotomy in fluid behavior for values of Wo < 1 and Wo > 1. When Wo < 1, the flow is predicted to faithfully track the oscillating pressure gradient, and the velocity profiles exhibit a parabolic shape such that the fluid oscillating with the greatest amplitude is farthest from the walls ("quasi-steady" behavior). When Wo > 1, the velocity profiles are no longer parabolic, and the flow is phase-shifted in time relative to the oscillating pressure gradient. The amplitude of the oscillating fluid may either increase or decrease as Wo > 1, as described in the text.


Axis I and personality comorbidity in adolescents with conduct disorder.
This study was undertaken to investigate psychiatric comorbidity in male and female adolescents with conduct disorder diagnoses. Twenty-five hospitalized adolescents (11 females, 14 males) with conduct disorder were evaluated using structured diagnostic interviews for Axis I and personality disorders. The most common Axis I comorbid diagnoses were: depressive disorders (major depression and/or dysthymia), 64 percent; anxiety disorders (separation anxiety disorder, overanxious disorder, panic disorder, obsessive-compulsive disorder, phobias, and/or posttraumatic stress disorder), 52 percent; substance abuse, 48 percent; and attention-deficit hyperactivity disorder, 28 percent. Common Axis II disorders included passive-aggressive personality disorder, 56 percent, and borderline personality disorder, 32 percent. When compared with the male subjects, the females had significantly more total Axis I disorders and a trend toward more total personality disorders, anxiety disorders, depression, and borderline personality disorders. These findings support conduct disorder as a complex illness with extensive Axis I and II involvement as well as some gender differences in presentation.


Diminazene or berenil, a classic duplex minor groove binder, binds to G-quadruplexes with low nanomolar dissociation constants and the amidine groups are also critical for G-quadruplex binding.
G-quadruplexes have shown great promise as chemotherapeutic targets, probably by inhibiting telomere elongation or downregulating oncogene expression. There have been many G-quadruplex ligands developed over the years but only a few have drug-like properties. Consequently only a few G-quadruplex ligands have entered clinical trials as cancer chemotherapeutic agents. The DNA minor groove ligand, berenil (diminazene aceturate or DMZ), is used to treat animal trypanosomiasis and hence its toxicological profile is already known, making it an ideal platform to engineer into new therapeutics. Herein, using a plethora of biophysical methods including UV, NMR, MS and ITC, we show that DMZ binds to several G-quadruplexes with a Kd of ∼1 nM. This is one of the strongest G-quadruplex binding affinities reported to date and is 10(3) tighter than the berenil affinity for an AT-rich duplex DNA. Structure-activity-relationship studies demonstrate that the two amidine groups on DMZ are important for binding to both G-quadruplex and duplex DNA. This work reveals that DMZ or berenil is not as selective for AT-rich duplexes as originally thought and that some of its biological effects could be manifested through G-quadruplex binding. The DMZ scaffold represents a good starting point to develop new G-quadruplex ligands for cancer cell targeting.


An inhibition mechanism of dihydromyricetin on tyrosinase and the joint effects of vitamins B6, D3 or E.
Dihydromyricetin (DMY), a natural flavonoid, was found to effectively inhibit tyrosinase activity in a mixed-type manner with an IC50 value of (3.66 ± 0.14) × 10-5 mol L-1. DMY combined with the dietary vitamin D3 at lower concentrations exhibited a synergistic effect on the inhibition of tyrosinase. The formation of a DMY-tyrosinase complex led to fluorescence quenching and conformational changes of tyrosinase, which was driven mainly by hydrophobic interactions and hydrogen bonds. The molecular simulation further found that DMY inserted into the active pocket of tyrosinase interacted with amino acid residues Tyr78, His85, and Ala323, occupying the catalytic center of tyrosinase to hinder entrance of the substrate, leading to the inhibition of tyrosinase. This study may provide a scientific foundation for screening effective tyrosinase inhibitors.


Managing conflicts of interest in the conduct of clinical trials.
The interaction between medical research and for-profit corporations is not new, but it has expanded considerably in recent years. Some of the recent trends may accelerate the research process, particularly when large clinical trials are required. However, a renewed commitment to the application of high ethical standards is essential to ensure that societal trust in research is not eroded, subjects enrolled in trials do not become merely a means to an end, and medical research is efficiently translated into clinical advances that will benefit future patients. This article focuses on the analysis of conflicts of interest in the conduct of clinical trials in both academic and community-based settings. Specifically, it discusses how the roles of research scientists and clinical practitioners differ and the importance of ensuring that participants' consent to enroll in clinical trials is not the result of confusion about the goals of an experimental treatment that may resemble clinical care. The article also discusses the potential conflicts of interest that can arise when clinicians stand to gain from enrolling their own patients as subjects in clinical trials and examines various instances in which disclosure of information regarding funding and compensation may serve to minimize such conflicts. This article emphasizes that to preserve the integrity of research and to protect the welfare of human subjects who enroll in trials, physicians should have adequate training in the conduct of research and be familiar with the ethics of research. When a physician has treated or continues to treat a patient who is eligible to enroll as a subject in a clinical trial conducted by the same physician, someone other than the treating physician should obtain the participant's informed consent. Finally, the article addresses disclosure of financial incentives and related funding issues.


The clubfoot assessment protocol (CAP); description and reliability of a structured multi-level instrument for follow-up.
In most clubfoot studies, the outcome instruments used are designed to evaluate classification or long-term cross-sectional results. Variables deal mainly with factors on body function/structure level. Wide scorings intervals and total sum scores increase the risk that important changes and information are not detected. Studies of the reliability, validity and responsiveness of these instruments are sparse. The lack of an instrument for longitudinal follow-up led the investigators to develop the Clubfoot Assessment Protocol (CAP). The aim of this article is to introduce and describe the CAP and evaluate the items inter- and intra reliability in relation to patient age. The CAP was created from 22 items divided between body function/structure (three subgroups) and activity (one subgroup) levels according to the International Classification of Function, Disability and Health (ICF). The focus is on item and subgroup development. Two experienced examiners assessed 69 clubfeet in 48 children who had a median age of 2.1 years (range, 0 to 6.7 years). Both treated and untreated feet with different grades of severity were included. Three age groups were constructed for studying the influence of age on reliability. The intra- rater study included 32 feet in 20 children who had a median age of 2.5 years (range, 4 months to 6.8 years). The Unweighted Kappa statistics, percentage observer agreement, and amount of categories defined how reliability was to be interpreted. The inter-rater reliability was assessed as moderate to good for all but one item. Eighteen items had kappa values > 0.40. Three items varied from 0.35 to 0.38. The mean percentage observed agreement was 82% (range, 62 to 95%). Different age groups showed sufficient agreement. Intra- rater; all items had kappa values > 0.40 [range, 0.54 to 1.00] and a mean percentage agreement of 89.5%. Categories varied from 3 to 5. The CAP contains more detailed information than previous protocols. It is a multi-dimensional observer administered standardized measurement instrument with the focus on item and subgroup level. It can be used with sufficient reliability, independent of age, during the first seven years of childhood by examiners with good clinical experience.A few items showed low reliability, partly dependent on the child's age and /or varying professional backgrounds between the examiners. These items should be interpreted with caution, until further studies have confirmed the validity and sensitivity of the instrument.


[Cancer Cells as Dynamic System - Molecular and Phenotypic Changes During Tumor Formation, Progression and Dissemination].
Dynamic, punctual and perfectly coordinated cellular response to internal and external stimuli is a crucial prerequisite for adaptation of mammalian cells to all changes that occur during cellular development under physiological conditions. Hijacking this ability is characteristic for tumor cells that are capable to adapt to unfavorable conditions which contribute to the formation and development of cancer during the process of tumor formation and progression. By changing key mechanisms, malignant cells can avoid cell death and thus allow development and spread of the tumor. The changes at the genetic level are manifested by various phenotypic characteristics, through which tumor cells are able to escape defense mechanisms, to acquire resistance to treatment, to invade and to create secondary tumors. In recent years, one of the most studied properties include changes in energy metabolism, when tumor cells specifically control reprogramming of the main metabolic pathways for their own benefit and to satisfy their increased needs not only for energy, but also for building materials required for increased proliferation. To adapt to extracellular conditions, it is necessary that cells undergo morphological changes, where modifications in the cell shape through reorganization of cytoskeletal filaments allow tumor cells to increase their invasiveness and other aggressive features. Clarifying these changes together with understanding of the switch in the genetic program within cancer cells, which allows them to overcome different stages of differentiation from cancer stem cells to fully differentiated cells, would be an important prerequisite for identification of the cancer cell "weaknesses" and may lead to improved cancer treatment. The ability of tumor cells to alter the rules of their own organism thus represents an important challenge for oncological research.Key words: cellular reprogramming - cancer cell plasticity - cancer metabolism - tumor heterogeneity - cytoskeleton remodeling - metastasis - oncogenesisThis work was supported by the project MEYS - NPS I - LO1413.The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 3. 7. 2016Accepted: 11. 8. 2016.


The imidazoacridinone antitumor drug, C-1311, is metabolized by flavin monooxygenases but not by cytochrome P450s.
5-Diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) is an antitumor agent that is also active against autoimmune diseases. The intention of the present studies was to elucidate the role of selected liver enzymes in metabolism of C-1311 and the less active 8-methyl derivative, 5-diethylaminoethylamino-8-methoxyimidazoacridinone (C-1330). Compounds were incubated with rat liver microsomal fraction, with a set of 16 human liver protein samples, and with human recombinant isoenzymes of cytochrome P450, flavin monooxygenases (FMO), and UDP-glucuronosyltransferase (UGT). Our results showed that C-1311 and C-1330 were metabolized with human liver microsomal enzymes but not with any tested human recombinant cytochromes P450 (P450s). Two of these, CYP1A2 and CYP3A4, were inhibited by both compounds. In addition, results of C-1311 elimination from hepatic reductase-null mice, in which liver NADPH-P450 oxidoreductase has been deleted indicated that liver P450s were slightly engaged in drug transformation. In contrast, both compounds were good substrates for human recombinant FMO1 and FMO3 but not for FMO5. The product of FMO metabolism, P(FMO), which is identified as an N-oxide derivative, was identical to P3(R) of liver microsomes. P3(R) was observed even in the presence of the P450 inhibitor, 1-aminobenzotriazole, and it disappeared after heating. Therefore, FMO enzymes could be responsible for microsomal metabolism to P3(R) = P(FMO). Glucuronidation on the 8-hydroxyl group of C-1311 was observed with liver microsomes supported by UDP-glucuronic acid and with recombinant UGT1A1, but it was not the case with UGT2B7. Summing up, we showed that, whereas liver P450 isoenzymes were involved in the metabolism of C-1311 to a limited extent, FMO plays a significant role in the microsomal transformations of this compound, which is also a specific substrate of UGT1A1.


Addition of nucleotides similar to deleted CAA repeats in the 5' non-coding region of tomato mosaic virus RNA following propagation.
Previously we made a series of deletion mutants in the 5' non-coding region of tomato mosaic tobamovirus (ToMV) RNA and checked their ability to replicate in tobacco protoplasts. Long deletions in this region caused the virus to lose the ability to replicate. Several mutants with deletions of about 10 nucleotides (short deletion mutants; SDM) retained the ability to replicate. In this study, we inoculated SDMs onto systemic host plants and observed their symptoms. One mutant (19/32) caused severe mosaic symptoms on some tobacco plants (Nicotiana tabacum cv. Samsun) but no symptoms on others. Virus accumulation in 19/32-inoculated plants paralleled the severity of symptoms. Four CAA repeat sequences were deleted in 19/32. Progeny 19/32 from plants showing severe systemic mosaic symptoms had acquired additional nucleotides in this region. We conclude that the CAA repeat sequence is related to the fitness of the virus population to replicate in whole plants rather than to translation of ToMV replicase genes.


Couple-based HIV prevention for low-income drug users from New York City: a randomized controlled trial to reduce dual risks.
Dual threats of injection drug use and risky sexual practices continue to increase transmission of HIV and other sexually transmitted Infections (STIs) among drug-using couples in low-income communities in the United States. Two hypotheses were tested: (1) "intervention effect"-whether the HIV risk-reduction intervention provided to the couple or individual partners would be more efficacious in decreasing number of unprotected sexual acts and having a lower cumulative incidence of biologically confirmed STIs over the 12-month follow-up period compared with the attention control condition; and (2) "modality effect"-whether the HIV risk-reduction intervention would be more likely to decrease the number of unprotected sexual acts and have a lower cumulative STI incidence when delivered to a couple compared with the same intervention delivered to an individual. Using a randomized controlled trial, 282 HIV-negative drug-using couples (564 individuals) were randomly assigned to receive either of the following: (1) couple-based risk reduction; (2) individual-based HIV risk reduction, or (3) couple-based wellness promotion, which served as an attention control condition. Over 12-month follow-up, there was a 30% reduction in the incidence rate of unprotected acts of intercourse with the study partners compared with participants in the attention control arm. Moreover, over 12-month follow-up there was a 29% reduction in the same outcome in the couple arm compared with the individual arm with a 41% reduction at the 12-month follow-up. A couple-based approach that addresses drug and sexual risks and targets low-income active drug users may help curb the HIV epidemic.


Gate-controlled surface conduction in Na-doped Bi2Te3 topological insulator nanoplates.
Exploring exciting and exotic physics, scientists are pursuing practical device applications for topological insulators. The Dirac-like surface states in topological insulators are protected by the time-reversal symmetry, which naturally forbids backscattering events during the carrier transport process, and therefore offers promising applications in dissipationless spintronic devices. Although considerable efforts have been devoted to controlling their surface conduction, limited work has been focused on tuning surface states and bulk carriers in Bi(2)Te(3) nanostructures by external field. Here we report gate-tunable surface conduction in Na-doped Bi(2)Te(3) topological insulator nanoplates. Significantly, by applying external gate voltages, such topological insulators can be tuned from p-type to n-type. Our results render a promise in finding novel topological insulators with enhanced surface states.


Mapping collective variable and synergy dynamics to task outcome in a perceptual-motor skill.
In complex adaptive systems approaches to perceptual-motor control the mapping between the different categories of task dynamics: namely, task outcome, collective variable, neuromuscular synergies and individual joint configurations is a central theoretical issue, that has been primarily studied in bimanual tasks. Here we report an investigation in the roller ball task of how the task goal and multiple degrees of freedom of the arm-hand complex affords degeneracy between the respective properties of the task dynamics. The relation of the candidate collective variable, namely, the synchrony of the inner ball to outer shell motion of the roller ball and its relation to the task goal (continued increasing in ball speed), was examined as a function of the initial ball speed acting as a control parameter. Within trial analysis revealed initial search behavior for synchrony of ball and shell motion that was longer in duration with initial lower ball speed conditions. In contrast, higher initial ball speed conditions reduced the search time for and enhanced the rate of stabilization of the synchrony of inner ball and outer shell motion-features that facilitated the continued increase of ball speed and the probability of task success. Participants adopted one of three wrist-elbow neuromuscular synergies to manipulate the roller ball, the distribution of which was not influenced by either initial ball speed or task outcome. The pattern of findings over the different properties of task analysis of the roller ball provides evidence for the distinct but complementary dynamics of searching to form, stabilize and exploit a collective variable that satisfies the task goal through a small redundant set of arm-hand synergy motions.


Global occurrence and emission of rotaviruses to surface waters.
Group A rotaviruses (RV) are the major cause of acute gastroenteritis in infants and young children globally. Waterborne transmission of RV and the presence of RV in water sources are of major public health importance. In this paper, we present the Global Waterborne Pathogen model for RV (GloWPa-Rota model) to estimate the global distribution of RV emissions to surface water. To our knowledge, this is the first model to do so. We review the literature to estimate three RV specific variables for the model: incidence, excretion rate and removal during wastewater treatment. We estimate total global RV emissions to be 2 × 1018 viral particles/grid/year, of which 87% is produced by the urban population. Hotspot regions with high RV emissions are urban areas in densely populated parts of the world, such as Bangladesh and Nigeria, while low emissions are found in rural areas in North Russia and the Australian desert. Even for industrialized regions with high population density and without tertiary treatment, such as the UK, substantial emissions are estimated. Modeling exercises like the one presented in this paper provide unique opportunities to further study these emissions to surface water, their sources and scenarios for improved management.


Study of calmodulin binding to the alternatively spliced C-terminal domain of the plasma membrane Ca2+ pump.
The C-terminal regions of the four human plasma membrane Ca2+ pump isoforms 1a-d generated from alternatively spliced RNA have been expressed in Escherichia coli, and the recombinant proteins have been purified to a very high degree. The C-termini of isoforms 1a, 1c, and 1d contain an insert encoded by an alternatively spliced exon which is homologous to the calmodulin binding domain of isoform 1b. In isoforms 1c and 1d (29 and 38 amino acid insertions, respectively), subdomain A of the original calmodulin binding site of isoform 1b is followed by the spliced-in domain, which is then followed by subdomain B of the original calmodulin binding site. The positive charges of histidine residues at positions 27, 28, and 38 of the alternatively spliced sequence are likely to be responsible for the observed pH-dependent calmodulin binding to the novel "duplicated" binding site. The affinity of calmodulin for the C-terminal domains of isoforms 1a, 1c, and 1d, which contain the histidine-rich inserts, is much higher at pH 5.9 than at pH 7.2. A synthetic peptide (I31) containing 31 amino acids of the alternatively spliced sequence (from residue 9 to 40) also binds calmodulin with strong pH dependency. Alternative splicing in the C-terminal domain is proposed to confer pH dependence to the regulation of the activity of Ca2+ pump isoforms.


The STEM Pipeline: The Role of Summer Research Experience in Minority Students' Ph.D. Aspirations.
Practical research experience has been seen as an important tool to enhance learning in STEM fields and shape commitment to science careers. Indeed, this was a prominent recommendation of the Boyer Commission. Further, there is evidence this is especially important for minority students. In this paper, we examine the role of practical research experience during the summer for talented minority undergraduates in STEM fields. We focus on the link between summer research and STEM Ph.D. program matriculation. We examine evidence on this question using detailed data on students participating in the Meyerhoff Scholarship Program over a 14 year period at the University of Maryland Baltimore County. Our results provide evidence of strong positive effects of summer research on participation in STEM Ph.D. programs. Further, we show that the effects of summer research vary with the frequency and timing of these experiences. The evidence that educational strategies such as summer research experiences improve academic outcomes of minorities is vital, given concern about the science pipeline in the U.S. and the continuing growth in the racial/ethnic diversity of the college-age population.


Site-directed mutagenesis of the CC chemokine binding protein 35K-Fc reveals residues essential for activity and mutations that increase the potency of CC chemokine blockade.
Chemokines of the CC class are key mediators of monocyte recruitment and macrophage differentiation and have a well documented role in many inflammatory diseases. Blockade of chemokine activity is therefore an attractive target for anti-inflammatory therapy. 35K (vCCI) is a high-affinity chemokine binding protein expressed by poxviruses, which binds all human and murine CC chemokines, preventing their interaction with chemokine receptors. We developed an Fc-fusion protein of 35K with a modified human IgG1 Fc domain and expressed this construct in human embryonic kidney 293T cells. Purified 35K-Fc is capable of inhibiting CC chemokine-induced calcium flux, chemotaxis, and β-arrestin recruitment in primary macrophages and transfected cells. To elucidate the residues involved in chemokine neutralization, we performed site-directed mutagenesis of six key amino acids in 35K and expressed the mutant Fc-fusion proteins in vitro. We screened the mutants for their ability to block chemokine-induced β-arrestin recruitment in transfected cells and to inhibit primary macrophage signaling in an electric cell substrate impedance sensing assay. Using a sterile model of acute inflammation, zymosan-induced peritonitis, we confirmed that wild-type 35K-Fc can reduce monocyte recruitment, whereas one mutant (R89A) showed a more pronounced blockade of monocyte influx and another mutant (E143K) showed total loss of function. We believe that 35K-Fc will be a useful tool for exploring the role of CC chemokines in chronic inflammatory pathologies, and we have identified a higher potency form of the molecule that may have potential therapeutic applications in chronic inflammatory disease.


Reasons for conversion from laparoscopic to open cholecystectomy: a 10-year review.
Laparoscopic cholecystectomy is now considered the "gold standard" operation for patients with gallstone disease. A number of patients require conversion to an open cholecystectomy for the safe completion of the procedure. This study investigates how the etiology and incidence of conversion from laparoscopic to open cholecystectomy has changed over time. All 5884 patients undergoing laparoscopic cholecystectomy between March 1991 and June 2001 were prospectively collected in a database. A total of 310 patients (5.2%) had had their cholecystectomies converted to an open procedure. The mortality rate for these patients was 0.7%. Causes for conversion were inability to correctly identify anatomy (50%), "other" indications (16%), bleeding (14%), suspected choledocholithiasis (11%), and suspected bile duct injury (8%). After an initial learning curve in thin patients with symptomatic cholelithiasis, inclusion of patients with acute cholecystitis, morbid obesity, or a prior celiotomy resulted in a peak conversion rate of 11% by 1994. From 1994 to the first half of 2001, the conversion rate has declined significantly for all patients (10% to 1%), as well as for patients with acute cholecystitis (26% to 1%). Although unclear anatomy secondary to inflammation remains the most common reason for conversion, the impact of acute cholecystitis on the operative outcome has decreased with time.


Oestrogen receptor and oestrogen regulated proteins in human breast cancer: a review.
Breast growth and development is influenced by oestrogens and the growth of many breast cancers is driven by oestrogens, an effect which is utilised in the endocrine treatment of breast cancer. Oestrogens act by binding to the oestrogen receptor, a specific protein which in turn binds to specific regulatory regions of DNA, thereby altering gene expression. The effects of oestrogens may be mediated by growth factors and other substances under oestrogen regulation. Oestrogen receptor status in breast tumours can be determined by cytosolic radioligand binding assays, enzyme linked immunoassay, immunohistochemistry and measurement of messenger RNA levels. Tumour oestrogen receptor content is an established but not absolute predictor of both response to endocrine therapy and prognosis in breast cancer. Paradoxically, a small proportion of apparently oestrogen receptor negative tumours do respond to endocrine therapy, perhaps reflecting expression of low and unmeasurable levels of receptor or tumour heterogeneity with respect to receptor expression. A larger proportion of oestrogen receptor positive tumours unexpectedly fail to respond to endocrine therapy; in these cases it is possible that oestrogen receptor has become dissociated from the transcriptional and translational events which it normally regulates. Determination of levels of expression of substances regulated by oestrogens can provide information regarding the functional integrity of the oestrogen response pathway and such substances include the progesterone receptor, plasminogen activator, cathepsin D and a variety of messenger RNA sequences.


Residential radon exposure and lung cancer: variation in risk estimates using alternative exposure scenarios.
The most direct way to derive risk estimates for residential radon progeny exposure is through epidemiologic studies that examine the association between residential radon exposure and lung cancer. However, the National Research Council concluded that the inconsistency among prior residential radon case-control studies was largely a consequence of errors in radon dosimetry. This paper examines the impact of applying various epidemiologic dosimetry models for radon exposure assessment using a common data set from the Iowa Radon Lung Cancer Study (IRLCS). The IRLCS uniquely combined enhanced dosimetric techniques, individual mobility assessment, and expert histologic review to examine the relationship between cumulative radon exposure, smoking, and lung cancer. The a priori defined IRLCS radon-exposure model produced higher odds ratios than those methodologies that did not link the subject's retrospective mobility with multiple, spatially diverse radon concentrations. In addition, the smallest measurement errors were noted for the IRLCS exposure model. Risk estimates based solely on basement radon measurements generally exhibited the lowest risk estimates and the greatest measurement error. The findings indicate that the power of an epidemiologic study to detect an excess risk from residential radon exposure is enhanced by linking spatially disparate radon concentrations with the subject's retrospective mobility.


Molecular population genetic evidence of horizontal spread of two alleles of the pyrogenic exotoxin C gene (speC) among pathogenic clones of Streptococcus pyogenes.
It has recently been demonstrated that the bacteriophage-borne gene (speC) encoding pyrogenic exotoxin C is harbored by phylogenetic lineages representing virtually the entire breadth of genomic differentiation present in the species Streptococcus pyogenes (J. M. Musser, A. R. Hauser, M. H. Kim, P. M. Schlievert, K. Nelson, and R. K. Selander, Proc. Natl. Acad. Sci. USA 88:2668-2672, 1991). To determine whether the speC genes occurring in association with divergent chromosomal genotypes (clones) are identical or represent a group of allelic variants, we sequenced speC from 23 S. pyogenes strains representing 15 clones identified by multilocus enzyme electrophoresis. Two alleles of speC are present in natural populations, and each allele occurs in clones that are well differentiated in overall chromosomal character; in one case, isolates of a single clone had different speC alleles. We interpret these patterns of toxin allele-clone distribution as evidence of occasional episodes of speC horizontal dissemination, presumably by bacteriophage-mediated gene transfer and recombination.


Association and Dose-Response Relationship of Self-Reported Physical Activity and Disability Among Adults ≥50 Years: National Health and Nutrition Examination Survey, 2011-2016.
Disability is a tremendous public health challenge. No study has assessed whether meeting U.S. Physical Activity guidelines is associated with disability in mobility tasks, activities of daily living, and social participation among U.S. older adults. Using 2011-2016 National Health and Nutrition Examination Survey data, this study examined this relationship among 8,309 individuals aged ≥50 years. Most participants (n = 4,272) did not achieve guidelines, and 2,912 participants were completely inactive. People who did not meet guidelines had higher odds of disability compared with those who did (adjusted odds ratio [AOR] = 1.80) in addition to difficulty with mobility tasks (AOR = 1.85), activities of daily living (AOR = 1.66), and social participation (AOR = 2.09). There was a dose-response effect for each level of activity (inactive, insufficient, and meeting and exceeding recommendations). Among adults aged ≥50 years, meeting the U.S. guidelines was associated with better social and physical functioning.


Aggregating UMLS semantic types for reducing conceptual complexity.
The conceptual complexity of a domain can make it difficult for users of information systems to comprehend and interact with the knowledge embedded in those systems. The Unified Medical Language System (UMLS) currently integrates over 730,000 biomedical concepts from more than fifty biomedical vocabularies. The UMLS semantic network reduces the complexity of this construct by grouping concepts according to the semantic types that have been assigned to them. For certain purposes, however, an even smaller and coarser-grained set of semantic type groupings may be desirable. In this paper, we discuss our approach to creating such a set. We present six basic principles, and then apply those principles in aggregating the existing 134 semantic types into a set of 15 groupings. We present some of the difficulties we encountered and the consequences of the decisions we have made. We discuss some possible uses of the semantic groups, and we conclude with implications for future work.


Evaluation of bacterial microleakage of root canals irrigated with different irrigation solutions and KTP laser system.
The aim of this study was to evaluate bacterial microleakage of the root canals irrigated with different irrigation solutions and the potassium-titanyl-phosphate (KTP) laser system and filled with gutta-percha and AH26 root canal sealer. In addition, the effect of the irrigation solutions on dentin surface was evaluated with a scanning electron microscope (SEM). A few studies have reported that KTP laser has the capacity to remove the smear layer. Many researchers have demonstrated that propolis has a bactericidal effect. Both are important effects on root canal treatments. One hundred and twenty single-root single-canal mandibular premolar teeth were used for this study. The root canals were prepared by Dentaport Root ZX and ProTaper rotary instruments with the crown-down technique. The specimens were randomly divided into five groups of 20 teeth each. Each group was irrigated with 17% ethylenediaminetetraacetic acid (EDTA), 20% propolis, 2.5% sodium hypochlorite (NaOCl), 2% chlorhexidine gluconate (CHX), and KTP laser, respectively. A total of 20 teeth were used as controls-10 positive controls and 10 negative controls-which were irrigated with distilled water. The root canals were filled with gutta-percha and AH-26. The external surfaces of specimens were covered with three layers of nail varnish except the apical third. The teeth were inserted into Eppendorf plastic tubes and suspended in glass bottles containing sterile broth. All specimens were inoculated every 5 days with Enterococcus faecalis. The contamination onset time was continuously recorded, as turbidity was the first indication of contamination in a period of 30 days. All statistical analysis was performed using the SPSS for Windows version 15.0 software. A χ(2) test was computed and the statistical significance was set at p<0.05. The controls behaved as expected. This study showed that different irrigation solutions and KTP laser allowed microleakage of E. faecalis.


Effect of compression release time of a hearing aid on sentence recognition and the quality judgment of speech.
The sentence recognition score and quality of speech differ when hearing aid compression is set at different release times at different signal to noise ratios (SNRs) for the normal and compressed rate of sentences. To investigate the effect of amplitude-compression release time of a hearing aid on sentence recognition and quality judgment: (1) for normal rate and time-compressed sentences (2) in quiet and noisy conditions. A post-test repeated measures design. We recruited fifteen adult participants with bilateral sensorineural hearing loss in each group, the younger (35-45 years), and the older ones (60-70 years). A gap detection test assessed temporal processing ability. We used three compression settings, fast-acting, slow-acting, and linear. Sentence recognition and quality and envelope difference index in normal and altered rates were assessed in quiet and in noise at these three compression settings. A repeated measure ANOVA. We found a significant improvement in recognition of sentences at a normal rate in slow compression release time, compared to fast and linear gain settings at each SNR. Similar results were observed for sentences compressed at the rate of 35% in quiet and +10 dB SNR. Further, the participants preferred the quality of speech in quiet with the hearing aid set to slow compared to fast compression release time. The benefit from the slow compression release time was higher than either linear or fast compression release time on sentence recognition. Further, we saw that there was a negative impact on sentence recognition at 3 dB SNR (normal-rate) and in quiet (35% compression rate) in older adults. The slow compression release time in a hearing aid is superior to the fast one in noisy conditions and also with higher subjective ratings of speech quality in quiet.


Pre- and postnatal determinants of childhood body size: cohort and sibling analyses.
Growing evidence suggests obesity may have its roots in early life but it is still uncertain whether prenatal factors operate primarily though altering early infant growth. It is also still unclear if rapid growth during selected time periods is more important than other time periods in predicting future body size. Using prospectively collected data on 20,523 participants born from 1959 to 1966 (10,327 boys; 10,196 girls) of the Collaborative Perinatal Project, we investigated the associations between pre- and postnatal factors and childhood body size at age 7 years and compared these associations across linear, logistic and quantile regression models. Maternal body mass index (BMI), maternal pregnancy weight gain, birth weight and postnatal weight change for three time periods (birth to 4 months; 4-12 months; 1-4 years) were all positively and independently associated with BMI at age 7 years. Rapid growth during each time period had a similar association BMI at age 7 years. For example, a 10-percentile increase in weight increased the probability of being overweight at age 7 years by approximately two-fold regardless of time period (OR = 1.8-2.2 for boys and girls). Using same-sex siblings (n = 571 boy sets; n = 651 girl sets) from the same cohort, we observed that siblings with higher BMI at age 7 years than their same-sex siblings were more likely to have higher maternal pregnancy weight gain, higher maternal pre-pregnancy BMI, higher birth weight and increased rate of weight gain during the three time periods. These consistent findings both from the overall cohort and the sibling analyses suggest that there are multiple, rather than specific critical periods of influence shaping childhood body size.


Resilience of tropical tree cover: The roles of climate, fire, and herbivory.
Fires and herbivores shape tropical vegetation structure, but their effects on the stability of tree cover in different climates remain elusive. Here, we integrate empirical and theoretical approaches to determine the effects of climate on fire- and herbivore-driven forest-savanna shifts. We analyzed time series of remotely sensed tree cover and fire observations with estimates of herbivore pressure across the tropics to quantify the fire-tree cover and herbivore-tree cover feedbacks along climatic gradients. From these empirical results, we developed a spatially explicit, stochastic fire-vegetation model that accounts for herbivore pressure. We find emergent alternative stable states in tree cover with hysteresis across rainfall conditions. Whereas the herbivore-tree cover feedback can maintain low tree cover below 1,100 mm mean annual rainfall, the fire-tree cover feedback can maintain low tree cover at higher rainfall levels. Interestingly, the rainfall range where fire-driven alternative vegetation states can be found depends strongly on rainfall variability. Both higher seasonal and interannual variability in rainfall increase fire frequency, but only seasonality expands the distribution of fire-maintained savannas into wetter climates. The strength of the fire-tree cover feedback depends on the spatial configuration of tree cover: Landscapes with clustered low tree-cover areas are more susceptible to cross a tipping point of fire-driven forest loss than landscapes with scattered deforested patches. Our study shows how feedbacks involving fire, herbivores, and the spatial structure of tree cover explain the resilience of tree cover across climates.


In vitro cultivation of nonlymphoid thymic cells: morphological and immunological characterization.
Nonlymphoid thymic elements play an important role in T-lymphocyte development, especially in the development of recognition of transplantation antigens (H-2 in the mouse). Understanding this process will require the isolation and characterization of these cells. A simple technique for the culture of an enriched population of murine thymic epithelium is described. The epithelial nature of these cells is evidenced by their morphology, electron microscopy, and keratin content. Readily distinguishable macrophages comprise a secondary population within these cultures. Antigens encoded in the I-A region of H-2 were found on 70% of thymic epithelial cells and H-2K on 30% of thymic epithelial cells. These antigens were generally present on distinct populations but doubly positive cells were observed. Thymic macrophages were found to have conventional receptors for the Fc fragment of immunoglobulin on their surface and could ingest antibody-coated sheep erythrocytes. Thymic epithelial cells did not have such Fc receptors. A striking observation was that thymic epithelial cells could bind and internalize autologous thymocytes. This selective thymocyte ingestion by thymic epithelium may have important implications in regard to processing of T-lymphocyte precursors.


'For a mere cough, men must just chew Conjex, gain strength, and continue working': the provider construction and tuberculosis care-seeking implications in Blantyre, Malawi.
Delay by men in seeking healthcare results in their higher mortality while on HIV or tuberculosis (TB) treatment and contributes to ongoing community-level disease transmission before going on treatment. To understand masculinity's role in delay in healthcare seeking for men, with a focus on TB-suggestive symptoms. Data were collected between March 2011 and March 2012 in low-income suburbs in urban Blantyre using focus group discussions with community members (n=8) and health workers (n=2), in-depth interviews with 20 TB patients (female=14) and 20 uninvestigated chronic coughers (female=8), and a 3-day participatory workshop with 27 health stakeholder representatives. The research process drew to a large extent on grounded theory principles in the manner of Strauss and Corbin (1998) and also Charmaz (1995). Role descriptions by both men and women in the study universally assigned men as primary material providers for their immediate family, that is, the ones earning and bringing livelihood and additional material needs. In a context where collectivism was valued, men were also expected to lead the provision of support to wider kin. Successful role enactment was considered key to achieving recognition as an adequate man; at the same time, job scarcity and insecurity, and low earnings gravely impeded men. Pressures to generate continuing income then meant constantly looking for jobs, or working continuously to retain insecure jobs or to raise money through self-employment. All this led men to relegate their health considerations. Early engagement with formal healthcare is critical to dealing with TB and HIV. However, role constructions as portrayed for men in this study, along with the opportunity costs of acknowledging illness seem, in conditions of vulnerability, important barriers to care-seeking. There is a need to address hidden care-seeking costs and to consider more complex interventions, including reducing precarity, in efforts to improve men's engagement with their health.


Epitope topography controls bioactivity in supramolecular nanofibers.
Incorporating bioactivity into artificial scaffolds using peptide epitopes present in the extracellular matrix (ECM) is a well-known approach. A common strategy has involved epitopes that provide cells with attachment points and external cues through interaction with integrin receptors. Although a variety of bioactive sequences have been identified so far, less is known about their optimal display in a scaffold. We report here on the use of self-assembled peptide amphiphile (PA) nanofiber matrices to investigate the impact of spatial presentation of the fibronectin derived epitope RGDS on cell response. Using one, three, or five glycine residues, RGDS epitopes were systematically spaced out from the surface of the rigid nanofibers. We found that cell morphology was strongly affected by the separation of the epitope from the nanofiber surface, with the longest distance yielding the most cell-spreading, bundling of actin filaments, and a round-to-polygonal transformation of cell shape. Cell response to this type of epitope display was also accompanied with activated integrin-mediated signaling and formation of stronger adhesions between cells and substrate. Interestingly, unlike length, changing the molecular flexibility of the linker had minimal influence on cell behavior on the substrate for reasons that remain poorly understood. The use in this study of high persistence length nanofibers rather than common flexible polymers allows us to conclude that epitope topography at the nanoscale structure of a scaffold influences its bioactive properties independent of epitope density and mechanical properties.


Adaptive flexibility in the feeding behaviour of brown trout: optimal prey size.
Browntrout, Salmotrutta Linnaeus,1758, is a species of significant conservation and socio-economic importance. A consequence of this importance is the enormous amount of literature that has been published on the species in the last few decades. In general terms, brown trout has been considered as a size-selective predator, even though it is able to feed on a wide range of prey sizes. Nevertheless, there are still some gaps in our knowledge, for example the theoretical relationship between prey numbers and prey sizes eaten by the fish need to be addressed. This research aimed to study optimal prey size in the environment (benthos and drift) as well as the potential relationship between prey size and two other feeding variables (prey numbers and stomach fullness). Additionally, ontogenetic shifts in these variables were addressed. Brown trout showed a clear preference for 4- to 6-mm-length prey, although the use of prey larger than 10-mm length may be feasible. The similarity of the prey size frequency distribution between the environment (benthos and drift) and the diet in some cases was considerable (from 57.7% to 95.9%). Moreover, the results revealed that the feeding strategy can be related to prey size and the numbers of prey eaten by the brown trout; as food size decreased, prey numbers increased. On the contrary, the correlation between the average prey size and fish length was positive but statistically nonsignificant. A significant ontogenetic shift, in terms of prey size sorted by age classes, was found in only two of eight studied populations. No clear relationship between prey size and stomach fullness was found. The feeding strategy of this species is flexible and clearly influenced by the size frequency distribution of potential prey: trout fed on either small numbers of large prey or large numbers of small, and theoretically low energy, prey. Our approach covers a general subject in trophic ecology and animal behaviour that may be applicable to other fish species to improve our understanding of predator feeding behaviour.


The effect of FMR1 CGG repeat interruptions on mutation frequency as measured by sperm typing.
Fragile X syndrome results from the unstable expansion of a CGG repeat within the FMR1 gene. Three classes of FMR1 alleles have been identified, normal alleles with 6-60 repeats, premutations with 60-200 repeats, and full mutations with > 230 repeats. Premutations are exquisitely unstable upon transmission. Normal alleles, while generally stable upon transmission, are thought to have different intrinsic mutation frequencies, such that some normal alleles may be predisposed towards expansion while others may be more resistant to such change. One variable that may account for this difference is the occurrence of one or more AGG triplets punctuating the normal CGG repeat. The AGG interruptions lead to alleles that have equivalent overall length but different lengths of perfect repeats. To test the influence of the length of perfect repeats on stability, we examined the CGG repeat of single sorted sperm from two males, each with 39 total repeats, but distinct AGG interruption patterns. Sorted sperm of each donor showed -15% variation in repeat length, consistent with previous studies of sorted sperm at other triplet repeat loci. However, when discounting the majority variation of +/-1 repeat, the male with 29 perfect repeats showed 3% expansion changes while the donor with only 19 perfect repeats had none (< 0.9%). Moreover, > 90% of all variant sperm, including all those observed with expansions, showed expansion or contraction of the 3' end of the repeat array. These data are consistent with the hypothesis that perfect repeat tracts influence the repeat stability and that changes of the FMR1 repeat exhibit polarity.


Does application of phase-separated self-etching adhesives affect bond strength?
To investigate whether application of three all-in-one self-etching adhesives in a phase-separated stage has an adverse effect on bonding to enamel and dentin. The shear bond strengths (SBSs) on ground enamel and dentin of the adhesives G-Bond, Hybrid Bond, and iBond, combined with Venus composite, were determined. The adhesives were dispensed in a dish and applied either 1) immediately, 2) after 2 min, or 3) after 5 min dark storage under ambient conditions. The adhesives were shortly stirred with a microbrush and applied. Prior to light activation, the adhesives were air dried for 10 s with a strong air blast. Composite cylinders were produced in a cylindrical mold clamped on the treated surface. SBSs (n = 8) were determined in a universal testing machine at 1 mm/min crosshead speed after 24 h storage in 37 degrees C water. Data were statistically analyzed with Kruskal-Wallis ANOVA and the Mann-Whitney U-Test (p < 0.05). The qualitative compositions of the separated phases were determined by FTIR spectroscopy. In the separated stage, the adhesives showed acidic monomer-rich phases, containing all components of the original adhesive composition, and water-rich phases with minor amounts of mainly functional monomers dissolved. The SBSs of the individual adhesives applied on enamel or dentin at the different times after dispensing were not significantly different. Application of the adhesives tested either as homogeneous solution or in a phase-separated stage has no adverse effect on bonding strength to enamel or dentin when applied under the present study conditions.


Pedunculopontine Nucleus Region Deep Brain Stimulation in Parkinson Disease: Surgical Anatomy and Terminology.
Several lines of evidence over the last few years have been important in ascertaining that the pedunculopontine nucleus (PPN) region could be considered as a potential target for deep brain stimulation (DBS) to treat freezing and other problems as part of a spectrum of gait disorders in Parkinson disease and other akinetic movement disorders. Since the introduction of PPN DBS, a variety of clinical studies have been published. Most indicate improvements in freezing and falls in patients who are severely affected by these problems. The results across patients, however, have been variable, perhaps reflecting patient selection, heterogeneity in target selection and differences in surgical methodology and stimulation settings. Here we outline both the accumulated knowledge and the domains of uncertainty in surgical anatomy and terminology. Specific topics were assigned to groups of experts, and this work was accumulated and reviewed by the executive committee of the working group. Areas of disagreement were discussed and modified accordingly until a consensus could be reached. We demonstrate that both the anatomy and the functional role of the PPN region need further study. The borders of the PPN and of adjacent nuclei differ when different brainstem atlases and atlas slices are compared. It is difficult to delineate precisely the PPN pars dissipata from the nucleus cuneiformis, as these structures partially overlap. This lack of clarity contributes to the difficulty in targeting and determining the exact localization of the electrodes implanted in patients with akinetic gait disorders. Future clinical studies need to consider these issues.


Franck-Condon-like Progressions in Infrared Spectra of Biological Molecules.
Infrared spectra in the NH stretch region are often used for structure determination of gas-phase biological molecules. Vibrational couplings complicate the structure determination process by giving rise to additional vibrational bands along with the expected fundamental transitions. We present an example of a strong anharmonic coupling in a biological molecule, Ac-Phe-Ala-LysH(+), which causes the appearance of long vibrational progressions in the infrared spectrum. By analyzing the spectra of the ground and the electronically excited state, we determined that the coupling occurs between the NH stretch (ωNH) and a low-frequency torsion of the phenyl ring (ωτ). We describe the vibrational progressions using a Born-Oppenheimer-like separation of the high-frequency stretch and low-frequency torsion with a quartic Taylor expansion for the potential energy surface that accounts for the equilibrium distance and frequency change of the torsional vibration upon the NH stretch excitation. We also demonstrate that small conformational changes in the peptide are sufficient to break this coupling.


Gene therapy: what have we accomplished and where do we go from here?
As a potential treatment for arthritis, gene transfer should be viewed within the context of biological therapy. Its particular strengths include the ability to deliver therapeutic gene products, both RNA and protein, to specific cells or tissues in a targeted, sustained, and potentially regulated, cost-effective fashion. An expanded definition of gene therapy includes the delivery of noncoding nucleotide sequences that act, for example, as decoy molecules. Considerable experimental progress has been made in the preclinical development of gene therapies for arthritis. Indeed, there is overwhelming proof of principle in animal models of rheumatoid arthritis (RA) and accumulating evidence of efficacy in animal models of osteoarthritis (OA). Early-phase human clinical trials have been successfully conducted and others are in progress. Additional research is necessary to optimize gene transfer technologies and achieve regulated transgene expression. However, the most urgent need is for interventional studies in human disease and the funding with which to implement them.


The area under the curve of metabolites for drugs and metabolites cleared by the liver and extrahepatic organs. Its dependence on the administration route of precursor drug.
The venous equilibrium model (or well-stirred model) is used to determine the area under the blood concentration vs. time curve of a metabolite formed from a precursor drug. It will be shown that the AUC of a metabolite will change according to the route of precursor drug administration(whether intraarterially, intravenously, via the portal vein, or orally) when the drug and/or metabolite is eliminated by more than one organ. Elimination includes hepatic and extrahepatic metabolism and renal excretion. The validity of the model is probed by using literature data for drug and metabolite areas. Finally, the use of metabolite areas for evaluating the complete/incomplete absorption or orally administered precursor drug is discussed.


Cooperative problem solving in a cooperatively breeding primate (Saguinus oedipus).
We investigated cooperative problem solving in unrelated pairs of the cooperatively breeding cottontop tamarin, Saguinus oedipus, to assess the cognitive basis of cooperative behaviour in this species and to compare abilities with other apes and monkeys. A transparent apparatus was used that required extension of two handles at opposite ends of the apparatus for access to rewards. Resistance was applied to both handles so that two tamarins had to act simultaneously in order to receive rewards. In contrast to several previous studies of cooperation, both tamarins received rewards as a result of simultaneous pulling. The results from two experiments indicated that the cottontop tamarins (1) had a much higher success rate and efficiency of pulling than many of the other species previously studied, (2) adjusted pulling behaviour to the presence or absence of a partner, and (3) spontaneously developed sustained pulling techniques to solve the task. These findings suggest that cottontop tamarins understand the role of the partner in this cooperative task, a cognitive ability widely ascribed only to great apes. The cooperative social system of tamarins, the intuitive design of the apparatus, and the provision of rewards to both participants may explain the performance of the tamarins.


[Prevalence of chronic complications in patients with over 30-year history of type 1 diabetes depending on the age of onset of diabetes].
The aim of this study was to evaluate the prevalence of chronic complications in patients with type 1 diabetes with more than 30 years of history of the disease, depending on the age of onset of diabetes. The criterion for inclusion in the study was over 30-year history of type 1 diabetes. The study group was divided into two subgroups according to the age of diagnosis of type 1 diabetes (either before or after 18 years of age). Anthropometric parameters, degree of metabolic control and the presence of markers of chronic diabetic micro- and macrovascular complications were assessed. The study was performed in 215 type 1 diabetic patients with more than 30 years history of the disease, aged 54±10 years, 98 men, 117 women. In 110 patients (group I), type 1 diabetes was diagnosed before age of 18 years, in 105 patients (group II) after 18 years of age. Patients in group I were younger, with a longer duration of the disease, more often treated with intensive functional insulin. There were no differences in terms of metabolic control between the assessed groups. Patients in group I were significantly more often diagnosed with chronic diabetic kidney disease, in group II hypertension was more often observed. The diagnosis of type 1 diabetes before or after the age of 18 had no significant effect on the lack of chronic complications. Patients with diabetes diagnosed in childhood, after 30 years of disease, presented a higher incidence of diabetic kidney disease.


Power laws from linear neuronal cable theory: power spectral densities of the soma potential, soma membrane current and single-neuron contribution to the EEG.
Power laws, that is, power spectral densities (PSDs) exhibiting 1/f(α) behavior for large frequencies f, have been observed both in microscopic (neural membrane potentials and currents) and macroscopic (electroencephalography; EEG) recordings. While complex network behavior has been suggested to be at the root of this phenomenon, we here demonstrate a possible origin of such power laws in the biophysical properties of single neurons described by the standard cable equation. Taking advantage of the analytical tractability of the so called ball and stick neuron model, we derive general expressions for the PSD transfer functions for a set of measures of neuronal activity: the soma membrane current, the current-dipole moment (corresponding to the single-neuron EEG contribution), and the soma membrane potential. These PSD transfer functions relate the PSDs of the respective measurements to the PSDs of the noisy input currents. With homogeneously distributed input currents across the neuronal membrane we find that all PSD transfer functions express asymptotic high-frequency 1/f(α) power laws with power-law exponents analytically identified as α∞(I) = 1/2 for the soma membrane current, α∞(p) = 3/2 for the current-dipole moment, and α∞(V) = 2 for the soma membrane potential. Comparison with available data suggests that the apparent power laws observed in the high-frequency end of the PSD spectra may stem from uncorrelated current sources which are homogeneously distributed across the neural membranes and themselves exhibit pink (1/f) noise distributions. While the PSD noise spectra at low frequencies may be dominated by synaptic noise, our findings suggest that the high-frequency power laws may originate in noise from intrinsic ion channels. The significance of this finding goes beyond neuroscience as it demonstrates how 1/f(α) power laws with a wide range of values for the power-law exponent α may arise from a simple, linear partial differential equation.


Identification of the Chromosomal Region Essential for Serovar-Specific Antigen and Virulence of Serovar 1 and 2 Strains of Erysipelothrix rhusiopathiae.
Erysipelothrix rhusiopathiae causes swine erysipelas, an infection characterized by acute septicemia or chronic endocarditis and polyarthritis. Among 17 E. rhusiopathiae serovars, determined based on heat-stable peptidoglycan antigens, serovars 1 and 2 are most commonly associated with the disease; however, the molecular basis for the association between these serovars and virulence is unknown. To search for the genetic region defining serovar 1a (Fujisawa) strain antigenicity, we examined the 15-kb chromosomal region encompassing a putative pathway for polysaccharide biosynthesis, which was previously identified in the E. rhusiopathiae Fujisawa strain. Six transposon mutants of Fujisawa strain possessing a mutation in this region lost antigenic reactivity with serovar 1a-specific rabbit serum. Sequence analysis of this region in wild-type strains of serovars 1a, 1b, and 2 and serovar N, which lacks serovar-specific antigens, revealed that gene organization was similar among the strains and that serovar 2 strains showed variation. Serovar N strains displayed the same gene organization as the serovar 1a, 1b, or 2 strain and possessed certain mutations in this region. In two of the analyzed serovar N strains, restoration of the mutations via complementation with sequences derived from serovar 1a and 2 strains recovered antigenic reactivity with 1a- and 2-specific rabbit serum, respectively. Several gene mutations in this region resulted in altered capsule expression and attenuation of virulence in mice. These results indicate a functional connection between the biosynthetic pathways for the capsular polysaccharide and peptidoglycan antigens used for serotyping, which may explain variation in virulence among strains of different serovars.


Nanoparticles and nanothermia for malignant brain tumors, a suggestion of treatment for further investigations.
The current treatment for brain tumors, such as glioblastoma multiforme (GBM), has not been developed enough yet in order to fully heal them. The main causes are the lack of specificity of the treatments, the difficulty of passage of drugs through the blood-brain barrier, heterogeneity and tumor aggressiveness, and widespread dissemination in the brain. The application of nanoparticles (Nps) have been a breakthrough for both diagnostic imaging and targeted therapies. There have been numerous studies with different types of Nps in brain tumors, but we have focused on thermosensitive liposomes, which are characterized by releasing the chemotherapeutic agent included within its lipophilic membranes through heat. Furthermore, increasing the temperature in brain tumors through hyperthermia has been proven therapeutically beneficial. Nanothermia or modulated-electro-hyperthermia (MEHT) is an improved technique that allows to create hot spots in nanorange at the membrane rafts, specifically in tumor cells, theoretically increasing the selectivity of the damage. In scientific records, experiments that combine both techniques (thermosensitive liposomes and nanothermia) have never been conducted. We propose a hypothesis for further research.


DNA methylation profile of triple negative breast cancer-specific genes comparing lymph node positive patients to lymph node negative patients.
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with no targeted treatment available. Our previous study identified 38 TNBC-specific genes with altered expression comparing tumour to normal samples. This study aimed to establish whether DNA methylation contributed to these expression changes in the same cohort as well as disease progression from primary breast tumour to lymph node metastasis associated with changes in the epigenome. We obtained DNA from 23 primary TNBC samples, 12 matched lymph node metastases, and 11 matched normal adjacent tissues and assayed for differential methylation profiles using Illumina HumanMethylation450 BeadChips. The results were validated in an independent cohort of 70 primary TNBC samples. The expression of 16/38 TNBC-specific genes was associated with alteration in DNA methylation. Novel methylation changes between primary tumours and lymph node metastases, as well as those associated with survival were identified. Altered methylation of 18 genes associated with lymph node metastasis were identified and validated. This study reveals the important role DNA methylation plays in altered gene expression of TNBC-specific genes and lymph node metastases. The novel insights into progression of TNBC to secondary disease may provide potential prognostic indicators for this hard-to-treat breast cancer subtype.


Association of the Duration of Ideal Cardiovascular Health Through Adulthood With Cardiometabolic Outcomes and Mortality in the Framingham Offspring Study.
The American Heart Association ideal cardiovascular health (CVH) score is associated with the risk of cardiovascular disease (CVD) and mortality. However, it is unclear whether the number of years spent in ideal CVH is associated with morbidity or with mortality. To evaluate whether living longer with a higher CVH score in midlife is associated with lower risk of hypertension, diabetes, chronic kidney disease, CVD and its subtypes (coronary heart disease, stroke, congestive heart failure, and peripheral artery disease), or all-cause mortality in later life. This prospective cohort study used data from 1445 participants from 1991 to 2015 who participated in the community-based Framingham Heart Study Offspring investigation conducted in Massachusetts. The CVH scores of participants were assessed at examination cycles 5, 6, and 7 (1991-1995; 1995-1998; and 1998-2001, respectively). Individuals were excluded from analyses of the association between duration of CVH score and outcomes if they had the outcome of interest at the seventh examination. The median follow-up was approximately 16 years. Data were analyzed from April 2018 to October 2019. The CVH score categories were poor for scores 0 to 7, intermediate for scores 8 to 11, and ideal for scores 12 to 14. A composite score was derived based on smoking status, diet, physical activity, resting blood pressure levels, body mass index, fasting blood glucose levels, and total serum cholesterol levels. Number of events and number at risk for each main outcome, including incident hypertension, diabetes, chronic kidney disease, CVD, and all-cause mortality, after the seventh examination. Of 1445 eligible participants, the mean (SD) age was 60 (9) years, and 751 (52%) were women. Number of events/number at risk for each main outcome after the seventh examination were 348/795 for incident hypertension, 104/1304 for diabetes, 198/918 for chronic kidney disease, 210/1285 for CVD, and 300/1445 for all-cause mortality. At the seventh examination, participants mostly had poor (568 [39%]) or intermediate (782 [54%]) CVH scores. For each antecedent (before examination cycle 7) 5-year duration that participants had intermediate or ideal CVH, they were less likely to develop adverse outcomes (hazards ratios of 0.67 [95% CI, 0.56-0.80] for incident hypertension, 0.73 [95% CI, 0.57-0.93] for diabetes, 0.75 [95% CI, 0.63-0.89] for chronic kidney disease, 0.73 [95% CI, 0.63-0.85] for CVD, and 0.86 [95% CI, 0.76-0.97] for all-cause mortality) relative to living the same amount of time in poor CVH (referent group). No effect modification was observed by age or by sex. These results suggest that more time spent in better CVH in midlife may have salutary cardiometabolic benefits and may be associated with lower mortality later in life.


A double blind randomized controlled trial of Maharishi Vedic vibration technology in subjects with arthritis.
To explore ancient Vedic medical techniques, one hundred and seventy-six subjects with arthritis participated in a controlled study through the non-pharmacologic approach known as the Maharishi Vedic Vibration Technology (MVVT). Using a double-blinded and randomized experimental design, the findings showed significant reductions of pain and stiffness, and improvement in range of motion in the study sample. One hundred percent relief of symptoms was the most commonly reported category of improvement due to treatment. For the group as a whole, differences in mean response of treatment and control conditions with respect to relief of pain, limitation of motion, and reduction in stiffness were highly significant: t values ranged from a low of 5.609 in stiffness to a high of 20.950 in pain, p = 0.000009 to <10-49 respectively. Analysis by sub-categories of peripheral arthritis, painful conditions of the spine, and rheumatoid arthritis likewise produced significant results. Mechanisms of action were proposed, drawing on Maharishi Vedic Science, developments in quantum field theory, and specifically the theories of chaos and self-organizing systems as they relate to physiological functioning. The instantaneous relief of pain and improvement in function in such a high proportion of subjects with chronic arthritis is unparalleled in modern medical science


2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibits neurite outgrowth in differentiating human SH-SY5Y neuroblastoma cells.
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), a highly toxic environmental pollutant, is known to induce neurodevelopmental and neurobehavioral deficits. However, the underlying mechanism of TCDD-mediated neurotoxicity has remained unclear. We have studied TCDD inhibition of neurite outgrowth using human SH-SY5Y neuroblastoma cells induced to differentiate by all-trans-retinoic acid (RA). TCDD, at concentrations of 3 nM or 5 nM, had no significant effect on the viability of either undifferentiating or differentiated SH-SY5Y cells. However, differentiating SH-SY5Y cells exhibited a distinct decrease of neurite outgrowth 48 h after TCDD treatment in a dose-dependent manner. TCDD treatment 12h or 24h after RA stimulation did not elicit a significant inhibition of neurite outgrowth, whereas TCDD cotreatment with RA or TCDD treatment at 6h after RA stimulation significantly inhibited neurite outgrowth. Western blot analysis of cell extracts of RA-stimulated differentiating SH-SY5Y cells showed increased level of cross reactivities with tissue glutaminase (TGase) antibody compared to control extracts, in a time-dependent manner. By contrast, treatment of differentiating SH-SY5Y cells with 1-5 nM TCDD resulted in decreased level of cross-reactivities with TGase antibody in a dose-dependent manner. The results indicate that TCDD is able to inhibit neurite outgrowth by differentiating SH-SY5Y cells and that this effect might result from reduced levels of TGase.


Are you working too hard? A conversation with mind/body researcher Herbert Benson.
Stress is an essential response in highly competitive environments. Before a race, before an exam, before an important meeting, your heart rate and blood pressure rise, your focus tightens, you become more alert and more efficient. But beyond a certain level, stress overloads your system, compromising your performance and, eventually, your health. So the question is: When does stress help and when does it hurt? To find out, HBR talked with Harvard Medical School professor Herbert Benson, M.D., founder of the Mind/Body Medical Institute. Having spent more than 35 years conducting worldwide research in the fields of neuroscience and stress, Benson is best known for his 1975 best seller The Relaxation Response, in which he describes how the mind can influence stress levels through such tools as meditation. His most recent research centers on what he calls"the breakout principle," a method by which stress is not simply reduced but carefully controlled so that you reap its benefits while avoiding its dangers. He describes a four-step process in which you first push yourself to the most productive stress level by grappling intently with a problem. Next, just as you feel yourself flagging, you disengage entirely by doing something utterly unrelated-going for a walk, petting a dog, taking a shower. In the third step, as the brain quiets down, activity paradoxically increases in areas associated with attention, space-time concepts, and decision making, leading to a sudden, creative insight-the breakout. Step four is achievement of a "new-normal state," in which you find that the improved performance is sustained, sometimes indefinitely. As counterintuitive as this research may seem, managers can doubtless recall times when they've had an "aha" moment at the gym, on the golf course, or in the shower. What Benson describes here is a way to tap into this invaluable biological tool whenever we want.