Shopper Purchasing Trends at Small Stores on the Navajo Nation since the Passage of the Healthy Diné Nation Act Tax: A Multi-Year Cross-sectional Survey.
In 2014, the Navajo Nation passed the Healthy Diné Nation Act (HDNA), which applies an additional 2% tax on unhealthy foods and beverages and a waiver of Navajo sales tax on healthy foods and beverages. However, the HDNA's impact on purchasing behavior has not been explored. We assessed beverage and produce purchasing trends among shoppers at small Navajo stores between 2017 and 2019, shopper characteristics associated with buying water, and whether HDNA awareness was associated with purchasing behaviors. A total of 332 shoppers at 34 stores in 2017 and 274 shoppers at 44 stores in 2019 were surveyed to assess HDNA awareness and same-day purchasing of water, sugar-sweetened beverages (SSBs), fruits, and vegetables. Hypotheses were tested using chi-square analyses and multivariate analysis. Water purchasing among respondents increased significantly from 2017 to 2019 (24.4% to 32.8%; P = 0.03). Shoppers in 2019 were 1.5 times more likely to purchase water compared with 2017 (adjusted P = 0.01). There was a trend toward reduced SSB purchasing (85.8% in 2017, 80.3% in 2019, P = 0.068), while produce purchasing remained unchanged over time, at approximately 17%. Shoppers were more likely to buy water if they relied on that store for the majority of their groceries (P = 0.006) and if they did not have their own transportation to get to the store (P = 0.004). Most shoppers (56.6%) were aware of the HDNA; of these, 35.6% attributed healthier habits to the HDNA, most commonly buying more healthy drinks (49.2%), fewer unhealthy drinks (37.7%), more healthy snacks (31.1%), and fewer unhealthy snacks (26.2%). Shopper habits at small stores located on the Navajo Nation have shifted towards healthier purchasing from 2017 to 2019. Shoppers who were aware of the HDNA reported purchasing more healthy and fewer unhealthy food and drinks as a result of this legislation.


Phase I trial and clinical pharmacological evaluation of 10-ethyl-10-deazaaminopterin in adult patients with advanced cancer.
10-Ethyl-10-deazaaminopterin (10-EDAM) is an analogue of methotrexate with improved preclinical anticancer activity, more selective entry, and greater conversion to polyglutamate forms in neoplastic cells. In this Phase I trial, we have treated 62 adults with advanced solid tumors, giving 10-EDAM i.v. on either a weekly x 3 schedule (35 patients) or a weekly schedule (27 patients). The dosage levels ranged from 5 to 120 mg/m2. The toxicity observed with 10-EDAM was qualitatively similar to that of methotrexate. Oral mucositis was the dose-limiting toxicity; diarrhea, skin rash, leukopenia, thrombocytopenia, and mild elevations of serum glutamic-oxaloacetic transaminase, prothrombin, and partial thromboplastin times were also observed, but were not dose limiting. A weekly dosage of 80 mg/m2 with escalation or attenuation in accordance with patient tolerance, or 100 mg/m2 weekly for 3 weeks, followed by a 2-week "rest period" are recommended for Phase II assessment. 10-EDAM produced partial remissions in three patients with non-small cell lung cancer and one patient with breast cancer lasting 6, 40+, 26+, and 15 months, respectively. Pharmacokinetic studies carried out at the 5, 30, and 100 mg/m2 dosage levels demonstrated the drug to have a triphasic disappearance from plasma. Elimination was independent of dose over the range tested, with mean plasma half-lives of: alpha = 12.9 min, beta = 1.5 h, and gamma = 11.9 h. Cumulative urinary excretion of the drug ranged from 13 to 55% of the administered dose (mean = 33%); 88% of the urinary drug appeared within the first 4 h following drug administration. The pharmacokinetic behavior of the first and second weekly dosages were consistent within a given patient. The metabolites 7-hydroxy-10-EDAM, and 10-ethyl-10-deaza-2,4-diamino-pteroic acid were demonstrated in the plasma and urine of treated patients. In studies of tissue homogenates from two patients with skin metastases, more extensive retention of the drug and of its polyglutamates was observed in the breast cancer metastases than in the metastases from a kidney cancer or in normal skin.


Metal nanoslit lenses with polarization-selective design.
We present comprehensive studies on thin diffraction lenses made of arrays of subwavelength, parallel nanoslits in a gold film. Such a nanoslit lens can operate either as a conventional convex or concave lens. The lenses can be designed to focus linearly polarized light with polarization either perpendicular (TM-lens) or parallel to the slits (TE-lens), while the orthogonal polarization diverges when passing through the lens. The designs of each lens are initially built on the dispersion relations for wave propagation through a parallel-plate waveguide. Both TM- and TE-lenses were realized experimentally, and full-wave numerical simulations fully support the experimental results.


Cortisol metabolism and the role of 11beta-hydroxysteroid dehydrogenase.
Two isoforms of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert the active glucocorticoid, cortisol, and inactive cortisone. 11beta-HSD1 is believed to act in vivo predominantly as an oxo-reductase using NADP(H) as a cofactor to generate cortisol. In contrast, 11beta-HSD2 acts exclusively as an NAD-dependent dehydrogenase inactivating cortisol to cortisone, thereby protecting the mineralocorticoid receptor from occupation by cortisol. In peripheral tissues, both enzymes serve to control the availability of cortisol to bind to the corticosteroid receptors. Defective expression of 11beta-HSD2 is implicated in patients with hypertension and intra-uterine growth retardation, while 11beta-HSD1 appears to be intricately involved in the conditions of apparent cortisone reductase deficiency, insulin resistance and visceral obesity. The ability of peripheral tissues to regulate corticosteroid concentrations through 11beta-HSD isozymes is established as an important mechanism in the pathogenesis of diverse human diseases. Modulation of enzyme activity may offer a novel therapeutic approach to treating human disease while circumventing the consequences of systemic glucocorticoid excess or deficiency.


High levels of circulating triiodothyronine induce plasma cell differentiation.
The effects of hyperthyroidism on B-cell physiology are still poorly known. In this study, we evaluated the influence of high-circulating levels of 3,5,3'-triiodothyronine (T3) on bone marrow, blood, and spleen B-cell subsets, more specifically on B-cell differentiation into plasma cells, in C57BL/6 mice receiving daily injections of T3 for 14 days. As analyzed by flow cytometry, T3-treated mice exhibited increased frequencies of pre-B and immature B-cells and decreased percentages of mature B-cells in the bone marrow, accompanied by an increased frequency of blood B-cells, splenic newly formed B-cells, and total CD19(+)B-cells. T3 administration also promoted an increase in the size and cellularity of the spleen as well as in the white pulp areas of the organ, as evidenced by histological analyses. In addition, a decreased frequency of splenic B220(+) cells correlating with an increased percentage of CD138(+) plasma cells was observed in the spleen and bone marrow of T3-treated mice. Using enzyme-linked immunospot assay, an increased number of splenic immunoglobulin-secreting B-cells from T3-treated mice was detected ex vivo. Similar results were observed in mice immunized with hen egg lysozyme and aluminum adjuvant alone or together with treatment with T3. In conclusion, we provide evidence that high-circulating levels of T3 stimulate plasma cytogenesis favoring an increase in plasma cells in the bone marrow, a long-lived plasma cell survival niche. These findings indicate that a stimulatory effect on plasma cell differentiation could occur in untreated patients with Graves' disease.


Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial.
Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer, but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain. Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer. In this open-label, randomised trial, we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK. From December, 2006 until June, 2008, molecularly unselected patients were recruited to a three-arm design including irinotecan (control), irinotecan plus ciclosporin, and irinotecan plus panitumumab (IrPan) groups. From June 10, 2008, in response to new data, the trial was amended to a prospectively stratified design, restricting panitumumab randomisation to patients with KRAS wild-type tumours; the results of the comparison between the irinotcan and IrPan groups are reported here. We used a computer-generated randomisation sequence (stratified by previous EGFR targeted therapy and then minimised by centre, WHO performance status, previous oxaliplatin, previous bevacizumab, previous dose modifications, and best previous response) to randomly allocate patients to either irinotecan or IrPan. Patients in both groups received 350 mg/m(2) intravenous irinotecan every 3 weeks (300 mg/m(2) if aged ≥70 years or a performance status of 2); patients in the IrPan group also received intravenous panitumumab 9 mg/kg every 3 weeks. The primary endpoint was overall survival in KRAS wild-type patients who had not received previous EGFR targeted therapy, analysed by intention to treat. Tumour DNA was pyrosequenced for KRASc.146, BRAF, NRAS, and PIK3CA mutations, and predefined molecular subgroups were analysed for interaction with the effect of panitumumab. This study is registered, number ISRCTN93248876. Between Dec 4, 2006, and Aug 31, 2010, 1198 patients were enrolled, of whom 460 were included in the primary population of patients with KRASc.12-13,61 wild-type tumours and no previous EGFR targeted therapy. 230 patients were randomly allocated to irinotecan and 230 to IrPan. There was no difference in overall survival between groups (HR 1·01, 95% CI 0·83-1·23; p=0·91), but individuals in the IrPan group had longer progression-free survival (0·78, 0·64-0·95; p=0·015) and a greater number of responses (79 [34%] patients vs 27 [12%]; p<0·0001) than did individuals in the irinotecan group. Grade 3 or worse diarrhoea (64 [29%] of 219 patients vs 39 [18%] of 218 patients), skin toxicity (41 [19%] vs none), lethargy (45 [21]% vs 24 [11%]), infection (42 [19%] vs 22 [10%]) and haematological toxicity (48 [22%] vs 27 [12%]) were reported more commonly in the IrPan group than in the irinotecan group. We recorded five treatment-related deaths, two in the IrPan group and three in the irinotecan group. Adding panitumumab to irinotecan did not improve the overall survival of patients with wild-type KRAS tumours. Further refinement of molecular selection is needed for substantial benefits to be derived from EGFR targeting agents. Cancer Research UK, Amgen Inc.


Nutritional manipulation of primate retinas. IV. Effects of n--3 fatty acids, lutein, and zeaxanthin on S-cones and rods in the foveal region.
Lutein and zeaxanthin are xanthophylls selectively accumulated by primate retinas that may protect the macula from age-related macular degeneration. In this project, we manipulated n-3 fatty acids, lutein and/or zeaxanthin levels in the diet and studied their possible outcome on S-cone and rod cell density in the foveal region. Rhesus monkeys (7-16 year, n=17) were fed from birth xanthophyll-free semipurified diets with either adequate or low n-3 fatty acids. Five monkeys were supplemented with lutein and six with zeaxanthin for 6-24 months, while six remained xanthophyll-free until sacrifice. Retinas were embedded in methacrylate and serial 2 microm sections were cut along the vertical meridian. Rod nuclei, and immuno-labelled outer segments of S-cones and rods, were reconstructed and counted in an 8 microm strip. The density profiles were compared with data from control monkeys (n=7) fed a standard laboratory diet. S-cone density profiles were symmetrical along the vertical meridian and the densities decreased rapidly with retinal eccentricity. Rod densities were higher in the superior region than the inferior region in most of the control and experimental animals. Unlike the significant effects observed for retinal pigment epithelial cells of these same monkeys (Leung, I.Y-F., Sandstrom, M.M., Zucker, C.L., Neuringer, M., Snodderly, D.M., 2004. Nutritional manipulation of primate retinas. II. Effects of age, n-3 fatty acids, lutein, and zeaxanthin on retinal pigment epithelium. Invest. Ophthalmol. Vis. Sci. 45, 3244-3256), neither xanthophyll supplementation nor low dietary n-3 fatty acids produced consistent effects on S-cone or rod density profiles of the experimental animals. However, monkeys low in n-3 fatty acids had increased variability of S-cone density in the fovea and low density of foveal rod outer segments. The high variability suggests that the photoreceptors of some animals were resistant to the nutritional manipulations, while others may have been affected. Thus, the photoreceptors appear less sensitive than the retinal pigment epithelium to these nutritional manipulations. However, it is possible that more consistent effects would emerge at a later age or after exposure to stressors such as high light levels.


Influence of glucagon-like peptide 1 on fasting glycemia in type 2 diabetic patients treated with insulin after sulfonylurea secondary failure.
Glucagon-like peptide 1 (GLP-1) has glucose-dependent insulinotropic and glucagonostatic actions in type 2 diabetic patients on diet and on oral agents. It is not known, however, whether after secondary sulfonylurea failure, GLP-1 is still effective. Therefore, 10 type 2 diabetic patients (6 women, 4 men; age 65+/-10 years, BMI 30.4+/-5.1 kg/m2, HbA1c 8.2+/-1.5%, 6+/-3 [2-13] years after starting insulin treatment) were examined in the fasting state after discontinuing NPH insulin on the evening before the two study days. GLP-1 (1.2 pmol x kg(-1) x min(-1) or placebo (NaCl with 1% human serum albumin) were infused over 6 h. Plasma glucose (glucose oxidase) insulin (IMx), and C-peptide (enzyme-linked immunosorbent assay) were measured. Statistical analysis was performed using repeated measures analysis of variance. Fasting plasma glucose was 9.4+/-0.5 mmol/l and was reduced by GLP-1 to 5.3+/-0.3 (3.9-7.3) mmol/l (placebo: 8.2+/-0.7 mmol/l; P < 0.0001). GLP-1 transiently increased insulin (from 115+/-31 to 222+/-64 pmol/l at 150 min; P < 0.0001) and C-peptide (from 1.00+/-0.12 to 1.90+/-0.23 nmol/l at 120 min; P < 0.0001) with no effect of placebo. Glucagon and free fatty acids were lowered transiently. After normalization of plasma glucose, insulin and C-peptide concentrations became lower again during the ongoing administration of exogenous GLP-1, and no hypoglycemia occurred. It is concluded that exogenous GLP-1 effectively lowers plasma glucose concentrations in advanced type 2 diabetes long after sulfonylurea secondary failure. These findings may broaden the applicability of GLP-1-derived drugs as a new treatment to nearly all type 2 diabetic patients.


General practitioner psychological management of common emotional problems (I): Definitions and literature review.
General practitioners' (GPs') treatment of patients with common emotional problems often includes some form of psychological management within the consultation. Such psychological management may be limited to listening and discussion or may also include more specific psychological approaches, such as use of counselling, problem-solving, or cognitive-behavioural techniques. This paper defines GP psychological management and reviews what is known about its frequency and effectiveness. MEDLINE and PsychLIT searches were undertaken of empirical studies of the psychological management of emotional problems by GPs in routine consultations published up to 1998. Thirty-six studies were identified. Most lacked details of the nature of the psychological management reported, making it difficult to compare studies. The frequency of use of psychological management by GPs was found to be generally less when rated by external observers than when assessed by GP self-report. There is preliminary evidence from a few studies of the clinical effectiveness of GP psychological management in routine consultations.


Patients on state organ donor registries receive similar levels of intensive care compared to those who are not: an opportunity to increase public intent to donate.
The intent to donate organs is affected by the public perception that patients on state registries receive less aggressive life-saving care in order to allow organ donation to proceed. However, the association between first person authorization to donate organs and the actual care received by eventual organ donors in hospitals is unknown. From August 2010 to April 2011, all eight organ procurement organizations in United Network for Organ Sharing Region 5 prospectively recorded demographic data and organ utilization rates on all donors after neurologic determination of death (DNDDs). Critical care and physiologic parameters were also recorded at referral for imminent neurologic death and prior to authorization for donation to reflect the aggressiveness of provided care. There were 586 DNDDs and 23% were on a state registry. Compared to non-registered DNDDs, those on state registries were older but were noted to have similar critical care parameters at both referral and authorization. Furthermore, there was no significant difference in organs procured per donor or organs transplanted per donor between registered and non-registered DNDDs. Thus, DNDDs who are on state donor registries receive similar levels of intensive care compared to non-registered donors. The association noted in this study may therefore help to dispel a common misperception that decreases the intent to donate.


Lipid-packing perturbation of model membranes by pH-responsive antimicrobial peptides.
The indiscriminate use of conventional antibiotics is leading to an increase in the number of resistant bacterial strains, motivating the search for new compounds to overcome this challenging problem. Antimicrobial peptides, acting only in the lipid phase of membranes without requiring specific membrane receptors as do conventional antibiotics, have shown great potential as possible substituents of these drugs. These peptides are in general rich in basic and hydrophobic residues forming an amphipathic structure when in contact with membranes. The outer leaflet of the prokaryotic cell membrane is rich in anionic lipids, while the surface of the eukaryotic cell is zwitterionic. Due to their positive net charge, many of these peptides are selective to the prokaryotic membrane. Notwithstanding this preference for anionic membranes, some of them can also act on neutral ones, hampering their therapeutic use. In addition to the electrostatic interaction driving peptide adsorption by the membrane, the ability of the peptide to perturb lipid packing is of paramount importance in their capacity to induce cell lysis, which is strongly dependent on electrostatic and hydrophobic interactions. In the present research, we revised the adsorption of antimicrobial peptides by model membranes as well as the perturbation that they induce in lipid packing. In particular, we focused on some peptides that have simultaneously acidic and basic residues. The net charges of these peptides are modulated by pH changes and the lipid composition of model membranes. We discuss the experimental approaches used to explore these aspects of lipid membranes using lipid vesicles and lipid monolayer as model membranes.


Polyvalent side chain peptide-synthetic polymer conjugates as HIV-1 entry inhibitors.
This report describes the synthesis and properties of a series of polyvalent side chain peptide-synthetic polymer conjugates designed to block the CD4 binding site on gp120 and inhibit HIV-1 entry into a host cell. The peptide sequences in the conjugates are based on the CDR H3 region of the neutralizing anti-HIV-1 antibody IgG1 b12. Using a consecutive ester-amide/thiol-ene postpolymerization modification strategy, a library of polymer conjugates was prepared. Evaluation of the HIV-1 inhibitory properties revealed that midsized polymer conjugates displayed the highest antiviral activity, while shorter and longer conjugates proved to be less efficacious inhibitors. The lower molecular weight conjugates may not have sufficient length to span the distance between two neighboring gp120 containing spikes, while the higher molecular weight conjugates may be compromised due to a higher entropic penalty that would accompany their binding to the viral envelope. Although the IC(50) values for these polymer conjugates are higher than that of the parent IgG1 b12 antibody, the strategy presented here may represent an interesting antiviral approach due to the attractive properties of such polymer therapeutics (relatively inexpensive production and purification costs, high thermal and chemical stability in storage conditions, long half-life in biological tissues, low immunogenicity, and protection from proteolytic degradation).


Postdisaster psychosocial intervention: a field study of the impact of debriefing on psychological distress.
Following a catastrophic natural disaster, the authors evaluated whether brief psychological intervention (debriefing 6 months later) reduced disaster-related psychological distress as measured by the Impact of Event Scale. Two groups of subjects who had been exposed to Hurricane Iniki in Hawaii were assessed before and after participating in a multihour debriefing group. The intervention aimed to provide ventilation of feelings, normalization of responses, and education about normal psychological reactions to the disaster in a context of group support. To provide a partial control for the passage of time, the pretreatment assessment of the second group was concurrent with the posttreatment assessment of the first group. A repeated measures analysis of variance indicated that Impact of Event Scale scores were reduced in both groups after the treatment. There is preliminary empirical support for the effectiveness of postdisaster psychological intervention and for the feasibility of treatment research in postdisaster environments.


[The theorotical basis for chronic fatigue syndrome from bladder meridian of foot-taiyang].
The bladder meridian of foot-taiyang is considered as key of six meridians and the yang of the yang, which is the pivot of transportation for qi and blood in the meridians and zang-fu. The running route and treatment characteristic of bladder meridian is closely related with chronic fatigue syndrome (CFS). The bladder meridian belongs to brain and connects with governor vessel, which has a close relationship with zang-fu function, quality of sleep and fatigue. Besides, the running route of bladder meridian is highly consistent with the surface projections of important anatomical structures such as muscle, nerve and sympathetic trunk, etc. Therefore, regulating the meridian-qi of bladder meridian can harmonize five-zang and calm the mind, but also effectively relieve physical and mental fatigue in CFS.


Frontline approach to metastatic BRAF-mutant melanoma diagnosis, molecular evaluation, and treatment choice.
An estimated 76,100 patients will be diagnosed with invasive melanoma in the United States in 2014, and 9,710 patients will die from the disease. In almost all cases, the cause of death is related to the development of widespread metastatic disease. Although death rates from most types of cancer have steadily decreased in the United States--a 20% decrease during two decades from a peak of 215.1 deaths per 100,000 population in 1991 to 171.8 in 2010--death rates from melanoma have steadily increased during the same time, especially among males. The news regarding melanoma is far from all bad. Increases in our understanding of the human immune system have led to the development of new immunotherapeutic drugs such as ipilimumab, which has been shown to improve survival in phase III trials in metastatic melanoma, and anti-programmed death 1 (anti-PD1) antibodies, recently hailed by ASCO as one of the past year's most noteworthy clinical cancer advances. However, no discovery has influenced and, indeed, transformed the management of metastatic melanoma more than the identifıcation of activating mutations in the BRAF gene in the mitogen-activated protein kinase (MAPK) pathway, which occur in about half of cutaneous melanomas and can be targeted with small molecule inhibitors of the BRAF protein, the downstream MEK protein, or both. This article will address how patients with metastatic melanoma are evaluated for their mutation status and how the presence of a targetable mutation influences therapeutic decisions regarding systemic therapy and even surgery.


Estimating the long-term clinical impact of cervical cancer vaccination in Taiwan.
The high burden of human papillomavirus (HPV) infection and subsequent cervical cancer in the presence of screening in Taiwan suggests the need for further prevention strategies. Epidemiology and screening practices vary considerably between countries, and specific analyses are required to estimate the impact of HPV vaccination. This study adapted a computer-based health economic model to Taiwan to project the clinical impact of the introduction of a prophylactic vaccine against persistent HPV 16/18 infection on cervical disease. A Markov model based on the natural history of HPV and cervical cancer was developed to simulate transitions between health states (normal, HPV, cervical intraepithelial neoplasia [CIN] stages I to III, cervical cancer stages I to IV, and death) in the presence of screening. The model was calibrated to Taiwan epidemiological end points including age-specific HPV prevalence, prevalence of CIN lesions, and predicted cervical cancer incidence and mortality. Taiwanese screening and treatment practices were modeled, and published clinical trial data were used to estimate vaccine efficacy. With 100% vaccine coverage in a 13-year-old cohort of females, there is estimated to be a 71% reduction in cervical cancer cases and deaths due to all HPV types and substantial reductions in the prevalence of precancerous lesions and screening outcomes. Removing the risk of HPV infection of a large proportion of Taiwanese females, with a high underlying cervical cancer incidence rate, would be expected to have dramatic effects on the health care system and mortality in Taiwan.


Enhanced Surveillance of Infectious Diseases : the 2006 FIFA World Cup experience, Germany.
The 2006 FIFA World Cup was held in 12 German cities between 9 June and 9 July 2006. We identified a need to accelerate and sensitise the pre-existing surveillance system for infectious diseases in order to timely detect adverse health events during the World Cup. Enhanced surveillance, based on Germany's pre-existing system of mandatory notifications was conducted between 7 June and 11July 2006 in the 12 World Cup cities by: accelerating frequency of electronic data transmission of case-definition based notifiable diseases from weekly to daily transmission, additional reporting of non-case definition-based infectious disease events, lay and expert press screening and intensifying communication between all stakeholders of the surveillance system. Median delay of notification data transmission from the community to the federal level was reduced from three days to one day. The enhanced reporting system detected a norovirus outbreak in the International Broadcast Centre in Munich with 61 epidemiologically linked cases within the first week after onset, as well as four single cases related to the World Cup, two of them with relevance for the International Health Regulations. After the World Cup, all surveillance stakeholders agreed that communication between local, state and federal levels had improved considerably. Unlike the majority of health planners of previous mass gatherings in the last decade we did not introduce syndromic surveillance. Nevertheless, enhancement of infectious disease surveillance successfully detected adverse health events in a timely manner during the FIFA World Cup. Additionally, it provided a valuable communication and networking exercise for potentially critical health-related events. We recommend continuing daily notification data transmission for routine infectious disease surveillance in Germany.


Enhanced development of caspase-independent cortical cell death during cold storage in kidneys of non-heart-beating donors.
Understanding the mechanisms of injury associated with cardiac arrest is essential for defining strategies aimed at improving preservation and function of kidneys harvested in non-heart-beating (NHB) donors. We standardized a model of NHB donors in rats and studied the kinetics and types (apoptosis vs. necrosis) of renal cell death developing during cold storage. Using quantitative polymerase chain reaction, immunoblotting, and caspase inhibition, we also studied the molecular pathways regulating renal cell death in this model. The kinetics and extent of cell death developing in cortical tubules during cold storage were found to be increased in non-heart-beating (NHB) kidneys. Apoptosis of cortical tubules predominated in NHB kidneys exposed to 10 hr of cold storage, whereas necrosis increased after longer periods of cold ischemia. Shortly after cardiac arrest, a rapid up-regulation of Bax and Hsp 70 was found at the protein level in NHB kidneys. After 24 hr of cold storage, induction of Bax was maintained, whereas protein levels of Hsp70 returned to levels comparable to heart-beating (HB) controls. Also, mRNA levels of Bax were found to increase during cold storage in NHB kidneys. Cortical cell death was found to be largely caspase-independent but responsive to hydroxyl-radical scavenging with dimethyl sulfoxide (DMSO). Cardiac arrest promotes activation of death-inducing molecules such as Bax and is associated with increased development of caspase-independent renal cell death during cold storage. Developing strategies, such as free radical scavenging, aimed at inhibiting cell death during cold storage, could prove useful for improving preservation of NHB kidneys.


Acute respiratory distress syndrome in patients with hematological malignancies.
We investigated the clinical course and mortality of acute respiratory distress syndrome (ARDS) in patients with hematological malignancies. Sixty-eight patients with hematological malignancies and ARDS admitted to medical intensive care unit (ICU) of a university hospital were analyzed semi-prospectively in the study. The most common etiology of ARDS was pneumonia. The ratio of partial pressure of oxygen in arterial blood to fractional concentration of inspired oxygen (PO2/FiO2) was 104 (74-165). Ten patients (15%) received non-invasive mechanical ventilation (NIV), 21 (31%) received invasive mechanical ventilation (MV), and 36 (53%) received both NIV and invasive MV. ICU mortality was 77% in the cohort. None of the variables with relevance to the underlying hematological disease was associated with mortality. The presence of two or more organ failures was the only independent risk factor for mortality (P = 0.045), whereas NIV was associated with low mortality (P = 0.001). The Kaplan-Meier curve of mortality, with respect to the type of MV support, demonstrated that NIV was associated with the lowest mortality (P < 0.001). The mortality of ARDS in critically ill patients with hematological malignancies is quite high. The presence of multi-organ failure is independently associated with high mortality whereas the use of NIV is independently associated with low mortality.


Evodiamine Induces Apoptosis, G2/M Cell Cycle Arrest, and Inhibition of Cell Migration and Invasion in Human Osteosarcoma Cells via Raf/MEK/ERK Signalling Pathway.
BACKGROUND Osteosarcoma is a prevalent type of bone tumor mainly reported in children and adolescents. The treatments for osteosarcoma are limited and are associated with serious adverse effects. In this study we evaluated the anticancer activity of Evodiamine, a plant-derived natural product, against a panel of osteosarcoma cells and explored the underlying mechanisms. MATERIAL AND METHODS The viability of osteosarcoma cell lines was investigated by MTT assay. Apoptosis was detected by DAPI and annexin V/PI staining and cell cycle analysis was performed by flow cytometry. The expression of the proteins was examined by Western blotting. RESULTS The results of the present study indicated that Evodiamine inhibited the proliferation of U2OS osteosarcoma cells with an IC50 of 6 µM. Further investigations indicated the antiproliferative effects of Evodiamine are due to induction of apoptosis and G2/M cell cycle arrest. The results of Western blotting revealed that the expression of several apoptosis (Cytochrome c, Bax, Bid, Caspase 3, 9, 8, and PARP) and cell cycle-related proteins (cyclin B1, Cdc25c, and Cdc2) was significantly altered. Evodiamine also suppressed the migration and invasion of U2OS osteosarcoma cells. Moreover, Evodiamine downregulated the expression of important regulatory proteins such as p-MEK and p-ERK, leading to the inhibition of Raf/MEK/ERK signalling pathways. CONCLUSIONS We found that Evodiamine exerts anticancer effects on osteosarcoma cells and has potential in the treatment of osteosarcoma.


The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in the United States--a 24-year population-based study.
The aim of this study was to compare the age-adjusted incidence and survival for invasive adenocarcinoma and squamous cell carcinoma of the uterine cervix using population-based data. The SEER database was used to identify all cases of cervical cancer registered between 1973 and 1996. Stage was defined as localized, regional, or distant. Age-adjusted incidence rates were analyzed statistically using the Jonchkeere-Terpstra exact test for trends. Relative and observed survival rates, respectively, were compared using z tests and log-rank tests. The age-adjusted incidence rates per 100,000 for all invasive cervical cancers decreased by 36.9% over 24 years [12.35 (1973-1977) vs 7.79 (1993-1996)]. Similarly, the age-adjusted incidence rates for squamous cell carcinoma declined by 41.9% [9.45 (1973-1977) vs 5.49 (1993-1996)]. In contrast, the age-adjusted incidence rates for adenocarcinoma increased by 29.1% [1.34 (1973-1977) vs 1.73 (1993-1996)]. The proportion of adenocarcinoma increased 107.4% relative to all cervical cancer, 95.2% relative to squamous cell carcinoma, and 49.3% relative to the population of women at risk [10. 8% vs 22.4% (P < 0.001), 12.4% vs 24.0% (P < 0.001), and 1.40 vs 2. 09 per 100,000 women (P < 0.001), respectively]. Observed survival rates for adenocarcinoma vs squamous cell carcinoma were poorer for regional (P = 0.04), but not localized or distant disease. Over the past 24 years, the incidence of all cervical cancer and squamous cell carcinoma has continued to decline. However, the proportion of adenocarcinoma relative to squamous cell carcinoma and to all cervical cancers has doubled, and the rate of adenocarcinoma per population at risk has also increased. These results suggest that current screening practices in the United States are insufficient to detect a significant proportion of adenocarcinoma precursor lesions.


Genomic imprinting in the Arabidopsis embryo is partly regulated by PRC2.
Genomic imprinting results in monoallelic gene expression in a parent-of-origin-dependent manner and is regulated by the differential epigenetic marking of the parental alleles. In plants, genomic imprinting has been primarily described for genes expressed in the endosperm, a tissue nourishing the developing embryo that does not contribute to the next generation. In Arabidopsis, the genes MEDEA (MEA) and PHERES1 (PHE1), which are imprinted in the endosperm, are also expressed in the embryo; whether their embryonic expression is regulated by imprinting or not, however, remains controversial. In contrast, the maternally expressed in embryo 1 (mee1) gene of maize is clearly imprinted in the embryo. We identified several imprinted candidate genes in an allele-specific transcriptome of hybrid Arabidopsis embryos and confirmed parent-of-origin-dependent, monoallelic expression for eleven maternally expressed genes (MEGs) and one paternally expressed gene (PEG) in the embryo, using allele-specific expression analyses and reporter gene assays. Genetic studies indicate that the Polycomb Repressive Complex 2 (PRC2) but not the DNA METHYLTRANSFERASE1 (MET1) is involved in regulating imprinted expression in the embryo. In the seedling, all embryonic MEGs and the PEG are expressed from both parents, suggesting that the imprint is erased during late embryogenesis or early vegetative development. Our finding that several genes are regulated by genomic imprinting in the Arabidopsis embryo clearly demonstrates that this epigenetic phenomenon is not a unique feature of the endosperm in both monocots and dicots.


Topoisomerase II alpha co-amplification with erbB2 in human primary breast cancer and breast cancer cell lines: relationship to m-AMSA and mitoxantrone sensitivity.
Topoisomerase II alpha (topo II alpha) is a key enzyme in DNA replication and a target for many anti-cancer drugs. High levels are associated with sensitivity to topoisomerase II inhibitors. Because its chromosome location is similar to erbB2 (17q21-22), which is frequently amplified in breast cancer, co-amplification of these genes was assessed. In 117 primary breast cancers, 25 were amplified for erbB2. Three of these cases showed co-amplification of topo II alpha. Topo II beta was not amplified. Four human breast cancer cell lines were assessed for erbB2 and topo II alpha co-amplification. They were also analysed for sensitivity to the topoisomerase inhibitors m-AMSA and mitoxantrone. The most sensitive cell line was SKBr3, which was the only one with erbB2 amplification. Topo II alpha was co-amplified to a similar extent as in tumours. This suggests that patients whose tumours show topo II alpha amplification should be assessed specifically for therapy with topoisomerase inhibitors.


Usability and acceptability of an automated respiratory rate counter to assess children for symptoms of pneumonia: A cross-sectional study in Ethiopia.
Manually counting respiratory rate (RR) is commonly practiced by community health workers to detect fast breathing, an important sign of childhood pneumonia. Correctly counting and classifying breaths manually is challenging, often leading to inappropriate treatment. This study aimed to determine the usability of a new automated RR counter (ChARM) by health extension workers (HEWs), and its acceptability to HEWs, first-level health facility workers (FLHFWs) and caregivers in Ethiopia. A cross-sectional study was conducted in one region of Ethiopia between May and August 2018. A total of 131 HEWs were directly observed conducting 262 sick child consultations after training and 337 after 2 months. Usability was measured as adherence to the WHO requirements to assess fast breathing and device manufacturer instructions for use (IFU). Acceptability was measured through semi-structured interviews. After 2 months, HEWs were shown to adhere to the requirements in 74.6% consultations; an increase of 18.6% after training (P < .001). ChARM is acceptable to users and caregivers, with HEWs suggesting that ChARM increased client flow and stating a willingness to use ChARM in future. Further research on the performance, cost-effectiveness and implementation of this device is warranted to inform policy decisions in countries with a high childhood pneumonia burden.


Enterovirus related metabolic myopathy: a postviral fatigue syndrome.
To detect and characterise enterovirus RNA in skeletal muscle from patients with chronic fatigue syndrome (CFS) and to compare efficiency of muscle energy metabolism in enterovirus positive and negative CFS patients. Quadriceps muscle biopsy samples from 48 patients with CFS were processed to detect enterovirus RNA by two stage, reverse transcription, nested polymerase chain reaction (RT-NPCR), using enterovirus group specific primer sets. Direct nucleotide sequencing of PCR products was used to characterise the enterovirus. Controls were 29 subjects with normal muscles. On the day of biopsy, each CFS patient undertook a subanaerobic threshold exercise test (SATET). Venous plasma lactate was measured immediately before and after exercise, and 30 minutes after testing. An abnormal lactate response to exercise (SATET+) was defined as an exercise test in which plasma lactate exceeded the upper 99% confidence limits for normal sedentary controls at two or more time points. Muscle biopsy samples from 20.8% of the CFS patients were positive for enterovirus sequences by RT-NPCR, while all the 29 control samples were negative; 58.3% of the CFS patients had a SATET+ response. Nine of the 10 enterovirus positive cases were among the 28 SATET+ patients (32.1%), compared with only one (5%) of the 20 SATET- patients. PCR products were most closely related to coxsackie B virus. There is an association between abnormal lactate response to exercise, reflecting impaired muscle energy metabolism, and the presence of enterovirus sequences in muscle in a proportion of CFS patients.


Bilateral Pneumothoraces in a Tandem Parachuting Passenger Without Traumatic Impact: A Case Report.
In parachuting, orthopedic and head injuries are well-documented risks associated with the parachute deployment and landing phases. Thoracic injuries have only been seen on rare occasion in conjunction with direct impact trauma. In this report, we detail a case of a young, healthy, tandem skydiving passenger who suffered bilateral pneumothoraces with delayed symptom onset, with no identifiable injury during the jump or landing. Exploring the forces of the parachute "opening shock," we suggest a plausible compressive mechanism for this novel presentation, as well as briefly discuss the options for diagnosis and conservative management of pneumothorax in the operational context. While this is an exceedingly rare event, pneumothorax should be considered in patients complaining of thoracic symptoms following a skydive.


Two modes of regulation of the fatty acid elongase ELOVL6 by the 3-ketoacyl-CoA reductase KAR in the fatty acid elongation cycle.
Fatty acids (FAs) are diverse molecules, and such diversity is important for lipids to exert their functions under several environmental conditions. FA elongation occurs at the endoplasmic reticulum and produces a variety of FA species; the FA elongation cycle consists of four distinct enzyme reactions. For this cycle to be driven efficiently, there must exist coordinated regulation of protein components of the FA elongation machinery. However, such regulation is poorly understood. In the present study, we performed biochemical analyses using the FA elongase ELOVL6 and the 3-ketoacyl-CoA reductase KAR, which catalyze the first and second steps of the FA elongation cycle, respectively. In vitro FA elongation assays using membrane fractions demonstrated that ELOVL6 activity was enhanced ∼10-fold in the presence of NADPH, although ELOVL6 itself did not require NADPH for its catalysis. On the other hand, KAR does use NADPH as a reductant in its enzyme reaction. Activity of purified ELOVL6 was enhanced by ∼3-fold in the presence of KAR. This effect was KAR enzyme activity-independent, since it was observed in the absence of NADPH and in the KAR mutant. However, ELOVL6 enzyme activity was further enhanced in a KAR enzyme activity-dependent manner. Therefore, KAR regulates ELOVL6 via two modes. In the first mode, KAR may induce conformational changes in ELOVL6 to become structure that can undergo catalysis. In the second mode, conversion of 3-ketoacyl-CoA to 3-hydroxyacyl-CoA by KAR may facilitate release of the product from the presumed ELOVL6-KAR complex.


Interpedicular graft using a titanium mesh cage in a patient with lumbar scoliosis associated with a congenital butterfly vertebra.
A butterfly vertebra is a congenital anomaly often associated with a series of syndromic diseases and is often recognized incidentally without any presenting symptoms. The authors report the case of a 13-year-old girl with lumbar scoliosis and mild spondylolisthesis associated with a butterfly vertebra at L-6 causing radiculopathy. The L-5 and L-6 nerve roots were entrapped at the intervertebral foramina between L-5 and the butterfly vertebra (L-6) and between L-6 and S-1 in the concave side. To decompress and preserve the two nerve roots, correct the deformity, and obtain a solid bone fusion, surgery involving the thorough removal of the facet joints between L-5 and L-6 and between L-6 and S-1 in the concave side was performed, with a partial resection of the butterfly vertebra and the placement of a titanium mesh cage between the L-5 and S-1 pedicles dorsal to the nerve roots. Complete pain relief and correction of the deformity with solid bone fusion was obtained after a 2-year follow-up period.


State of diagnostic quandary solved by modern technology: a rare case of Madelung's disease.
Madelung's disease is a neglected metabolic disease characterised by generalised multiple fatty tissue deposits. A 64-year-old Caucasian woman presented with generalised weakness and symptomatic hypoglycaemia with altered mental status. Physical examination showed very distinct physical characteristics with multiple lumps distributed over the upper body. Her neurological symptoms were solved by giving intravenous glucose and optimisation of medical treatment. Even though she had unique characteristics of Madelung's disease, many physicians, on several occasions, failed to recognise her 'hidden diagnosis'. This diagnostic uncertainty was able to be solved by searching the Internet for similar clinical features and images. This case demonstrates characteristics and unique features of a rare disease that can be seen in a female patient even though it is mostly found in males.


Selectivity problems with drugs acting on cardiac Na⁺ and Ca²⁺ channels.
With the increase of our knowledge on cardioactive agents it comes more and more clear that practically none of the currently used compounds shows absolute selectivity to one or another ion channel type. This is particularly true for Na(+) and Ca(2+) channel modulators, which are widely applied in the clinical practice and biomedical research. The best example might be probably the marine guanidine poison tetrodotoxin, which has long been considered as a selective Na(+) channel blocker, while recently it turned out to effectively inhibit cardiac Ca(2+) currents as well. In the present study the cross actions observed between the effects of various blockers of Na(+) channels (such as toxin inhibitors, class I antiarrhythmics and local anesthetics) and Ca(2+) channels (like phenylalkylamines, dihydropyridine compounds, diltiazem and mibefradil) are overviewed in light of the known details of the respective channel structures. Similarly, activators of Na(+) channels, including veratridine and batrachotoxin, are also compared. The binding of tetrodotoxin and saxitoxin to Cav1.2 and Nav1.5 channel proteins is presented by construction of theoretical models to reveal common structures in their pore forming regions to explain cross reactions. Since these four domain channels can be traced back to a common ancestor, a close similarity in their structure can well be demonstrated. Thus, the poor selectivity of agents acting on cardiac Na(+) and Ca(2+) channels is a consequence of evolution. As a conclusion, since the limited selectivity is an intrinsic property of drug receptors, it has to be taken into account when designing new cardioactive compounds for either medical therapy or experimental research in the future.


Evaluating the swelling, erosion, and compaction properties of cellulose ethers.
Swelling, erosion, deformation, and consolidation properties can affect the performance of cellulose ethers, the most commonly used matrix former in hydrophilic sustained tablet formulations. The present study was designed to comparatively evaluate the swelling, erosion, compression, compaction, and relaxation properties of the cellulose ethers in a comprehensive study using standardised conditions. The interrelationship between various compressional models and the inherent deformation and consolidation properties of the polymers on the derived swelling and erosion parameters are consolidated. The impact of swelling (Kw) on erosion rates (KE) and the inter-relationship between Heckel and Kawakita plasticity constants was also investigated. It is evident from the findings that the increases in both substitution and polymer chain length led to higher Kw, but a lower KE; this was also true for all particle size fractions regardless of polymer grade. Smaller particle size and high substitution levels tend to increase the relative density of the matrix but reduce porosity, yield pressure (Py), Kawakita plasticity parameter (b-1) and elastic relaxation. Both KW versus KE (R2 = 0.949-0.980) and Py versus. b-1 correlations (R2 = 0.820-0.934) were reasonably linear with regards to increasing hydroxypropyl substitution and molecular size. Hence, it can be concluded that the combined knowledge of swelling and erosion kinetics in tandem with the in- and out-of-die compression findings can be used to select a specific polymer grade and further to develop and optimize formulations for oral controlled drug delivery applications.


Extracting and connecting chemical structures from text sources using chemicalize.org.
Exploring bioactive chemistry requires navigating between structures and data from a variety of text-based sources. While PubChem currently includes approximately 16 million document-extracted structures (15 million from patents) the extent of public inter-document and document-to-database links is still well below any estimated total, especially for journal articles. A major expansion in access to text-entombed chemistry is enabled by chemicalize.org. This on-line resource can process IUPAC names, SMILES, InChI strings, CAS numbers and drug names from pasted text, PDFs or URLs to generate structures, calculate properties and launch searches. Here, we explore its utility for answering questions related to chemical structures in documents and where these overlap with database records. These aspects are illustrated using a common theme of Dipeptidyl Peptidase 4 (DPPIV) inhibitors. Full-text open URL sources facilitated the download of over 1400 structures from a DPPIV patent and the alignment of specific examples with IC50 data. Uploading the SMILES to PubChem revealed extensive linking to patents and papers, including prior submissions from chemicalize.org as submitting source. A DPPIV medicinal chemistry paper was completely extracted and structures were aligned to the activity results table, as well as linked to other documents via PubChem. In both cases, key structures with data were partitioned from common chemistry by dividing them into individual new PDFs for conversion. Over 500 structures were also extracted from a batch of PubMed abstracts related to DPPIV inhibition. The drug structures could be stepped through each text occurrence and included some converted MeSH-only IUPAC names not linked in PubChem. Performing set intersections proved effective for detecting compounds-in-common between documents and merged extractions. This work demonstrates the utility of chemicalize.org for the exploration of chemical structure connectivity between documents and databases, including structure searches in PubChem, InChIKey searches in Google and the chemicalize.org archive. It has the flexibility to extract text from any internal, external or Web source. It synergizes with other open tools and the application is undergoing continued development. It should thus facilitate progress in medicinal chemistry, chemical biology and other bioactive chemistry domains.


Exploring the experiences of Aboriginal and Torres Strait Islander patients admitted to a metropolitan health service.
Objective There continue to be disparate health outcomes for people who are Aboriginal and Torres Strait Islander. The aim of the present study was to measure whether there were any differences in in-patient experiences between Aboriginal and Torres Strait Islander people and those without an Aboriginal or Torres Strait Islander background. Methods Random samples of people were invited to complete a survey following admission at the hospitals at Peninsula Health, Victoria, Australia. This survey was based on the Victorian Patient Satisfaction Monitor. Open-ended questions were also asked to gauge perspectives on how the services could better meet needs of Aboriginal and Torres Strait Islander patients. Results A total of 154 responses was obtained. There were differences between the two groups of participants in the following variables: respect of privacy, representation of culture, assistance with meals and access to a culturally specific worker if needed. This was reflected in thematic analysis, with three main themes identified: (1) interactions with staff; (2) the challenging environment; and (3) not just about me, but my family too. Conclusion There were systemic differences in in-patient experiences. Healthcare services have a responsibility to make systemic changes to improve the health care of all Australians by understanding and reforming how services can be appropriately delivered. What is known about the topic? There is a disparity in health outcomes between Aboriginal and Torres Strait Islander Australians and those who do not identify as Aboriginal and/or Torres Strait Islander. In addition, Aboriginal and Torres Strait Islanders have different interactions within healthcare services. Many rural health services have models that aim to deliver culturally appropriate services, but it is unknown whether the same challenges apply for this group of Australians within metropolitan health services. What does this paper add? This paper identifies the structural supports that are required to help close the gap in health care provision inequality. Many of the key issues identified are not people but system based. Healthcare administrators should consider the factors identified and address these at a whole-of-service level. What are the implications for practitioners? Many practitioners are aware of the challenges of providing culturally appropriate services. This research raises awareness of how traditional healthcare is not a one size fits all and flexibility is required to improve health outcomes.


Arthroscopic Capsular Reconstruction of the Hip With Acellular Dermal Extracellular Matrix: Surgical Technique.
Atraumatic instability of the hip has become an increasingly studied occurrence in recent years. There are several established surgical techniques that help restore stability of the native hip joint. In some cases, these procedures are not an option. As the phenomenon has become recognized more frequently, a greater number of revision surgeries are warranted in patients with ligamentous laxity. A durable solution for irreparable microinstability needs to be formulated to address this vulnerable patient demographic. We describe the surgical technique for capsular reconstruction with acellular dermal extracellular matrix.


Diet and colorectal cancer prevention.
The majority of cancers are sporadic and epidemiological estimates suggest that up to 80% of colorectal cancer is attributable to diet. Epidemiologically, cross-sectional comparisons, case-control studies and trends in food intake show high rates of colorectal cancer in populations consuming diets high in meat and fat, and low in starch, NSP (non-starch polysaccharides, fibre) and vegetables. In general, prospective studies tend to support these findings although estimates of relative risk are not high. Existing prospective studies have however used crude indices of diet subject to substantial measurement error, and interactions with genetic polymorphisms in, for example, phase-I and -II enzymes have been studied only rarely. The association between meat consumption and colorectal cancer is usually attributed to the formation of heterocyclic amines in meat when it is cooked. In addition, in humans high-meat diets increase the level of nitrosatable material entering the colon so that faecal N-nitroso compounds (NOCs) increase in a dose-responsive manner following endogenous synthesis in the colon. Some of the mutations and guanine adducts accumulated during colorectal cancer progression are characteristic of alkylative damage, which would be compatible with NOC exposure. To date, NSP, resistant starch and vegetables have not reduced faecal NOC levels.


Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects.
The cannabinoid CB1 receptor has been shown to be the primary site of action for cannabinoid-induced effects on the central nervous system. Activation of this receptor has proven to dampen neurotransmission and produce an overall reduction in neuronal excitability. Cannabinoid compounds like delta9-tetrahydrocannabinol and cannabidiol have been shown to be anticonvulsant in maximal electroshock, a model of partial seizure with secondary generalization. However, until now, it was unknown if these anticonvulsant effects are mediated by the cannabinoid CB1 receptor. Likewise, (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN 55,212-2), a cannabimimetic compound that has been shown to decrease hyperexcitability in cell culture models via the cannabinoid CB1 receptor, has never been evaluated for anticonvulsant activity in an animal seizure model. We first show that the cannabinoid compounds delta9-tetrahydrocannabinol (ED50 = 42 mg/kg), cannabidiol (ED50 = 80 mg/kg), and WIN 55,212-2 (ED50 = 47 mg/kg) are anticonvulsant in maximal electroshock. We further establish, using the cannabinoid CB1 receptor specific antagonist N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A) (AD50 = 2.5 mg/kg), that the anticonvulsant effects of delta9-tetrahydrocannabinol and WIN 55,212-2 are cannabinoid CB1 receptor-mediated while the anticonvulsant activity of cannabidiol is not. This study establishes a role for the cannabinoid CB1 receptor in modulating seizure activity in a whole animal model.


Clinical data and basal gonadotropins in the diagnosis of central precocious puberty in girls.
The objective of this study was to analyze whether some auxological characteristics or a single basal gonadotropin measurement will be sufficient to distinguish the prepubertal from pubertal status. Auxologycal characteristics were recorded and serum LH and FSH were measured by immunochemiluminescence assays before and after GnRH stimulation test in a sample of 241 Caucasian girls with breast budding between 6- and 8-years old. Peak LH levels higher than 5 IU/L were considered a pubertal response. Area under the curve, cut-off points, sensitivity, and specificity for auxologycal variables and basal gonadotropins levels were determined by receiver operating curves. There were no significant differences in age at onset, weight, height, BMI and height velocity between both groups. Bone age was significantly higher in pubertal girls (P < 0.05), although with limited discriminatory capacity. The sensitivity and specificity for the basal LH levels were 89 and 82%, respectively, for a cut off point of 0.1 IU/L. All girls in the pubertal group had a basal LH higher than 1.0 IU/L (positive predictive value of 100%). There was a wide overlap of basal FSH and LH/FSH ratio between prepubertal and pubertal girls. Auxologycal characteristics should not be used only in the differential diagnosis between prepubertal from pubertal status in 6- to 8-year-old girls. We found a high specificity of a single basal LH sample and it would be useful for establishing the diagnosis of puberty in this age group, reducing the need for GnRH stimulation testing.


Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages.
A large amount of chromosomal DNA is degraded during programmed cell death and definitive erythropoiesis. DNase II is an enzyme that digests the chromosomal DNA of apoptotic cells and nuclei expelled from erythroid precursor cells after macrophages have engulfed them. Here we show that DNase II-/-IFN-IR-/- mice and mice with an induced deletion of the DNase II gene develop a chronic polyarthritis resembling human rheumatoid arthritis. A set of cytokine genes was strongly activated in the affected joints of these mice, and their serum contained high levels of anti-cyclic citrullinated peptide antibody, rheumatoid factor and matrix metalloproteinase-3. Early in the pathogenesis, expression of the gene encoding tumour necrosis factor (TNF)-alpha was upregulated in the bone marrow, and administration of anti-TNF-alpha antibody prevented the development of arthritis. These results indicate that if macrophages cannot degrade mammalian DNA from erythroid precursors and apoptotic cells, they produce TNF-alpha, which activates synovial cells to produce various cytokines, leading to the development of chronic polyarthritis.


Immunohistochemical analysis-based proteomic subclassification of newly diagnosed glioblastomas.
Recent gene expression and copy number profilings of glioblastoma multiforme (GBM) by The Cancer Genome Atlas (TCGA) Research Network suggest the existence of distinct subtypes of this tumor. However, these approaches might not be easily applicable in routine clinical practice. In the current study, we aimed to establish a proteomics-based subclassification of GBM by integrating their genomic and epigenomic profiles. We subclassified 79 newly diagnosed GBM based on expression patterns determined by comprehensive immunohistochemical observation in combination with their DNA copy number and DNA methylation patterns. The clinical relevance of our classification was independently validated in TCGA datasets. Consensus clustering identified the four distinct GBM subtypes: Oligodendrocyte Precursor (OPC) type, Differentiated Oligodendrocyte (DOC) type, Astrocytic Mesenchymal (AsMes) type and Mixed type. The OPC type was characterized by highly positive scores of Olig2, PDGFRA, p16, p53 and synaptophysin. In contrast, the AsMes type was strongly associated with strong expressions of nestin, CD44 and podoplanin, with a high glial fibrillary acidic protein score. The median overall survival of OPC-type patients was significantly longer than that of the AsMes-type patients (19.9 vs 12.8 months). This finding was in agreement with the Oncomine analysis of TCGA datasets, which revealed that PDGFRA and Olig2 were favorable prognostic factors and podoplanin and CD44 were associated with a poor clinical outcome. This is the first study to establish a subclassification of GBM on the basis of immunohistochemical analysis. Our study will shed light on personalized therapies that might be feasible in daily neuropathological practice.


Mapping the global distribution of livestock.
Livestock contributes directly to the livelihoods and food security of almost a billion people and affects the diet and health of many more. With estimated standing populations of 1.43 billion cattle, 1.87 billion sheep and goats, 0.98 billion pigs, and 19.60 billion chickens, reliable and accessible information on the distribution and abundance of livestock is needed for a many reasons. These include analyses of the social and economic aspects of the livestock sector; the environmental impacts of livestock such as the production and management of waste, greenhouse gas emissions and livestock-related land-use change; and large-scale public health and epidemiological investigations. The Gridded Livestock of the World (GLW) database, produced in 2007, provided modelled livestock densities of the world, adjusted to match official (FAOSTAT) national estimates for the reference year 2005, at a spatial resolution of 3 minutes of arc (about 5×5 km at the equator). Recent methodological improvements have significantly enhanced these distributions: more up-to date and detailed sub-national livestock statistics have been collected; a new, higher resolution set of predictor variables is used; and the analytical procedure has been revised and extended to include a more systematic assessment of model accuracy and the representation of uncertainties associated with the predictions. This paper describes the current approach in detail and presents new global distribution maps at 1 km resolution for cattle, pigs and chickens, and a partial distribution map for ducks. These digital layers are made publically available via the Livestock Geo-Wiki (http://www.livestock.geo-wiki.org), as will be the maps of other livestock types as they are produced.


1-Oxo-1,3-dithiolanes--synthesis and stereochemistry.
1-Oxo-1,3-dithiolane (4) and its cis- and trans-2-methyl (5,6), -4-methyl (7,8) and -5-methyl (9,10) derivatives were prepared by oxidizing the corresponding 1,3-dithiolanes (1-3) with NaIO(4) in water. The oxides were purified and their isomers separated using thin layer chromatography. The structural characterization was carried out with (1)H and (13)C NMR spectroscopy and molecular modelling. The sulfoxides 4-6 and 8-10 attain two S(1) type envelopes (sometimes slightly distorted) the S=O(ax) envelope greatly dominating. Cis-4-methyl-1-oxo-1,3-dithiolane is a special case exhibiting both two closely related S=O(ax) (30 and 27%) as well as S=O(eq) (21 and 22%) forms [S(1) and C(4) envelopes, respectively]. The relative energies of these conformations, the values of (1)H-(1)H coupling constants and (1)H and (13)C chemical shifts were estimated by computational methods and they support well the conclusions based on the experimental data.


Regulation of autoinducer production in Salmonella typhimurium.
Salmonella typhimurium strain LT2 secretes an organic signalling molecule that can be assayed by its ability to activate one of two specific quorum-sensing systems in Vibrio harveyi. Maximal activity is produced during mid- to late exponential phase when S. typhimurium is grown in the presence of glucose or other preferred carbohydrates. The signal is degraded by the onset of stationary phase or when the carbohydrate is depleted from the medium. Presumably, quorum sensing in S. typhimurium is operational during periods of rapid, nutrient-rich growth. Protein synthesis is required for degradation of the activity, suggesting that a complex regulatory circuitry controls signal production and detection in S. typhimurium. Increased signalling activity is observed if, after growth in the presence of glucose, S. typhimurium is transferred to a high-osmolarity (0.4 M NaCl) or to a low-pH (pH 5.0) environment. Degradation of the signal is induced by conditions of low osmolarity (0.1 M NaCl). High osmolarity and low pH are two conditions encountered by S. typhimurium cells when they undergo the transition to a pathogenic existence inside a host organism, suggesting that quorum sensing may have a role in the regulation of virulence in S. typhimurium.


Immunologic characteristics of human gingival fibroblasts in response to oral bacteria.
There is ample evidence that gingival fibroblasts (GFs) participate in the immune response to oral bacteria and serve as immune-regulatory cells. The objective of this study was to investigate the innate immune response of GFs to oral bacteria. Human GFs were cocultured with relatively less-pathogenic (Leptotrichia wadei, Fusobacterium nucleatum and Campylobacter gracilis) and pathogenic red-complex bacteria. The expression of mRNA for antimicrobial peptides [AMPs; namely human beta defensins (HBDs)], chemokines with antimicrobial activity [chemokine C-X-C motif (CXCL)10, CXCL11 and chemokine C-C motif ligand 20 (CCL20)] and proinflammatory mediators [interleukin (IL)6 and IL8] and the levels of CXCL11, CCL20, IL-6 and IL-8 accumulated in supernatants were analyzed using real-time PCR and ELISA, respectively. The proteolytic activities of CXCL11, CCL20, IL-6 and IL-8 produced by six species of bacteria were also determined. The relatively less-pathogenic bacteria strongly up-regulated the expression of antimicrobial chemokines and proinflammatory mediators, whereas the red-complex bacteria stimulated low levels, or often suppressed, expression of these factors. Regarding the regulation of AMPs, the inhibition of HBD3, HBD106 and HBD107 mRNAs by Porphyromonas gingivalis was noticeable; however, differences between the two bacterial groups were not conspicuous. Differential degradation of proteins by the six bacterial species was observed: P. gingivalis and Treponema denticola degraded proteins well, whereas the other species degraded proteins to a relatively lower degree. The invasion of red-complex bacteria into gingival connective tissue can suppress the immune response of GFs and can be a source of persistent infection in connective tissue.


Salmon immunological defence and interplay with the modulatory capabilities of its ectoparasite Lepeophtheirus salmonis.
The salmon louse Lepeophtheirus salmonis (Lsal) is an ectoparasitic copepod that exerts immunomodulatory and physiological effects on its host Atlantic salmon. Over 30 years of research on louse biology, control, host responses and the host-parasite relationship has provided a plethora of information on the intricacies of host resistance and parasite adaptation. Atlantic salmon exhibit temporal and spatial impairment of the immune system and wound healing ability during infection. This immunosuppression may render Atlantic salmon less tolerant to stress and other confounders associated with current management strategies. Contrasting susceptibility of salmonid hosts exists, and early pro-inflammatory Th1 type responses are associated with resistance. Rapid cellular responses to larvae appear to tip the balance of the host-parasite relationship in favour of the host, preventing severe immune-physiological impacts of the more invasive adults. Immunological, transcriptomic, genomic and proteomic evidence suggests pathological impacts occur in susceptible hosts through modulation of host immunity and physiology via pharmacologically active molecules. Co-evolutionary and farming selection pressures may have incurred preference of Atlantic salmon as a host for Lsal reflected in their interactome. Here, we review host-parasite interactions at the primary attachment/feeding site, and the complex life stage-dependent molecular mechanisms employed to subvert host physiology and immune responses.


Single nucleotide patch base excision repair is the major pathway for removal of thymine glycol from DNA in human cell extracts.
The repair pathways involved in the removal of thymine glycol (TG) from DNA by human cell extracts have been examined. Closed circular DNA constructs containing a single TG at a defined site were used as substrates to determine the patch size generated after in vitro repair by cell extracts. Restriction analysis of the repair incorporation in the vicinity of the lesion indicated that the majority of TG was repaired through the base excision repair (BER) pathways. Repair incorporation 5' to the lesion, characteristic for the nucleotide excision repair pathway, was not found. More than 80% of the TG repair was accomplished by the single-nucleotide repair mechanism, and the remaining TGs were removed by the long patch BER pathway. We also analyzed the role of the xeroderma pigmentosum, complementation group G (XPG) protein in the excision step of BER. Cell extracts deficient in XPG protein had an average 25% reduction in TG incision. These data show that BER is the primary pathway for repair of TG in DNA and that XPG protein may be involved in repair of TG as an accessory factor.


Gene duplication and genetic exchange drive the evolution of S-RNase-based self-incompatibility in Petunia.
Self-incompatibility (SI) systems in flowering plants distinguish self- and non-self pollen to prevent inbreeding. While other SI systems rely on the self-recognition between specific male- and female-determinants, the Solanaceae family has a non-self recognition system resulting in the detoxification of female-determinants of S-ribonucleases (S-RNases), expressed in pistils, by multiple male-determinants of S-locus F-box proteins (SLFs), expressed in pollen. It is not known how many SLF components of this non-self recognition system there are in Solanaceae species, or how they evolved. We identified 16-20 SLFs in each S-haplotype in SI Petunia, from a total of 168 SLF sequences using large-scale next-generation sequencing and genomic polymerase chain reaction (PCR) techniques. We predicted the target S-RNases of SLFs by assuming that a particular S-allele must not have a conserved SLF that recognizes its own S-RNase, and validated these predictions by transformation experiments. A simple mathematical model confirmed that 16-20 SLF sequences would be adequate to recognize the vast majority of target S-RNases. We found evidence of gene conversion events, which we suggest are essential to the constitution of a non-self recognition system and also contribute to self-compatible mutations.


Whole-genome amplification in double-digest RADseq results in adequate libraries but fewer sequenced loci.
Whole-genome amplification by multiple displacement amplification (MDA) is a promising technique to enable the use of samples with only limited amount of DNA for the construction of RAD-seq libraries. Previous work has shown that, when the amount of DNA used in the MDA reaction is large, double-digest RAD-seq (ddRAD) libraries prepared with amplified genomic DNA result in data that are indistinguishable from libraries prepared directly from genomic DNA. Based on this observation, here we evaluate the quality of ddRAD libraries prepared from MDA-amplified genomic DNA when the amount of input genomic DNA and the coverage obtained for samples is variable. By simultaneously preparing libraries for five species of weevils (Coleoptera, Curculionidae), we also evaluate the likelihood that potential contaminants will be encountered in the assembled dataset. Overall, our results indicate that MDA may not be able to rescue all samples with small amounts of DNA, but it does produce ddRAD libraries adequate for studies of phylogeography and population genetics even when conditions are not optimal. We find that MDA makes it harder to predict the number of loci that will be obtained for a given sequencing effort, with some samples behaving like traditional libraries and others yielding fewer loci than expected. This seems to be caused both by stochastic and deterministic effects during amplification. Further, the reduction in loci is stronger in libraries with lower amounts of template DNA for the MDA reaction. Even though a few samples exhibit substantial levels of contamination in raw reads, the effect is very small in the final dataset, suggesting that filters imposed during dataset assembly are important in removing contamination. Importantly, samples with strong signs of contamination and biases in heterozygosity were also those with fewer loci shared in the final dataset, suggesting that stringent filtering of samples with significant amounts of missing data is important when assembling data derived from MDA-amplified genomic DNA. Overall, we find that the combination of MDA and ddRAD results in high-quality datasets for population genetics as long as the sequence data is properly filtered during assembly.


Characterizing responses of translation-invariant neurons to natural stimuli: maximally informative invariant dimensions.
The human visual system is capable of recognizing complex objects even when their appearances change drastically under various viewing conditions. Especially in the higher cortical areas, the sensory neurons reflect such functional capacity in their selectivity for complex visual features and invariance to certain object transformations, such as image translation. Due to the strong nonlinearities necessary to achieve both the selectivity and invariance, characterizing and predicting the response patterns of these neurons represents a formidable computational challenge. A related problem is that such neurons are poorly driven by randomized inputs, such as white noise, and respond strongly only to stimuli with complex high-order correlations, such as natural stimuli. Here we describe a novel two-step optimization technique that can characterize both the shape selectivity and the range and coarseness of position invariance from neural responses to natural stimuli. One step in the optimization is finding the template as the maximally informative dimension given the estimated spatial location where the response could have been triggered within each image. The estimates of the locations that triggered the response are updated in the next step. Under the assumption of a monotonic relationship between the firing rate and stimulus projections on the template at a given position, the most likely location is the one that has the largest projection on the estimate of the template. The algorithm shows quick convergence during optimization, and the estimation results are reliable even in the regime of small signal-to-noise ratios. When we apply the algorithm to responses of complex cells in the primary visual cortex (V1) to natural movies, we find that responses of the majority of cells were significantly better described by translation-invariant models based on one template compared with position-specific models with several relevant features.


Parguerenes: Marine red alga bromoditerpenes as inhibitors of P-glycoprotein (ABCB1) in multidrug resistant human cancer cells.
High intrinsic or acquired expression of membrane spanning, adenosine triphosphate binding cassette (ABC) transporter proteins, such as P-glycoprotein (P-gp), in cancers represents a major impediment to chemotherapy, with accelerated drug efflux leading to multi-drug resistance (MDR). Although ABC transporter inhibitors offer the prospect of reversing the MDR phenotype, no inhibitors have advanced to the clinic. We employed a range of intracellular fluorescence and radio-ligand accumulation and efflux assays, together with cytotoxicity and MDR reversal assays, as well as flow cytometry, fluorescence microscopy and radioimmunoprecipitation, to discover and evaluate new P-gp inhibitors from a unique library of southern Australian and Antarctic marine natural products. This study successfully characterized two rare bromoditerpenes, parguerenes I and II, sourced from a southern Australian collection of the red alga Laurencia filiformis, as P-gp inhibitors. We determined that the parguerenes were non-cytotoxic, dose-dependent inhibitors of P-gp mediated drug efflux, that modify the extracellular antibody binding epitope of P-gp in a manner that differs markedly from that of the known inhibitors verapamil and cyclosporine A. We confirmed that parguerenes were capable of reversing P-gp mediated vinblastine, doxorubicin and paclitaxel MDR, that inhibitory properties span both P-gp and multidrug resistant protein 1 (MRP1), but do not extend to breast cancer resistance protein (BCRP), and that parguerene II is superior (more potent) to verapamil. Our investigations validate the proposition that marine natural products can deliver new ABC transporter inhibitor scaffolds, with structure characteristics fundamentally different from existing inhibitor classes.


β-Klotho deficiency protects against obesity through a crosstalk between liver, microbiota, and brown adipose tissue.
β-Klotho (encoded by Klb) is the obligate coreceptor mediating FGF21 and FGF15/19 signaling. Klb-/- mice are refractory to beneficial action of pharmacological FGF21 treatment including stimulation of glucose utilization and thermogenesis. Here, we investigated the energy homeostasis in Klb-/- mice on high-fat diet in order to better understand the consequences of abrogating both endogenous FGF15/19 and FGF21 signaling during caloric overload. Surprisingly, Klb-/- mice are resistant to diet-induced obesity (DIO) owing to enhanced energy expenditure and BAT activity. Klb-/- mice exhibited not only an increase but also a shift in bile acid (BA) composition featured by activation of the classical (neutral) BA synthesis pathway at the expense of the alternative (acidic) pathway. High hepatic production of cholic acid (CA) results in a large excess of microbiota-derived deoxycholic acid (DCA). DCA is specifically responsible for activating the TGR5 receptor that stimulates BAT thermogenic activity. In fact, combined gene deletion of Klb and Tgr5 or antibiotic treatment abrogating bacterial conversion of CA into DCA both abolish DIO resistance in Klb-/- mice. These results suggested that DIO resistance in Klb-/- mice is caused by high levels of DCA, signaling through the TGR5 receptor. These data also demonstrated that gut microbiota can regulate host thermogenesis via conversion of primary into secondary BA. Pharmacologic or nutritional approaches to selectively modulate BA composition may be a promising target for treating metabolic disorders.


Patterning of cognitive and somatic processes in the self-regulation of anxiety: effects of meditation versus exercise.
Davidson and Schwartz (1) have proposed a psychobiological analysis of anxiety that emphasizes the patterning of multiple processes in the generation and self-regulation of this state. The present article specifically reviews recent research on cognitive and somatic components of anxiety. A dual component scale which separately assesses cognitive and somatic trait anxiety is described and applied to the study of the differential effects of a somatic (physical exercise) and a cognitive (meditation) relaxation procedure. A total of 77 subjects was employed; 44 regularly practiced physical exercise and 33 regularly practiced meditation for comparable periods of time. As predicted, subjects practicing physical exercise reported relatively less somatic and more cognitive anxiety than meditators. These data suggest that specific subcomponents of anxiety may be differentially associated with relaxation techniques engaging primarily cognitive versus somatic subsystems. It is proposed that relaxation consists of (1) a generalized reduction to multiple physiological systems (termed the relaxation response by Benson) and (2) a more specific pattern of changes superimposed upon this general reduction, which is elicited by the particular techniques employed. The data from this retrospective study need to be followed up by prospective studies to establish the precise mechanisms for these effects.


Photoassisted degradation of a herbicide derivative, dinoseb, in aqueous suspension of titania.
The titanium dioxide (TiO(2)) photoassisted degradation of herbicide dinoseb has been examined in aqueous suspensions under UV light irradiation. The degradation kinetics were studied under various conditions such as substrate concentration, type of catalyst, catalyst dosage, pH, and light intensity as well as in presence of electron acceptors such as hydrogen peroxide, potassium bromate, and potassium persulphate under continuous air purging, and the degradation rates were found to be strongly influenced by these parameters. The Degussa P25 was found to be more efficient photocatalyst as compared to other photocatalysts tested. Dinoseb was found to degrade efficiently in acidic pH and all the electron acceptors studied enhanced the degradation rate. The results manifested that the photocatalysis of dinoseb followed pseudo-first-order kinetics. A qualitative study of the degradation products generated during the process was performed by GC-MS, and a degradation mechanism was proposed.


Requirement for cholinergic synaptic transmission in the propagation of spontaneous retinal waves.
Highly correlated neural activity in the form of spontaneous waves of action potentials is present in the developing retina weeks before vision. Optical imaging revealed that these waves consist of spatially restricted domains of activity that form a mosaic pattern over the entire retinal ganglion cell layer. Whole-cell recordings indicate that wave generation requires synaptic activation of neuronal nicotinic acetylcholine receptors on ganglion cells. The only cholinergic cells in these immature retinas are a uniformly distributed bistratified population of amacrine cells, as assessed by antibodies to choline acetyltransferase. The results indicate that the major source of synaptic input to retinal ganglion cells is a system of cholinergic amacrine cells, whose activity is required for wave propagation in the developing retina.


Paradoxical effects of increased expression of PGC-1alpha on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism.
Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha has been shown to play critical roles in regulating mitochondria biogenesis, respiration, and muscle oxidative phenotype. Furthermore, reductions in the expression of PGC-1alpha in muscle have been implicated in the pathogenesis of type 2 diabetes. To determine the effect of increased muscle-specific PGC-1alpha expression on muscle mitochondrial function and glucose and lipid metabolism in vivo, we examined body composition, energy balance, and liver and muscle insulin sensitivity by hyperinsulinemic-euglycemic clamp studies and muscle energetics by using (31)P magnetic resonance spectroscopy in transgenic mice. Increased expression of PGC-1alpha in muscle resulted in a 2.4-fold increase in mitochondrial density, which was associated with an approximately 60% increase in the unidirectional rate of ATP synthesis. Surprisingly, there was no effect of increased muscle PGC-1alpha expression on whole-body energy expenditure, and PGC-1alpha transgenic mice were more prone to fat-induced insulin resistance because of decreased insulin-stimulated muscle glucose uptake. The reduced insulin-stimulated muscle glucose uptake could most likely be attributed to a relative increase in fatty acid delivery/triglyceride reesterfication, as reflected by increased expression of CD36, acyl-CoA:diacylglycerol acyltransferase1, and mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase, that may have exceeded mitochondrial fatty acid oxidation, resulting in increased intracellular lipid accumulation and an increase in the membrane to cytosol diacylglycerol content. This, in turn, caused activation of PKC, decreased insulin signaling at the level of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and skeletal muscle insulin resistance.


Heterostructure Manipulation via in Situ Localized Phase Transformation for High-Rate and Highly Durable Lithium Ion Storage.
Recently, heterostructures have attracted much attention in widespread research fields. By tailoring the physicochemical properties of the two components, creating heterostructures endows composites with diverse functions due to the synergistic effects and interfacial interaction. Here, a simple in situ localized phase transformation method is proposed to transform the transition-metal oxide electrode materials into heterostructures. Taking molybdenum oxide as an example, quasi-core-shell MoO3@MoO2 heterostructures were successfully fabricated, which were uniformly anchored on reduced graphene oxide (rGO) for high-rate and highly durable lithium ion storage. The in situ introduction of the MoO2 shell not only effectively enhances the electronic conductivity but also creates MoO3@MoO2 heterojunctions with abundant oxygen vacancies, which induces an inbuilt driving force at the interface, enhancing ion/electron transfer. In operando synchrotron X-ray powder diffraction has confirmed the excellent phase reversibility of the MoO2 shell during charge/discharge cycling, which contributes to the excellent cycling stability of the MoO3@MoO2/rGO electrode (1208.9 mAh g-1 remaining at 5 A g-1 after 2000 cycles). This simple in situ heterostructure fabrication method provides a facile way to optimize electrode materials for high-performance lithium ion batteries and possibly other energy storage devices.


Health workers' experiences of collaborative quality improvement for maternal and newborn care in rural Tanzanian health facilities: A process evaluation using the integrated 'Promoting Action on Research Implementation in Health Services' framework.
Quality Improvement (QI) approaches are increasingly used to bridge the quality gap in maternal and newborn care (MNC) in Sub Saharan Africa. Health workers typically serve as both recipients and implementers of QI activities; their understanding, motivation, and level of involvement largely determining the potential effect. In support of efforts to harmonise and integrate the various QI approaches implemented in parallel in Tanzanian health facilities, our objective was to investigate how different components of a collaborative QI intervention were understood and experienced by health workers, and therefore contributed positively to its mechanisms of effect. A qualitative process evaluation of a collaborative QI intervention for MNC in rural Tanzania was carried out. Semi-structured interviews were conducted with 16 health workers in 13 purposively sampled health facilities. A deductive theory-driven qualitative content analysis was employed using the integrated Promoting Action on Research Implementation in Health services (i-PARIHS) framework as a lens with its four constructs innovation, recipients, facilitation, and context as guiding themes. Health workers valued the high degree of fit between QI topics and their everyday practice and appreciated the intervention's comprehensive approach. The use of run-charts to monitor progress was well understood and experienced as motivating. The importance and positive experience of on-site mentoring and coaching visits to individual health facilities was expressed by the majority of health workers. Many described the parallel implementation of various health programs as a challenge. Components of QI approaches that are well understood and experienced as supportive by health workers in everyday practice may enhance mechanisms of effect and result in more significant change. A focus on such components may also guide harmonisation, to avoid duplication and the implementation of parallel programs, and country ownership of QI approaches in resource limited settings.


TeamSTEPPS Improves Operating Room Efficiency and Patient Safety.
The objective was to evaluate the effect of TeamSTEPPS on operating room efficiency and patient safety. TeamSTEPPS consisted of briefings attended by all health care personnel assigned to the specific operating room to discuss issues unique to each case scheduled for that day. The operative times, on-time start rates, and turnover times of all cases performed by the urology service during the initial year with TeamSTEPPS were compared to the prior year. Patient safety issues identified during postoperative briefings were analyzed. The mean case time was 12.7 minutes less with TeamSTEPPS (P < .001). The on-time first-start rate improved by 21% with TeamSTEPPS (P < .001). The mean room turnover time did not change. Patient safety issues declined from an initial rate of 16% to 6% at midyear and remained stable (P < 0.001). TeamSTEPPS was associated with improved operating room efficiency and diminished patient safety issues in the operating room.


Molecular phylogenetics of porcini mushrooms (Boletus section Boletus).
Porcini (Boletus section Boletus: Boletaceae: Boletineae: Boletales) are a conspicuous group of wild, edible mushrooms characterized by fleshy fruiting bodies with a poroid hymenophore that is "stuffed" with white hyphae when young. Their reported distribution is with ectomycorrhizal plants throughout the Northern Hemisphere. Little progress has been made on the systematics of this group using modern molecular phylogenetic tools because sampling has been limited primarily to European species and the genes employed were insufficient to resolve the phylogeny. We examined the evolutionary history of porcini by using a global geographic sampling of most known species, new discoveries from little explored areas, and multiple genes. We used 78 sequences from the fast-evolving nuclear internal transcribed spacers and are able to recognize 18 reciprocally monophyletic species. To address whether or not porcini form a monophyletic group, we compiled a broadly sampled dataset of 41 taxa, including other members of the Boletineae, and used separate and combined phylogenetic analysis of sequences from the nuclear large subunit ribosomal DNA, the largest subunit of RNA polymerase II, and the mitochondrial ATPase subunit six gene. Contrary to previous studies, our separate and combined phylogenetic analyses support the monophyly of porcini. We also report the discovery of two taxa that expand the known distribution of porcini to Australia and Thailand and have ancient phylogenetic connections to the rest of the group. A relaxed molecular clock analysis with these new taxa dates the origin of porcini to between 42 and 54 million years ago, coinciding with the initial diversification of angiosperms, during the Eocene epoch when the climate was warm and humid. These results reveal an unexpected diversity, distribution, and ancient origin of a group of commercially valuable mushrooms that may provide an economic incentive for conservation and support the hypothesis of a tropical origin of the ectomycorrhizal symbiosis.


Open core control software for surgical robots.
In these days, patients and doctors in operation room are surrounded by many medical devices as resulting from recent advancement of medical technology. However, these cutting-edge medical devices are working independently and not collaborating with each other, even though the collaborations between these devices such as navigation systems and medical imaging devices are becoming very important for accomplishing complex surgical tasks (such as a tumor removal procedure while checking the tumor location in neurosurgery). On the other hand, several surgical robots have been commercialized, and are becoming common. However, these surgical robots are not open for collaborations with external medical devices in these days. A cutting-edge "intelligent surgical robot" will be possible in collaborating with surgical robots, various kinds of sensors, navigation system and so on. On the other hand, most of the academic software developments for surgical robots are "home-made" in their research institutions and not open to the public. Therefore, open source control software for surgical robots can be beneficial in this field. From these perspectives, we developed Open Core Control software for surgical robots to overcome these challenges. In general, control softwares have hardware dependencies based on actuators, sensors and various kinds of internal devices. Therefore, these control softwares cannot be used on different types of robots without modifications. However, the structure of the Open Core Control software can be reused for various types of robots by abstracting hardware dependent parts. In addition, network connectivity is crucial for collaboration between advanced medical devices. The OpenIGTLink is adopted in Interface class which plays a role to communicate with external medical devices. At the same time, it is essential to maintain the stable operation within the asynchronous data transactions through network. In the Open Core Control software, several techniques for this purpose were introduced. Virtual fixture is well known technique as a "force guide" for supporting operators to perform precise manipulation by using a master-slave robot. The virtual fixture for precise and safety surgery was implemented on the system to demonstrate an idea of high-level collaboration between a surgical robot and a navigation system. The extension of virtual fixture is not a part of the Open Core Control system, however, the function such as virtual fixture cannot be realized without a tight collaboration between cutting-edge medical devices. By using the virtual fixture, operators can pre-define an accessible area on the navigation system, and the area information can be transferred to the robot. In this manner, the surgical console generates the reflection force when the operator tries to get out from the pre-defined accessible area during surgery. The Open Core Control software was implemented on a surgical master-slave robot and stable operation was observed in a motion test. The tip of the surgical robot was displayed on a navigation system by connecting the surgical robot with a 3D position sensor through the OpenIGTLink. The accessible area was pre-defined before the operation, and the virtual fixture was displayed as a "force guide" on the surgical console. In addition, the system showed stable performance in a duration test with network disturbance. In this paper, a design of the Open Core Control software for surgical robots and the implementation of virtual fixture were described. The Open Core Control software was implemented on a surgical robot system and showed stable performance in high-level collaboration works. The Open Core Control software is developed to be a widely used platform of surgical robots. Safety issues are essential for control software of these complex medical devices. It is important to follow the global specifications such as a FDA requirement "General Principles of Software Validation" or IEC62304. For following these regulations, it is important to develop a self-test environment. Therefore, a test environment is now under development to test various interference in operation room such as a noise of electric knife by considering safety and test environment regulations such as ISO13849 and IEC60508. The Open Core Control software is currently being developed software in open-source manner and available on the Internet. A communization of software interface is becoming a major trend in this field. Based on this perspective, the Open Core Control software can be expected to bring contributions in this field.