Brain metabolism is significantly impaired at blood glucose below 6 mM and brain glucose below 1 mM in patients with severe traumatic brain injury.
The optimal blood glucose target following severe traumatic brain injury (TBI) must be defined. Cerebral microdialysis was used to investigate the influence of arterial blood and brain glucose on cerebral glucose, lactate, pyruvate, glutamate, and calculated indices of downstream metabolism. In twenty TBI patients, microdialysis catheters inserted in the edematous frontal lobe were dialyzed at 1 microl/min, collecting samples at 60 minute intervals. Occult metabolic alterations were determined by calculating the lactate- pyruvate (L/P), lactate- glucose (L/Glc), and lactate- glutamate (L/Glu) ratios. Brain glucose was influenced by arterial blood glucose. Elevated L/P and L/Glc were significantly reduced at brain glucose above 1 mM, reaching lowest values at blood and brain glucose levels between 6-9 mM (P < 0.001). Lowest cerebral glutamate was measured at brain glucose 3-5 mM with a significant increase at brain glucose below 3 mM and above 6 mM. While L/Glu was significantly increased at low brain glucose levels, it was significantly decreased at brain glucose above 5 mM (P < 0.001). Insulin administration increased brain glutamate at low brain glucose, but prevented increase in L/Glu. Arterial blood glucose levels appear to be optimal at 6-9 mM. While low brain glucose levels below 1 mM are detrimental, elevated brain glucose are to be targeted despite increased brain glutamate at brain glucose >5 mM. Pathogenity of elevated glutamate appears to be relativized by L/Glu and suggests to exclude insulin- induced brain injury.


Coffee consumption and risk of nonmelanoma skin cancer: a dose-response meta-analysis.
Several epidemiological studies have evaluated the associations between coffee consumption and the risk of skin cancer; however, the results were not conclusive. This systematic review and meta-analysis of the cohort and case-control studies was carried out to determine the association between coffee intake and the risk of nonmelanoma skin cancer. Studies were identified by searching the PubMed and MEDLINE databases (to November 2015). Study-specific risk estimates were pooled under the random-effects model. We separately estimated the relative risk of the three conditions, for exposure to different doses of coffee consumption, kind of study design, and analysis restricted to the basal cell carcinoma type. The summary relative risks for nonmelanoma skin cancer were 0.96 [95% confidence interval (CI): 0.92-0.99] for one cup of coffee, 0.92 (95% CI: 0.88-0.97) for one to two cups of coffee, 0.89 (95% CI: 0.86-0.93) for two to three cups of coffee, and 0.81 (95% CI: 0.77-0.85) for more than three cups of coffee per day, respectively. This meta-analysis suggested that caffeinated coffee might have chemopreventive effects against basal cell carcinoma dose dependently. However, other prospective studies are warranted to confirm these effects.


The role of stem cells and tissue engineering in orthopaedic sports medicine: current evidence and future directions.
The use of stem cell therapies for the treatment of orthopaedic injuries continues to advance. The purpose of this review was to provide an update of the current role and future directions of stem cell strategies in sports medicine. The application of cell-based treatments in the sports medicine arena has expanded in recent years. Promising preclinical results have led to translation of these novel therapies into the clinical setting. Early well-designed comparative clinical studies have also shown positive outcomes. Despite significant advances in this arena, there remains a need for additional high-powered and well-designed clinical trials to confirm the safety and efficacy of treatment.


Gene and protein expression profiling of human ovarian cancer cells treated with the heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin.
The promising antitumor activity of 17-allylamino-17-demethoxygeldanamycin (17AAG) results from inhibition of the molecular chaperone heat shock protein 90 (HSP90) and subsequent degradation of multiple oncogenic client proteins. Gene expression microarray and proteomic analysis were used to profile molecular changes in the A2780 human ovarian cancer cell line treated with 17AAG. Comparison of results with an inactive analogue and an alternative HSP90 inhibitor radicicol indicated that increased expression of HSP72, HSC70, HSP27, HSP47, and HSP90beta at the mRNA level were on-target effects of 17AAG. HSP27 protein levels were increased in tumor biopsies following treatment of patients with 17AAG. A group of MYC-regulated mRNAs was decreased by 17AAG. Of particular interest and novelty were changes in expression of chromatin-associated proteins. Expression of the heterochromatin protein 1 was increased, and expression of the histone acetyltransferase 1 and the histone arginine methyltransferase PRMT5 was decreased by 17AAG. PRMT5 was shown to be a novel HSP90-binding partner and potential client protein. Cellular protein acetylation was reduced by 17AAG, which was shown to have an antagonistic interaction on cell proliferation with the histone deacetylase inhibitor trichostatin A. This mRNA and protein expression analysis has provided new insights into the complex molecular pharmacology of 17AAG and suggested new genes and proteins that may be involved in response to the drug or be potential biomarkers of drug action.


The polarizing Sagnac interferometer: a tool for light orbital angular momentum sorting and spin-orbit photon processing.
In this paper we show that an optical setup based on a polarizing Sagnac interferometer combined with a Dove prism can be used as a convenient general-purpose tool for the generation, detection and sorting of spin-orbit states of light. This device can work both in the classical and in the quantum single-photon regime, provides higher sorting efficiency and extinction ratio than usual hologram-fiber combinations, and shows much higher stability and ease of alignment than Mach-Zehnder interferometer setups. To demonstrate the full potential of this setup, we also report some demonstrative experiments of several possible applications of this setup.


Mechanical trauma and urticaria.
Urticarial responses in skin may be elicited in different ways, viz, stroking (dermographism), after sustained pressure (delayed pressure urticaria), and after vibration (vibratory angio-oedema). Pressure may localise lesions of chronic idiopathic urticaria. Trauma may exacerbate hereditary angio-oedema. The extent of the morbidity caused by trauma-induced urticaria among workers is unknown.


Acid violet 7 and its biodegradation products induce chromosome aberrations, lipid peroxidation, and cholinesterase inhibition in mouse bone marrow.
Acid violet 7 (AV7), mostly used in food, paper, cosmetic, and especially in textile industries, was degraded by Pseudomonas putida mt-2 at concentrations up to 200 mg/l. In this study, toxicity of AV7, before and after biodegradation, was evaluated in vivo, in mouse bone marrow, by assessing the percentage of cells bearing different chromosome aberrations, membrane lipid peroxidation, and acetylcholinesterasic activity inhibition. The studies included same conditions for animal treatment, corresponding to increasing doses by intraperitoneal (ip) injection. Results indicated that AV7 showed a significant ability to induce chromosome aberrations, lipid peroxidation, and acetylcholinesterase inhibitory effect. The toxicity of AV7 increased significantly after static biodegradation with P. putida mt-2 and totally disappeared after shaken incubation. In addition, the toxicity generated by the pure azo dye and the corresponding azoreduction metabolites (4'-aminoacetanilide (4'-AA) and 5-acetamido-2-amino-1-hydroxy-3,6-naphtalene disulfonic acid (5-ANDS)) were compared. 4'-AA and 5-ANDS would be responsible of static biodegradation medium toxicity. The present study demonstrates that P. putida mt-2, incubated under aerobic condition, has a catabolism which enables it to degrade AV7, and especially to completely detoxify the dye mixture.


Comparative chronic toxicity of three neonicotinoids on New Zealand packaged honey bees.
Thiamethoxam, clothianidin, and imidacloprid are the most commonly used neonicotinoid insecticides on the Canadian prairies. There is widespread contamination of nectar and pollen with neonicotinoids, at concentrations which are sublethal for honey bees (Apis mellifera Linnaeus). We compared the effects of chronic, sublethal exposure to the three most commonly used neonicotinoids on honey bee colonies established from New Zealand packaged bees using colony weight gain, brood area, and population size as measures of colony performance. From May 7 to July 29, 2016 (12 weeks), sixty-eight colonies received weekly feedings of sugar syrup and pollen patties containing 0 nM, 20 nM (median environmental dose), or 80 nM (high environmental dose) of one of three neonicotinoids (thiamethoxam, clothianidin, and imidacloprid). Colonies were weighed at three-week intervals. Brood area and population size were determined from digital images of colonies at week 12. Statistical analyses were performed by ANOVA and mixed models. There was a significant negative effect (-30%, p<0.01) on colony weight gain (honey production) after 9 and 12 weeks of exposure to 80 nM of thiamethoxam, clothianidin, or imidacloprid and on bee cluster size (-21%, p<0.05) after 12 weeks. Analysis of brood area and number of adult bees lacked adequate (>80%) statistical power to detect an effect. Chronic exposure of honey bees to high environmental doses of neonicotinoids has negative effects on honey production. Brood area appears to be less sensitive to detect sublethal effects of neonicotinoids.


Different properties of P2X(7) receptor in hippocampal and cortical astrocytes.
P2X(7) receptor is a ligand-gated ion channel, which can induce the opening of large membrane pores. Here, we provide evidence that the receptor induces pore formation in astrocytes cultured from cortex, but not from the hippocampus. Furthermore, P2X(7) receptor activation promptly induces p38 mitogen-activated protein kinase (MAPK) phosphorylation in cortical but not in hippocampal astrocytes. Given the role of p38 MAPK activation in pore opening, these data suggest that defective coupling of the receptor to the enzyme could occur in hippocampal cultures. The different capabilities of the receptor to open membrane pores cause relevant functional consequences. Upon pore formation, caspase-1 is activated and pro-IL1-beta is cleaved and released extracellularly. The receptor stimulation does not result in interleukin-1beta secretion from hippocampal astrocytes, although the pro-cytokine is present in the cytosol of lipopolysaccharide-primed cultures. These results open the possibility that activation of P2X(7) receptors differently influences the neuroinflammatory processes in distinct brain regions.


Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial.
Although initially effective, sulfonylureas are associated with poor glycemic durability, weight gain, and hypoglycemia. Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycemia by increasing urinary glucose excretion independent of insulin and may cause fewer of these adverse effects. We compared the efficacy, safety, and tolerability of dapagliflozin with the sulfonylurea glipizide in patients with type 2 diabetes inadequately controlled with metformin monotherapy. This 52-week, double-blind, multicenter, active-controlled, noninferiority trial randomized patients with type 2 diabetes (baseline mean HbA(1c), 7.7%), who were receiving metformin monotherapy, to add-on dapagliflozin (n = 406) or glipizide (n = 408) up-titrated over 18 weeks, based on glycemic response and tolerability, to ≤10 or ≤20 mg/day, respectively. The primary end point, adjusted mean HbA(1c) reduction with dapagliflozin (-0.52%) compared with glipizide (-0.52%), was statistically noninferior at 52 weeks. Key secondary end points: dapagliflozin produced significant adjusted mean weight loss (-3.2 kg) versus weight gain (1.2 kg; P < 0.0001) with glipizide, significantly increased the proportion of patients achieving ≥5% body weight reduction (33.3%) versus glipizide (2.5%; P < 0.0001), and significantly decreased the proportion experiencing hypoglycemia (3.5%) versus glipizide (40.8%; P < 0.0001). Events suggestive of genital infections and lower urinary tract infections were reported more frequently with dapagliflozin compared with glipizide but responded to standard treatment and rarely led to study discontinuation. Despite similar 52-week glycemic efficacy, dapagliflozin reduced weight and produced less hypoglycemia than glipizide in type 2 diabetes inadequately controlled with metformin. Long-term studies are required to further evaluate genital and urinary tract infections with SGLT2 inhibitors.


Morphology and Description of Bursaphelenchus platzeri n. sp. (Nematoda: Parasitaphelenchidae), an Associate of Nitidulid Beetles.
Bursaphelenchus platzeri n. sp., an associate of nitidulid beetles in southern California, is described and illustrated. Adult males and females of B. platzeri n. sp. were examined by scanning electron microscopy for ultrastructural comparisons with other members of the genus. Bursaphelenchus cocophilus (red ring nematode) appears to be the closest related taxon to B. platzeri n. sp. based upon shared morphological features of the fused spicules, female tail shape, phoresy with non-scolytid beetles, and molecular analysis of the near full-length small subunit (SSU) rDNA. Unfortunately, sequence data from the D2D3 expansion segments of the large subunit (LSU) rDNA and partial mitochondrial DNA COI did not help resolve the relationship of nearest relative. In addition to significant molecular sequence differences in SSU, LSU, and COI, B. platzeri n. sp., which is an obligate fungal feeder, can be differentiated from B. cocophilus because it is an obligate parasite of palms. Bursaphelenchus platzeri n. sp. can be differentiated from all other species of Bursaphelenchus by the length and shape of the female tail and spicule morphology. The spicules are fused along the ventral midline and possess unfused cucullae; the fused unit appears to function as a conduit for sperm. Population growth of B. platzeri n. sp. was measured in a time-course experiment at 25 degrees C in the laboratory on cultures of the fungus Monilinia fructicola grown on 5% glycerol-supplemented potato dextrose agar (GPDA). Nematode population densities rapidly increased from 25 to approximately 200,000/culture within 14 d and then plateaued for up to 28 d.


Validation of an Accelerometer to Quantify a Comprehensive Battery of Gait Characteristics in Healthy Older Adults and Parkinson's Disease: Toward Clinical and at Home Use.
Measurement of gait is becoming important as a tool to identify disease and disease progression, yet to date its application is limited largely to specialist centers. Wearable devices enables gait to be measured in naturalistic environments, however questions remain regarding validity. Previous research suggests that when compared with a laboratory reference, measurement accuracy is acceptable for mean but not variability or asymmetry gait characteristics. Some fundamental reasons for this have been presented, (e.g., synchronization, different sampling frequencies) but to date this has not been systematically examined. The aims of this study were to: 1) quantify a comprehensive range of gait characteristics measured using a single triaxial accelerometer-based monitor; 2) examine outcomes and monitor performance in measuring gait in older adults and those with Parkinson's disease (PD); and 3) carry out a detailed comparison with those derived from an instrumented walkway to account for any discrepancies. Fourteen gait characteristics were quantified in 30 people with incident PD and 30 healthy age-matched controls. Of the 14 gait characteristics compared, agreement between instruments was excellent for four (ICCs 0.913-0.983); moderate for four (ICCs 0.508-0.766); and poor for six characteristics (ICCs 0.637-0.370). Further analysis revealed that differences reflect an increased sensitivity of accelerometry to detect motion, rather than measurement error. This is most likely because accelerometry measures gait as a continuous activity rather than discrete footfall events, per instrumented tools. The increased sensitivity shown for these characteristics will be of particular interest to researchers keen to interpret "real-world" gait data. In conclusion, use of a body-worn monitor is recommended for the measurement of gait but is likely to yield more sensitive data for asymmetry and variability features.


Infiltration of Matrix-Non-producers Weakens the Salmonella Biofilm and Impairs Its Antimicrobial Tolerance and Pathogenicity.
Bacterial biofilms display a collective lifestyle, wherein the cells secrete extracellular polymeric substances (EPS) that helps in adhesion, aggregation, stability, and to protect the bacteria from antimicrobials. We asked whether the EPS could act as a public good for the biofilm and observed that infiltration of cells that do not produce matrix components weakened the biofilm of Salmonella enterica serovar Typhimurium. EPS production was costly for the producing cells, as indicated by a significant reduction in the fitness of wild type (WT) cells during competitive planktonic growth relative to the non-producers. Infiltration frequency of non-producers in the biofilm showed a concomitant decrease in overall productivity. It was apparent in the confocal images that the non-producing cells benefit from the EPS produced by the Wild Type (WT) to stay in the biofilm. The biofilm containing non-producing cells were more significantly susceptible to sodium hypochlorite and ciprofloxacin treatment than the WT biofilm. Biofilm infiltrated with non-producers delayed the pathogenesis, as tested in a murine model. The cell types were spatially assorted, with non-producers being edged out in the biofilm. However, cellulose was found to act as a barrier to keep the non-producers away from the WT microcolony. Our results show that the infiltration of non-cooperating cell types can substantially weaken the biofilm making it vulnerable to antibacterials and delay their pathogenesis. Cellulose, a component of EPS, was shown to play a pivotal role of acting as the main public good, and to edge-out the non-producers away from the cooperating microcolony.


Inulin-type fructans and bone health: state of the art and perspectives in the management of osteoporosis.
If the primary role of diet is to provide sufficient nutrients to meet the metabolic requirements of an individual, there is an emerging rationale to support the hypothesis that, by modulating specific target functions in the body, it can help achieve optimal health. Regarding osteoporosis prevention, since Ca is most likely to be inadequate in terms of dietary intake, every strategy targeting an improvement in Ca absorption is very interesting. Actually, this process may be susceptible to manipulation by fermentable substrates. In this light, inulin-type fructans are very interesting, even if we need to gather more data targeting bone metabolism before health professionals can actively advocate their consumption to prevent senile osteoporosis. Besides targeting the prevention of postmenopausal osteoporosis, inulin-type fructans still remain a source for putative innovative dietary health intervention. Indeed, given in combination with isoflavones, they may have a potential for maintaining or improving the bone mass of human subjects, by modulating the bioavailability of phyto-oestrogens.


Outcomes of irinotecan-based chemotherapy regimens in elderly Medicare patients with metastatic colorectal cancer.
Several population-based studies have confirmed the benefits of adjuvant chemotherapy with 5-fluorouracil/leucovorin for treatment of colorectal cancer. Few population-based studies have evaluated other chemotherapies that are now available for colorectal cancer management. This study primarily sought to evaluate the survival benefit of first-line irinotecan use in a group of Medicare patients with stage IV (metastatic) colorectal cancer. Data on chemotherapy users with a diagnosis of colorectal cancer reported between 1998 and 2002 were obtained from the Surveillance Epidemiology and End Results (SEER)-Medicare database. Irinotecan, marketed in 1997, was one of the newer chemotherapy agents in the available data. Chemotherapy episodes, defined as periods of continuous chemotherapy treatment with no gaps >90 days between successive claims, were identified. The first chemotherapy episode after diagnosis was used to identify lines of treatment: patients may have initiated irinotecan therapy within 2 months (first-line), used irinotecan later in the first episode (second-line), or not used irinotecan at all. Descriptive statistics were generated and a multivariable Cox proportional hazards model was used to determine the survival benefit of irinotecan. Secondary analyses explored the survival benefit in specific patient subgroups. The impact of irinotecan use on health care utilization also was assessed. Of 3327 chemotherapy users (mean/median age, 75 years), 842 (25.3%) initiated chemotherapy using irinotecan. No overall survival benefit for irinotecan was observed in the primary analysis comparing irinotecan initiators with all other chemotherapy users (including those who used irinotecan subsequently). Covariates that were negatively associated with survival included older age, presence of >1 comorbidity, a high tumor grade, lymph node involvement, and a primary tumor site in the colon. Surgery was positively associated with a lower hazard of death. In subgroup analyses that excluded subsequent irinotecan users, a survival benefit for irinotecan was observed but diminished over time. Irinotecan users had higher rates of hospitalizations possibly due to chemotherapy-related adverse effects. This retrospective claims study had limitations such as a lack of information on patient performance status, dosing, and the types of regimens used; hence, certain assumptions had to be made and selection bias may have been involved. The definitive survival advantage of irinotecan observed in clinical trials was not reproducible in this population of elderly Medicare patients. The results emphasize the need for expansion of trials to include a more diverse patient group as well as continued evaluation of more recent chemotherapies in real-world settings.


Elevated first trimester PAPP--a is associated with increased risk of placenta accreta.
The objective of this article is to determine whether there were differences in first trimester serum analytes between cases of placenta previa with and without accreta. Cases of placenta previa in which the patient had first trimester aneuploidy screening were identified. Pregnancy-associated plasma protein A (PAPP-A) and free beta human chorionic gonadotropin (fbhCG) MoMs were compared with those with an accreta. Accreta cases were also compared with published distributions to determine significance and to develop likelihood ratios based on MoM values. Eighty-two cases of previa were identified, including 16 with a histological diagnosis of placenta accreta. The median PAPP-A MoM of 1.68 in accreta was significantly greater than that of 0.98 in non-accreta (P = 0.002). For fbhCG, the median MoM was 1.00 and 1.01 in accreta and non-accreta, respectively. Of the 16 patients with accreta, 14 (87.5%, 95% confidence interval: [61.6%, 98.4%]) had PAPP-A MoM above 1.0. Six of 16 (37.5%) accreta cases were above the 90th percentile of the unaffected distribution. The likelihood ratios for accreta were 0.5, 2.0, and 3.0. PAPP-A MoMs were 0.19, 2.11, and 4.27, respectively. First trimester PAPP-A levels may be useful in identifying pregnancies at high risk for placenta accreta. Larger studies could incorporate both clinical and biochemical data into a risk algorithm.


Digoxin-induced reversible dysfunction of the cone photoreceptors in monkeys.
To investigate functional alteration of the retina induced by digoxin in monkeys. Digoxin was intravenously administered to cynomolgus monkeys and standard full-field electroretinograms (ERGs) were serially recorded. In other digoxin-treated monkeys, the rod and cone a-waves to high-intensity flashes were obtained and analyzed by the a-wave fitting model (a-wave analysis). The following responses were also recorded: dark- and light-adapted responses to flashes of different intensities (dark- and light-adapted luminance responses), photopic ERG elicited by long-duration stimulus (ON-OFF response), and the photopic negative response (PhNR). Delayed b-wave was observed in all responses of the standard full-field ERGs; amplitude of the b-wave was increased in the rod response, but was decreased in the single-flash cone response and the 30-Hz flicker. These changes recovered gradually after elimination of digoxin from the blood. Digoxin enhanced and delayed the b-wave in the dark-adapted luminance-response analysis regardless of stimulus intensity. In the light-adapted luminance-response analysis, digoxin attenuated the a- and b-waves only at high and middle stimulus intensity, respectively. The a-wave analysis revealed selective decrease in the maximum response parameter (Rmax) in the cone a-wave. Both the b- and d-waves of the ON-OFF response were delayed. The selectively reduced Rmax in the cone a-wave indicated dysfunction of the cone photoreceptors in digoxin-treated monkeys. Meanwhile, the enhanced and delayed rod response suggested alteration of retinal components other than the cone photoreceptors. These results may contribute to the understanding of digoxin-induced visual disturbances in humans. It is suggested that the cone function is markedly, but not exclusively, affected in the retina of such patients.


Methicillin-resistant Staphylococcus aureus colonization and its association with infection among infants hospitalized in neonatal intensive care units.
We conducted this study to assess the rate of methicillin-resistant Staphylococcus aureus colonization and its association with infection among infants hospitalized in methicillin-resistant S aureus-endemic NICUs. Between March 2003 and February 2004, surveillance culture specimens from the nares, postauricular areas, axillae, and umbilicus of infants admitted to the NICUs at a children's hospital in Taiwan were obtained weekly for the detection of methicillin-resistant S aureus. All colonized and clinical isolates from each study infant with methicillin-resistant S aureus infection were genotyped with pulsed-field gel electrophoresis, with Sma1 digestion, and compared. A total of 783 infants were included in this study. Methicillin-resistant S aureus colonization was detected for 323 infants during their NICU stays, with detection with the first 2 samples for 89%. Nares and umbilicus were the 2 most common sites of initial colonization. Methicillin-resistant S aureus colonization was associated significantly with premature birth (< or = 28 weeks) and low birth weight (< or = 1500 g), and infants with colonization had a significantly higher rate of methicillin-resistant S aureus infection, compared with those without colonization (26% vs 2%). Methicillin-resistant S aureus colonization was noted for 84 of 92 infants with methicillin-resistant S aureus infections. Of the 68 episodes with previous colonization and isolates available for genotyping analysis, colonized and clinical isolates were indistinguishable in 63 episodes, highly related in 2 episodes, and distinct in 3 episodes. More than 40% of the hospitalized infants were colonized with methicillin-resistant S aureus during their stay in methicillin-resistant S aureus-endemic NICUs; this was associated significantly with methicillin-resistant S aureus infection. Most infants with methicillin-resistant S aureus infections had previous colonization with an indistinguishable strain.


The many roads to and from multicellularity.
The multiple origins of multicellularity had far-reaching consequences ranging from the appearance of phenotypically complex life-forms to their effects on Earth's aquatic and terrestrial ecosystems. Yet, many important questions remain. For example, do all lineages and clades share an ancestral developmental predisposition for multicellularity emerging from genomic and biophysical motifs shared from a last common ancestor, or are the multiple origins of multicellularity truly independent evolutionary events? In this review, we highlight recent developments and pitfalls in understanding the evolution of multicellularity with an emphasis on plants (here defined broadly to include the polyphyletic algae), but also draw upon insights from animals and their holozoan relatives, fungi and amoebozoans. Based on our review, we conclude that the evolution of multicellular organisms requires three phases (origination by disparate cell-cell attachment modalities, followed by integration by lineage-specific physiological mechanisms, and autonomization by natural selection) that have been achieved differently in different lineages.


Monitoring hepatitis C virus treatment rates in an Opioid Treatment Program: A longitudinal study.
Direct-acting antivirals (DAAs) are recommended for the treatment of hepatitis C virus (HCV) infection in patients treated with methadone or buprenorphine. To assess HCV treatment rates in an Opioid Treatment Program (OTP). This longitudinal study included 501 patients (81.4% men, median age: 45 years; interquartile range: 39-50 years) enrolled in an OTP between October 2015 and September 2017. Patients were followed until September 2019. Data on socio-demographics, substance use, HCV infection, human immunodeficiency virus (HIV) infection and laboratory parameters were collected at entry. We analyzed medical records to evaluate HCV treatment. Kaplan-Meier methods and Cox regression models were used to analyze the DAA treatment uptake and to identify treatment predictors. Prevalence of HCV and HIV infection was 70% and 34%, respectively. Among anti-HCV-positive (n = 336) patients, 47.2%, 41.3%, and 31.9% used alcohol, cannabis, and cocaine, respectively. HCV-RNA tests were positive in 233 (69.3%) patients. Twentyeight patients (8.3%) cleared the infection, and 59/308 (19.1%) had received interferon-based treatment regimens before 2015. Among 249 patients eligible, 111 (44.6%) received DAAs. Treatment rates significantly increased over time from 7.8/100 person-years (p-y) (95%CI: 5.0-12.3) in 2015 to 18.9/100 p-y (95%CI: 11.7-30.3) in 2019. In a multivariate analysis, patients with HIV co-infection were twice as likely to receive DAAs (HR = 1.94, 95%CI: 1.21-3.12) than patients with HCV mono-infection. Current drug use was an independent risk factor for not receiving treatment against infection (HR = 0.48, 95%CI: 0.29-0.80). HCV treatment is evolving in patients with HCV-HIV co-infection. Ongoing drug use while in an OTP might negatively impact the readiness to treat infection.


Genetics in Retinal Diseases.
The phenotypic presentation of retinal diseases is typically underpinned by the presence of genetic variation represented by either polymorphic changes, mutations, copy number variations or epigenetic changes. Retinal dystrophies can broadly be divided into two forms, either monogenic (single-gene) or complex (multifactorial) diseases. Recent advances in molecular techniques such as genome-wide association studies and next-generation sequencing have revolutionized the discovery of genetic variants associated with different retinal disorders, including retinitis pigmentosa and age-related macular degeneration. Understanding the genetic profile of the disease not only helps in diagnostics but also in gene therapy, as recently shown for Leber's congenital amaurosis. Following the elucidation of many genetic features of retinal diseases, the task is now to make sense of this large amount of data to better understand as well as experimentally prove the physiological process of the retinal disease genes and the mechanisms behind the diseases. This in turn will lead to improved gene-based therapies and personalize treatments for patients.


Antenatal mindfulness intervention to reduce depression, anxiety and stress: a pilot randomised controlled trial of the MindBabyBody program in an Australian tertiary maternity hospital.
Mindfulness interventions to reduce psychological distress are well-suited to pregnancy, due to their brief and non-pharmacological nature, but there is a need for more robust evidence determining their usefulness. This pilot study was designed to explore the feasibility of a randomised controlled trial of a mindfulness intervention to reduce antenatal depression, anxiety and stress. The study was designed in two parts 1) a non-randomised trial targeting women at risk of mental health problems (a selected population) and 2) a randomised controlled trial (RCT) of a universal population. Process evaluation focused on feasibility of recruitment pathways, participant retention, acceptability of study measures, and engagement with mindfulness practices. Measurement of psychological distress was taken pre and post intervention through the Centre for Epidemiologic Studies Depression Scale Revised, the Depression Anxiety and Stress Scale-21, the State-Trait Anxiety Inventory, and the Perceived Stress Scale. 20 women were recruited to the non-randomised trial, and 32 to the RCT. Recruitment through a mailed study brochure at the time of booking-in to the hospital resulted in the largest number of participants in the RCT (16/32; 50%), and resulted in considerably earlier recruitment (50% in first trimester, 50% second trimester) compared to recruitment through the antenatal clinic waiting room (86% in second trimester, 14% third trimester). Over a third of women in the universal population scored above clinical cut-offs for depression and anxiety, indicating a sample with more symptomology than the general population. The most common reason for loss to follow-up was delivery of baby prior to follow-up (n = 9). In the non-randomised study, significant within group improvements to depression and anxiety were observed. In the intervention arm of the RCT there were significant within group improvements to anxiety and mindfulness. No between group differences for the intervention and 'care as usual' control group were observed. This small pilot study provides evidence on the feasibility of an antenatal mindfulness intervention to reduce psychological distress. Major challenges include: finding ways to facilitate recruitment in early pregnancy and engaging younger women and other vulnerable populations. Australian New Zealand Clinical Trials Registry ACTRN12613000742774 (31/10/2012).


Uncertainty analysis of vegetation distribution in the northern high latitudes during the 21st century with a dynamic vegetation model.
This study aims to assess how high-latitude vegetation may respond under various climate scenarios during the 21st century with a focus on analyzing model parameters induced uncertainty and how this uncertainty compares to the uncertainty induced by various climates. The analysis was based on a set of 10,000 Monte Carlo ensemble Lund-Potsdam-Jena (LPJ) simulations for the northern high latitudes (45(o)N and polewards) for the period 1900-2100. The LPJ Dynamic Global Vegetation Model (LPJ-DGVM) was run under contemporary and future climates from four Special Report Emission Scenarios (SRES), A1FI, A2, B1, and B2, based on the Hadley Centre General Circulation Model (GCM), and six climate scenarios, X901M, X902L, X903H, X904M, X905L, and X906H from the Integrated Global System Model (IGSM) at the Massachusetts Institute of Technology (MIT). In the current dynamic vegetation model, some parameters are more important than others in determining the vegetation distribution. Parameters that control plant carbon uptake and light-use efficiency have the predominant influence on the vegetation distribution of both woody and herbaceous plant functional types. The relative importance of different parameters varies temporally and spatially and is influenced by climate inputs. In addition to climate, these parameters play an important role in determining the vegetation distribution in the region. The parameter-based uncertainties contribute most to the total uncertainty. The current warming conditions lead to a complexity of vegetation responses in the region. Temperate trees will be more sensitive to climate variability, compared with boreal forest trees and C3 perennial grasses. This sensitivity would result in a unanimous northward greenness migration due to anomalous warming in the northern high latitudes. Temporally, boreal needleleaved evergreen plants are projected to decline considerably, and a large portion of C3 perennial grass is projected to disappear by the end of the 21st century. In contrast, the area of temperate trees would increase, especially under the most extreme A1FI scenario. As the warming continues, the northward greenness expansion in the Arctic region could continue.


Geographical accessibility and duration of untreated psychosis: distance as a determinant of treatment delay.
The duration of untreated psychosis is determined by both patient and service related factors. Few studies have considered the geographical accessibility of services in relation to treatment delay in early psychosis. To address this, we investigated whether treatment delay is co-determined by straight-line distance to hospital based specialist services in a mainly rural mental health context. A naturalistic cross-sectional study was conducted among a sample of recent onset psychosis patients in northern Norway (n = 62). Data on patient and service related determinants were analysed. Half of the cohort had a treatment delay longer than 4.5 months. In a binary logistic regression model, straight-line distance was found to make an independent contribution to delay in which we controlled for other known risk factors. The determinants of treatment delay are complex. This study adds to previous studies on treatment delay by showing that the spatial location of services also makes an independent contribution. In addition, it may be that insidious onset is a more important factor in treatment delay in remote areas, as the logistical implications of specialist referral are much greater than for urban dwellers. The threshold for making a diagnosis in a remote location may therefore be higher. Strategies to reduce the duration of untreated psychosis in rural areas would benefit from improving appropriate referral by crisis services, and the detection of insidious onset of psychosis in community based specialist services.


Recombination-Aware Phylogenomics Reveals the Structured Genomic Landscape of Hybridizing Cat Species.
Current phylogenomic approaches implicitly assume that the predominant phylogenetic signal within a genome reflects the true evolutionary history of organisms, without assessing the confounding effects of postspeciation gene flow that can produce a mosaic of phylogenetic signals that interact with recombinational variation. Here, we tested the validity of this assumption with a phylogenomic analysis of 27 species of the cat family, assessing local effects of recombination rate on species tree inference and divergence time estimation across their genomes. We found that the prevailing phylogenetic signal within the autosomes is not always representative of the most probable speciation history, due to ancient hybridization throughout felid evolution. Instead, phylogenetic signal was concentrated within regions of low recombination, and notably enriched within large X chromosome recombination cold spots that exhibited recurrent patterns of strong genetic differentiation and selective sweeps across mammalian orders. By contrast, regions of high recombination were enriched for signatures of ancient gene flow, and these sequences inflated crown-lineage divergence times by ∼40%. We conclude that existing phylogenomic approaches to infer the Tree of Life may be highly misleading without considering the genomic architecture of phylogenetic signal relative to recombination rate and its interplay with historical hybridization.


Clinical features of Alzheimer's disease.
The preclinical stage of Alzheimer's disease is inconspicuous and there are - almost by definition - no reliable and valid symptoms and signs which would allow a very early diagnosis before the manifestation of irreversible deficits. For a clinical diagnosis of dementia, cognitive impairment has to be severe enough to compromise the activities of daily living. In the mild dementia stage, difficulties with declarative memory are usually prominent; depressive symptoms are not infrequent, but the patient usually manages to live alone. Supervision is needed in the moderate dementia stage, when other cognitive domains are affected in a more obvious manner and non-cognitive disturbances of thought, perception, affect, and behavior put increasing stress on the caregivers. Complete dependence of the patients, who frequently develop neurological disturbances, is typical of the late stage of illness. The life expectancy of patients with a clinical diagnosis of Alzheimer's disease is significantly reduced, but to date there is hope that the period of relative well-being and not of suffering can be prolonged with modern symptomatic treatment interventions.


Regulation of protein kinase Cδ Nuclear Import and Apoptosis by Mechanistic Target of Rapamycin Complex-1.
Inactivation of the protein complex 'mechanistic target of rapamycin complex 1' (mTORC1) can increase the nuclear content of transcriptional regulators of metabolism and apoptosis. Previous studies established that nuclear import of signal transducer and activator of transcription-1 (STAT1) requires the mTORC1-associated adaptor karyopherin-α1 (KPNA1) when mTORC1 activity is reduced. However, the role of other mTORC1-interacting proteins in the complex, including 'protein kinase C delta' (PKCδ), have not been well characterized. In this study, we demonstrate that PKCδ, a STAT1 kinase, contains a functional 'target of rapamycin signaling' (TOS) motif that directs its interaction with mTORC1. Depletion of KPNA1 by RNAi prevented the nuclear import of PKCδ in cells exposed to the mTORC1 inhibitor rapamycin or amino acid restriction. Mutation of the TOS motif in PKCδ led to its loss of regulation by mTORC1 or karyopherin-α1, resulting in increased constitutive nuclear content. In cells expressing wild-type PKCδ, STAT1 activity and apoptosis were increased by rapamycin or interferon-β. Those expressing the PKCδ TOS mutant exhibited increased STAT1 activity and apoptosis; further enhancement by rapamycin or interferon-β, however, was lost. Therefore, the TOS motif in PKCδ is a novel structural mechanism by which mTORC1 prevents PKCδ and STAT1 nuclear import, and apoptosis.


Epilepsy in Onchocerca volvulus Sero-Positive Patients From Northern Uganda-Clinical, EEG and Brain Imaging Features.
Globally, epilepsy is the most common chronic neurological disorder. The incidence in sub-Saharan Africa is 2-3 times higher than that in high income countries. Infection by Onchocerca volvulus may be an underlying risk factor for the high burden and based upon epidemiological associations, has been proposed to cause a group of disorders-Onchocerca associated epilepsies (OAE) like nodding syndrome (NS). To improve our understanding of the disease spectrum, we described the clinical, electroencephalographic (EEG) and magnetic resonance imaging (MRI) features of children with epilepsy and sero-positive for Onchocerca volvulus (possible OAEs other than nodding syndrome). Twenty-nine children and adolescents with non-nodding syndrome OAE in northern Uganda were enrolled. A diagnosis of OAE was made in patients with epilepsy and seizure onset after age 3 years, no reported exposure to perinatal severe febrile illness or traumatic brain injury, no syndromic epilepsy diagnosis and a positive Ov-16 ELISA test. Detailed clinical evaluation including psychiatric, diagnostic EEG, a diagnostic brain MRI (in 10 patients) and laboratory testing were performed. Twenty participants (69%) were male. The mean age was 15.9 (standard deviation [SD] 1.9) years while the mean age at seizure onset was 9.8 (SD 2.9) years. All reported normal early childhood development. The most common clinical presentation was a tonic-clonic seizure. The median number of seizures was 2 (IQR 1-4) in the previous month. No specific musculoskeletal changes, or cranial nerve palsies were reported, neither were any vision, hearing and speech difficulties observed. The interictal EEG was abnormal in the majority with slow wave background activity in 52% (15/29) while 41% (12/29) had focal epileptiform activity. The brain MRI showed mild to moderate cerebellar atrophy and varying degrees of atrophy of the frontal, parietal and occipital lobes. The clinical spectrum of epilepsies associated with Onchocerca may be broader than previously described. In addition, focal onset tonic-clonic seizures, cortical and cerebellar atrophy may be important brain imaging and clinical features.


Does a Large Ear Type Wheat Variety Benefit More From Elevated CO2 Than That From Small Multiple Ear-Type in the Quantum Efficiency of PSII Photochemistry?
Recently, several reports have suggested that the growth and grain yield of wheat are significantly influenced by high atmospheric carbon dioxide concentration (CO2) because of it photosynthesis enhancing effects. Moreover, it has been proposed that plants with large carbon sink size will benefit more from CO2 enrichment than those with small carbon sink size. However, this hypothesis is yet to be test in winter wheat plant. Therefore, the aim of this study was to examine the effect of elevated CO2 (eCO2) conditions on the quantum efficiency of photosystem II (PSII) photochemistry in large ear-type (cv. Shanhan 8675; greater ear C sink strength) and small multiple ear-type (cv. Early premium; greater vegetative C source strength) winter wheat varieties. The experiment was conducted in a free air CO2 enrichment (FACE) facility, and three de-excitation pathways of the primary reaction of PSII of flag leaf at the anthesis stage were evaluated under two CO2 concentrations (ambient [CO2], ∼415 μmol⋅mol-1, elevated [CO2], ∼550 μmol⋅mol-1) using a non-destructive technique of modulated chlorophyll fluorescence. Additionally, the grain yield of the two varieties was determined at maturity. Although elevated CO2 increased the quantum efficiency of PSII photochemistry (ΦPSII) of Shanhan 8675 (SH8675) flag leaves at the anthesis stage, the grain number per ear and 1,000-kernel weight were not significantly affected. In contrast, the ΦPSII of early premium (ZYM) flag leaves was significantly lower than that of SH8675 flag leaves at the anthesis stage, which was caused by an increase in the regulatory non-photochemical energy dissipation quantum (ΦNPQ) of PSII, suggesting that light energy absorbed by PSII in ZYM flag leaf was largely dissipated as thermal energy. The findings of our study showed that although SH8675 flag leaves exhibited higher C sink strength and quantum efficiency of PSII photochemistry at the anthesis stage, these factors alone do not ensure improved grain yield under eCO2 conditions.


Degradative capacities and 16S rRNA-targeted whole-cell hybridization of sulfate-reducing bacteria in an anaerobic enrichment culture utilizing alkylbenzenes from crude oil.
A mesophilic sulfate-reducing enrichment culture growing anaerobically on crude oil was used as a model system to study which nutritional types of sulfate-reducing bacteria may develop on original petroleum constituents in oil wells, tanks, and pipelines. Chemical analysis of oil hydrocarbons during growth revealed depletion of toluene and o-xylene within 1 month and of m-xylene, o-ethyltoluene, m-ethyltoluene, m-propyltoluene, and m-isopropyltoluene within approximately 2 months. In anaerobic counting series, the highest numbers of CFU (6 x 10(6) to 8 x 10(6) CFU ml-1) were obtained with toluene and benzoate. Almost the same numbers were obtained with lactate, a substrate often used for detection of the vibrio-shaped, incompletely oxidizing Desulfovibrio sp. In the present study, however, lactate yielded mostly colonies of oval to rod-shaped, completely oxidizing, sulfate-reducing bacteria which were able to grow slowly on toluene or crude oil. Desulfovibrio species were detected only at low numbers (3 x 10(5) CFU ml-1). In agreement with this finding, a fluorescently labeled, 16S rRNA-targeted oligonucleotide probe described in the literature as specific for members of the Desulfovibrionaceae (suggested family) hybridized only with a small portion (< 5%) of the cells in the enrichment culture. These results are consistent with the observation that known Desulfovibrio species do not utilize aromatic hydrocarbons, the predominant substrates in the enrichment culture. All known sulfate-reducing bacteria which utilize aromatic compounds belong to a separate branch, the Desulfobacteriaceae (suggested family). Most members of this family are complete oxidizers. For specific hybridization with members of this branch, the probe had to be modified by a nucleotide exchange. Indeed, this modified probe hybridized with more than 95% of the cells in the enrichment culture. The results show that completely oxidizing, alkylbenzene-utilizing sulfate-reducing bacteria rather than Desulfovibrio species have to be considered in attempts to understand the microbiology of sulfide production in oil wells, tanks, and pipelines when no electron donors other than the indigenous oil constituents are available.


Increased severity of respiratory infections associated with elevated anti-LPS IgG2 which inhibits serum bactericidal killing.
Although specific antibody induced by pathogens or vaccines is a key component of protection against infectious threats, some viruses, such as dengue, induce antibody that enhances the development of infection. In contrast, antibody-dependent enhancement of bacterial infection is largely unrecognized. Here, we demonstrate that in a significant portion of patients with bronchiectasis and Pseudomonas aeruginosa lung infection, antibody can protect the bacterium from complement-mediated killing. Strains that resist antibody-induced, complement-mediated killing produce lipopolysaccharide containing O-antigen. The inhibition of antibody-mediated killing is caused by excess production of O-antigen-specific IgG2 antibodies. Depletion of IgG2 to O-antigen restores the ability of sera to kill strains with long-chain O-antigen. Patients with impaired serum-mediated killing of P. aeruginosa by IgG2 have poorer respiratory function than infected patients who do not produce inhibitory antibody. We suggest that excessive binding of IgG2 to O-antigen shields the bacterium from other antibodies that can induce complement-mediated killing of bacteria. As there is significant sharing of O-antigen structure between different Gram-negative bacteria, this IgG2-mediated impairment of killing may operate in other Gram-negative infections. These findings have marked implications for our understanding of protection generated by natural infection and for the design of vaccines, which should avoid inducing such blocking antibodies.


On euthanasia: blindspots in the argument from mercy.
In the euthanasia debate, the argument from mercy holds that if someone is in unbearable pain and is hopelessly ill or injured, then mercy dictates that inflicting death may be morally justified. One common way of setting the stage for the argument from mercy is to draw parallels between human and animal suffering, and to suggest that insofar as we are prepared to relieve an animal's suffering by putting it out of its misery we should likewise be prepared to offer the same relief to human beings. In this paper, I will argue that the use of parallels between human and animal suffering in the argument from mercy relies upon truncated views of how the concept of a human being enters our moral thought and responsiveness. In particular, the focus on the nature and extent of the empirical similarities between human beings and animals obscures the significance for our moral lives of the kind of human fellowship which is not reducible to the shared possession of empirical capacities. I will suggest that although a critical examination of the blindspots in these arguments does not license the conclusion that euthanasia for mercy's sake is never morally permissible, it does limit the power of arguments such as those provided by Rachels and Singer to justify it. I will further suggest that examination of these blindspots helps to deepen our understanding of what is at stake in the question of euthanasia in ways that tend otherwise to remain obscured.


Embryonic stem cell-derived hemangioblasts remain epigenetically plastic and require PRC1 to prevent neural gene expression.
Many lineage-specific developmental regulator genes are transcriptionally primed in embryonic stem (ES) cells; RNA Pol(II) is bound at their promoters but is prevented from productive elongation by the activity of polycomb repressive complexes (PRC) 1 and 2. This epigenetically poised state is thought to enable ES cells to rapidly execute multiple differentiation programs and is recognized by a simultaneous enrichment for trimethylation of lysine 4 and trimethylation of lysine 27 of histone H3 (bivalent chromatin) across promoter regions. Here we show that the chromatin profile of this important cohort of genes is progressively modified as ES cells differentiate toward blood-forming precursors. Surprisingly however, neural specifying genes, such as Nkx2-2, Nkx2-9, and Sox1, remain bivalent and primed even in committed hemangioblasts, as conditional deletion of PRC1 results in overt and inappropriate expression of neural genes in hemangioblasts. These data reinforce the importance of PRC1 for normal hematopoietic differentiation and reveal an unexpected epigenetic plasticity of mesoderm-committed hemangioblasts.


Endospores and other lysis-resistant bacteria comprise a widely shared core community within the human microbiota.
Endospore-formers in the human microbiota are well adapted for host-to-host transmission, and an emerging consensus points to their role in determining health and disease states in the gut. The human gut, more than any other environment, encourages the maintenance of endospore formation, with recent culture-based work suggesting that over 50% of genera in the microbiome carry genes attributed to this trait. However, there has been limited work on the ecological role of endospores and other stress-resistant cellular states in the human gut. In fact, there is no data to indicate whether organisms with the genetic potential to form endospores actually form endospores in situ and how sporulation varies across individuals and over time. Here we applied a culture-independent protocol to enrich for endospores and other stress-resistant cells in human feces to identify variation in these states across people and within an individual over time. We see that cells with resistant states are more likely than those without to be shared among multiple individuals, which suggests that these resistant states are particularly adapted for cross-host dissemination. Furthermore, we use untargeted fecal metabolomics in 24 individuals and within a person over time to show that these organisms respond to shared environmental signals, and in particular, dietary fatty acids, that likely mediate colonization of recently disturbed human guts.


High-precision force sensing using a single trapped ion.
We introduce quantum sensing schemes for measuring very weak forces with a single trapped ion. They use the spin-motional coupling induced by the laser-ion interaction to transfer the relevant force information to the spin-degree of freedom. Therefore, the force estimation is carried out simply by observing the Ramsey-type oscillations of the ion spin states. Three quantum probes are considered, which are represented by systems obeying the Jaynes-Cummings, quantum Rabi (in 1D) and Jahn-Teller (in 2D) models. By using dynamical decoupling schemes in the Jaynes-Cummings and Jahn-Teller models, our force sensing protocols can be made robust to the spin dephasing caused by the thermal and magnetic field fluctuations. In the quantum-Rabi probe, the residual spin-phonon coupling vanishes, which makes this sensing protocol naturally robust to thermally-induced spin dephasing. We show that the proposed techniques can be used to sense the axial and transverse components of the force with a sensitivity beyond the range, i.e. in the (xennonewton, 10(-27)). The Jahn-Teller protocol, in particular, can be used to implement a two-channel vector spectrum analyzer for measuring ultra-low voltages.


Evolutionary trends of the pharyngeal dentition in Cypriniformes (Actinopterygii: Ostariophysi).
The fish order Cypriniformes is one of the most diverse ray-finned fish groups in the world with more than 3000 recognized species. Cypriniformes are characterized by a striking distribution of their dentition: namely the absence of oral teeth and presence of pharyngeal teeth on the last gill arch (fifth ceratobranchial). Despite this limited localisation, the diversity of tooth patterns in Cypriniformes is astonishing. Here we provide a further description of this diversity using X-ray microtomography and we map the resulting dental characters on a phylogenetic tree to explore evolutionary trends. We performed a pilot survey of dental formulae and individual tooth shapes in 34 adult species of Cypriniformes by X-ray microtomography (using either conventional X-ray machine, or synchrotron microtomography when necessary) or by dissecting. By mapping morphological results in a phylogenetic tree, it emerges that the two super-families Cobitoidea and Cyprinoidea have followed two distinct evolutionary pathways. Furthermore, our analysis supports the hypothesis of a three-row dentition as ancestral for Cyprinoidea and a general trend in tooth row reduction in most derived lineages. Yet, this general scheme must be considered with caution as several events of tooth row gain and loss have occurred during evolutionary history of Cyprinoidea. Dentition diversity in Cypriniformes constitutes an excellent model to study the evolution of complex morphological structures. This morphological survey clearly advocates for extending the use of X-ray microtomography to study tooth morphology in Cypriniformes. Yet, our survey also underlines that improved knowledge of Cypriniformes life traits, such as feeding habits, is required as current knowledge is not sufficient to conclude on the link between diet and dental morphology.


Minimally invasive parathyroid surgery.
Traditionally, bilateral cervical exploration for localization of all four parathyroid glands and removal of any that are grossly enlarged has been the standard surgical treatment for primary hyperparathyroidism (PHPT). With the advances in preoperative localization studies and greater public demand for less invasive procedures, novel targeted, minimally invasive techniques to the parathyroid glands have been described and practiced over the past 2 decades. Minimally invasive parathyroidectomy (MIP) can be done either through the standard Kocher incision, a smaller midline incision, with video assistance (purely endoscopic and video-assisted techniques), or through an ectopically placed, extracervical, incision. In current practice, once PHPT is diagnosed, preoperative evaluation using high-resolution radiographic imaging to localize the offending parathyroid gland is essential if MIP is to be considered. The imaging study results suggest where the surgeon should begin the focused procedure and serve as a road map to allow tailoring of an efficient, imaging-guided dissection while eliminating the unnecessary dissection of multiple glands or a bilateral exploration. Intraoperative parathyroid hormone (IOPTH) levels may be measured during the procedure, or a gamma probe used during radioguided parathyroidectomy, to ascertain that the correct gland has been excised and that no other hyperfunctional tissue is present. MIP has many advantages over the traditional bilateral, four-gland exploration. MIP can be performed using local anesthesia, requires less operative time, results in fewer complications, and offers an improved cosmetic result and greater patient satisfaction. Additional advantages of MIP are earlier hospital discharge and decreased overall associated costs. This article aims to address the considerations for accomplishing MIP, including the role of preoperative imaging studies, intraoperative adjuncts, and surgical techniques.


Rod and cone contributions to horizontal cell light responses in the mouse retina.
Mammalian B-type horizontal cells make contact with both photoreceptor types: the dendrites contact cone photoreceptors, whereas the axon terminal processes contact rods. Despite their distinct synaptic contacts, horizontal cell somata and axon terminals receive a mixture of rod and cone inputs. Interaction of the two photoreceptor systems is essential for adaptation of photoreceptor sensitivity to different levels of background illumination, and horizontal cells play a key role in this adaptation. In this study, we used transgenic mouse lines to examine the contributions of rod and cone photoreceptor inputs to horizontal cell light responses in the mouse retina: rod signals were isolated by recording intracellularly from horizontal cells in a mouse lacking the cone cyclic nucleotide-gated channel, which lacks cone function, and cone signals were assessed using the rhodopsin knock-out mouse, which is a model for pure cone function. We found that both horizontal cell compartments receive a mixture of inputs from both photoreceptor types. To determine whether these inputs arrive via the long axon connecting the compartments or by way of rod-cone gap junctional coupling, we assessed the rod and cone contributions to horizontal cell somatic and axon terminal light responses in the connexin36-deficient mouse retina, which lacks rod-cone coupling. Our results confirm that rods and cones are coupled by connexin36, and suggest that signal transmission along the axon is unidirectional: signals are passed from horizontal cell soma to axon terminal but not from axon terminal to soma.


A Placebo-Controlled Double-Blind Study Demonstrates the Clinical Efficacy of a Novel Herbal Formulation for Relieving Joint Discomfort in Human Subjects with Osteoarthritis of Knee.
LI73014F2 is a novel composition prepared from extracts of Terminalia chebula fruit, Curcuma longa rhizome, and Boswellia serrata gum resin with synergistic benefit in 5-Lipoxygenase (5-LOX) inhibition. This herbal composition with strong anti-5-LOX activity exhibited significant pain relief as indicated through improvements in weight-bearing capacity in a monosodium iodoacetate-induced osteoarthritis (OA) model of Sprague-Dawley rats. A 90-day randomized, placebo-controlled double-blind study evaluates the clinical efficacy and tolerability of LI73014F2 in the management of symptoms of OA of the knee (Clinical Trial Registration No. CTRI/2014/01/004338). Subjects, (n = 105), were randomized into three groups: placebo (n = 35), 200 mg/day of LI73014F2 (n = 35), and 400 mg/day of LI73014F2 (n = 35). All study participants were evaluated for pain and physical function by using standard tools, that is, Visual Analog Scale, Lequesne's Functional Index, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at the baseline (day 0) and on day 14 ± 3, 30 ± 3, 60 ± 3, and at the end of the study (day 90 ± 3). In addition, routine examinations on biochemical parameters in serum, urine, and hematological parameters were conducted on each visit to assess the safety of the study material. At the end of the trial period, LI73014F2 conferred significant pain relief, improved physical function, and quality of life in OA patients. In conclusion, preclinical and clinical data together strongly suggest that the herbal formulation LI73014F2 is a safe and effective intervention for management of joint discomfort, demonstrating efficacy as early as 14 days.


Modulation of N-type Ca2+ currents by A1-adenosine receptor activation in male rat pelvic ganglion neurons.
Modulation of voltage-activated Ca2+ channels by adenosine was investigated in male rat major pelvic ganglion (MPG) neurons by using the whole-cell variant of the patch-clamp technique. Adenosine inhibited high voltage-activated (HVA) Ca2+ currents in a concentration-dependent manner with an EC50 of 313 nM and a maximal inhibition of 36%, respectively. Inhibition of HVA Ca2+ currents in adrenergic and cholinergic MPG neurons was similar. Adenosine did not modulate T-type Ca2+ channels present in adrenergic MPG neurons. Reverse transcription-polymerase chain reaction analysis indicated that MPG neurons express mRNAs encoding A1 and A2a receptors. Ca2+ current inhibition by adenosine was mimicked by N6-cyclopentyladenosine, an A1-selective agonist (EC50 = 63 nM) and prevented by 100 nM 8-cyclopentyl-1,3-dipropylxanthine, an A1-selective antagonist. Conversely, CGS 21680, an A2a-selective agonist, displayed a relatively low potency (EC50 = 2200 nM) for inhibiting Ca2+ currents. The action of adenosine was significantly attenuated by 2 mM guanosine-5'-thiodiphosphate or 500 ng/ml pertussis toxin. The voltage dependence of adenosine-induced current inhibition was evident by 1) a bell-shaped profile between the current inhibition and test potentials, 2) kinetic slowing in the presence of agonist, and 3) relief of the current inhibition by a conditioning prepulse to +80 mV. Finally, 1 microM omega-conotoxin GVIA occluded adenosine-induced current inhibition. Taken together, we concluded that adenosine inhibits N-type Ca2+ currents by activation of A1 receptors via a voltage-dependent and PTX-sensitive pathway in rat MPG neurons. Our data may explain how adenosine acts as an inhibitory modulator of ganglionic and neuromuscular transmission in the pelvic plexus.


Survey response rates: national and regional differences in a European multicentre study of vertebral osteoporosis.
This analysis aimed to compare the response rates of those invited to attend for screening in a multicentre, multinational study within Europe. This was a population survey. Thirty four centres in 16 European countries. Men and women aged 50 years and over were recruited from population based sampling frames to participate in a prevalence survey of osteoporosis. Subjects were invited by post to attend for radiological screening and interview, and non-responders were followed up by repeat mailing. There was a substantial variation between centres in response rates: the mean was 49% and the range 5-83%. Adjusting for those known to have died or moved house did not affect the overall ranking. The response rates to each mailing also varied between centres: first mailing 45% (range 5-83%) and second mailing mean 10% (range 0-23%). The response rates varied in relation to age and sex and were higher in women than men. Rates fell gradually with age in women but rose in men until the age of 65 years. Response rates varied regionally. These were highest in countries from northern Europe and lowest in southern European countries, but there was wide variation both within regions and within countries. Multicentre, multinational studies within Europe will probably become increasingly popular. In this study, despite a standardised approach, the range in response rates between centres both within and between countries was substantial. Attempts at cross national standardisation in survey design can have only a limited effect on yielding uniformity in response.


Molecular characterization of diverse CIMMYT maize inbred lines from eastern and southern Africa using single nucleotide polymorphic markers.
Knowledge of germplasm diversity and relationships among elite breeding materials is fundamentally important in crop improvement. We genotyped 450 maize inbred lines developed and/or widely used by CIMMYT breeding programs in both Kenya and Zimbabwe using 1065 SNP markers to (i) investigate population structure and patterns of relationship of the germplasm for better exploitation in breeding programs; (ii) assess the usefulness of SNPs for identifying heterotic groups commonly used by CIMMYT breeding programs; and (iii) identify a subset of highly informative SNP markers for routine and low cost genotyping of CIMMYT germplasm in the region using uniplex assays. Genetic distance for about 94% of the pairs of lines fell between 0.300 and 0.400. Eighty four percent of the pairs of lines also showed relative kinship values ≤ 0.500. Model-based population structure analysis, principal component analysis, neighbor-joining cluster analysis and discriminant analysis revealed the presence of 3 major groups and generally agree with pedigree information. The SNP markers did not show clear separation of heterotic groups A and B that were established based on combining ability tests through diallel and line x tester analyses. Our results demonstrated large differences among the SNP markers in terms of reproducibility, ease of scoring, polymorphism, minor allele frequency and polymorphic information content. About 40% of the SNPs in the multiplexed chip-based GoldenGate assays were found to be uninformative in this study and we recommend 644 of the 1065 for low to medium density genotyping in tropical maize germplasm using uniplex assays. There were high genetic distance and low kinship coefficients among most pairs of lines, clearly indicating the uniqueness of the majority of the inbred lines in these maize breeding programs. The results from this study will be useful to breeders in selecting best parental combinations for new breeding crosses, mapping population development and marker assisted breeding.


Variation in perceptions of physical dominance and trustworthiness predicts individual differences in the effect of relationship context on women's preferences for masculine pitch in men's voices.
Several studies have found that women tend to demonstrate stronger preferences for masculine men as short-term partners than as long-term partners, though there is considerable variation among women in the magnitude of this effect. One possible source of this variation is individual differences in the extent to which women perceive masculine men to possess antisocial traits that are less costly in short-term relationships than in long-term relationships. Consistent with this proposal, here we show that the extent to which women report stronger preferences for men with low (i.e., masculine) voice pitch as short-term partners than as long-term partners is associated with the extent to which they attribute physical dominance and low trustworthiness to these masculine voices. Thus, our findings suggest that variation in the extent to which women attribute negative personality characteristics to masculine men predicts individual differences in the magnitude of the effect of relationship context on women's masculinity preferences, highlighting the importance of perceived personality attributions for individual differences in women's judgments of men's vocal attractiveness and, potentially, their mate preferences.


Loss of T cells influences sex differences in behavior and brain structure.
Clinical and animal studies demonstrate that immune-brain communication influences behavior and brain function. Mice lacking T cell receptor β and δ chains were tested in the elevated plus maze, open field, and light-dark test and showed reduced anxiety-like behavior compared to wild type. Interestingly sex differences were observed in the behavioural phenotype of TCRβ-/-δ- mice. Specifically, female TCRβ-/-δ- mice spent more time in the light chamber compared to wild type females, whereas male TCRβ-/-δ- spent more time in the center of the open field compared to wild type males. In addition, TCRβ-/-δ- mice did not show sex differences in activity-related behaviors observed in WT mice. Ex vivo brain imaging (7 Tesla MRI) revealed volume changes in hippocampus, hypothalamus, amygdala, periaqueductal gray, and dorsal raphe and other brain regions between wild type and T cell receptor knockout mice. There was also a loss of sexual dimorphism in brain volume in the bed nucleus of the stria terminalis, normally the most sexually dimorphic region in the brain, in immune compromised mice. These data demonstrate the presence of T cells is important in the development of sex differences in CNS circuitry and behavior.


BRAZILIAN GASTRIC CANCER ASSOCIATION GUIDELINES (PART 1): AN UPDATE ON DIAGNOSIS, STAGING, ENDOSCOPIC TREATMENT AND FOLLOW-UP.
The II Brazilian Consensus on Gastric Cancer by the Brazilian Gastric Cancer Association (ABCG) was recently published. On this occasion, several experts in gastric cancer expressed their opinion before the statements presented. To present the ABCG Guidelines (part 1) regarding the diagnosis, staging, endoscopic treatment and follow-up of gastric cancer patients. To forge these Guidelines, the authors carried out an extensive and current review regarding each statement present in the II Consensus, using the Medline/PubMed, Cochrane Library and SciELO databases with the following descriptors: gastric cancer, staging, endoscopic treatment and follow-up. In addition, each statement was classified according to the level of evidence and degree of recommendation. Of the 24 statements, two (8.3%) were classified with level of evidence A, 11 (45.8%) with B and 11 (45.8%) with C. As for the degree of recommendation, six (25%) statements obtained grade of recommendation 1, nine (37.5%) recommendation 2a, six (25%) 2b and three (12.5%) grade 3. The guidelines presented here are intended to assist professionals working in the fight against gastric cancer with relevant and current information, granting them to be applied in the daily medical practice.


Clinical burden of herpes simplex virus disease in people with human immunodeficiency virus.
Serologic studies indicate that herpes simplex virus (HSV)-1 and HSV-2 infections are highly prevalent among people infected with HIV. As an ulcerative genital disease, HSV may be important to HIV transmission and HIV-comorbidity. Routine clinical care of HSV in this population has not been described. Data were abstracted from medical records of HIV-infected individuals by the Adult/Adolescent Spectrum of HIV Disease Project. Clinician-documented HSV diagnosis and HSV treatment, defined as any prescription for acyclovir, valacyclovir, or famciclovir, were the outcomes of interest. We present descriptive statistics and trends in HSV diagnosis and treatment. Between 1989 and 2004, 61,299 people were followed in this study. HSV was diagnosed in 20% of the population, and 32% of the population received HSV antiviral prescriptions. Prescriptions for episodic treatment were given to 28% of patients, and 11% received prescriptions for suppressive therapy. The average annual rate of HSV diagnosis declined by 31% during the course of the study. Clinically recognized HSV infections were frequent despite declining rates of diagnosis. Providers should have a high index of suspicion for HSV and consider routine screening and suppressive therapy for patients at risk of clinical disease.


The association between the exacerbation of irritable bowel syndrome and menstrual symptoms in young Taiwanese women.
Studies of irritable bowel syndrome (IBS) have focused on the relationship between IBS and the menstrual cycle in Western societies. Specifically, an exacerbation of bowel symptoms, gas, distention, diarrhea, and constipation in the premenstrual and menstrual phases has been recognized among female IBS clients. Menstrual experience is culturally specific. Thus, the purpose of this study is to determine the prevalence rate of IBS in young Taiwanese women and to identify the most prevalent symptoms of IBS among this population. Moreover, this study explores the exacerbation of IBS during menses among young Taiwanese women. A cross-sectional survey was applied. A composite of validated questionnaires including the Modified Woods Daily Health Diary and Talley's Bowel Disease Questionnaire were administered to a stratified random sample of 971 female high school students in Taipei City, Taiwan. The results indicated that exacerbation of gastrointestinal symptoms during menstruation is present among young Taiwanese women with IBS. The IBS prevalence rate was 16.2% based on the Rome II criteria. Abdominal pain had the highest severity level, and bloating was ranked second among young Taiwanese women with IBS. These symptoms significantly increased in magnitude across time from postmenstrual to premenstrual to menses.


Analysis of spatio-temporal variations in stroke incidence and case-fatality in Hong Kong.
Geographical variations in stroke incidence and case-fatality have been documented worldwide. This study examines whether there are spatio-temporal variations in stroke incidence and case-fatality in Hong Kong and attempts to determine to what extent socioeconomic status (SES) and healthcare provision account for these variations. Residence-based hospital discharge data from the Hospital Authority (HA) in Hong Kong were geo-referenced and used to examine incidence rates and case-fatality rates by stroke subtype among the population aged 35 years and above in 1999-2007. Multilevel models were used to examine the spatio-temporal variations. Ischemic stroke incidence was found to decrease among those aged above 55 years, while hemorrhagic stroke incidence increased. Ischemic stroke case-fatality was found to decrease but hemorrhagic stroke case-fatality remained stable. For both subtypes, there were significant variations in stroke incidence and case-fatality across the districts of residence, but insignificant variations across HA service clusters. Only variations in ischemic stroke incidence and hemorrhagic stroke case-fatality at the district level could be partly explained by district-level SES. Identification of districts with higher risk for stroke incidence and case-fatality would help to formulate enhanced preventive measures. Future studies are needed to identify factors that contribute to the geographical variations.


Reconstructing long-term human impacts on plant communities: an ecological approach based on lake sediment DNA.
Paleoenvironmental studies are essential to understand biodiversity changes over long timescales and to assess the relative importance of anthropogenic and environmental factors. Sedimentary ancient DNA (sedaDNA) is an emerging tool in the field of paleoecology and has proven to be a complementary approach to the use of pollen and macroremains for investigating past community changes. SedaDNA-based reconstructions of ancient environments often rely on indicator taxa or expert knowledge, but quantitative ecological analyses might provide more objective information. Here, we analysed sedaDNA to investigate plant community trajectories in the catchment of a high-elevation lake in the Alps over the last 6400 years. We combined data on past and present plant species assemblages along with sedimentological and geochemical records to assess the relative impact of human activities through pastoralism, and abiotic factors (temperature and soil evolution). Over the last 6400 years, we identified significant variation in plant communities, mostly related to soil evolution and pastoral activities. An abrupt vegetational change corresponding to the establishment of an agropastoral landscape was detected during the Late Holocene, approximately 4500 years ago, with the replacement of mountain forests and tall-herb communities by heathlands and grazed lands. Our results highlight the importance of anthropogenic activities in mountain areas for the long-term evolution of local plant assemblages. SedaDNA data, associated with other paleoenvironmental proxies and present plant assemblages, appear to be a relevant tool for reconstruction of plant cover history. Their integration, in conjunction with classical tools, offers interesting perspectives for a better understanding of long-term ecosystem dynamics under the influence of human-induced and environmental drivers.


Serological procedure for the detection of antibodies to penicillin.
A hemagglutination technique for demonstrating antibodies to penicillin in sera from penicillin-allergic subjects is described. Erythrocytes coupled to penicillin T by means of bis-diazotized-benzidine constitute the "antigen" used to measure the antipenicillin antibody. The hemagglutination reaction is highly specific. as indicated by hemagglutination-inhibition studies. The clinical significance of these antibodies remains to be elucidated.


Synthesis and properties of oligo[n]cruciforms: nanosized sterically encumbered tetraethynylphenyl-homologated fluorophores.
A series of nanosized phenyleneethynylenes have been prepared which are sterically insulated from the surrounding environment by multiple functionalization with triisopropylsilyl (TIPS) substituents. The phenyleneethynylenes comprise oligo[n]cruciforms 1-4 (n = 3-5) and a dehydrotribenzo[12]annulene 5, the former of which possess para-acyclic and the latter ortho-cyclic electronic conjugation pathways. All compounds were characterized by (1)H and (13)C NMR, IR, and mass spectroscopic techniques. The X-ray crystal structure of 1 confirmed the sterically isolating properties of the TIPS substituents. A comparison of the physical properties of these electronically differing systems revealed that they were all luminescent upon UV irradiation displayed negligible aggregation in dilute solution and that particular members of the series studied were electrochemically active, undergoing facile reversible reductions. The phenyleneethynylenes also exhibited significantly enhanced thermal stability by virtue of the presence of the TIPS substituents. The properties of 1-5 suggest that they are promising building blocks for the construction of materials for novel molecular electronics applications.


Macromolecular adducts of ethylene oxide: a literature review and a time-course study on the formation of 7-(2-hydroxyethyl)guanine following exposures of rats by inhalation.
The results of efforts to identify and quantify macromolecular adducts of ethylene oxide (ETO), to determine the source and significance of background levels of these adducts, and to generate molecular dosimetry data on these adducts are reviewed. A time-course study was conducted to investigate the formation and persistence of 7-(2-hydroxyethyl)guanine (7-HEG; Fig. 1) in various tissues of rats exposed to ETO by inhalation, providing information necessary for designing investigations on the molecular dosimetry of adducts of ETO. Male F344 rats were exposed 6 h/day for up to 4 weeks (5 days/wk) to 300 ppm ETO by inhalation. Another set of rats was exposed for 4 weeks to 300 ppm ETO, and then killed 1-10 days after cessation of exposures. DNA samples from control and treated rats were analyzed for 7-HEG using neutral thermal hydrolysis, HPLC separation, and fluorescence detection. The adduct was detectable in all tissues of treated rats following 1 day of ETO exposure and increased approximately linearly for 3-5 days before the rate of increase began to level off. Concentrations of 7-HEG were greatest in brain, but the extent of formation was similar in all tissues studied. The adduct disappeared slowly from DNA, with an apparent half-life of approx. 7 days. The shape of the formation curve and the in vivo half-life indicate that 7-HEG will approach steady-state concentrations in rat DNA by 28 days of ETO exposure. The similarity in 7-HEG formation in target and nontarget tissues indicates that the tissue specificity for tumor induction is due to factors in addition to DNA-adduct formation.


Irreversible tubulointerstitial damage associated with chronic aminonucleoside nephrosis. Amelioration by angiotensin I converting enzyme inhibition.
Chronic aminonucleoside nephrosis is variably associated with tubulointerstitial damage, depending on the route and frequency of drug administration. Recently, different groups have shown this injurious tubulointerstitial process to be reversible, coinciding with the resolution of heavy proteinuria to normal values. The authors have previously shown that a single jugular intravenous administration of puromycin aminonucleoside (PA) to male Munich-Wistar rats produces a triphasic pattern of glomerular injury and proteinuria, which culminates in focal glomerulosclerosis 70 weeks after drug administration. The authors now report the later progression of the tubulointerstitial morphologic abnormalities associated with acute nephrosis (phase I), despite spontaneous resolution of glomerular injury during the intermediate period (phase II) in this model. Although treatment of rats with the angiotensin I converting enzyme inhibitor enalapril (50 mg/l drinking water) over the 70-week period did not affect the magnitude of proteinuria during the acute nephrotic phase, enalapril prevented the recurrence of proteinuria (phase III), as well as significantly reducing the severity of interstitial fibrosis, extent of tubular dilatation, and number of intratubular casts on semiquantitative scoring at the conclusion of the study. In addition, enalapril-treated rats had less low-molecular-weight protein excretion during the recurrent phase of proteinuria, suggesting a preservation of tubular functional capacity to reabsorb these proteins. In vitro cytotoxicity studies showed only the glomerular visceral epithelial cell to be sensitive to PA, in contrast with rat tubular epithelium and other cellular controls. Although the exact pathogenetic mechanism responsible for the development of the tubulointerstitial damage remains unknown, PA in vitro does not adversely affect rat tubular epithelium; there is however a clear correlation between the magnitude of recurrent proteinuria and the severity of tubulointerstitial morphologic abnormalities, as suggested by the beneficial effect of converting enzyme inhibition on both of these untoward processes.


Getting ready for climate change implications for the western USA.
Water users throughout the western United States have faced supply problems from the conception of modern civilization. Today, climate change, population growth, and declining water quality combine with the age-old problem of finding sufficient water resources in a region with a largely arid climate. Climate change in particular poses a significant threat to the sustainability of water supplies in the western United States (the West). Casting aside all debate about who and what is responsible for climate change, the public and water utilities alike must be prepared to address its effects on water supplies.


Internet gamblers: a latent class analysis of their behaviours and health experiences.
In order to learn about the behaviours and health experiences of people who gamble on the Internet, we conducted an international online survey with respondents recruited via gambling and gambling-related websites. The mean (SD) age of the 4,125 respondents completing the survey was 35.5 (11.8) years, with 79.1% being male and 68.8% UK residents. Respondents provided demographic details and completed validated psychometric screening instruments for problem gambling, mood disturbances, as well as alcohol and substance misuse, and history of deliberate self harm. We applied latent class analysis to respondents' patterns of regular online gambling activities, and identified subgroups of individuals who used the Internet to gamble in different ways (L (2) = 44.27, bootstrap P = 0.07). We termed the characteristic profiles as 'non-to-minimal gamblers'; 'sports bettors'; 'casino & sports gamblers'; 'lottery players'; and 'multi-activity gamblers'. Furthermore, these subgroups of respondents differed on other demographic and psychological dimensions, with significant inter-cluster differences in proportion of individuals scoring above threshold for problem gambling, mood disorders and substance misuse, and history of deliberate self harm (all Chi (2)s > 23.4, all P-values <0.001). The 'casino & sports' and 'multi-activity-gamblers' clusters had the highest prevalence of mental disorder. Internet gamblers appear to be heterogeneous but composed of several subgroups, differing markedly on both demographic and clinical characteristics.


Botulinum toxin potentiates cancer radiotherapy and chemotherapy.
Structural and functional abnormalities in the tumor vascular network are considered factors of resistance of solid tumors to cytotoxic treatments. To increase the efficacy of anticancer treatments, efforts must be made to find new strategies for transiently opening the tumor vascular bed to alleviate tumor hypoxia (source of resistance to radiotherapy) and improve the delivery of chemotherapeutic agents. We hypothesized that Botulinum neurotoxin type A (BoNT-A) could interfere with neurotransmitter release at the perivascular sympathetic varicosities, leading to inhibition of the neurogenic contractions of tumor vessels and therefore improving tumor perfusion and oxygenation. To test this hypothesis, BoNT-A was injected locally into mouse tumors (fibrosarcoma FSaII, hepatocarcinoma transplantable liver tumor), and electron paramagnetic resonance oximetry was used to monitor pO(2) in vivo repeatedly for 4 days. Additionally, contrast-enhanced magnetic resonance imaging was used to measure tumor perfusion in vivo. Finally, isolated arteries were mounted in wire myograph to monitor specifically the neurogenic tone developed by arterioles that were co-opted by the surrounding growing tumor cells. Using these tumor models, we showed that local administration of BoNT-A (two sites; dose, 29 units/kg) substantially increases tumor oxygenation and perfusion, leading to a substantial improvement in the tumor response to radiotherapy (20 Gy of 250-kV radiation) and chemotherapy (cyclophosphamide, 50 mg/kg). This observed therapeutic gain results from an opening of the tumor vascular bed by BoNT-A because we showed that BoNT-A could inhibit neurogenic tone in the tumor vasculature. The opening of the vascular bed induced by BoNT-A offers a way to significantly increase the response of tumors to radiotherapy and chemotherapy.


Precision Health: The Role of the Social and Behavioral Sciences in Advancing the Vision.
In 2015, Collins and Varmus articulated a vision for precision medicine emphasizing molecular characterization of illness to identify actionable biomarkers to support individualized treatment. Researchers have argued for a broader conceptualization, precision health. Precision health is an ambitious conceptualization of health, which includes dynamic linkages between research and practice as well as medicine, population health, and public health. The goal is a unified approach to match a full range of promotion, prevention, diagnostic, and treatment interventions to fundamental and actionable determinants of health; to not just address symptoms, but to directly target genetic, biological, environmental, and social and behavioral determinants of health. The purpose of this paper is to elucidate the role of social and behavioral sciences within precision health. Recent technologies, research frameworks, and methods are enabling new approaches to measure, intervene, and conduct social and behavioral science research. These approaches support three opportunities in precision health that the social and behavioral sciences could colead including: (a) developing interventions that continuously "tune" to each person's evolving needs; (b) enhancing and accelerating links between research and practice; and (c) studying mechanisms of change in real-world contexts. There are three challenges for precision health: (a) methods of knowledge organization and curation; (b) ethical conduct of research; and (c) equitable implementation of precision health. Precision health requires active coleadership from social and behavioral scientists. Prior work and evidence firmly demonstrate why the social and behavioral sciences should colead with regard to three opportunity and three challenge areas.


Pharmacology of immunosuppressive drugs.
Immunosuppressive therapy of solid organ transplantation has become more potent, effective and selective since the results of earlier use of prednisone and azathioprine post renal transplantation. Calcineurin inhibitors and mycophenolate mofetil have been important additions to the effective antirejection armamentarium. Today, cyclosporin, tacrolimus, azathioprine, mycophenolate and prednisone are all effective immunosuppressive agents and are the cornerstone of immunosuppressive protocols used posttransplant. However, the use of these agents is hindered by a 20% rate of rejection, lack of selectivity and a high rate of major adverse drug reactions which ultimately lead to a decrease in patient and graft survival. A number of clinical trials are underway to compare efficacy, safety and tolerability of different combination protocols to improve patient and allograft survival and decrease adverse drug reactions. Clinical knowledge of the pharmacology, pharmacokinetics, pharmacodynamics, adverse drug reactions and therapeutic drug monitoring of antirejection agents is essential for designing an effective immunosuppressive protocol for individual solid organ transplant recipients. The clinical application of pharmacotherapeutic principles into the clinical practice will improve both long-term patient and allograft survival while minimizing systemic toxicity of immunosuppressive drugs.


Quantifying long-term plant community dynamics with movement models: implications for ecological resilience.
Quantification of rates and patterns of community dynamics is central for understanding the organization and function of ecosystems. These insights may support a greater empirical understanding of ecological resilience, and the application of resilience concepts toward ecosystem management. Distinct types of dynamics in natural communities can be used to interpret and apply resilience concepts, but quantitative methods that can systematically distinguish among them are needed. We develop a quantitative method to analyze long-term records of plant community dynamics using principles of movement ecology. We analyzed dissimilarity of species composition through time with linear and nonlinear statistical models to assign community change to four classes of movement trajectories. Compositional change in each sampled plot through time was classified into four classes, stability, abrupt nonlinear change, transient reversible change, and gradual linear drift, each representing a different aspect of ecological resilience. These competing models were evaluated based on estimated coefficients, goodness of fit, and parsimony. We tested our method's accuracy and robustness through simulations, or the ability to distinguish among trajectories and classify them correctly. We simulated 16,000 trajectories of four types, of which 94-100% were correctly classified. Next, we analyzed 13 long-term vegetation records from North American grasslands (annual grasslands with warm-season and cool-season communities, shortgrass, mixedgrass, and tallgrass prairies, and sagebrush steppe), and a record of primary succession at Mt. St. Helens volcano. Collectively, we analyzed 14,647 observations from 775 plots, between 1915 and 2012. Dynamics could be reliably assigned for 705 plots (91%), and overall statistical fit was high (goodness of fit, 0.77 ± 0.15 SD). Among the perennial grasslands, stability was most common (44% of all plots), followed by gradual linear (22%), abrupt nonlinear (17%), and reversible (6%) change. Among annual grasslands, abrupt nonlinear shifts (33%) were more common in the warm-season community than in the cool-season (20%). As expected, abrupt nonlinear change was common during primary succession (51%) while reversible change was rare (3%). Generally, reversible dynamics often required 2-3 decades. Analysis of long-term community change, or trajectories, with principles of movement ecology provides a quantitative basis to compare and interpret ecological resilience within and among ecosystems.


Circulating APRIL levels are correlated with advanced disease and prognosis in rectal cancer patients.
We have previously shown that the tumor necrosis factor family member a proliferation-inducing ligand (APRIL) enhances intestinal tumor growth in various preclinical tumor models. Here, we have investigated whether APRIL serum levels at time of surgery predict survival in a large cohort of colorectal cancer (CRC) patients. We measured circulating APRIL levels in a cohort of CRC patients (n=432) using a novel validated monoclonal APRIL antibody (hAPRIL.133) in an enzyme-linked immunosorbent assay (ELISA) setup. APRIL levels were correlated with clinicopathological features and outcome. Overall survival was examined with Kaplan-Meier survival analysis, and Cox proportional hazards ratios were calculated. We observed that circulating APRIL levels were normally distributed among CRC patients. High APRIL expression correlated significantly with poor outcome measures, such as higher stage at presentation and development of lymphatic and distant metastases. Within the group of rectal cancer patients, higher circulating APRIL levels at time of surgery were correlated with poor survival (log-rank analysis P-value 0.008). Univariate Cox regression analysis for overall survival in rectal cancer patients showed that patients with elevated circulating APRIL levels had an increased risk of poor outcome (hazard ratio (HR) 1.79; 95% confidence interval (CI) 1.16-2.76; P-value 0.009). Multivariate analysis in rectal cancer patients showed that APRIL as a prognostic factor was dependent on stage of disease (HR 1.25; 95% CI 0.79-1.99; P-value 0.340), which was related to the fact that stage IV rectal cancer patients had significantly higher levels of APRIL. Our results revealed that APRIL serum levels at time of surgery were associated with features of advanced disease and prognosis in rectal cancer patients, which strengthens the previously reported preclinical observation of increased APRIL levels correlating with disease progression.