Effect of priming time on tensile bond strength to bovine teeth and morphologic structure of interfaces created by self-etching primers.
The purpose of this study was to investigate the effect of priming time on bovine enamel and dentin adhesion promoted by self-etching primer systems. Two commercial self-etching primer systems, Clearfil SE Bond (SE) and Unifil Bond (UB), were used. Bovine enamel and dentin were treated with each system with various priming times (5, 20, and 60 seconds), and the tensile bond strength was measured. Scanning electron microscopic (SEM) observation was also performed to examine the effect of priming time on the morphology of the resin-tooth interface. The tensile bond strength to enamel ranged from 10.6 to 14.3 MPa, and no statistically significant difference was detected among products or priming times. To dentin, UB showed the statistically significantly lowest tensile bond strength when primed for 5 seconds, 6.9 +/- 1.1 MPa, but there was no significant difference between the groups primed for 20 and 60 seconds, 13.5 +/- 4.1 MPa and 13.8 +/- 4.6 MPa, respectively. SE created tensile bond strengths ranging from 13.9 to 15.7 MPa and showed no effect of priming time on dentin adhesion. SEM observation revealed that resin penetrated into both enamel and dentin more deeply with extension of priming time. Priming times longer than those recommended by the manufacturers did not influence the tensile bond strength to enamel and dentin when using two commercial self-etching primers. In contrast, a shortened priming time, 5 seconds, carried a risk of decreasing dentin adhesion, although it had no adverse effect on enamel adhesion.


Sexually transmitted infections, benign prostatic hyperplasia and lower urinary tract symptom-related outcomes: results from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.
To examine whether a history of sexually transmitted infections (STIs) or positive STI serology is associated with prevalent and incident benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS)-related outcomes in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Self-reported history of STIs (gonorrhoea, syphilis) was ascertained at baseline, and serological evidence of STIs (Chlamydia trachomatis, Trichomonas vaginalis, human papillomavirus (HPV)-16, HPV-18, herpes simplex virus type 2, human herpesvirus type 8 and cytomegalovirus) was detected in baseline serum specimens. We used data collected on the baseline questionnaire, as well as results from the baseline prostate-specific antigen (PSA) test and digital rectal examination (DRE), to define prevalent BPH/LUTS-related outcomes as evidence of LUTS (self-reported diagnosis of an enlarged prostate/BPH, BPH surgery or nocturia [waking ≥2 times/night to urinate]) and evidence of prostate enlargement (PSA > 1.4 ng/mL or prostate volume ≥30 mL) in men without prostate cancer. We created a similar definition of incident BPH using data from the follow-up questionnaire completed 5-13 years after enrolment (self-reported diagnosis of an enlarged prostate/BPH or nocturia), data on finasteride use during follow-up, and results from the follow-up PSA tests and DREs. We used Poisson regression with robust variance estimation to calculate prevalence ratios (PRs) in our cross-sectional analysis of self-reported (n = 32 900) and serologically detected STIs (n = 1 143) with prevalent BPH/LUTS, and risk ratios in our prospective analysis of self-reported STIs with incident BPH/LUTS (n = 5 226). Generally null results were observed for associations of a self-reported history of STIs and positive STI serologies with prevalent and incident BPH/LUTS-related outcomes, with the possible exception of T. vaginalis infection. This STI was positively associated with prevalent nocturia (PR 1.36, 95% confidence interval (CI) 1.18-1.65), prevalent large prostate volume (PR 1.21 95% CI 1.02-1.43), and any prevalent BPH/LUTS (PR 1.32 95% CI 1.09-1.61); too few men had information on both STI serologies and incident BPH/LUTS to investigate the associations between T. vaginalis infection and incident BPH/LUTS-related outcomes. Our findings do not support associations of several known STIs with BPH/LUTS-related outcomes, although T. vaginalis infection may warrant further study.


Expanded newborn screening: reducing harm, assessing benefit.
Achieving the goals of newborn screening is, as for any screening, a balancing act: getting the maximum benefit from screening while producing the minimum harm. The advent of "expanded" newborn screening, with a large number of disorders detectable using a single test, has also posed problems, not new, but now more obvious. One is the finding of many more cases by screening, the extra cases being largely patients who have attenuated phenotypes and may remain asymptomatic for many years, even throughout life. These may or may not require active management in the short term, but do need lifelong awareness. Additionally, disorders have been included that are now thought benign or largely so. Babies risk being unnecessarily medicalized. Assessing outcome has also proved difficult because of the rarity of some disorders and the impracticality of randomized controlled trials. The requirements for valid studies include the need for case definitions, comparable comparison groups and probably assessment on a whole-population basis. An Australia-wide study of tandem mass spectrometry newborn screening involving 2 million screened and unscreened babies has demonstrated benefits overall to screened patients at age 6 years. The study was too small to provide conclusions for individual disorders other than for medium-chain acyl-CoA dehydrogenase deficiency.


Potential health impacts of changes in air pollution exposure associated with moving traffic into a road tunnel.
A planned 21 km bypass (18 km within a tunnel) in Stockholm is expected to reduce ambient air exposure to traffic emissions, but same time tunnel users could be exposed to high concentrations of pollutants. For the health impacts calculations in 2030, the change in annual ambient NOX and PM10 exposure of the general population was modelled in 100 × 100 m(2) grids for Greater Stockholm area. The tunnel exposure was estimated based on calculated annual average NOX concentrations, time spent in tunnel and number of tunnel users. For the general population, we estimate annually 23.7 (95% CI: 17.7-32.3) fewer premature deaths as ambient concentrations are reduced. At the same time, tunnel users will be exposed to NOX levels up to 2000 μg/m(-3). Passing through the whole tunnel two times on working days would correspond to an additional annual NOX exposure of 9.6 μg/m(3). Assuming that there will be ~55,000 vehicles daily each way and 1.3 persons of 30-74 years of age in each vehicle, we estimate the tunnel exposure to result in 20.6 (95% CI: 14.1-25.6) premature deaths annually. If there were more persons per vehicle, or older and vulnerable people travelling, or tunnel dispersion conditions worsen, the adverse effect would become larger.


Coumarins and Coumarin-Related Compounds in Pharmacotherapy of Cancer.
Cancer is one of the most common causes of disease-related deaths worldwide. Despite the discovery of many chemotherapeutic drugs that inhibit uncontrolled cell division processes for the treatment of various cancers, serious side effects of these drugs are a crucial disadvantage. In addition, multi-drug resistance is another important problem in anticancer treatment. Due to problems such as cytotoxicity and drug resistance, many investigations are being conducted to discover and develop effective anticancer drugs. In recent years, researchers have focused on the anticancer activity coumarins, due to their high biological activity and low toxicity. Coumarins are commonly used in the treatment of prostate cancer, renal cell carcinoma and leukemia, and they also have the ability to counteract the side effects caused by radiotherapy. Both natural and synthetic coumarin derivatives draw attention due to their photochemotherapy and therapeutic applications in cancer. In this review, a compilation of various research reports on coumarins with anticancer activity and investigation and a review of structure-activity relationship studies on coumarin core are presented. Determination of important structural features around the coumarin core may help researchers to design and develop new analogues with a strong anticancer effect and reduce the potential side effects of existing therapeutics.


Prevalence [correction of prevalance] of functional blindness, visual impairment, and related functional deficits among elderly Mexican Americans.
This report describes the prevalence and correlates of functional blindness and visual impairment among older Mexican Americans, using data on 2800 respondents from the Hispanic Established Populations for the Epidemiological Study of the Elderly. Bivariate and multivariate logistic regression analyses were used to examine the associations between corrected bilateral distant vision and sociodemographic characteristics, selected health conditions, self-reported health status, health care utilization, and functional dependence on the basis of assistance needed for basic and instrumental activities of daily living (ADLs). Using a modified Snellen test for distance visual acuity, 5% of older Mexican Americans were found to be functionally blind, and 13.5% were found to be visually impaired. Vision loss was significantly associated with older age, lower education, hypertension, diabetes, poor self-rated health, and hospitalization during the year prior to the interview. Over 50% of functionally blind subjects required assistance with at least one basic ADL, compared with 15% of those who were visually impaired and 8% of those who were not visually impaired. The prevalence of functional blindness in this sample of elderly Mexican Americans was higher than reported for the general elderly population, yet they also have higher rates of adequate vision because of the low prevalence of visual impairment. The results suggest a need for more research on the prevalence and impact of functional blindness and visual impairment on the health of older Mexican Americans.


Atypical angiopoietin-like protein that regulates ANGPTL3.
Angiopoietin-like proteins (ANGPTLs) play major roles in the trafficking and metabolism of lipids. Inactivation of ANGPTL3, a gene located in an intron of DOCK7, results in very low levels of LDL-cholesterol (C), HDL-C and triglyceride (TAG). We identified another ANGPTL family member, ANGPTL8, which is located in the corresponding intron of DOCK6. A variant in this family member (rs2278426, R59W) was associated with lower plasma LDL-C and HDL-C levels in three populations. ANGPTL8 is expressed in liver and adipose tissue, and circulates in plasma of humans. Expression of ANGPTL8 was reduced by fasting and increased by refeeding in both mice and humans. To examine the functional relationship between the two ANGPTL family members, we expressed ANGPTL3 at physiological levels alone or together with ANGPTL8 in livers of mice. Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3. ANGPTL8 coimmunoprecipitated with the N-terminal domain of ANGPTL3 in plasma of these mice. In cultured hepatocytes, ANGPTL8 expression increased the appearance of N-terminal ANGPTL3 in the medium, suggesting ANGPTL8 may activate ANGPTL3. Consistent with this scenario, expression of ANGPTL8 in Angptl3(-/-) mice failed to promote hypertriglyceridemia. Thus, ANGPTL8, a paralog of ANGPTL3 that arose through duplication of an ancestral DOCK gene, regulates postprandial TAG and fatty acid metabolism by controlling activation of its progenitor, and perhaps other ANGPTLs. Inhibition of ANGPTL8 provides a new therapeutic strategy for reducing plasma lipoprotein levels.


Familial atrial tachyarrhythmia with short PR interval.
A family had an unusual and perhaps unique familial dysrhythmia. The proband had a short PR interval with normal QRS and chronic recurrent paroxysmal atrial tachycardia (Lown-Ganong-Levine syndrome). The arrhythmia produced left ventricular dysfunction. Both paroxysmal atrial tachycardia (PAT) and left ventricular dysfunction were reversed with administration of digoxin and propranolol hydrochloride. Three family members had paroxysmal or chronic atrial fibrillation, first diagnosed at a relatively young age (23 years, 38 years, and early 40s, respectively). Five additional family members had short PR intervals with normal QRS, and eight other family members had borderline short PR intervals. The mode of inheritance appeared to be autosomal dominant with varying expressivity. We have described a familial syndrome characterized by PAT or atrial fibrillation in its advanced form with short PR interval as a possible identifying trait. The future course of members with isolated short PR is unknown.


Ultraviolet and visible imaging and spectrographic imaging instrument.
The Ultraviolet and Visible Imaging and Spectrographic Imaging experiment consists of five spectrographic imagers and four imagers. These nine sensors provide spectrographic and imaging capabilities from 110 to 900 nm. The spectrographic imagers share an off-axis design in which selectable slits alternate fields of view (1.00° × 0.10° or 1.00° × 0.05°) and spectral resolutions between 0.5 and 4 nm. Image planes of the spectrographic imager have a programmable spectral dimension with 68, 136, or 272 pixels across each individual spectral band, and a programmable spatial dimension with 5, 10, 20, or 40 pixels across the 1° slit length. A scan mirror sweeps the slit through a second spatial dimension to generate a 1° × 1° spectrographic image once every 5, 10, or 20 s, depending on the scan rate. The four imagers provide narrow-field (1.28° × 1.59°) and wide-field (10.5° × 13.1°) viewing. Each imager has a six-position filter wheel that selects various spectral regimes and neutral densities. The nine sensors ut lize intensified CCD detectors that have an intrascene dynamic range of ~ 10(3) and an interscene dynamic range of ~ 10(5); neutral-density filters provide an additional dynamic range of ~ 10(2-3). The detector uses an automatic gain control that permits the sensors to adjust to scenes of varying intensity. The sensors have common boresights and can operate separately, simultaneously, or synchronously. To be launched aboard the Midcourse Space Experiment spacecraft in the mid-1990's, the ultraviolet and visible imaging and spectrographic imaging instrument will investigate a multitude of celestial, atmospheric, and point sources during its planned 4-yr life.


Oral manifestations of viral infections in immunocompromised patients.
Viral infections are a significant cause of morbidity and mortality in immunosuppressed patients. It is clear that diseases or medical treatments that have cytostatic or cytotoxic effects on lymphocytes and disrupt cytokine production or activity increase the risk of viral infections. While the rate of viral infection varies with the nature and degree of immunosuppression, it is clear that reactivation of latent virus is the most important determinant of the types of viral infections most frequently noted in immunosuppressed patients result from the reactivation of latent virus. Herpesviruses account for the majority of oral viral infections. Herpes simplex virus, varicella-zoster virus, and Epstein-Barr virus infections nearly always result from reactivation of latent virus, while cytomegalovirus infections, besides presenting as reactivated disease, are almost as likely to present as a primary infection in susceptible hosts. Other viral pathogens potentially of concern in immunocompromised patients are enteric viruses (adenoviruses and coxsackieviruses), human papillomaviruses, and possibly the recently identified human herpesvirus type 6. Ninety-eight percent of herpes simplex virus lesions are caused by reactivated disease and tend to be characterized by large, very painful ulcerative lesions throughout the mouth. Varicella-zoster virus is also rarely seen as primary infection, and the herpes zoster lesions involving cranial nerves can cause significant morbidity, including postherpetic neuralgia, corneal scarring, cranial nerve palsies, and deafness. Distinct oral ulcerative lesions caused by Epstein-Barr virus and cytomegalovirus have only recently been described in detail and are usually associated with disseminated disease. Oral human papillomavirus lesions are noted as warts and condylomas. The contribution of enteric viruses and human herpesvirus type 6 to oral disease in immunosuppressed patients is yet to be determined.


Maternal environmental risk factors and the development of internalizing and externalizing problems in childhood: The complex role of genetic factors.
The development of problem behavior in children is associated with exposure to environmental factors, including the maternal environment. Both are influenced by genetic factors, which may also be correlated, that is, environmental risk and problem behavior in children might be influenced by partly the same genetic factors. In addition, environmental and genetic factors could interact with each other increasing the risk of problem behavior in children. To date, limited research investigated these mechanisms in a genome-wide approach. Therefore, the goal of this study was to investigate the association between genetic risk for psychiatric and related traits, as indicated by polygenetic risk scores (PRSs), exposure to previously identified maternal risk factors, and problem behavior in a sample of 1,154 children from the Amsterdam Born Children and their Development study at ages 5-6 and 11-12 years old. The PRSs were derived from genome-wide association studies (GWASs) on schizophrenia, major depressive disorder, neuroticism, and wellbeing. Regression analysis showed that the PRSs were associated with exposure to multiple environmental risk factors, suggesting passive gene-environment correlation. In addition, the PRS based on the schizophrenia GWAS was associated with externalizing behavior problems in children at age 5-6. We did not find any association with problem behavior for the other PRSs. Our results indicate that genetic predispositions for psychiatric disorders and wellbeing are associated with early environmental risk factors for children's problem behavior.


One universal common endpoint in mouse models of amyotrophic lateral sclerosis.
There is no consensus among research laboratories around the world on the criteria that define endpoint in studies involving rodent models of amyotrophic lateral sclerosis (ALS). Data from 4 nutrition intervention studies using 162 G93A mice, a model of ALS, were analyzed to determine if differences exist between the following endpoint criteria: CS 4 (functional paralysis of both hindlimbs), CS 4+ (CS 4 in addition to the earliest age of body weight loss, body condition deterioration or righting reflex), and CS 5 (CS 4 plus righting reflex >20 s). The age (d; mean ± SD) at which mice reached endpoint was recorded as the unit of measurement. Mice reached CS 4 at 123.9±10.3 d, CS 4+ at 126.6±9.8 d and CS 5 at 127.6±9.8 d, all significantly different from each other (P<0.001). There was a significant positive correlation between CS 4 and CS 5 (r = 0.95, P<0.001), CS 4 and CS 4+ (r = 0.96, P<0.001), and CS 4+ and CS 5 (r = 0.98, P<0.001), with the Bland-Altman plot showing an acceptable bias between all endpoints. Logrank tests showed that mice reached CS 4 24% and 34% faster than CS 4+ (P = 0.046) and CS 5 (P = 0.006), respectively. Adopting CS 4 as endpoint would spare a mouse an average of 4 days (P<0.001) from further neuromuscular disability and poor quality of life compared to CS 5. Alternatively, CS 5 provides information regarding proprioception and severe motor neuron death, both could be important parameters in establishing the efficacy of specific treatments. Converging ethics and discovery, would adopting CS 4 as endpoint compromise the acquisition of insight about the effects of interventions in animal models of ALS?


Conservation of short patches of amino acid sequence amongst proteins with a common function but evolutionarily distinct origins: implications for cloning genes and for structure-function analysis.
Small patches of identical amino acid sequences commonly occur in proteins that have the same function but are derived from evolutionarily distant organisms. Reverse translation of such patches into degenerate pools of oligonucleotides provide useful hybridization probes for cloning the gene for the corresponding protein from other organisms. Since the conserved patches of identical amino acid sequence are probably important for the protein's biological function, they are preferred targets for reverse genetic studies aimed at defining structure-function relationships.


Patient-related beliefs and adherence toward their medications among the adult hypertensive outpatients in Tanzania.
Hypertension is a leading global health problem requiring lifelong treatment. However, adherence to antihypertensive medicines is a problem, greater among developing countries. Consequently, there is a need to determine current adherence rates and their associations among developing countries to plan future initiatives. Cross-sectional study among adult outpatients with essential hypertension in Tanzania. Predesigned questionnaires were used to gather information on adherence rates and patient-related beliefs. The main outcome measure was adherence. A total of 180 participants were included, with females making up 65%. High-adherence rates were seen in 54% of the patients. Patients' belief about their medication and its necessity was higher in the high adherent group and concerns about their medicines and their necessity were higher in the low adherent group. Conclusion & recommendations: Adherence rates were low compared with a suggested level ≥80%. Educational initiatives are needed to address knowledge and concerns with hypertension to improve future outcomes.


Considering climate and conflict conditions together to improve interventions that prevent child acute malnutrition.
Despite early warning signs about threats to food security, humanitarian interventions often lag behind these warning signs. Climate and conflict conditions are among the most important factors preceding food system failures and malnutrition crises around the world. Research shows how conflict and climate conditions can upend functional food and economic systems, but this research does not address the severe health impacts of these conditions on infants and young children. Translating quantitative research findings into humanitarian interventions requires geographical detail, resulting in location-specific alerts of risks of food insecurity. We describe how the use of readily available, spatially referenced quantitative data can support targeted interventions for nutrition resiliency. Effective humanitarian programmes for targeted nutrition interventions require real-time datasets on food security drivers and models that can provide actionable guidance to mitigate negative impacts of conflict and climate conditions on the people most susceptible to food insecurity. Although treatment of acute malnutrition is important, treating existing malnutrition is not enough. Instead, action to prevent acute malnutrition should be taken to minimise suffering and to maximise wellbeing, particularly in contexts prone to worsening climate and conflict conditions.


Modulating pathological oscillations by rhythmic non-invasive brain stimulation-a therapeutic concept?
A large amount of studies of the last decades revealed an association between human behavior and oscillatory activity in the human brain. Alike, abnormalities of oscillatory activity were related with pathological behavior in many neuropsychiatric disorders, such as in Parkinson's disease (PD) or in schizophrenia (SCZ). As a therapeutic tool, non-invasive brain stimulation (NIBS) has demonstrated the potential to improve behavioral performance in patients suffering from neuropsychiatric disorders. Since evidence accumulates that NIBS might be able to modulate oscillatory activity and related behavior in a scientific setting, this review focuses on discussing potential interventional strategies to target abnormalities in oscillatory activity in neuropsychiatric disorders. In particular, we will review oscillatory changes described in patients after stroke, with PD or suffering from SCZ. Potential ways of targeting interventionally the underlying pathological oscillations to improve related pathological behavior will be further discussed.


Strain and scattering related spectral output of 1.3microm InGaAsP semiconductor diode lasers.
A correlation between the spectral output of 1.3 microm InGaAsP semiconductor diode lasers and the distribution along the length and width of the active region of strain and scattering centers is reported. The strain and scattering center distributions in the active region were obtained by measuring and analyzing the spatially resolved and polarization resolved electroluminescence along the active region of the lasers. Measurements were made on gain-guided, planar buried heterostructure, and arrowhead buried crescent lasers. The results suggest that the material properties of the laser structure affect the longitudinal mode spectrum.


Towards detection and identification of circulating tumour cells using Raman spectroscopy.
Body fluids are easily accessible and contain valuable indices for medical diagnosis. Fascinating tools are tumour cells circulating in the peripheral blood of cancer patients. As these cells are extremely rare, they constitute a challenge for clinical diagnostics. In this contribution we present the Raman spectroscopic-based identification of different single cells in suspension that are found in peripheral blood of cancer patients including healthy cells like leukocytes and erythrocytes, and tumour cells like leukaemic cells and cells originating from solid tumours. Leukocytes and erythrocytes were isolated from the peripheral blood of healthy donors while myeloid leukaemia cells (OCI-AML3) and breast carcinoma derived cells (MCF-7, BT-20) were obtained from cell cultures. A laser emitting 785 nm light was used for optical trapping the single cells in the laser focus and to excite the Raman spectrum. Support vector machines were applied to develop a supervised classification model with spectra of 1210 cells originating from three different donors and three independent cultivation batches. Distinguishing tumour cells from healthy cells was achieved with a sensitivity of >99.7% and a specificity of >99.5%. In addition, the correct cell types were predicted with an accuracy of approximately 92%.


Systems biology approaches for inflammatory bowel disease: emphasis on gut microbial metabolism.
Although the prevalence of main idiopathic forms of inflammatory bowel disease (IBD) has risen considerably over the last decades, their clinical features do not allow accurate prediction of prognosis, likelihood of disease progression, or response to specific therapy. Through a better understanding of the molecular pathways involved in IBD and the promise of more targeted therapies, the personalized approach to the management of IBD shows potential. To achieve this, there remains a significant need to better understand the disease process at cellular and molecular levels for any given individual with IBD. The complexity of biological functional networks behind the etiology of IBD highlights the need for their comprehensive analysis. In this, omics technologies can generate a systemic view of IBD pathogenesis on which to base novel, multiple pathway-integrated therapies. Omics sciences have just started to contribute here by generating gene, protein expression, metabolite data at global level and large scale, and more recently by offering new opportunities to explore gut functional ecology. In particular, there is much expectation regarding the putative role of the gut microbiome in IBD. No doubt it will provide additional insights and lead to the development of alternative, hopefully better, diagnostic, prognostic, and monitoring tools in the management of IBD. This review discusses perspectives of relevance to clinical translation with emphasis on gut microbial metabolic activities.


A new biology for a new century.
Biology today is at a crossroads. The molecular paradigm, which so successfully guided the discipline throughout most of the 20th century, is no longer a reliable guide. Its vision of biology now realized, the molecular paradigm has run its course. Biology, therefore, has a choice to make, between the comfortable path of continuing to follow molecular biology's lead or the more invigorating one of seeking a new and inspiring vision of the living world, one that addresses the major problems in biology that 20th century biology, molecular biology, could not handle and, so, avoided. The former course, though highly productive, is certain to turn biology into an engineering discipline. The latter holds the promise of making biology an even more fundamental science, one that, along with physics, probes and defines the nature of reality. This is a choice between a biology that solely does society's bidding and a biology that is society's teacher.


The temporal binding deficit hypothesis of autism.
Frith has argued that people with autism show "weak central coherence," an unusual bias toward piecemeal rather than configurational processing and a reduction in the normal tendency to process information in context. However, the precise cognitive and neurological mechanisms underlying weak central coherence are still unknown. We propose the hypothesis that the features of autism associated with weak central coherence result from a reduction in the integration of specialized local neural networks in the brain caused by a deficit in temporal binding. The visuoperceptual anomalies associated with weak central coherence may be attributed to a reduction in synchronization of high-frequency gamma activity between local networks processing local features. The failure to utilize context in language processing in autism can be explained in similar terms. Temporal binding deficits could also contribute to executive dysfunction in autism and to some of the deficits in socialization and communication.


The cellular analog of sensitization in Aplysia emerges at the same time in development as behavioral sensitization.
Recent studies examining the development of learning and memory in the gill and siphon withdrawal reflex of Aplysia have shown that different forms of learning emerge according to very different developmental timetables. For example, in the previous paper, Rankin and Carew (1988) showed that, whereas habituation and dishabituation emerge early in juvenile development (in stages 9 and 10, respectively), sensitization emerges at least 60 d later (in late stage 12). This developmental separation of different learning processes provides the opportunity to examine the unique contribution of specific cellular mechanisms to each form of learning. As a first step in this cellular analysis, in the present paper we have examined the development of the cellular analog of sensitization (facilitation of nondecremented EPSPs) in the identified giant neuron R2, which can serve as a monitor of the afferent input in the gill and siphon withdrawal reflex (Rayport and Camardo, 1984). We have found 2 striking parallels between the development of behavioral sensitization and the development of its cellular analog: (1) Behavioral sensitization, produced by tail shock, emerges very late in juvenile development (stage 12), and the cellular analog of sensitization (produced by activation of the tail pathway) emerges by exactly the same late juvenile stage; (2) prior to the emergence of behavioral sensitization, tail shock unexpectedly was found to produce significant reflex depression (Rankin and Carew, 1988), and prior to the emergence of the cellular analog of sensitization, activation of the tail pathway was found to produce significant depression of the synaptic input in the reflex pathway. Thus, the cellular analog of sensitization in the CNS develops and matures in close temporal register with the development of behavioral sensitization in juvenile Aplysia.


Complications and outcomes of JJ stenting of the ureter in urological practice: A single-centre experience.
To determine the factors affecting the development of complications and the outcomes of JJ stenting. The study included 220 patients (133 males and 87 females, mean age 39.5 years, SD 15.4) who had self-retaining JJ ureteric stents placed while in the authors' institution. Univariate and multivariate analyses were used to identify the significant variables affecting the development of complications and outcome of stenting (condition 'improved' or 'not improved'). Using a modified Clavien classification, there were grade I, II, IIIa, IIIb complications in 67 (30.4%), 39 (17.7%), two (0.9%) and 23 (10.5%) patients, respectively, and none of grades IVa, IVb and V. Loin pain (10.9%) and urinary tract infection (10.9%) were the most common complications, followed by dysuria (7.7%). There were significant complications requiring treatment in 29% of patients, and 71.4% of patients improved after stenting. On multivariate analysis the significant independent factor affecting the complication rate was the stent length (P = 0.016), and the significant independent factor affecting the 'improved' outcome was age (P = 0.014). Longer stents are associated with increased complication rates, and the older the patient the more likely they are to have a poor outcome after stenting. Future prospective multicentre studies with more patients are needed to confirm the present conclusions.


Disposition of valproic acid in the rat: dose-dependent metabolism, distribution, enterohepatic recirculation and choleretic effect.
A specific gas chromatographic assay has been developed for measurement of valproic acid (VPA) and its major conjugated metabolites. In rats given single intravenous doses, the decline in blood concentration of VPA was dose-dependent and followed first-order kinetics only at the lowest dose. The time required for the maximum concentration of VPA, after completion of the brief distribution phase, to decline by 50% was 11.7, 41 and 125 min at doses of 15, 150 and 600 mg of NaVPA per kg, respectively. A secondary increase in drug concentration, abolished by exteriorization of the bile, was observed in all intact rats with all doses. Some 45 to 55% of the dose appeared in the bile in 5 hr as VPA glucuronide. Urinary excretion of VPA glucuronide in intact animals accounted for 23 and 51% of the 15 and 150 mg/kg doses, respectively. Tissue distribution studies in rats sacrificed 20 and 90 min after dosage with [14C] NaVPA (150 mg/kg) showed that the drug concentration was highest in blood, moderate in liver, kidney, heart and lung and low in brain, fat, testis and skeletal muscle. During this interval the drug concentration declined in all tissues, whereas the total conjugated metabolites in the small intestine increased from 7 to 28% of the administered dose. The large intestine contained 30 times as much free drug as conjugate. Reabsorption of free VPA, released by hydrolysis of conjugate in the large bowel, accounted for the secondary rise in concentration of VPA observed in blood after single doses. The major urinary metabolites, VPA-glucuronide and 2-n-propylgutaric acid, were identified by gas chromatography/chemical ionization mass spectrometry. Sodium VPA caused a dose-dependent stimulation of bile flow, the magnitude and duration of which closely followed the blood concentration of VPA.


Marketization in Crisis: The Political Economy of COVID-19 and the Unmaking of Public Transport in Stockholm.
While measures to prevent the spread of COVID-19 disturbed both global and local markets, some commentators also argued that the pandemic could be seen as the beginning of the end of neoliberalism. Although neoliberal reforms have come under pressure, little is known about the implications of COVID-19 in or across specific sectors. Scaling down the rich theoretical-historical debates about neoliberalism to the regional level, we study the impact of COVID-19 on the marketized public transport system in Stockholm, Sweden. During COVID-19, ridership dropped as did ticket revenues, which put the market under operational and financial distress. Drawing on a discussion of the norms and techniques of marketization, we probe how the contracted bus operators responded to the pandemic, how they tried to save the market from collapsing, and whether the measures taken suggest an organized move away from neoliberal policies. Adding to recent debates of COVID-19 and neoliberalism's longevity, we conclude that although the norms underpinning marketization remained unquestioned, the techniques were partly re-evaluated in the midst of the global crisis as a way to protect the established neoliberal policies from falling apart.


Mixed connective tissue disease.
Three patients with mixed connective tissue disease (MCTD) had clinical features that included a high incidence of Raynaud phenomenon, arthritis, myositis, and swollen hands. The diagnostic laboratory test result was the presence of high titers of antibody to extractable nuclear antigen. These antibody titers are notably reduced or abolished in patients with MCTD when the tanned red blood cells that are used in the test are pretreated with ribonuclease. Speckled antinuclear antibodies were present in all patients. Patients with MCTD have a low incidence of renal disease, are responsive to treatment with prednisone, and have a good prognosis.


Dynamic switching of the chiral beam on the spiral plasmonic bull's eye structure [Invited].
A polarization-dependent switchable plasmonic beaming structure composed of metallic hole surrounded by double spiral dielectric gratings is proposed. The main mechanism of the proposed structure is based on the angular momentum change of surface plasmon caused by the spiral geometry. On- and off-states of the proposed device are determined by the condition whether the rotating direction of incident polarization is the same as or opposite of the direction of the spiral rotations. Qualitative analytical expressions of the switching mechanisms and full-vectorial numerical results are presented.


The natriuretic peptide MR-proANP predicts all-cause mortality and adverse outcome in community patients: a 10-year follow-up study.
The precursor peptide of atrial natriuretic peptide (MR-proANP) has a physiological role in fluid homeostasis and is associated with mortality and adverse clinical outcomes in heart failure patients. Little is known about the prognostic potential of this peptide for long-term mortality prediction in community-dwelling patients. We evaluated associations of MR-proANP levels with 10-year all-cause mortality in patients visiting their general practitioner for a respiratory tract infection. In this post-hoc analysis including 359 patients (78.5%) of the original trial, we calculated cox regression models and area under the receiver operating characteristic curve (AUC) to assess associations of MR-proANP blood levels with mortality and adverse outcome including death, pulmonary embolism, and major adverse cardiac or cerebrovascular events. After a median follow-up of 10.0 years, 9.8% of included patients died. Median admission MR-proANP levels were significantly elevated in non-survivors compared to survivors (80.5 pmol/L, IQR 58.6-126.0; vs. 45.6 pmol/L, IQR 34.2-68.3; p<0.001) and associated with 10-year all-cause mortality (age-adjusted HR 2.0 [95% CI 1.3-3.1, p=0.002]; AUC 0.79). Results were similar for day 7 blood levels and also for the prediction of other adverse outcomes. Increased MR-proANP levels were associated with 10-year all-cause mortality and adverse clinical outcome in a sample of community-dwelling patients. If diagnosis-specific cut-offs are confirmed in future studies, this marker may help to direct preventive measures in primary care.


Ectomycorrhizal colonization slows root decomposition: the post-mortem fungal legacy.
The amount of carbon plants allocate to mycorrhizal symbionts exceeds that emitted by human activity annually. Senescent ectomycorrhizal roots represent a large input of carbon into soils, but their fate remains unknown. Here, we present the surprising result that, despite much higher nitrogen concentrations, roots colonized by ectomycorrhizal (EM) fungi lost only one-third as much carbon as non-mycorrhizal roots after 2 years of decomposition in a piñon pine (Pinus edulis) woodland. Experimentally excluding live mycorrhizal hyphae from litter, we found that live mycorrhizal hyphae may alter nitrogen dynamics, but the afterlife (litter-mediated) effects of EM fungi outweigh the influences of live fungi on root decomposition. Our findings indicate that a shift in plant allocation to mycorrhizal fungi could promote carbon accumulation in soil by this pathway. Furthermore, EM litters could directly contribute to the process of stable soil organic matter formation, a mechanism that has eluded soil scientists.


A high-temperature superconducting Helmholtz probe for microscopy at 9.4 T.
The design and operation of a high-temperature superconducting (HTS) probe for magnetic resonance microscopy (MRM) at 400 MHz are presented. The design of the probe includes a Helmholtz coil configuration and a stable open-cycle cooling mechanism. Characterization of coil operating parameters is presented to demonstrate the suitability of cryo-cooled coils for MRM. Specifically, the performance of the probe is evaluated by comparison of signal-to-noise (SNR) performance with that of a copper Helmholtz pair, analysis of B1 field homogeneity, and quantification of thermal stability. Images are presented to demonstrate the SNR advantage of the probe for typical MRM applications.


Delta13C stable isotope analysis of atmospheric oxygenated volatile organic compounds by gas chromatography-isotope ratio mass spectrometry.
We present a new method for analyzing the delta(13)C isotopic composition of several oxygenated volatile organic compounds (OVOCs) from direct sources and ambient atmospheric samples. Guided by the requirements for analysis of trace components in air, a gas chromatograph isotope ratio mass spectrometer (GC-IRMS) system was developed with the goal of increasing sensitivity, reducing dead-volume and peak band broadening, optimizing combustion and water removal, and decreasing the split ratio to the isotope ratio mass spectrometer (IRMS). The technique relies on a two-stage preconcentration system, a low-volume capillary reactor and water trap, and a balanced reference gas delivery system. The instrument's measurement precision is 0.6 to 2.9 per thousand (1sigma), and results indicate that negligible sample fractionation occurs during gas sampling. Measured delta(13)C values have a minor dependence on sample size; linearity for acetone was 0.06 per thousand ng C(-1) and was best over 1-10 ng C. Sensitivity is approximately 10 times greater than similar instrumentation designs, incorporates the use of a diluted working reference gas (0.1% CO(2)), and requires collection of >0.7 ng C to produce accurate and precise results. With this detection limit, a 1.0 L sample of ambient air provides sufficient carbon for isotopic analysis. Emissions from vegetation and vehicle exhaust are compared and show clear differences in isotopic signatures. Ambient samples collected in metropolitan Miami and the Everglades National Park can be differentiated and reflect multiple sources and sinks affecting a single sampling location. Vehicle exhaust emissions of ethanol, and those collected in metropolitan Miami, have anomalously enriched delta(13)C values ranging from -5.0 to -17.2 per thousand; we attribute this result to ethanol's origin from corn and use as an additive in automotive fuels.


Genome-wide mRNA sequencing of a single canine cerebellar cortical degeneration case leads to the identification of a disease associated SPTBN2 mutation.
Neonatal cerebellar cortical degeneration is a neurodegenerative disease described in several canine breeds including the Beagle. Affected Beagles are unable to ambulate normally from the onset of walking and the main pathological findings include Purkinje cell loss with swollen dendritic processes. Previous reports suggest an autosomal recessive mode of inheritance. The development of massively parallel sequencing techniques has presented the opportunity to investigate individual clinical cases using genome-wide sequencing approaches. We used genome-wide mRNA sequencing (mRNA-seq) of cerebellum tissue from a single Beagle with neonatal cerebellar cortical degeneration as a method of candidate gene sequencing, with the aim of identifying the causal mutation. A four-week old Beagle dog presented with progressive signs of cerebellar ataxia and the owner elected euthanasia. Histopathology revealed findings consistent with cerebellar cortical degeneration. Genome-wide mRNA sequencing (mRNA-seq) of RNA from cerebellum tissue was used as a method of candidate gene sequencing. After analysis of the canine orthologues of human spinocerebellar ataxia associated genes, we identified a homozygous 8 bp deletion in the β-III spectrin gene, SPTBN2, associated with spinocerebellar type 5 in humans. Genotype analysis of the sire, dam, ten clinically unaffected siblings, and an affected sibling from a previous litter, showed the mutation to fully segregate with the disorder. Previous studies have shown that β-III spectrin is critical for Purkinje cell development, and the absence of this protein can lead to cell damage through excitotoxicity, consistent with the observed Purkinje cell loss, degeneration of dendritic processes and associated neurological dysfunction in this Beagle. An 8 bp deletion in the SPTBN2 gene encoding β-III spectrin is associated with neonatal cerebellar cortical degeneration in Beagle dogs. This study shows that mRNA-seq is a feasible method of screening candidate genes for mutations associated with rare diseases when a suitable tissue resource is available.


Compensation for Atmospheric Phase Effects at 10.6 micro.
A holographic technique to compensate for atmospherically induced phase distortion of a 10.6-micro laser beam is presented. After a brief outline of the principle of adaptive phase-distortion compensation, the experimental setup to demonstrate feasibility is described. Results obtained for a reflecting target at distances of 150 m and 4600 m are presented and discussed in detail. It is shown that the power delivered onto a target and thus the return signal can be significantly increased by the principle of adaptive phase-distortion compensation. By compensating for phase distortions in both the transmitted and received beams, the signal-to-noise ratio of the received signal can be improved by a factor of N(2), N being the number of apertures used, if the phase relation was completely random beforehand. The results of these tests demonstrate that large arrays can be utilized in spite of the distorting effects which are normally produced by the atmosphere.


Asymmetrical genetic attributions for prosocial versus antisocial behaviour.
Genetic explanations of human behaviour are increasingly common. While genetic attributions for behaviour are often considered relevant for assessing blameworthiness, it has not yet been established whether judgements about blameworthiness can themselves impact genetic attributions. Across six studies, participants read about individuals engaging in prosocial or antisocial behaviour, and rated the extent to which they believed that genetics played a role in causing the behaviour. Antisocial behaviour was consistently rated as less genetically influenced than prosocial behaviour. This was true regardless of whether genetic explanations were explicitly provided or refuted. Mediation analyses suggested that this asymmetry may stem from people's motivating desire to hold wrongdoers responsible for their actions. These findings suggest that those who seek to study or make use of genetic explanations' influence on evaluations of, for example, antisocial behaviour should consider whether such explanations are accepted in the first place, given the possibility of motivated causal reasoning.


Reaction-diffusion finite element model of lateral line primordium migration to explore cell leadership.
Collective cell migration plays a fundamental role in many biological phenomena such as immune response, embryogenesis and tumorigenesis. In the present work, we propose a reaction-diffusion finite element model of the lateral line primordium migration in zebrafish. The population is modelled as a continuum with embedded discrete motile cells, which are assumed to be viscoelastic and able to undergo large deformations. The Wnt/ß-catenin-FGF and cxcr4b-cxcr7b signalling pathways inside the cohort regulating the migration are described through coupled reaction-diffusion equations. The coupling between mechanics and the molecular scenario occurs in two ways. Firstly, the intensity of the protrusion-contraction movement of the cells depends on the cxcr4b concentration. Secondly, the intra-synchronization between the active deformations and the adhesion forces inside each cell is triggered by the cxcr4b-cxcr7b polarity. This influences the inter-synchronization between the cells and results in two main modes of migration: uncoordinated and coordinated. The main objectives of the work were (i) to validate our assumptions with respect to the experimental observations and (ii) to decipher the mechanical conditions leading to efficient migration of the primordium. To achieve the second goal, we will specifically focus on the role of the leader cells and their position inside the population.


Macrophage oxygen-dependent antimicrobial activity. III. Enhanced oxidative metabolism as an expression of macrophage activation.
The capacity of 15 separate populations of mouse peritoneal macrophages to generate and release H2O2 (an index of oxidative metabolism) was compared with their ability to inhibit the intracellular replication of virulent Toxoplasma gondii. Resident macrophages and those elicited by inflammatory agents readily supported toxoplasma multiplication and released 4-20X less H2O2 than macrophages activated in vivo by systemic infection with Bacille Calmette-Guérin or T. gondii, or by immunization with Corynebacterium parvum. Immunologically activated cells consistently displayed both enhanced H2O2 production and antitoxoplasma activity. Exposure to lymphokines generated from cultures of spleen cells from T. gondii immune mice and toxoplasma antigen preserved both the antitoxoplasma activity and the heightened H2O2 release of toxoplasma immune and immune-boosted macrophages, which otherwise were lost after 48-72 h of cultivation. In vitro activation of resident and chemically-elicited cells by 72 h of exposure to mitogen- and antigen-prepared lymphokines, conditions that induce trypanocidal (5) and leishmanicidal activity (14), stimulated O2- and H2O2 release, and enhanced nitroblue tetrazolium reduction in response to toxoplasma ingestion. Such treatment, however, failed to confer any antitoxoplasma activity, indicating that intracellular pathogens may vary in their susceptibility to macrophage microbicidal mechanisms, including specific oxygen intermediates. In contrast, cocultivating normal macrophages with lymphokine plus heart infusion broth for 18H rendered these cells toxoplasmastatic. This in vitro-acquired activity was inhibited by scavengers of O2-, H2O2, OH., and 1O2, demonstrating a role for oxidative metabolites in lymphokine-induced enhancement of macrophage antimicrobial activity. These findings indicate that augmented oxidative metabolism is an consistent marker of macrophage activation, and that oxygen intermediates participate in the resistance of both in vivo- and vitro-activated macrophages toward the intracellular parasite, T. gondii.


Tropism of AAV Vectors in Photoreceptor-Like Cells of Human iPSC-Derived Retinal Organoids.
To expand the use of human retinal organoids from induced pluripotent stem cells (iPSCs) as an in vitro model of the retina for assessing gene therapy treatments, it is essential to establish efficient transduction. To date, targeted transduction of the photoreceptor-like cells of retinal organoids with adeno-associated virus (AAV) vectors has had varied degrees of success, which we have looked to improve in this study. Retinal organoids were differentiated from iPSCs of healthy donors and transduced with reporter AAV containing a CAG.GFP, CAG.RFP, GRK1.GFP, or EFS.GFP transgene. Capsid variants assessed were AAV5, AAV2 7m8, AAV2 quad mutant, AAV2 Y444F, and AAV8 Y733F. At 27 days post-transduction, retinal organoids were assessed for reporter expression and viability. The short intron-less elongation factor 1 alpha (EFS) promoter provided minimal reporter expression, whereas vectors containing the CAG promoter enabled transduction in 1% to 37% of cells depending on the AAV serotype; the AAV2 quad mutant (average 19.4%) and AAV2 7m8 (16.4%) outperformed AAV5 (12%) and AAV8 Y733F (2.1%). Reporter expression from rhodopsin kinase (GRK1) promoter transgenes occurred in ∼5% of cells regardless of the serotype. Positive co-localization with recoverin-expressing cells was achieved from all GRK1 vectors and the CAG AAV2 quad mutant variant. Treatment with the AAV vectors did not influence retinal organoid viability. Reliable transduction of the photoreceptor-like cells of retinal organoids can be readily achieved. When using a CAG-driven transgene, transduction of a broad range of cell types is observed, and GRK1 transgenes provide a more restricted expression profile locating to the outer layer of photoreceptor-like cells of retinal organoids. This study expands the AAV capsid and transgene options for preclinical testing of gene therapy in iPSC-derived human retinal organoids.


Comparison of the consumption of antidepressants in the immigrant and native populations in a Spanish health region: an observational study.
Health professionals and organizations in developed countries adapt slowly to the increase of ethnically diverse populations attending health care centres. Several studies report that attention to immigrant mental health comes up with barriers in access, diagnosis and therapeutics, threatening equity. This study analyzes differences in exposure to antidepressant drugs between the immigrant and the native population of a Spanish health region. Cross-sectional study of the dispensation of antidepressant drugs to the population aged 15 years or older attending the public primary health centres of a health region, 232,717 autochthonous and 33,361 immigrants, during 2008. Data were obtained from computerized medical records and pharmaceutical records of medications dispensed in pharmacies. Age, sex, country of origin, visits, date of entry in the regional health system, generic drugs and active ingredients were considered. Statistical analysis expressed the percentage of persons exposed to antidepressants stratified by age, gender, and country of origin and prevalence ratios of antidepressant exposition were calculated. Antidepressants were dispensed to 11% of native population and 2.6% of immigrants. Depending on age, native women were prescribed antidepressants between 1.9 and 2.7 times more than immigrant women, and native men 2.5 and 3.1 times more than their immigrant counterparts. Among immigrant females, the highest rate was found in the Latin Americans (6.6%) and the lowest in the sub-Saharans (1.4%). Among males, the highest use was also found in the Latin Americans (1.6%) and the lowest in the sub-Saharans (0.7%). The percentage of immigrants prescribed antidepressants increased significantly in relation to the number of years registered with the local health system. Significant differences were found for the new antidepressants, prescribed 8% more in the native population than in immigrants, both in men and in women. All the immigrants, regardless of the country of origin, had lower antidepressant consumption than the native population of the same age and sex. Latin American women presented the highest levels of consumption, and the sub-Saharan men the lowest. The prescription profiles also differed, since immigrants consumed more generics and fewer recently commercialized active ingredients.


Antimicrobial stewardship programs in freestanding children's hospitals.
Single-center evaluations of pediatric antimicrobial stewardship programs (ASPs) suggest that ASPs are effective in reducing and improving antibiotic prescribing, but studies are limited. Our objective was to compare antibiotic prescribing rates in a group of pediatric hospitals with formalized ASPs (ASP+) to a group of concurrent control hospitals without formalized stewardship programs (ASP-). We evaluated the impact of ASPs on antibiotic prescribing over time measured by days of therapy/1000 patient-days in a group of 31 freestanding children's hospitals (9 ASP+, 22 ASP-). We compared differences in average antibiotic use for all ASP+ and ASP- hospitals from 2004 to 2012 before and after release of 2007 Infectious Diseases Society of America guidelines for developing ASPs. Antibiotic use was compared for both all antibacterials and for a select subset (vancomycin, carbapenems, linezolid). For each ASP+ hospital, we determined differences in the average monthly changes in antibiotic use before and after the program was started by using interrupted time series via dynamic regression. In aggregate, as compared with those years preceding the guidelines, there was a larger decline in average antibiotic use in ASP+ hospitals than in ASP- hospitals from 2007 to 2012, the years after the release of Infectious Diseases Society of America guidelines (11% vs 8%, P = .04). When examined individually, relative to preimplementation trends, 8 of 9 ASP+ hospitals revealed declines in antibiotic use, with an average monthly decline in days of therapy/1000 patient-days of 5.7%. For the select subset of antibiotics, the average monthly decline was 8.2%. Formalized ASPs in children's hospitals are effective in reducing antibiotic prescribing.


A monoclonal antibody specific for reovirus outer-capsid protein sigma3 inhibits sigma1-mediated hemagglutination by steric hindrance.
Reovirus virions are nonenveloped icosahedral particles consisting of two concentric protein shells, termed outer capsid and core. Outer-capsid protein sigma1 is the viral attachment protein and binds carbohydrate molecules on the surface of host cells. Monoclonal antibody (MAb) 4F2, which is specific for outer-capsid protein sigma3, blocks the binding of sigma1 protein to sialic acid and inhibits reovirus-induced hemagglutination (HA). To determine whether MAb 4F2 inhibits HA by altering sigma1-sigma3 interactions or by steric hindrance, we analyzed the effect of 4F2 immunoglobulin G (IgG) and Fab fragments (Fabs) on HA induced by reovirus strain type 3 Dearing (T3D). The concentration of 4F2 IgG sufficient to inhibit T3D-induced HA was 12.5 microg per ml, whereas that of Fabs was >200 microg per ml. Dynamic light scattering analysis showed that at the concentration of IgG sufficient to inhibit HA, virion-antibody complexes were monodispersed and not aggregated. The affinity of 4F2 Fabs for T3D virions was only threefold less than that of intact IgG, which suggests that differences in HA inhibition titer exhibited by 4F2 IgG and Fabs are not attributable to differences in the affinity of these molecules for T3D virions. We used cryoelectron microscopy and three-dimensional image analysis to visualize T3D virions alone and in complex with either IgG or Fabs of MAb 4F2. IgG and Fabs bind the same site at the distal portion of sigma3, and binding of IgG and Fabs induces identical conformational changes in outer-capsid proteins sigma3 and mu1. These results suggest that MAb 4F2 inhibits reovirus binding to sialic acid by steric hindrance and provide insight into the conformational flexibility of reovirus outer-capsid proteins.


Ribosomal RNA genes of Drosophila melanogaster have a novel chromatin structure.
We have examined the chromatin organization of the Drosophila melanogaster ribosomal RNA genes using both micrococcal nuclease and DNase I. Several findings are of interest. First, the transcribed DNA segments of the rRNA repeat unit appear to be packaged into an unstable or "multiphasic" nucleosome structure. Second, the 5' end of the transcription unit is preferentially exposed to nuclease attack. Third, the non-transcribed spacer immediately upstream from the transcription start site has a novel chromatin organization with micrococcal nuclease and DNase I cleavage sites spaced at intervals of about 240 base-pairs. This unusual fragment distribution appears to reflect the underlying sequence organization of the spacer DNA segment, which consists of a series of tandemly repeated 239 base-pair sequence blocks. We have also examined the chromatin structure of the rRNA repeat unit after extraction of nuclei with different concentrations of salt. Our results suggest that the higher order structures may be of importance in determining the novel chromatin organization of the rRNA repeat unit.


Prehospital Analgesia With Intranasal Ketamine (PAIN-K): A Randomized Double-Blind Trial in Adults.
We compare intranasal ketamine with intranasal placebo in providing pain reduction at 30 minutes when added to usual paramedic care with nitrous oxide. This was a randomized double-blind study of out-of-hospital patients with acute pain who reported a verbal numeric rating scale (VNRS) pain score greater than or equal to 5. Exclusion criteria were younger than 18 years, known ketamine intolerance, nontraumatic chest pain, altered mental status, pregnancy, and nasal occlusion. Patients received usual paramedic care and were randomized to receive either intranasal ketamine or intranasal saline solution at 0.75 mg/kg. The primary outcome was the proportion of patients with VNRS score reduction greater than or equal to 2 at 30 minutes. Secondary outcomes were pain reduction at 15 minutes, patient-reported comfort, satisfaction scores, nitrous oxide consumption, and incidence of adverse events. One hundred twenty subjects were enrolled. Seventy-six percent of intranasal ketamine patients versus 41% of placebo patients reported a greater than or equal to 2-point VNRS reduction at 30 minutes (difference 35%; 95% confidence interval 17% to 51%). Median VNRS reduction at 15 minutes was 2.0 and 1.0 and at 30 minutes was 3.0 and 1.0 for ketamine and placebo, respectively. Improved comfort at 15 and 30 minutes was reported for 75% versus 57% and 61% versus 46% of ketamine and placebo patients, respectively. Sixty-two percent of patients (95% confidence interval 49% to 73%) versus 20% (95% confidence interval 12% to 32%) reported adverse events with ketamine and placebo, respectively. Adverse events were minor, with no patients requiring physical or medical intervention. Added to nitrous oxide, intranasal ketamine provides clinically significant pain reduction and improved comfort compared with intranasal placebo, with more minor adverse events.


The C-terminal SH3 domain of CRKL as a dynamic dimerization module transiently exposing a nuclear export signal.
CRKL plays essential roles in cell signaling. It consists of an N-terminal SH2 domain followed by two SH3 domains. SH2 and SH3N bind to signaling proteins, but the function of the SH3C domain has remained largely enigmatic. We show here that the SH3C of CRKL forms homodimers in protein crystals and in solution. Evidence for dimer formation of full-length CRKL is also presented. In the SH3C dimer, a nuclear export signal (NES) is mostly buried under the domain surface. The same is true for a monomeric SH3C obtained under different crystallization conditions. Interestingly, partial SH3 unfolding, such as occurs upon dimer/monomer transition, produces a fully-accessible NES through translocation of a single beta strand. Our results document the existence of an SH3 domain dimer formed through exchange of the first SH3 domain beta strand and suggest that partial unfolding of the SH3C is important for the relay of information in vivo.


Ecuador's mangrove forest carbon stocks: a spatiotemporal analysis of living carbon holdings and their depletion since the advent of commercial aquaculture.
In this paper we estimate the living carbon lost from Ecuador's mangrove forests since the advent of export-focused shrimp aquaculture. We use remote sensing techniques to delineate the extent of mangroves and aquaculture at approximately decadal periods since the arrival of aquaculture in each Ecuadorian estuary. We then spatiotemporally calculate the carbon values of the mangrove forests and estimate the amount of carbon lost due to direct displacement by aquaculture. Additionally, we calculate the new carbon stocks generated due to mangrove reforestation or afforestation. This research introduces time and LUCC (land use / land cover change) into the tropical forest carbon literature and examines forest carbon loss at a higher spatiotemporal resolution than in many earlier analyses. We find that 80 percent, or 7,014,517 t of the living carbon lost in Ecuadorian mangrove forests can be attributed to direct displacement of mangrove forests by shrimp aquaculture. We also find that IPCC (Intergovernmental Panel on Climate Change) compliant carbon grids within Ecuador's estuaries overestimate living carbon levels in estuaries where substantial LUCC has occurred. By approaching the mangrove forest carbon loss question from a LUCC perspective, these findings allow for tropical nations and other intervention agents to prioritize and target a limited set of land transitions that likely drive the majority of carbon losses. This singular cause of transition has implications for programs that attempt to offset or limit future forest carbon losses and place value on forest carbon or other forest good and services.


Learning objects? Nurse educators' views on using patients for student learning : ethics and consent.
This study explored the views of nursing lecturers concerning the use of patients in nursing education, particularly in light of the development of additional learning opportunities such as clinical simulation. Focus group interviews involving 19 educators from one school of nursing in the United Kingdom were held. An interview schedule was developed by the study team from the findings of a focused literature review of the area. The focus groups were audio-taped and transcribed into NVivo (version 8) for analysis and identification of emergent themes. Four major categories emerged from the data analysis: clinical placement; patient consent; educator conflict; and developing competency. The themes of clinical placement and patient consent are presented in this paper. Clinical placement revealed two sub-themes: historical custom and practice and safety. Four sub-themes emerged from the theme of patient consent: informed consent; implied consent; capacity to consent; and patients' value of student involvement in their care. Educators believed that patients benefit from being cared for by well-qualified nurses and to achieve this it is necessary for patients to participate in clinical training. The predominant view seemed to be one of historical necessity; essentially, it has always been done that way so it has to continue that way. There was an awareness of the need for staff and students to consider the patient's rights and wishes, but the prevailing sentiment seemed to be that informed consent and choice were secondary to patient safety and the need to train student nurses. There is some conflict between the need for educating health professions and the Kantian view of never using the patients as a means to an end. Using patients for nursing education may be ethical as long as the patient is fully informed and involved in the decision-making process.


Early infection events highlight the limited transmissibility of hepatitis C virus in vitro.
Hepatitis C virus (HCV) poses a global health problem, with over 170 million chronically infected individuals at risk of developing progressive liver disease. The ability of a virus to spread within a host is a key determinant of its persistence and virulence. HCV can transmit in vitro by cell-free particle diffusion or via contact(s) between infected and naïve hepatocytes. However, limited information is available on the relative efficiency of these routes, our aim is to develop physiologically relevant assays to quantify these processes. We developed a single-cycle infection assay to measure HCV transmission rates. We compared HCV spread in proliferating and arrested cell systems and demonstrated a significant reduction in cell-to-cell infection of arrested target cells. Comparison of cell-free and cell-to-cell virus spread demonstrated relatively poor transmission rates, with 10-50 infected producer cells required to infect a single naïve target cell. We found HCV strain J6/JFH to be 10-fold more efficient at spreading via the cell-to-cell route than cell-free, whereas SA13/JFH and HK6/JFH strains showed comparable rates of infection via both routes. Importantly, the level of infectious virus released from cells did not predict the ability of a virus to spread in vitro, highlighting the importance of studying cell-associated viruses. These studies demonstrate the relatively poor infectivity of HCV and highlight differences between strains in their efficiency and preferred route of transmission that may inform future therapeutic strategies that target virus entry.


3D Printing of Intracranial Aneurysms Using Fused Deposition Modeling Offers Highly Accurate Replications.
As part of a multicenter cooperation (Aneurysm-Like Synthetic bodies for Testing Endovascular devices in 3D Reality) with focus on implementation of additive manufacturing in neuroradiologic practice, we systematically assessed the technical feasibility and accuracy of several additive manufacturing techniques. We evaluated the method of fused deposition modeling for the production of aneurysm models replicating patient-specific anatomy. 3D rotational angiographic data from 10 aneurysms were processed to obtain volumetric models suitable for fused deposition modeling. A hollow aneurysm model with connectors for silicone tubes was fabricated by using acrylonitrile butadiene styrene. Support material was dissolved, and surfaces were finished by using NanoSeal. The resulting models were filled with iodinated contrast media. 3D rotational angiography of the models was acquired, and aneurysm geometry was compared with the original patient data. Reproduction of hollow aneurysm models was technically feasible in 8 of 10 cases, with aneurysm sizes ranging from 41 to 2928 mm(3) (aneurysm diameter, 3-19 mm). A high level of anatomic accuracy was observed, with a mean Dice index of 93.6% ± 2.4%. Obstructions were encountered in vessel segments of <1 mm. Fused deposition modeling is a promising technique, which allows rapid and precise replication of cerebral aneurysms. The porosity of the models can be overcome by surface finishing. Models produced with fused deposition modeling may serve as educational and research tools and could be used to individualize treatment planning.


The translationally relevant mouse model of the 15q13.3 microdeletion syndrome reveals deficits in neuronal spike firing matching clinical neurophysiological biomarkers seen in schizophrenia.
To date, the understanding and development of novel treatments for mental illness is hampered by inadequate animal models. For instance, it is unclear to what extent commonly used behavioural tests in animals can inform us on the mental and affective aspects of schizophrenia. To link pathophysiological processes in an animal model to clinical findings, we have here utilized the recently developed Df(h15q13)/+ mouse model for detailed investigations of cortical neuronal engagement during pre-attentive processing of auditory information from two back-translational auditory paradigms. We also investigate if compromised putative fast-spiking interneurone (FSI) function can be restored through pharmacological intervention using the Kv3.1 channel opener RE1. Chronic multi-array electrodes in primary auditory cortex were used to record single cell firing from putative pyramidal and FSI in awake animals during processing of auditory sensory information. We find a decreased amplitude in the response to auditory stimuli and reduced recruitment of neurones to fast steady-state gamma oscillatory activity. These results resemble encephalography recordings in patients with schizophrenia. Furthermore, the probability of interneurones to fire with low interspike intervals during 80 Hz auditory stimulation was reduced in Df(h15q13)/+ mice, an effect that was partially reversed by the Kv3.1 channel modulator, RE1. This study offers insight into the consequences on a neuronal level of carrying the 15q13.3 microdeletion. Furthermore, it points to deficient functioning of interneurones as a potential pathophysiological mechanism in schizophrenia and suggests a therapeutic potential of Kv3.1 channel openers.


Regulation of gene expression by photosynthetic signals triggered through modified CO2 availability.
To coordinate metabolite fluxes and energy availability, plants adjust metabolism and gene expression to environmental changes through employment of interacting signalling pathways. Comparing the response of Arabidopsis wild-type plants with that of the mutants adg1, pgr1 and vtc1 upon altered CO2-availability, the regulatory role of the cellular energy status, photosynthetic electron transport, the redox state and concentration of ascorbate and glutathione and the assimilatory force was analyzed in relation to the transcript abundance of stress-responsive nuclear encoded genes and psaA and psbA encoding the reaction centre proteins of photosystem I and II, respectively. Transcript abundance of Bap1, Stp1, psaA and psaB was coupled with seven metabolic parameters. Especially for psaA and psaB, the complex analysis demonstrated that the assumed PQ-dependent redox control is subordinate to signals linked to the relative availability of 3-PGA and DHAP, which define the assimilatory force. For the transcripts of sAPx and Csd2 high correlations with the calculated redox state of NADPH were observed in pgr1, but not in wild-type, suggesting that in wild-type plants signals depending on thylakoid acidification overlay a predominant redox-signal. Strongest correlation with the redox state of ascorbate was observed for 2CPA, whose transcript abundance regulation however was almost insensitive to the ascorbate content demonstrating dominance of redox regulation over metabolite sensing. In the mutants, signalling pathways are partially uncoupled, demonstrating dominance of metabolic control of photoreaction centre expression over sensing the redox state of the PQ-pool. The balance between the cellular redox poise and the energy signature regulates sAPx and Csd2 transcript abundance, while 2CPA expression is primarily redox-controlled.


Rheumatoid arthritis antirheumatic drug trials. II. Tables for calculating sample size for clinical trials of antirheumatic drugs.
The calculation of sample size requires knowledge of the standard deviation (SD) of index variables. Unfortunately, there are no published lists of SD and it is exceedingly difficult to locate variance estimates based on relevant populations. We used standardized procedures to determine in 60 patients with rheumatoid arthritis (RA) the SD of key outcome measures recommended in current Food and Drug Administration and European League Against Rheumatism guidelines for RA clinical trials. We anticipate that these tables will be useful to clinical researchers in selecting outcome measures as well as for calculating sample size requirements for future clinical studies in RA.


Clinician's guide to human papillomavirus immunology: knowns and unknowns.
Oncogenic human papillomavirus (HPV) is a common genital infection that has the potential to develop into cervical cancer in some women. This Review summarises current knowledge on the mechanisms of host immunity that help prevent and control HPV infection and the viral factors that exist to avoid immune surveillance. Although most women clear the infection within a few months, the virus induces a shift towards immune tolerance that can facilitate persistence and permit tumorigenesis. Mechanisms used by HPV to avoid immune surveillance and control include infecting only the basal layer of the cervical epithelium, limiting expression of viral proteins until later stages of epithelial differentiation, undergoing non-lytic replication, and downregulating the expression of important receptors on cells of the innate immune system. Furthermore, HPV suppresses the expression of several proinflammatory proteins that are crucial in clearing infection and activating the cytotoxic T lymphocytes involved in killing virus-infected cells. Interestingly, neutralising antibodies, although of uncertain effectiveness in preventing infection or reinfection after natural exposure (prior infection), are highly protective after immunisation with HPV virus-like-particle-based vaccines. Understanding what is known and unknown about the interaction between the immune system and HPV is important in the assessment of the potential contribution of prophylactic vaccination in reducing the incidence of cervical cancer. However, despite our growing understanding, many aspects of the interactions between HPV and the host immune system remain unknown, and this Review draws attention to several of these unresolved issues and their implications.


The Citrus leaf blotch virus movement protein acts as silencing suppressor.
To counteract plant antiviral defense based on RNA silencing, many viruses express proteins that inhibit this mechanism at different levels. The genome of Citrus leaf blotch virus (CLBV) encodes a 227-kDa protein involved in replication, a 40-kDa movement protein (MP), and a 41-kDa coat protein (CP). To determine if any of these proteins might have RNA silencing suppressor activities, we have used Agrobacterium-mediated transient assays in the green fluorescent protein (GFP)-expressing Nicotiana benthamiana line 16c. Only CLBV MP was able to suppress intracellular GFP silencing induced by expression of either single- or double-stranded (ds) GFP RNA, but not cell-to-cell or long distance spread of the silencing signal. The MP suppressor activity was weak compared to other characterized viral suppressor proteins. Overall our data indicate that MP acts as a suppressor of local silencing probably by interfering in the silencing pathway downstream of the steps of dsRNA and small RNAs generation.


A conditional trophic cascade: birds benefit faster growing trees with strong links between predators and plants.
Terrestrial systems are thought to be organized predominantly from the bottom-up, but there is a growing literature documenting top-down trophic cascades under certain ecological conditions. We conducted an experiment to examine how arthropod community structure on a foundation riparian tree mediates the ability of insectivorous birds to influence tree growth. We built whole-tree bird exclosures around 35 mature cottonwood (Populus spp.) trees at two sites in northern Utah, USA, to measure the effect of bird predation on arthropod herbivore and predator species richness, abundance, and biomass, and on tree performance. We maintained bird exclosures over two growing seasons and conducted nondestructive arthropod surveys that recorded 63652 arthropods of 689 morphospecies representing 19 orders. Five major patterns emerged: (1) We found a significant trophic cascade (18% reduction in trunk growth when birds were excluded) only at one site in one year. (2) The significant trophic cascade was associated with higher precipitation, tree growth, and arthropod abundance, richness, and biomass than other site-year combinations. (3) The trophic cascade was weak or not evident when tree growth and insect populations were low apparently due to drought. (4) Concurrent with the stronger trophic cascade, bird predation significantly reduced total arthropod abundance, richness, and biomass. Arthropod biomass was 67% greater on trees without bird predation. This pattern was driven largely by two herbivore groups (folivores and non-aphid sap-feeders) suggesting that birds targeted these groups. (5) Three species of folivores (Orthoptera: Melanoplus spp.) were strong links between birds and trees and were only present in the site and the year in which the stronger trophic cascade occurred. Our results suggest that this trophic system is predominately bottom-up driven, but under certain conditions the influence of top predators can stimulate whole tree growth. When the most limiting factor for tree growth switched from water availability to herbivory, the avian predators gained the potential to reduce herbivory. This potential could be realized when strong links between the birds and plant, i.e., species that were both abundant herbivores and preferred prey, were present.


Odour-based kin discrimination in the cooperatively breeding meerkat.
Kin recognition is a useful ability for animals, facilitating cooperation among relatives and avoidance of excessive kin competition or inbreeding. In meerkats, Suricata suricatta, encounters between unfamiliar kin are relatively frequent, and kin recognition by phenotype matching is expected to avoid inbreeding with close relatives. Here, we investigate whether female meerkats are able to discriminate the scent of unfamiliar kin from unfamiliar non-kin. Dominant females were presented with anal gland secretion from unfamiliar individuals that varied in their relatedness. Our result indicates that females spent more time investigating the scent of related than unrelated unfamiliar individuals, suggesting that females may use a phenotype matching mechanism (or recognition alleles) to discriminate the odour of their kin from the odour of their non-kin. Our study provides a key starting point for further investigations into the use of kin recognition for inbreeding avoidance in the widely studied meerkat.


Environmental correlates of chronic obstructive pulmonary disease in 96 779 participants from the UK Biobank: a cross-sectional, observational study.
The role of environmental exposures in chronic obstructive pulmonary disease (COPD) remains inconclusive. We examined the association between environmental exposures (PM2·5, greenness, and urbanicity) and COPD prevalence using the UK Biobank cohort data to identify key built environment correlates of COPD. In this cross-sectional, observational study we used baseline data for UK Biobank participants. Included participants were aged 39 years and older, white, had available spirometry data, and had complete data for phenotypes and exposures. COPD was defined by spirometry with the 2017 Global Initiative for Chronic Obstructive Lung Disease criteria. Environmental exposures were PM2·5 derived from monitoring data and interpolated using land-use regression at the participants' geocoded residential addresses. Built environment metrics of residential greenness were modelled in terms of normalised difference vegetation index from remotely sensed colour infrared data within a 500 m residential catchment, and an urbanicity index derived from spatial analyses and measured with a 1 km buffer around each participant's residential address. Logistic regression models examined the associations between environmental exposures and COPD prevalence adjusting for a range of confounders. Subgroup analyses by urbanicity and effect modification by white blood cell count as an inflammatory marker were also done. We assessed 96 779 participants recruited between April 4, 2006, and Oct 1, 2010, of which 5391 participants had COPD with a prevalence of 5·6%. Each 10 μg/m3 increment in ambient PM2·5 exposure at a participant's residential location was associated with higher odds of COPD (odds ratio 1·55, 95% CI 1·14-2·10). Among the built environment metrics, urbanicity was associated with higher odds of COPD (1·05, 1·01-1·08 per interquartile increment), whereas residential greenness was protective, being associated with lower odds of COPD (0·89, 0·84-0·93 for each interquartile increment in greenness). The results remained consistent in models of COPD defined as per lower limit of normal criteria. The highest quartile of white blood cell count was associated with lower lung function and higher COPD risk with a significant interaction between PM2·5 and white blood cell count only in the model of lung function (p=0·0003). In this study of the built environment and COPD, to our knowledge the largest done in the UK, we found that exposure to ambient PM2·5 and urbanicity were associated with a higher risk of COPD. Residing in greener areas, as measured by normalised difference vegetation index, was associated with lower odds of COPD, suggesting the potential value of urban planning and design in minimising or offsetting environmental risks for the prevention and management of COPD. University of Hong Kong, UK Biobank, and UK Economic & Social Research Council.


ROS1 mutation non-small cell lung cancer-access to optimal treatment and outcomes.
ROS1 oncogenic fusion, which was first identified by Rikova et al, is reported to be present in 1%-2% of non-small cell lung cancers (NSCLCs) and is defined as a distinct molecular sub-group. Crizotinib is very effective in ROS1-positive patients and is now Food and Drug Administration (FDA) approved for the treatment of patients with advanced ROS1-positive NSCLC. We report our experience in a tertiary cancer care hospital in India in ROS-1 positive patients. The present series is a retrospective analysis of 22 patients from the prospectively maintained lung cancer audit. Demographic data were collected which included age, performance status, gender, stage, co-morbidities, sites of metastasis and smoking history. Data were also collected regarding the source of financing for crizotinib whether self-financed, through insurance or Non-Governmental Organisation (NGO) sponsored. Patients who had tested negative for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) and were subsequently found to be ROS1-mutation negative by fluorescence in situ hybridization (FISH) were evaluated on similar lines. All the data were entered and statistical analyses were performed using the SPSS software version 22.0. Response evaluation was done by RECIST 1.1 criteria. Between January 2015 and December 2017, there were 22 patients who were ROS1 positive from a total of 535 patients in whom ROS1 testing was performed. A total of 16 patients could receive crizotinib and 6 patients were never exposed to crizotinib. Among the 16 patients who received crizotinib, 2 (12.5%) achieved complete response (CR) as their best response and continue to remain in CR at follow-up. 13 (81%) had a partial response as best response and of which on follow-up 5 (38%) have progressed, while 8 (62%) continue to maintain response. The patients who were on crizotinib had good tolerance with none experiencing any grade 3/4 toxicity. The median follow-up of the entire cohort was 15.2 months in ROS1-positive cohort and 11.4 months in ROS1-negative cohort. In ROS1-positive cohort median, progression-free survival (PFS) was not reached and the estimated 2-year PFS was 54% and in ROS1-negative cohort, it was 5.1 months. The median overall survival of the entire ROS1-positive cohort was not reached and the estimated 1- and 2-year overall survival (OS) was 72% and 54%, respectively, and was 8.8 months in ROS1-negative cohort. ROS1 rearrangement with an incidence of 4% of lung adenocarcinoma which is EGFR and ALK negative represents an important targetable driver mutation in the Indian population. Crizotinib also represents an effective treatment option with outcomes similar to those reported. Access to treatment remains an important roadblock to improve outcomes but innovative methods may improve access to these drugs.


Between data providers and concerned citizens: Exploring participation in precision public health in Switzerland.
This empirical article explores the dynamics of exchange and reciprocity between cohorters, that is, study organizers, and cohortees, that is, study participants. Drawing on literature on bioeconomy and valuation, we analyze cohortees' expectations in return for the "clinical labor" they perform in the pilot phase of a Swiss precision public health study. Based on an ethnography of this cohort and data from seven focus groups with cohortees (n = 37), we identified four positions: (1) the good citizen participant, (2) the critical participant, (3) the concerned participant, and (4) the self-oriented participant. These reveal that cohortees' participation, still framed in altruistic terms, nevertheless engages expectations about reciprocal obligations of the state and science in terms of public health, confirming the deep entanglement of gift-based, financial, and moral economies of participation. The different values emerging from these expectations-robust scientific evidence about environmental exposure and a socially oriented public health-provide rich indications about stake making which might matter for the future of precision public health.


Bad sleep? Don't blame the moon! A population-based study.
The aim of this study was to evaluate if there is a significant effect of lunar phases on subjective and objective sleep variables in the general population. A total of 2125 individuals (51.2% women, age 58.8 ± 11.2 years) participating in a population-based cohort study underwent a complete polysomnography (PSG) at home. Subjective sleep quality was evaluated by a self-rating scale. Sleep electroencephalography (EEG) spectral analysis was performed in 759 participants without significant sleep disorders. Salivary cortisol levels were assessed at awakening, 30 min after awakening, at 11 am, and at 8 pm. Lunar phases were grouped into full moon (FM), waxing/waning moon (WM), and new moon (NM). Overall, there was no significant difference between lunar phases with regard to subjective sleep quality. We found only a nonsignificant (p = 0.08) trend toward a better sleep quality during the NM phase. Objective sleep duration was not different between phases (FM: 398 ± 3 min, WM: 402 ± 3 min, NM: 403 ± 3 min; p = 0.31). No difference was found with regard to other PSG-derived parameters, EEG spectral analysis, or in diurnal cortisol levels. When considering only subjects with apnea/hypopnea index of <15/h and periodic leg movements index of <15/h, we found a trend toward shorter total sleep time during FM (FM: 402 ± 4, WM: 407 ± 4, NM: 415 ± 4 min; p = 0.06) and shorter-stage N2 duration (FM: 178 ± 3, WM: 182 ± 3, NM: 188 ± 3 min; p = 0.05). Our large population-based study provides no evidence of a significant effect of lunar phases on human sleep.


High-resolution timing of cell cycle-regulated gene expression.
The eukaryotic cell division cycle depends on an intricate sequence of transcriptional events. Using an algorithm based on maximum-entropy deconvolution, and expression data from a highly synchronized yeast culture, we have timed the peaks of expression of transcriptionally regulated cell cycle genes to an accuracy of 2 min (approximately equal to 1% of the cell cycle time). The set of 1,129 cell cycle-regulated genes was identified by a comprehensive analysis encompassing all available cell cycle yeast data sets. Our results reveal distinct subphases of the cell cycle undetectable by morphological observation, as well as the precise timeline of macromolecular complex assembly during key cell cycle events.


Mechanisms involved in the death of steatotic WIF-B9 hepatocytes co-exposed to benzo[a]pyrene and ethanol: a possible key role for xenobiotic metabolism and nitric oxide.
We previously demonstrated that co-exposing pre-steatotic hepatocytes to benzo[a]pyrene (B[a]P), a carcinogenic environmental pollutant, and ethanol, favored cell death. Here, the intracellular mechanisms underlying this toxicity were studied. Steatotic WIF-B9 hepatocytes, obtained by a 48h-supplementation with fatty acids, were then exposed to B[a]P/ethanol (10 nM/5 mM, respectively) for 5 days. Nitric oxide (NO) was demonstrated to be a pivotal player in the cell death caused by the co-exposure in steatotic hepatocytes. Indeed, by scavenging NO, CPTIO treatment of co-exposed steatotic cells prevented not only the increase in DNA damage and cell death, but also the decrease in the activity of CYP1, major cytochrome P450s of B[a]P metabolism. This would then lead to an elevation of B[a]P levels, thus possibly suggesting a long-lasting stimulation of the transcription factor AhR. Besides, as NO can react with superoxide anion to produce peroxynitrite, a highly oxidative compound, the use of FeTPPS to inhibit its formation indicated its participation in DNA damage and cell death, further highlighting the important role of NO. Finally, a possible key role for AhR was pointed out by using its antagonist, CH-223191. Indeed it prevented the elevation of ADH activity, known to participate to the ethanol production of ROS, notably superoxide anion. The transcription factor, NFκB, known to be activated by ROS, was shown to be involved in the increase in iNOS expression. Altogether, these data strongly suggested cooperative mechanistic interactions between B[a]P via AhR and ethanol via ROS production, to favor cell death in the context of prior steatosis.


Examination of a large patient population for the presence of symptoms and signs of temporomandibular disorders.
Temporomandibular Disorder (TMD) is a term generally applied to a condition or conditions characterized by pain and/or dysfunction of the masticatory apparatus. Its characterization has been difficult because of the large number of symptoms and signs attributed to this disorder and to variation in the number and types manifested in any particular patient. For this study, data on 4,528 patients, presenting over a period of 25 years to a single examiner for TMD treatment, was made available for retrospective analysis and determination of whether the TMD care-seeking patient can be profiled, particularly pain difficulties. All patients in this database filled out a questionnaire and were examined for the prevalence of a range of symptoms and clinical examination findings (signs) commonly attributed to TMD. There was no attempt in this study to assign patients to TMD diagnostic subcategories. The data collected were analyzed to determine which of these symptoms and signs were sufficiently "characteristic of the TMD condition" that they might be used in diagnosis, research and treatment, especially in patients needing relief from pain and discomfort. All 4,528 patients reported symptoms and all but 190 of them also showed signs upon examination. Symptoms most commonly reported on the questionnaire included (i) pain (96.1%), (ii) headache (79.3%), (iii) temporomandibular joint discomfort or dysfunction (75.0%) and (iv) ear discomfort or dysfunction (82.4%). In the 4,338 patients who showed signs, the most prevalent was tenderness to palpation of the pterygoid muscles (85.1%), followed by tenderness to palpation of the temporomandibular joints (62.4%). Pain symptoms and signs were often accompanied by compromised mandibular movements, TMJ sounds and dental changes, such as incisal edge wear and excessive overbite. Clearly prevalence of pain disclosed by the symptoms and signs examinations was high. Patients showed variable prevalence and nonprevalence of eight categories of painful symptoms and seven categories of painful signs. Despite the variability, these might be developed in the future into TMD scores or indices for studying and unraveling the TMD conundrum.


Single- and cross-commodity discounting among cocaine addicts: the commodity and its temporal location determine discounting rate.
Intertemporal choice has provided important insights into understanding addiction, predicted drug-dependence status, and outcomes of treatment interventions. However, such analyses have largely been based on the choice of a single commodity available either immediately or later (e.g., money now vs. money later). In real life, important choices for those with addiction depend on making decisions across commodities, such as between drug and non-drug reinforcers. To date, no published study has systematically evaluated intertemporal choice using all combinations of a drug and a non-drug commodity. In this study, we examine the interaction between intertemporal choice and commodity type in the decision-making process of cocaine-dependent individuals. This study of 47 treatment-seeking cocaine addicts analyzes intertemporal choices of two commodities (equated amounts of cocaine and money), specifically between cocaine now vs. cocaine later (C-C), money now vs. money later (M-M), cocaine now vs. money later (C-M), and money now vs. cocaine later (M-C). Cocaine addicts discounted significantly more in the C-C condition than in M-M (P = 0.032), consistent with previous reports. Importantly, the two cross-commodity discounting conditions produced different results. Discounting in C-M was intermediate to the C-C and M-M rates, while the greatest degree of discounting occurred in M-C. These data indicate that the menu of commodities offered alter discounting rates in intertemporal choice and that the greatest rate is obtained when the drug is the later available commodity. Implications for understanding intertemporal choices and addiction are addressed.