The efficacy and safety of autologous conditioned serum (ACS) injections compared with betamethasone and placebo injections in the treatment of chronic shoulder joint pain due to supraspinatus tendinopathy: a prospective, randomized, double-blind, controlled study.
Autologous conditioned serum (ACS; marketed as Orthokine®) is an autologous blood product that has previously shown efficacy in treatment of joint osteoarthritis, spinal radiculopathy, tendon and muscle injuries in randomized controlled trials. In this 24-week, randomized, double-blind study, we compared the efficacy and safety of ACS with glucocorticoid (betamethasone) injections in chronic supraspinatus tendinopathy patients. Thirty-two patients with chronic supraspinatus tendinopathy were enrolled in the study. The ACS group received four ACS injections once weekly over four weeks and the glucocorticoid group received three betamethasone injections once weekly over three weeks with a placebo (saline) injection at week 4 into the enthesis and paratenon of the supraspinatus tendon. Study endpoints were pain intensity (VAS) and Constant Shoulder Score (CSS) assessed at weeks 0, 4 and 24. Shoulder pain intensity improved after 4 weeks and significantly improved after 24 weeks in patients treated with ACS compared with those treated with glucocorticoids (pain intensity week 4: ACS=22.0, glucocorticoid=32.0; week 24: ACS=15.0, glucocorticoid=40.0). CSS improved to a similar extent in both groups after 4 weeks. After 24 weeks, ACS patients exhibited significantly greater CSS improvements than glucocorticoid patients. Adverse events (n=8) were reported in betamethasone patients. Compared with betamethasone, ACS therapy improved joint function and reduced shoulder pain more effectively after 4 weeks of treatment; these improvements were sustained to week 24. Combined with its favorable safety profile, ACS appears to be a more effective treatment than glucocorticoids and could enhance the quality of life in patients with chronic rotator cuff tendinopathy.


Longitudinal evaluation of sexual function in a cohort of pre- and postmenopausal women.
Aspects of women's sexual functioning that have received relatively little attention are its stability and how changes in the different sexual response domains influence each other over time. The aim of this study was to describe the changes and to evaluate the stability of self-reported sexual functioning over a 4-year period in a population sample of British women. A 4-year follow-up study on N = 507 women, including 178 pre- and 329 postmenopausal women, was conducted. The validated Female Sexual Function Index (FSFI) was applied. A multigroup path analytical model was used to examine autoregressive effects (the effect of a domain on itself at a later point in time) and cross-lag effects (one variable affecting another variable at a later point in time) across all FSFI domains of sexual functioning between pre- and postmenopausal women. Overall, the proportion of postmenopausal women suffering from a sexual dysfunction at measurement point 1 (T1) was higher compared with premenopausal women (pre: 34.3% vs. post: 14.5%). However, both groups showed a comparable number of women developing a sexual problem (pre: 22.2% vs. post: 23.2%) or improving their sexual functioning (7.4% vs. 7.6%) after the 4 years. Furthermore, path model analyses revealed that each domain at T1 significantly predicted its level 4 years later (βs ranging from 0.33 for arousal to 0.57 for lubrication), with the exception of sexual satisfaction. In terms of cross-lag effects, the changes in all domains except for pain were predicted either by levels of desire, arousal, or orgasm at T1 (βs ranging from 0.18 to 0.36) in both groups. Women's sexual functioning was moderately stable across the 4 years. The main predictors of changes in sexual functioning and satisfaction were desire and arousal, highlighting their role as possible key players in women's sexual health.


Integrating nutrition and immunology: a new frontier.
Nutrition is critical to immune defence and parasite resistance, which not only affects individual organisms, but also has profound ecological and evolutionary consequences. Nutrition and immunity are complex traits that interact via multiple direct and indirect pathways, including the direct effects of nutrition on host immunity but also indirect effects mediated by the host's microbiota and pathogen populations. The challenge remains, however, to capture the complexity of the network of interactions that defines nutritional immunology. The aim of this paper is to discuss the recent findings in nutritional research in the context of immunological studies. By taking examples from the entomological literature, we argue that insects provide a powerful tool for examining the network of interactions between nutrition and immunity due to their tractability, short lifespan and ethical considerations. We describe the relationships between dietary composition, immunity, disease and microbiota in insects, and highlight the importance of adopting an integrative and multi-dimensional approach to nutritional immunology.


A randomized trial of yogurt for prevention of antibiotic-associated diarrhea.
Antibiotic-associated diarrhea (AAD) is the most common adverse effect of antibiotic therapy. Our aim was to determine the effectiveness of a dietary supplement of yogurt for prevention of AAD. Two hundred two hospitalized patients receiving oral or intravenous antibiotics were randomized to receive or not receive a dietary yogurt supplement, consisting of 227 grams of commercial yogurt, and followed for 8 days. Mean age of the study group was 70 years and 43% were male. Compliance and 8-day follow-up were 85% and 91%, respectively. Patients receiving yogurt reported less frequent diarrhea (12% vs 24%; P = 0.04), and significantly less total diarrhea] days (23 vs 60). The cumulative proportions of patients without diarrhea were significantly different (P = 0.02) between patients receiving and not receiving yogurt. For conclusion, dietary supplementation with yogurt is a simple, effective, and safe treatment that decreases the incidence and duration of AAD.


Current and past smoking patterns in a Central European urban population: a cross-sectional study in a high-burden country.
Many studies have examined the socioeconomic variations in smoking and quitting rates across the European region; however, data from Central and East European countries, where the tobacco burden is especially high, are sparse. This study aimed to assess the patterns in current and past smoking prevalence based on cross-sectional data from a Central European urban population sample. Data from 2160 respondents aged 25-64 years in Brno, Czech Republic were collected in 2013-2014 using the Czech post-MONICA survey questionnaire to assess the prevalence of cardiovascular risk factors, including smoking status. The age- and sex-stratified randomized sample was drawn using health insurance registries. Descriptive statistics and quit ratios were calculated, and chi-square and multivariate logistic analyses conducted to examine relationships between current and past smoking and demographic (age, gender, marital status) and socioeconomic variables (education, income, occupation). The prevalence of current and past smoking was 23.6 and 31.3 % among men and 20.5 and 23.2 % among women, respectively. Education reliably predicted smoking and quitting rates in both genders. Among men, being unemployed was associated with greater odds of smoking (OR 3.6; 1.6-8.1) and lower likelihood of quitting (OR 0.2: 0.1-0.6); the likelihood of quitting also increased with age (OR 1.8; 1.2-2.8). Among women, marital status (being married) decreased the odds of current smoking (OR 0.6; 0.4-0.9) and increased the odds of quitting (OR 2.2; 1.2-3.9). Quit ratios were the lowest in the youngest age group (25-34 years) where quitting was more strongly associated with middle income (OR 2.7; 95 % CI 1.2-5.9) than with higher education (OR 2.9; 95 % CI 0.9-8.2). Interventions to increase cessation rates and reduce smoking prevalence need to be gender-specific and carefully tailored to the needs of the disadvantaged groups of the population, especially the less well-off young adults. Future studies should examine the equity impact of the tobacco control policies and be inclusive of the Central and East European countries.


Awareness of osteoporotic patients.
Osteoporosis has recently been recognized as a major public health problem by some governments and health care providers. Despite significant progress in knowledge about osteoporosis, public awareness is required for effective management if precautions are to be taken. The aim of this study was to evaluate the educational status of osteoporotic individuals, and their awareness about the disease and sources of information. We also aimed to compare the variables between the geographical regions of the country, since significant differences exist in socioeconomic status and lifestyle within the same cultural context. This multicenter study was carried out in eight cities located in six different geographical regions between September 2001 and January 2002. To our knowledge, this is the first multicenter study in Turkey evaluating the relationship between awareness of osteoporotic patients and other variables such as educational level and economic factors. Ten centers took part in this study and consecutive patients with either femoral or lumbar T-scores below -2.5 SD were enrolled into the study group. Bone mineral density was measured using dual energy X-ray absorptiometry (DXA). Patients were interviewed using a questionnaire on past medical history, education, awareness about their disease and risk factors for osteoporosis. A total of 540 women (93.8%) and 36 men (6.3%) were included in the study. Fifty-four percent of patients declared that they were aware of osteoporosis. With regard to sources of information, 56.8% of patients reported physicians as the main source of information. Awareness of the patients was negatively correlated with age (P=0.025, r=-0,94) but positively correlated with education (P=0.0001, r=0.327), level of physical activity (P=0.001, r=143), calcium intake (P=0.005, r=119) and modern clothing style (P=0.0001, r=309). Educational status of the patients was negatively correlated with BMI (P=0.0001, r=-283) and positively correlated with physical activity (P=0.0001, r=268), modern clothing style (P=0.0001, r=600) and smoking (P=0.0001, r=273). Regional comparison of female patients demonstrated that significant differences exist in terms of educational status, clothing style, smoking, level of physical activity, calcium intake, and knowledge about osteoporosis. As a result, education has profound effects on awareness about osteoporosis and many aspects of human behavior, such as calcium intake, physical activity, clothing style and smoking. Significant disparities may be observed between the geographical regions of the same country.


Glucocorticoid-induced osteoporosis.
Glucocorticoid treatment can alter bone metabolism, reduce bone strength, and increase the risk for osteoporotic fractures. Risk factors for glucocorticoid-induced osteoporosis (GIO) include older age, high doses, and longer duration of glucocorticoid use. The bone loss that accompanies glucocorticoid use is rapid, and early treatment with bone-sparing agents can prevent bone loss and reduce fracture risk. Several randomized controlled clinical trials have found prevention and treatment of GIO with bisphosphonates, and recently the treatment of GIO with teriparatide, to be effective. This article reviews current information on the epidemiology, pathophysiology, and clinical studies that support using bone-active agents to prevent and treat GIO.


Molecularly imprinted hydrogels as functional active packaging materials.
This paper describes the synthesis of novel molecularly imprinted hydrogels (MIHs) for the natural antioxidant ferulic acid (FA), and their application as packaging materials to prevent lipid oxidation of butter. A library of MIHs was synthesized using a synthetic surrogate of FA, 3-(4-hydroxy-3-methoxyphenyl)propionic acid (HFA), as template molecule, ethyleneglycol dimethacrylate (EDMA) as cross-linker, and 1-allylpiperazine (1-ALPP) or 2-(dimethylamino)ethyl methacrylate (DMAEMA), in combination with 2-hydroxyethyl methacrylate (HEMA) as functional monomers, at different molar concentrations. The DMAEMA/HEMA-based MIHs showed the greatest FA loading capacity, while the 1-ALLP/HEMA-based polymers exhibited the highest imprinting effect. During cold storage, FA-loaded MIHs protected butter from oxidation and led to TBARs values that were approximately half those of butter stored without protection and 25% less than those recorded for butter covered with hydrogels without FA, potentially extending the shelf life of butter. Active packaging is a new field of application for MIHs with great potential in the food industry.


Gender and Time for Sleep among U.S. Adults.
Do women really sleep more than men? Biomedical and social scientific studies show longer sleep durations for women, a surprising finding given sociological research showing women have more unpaid work and less high-quality leisure time compared to men. We assess explanations for gender differences in time for sleep, including compositional differences in levels of engagement in paid and unpaid labor, gendered responses to work and family responsibilities, and differences in napping, bedtimes, and interrupted sleep for caregiving. We examine the overall gender gap in time for sleep as well as gaps within family life-course stages based on age, partnership, and parenthood statuses. We analyze minutes of sleep from a diary day collected from nationally representative samples of working-age adults in the American Time Use Surveys of 2003 to 2007. Overall and at most life course stages, women slept more than men. Much of the gap is explained by work and family responsibilities and gendered time tradeoffs; as such, gender differences vary across life course stages. The gender gap in sleep time favoring women is relatively small for most comparisons and should be considered in light of the gender gap in leisure time favoring men at all life course stages.


Barriers to mucosal transmission of immunodeficiency viruses.
Lentiviruses such as HIV have a daunting challenge in gaining access to a new host predominantly through the penile, rectal, or vaginal/cervical mucosal tissue after sexual exposure. Multiple mechanisms have evolved to help prevent such infections, including anatomical barriers, innate inhibitors, and adaptive immune responses. For lentiviruses, it appears that in naive or even conventionally vaccinated hosts, typical adaptive immune responses are generally too little and too late to prevent infection. Nevertheless, a combination of anatomical barriers and innate immune responses may limit transmission, especially in patients without predisposing conditions such as mucosal lesions or preexisting sexually transmitted infections. Furthermore, when infection does occur, most often the primary viremia of the acute infection can be traced back genetically to a single founder virus. Unfortunately, even a single virion can establish an infection that will ultimately lead to the demise of the host. This review seeks to describe the biology of and barriers to establishment of systemic, disseminated productive infection with HIV after sexual exposure and to discuss the possible mechanisms leading to infection by a single viral variant. Understanding the initial events of infection, before systemic spread, could provide insights into strategies for reducing acquisition or ameliorating clinical outcome.


Association of Topoisomerase II (TOP2A) and Dual-Specificity Phosphatase 6 (DUSP6) Single Nucleotide Polymorphisms with Radiation Treatment Response and Prognosis of Lung Cancer in Han Chinese.
BACKGROUND Mutations of DNA topoisomerase II (TOP2A) are associated with chemotherapy resistance, whereas dual-specificity phosphatase 6 (DUSP6) negatively regulates members of the mitogen-activated protein (MAP) kinase superfamily to control cell proliferation. This study assessed TOP2A and DUSP6 single nucleotide polymorphisms (SNPs) in non-small cell lung cancer (NSCLC) patients for association with chemoradiotherapy responses and prognosis. MATERIAL AND METHODS A total of 140 Chinese patients with histologically confirmed NSCLC were enrolled and subjected to genotyping of TOP2A rs471692 and DUSP6 rs2279574 using Taqman PCR. An independent sample t test was used to analyze differences in tumor regression after radiotherapy versus SNP risk factors. Kaplan-Meier curves analyzed overall survival, followed by the log-rank test and Cox proportional hazard models. RESULTS There were no significant associations of TOP2A rs471692 and DUSP6 rs2279574 polymorphisms or clinicopathological variables with response to chemoradiotherapy (p>0.05). Comparing overall survival of 87 patients with stage I-III NSCLC treated with radiotherapy or chemoradiotherapy to clinicopathological variables, the data showed that tumor regression, weight loss, clinical stage, and cigarette smoking were independent prognostic predictors (p=0.009, 0.043, 0.004, and 0.025, respectively). Tumor regression rate >0.34 was associated with patent survival versus tumor regression rate ≤0.34 (p=0.007). CONCLUSIONS TOP2A rs471692 and DUSP6 rs2279574 SNPs were not associated with chemoradiotherapy response, whereas tumor regression, weight loss, clinical stage, and cigarette smoking were independent prognostic predictors for these Chinese patients with NSCLC.


The (cost-)effectiveness of an individually tailored long-term worksite health promotion programme on physical activity and nutrition: design of a pragmatic cluster randomised controlled trial.
Cardiovascular disease is the leading cause of disability and mortality in most Western countries. The prevalence of several risk factors, most notably low physical activity and poor nutrition, is very high. Therefore, lifestyle behaviour changes are of great importance. The worksite offers an efficient structure to reach large groups and to make use of a natural social network. This study investigates a worksite health promotion programme with individually tailored advice in physical activity and nutrition and individual counselling to increase compliance with lifestyle recommendations and sustainability of a healthy lifestyle. The study is a pragmatic cluster randomised controlled trial with the worksite as the unit of randomisation. All workers will receive a standard worksite health promotion program. Additionally, the intervention group will receive access to an individual Health Portal consisting of four critical features: a computer-tailored advice, a monitoring function, a personal coach, and opportunities to contact professionals at request. Participants are employees working for companies in the Netherlands, being literate enough to read and understand simple Internet-based messages in the Dutch language.A questionnaire to assess primary outcomes (compliance with national recommendations on physical activity and on fruit and vegetable intake) will take place at baseline and after 12 and 24 months. This questionnaire also assesses secondary outcomes including fat intake, self-efficacy and self-perceived barriers on physical activity and fruit and vegetable intake. Other secondary outcomes, including a cardiovascular risk profile and physical fitness, will be measured at baseline and after 24 months. Apart from the effect evaluation, a process evaluation will be carried out to gain insight into participation and adherence to the worksite health promotion programme. A cost-effectiveness analysis and sensitivity analysis will be carried out as well. The unique combination of features makes the individually tailored worksite health promotion programme a promising tool for health promotion. It is hypothesized that the Health Portal's features will counteract loss to follow-up, and will increase compliance with the lifestyle recommendations and sustainability of a healthy lifestyle. Current Controlled Trials ISRCTN52854353.


Social Impact Bonds as a Funding Method for Health and Social Programs: Potential Areas of Concern.
Social Impact Bonds (SIBs) represent a new way to finance social service and health promotion programs whereby different types of investors provide an upfront investment of capital. If a given program meets predetermined criteria for a successful outcome, the government pays back investors with interest. Introduced in the United Kingdom in 2010, SIBs have since been implemented in the United States and across Europe, with some uptake in other jurisdictions. We identify and explore selected areas of concern related to SIBs, drawing from literature examining market-based reforms to health and social services and the evolution of the SIB funding mechanism. These areas of concern include increased costs to governments, restricted program scope, fragmented policymaking, undermining of public-sector service provision, mischaracterization of the root causes of social problems, and entrenchment of systemically produced vulnerabilities. We argue that it is essential to consider the long-term, aggregate, and contextualized effects of SIBs in order to evaluate their potential to contribute to public health. We conclude that such evaluations must explore the assumptions underlying the "common sense" arguments often used in support of SIBs.


Alcohol and drug misuse, abuse, and dependence in women veterans.
We conducted a systematic literature review on substance misuse, abuse, and dependence in women veterans, including National Guard/reserve members. We identified 837 articles published between 1980 and 2013. Of 56 included studies, 32 reported rates of alcohol misuse, binge drinking, or other unhealthy alcohol use not meeting diagnostic criteria for abuse or dependence, and 33 reported rates of drug misuse or diagnosed alcohol or drug use disorders. Rates ranged from 4% to 37% for alcohol misuse and from 7% to 25% for binge drinking; among Veterans Health Administration (VA) health-care system outpatients, rates ranged from 3% to 16% for substance use disorder. Studies comparing women veterans and civilians reported no clear differences in binge or heavy drinking. Substance misuse rates were generally lower among women veterans than men veterans. Substance misuse was associated with higher rates of trauma, psychiatric and medical conditions, and increased mortality and suicide rates. Most studies included only VA patients, and many used only VA medical record data; therefore, the reported substance misuse rates likely do not reflect true prevalence. Rates also varied by assessment method, source of data, and the subgroups studied. Further efforts to develop epidemiologically valid prevalence estimates are needed to capture the true health burden of substance misuse in women veterans, particularly those not using VA care.


Glaucoma-Related Adverse Events in the First 5 Years After Unilateral Cataract Removal in the Infant Aphakia Treatment Study.
Glaucoma-related adverse events constitute major sight-threatening complications of cataract removal in infancy, yet their relationship to aphakia vs primary intraocular lens (IOL) implantation remains unsettled. To identify and characterize cases of glaucoma and glaucoma-related adverse events (glaucoma + glaucoma suspect) among children in the Infant Aphakia Treatment Study by the age of 5 years. A multicenter randomized clinical trial of 114 infants with unilateral congenital cataract in referral centers who were between ages 1 and 6 months at surgery. Mean follow-up was 4.8 years. This secondary analysis was conducted from December 23, 2004, to November 13, 2013. Participants were randomized at cataract surgery to either primary IOL or no IOL implantation (contact lens). Standardized definitions of glaucoma and glaucoma suspect were created for the Infant Aphakia Treatment Study and applied for surveillance and diagnosis. Development of glaucoma and glaucoma + glaucoma suspect in operated on eyes for children up to age 5 years, plus intraocular pressure, visual acuity, and axial length at age 5 years. Product limit estimates of the risk for glaucoma and glaucoma + glaucoma suspect at 4.8 years after surgery were 17% (95% CI, 11%-25%) and 31% (95% CI, 24%-41%), respectively. The contact lens and IOL groups were not significantly different for either outcome: glaucoma (hazard ratio [HR], 0.8; 95% CI, 0.3-2.0; P = .62) and glaucoma + glaucoma suspect (HR, 1.3; 95% CI, 0.6-2.5; P = .58). Younger (vs older) age at surgery conferred an increased risk for glaucoma (26% vs 9%, respectively) at 4.8 years after surgery (HR, 3.2; 95% CI, 1.2-8.3), and smaller (vs larger) corneal diameter showed an increased risk for glaucoma + glaucoma suspect (HR, 2.5; 95% CI, 1.3-5.0). Age and corneal diameter were significantly positively correlated. Glaucoma was predominantly open angle (19 of 20 cases, 95%), most eyes received medication (19 of 20, 95%), and 8 of 20 eyes (40%) underwent surgery. These results suggest that glaucoma-related adverse events are common and increase between ages 1 and 5 years in infants after unilateral cataract removal at 1 to 6 months of age; primary IOL placement does not mitigate their risk but surgery at a younger age increases the risk. Longer follow-up of these children may further characterize risk factors, long-term outcomes, potential differences between eyes having primary IOL vs aphakia, and optimal timing of unilateral congenital cataract removal. clinicaltrials.gov Identifier: NCT00212134.


A broad range assay for rapid detection and etiologic characterization of bacterial meningitis: performance testing in samples from sub-Sahara.
This study aimed to conduct a pilot evaluation of broad-based multiprobe polymerase chain reaction (PCR) in clinical cerebrospinal fluid (CSF) samples compared to local conventional PCR/culture methods used for bacterial meningitis surveillance. A previously described PCR consisting of initial broad-based detection of Eubacteriales by a universal probe, followed by Gram typing, and pathogen-specific probes was designed targeting variable regions of the 16S rRNA gene. The diagnostic performance of the 16S rRNA assay in ""127 CSF samples was evaluated in samples from patients from Togo, Africa, by comparison to conventional PCR/culture methods. Our probes detected Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. Uniprobe sensitivity and specificity versus conventional PCR were 100% and 54.6%, respectively. Sensitivity and specificity of uniprobe versus culture methods were 96.5% and 52.5%, respectively. Gram-typing probes correctly typed 98.8% (82/83) and pathogen-specific probes identified 96.4% (80/83) of the positives. This broad-based PCR algorithm successfully detected and provided species level information for multiple bacterial meningitis agents in clinical samples.


Catalan speakers' perception of word stress in unaccented contexts.
In unaccented contexts, formant frequency differences related to vowel reduction constitute a consistent cue to word stress in English, whereas in languages such as Spanish that have no systematic vowel reduction, stress perception is based on duration and intensity cues. This article examines the perception of word stress by speakers of Central Catalan, in which, due to its vowel reduction patterns, words either alternate stressed open vowels with unstressed mid-central vowels as in English or contain no vowel quality cues to stress, as in Spanish. Results show that Catalan listeners perceive stress based mainly on duration cues in both word types. Other cues pattern together with duration to make stress perception more robust. However, no single cue is absolutely necessary and trading effects compensate for a lack of differentiation in one dimension by changes in another dimension. In particular, speakers identify longer mid-central vowels as more stressed than shorter open vowels. These results and those obtained in other stress-accent languages provide cumulative evidence that word stress is perceived independently of pitch accents by relying on a set of cues with trading effects so that no single cue, including formant frequency differences related to vowel reduction, is absolutely necessary for stress perception.


Bioclimatic niches are conserved and unrelated to pollination syndromes in Antillean Gesneriaceae.
The study of the evolution of abiotic niches can be informative regarding the speciation drivers in a given group. Yet, two factors that could potentially affect niche evolution have seldom been addressed concomitantly, which are biotic interactions and geographical isolation. In this study, we used as a model group the Antillean plant genera Gesneria and Rhytidophyllum (Gesneriaceae) to evaluate the effect of pollinators and geographical isolation on the bioclimatic niche. These genera possess species characterized by interspecific geographical isolation in different islands and are pollinated by different pollinators. Some species are pollinated by hummingbirds, other by bats, while some are more generalists and are pollinated by pollinators from both functional groups. After describing the bioclimatic niches of plant species, we measured niche overlap for species pairs and we fitted Brownian motion and Ornstein-Uhlenbeck (OU) evolution models with multiple evolutionary regimes to test for an effect of pollination strategy or geographical isolation on bioclimatic niche evolution of these plants. The analysis of niche overlap between plant species, which could not be corrected for phylogenetic relationships, showed that it was significantly influenced by pollination mode and island distribution. By contrast, the best fitting evolutionary model on niche optima and tolerance was always an OU model with a unique selective regime, suggesting that neither pollination strategy nor island isolation had an important effect on bioclimatic niches at a macroevolutionary scale. Instead, we conclude that bioclimatic niches of Antillean Gesneriaceae evolved under phylogenetic conservatism and hypothesize that this macroevolutionary pattern could result from adaptation to temporally variable climates in the Antilles.


Psychometric properties of an African symptoms check list scale: the Ndetei-Othieno-Kathuku scale.
To profile and quantify the psychometric properties of the NOK (Ndetei-Othieno-Kathuku) scale against internationally used Gold-standards and benchmarks for mild psychiatric disorders and post-traumatic stress disorders and to provide a potential easy to administer culture sensitive instrument for screening and assessing those with possible psychiatric disorders for the Kenyan and similar social-cultural situations. Cross-Sectional quantitative study. A psychiatric clinical consultation setting and Kyanguli Secondary School psychotrauma counselling clinical set-up. Survivors of the Nairobi USA Embassy bombing who were referred for psychiatric treatment and survivors of a fire disaster from a rural Kenyan school (Kyanguli School fire disaster) including students, parents of the diseased children and staff members. Positive correlation was found between the NOK and all the instruments. The highest correlations were between the NOK and the BDI and SCL-90 (r = 0.557 to 0.786). The differences between the NOK scores among the different groups were statistically significant (F ratio = 13.54 to 160.34, p < 0.01). The reliability coefficient (internal consistency) of the scale, alpha = 0.9733. Other item statistics and correlations of the scale are discussed. It is concluded that the NOK has high concurrent and discriminant validity as well as a high internal consistency and that it can be used for the rapid assessment of psychotrauma victims of all age groups; and stress in general in similar age groups in the local setting. It is culture appropriate and sensitive.


Forest succession and population viability of grassland plants: long repayment of extinction debt in Primula veris.
Time lags in responses of organisms to deteriorating environmental conditions delay population declines and extinctions. We examined how local processes at the population level contribute to extinction debt, and how cycles of habitat deterioration and recovery may delay extinction. We carried out a demographic analysis of the fate of the grassland perennial Primula veris after the cessation of grassland management, where we used either a unidirectional succession model for forest habitat or a rotation model with a period of forest growth followed by a clear-cut and a new successional cycle. The simulations indicated that P. veris populations may have an extinction time of decades to centuries after a detrimental management change. A survey of the current incidence and abundance of P. veris in sites with different histories of afforestation confirmed the simulation results of low extinction rates. P. veris had reduced incidence and abundance only at sites with at least 100 years of forest cover. Time to extinction in simulations was dependent on the duration of the periods with favourable and unfavourable conditions after management cessation, and the population sizes and growth rates in these periods. Our results thus suggest that the ability of a species to survive is a complex function of disturbance regimes, rates of successional change, and the demographic response to environmental changes. Detailed demographic studies over entire successional cycles are therefore essential to identify the environmental conditions that enable long-term persistence and to design management for species experiencing extinction debts.


Oxidative mutagenesis, mismatch repair, and aging.
A PubMed search for the term "oxidative stress" yields over 29,000 articles published on the subject over the past 10 years; more than 2000 of these articles also include the term "aging" in their title or abstract. Many theories of aging predict causal roles for oxidative stress in the myriad of pathological changes that occur as a function of age, including an increasing propensity to develop cancer. A possible link between aging and cancer is the induction and accumulation of somatic mutations caused by oxidative stress. This Review focuses on small mutational events that are induced by oxidative stress and the role of mismatch repair (MMR) in preventing their formation. It also discusses a possible inhibitory effect of oxidative stress on MMR. We speculate that a synergistic interaction between oxidative damage to DNA and reduced MMR levels will, in part, account for an accumulation of small mutational events, and hence cancer, with aging.


On the proportion of cancer stem cells in a tumour.
It is now generally accepted that cancers contain a sub-population, the cancer stem cells (CSCs), which initiate and drive a tumour's growth. At least until recently it has been widely assumed that only a small proportion of the cells in a tumour are CSCs. Here we use a mathematical model, supported by experimental evidence, to show that such an assumption is unwarranted. We show that CSCs may comprise any possible proportion of the tumour, and that the higher the proportion the more aggressive the tumour is likely to be.


Uncommon Histopathological Variants of Malignant Melanoma. Part 2.
Despite new horizons opened by recent advances in molecular pathology, histological evaluation still remains the diagnostic gold standard regarding cutaneous melanocytic neoplasms. Several histological variants of melanoma have been described, and their knowledge is crucial for accurate diagnosis and classification of cases with unusual clinico-pathological features. Uncommon histological variants of melanoma have been described based on a broad constellation of features, including architectural pattern, stromal alterations, cytological attributes, and other morphological properties. This review is aimed at providing an extensive discussion of unusual but distinctive histopathological variants of melanoma.


Peripherally inserted central catheter-related bloodstream infection caused by Kocuria marina in an elderly man.
Kocuria species are Gram-positive, aerobic cocci, and members of the Micrcoccaceae family that are known to be opportunistic pathogens. Although there have been sporadic reports of infections caused by Kocuria species, little is known regarding their human pathogenicity and clinical characteristics. We herein report a case of a peripherally inserted central catheter (PICC)-related bloodstream infection caused by Kocuria marina in a 90-year-old Japanese with multiple cancer. The patient, who was admitted due to adhesive intestinal obstruction, suddenly developed sepsis on day 29 following admission. Three sets of blood cultures and a culture of the PICC tip revealed the growth of Gram-positive cocci arranged in clusters. The patient improved quickly after treatment with an antimicrobial agent and catheter removal. The organism was identified as Kocuria varians using the MicroScan Walkaway system and K. varians/Kocuria rosea with a 99.7% probability using an API Staph system. However, 16S rRNA gene sequencing analysis identified the pathogen as K. marina. Although K. marina is a rare pathogen, physicians should consider it in case of catheter-related infections in patients with serious underlying conditions. As commercial identification systems can misidentify species within the Kocuria genus, the use of genomic methods such as 16S rRNA sequencing and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry may be useful for the precise identification of Kocuria to the species level.


Stress, intertemporal choice, and mitigation behavior during the COVID-19 pandemic.
Delayed gratification is an important focus of research, given its potential relationship to forms of behavior, such as savings, susceptibility to addiction, and pro-social behaviors. The COVID-19 pandemic may be one of the most consequential recent examples of this phenomenon, with people's willingness to delay gratification affecting their willingness to socially distance themselves. COVID-19 also provides a naturalistic context by which to evaluate the ecological validity of delayed gratification. This article outlines four large-scale online experiments (total N = 12, 906) where we ask participants to perform Money Earlier or Later (MEL) decisions (e.g., $5 today vs. $10 tomorrow) and to also report stress measures and pandemic mitigation behaviors. We found that stress increases impulsivity and that less stressed and more patient individuals socially distanced more throughout the pandemic. These results help resolve longstanding theoretical debates in the MEL literature as well as provide policymakers with scientific evidence that can help inform response strategies in the future. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Rheological and biological properties of a hydrogel support for cells intended for intervertebral disc repair.
Cell-based approaches towards restoration of prolapsed or degenerated intervertebral discs are hampered by a lack of measures for safe administration and placement of cell suspensions within a treated disc. In order to overcome these risks, a serum albumin-based hydrogel has been developed that polymerizes after injection and anchors the administered cell suspension within the tissue. A hydrogel composed of chemically activated albumin crosslinked by polyethylene glycol spacers was produced. The visco-elastic gel properties were determined by rheological measurement. Human intervertebral disc cells were cultured in vitro and in vivo in the hydrogel and their phenotype was tested by reverse-transcriptase polymerase chain reaction. Matrix production and deposition was monitored by immuno-histology and by biochemical analysis of collagen and glycosaminoglycan deposition. Species specific in situ hybridization was performed to discriminate between cells of human and murine origin in xenotransplants. The reproducibility of the gel formation process could be demonstrated. The visco-elastic properties were not influenced by storage of gel components. In vitro and in vivo (subcutaneous implants in mice) evidence is presented for cellular differentiation and matrix deposition within the hydrogel for human intervertebral disc cells even for donor cells that have been expanded in primary monolayer culture, stored in liquid nitrogen and re-activated in secondary monolayer culture. Upon injection into the animals, gels formed spheres that lasted for the duration of the experiments (14 days). The expression of cartilage- and disc-specific mRNAs was maintained in hydrogels in vitro and in vivo, demonstrating the maintenance of a stable specific cellular phenotype, compared to monolayer cells. Significantly higher levels of hyaluronan synthase isozymes-2 and -3 mRNA suggest cell functionalities towards those needed for the support of the regeneration of the intervertebral disc. Moreover, mouse implanted hydrogels accumulated 5 times more glycosaminoglycans and 50 times more collagen than the in vitro cultured gels, the latter instead releasing equivalent quantities of glycosaminoglycans and collagen into the culture medium. Matrix deposition could be specified by immunohistology for collagen types I and II, and aggrecan and was found only in areas where predominantly cells of human origin were detected by species specific in situ hybridization. The data demonstrate that the hydrogels form stable implants capable to contain a specifically functional cell population within a physiological environment.


Synergistic interaction between the HDAC inhibitor, MPT0E028, and sorafenib in liver cancer cells in vitro and in vivo.
To investigate the antitumor activities of a histone deacetylase (HDAC) inhibitor, MPT0E028, plus sorafenib in liver cancer cells in vitro and in vivo. Different liver cancer cell lines were exposed to sorafenib in the presence or absence of MPT0E028, and cell viability was determined by MTT assay. Effects of combined treatment on cell cycle and intracellular signaling pathways were assessed by flow cytometry and Western blot analysis. The Hep3B xenograft model was used to examine the antitumor activity in vivo. Our data indicate that sorafenib and MPT0E028 synergistically reduced cell viability in liver cancer cells, and also markedly induced apoptotic cell death in these cells, as evidenced by the cleavage of caspase-3, PARP, and DNA fragmentation. MPT0E028 altered the global modifications of histone and nonhistone proteins regardless of the presence of sorafenib. However, sorafenib blocked MPT0E028-induced Erk activation and its downstream signaling cascades, such as Stat3 phosphorylation (Ser(727)) and Mcl-1 upregulation. Ectopic expression of constitutively active Mek successively reversed the apoptosis triggered by the combined treatment. Pharmacologic inhibition of Mek by PD98059 potentiated MPT0E028-induced apoptosis, suggesting that the synergistic interaction between MPT0E028 and sorafenib occurs at least partly through inhibition of Erk signaling. The data demonstrated that transcriptional activation of fibroblast growth factor receptor 3 (FGFR3) contributes to MPT0E028-mediated Erk phosphorylation. Finally, MPT0E028 plus sorafenib significantly improved the tumor growth delay (TGD) in a Hep3B xenograft model. These findings suggest that MPT0E028 in combination with sorafenib has significant anti-hepatocellular carcinoma activity in preclinical models, potentially suggesting a novel therapeutic strategy for patients with advanced hepatocellular carcinoma.


Computer-assisted cognitive-behavioral therapy for adolescent depression in primary care clinics in Santiago, Chile (YPSA-M): study protocol for a randomized controlled trial.
Depression is a common and disabling condition. In Chile, assistance is guaranteed by law through a national program for depression in primary care services, and there is evidence of effective treatment for depressed women. However, there is a shortage of evidence-based treatments for depression in adolescents. The incorporation of technology to expand therapeutic options is becoming more common. This proposal aims to compare the efficacy of therapy that enhances traditional face-to-face cognitive-behavioral therapy (CBT) with a computer-based program versus usual care to treat depression in adolescents in primary care clinics in Santiago, Chile. This is a two-arm, single-blind, randomized controlled trial with a target enrollment of 216 depressed adolescents between 15 and 19 years of age, attending four primary care clinics in Santiago, Chile. In the active arm, depressed adolescents will receive eight sessions of computer-assisted CBT, led by trained psychologists on a weekly basis. In the control arm, depressed adolescents will receive treatment as usual from the primary care centers. Mean depression scores and indicators of dysfunctional thoughts, problem-solving strategies, and health-related quality of life will be measured at baseline and four and six months after randomization. As far as we know, this is the first randomized controlled trial of a computer-assisted CBT intervention for depressed adolescents in a Latin American country. Clinical Trials: NCT01862913.


Protective effects of royal jelly against testicular damage in streptozotocin-induced diabetic rats.
TO examine the effects of royal jelly (RJ) on testicular damage in streptozotocin (STZ)-induced diabetic rats. Eighteen adult Wistar albino rats were used, 6 in each of the 3 treatment groups: Group A: control, Group B: STZ-induced diabetes (untreated), Group C: STZ-induced diabetes plus RJ (400 mg/kg daily for 4 weeks). Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg). Four weeks after the onset of diabetes, testicular apoptotic cell death was examined using immunohistochemical staining for caspase-3 and Ki67 staining for localization of proliferative cells. Compared with the control, the body and testicular weights of the RJ-treated and untreated diabetic rats were decreased (P < 0.05). The histopathological examination showed a significant increase in degenerative changes in the seminiferous tubules and in spermatogenesis of the STZ-treated rats. In contrast, the RJ treatment group showed near-normal morphology, in addition to an increased intensity of immunohistochemical staining for Ki67-positive cells. Diabetes induced a significant increase in testicular apoptotic cell death (caspase-3-positive cells). Caspase-3-positive cells were significantly decreased in the STZ plus RJ-treated group compared with the untreated STZ-induced diabetic group (P < 0.05).


Individual Moral Disengagement and Bullying Among Swedish Fifth Graders: The Role of Collective Moral Disengagement and Pro-Bullying Behavior Within Classrooms.
School bullying is a complex social and relational phenomenon with severe consequences for those involved. Most children view bullying as wrong and recognize its harmful consequences; nevertheless, it continues to be a persistent problem within schools. Previous research has shown that children's engagement in bullying perpetration can be influenced by multiple factors (e.g., different forms of cognitive distortions) and at different ecological levels (e.g., child, peer-group, school, and society). However, the complexity of school bullying warrants further investigation of the interplay between factors, at different levels. Grounded in social cognitive theory, which focuses on both cognitive factors and social processes, this study examined whether children's bullying perpetration was associated with moral disengagement at the child level and with collective moral disengagement and prevalence of pro-bullying behavior at the classroom level. Cross-level interactions were also tested to examine the effects of classroom-level variables on the association between children's tendency to morally disengage and bullying perpetration. The study's analyses were based on cross-sectional self-report questionnaire data from 1,577 Swedish fifth-grade children from 105 classrooms (53.5% girls; Mage = 11.3, SD = 0.3). Multilevel modeling techniques were used to analyze the data. The results showed that bullying perpetration was positively associated with moral disengagement at the child level and with collective moral disengagement and pro-bullying behavior at the classroom level. Furthermore, the effect of individual moral disengagement on bullying was stronger for children in classrooms with higher levels of pro-bullying behaviors. These findings further support the argument that both moral processes and behaviors within classrooms, such as collective moral disengagement and pro-bullying behavior, need to be addressed in schools' preventive work against bullying.


Extending comprehensive cancer center expertise in clinical cancer genetics and genomics to diverse communities: the power of partnership.
Rapidly evolving genetic and genomic technologies for genetic cancer risk assessment (GCRA) are revolutionizing the approach to targeted therapy and cancer screening and prevention, heralding the era of personalized medicine. Although many academic medical centers provide GCRA services, most people receive their medical care in the community setting. However, few community clinicians have the knowledge or time needed to adequately select, apply, and interpret genetic/genomic tests. This article describes alternative approaches to the delivery of GCRA services, profiling the City of Hope Cancer Screening & Prevention Program Network (CSPPN) academic and community-based health center partnership as a model for the delivery of the highest-quality evidence-based GCRA services while promoting research participation in the community setting. Growth of the CSPPN was enabled by information technology, with videoconferencing for telemedicine and Web conferencing for remote participation in interdisciplinary genetics tumor boards. Grant support facilitated the establishment of an underserved minority outreach clinic in the regional County hospital. Innovative clinician education, technology, and collaboration are powerful tools to extend GCRA expertise from a National Cancer Institute-designated Comprehensive Cancer Center, enabling diffusion of evidenced-base genetic/genomic information and best practice into the community setting.


The use of nanobodies in a sensitive ELISA test for SARS-CoV-2 Spike 1 protein.
Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in the fluid has important uses in biotechnology, and is integral to many point-of-care SARS-CoV-2 diagnostics. Sandwich enzyme-linked immunosorbent assays (ELISAs) are a sensitive, well-established method of measuring antigens in solutions. They use one ligand to capture and the other ligand to detect the target analyte. Detection is commonly achieved using colorimetric readout obtained upon the reaction of a substrate with HRP-conjugated secondary ligand. Nanobodies, the VHH domain of camelid antibodies, have expanded the repertoire of molecules used in antigen detection. Nanobodies' high affinity for target antigens, their compact structure, their high stability and ease of production has driven research into their use as diagnostic reagents. Guided by a structural understanding of epitopes on the receptor-binding domain of the SARS-CoV-2 Spike protein, we investigated various combinations of engineered nanobodies in a sandwich ELISA to detect the Spike protein of SARS-CoV-2. We have identified an optimal combination of nanobodies. These were selectively functionalized to further improve antigen capture, enabling the measurement of sub-picomolar amounts of SARS-CoV-2 Spike protein in solution. With this combination, the routine detection limit in samples inactivated by heat and detergent corresponded to less than seven focus-forming units of infectious SARS-CoV-2.


The effect of growth hormone on gut mucosal homeostasis and cellular mediators after severe trauma.
Gut mucosal integrity and function is impaired after severe trauma with associated increases in small bowel epithelial cell apoptosis and decreases in cell proliferation. Growth hormone improves gastrointestinal function during chemotherapy and has anabolic effects on protein synthesis. The purpose of this study was to determine whether growth hormone can improve small bowel homeostasis after injury and by which cellular mechanisms these changes occur. Rats were pair-fed, given a thermal trauma, and received saline (n = 28) or GH (2.5 mg/kg every 24 h, n = 28). Small intestine and serum were taken at 1, 2, 5, and 7 days after injury. Measures were mucosal apoptosis, proliferation, villous morphology, apoptotic, and proliferative mediators, such as Caspases-3, -8, Fas and Fas-Ligand, Bcl-2, and Bcl-x. In addition serum cytokines were determined. Gut epithelial cell apoptosis and proliferation were increased in both groups after the thermal injury (P < 0.05). GH had neither an effect on small bowel epithelial cell apoptosis or proliferation, nor dependent cellular mediators after thermal injury. However, GH significantly improved villous morphology (height and cell number) when compared with controls (P < 0.05). RhGH was found to significantly increase serum TNF-alpha compared to controls (P < 0.05). Growth hormone improves small bowel homeostasis after severe trauma independent from small bowel epithelial cell apoptosis or proliferation, probably by increasing the life span.


Exposure of coastal environments to river-sourced plastic pollution.
Marine litter is a global problem which poses an increasing threat to ecosystem services, human health, safety and sustainable livelihoods. In order to better plan plastic pollution monitoring and clean-up activities, and to develop policies and programmes to deter and mitigate plastic pollution, information is urgently needed on the different types of coastal ecosystem that are impacted by land-sourced plastic inputs, especially those located in proximity to river mouths where plastic waste is discharged into the ocean. We overlayed the most current existing information on the input of plastic to the sea from land-based sources with maps of coastal environments and ecosystems. We found an inverse relationship exists between coastal geomorphic type, plastic trapping efficiency and the mass of plastic received. River-dominated coasts comprise only 0.87% of the global coast and yet they receive 52% of plastic pollution delivered by fluvial systems. Tide-dominated coasts receive 29.9% of river-borne plastic pollution and this is also where mangrove and salt marsh habitats are most common. Wave-dominated coasts receive 11.6% of river-borne plastic pollution and this is where seagrass habitat is most common. Finally, rocky shores comprise 72.5% of the global coast, containing fjords and coral reefs, while only receiving 6.4% of river-borne plastic pollution. Mangroves are the most proximal to river-borne plastic pollution point sources of the four habitat types studied here; 54.0% of mangrove habitat is within 20 km of a river that discharges more than 1 t/yr of plastic pollution into the ocean. For seagrass, salt marsh and coral reefs the figures are 24.1%, 22.7% and 16.5%, respectively. The findings allow us to better understand the environmental fate of plastic pollution, to advance numerical models and to guide managers and decision-makers on the most appropriate responses and actions needed to monitor and reduce plastic pollution.


Estrogen accelerates heart regeneration by promoting the inflammatory response in zebrafish.
Sexual differences have been observed in the onset and prognosis of human cardiovascular diseases, but the underlying mechanisms are not clear. Here, we found that zebrafish heart regeneration is faster in females, can be accelerated by estrogen and is suppressed by the estrogen-antagonist tamoxifen. Injuries to the zebrafish heart, but not other tissues, increased plasma estrogen levels and the expression of estrogen receptors, especially esr2a. The resulting endocrine disruption induces the expression of the female-specific protein vitellogenin in male zebrafish. Transcriptomic analyses suggested heart injuries triggered pronounced immune and inflammatory responses in females. These responses, previously shown to elicit heart regeneration, could be enhanced by estrogen treatment in males and reduced by tamoxifen in females. Furthermore, a prior exposure to estrogen preconditioned the zebrafish heart for an accelerated regeneration. Altogether, this study reveals that heart regeneration is modulated by an estrogen-inducible inflammatory response to cardiac injury. These findings elucidate a previously unknown layer of control in zebrafish heart regeneration and provide a new model system for the study of sexual differences in human cardiac repair.


An aeroponic culture system for the study of root herbivory on Arabidopsis thaliana.
Plant defense against herbivory has been studied primarily in aerial tissues. However, complex defense mechanisms have evolved in all parts of the plant to combat herbivore attack and these mechanisms are likely to differ in the aerial and subterranean environment. Research investigating defense responses belowground has been hindered by experimental difficulties associated with the accessibility and quality of root tissue and the lack of bioassays using model plants with altered defense profiles. We have developed an aeroponic culture system based on a calcined clay substrate that allows insect herbivores to feed on plant roots while providing easy recovery of the root tissue. The culture method was validated by a root-herbivore system developed for Arabidopsis thaliana and the herbivore Bradysia spp. (fungus gnat). Arabidopsis root mass obtained from aeroponically grown plants was comparable to that from other culture systems, and the plants were morphologically normal. Bradysia larvae caused considerable root damage resulting in reduced root biomass and water absorption. After feeding on the aeroponically grown root tissue, the larvae pupated and emerged as adults. Root damage of mature plants cultivated in aeroponic substrate was compared to that of Arabidopsis seedlings grown in potting mix. Seedlings were notably more susceptible to Bradysia feeding than mature plants and showed decreased overall growth and survival rates. A root-herbivore system consisting of Arabidopsis thaliana and larvae of the opportunistic herbivore Bradysia spp. has been established that mimics herbivory in the rhizosphere. Bradysia infestation of Arabidopsis grown in this culture system significantly affects plant performance. The culture method will allow simple profiling and in vivo functional analysis of root defenses such as chemical defense metabolites that are released in response to belowground insect attack.


Application of the tissue residue approach in ecological risk assessment.
The objective of this work is to present a critical review of the application of the tissue residue approach (TRA) in ecological risk and/or impact assessment (ERA) of chemical stressors and environmental criteria development. A secondary goal is to develop a framework for integrating the TRA into ecological assessments along with traditional, exposure concentration-based assessment approaches. Although widely recognized for its toxicological appeal, the utility of the TRA in specific applications will depend on numerous factors, such as chemical properties, exposure characteristics, assessment type, availability of tissue residue-response data, and ability to quantify chemical exposure. Therefore, the decision to use the TRA should include an evaluation of the relative strengths, limitations, and uncertainties among exposure and residue-based methods for characterizing toxicological effects. Furthermore, rather than supplanting exposure concentration-based toxicity assessments, the TRA can be highly effective for evaluating and reducing uncertainty when used in a complementary manner (e.g., when evaluating multiple lines of evidence in field studies). To address limitations with the available tissue residue-response data, approaches for extrapolating residue-based toxicity data across species, tissues, and exposure durations are discussed. Some of these approaches rely on predicted residue-response relationships or toxicological models that have an implicit residue-response basis (e.g., biotic ligand model). Because risk to an organism is a function of both its exposure potential and inherent sensitivity (i.e., on a residue basis), bioaccumulation models will be required not only for translating tissue residue criteria into corresponding water and sediment criteria, but also for defining the most vulnerable species in an assemblage (i.e., highly exposed and highly sensitive species). Application of the TRA in ecological assessments and criteria development are summarized for bioaccumulative organic chemicals, TBT, and in situ bioassays using bivalve molluscs.


Optimisation of the synthesis of vancomycin-selective molecularly imprinted polymer nanoparticles using automatic photoreactor.
A novel optimized protocol for solid-state synthesis of molecularly imprinted polymer nanoparticles (nanoMIPs) with specificity for antibiotic vancomycin is described. The experimental objective was optimization of the synthesis parameters (factors) affecting the yield of obtained nanoparticles which have been synthesized using the first prototype of an automated solid-phase synthesizer. Applications of experimental design (or design of experiments) in optimization of nanoMIP yield were carried out using MODDE 9.0 software. The factors chosen in the model were the amount of functional monomers in the polymerization mixture, irradiation time, temperature during polymerization, and elution temperature. In general, it could be concluded that the irradiation time is the most important and the temperature was the least important factor which influences the yield of nanoparticles. Overall, the response surface methodology proved to be an effective tool in reducing time required for optimization of complex experimental conditions.


Multiscale hybrid linear models for lossy image representation.
In this paper, we introduce a simple and efficient representation for natural images. We view an image (in either the spatial domain or the wavelet domain) as a collection of vectors in a high-dimensional space. We then fit a piece-wise linear model (i.e., a union of affine subspaces) to the vectors at each downsampling scale. We call this a multiscale hybrid linear model for the image. The model can be effectively estimated via a new algebraic method known as generalized principal component analysis (GPCA). The hybrid and hierarchical structure of this model allows us to effectively extract and exploit multimodal correlations among the imagery data at different scales. It conceptually and computationally remedies limitations of many existing image representation methods that are based on either a fixed linear transformation (e.g., DCT, wavelets), or an adaptive uni-modal linear transformation (e.g., PCA), or a multimodal model that uses only cluster means (e.g., VQ). We will justify both quantitatively and experimentally why and how such a simple multiscale hybrid model is able to reduce simultaneously the model complexity and computational cost. Despite a small overhead of the model, our careful and extensive experimental results show that this new model gives more compact representations for a wide variety of natural images under a wide range of signal-to-noise ratios than many existing methods, including wavelets. We also briefly address how the same (hybrid linear) modeling paradigm can be extended to be potentially useful for other applications, such as image segmentation.


Physiological environment induces quick response - slow exhaustion reactions.
In vivo environments are highly crowded and inhomogeneous, which may affect reaction processes in cells. In this study we examined the effects of intracellular crowding and an inhomogeneity on the behavior of in vivo reactions by calculating the spectral dimension (d(s)), which can be translated into the reaction rate function. We compared estimates of anomaly parameters obtained from fluorescence correlation spectroscopy (FCS) data with fractal dimensions derived from transmission electron microscopy (TEM) image analysis. FCS analysis indicated that the anomalous property was linked to physiological structure. Subsequent TEM analysis provided an in vivo illustration; soluble molecules likely percolate between intracellular clusters, which are constructed in a self-organizing manner. We estimated a cytoplasmic spectral dimension d(s) to be 1.39 ± 0.084. This result suggests that in vivo reactions initially run faster than the same reactions in a homogeneous space; this conclusion is consistent with the anomalous character indicated by FCS analysis. We further showed that these results were compatible with our Monte-Carlo simulation in which the anomalous behavior of mobile molecules correlates with the intracellular environment, leading to description as a percolation cluster, as demonstrated using TEM analysis. We confirmed by the simulation that the above-mentioned in vivo like properties are different from those of homogeneously concentrated environments. Additionally, simulation results indicated that crowding level of an environment might affect diffusion rate of reactant. Such knowledge of the spatial information enables us to construct realistic models for in vivo diffusion and reaction systems.


Subdural empyema secondary to pansinusitis after coronavirus disease 2019 infection in an immunocompetent patient: illustrative case.
Superimposed intracranial infection is an uncommon but clinically significant complication in patients with active coronavirus disease 2019 (COVID-19), particularly in those with predisposing immunocompromising conditions. The authors describe a case of subdural empyema, secondary to extension from pansinusitis, in a 20-year-old otherwise healthy immunocompetent male who was recently diagnosed with COVID-19. Despite his critical condition at time of presentation, he made a full clinical recovery with aggressive multidisciplinary surgical management between neurosurgery and otolaryngology, despite negative cultures to guide directed antimicrobial therapy. Ultimately, use of molecular-based polymerase chain reaction testing diagnosed Aspergillus fumigatus as the offending pathogen after the patient had already recovered and was discharged from the hospital. This case demonstrates the potential for significant superimposed intracranial infection even in young, healthy individuals, infected by COVID-19 and suggests an aggressive surgical approach to achieve source control, particularly in the absence of positive cultures to guide antimicrobial therapies, may lead to rapid clinical improvement.


Supraorbital nerve conduction study in normal subjects.
There is currently no examination technique that allows direct measurement of supraorbital nerve conduction velocity and amplitude. Therefore, in this study we describe a novel nerve conduction technique that allows measurement of the supraorbital sensory nerve action potential (SNAP) distal to the supraorbital foramen. Supraorbital SNAPs were recorded bilaterally from 17 healthy volunteers using an antidromic technique. The SNAPs were consistently recordable over the site 6 cm lateral to the midline point that was marked 10 cm above the nasion. Measured parameters included peak latency (mean 2.3 ms, SD 0.3), amplitude (mean 14.6 μV; SD 10.5), and velocity (mean 51.3 m/s, SD 6.8). The mean percentage of interside difference in amplitude was 25.6% (SD 17.3). Cut-off values (97th percentile) were 2.7 ms (peak latency), 3.3 μV (amplitude), 41.9 m/s (conduction velocity), and 54.9% (interside difference in amplitude). Supraorbital SNAPs can be recorded in all normal subjects and used as a quantitative measure of the functioning large fibers in the nerve.


Requirement of argininosuccinate lyase for systemic nitric oxide production.
Nitric oxide (NO) is crucial in diverse physiological and pathological processes. We show that a hypomorphic mouse model of argininosuccinate lyase (encoded by Asl) deficiency has a distinct phenotype of multiorgan dysfunction and NO deficiency. Loss of Asl in both humans and mice leads to reduced NO synthesis, owing to both decreased endogenous arginine synthesis and an impaired ability to use extracellular arginine for NO production. Administration of nitrite, which can be converted into NO in vivo, rescued the manifestations of NO deficiency in hypomorphic Asl mice, and a nitric oxide synthase (NOS)-independent NO donor restored NO-dependent vascular reactivity in humans with ASL deficiency. Mechanistic studies showed that ASL has a structural function in addition to its catalytic activity, by which it contributes to the formation of a multiprotein complex required for NO production. Our data demonstrate a previously unappreciated role for ASL in NOS function and NO homeostasis. Hence, ASL may serve as a target for manipulating NO production in experimental models, as well as for the treatment of NO-related diseases.


Evaluation of aerosol optical depth and aerosol models from VIIRS retrieval algorithms over North China Plain.
The first Visible Infrared Imaging Radiometer Suite (VIIRS) was launched on Suomi National Polar-orbiting Partnership (S-NPP) satellite in late 2011. Similar to the Moderate resolution Imaging Spectroradiometer (MODIS), VIIRS observes top-of-atmosphere spectral reflectance and is potentially suitable for retrieval of the aerosol optical depth (AOD). The VIIRS Environmental Data Record data (VIIRS_EDR) is produced operationally by NOAA, and is based on the MODIS atmospheric correction algorithm. The "MODIS-like" VIIRS data (VIIRS_ML) are being produced experimentally at NASA, from a version of the "dark-target" algorithm that is applied to MODIS. In this study, the AOD and aerosol model types from these two VIIRS retrieval algorithms over the North China Plain (NCP) are evaluated using the ground-based CE318 Sunphotometer (CE318) measurements during 2 May 2012 - 31 March 2014 at three sites. These sites represent three different surface types: urban (Beijing), suburban (XiangHe) and rural (Xinglong). Firstly, we evaluate the retrieved spectral AOD. For the three sites, VIIRS_EDR AOD at 550 nm shows a positive mean bias (MB) of 0.04-0.06 and the correlation of 0.83-0.86, with the largest MB (0.10-0.15) observed in Beijing. In contrast, VIIRS_ML AOD at 550 nm has overall higher positive MB of 0.13-0.14 and a higher correlation (0.93-0.94) with CE318 AOD. Secondly, we evaluate the aerosol model types assumed by each algorithm, as well as the aerosol optical properties used in the AOD retrievals. The aerosol model used in VIIRS_EDR algorithm shows that dust and clean urban models were the dominant model types during the evaluation period. The overall accuracy rate of the aerosol model used in VIIRS_ML over NCP three sites (0.48) is higher than that of VIIRS_EDR (0.27). The differences in Single Scattering Albedo (SSA) at 670 nm between VIIRS_ML and CE318 are mostly less than 0.015, but high seasonal differences are found especially over the Xinglong site. The values of SSA from VIIRS_EDR are higher than that observed by CE318 over all sites and all assumed aerosol modes, with a positive bias of 0.02-0.04 for fine mode, 0.06-0.12 for coarse mode and 0.03-0.05 for bi-mode at 440nm. The overestimation of SSA but positive AOD MB of VIIRS_EDR indicate that other factors (e.g. surface reflectance characterization or cloud contamination) are important sources of error in the VIIRS_EDR algorithm, and their effects on aerosol retrievals may override the effects from non-ideality in these aerosol models.


Crocodylomorph cranial shape evolution and its relationship with body size and ecology.
Crocodylomorpha, which includes living crocodylians and their extinct relatives, has a rich fossil record, extending back for more than 200 million years. Unlike modern semi-aquatic crocodylians, extinct crocodylomorphs exhibited more varied lifestyles, ranging from marine to fully terrestrial forms. This ecological diversity was mirrored by a remarkable morphological disparity, particularly in terms of cranial morphology, which seems to be closely associated with ecological roles in the group. Here, I use geometric morphometrics to comprehensively investigate cranial shape variation and disparity in Crocodylomorpha. I quantitatively assess the relationship between cranial shape and ecology (i.e. terrestrial, aquatic, and semi-aquatic lifestyles), as well as possible allometric shape changes. I also characterize patterns of cranial shape evolution and identify regime shifts. I found a strong link between shape and size, and a significant influence of ecology on the observed shape variation. Terrestrial taxa, particularly notosuchians, have significantly higher disparity, and shifts to more longirostrine regimes are associated with large-bodied aquatic or semi-aquatic species. This demonstrates an intricate relationship between cranial shape, body size and lifestyle in crocodylomorph evolutionary history. Additionally, disparity-through-time analyses were highly sensitive to different phylogenetic hypotheses, suggesting the description of overall patterns among distinct trees. For crocodylomorphs, most results agree in an early peak during the Early Jurassic and another in the middle of the Cretaceous, followed by nearly continuous decline until today. Since only crown-group members survived through the Cenozoic, this decrease in disparity was likely the result of habitat loss, which narrowed down the range of crocodylomorph lifestyles.


Mitf regulation of Dia1 controls melanoma proliferation and invasiveness.
It is widely held that cells with metastatic properties such as invasiveness and expression of matrix metalloproteinases arise through the stepwise accumulation of genetic lesions arising from genetic instability and "clonal evolution." By contrast, we show here that in melanomas invasiveness can be regulated epigenetically by the microphthalmia-associated transcription factor, Mitf, via regulation of the DIAPH1 gene encoding the diaphanous-related formin Dia1 that promotes actin polymerization and coordinates the actin cytoskeleton and microtubule networks at the cell periphery. Low Mitf levels lead to down-regulation of Dia1, reorganization of the actin cytoskeleton, and increased ROCK-dependent invasiveness, whereas increased Mitf expression leads to decreased invasiveness. Significantly the regulation of Dia1 by Mitf also controls p27(Kip1)-degradation such that reduced Mitf levels lead to a p27(Kip1)-dependent G1 arrest. Thus Mitf, via regulation of Dia1, can both inhibit invasiveness and promote proliferation. The results imply variations in the repertoire of environmental cues that determine Mitf activity will dictate the differentiation, proliferative, and invasive/migratory potential of melanoma cells through a dynamic epigenetic mechanism.


Fibrin microthreads support mesenchymal stem cell growth while maintaining differentiation potential.
We developed a method to produce discrete fibrin microthreads, which can be seeded with human mesenchymal stem cells (hMSCs) and used as a suture to enhance the efficiency and localization of cell delivery. To assess the efficacy of fibrin microthreads to support hMSC attachment, proliferation, and survival, microthreads (100 μm diameter per microthread) were bundled together, seeded with 50,000 hMSCs for 2 h, and cultured for 5 days. Cell density on microthread bundles increased over time in culture to a maximum average density of 731 ± 101 cells/mm(2) after 5 days. A LIVE/DEAD assay confirmed that the cells were viable, and Ki-67 staining verified hMSC proliferation. In addition, functional differentiation assays demonstrated that hMSCs cultured on microthreads retained their ability to differentiate into adipocytes and osteocytes. The results of this study demonstrate that fibrin microthreads support hMSC viability and proliferation, while maintaining their multipotency. We anticipate that these cell-seeded fibrin microthreads will serve as a platform technology to improve localized delivery and engraftment of viable cells to damaged tissue.


Case series of choroid plexus papilloma in children at uncommon locations and review of the literature.
Choroid plexus papillomas (CPPs) comprise around 1% of intracranial neoplasms. The most common location is atrium of the lateral ventricle in children and fourth ventricle in adults. Other rare locations include third ventricle, cerebellopontine (CP) angle and cerebral parenchyma, with only a few cases reported. Authors report three cases of CPP at uncommon locations in pediatric patients. The rarity of these locations, diagnostic dilemma and management aspects are discussed along with an extensive review of the literature. Retrospective institutional data analysis of histopathologically confirmed pediatric CPPs from 2010 to 2014. Authors noted three cases of CPP in children in uncommon locations-one each in the posterior third ventricle, fourth ventricle, and CP angle. All were males in the first decade. Two cases presented with features of obstructive hydrocephalus while the latter presented with compressive effects. Complete excision was achieved in two cases while subtotal removal was performed in one case (fourth ventricular) because of excess blood loss. Mean follow-up duration was 24.6 months (range 20-30 months). One case (of subtotal removal) had fair recovery while other two had excellent outcomes. Posterior third ventricle, fourth ventricle, and CP angle are uncommon locations for these tumors in children. Complete surgical removal is the treatment of choice and approach needs to be tailored according to the site and size of the lesion. Blood loss is a major concern in young children as they are highly vascular tumors. Complete removal leads to excellent long-term survival rates. Adjuvant treatment is not required.


Meeting End User Needs in Collaborative Medical Device Technology Development Research Projects: A Qualitative Case Study.
The aim of this case study has been to investigate to what extent user centered design (UCD) methodologies have been applied, how the process and outcomes were perceived by project team members, and what were potential barriers towards meeting end user needs. The case studied was the European Union Framework 7 integrated project d-LIVER (2011-2015), which aimed at developing an integrated care system for chronic liver disease patient management. d-LIVER is an example of a public funded, international, multidisciplinary, collaborative research project where development starts from a low technology readiness level, but where research is motivated by societal needs for better health care solutions. Awareness of central end user needs are therefore crucial. 14 project participants were interviewed. To meet societal and end user needs represent a prominent motivation factor for participants. The project organization with only clinical partners interacting with end users was accepted as a fact of life and not as a project pain point. A summary of observations and recommendations for good practice is given.


Antimicrobial resistance to ceftazidime involving loss of penicillin-binding protein 3 in Burkholderia pseudomallei.
Known mechanisms of resistance to β-lactam antibiotics include β-lactamase expression, altered drug target, decreased bacterial permeability, and increased drug efflux. Here, we describe a unique mechanism of β-lactam resistance in the biothreat organism Burkholderia pseudomallei (the cause of melioidosis), associated with treatment failure during prolonged ceftazidime therapy of natural infection. Detailed comparisons of the initial ceftazidime-susceptible infecting isolate and subsequent ceftazidime-resistant variants from six patients led us to identify a common, large-scale genomic loss involving a minimum of 49 genes in all six resistant strains. Mutational analysis of wild-type B. pseudomallei demonstrated that ceftazidime resistance was due to deletion of a gene encoding a penicillin-binding protein 3 (BPSS1219) present within the region of genomic loss. The clinical ceftazidime-resistant variants failed to grow using commonly used laboratory culture media, including commercial blood cultures, rendering the variants almost undetectable in the diagnostic laboratory. Melioidosis is notoriously difficult to cure and clinical treatment failure is common in patients treated with ceftazidime, the drug of first choice across most of Southeast Asia where the majority of cases are reported. The mechanism described here represents an explanation for ceftazidime treatment failure, and may be a frequent but undetected resistance event.


Strategies for validating biomarkers using data from a reference set.
Candidate biomarkers discovered in the laboratory need to be rigorously validated before advancing to clinical application. However, it is often expensive and time-consuming to collect the high quality specimens needed for validation; moreover, such specimens are often limited in volume. The Early Detection Research Network has developed valuable specimen reference sets that can be used by multiple labs for biomarker validation. To optimize the chance of successful validation, it is critical to efficiently utilize the limited specimens in these reference sets on promising candidate biomarkers. Towards this end, we propose a novel two-stage validation strategy that partitions the samples in the reference set into two groups for sequential validation. The proposed strategy adopts the group sequential testing method to control for the type I error rate and rotates group membership to maximize the usage of available samples. We develop analytical formulas for performance parameters of this strategy in terms of the expected numbers of biomarkers that can be evaluated and the truly useful biomarkers that can be successfully validated, which can provide valuable guidance for future study design. The performance of our proposed strategy for validating biomarkers with respect to the points on the receiver operating characteristic curve are evaluated via extensive simulation studies and compared with the default strategy of validating each biomarker using all samples in the reference set. Different types of early stopping rules and boundary shapes in the group sequential testing method are considered. Compared with the default strategy, our proposed strategy makes more efficient use of the limited resources in the reference set by allowing more candidate biomarkers to be evaluated, giving a better chance of having truly useful biomarkers successfully validated.


Meiotic recombination, cross-reactivity, and persistence in Plasmodium falciparum.
We incorporate a representation of Plasmodium falciparum recombination within a discrete-event model of malaria transmission. We simulate the introduction of a new parasite genotype into a human population in which another genotype has reached equilibrium prevalence and compare the emergence and persistence of the novel recombinant forms under differing cross-reactivity relationships between the genotypes. Cross-reactivity between the parental (initial and introduced) genotypes reduces the frequency of appearance of recombinants within three years of introduction from 100% to 14%, and delays their appearance by more than a year, on average. Cross-reactivity between parental and recombinant genotypes reduces the frequency of appearance to 36% and increases the probability of recombinant extinction following appearance from 0% to 83%. When a recombinant is cross-reactive with its parental types, its probability of extinction is influenced by cross-reactivity between the parental types in the opposite manner; that is, its probability of extinction after appearance decreases. Frequencies of P. falciparum outcrossing are mediated by frequencies of mixed-genotype infections in the host population, which are in turn mediated by the structure of cross-reactivity between parasite genotypes. The three leading hypotheses about how meiosis relates to oocyst production lead to quantitative, but no qualitative, differences in these results.


The value of pain coping constructs in subcategorising back pain patients according to risk of poor outcome.
Subcategorising patients with chronic low back pain (CLBP) could improve patient outcomes and facilitate prioritisation of treatment resources. This study aimed to develop a subcategorising method for individuals with CLBP using the Coping Strategies Questionnaire 24 (CSQ24) and to investigate the methods potential validity. 196 patients were recruited from a physiotherapy outpatients department. All participants completed a battery of questionnaires before and after treatment including the CSQ24 and a measure of pain, disability, and mood. At discharge participants also completed a global subjective outcomes scale consisting of a 6-point Likert scale. All participants received usual physiotherapy. Cut-off values for the CSQ24 were calculated using triangulation of the findings from three different statistical methods. Cut-off values were identified for the Catastrophising and Cognitive Coping subscales of the CSQ24. Participants were categorised into low, medium, and high risk of a poor outcome. The cut-off values for these were ≥21 on Cognitive Coping and ≤9 on Catastrophising for low risk and ≤15 on Cognitive Coping for high risk, with all other patients being classified as being at moderate risk. Further validation is required before this approach can be recommended for clinical practice.


Interventions used to improve control of blood pressure in patients with hypertension.
Patients with high blood pressure (hypertension) in the community frequently fail to meet treatment goals - a condition labelled as "uncontrolled" hypertension. The optimal way to organize and deliver care to hypertensive patients has not been clearly identified. To determine the effectiveness of interventions to improve control of blood pressure in patients with hypertension. To evaluate the effectiveness of reminders on improving the follow-up of patients with hypertension. All-language search of all articles (any year) in the Cochrane Controlled Trials Register (CCTR) and Medline; and Embase from January 1980. Randomized controlled trials (RCTs) of patients with hypertension that evaluated the following interventions: (1) self-monitoring (2) educational interventions directed to the patient (3) educational interventions directed to the health professional (4) health professional (nurse or pharmacist) led care (5) organisational interventions that aimed to improve the delivery of care (6) appointment reminder systemsOutcomes assessed were: (1) mean systolic and diastolic blood pressure (2) control of blood pressure (3) proportion of patients followed up at clinic Two authors extracted data independently and in duplicate and assessed each study according to the criteria outlined by the Cochrane Handbook. 72 RCTs met our inclusion criteria. The methodological quality of included studies varied. An organized system of regular review allied to vigorous antihypertensive drug therapy was shown to reduce systolic blood pressure (weighted mean difference (WMD) -8.0 mmHg, 95% CI: -8.8 to -7.2 mmHg) and diastolic blood pressure (WMD -4.3 mmHg, 95% CI: -4.7 to -3.9 mmHg) for three strata of entry blood pressure, and all-cause mortality at five years follow-up (6.4% versus 7.8%, difference 1.4%) in a single large RCT- the Hypertension Detection and Follow-Up study. Other interventions had variable effects. Self-monitoring was associated with moderate net reduction in systolic blood pressure (WMD -2.5 mmHg, 95% CI: -3.7 to -1.3 mmHg) and diastolic blood pressure (WMD -1.8 mmHg, 95% CI: -2.4 to -1.2 mmHg). RCTs of educational interventions directed at patients or health professionals were heterogeneous but appeared unlikely to be associated with large net reductions in blood pressure by themselves. Nurse or pharmacist led care may be a promising way forward, with the majority of RCTs being associated with improved blood pressure control and mean SBP and DBP but these interventions require further evaluation. Appointment reminder systems also require further evaluation due to heterogeneity and small trial numbers, but the majority of trials increased the proportion of individuals who attended for follow-up (odds ratio 0.41, 95% CI 0.32 to 0.51) and in two small trials also led to improved blood pressure control, odds ratio favouring intervention 0.54 (95% CI 0.41 to 0.73). Family practices and community-based clinics need to have an organized system of regular follow-up and review of their hypertensive patients. Antihypertensive drug therapy should be implemented by means of a vigorous stepped care approach when patients do not reach target blood pressure levels. Self-monitoring and appointment reminders may be useful adjuncts to the above strategies to improve blood pressure control but require further evaluation.


The structure and function of the outer coat protein VP9 of Banna virus.
Banna virus (BAV: genus Seadornavirus, family Reoviridae) has a double-shelled morphology similar to rotavirus and bluetongue virus. The structure of BAV outer-capsid protein VP9 was determined by X-ray crystallography at 2.6 A resolution, revealing a trimeric molecule, held together by an N-terminal helical bundle, reminiscent of coiled-coil structures found in fusion-active proteins such as HIV gp41. The major domain of VP9 contains stacked beta sheets with marked structural similarities to the receptor binding protein VP8 of rotavirus. Anti-VP9 antibodies neutralize viral infectivity, and, remarkably, pretreatment of cells with trimeric VP9 increased viral infectivity, indicating that VP9 is involved in virus attachment to cell surface and subsequent internalization. Sequence similarities were also detected between BAV VP10 and VP5 portion of rotavirus VP4, suggesting that the receptor binding and internalization apparatus, which is a single gene product activated by proteoloysis in rotavirus, is the product of two separate genome segments in BAV.


Saturated fat and cardiometabolic risk factors, coronary heart disease, stroke, and diabetes: a fresh look at the evidence.
Dietary and policy recommendations frequently focus on reducing saturated fatty acid consumption for improving cardiometabolic health, based largely on ecologic and animal studies. Recent advances in nutritional science now allow assessment of critical questions about health effects of saturated fatty acids (SFA). We reviewed the evidence from randomized controlled trials (RCTs) of lipid and non-lipid risk factors, prospective cohort studies of disease endpoints, and RCTs of disease endpoints for cardiometabolic effects of SFA consumption in humans, including whether effects vary depending on specific SFA chain-length; on the replacement nutrient; or on disease outcomes evaluated. Compared with carbohydrate, the TC:HDL-C ratio is nonsignificantly affected by consumption of myristic or palmitic acid, is nonsignificantly decreased by stearic acid, and is significantly decreased by lauric acid. However, insufficient evidence exists for different chain-length-specific effects on other risk pathways or, more importantly, disease endpoints. Based on consistent evidence from human studies, replacing SFA with polyunsaturated fat modestly lowers coronary heart disease risk, with ~10% risk reduction for a 5% energy substitution; whereas replacing SFA with carbohydrate has no benefit and replacing SFA with monounsaturated fat has uncertain effects. Evidence for the effects of SFA consumption on vascular function, insulin resistance, diabetes, and stroke is mixed, with many studies showing no clear effects, highlighting a need for further investigation of these endpoints. Public health emphasis on reducing SFA consumption without considering the replacement nutrient or, more importantly, the many other food-based risk factors for cardiometabolic disease is unlikely to produce substantial intended benefits.


A Formative Assessment of Social Determinants of Health Related to Early Childhood Caries in Two American Indian Communities.
In the United States, children from diverse ethnic groups and those with low socioeconomic status are at a significantly increased risk for early childhood caries. Despite the efforts focused on decreasing early childhood caries in American Indian (AI) populations, these children have the highest incidence of dental caries of any ethnic group, with four times the cases of untreated dental caries compared to white children. This qualitative formative assessment was conducted in two AI communities. Semi-structured interviews (n = 57) were conducted with caregivers and providers to understand the social and community contexts in which oral health behaviors and practices occur from the perspective of the caregivers, oral health care providers, and social service providers in the communities. The analysis was informed by the social determinants of health framework. The key social determinants of pediatric oral health relevant to our study communities included limited access to: oral health promoting nutritious foods, transportation for oral health appointments, and pediatric specialty care. This formative assessment provided locally and contextually relevant information to shape the development of an oral health clinical trial intervention to address early childhood caries in these two communities.


N-methyl-D-aspartate receptor channel block by the enantiomeric 6,7-benzomorphans BIII 277 CL and BIII 281 CL.
BIII 277 CL ((-)-2R-[2 alpha, 3(R*),6 alpha]-3-(2-methoxypropyl)-6,11, 11-trimethyl-2,6-methano-1,2,3,4,5,6-hexahydro-3-benzazocin-9-ol hydrochloride) is a novel benzomorphan with neuroprotective and anticonvulsant properties that exhibits high affinity binding to the N-methyl-D-aspartate (NMDA) receptor but, in contrast to other structurally related benzomorphans, low affinity for mu opiate and sigma sites. Whole-cell voltage-clamp and single-channel recording were used to study the interaction of BIII 277 CL and its enantiomer BIII 281 CL with native NMDA receptors in cultured hippocampal neurons. BIII 277 CL and BIII 281 CL produced a slow use-dependent block of whole-cell NMDA receptor currents. Once block was established, recovery was slow (< 50% in > or = 40 min). The steady-state IC50 (nH) values derived from logistic fits to concentration-block isotherms obtained at -60 mV were 5.3 nM (0.67) and 58 nM (1.2), respectively. The benzomorphans had no effect on currents evoked by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate and gamma-aminobutyric acid but minimally inhibited kainate-evoked currents at high (> or = 30 microM) concentrations. BIII 277 CL and BIII 281 CL failed to bind and block closed NMDA receptor channels, and the block was occluded by Mg++, consistent with an open channel-blocking mechanism. Steady-state block was diminished by depolarization; analysis of the voltage-dependence of block indicated that BIII 281 CL binds within the channel at a site that senses 46% of the transmembrane electric field. Recordings of single NMDA receptor channels in outside-out membrane patches confirmed the slow, persistent blocking action obtained in whole-cell recordings. In addition, at high concentrations, flickering of the unitary currents was observed consistent with a low-affinity channel-blocking action. Taking the present data in conjunction with previously obtained structure-activity information for N-substituted benzomorphans, a three-mode-blocking model was developed in which there are three interaction sites for binding of the high-affinity ligand BIII 277 CL. In this model, the drug can bind in one of three modes by docking at one, two or all three interaction points but cannot transition between modes. The model further proposes that the lower-affinity enantiomer BIII 281 CL binds in modes with one and two but not all three interaction points docked. We conclude that BIII 277 CL and BIII 281 CL are potent and selective, use-dependent (uncompetitive) channel-blocking NMDA receptor antagonists. The substantially higher affinity that BIII 277 CL exhibits for the NMDA receptor in comparison with its enantiomer and other benzomorphans appears to be due to stabilization of binding at three sites within the channel.


Musical familiarity in congenital amusia: evidence from a gating paradigm.
Congenital amusia has been described as a lifelong deficit of music perception and production, notably including amusic individuals' difficulties to recognize a familiar tune without the aid of lyrics. The present study aimed to evaluate whether amusic individuals might have acquired long-term knowledge of familiar music, and to test for the minimal amount of acoustic information necessary to access this knowledge (if any) in amusia. Segments of familiar and unfamiliar instrumental musical pieces were presented with increasing duration (250, 500, 1000 msec etc.), and participants provided familiarity judgments for each segment. Results showed that amusic individuals succeeded in differentiating familiar from unfamiliar excerpts with as little acoustic information as did control participants (i.e., within 500 msec). The findings reveal that amusic individuals have stored musical pieces in long-term memory (LTM), and, together with other recent findings, they suggest that congenital amusia might impair conscious access to music processing rather than music processing per se.


Singular-value decomposition of a tomosynthesis system.
Tomosynthesis is an emerging technique with potential to replace mammography, since it gives 3D information at a relatively small increase in dose and cost. We present an analytical singular-value decomposition of a tomosynthesis system, which provides the measurement component of any given object. The method is demonstrated on an example object. The measurement component can be used as a reconstruction of the object, and can also be utilized in future observer studies of tomosynthesis image quality.