Solifenacin succinate versus percutaneous tibial nerve stimulation in women with overactive bladder syndrome: results of a randomized controlled crossover study.
This study compared the effectiveness of solifenacin succinate (SS) versus percutaneous tibial nerve stimulation (PTNS) in women with overactive bladder syndrome (OABS). A randomized controlled crossover study of 40 women with OABS was performed. Patients were randomized into two groups. In group A, patients received SS and then PTNS. In group B, patients underwent PTNS and then SS. Voiding diaries, quality of life surveys and patient perception of intensity of urgency questionnaire were performed before and after each treatment. The global impression of improvement questionnaire was performed at the end of the study. A reduction in the number of daily micturitions, episodes of nocturia and urge incontinence were found with both SS and PTNS in all groups, but PTNS showed a greater effectiveness than SS. There was an increase in voided volume in all groups with both SS and PTNS, but patients treated with PTNS had a greater increase. PTNS showed greater effectiveness in patient perception of urgency and quality of life. This study demonstrates the effectiveness of SS and PTNS In women with overactive bladder symptoms. However, greater improvements were found with PTNS.


Cascading effects of bird functional extinction reduce pollination and plant density.
Reductions in bird numbers could hamper ecosystem services such as pollination, but experimental proof is lacking. We show that functional extinction of bird pollinators has reduced pollination, seed production, and plant density in the shrub Rhabdothamnus solandri (Gesneriaceae) on the North Island ("mainland") of New Zealand but not on three nearby island bird sanctuaries where birds remain abundant. Pollen limitation of fruit set is strong [pollen limitation index (PLI) = 0.69] and significant on the mainland but small (PLI = 0.15) and nonsignificant on islands. Seed production per flower on the mainland is reduced 84%. Mainland sites have similar adult densities, but 55% fewer juvenile plants per adult, than island sites. Seed addition experiments near adult R. solandri plants on the mainland found strong seed limitation 5 years after sowing for R. solandri but not for two other co-occurring woody species. This demonstrates a terrestrial trophic cascade.


Time-to-event analysis of predictors for recovery from Salmonella Dublin infection in Danish dairy herds between 2002 and 2012.
Salmonella Dublin infections reduce gross margins and compromise animal health and welfare in dairy cattle herds. Despite on-going control efforts in several countries the duration and risk factors of a persistent infection have been difficult to study due to a lack of suitable data. This study utilised the unique opportunity to extract systematically collected repeated bulk-tank milk antibody measurements from all the Danish dairy herds during a 10-year period to perform a time-to-event analysis of the factors that affect the duration of test-positivity and the hazards of recovery from S. Dublin at herd level. Recovery was defined as a shift from test-positive to test-negative between two year-quarters followed by at least three more test-negative year-quarters. The average duration of infection was approximately 2 years. Predictors of recovery were tested in a multivariable Cox proportional hazard model allowing herds to recover from infection multiple times over the 10-year surveillance period. The model results were based on 36,429 observations with data on all the predictors, representing 3563 herds with a total of 3246 recoveries. Sixty-seven herds (2.4%) remained test-positive throughout the study period. The rest of the 317 herds that did not have any recoveries were censored, mainly due to a cessation of milk production. Prior recovery from test-positivity turned out not to be a significant predictor of recovery in the model. The effect of the duration of infection on the conditional probability of recovery (i.e. the hazard) was time-dependent: early in the study period, long durations of infection were predictive of a low hazard of recovery. Later in the control programme the effect of duration of infection was reduced indicating a desired effect of an intensified control programme. There was an increasing tendency towards longer durations and lower hazard of recovery with: (i) increasing herd sizes, (ii) increasing bulk-tank milk somatic cell counts, (iii) increasing local prevalence within a 5 km radius, (iv) organic farming and (v) recent purchase of cattle from test-positive herds. Participation in a voluntary paratuberculosis control programme reduced the duration of infection, and there were indications that recovery from S. Dublin infection was stimulated by a centrally organised and targeted control campaign. This is the first large-scale study that investigated duration of infection and predictors of recovery from S. Dublin in cattle herds over an extended period of time. The results provide useful knowledge for the design of control programmes for S. Dublin.


Causal role of lateral prefrontal cortex in mental effort and fatigue.
Dorsolateral prefrontal cortex (DLPFC) is well-known for its role in exerting mental work, however the contribution of DLPFC for deciding whether or not to engage in effort remains unknown. Here, we assessed the causal role of DLPFC in effort-based decision making. We disrupted functioning of DLPFC with noninvasive brain stimulation before participants repeatedly decided whether to exert mental effort in a working memory task. We found the same DLPFC subregion involved in mental effort exertion to influence also effort-based decisions: First, it enhanced effort discounting, suggesting that DLPFC may signal the capacity to successfully deal with effort demands. Second, a novel computational model integrating the costs of enduring effort into the effort-based decision process revealed that DLPFC disruption reduced fatigue after accumulated effort exertion, linking DLPFC activation with fatigue. Together, our findings indicate that in effort-based decisions DLPFC represents the capacity to exert mental effort and the updating of this information with enduring time-on-task, informing theoretical accounts on the role of DLPFC in the motivation to exert mental effort and the fatigue arising from it.


Studies on the nature and mode of action of the insulin-sensitive glucoregulator receptor in the central nervous system.
In vivo studies were undertaken in rats to provide evidence of the neural nature, tentative localization and mode of excitation of the insulin-sensitive central nervous system (CSN) glucoregulator center. In rats under light barbiturate anesthesia minute amounts of insulin injected into the carotid artery resulted in an immediate decrease of the systemic blood sugar. This hypoglycemic action of regional insulinzation of the CSN was lost when the animals were subjected to prolonged, deep barbiturate narcosis. Competitive inhibition of glucose utilization in the CSN region by intracarotid administration of 2-deoxy-D-glucose did not block the systemic hypoglycemic effect of subsequent intracarotid insulin injection. Chronic endogenous hyperinsulinemia produced by daily growth hormone treatment resulted in an insensitivity of the CNS glucoregulator center to exogenous insulin. The ratio of the quantity of the injected insulin and the pre-existent plasma insulin concentration showed direct correlation with the systemic hypoglycemic response that followed intracarotid injection. Present data support the hypothesis that the insulin-sensitive glucoregulator center located in the area supplied by the carotid artery is neural in nature, because of its inhibition by barbiturate anesthesia. The data are compatable with the working hypothesis that the center is located in the hypothalamus, since light cortical barbiturate anesthesia did not, but deep anesthesia did have an inhibitory effect on it. Marked interference by chronic hyperinsulinemia suggests that the receptor center estimates the metabolic status of the animal through means related to physicochemical binding of insulin to specific receptors. However, since our attempt to inhibit glucose utilization in the CNS was without effect on the activity of the center, it appears that the singal for the glucoregulatory impulse is not insulin facilitation of glucose utilization in the receptor area, but another parameter of insulin action.


Carbon dioxide insufflation during colonoscopy in deeply sedated patients.
To compare the impact of carbon dioxide (CO₂) and air insufflation on patient tolerance/safety in deeply sedated patients undergoing colonoscopy. Patients referred for colonoscopy were randomized to receive either CO₂ or air insufflation during the procedure. Both the colonoscopist and patient were blinded to the type of gas used. During the procedure, insertion and withdrawal times, caecal intubation rates, total sedation given and capnography readings were recorded. The level of sedation and magnitude of patient discomfort during the procedure was assessed by a nurse using a visual analogue scale (VAS) (0-3). Patients then graded their level of discomfort and abdominal bloating using a similar VAS. Complications during and after the procedure were recorded. A total of 142 patients were randomized with 72 in the air arm and 70 in the CO₂ arm. Mean age between the two study groups were similar. Insertion time to the caecum was quicker in the CO₂ group at 7.3 min vs 9.9 min with air (P = 0.0083). The average withdrawal times were not significantly different between the two groups. Caecal intubation rates were 94.4% and 100% in the air and CO₂ groups respectively (P = 0.012). The level of discomfort assessed by the nurse was 0.69 (air) and 0.39 (CO₂) (P = 0.0155) and by the patient 0.82 (air) and 0.46 (CO₂) (P = 0.0228). The level of abdominal bloating was 0.97 (air) and 0.36 (CO₂) (P = 0.001). Capnography readings trended to be higher in the CO₂ group at the commencement, caecal intubation, and conclusion of the procedure, even though this was not significantly different when compared to readings obtained during air insufflation. There were no complications in both arms. CO₂ insufflation during colonoscopy is more efficacious than air, allowing quicker and better cecal intubation rates. Abdominal discomfort and bloating were significantly less with CO₂ insufflation.


Targeting interhemispheric inhibition with neuromodulation to enhance stroke rehabilitation.
Interhemispheric inhibition in the brain plays a dynamic role in the production of voluntary unimanual actions. In stroke, the interhemispheric imbalance model predicts the presence of asymmetry in interhemispheric inhibition, with excessive inhibition from the contralesional hemisphere limiting maximal recovery. Stimulation methods to reduce this asymmetry in the brain may be promising as a stroke therapy, however determining how to best measure and modulate interhemispheric inhibition and who is likely to benefit, remain important questions. This review addresses current understanding of interhemispheric inhibition in the healthy and stroke lesioned brain. We present a review of studies that have measured interhemispheric inhibition using different paradigms in the clinic, as well as results from recent animal studies investigating stimulation methods to target abnormal inhibition after stroke. The degree to which asymmetric interhemispheric inhibition impacts on stroke recovery is controversial, and we consider sources of variation between studies which may contribute to this debate. We suggest that interhemispheric inhibition is not static following stroke in terms of the movement phase in which it is aberrantly engaged. Instead it may be dynamically increased onto perilesional areas during early movement, thus impairing motor initiation. Hence, its effect on stroke recovery may differ between studies depending on the technique and movement phase of eliciting the measurement. Finally, we propose how modulating excitability in the brain through more specific targeting of neural elements underlying interhemispheric inhibition via stimulation type, location and intensity may raise the ceiling of recovery following stroke and enhance functional return.


Antibacterial properties of PEKK for orthopedic applications.
Orthopedic implant infections have been steadily increasing while, at the same time, antibiotics developed to kill such bacteria have proven less and less effective with every passing day. It is clear that new approaches that do not rely on the use of antibiotics are needed to decrease medical device infections. Inspired by cicada wing surface topographical features, nanostructured surfaces represent a new approach for imposing antibacterial properties to biomaterials without using drugs. Moreover, new chemistries with altered surface energetics may decrease bacterial attachment and growth. In this study, a nanostructured surface was fabricated on poly-ether-ketone-ketone (PEKK), a new orthopedic implant chemistry, comprised of nanopillars with random interpillar spacing. Specifically, after 5 days, when compared to the orthopedic industry standard poly-ether-ether-ketone (PEEK), more than 37% less Staphylococcus epidermidis were found on the PEKK surface. Pseudomonas aeruginosa attachment and growth also decreased 28% after one day of culture, with around a 50% decrease after 5 days of culture when compared to PEEK. Such decreases in bacteria function were achieved without using antibiotics. In this manner, this study demonstrated for the first time, the promise that nanostructured PEKK has for numerous anti-infection orthopedic implant applications.


Overcoming foreign-body reaction through nanotopography: Biocompatibility and immunoisolation properties of a nanofibrous membrane.
Implantable immunoisolation membranes need to possess superior biocompatibility to prohibit the fibrotic deposition that would reduce the nutrient supply and impair the viability/function of the encapsulated cells. Here, electrospun membranes based on thermoplastic polyurethane (TPU) were fabricated to contain microfibers (PU-micro) or nanofibers (PU-nano). The two types of membranes were compared in terms of their interaction with macrophage cells and the host tissues. It was found that the fibrous membranes of different topographies possess distinct material properties: PU-nano caused minimal macrophage responses in vitro and in vivo and induced only mild foreign body reactions compared to PU-micro membranes. A flat macroencapsulation device was fabricated using PU-nano membranes and its immunoisolation function investigated in subcutaneous transplantation models. The nanofibrous device demonstrated the capability to effectively shield the allografts from the immune attack of the host. Nanotopography may confer biocompatibility to materials and nanofibrous materials warrant further study for development of "invisible" immunoisolation devices for cell transplantation.


Patient reports of undesirable events during hospitalization.
Thus far, incident reporting in health care has relied on health professionals. However, patients too may be able to signal the occurrence of undesirable events. To estimate the frequency of undesirable events reported by recently discharged patients, and to identify correlates of undesirable events. Mailed patient survey. Swiss public teaching hospital. Adult patients (N=1,518) discharged from hospital. Self-reports of 27 undesirable events during hospitalization, including 9 medical complications, 9 interpersonal problems, and 9 incidents related to the health care process. Most survey respondents (1,433, 94.4%) completed the section about undesirable events, and 725 (50.6%) reported at least 1 event. The most frequent events were phlebitis (11.0%), unavailable medical record (9.5%), failure to respect confidentiality (8.4%), and hospital-acquired infection (8.2%). The odds of an unfavorable rating increased with each additional interpersonal problem (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.3 to 1.8), each additional process-related problem (OR 1.5, 95% CI 1.3 to 1.9), but not with each additional medical complication (OR 1.0, 95% CI 0.9 to 1.2). Longer duration of stay, poor health, and depressed mood were all related to a greater reported frequency of undesirable events. Patients are able to report undesirable events that occur during hospital care. Such events occur in about a half of the hospitalizations, and have a negative impact on satisfaction with care.


Optimization of aquatic-terrestrial ecosystem in relation to soil nitrogen status for the cultivation of fish and aquatic food crops of the Indian subtropics.
A case study was undertaken during wet and postwet seasons to improve the perennial and alternate submerged saucer-shaped ponded lands (tal and semi-tal lands) in the coasts and northeastern plains of the Indian subtropics through pisciculture and cultivation of starch- and protein-rich aquatic food crops like water chestnut (Trapa bispinosa Roxb.) and makhana or fox nut (Euryale ferox Salisb.). The study revealed that the physico-chemical properties of soils (pH, organic C, organic matter, available N, P, and K) as well as quality of water (pH, EC, BOD, COD, CO3 +, HCO3-, NO3-N, SO4-S-, and Cl-), growing fish, makhana, and water chestnut was remarkably influenced by different moisture regimes and exhibited a significant improvement of soil health. The amount of organic C, available N, P, and K content were found significantly highest in the treatment where makhana was grown under alternate flooding and drying situation with a depth >2 m as compared to other treatments. Such enrichment of soil fertility, particularly in available N and P content, might be due to the accumulation of considerable amounts of biomass and fish excreta and their subsequent decomposition in situ in the soils. Therefore, the present study suggests that the N-enriched soil may effectively be utilized further for growing subsequent arable crops surroundings during summer season, which not only saves the amount of applied N fertilizer but also increases the apparent N efficiency with simultaneous increase in yield, and would benefit the farmers in this region.


Sanitation for all: the global opportunity to increase transgenerational health gains and better understand the link between NCDs and NTDs, a scoping review.
The global sanitation divide is narrowing. However, in many countries in Asia and Africa, the gap between rural and urban sanitation coverage is rather widening. Moreover, there is an increase in the burden of non-communicable diseases (NCDs), notwithstanding to the already high burden of neglected tropical diseases (NTDs). A scientific query is building on how the global 'sanitation for all' goal will address the dual burden of NTDs and NCDs, and help further understand the link between the two. This paper aims to discuss the link between i) sanitation and NTDs, and ii) sanitation and NCDs through a scoping review of the literature.


MEFV Variants in Patients with PFAPA Syndrome in Japan.
The pathogenesis of PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis) syndrome is unknown as yet. In order to understand whether genes implicated in other auto-inflammatory diseases might be involved in the pathogenesis of PFAPA, all variants in the genes causing familial Mediterranean fever (FMF), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), and Hyper IgD syndrome were analyzed in children with PFAPA. All variants in MEFV, TNFRSF1A, and MVK were analyzed in 20 patients with PFAPA. PFAPA were diagnosed by previous published criteria. The findings of all analyses in PFAPA patients were compared with those of unaffected normal subjects (n=62). In the 13 children of 20 with PFAPA, the heterozygous variants of MEFV (5 patients: E148Q-L110P, 2 patients: E148Q, 1 patient: E148Q-L110P/E148Q, 1 patient: E148Q-P369S-R408Q-E84K, 1 patient: E148Q-L110P-P369S-A408G, 1 patient: R202Q, 1 patient: P115R) were found. No variants belonging to TNFRSF1A or MVK were detected in children with PFAPA. The frequency of the E148Q-L110P variants in children with PFAPA was significantly higher than that observed in unaffected normal subjects (7/20 versus 8/62). The duration of the episodes of illness in PFAPA children with MEFV variants was shorter than that of patients without variants. Genes involved in the development and progression of MEFV may affect the incidence and the phenotype of PFAPA in children.


Captopril or conventional therapy in hypertensive type II diabetics. Three-year analysis.
The effects of long-term treatment with captopril and conventional therapy on albuminuria and metabolic parameters were compared in 74 hypertensive type II diabetics with normal serum creatinine. Patients were treated double-blind with either captopril monotherapy or combined with hydrochlorothiazide or therapy with metoprolol, hydrochlorothiazide, or both for 36 months. The treatment was titrated to achieve goal diastolic blood pressure of < or = 85 mm Hg. The reductions in blood pressures during treatment were similar in patients with (n = 21) and without (n = 53) microalbuminuria treated with either captopril or conventional therapy. No significant changes in albuminuria occurred in normoalbuminuric patients with either therapy. Although albuminuria fell in nearly all patients with microalbuminuria treated with captopril, it rose in eight of 12 patients on conventional therapy, with macroalbuminuria developing in two of them. Renal function was preserved by both types of treatment in both patient groups. Long-term treatment with either conventional therapy or captopril did not alter metabolic variables. We conclude that captopril alone or in combination decreases albuminuria and prevents the development of macroalbuminuria in hypertensive type II diabetics with persistent microalbuminuria. The renoprotective effect of this agent, however, remains to be demonstrated with longer term data on renal function. Aggressive antihypertensive treatment with either captopril or conventional therapy appears to be effective in preventing the onset of microalbuminuria in most normoalbuminuric patients. In contrast, with previous short-term studies, the use of converting enzyme inhibitors or conventional therapy did not cause adverse metabolic effects.


Safety and efficacy of a novel bioabsorbable, steroid-eluting sinus stent.
Inflammation/polyp recurrence, adhesions, and middle turbinate lateralization are causes of suboptimal outcomes following sinus surgery and lead to increased rates of revision. A bioabsorbable, drug-eluting stent was evaluated for its ability to preserve sinus patency by providing controlled steroid delivery to the sinus mucosa. The study objective was to assess safety and efficacy of a steroid-eluting sinus stent when used following functional endoscopic sinus surgery (FESS) in patients with chronic rhinosinusitis (CRS). Prospective, multicenter, randomized, double-blind clinical trial, enrolling 43 patients in 2 groups. One group (n = 38) used an intrapatient control design comparing drug-eluting to non-drug-eluting stents. The other group (n = 5) received bilateral drug-eluting stents to assess systemic safety. Endoscopic follow-up was performed for 60 days. Efficacy endpoints included assessment of inflammation, polyp formation, adhesions, and middle turbinate position. Stents were successfully deployed in all 86 sinuses. Compared to the control stent, the drug-eluting stent provided statistically significant reduction in inflammation at days 21 to 45 (p < 0.003), frequency of polyp formation (p = 0.0391), and frequency of significant adhesion (p = 0.0313). Reduced frequency of middle turbinate lateralization was also apparent though not statistically significant. No device-related adverse events occurred. Eluted steroid was unquantifiable systemically and there was no evidence of adrenal cortical suppression. This study demonstrates the safety and efficacy of a novel bioabsorbable, steroid-eluting stent for use in CRS patients. The steroid-eluting stent is effective in improving wound healing by preserving sinus patency, reducing inflammation, and minimizing adhesions via controlled local steroid delivery without measurable systemic exposure.


Multiple extraordinary optical transmission peaks from evanescent coupling in perforated metal plates surrounded by dielectrics.
We study numerically and theoretically the optical transmission of nanostructured gold films embedded in dielectric claddings. We show how multiple transmission peaks appear as the claddings thickness increases. These transmission peaks come not only from surface plasmon polariton excitations but also from the excitation of Fabry-Perot modes sustained at the claddings, coupled through the metal, as long as a periodic pattern is milled in the metal film. We propose that this structure could be used as an ultracompact all-optical switch by surrounding the metal film with Kerr nonlinear dielectric layers.


Methodology for a vaginal and urinary microbiome study in women with mixed urinary incontinence.
We describe the rationale and methods of a study designed to compare vaginal and urinary microbiomes in women with mixed urinary incontinence (MUI) and similarly aged, asymptomatic controls. This paper delineates the methodology of a supplementary microbiome study nested in an ongoing randomized controlled trial comparing a standardized perioperative behavioral/pelvic floor exercise intervention plus midurethral sling versus midurethral sling alone for MUI. Women in the parent study had at least "moderate bother" from urgency and stress urinary incontinence symptoms (SUI) on validated questionnaire and confirmed MUI on bladder diary. Controls had no incontinence symptoms. All participants underwent vaginal and urine collection for DNA analysis and conventional urine culture. Standardized protocols were designed, and a central lab received samples for subsequent polymerase chain reaction (PCR) amplification and sequencing of the bacterial16S ribosomal RNA (rRNA) gene. The composition of bacterial communities will be determined by dual amplicon sequencing of variable regions 1-3 and 4-6 from vaginal and urine specimens to compare the microbiome of patients with controls. Sample-size estimates determined that 126 MUI and 84 control participants were sufficient to detect a 20 % difference in predominant urinary genera, with 80 % power and 0.05 significance level. Specimen collection commenced January 2015 and finished April 2016. DNA was extracted and stored for subsequent evaluation. Methods papers sharing information regarding development of genitourinary microbiome studies, particularly with control populations, are few. We describe the rigorous methodology developed for a novel urogenital microbiome study in women with MUI.


Francisella novicida Cas9 interrogates genomic DNA with very high specificity and can be used for mammalian genome editing.
Genome editing using the CRISPR/Cas9 system has been used to make precise heritable changes in the DNA of organisms. Although the widely used Streptococcus pyogenes Cas9 (SpCas9) and its engineered variants have been efficiently harnessed for numerous gene-editing applications across different platforms, concerns remain regarding their putative off-targeting at multiple loci across the genome. Here we report that Francisella novicida Cas9 (FnCas9) shows a very high specificity of binding to its intended targets and negligible binding to off-target loci. The specificity is determined by its minimal binding affinity with DNA when mismatches to the target single-guide RNA (sgRNA) are present in the sgRNA:DNA heteroduplex. FnCas9 produces staggered cleavage, higher homology-directed repair rates, and very low nonspecific genome editing compared to SpCas9. We demonstrate FnCas9-mediated correction of the sickle cell mutation in patient-derived induced pluripotent stem cells and propose that it can be used for precise therapeutic genome editing for a wide variety of genetic disorders.


Evidence for differing roles for each lobe of the calmodulin-like domain in a calcium-dependent protein kinase.
Calcium-dependent protein kinases (CDPKs) are structurally unique Ser/Thr kinases found in plants and certain protozoa. They are distinguished by a calmodulin-like regulatory apparatus (calmodulin-like domain (CaM-LD)) that is joined via a junction (J) region to the C-terminal end of the kinase catalytic domain. Like CaM, the CaM-LD is composed of two globular EF structural domains (N-lobe, C-lobe), each containing a pair of Ca(2+) binding sites. Spectroscopic analysis shows that the CaM-LD is comprised of helical elements, but the isolated CaM-LD does not form a conformationally homogeneous tertiary structure in the absence of Ca(2+). The addition of substoichiometric amounts of Ca(2+) is sufficient to stabilize the C-terminal lobe in a construct containing J and CaM-LD (JC) but not in the CaM-LD alone. Moreover, as J is titrated into Ca(2+)-saturated CaM-LD, interactions are stronger with the C-lobe than the N-lobe of the CaM-LD. Measurements of Ca(2+) affinity for JC reveal two cooperatively interacting high affinity binding sites (K(d)(,mean) = 5.6 nm at 20 mm KCl) in the C-lobe and two weaker sites in the N-lobe (K(d,mean) = 110 nm at 20 mm KCl). The corresponding Ca(2+) binding constants in the isolated CaM-LD are lower by more than 2 orders of magnitude, which indicates that the J region has an essential role in stabilizing the structure of the CDPK regulatory apparatus. The large differential affinity between the two domains together with previous studies on a plasmodium CDPK (Zhao, Y., Pokutta, S., Maurer, P., Lindt, M., Franklin, R. M., and Kappes, B. (1994) Biochemistry 33, 3714-3721) suggests a model whereby even at normally low cytosolic levels of Ca(2+), the C-lobe interacts with the junction, but the kinase remains in an autoinhibited state. Activation then occurs when Ca(2+) levels rise to fill the two weaker affinity binding sites in the N-lobe, thereby triggering a conformational change that leads to release of the autoinhibitory region.


Productivity and fishing pressure drive variability in fish parasite assemblages of the Line Islands, equatorial Pacific.
Variability in primary productivity and fishing pressure can shape the abundance, species composition, and diversity of marine life. Though parasites comprise nearly half of marine species, their responses to these important forces remain little explored. We quantified parasite assemblages at two spatial scales, across a gradient in productivity and fishing pressure that spans six coral islands of the Line Islands archipelago and within the largest Line Island, Kiritimati, which experiences a west-to-east gradient in fishing pressure and upwelling-driven productivity. In the across-islands data set, we found that increasing productivity was correlated with increased parasite abundance overall, but that the effects of productivity differed among parasite groups. Trophically transmitted parasites increased in abundance with increasing productivity, but directly transmitted parasites did not exhibit significant changes. This probably arises because productivity has stronger effects on the abundance of the planktonic crustaceans and herbivorous snails that serve as the intermediate hosts of trophically transmitted parasites than on the higher-trophic level fishes that are the sole hosts of directly transmitted parasites. We also found that specialist parasites increased in response to increasing productivity, while generalists did not, possibly because specialist parasites tend to be more strongly limited by host availability than are generalist parasites. After the effect of productivity was controlled for, fishing was correlated with decreases in the abundance of trophically transmitted parasites, while directly transmitted parasites appeared to track host density; we observed increases in the abundance of parasites using hosts that experienced fishing-driven compensatory increases in abundance. The within-island data set confirmed these patterns for the combined effects of productivity and fishing on parasite abundance, suggesting that our conclusions are robust across a span of spatial scales. Overall, these results indicate that there are strong and variable effects of anthropogenic and natural drivers on parasite abundance and taxonomic richness. These effects are likely to be mediated by parasite traits, particularly by parasite transmission strategies.


MicroRNA-9: functional evolution of a conserved small regulatory RNA.
The functional significance of microRNA-9 (miR-9) during evolution is evidenced by its conservation at the nucleotide level from flies to humans but not its diverse expression patterns. Recent studies in several model systems reveal that miR-9 can regulate neurogenesis through its actions in neural or non-neural cell lineages. In vertebrates, miR-9 exerts diverse cell-autonomous effects on the proliferation, migration, and differentiation of neural progenitor cells by modulating different mRNA targets. In some developmental contexts, miR-9 suppresses apoptosis and is misregulated in several types of cancer cells, influencing proliferation or metastasis formation. Moreover, downregulation of miR-9 in postmitotic neurons is also implicated in some neurodegenerative diseases. Thus, miR-9 is emerging as an important regulator in development and disease through its ability to modulate different targets in a manner dependent on the developmental stage and the cellular context.


Inhibition of autophagy contributes to melatonin-mediated neuroprotection against transient focal cerebral ischemia in rats.
Melatonin, a natural product of the pineal gland, has been shown to protect against ischemic stroke, but the molecular mechanisms underlying its protective function are not fully understood. In the present study, we tested whether melatonin could protect against ischemia-reperfusion (I/R) injury to rat brain by targeting the autophagy pathway. The I/R brain injury was induced by the established rat transient middle cerebral artery occlusion model. We found intraperitoneal injection of melatonin can ameliorate rat brain injury as evidenced by multiple morphological and behavioral criteria, such as infarct size, neurological score, serum creatine kinase, and lactate dehydrogenase content, as well as pyknotic-positive cells. Further studies revealed that the beneficial effects of melatonin is through targeting the autophagy pathway by inhibiting expression of beclin-1 and conversion of LC3, as well as activating the PI3K/Akt pro-survival pathway. To further confirm this finding, the autophagy pathway was activated by lentiviral mediated beclin-1 delivery and the PI3K/Akt pathway was inhibited by a pharmacological inhibitor, LY294002. In both manipulations, the beneficial effects of melatonin were greatly abolished. Taken together, our study suggested melatonin plays a protective role against I/R brain injury by inhibiting autophagy and activating the PI3K/Akt pro-survival pathway.


Physical Activity and Variation in Momentary Behavioral Cognitions: An Ecological Momentary Assessment Study.
Decisions to perform moderate-to-vigorous physical activity (MVPA) involve behavioral cognitive processes that may differ within individuals depending on the situation. Ecological momentary assessment (EMA) was used to examine the relationships of momentary behavioral cognitions (ie, self-efficacy, outcome expectancy, intentions) with MVPA (measured by accelerometer). A sample of 116 adults (mean age, 40.3 years; 72.4% female) provided real-time EMA responses via mobile phones across 4 days. Multilevel models were used to test whether momentary behavioral cognitions differed across contexts and were associated with subsequent MVPA. Mixed-effects location scale models were used to examine whether subject-level means and within-subjects variances in behavioral cognitions were associated with average daily MVPA. Momentary behavioral cognitions differed across contexts for self-efficacy (P = .007) but not for outcome expectancy (P = .53) or intentions (P = .16). Momentary self-efficacy, intentions, and their interaction predicted MVPA within the subsequent 2 hours (Ps < .01). Average daily MVPA was positively associated with within-subjects variance in momentary self-efficacy and intentions for physical activity (Ps < .05). Although momentary behavioral cognitions are related to subsequent MVPA, adults with higher average MVPA have more variation in physical activity self-efficacy and intentions. Performing MVPA may depend more on how much behavioral cognitions vary across the day than whether they are generally high or low.


Cell biology and genetics of root hair formation in Arabidopsis thaliana.
In this review we integrate the information available on the cell biology of root hair formation with recent findings from the analysis of root hair mutants of Arabidopsis thaliana. The mature Arabidopsis root epidermis consists of root-hair-producing cells and non-root-hair-producing cells. Root hair growth begins with a swelling of the outer epidermal wall. It has been postulated that this is due to a pH-mediated localised cell wall loosening. From the bulge a single root hair emerges which grows by tip growth. The root hair tip consists of a vesicle-rich zone and an organelle-rich subapical zone. The vesicles supply new plasma membrane and cell wall material for elongation. The cytoskeleton and its associated regulatory proteins such as profilin and spectrin are proposed to be involved in the targeting of vesicles. Ca2+ influxes and gradients are present in hair tips, but their function is still unclear. Mutants have been isolated with lesions in various parts of the root hair developmental pathway from bulge identity and initiation to control of tip diameter and extent and polarity of elongation.


Novel inulin-based mucoadhesive micelles loaded with corticosteroids as potential transcorneal permeation enhancers.
In this work a new copolymer of inulin (INU) derivatized with ethylendiamine (EDA) and retinoic acid (RA), named INU-EDA-RA, was synthetized, characterized and employed to produce micelles as carriers for topical administration of corticosteroids for the potential treatment of diseases of posterior eye segment. Spectroscopic analysis confirmed a molar derivatization degree of 11.30 and 4.30% in EDA and RA, respectively. INU-EDA-RA micelles are capable of strong mucoadhesive interactions which result time-independent and stable over time but concentration depending. Moreover micelles are able to encapsulate efficiently from 3 to 13% (w/w) of lipophilic drugs, as dexamethasone, triamcinolone and triamcinolone acetonide. Drug loaded micelles are stable for three months when stored as freeze-dried powders and able to release high amount of drug when compared to drug dissolution profiles from suspensions. Moreover, drug loaded micelles are compatible with different ocular cell lines that are also able to internalize fluorescent micelles. Finally, drug loaded micelles enhance drug fluxes and permeability coefficients across corneal epithelial cells, thus reducing drug loss due to retention inside the cells.


Adipokines and dietary interventions in human obesity.
Obesity is a multisystem disorder associated with cardiovascular and metabolic complications. According to recent studies, it is characterized as a condition of low-grade inflammation with altered adipose tissue function and secretion of various adipokines. One of the strategies in obesity treatment is dietary intervention (DI) that could modulate cytokine levels in a favourable way. The aim of this review was to summarize the results of studies performed in the last 13 years investigating DI programmes accompanied with weight loss in relation to profile of adipokines at different level (adipose tissue mRNA, adipose tissue secretion and circulating level) and identify whether modulations of adipokines are implicated in the positive effects of DIs. The overall finding is that DIs leading to 5-10% weight loss modulate production of certain adipokines and generally induce improvement of clinical parameters, e.g. insulin sensitivity, but the amelioration of obesity complications is not coherent with the pattern of adipokine regulation, except maybe for leptin. Global analysis of the adipose tissue secretome and measurement of panels of adipokines may prove more informative than studies on individual molecules.


Autophagy-inducing agents augment the antitumor effect of telerase-selve oncolytic adenovirus OBP-405 on glioblastoma cells.
Oncolytic adenoviruses are a promising tool in cancer therapy. In this study, we characterized the role of autophagy in oncolytic adenovirus-induced therapeutic effects. OBP-405, an oncolytic adenovirus regulated by the human telomerase reverse transcriptase promoter (hTERT-Ad, OBP-301) with a tropism modification (RGD) exhibited a strong antitumor effect on glioblastoma cells. When autophagy was inhibited pharmacologically, the cytotoxicity of OBP-405 was attenuated. In addition, autophagy-deficient Atg5(-/-) mouse embryonic fibroblasts (MEFs) were less sensitive than wild-type MEFs to OBP-405. These findings indicate that OBP-405-induced autophagy is a cell killing effect. Moreover, autophagy-inducing therapies (temozolomide and rapamycin) synergistically sensitized tumor cells to OBP-405 by stimulating the autophagic pathway without altering OBP-405 replication. Mice harboring intracranial tumors treated with OBP-405 and temozolomide survived significantly longer than those treated with temozolomide alone, and mice treated with OBP-405 and the rapamycin analog RAD001 survived significantly longer than those treated with RAD001 alone. The observation that autophagy inducers increase OBP-405 antitumor activity suggests a novel strategy for treating patients with glioblastoma.


Function of the Shaw potassium channel within the Drosophila circadian clock.
In addition to the molecular feedback loops, electrical activity has been shown to be important for the function of networks of clock neurons in generating rhythmic behavior. Most studies have used over-expression of foreign channels or pharmacological manipulations that alter membrane excitability. In order to determine the cellular mechanisms that regulate resting membrane potential (RMP) in the native clock of Drosophila we modulated the function of Shaw, a widely expressed neuronal potassium (K(+)) channel known to regulate RMP in Drosophila central neurons. We show that Shaw is endogenously expressed in clock neurons. Differential use of clock gene promoters was employed to express a range of transgenes that either increase or decrease Shaw function in different clusters of clock neurons. Under LD conditions, increasing Shaw levels in all clock neurons (LNv, LNd, DN(1), DN(2) and DN(3)), or in subsets of clock neurons (LNd and DNs or DNs alone) increases locomotor activity at night. In free-running conditions these manipulations result in arrhythmic locomotor activity without disruption of the molecular clock. Reducing Shaw in the DN alone caused a dramatic lengthening of the behavioral period. Changing Shaw levels in all clock neurons also disrupts the rhythmic accumulation and levels of Pigment Dispersing Factor (PDF) in the dorsal projections of LNv neurons. However, changing Shaw levels solely in LNv neurons had little effect on locomotor activity or rhythmic accumulation of PDF. Based on our results it is likely that Shaw modulates pacemaker and output neuronal electrical activity that controls circadian locomotor behavior by affecting rhythmic release of PDF. The results support an important role of the DN clock neurons in Shaw-mediated control of circadian behavior. In conclusion, we have demonstrated a central role of Shaw for coordinated and rhythmic output from clock neurons.


The Negative Association between Religiousness and Children's Altruism across the World.
Prosocial behaviors are ubiquitous across societies. They emerge early in ontogeny and are shaped by interactions between genes and culture. Over the course of middle childhood, sharing approaches equality in distribution. Since 5.8 billion humans, representing 84% of the worldwide population, identify as religious, religion is arguably one prevalent facet of culture that influences the development and expression of prosociality. While it is generally accepted that religion contours people's moral judgments and prosocial behavior, the relation between religiosity and morality is a contentious one. Here, we assessed altruism and third-party evaluation of scenarios depicting interpersonal harm in 1,170 children aged between 5 and 12 years in six countries (Canada, China, Jordan, Turkey, USA, and South Africa), the religiousness of their household, and parent-reported child empathy and sensitivity to justice. Across all countries, parents in religious households reported that their children expressed more empathy and sensitivity for justice in everyday life than non-religious parents. However, religiousness was inversely predictive of children's altruism and positively correlated with their punitive tendencies. Together these results reveal the similarity across countries in how religion negatively influences children's altruism, challenging the view that religiosity facilitates prosocial behavior.


Probing the interactions of organic molecules, nanomaterials, and microbes with solid surfaces using quartz crystal microbalances: methodology, advantages, and limitations.
Quartz crystal microbalances (QCMs) provide a new analytical opportunity and prospect to characterize many environmental processes at solid/liquid interfaces, thanks to their almost real-time measurement of physicochemical changes on their quartz sensor. This work reviews the applications of QCMs in probing the interactions of organic molecules, nanomaterials (NMs) and microbes with solid surfaces. These interfacial interactions are relevant to critical environmental processes such as biofilm formation, fate and transport of NMs, fouling in engineering systems and antifouling practices. The high sensitivity, real-time monitoring, and simultaneous frequency and dissipation measurements make QCM-D a unique technique that helps reveal the interaction mechanisms for the abovementioned processes (e.g., driving forces, affinity, kinetics, and the interplay between surface chemistry and solution chemistry). On the other hand, QCM measurement is nonselective and spatially-dependent. Thus, caution should be taken during data analysis and interpretation, and it is necessary to cross-validate the results using complementary information from other techniques for more quantitative and accurate interpretation. This review summarizes the general methodologies for collecting and analyzing raw QCM data, as well as for evaluating the associated uncertainties. It serves to help researchers gain deeper insights into the fundamentals and applications of QCMs, and provides new perspectives on future research directions.


DNA replication and the GINS complex: localization on extended chromatin fibers.
The GINS complex is thought to be essential for the processes of initiation and elongation of DNA replication. This complex contains four subunits, one of which (Psf1) is proposed to bind to both chromatin and DNA replication-associated proteins. To date there have been no microscopic analyses to evaluate the chromatin distribution of this complex. Here, we show the organization of GINS complexes on extended chromatin fibers in relation to sites of DNA replication and replication-associated proteins. Using immunofluorescence microscopy we were able to visualize ORC1, ORC2, PCNA, and GINS complex proteins Psf1 and Psf2 bound to extended chromatin fibers. We were also able to detect these proteins concurrently with the visualization of tracks of recently replicated DNA where EdU, a thymidine analog, was incorporated. This allowed us to assess the chromatin association of proteins of interest in relation to the process of DNA replication. ORC and GINS proteins were found on chromatin fibers before replication could be detected. These proteins were also associated with newly replicated DNA in bead-like structures. Additionally, GINS proteins co-localized with PCNA at sites of active replication. In agreement with its proposed role in the initiation of DNA replication, GINS proteins associated with chromatin near sites of ORC binding that were devoid of EdU (absence of DNA replication). The association of GINS proteins with PCNA was consistent with a role in the process of elongation. Additionally, the large size of our chromatin fibers (up to approximately 7 Mb) allowed for a more expansive analysis of the distance between active replicons than previously reported.


Endoscopic en bloc resection of an exophytic gastrointestinal stromal tumor with suction excavation technique.
Here, we report the first successful endoscopic resection of an exophytic gastrointestinal stromal tumor (GIST) using a novel perforation-free suction excavation technique. A 49-year-old woman presented for further management of a gastric subepithelial tumor on the lesser curvature of the lower body, originally detected via routine upper gastrointestinal endoscopy. Abdominal computed tomography and endoscopic ultrasound showed a 4-cm extraluminally protruding mass originating from the muscularis propria layer. The patient firmly refused surgical resection owing to potential cardiac problems, and informed consent was obtained for endoscopic removal. Careful dissection and suction of the tumor was repeated until successful extraction was achieved without serosal injury. We named this procedure the suction excavation technique. The tumor's dimensions were 3.5 cm × 2.8 cm × 2.5 cm. The tumor was positive for C-KIT and CD34 by immunohistochemical staining. The mitotic count was 6/50 high-power fields. The patient was followed for 5 years without tumor recurrence. This case demonstrated the use of endoscopic resection of an exophytic GIST using the suction excavation technique as a potential therapy without surgical resection.


Revealing the role of glutathione S-transferase omega in age-at-onset of Alzheimer and Parkinson diseases.
We previously reported a linkage region on chromosome 10q for age-at-onset (AAO) of Alzheimer (AD) and Parkinson (PD) diseases. Glutathione S-transferase, omega-1 (GSTO1) and the adjacent gene GSTO2, located in this linkage region, were then reported to associate with AAO of AD and PD. To examine whether GSTO1 and GSTO2 (hereafter referred to as GSTO1h) are responsible for the linkage evidence, we identified 39 families in AD that lead to our previous linkage and association findings. The evidence of linkage and association was markedly diminished after removing these 39 families from the analyses, thus providing support that GSTO1h drives the original linkage results. The maximum average AAO delayed by GSTO1h SNP 7-1 (rs4825, A nucleotide) was 6.8 (+/-4.41) years for AD and 8.6(+/-5.71) for PD, respectively. This is comparable to the magnitude of AAO difference by APOE-4 in these same AD and PD families. These findings suggest the presence of genetic heterogeneity for GSTO1h's effect on AAO, and support GSTO1h's role in modifying AAO in these two disorders.


Maternal cholestasis during pregnancy programs metabolic disease in offspring.
The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%-2% of pregnant women and is characterized by increased bile acid levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown. We analyzed the Northern Finland birth cohort 1985-1986 database and found that 16-year-old children of mothers with ICP had altered lipid profiles. Males had increased BMI, and females exhibited increased waist and hip girth compared with the offspring of uncomplicated pregnancies. We further investigated the effect of maternal cholestasis on the metabolism of adult offspring in the mouse. Females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following a Western diet, whereas matched mice not exposed to cholestasis in utero did not. Female littermates were susceptible to metabolic disease before dietary challenge. Human and mouse studies showed an accumulation of lipids in the fetoplacental unit and increased transplacental cholesterol transport in cholestatic pregnancy. We believe this is the first report showing that cholestatic pregnancy in the absence of altered maternal BMI or diabetes can program metabolic disease in the offspring.


Optimising assessments of the epidemiological impact in The Netherlands of paediatric immunisation with 13-valent pneumococcal conjugate vaccine using dynamic transmission modelling.
This work is the first attempt to quantify the overall effects of a 13-valent pneumococcal conjugate vaccine (PCV13) vaccination programme in the Dutch population taking into account all the direct and indirect effects of the vaccine on invasive pneumococcal disease. Using available Dutch data, a dynamic transmission model for the spread of pneumococci and potential subsequent invasive pneumococcal disease has been adapted to the Dutch setting. Overall, invasive pneumococcal disease cases in the Netherlands are predicted to decrease from a pre-vaccination level of 2623 cases annually to 2475, 2289, 2185, 2179, and 2178 cases annually 5-, 10-, 20-, 30-, and 40-years, respectively, post-vaccination. Therefore, vaccination with PCV13 in the Netherlands is predicted to lower invasive pneumococcal disease cases per year by up to 445 cases in the medium- to long-term. The results are quite robust for the sensitivity analyses performed on the parameters that regulate herd immunity and competition between vaccine and non-vaccine types.


Problems recruiting and retaining postnatal women to a pilot randomised controlled trial of a web-delivered weight loss intervention.
This paper highlights recruitment and retention problems identified during a pilot randomised controlled trial and process evaluation. The pilot trial aimed to evaluate the feasibility and acceptability of a web-delivered weight loss intervention for postnatal women and associated trial protocol. General practice database searches revealed low rates of eligible postnatal women per practice. 16 (10%) of the 168 identified women were recruited and randomised, seven to the intervention and nine to the control. 57% (4/7) of the intervention women completed 3 month follow-up measurements in comparison to 56% (5/9) in the control group. By 12 months, retention in the intervention group was 43% (3/7), with 2/7 women active on the website, in comparison to 44% (4/9) of the control group. Interview findings revealed the web as an acceptable method for delivery of the intervention, with the suggestion of an addition of a mobile application. Alternative recruitment strategies, using health visitor appointments, midwifery departments or mother and baby/toddler groups, should be explored. Greater involvement of potential users should enable better recruitment methods to be developed. Trial registration ISRCTN: ISRCTN48086713, Registered 26 October 2012.


Factors Influencing Parental and Individual COVID-19 Vaccine Decision Making in a Pediatric Network.
Aspects of the COVID-19 vaccination campaign differed from routine vaccines, including emergency use authorizations, the prioritization of access, and the politicization of messaging. Subsequently, many parents reported lower vaccine confidence relative to routine vaccines, and vaccination coverage stalled below targets. This study aimed to understand parental vaccine decision making and compare COVID-19 versus routine vaccine decision making. We conducted nine virtual focus groups between 25 February 2022-11 March 2022 with parents (n = 41) of the Children's Hospital of Philadelphia's patients, recruited via email and stratified by vaccine hesitancy status (non-hesitant vs. hesitant). Transcripts were analyzed using the vaccine hesitancy matrix domains. Of 41 total participants, 25 (61.0%) were non-hesitant, 16 (39.0%) were hesitant or their children were not up-to-date on adolescent vaccines, and most self-identified as female (95.1%) and White/Caucasian (61.0%). Most participants (87.5%) were fully vaccinated against COVID-19 and many of their first children (n = 26, 63.4%) were vaccinated against influenza. Several themes emerged regarding decision making: individual influences, group influences, vaccine and vaccine program influences, and contextual influences. While some influences were similar for routine and COVID-19 vaccine decision making (e.g., needing evidence-based information), other factors were vaccine- or situation-specific. Building trust requires a multi-faceted concerted effort that involves addressing the complex vaccine decision-making process.


Green tea constituent epigallocatechin-3-gallate inhibits angiogenic differentiation of human endothelial cells.
Several independent research studies have shown that consumption of green tea reduces the development of cancer in many animal models. Epidemiological observations, though inconclusive, are suggesting that green tea consumption may also reduce the risk of some cancers in humans. These anti-carcinogenic effects of green tea have been attributed to its constituent polyphenols. Angiogenesis is a crucial step in the growth and metastasis of cancers. We have investigated the effect of the major polyphenolic constituent of green tea, epigallocatechin-3-gallate (EGCG), on the tube formation of human umbilical vein endothelial cells (HUVEC) on matrigel. Tube formation was inhibited by treatment both prior to plating and after plating endothelial cells on matrigel. EGCG treatment also was found to reduce the migration of endothelial cells in matrigel plug model. The role of matrix metalloproteinases (MMP) has been shown to play an important role during angiogenesis. Zymography was performed to determine if EGCG had any effect on MMPs. Zymographs of EGCG-treated culture supernatants modulated the gelatinolytic activities of secreted proteinases indicating that EGCG may be exerting its inhibitory effect by regulating proteinases. These findings suggest that EGCG acts as an angiogenesis inhibitor by modulating protease activity during endothelial morphogenesis.


SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues.
There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.


Transungual iontophoresis of lithium and sodium: effect of pH and co-ion competition on cationic transport numbers.
Iontophoresis has been proposed as an alternative method to deliver drugs into and across the nail plate. However, the knowledge about the rules governing transungual iontophoretic transport numbers is still uncomplete. This work investigated the iontophoretic and passive transungual fluxes of sodium and lithium and the effect of pH and co-ion competition on the cations' transport numbers. The objective was to further investigate whether nails show cation permselectivity at physiological pH and to improve our understanding of transport numbers during transungual iontophoresis. The donor solutions comprised the single ion and binary mixtures of the two cations at different pH. Sodium and lithium iontophoretic fluxes showed low inter-nail variability and were significantly greater than passive fluxes. Cationic transport numbers clearly increased as the pH was sequentially raised from 4.0 to 5.0 and then to 7.0, in agreement with a net negative charge of the human nails at physiological pH. Sodium transport number was maximal when the ion was formulated as a single ion (absence of competing co-ions) and decreased as the molar fraction of lithium was increased in the vehicle. The magnitude of the transport numbers measured and their response to changes in the cations' molar fraction and pH in the donor solution were remarkably similar to those observed during the transdermal iontophoresis. The ratio of lithium and sodium transport numbers was directly proportional to their relative concentration ratios; the proportionality constant being remarkably similar in the 4.0-7.0 pH range as well as to the ratio of the cations' aqueous mobilities. Another interesting similarity with transdermal iontophoresis was the existence of a cationic transport number threshold. On the whole, this work provided some key information about nail permselectivity and transungual transport numbers which will assist to formulate efficiently therapeutic compounds to be delivered iontophoretically into and across the nail plate.


Stepping towards More Intuitive Physical Activity Metrics with Wrist-Worn Accelerometry: Validity of an Open-Source Step-Count Algorithm.
Stepping-based targets such as the number of steps per day provide an intuitive and commonly used method of prescribing and self-monitoring physical activity goals. Physical activity surveillance is increasingly being obtained from wrist-worn accelerometers. However, the ability to derive stepping-based metrics from this wear location still lacks validation and open-source methods. This study aimed to assess the concurrent validity of two versions (1. original and 2. optimized) of the Verisense step-count algorithm at estimating step-counts from wrist-worn accelerometry, compared with steps from the thigh-worn activPAL as the comparator. Participants (n = 713), across three datasets, had >24 h continuous concurrent accelerometry wear on the non-dominant wrist and thigh. Compared with activPAL, total daily steps were overestimated by 913 ± 141 (mean bias ± 95% limits of agreement) and 742 ± 150 steps/day with Verisense algorithms 1 and 2, respectively, but moderate-to-vigorous physical activity (MVPA) steps were underestimated by 2207 ± 145 and 1204 ± 103 steps/day in Verisense algorithms 1 and 2, respectively. In summary, the optimized Verisense algorithm was more accurate in detecting total and MVPA steps. Findings highlight the importance of assessing algorithm performance beyond total step count, as not all steps are equal. The optimized Verisense open-source algorithm presents acceptable accuracy for derivation of stepping-based metrics from wrist-worn accelerometry.


Alcohol affects the late differentiation of progenitor B cells.
Previous studies show that alcohol exposure can affect the differentiation of progenitor B cells. Before final commitment to a B lineage, progenitor B cells usually undergo several important stages. However, it is still unclear whether alcohol alters B cell differentiation at which stages. The aim of this study was to determine which stage(s) of progenitor cell differentiation are affected by alcohol and to elucidate the mechanism(s) responsible for the effect of alcohol on B cell differentiation. Oligoclonal-neonatal-progenitor (ONP) cells from bone marrow cells of 2-week-old mice were cultured under different conditions in vitro with or without the exposure of 100 mM alcohol. Phenotype analysis was performed at different time points and expression levels of transcription factors (TFs) and cytokine receptors were measured quantitatively and kinetically. After 3 days in vitro culture, ONP cells differentiated into two populations: B220(-)CD11b(-) and B220(-)CD11b(+) cells. B220(-)CD11b(-) cells can further differentiate into B lineage cells only with the support of B220(-)CD11b(+) cells. Cells exposed to 100 mM of alcohol during the first 3 days of culture showed no statistically significant difference in B cell formation after 12 days compared with the control group. However, cells exposed to alcohol from Day 4 till the end of culture yield very few B cells. Expression levels of TFs and cytokine receptors were down-regulated kinetically among ONP cells co-cultured with the addition of 100 mM alcohol. Alcohol affects the ONP cell differentiation into B lineage at a late stage. Alcohol also down-regulates the expression level of TFs and cytokine receptors resulting in the impairment of B cell differentiation.


A New Method for Acoustic Priority Vehicle Detection Based on a Self-Powering Triboelectric Acoustic Sensor Suitable for Low-Power Wireless Sensor Networks.
Traffic congestion is, on a daily basis, responsible for a significant amount of economic and social costs. One of the critical examples is the obstruction of priority vehicles during fast trajectories, which potentially costs lives and property in case of delay that is too great. By means of visual sensing methods, solutions and schedules have already been proposed for adjusting traffic light sequences depending on a priority vehicle's position. However, these mechanisms are computation and power intensive. Deploying and powering a large-scale network will have a crucial economical cost. Furthermore, these devices will not always have access to sufficient power. To provide a solution, we developed an acoustic and self-powered device that can detect priority vehicles and can be cost effectively deployed to define a sensor network. The device combines the detection of priority vehicles and the harvesting of sound energy through triboelectrification. This paper will introduce the use of triboelectric energy harvesting, specifically in a self-powered wireless sensor network for priority vehicle detection. Furthermore, it shows how to increase the power performance of such a generator. Finally, the results are analyzed.


Mass and stiffness calibration of nanowires using thermally driven vibration.
Cantilevered or suspended nanowires show promise for force or mass sensing applications due to their small mass, high force sensitivity and high frequency bandwidth. To use these as quantitative sensors, their bending stiffness or mass must be calibrated experimentally, often using thermally driven vibration. However, this can be difficult because nanowires are slightly asymmetric, which results in two spatially orthogonal bending eigenmodes with closely spaced frequencies. This asymmetry presents problems for traditional stiffness calibration methods, which equate the measured thermal vibration spectrum near a resonance to that of a single eigenmode. Moreover, the principal axes may be arbitrarily rotated with respect to the measurement direction. In this work, the authors propose a method for calibrating the bending stiffness and mass of such nanowires' eigenmodes using a single measurement taken at an arbitrary orientation with respect to the principal axes.


Target cells during early SIV encephalopathy.
Early encephalopathy was studied in rhesus macaques in the first month following intravenous (i.v.) infection with SIV-mac-251. Histopathological analysis of brain tissues showed slight gliosis, associated with perivascular infiltrates and occasional glial nodules. Immunophenotyping of brain tissue showed microgliosis with expression of MHC class II molecule and macrophage infiltration associated with a few lymphocytes. At the early stage of infection, most infected cells were perivascular, suggesting that infiltrating cells are the main route of entry of the virus into the brain. Using combined immunochemistry and in situ hybridization, it was shown that these infected perivascular cells were mostly macrophages. Later, SIV infected a limited number of cells expressing the same CD68 monocyte/macrophage/microglia marker. Using different genome probes, hypotheses concerning SIV RNA expression during early brain infection were tested. It was shown that the latent brain infection was not due to a complete transcription block, but rather to productive replication of SIV at a low level in a small number of target cells in the brain. Injection of SIV by the intracerebral (i.c.) route induced the same slight encephalitis as observed in i.v. inoculated animals. The very small number of infected cells found around the site of i.c. inoculation suggests that resident microglia are poorly susceptible to infection by SIV.


The role of patient pain and physical function on depressive symptoms in couples with lung cancer: a longitudinal dyadic analysis.
Drawing on the Developmental-Contextual Model (Berg & Upchurch, 2007), we examined the association between changes in patient physical health (pain severity and physical function) and changes in depressive symptoms in couples with lung cancer over a 12-month period. Patients and their spouses or partners (n = 77) were recruited using rapid case ascertainment and completed five waves of data collection (baseline, 3, 6, 9, and 12 months). Multilevel modeling was used to examine aggregate and time-varying effects of patient physical health on depressive symptoms. Results indicated that for patients and spouses, patient-rated mean pain severity was significantly positively associated with patient and spouse depressive symptoms and patient-rated mean physical function was significantly negatively associated with patient and spouse depressive symptoms. More importantly, increases in patient pain severity and declines in patient physical function were significantly associated with increases in patient depressive symptoms. However, only declines in patient physical function were significantly associated with increases in spouse depressive symptoms. These time-varying effects remained even when controlling for patient gender, patient age, patient stage of disease, spouse physical health, and relationship quality. Findings suggest the importance of examining the changing illness context on the couple as a unit and the complexity of interpersonal processes in the presence of a life-threatening illness.


Emergence and function of cortical offset responses in sound termination detection.
Offset responses in auditory processing appear after a sound terminates. They arise in neuronal circuits within the peripheral auditory system, but their role in the central auditory system remains unknown. Here, we ask what the behavioral relevance of cortical offset responses is and what circuit mechanisms drive them. At the perceptual level, our results reveal that experimentally minimizing auditory cortical offset responses decreases the mouse performance to detect sound termination, assigning a behavioral role to offset responses. By combining in vivo electrophysiology in the auditory cortex and thalamus of awake mice, we also demonstrate that cortical offset responses are not only inherited from the periphery but also amplified and generated de novo. Finally, we show that offset responses code more than silence, including relevant changes in sound trajectories. Together, our results reveal the importance of cortical offset responses in encoding sound termination and detecting changes within temporally discontinuous sounds crucial for speech and vocalization.


Effects of Noise Exposure on the Auditory Function of Ovariectomized Rats with Estrogen Deficiency.
The benefits of estrogen for the auditory function of women depend on a number of factors. In this study, we aimed to examine the impact of noise trauma on the auditory function of ovariectomized rats with estrogen deficiency. Twenty-eight young, female Sprague-Dawley rats were assigned to three groups (OVX+N, OVX-N, Sham+N). Rats in the OVX+N group and the OVX-N group underwent bilateral ovariectomy (OVX); the OVX+N group alone was also exposed to white noise (N) of 115 dB SPL for 8 hours a day over 14 days. The Sham+N group consisted of rats with intact ovaries that were exposed to the same noise. The auditory function of all rats was measured before treatment and after noise exposure by the signal-to-noise ratio (SNR) of distortion-product otoacoustic emissions (DPOAE) and the threshold of auditory-evoked brainstem response (ABR). The Sham+N group (intact ovaries, noise-exposed) had worse auditory function than the OVX-N group (ovariectomy, no noise). The OVX+N group had decreased SNRs of DPOAE and increased ABR thresholds relative to the Sham+N group. Noise exposure may cause greater damage to auditory function when estrogen levels are low in females.


Regulation of equilibrative nucleoside uptake by protein kinase inhibitors.
The uptake of nucleosides and nucleoside analogs into human leukemia K562 cells is facilitated by the equilibrative transporters ENT1 and ENT2. Incubation of K562 cells with a variety of protein kinase inhibitors inhibited the transport of both uridine (ARA-C) and cytidine (CPEC) analogs. These inhibitory effects were observed for a large number of kinase inhibitors including those against p38 MAPK, the EGF receptor kinase, protein kinase C, TOR and others. Thus these results suggest that the nucleoside transporters are unexpected targets for kinase inhibitors and may influence the design and application of combinatorial approaches of nucleoside analogs and kinase inhibitors in clinical applications.


Yoga for breast cancer patients and survivors: a systematic review and meta-analysis.
Many breast cancer patients and survivors use yoga to cope with their disease. The aim of this review was to systematically assess and meta-analyze the evidence for effects of yoga on health-related quality of life and psychological health in breast cancer patients and survivors. MEDLINE, PsycInfo, EMBASE, CAMBASE, and the Cochrane Library were screened through February 2012. Randomized controlled trials (RCTs) comparing yoga to controls were analyzed when they assessed health-related quality of life or psychological health in breast cancer patients or survivors. Risk of bias was assessed using the Cochrane risk of bias tool. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated. Twelve RCTs with a total of 742 participants were included. Seven RCTs compared yoga to no treatment; 3 RCTs compared yoga to supportive therapy; 1 RCT compared yoga to health education; and 1 RCT compared a combination of physiotherapy and yoga to physiotherapy alone. Evidence was found for short-term effects on global health-related quality of life (SMD = 0.62 [95% CI: 0.04 to 1.21]; P = 0.04), functional (SMD = 0.30 [95% CI: 0.03 to 0.57), social (SMD = 0.29 [95% CI: 0.08 to 0.50]; P < 0.01), and spiritual well-being (SMD = 0.41 [95% CI: 0.08; 0.74]; P = 0.01). These effects were, however, only present in studies with unclear or high risk of selection bias. Short-term effects on psychological health also were found: anxiety (SMD = -1.51 [95% CI: -2.47; -0.55]; P < 0.01), depression (SMD = -1.59 [95% CI: -2.68 to -0.51]; P < 0.01), perceived stress (SMD = -1.14 [95% CI:-2.16; -0.12]; P = 0.03), and psychological distress (SMD = -0.86 [95% CI:-1.50; -0.22]; P < 0.01). Subgroup analyses revealed evidence of efficacy only for yoga during active cancer treatment but not after completion of active treatment. This systematic review found evidence for short-term effects of yoga in improving psychological health in breast cancer patients. The short-term effects on health-related quality of life could not be clearly distinguished from bias. Yoga can be recommended as an intervention to improve psychological health during breast cancer treatment.


Sleep disturbances in aspartylglucosaminuria (AGU): a questionnaire study.
Sleep disturbances are common in many progressive metabolic encephalopathies. The possible presence of disturbed sleep-wake behaviour in the lysosomal storage disorder aspartylglucosaminuria, has not been previously studied, however. The sleep-wake behaviour of 81 patients with aspartylglucosaminuria (AGU, age 3-55 years, median 22 years; 42 female and 39 male) and 49 controls (age 2-57 years, median 18 years; 25 female and 24 male) was assessed through a postal survey. A slightly modified version of the validated Basic Nordic Sleep Questionnaire was used. Fifty-eight per cent of the AGU patients were reported to suffer daily from a sleep-related problem (controls 31%, p < 0.01). In AGU adults (age >17 years) and children (age < or =17 years), the corresponding figures were 52% and 61%, respectively (control children 22%, p < 0.05 and control adults 38%, p = 0.06). In AGU children, settling difficulties were reported to occur significantly more commonly than in control children. Children with AGU were also reported to snore more often than were the controls. Adults with this disorder were found to suffer from severely fragmented night-time sleep, which was experienced as highly distressing by the parents and other caregivers. A long night sleep period was reported to be common in the ageing AGU patients (AGU 9.5 +/- 1.7 vs controls 7.2 +/- 1.0 h, mean +/- SD, p < 0.001). Parents and caregivers also often complained about disturbing movements during sleep in AGU patients. In conclusion, both children and adults with aspartylglucosaminuria were reported to display several types of sleep disturbances significantly more commonly than healthy controls.


The incidence of type 1 (insulin-dependent) diabetes mellitus in subjects aged 0-19 years in Luxembourg: a retrospective study from 1977 to 1986.
A decrease in the incidence of Type 1 (insulin-dependent) diabetes mellitus in the age group 0-14 years has been observed from north to south over north-western Europe. To evaluate whether this trend could be found in Luxembourg (a small country between the Netherlands and France) we performed a retrospective study over a period of 10 years. Information concerning all Type 1 diabetic patients (aged 0-19 years at diagnosis), diagnosed between January 1, 1977 and December 31, 1986 was obtained through paediatricians, internists, general practitioners and the Luxembourg Diabetes Association (LDA). The LDA was used as the ascertainment group (to estimate the real number and incidence of Type 1 diabetes mellitus). During the study period 91 Type 1 diabetic patients aged between 0-19 years were diagnosed. An incidence of 11.2 was found in boys (0-19 years). Girls in the same age group showed a considerably lower incidence of 8.8. Standardised incidence (using as standard the world population) revealed an almost similar incidence in the Netherlands and Luxembourg (respectively 10.3 and 10.2) for the age group aged 0-14 years. In France a considerably lower incidence is found (3.6). To what extent different methodology contributes to the differences remains to be clarified. Further prospective studies are necessary to investigate the role of environmental and genetic factors.


Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment.
Specific language impairment (SLI), an unexpected failure to develop appropriate language skills despite adequate non-verbal intelligence, is a heterogeneous multifactorial disorder with a complex genetic basis. We identified a homozygous microdeletion of 21,379 bp in the ZNF277 gene (NM_021994.2), encompassing exon 5, in an individual with severe receptive and expressive language impairment. The microdeletion was not found in the proband's affected sister or her brother who had mild language impairment. However, it was inherited from both parents, each of whom carries a heterozygous microdeletion and has a history of language problems. The microdeletion falls within the AUTS1 locus, a region linked to autistic spectrum disorders (ASDs). Moreover, ZNF277 is adjacent to the DOCK4 and IMMP2L genes, which have been implicated in ASD. We screened for the presence of ZNF277 microdeletions in cohorts of children with SLI or ASD and panels of control subjects. ZNF277 microdeletions were at an increased allelic frequency in SLI probands (1.1%) compared with both ASD family members (0.3%) and independent controls (0.4%). We performed quantitative RT-PCR analyses of the expression of IMMP2L, DOCK4 and ZNF277 in individuals carrying either an IMMP2L_DOCK4 microdeletion or a ZNF277 microdeletion. Although ZNF277 microdeletions reduce the expression of ZNF277, they do not alter the levels of DOCK4 or IMMP2L transcripts. Conversely, IMMP2L_DOCK4 microdeletions do not affect the expression levels of ZNF277. We postulate that ZNF277 microdeletions may contribute to the risk of language impairments in a manner that is independent of the autism risk loci previously described in this region.


The complete genome sequence and analysis of the human pathogen Campylobacter lari.
Campylobacter lari is a member of the epsilon subdivision of the Proteobacteria and is part of the thermotolerant Campylobacter group, a clade that includes the human pathogen C. jejuni. Here we present the complete genome sequence of the human clinical isolate, C. lari RM2100. The genome of strain RM2100 is approximately 1.53 Mb and includes the 46 kb megaplasmid pCL2100. Also present within the strain RM2100 genome is a 36 kb putative prophage, termed CLIE1, which is similar to CJIE4, a putative prophage present within the C. jejuni RM1221 genome. Nearly all (90%) of the gene content in strain RM2100 is similar to genes present in the genomes of other characterized thermotolerant campylobacters. However, several genes involved in amino acid biosynthesis and energy metabolism, identified previously in other Campylobacter genomes, are absent from the C. lari RM2100 genome. Therefore, C. lari RM2100 is predicted to be multiply auxotrophic, unable to synthesize eight different amino acids, acetyl-coA, and pantothenate. Additionally, strain RM2100 does not contain a complete TCA cycle and is missing the CydAB terminal oxidase of the respiratory chain. Defects in the amino acid biosynthetic pathways in this organism could be potentially compensated by the large number of encoded peptidases. Nevertheless, the apparent absence of certain key enzymatic functions in strain RM2100 would be expected to have an impact on C. lari biology. It is also possible that the reduction in the C. lari metabolic machinery is related to its environmental range and host preference.


A history of abuse and operative delivery--results from a European multi-country cohort study.
The main aim of this study was to assess whether a history of abuse, reported during pregnancy, was associated with an operative delivery. Secondly, we assessed if the association varied according to the type of abuse and if the reported abuse had been experienced as a child or an adult. The Bidens study, a cohort study in six European countries (Belgium, Iceland, Denmark, Estonia, Norway, and Sweden) recruited 6724 pregnant women attending routine antenatal care. History of abuse was assessed through questionnaire and linked to obstetric information from hospital records. The main outcome measure was operative delivery as a dichotomous variable, and categorized as an elective caesarean section (CS), or an operative vaginal birth, or an emergency CS. Non-obstetrically indicated were CSs performed on request or for psychological reasons without another medical reason. Binary and multinomial regression analysis were used to assess the associations. Among 3308 primiparous women, sexual abuse as an adult (≥ 18 years) increased the risk of an elective CS, Adjusted Odds Ratio 2.12 (1.28-3.49), and the likelihood for a non-obstetrically indicated CS, OR 3.74 (1.24-11.24). Women expressing current suffering from the reported adult sexual abuse had the highest risk for an elective CS, AOR 4.07 (1.46-11.3). Neither physical abuse (in adulthood or childhood <18 years), nor sexual abuse in childhood increased the risk of any operative delivery among primiparous women. Among 3416 multiparous women, neither sexual, nor emotional abuse was significantly associated with any kind of operative delivery, while physical abuse had an increased AOR for emergency CS of 1.51 (1.05-2.19). Sexual abuse as an adult increases the risk of an elective CS among women with no prior birth experience, in particular for non-obstetrical reasons. Among multiparous women, a history of physical abuse increases the risk of an emergency CS.


Human IL-34 and CSF-1 establish structurally similar extracellular assemblies with their common hematopoietic receptor.
The discovery that hematopoietic human colony stimulating factor-1 receptor (CSF-1R) can be activated by two distinct cognate cytokines, colony stimulating factor-1 (CSF-1) and interleukin-34 (IL-34), created puzzling scenarios for the two possible signaling complexes. We here employ a hybrid structural approach based on small-angle X-ray scattering (SAXS) and negative-stain EM to reveal that bivalent binding of human IL-34 to CSF-1R leads to an extracellular assembly hallmarked by striking similarities to the CSF-1:CSF-1R complex, including homotypic receptor-receptor interactions. Thus, IL-34 and CSF-1 have evolved to exploit the geometric requirements of CSF-1R activation. Our models include N-linked oligomannose glycans derived from a systematic approach resulting in the accurate fitting of glycosylated models to the SAXS data. We further show that the C-terminal region of IL-34 is heavily glycosylated and that it can be proteolytically cleaved from the IL-34:hCSF-1R complex, providing insights into its role in the functional nonredundancy of IL-34 and CSF-1.


Magnesium in the management of asthma: critical review of acute and chronic treatments, and Deutsches Medizinisches Zentrum's (DMZ's) clinical experience at the Dead Sea.
The recognition of asthma as an inflammatory disease has led over the past 20 years to a major shift in its pharmacotherapy. The previous emphasis on using relatively short-acting agents for relieving bronchospasms and for removing bronchial mucus has shifted toward long-term strategies with the use of inhaled corticosteroids, which successfully prevent and abolish airway inflammation. Because some of the biological, chemical, and immunological processes that characterize asthma also underly arthritis and other inflammatory diseases, and because many of these conditions have been successfully treated for the past 40 years at the Dead Sea, we were not surprised to realize and record the significant improvement of asthmatic condition after a 4-week stay at the Dead Sea: lung function was improved, the number and severity of attacks was reduced, and the efficacy of beta2-agonist treatments was improved. After reviewing the acute and chronic treatments of asthma in the clinic (including emergency rooms) with magnesium compounds, and the use of such salts as supplementary agents in respiratory diseases, we suggest that the improvement in the asthmatic condition at the Dead Sea may be due to absorption of this element through the skin and via the lungs, and due to its involvement in anti-inflammatory and vasodilatatory processes.


Efficacy of sodium hypochlorite and peracetic acid against Aspergillus nomius in Brazil nuts.
The objective of this work was to assess the efficacy of sodium hypochlorite and peracetic acid for sanitization of Brazil nuts. To evaluate the natural microbiota of the nuts, the total bacteria and fungi as well as the Aspergillus section Flavi were counted. The moisture, water activity and the presence of aflatoxins was quantified. The response surface method was used to determine the influence of exposure time and sanitizers concentration on the reduction of Aspergillus nomius inoculated on the nuts. Microbiological, sensory and quantification analyzes of aflatoxins were performed under optimum conditions The evaluation of the initial contamination of the nuts, despite presenting high microbiological contamination, humidity and water activity, was not detected aflatoxins in any samples. In artificially inoculated samples, the response surface and the desirability function were obtained to determine the optimal point of use for each sanitizer. The nuts had high microbiological contamination, moisture content and water activity. Aflatoxins were not detected in any samples. The response surface and desirability function indicated the optimal sanitization conditions were 250 mg/L and 8.5 min and 140 mg/L and 15 min for sodium hypochlorite and peracetic acid, respectively. Reductions greater than 2 log CFU/g were obtained with sodium hypochlorite and of 1 log CFU/g for peracetic acid. In the tests performed with new Brazil nuts samples under the optimized conditions, reductions of less than 2 log CFU/g were obtained. Aflatoxin B1 was detected in one untreated sample (1.51 μg/kg), one sample treated with sodium hypochlorite (0.60 μg/kg) and two samples treated with peracetic acid (0.64 and 0.72 μg/kg). Demonstrating that the sanitizers in the concentrations used had no action on aflatoxins, despite being efficient for fungal control. The treatments did not cause an unacceptable sensorial impact on the samples.


A New Perspective on Ecological Prediction Reveals Limits to Climate Adaptation in a Temperate Tree Species.
Forests absorb a large fraction of anthropogenic CO2 emission, but their ability to continue to act as a sink under climate change depends in part on plant species undergoing rapid adaptation. Yet models of forest response to climate change currently ignore local adaptation as a response mechanism. Thus, considering the evolution of intraspecific trait variation is necessary for reliable, long-term species and climate projections. Here, we combine ecophysiology and predictive climate modeling with analyses of genomic variation to determine whether sugar and starch storage, energy reserves for trees under extreme conditions, have the heritable variation and genetic diversity necessary to evolve in response to climate change within populations of black cottonwood (Populus trichocarpa). Despite current patterns of local adaptation and extensive range-wide heritable variation in storage, we demonstrate that adaptive evolution in response to climate change will be limited by a lack of heritable variation within northern populations and by a need for extreme genetic changes in southern populations. Our method can help design more targeted species management interventions and highlights the power of using genomic tools in ecological prediction to scale from molecular to regional processes to determine the ability of a species to respond to future climates.


Genetic variation in defense chemistry in wild cabbages affects herbivores and their endoparasitoids.
Populations of wild Brassica oleracea L. grow naturally along the Atlantic coastlines of the United Kingdom and France. Over a very small spatial scale (i.e., <15 km) these populations differ in the expression of the defensive compounds, glucosinolates (GS). Thus far, very few studies have examined interactions between genetically distinct populations of a wild plant species and associated consumers in a multitrophic framework. Here, we compared the development of a specialist (Pieris rapae) and a generalist (Mamestra brassicae) insect herbivore and their endoparasitoids (Cotesia rubecula and Microplitis mediator, respectively) on three wild populations and one cultivar of B. oleracea under controlled greenhouse conditions. Herbivore performance was differentially affected by the plant population on which they were reared. Plant population influenced only development time and pupal mass in P. rapae, whereas plant population also had a dramatic effect on survival of M. brassicae. Prolonged development time in P. rapae corresponded with high levels of the indole GS, neoglucobrassicin, whereas reduced survival in M. brassicae coincided with high levels of the aliphatic GS, gluconapin and sinigrin. The difference between the two species can be explained by the fact that the specialist P. rapae is adapted to feed on plants containing GS and has evolved an effective detoxification system against aliphatic GS. The different B. oleracea populations also affected development of the endoparasitoids. Differences in food-plant quality for the hosts were reflected in adult size in C. rubecula and survival in M. mediator, and further showed that parasitoid performance is also affected by herbivore diet.


Loss of intra-islet heparan sulfate is a highly sensitive marker of type 1 diabetes progression in humans.
Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells in pancreatic islets are progressively destroyed. Clinical trials of immunotherapies in recently diagnosed T1D patients have only transiently and partially impacted the disease course, suggesting that other approaches are required. Our previous studies have demonstrated that heparan sulfate (HS), a glycosaminoglycan conventionally expressed in extracellular matrix, is present at high levels inside normal mouse beta cells. Intracellular HS was shown to be critical for beta cell survival and protection from oxidative damage. T1D development in Non-Obese Diabetic (NOD) mice correlated with loss of islet HS and was prevented by inhibiting HS degradation by the endoglycosidase, heparanase. In this study we investigated the distribution of HS and heparan sulfate proteoglycan (HSPG) core proteins in normal human islets, a role for HS in human beta cell viability and the clinical relevance of intra-islet HS and HSPG levels, compared to insulin, in human T1D. In normal human islets, HS (identified by 10E4 mAb) co-localized with insulin but not glucagon and correlated with the HSPG core proteins for collagen type XVIII (Col18) and syndecan-1 (Sdc1). Insulin-positive islets of T1D pancreases showed significant loss of HS, Col18 and Sdc1 and heparanase was strongly expressed by islet-infiltrating leukocytes. Human beta cells cultured with HS mimetics showed significantly improved survival and protection against hydrogen peroxide-induced death, suggesting that loss of HS could contribute to beta cell death in T1D. We conclude that HS depletion in beta cells, possibly due to heparanase produced by insulitis leukocytes, may function as an important mechanism in the pathogenesis of human T1D. Our findings raise the possibility that intervention therapy with dual activity HS replacers/heparanase inhibitors could help to protect the residual beta cell mass in patients recently diagnosed with T1D.


Review of 39 years of randomized controlled trials in the British Journal of General Practice.
Randomized controlled trials are being used increasingly to evaluate the effectiveness of health care interventions, including those in primary care. A study was undertaken to document the topic areas addressed by randomized controlled trials conducted in primary care and the methodological characteristics of these, based on a historical review of all trials published in the British Journal of General Practice (formerly the Research Newsletter and Journal of the Royal College of General Practitioners) between 1953 and 1991 inclusive. Trials were identified by systematically hand searching all back issues. A total of 90 randomized controlled trials were identified, 78% of which were undertaken in general practice. The trials covered a wide range of topics; 62% examined pharmacological interventions, 21% non-pharmacological interventions, and 16% an intervention related to provision of an aspect of health service. Among the randomized controlled trials published there was a significant trend towards more reports on non-pharmacological trials in recent years (P < 0.001). The quality of trials, judged by the extent to which bias was controlled, varied considerably. Trials of pharmacological interventions generally controlled for selection bias at entry and at assessment of outcome more effectively than trials of non-pharmacological interventions. Some imaginative solutions to the logistic difficulties of conducting randomized trials in general practice were noted. These may serve as an incentive to those undertaking such studies in the future.


Casualty management: scud missile attack, Dhahran, Saudi Arabia.
On the evening of February 25, 1991, an Iraqi scud missile plunged into a "barracks/warehouse" used to house U.S. Army soldiers assigned to the 475th Quartermaster Group in Dhahran, Saudi Arabia. As a consequence of this scud attack, 28 soldiers died, 110 were hospitalized, and 150 experienced minor physical injuries and/or subsequent mental health problems. This one scud's impact accounted for more than one-third of all U.S. soldiers killed during the war. Fortunately, there were very few "models" of mass casualty experiences during the Persian Gulf War to evaluate the critical clinical outcomes to the soldiers. An analysis of this event has important implications for future military operations that feature a multinational medical force structure. This article summarizes the medical preparations before the war, the key, chronological events, and the medical outcomes of the mass casualty event. Lessons learned in casualty management for future Army contingency medical planners are identified.