Helminth therapy (worms) for induction of remission in inflammatory bowel disease.
Inflammatory bowel disease (IBD) is a chronic, globally-occurring gastrointestinal disorder and a major cause of illness and disability. It is conventionally classified into Crohn's disease (CD) and ulcerative colitis (UC). Helminths are parasitic worms with complex life cycles involving tissue- or lumen-dwelling stages in their hosts, and causing long-lasting or chronic infections that are frequently asymptomatic. Helminths modulate immune responses of their hosts, and many observational and experimental studies support the hypothesis that helminths suppress immune-mediated chronic inflammation that occurs in asthma, allergy and IBD. The objective was to evaluate the efficacy and safety of helminth treatment for induction of remission in IBD. We searched the following databases from inception to 13 July 2013: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register. We also searched four online trials registries, and abstracts from major meetings. There were no language restrictions. Randomised controlled trials (RCTs) where the intervention was any helminth species or combination of helminth species, administered in any dose and by any route and for any duration of exposure to people with active CD or UC, confirmed through any combination of clinical, endoscopic and histological criteria were eligible for inclusion. Two authors independently extracted data and assessed eligibility using a standardized data collection form. We used the RevMan software for analyses. The primary outcome was induction of remission as defined by the included studies. Secondary outcomes included clinical, histologic, or endoscopic improvement as defined by the authors, endoscopic mucosal healing, change in disease activity index score, change in quality of life score, hospital admissions, requirement for intravenous corticosteroids, surgery, study withdrawal and the incidence of adverse events. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for dichotomous outcomes. We calculated the mean difference (MD) and 95% CI for continuous outcomes. We assessed the methodological quality of included studies using the Cochrane risk of bias tool. The overall quality of the evidence supporting each outcome was assessed using the GRADE criteria. Two RCTs (90 participants) were included. One trial assessed the efficacy and safety of Trichuris suis (T. suis) ova in patients with UC (n = 54). The other RCT was a phase one that assessed the safety and tolerability of T. suis ova in patients with CD (n = 36). The risk of bias in both studies was judged to be low. In the UC study, during the 12-week study period, participants in the active arm received 2-weekly aliquots of 2500 T. suis eggs, added to 0.8 mL of saline; those in the placebo arm received 0.8 mL saline only. There were sparse data available for the outcomes clinical remission and clinical improvement. Ten per cent (3/30) of patients in the T. suis arm entered remission compared to 4% (1/24) of patients in the placebo arm (RR 2.40, 95% CI 0.27 to 21.63). Forty-three per cent (13/30) of patients in the T. suis group achieved clinical improvement compared to 17% (4/24) of placebo patients (RR 2.60, 95% CI 0.97 to 6.95). The mean ulcerative colitis disease activity index (UCDAI) score was lower in the T. suis group (6.1 +/- 0.61) compared to the placebo group (7.5 +/- 0.66) after 12 weeks of treatment (MD -1.40, 95% CI -1.75 to -1.05). There was only limited evidence relating to the proportion of patients who experienced an adverse event. Three per cent (1/30) of patients in the T. suis group experienced at least one adverse event compared to 12% (3/24) of placebo patients (RR 0.27, 95% CI 0.03 to 2.40). None of the adverse events reported in this study were judged to be related to the study treatment. GRADE analyses rated the overall quality of the evidence for the primary and secondary outcomes (i.e. clinical remission and improvement) as low due to serious imprecision. In the CD study, participants received a single treatment of T. suis ova at a dosage of 500 (n = 9), 2500 (n = 9), or 7500 (n = 9) embryonated eggs or matching placebo (n = 9). The CD study did not assess clinical remission or improvement as outcomes. There were sparse data on adverse events at two weeks. Thirty-seven per cent (10/27) of patients in the T. suis group experienced at least one adverse event compared to 44% (4/9) of placebo patients (RR 0.83, 95% CI 0.35 to 2.01). Only one adverse event (dysgeusia) was judged to be possibly related to treatment in this study. Dysgeusia was reported in one patient in the T. suis group and in one patient in the placebo group. Currently, there is insufficient evidence to allow any firm conclusions regarding the efficacy and safety of helminths used to treat patients with IBD. The evidence for our primary efficacy outcomes in this review comes from one small study and is of low quality due to serious imprecision. We do not have enough evidence to determine whether helminths are safe when used in patients with UC and CD. Further RCTs are required to assess the efficacy and safety of helminth therapy in IBD.


Defining the estimated core genome of bacterial populations using a Bayesian decision model.
The bacterial core genome is of intense interest and the volume of whole genome sequence data in the public domain available to investigate it has increased dramatically. The aim of our study was to develop a model to estimate the bacterial core genome from next-generation whole genome sequencing data and use this model to identify novel genes associated with important biological functions. Five bacterial datasets were analysed, comprising 2096 genomes in total. We developed a Bayesian decision model to estimate the number of core genes, calculated pairwise evolutionary distances (p-distances) based on nucleotide sequence diversity, and plotted the median p-distance for each core gene relative to its genome location. We designed visually-informative genome diagrams to depict areas of interest in genomes. Case studies demonstrated how the model could identify areas for further study, e.g. 25% of the core genes with higher sequence diversity in the Campylobacter jejuni and Neisseria meningitidis genomes encoded hypothetical proteins. The core gene with the highest p-distance value in C. jejuni was annotated in the reference genome as a putative hydrolase, but further work revealed that it shared sequence homology with beta-lactamase/metallo-beta-lactamases (enzymes that provide resistance to a range of broad-spectrum antibiotics) and thioredoxin reductase genes (which reduce oxidative stress and are essential for DNA replication) in other C. jejuni genomes. Our Bayesian model of estimating the core genome is principled, easy to use and can be applied to large genome datasets. This study also highlighted the lack of knowledge currently available for many core genes in bacterial genomes of significant global public health importance.


Vascular calcification and bone mineral density in recurrent kidney stone formers.
Recent epidemiologic studies have provided evidence for an association between nephrolithiasis and cardiovascular disease, although the underlying mechanism is still unclear. Vascular calcification (VC) is a strong predictor of cardiovascular morbidity and the hypothesis explored in this study is that VC is more prevalent in calcium kidney stone formers (KSFs). The aims of this study were to determine (1) whether recurrent calcium KSFs have more VC and osteoporosis compared with controls and (2) whether hypercalciuria is related to VC in KSFs. This is a retrospective, matched case-control study that included KSFs attending an outpatient nephrology clinic of the Royal Free Hospital (London, UK) from 2011 to 2014. Age- and sex-matched non-stone formers were drawn from a list of potential living kidney donors from the same hospital. A total of 111 patients were investigated, of which 57 were KSFs and 54 were healthy controls. Abdominal aortic calcification (AAC) and vertebral bone mineral density (BMD) were assessed using available computed tomography (CT) imaging. The prevalence, severity, and associations of AAC and CT BMD between KSFs and non-stone formers were compared. Mean age was 47±14 years in KSFs and 47±13 in non-stone formers. Men represented 56% and 57% of KSFs and non-stone formers, respectively. The prevalence of AAC was similar in both groups (38% in KSFs versus 35% in controls, P=0.69). However, the AAC severity score (median [25th percentile, 75th percentile]) was significantly higher in KSFs compared with the control group (0 [0, 43] versus 0 [0, 10], P<0.001). In addition, the average CT BMD was significantly lower in KSFs (159±53 versus 194 ±48 Hounsfield units, P<0.001). A multivariate model adjusted for age, sex, high BP, diabetes, smoking status, and eGFR confirmed that KSFs have higher AAC scores and lower CT BMD compared with non-stone formers (P<0.001 for both). Among stone formers, the association between AAC score and hypercalciuria was not statistically significant (P=0.86). This study demonstrates that patients with calcium kidney stones suffer from significantly higher degrees of aortic calcification than age- and sex-matched non-stone formers, suggesting that VC may be an underlying mechanism explaining reported associations between nephrolithiasis and cardiovascular disease. Moreover, bone demineralization is more prominent in KSFs. However, more data are needed to confirm the possibility of potentially common underlying mechanisms leading to extraosseous calcium deposition and osteoporosis in KSFs.


Swimming with limb absence: A systematic review.
Swimming with limb absence is undertaken as a source of leisure or rehabilitation and forms part of the current Paralympic Games competition programme. Whilst it is often proposed that research into sport with limb absence can be limited, this study identified the volume, type and historical interest of research regarding swimming with limb absence. A modified PRISMA search protocol was adopted for this review, and five bibliographic databases were used to identify relevant articles. The review identified 24 papers which met the pre-defined inclusion criteria. The identified peer-reviewed publications dated from 1983 to 2015. The trend of publication indicated an initial focus on the design of prosthetics technology with emphasis then shifting specifically to an interest in swimming biomechanics from 2006. The overall trend of publication in this field is a positive one. In this review, four clear themes emerged. These included the general background of swimming with limb absence, the development of lower limb prosthetics technology, swimming with limb absence whilst performing the front crawl stroke and the technique used by those with unilateral elbow disarticulation. From these, four further themes have been identified for pursuit in the immediate future. This review will assist those who are interested in prescribing swimming with limb absence as a form of exercise or to those who wish to pursue it competitively.


Generic legislation of new psychoactive drugs.
New psychoactive drugs (NPDs, new psychoactive substances) enter the market all the time. However, it takes several months to ban these NPDs and immediate action is generally not possible. Several European countries and drug enforcement officers insist on a faster procedure to ban NPDs. Introduction of generic legislation, in which clusters of psychotropic drugs are banned in advance, has been mentioned as a possible solution. Here we discuss the pros and cons of such an approach. First, generic legislation could unintentionally increase the expenditures of enforcement, black market practices, administrative burden and health risks for users. Second, it may have a negative impact on research and the development of new treatments. Third, due to the complexity of generic legislation, problems in the enforcement are anticipated due to lack of knowledge about the chemical nomenclature. Finally, various legal options are already available to ban the use, sale and trade of NPDs. We therefore conclude that the currently used scientific benefit-risk evaluation should be continued to limit the adverse health effects of NPDs. Only in emergency cases, where fatal incidents (may) occur, should this approach be overruled.


Yoga for bronchial asthma: a controlled study.
Fifty three patients with asthma underwent training for two weeks in an integrated set of yoga exercises, including breathing exercises, suryanamaskar, yogasana (physical postures), pranayama (breath slowing techniques), dhyana (meditation), and a devotional session, and were told to practise these exercises for 65 minutes daily. They were then compared with a control group of 53 patients with asthma matched for age, sex, and type and severity of asthma, who continued to take their usual drugs. There was a significantly greater improvement in the group who practised yoga in the weekly number of attacks of asthma, scores for drug treatment, and peak flow rate. This study shows the efficacy of yoga in the long term management of bronchial asthma, but the physiological basis for this beneficial effect needs to be examined in more detail.


An in vivo verification of the intravoxel incoherent motion effect in diffusion-weighted imaging of the abdomen.
To investigate the vascular contribution to the measured apparent diffusion coefficient and to validate the Intra Voxel Incoherent Motion theory, the signal as a function of the b-value was measured in the healthy pancreas with and without suppression of the vascular component and under varying echo times (TE = 50, 70, and 100 msec). The perfusion fraction f and the diffusion coefficient D were extracted from the measured DW-data using the original Intra Voxel Incoherent Motion-equation and a modified version of this equation incorporating relaxation effects. First, the perfusion fraction f in the blood suppressed pancreatic tissue decreased significantly (P = 0.03), whereas the diffusion coefficient D did not change with suppression (P = 0.43). Second, the perfusion fraction f increased significantly with increasing echo time (P = 0.0025), whereas the relaxation time compensated perfusion fraction f' showed no significant dependence on TE (P = 0.31). These results verify a vascular contribution to the diffusion weighted imaging measurement at low b values and support the Intra Voxel Incoherent Motion-theory.


The Positive Switching Fluorescent Protein Padron2 Enables Live-Cell Reversible Saturable Optical Linear Fluorescence Transitions (RESOLFT) Nanoscopy without Sequential Illumination Steps.
Reversibly switchable fluorescent proteins (RSFPs) can be repeatedly transferred between a fluorescent on- and a nonfluorescent off-state by illumination with light of different wavelengths. Negative switching RSFPs are switched from the on- to the off-state with the same wavelength that also excites fluorescence. Positive switching RSFPs have a reversed light response, where the fluorescence excitation wavelength induces the transition from the off- to the on-state. Reversible saturable optical linear (fluorescence) transitions (RESOLFT) nanoscopy utilizes these switching states to achieve diffraction-unlimited resolution but so far has primarily relied on negative switching RSFPs by using time sequential switching schemes. On the basis of the green fluorescent RSFP Padron, we engineered the positive switching RSFP Padron2. Compared to its predecessor, it can undergo 50-fold more switching cycles while displaying a contrast ratio between the on- and the off-states of more than 100:1. Because of its robust switching behavior, Padron2 supports a RESOLFT imaging scheme that entirely refrains from sequential switching as it only requires beam scanning of two spatially overlaid light distributions. Using Padron2, we demonstrate live-cell RESOLFT nanoscopy without sequential illumination steps.


Fecal microbiota transplantation for the treatment of recurrent and severe Clostridium difficile infection in solid organ transplant recipients: A multicenter experience.
Fecal microbiota transplant (FMT) is recommended for Clostridium difficile infection (CDI) treatment; however, use in solid organ transplantation (SOT) patients has theoretical safety concerns. This multicenter, retrospective study evaluated FMT safety, effectiveness, and risk factors for failure in SOT patients. Primary cure and overall cure were defined as resolution of diarrhea or negative C difficile stool test after a single FMT or after subsequent FMT(s) ± anti-CDI antibiotics, respectively. Ninety-four SOT patients underwent FMT, 78% for recurrent CDI and 22% for severe or fulminant CDI. FMT-related adverse events (AE) occurred in 22.3% of cases, mainly comprising self-limiting conditions including nausea, abdominal pain, and FMT-related diarrhea. Severe AEs occurred in 3.2% of cases, with no FMT-related bacteremia. After FMT, 25% of patients with underlying inflammatory bowel disease had worsening disease activity, while 14% of cytomegalovirus-seropositive patients had reactivation. At 3 months, primary cure was 58.7%, while overall cure was 91.3%. Predictors of failing a single FMT included inpatient status, severe and fulminant CDI, presence of pseudomembranous colitis, and use of non-CDI antibiotics at the time of FMT. These data suggest FMT is safe in SOT patients. However, repeated FMT(s) or additional antibiotics may be needed to optimize rates of cure with FMT.


Molecular cloning of cDNA for the zeta isoform of the 14-3-3 protein: homologous sequences in the 3'-untranslated region of frog and human zeta isoforms.
14-3-3 proteins constitute a family of well-conserved eukaryotic proteins that possess diverse biochemical activities such as regulation of gene transcription, cell proliferation and activation of protein kinase C. At least 7 subtypes (alpha to theta) of 14-3-3 protein are known, but the zeta subtype of this protein has been cloned only in mammals. We cloned the zeta subtype of 14-3-3 protein (14-3-3 zeta) from the frog, Rana rugosa. The sequence encoded 245 amino acids that share 92% identity with rat and bovine 14-3-3 zeta s, and 92% with human phospholipase A2 (PLA2; 14-3-3 zeta). Northern blot analysis revealed a single band of about 1.8 kb in tadpoles at stage 25. The 14-3-3 zeta mRNA level was high in the brain, lung, spleen and kidney, and low in the heart and testis, as opposed to the mRNA level, which was only faintly detected in the liver, pancreas, ovary and muscle. Furthermore, high similarity in the 3'-untranslated region (3'-UTR) was observed between frog and human 14-3-3 zeta cDNA. The results suggest that 14-3-3 zeta is highly conserved throughout eukaryotic evolution, and that the homologous sequence in the 3'-UTR of 14-3-3 zeta cDNA may be conserved in frogs and humans.


Effects of alpha-lipoic Acid on body weight in obese subjects.
alpha-lipoic acid is an essential cofactor for mitochondrial respiratory enzymes that improves mitochondrial function. We previously reported that alpha-lipoic acid markedly reduced body weight gain in rodents. The purpose of this study was to determine whether alpha-lipoic acid reduces body weight in obese human subjects. in this randomized, double-blind, placebo-controlled, 20-week trial, 360 obese individuals (body mass index [BMI] ≥ 30 kg/m(2) or BMI 27-30 kg/m(2) plus hypertension, diabetes mellitus, or hypercholesterolemia) were randomized to alpha-lipoic acid 1200 or 1800 mg/d or placebo. The primary end point was body weight change from baseline to end point. the 1800 mg alpha-lipoic acid group lost significantly more weight than the placebo group (2.1%; 95% confidence interval, 1.4-2.8; P<.05). Urticaria and itching sensation were the most common adverse events in the alpha-lipoic acid groups, but these were generally mild and transient. alpha-lipoic acid 1800 mg/d led to a modest weight loss in obese subjects. Alpha-lipoic acid may be considered as adjunctive therapy for obesity.


Epidemiology of acute liver failure.
Acute liver failure (ALF) is an uncommon disorder that leads to jaundice, coagulopathy, and multisystem organ failure. Its definition is based on the timing from onset of jaundice to encephalopathy. In 2005, ALF accounted for 6% of liver-related deaths and 7% of orthotopic liver transplants (OLT) in the United States. Several classification systems have been developed for ALF, with the King's College criteria most widely used for prediction of OLT. Specific diagnostic tests should be implemented to identify the cause of ALF, which will help to determine its treatment and prognosis. Viral hepatitis was previously reported to be the most common cause of ALF in the United States, but acetaminophen overdose and idiosyncratic drug reactions have emerged as the most frequent causes in recent studies. Malignancy is an uncommon cause of ALF, and thus imaging studies may not be useful in this setting, but liver biopsy may be beneficial in selected cases. An overall strategy for ALF should start with identifying the cause, assessing the prognosis, and early transfer to a transplantation center for suitable candidates. OLT has emerged as a life-saving procedure leading to marked improvement in survival rates. Improved surgical techniques, immunosuppression, and comprehensive care have led to an overall survival rate of approximately 65% with OLT. N-acetylcysteine is effective in ALF caused by acetaminophen overdose, with results strongly related to how soon it is given rather than the route of administration. Liver support systems show potential for the treatment of ALF, but their role needs validation in large multicenter randomized trials.


Functional Interactions between Distinct Sodium Channel Cytoplasmic Domains through the Action of Calmodulin.
Sodium channels are fundamental signaling molecules in excitable cells, and are molecular targets for local anesthetic agents and intracellular free Ca(2+) ([Ca(2+)](i)). Two regions of Na(V)1.5 have been identified previously as [Ca(2+)](i)-sensitive modulators of channel inactivation. These include a C-terminal IQ motif that binds calmodulin (CaM) in different modes depending on Ca(2+) levels, and an immediately adjacent C-terminal EF-hand domain that directly binds Ca(2+). Here we show that a mutation of the IQ domain (A1924T; Brugada Syndrome) that reduces CaM binding stabilizes Na(V)1.5 inactivation, similarly and more extensively than even reducing [Ca(2+)](i). Because the DIII-DIV linker is an essential structure in Na(V)1.5 inactivation, we evaluated this domain for a potential CaM binding interaction. We identified a novel CaM binding site within the linker, validated its interaction with CaM by NMR spectroscopy, and revealed its micromolar affinity by isothermal titration calorimetry. Mutation of three consecutive hydrophobic residues (Phe(1520)-Ile(1521)-Phe(1522)) to alanines in this CaM-binding domain recapitulated the electrophysiology phenotype observed with mutation of the C-terminal IQ domain: Na(V)1.5 inactivation was stabilized; moreover, mutations of either CaM-binding domain abolish the well described stabilization of inactivation by lidocaine. The direct physical interaction of CaM with the C-terminal IQ domain and the DIII-DIV linker, combined with the similarity in phenotypes when CaM-binding sites in either domain are mutated, suggests these cytoplasmic structures could be functionally coupled through the action of CaM. These findings have bearing upon Na(+) channel function in genetically altered channels and under pathophysiologic conditions where [Ca(2+)](i) impacts cardiac conduction.


Plasma homocysteine is associated with the risk of mild cognitive impairment in an elderly Korean population.
Elderly individuals with mild cognitive impairment (MCI) are at high risk for developing dementia, including Alzheimer's disease. Previous studies have proposed that elevated plasma homocysteine might be a risk factor for dementia. However, the impact of plasma homocysteine on MCI remains controversial. We investigated the relation between hyperhomocysteinemia and the risk of MCI in an elderly Korean population. A total of 1215 elderly subjects (aged 60-85 y) were selected from the Ansan Geriatric study to participate in this study. MCI was diagnosed on the basis of the Mayo Clinic criteria. Mean plasma homocysteine concentrations were higher in elderly subjects with MCI than in normal elderly subjects (17.6 +/- 7.4 vs. 15.7 +/- 4.8 micromol/L; P < 0.001). Subjects with hyperhomocysteinemia (>15 micromol/L) also had a higher prevalence of MCI. The unadjusted OR for MCI was greater in subjects with hyperhomocysteinemia than in normal subjects and it increased according to the degree of hyperhomocysteinemia (OR = 1.39; 95% CI = 1.09-1.79 vs. OR = 2.61; 95% CI = 1.22-5.61). These trends did not differ after adjustment for age, sex, and other putative risk factors for cognitive dysfunction (OR = 1.40; 95% CI = 1.07-1.83 vs. OR = 2.40; 95% CI = 1.08-5.31). In conclusion, hyperhomocysteinemia may be an independent risk factor for MCI in elderly Koreans. A causal relationship between plasma homocysteine levels and cognitive impairment should be evaluated in a follow-up study of elderly Korean subjects.


Evaluation of Alternative Methods of Tunnel Composting (submitted by the European Composting Network).
Two alternative methods for the production of compost from certain category 3 animal by-products (catering waste and processed foodstuffs of animal origin) were assessed. The first proposed a minimum temperature of 55°C for 72 h; the second 60°C for 48 h, each with a maximum particle size of 200 mm. The proposed composting processes were assessed by the BIOHAZ Panel for their efficacy to achieve a reduction of 5 log10 of Enterococcus faecalis or Salmonella Senftenberg (775W, H2S negative) and a 3 log10 reduction of the infectivity titre of thermoresistant viruses, such as parvovirus, in the composted material, as set out in Annex V, Chapter 3, Section 2 of Commission Regulation (EU) No 142/2011. The assessment of the BIOHAZ Panel exclusively focused on the ABP raw materials (catering waste and processed foodstuffs) intended for human consumption. The applicant did not provide any validation experiments with direct measurement of the reduction of viability of endogenous indicators or spiked surrogate bacteria. However, from thermal inactivation parameters reported in the literature, it can be concluded that the proposed composting standards can achieve at least a 5 log10 reduction of Enterococcus faecalis or Salmonella Senftenberg 775W. The applicant did not consider thermoresistant viruses as a relevant hazard and therefore did not provide any data from direct measurements of the reduction of infectivity of spiked thermoresistant viruses, nor provide data from validation studies undertaken at national level or data from literature supporting the efficacy of the proposed composting standards on thermoresistant viruses. However, thermoresistant viruses should be considered to be a relevant hazard in this context and validation data should have been provided accordingly. The BIOHAZ Panel considers that the evidence provided by the applicant does not demonstrate that the requirements of Annex V, Chapter 3, Section 2 of Commission Regulation (EU) No 142/2011 are achieved.


Transient cross-reactive immune responses can orchestrate antigenic variation in malaria.
The malaria parasite Plasmodium falciparum has evolved to prolong its duration of infection by antigenic variation of a major immune target on the surface of the infected red blood cell. This immune evasion strategy depends on the sequential, rather than simultaneous, appearance of immunologically distinct variants. Although the molecular mechanisms by which a single organism switches between variants are known in part, it remains unclear how an entire population of parasites within the host can synchronize expression to avoid rapidly exhausting the variant repertoire. Here we show that short-lived, partially cross-reactive immune responses to parasite-infected erythrocyte surface antigens can produce a cascade of sequentially dominant antigenic variants, each of which is the most immunologically distinct from its preceding types. This model reconciles several previously unexplained and apparently conflicting epidemiological observations by demonstrating that individuals with stronger cross-reactive immune responses can, paradoxically, be more likely to sustain chronic infections. Antigenic variation has always been seen as an adaptation of the parasite to evade host defence: we show that the coordination necessary for the success of this strategy might be provided by the host.


Hedgehog signaling in basal cell carcinoma.
Basal cell carcinoma (BCC), the most common type of skin cancer, is occasionally aggressive with deep invasion, destruction of adjacent structures, recurrence and, on very rare occasions, regional and distant metastases. Mutations that occur in BCC in hedgehog (Hh) pathway genes primarily involve the genes encoding patched homolog (PTCH) and smoothened homolog (SMO). Several animal models have demonstrated the functional relevance of genetic alterations in the Hh pathway during tumorigenesis. Recently, targeted therapy has become available both commercially and in the context of human clinical trials. Interestingly, Hh pathway inhibitors not only suppress BCC progression but also promote acquired immune responses. Since immune responses are crucial for long-term tumor control, new clinical trials, such as those involving a combination of Hh inhibitors with immune modifiers, are needed to supplement standard methods of tumor control.


Estimation of aortic pulse wave transit time in cardiovascular magnetic resonance using complex wavelet cross-spectrum analysis.
Aortic pulse wave velocity (PWV), which substantially increases with arterial stiffness and aging, is a major predictor of cardiovascular mortality. It is commonly estimated using applanation tonometry at carotid and femoral arterial sites (cfPWV). More recently, several cardiovascular magnetic resonance (CMR) studies have focused on the measurement of aortic arch PWV (archPWV). Although the excellent anatomical coverage of CMR offers reliable segmental measurement of arterial length, accurate transit time (TT) determination remains a challenge. Recently, it has been demonstrated that Fourier-based methods were more robust to low temporal resolution than time-based approaches. We developed a wavelet-based method, which enables temporal localization of signal frequencies, to estimate TT from ascending and descending aortic CMR flow curves. This method (archPWVWU) combines the robustness of Fourier-based methods to low temporal resolution with the possibility to restrict the analysis to the reflectionless systolic upslope. We compared this method with Fourier-based (archPWVF) and time domain upslope (archPWVTU) methods in relation to linear correlations with age, cfPWV and effects of decreasing temporal resolution by factors of 2, 3 and 4. We studied 71 healthy subjects (45 ± 15 years, 29 females) who underwent CMR velocity acquisitions and cfPWV measurements. Comparison with age resulted in the highest correlation for the wavelet-based method (archPWVWU:r = 0.84,p < 0.001; archPWVTU:r = 0.74,p < 0.001; archPWVF:r = 0.63,p < 0.001). Associations with cfPWV resulted in the highest correlations for upslope techniques whether based on wavelet (archPWVWU:r = 0.58,p < 0.001) or time (archPWVTU:r = 0.58,p < 0.001) approach. Furthermore, while decreasing temporal resolution by 4-fold induced only a minor decrease in correlation of both archPWVWU (r decreased from 0.84 to 0.80) and archPWVF (r decreased from 0.63 to 0.51) with age, it induced a major decrease for the archPWVTU age relationship (r decreased from 0.74 to 0.38). By CMR, measurement of aortic arch flow TT using systolic upslopes resulted in a better correlation with age and cfPWV, as compared to the Fourier-based approach applied on the entire cardiac cycle. Furthermore, methods based on harmonic decomposition were less affected by low temporal resolution. Since the proposed wavelet approach combines these two advantages, it might help to overcome current technical limitations related to CMR temporal resolution and evaluation of patients with highly stiff arteries.


The predicted impact of immunosuppression upon population age-intensity profiles for schistosomiasis.
The slow development of acquired immunity is thought to be responsible for the characteristic convex age-intensity curve seen in human schistosome infection, which peaks earlier in more heavily infected populations (this is described as a peak shift). Schistosomes are able to suppress protective host responses, and it is hypothesized that this suppression is responsible for the delayed development of protective responses. A deterministic mathematical model is used to describe levels of infection and immunity in an endemic population, incorporating protective immune responses which either reduce adult worm burden or reduce superinfection. Suppression, related to current worm burden, is also included and acts against one or both protective responses. If suppression acts against the entire protective response, it is able to delay the development of protective immunity, and the peak shift is predicted to be reversed at higher infection intensities, with removal of the peaks altogether at the highest levels of infection and/or suppression. If only the anti-adult worm protective immune response is vulnerable to suppression, while the anti-reinfection response remains intact, then suppression does not remove the peak in the age-intensity curve. These findings are discussed in the light of existing field and experimental data.


The Motivation and Opportunity for Socially Desirable Responding Does Not Alter the General Factor of Personality.
Socially desirable responding may affect the factor structure of personality questionnaires and may be one of the reasons for the common variance among personality traits. In this study, we test this hypothesis by investigating the influence of the motivational test-taking context (development vs. selection) and the opportunity to distort responses (forced-choice vs. Likert response format) on personality questionnaire scores. Data from real selection and assessment candidates (total N = 3,980) matched on gender, age, and educational level were used. Mean score differences were found between the selection and development groups, with smaller differences for the FC version. Yet, exploratory structural equation models showed that the overall factor structures as well as the general factor were highly similar across the four groups. Thus, although socially desirable responding may affect mean scores on personality traits, it does not appear to affect factor structures. This study further suggests that the common variance in personality questionnaires is consistent and appears to be little influenced by motivational pressures for response distortion.


DENSITY-DEPENDENT EFFECTS OF PREDATOR SPECIES-RICHNESS IN DIVERSITY-FUNCTION STUDIES.
Ecological systems often exhibit a positive but saturating diversity-function curve. Variation in the mechanisms generating this relationship can alter the slope and variance of the curve, with implications for the optimal management of biodiversity for ecosystem services. In biological control, prevalence of selection effects supports augmentation of the most effective natural enemy, but complementarity effects support augmentation of natural enemy diversity. Optimization of biological control strategies from the results of diversity-function studies is limited because few consider changes in function with relative or absolute changes in abundance, and many confound the relative importance of richness and density through experimental designs (additive and substitutive). By manipulating species richness across an abundance gradient we show that effects of species richness are density dependent and indicate how this may be incorporated into experimental designs or models predicting resource consumption in diverse communities. Furthermore, the underlying mechanisms causing an observed diversity-function response, and its associated variation, changed across the richness-abundance gradient. Finally, species-rich assemblages provided higher levels of minimum function than species-poor assemblages, without any compromise on the maximum function possible.


Dental awareness and oral health of pregnant women in Poland.
The level of dental awareness of a pregnant woman affects the sanitary condition of her own teeth and the health of the child to be born. Poor oral health is considered to be a probable risk factor for the pre-term birth or low birth weight. The aim of this work was to assess the level of oral health knowledge that determines oral health condition of pregnant women in Poland. Empirical data were obtained from the National Monitoring of Oral Health and Its Determinants, financed by the Ministry of Health. This socio-epidemiological study assessed oral health status and dental health awareness, which affects that status. Study subjects included 1380 pregnant women at the age ranging from 15 to 44, randomly-selected from urban and rural environments. Dental health status was recorded in the clinical examination sheets supplied by the World Health Organization, and the socio-medical data were recorded in the questionnaire interview sheets. Almost 3/4 of the pregnant women evaluated their dental health as unsatisfactory or poor. Over 60% of the pregnant women rated their knowledge and practical skills concerning care of their own teeth and of the child to be born as limited, inadequate or none. Only 40% of the pregnant women provided right answers to the questions about dental issues. Low oral health awareness results in poor oral health status of the study subjects. A statistical pregnant woman has a total of 13 teeth showing the symptoms of tooth decay or caries. Over 70% of the pregnant women developed gingivitis or periodontitis. There is an urgent need in Poland to make the European principle of treating pregnant women as a dentally vulnerable group obligatory.


The effects of glucose-lowering therapies on diabetic kidney disease.
Chronic hyperglycemia and its associated metabolic products are key factors responsible for the development and progression of diabetic chronic kidney disease (CKD). Endocrinologists are tasked with detection and management of early CKD before patients need referral to a nephrologist for advanced CKD or dialysis evaluation. Primary care physicians are increasingly becoming aware of the importance of managing hyperglycemia to prevent or delay progression of CKD. Glycemic control is an integral part of preventing or slowing the advancement of CKD in patients with diabetes; however, not all glucose-lowering agents are suitable for this patient population. The availability of the latest information on treatment options may enable physicians to thwart advancement of serious renal complication in patients suffering from diabetes. This review presents clinical data that shed light on the risk/benefit profiles of three relatively new antidiabetes drug classes, the dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 analogs, and sodium glucose co-transporter 2 inhibitors, particularly for patients with diabetic CKD, and summarizes the effects of these therapies on renal outcomes and glycemic control for endocrinologists and primary care physicians. Current recommendations for screening and diagnosis of CKD in patients with diabetes are also discussed.


Prehospital Frailty and Screening Criteria for Palliative Care Services in Critically Ill Older Adults: An Observational Cohort Study.
Background: The use of formalized criteria (or triggers) for palliative care services (PCSs) has been associated with increased use of PCSs in the intensive care unit (ICU). Objective: To explore the utility/validity of frailty as a trigger for providing PCSs. Design: This is a prospective cohort study. Setting/Subjects: Older adults (age ≥50 years) admitted to ICUs were enrolled. Measurements: We measured frailty using the Clinical Frailty Scale. We reviewed electronic health records for the presence/absence of six evidence-based triggers, the use and quality of specialty palliative care (SPC), and markers of primary palliative care (PPC). We used descriptive statistics to describe the differences in PPC, SPC, and six-month mortality by frailty and by the presence/absence of triggers. Results: In a study population of 302 older adults, mean (standard deviation) age 67.2 years (10.5), 151 (50%) were frail and 105 (34.8%) had ≥1 trigger for PCSs. Of the 151 (55.6%) frail patients, 84 had no triggers for PCSs, despite a 46.4% six-month mortality in this group. Patients with ≥1 trigger had higher rates of SPC than those without (39.1% vs. 18.3%, p < 0.001); frail patients also had higher SPC than nonfrail patients (32.5% vs. 18.5%, p = 0.006). Patients with ≥1 trigger had higher rates of PPC than those without (66.7% vs. 44.2%, p < 0.001); no statistically significant difference in PPC was found by frailty (56.3% vs. 47.7%, p = 0.134). Conclusion: The rates of PCSs and six-month mortality by frailty are consistent with frailty being a valid trigger for PCSs in ICUs; the high prevalence of frailty relative to triggers suggests that ways to increase PCSs would be needed.


Desires for beverages and liking of skin care product odors in imaginative and immersive virtual reality beach contexts.
Immersive technologies simulating real-life environments allow repeated simulation of complex real-life situations at one location and, therefore, bear potential for consumer product evaluations and food behavior studies. This study aimed to assess whether a contextual exposure by immersive virtual reality (VR) or a photo-enhanced imaginative (PIC) condition could induce effects on desires and liking aligning with the situation. A total of 60 subjects (30 females) were presented to VR and PIC beach settings in a randomized balanced design performed in a laboratory one week apart. A follow-up test in the same room but without the contextual exposure was also performed (Neutral). Subjects rated their desires for hot and cold beverages during and just after the contextual exposure. Liking for skin care samples (sun screen and regular lotion) were assessed during exposure. The retention of the contextual exposure was further explored in a food choice behavior test. A similar test setup was followed in the Neutral condition. Engagement by presence dimensions (e.g., felt like being on a beach) and level of excitement was scored following the contextual exposure. The VR condition induced a significantly stronger engagement, compared with the PIC condition. During each beach exposure a significantly stronger desire for cold beverages compared to hot beverages was induced. The desire for cold versus hot beverages was, however, significantly larger in the VR simulation compared to the PIC context. Results from the Neutral condition provided no significant difference in the desires for hot versus cold beverages. A significant shift in desires was observed after the completion of the contextual beach exposures, as desire scores became aligned with scores assessed in the Neutral condition. The shift in desires was, however, more pronounced after VR. Variations in the contextual settings had little effect on odor liking and no retention effect on choice behavior was observed. Immersive VR induced a positive sensation of presence less dependent on the level of excitement and had a stronger effect on beverage-related desires. The VR technology seems to be a promising tool for evaluating contextual influences in food consumer research.


Hepatitis C in the era of direct-acting antivirals: real-world costs of untreated chronic hepatitis C; a cross-sectional study.
Recent advances in Hepatitis C therapeutics offer the possibility of cure but will be expensive. The cost of treatment may be partially offset by the avoidance of advanced liver disease. We performed a micro-costing study of the ambulatory healthcare utilisation of patients with Hepatitis C supplemented with inpatient diagnosis related group costs. The staff utilisation costs associated with a Hepatitis C ambulatory visit were measured and combined with the costs of investigations to establish a mean cost per consultation. An annualised estimate of cost was produced by multiplying this by the number of consultations accessed, stratified by degree of liver impairment. Inpatient costs were established by identifying the number of inpatient episodes and multiplying by Irish diagnosis related group costs. Non-parametric bootstrapping was performed to derive mean and 95%CI values. Two hundred and twenty-five patients were identified. The cost of an outpatient medical review was €136 (€3.60 SD). The cost of a Hepatitis C nursing review was €128 (€7.30 SD). The annual mean costs of care were as follows (95%CI): Mild €398 (€336, €482), Moderate €417(€335, €503), Compensated cirrhosis €1790 (€990, €3164), Decompensated cirrhosis €8302 (€3945, €14,637), Transplantation Year 1 €137,176 (€136,024, €138,306), Transplantation after Year 1 €5337 (€4942, €5799), Hepatocellular carcinoma €21,992 (€15,222, €29,467), Sustained virological response €44 (€16, €73). The direct medical cost associated with Hepatitis C care in Ireland is substantial and increases exponentially with progression of liver disease. The follow-up costs of patients with a sustained virological response in this cohort were low in comparison to patients with chronic infection.


Patient-Reported Barriers to Adherence to Antiretroviral Therapy: A Systematic Review and Meta-Analysis.
Maintaining high levels of adherence to antiretroviral therapy (ART) is a challenge across settings and populations. Understanding the relative importance of different barriers to adherence will help inform the targeting of different interventions and future research priorities. We searched MEDLINE via PubMed, Embase, Web of Science, and PsychINFO from 01 January 1997 to 31 March 2016 for studies reporting barriers to adherence to ART. We calculated pooled proportions of reported barriers to adherence per age group (adults, adolescents, and children). We included data from 125 studies that provided information about adherence barriers for 17,061 adults, 1,099 children, and 856 adolescents. We assessed differences according to geographical location and level of economic development. The most frequently reported individual barriers included forgetting (adults 41.4%, 95% CI 37.3%-45.4%; adolescents 63.1%, 95% CI 46.3%-80.0%; children/caregivers 29.2%, 95% CI 20.1%-38.4%), being away from home (adults 30.4%, 95% CI 25.5%-35.2%; adolescents 40.7%, 95% CI 25.7%-55.6%; children/caregivers 18.5%, 95% CI 10.3%-26.8%), and a change to daily routine (adults 28.0%, 95% CI 20.9%-35.0%; adolescents 32.4%, 95% CI 0%-75.0%; children/caregivers 26.3%, 95% CI 15.3%-37.4%). Depression was reported as a barrier to adherence by more than 15% of patients across all age categories (adults 15.5%, 95% CI 12.8%-18.3%; adolescents 25.7%, 95% CI 17.7%-33.6%; children 15.1%, 95% CI 3.9%-26.3%), while alcohol/substance misuse was commonly reported by adults (12.9%, 95% CI 9.7%-16.1%) and adolescents (28.8%, 95% CI 11.8%-45.8%). Secrecy/stigma was a commonly cited barrier to adherence, reported by more than 10% of adults and children across all regions (adults 13.6%, 95% CI 11.9%-15.3%; children/caregivers 22.3%, 95% CI 10.2%-34.5%). Among adults, feeling sick (15.9%, 95% CI 13.0%-18.8%) was a more commonly cited barrier to adherence than feeling well (9.3%, 95% CI 7.2%-11.4%). Health service-related barriers, including distance to clinic (adults 17.5%, 95% CI 13.0%-21.9%) and stock outs (adults 16.1%, 95% CI 11.7%-20.4%), were also frequently reported. Limitations of this review relate to the fact that included studies differed in approaches to assessing adherence barriers and included variable durations of follow up. Studies that report self-reported adherence will likely underestimate the frequency of non-adherence. For children, barriers were mainly reported by caregivers, which may not correspond to the most important barriers faced by children. Patients on ART face multiple barriers to adherence, and no single intervention will be sufficient to ensure that high levels of adherence to treatment and virological suppression are sustained. For maximum efficacy, health providers should consider a more triaged approach that first identifies patients at risk of poor adherence and then seeks to establish the support that is needed to overcome the most important barriers to adherence.


Remodeling of neuromuscular junctions in aged rat genioglossus muscle.
Speech and swallowing disorders represent a large clinical problem in elderly persons. Poor lingual control is associated with both speech and swallowing impairment. Studies of limb and laryngeal muscles suggest that age-related musculoskeletal changes may be characterized by remodeling of muscles, nerves, and their connections at neuromuscular junctions (NMJs). To evaluate dynamic remodeling of NMJ structure in the tongue as a function of aging, we studied tongues from 10 aged and 10 young rats. A fluorescent, triple-labeled, immunohistochemical technique was used with genioglossus (GG) muscle samples to allow confocal microscopic visualization of receptor clusters, nerve terminals, axons, and synaptic vesicles. Normal axon terminals and receptor clusters were easily identified in young rat GG muscles, whereas aging induced a significantly higher degree of receptor dispersal. These results suggest that NMJ remodeling is found in aged GG muscles and may underlie the progressive neuromuscular changes observed in the elderly.


Visual motion sensitivity and reading.
Reading is more difficult than speaking because an arbitrary set of visual symbols must be rapidly identified, ordered and translated into the sounds they represent. Many poor readers have particular problems with the rapid visual processing required for these tasks because they have a mild impairment of the visual magnocellular system. This deficit has been demonstrated using neuropathological, evoked potential, functional magnetic resonance imaging and psychophysical techniques. The sensitivity of the M-system in both good and bad readers correlates with their orthographic abilities, suggesting that the M-system plays an important part in their development. This role is probably to mediate steady direction of visual attention and eye fixations on words. Thus many children with reading difficulties have unsteady eye control and this causes the letters they are trying to read to appear to move around, so that they cannot tell what order they are meant to be in. Therefore, boosting M-performance using yellow filters, or training eye fixation, can improve reading performance very significantly. Several genetic linkage studies have associated reading difficulties with the MHC control region on the short arm of chromosome 6. This system has recently been shown to help regulate the differentiation of M-cells. This association could also explain the high incidence of autoimmune conditions in poor readers. Other chromosomal sites are associated with the metabolism of polyunsaturated fatty acids (PUFAs) as found in fish oils, and this could explain why PUFA supplements can improve reading.


Infections in patients with chronic lymphocytic leukemia treated with fludarabine.
Fludarabine, a purine analogue with activity in chronic lymphocytic leukemia, is usually well tolerated. Although serious infections after fludarabine therapy have been described, a systematic analysis of the risk factors for such infections in chronic lymphocytic leukemia is lacking. To determine the risk factors for major infection in patients with chronic lymphocytic leukemia treated with fludarabine. Retrospective review of medical records. Cancer center. 402 patients with chronic lymphocytic leukemia not previously treated or treated with chlorambucil (with or without prednisone) who received fludarabine (30 mg/m2 of body surface area per day for 5 days) with or without prednisone at 4-week intervals. Infections occurred more often in previously treated (144 of 248 [58%]) than in previously untreated (53 of 154 [34%]) patients (P < 0.001). Listeriosis or pneumocystosis occurred in 12 of 170 (7%) previously treated patients receiving fludarabine plus prednisone, 0 of 78 previously treated patients receiving fludarabine alone, and 2 of 154 (1%) previously untreated patients receiving fludarabine plus prednisone (P = 0.003). Univariate analysis identified previous chemotherapy, advanced disease, failure to respond to fludarabine, elevated serum beta2-microglobulin level (P < 0.001), low serum albumin level (P = 0.024), elevated serum creatinine concentration (P = 0.008), and low granulocyte count (P = 0.003) as risk factors for infection. Multivariate analysis identified Rai stage III or IV (odds ratio, 1.98 [95% CI, 1.17 to 3.94]), previous treatment (odds ratio, 2.24 [CI, 1.43 to 3.51]), and elevated serum creatinine concentration (odds ratio, 1.98 [CI, 1.09 to 3.67]) as statistically significant independent risk factors for major infection. A baseline granulocyte count of more than 1000 cells/microL was protective (odds ratio, 0.54 [CI, 0.29 to 0.99]). Five (26%) of 19 patients with a CD4 count less than 50 cells/mL developed cutaneous zoster compared with 9 (6%) of 139 patients with a CD4 count greater than 50 cells/mL (P = 0.01). Fludarabine used in previously treated patients with chronic lymphocytic leukemia may be associated with infections involving T-cell dysfunction, such as listeriosis, pneumocystosis, mycobacterial infections, and opportunistic fungal and viral infections. Prophylaxis or presumptive therapy should be initiated in the appropriate setting.


Could Have Gone Wrong: Effects of Abrupt Changes in Migratory Behaviour on Harvest in a Waterbird Population.
To sustainably exploit a population, it is crucial to understand and reduce uncertainties about population processes and effects of harvest. In migratory species, management is challenged by geographically separated changing environmental conditions, which may cause unexpected changes in species distribution and harvest. We describe the development in the harvest of Svalbard-breeding pink-footed geese (Anser brachyrhynchus) in relation to the observed trajectory and migratory behaviour of the population. In autumn, geese migrate via stopover sites in Norway and Denmark (where they are hunted) to wintering grounds in the Netherlands and Belgium (where they are protected). In Denmark and Norway harvesting increased stepwise during the 2000s. The increase in the population size only partly explained the change. The change corresponded to a simultaneous stepwise increase in numbers of geese staging in Denmark throughout autumn and winter; geese also moved further inland to feed which collectively increased their exposure to hunting. In Norway the increase in harvest reflected greater utilisation of lowland farmland areas by geese, increasing their hunting exposure. The study demonstrates how changes in migratory behaviour can abruptly affect exposure to hunting, which showed a functional response to increased temporal and spatial availability of geese. The harvest has now reached a level likely to cause a population decline. It highlights the need for flexible, internationally coordinated hunting regulations and reliable up-to-date population estimates and hunting bag statistics, which are rare in European management of migratory waterbirds. Without such information decisions are left with judgments based on population estimates, which often have time lags of several years between recording and reporting, hampering possibilities for the timely adjustment of management actions.


A systematic review and meta-analysis of the global seasonality of norovirus.
Noroviruses are the most common cause of acute gastroenteritis across all ages worldwide. These pathogens are generally understood to exhibit a wintertime seasonality, though a systematic assessment of seasonal patterns has not been conducted in the era of modern diagnostics. We conducted a systematic review of the Pubmed Medline database for articles published between 1997 and 2011 to identify and extract data from articles reporting on monthly counts of norovirus. We conducted a descriptive analysis to document seasonal patterns of norovirus disease, and we also constructed multivariate linear models to identify factors associated with the strength of norovirus seasonality. The searched identified 293 unique articles, yielding 38 case and 29 outbreak data series. Within these data series, 52.7% of cases and 41.2% of outbreaks occurred in winter months, and 78.9% of cases and 71.0% of outbreaks occurred in cool months. Both case and outbreak studies showed an earlier peak in season-year 2002-03, but not in season-year 2006-07, years when new genogroup II type 4 variants emerged. For outbreaks, norovirus season strength was positively associated with average rainfall in the wettest month, and inversely associated with crude birth rate in both bivariate and multivariate analyses. For cases, none of the covariates examined was associated with season strength. When case and outbreaks were combined, average rainfall in the wettest month was positively associated with season strength. Norovirus is a wintertime phenomenon, at least in the temperate northern hemisphere where most data are available. Our results point to possible associations of season strength with rain in the wettest month and crude birth rate.


Land-based measures to mitigate climate change: Potential and feasibility by country.
Land-based climate mitigation measures have gained significant attention and importance in public and private sector climate policies. Building on previous studies, we refine and update the mitigation potentials for 20 land-based measures in >200 countries and five regions, comparing "bottom-up" sectoral estimates with integrated assessment models (IAMs). We also assess implementation feasibility at the country level. Cost-effective (available up to $100/tCO2 eq) land-based mitigation is 8-13.8 GtCO2 eq yr-1 between 2020 and 2050, with the bottom end of this range representing the IAM median and the upper end representing the sectoral estimate. The cost-effective sectoral estimate is about 40% of available technical potential and is in line with achieving a 1.5°C pathway in 2050. Compared to technical potentials, cost-effective estimates represent a more realistic and actionable target for policy. The cost-effective potential is approximately 50% from forests and other ecosystems, 35% from agriculture, and 15% from demand-side measures. The potential varies sixfold across the five regions assessed (0.75-4.8 GtCO2eq yr-1 ) and the top 15 countries account for about 60% of the global potential. Protection of forests and other ecosystems and demand-side measures present particularly high mitigation efficiency, high provision of co-benefits, and relatively lower costs. The feasibility assessment suggests that governance, economic investment, and socio-cultural conditions influence the likelihood that land-based mitigation potentials are realized. A substantial portion of potential (80%) is in developing countries and LDCs, where feasibility barriers are of greatest concern. Assisting countries to overcome barriers may result in significant quantities of near-term, low-cost mitigation while locally achieving important climate adaptation and development benefits. Opportunities among countries vary widely depending on types of land-based measures available, their potential co-benefits and risks, and their feasibility. Enhanced investments and country-specific plans that accommodate this complexity are urgently needed to realize the large global potential from improved land stewardship.


Patient Safety in Medication Nomenclature: Orthographic and Semantic Properties of International Nonproprietary Names.
Confusion between look-alike and sound-alike (LASA) medication names (such as mercaptamine and mercaptopurine) accounts for up to one in four medication errors, threatening patient safety. Error reduction strategies include computerized physician order entry interventions, and 'Tall Man' lettering. The purpose of this study is to explore the medication name designation process, to elucidate properties that may prime the risk of confusion. We analysed the formal and semantic properties of 7,987 International Non-proprietary Names (INNs), in relation to naming guidelines of the World Health Organization (WHO) INN programme, and have identified potential for errors. We explored: their linguistic properties, the underlying taxonomy of stems to indicate pharmacological interrelationships, and similarities between INNs. We used Microsoft Excel for analysis, including calculation of Levenshtein edit distance (LED). Compliance with WHO naming guidelines was inconsistent. Since the 1970s there has been a trend towards compliance in formal properties, such as word length, but longer names published in the 1950s and 1960s are still in use. The stems used to show pharmacological interrelationships are not spelled consistently and the guidelines do not impose an unequivocal order on them, making the meanings of INNs difficult to understand. Pairs of INNs sharing a stem (appropriately or not) often have high levels of similarity (<5 LED), and thus have greater potential for confusion. We have revealed a tension between WHO guidelines stipulating use of stems to denote meaning, and the aim of reducing similarities in nomenclature. To mitigate this tension and reduce the risk of confusion, the stem system should be made clear and well ordered, so as to avoid compounding the risk of confusion at the clinical level. The interplay between the different WHO INN naming principles should be further examined, to better understand their implications for the problem of LASA errors.


Estimating the transmission parameters of pneumococcal carriage in households.
This paper analyses Streptococcus pneumoniae transmission dynamics in households using longitudinal data on pneumococcal (Pnc) carriage in the United Kingdom. Ten consecutive swabs were taken at 4-week intervals from all members of 121 households. The family status is derived from the observed Pnc carriage status of each family member. Transition matrices are built for each family size and composition containing the observed frequency of transitions between family statuses over a 28-day interval. A density-dependent transmission model is fitted to derive maximum-likelihood estimates of the duration of carriage and acquisition rates from the community and from infected individuals within the household. Parameter values are estimated for children (< 5 years) and adults (5+ years). The duration of carriage is longer in children < 5 years of age than in older family members (51 vs. 19 days). Children are 3-4 times more likely than adults to acquire Pnc infection from the community. Transmission rates within the household suggest that adults are more infectious but less susceptible than children. Transmission within the household is most important in large families. The proportion of household-acquired infection ranges from 29 to 46% in households of three persons to 38-50% in larger households. Evidence of density-dependent within-household transmission is found, although the strength of this relationship is not clear from the model estimates.


Differences in readmissions after open repair versus endovascular aneurysm repair.
Reintervention rates after repair of abdominal aortic aneurysm (AAA) are higher for endovascular repair (EVAR) than for open repair, mostly due to treatment for endoleaks, whereas open surgical operations for bowel obstruction and abdominal hernias are higher after open repair. However, readmission rates after EVAR or open repair for nonoperative conditions and complications that do not require an intervention are not well documented. We sought to determine reasons for all-cause readmissions within the first year after open repair and EVAR. Patients who underwent elective AAA repair in California during a 6-year period were identified from the Health Care and Utilization Project State Inpatient Database. All patients who had a readmission in California ≤1 year of their index procedure were included for evaluation. Readmission rates and primary and secondary diagnoses associated with each readmission were analyzed and recorded. From 2003 to 2008, there were 15,736 operations for elective AAA repair, comprising 9356 EVARs (60%) and 6380 open repairs (40%). At 1 year postoperatively, the readmission rate was 52.1% after open repair and 55.4% after EVAR (P=.0003). The three most common principle diagnoses associated with readmission after any type of AAA repair were failure to thrive, cardiac issues, and infection. When stratified by repair type, patients who underwent open repair were more likely to be readmitted with primary diagnoses associated with failure to thrive, cardiac complications, and infection compared with EVAR (all P<.001). Those who underwent EVAR were more likely, however, to be readmitted with primary diagnoses of device-related complications (P=.05), cardiac complications, and infection. Total readmission rates within 1 year after elective AAA repair are greater after EVAR than after open repair. Reasons for readmission vary between the two cohorts but are related to the magnitude of open surgery after open repair, device issues after EVAR, and the usual cardiac and infectious complications after either intervention. Systems-based analysis of these causes of readmission can potentially improve patient expectations and care after elective aneurysm repair.


Electronic switching of single silicon atoms by molecular field effects.
We have observed on-off switching of scanning tunneling microscope current flow to silicon adatoms of the Si(111)-(7 x 7) surface that are enclosed within a bistable dimeric corral of self-assembled chlorododecane molecules. These thermally activated oscillations amounted to an order of magnitude change in the current. Theory showed that small changes in molecular configuration could cause alterations in the corralled adatom's electronic energy by as much as 1 eV due to local field effects, accounting for the observed current switching.


Role of natural killer cells in intraocular melanoma metastasis.
The authors studied the role of natural killer (NK) cells in spontaneous metastasis of murine intraocular melanoma by transplanting murine B16 melanoma cells into the anterior chamber of the eye in syngeneic C57BL/6 mice and determining the number of metastatic lung tumor colonies after 40 days. Depletion of NK activity by anti-asialo GM1 serum dramatically enhanced metastasis and augmentation of NK activity by interferon inhibited it. The strong correlation between host NK activity and intraocular melanoma metastasis indicated that NK cells have an important role in spontaneous metastasis of intraocular melanoma.


Clinical Efficacy of Allergen-Specific Immunotherapy from Patient and Physician Perspectives.
Allergen-specific immunotherapy (AIT) is the only curative treatment for allergic diseases, but a few allergic patients receive AIT. In this multicenter cross-sectional study, we aimed to explore patient and physician perspectives on AIT through a questionnaire survey. Allergic patients who received subcutaneous immunotherapy for at least 1 year were asked to answer a questionnaire developed by an expert panel of allergen and immunotherapy workgroup in Korea. A total of 267 patients (adults, 60.3%) with allergic rhinitis (91.4%), asthma (42.7%), or atopic dermatitis (20.2%) from referred hospitals completed the survey. Among patients and physicians, respectively, the overall rates of satisfaction with AIT for allergic rhinitis were 86.4% and 83.3% (kappa agreement=0.234, p<0.001), and those for asthma were 85.3% and 72.9% (kappa agreement=0.373, p<0.001). Moreover, pediatric asthmatic patients reported a significantly higher satisfaction rate than adult asthmatic patients after AIT (p=0.040). Symptom severity (p<0.001, respectively) and drug use for allergic rhinitis and asthma decreased after AIT. However, there was no significant difference in satisfaction rates between children and adults in allergic rhinitis (p=0.736). Interestingly, 35.7% and 35% of allergic rhinitis and asthma patients, respectively, reported experiencing improvement in their symptoms within 6 months of starting AIT. In this study evaluating the perspectives of patients and physicians on AIT, the majority of patients were satisfied with the efficacy and safety of AIT, but not its cost. AIT should be recommended for AR and allergic patients.


Prevention of photocarcinogenesis by topical administration of pure epigallocatechin gallate isolated from green tea.
Topical application of purified (-)-epigallocatechin-3-gallate (EGCG), a polyphenolic antioxidant isolated from green tea, inhibited photocarcinogenesis in BALB/cAnNHsd mice with no visible toxicity. Mice were treated with 0, 10, or 50 mg of EGCG in 200 microliters of acetone three times weekly for three weeks before ultraviolet (UV) treatments began and throughout the experiment. UV radiation consisted of five 30-minute exposures per week to banks of six FS40 Westinghouse sunlamps for 25 weeks. In the photocarcinogenesis study, mice received a total dose of approximately 2.1 x 10(6) J/m2. Skin cancer incidence in UV-irradiated mice was 96% at 28 weeks after the first UV treatment; EGCG at 10 or 50 mg reduced this incidence to 62% and 29%, respectively. UV-induced immunosuppression, assessed by the inability of UVB-irradiated mice to reject a syngeneic antigenic tumor, was not influenced by topical EGCG. Oral administration of 0, 100, or 500 mg of pure EGCG per liter of drinking water (approximately 0, 0.56, or 2.8 mg/day, respectively) did not decrease UV-induced skin tumor incidence, rate of primary tumor growth, or inability to reject antigenic tumors. Thus induction of skin tumors by UV radiation was significantly reduced by topical, but not by oral, administration of purified EGCG through a mechanism distinct from inhibition of photoimmunosuppression.


First Report of Nothofagus macrocarpa Dieback Caused by Phytophthora citrophthora and P. nicotianae in Chile.
The genus Nothofagus, family Nothofagaceae, comprises 36 species of trees that are native to the Southern Hemisphere. N. macrocarpa (DC.) F.M. Vásquez & R.A. Rodríguez (Roble de Santiago) is an important deciduous tree, endemic to central Chile (32 to 35°S), and found above 800 m altitude. There is an increasing interest in N. macrocarpa as an ornamental. However, a general dieback (40 to 50% prevalence) was observed at a commercial nursery in Santiago in 2009, limiting its multiplication. Symptoms are wilting, partial defoliation, reddish brown cankers on the crowns, and root necrosis. The purpose of this work was to study the etiology of the dieback in nurseries. Phytophthora was isolated from the roots and cankers of symptomatic plants (n = 3) and soil samples (using apples and avocados as baits) on amended corn meal agar (3) at 20°C for 5 days in the dark. Morphologically, P. citrophthora (Smith & Smith) Leonian, and P. nicotianae Breda de Haan were identified (2). On V8 juice agar (V8) (1), P. citrophthora formed petaloid colonies, grew between 5 and 30°C (optimum of 25°C), and produced deciduous, mono- or bipapillated sporangia of (28.1) 45.0 to 64.1 × (18.8) 32.0 to 39.2 μm. On V8, P. nicotianae produced cottony colonies, grew between 10 and 30°C (optimum of 25°C), and produced spherical, intercalary chlamydospores (mean diameter of 19.6 μm) and persistent, papillate, spherical to ovoid, ellipsoid, obpyriform sporangia of (33.2) 47.5 to 67.6 × (24.1) 30.0 to 48.9 μm. Isolates of P. citrophthora were sexually sterile, but P. nicotianae formed oogonia with amphigenous antheridia in dual cultures with P. cinnamomi (A2 compatibility type). BLAST analysis of the internal transcribed spacer (ITS) region of rDNA of isolates identified as P. citrophthora (IMI 399056 and IMI 399054, GenBank Accession Nos. JF699756 and JF699755) and P. nicotianae (IMI 399055, Accession No. JF699757), amplified by PCR using ITS universal primers (4), revealed 100% similarity with reference isolates of P. citrophthora (Accession Nos. GU259324.1 and GU259317.1) and P. nicotianae (Accession No. GU983635.1). P. citrophthora (n = 2) and P. nicotianae (n = 1) were pathogenic when wounded detached twigs (n = 5) of N. macrocarpa and N. obliqua were inoculated with 20 μl of a mycelial suspension (106 CFU/ml) of either Phytophthora spp. Twigs were placed in a moist chamber at 20°C for 12 days prior to determine the length of the necrotic lesions that developed. An equal number of noninoculated twigs were left as control. Reisolation of P. citrophthora and P. nicotianae from inoculated material was 100%. The length of the necrotic lesions (13 to 80 mm) from inoculated N. macrocarpa and N. obliqua was significantly greater (P < 0.05) compared with the controls. Regardless of Phytophthora isolates, necrotic lesions (53.9 ± 15.8 mm) in infected N. macrocarpa were significantly longer than in N. obliqua (28.6 ± 13.1 mm) (P < 0.0001). To our knowledge, this is the first report of P. citrophthora and P. nicotianae associated with dieback on N. macrocarpa in Chile. Therefore, there is a potential risk of Phytophthora dieback in N. macrocarpa in nature. References: (1) J. Ampuero et al. Plant Dis. 92:1529, 2008. (2) D. C. Erwin and O. K. Ribeiro. Phytophthora Diseases Worldwide. The American Phytopathological Society, St. Paul, MN, 1996. (3) B. A. Latorre and R. Muñoz. Plant Dis. 77:715, 1993. (4) T. J. White et al. PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, 1990.


Recognition of the Major Histocompatibility Complex (MHC) Class Ib Molecule H2-Q10 by the Natural Killer Cell Receptor Ly49C.
Murine natural killer (NK) cells are regulated by the interaction of Ly49 receptors with major histocompatibility complex class I molecules (MHC-I). Although the ligands for inhibitory Ly49 were considered to be restricted to classical MHC (MHC-Ia), we have shown that the non-classical MHC molecule (MHC-Ib) H2-M3 was a ligand for the inhibitory Ly49A. Here we establish that another MHC-Ib, H2-Q10, is a bona fide ligand for the inhibitory Ly49C receptor. H2-Q10 bound to Ly49C with a marginally lower affinity (∼5 μm) than that observed between Ly49C and MHC-Ia (H-2K(b)/H-2D(d), both ∼1 μm), and this recognition could be prevented by cis interactions with H-2K in situ To understand the molecular details underpinning Ly49·MHC-Ib recognition, we determined the crystal structures of H2-Q10 and Ly49C bound H2-Q10. Unliganded H2-Q10 adopted a classical MHC-I fold and possessed a peptide-binding groove that exhibited features similar to those found in MHC-Ia, explaining the diverse peptide binding repertoire of H2-Q10. Ly49C bound to H2-Q10 underneath the peptide binding platform to a region that encompassed residues from the α1, α2, and α3 domains, as well as the associated β2-microglobulin subunit. This docking mode was conserved with that previously observed for Ly49C·H-2K(b) Indeed, structure-guided mutation of Ly49C indicated that Ly49C·H2-Q10 and Ly49C·H-2K(b) possess similar energetic footprints focused around residues located within the Ly49C β4-stand and L5 loop, which contact the underside of the peptide-binding platform floor. Our data provide a structural basis for Ly49·MHC-Ib recognition and demonstrate that MHC-Ib represent an extended family of ligands for Ly49 molecules.


Balancing body ownership: Visual capture of proprioception and affectivity during vestibular stimulation.
The experience of our body as our own (i.e. body ownership) involves integrating different sensory signals according to their contextual relevance (i.e. multisensory integration). Until recently, most studies of multisensory integration and body ownership concerned only vision, touch and proprioception; the role of other modalities, such as the vestibular system and interoception, has been neglected and remains poorly understood. In particular, no study to date has directly explored the combined effect of vestibular and interoceptive signals on body ownership. Here, we investigated for the first time how Galvanic Vestibular Stimulation (left, right, sham), tactile affectivity (a reclassified interoceptive modality manipulated by applying touch at C-tactile optimal versus non-optimal velocities), and their combination, influence proprioceptive and subjective measures of body ownership during a rubber hand illusion paradigm with healthy participants (N = 26). Our results show that vestibular stimulation (left GVS) significantly increased proprioceptive drift towards the rubber hand during mere visual exposure to the rubber hand. Moreover, it also enhanced participants' proprioceptive drift towards the rubber hand during manipulations of synchronicity and affective touch. These findings suggest that the vestibular system influences multisensory integration, possibly by re-weighting both the two-way relationship between proprioception and vision, as well as the three-way relationship between proprioception, vision and affective touch. We discuss these findings in relation to current predictive coding models of multisensory integration and body ownership.


Portable open-source autosampler for shallow waters.
Automated water sampling can be very useful, but open-source choices are limited. Here I present an autosampler which consists of a gantry robot that delivers water from a syringe pump to 24 capped 40 ml vials. The autosampler is controlled using an Android tablet automatized using Macrodroid. Three rinsing cycles ensure negligible carryover between consecutive samples. Hourly sampling from a creek under rainy conditions suggested that total organic carbon in water was diluted by the rain. Some important limitations: 1) the autosampler must be on a steady, flat, horizontal surface; 2) unattended sampling can only last as long as the batteries powering the tablet and the motors; 3) distance from the syringe pump to water cannot exceed ~2 m in height and ~4 m in length for 3 mm tubing; 4) sampling frequency does not exceed one sample every eleven minutes. However, because of its open design, the autosampler can be modified and improved to not only overcome these limitations, but also potentially expand its scope to more demanding sampling if necessary.


MER41 repeat sequences contain inducible STAT1 binding sites.
Chromatin immunoprecipitation combined with massively parallel sequencing methods (ChIP-seq) is becoming the standard approach to study interactions of transcription factors (TF) with genomic sequences. At the example of public STAT1 ChIP-seq data sets, we present novel approaches for the interpretation of ChIP-seq data.We compare recently developed approaches to determine STAT1 binding sites from ChIP-seq data. Assessing the content of the established consensus sequence for STAT1 binding sites, we find that the usage of "negative control" ChIP-seq data fails to provide substantial advantages. We derive a single refined probabilistic model of STAT1 binding sequences from these ChIP-seq data. Contrary to previous claims, we find no evidence that STAT1 binds to multiple distinct motifs upon interferon-gamma stimulation in vivo. While a large majority of genomic sites with high ChIP-seq signal is associated with a nucleotide sequence resembling a STAT1 binding site, only a very small subset of the over 5 million potential STAT1 binding sites in the human genome is covered by ChIP-seq data. Furthermore a surprisingly large fraction of the ChIP-seq signal (5%) is absorbed by a small family of repetitive sequences (MER41). The observation of the binding of activated STAT1 protein to a specific repetitive element bolsters similar reports concerning p53 and other TFs, and strengthens the notion of an involvement of repeats in gene regulation. Incidentally MER41 are specific to primates, consequently, regulatory mechanisms in the IFN-STAT pathway might fundamentally differ between primates and rodents. On a methodological aspect, the presence of large numbers of nearly identical binding sites in repetitive sequences may lead to wrong conclusions about intrinsic binding preferences of TF as illustrated by the spacing analysis STAT1 tandem motifs. Therefore, ChIP-seq data should be analyzed independently within repetitive and non-repetitive sequences.


Dopamine increases risky choice while D2 blockade shortens decision time.
Dopamine is crucially involved in decision-making and overstimulation within dopaminergic pathways can lead to impulsive behaviour, including a desire to take risks and reduced deliberation before acting. These behavioural changes are side effects of treatment with dopaminergic drugs in Parkinson disease, but their likelihood of occurrence is difficult to predict and may be influenced by the individual's baseline endogenous dopamine state, and indeed correlate with sensation-seeking personality traits. We here collected data on a standard gambling task in healthy volunteers given either placebo, 2.5 mg of the dopamine antagonist haloperidol or 100/25 mg of the dopamine precursor levodopa in a within-subject design. We found an increase in risky choices on levodopa. Choices were, however, made faster on haloperidol with no effect of levodopa on deliberation time. Shortened deliberation times on haloperidol occurred in low sensation-seekers only, suggesting a correlation between sensation-seeking personality trait and baseline dopamine levels. We hypothesise that levodopa increases risk-taking behaviour via overstimulation at both D1 and D2 receptor level, while a single low dose of haloperidol, as previously reported (Frank and O'Reilly 2006), may block D2 receptors pre- and post-synaptically and may paradoxically lead to higher striatal dopamine acting on remaining striatal D1 receptors, causing speedier decision without influencing risk tolerance. These effects could also fit with a recently proposed computational model of the basal ganglia (Moeller and Bogacz 2019; Moeller et al. 2021). Furthermore, our data suggest that the actual dopaminergic drug effect may be dependent on the individual's baseline dopamine state, which may influence our therapeutic decision as clinicians in the future.


Endothelial production of C-type natriuretic peptide and its marked augmentation by transforming growth factor-beta. Possible existence of "vascular natriuretic peptide system".
C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family, is thus far known to be distributed mainly in the central nervous system and is considered to act as a neuropeptide, in contrast to atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which act as cardiac hormones. Recently, we and others have demonstrated that the ANP-B receptor, which is selectively activated by CNP, is localized not only in the central nervous system but in peripheral tissues, including blood vessels. This finding has made us speculate regarding the peripheral production of CNP. In the present study, cultured endothelial cells were examined for CNP production by RIA and Northern blot analysis. CNP-like immunoreactivity was detected in the conditioned media of endothelial cells. Northern blot analysis detected CNPmRNA with a size of 1.2 kb. In addition, transforming growth factor (TGF)-beta, one of the key growth factors for vascular remodeling, markedly stimulated the expression of CNPmRNA and induced a tremendous increase in CNP secretion. We could also detect CNP transcript in the bovine thoracic aorta using the reverse transcription-polymerase chain reaction method. The present study demonstrates the endothelial production of CNP and suggests that a member of the natriuretic peptide family may act as a local regulator in vascular walls. Since evidence for the pathophysiological importance of the vascular renin-angiotensin system has been accumulating and the natriuretic peptide system is known to be antagonistic to the renin-angiotensin system, the possible existence of "vascular natriuretic peptide system" may prove to be of physiological and clinical relevance.


Estimating primary production at depth from remote sensing.
By use of a common primary-production model and identical photosynthetic parameters, four different methods were used to calculate quanta (Q) and primary production (P) at depth for a study of high-latitude North Atlantic waters. The differences among the four methods relate to the use of pigment information in the upper water column. Methods 1 and 2 use pigment biomass (B) as an input and a subtropical, empirical relation between K(d) (diffuse attenuation coefficient) and B to estimate Q at depth. Method 1 uses measured B, but Method 2 uses B derived from the Coastal Zone Color Scanner (subtropical algorithm) as inputs. Methods 3 and 4 use the phytoplankton absorption coefficient (a(ph)) instead of B as input, and Method B uses empirically derived a(ph)(440) and K(d) values, and Method 4 uses analytically derived a(ph)(440) and a (total absorption coefficient) values based on the same remote measurements as Method 2. When the calculated and the measured values of Q(z) and P(z) were compared, Method 4 provided the closest results [for P(z), r(2) = 0.95 (n = 24), and for Q(z), r(2) = 0.92 (n = 11)]. Method 1 yielded the worst results [for P(z), r(2) = 0.56 and for Q(z), r(2) = 0.81]. These results indicate that one of the greatest uncertainties in the remote estimation of P can come from a potential mismatch of the pigment-specific absorption coefficient (a(ph)*), which is needed implicitly in current models or algorithms based on B. We point out that this potential mismatch can be avoided if we arrange the models or algorithms so that they are based on the pigment absorption coefficient (a(ph)). Thus, except for the accuracy of the photosynthetic parameters and the above-surface light intensity, the accuracy of the remote estimation of P depends on how accurately a(ph) can be estimated, but not how accurately B can be estimated. Also, methods to derive a(ph) empirically and analytically from remotely sensed data are introduced. Curiously, combined application of subtropical algorithms for both B and K(d) to subarctic waters apparently compensates to some extent for effects that are due to their similar and implicit pigment-specific absorption coefficients for the calculation of Q(z).


Construct and discriminant validity and dimensionality of the Interview Schedule for Social Interaction (ISSI) in three psychiatric samples.
This study was aimed at investigating the psychometric properties of the Interview Schedule for Social Interaction (ISSI), in terms of construct and discriminant validity and unidimensionality, in three psychiatric samples with varying prerequisites for social interaction: 1) an outpatient sample of working age with mixed diagnoses, 2) an outpatient sample with schizophrenia, and 3) an inpatient sample composed of mentally ill, male offenders. The target constructs were psychosocial functioning and satisfaction in different life domains. It was hypothesized that the ISSI would mainly be related to psychosocial functioning and life domains characterized by social interaction, such as friends and family. A second hypothesis was that the ISSI ratings would discriminate between the three samples. The first hypothesis was confirmed, but the pattern of relationships was somewhat different between the groups. Whereas family contacts were of great importance for social integration in Samples 1 and 2, friends seemed more important for the mentally ill offenders. The second hypothesis was partly confirmed: three ISSI sub-scales out of four discriminated between the samples. Moreover, the ISSI proved to be a unidimensional construct. The support for the four proposed sub-scales was not unanimous, however, and the sub-scales targeting attachment constituted less stable factors. This study demonstrated the construct and discriminant validity of the ISSI when applied to samples with various mental disorders. The fact that similar results were obtained in all three samples, despite varying prerequisites for social interaction, strongly supports the validity of the ISSI. Providing the sub-scales are used with caution, the ISSI seems to be a reliable tool for use with patients with severe mental disorders.


New structural approach to rationalize the foam film stability of oppositely charged polyelectrolyte/surfactant mixtures.
A novel structural framework is presented to rationalize the foam film stability of polyelectrolyte/surfactant mixtures using neutron reflectivity data. Provision of electrostatic or steric stabilization in thin foam films is related to the spatial distributions of molecules interacting from opposing air/water interfaces. The advance is discussed in the context of many studies on mixed systems over two decades that focused on macroscopic properties such as the surface tension, elasticity, potential and composition, but for which no robust correlations have been established. This concept can now be broadened to other colloidal dispersions of high impact for technical, environmental and life science applications.


Palliation of tricuspid atresia. Potts-Smith, Glenn, and Blalock-Taussig shunts.
Aortopulmonary (Potts-Smith), subclavian-pulmonary (Blalock-Taussig), and cavopulmonary (Glenn) shunts are the commonly performed operations for palliation of tricuspid atresia. A total of 104 patients with tricuspid atresia have undergone these procedures, either alone or in combination over a 28-year-period at the Hospital for Sick Children, Toronto. Operative risk is high in the first six months of life (44%), reasonable after six months of age (7.4%), and low for reoperation (3.5%). Long-term palliation of the 75 survivors (mean follow-up, 8,5 years) is compared for the three operative groups and charted on an actuarial table. Potts shunt offers superior long-term palliation. Therefore, as an overall plan of management, a Potts shunt with restriction of its anastomotic growth is the initial procedure of choice. When the patient outgrows the Potts shunt, a Glenn anastomosis is constructed. Ideally, the combination of these two shunts will produce a balanced circulation offering excellent long-term palliation.


B-lymphocyte homeostasis and BLyS-directed immunotherapy in transplantation.
Current strategies for immunotherapy after transplantation are primarily T-lymphocyte directed and effectively abrogate acute rejection. However, the reality of chronic allograft rejection attests to the fact that transplantation tolerance remains an elusive goal. Donor-specific antibodies are considered the primary cause of chronic rejection. When naive, alloreactive B-cells encounter alloantigen and are activated, a resilient "sensitized" state, characterized by the presence of high-affinity antibody, is established. Here, we will delineate findings that support transient B-lymphocyte depletion therapy at the time of transplantation to preempt sensitization by eliminating alloreactive specificities from the recipient B-cell pool (ie, "repertoire remodeling"). Recent advances in our understanding of B-lymphocyte homeostasis provide novel targets for immunomodulation in transplantation. Specifically, the tumor necrosis factor-related cytokine BLyS is the dominant survival factor for "tolerance-susceptible" transitional and "preimmune" mature follicular B-cells. The transitional phenotype is the intermediate through which all newly formed B-cells pass before maturing into the follicular subset, which is responsible for mounting an alloantigen-specific antibody response. Systemic BLyS levels dictate the stringency of negative selection during peripheral B-cell repertoire development. Thus, targeting BLyS will likely provide an opportunity for repertoire-directed therapy to eliminate alloreactive B-cell specificities in transplant recipients, a requirement for the achievement of humoral tolerance and prevention of chronic rejection. In this review, the fundamentals of preimmune B-cell selection, homeostasis, and activation will be described. Furthermore, new and current B-lymphocyte-directed therapy for antibody-mediated rejection and the highly sensitized state will be discussed. Overall, our objective is to propose a rational approach for induction of humoral transplantation tolerance by remodeling the primary B-cell repertoire of the allograft recipient.


Inhibition of carcinogenesis by polyphenols: evidence from laboratory investigations.
Many plant polyphenolic compounds have been shown to have cancer-preventing activities in laboratory studies. For example, tea and tea preparations have been shown to inhibit tumorigenesis in a variety of animal models of carcinogenesis, involving organ sites such as the skin, lungs, oral cavity, esophagus, stomach, liver, pancreas, small intestine, colon, and prostate. In some of these models, inhibitory activity was demonstrated when tea was administered during the initiation, promotion, or progression stage of carcinogenesis. The cancer-preventing activities of these and other polyphenols, such as curcumin, genistein, and quercetin, are reviewed. In studies in vitro, many of these compounds have been shown to affect signal transduction pathways, leading to inhibition of cell growth and transformation, enhanced apoptosis, reduced invasive behavior, and slowed angiogenesis. However, the concentrations used in cell culture studies were much higher than those found in vivo. If we propose mechanisms for cancer prevention on the basis of cell line experiments, then these activities must be demonstrated in vivo. The bioavailability, ie, tissue and cellular concentrations, of dietary polyphenols is a determining factor in their cancer-preventing activity in vivo. For example, compounds such as curcumin are effective when applied topically to the skin or administered orally to affect the colon but are not effective in internal organs such as the lungs. More in-depth studies on bioavailability should facilitate correlation of mechanisms determined in vitro with in vivo situations, increase our understanding of dose-response relationships, and facilitate extrapolation of results from animal studies to human situations.


The lipopolysaccharide of the mastitis isolate Escherichia coli strain 1303 comprises a novel O-antigen and the rare K-12 core type.
Mastitis represents one of the most significant health problems of dairy herds. The two major causative agents of this disease are Escherichia coli and Staphylococcus aureus. Of the first, its lipopolysaccharide (LPS) is thought to play a prominent role during infection. Here, we report the O-antigen (OPS, O-specific polysaccharide) structure of the LPS from bovine mastitis isolate E. coli 1303. The structure was determined utilizing chemical analyses, mass spectrometry, and 1D and 2D NMR spectroscopy methods. The O-repeating unit was characterized as -[→4)-β-D-Quip3NAc-(1→3)-α-L-Fucp2OAc-(1→4)-β-D-Galp-(1→3)-α-D-GalpNAc-(1→]- in which the O-acetyl substitution was non-stoichiometric. The nucleotide sequence of the O-antigen gene cluster of E. coli 1303 was also determined. This cluster, located between the gnd and galF genes, contains 13 putative open reading frames, most of which represent unknown nucleotide sequences that have not been described before. The O-antigen of E. coli 1303 was shown to substitute O-7 of the terminal LD-heptose of the K-12 core oligosaccharide. Interestingly, the non-OPS-substituted core oligosaccharide represented a truncated version of the K-12 outer core - namely terminal LD-heptose and glucose were missing; however, it possessed a third Kdo residue in the inner core. On the basis of structural and genetic data we show that the mastitis isolate E. coli 1303 represents a new serotype and possesses the K-12 core type, which is rather uncommon among human and bovine isolates.


Purified perforin induces target cell lysis but not DNA fragmentation.
Rapid and extensive target cell DNA fragmentation is a unique characteristic of CTL-mediated killing. We studied the role of the granule pore-forming protein (PFP/perforin/cytolysin) of CTL in mediating lysis and DNA fragmentation of target cells. Perforin was isolated from murine CTL by sequential application of perforin-enriched granule fractions to four chromatographic columns: DEAE-Sepharose, Q-Sepharose, Polyanion SI, and Superose 12. Purified perforin was eluted as a single band of 70 kD in SDS-PAGE. While purified perforin produced potent lysis of a variety of target cells tested, it did not induce any measurable amount of DNA fragmentation. In parallel experiments, intact CTL produced marked DNA fragmentation of the same target cell populations. Our results suggest that perforin alone is not responsible for the DNA fragmentation observed during CTL-mediated killing and that other, as yet unknown, mediators or mechanisms are likely to be involved in the induction of target cell nuclear damage.