Assessment of venous leg symptoms in patients with hemorrhoidal disease (VEIN-HEMORRHOID study).
Coexistence of dilating venous diseases in different vascular territories has raised the idea that they have similar vascular wall abnormality in their evolutionary process. Accordingly, we aimed to evaluate venous leg symptoms in patients with hemorrhoidal disease (HD) by means of VEINES-Sym questionnaire. The study involved 249 consecutive patients who underwent colonoscopy and met the inclusion criteria. Presence and grading of HD were made according to Goligher's classification. All patients were examined for the existing of varicose vein and classified in respect of CEAP classification. All participants were requested to answer the VEINES-Sym questionnaire. There was not statistically significant differences between the patients without HD (grade 0 or I) and with HD (Grade II or III) in respect to clinical characteristics except female predominance in hemorrhoid group (p = 0.07). Scores of heavy legs, swelling, burning sensation, restless leg, throbbing, tingling, and total VEINES score were significantly lower (ie: worse) in hemorrhoid group. Logistic regression analysis revealed that female gender and total VEINES score were independently associated with HD (OR: 2.03, 95% CI: 1.17-3.52, p = 0.01; OR: 0.96, 95% CI: 0.92-0.99, p = 0.02, respectively). Among all venous leg symptoms, severity of heavy legs, night cramps, swelling and aching were significantly correlated with the grades of HD. We have shown significant association between the HD and venous leg symptoms reflected by total VEINES score and significant correlation between the HD grade and venous leg symptoms severity including heavy legs, swelling, night cramps and aching legs.


A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice.
Mcm4 (minichromosome maintenance-deficient 4 homolog) encodes a subunit of the MCM2-7 complex (also known as MCM2-MCM7), the replication licensing factor and presumptive replicative helicase. Here, we report that the mouse chromosome instability mutation Chaos3 (chromosome aberrations occurring spontaneously 3), isolated in a forward genetic screen, is a viable allele of Mcm4. Mcm4(Chaos3) encodes a change in an evolutionarily invariant amino acid (F345I), producing an apparently destabilized MCM4. Saccharomyces cerevisiae strains that we engineered to contain a corresponding allele (resulting in an F391I change) showed a classical minichromosome loss phenotype. Whereas homozygosity for a disrupted Mcm4 allele (Mcm4(-)) caused preimplantation lethality, Mcm(Chaos3/-) embryos died late in gestation, indicating that Mcm4(Chaos3) is hypomorphic. Mutant embryonic fibroblasts were highly susceptible to chromosome breaks induced by the DNA replication inhibitor aphidicolin. Most notably, >80% of Mcm4(Chaos3/Chaos3) females succumbed to mammary adenocarcinomas with a mean latency of 12 months. These findings suggest that hypomorphic alleles of the genes encoding the subunits of the MCM2-7 complex may increase breast cancer risk.


Is horizontal transmission really a problem for phylogenetic comparative methods? A simulation study using continuous cultural traits.
Phylogenetic comparative methods (PCMs) provide a potentially powerful toolkit for testing hypotheses about cultural evolution. Here, we build on previous simulation work to assess the effect horizontal transmission between cultures has on the ability of both phylogenetic and non-phylogenetic methods to make inferences about trait evolution. We found that the mode of horizontal transmission of traits has important consequences for both methods. Where traits were horizontally transmitted separately, PCMs accurately reported when trait evolution was not correlated even at the highest levels of horizontal transmission. By contrast, linear regression analyses often incorrectly concluded that traits were correlated. Where simulated trait evolution was not correlated and traits were horizontally transmitted as a pair, both methods inferred increased levels of positive correlation with increasing horizontal transmission. Where simulated trait evolution was correlated, increasing rates of separate horizontal transmission led to decreasing levels of inferred correlation for both methods, but increasing rates of paired horizontal transmission did not. Furthermore, the PCM was also able to make accurate inferences about the ancestral state of traits. These results suggest that under certain conditions, PCMs can be robust to the effects of horizontal transmission. We discuss ways that future work can investigate the mode and tempo of horizontal transmission of cultural traits.


Nucleolar organization, ribosomal DNA array stability, and acrocentric chromosome integrity are linked to telomere function.
The short arms of the ten acrocentric human chromosomes share several repetitive DNAs, including ribosomal RNA genes (rDNA). The rDNA arrays correspond to nucleolar organizing regions that coalesce each cell cycle to form the nucleolus. Telomere disruption by expressing a mutant version of telomere binding protein TRF2 (dnTRF2) causes non-random acrocentric fusions, as well as large-scale nucleolar defects. The mechanisms responsible for acrocentric chromosome sensitivity to dysfunctional telomeres are unclear. In this study, we show that TRF2 normally associates with the nucleolus and rDNA. However, when telomeres are crippled by dnTRF2 or RNAi knockdown of TRF2, gross nucleolar and chromosomal changes occur. We used the controllable dnTRF2 system to precisely dissect the timing and progression of nucleolar and chromosomal instability induced by telomere dysfunction, demonstrating that nucleolar changes precede the DNA damage and morphological changes that occur at acrocentric short arms. The rDNA repeat arrays on the short arms decondense, and are coated by RNA polymerase I transcription binding factor UBF, physically linking acrocentrics to one another as they become fusogenic. These results highlight the importance of telomere function in nucleolar stability and structural integrity of acrocentric chromosomes, particularly the rDNA arrays. Telomeric stress is widely accepted to cause DNA damage at chromosome ends, but our findings suggest that it also disrupts chromosome structure beyond the telomere region, specifically within the rDNA arrays located on acrocentric chromosomes. These results have relevance for Robertsonian translocation formation in humans and mechanisms by which acrocentric-acrocentric fusions are promoted by DNA damage and repair.


Multicenter study of the association between betapapillomavirus infection and cutaneous squamous cell carcinoma.
Human papillomaviruses (betaPV) from the beta genus cannot be classified according to their oncogenicity due to a paucity of information. This study evaluates the association between betaPV infection and cutaneous squamous cell carcinoma in conjunction with measures of UV exposure and susceptibility. We performed case-control studies in the Netherlands, Italy, and Australia, countries with profoundly different UV exposures. The presence of 25 betaPV types in eyebrow hair follicles was determined using a highly sensitive HPV DNA genotyping assay, and antibodies for the 15 most prevalent betaPV types in a total of 689 squamous cell carcinoma cases and 845 controls were detected using multiplex serology. Multivariate logistic regression models were used for case-control comparisons and interaction analyses. BetaPV DNA was detected in eyebrow hairs of more than 90% of all participants. The presence of betaPV DNA was associated with an increased risk of squamous cell carcinoma in the Netherlands (OR = 2.8; 95% CI 1.3-5.8) and Italy (OR = 1.7; 95% CI 0.79-3.6), but not in Australia (OR = 0.91; 95% CI 0.53-1.6). Seropositivity for betaPV in controls ranged between 52% and 67%. A positive antibody response against 4 or more betaPV types was associated with squamous cell carcinoma in Australia (OR = 2.2; 95% CI 1.4-3.3), the Netherlands (OR = 2.0; 95% CI 1.2-3.4) and fair-skinned Italians (OR = 1.6, 95% CI 0.94- 2.7). The association between UV susceptibility and squamous cell carcinoma was stronger in betaPV-seropositive people. These combined data support the hypothesis that betaPV may play a role in the development of cutaneous squamous cell carcinoma.


A case of fucosidosis type II: diagnosed with dysmorphological and radiological findings.
Fucosidosis is a rare autosomal recessive lysosomal storage disorder in which fucose-containing glycolipids, glycoproteins and oligosaccharides accumulate in tissues, as a result of a deficiency of α-L-fucosidase. In this report we describe clinical, dysmorphological and radiological findings of a boy with this disorder. Developmental delay, skeletal deformities and mild coarsening of the face began at two years of age. Clinical signs typical for fucosidosis evolved over time. Psychomotor deterioration progressed slowly. At age 12, he could not walk without help; he was admitted to the hospital with intellectual disability, short stature and coarse facial features. A skeletal survey showed dysostosis multiplex. Cranial MRI demonstrated high intensities on the periventricular white matter and low intensities on the basal ganglia on T2-weighted images. Despite the absence of angiokeratoma on the skin, type II fucosidosis with clinical, dysmorphological and radiological signs was suspected. The diagnosis was established on the basis of severely decreased activity of α-L-fucosidase in the leukocytes. The natural history and specific dysmorphic and radiological findings should, even in the absence of angiokeratoma, assist in the differential diagnosis of this rare condition when lysosomal storage disorders are suspected, particularly in populations in which consanguineous marriages are common.


The Impact of Survey and Response Modes on Current Smoking Prevalence Estimates Using TUS-CPS: 1992-2003.
This study identified whether survey administration mode (telephone or in-person) and respondent type (self or proxy) result in discrepant prevalence of current smoking in the adult U.S. population, while controlling for key sociodemographic characteristics and longitudinal changes of smoking prevalence over the 11-year period from 1992-2003. We used a multiple logistic regression analysis with replicate weights to model the current smoking status logit as a function of a number of covariates. The final model included individual- and family-level sociodemographic characteristics, survey attributes, and multiple two-way interactions of survey mode and respondent type with other covariates. The respondent type is a significant predictor of current smoking prevalence and the magnitude of the difference depends on the age, sex, and education of the person whose smoking status is being reported. Furthermore, the survey mode has significant interactions with survey year, sex, and age. We conclude that using an overall unadjusted estimate of the current smoking prevalence may result in underestimating the current smoking rate when conducting proxy or telephone interviews especially for some sub-populations, such as young adults. We propose that estimates could be improved if more detailed information regarding the respondent type and survey administration mode characteristics were considered in addition to commonly used survey year and sociodemographic characteristics. This information is critical given that future surveillance is moving toward more complex designs. Thus, adjustment of estimates should be contemplated when comparing current smoking prevalence results within a given survey series with major changes in methodology over time and between different surveys using various modes and respondent types.


Mitotic apparatus: the selective extraction of protein with mild acid.
The treatment of isolated mitotic apparatus with mild (pH 3) hydrochloric acid results in the extraction of less than 10 percent of its protein, accompanied by the selective morphological disappearance of the microtubules. The same extraction can be shown to dissolve outer doublet microtubules from sperm flagella. A protein with points of similarity to the flagellar microtubule protein is the major component of the extract from mitotic apparatus.


Dianhydrogalactitol and cisplatin in combination for advanced cancer of the uterine cervix.
Eighteen evaluable patients with squamous cancer of the uterine cervix recurrent after radiation therapy or with distant metastases were treated with dianhydrogalactitol (150 mg/m2) and cisplatin (DDP) (50 mg/m2), both given iv every 3 weeks. Only 39% of the patients responded, a result no better than that previously reported for DDP alone and only one-half as good as that previously reported by our group for a combination of this drug with mitomycin, vincristine, and bleomycin. Responses lasted a median of only 5 months. Hematologic toxicity was life-threatening in 22% of the patients and was severe in all but 11% of the remaining patients. We conclude that the addition of substantial and toxic doses of dianhydrogalactitol to DDP failed to substantially enhance the rate, quality, or duration of response compared to DDP alone.


Natural products: potential for developing Phellodendron amurense bark extract for prostate cancer management.
Our ability to detect and treat most primary cancers has improved dramatically given the advances in our understanding of cancer biology. However, with increased life expectancy and our inability to treat or cure advanced stages of cancers, the number of cancer-related deaths is expected to double in the next decade. Epidemiological studies suggest that dietary factors are an important aspect that influences cancer risk. Despite a lack of scientific evidence in most cases, cancer patients have whole-heartedly accepted the concept of "alternative medicine" using natural compounds and spent more than $1B a year on herbal supplements. Given the significant toxicity-associated problems with current long-term standard of care, scientifically validated natural supplements can serve as novel and effective alternative strategies for effective cancer management. We will discuss the utility of natural products in modulating critical signaling pathways for effective cancer prevention with special emphasis on prostate cancer and their potential translational benefit.


The Site of Oxygen Delivery Into a Home Ventilator Affects Recorded Volumes.
Long-term home mechanical ventilation is increasingly used by patients with chronic respiratory failure. Storage of medical data in the cloud is expanding, and ventilation can be monitored remotely. The aim of this bench study was to determine whether tidal volume (VT) can be affected by the location of supplemental oxygen placement. We tested 4 home ventilators in a bench test using a dual-chamber test lung to test the addition of supplemental oxygen placement via a connector in the circuit (ie, front intake port) versus via the manufacturer's rear intake port, with different oxygen supply flows of 2, 4, 6, and 8 L/min. We compared the effectively delivered VT as measured with a pneumotachograph (ie, measured VT) versus the VT reported by each home ventilator (ie, monitored VT). For all of the home ventilators, the monitored VT and measured VT were comparable when the rear oxygen intake was used, regardless of oxygen flow. However, when the front oxygen intake was used, the monitored VT as measured by the ventilators was significantly lower than the measured VT, with the greatest difference reaching 29% for the highest oxygen flow tested (8 L/min). The monitored VT may be inaccurate if oxygen is added with a connector in the circuit, which may have consequences on both the individual level and collective level (ie, big data analysis). Physicians who analyze data from home ventilators should be aware of the site of oxygen supplementation and promote use of only the rear oxygen intake.


Pediatric Fulminant Leptospirosis Complicated by Pericardial Tamponade, Macrophage Activation Syndrome and Sclerosing Cholangitis.
Leptospirosis is a zoonotic infectious disease caused by pathogenic spirochetes of the genus Leptospira. Although it is usually asymptomatic and self-limited, severe potentially fatal illness accompanied by multi-organ failure may occur. Here we report an unusual case of severe leptospirosis successfully treated with continuous venovenous hemofiltration (CVVHF) and therapeutic plasma exchange (TPE). The patient presented with pericardial tamponade, renal failure and macrophage activation syndrome, and later suffered prolonged jaundice and sclerosing cholangitis during hospitalization in the pediatric intensive care unit (PICU). To the best of our knowledge, sclerosing cholangitis due to leptospirosis has not been reported in the literature. Leptospirosis should be kept in mind in the differential diagnosis of sepsis and septic shock with fever, thrombocytopenia, jaundice and renal failure. TPE and CVVHF should start early after the diagnosis of leptospirosis with multiorgan failure.


Prior elicitation and Bayesian analysis of the Steroids for Corneal Ulcers Trial.
To elicit expert opinion on the use of adjunctive corticosteroid therapy in bacterial corneal ulcers. To perform a Bayesian analysis of the Steroids for Corneal Ulcers Trial (SCUT), using expert opinion as a prior probability. The SCUT was a placebo-controlled trial assessing visual outcomes in patients receiving topical corticosteroids or placebo as adjunctive therapy for bacterial keratitis. Questionnaires were conducted at scientific meetings in India and North America to gauge expert consensus on the perceived benefit of corticosteroids as adjunct treatment. Bayesian analysis, using the questionnaire data as a prior probability and the primary outcome of SCUT as a likelihood, was performed. For comparison, an additional Bayesian analysis was performed using the results of the SCUT pilot study as a prior distribution. Indian respondents believed there to be a 1.21 Snellen line improvement, and North American respondents believed there to be a 1.24 line improvement with corticosteroid therapy. The SCUT primary outcome found a non-significant 0.09 Snellen line benefit with corticosteroid treatment. The results of the Bayesian analysis estimated a slightly greater benefit than did the SCUT primary analysis (0.19 lines verses 0.09 lines). Indian and North American experts had similar expectations on the effectiveness of corticosteroids in bacterial corneal ulcers; that corticosteroids would markedly improve visual outcomes. Bayesian analysis produced results very similar to those produced by the SCUT primary analysis. The similarity in result is likely due to the large sample size of SCUT and helps validate the results of SCUT.


[Characterization of the leadership subject areas in the respiratory field in Spain].
The aim of this study was to characterize the leading topics in respiratory system in Spain through a bibliometric analysis. For identify and characterize the performance of the different research topics in respiratory system in Spain, we compile the production using a journal that turn out representative of a broad group of researcher. In this sense the journal Archivos de Bronconeumología is the most important publication in Spanish language of this field. A total of 2198 articles published in Archivos Bronconeumología from 1970 to 2000 were analyzed. In each three decades, we did not found differences except in the productivity index in oncology in the eighty decade and in respiratory failure and sleep disturbance (RFSD) and oncology areas in the ninetieth decade and in the Price index (consumption indicators) in the diagnostic and therapeutic techniques area in seventy decade. When we compare the productivity index of each subject areas between decades, we found a significant production increase in the ninetieth decade in asthma, RFSD, tuberculosis, non tuberculosis infection, circulation, oncology, pleural disease and interstitial areas versus the same in seventy decade, and also, we found significant differences between ninetieth and eighty decades in the asthma, RFSD, non tuberculosis infection, circulation and pleural disease areas. Tuberculosis area maintains an insularity index higher than the other areas. We also found a progressive increase in the insularity index of RFSD, non tuberculosis infection, oncology and interstitial disease areas. In general all the indicators maintains stable although the more productivity topics were respiratory failure and sleep disturbances, and oncology. The productivity has increased in asthma, respiratory failure and sleep disturbances, tuberculosis, non - tuberculosis respiratory infections, oncology, pulmonary circulation, pleura and interstitial disease.


In situ identification and quantification of starch-hydrolyzing bacteria attached to barley and corn grain in the rumen of cows fed barley-based diets.
Cereal grains rich in starch are widely used to meet the energy demands of high-producing beef and dairy cattle. Bacteria are important players in starch digestion in the rumen, and thus play an important role in the hydrolysis and fermentation of cereal grains. However, our understanding of the composition of the rumen starch-hydrolyzing bacteria (SHB) is limited. In this study, BODIPY FL DQ starch staining combined with fluorescence in situ hybridization (FISH) and quantitative FISH were applied to label, identify and quantify SHB possessing active cell-surface-associated (CSA) α-amylase activity in the rumen of heifers fed barley-based diets. When individual cells of SHB with active CSA α-amylase activity were enumerated, they constituted 19-23% of the total bacterial cells attached to particles of four different cultivars of barley grain and corn. Quantitative FISH revealed that up to 70-80% of these SHB were members of Ruminococcaceae in the phylum Firmicutes but were not Streptococcus bovis, Ruminobacter amylophilus, Succinomonas amylolytica, Bifidobacterium spp. or Butyrivibrio fibrisolvens, all of whose amylolytic activities have been demonstrated previously in vitro. The proportion of barley grain in the diet had a large impact on the percentage abundance of total SHB and Ruminococcaceae SHB in these animals.


Interaction of polyphenols with proteins: binding of (-)-epigallocatechin gallate to serum albumin, estimated by induced circular dichroism.
The binding of (-)-epigallocatechin gallate (EGCG), a representative natural polyphenol, to human serum albumin (HSA) and bovine serum albumin (BSA) was investigated using induced circular dichroism (CD). The site of the binding EGCG-HSA was analyzed based on the competition with drugs with known binding sites on HSA, such as phenylbutazone (PB) and diazepam (DP). Double-reciprocal plot analyses showed the competitive relations with the site-I- (PB and tolbutamide, TB) and site-II-binding drugs (DP and ibuprofen, IP) indicating the binding of EGCG to sites I and II on HSA, while digitoxin (DG), a site-III-binding drug, did not affect the binding of EGCG. In an analogous way, the competitive relations were observed between EGCG and the site-I- (PB and TB) and site-II-binding (ethacrynic acid, EA) drugs for the binding of EGCG and BSA. The site-III drug DG also showed competitive binding with EGCG to BSA. The binding of EGCG to the albumins indicated its affinity to sites I and II on HSA, while competitive binding for all three sites was observed on BSA.


In silico study on binding specificity of gonadotropins and their receptors: design of a novel and selective peptidomimetic for human follicle stimulating hormone receptor.
Gonadotropins bind to specific receptors in spite of sharing a high level of sequence and structural similarity. This specific binding is crucial for maintaining the reproductive health of an organism. In this study, residues that dictate the receptor binding specificity of the gonadotropins (FSH and LH) have been identified using combination of in silico methods. Docking studies (ZDOCK), based on the systematic replacement of these residues, confirmed its importance in receptor binding. An interesting observation is that the relative positioning of the residues conferring binding specificity varied for the gonadotropin-receptor complexes. This spatial difference of the key residues could be exploited for design of specific modulators. Based on the identified residues, we have rationally designed a peptidomimetic (FSHP) that displays good binding affinity and specificity for hFSHR. FSHP was developed by screening 3.9 million compounds using pharmacophore-shape similarity followed by fragment-based approach. It was observed that FSHP and hFSHâ can share the same receptor binding site thereby mimicking the native hFSHR-FSH interactions. FSHP also displayed higher binding affinity to hFSHR as compared to two reported hFSHR antagonists. MD simulation studies on hFSHR-FSHP complex revealed that FSHP is conformationally rigid and the intermolecular interactions are maintained during the course of simulation.


Improved Monte Carlo methods for estimating confidence intervals for eleven commonly used health disparity measures.
Health disparities are commonplace and of broad interest to policy makers, but are also challenging to measure and communicate. The Health Disparity Calculator software (HD*Calc, v1.2.4) offers Monte Carlo simulation (MCS)-based confidence interval (CI) estimation of eleven disparity measures. The MCS approach provides accurate CI estimation, except when data are scarce (e.g., rare cancers). To address sparse data challenges to CI estimation, we propose two solutions: 1) employing the gamma distribution in the MCS and 2) utilizing a zero-inflated Poisson estimate for Poisson sampling in simulation experiments. We evaluate each solution through simulation studies using female breast, female brain, lung, and cervical cancer data from the Surveillance, Epidemiology, and End Results (SEER) program. We compare the coverage probabilities (CPs) of eleven health disparity measures based on simulated datasets. The truncated normal distribution implemented in the MCS with the standard Poisson samples (the default setting of HD*Calc) leads to less-than-optimal coverage probabilities (<95%). When both the gamma distribution and the estimated mean from the zero-inflated Poisson are used for the MCS, the coverage probabilities are close to the nominal level of 95%. Simulation studies also demonstrate that collapsing age categories for better CI estimation is not a pragmatic solution.


Experimental verification of the modified spring-mass theory of fiber Bragg grating accelerometers using transverse forces.
A fiber Bragg grating (FBG) accelerometer using transverse forces is more sensitive than one using axial forces with the same mass of the inertial object, because a barely stretched FBG fixed at its two ends is much more sensitive to transverse forces than axial ones. The spring-mass theory, with the assumption that the axial force changes little during the vibration, cannot accurately predict its sensitivity and resonant frequency in the gravitational direction because the assumption does not hold due to the fact that the FBG is barely prestretched. It was modified but still required experimental verification due to the limitations in the original experiments, such as the (1) friction between the inertial object and shell; (2) errors involved in estimating the time-domain records; (3) limited data; and (4) large interval ~5 Hz between the tested frequencies in the frequency-response experiments. The experiments presented here have verified the modified theory by overcoming those limitations. On the frequency responses, it is observed that the optimal condition for simultaneously achieving high sensitivity and resonant frequency is at the infinitesimal prestretch. On the sensitivity at the same frequency, the experimental sensitivities of the FBG accelerometer with a 5.71 gram inertial object at 6 Hz (1.29, 1.19, 0.88, 0.64, and 0.31 nm/g at the 0.03, 0.69, 1.41, 1.93, and 3.16 nm prestretches, respectively) agree with the static sensitivities predicted (1.25, 1.14, 0.83, 0.61, and 0.29 nm/g, correspondingly). On the resonant frequency, (1) its assumption that the resonant frequencies in the forced and free vibrations are similar is experimentally verified; (2) its dependence on the distance between the FBG's fixed ends is examined, showing it to be independent; (3) the predictions of the spring-mass theory and modified theory are compared with the experimental results, showing that the modified theory predicts more accurately. The modified theory can be used more confidently in guiding its design by predicting its static sensitivity and resonant frequency, and may have applications in other fields for the scenario where the spring-mass theory fails.


Relevance of the antibody response against human immunodeficiency virus type 1 envelope to vaccine design.
Understanding the antibody response in HIV-1 infection is important to vaccine design. We have studied the antibody response to HIV-1 envelope at the molecular level and determined the characteristics of neutralizing and non-neutralizing antibodies. These antibodies were isolated from phage display libraries prepared from long-term seropositive asymptomatic individuals. The HIV-1 envelope is presented to the immune system in several antigenically distinct configurations: unprocessed gp160, gp120 and gp41 subunits and native envelope, each of which may be important in eliciting an antibody response in HIV-1 infection. The antibodies tested characteristically had poor affinities for native envelope as expressed on the surface of virions or infected cells, but had high affinities against non-native forms of HIV-1 envelope (viral debris). An exceptionally potent neutralizing antibody in contrast, bound native envelope with equivalent or somewhat higher affinity than this. This indicates that the antibody response in HIV-1 infection is principally elicited by viral debris rather than virions, and that these antibodies bind and neutralize viruses sub-optimally. Potential vaccines should be designed to elicit responses against native envelope.


Purkinje cell NMDA receptors assume a key role in synaptic gain control in the mature cerebellum.
A classic view in cerebellar physiology holds that Purkinje cells do not express functional NMDA receptors and that, therefore, postsynaptic NMDA receptors are not involved in the induction of long-term depression (LTD) at parallel fiber (PF) to Purkinje cell synapses. Recently, it has been demonstrated that functional NMDA receptors are postsynaptically expressed at climbing fiber (CF) to Purkinje cell synapses in mice, reaching full expression levels at ∼2 months after birth. Here, we show that in the mature mouse cerebellum LTD (induced by paired PF and CF activation), but not long-term potentiation (LTP; PF stimulation alone) at PF to Purkinje cell synapses is blocked by bath application of the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid (D-APV). A blockade of LTD, but not LTP, was also observed when the noncompetitive NMDA channel blocker MK-801 was added to the patch-pipette saline, suggesting that postsynaptically expressed NMDA receptors are required for LTD induction. Using confocal calcium imaging, we show that CF-evoked calcium transients in dendritic spines are reduced in the presence of D-APV. This observation confirms that NMDA receptor signaling occurs at CF synapses and suggests that NMDA receptor-mediated calcium transients at the CF input site might contribute to LTD induction. Finally, we performed dendritic patch-clamp recordings from rat Purkinje cells. Dendritically recorded CF responses were reduced when D-APV was bath applied. Together, these data suggest that the late developmental expression of postsynaptic NMDA receptors at CF synapses onto Purkinje cells is associated with a switch toward an NMDA receptor-dependent LTD induction mechanism.


Neutrophil ageing is regulated by the microbiome.
Blood polymorphonuclear neutrophils provide immune protection against pathogens, but may also promote tissue injury in inflammatory diseases. Although neutrophils are generally considered to be a relatively homogeneous population, evidence for heterogeneity is emerging. Under steady-state conditions, neutrophil heterogeneity may arise from ageing and replenishment by newly released neutrophils from the bone marrow. Aged neutrophils upregulate CXCR4, a receptor allowing their clearance in the bone marrow, with feedback inhibition of neutrophil production via the IL-17/G-CSF axis, and rhythmic modulation of the haematopoietic stem-cell niche. The aged subset also expresses low levels of L-selectin. Previous studies have suggested that in vitro-aged neutrophils exhibit impaired migration and reduced pro-inflammatory properties. Here, using in vivo ageing analyses in mice, we show that neutrophil pro-inflammatory activity correlates positively with their ageing whilst in circulation. Aged neutrophils represent an overly active subset exhibiting enhanced αMβ2 integrin activation and neutrophil extracellular trap formation under inflammatory conditions. Neutrophil ageing is driven by the microbiota via Toll-like receptor and myeloid differentiation factor 88-mediated signalling pathways. Depletion of the microbiota significantly reduces the number of circulating aged neutrophils and dramatically improves the pathogenesis and inflammation-related organ damage in models of sickle-cell disease or endotoxin-induced septic shock. These results identify a role for the microbiota in regulating a disease-promoting neutrophil subset.


Restoration of afforested peatland: Immediate effects on aquatic carbon loss.
Peatland restoration is undertaken to bring back key peatland ecosystem services, including carbon storage. In the case of drained, afforested blanket peatlands, restoration through drain blocking and tree removal may impact upon aquatic carbon concentrations and export, which needs to be accounted for when considering the carbon benefits of restoration. This study investigated concentrations and export of aquatic carbon from a drained, afforested blanket bog catchment, where 12% of the catchment underwent drain blocking and conifer removal (termed 'forest-to-bog' restoration), and from two control catchments: one in open bog and one that remained afforested. Using a before-after-control-impact (BACI) design, we found no significant increases in concentrations or export of aquatic carbon (DOC, POC or DIC) in the first year following forest-to-bog restoration (i.e. across the whole post-restoration period). However, increased DOC concentrations were observed in the first summer (2015) post-restoration, and seasonally increased DOC export was noted during storm events in the autumn of the same year. The lack of significant effects of forest-to-bog restoration on aquatic carbon export may be a consequence of the small proportion of the catchment (12%) undergoing management. In terms of management, the removal of more of the forestry residues (i.e., brash) may help to mitigate effects on aquatic carbon, by removing a potential DOC and POC source. Restoring small areas at a time (≤12%) should result in minimal aquatic carbon export issues, in contexts similar to the current study.


N-Heterocyclic carbene transition metal complexes for catalysis in aqueous media.
The last decade has seen an increasing number of reports on the use of NHC-metal complexes for catalysis in water, therefore this review is aimed to introduce the whole research on this area, in which the use of water or aqueous/organic media is to be applied. Since the first discovery of the NHC carbenes by Arduengo, work on the synthesis of NHC-metal organometallic compounds has revolutionized the field of catalysis, gradually displacing the typical phosphine and amine-type ligands in view of their higher stability and reactivity. Aqueous catalysis has become a hot topic in Green Chemistry due to the positive implications for the use of water as reaction media.


Estimating influenza attack rates in the United States using a participatory cohort.
We considered how participatory syndromic surveillance data can be used to estimate influenza attack rates during the 2012-2013 and 2013-2014 seasons in the United States. Our inference is based on assessing the difference in the rates of self-reported influenza-like illness (ILI, defined as presence of fever and cough/sore throat) among the survey participants during periods of active vs. low influenza circulation as well as estimating the probability of self-reported ILI for influenza cases. Here, we combined Flu Near You data with additional sources (Hong Kong household studies of symptoms of influenza cases and the U.S. Centers for Disease Control and Prevention estimates of vaccine coverage and effectiveness) to estimate influenza attack rates. The estimated influenza attack rate for the early vaccinated Flu Near You members (vaccination reported by week 45) aged 20-64 between calendar weeks 47-12 was 14.7%(95% CI(5.9%,24.1%)) for the 2012-2013 season and 3.6%(-3.3%,10.3%) for the 2013-2014 season. The corresponding rates for the US population aged 20-64 were 30.5% (4.4%, 49.3%) in 2012-2013 and 7.1%(-5.1%, 32.5%) in 2013-2014. The attack rates in women and men were similar each season. Our findings demonstrate that participatory syndromic surveillance data can be used to gauge influenza attack rates during future influenza seasons.


Survival of autologous osteochondral grafts in the knee and factors influencing outcome.
The primary aim of this retrospective study was to determine the medium-term survival of autologous osteochondral grafts (mosaicplasty) in the knee. The secondary aims were to evaluate any reason for failure, and to ascertain if age, gender, BMI, previous or associated knee surgery, site or size of the osteochondral graft had any influence on outcome. Fifty-five patients undergoing an autologous osteochondral graft procedure between 1999 and 2008 were evaluated, with a mean follow-up of 5.9 years (range 0.5 to 10.5). Loosening, graft degeneration or subsequent surgery in the form of arthroplasty, revision autologous osteochondral graft or any other osteochondral procedure, and an Oxford knee score above 49.7 (see text) were considered as failure. Kaplan-Meier analysis demonstrated an 87.5% survival at 8 years (95% CI 72% to 97%). The mean Oxford score at follow-up was 163% (95% CI 10.6% to 22.1%) at follow-up. Two of 6 failures occurred in patients with varus malalignment. Linear regression analysis demonstrated an improved outcome in Oxford knee score in younger patients. Gender, BMI, previous or associated knee surgery, site and size of the graft had no influence on outcome. The authors consider autologous osteochondral grafting as a reliable method of treatment in the medium-term for young patients with small contained articular cartilage lesions up to 4 cm2. Careful attention should be paid to the mechanical axis (varus) prior to grafting. Long-term studies are necessary.


Prediction of central venous catheter-related bloodstream infections (CRBSIs) in patients with haematologic malignancies using a modified Infection Probability Score (mIPS).
The aim of this study was to predict the probability of central venous catheter-related bloodstream infections (CRBSIs) in patients with haematologic malignancies using a modified version of the Infection Probability Score (mIPS). In order to perform a prospective, mono-centric surveillance of complications in clinical routine due to short-term central venous catheters (CVCs) in consecutive patients receiving chemotherapy from March 2013 to September 2014, IPS was calculated at CVC insertion and removal (mIPSin and mIPSex, respectively). We used the 2012 Infectious Diseases Working Party of the German Society of Haematology and Medical Oncology (AGIHO/DGHO) criteria to define CRBSI. In total, 143 patients (mean 59.5 years, 61.4 % male) with 267 triple-lumen CVCs (4044 CVC days; mean 15.1 days, range 1-60 days) were analysed. CVCs were inserted for therapy of acute leukaemia (53.2 %), multiple myeloma (24.3 %) or lymphoma (11.2 %), and 93.6 % were inserted in the jugular vein. A total of 66 CRBSI cases (24.7 %) were documented (12 definite/13 probable/41 possible). The incidence was 16.3/1000 CVC days (2.9/3.1/10.1 per 1000 CVC days for definite/probable/possible CRBSI, respectively). In CRBSI cases, the mIPSex was higher as compared to cases without CRBSI (13.1 vs. 7.1; p < 0.001). The best mIPSex cutoff for CRBSI prediction was 8 points (area under the curve (AUC) = 0.77; sensitivity = 84.9 %, specificity = 60.7 %, negative predictive value = 92.4 %). For patients with an mIPSex ≥8, the risk for a CRBSI was high (odds ratio [OR] = 5.9; p < 0.001) and even increased if, additionally, CVC had been in use for about 10 days (OR = 9.8; p < 0.001). In case other causes of infection are excluded, a mIPSex ≥8 and duration of CVC use of about 10 days predict a very high risk of CRBSI. Patients with a mIPSex <8 have a low risk of CRBSI of 8 %.


Equivalence of phase-oscillator and integrate-and-fire models.
A quantitative comparison of various classes of oscillators (integrate-and-fire, Winfree, and Kuramoto-Daido type) is performed in the weak-coupling limit for a fully connected network of identical units. An almost perfect agreement is found, with only tiny differences among the models. We also show that the regime of self-consistent partial synchronization is rather general and can be observed for arbitrarily small coupling strength in any model class. As a byproduct of our study, we are able to show that an integrate-and-fire model with a generic pulse shape can be always transformed into a similar model with δ pulses and a suitable phase response curve.


Shear shocks in fragile networks.
A minimal model for studying the mechanical properties of amorphous solids is a disordered network of point masses connected by unbreakable springs. At a critical value of its mean connectivity, such a network becomes fragile: it undergoes a rigidity transition signaled by a vanishing shear modulus and transverse sound speed. We investigate analytically and numerically the linear and nonlinear visco-elastic response of these fragile solids by probing how shear fronts propagate through them. Our approach, which we tentatively label shear front rheology, provides an alternative route to standard oscillatory rheology. In the linear regime, we observe at late times a diffusive broadening of the fronts controlled by an effective shear viscosity that diverges at the critical point. No matter how small the microscopic coefficient of dissipation, strongly disordered networks behave as if they were overdamped because energy is irreversibly leaked into diverging nonaffine fluctuations. Close to the transition, the regime of linear response becomes vanishingly small: the tiniest shear strains generate strongly nonlinear shear shock waves qualitatively different from their compressional counterparts in granular media. The inherent nonlinearities trigger an energy cascade from low to high frequency components that keep the network away from attaining the quasi-static limit. This mechanism, reminiscent of acoustic turbulence, causes a superdiffusive broadening of the shock width.


The effect of resonance on transient microbubble acoustic response: Experimental observations and numerical simulations.
A large number of acoustic signals from single lipid-shelled Definity® (Lantheus Medical Imaging, N. Billerica, MA) microbubbles have been measured using a calibrated microacoustic system, and a unique transient characteristic of resonance has been identified in the onset of scatter. Comparison of the numerically obtained response of microbubbles with acoustic measurements provides good agreement for a soft shell that is characterized by small area dilatation modulus and strain softening behavior, and identifies time to maximum radial excursion and scatter as a robust marker of resonance during transient response. As the sound amplitude increases a two-population pattern emerges in the time delay vs the fundamental acoustic scatter plots, consisting of an initial part pertaining to microbubbles with less than resonant rest radii, which corresponds to the weaker second harmonic resonance, and the dominant resonant envelope pertaining to microbubbles with resonant and greater than resonant rest radii, which corresponds to the primary and subharmonic resonances. Consequently, a wider resonant spectrum is observed. It is a result of the strain softening nature of soft lipid shells, based on which the microbubble sizes corresponding to the above resonances decrease as the sound amplitude increases. This bares an impact on the selection of an optimal microbubble size pertaining to subharmonic imaging.


Protective antigens against glanders identified by expression library immunization.
Burkholderia are highly evolved Gram-negative bacteria that primarily infect solipeds but are transmitted to humans by ingestion and cutaneous or aerosol exposures. Heightened concern over human infections of Burkholderia mallei and the very closely related species B. pseudomallei is due to the pathogens' proven effectiveness as bioweapons, and to the increased potential for natural opportunistic infections in the growing diabetic and immuno-compromised populations. These Burkholderia species are nearly impervious to antibiotic treatments and no vaccine exists. In this study, the genome of the highly virulent B. mallei ATCC23344 strain was examined by expression library immunization for gene-encoded protective antigens. This protocol for genomic-scale functional screening was customized to accommodate the unusually large complexity of Burkholderia, and yielded 12 new putative vaccine candidates. Five of the candidates were individually tested as protein immunogens and three were found to confer significant partial protection against a lethal pulmonary infection in a murine model of disease. Determinations of peripheral blood cytokine and chemokine profiles following individual protein immunizations show that interleukin-2 (IL-2) and IL-4 are elicited by the three confirmed candidates, but unexpectedly interferon-γ and tumor necrosis factor-α are not. We suggest that these pathogen components, discovered using genetic immunization and confirmed in a conventional protein format, will be useful toward the development of a safe and effective glanders vaccine.


Examining the Limits of Predictability of Human Mobility.
We challenge the upper bound of human-mobility predictability that is widely used to corroborate the accuracy of mobility prediction models. We observe that extensions of recurrent-neural network architectures achieve significantly higher prediction accuracy, surpassing this upper bound. Given this discrepancy, the central objective of our work is to show that the methodology behind the estimation of the predictability upper bound is erroneous and identify the reasons behind this discrepancy. In order to explain this anomaly, we shed light on several underlying assumptions that have contributed to this bias. In particular, we highlight the consequences of the assumed Markovian nature of human-mobility on deriving this upper bound on maximum mobility predictability. By using several statistical tests on three real-world mobility datasets, we show that human mobility exhibits scale-invariant long-distance dependencies, contrasting with the initial Markovian assumption. We show that this assumption of exponential decay of information in mobility trajectories, coupled with the inadequate usage of encoding techniques results in entropy inflation, consequently lowering the upper bound on predictability. We highlight that the current upper bound computation methodology based on Fano's inequality tends to overlook the presence of long-range structural correlations inherent to mobility behaviors and we demonstrate its significance using an alternate encoding scheme. We further show the manifestation of not accounting for these dependencies by probing the mutual information decay in mobility trajectories. We expose the systematic bias that culminates into an inaccurate upper bound and further explain as to why the recurrent-neural architectures, designed to handle long-range structural correlations, surpass this upper limit on human mobility predictability.


Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma.
This phase 1/2 trial evaluated the maximum tolerated doses, safety, and efficacy of pomalidomide, bortezomib, and dexamethasone (PVD) combination in patients with relapsed lenalidomide-refractory multiple myeloma (MM). In phase 1, dose level 1 consisted of pomalidomide (4 mg by mouth on days 1 to 21), IV or subcutaneous bortezomib (1.0 mg/m2 on days 1, 8, 15, and 22), and dexamethasone (40 mg by mouth on days 1, 8, 15, and 22) given every 28 days. Bortezomib was increased to 1.3 mg/m2 for dose level 2 and adopted in the phase 2 expansion cohort. We describe the results of 50 patients. Objective response rate was 86% (95% confidence interval [CI], 73-94) among all evaluable patients (stringent complete response, 12%; complete response, 10%; very good partial response, 28%; and partial response, 36%) and 100% among high-risk patients. Within a median follow-up of 42 months, 20% remain progression free, 66% are alive, and 4% remain on treatment. Median progression-free survival was 13.7 months (95% CI, 9.6-17.7). The most common toxicities were neutropenia (96%), leukopenia (84%), thrombocytopenia (82%), anemia (74%), and fatigue (72%); however, the majority of these were grade 1 or 2. The most common grade ≥3 toxicities included neutropenia (70%), leukopenia (36%), and lymphopenia (20%). Deep vein thrombosis occurred in 5 patients. In conclusion, PVD is a highly effective combination in lenalidomide-refractory MM patients. Weekly administration of bortezomib enhanced tolerability and convenience. Toxicities are manageable, mostly consisting of mild cytopenias with no significant neuropathy. This trial was registered at www.clinicaltrials.gov as #NCT01212952.


The FLUSH study--flush the line and ultrasound the heart: ultrasonographic confirmation of central femoral venous line placement.
Inadvertent arterial placement of a femoral venous catheter may result in serious morbidity, including limb necrosis. The Flush the Line and Ultrasound the Heart (FLUSH) test is visualization of the heart by a subxiphoid ultrasonic view while the central catheter is flushed with agitated saline solution. We wish to determine whether the FLUSH test can verify proper femoral venous line placement. We prospectively studied a convenience sample of children undergoing cardiac catheterization, for whom both femoral venous and arterial access were part of their standard care. The cardiologist flushed manually agitated saline solution through each catheter in randomized sequence while the blinded physician sonographer recorded the presence or absence of right atrial opacification. We calculated the sensitivity and specificity of the FLUSH test relative to our reference standard, the cardiologist's fluoroscopic visualization of catheter wire placement. Of the 51 subjects enrolled, the FLUSH test was 100% sensitive (95% confidence interval 95% to 100%) and 90.3% specific (95% confidence interval 81% to 96%) in confirming femoral catheter placement. In no case was an arterial flush misidentified as a femoral flush. The interrater reliability of the test was strong: κ 0.82 for all images and 0.9 for those of good quality. The FLUSH test is simple and reliable, and appears to accurately confirm femoral venous line placement.


A review of the literature: midwifery decision-making and birth.
Clinical decision-making was initially studied in medicine where hypothetico-deductive reasoning is the model for decision-making. The nursing perspective on clinical decision-making has largely been shaped by Patricia Benner's ground breaking work. Benner claimed expert nurses use humanistic-intuitive ways of making clinical decisions rather than the 'rational reasoning' as claimed by medicine. Clinical decision-making in midwifery is not the same as either nursing or medical decision-making because of the woman-midwife partnership where the woman is the ultimate decision-maker. CINHAL, Medline and Cochrane databases were systematically searched using key words derived from the guiding question. A review of the decision-making research literature in midwifery was undertaken where studies were published in English. The selection criteria for papers were: only research papers of direct relevance to the guiding research question were included in the review. Decision-making is under-researched in midwifery and more specifically birth, as only 4 research articles met the inclusion criteria in this review. Three of the studies involved qualified midwives, and one involved student midwives. Two studies were undertaken in England, one in Scotland and one in Sweden. The major findings synthesised from this review, are that; (1) midwifery decision-making during birth is socially negotiated involving hierarchies of surveillance and control; (2) the role of the woman in shared decision-making during birth has not been explored by midwifery research; (3) clinical decision-making encompasses clinical reasoning as essential but not sufficient for midwives to actually implement their preferred decision. We argue that existing research does not inform the discipline of the complexity of midwifery clinical decision-making during birth. A well-designed study would involve investigating the clinical reasoning skills of the midwife, her relationship with the woman, the context of the particular birthing unit and the employment status of the midwife. The role of the woman as decision-maker in her own care during birth also needs careful research attention.


Omega-3 fatty acids from fish oil lower anxiety, improve cognitive functions and reduce spontaneous locomotor activity in a non-human primate.
Omega-3 (ω3) polyunsaturated fatty acids (PUFA) are major components of brain cells membranes. ω3 PUFA-deficient rodents exhibit severe cognitive impairments (learning, memory) that have been linked to alteration of brain glucose utilization or to changes in neurotransmission processes. ω3 PUFA supplementation has been shown to lower anxiety and to improve several cognitive parameters in rodents, while very few data are available in primates. In humans, little is known about the association between anxiety and ω3 fatty acids supplementation and data are divergent about their impact on cognitive functions. Therefore, the development of nutritional studies in non-human primates is needed to disclose whether a long-term supplementation with long-chain ω3 PUFA has an impact on behavioural and cognitive parameters, differently or not from rodents. We address the hypothesis that ω3 PUFA supplementation could lower anxiety and improve cognitive performances of the Grey Mouse Lemur (Microcebus murinus), a nocturnal Malagasy prosimian primate. Adult male mouse lemurs were fed for 5 months on a control diet or on a diet supplemented with long-chain ω3 PUFA (n = 6 per group). Behavioural, cognitive and motor performances were measured using an open field test to evaluate anxiety, a circular platform test to evaluate reference spatial memory, a spontaneous locomotor activity monitoring and a sensory-motor test. ω3-supplemented animals exhibited lower anxiety level compared to control animals, what was accompanied by better performances in a reference spatial memory task (80% of successful trials vs 35% in controls, p<0.05), while the spontaneous locomotor activity was reduced by 31% in ω3-supplemented animals (p<0.001), a parameter that can be linked with lowered anxiety. The long-term dietary ω3 PUFA supplementation positively impacts on anxiety and cognitive performances in the adult mouse lemur. The supplementation of human food with ω3 fatty acids may represent a valuable dietary strategy to improve behavioural and cognitive functions.


Wild mice with different social network sizes vary in brain gene expression.
Appropriate social interactions influence animal fitness by impacting several processes, such as mating, territory defense, and offspring care. Many studies shedding light on the neurobiological underpinnings of social behavior have focused on nonapeptides (vasopressin, oxytocin, and homologues) and on sexual or parent-offspring interactions. Furthermore, animals have been studied under artificial laboratory conditions, where the consequences of behavioral responses may not be as critical as when expressed under natural environments, therefore obscuring certain physiological responses. We used automated recording of social interactions of wild house mice outside of the breeding season to detect individuals at both tails of a distribution of egocentric network sizes (characterized by number of different partners encountered per day). We then used RNA-seq to perform an unbiased assessment of neural differences in gene expression in the prefrontal cortex, the hippocampus and the hypothalamus between these mice with naturally occurring extreme differences in social network size. We found that the neurogenomic pathways associated with having extreme social network sizes differed between the sexes. In females, hundreds of genes were differentially expressed between animals with small and large social network sizes, whereas in males very few were. In males, X-chromosome inactivation pathways in the prefrontal cortex were the ones that better differentiated animals with small from those with large social network sizes animals. In females, animals with small network size showed up-regulation of dopaminergic production and transport pathways in the hypothalamus. Additionally, in females, extracellular matrix deposition on hippocampal neurons was higher in individuals with small relative to large social network size. Studying neural substrates of natural variation in social behavior in traditional model organisms in their habitat can open new targets of research for understanding variation in social behavior in other taxa.


Measuring the contribution of atmospheric scatter to laser eye dazzle.
An experiment has been conducted to determine the contribution of atmospheric scatter to the severity of the dazzle experienced by a human under illumination from a visible laser. A 15 W 532 nm laser was propagated over a 380 m outdoor range in San Antonio, Texas, over nine data collection sessions spanning June and July 2014. A narrow acceptance angle detector was used to measure scattered laser radiation within the laser beam at different angles from its axis. Atmospheric conditions were logged via a local weather station, and air quality data were taken from a nearby continuous air monitoring station. The measured laser irradiance data showed very little variation across the sessions and a single fitting equation was derived for the atmospheric scatter function. With very conservative estimates of the scatter from the human eye, atmospheric scatter was found to contribute no more than 5% to the overall veiling luminance across the scene for a human observer experiencing laser eye dazzle. It was concluded that atmospheric scatter does not make a significant contribution to laser eye dazzle for short-range laser engagements in atmospheres of good to moderate air quality, which account for 99.5% of conditions in San Antonio, Texas.


Arterio-portal shunts in the cirrhotic liver: perfusion computed tomography for distinction of arterialized pseudolesions from hepatocellular carcinoma.
To determine perfusion computed tomography (P-CT) findings for distinction of arterial pseudolesions (APL) from hepatocellular carcinoma (HCC) in the cirrhotic liver. 32 APL and 21 HCC in 20 cirrhotic patients (15 men; 65 ± 10 years), who underwent P-CT for evaluation of HCC pre- (N = 9) or post- (N = 11) transarterial chemoembolization, were retrospectively included using CT follow-up as the standard of reference. All 53 lesions were qualitatively (visual) and quantitatively (perfusion parameters) analysed according to their shape (wedge, irregular, nodular), location (not-/adjunct to a fistula), arterial liver perfusion (ALP), portal venous liver perfusion (PLP), hepatic perfusion index (HPI). Accuracy for diagnosis of HCC was determined using receiver operating characteristics. 18/32 (56 %) APL were wedge shaped, 10/32 (31 %) irregular and 4/32 (12 %) nodular, while 11/21 (52 %) HCC were nodular or 10/21 (48 %) irregular, but never wedge shaped. Significant difference between APL and HCC was seen for lesion shape in pretreated lesions (P < 0.001), and for PLP and HPI in both pre- and post-treated lesions (all, P < 0.001). Diagnostic accuracy for HCC was best for combined assessment of lesion configuration and PLP showing an area under the curve of 0.901. Combined assessment of lesion configuration and portal venous perfusion derived from P-CT allows best to discriminate APL from HCC with high diagnostic accuracy. • Arterio-portal shunting is common in the cirrhotic liver, especially after local treatment. • Arterial pseudolesions (APL) due to shunting might mimic hepatocellular carcinoma (HCC). • Perfusion-CT allows for qualitative and quantitative assessment of liver lesions. • Lesion configuration fails to discriminate APL from HCC in locally treated patients. • Integration of quantitative perfusion analysis improves accuracy for diagnosis of HCC.


The COVID-19 Pandemic Changed the Prevalence of Plastic Surgery in Israel.
In late 2019, a new strain of coronavirus (coronavirus disease 2019 [COVID-19]) spread rapidly throughout the world. The American Society of Plastic Surgeons reported a pandemic-related surge in the demand for aesthetic surgery compared to the same popularity of procedures prior to the pandemic. To determine whether this phenomenon also occurred in Israel. We collected data from three leading private medical centers in Tel Aviv. Data were compared for the years 2019 and 2020 by surgical procedure. Number of orthopedic, gynecologic, and hand procedures served as control data. We present a detailed pandemic-related timeline relevant to aesthetic surgery in Israel. Overall, the demand for aesthetic surgery increased, with a marked trend toward body contouring procedures. The Israeli aesthetic surgery market was affected by the COVID-19 pandemic, with a post-closure surge. The popularity and number of procedures are unique to the Israeli market.


A concise total synthesis of breitfussin A and B.
The first total synthesis of breitfussin A and B is described. The approach features two palladium-catalyzed cross-couplings installing the indole and pyrrole onto the oxazole core and selective lithiation/iodination of a common indole-oxazole fragment providing 2,4-diiodinated or 2-iodinated oxazoles as potential precursors for breitfussin A and B, respectively. An unexpected acid promoted deiodination was utilized in the synthesis of breitfussin B. Comparison of the synthetic material with previously reported spectral data of isolated breitfussin A and B verified the structure of the breitfussin framework.


Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial.
Limited treatment options exist for patients with thymic epithelial tumor (TET) whose disease progresses after platinum-based chemotherapy. We conducted a phase II study of pembrolizumab in patients with TET to evaluate its efficacy and safety. Patients with histologically confirmed TET whose disease progressed after at least one line of platinum-based chemotherapy were eligible for the study. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past year or documented history of clinically severe autoimmune disease. Patients received 200 mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. The primary objective of response rate was assessed every 9 weeks by investigators. Of 33 patients enrolled, 26 had thymic carcinoma and seven had thymoma. Of seven thymoma, two (28.6%; 95% CI, 8.2% to 64.1%) had partial response, and five (71.6%) had stable disease. Of 26 thymic carcinoma, five (19.2%; 95% CI, 8.5% to 37.9%) had partial response and 14 (53.8%) had stable disease. The median progression-free survival was 6.1 months for both groups. The most common adverse events of any grade included dyspnea (11; 33.3%), chest wall pain (10; 30.3%), anorexia (seven; 21.2%), and fatigue (seven; 21.2%). Five (71.4%) of seven patients with thymoma and four (15.4%) of 26 patients with thymic carcinoma reported grade ≥ 3 immune-related adverse events, including hepatitis (four; 12.1%), myocarditis (three; 9.1%), myasthenia gravis (two; 6.1%), thyroiditis (one; 3.0%), antineutrophil cytoplasmic antibody-associated rapidly progressive glomerulonephritis (one; 3.0%), colitis (one; 3.0%), and subacute myoclonus (one; 3.0%). Pembrolizumab showed encouraging antitumor activity in patients with advanced TET. Given the high incidence of autoimmunity, additional studies are needed to identify those who can benefit from pembrolizumab without immune-related adverse events.


Basal Ganglia Activity Mirrors a Benefit of Action and Reward on Long-Lasting Event Memory.
The expectation of reward is known to enhance a consolidation of long-term memory for events. We tested whether this effect is driven by positive valence or action requirements tied to expected reward. Using a functional magnetic resonance imaging (fMRI) paradigm in young adults, novel images predicted gain or loss outcomes, which in turn were either obtained or avoided by action or inaction. After 24 h, memory for these images reflected a benefit of action as well as a congruence of action requirements and valence, namely, action for reward and inaction for avoidance. fMRI responses in the hippocampus, a region known to be critical for long-term memory function, reflected the anticipation of inaction. In contrast, activity in the putamen mirrored the congruence of action requirement and valence, whereas other basal ganglia regions mirrored overall action benefits on long-lasting memory. The findings indicate a novel type of functional division between the hippocampus and the basal ganglia in the motivational regulation of long-term memory consolidation, which favors remembering events that are worth acting for.


Plasma steroid hormone concentrations, aromatase activities and GSI in ranid frogs collected from agricultural and non-agricultural sites in Michigan (USA).
The triazine herbicide atrazine has been hypothesized to disrupt sexual development in frogs by up-regulating aromatase activity, resulting in greater estradiol (E2) concentrations and causing feminization in males. The goal of this study was to collect native ranid frogs from atrazine-exposed ponds and determine whether relationships exist between measured atrazine concentrations and the gonadosomatic index (GSI), plasma concentrations of testosterone (T), E2 or 11-ketotestosterone (KT), or with aromatase activity. In the summer of 2002 and 2003, adult and juvenile green frogs (Rana clamitans), bullfrogs (R. catesbeiana) and Northern leopard frogs (R. pipiens) were collected from areas with extensive corn cultivation and areas where there was little agricultural activity in south-central Michigan. Atrazine concentrations were below the limit of quantification at non-agricultural sites. Atrazine concentrations did not exceed 2 microg/L at most agricultural sites, but a concentration of 250 microg atrazine/L was measured in one sample from one site in 2002. Plasma steroid concentrations varied among locations. Aromatase activity was measurable in less than 11% of testes in adult males, and in less than 4% of testes in juvenile males. Median aromatase activities in ovaries of adult females ranged from 3 to 245 pmol/h/mg protein, and maximum activities were 2.5-fold greater in juveniles than in adults. Atrazine concentrations were not significantly correlated with any of the parameters measured in this study. These results indicate that atrazine does not up-regulate aromatase in green frogs in the wild, and does not appear to affect plasma steroid hormone concentrations.


Projected fringe profilometry using a liquid-crystal spatial light modulator to extend the depth measuring range.
An approach using a liquid-crystal spatial light modulator (LC-SLM) to enlarge the depth measuring range of the projected fringe profilometry is presented. This approach is especially applicable to detect dynamic objects with micro-scale sizes. Compared with a typical 2D image system, the LC-SLM provides a better performance for a 3D shape sensing system. The main advantages include (1) a much higher allowance to increase in the depth measuring range, (2) easiness to compensate perspective distortion and geometric distortion, (3) very high accuracy (in the micron-range) and (4) only one phase measurement needed for operation.


Tracking HCV protease population diversity during transmission and susceptibility of founder populations to antiviral therapy.
Due to the highly restricted species-tropism of Hepatitis C virus (HCV) a limited number of animal models exist for pre-clinical evaluation of vaccines and antiviral compounds. The human-liver chimeric mouse model allows heterologous challenge with clinically relevant strains derived from patients. However, to date, the transmission and longitudinal evolution of founder viral populations in this model have not been characterized in-depth using state-of-the-art sequencing technologies. Focusing on NS3 protease encoding region of the viral genome, mutant spectra in a donor inoculum and individual recipient mice were determined via Illumina sequencing and compared, to determine the effects of transmission on founder viral population complexity. In all transmissions, a genetic bottleneck was observed, although diverse viral populations were transmitted in each case. A low frequency cloud of mutations (<1%) was detectable in the donor inoculum and recipient mice, with single nucleotide variants (SNVs) > 1% restricted to a subset of nucleotides. The population of SNVs >1% was reduced upon transmission while the low frequency SNV cloud remained stable. Fixation of multiple identical synonymous substitutions was apparent in independent transmissions, and no evidence for reversion of T-cell epitopes was observed. In addition, susceptibility of founder populations to antiviral therapy was assessed. Animals were treated with protease inhibitor (PI) monotherapy to track resistance associated substitution (RAS) emergence. Longitudinal analyses revealed a decline in population diversity under therapy, with no detectable RAS >1% prior to therapy commencement. Despite inoculation from a common source and identical therapeutic regimens, unique RAS emergence profiles were identified in different hosts prior to and during therapeutic failure, with complex mutational signatures at protease residues 155, 156 and 168 detected. Together these analyses track viral population complexity at high-resolution in the human-liver chimeric mouse model post-transmission and under therapeutic intervention, revealing novel insights into the evolutionary processes which shape viral protease population composition at various critical stages of the viral life-cycle.


Hydrodynamic advantages of in-line schooling.
Fish benefit energetically when swimming in groups, which is reflected in lower tail-beat frequencies for maintaining a given speed. Recent studies further show that fish save the most energy when swimming behind their neighbor such that both the leader and the follower benefit. However, the mechanisms underlying such hydrodynamic advantages have thus far not been established conclusively. The long-standing drafting hypothesis-reduction of drag forces by judicious positioning in regions of reduced oncoming flow-fails to explain advantages of in-line schooling described in this work. We present an alternate hypothesis for the hydrodynamic benefits of in-line swimming based on enhancement of propulsive thrust. Specifically, we show that an idealized school consisting of in-line pitching foils gains hydrodynamic benefits via two mechanisms that are rooted in the undulatory jet leaving the leading foil and impinging on the trailing foil: (i) leading-edge suction on the trailer foil, and (ii) added-mass push on the leader foil. Our results demonstrate that the savings in power can reach as high as 70% for a school swimming in a compact arrangement. Informed by these findings, we designed a modification of the tail propulsor that yielded power savings of up to 56% in a self-propelled autonomous swimming robot. Our findings provide insights into hydrodynamic advantages of fish schooling, and also enable bioinspired designs for significantly more efficient propulsion systems that can harvest some of their energy left in the flow.


Glycemic index and pregnancy: a systematic literature review.
Background/Aim. Dietary glycemic index (GI) has received considerable research interest over the past 25 years although its application to pregnancy outcomes is more recent. This paper critically evaluates the current evidence regarding the effect of dietary GI on maternal and fetal nutrition. Methods. A systematic literature search using MEDLINE, EMBASE, CINAHL, Cochrane Library, SCOPUS, and ISI Web of Science, from 1980 through September 2010, was conducted. Results. Eight studies were included in the systematic review. Two interventional studies suggest that a low-GI diet can reduce the risk of large-for-gestational-age (LGA) infants in healthy pregnancies, but one epidemiological study reported an increase in small-for-gestational-age (SGA) infants. Evidence in pregnancies complicated by gestational diabetes mellitus (GDM), though limited (n = 3), consistently supports the advantages of a low-GI diet. Conclusion. There is insufficient evidence to recommend a low-GI diet during normal pregnancy. In pregnancy complicated by GDM, a low-GI diet may reduce the need for insulin without adverse effects on pregnancy outcomes. Until larger-scale intervention trials are completed, a low-GI diet should not replace the current recommended pregnancy diets from government and health agencies. Further research regarding the optimal time to start a low-GI diet for maximum protection against adverse pregnancy outcomes is warranted.


Usefulness of subjective ovine milk scores: I. Associations with range ewe characteristics and lamb production.
Range ewes are commonly evaluated for milking ability by producers to determine the ewe's ability to rear lamb(s). The U.S. Sheep Experiment Station has subjectively scored (low, average, high) a ewe's milking ability within 24 h of lambing for many years. The relationship of subjective milk scores with lamb production was investigated using lambing records of Columbia (n = 1,731), Polypay (n = 1,129), Rambouillet (n = 1,704), and Targhee (n = 1,638) ewes. The incidence of high milk scores increased from less than 10% at first parity to 29 to 40% at second and greater parities. At maturity, Columbia ewes (38%) had the highest percentage of high milk scores. A positive association existed between ewe BW and her milk score at third and later parities. Ewes with high milk scores gave birth to heavier lambs (P < 0.05), whereas ewes with low milk scores were associated with lighter (P < 0.05) lambs at birth. Ewes with low milk scores weaned less (P < 0.05) total weight than ewes with better milk scores across all age groups for all breeds. Lighter weaned litter weights from ewes with low milk scores were linked to lighter birth weights and fewer weaned lambs. Differences for litter weight weaned between ewes with average and high milk scores were generally observed at 2 and 3 yr of age, when litter weights were heavier among ewes with high milk scores (P < 0.05) for all breeds. Between the ages of 1 and 3 yr, Columbia, Polypay, Rambouillet, and Targhee ewes with an average milk score weaned heavier (P < 0.05) litters (average differences of 10, 9, 13, and 12%, respectively) than ewes with low milk scores. For all breeds at all ages, individual lamb weaning weights were heavier (P < 0.05) when they were reared by ewes with high milk scores compared to lambs reared by ewes with low milk scores. Results suggest that milk score is an economically important trait in these four breeds and should be considered in management and breeding objectives; at a minimum, the incidence of low milk scores should be kept as small as possible.


Quantitative study of the association thermodynamics and kinetics of DNA-coated particles for different functionalization schemes.
Surface functionalization with complementary single-stranded DNA sticky ends is increasingly used for guiding the self-assembly of nano- and micrometer-sized particles into larger scale ordered structures. Here we present measurements, formulas, and graphs that allow one to quantitatively predict the association behavior of DNA-coated particles from readily available Web-based data. From experiments it appears that the suspension behavior is very sensitive to the grafting details, such as the length and flexibility of the tether constructs and the particles' surface coverage. Thus, if one wants to control the interactions and assembly processes, insight is needed into the structural and dynamical features of the DNA coatings. We demonstrate how a straightforward measurement of the particles' association-dissociation kinetics during selected temperature cycles, combined with a simple quantitative model, can reveal the relevant properties. We used this method in a systematic study where we varied the temperature cycle, the bead concentration, the particles' surface coverage, and the DNA construct. Among other things, we find that the backbone that tethers the sticky ends to the surface can have a significant impact on the particles' dissociation properties, as it affects the total number of interparticle bonds and the configurational entropy cost associated with these bonds. We further find that, independent of the tether backbone, self-complementary "palindromic" sticky ends readily form intraparticle hairpins and loops, which greatly affect the particles' association behavior. Such secondary structure formation is increasingly important in faster temperature quenches, at lower particle concentration, and at lower surface coverage. The latter observations are especially useful for the design of so-called self-protected DNA-mediated interactions, which we pioneered recently and for which we expect to find an increasing use, as they enable more versatile assembly schemes.


Fixed bed reactor for solid-phase surface derivatization of superparamagnetic nanoparticles.
The functionalization of nanoparticles is conditio sine qua non in studies of specific interaction with a biological target. Often, their biological functionality is achieved by covalent binding of bioactive molecules on a preexisting single surface coating. The yield and quality of the resulting coated and functionalized superparamagnetic iron oxide nanoparticles (SPIONs) can be significantly improved and reaction times reduced by using solid-phase synthesis strategies. In this study, a fixed bed reactor with a quadrupole repulsive arrangement of permanent magnets was assayed for SPION surface derivatization. The magnet array around the fixed bed reactor creates very high magnetic field gradients that enables the immobilization of SPIONs with a diameter as low as 9 nm. The functionalization on the surface of immobilized 25 nm 3-(aminopropyl)trimethoxysilane-coated SPIONs (APS-SPIONs) was performed using fluorescein-isothiocyanate directly, and by the SV40 large T-antigen nuclear localization signal peptide (PKKKRKVGC) conjugated to acryloylpoly(ethylene glycol)-N-hydroxysuccinimide, where the PEG reagent is conjugated first to create a functionalized nanoparticle and the peptide is added to the acryloyl group. We show that the yield of reactant grafted on the surface of the APS-coated SPIONs was higher in solid-phase within the fixed bed reactor compared to conventional liquid-phase chemistry. In summary, the functionalization of SPIONs using a magnetically fixed bed reactor was superior to the liquid-phase reaction in terms of the yield, reaction times required for derivatization, size distribution, and scalability.


Content and relative bioavailability of phosphorus in distillers dried grains with solubles in chicks.
Total phosphorus analysis was performed on 20 samples of corn distillers dried grains with solubles (DDGS), and three experiments were conducted to determine the bioavailability of P in different samples of DDGS varying in Lys digestibility and heat processing (autoclaving). Relative bioavailability of P was estimated from tibia ash using the slope ratio method after chicks were fed a P-deficient corn-soybean meal diet supplemented with 0.05 or 0.10% P from KH2PO4 or supplemented with 2 levels of the test DDGS (7 to 25%). The mean total P value for the 20 DDGS samples was 0.73 +/- 0.04% (SD), with an average dry matter value of 88 +/- 0.8% (SD). In experiment 1, the bioavailability coefficient for P in a random sample of DDGS relative to KH2PO4 was 69%. In experiment 2, the relative bioavailabilities of P in low digestible Lys DDGS 1, low digestible Lys DDGS 2, and high digestible Lys DDGS 3 were 102, 82 and 75%, respectively (P < 0.05). For experiment 3, the P bioavailability coefficients for a light-colored nonautoclaved DDGS and the same DDGS autoclaved at 121 degrees C and 124 pKa were 75 and 87%, respectively (P < 0.05). Our results showed that the total P content of DDGS was similar to the 0.72% value reported by the NRC (1994), but the relative P bioavailability is higher than the value estimated from NRC (1994) based on table values for total and nonphytate P content. Our results also indicated that there is substantial variability in P bioavailability among different DDGS samples and suggest that increased heat processing may increase the bioavailability of P in DDGS.


Experimental and molecular study of cercariae of Clinostomum sp. (Trematoda: Clinostomidae) from Biomphalaria spp. (Mollusca: Planorbidae) in Brazil.
Despite the large number of reports of species of Clinostomum from vertebrate hosts in South America, studies evaluating the molluscan transmitters of these parasites are scarce. In the present study, clinostomatoid cercariae shed from 0.02% (4/17,485) specimens of Biomphalaria spp., collected at the Pampulha reservoir, Belo Horizonte, Minas Gerais, Brazil, were used for experimental infection of Poecilia reticulata . Samples of cercariae from molluscs and metacercariae experimentally obtained from fish were subjected to morphological and molecular analyses and compared with species of Clinostomum reported in the Americas. The cercariae and metacercariae, here identified as Clinostomum sp., present general morphology similar to that reported for Clinostomum marginatum , however, from molecular point of view, differ significantly from North American C. marginatum and other species of Clinostomum reported in South America. These results suggest that the diversity of Clinostomum found in Brazil may be underestimated. Additional studies aimed at molecular characterization of South American species of Clinostomum, including the finding of specimens with sequences similar to that reported for C. marginatum in North America are required.


Dynamics of accommodative facility in myopes.
To evaluate the dynamic changes in refraction during the accommodative facility test in myopes and emmetropes. Ten myopes and 10 emmetropes participated in the study. All were young adults, and refractive error in the myopes was corrected with soft contact lenses. Monocular accommodative facility measurements were taken for a 40-cm and a 6-m working distance with +2.00/-2.00-D and Plano/-2.00-D flippers, respectively. Subjective facility was recorded with automated flippers and objective measurements of dynamic accommodation response were simultaneously taken with a photorefractor. Subjective and objective facility measurements showed a significantly lower facility rate in myopes when compared with emmetropes at distance (P < 0.05) but not at near (P > 0.05). The response amplitude of accommodation during facility tasks was found to be similar in the two refractive groups. However, the velocity of accommodation was found to be lower in myopes than in emmetropes for distance facility (P < 0.05) but not for near facility (P > 0.05). Velocity of disaccommodation was lower in myopes than in emmetropes at both distance and near (P < 0.05). During distance accommodative facility testing, myopes exhibited a lower velocity of accommodation and disaccommodation, which led to a lower distance accommodative facility rate. For near facility measurements, however, although velocity of disaccommodation was lower in myopes, velocity of accommodation was found to be similar in the two refractive groups. A variety of factors that contribute to these differences are discussed.


Bone mineral content and density in the humerus of adult myostatin-deficient mice.
Myostatin (GDF-8), a member of the transforming growth factor-b superfamily of secreted growth and differentiation factors, is a negative regulator of skeletal muscle growth. We investigated the effects of increased muscle mass on bone morphology by examining bone mineral content and density in the humeri of myostatin-deficient mice. We compared the humeri of 11 mixed-gender, adult mice homozygous for the disrupted myostatin sequence with those from 11 mixed-gender, adult wild-type mice. Body mass, deltoid mass, and triceps mass were recorded from each animal and densitometric and geometric parameters were collected from the humerus using peripheral quantitative computed tomography (pQCT). Cross-sectional slices were scanned at four different positions along the humerus corresponding to 15%, 40%, 60%, and 85% of total humerus length. Results show that the myostatin- deficient mice weigh more than controls and have significantly larger triceps and deltoid muscles. The myostatin-deficient animals also have significantly (P < 0.05) higher trabecular area and trabecular bone mineral content (BMC) in the proximal humerus (15% length) and significantly (P < 0.01) higher cortical BMC, cortical area, and periosteal circumference in the region of the deltoid crest (40% length). The myostatin knockouts otherwise do not differ from controls in cortical BMC. Moreover, experimental and control mice do not differ significantly from one another in cortical bone mineral density (BMD) at any of the sites examined. These results suggest that the effects of increased muscle mass on the mouse humerus are localized to regions where muscles attach; furthermore, these effects include increased mineral content of both trabecular and cortical bone.


Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model.
Individuals with metabolic syndrome are at high risk of developing chronic kidney disease (CKD) through unclear pathogenic mechanisms. Obesity and diabetes are known to induce glucolipotoxic effects in metabolically relevant organs. However, the pathogenic role of glucolipotoxicity in the aetiology of diabetic nephropathy is debated. We generated a murine model, the POKO mouse, obtained by crossing the peroxisome proliferator-activated receptor gamma 2 (PPARγ2) knockout (KO) mouse into a genetically obese ob/ob background. We have previously shown that the POKO mice showed: hyperphagia, insulin resistance, hyperglycaemia and dyslipidaemia as early as 4 weeks of age, and developed a complete loss of normal β-cell function by 16 weeks of age. Metabolic phenotyping of the POKO model has led to investigation of the structural and functional changes in the kidney and changes in blood pressure in these mice. Here we demonstrate that the POKO mouse is a model of renal disease that is accelerated by high levels of glucose and lipid accumulation. Similar to ob/ob mice, at 4 weeks of age these animals exhibited an increased urinary albumin:creatinine ratio and significantly increased blood pressure, but in contrast showed a significant increase in the renal hypertrophy index and an associated increase in p27(Kip1) expression compared with their obese littermates. Moreover, at 4 weeks of age POKO mice showed insulin resistance, an alteration of lipid metabolism and glomeruli damage associated with increased transforming growth factor beta (TGFβ) and parathyroid hormone-related protein (PTHrP) expression. At this age, levels of proinflammatory molecules, such as monocyte chemoattractant protein-1 (MCP-1), and fibrotic factors were also increased at the glomerular level compared with levels in ob/ob mice. At 12 weeks of age, renal damage was fully established. These data suggest an accelerated lesion through glucolipotoxic effects in the renal pathogenesis in POKO mice.


Armored with skin and bone: A combined histological and μCT-study of the exceptional integument of the Antsingy leaf chameleon Brookesia perarmata (Angel, 1933).
Madagascar's endemic ground-dwelling leaf chameleons (Brookesiinae: Brookesia Gray, 1865 + Palleon Glaw, et al., Salamandra, 2013, 49, pp. 237-238) form the sister taxon to all other chameleons (i.e., the Chamaeleoninae). They possess a limited ability of color change, a rather dull coloration, and a nonprehensile tail assisting locomotion in the leaf litter on the forest floor. Most Brookesia species can readily be recognized by peculiar spiky dorsolateral projections ("Rückensäge"), which are caused by an aberrant vertebral structure and might function as body armor to prevent predation. In addition to a pronounced Rückensäge, the Antsingy leaf chameleon Brookesia perarmata (Angel, 1933) exhibits conspicuous, acuminate tubercle scales on the lateral flanks and extremities, thereby considerably enhancing the overall armored appearance. Such structures are exceptional within the Chamaeleonidae and despite an appreciable interest in the integument of chameleons in general, the morphology of these integumentary elements remains shrouded in mystery. Using various conventional and petrographic histological approaches combined with μCT-imaging, we reveal that the tubercle scales consist of osseous, multicusped cores that are embedded within the dermis. Based on this, they consequently can be interpreted as osteoderms, which to the best of our knowledge is the first record of such for the entire Chamaeleonidae and only the second one for the entire clade Iguania. The combination of certain aspects of tissue composition (especially the presence of large, interconnected, and marrow-filled cavities) together with the precise location within the dermis (being completely enveloped by the stratum superficiale), however, discriminate the osteoderms of B. perarmata from those known for all other lepidosaurs.


Irritable bowel syndrome patients' ideal expectations and recent experiences with healthcare providers: a national survey.
The purpose of this paper is to identify patients' ideal expectations from their healthcare providers. The IBS-Patient Education Questionnaire was developed using focus groups, and was administered to a national sample of IBS patients. Frequencies of item endorsements were obtained. Subgroup analysis was done comparing the responses for patients' ideal expectations of their healthcare providers vs. their experiences with their last provider. Among the 1,242 patients who completed the survey, the mean age was 39.3 years, educational attainment 15 years, 85% female, IBS duration 6.9 years, 1,028 (83%) had seen a physician for IBS in the past, and 92.6% have used the Internet to obtain health information. Among the subjects who have seen a physician for IBS, the most desired qualities of providers were to give comprehensive information (96%), to refer to a source for additional information (95.8%), to answer questions (95.9%), to listen (94.4%), to provide information about IBS studies and medications (94%), and to provide support (88.6%) and hope (82.1%). Importantly, patients' prior experiences with their last healthcare provider differed from their ideal expectations: "provide information" (38.3%); answer questions during the visit (68%), "to listen" (63.8%), and support (47.1%). Patients' ideal expectations from healthcare providers (what patients ideally would like to experience) relate to obtaining information and relationship needs of receiving support and hope. Notably, their prior experiences with recent healthcare providers (what patients perceived actually occurred) were different from their ideal expectations. A better understanding of different types of expectations is necessary in order to construct an effective therapeutic relationship, which is critical for the management of IBS. Practice guidelines for IBS should emphasize a better understanding of a patient's expectations and the therapeutic value of patient-provider communication.


Hormone-sensitive lipase activity and triacylglycerol hydrolysis are decreased in rat soleus muscle by cyclopiazonic acid.
Cyclopiazonic acid (CPA) is a sarcoplasmic reticulum Ca2+-ATPase inhibitor that increases intracellular calcium. The role of CPA in regulating the oxidation and esterification of palmitate, the hydrolysis of intramuscular lipids, and the activation of hormone-sensitive lipase (HSL) was examined in isolated rat soleus muscles at rest. CPA (40 micro M) was added to the incubation medium to levels that resulted in subcontraction increases in muscle tension, and lipid metabolism was monitored using the previously described pulse-chase procedure. CPA did not alter the cellular energy state, as reflected by similar muscle contents of ATP, phosphocreatine, free AMP, and free ADP. CPA increased total palmitate uptake into soleus muscle (11%, P < 0.05) and was without effect on palmitate oxidation. This resulted in greater esterification of exogenous palmitate into the triacylglycerol (18%, P < 0.05) and phospholipid (89%, P < 0.05) pools. CPA decreased (P < 0.05) intramuscular lipid hydrolysis, and this occurred as a result of reduced HSL activity (20%, P < 0.05). Incubation of muscles with 3 mM caffeine, which is also known to increase Ca2+ without affecting the cellular energy state, reduced HSL activity (24%, P < 0.05). KN-93, a calcium/calmodulin-dependent kinase inhibitor (CaMKII), blocked the effects of CPA and caffeine, and HSL activity returned to preincubation values. The results of the present study demonstrate that CPA simultaneously decreases intramuscular triacylglycerol (IMTG) hydrolysis and promotes lipid storage in isolated, intact soleus muscle. The decreased IMTG hydrolysis is likely mediated by reduced HSL activity, possibly via the CaMKII pathway. These responses are not consistent with the increased hydrolysis and decreased esterification observed in contracting muscle when substrate availability and the hormonal milieu are tightly controlled. It is possible that more powerful signals or a higher [Ca2+] may override the lipid-storage effect of the CPA-mediated effects during muscular contractions.


Latent toxoplasmosis and human.
Toxoplasmosis is one of the most common parasitic diseases worldwide. Although estimated that one third of the world's population are infected with Toxoplasma gondii, but the most common form of the disease is latent (asymptomatic). On the other hand, recent findings indicated that latent toxoplasmosis is not only unsafe for human, but also may play various roles in the etiology of different mental disorders. This paper reviews new findings about importance of latent toxoplasmosis (except in immunocompromised patients) in alterations of behavioral parameters and also its role in the etiology of schizophrenia and depressive disorders, obsessive-compulsive disorder, Alzheimer's diseases and Parkinson's disease, epilepsy, headache and or migraine, mental retardation and intelligence quotients, suicide attempt, risk of traffic accidents, sex ratio and some possible mechanisms of T. gondii that could contribute in the etiology of these alterations.


Altered proliferation of retinal microvascular cells on glycated matrix.
To investigate the effect of nonenzymatic glycosylation (glycation) of basement membranes (BM) and isolated BM proteins on the growth of retinal pericytes and retinal endothelial cells. Type IV collagen, laminin, Engelbreth-Holm-Swarm tumor basement membrane (EHS-BM) and bovine retinal basement membrane (RBM), after incubation in the presence of reducing sugars to induce glucose-mediated modifications, or in the absence of any sugar (control), were used as a substrate to culture bovine retinal microvascular cells. Cell growth on the nonenzymatically glycosylated and the corresponding control substrates was measured daily, using an automated cell counter. Retinal pericytes seeded on glycated type IV collagen proliferated consistently more slowly than on control type IV collagen (P = 0.02), showing a 20% to 33% decrease throughout most of the growth curve, whereas on glycated laminin the difference from control was not significant. In contrast, proliferation increased by 16% to 25% for retinal endothelial cells on glycated laminin compared with control substrate (P = 0.025), whereas on glycated type IV collagen the growth curve was not significantly different from the curve for the control. When seeded on whole glycated EHS-BM or RBM, proliferation of pericytes decreased by 20% to 30% (P = 0.04); the endothelial cells showed no difference on glycated EHS-BM, however, the growth rate increased on glycated RBM by 25% to 30% more than it did for the control (P = 0.01). Nonenzymatic glycosylation of intact BM or individual BM macromolecules resulted in reduced proliferation of retinal pericytes and increased proliferation of retinal endothelial cells. These in vitro observations resemble some of the pathologic changes of the retinal microvascular cells observed in situ, when diabetic retinopathy develops.