Rapid detection of drought stress in plants using femtosecond laser-induced breakdown spectroscopy.
Drought stress disrupts the balance of macro- and micronutrients and affects the yield of agriculturally and economically significant plants. Rapid detection of stress-induced changes of relative content of elements such as sodium (Na), potassium (K), calcium (Ca) and iron (Fe) in the field may allow farmers and crop growers to counter the effects of plant stress and to increase their crop return. Unfortunately, the analytical methods currently available are time-consuming, expensive and involve elaborate sample preparation such as acid digestion which hinders routine daily monitoring of crop health on a field scale. We report application of an alternative method for rapid detection of drought stress in plants using femtosecond laser-induced breakdown spectroscopy (LIBS). We demonstrate daily monitoring of relative content of Na, K, Ca and Fe in decorative indoor (gardenia) and cultivated outdoor (wheat) plant species under various degrees of drought stress. The observed differences in spectral and temporal responses indicate different mechanisms of drought resistance. We identify spectroscopic markers of drought stress which allow for distinguishing mild environmental and severe drought stress in wheat and may be used for remote field-scale estimation of plant stress resistance and health.


Non-reversible airway obstruction in never smokers: results from the Austrian BOLD study.
The presence of non-reversible airway obstruction (AO) in never smokers has only received limited attention until now. We analyzed data from the Austrian Burden of Obstructive Lung Disease (BOLD) study. We defined non-reversible AO as post-bronchodilator FEV(1)/FVC <0.7 which corresponds to COPD I and higher (COPD I+) according to current GOLD guidelines. Significant AO was defined as FEV(1)/FVC <0.7 and FEV(1) <80% predicted (GOLD II and higher, GOLD II+). The prevalence and characteristics of non-reversible AO in never smokers were analyzed in relation to the severity of the disease. Never smokers comprised 47.3% of the study population. Non-reversible AO was seen in 18.2% of never smokers, and 5.5% of never smokers fulfilled criteria for significant non-reversible AO (GOLD stage II+). Therefore, the resulting population prevalence of significant non-reversible AO (GOLD stage II+) was 2.6%. Never smokers with non-reversible AO were predominantly female and slightly older. The airway obstruction was found to be less severe as compared with ever smokers. Despite this, 20% of never smokers with significant non-reversible AO (GOLD stage II+) reported respiratory symptoms and 50% reported impairment of quality of life. This burden of illness in never smokers was similar to that in smokers when severity of AO was taken into account. Approximately every third subject with non-reversible AO has never smoked, yet still demonstrates a substantial burden of symptoms and impairment of quality of life. Never smokers should receive far greater attention when efforts are undertaken to prevent and treat chronic airway obstruction.


Gambling Harm and Crime Careers.
Incarcerated populations across the world have been found to be consistently and significantly more vulnerable to problem gambling than general populations in the same countries. In an effort to gain a more specific understanding of this vulnerability the present study applied latent class analysis and criminal career theory to gambling data collected from a sample of English and Scottish, male and female prisoners (N = 1057). Theoretical links between gambling and crime were tested through three hypotheses: (1) that prisoners in the UK would have higher rates of problem gambling behaviour than the national population; (2) that if the link between gambling and crime is coincidental, gambling behaviour would be highly prevalent in an offending population, and (3) if connections between gambling behaviour and offending are co-symptomatic a mediating factor would show a strong association. The first of these was supported, the second was not supported and the third was partially supported. Latent class analysis found six gambling behaviour clusters measured by responses to the Problem Gambling Severity Index, primarily distinguished by loss chasing behaviour. Longitudinal offending data drawn from the Police National Computer database found four criminal career types, distinguished by frequency and persistence over time. A significant association was found between higher level loss chasing and high rate offending in criminal careers suggesting that impulse control may be a mediating factor for both gambling harm and criminal careers.


[Comparative study of the monosaccharide glycocalyx composition of Bacillus--Lactobacillus--Streptococcus bacteria group by biochemical methods and electron microscopy].
Results of comparison of the data on monosaccharide composition of glycocalix in group Bacillus--Lactobacillus--Streptococcus bacteria using biochemical and electronmicroscopic methods prove that the composition and quantity of monosaccharides varied depending on the genus and peculiarities of microorganisms strains (biological activity in respect of people and warm-blooded animals). At the same time, representatives of this group of microorganisms in the glycocalix had common monosaccharides: glucosamine, sialic acids, galactosamine, galactose, glucose, mannose, fucose, that is the phenotypical display of genetic relations.


[Effect of N-oxidized pyridine derivatives on lipid peroxidation in the livers of rats].
Effects of N-oxide 2,6-dimetilpyridine (ivin) on the intensity of lipid peroxidation (in vivo and in vitro), microsomal hydroxylation and secretion of the bile (in vivo) were investigated. It has been shown that the preparation did not act significantly on the rate of lipid peroxidation in the liver homogenates both in vivo (5 mg/100 g, 4 weeks) and in vitro (10(-6)-10(-2) mol, incubation). Ivin did not change the activity of the microsomal hydroxylation (hexenal), but stimulated the excretion of biliary organic and inorganic components. The role of NO as a transmitter for effects of N-oxide 2,6-dimetilpyridine and the possibility of its influence on the processes under exploration via the modification of the structure of a biomembrane have being discussed to be one of the basic mechanisms.


A qualitative study with people with young-onset dementia and their family caregivers on advance care planning: A holistic, flexible, and relational approach is recommended.
Broad consensus exists on the relevance of advance care planning in dementia. Although people with young-onset dementia and their family are hypothesized to have distinct needs and preferences in this area, they are hardly ever included in studies. We aim to explore the experiences with and views on advance care planning of people with young-onset dementia and their family caregivers. A qualitative study was conducted, analyzing semi-structured interviews through the method of constant comparative analysis. We included 10 people with young-onset dementia and 10 of their family caregivers in Flanders. Participants lacked awareness about the concept of advance care planning, especially as a communication process. They had not or barely engaged in planning future care yet pointed out possible benefits of doing so. Initially, people with young-onset dementia and their caregivers directly associated advance care planning with planning for the actual end of life. When discussing advance care planning as a communication process, they paid ample attention to non-medical aspects and did not distinguish between medical, mental, and social health. Rather, respondents thought in the overarching framework of what is important to them now and in the future. Engagement in advance care planning might be hindered if it is too medicalized and exclusively patient-centered. To accommodate advance care planning to people with young-onset dementia's and their caregivers' needs, it should be presented and implemented as a holistic, flexible, and relational communication process. Policy and practice recommendations are provided on how to do so.


[Usefulness of the relationship between follicular stimulating hormone, deoxypyridinoline, estradiol, and inhibin as decision criterion for starting replacement hormone therapy in climacteric and its correlation with symptomatology].
There is no precise indication for the adequate moment to start hormone replacement therapy (HRT). To evaluate several indexes obtained with serum levels of follicle stimulating hormone (FSH), estradiol (E2), estrone (E) and inhibin and urinary deoxypyridinoline (DPD) and correlate them with Kupperman index as decision criteria for the beginning of hormone replacement therapy (HRT) in the climatery. In 53 patients the presence and intensity of climateric symptoms was evaluated using the modified Kupperman's index. They were divided in: premenopausal, perimenopausal or postmenopausal. groups FSH, E2, E and inhibin blood levels, as well as urinary DPD were measured. Several indexes were calculated, and then were compared between the groups and correlated with Kupperman's index score. Statistical analysis. Kruskall-Wallis and Mann-Whitney U test were done, as well as Spearman's correlation analysis. After comparing the indexes, the Log FSH/E2, Log FSH/E2, Log FSH/E2/E, Log FSH(DPD)/E2, Log FSH(DPD)/E2/E and Log FSH (DPD)/Inhibin(E2) were significantly greater in postmenopausal group. Only there was a significant correlation between Log FSH/Inhibin(E2) index, and Log FSH(DPD)/Inhibin(E2) index with Kupperman's index. Log FSH (DPD)/E2/E index seems to be the more suitable, index because it had a progressive increase as the patients advanced towards postmenopause. The afore mentioned index must be validated with a greater number of patients to assess a cut point that can define in which patients HRT must be administered.


Suppression of progenitor cell growth by vancomycin following autologous stem cell transplantation.
The occurrence of hematologic side-effects resulting from the use of vancomycin is rare. Prior to this report, vancomycin-induced neutropenia was believed to be due to a hypersensitivity reaction since antibodies directed against circulating neutrophils have been discovered in the serum of some patients. We demonstrate suppression of hematopoietic bone marrow progenitor cells in a patient experiencing vancomycin-induced neutropenia after an autologous hematopoietic stem cell transplantation for multiple myeloma. A bone marrow (BM) specimen obtained at the time of neutropenia demonstrated direct suppression of progenitor cell growth in vitro when vancomycin was added at increasing concentrations (1, 10 and 50 microg/ml). No such trend was noted in a BM sample from the same patient obtained 11 months prior to transplantation and a normal control BM. The decrease in the total number of colony-forming units (CFU) was statistically significant at all the dose levels of vancomycin when compared to the number of CFU in the baseline BM sample (P < 0.05). The myeloid maturation arrest observed in the bone marrow sample obtained during the period of neutropenia and the dose dependent growth inhibition by vancomycin observed in vitro suggest a novel nonimmune mechanism of hematologic effects due to suppression of bone marrow progenitor cell growth.


11C-acetate PET imaging of prostate cancer: detection of recurrent disease at PSA relapse.
Patients with rising prostate-specific antigen (PSA) levels after definitive local therapy of prostate carcinoma present a diagnostic dilemma. A local recurrence would be amenable to additional local therapy with curative intent, whereas metastatic disease would require palliative androgen ablation therapy. In this study, we evaluated the effectiveness of PET with (11)C-acetate (AC PET) for evaluation of patients with rising PSA after radical prostatectomy or radiation therapy. We also compared the reliability of AC PET in detecting recurrent prostate cancer with that of PET with (18)F-FDG. Two groups of patients with PSA recurrence were enrolled in this study: group A, 30 patients after prostatectomy, and group B, 16 patients after radiation therapy. After administration of 1,110 MBq (30 mCi) of (11)C-acetate, whole-body PET images were obtained. After allowing for (11)C decay, 555 MBq (15 mCi) of (18)F-FDG were administered and repeated whole-body imaging was performed. The PET findings were scored as positive or negative in each of the following regions: prostatic bed, pelvic nodes, paraaortic nodes, and other sites (bone or soft tissue). PET findings were correlated with those of CT, bone scintigraphy, and biopsy. Twenty-seven of 46 AC PET studies (59%) had positive findings, whereas only 8 (18)F-FDG PET studies had positive findings (17%). Limiting the analysis to patients with findings confirmed by CT, bone scintigraphy, or biopsy or considered highly likely to represent tumor, 14 (30%) had disease identified by AC PET, whereas only 4 (9%) had disease identified by (18)F-FDG PET. CT was performed on 22 patients and had positive findings in 3 (14%). Thirteen of 22 patients (59%) with serum PSA > 3 ng/mL had positive AC PET findings, whereas only 1 of 24 patients (4%) with serum PSA levels < or = 3 ng/mL had positive findings. AC PET demonstrates marked uptake in prostate cancer and has higher sensitivity than (18)F-FDG PET. These preliminary data show that (11)C-acetate is a promising tracer for detection of recurrent prostate cancer.


Differences in TCR repertoire and T cell activation underlie the divergent outcomes of antitumor immune responses in tumor-eradicating versus tumor-progressing hosts.
Antitumor immunity is highly heterogeneous between individuals; however, underlying mechanisms remain elusive, despite their potential to improve personalized cancer immunotherapy. Head and neck squamous cell carcinomas (HNSCCs) vary significantly in immune infiltration and therapeutic responses between patients, demanding a mouse model with appropriate heterogeneity to investigate mechanistic differences. We developed a unique HNSCC mouse model to investigate underlying mechanisms of heterogeneous antitumor immunity. This model system may provide a better control for tumor-intrinsic and host-genetic variables, thereby uncovering the contribution of the adaptive immunity to tumor eradication. We employed single-cell T-cell receptor (TCR) sequencing coupled with single-cell RNA sequencing to identify the difference in TCR repertoire of CD8 tumor-infiltrating lymphocytes (TILs) and the unique activation states linked with different TCR clonotypes. We discovered that genetically identical wild-type recipient mice responded heterogeneously to the same squamous cell carcinoma tumors orthotopically transplanted into the buccal mucosa. While tumors initially grew in 100% of recipients and most developed aggressive tumors, ~25% of recipients reproducibly eradicated tumors without intervention. Heterogeneous antitumor responses were dependent on CD8 T cells. Consistently, CD8 TILs in regressing tumors were significantly increased and more activated. Single-cell TCR-sequencing revealed that CD8 TILs from both growing and regressing tumors displayed evidence of clonal expansion compared with splenic controls. However, top TCR clonotypes and TCR specificity groups appear to be mutually exclusive between regressing and growing TILs. Furthermore, many TCRα/TCRβ sequences only occur in one recipient. By coupling single-cell transcriptomic analysis with unique TCR clonotypes, we found that top TCR clonotypes clustered in distinct activation states in regressing versus growing TILs. Intriguingly, the few TCR clonotypes shared between regressors and progressors differed greatly in their activation states, suggesting a more dominant influence from tumor microenvironment than TCR itself on T cell activation status. We reveal that intrinsic differences in the TCR repertoire of TILs and their different transcriptional trajectories may underlie the heterogeneous antitumor immune responses in different hosts. We suggest that antitumor immune responses are highly individualized and different hosts employ different TCR specificities against the same tumors, which may have important implications for developing personalized cancer immunotherapy.


Online Supplementary ADP Learning Controller Design and Application to Power System Frequency Control With Large-Scale Wind Energy Integration.
The emergence of smart grids has posed great challenges to traditional power system control given the multitude of new risk factors. This paper proposes an online supplementary learning controller (OSLC) design method to compensate the traditional power system controllers for coping with the dynamic power grid. The proposed OSLC is a supplementary controller based on approximate dynamic programming, which works alongside an existing power system controller. By introducing an action-dependent cost function as the optimization objective, the proposed OSLC is a nonidentifier-based method to provide an online optimal control adaptively as measurement data become available. The online learning of the OSLC enjoys the policy-search efficiency during policy iteration and the data efficiency of the least squares method. For the proposed OSLC, the stability of the controlled system during learning, the monotonic nature of the performance measure of the iterative supplementary controller, and the convergence of the iterative supplementary controller are proved. Furthermore, the efficacy of the proposed OSLC is demonstrated in a challenging power system frequency control problem in the presence of high penetration of wind generation.


Environmental fate of tungsten from military use.
This manuscript describes the distribution, fate and transport of tungsten used in training rounds at three small arms ranges at Camp Edwards on the Massachusetts Military Reservation (MMR), USA. Practice with tungsten/nylon rounds began in 2000 subsequent to a 1997 US Environmental Protection Agency ban on training with lead. Training with the tungsten rounds was halted in 2005 because of concerns regarding tungsten's environmental mobility and potential toxicity. This study, therefore, examines how tungsten partitions in the environment when fired on a small arms training range. Soil sampling revealed surface soil concentrations, highest at the berm face, up to 2080 mg/kg. Concentrations decreased rapidly with depth--at least by an order of magnitude by 25 cm. Nonetheless, tungsten concentrations remained above background to at least 150 cm. Pore-water samples from lysimeters installed in berm areas revealed a range of concentrations (<1-400 mg/L) elevated with respect to background although there was no discernable trend with depth. Groundwater monitoring well samples collected approximately 30 m below ground surface showed tungsten (0.001-0.56 mg/L) attributable to range use.


Projecting social contact matrices to different demographic structures.
The modeling of large-scale communicable epidemics has greatly benefited in the last years from the increasing availability of highly detailed data. Particullarly, in order to achieve quantitative descriptions of the evolution of epidemics, contact networks and mixing patterns are key. These heterogeneous patterns depend on several factors such as location, socioeconomic conditions, time, and age. This last factor has been shown to encapsulate a large fraction of the observed inter-individual variation in contact patterns, an observation validated by different measurements of age-dependent contact matrices. Recently, several works have studied how to project those matrices to areas where empirical data are not available. However, the dependence of contact matrices on demographic structures and their time evolution has been largely neglected. In this work, we tackle the problem of how to transform an empirical contact matrix that has been obtained for a given demographic structure into a different contact matrix that is compatible with a different demography. The methodology discussed here allows to extrapolate a contact structure measured in a particular area to any other whose demographic structure is known, as well as to obtain the time evolution of contact matrices as a function of the demographic dynamics of the populations they refer to. To quantify the effect of considering time-dynamics of contact patterns on disease modeling, we implemented a Susceptible-Exposed-Infected-Recovered (SEIR) model on 16 different countries and regions and evaluated the impact of neglecting the temporal evolution of mixing patterns. Our results show that simulated disease incidence rates, both at the aggregated and age-specific levels, are significantly dependent on contact structures variation driven by demographic evolution. The present work opens the path to eliminate technical biases from model-based impact evaluations of future epidemic threats and warns against the use of contact matrices to model diseases without correcting for demographic evolution or geographic variations.


Sex-Related Differences in Acuity and Postoperative Complications, Mortality and Failure to Rescue.
Yentl syndrome describing sex-related disparities has been extensively studied in medical conditions but not after surgery. This retrospective cohort study assessed the association of sex, frailty, presenting with preoperative acute serious conditions (PASC), and the expanded Operative Stress Score (OSS) with postoperative complications, mortality, and failure-to-rescue. The National Surgical Quality Improvement Program from 2015 to 2019 evaluating 30-d complications, mortality, and failure-to-rescue. Of 4,860,308 cases (43% were male; mean [standard deviation] age of 56 [17] y), 6.0 and 0.8% were frail and very frail, respectively. Frailty score distribution was higher in men versus women (P < 0.001). Most cases were low-stress OSS2 (44.9%) or moderate-stress OSS3 (44.5%) surgeries. While unadjusted 30-d mortality rates were higher (P < 0.001) in males (1.1%) versus females (0.8%), males had lower odds of mortality (adjusted odds ratio (aOR) = 0.92, 95% confidence interval [CI] = 0.90-0.94, P < 0.001) after adjusting for frailty, OSS, case status, PASC, and Clavien-Dindo IV (CDIV) complications. Males have higher odds of PASC (aOR = 1.33, CI = 1.31-1.35, P < 0.001) and CDIV complications (aOR = 1.13, CI = 1.12-1.15, P < 0.001). Male-PASC (aOR = 0.76, CI = 0.72-0.80, P < 0.001) and male-CDIV (aOR = 0.87, CI = 0.83-0.91, P < 0.001) interaction terms demonstrated that the increased odds of mortality associated with PASC or CDIV complications/failure-to-rescue were lower in males versus females. Our study provides a comprehensive analysis of sex-related surgical outcomes across a wide range of procedures and health care systems. Females presenting with PASC or experiencing CDIV complications had higher odds of mortality/failure to rescue suggesting sex-related care differences. Yentl syndrome may be present in surgical patients; possibly related to differences in presenting symptoms, patient care preferences, or less aggressive care in female patients and deserves further study.


[Temporal trends in nosocomial infections in a unit of pediatric cardiac surgery (1984-1988)].
We have evaluated the variations and the evolution of the temporal trends of cumulative incidence of hospital infections, their different localizations and causative organisms in a hospital ward and intensive care area from a pediatric cardiac surgery unit during the period 1984-1988. We also evaluated the effectiveness of our control and surveillance program by calculating from monthly records the cumulative incidence of monthly ad yearly rates of hospital infections and their localizations. The cumulative yearly incidence showed a decreasing trend (CI x 100 = 4.30-0.492 years) (SE, beta = 0.144; p less than 0.001), mainly owing to the reduction in urinary tract infections (CI x 100 = 6.93-1.426 years) (SE, beta = 0.452; p less than 0.001) and other infections (CI x 100 = 1.1-0.232 years) (SE, beta = 0.062; p less than 0.01). The most commonly isolated pathogens were E. coli, Pseudomonas sp and K. pneumoniae. The patients from that unit had a low risk of hospital infection during the 1984-1988 period, and this risk decreased concomitantly with the development of the program.


Occupational Risk Factors for Laryngeal Cancer in Tunisia: A Case Control Study.
Tobacco use and alcohol consumption are the primary risk factors for laryngeal cancer (LC). In most populations, occupational exposures are likely to play a minor role in laryngeal carcinogenesis. We aimed to investigate the association between occupational exposure and laryngeal cancer. It is a case-control study that included 140 cases diagnosed between January 2013 and December 2016 and 140 controls matched by sex, age, alcohol consumption, and tobacco consumption. Significantly increased risks were found amongst workers of the building sector (OR=4.621; 95% CI [1.826-11.693]) and the mechanical industry sector (OR=5.074; 95% CI [1.425-18.072]). Significant association of laryngeal cancer with various carcinogens was observed such as asbestos (p=0.009; OR=3.68; 95% CI [1.29-10.46]), paint vapors (p=0.005; OR=3.35; 95% CI [1.37-8.16]), solvents (p=0.001; OR=3.29: 95% CI [1.61-6.68]) and cement dust (p=0.003; OR=3.19: 95% CI [1.43-7.12]). After binary logistic regression, cement dust was independently correlated with LC (p=0.042; OR=3.93; 95% CI [1.04-14.78]. The administration sector was associated with decreased risk (p=0.001; OR=0.07; 95% CI [0.03-0.15]) as well as the health sector (p=0.001; OR=0.098; 95% CI [0.02-0.43]). Our results supported the role of occupational factors in developing LC. Further studies enabling an in-depth analysis of occupational exposures are necessary to provide a clearer definition of the etiological associations between single agents and circumstances of exposure and the genesis of LC.


AMPA-receptor activation is involved in the antiamnesic effect of DM 232 (unifiram) and DM 235 (sunifiram).
DM 232 and DM 235 are novel antiamnesic compounds structurally related to ampakines. The involvement of AMPA receptors in the mechanism of action of DM 232 and DM 235 was, therefore, investigated in vivo and in vitro. Both compounds (0.1 mg/kg(-1) i.p.) were able to reverse the amnesia induced by the AMPA receptor antagonist NBQX (30 mg/kg(-1) i.p.) in the mouse passive avoidance test. At the effective doses, the investigated compounds did not impair motor coordination, as revealed by the rota rod test, nor modify spontaneous motility and inspection activity, as revealed by the hole board test. DM 232 and DM 235 reversed the antagonism induced by kynurenic acid of the NMDA-mediated release of [(3)H]NA in the kynurenate test performed in rat hippocampal slices. This effect was abolished by NBQX. DM 232 increases, in a concentration dependent manner, excitatory synaptic transmission in the rat hippocampus in vitro. These results suggest that DM 232 and DM 235 act as cognition enhancers through the activation of the AMPA-mediated neurotransmission system.


Outcome-based education: evaluation, implementation and faculty development.
This article was migrated. The article was marked as recommended. Developments in Outcome-based education (OBE) and innovative shifts in its pedagogical approaches have reshaped the learning environment of curricula at medical schools. This instructional design has gained popularity due to its authenticity and systematic approach. However, this needs organized supervision and faculty training in order to achieve the desired goals for the program. Aim: This article examines the evaluation of OBE at a private medical school in Saudi Arabia. It describes the curriculum review process and the characteristics of the curriculum reviewers involved. It evaluates the curriculum using Harden's OBE implementation inventory. OBE reviewers' satisfaction about OBE implementation was evaluated using the OBE inventory. Results: This analysis shows our institutional profile to be similar to the 'transition to beavers' symbol in Harden's representation. At the program level, the study identifies gaps and suggests suitable recommendations to enhance the enactment of OBE. Conclusion: We strongly encourage medical educators to apply the nine components of the OBE implementation inventory to evaluate their level of implementation of OBE. To further build up this model, the authors propose a mnemonic "ADAPTIVE Species" as an instructional prompt to develop these qualities in medical faculty. "ADAPTIVE Species" stands for Assertive, Developer, Assessors, Prime-movers, Transparent, Innovators, Vigilant, Evaluators, and Selectors.


The vascular anatomy and angiosome of the posterior auricular artery. A cadaver study.
Pedicled flaps based on the posterior auricular artery have been used for small auricular and mastoid cavity defects. To precisely define the vascular anatomy and angiosome (cutaneous distribution) of the posterior auricular artery. A fresh cadaver model was used for 3 separate investigations, studying the posterior auricular artery. Intra-arterial ink injections defined the angiosome, and subtraction angiography and latex injection defined the vascular anatomy in relation to bony and soft tissue landmarks. Eight fresh cadavers, 6 men and 2 women, were used, varying in age from 58 to 85 years. The posterior auricular artery has a predictable course in the posterior auricular sulcus. The branching pattern over the auricle and temporal bone and the artery's relationship to bony and soft tissue landmarks were consistent. The angiosome includes the anterior and posterior surfaces of the auricle and the periauricular skin superiorly, posteriorly, and inferiorly. The investigation documented the consistent vascular anatomy and angiosome of the posterior auricular artery. The cutaneous distribution suggests that a large pedicled or island flap based on the posterior auricular artery may be raised safely as a myocutaneous or myofasciocutaneous flap with temporalis fascia and/or periosteum, extending previously published dimensions. Further studies may extend the clinical application to include free flaps based on the posterior auricular artery.


Genome-wide mapping of nucleotide excision repair with XR-seq.
Nucleotide excision repair is a versatile mechanism to repair a variety of bulky DNA adducts. We developed excision repair sequencing (XR-seq) to study nucleotide excision repair of DNA adducts in humans, mice, Arabidopsis thaliana, yeast and Escherichia coli. In this protocol, the excised oligomers, generated in the nucleotide excision repair reaction, are isolated by cell lysis and fractionation, followed by immunoprecipitation with damage- or repair factor-specific antibodies from the non-chromatin fraction. The single-stranded excised oligomers are ligated to adapters and re-immunoprecipitated with damage-specific antibodies. The DNA damage in the excised oligomers is then reversed by enzymatic or chemical reactions before being converted into a sequencing library by PCR amplification. Alternatively, the excised oligomers containing DNA damage, especially those containing irreversible DNA damage such as benzo[a]pyrene-induced DNA adducts, can be converted to a double-stranded DNA (dsDNA) form by using appropriate translesion DNA synthesis (TLS) polymerases and then can be amplified by PCR. The current genome-wide approaches for studying repair measure the loss of damage signal with time, which limits their resolution. By contrast, an advantage of XR-seq is that the repair signal is directly detected above a background of zero. An XR-seq library using the protocol described here can be obtained in 7-9 d.


Recent developments in superstring theory.
There have been many remarkable developments in our understanding of superstring theory in the past few years, a period that has been described as "the second superstring revolution." In particular, what once appeared to be five distinct theories are now recognized to be different manifestations of a single (unique) underlying theory. Some of the evidence for this, based on dualities and the appearance of an eleventh dimension, is presented. Also, a specific proposal for the underlying theory, called "Matrix Theory," is described. The presentation is intended primarily for the benefit of nonexperts.


Molecular analysis of group A rotaviruses detected in adults and adolescents with severe acute gastroenteritis in Italy in 2012.
Hospital-based surveillance of acute gastroenteritis caused by rotavirus has produced ample knowledge on the infection in children, whereas little is known on rotavirus infection among adults. The Italian surveillance program RotaNet-Italia collected 1,595 samples from patients admitted to hospital with gastroenteritis in 2012. All patients presented with vomiting, diarrhea, fever, and/or abdominal pain. Forty-two samples obtained by the RotaNet-Italia (2.6%) were from adolescents or adults (10-89 years). The study compared the genotypes and gene sequences of the rotavirus strains identified in adults with strains obtained from children worldwide. All 42 Italian strains were genotyped by the EuroRotaNet RT-nested-PCR protocols, and 12 rotaviruses from patients >13-year-old were subjected to nucleotide sequencing of their VP7 and/or VP4 genes. All strains analyzed belonged to the common human genotypes G1P[8], G2P[4], G4P[8], and G9P[8], except an uncommon G3P[19] genotype detected in a single patient. Phylogenetic analysis of the 12 strains showed that within each genotype they clustered in RVA lineages reported worldwide. The amino acid sequences of the VP7 and the VP8* hypervariable regions were highly conserved between the RVA strains collected from adults and children, in each lineage. Genotyping, phylogenetic analysis, and the study of viral epitopes revealed that rotaviruses circulating in adults in Italy are closely similar to the strains circulating in children, with high nucleotide identity particularly with strains reported in Europe and Asia. The circulation of the same rotavirus strains in both children and adults suggests that adults may contribute to sustain the circulation of rotaviruses through the population.


Childhood cerebellar tumours mirror conserved fetal transcriptional programs.
Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin+ stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.


Distribution of an allele associated with blond hair color across Northern Island Melanesia.
Pigmentation of the skin, hair, and eyes is a complex trait controlled by multiple genetic loci. Recently a non-synonymous mutation in the pigmentation candidate gene TYRP1 was shown to be significantly associated with a blond-hair phenotype in populations from the Solomon Islands. The distribution of this mutation in the islands of Northern Island Melanesia, where the blondism phenotype is also prevalent, was unknown. Here, we present data describing the distribution of this allele in 550 individuals sampled from across this region, and test for associations between genotype at this locus and quantitatively measured skin and hair pigmentation phenotype. We report that the frequency of the 93C allele is notably lower than observed in the Solomons (0.12 vs. 0.26). The allele exhibits significant geographic heterogeneity across the islands sampled (χ(2) = 108.4, P < 0.0001). It is observed at its highest frequencies on the islands of New Ireland and New Hanover, while being almost completely absent from the large island of New Britain. Using linear regression with age, sex, and island as covariates we report that, as in the Solomons, the 93C allele is significantly associated with a decrease in hair pigmentation but not skin pigmentation. We discuss the distribution of the 93C allele across the Southwest Pacific in light of its possible place of origin and dispersal.


Evaluation of Personal Exposure to Surgical Smoke Generated from Electrocautery Instruments: A Pilot Study.
Hospital technician surgical smoke exposures during several types of electrocautery-based procedures were evaluated. Personal and area air sampling was performed for 106 individual analytes including ultrafine particulate matter (UFP), volatile organic compounds, polycyclic aromatic hydrocarbons, phenol, aldehydes, carbon monoxide, hydrogen sulfide, and hydrogen cyanide. Acetone, d-limonene, ethanol, ethyl acetate, and fluorene were measured in surgical suites at concentrations 1.1- to 3.7-fold higher than those observed in background. Benzene, α-pinene, methylene chloride, and n-hexane were measured in the absence of a detectable background concentration. All analytes were measured at concentrations that were <1% of the corresponding US federal and state 8-h permissible exposure limits (PELs), if PELs existed. Full-shift average UFP concentrations ranged from 773 to 2257 particles/cm3, approximately one order of magnitude higher than surgical suite background concentrations. A comparison of two breast reduction procedures suggested that the use of smoke evacuators reduced UFP exposure by 6-fold. We concluded that selection and evaluation of key hazards, particularly UFP, under a variety of experimental conditions would be beneficial to elucidate potential health effects and causes osf employee complaints. Recommendations for successful sampling campaigns in future surgical smoke occupational exposure studies are provided. We also recommend the continued use of engineering controls, local exhaust ventilation, and surgical N95 respirators to reduce personal exposures to UFP in surgical smoke.


Large-scale label-free comparative proteomics analysis of polo-like kinase 1 inhibition via the small-molecule inhibitor BI 6727 (Volasertib) in BRAF(V600E) mutant melanoma cells.
Polo-like kinase 1 (Plk1) is a serine/threonine kinase that plays a key role during the cell cycle by regulating mitotic entry, progression, and exit. Plk1 is overexpressed in a variety of human cancers and is essential to sustained oncogenic proliferation, thus making Plk1 an attractive therapeutic target. However, the clinical efficacy of Plk1 inhibition has not emulated the preclinical success, stressing an urgent need for a better understanding of Plk1 signaling. This study addresses that need by utilizing a quantitative proteomics strategy to compare the proteome of BRAF(V600E) mutant melanoma cells following treatment with the Plk1-specific inhibitor BI 6727. Employing label-free nano-LC-MS/MS technology on a Q-exactive followed by SIEVE processing, we identified more than 20 proteins of interest, many of which have not been previously associated with Plk1 signaling. Here we report the down-regulation of multiple metabolic proteins with an associated decrease in cellular metabolism, as assessed by lactate and NAD levels. Furthermore, we have also identified the down-regulation of multiple proteasomal subunits, resulting in a significant decrease in 20S proteasome activity. Additionally, we have identified a novel association between Plk1 and p53 through heterogeneous ribonucleoprotein C1/C2 (hnRNPC), thus providing valuable insight into Plk1's role in cancer cell survival.


A clinicopathologic reappraisal of brain stem tumor classification. Identification of pilocystic astrocytoma and fibrillary astrocytoma as distinct entities.
Brain stem tumors in children have been classified pathologically as low grade or high grade gliomas and descriptively as diffuse gliomas, intrinsic gliomas, midbrain tumors, tectal gliomas, pencil gliomas, dorsal exophytic brain stem tumors, pontine gliomas, focal medullary tumors, cervicomedullary tumors, focal gliomas, or cystic gliomas. To search for a simplified and prognostic clinicopathologic scheme for brain stem tumors, the authors reviewed a consecutive cohort of patients younger than age 21 years with tumors diagnosed from 1980 through 1997. Pathology specimens and neuroimaging were classified by masked review. Statistical and survival analysis along with Cox proportional hazards regression was performed. Seventy-six patients were identified, with initial diagnostic magnetic resonance imaging available for 51 and pathology specimens for 48 patients. Twenty cases were classified histologically as pilocytic astrocytoma (PA), 14 as fibrillary astrocytoma (FA), and 14 as other tumors or indeterminate pathology. For all tumors, characteristics significantly associated with a worse survival rate were: symptom duration less than 6 months before diagnosis (P = 0.004); abducens palsy at presentation (P < 0.0001); pontine location (P = 0.0002); and engulfment of the basilar artery (P = 0.006). Pilocytic astrocytoma was associated with location outside the ventral pons (P = 0.001) and dorsal exophytic growth (P = 0.013); Fibrillary astrocytoma was associated with symptoms less than 6 months (P = 0. 006), abducens palsy (P < 0.001), and engulfment of the basilar artery (P = 0.002). Pilocytic astrocytoma showed 5-year overall survival (OS) of 95% (standard error [SE], 5%) compared with FA 1-year OS of 23% (SE, 11%;P < 0.0001). Brain stem tumors can be succinctly and better biologically classified as diffusely infiltrative brain stem gliomas-generally FA located in the ventral pons that present with abducens palsy, often engulf the basilar artery, and carry a grim prognosis-and focal brain stem gliomas-frequently PA arising outside the ventral pons, often with dorsal exophytic growth, a long clinical prodrome, and outstanding prognosis for survival. Our findings emphasize the individuality of PA as a distinct clinicopathologic entity with an exceptional prognosis.


In vivo approaches reveal a key role for DCs in CD4+ T cell activation and parasite clearance during the acute phase of experimental blood-stage malaria.
Dendritic cells (DCs) are phagocytes that are highly specialized for antigen presentation. Heterogeneous populations of macrophages and DCs form a phagocyte network inside the red pulp (RP) of the spleen, which is a major site for the control of blood-borne infections such as malaria. However, the dynamics of splenic DCs during Plasmodium infections are poorly understood, limiting our knowledge regarding their protective role in malaria. Here, we used in vivo experimental approaches that enabled us to deplete or visualize DCs in order to clarify these issues. To elucidate the roles of DCs and marginal zone macrophages in the protection against blood-stage malaria, we infected DTx (diphtheria toxin)-treated C57BL/6.CD11c-DTR mice, as well as C57BL/6 mice treated with low doses of clodronate liposomes (ClLip), with Plasmodium chabaudi AS (Pc) parasites. The first evidence suggesting that DCs could contribute directly to parasite clearance was an early effect of the DTx treatment, but not of the ClLip treatment, in parasitemia control. DCs were also required for CD4+ T cell responses during infection. The phagocytosis of infected red blood cells (iRBCs) by splenic DCs was analyzed by confocal intravital microscopy, as well as by flow cytometry and immunofluorescence, at three distinct phases of Pc malaria: at the first encounter, at pre-crisis concomitant with parasitemia growth and at crisis when the parasitemia decline coincides with spleen closure. In vivo and ex vivo imaging of the spleen revealed that DCs actively phagocytize iRBCs and interact with CD4+ T cells both in T cell-rich areas and in the RP. Subcapsular RP DCs were highly efficient in the recognition and capture of iRBCs during pre-crisis, while complete DC maturation was only achieved during crisis. These findings indicate that, beyond their classical role in antigen presentation, DCs also contribute to the direct elimination of iRBCs during acute Plasmodium infection.


Translocation of rubella virus glycoprotein E1 into the endoplasmic reticulum.
Rubella virus (RV) contains four structural proteins, C (capsid), E2a, E2b, and E1, which are derived from posttranslational processing of a single polyprotein precursor, p110. C protein is nonglycosylated and is thought to interact with RV RNA to form a nucleocapsid. E1 and E2 are membrane glycoproteins that form the spike complexes located on the virion exterior. Two different E1 cDNAs were used to analyze the requirements for translocation of E1 into the endoplasmic reticulum. Analysis of expression of these cDNAs both in vivo and in vitro showed that RV E1 was stably expressed and glycosylated in COS cells and correctly targeted into microsomes in the absence of E2 glycoprotein. The results provide experimental evidence that translocation of RV E1 glycoprotein into the endoplasmic reticulum is mediated by a signal peptide contained within the 69 carboxyl-terminal residues of E2.


Occupation related pesticide exposure and cancer of the prostate: a meta-analysis.
To summarise recent literature on the risk of prostate cancer in pesticide related occupations, to calculate the meta-rate ratio, and to compare it to data from meta-analyses previously published. A meta-analysis of 22 epidemiological studies, published between 1995 and 2001, was conducted in order to pool their rate ratio estimates. Studies were summarised and evaluated for homogeneity and publication bias. The meta-rate ratio estimate, based on 25 estimators of relative risk from 22 studies, was 1.13 (95% CI 1.04 to 1.22). Significant heterogeneity of rate ratios existed among the different studies. Therefore, a stratified analysis was carried out. Major sources of heterogeneity identified were geographic location, study design, and healthy worker effect. Overall, pooled risk estimates for studies derived from Europe were lower than those derived from the USA/Canada. A significant increase in rate ratio was observed for the occupation category of pesticide applicators, whereas no significant increase was observed for farmers. There was no evidence of publication bias. This increased meta-rate ratio for prostate cancer in different pesticide related occupations, including farmers, is very similar to three, previously published, meta-rate ratios for prostate cancer in farmers calculated from studies published before 1995. Although the underlying data do not identify pesticide exposure as an independent cause for prostate cancer, the fact that an increased meta-rate ratio is again obtained points to occupational exposure to pesticides as a possible factor. Future epidemiological studies should focus, as far as possible, on reliable methods to estimate actual exposure.


Long-term health effects after resolution of acute Cryptosporidium parvum infection: a 1-year follow-up of outbreak-associated cases.
We describe a longitudinal study carried out in an adult outbreak-associated cohort to investigate health effects, including post-infectious irritable bowel syndrome, occurring after resolution of acute Cryptosporidium parvum infection. New symptoms self-reported up to 12 months included: weight loss (31 %), abdominal pain (38 %), diarrhoea (33 %), eye pain (9 %), joint pain (33 %), fatigue (22 %) and symptoms consistent with irritable bowel syndrome (IBS) (28 %). Two people were medically diagnosed with IBS. This study describes for the first time sequelae reported by patients up to 12 months after infection with C. parvum, which appear to be similar to those described with C. hominis.


Elaboration in type, primary structure, and bioactivity of polysaccharides derived from mollusks.
Over the past decades, numerous Mollusca species have received more attention in development and utilization as valuable bio-resources. Many efforts have been focused on investigating mollusk polysaccharides because of their rich content, ease of extraction, diversified sorts, specific structure, various biofunctions and potent activities. To date, many mollusks, especially species of gastropods, bivalves, or cephalopods, have been reported containing polysaccharide compounds in tissues with abundant amount, and most of polysaccharides are obtainable through combining techniques of extraction, separation and purification. The polysaccharides isolated from mollusks appeared with various structural and physicochemical characteristics, ranged from neutral polysaccharides and sulfated polysaccharides, to GAGs series (including Hep/HS, CS/DS, HA and similarities), even to heterogeneous glycan with high molecular weight. This review article provides comprehensive knowledge of recent researches on type classification, tissue origins and possible biofunctions of various polysaccharides from mollusks. The highlights were placed in structure variation including molecular weight, sulfation pattern, linkages and monomer compositions for repeating unit, and primary molecular construction of the mollusks polysaccharides. In addition, this article covers general information on exhibition of mollusks polysaccharide extracts or preparations in the various bioactivities, such as anticoagulant, antiatherogenic, antioxidant, immunomodulatory, antivirus and antitumor activities, which would reveal their possible potentials in medical application. Furthermore, the article presents a brief overview on several challenges and future scope in this field.


Xenon-induced inhibition of Ca2+-regulated transitions in the cell cycle of human endothelial cells.
Xenon is an anesthetic with very few side-effects, yet its targets at the cellular level are still unclear. It interferes with many aspects of intracellular Ca2+ homeostasis, but so far no specific event or defined regulatory complex of the Ca2+-signaling system has been identified. Specific effects of xenon were found by investigating its effects on the cell cycle in human endothelial cells: there is a relationship between two cell cycle transition points, their regulation by Ca2+, and specific blocks induced by xenon. Within the group of substances studied (xenon, isoflurane, desflurane, helium, and N2), only xenon blocks the cells almost completely at the G2-M transition after a 2-h treatment; those cells that slip through this block are then arrested at metaphase. If xenon is removed, cells that have been accumulating at the G2-M boundary move into mitosis, and cells blocked at metaphase complete their mitosis normally. No such specific block of the cell cycle was found with the other substances studied. An artificial increase of intracellular Ca2+ in the submicromolar range, using a very low dose of the Ca2+ ionophore ionomycin, or a threefold increase of the external Ca2+ concentration suffices to lift the xenon-induced metaphase block; the cells enter anaphase despite the presence of xenon and complete cell division. Thus, the specific but completely reversible inhibition by xenon of the G2-M transition and the block at metaphase suggest an interaction with a Ca2+-dependent event involved in the control of these processes. The results are consistent with the hypothesis that suppression of Ca2+ signals can be considered as a common denominator of the effects of xenon on the cell cycle and on the neuronal system during anesthesia.


Distribution and substrate specificity of intracellular proteolytic processing enzyme(s) for paramyxovirus fusion glycoproteins.
Intracellular proteolytic processing of fusion glycoprotein precursors (F0) of paramyxoviruses, i.e. a virulent strain of Newcastle disease virus (NDV), parainfluenza virus type 3 (PIV3) and simian virus 5 (SV5), was examined in NALM6 and BSC40 cells and compared with that in LLCMK2 cells to investigate the distribution of the virus-activating protease(s) among the cells and its substrate specificity. BSC40 cells lack a processing endoprotease of the neuropeptide precursor, pro-opiomelanocortin (POMC), which possesses multiple cleavage sites at pairs of basic residues, Lys-Arg and Arg-Arg, a motif similar to that found in the cleavage site of the F0 proteins. In NALM6 cells, only small amounts of the F0 protein of virulent NDV was cleaved whereas those of PIV3 and SV5 were efficiently cleaved. In BSC40 cells the F0 proteins of these three viruses were cleaved normally as well as in LLCMK2 cells. The processing inhibitors monensin, chloroquine and A23187 suppressed the F0 cleavage in the three cell types. These results indicate that both NALM6 and BSC40 cells possess virus-activating proteases similar to that of LLCMK2 cells, but suggest that the enzyme of NALM6 may be slightly different in its substrate specificity from those of BSC40 and LLCMK2. The results also suggest that the virus-activating proteases are different in their distribution and substrate specificity from the processing enzyme of POMC.


Potential impacts of floating wind turbine technology for marine species and habitats.
Offshore wind energy is expanding globally and new floating wind turbine technology now allows wind energy developments in areas previously too deep for fixed-platform turbines. Floating offshore wind has the potential to greatly expand our renewable energy portfolio, but with rapid expansion planned globally, concerns exist regarding impacts to marine species and habitats. Floating turbines currently exist in three countries but large-scale and rapid expansion is planned in over a dozen. This technology comes with unique potential ecological impacts. Here, we outline the various floating wind turbine configurations, and consider the potential impacts on marine mammals, seabirds, fishes and benthic ecosystems. We focus on the unique risks floating turbines may pose with respect to: primary and secondary entanglement of marine life in debris ensnared on mooring lines used to stabilize floating turbines or dynamic inter-array cables; behavioral modification and displacement, such as seabird attraction to perching opportunities; turbine and vessel collision; and benthic habitat degradation from turbine infrastructure, for example from scour from anchors and inter-array cables. We highlight mitigation techniques that can be applied by managers or mandated through policy, such as entanglement deterrents or the use of cable and mooring line monitoring technologies to monitor for and reduce entanglement potential, or smart siting to reduce impacts to critical habitats. We recommend turbine configurations that are likely to have the lower ecological impacts, particularly taut or semi-taut mooring configurations, and we recommend studies and technologies still needed that will allow for floating turbines to be applied with limited ecological impacts, for example entanglement monitoring and deterrent technologies. Our review underscores additional research and mitigation techniques are required for floating technology, beyond those needed for pile-driven offshore or inshore turbines, and that understanding and mitigating the unique impacts from this technology is critical to sustainability of marine ecosystems.


Is integrated transit planar portal dosimetry able to detect geometric changes in lung cancer patients treated with volumetric modulated arc therapy?
Geometric changes are frequent during the course of treatment of lung cancer patients. This may potentially result in deviations between the planned and actual delivered dose. Electronic portal imaging device (EPID)-based integrated transit planar portal dosimetry (ITPD) is a fast method for absolute in-treatment dose verification. The aim of this study was to investigate if ITPD could detect geometric changes in lung cancer patients. A total of 460 patients treated with volumetric modulated arc therapy (VMAT) following daily cone beam computed tomography (CT)-based setup were visually inspected for geometrical changes on a daily basis. Forty-six patients were subject to changes and had a re-CT and an adaptive treatment plan. The reasons for adaptation were: change in atelectasis (n = 18), tumor regression (n = 9), change in pleural effusion (n = 8) or other causes (n = 11). The ITPDs were calculated on both the initial planning CT and the re-CT and compared with a global gamma (γ) evaluation (criteria: 3%\3mm). A treatment fraction failed when the percentage of pixels failing in the radiation fields exceeded 10%. Dose-volume histograms (DVHs) were compared between the initial plan versus the plan re-calculated on the re-CT. The ITPD threshold method detected 76% of the changes in atelectasis, while only 50% of the tumor regression cases and 42% of the pleural effusion cases were detected. Only 10% of the cases adapted for other reasons were detected with ITPD. The method has a 17% false-positive rate. No significant correlations were found between changes in DVH metrics and γ fail-rates. This study showed that most cases with geometric changes caused by atelectasis could be captured by ITPD, however for other causes ITPD is not sensitive enough to detect the clinically relevant changes and no predictive power of ITPD was found.


Early responses of SiHa human squamous carcinoma cells to hypoxic signals.
We compared the responses of c-Jun/AP-1 transcriptional complexes with those of NF-kappa B, an established hypoxia-inducible transcriptional complex, in hypoxic SiHa human squamous carcinoma cells. We observed that NF-kappa B was activated rapidly, while AP-1 activation was detectable only after prolonged hypoxia. However, in parallel with NF-kappa B activation, hypoxia induced a protein kinase activity that could phosphorylate the transactivation domain of the ATF-2 transcription factor in vitro. Taken together, these experiments indicate that NF-kappa B can rapidly transduce hypoxic signals through increased DNA-binding and transactivation activities, whereas specific AP-1 (ATF-2/c-Jun) complexes may be activated under the same hypoxic conditions by a stress-reponsive MAPK pathway.


Learning the mechanobiology of development from gastruloids.
Gastruloids acquire their organization and shape through cell biochemical and mechanical activities. Such activities determine the physical forces and changes in material properties that transform simple spherical aggregates into organized tissues. In this Perspective, we discuss why the concepts and approaches of mechanobiology, a discipline that focuses on cell and tissue mechanics and its contribution to the organization and functions of living systems, are essential to the gastruloid field and, in turn, what gastruloids may teach us about mechanobiology.


Resilience in children threatened by extreme adversity: frameworks for research, practice, and translational synergy.
This article delineates parallel frameworks that grew out of the research on risk and resilience over the past four decades, a framework for research and a framework for practice, and then discusses the promise of an emerging synthesis. The research framework defined the meaning, models, and methods that successfully guided four waves of research to date on the nature and processes involved in human resilience. The applied framework emerged in response to urgent needs of children and families faced by adversity and those charged with helping them, resulting in guidelines for translating the unfolding but incomplete research evidence into action. The application of a resilience approach transformed practice in many fields concerned with promoting resilience in people at risk for problems, revolutionizing the mission, models, measures, and methods of practice to align with the emphasis on positive adaptation and strengths defining a resilience-based approach. Yet these interventions rarely translated back to inform and refine resilience theory in ways that would accelerate progress to promote resilience more effectively. The concluding section on translational synergy discusses the potential for a synthesis of basic and applied resilience frameworks as the next steps toward realizing the original objective and promise of resilience science.


The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor alpha is inhibited by ethanol metabolism. A novel mechanism for the development of ethanol-induced fatty liver.
Fatty acids are ligands for the peroxisome proliferator-activated receptor alpha (PPAR alpha). Fatty acid levels are increased in liver during the metabolism of ethanol and might be expected to activate PPAR alpha. However, ethanol inhibited PPAR alpha activation of a reporter gene in H4IIEC3 hepatoma cells expressing alcohol-metabolizing enzymes but not in CV-1 cells, which lack these enzymes. Ethanol also reduced the ability of the PPAR alpha ligand WY14,643 to activate reporter constructs in the hepatoma cells or cultured rat hepatocytes. This effect of ethanol was abolished by the alcohol dehydrogenase inhibitor 4-methylpyrazole and augmented by the aldehyde dehydrogenase inhibitor cyanamide, indicating that acetaldehyde was responsible for the action of ethanol. PPAR alpha/retinoid X receptor extracted from hepatoma cells exposed to ethanol or acetaldehyde bound poorly to an oligonucleotide containing peroxisome proliferator response elements. This effect was also blocked by 4-methylpyrazole and augmented by cyanamide. Furthermore, in vitro translated PPAR alpha exposed to acetaldehyde failed to bind DNA. Thus, ethanol metabolism blocks transcriptional activation by PPAR alpha, in part due to impairment of its ability to bind DNA. This effect of ethanol may promote the development of alcoholic fatty liver and other hepatic consequences of alcohol abuse.


Transcription factor-driven alternative localization of Cryptococcus neoformans superoxide dismutase.
Cryptococcus neoformans is an opportunistic fungal pathogen whose pathogenic lifestyle is linked to its ability to cope with fluctuating levels of copper (Cu), an essential metal involved in multiple virulence mechanisms, within distinct host niches. During lethal cryptococcal meningitis in the brain, C. neoformans senses a Cu-deficient environment and is highly dependent on its ability to scavenge trace levels of Cu from its host and adapt to Cu scarcity to successfully colonize this niche. In this study, we demonstrate for this critical adaptation, the Cu-sensing transcription factor Cuf1 differentially regulates the expression of the SOD1 and SOD2 superoxide dismutases in novel ways. Genetic and transcriptional analysis reveals Cuf1 specifies 5'-truncations of the SOD1 and SOD2 mRNAs through specific binding to Cu responsive elements within their respective promoter regions. This results in Cuf1-dependent repression of the highly abundant SOD1 and simultaneously induces expression of two isoforms of SOD2, the canonical mitochondrial targeted isoform and a novel alternative cytosolic isoform, from a single alternative transcript produced specifically under Cu limitation. The generation of cytosolic Sod2 during Cu limitation is required to maintain cellular antioxidant defense against superoxide stress both in vitro and in vivo. Further, decoupling Cuf1 regulation of Sod2 localization compromises the ability of C. neoformans to colonize organs in murine models of cryptococcosis. Our results provide a link between transcription factor-mediated alteration of protein localization and cell proliferation under stress, which could impact tissue colonization by a fungal pathogen.


A survey of selected heavy metal concentrations in Wisconsin dairy feeds.
Heavy metals such as zinc (Zn), copper (Cu), chromium (Cr), arsenic (As), cadmium (Cd), and lead (Pb) are potential bioaccumulative toxins of the dairy production system. The heavy metal content of dairy feeds, however, remains poorly documented, particularly in the United States. This survey determined the heavy metal content of 203 typical dairy ration components sampled from 54 dairy farms in Wisconsin. Lowest heavy metal concentrations were found in homegrown alfalfa (Medicago sativa L.) hay and haylage, and corn (Zea mays L.) grain and silage. Highest metal concentrations were found in purchased feeds, particularly mineral supplements, and to a lesser extent corn- or soybean-based concentrates. Zinc and Cu were found at the highest concentration in complete dairy (total mixed and aggregated component) rations and reflected the deliberate addition of these metals to meet animal nutrient requirements although more than half the farms fed Cu and Zn above US recommended levels. Concentrations of Cr, As, Cd, and Pb were present in much lower concentrations and decreased in the order Cr > As > Pb > Cd. No complete Wisconsin dairy ration contained heavy metal concentrations above US maximum acceptable concentrations and would be unlikely to induce any toxic effects in dairy cattle. Concentrations of Cd in complete dairy rations were closest to US maximum acceptable concentrations, suggesting the greatest potential long-term risk to exceed US maximum acceptable concentrations if whole farm levels of Cd were to increase in the future. With the exception of Pb, the main sources of Zn, Cu, Cr, As, and Cd in the complete dairy feed ration originated from imported feed. The continued importation of heavy metals in dairy feed is likely to be associated with accumulation of these metals in soils where manure is applied. Although the cycling of many heavy metals through the dairy food chain will be limited by factors such as a soil's cation exchange capacity, pH, salinity, and phytotoxicity of the metal, these may be less limiting for Cd. It is important that sources of Cd in the dairy system are identified and minimized to prevent problems associated with Cd accumulation in the dairy soil system arising over the long-term.


Palmitoylation and Membrane Binding of Arc/Arg3.1: A Potential Role in Synaptic Depression.
Activity-regulated cytoskeletal-associated protein (Arc, also known as activity-regulated gene 3.1 or Arg3.1) is induced in neurons in response to salient experience and neural activity and is necessary for activity-induced forms of synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), cellular substrates of learning and memory. The best-characterized function of Arc is enhancement of the endocytic internalization of AMPA receptors in dendritic spines, a process associated with LTD. Arc has also been implicated in the proteolytic processing of amyloid precursor protein on the surface of endosomes. To mediate these activities, Arc must associate with cellular membranes, but it is unclear whether Arc binds directly to the lipid bilayer or requires protein-protein interactions for membrane recruitment. In this study, we show that Arc associates with pure phospholipid vesicles in vitro and undergoes palmitoylation in neurons, a modification that allows it to insert directly into the hydrophobic core of the bilayer. The palmitoylated cysteines are clustered in a motif, 94CLCRC98, located in the N-terminal half of the protein, which has not yet been structurally characterized. Expression of Arc with three mutated cysteines in that motif cannot support synaptic depression induced by the activity-dependent transcription factor, MEF2 (myocyte enhancer factor 2), in contrast to wild-type Arc. Thus, it appears that palmitoylation regulates at least a subset of Arc functions in synaptic plasticity.


Sinking towards destiny: High throughput measurement of phytoplankton sinking rates through time-resolved fluorescence plate spectroscopy.
Diatoms are marine primary producers that sink in part due to the density of their silica frustules. Sinking of these phytoplankters is crucial for both the biological pump that sequesters carbon to the deep ocean and for the life strategy of the organism. Sinking rates have been previously measured through settling columns, or with fluorimeters or video microscopy arranged perpendicularly to the direction of sinking. These side-view techniques require large volumes of culture, specialized equipment and are difficult to scale up to multiple simultaneous measures for screening. We established a method for parallel, large scale analysis of multiple phytoplankton sinking rates through top-view monitoring of chlorophyll a fluorescence in microtitre well plates. We verified the method through experimental analysis of known factors that influence sinking rates, including exponential versus stationary growth phase in species of different cell sizes; Thalassiosira pseudonana CCMP1335, chain-forming Skeletonema marinoi RO5A and Coscinodiscus radiatus CCMP312. We fit decay curves to an algebraic transform of the decrease in fluorescence signal as cells sank away from the fluorometer detector, and then used minimal mechanistic assumptions to extract a sinking rate (m d-1) using an RStudio script, SinkWORX. We thereby detected significant differences in sinking rates as larger diatom cells sank faster than smaller cells, and cultures in stationary phase sank faster than those in exponential phase. Our sinking rate estimates accord well with literature values from previously established methods. This well plate-based method can operate as a high throughput integrative phenotypic screen for factors that influence sinking rates including macromolecular allocations, nutrient availability or uptake rates, chain-length or cell size, degree of silification and progression through growth stages. Alternately the approach can be used to phenomically screen libraries of mutants.


New approach to investigate the cytotoxicity of nanomaterials using single cell mechanics.
Current in vitro methods to assess nanomaterial cytotoxicity involve various assays to monitor specific cellular dysfunction, such as metabolic imbalance or inflammation. Although high throughput, fast, and animal-free, these in vitro methods suffer from unreliability and lack of relevance to in vivo situations. New approaches, especially with the potential to reliably relate to in vivo studies directly, are in critical need. This work introduces a new approach, single cell mechanics, derived from atomic force microscopy-based single cell compression. The single cell based approach is intrinsically advantageous in terms of being able to directly correlate to in vivo investigations. Its reliability and potential to measure cytotoxicity is evaluated using known systems: zinc oxide (ZnO) and silicon dioxide (SiO2) nanoparticles (NP) on human aortic endothelial cells (HAECs). This investigation clearly indicates the reliability of single cell compression. For example, ZnO NPs cause significant changes in force vs relative deformation profiles, whereas SiO2 NPs do not. New insights into NPs-cell interactions pertaining to cytotoxicity are also revealed from this single cell mechanics approach, in addition to a qualitative cytotoxicity conclusion. The advantages and disadvantages of this approach are also compared with conventional cytotoxicity assays.


Aims and objectives in the infertility clinic: the practical issues.
Aims and objectives of infertility clinic staff and their patients may not coincide. Pregnancy may not always be desired or desirable. Investigations and treatment may enhance the problem rather than alleviate it and cause considerable stress. Coping mechanisms in clients and staff may need specific reinforcement in success and in failure.


Sp1 transcription factor represses transcription of phosphatase and tensin homolog to aggravate lung injury in mice with type 2 diabetes mellitus-pulmonary tuberculosis.
Type 2 diabetes mellitus (T2DM) can enhance the risk of mycobacterium tuberculosis (Mtb) infection and aggravate pulmonary tuberculosis (PTB). This study intended to explore the function of phosphatase and tensin homolog (PTEN) in T2DM-PTB and the molecules involved. Mice were treated with streptozotocin to induce T2DM and then infected with Mtb. The mice with T2DM had increased weight, blood glucose level, glucose intolerance and insulin resistance, and increased susceptibility to PTB after Mtb infection. PTEN was significantly downregulated in mice with T2DM-PTB and it had specific predictive value in patients. Overexpression of PTEN improved mouse survival and reduced bacterial load, inflammatory infiltration, cell apoptosis, and fibrosis in lung tissues. Sp1 transcription factor (SP1) was predicted and identified as an upstream regulator of PTEN. SP1 suppressed PTEN transcription. Silencing of SP1 enhanced mouse survival and alleviated the lung injury, and it promoted the M1 polarization of macrophages in murine lung tissues. However, further downregulation of PTEN increased protein kinase B (Akt) phosphorylation and blocked the alleviating roles of SP1 silencing in T2DM-PTB. This study demonstrates that SP1 represses PTEN transcription to promote lung injury in mice with T2DM-PTB through Akt activation.


Facile adsorption-dry process to incorporate Cu into TiO2 nanotube for highly efficient photocatalytic hydrogen production.
Cu species was introduced into TiO2 nanotube prepared by hydrothermal method via a facile adsorption-dry process. The fabricated sample exhibited excellent H2 generation activity (76.3 mmol h(-1) g(-1)(catalyst)), which was higher than most of the reported Cu incorporated TiO2 samples, even superior to some Pt/Pd/Au/Ni incorporated TiO2. Compared to wet impregnation and in-situ photo-deposition methods, the facile adsorption-dry process was much simpler but more efficient to introduce Cu species into TiO2 for H2 production. To fully understand the adsorption-dry process, characterizations of the samples were carried out by high-resolution transmission electron microscope, X-ray diffractometer, energy dispersive X-ray spectrometer, BET surface area analysis, UV-visible spectrophotometer and X-ray photoelectron spectroscopy. It was found that the facile adsorption-dry process could well maintain the morphology of TiO2 support, for instance, 1-D tubular structure and large BET surface area of TiO2 nanotube; moreover, the introduced Cu species was highly dispersed and intensively bonded with TiO2. All of these contributed to the high H2 generation activity.


Phylogenetics and ecomorphology of emarginate primary feathers.
Wing tip slots are a distinct morphological trait broadly expressed across the avian clade, but are generally perceived to be unique to soaring raptors. These slots are the result of emarginations on the distal leading and trailing edges of primary feathers, and allow the feathers to behave as individual airfoils. Research suggests these emarginate feathers are an adaptation to increase glide efficiency by mitigating induced drag in a manner similar to aircraft winglets. If so, we might expect birds known for gliding and soaring to exhibit emarginate feather morphology; however, that is not always the case. Here, we explore emargination across the avian clade, and examine associations between emargination and ecological and morphological variables. Pelagic birds exhibit pointed, high-aspect ratio wings without slots, whereas soaring terrestrial birds exhibit prominent wing-tip slots. Thus, we formed four hypotheses: (1) Emargination is segregated according to habitat (terrestrial, coastal/freshwater, pelagic). (2) Emargination is positively correlated with mass. (3) Emargination varies inversely with aspect ratio and directly with wing loading and disc loading. (4) Emargination varies according to flight style, foraging style, and diet. We found that emargination falls along a continuum that varies with habitat: Pelagic species tend to have zero emargination, coastal/freshwater birds have some emargination, and terrestrial species have a high degree of emargination. Among terrestrial and coastal/freshwater species, the degree of emargination is positively correlated with mass. We infer this may be the result of selection to mitigate induced power requirements during slow flight that otherwise scale adversely with increasing body size. Since induced power output is greatest during slow flight, we hypothesize that emargination may be an adaptation to assist vertical take-off and landing rather than glide efficiency as previously hypothesized.


Involvement of the DNA mismatch repair system in cisplatin sensitivity of testicular germ cell tumours.
Testicular germ cell tumours (TGCT) are highly sensitive to cisplatin-based chemotherapy, but patients with tumours containing differentiated teratoma components are less responsive to this treatment. The cisplatin sensitivity in TGCT has previously been linked to the embryonic phenotype in the majority of tumours, although the underlying mechanism largely remains to be elucidated. The aim of this study was to investigate the role of the DNA mismatch repair (MMR) system in the cisplatin sensitivity of TGCT. The expression pattern of key MMR proteins, including MSH2, MSH6, MLH1 and PMS2, were investigated during testis development and in the pathogenesis of TGCT, including germ cell neoplasia in situ (GCNIS). The TGCT-derived cell line NTera2 was differentiated using retinoic acid (10 μM, 6 days) after which MMR protein expression and activity, as well as cisplatin sensitivity, were investigated in both undifferentiated and differentiated cells. Finally, the expression of MSH2 was knocked down by siRNA in NTera2 cells after which the effect on cisplatin sensitivity was examined. MMR proteins were expressed in proliferating cells in the testes, while in malignant germ cells MMR protein expression was found to coincide with the expression of the pluripotency factor OCT4, with no or low expression in the more differentiated yolk sac tumours, choriocarcinomas and teratomas. In differentiated NTera2 cells we found a significantly (p < 0.05) lower expression of the MMR and pluripotency factors, as well as a reduced MMR activity and cisplatin sensitivity, compared to undifferentiated NTera2 cells. Also, we found that partial knockdown of MSH2 expression in undifferentiated NTera2 cells resulted in a significantly (p < 0.001) reduced cisplatin sensitivity. This study reports, for the first time, expression of the MMR system in fetal gonocytes, from which GCNIS cells are derived. Our findings in primary TGCT specimens and TGCT-derived cells suggest that a reduced sensitivity to cisplatin in differentiated TGCT components could result from a reduced expression of MMR proteins, in particular MSH2 and MLH1, which are involved in the recognition of cisplatin adducts and in activation of the DNA damage response pathway to initiate apoptosis.


High efficiency inorganic/organic hybrid tandem solar cells.
Hybrid tandem solar cells comprising an inorganic bottom cell and an organic top cell have been designed and fabricated. The interlayer combination and thickness matching were optimized in order to increase the overall photovoltaic conversion efficiency. A maximum power conversion efficiency of 5.72% was achieved along with a V(oc) of 1.42 V, reaching as high as 92% of the sum of the subcell V(oc) values.


Health indicators and intimate partner violence among women who are members of a managed care organization.
There have been no population-based studies estimating the prevalence of intimate partner violence (IPV) in an insured population. There is also little information on how well routinely collected health status information predicts IPV risk. Many women now obtain health care from providers who are members of a managed care organization (MCO). To justify efforts to routinely screen for IPV, it is essential to know the prevalence of IPV in this growing population and to identify correlates of IPV among female MCO members. A telephone survey with questions on health status, behavioral risk factors, preventive services use, and the Conflict Tactics Scale was completed by 2,415 female members of a New Mexico MCO. Overall, 13.5% of respondents reported experiencing major verbal aggression and 6.7% reported experiencing physical aggression. Younger age, degree of sadness, and inability to handle stress, and a perception of a poorer general health status were significantly associated with major verbal aggression. Race/ethnicity, degree of sadness, and average number of drinks consumed at one sitting were significantly associated with physical aggression. There is a low but important annual prevalence of IPV among female members of a MCO that occurs across all variables studied. This information is needed to develop appropriate screening protocols and interventions in this population.


[Immunologic processes in carcinogenesis in the intestine].
It is hard to believe that the development of intestinal carcinomas is not linked--to some degree with a failure of the immunological defense mechanisms. For this several reasons may be evoked (for all exist examples) like a neutralization or blind-folding of the immune recognition, an inhibition of the effector cell activation or else genetic syndromes. New insights by a more pronounced research of the immune phenomena in the immediate tumor surroundings are needed.


Biomarkers of mercury exposure at a mercury recycling facility in Ukraine.
This study evaluates biomarkers of occupational mercury exposure among workers at a mercury recycling operation in Gorlovka, Ukraine. The 29 study participants were divided into three occupational categories for analysis: (1) those who worked in the mercury recycling operation (Group A, n = 8), (2) those who worked at the facility but not in the yard where the recycling was done (Group B, n = 14), and (3) those who did not work at the facility (Group C, n = 7). Urine, blood, hair, and nail samples were collected from the participants, and a questionnaire was administered to obtain data on age, gender, occupational history, smoking, alcohol consumption, fish consumption, tattoos, dental amalgams, home heating system, education, source of drinking water, and family employment in the former mercury mine/smelter located on the site of the recycling facility. Each factor was tested in a univariate regression with total mercury in urine, blood, hair, and nails. Median biomarker concentrations were 4.04 microg/g-Cr (urine), 2.58 microg/L (blood), 3.95 microg/g (hair), and 1.16 microg/g (nails). Occupational category was significantly correlated (p < 0.001) with both blood and urinary mercury concentrations but not with hair or nail mercury. Four individuals had urinary mercury concentrations in a range previously found to be associated with subtle neurological and subjective symptoms (e.g., fatigue, loss of appetite, irritability), and one worker had a urinary mercury concentration in a range associated with a high probability of neurological effects and proteinuria. Comparison of results by occupational category found that workers directly involved with the recycling operation had the highest blood and urinary mercury levels. Those who worked at the facility but were not directly involved with the recycling operation had higher levels than those who did not work at the facility.


Replication in hydroxyurea: it's a matter of time.
Hydroxyurea (HU) is a DNA replication inhibitor that negatively affects both the elongation and initiation phases of replication and triggers the "intra-S phase checkpoint." Previous work with budding yeast has shown that, during a short exposure to HU, MEC1/RAD53 prevent initiation at some late S phase origins. In this study, we have performed microarray experiments to follow the fate of all origins over an extended exposure to HU. We show that the genome-wide progression of DNA synthesis, including origin activation, follows the same pattern in the presence of HU as in its absence, although the time frames are very different. We find no evidence for a specific effect that excludes initiation from late origins. Rather, HU causes S phase to proceed in slow motion; all temporal classes of origins are affected, but the order in which they become active is maintained. We propose a revised model for the checkpoint response to HU that accounts for the continued but slowed pace of the temporal program of origin activation.


[Clinical Analysis of Colistin Sulfate in the Treatment of Hematonosis Infected by Multidrug-Resistant Gram-Negative Bacteria].
To investigate the efficacy and safety of colistin sulfate in the treatment of hematonosis patients infected by multidrug-resistant (MDR) gram-negative bacteria (GNB), and discuss the possible factors that affect the efficacy of colistin sulfate. The clinical data of 85 hematologic patients infected with MDR GNB in the Soochow Hopes Hematonosis Hospital from April 2022 to November 2022 were collected and divided into clinically effective group with 71 cases and ineffective group with 14 cases according to the therapeutic efficacy of colistin sulfate. The age, gender, type of hematologic disease, status of hematopoietic stem cell transplantation, infection sites, type of pathogen, timing of administration, daily dose and duration of colistin sulfate, and combination with other antibacterial agents of patients in two groups were compared. Logistic regression was used to analyze on the meaningful variables to study the influencing factors of colistin sulfate. The adverse reactions of colistin sulfate were also evaluated. There were no significant differences in age, gender, type of hematologic disease, hematopoietic stem cell transplantation status, infection sites and pathogen type between the effective group and the ineffective group (P>0.05). Compared with the medication time more than 7 days, meropenem used within 7 days in the clinical effective group, and timely replacement with colistin sulfate could obtain better efficacy, the difference was statistically significant (P=0.018). The duration of tigacycline before colistin sulfate did not affect the efficacy, and there was no significant difference in efficacy between the effective and ineffective groups. The therapeutic effect of colistin sulfate at daily dose of 500 000 U q8h was better than that of 500 000 U q12h, the difference was statistically significant (P=0.035). The time of colistin sulfate use in the clinically effective group was longer than that in the ineffective group, which had a statistical difference (P=0.003). Compared with the clinical ineffective group, the efficacy of combination regimens with colistin sulfate was better than that of colistin sulfate monotherapy, and the difference was statistically significant (P=0.013). Multivariate logistic regression analysis was performed on the indicators with statistical differences in the two groups of patients, which suggested that the use time of colistin sulfate (B: 2.358; OR: 10.573; CI: 1.567-71.361; P=0.015) and the combination of colistin sulfate (B: 1.720; OR: 5.586; CI: 1.210-25.787; P=0.028) were influential factors in the efficacy of colistin sulfate. During the treatment, the incidence of nephrotoxicity, hepatotoxicity and peripheral neurotoxicity were 5.9%, 1.2% and 1.2%, respectively. The use of colistin sulfate improves the clinical efficacy of MDR GNB infections in hematological patients, and the timing of colistin sulfate administration and the combination of drugs are independent factors affecting its clinical efficacy, and the safety during treatment is high.


Adverse effects of aneuploidy on the outcome of remission induction therapy for acute nonlymphocytic leukaemia: analysis of types of treatment failure.
Cytogenetic studies were carried out on bone marrow specimens obtained from 98 patients with acute nonlymphocytic leukaemia. Patients were treated with cytosine arabinoside and an anthracycline antibiotic. The remission rate for patients in whom only normal metaphases were detected (NN patients) was 69% while the remission rates were 50% and 40% respectively for patients in whom both normal and abnormal metaphases were seen (NA patients) and for those in whom only abnormal metaphases were noted (AA patients). Analysis of remission induction failure types suggests that the differences in outcome were related to a tendency for patients with aneuploid leukaemia to be more likely to have drug resistant disease and to the lesser ability of NA and AA patients to survive and receive a second course of therapy if the first course failed to induce a complete remission.


Innovative uses of imiquimod.
Imiquimod (Aldara, 3M Pharmaceuticals) is a potent stimulator of the innate and adaptive arms of the immune system through induction, synthesis, and release of cytokines and chemokines. An extensive review of clinical trials, case reports, and letters published in peer-reviewed journals was performed regarding imiquimod use in skin disorders. A reference module was developed for physicians to consult as a guide. Studies have validated the benefit of imiquimod in treating external genital and perianal warts, superficial basal cell carcinomas, and actinic keratoses. This new topical therapeutic agent has shown to be of benefit in other various skin disorders through its broad immunomodulatory properties. Since many skin conditions are immunologically influenced, it is reasonable to expect several diseases to respond to imiquimod. Our research consolidates the therapeutic trials and reports on the innovative uses of imiquimod, thereby serving as a useful resource to benefit dermatologists treating patients with refractory or recalcitrant skin diseases.


Changed cortical thickness and sulcal depth in pediatric acute lymphoblastic leukemia survivors treated with chemotherapy only.
The purpose of this study is to observe the changes of cortical morphological characteristics and their potential contribution to cognitive function in ALL survivors by using surface-based morphometry (SBM). Using SBM analysis, we calculated and compared group differences in cortical thickness, sulcal depth, gyrification, and fractal dimension of the cerebral cortex between 18 pediatric ALL survivors treated on chemotherapy-only protocols and off treatment within 2 years, and 18 healthy controls (HCs) with two-sample t-tests [P < 0.05, family-wise error (FWE) corrected]. Relationships between abnormal cortical characteristic values and cognitive function parameters were investigated with partial correlation analysis, taking age as a covariate. We found decreased cortical thickness mainly located in the prefrontal and temporal region, and increased sulcal depth in left rostral middle frontal cortex and left pars orbitalis in the ALL survivors compared to HCs. There were no statistically significant differences in the gyrification and fractal dimension between the two groups. In ALL survivors, cortical thickness and sulcal depth of above areas values revealed no significant correlation with the cognitive function parameters. In conclusion, pediatric ALL survivors show decreased cortical thickness in prefrontal and temporal regions, and increased sulcal depth in prefrontal region. These results suggest that SBM-based approach can be used to assess changes of cortical morphological characteristics in pediatric ALL survivors.


Clinical Practice Guideline on management of older patients with chronic kidney disease stage 3b or higher (eGFR<45 mL/min/1.73 m2): a summary document from the European Renal Best Practice Group.
The population of patients with moderate and severe CKD is growing. Frail and older patients comprise an increasing proportion. Many studies still exclude this group, so the evidence base is limited. In 2013 the advisory board of ERBP initiated, in collaboration with European Union of Geriatric Medicine Societies (EUGMS), the development of a guideline on the management of older patients with CKD stage 3b or higher (eGFR >45 mL/min/1.73 m2). The full guideline has recently been published and is freely available online and on the website of ERBP (www.european-renal-best-practice.org). This paper summarises main recommendations of the guideline and their underlying rationales.


Volumetric laser endomicroscopy in Barrett's esophagus: ready for primetime.
Barrett's esophagus (BE) is the condition where intestinal metaplastic changes are found in the normal stratified squamous epithelium of the esophagus predisposing an individual to dysplasia and esophageal adenocarcinoma (EAC). It tends to affect males and is often the result of chronic gastroesophageal reflux disease (GERD). The current standard of therapy for diagnosing Barrett's is white light endoscopy (WLE) with biopsies obtained using the Seattle protocol. Multiple newer advanced modalities have been developed to improve diagnostic abilities, including volumetric laser endomicroscopy (VLE). This technique utilizes second generation optical coherence tomography (OCT) to provide an enhanced circumferential image to a depth of 3 mm with the potential for improved diagnostic yield for dysplasia, particularly submucosal lesions or lesions not seen by WLE. It has also been evaluated in guiding mapping of endotherapy as well as post therapy surveillance for recurrence. Although the results have been promising when used with current diagnostic standards, overall data are limited to support the routine use of VLE.


Loss-of-function and gain-of-function phenotypes of stomatocytosis mutant RhAG F65S.
Four patients with overhydrated cation leak stomatocytosis (OHSt) exhibited the heterozygous RhAG missense mutation F65S. OHSt erythrocytes were osmotically fragile, with elevated Na and decreased K contents and increased cation channel-like activity. Xenopus oocytes expressing wild-type RhAG and RhAG F65S exhibited increased ouabain and bumetanide-resistant uptake of Li(+) and (86)Rb(+), with secondarily increased (86)Rb(+) influx sensitive to ouabain and to bumetanide. Increased RhAG-associated (14)C-methylammonium (MA) influx was severely reduced in RhAG F65S-expressing oocytes. RhAG-associated influxes of Li(+), (86)Rb(+), and (14)C-MA were pharmacologically distinct, and Li(+) uptakes associated with RhAG and RhAG F65S were differentially inhibited by NH(4)(+) and Gd(3+). RhAG-expressing oocytes were acidified and depolarized by 5 mM bath NH(3)/NH(4)(+), but alkalinized and depolarized by subsequent bath exposure to 5 mM methylammonium chloride (MA/MA(+)). RhAG F65S-expressing oocytes exhibited near-wild-type responses to NH(4)Cl, but MA/MA(+) elicited attenuated alkalinization and strong hyperpolarization. Expression of RhAG or RhAG F65S increased steady-state cation currents unaltered by bath Li(+) substitution or bath addition of 5 mM NH(4)Cl or MA/MA(+). These oocyte studies suggest that 1) RhAG expression increases oocyte transport of NH(3)/NH(4)(+) and MA/MA(+); 2) RhAG F65S exhibits gain-of-function phenotypes of increased cation conductance/permeability, and loss-of-function phenotypes of decreased and modified MA/MA(+) transport, and decreased NH(3)/NH(4)(+)-associated depolarization; and 3) RhAG transports NH(3)/NH(4)(+) and MA/MA(+) by distinct mechanisms, and/or the substrates elicit distinct cellular responses. Thus, RhAG F65S is a loss-of-function mutation for amine transport. The altered oocyte intracellular pH, membrane potential, and currents associated with RhAG or RhAG F65S expression may reflect distinct transport mechanisms.


Self-nanoemulsifying drug delivery system to improve transcorneal permeability of voriconazole: in-vivo studies.
This study investigates the effectiveness of self-nanoemulsifying drug delivery system (SNEDDS) in improving voriconazole transcorneal permeability. Voriconazole-SNEDDS was prepared with isopropyl myristate, PEG 400, Tween 80® and Span 80® and was subjected for physicochemical characterization after reconstitution with NaCl 0.9% (1/9; v/v). In-vitro antifungal activity was assessed and compared with the marketed formulation. In-vivo studies, namely ocular irritation test via modified Draize test and pharmacokinetic study, were investigated using rabbit as animal model. Voriconazole-SNEDDS presented a droplet size of 21.353 ± 0.065 nm, a polydispersity index of 0.123 ± 0.003, a pH of 7.205 ± 0.006 and an osmolarity of 342.667 ± 2.517 mOsmol/l after reconstitution with NaCl 0.9%. Voriconazole-SNEDDS minimum inhibitory concentration (MIC90 ) was similar to the one of marketed formulation for Candida species while it was significantly lower (P < 0.001) for Aspergillus fumigatus. Draize test revealed that Voriconazole-SNEDDS was safe for ocular administration. Voriconazole maximum concentration (5.577 ± 0.852 µg/ml) from SNEDDS was higher than marketed formulation (Cmax = 4.307 ± 0.623 µg/ml), and the Tmax was delayed to 2 h. The area under the concentration-time curve value of Voriconazole-SNEDDS was improved by 2.419-fold. Our results suggest that SNEDDS is a promising carrier for voriconazole ocular delivery and this encourages further clinical studies.


The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors.
Numerous chemotherapeutic agents have been shown to have an inhibitory effect on endothelial cell proliferation and migration, and tubule formation. In this study, we examined the antiangiogenic activity of docetaxel. Docetaxel inhibited endothelial cell proliferation and tubule formation in vitro in a dose-dependent fashion. Docetaxel treatment also inhibited angiogenesis in an in vivo Matrigel plug assay. The endothelial stimulating factors, vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor are able to protect endothelial cells from the antiangiogenic properties of docetaxel. This protective effect can be overcome by a recombinant humanized monoclonal antibody directed against VEGF in both in vitro and in vivo models. Similarly, combination of docetaxel with the antiangiogenic agent 2-methoxyestradiol also overcomes the protective effect of VEGF in both in vitro and in vivo models. These data suggest that microenvironmental factors (e.g., local release of VEGF and basic fibroblast growth factor) could play a role in decreasing the antiangiogenic effects of docetaxel, whereas agents such as 2- methoxyestradiol and recombinant humanized monoclonal antibody directed against VEGF may reverse this protective effect.