Cost-effectiveness Analysis of Breast Cancer Screening Using Mammography in Singapore: A Modeling Study.
Limited research is available on the cost-effectiveness of breast cancer screening programs in Asian countries. We evaluated the cost-effectiveness of Singapore's national mammography screening program, implemented in 2002, recommending annual screening between ages 40 and 49 and biennial screening between ages 50 and 69, and alternative screening scenarios taking into account important country-specific factors. We used national data from Singapore in the MIcrosimulation SCreening ANalysis-Fatal diameter (MISCAN-Fadia) model to simulate 302 screening scenarios for 10 million women born between 1910 and 1969. Screening scenarios varied by starting and ending age, screening interval, and attendance. Outcome measures included life-years gained (LYG), breast cancer deaths averted, false positives, overdiagnosis, quality-adjusted life years (QALY), costs (in 2002 Singapore dollars; S$), and incremental cost-effectiveness ratios (ICER). Costs and effects were calculated and discounted with 3% using a health care provider's perspective. Singapore's current screening program at observed attendance levels required 54,158 mammograms per 100,000 women, yielded 1,054 LYG, and averted 57 breast cancer deaths. At attendance rates ≥50%, the current program was near the efficiency frontier. Most scenarios on the efficiency frontier started screening at age 40. The ICERs of the scenarios on the efficiency frontiers ranged between S$10,186 and S$56,306/QALY, which is considered cost-effective at a willingness-to-pay threshold of S$70,000/QALY gained. Singapore's current screening program lies near the efficiency frontier, and starting screening at age 40 or 45 is cost-effective. Furthermore, enhancing screening attendance rates would increase benefits while maintaining cost-effectiveness. Screening all women at age 40 or 45 is cost-efficient in Singapore, and a policy change may be considered.


Older Adults' Perspectives on Clinical Research: A Focus Group and Survey Study.
Clinical trials can benefit from patient perspectives to inform trial design, such as choice of outcome measures. We engaged older adults in focus groups and surveys to get their perspective regarding needs in clinical research. The goal was to inform the development of a new clinical trial of medication strategies for treatment-resistant depression in older adults. Older adults with depression participated in focus groups and a subsequent survey in St. Louis and New York. They were queried regarding research design features including outcomes, clinical management, mobile technology and iPad-administered assessments, the collection of DNA, and the receipt of their personal results. Patients told us: (1) psychological well-being and symptomatic remission are outcomes that matter to them; (2) it is important to measure not only benefits but risks (such as risk of falling) of medications; (3) for pragmatic trials in clinical settings, the research team should provide support to clinicians to ensure that medications are properly prescribed; (4) technology-based assessments are acceptable but there were concerns about data security and burden; (5) DNA testing is very important if it could improve precision care; (6) participants want to receive aggregate findings and their own personal results at the end of the study. Patients gave useful and wide-ranging guidance regarding clinical and comparative effectiveness research in older adults. We discuss these findings with the goal of making the next generation of geriatric studies more impactful and patient-centered.


[Clarity in general practice].
A random sample of 224 consultations and interviews was analyzed, regarding the structuring and sequences in each consultation. Most space in the unbiased doctor's descriptions took anamnesis, followed by therapy, investigation, followed by physical examination and, least, diagnosis. Urban doctors kept the classic scheme of succeeding anamnesis, investigation, diagnosis and therapy more often than their rural colleagues. Explanations to patients were more frequently done by country doctors. The words doctors used to indicate communication are listed. The term of resonance phase in consultation is discussed. To achieve clarity in the consultation is important for doctor's stress prophylaxis.


The risk of COVID-19 transmission upon return to sport: a systematic review.
To evaluate COVID-19 transmission rates in athletes upon return to sport (RTS), as well as the effectiveness of preventive and surveillance measures associated with RTS. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the PubMed, Embase, and Cochrane Library databases were searched to identify all articles reporting on RTS during COVID-19. Articles were excluded on the basis of the following criteria: (1) non-English text, (2) only abstract available, (3) population not athlete-specific, (4) outcome not RTS-specific, (5) COVID-19 transmission data not quantified, (6) editorial, or (7) review article or meta-analysis. Study characteristics; athlete demographics; COVID-19 preventive, surveillance, and diagnostic measures; COVID-19 transmission outcomes; and RTS recommendations were collected from each included article and analyzed. 10 studies were included in the final analysis, comprising over 97,000 athletes across a wide variety of sports, levels of play, and RTS settings. Of the 10 studies, eight identified low transmission rates and considered RTS to be safe/low risk. Overall, COVID-19 transmission rates were higher in athletes than in contacts, and more prevalent in the greater community than in athletes specifically. The risk of COVID-19 did not appear to be necessarily higher for athletes who played high-contact team sports, shared common facilities, or lived in communities impacted by high transmission rates, provided that rigorous COVID-19 safety and testing protocols were implemented and followed. Mask wearing and physical distancing during active play presented the greatest challenge to athletes. Rigorous preventive and surveillance measures can mitigate the risk of COVID-19 transmission in athletes upon RTS. However, the heterogeneity of RTS playing conditions, availability of COVID-19 resources, rise of unforeseen novel variants, and undetermined long-term impact of vaccination on athletes remain a challenge to safe and effective RTS in the era of COVID-19.


Insight into the gas-phase structure of a copper(II) L-histidine complex, the agent used to treat Menkes disease.
Copper(II) L-histidine is used in the treatment of a rare neurological disease called Menkes disease. An infrared multiple photon dissociation (IRMPD) vibrational spectrum of the gas-phase copper(II) L-histidine complex has been obtained. This spectrum was compared to lowest-energy computational spectra obtained at the B3LYP/6-311+G** level of theory. Two species, CuHis1 and CuHis2, are very close in Gibbs free energy, and both have computed vibrational spectra in good agreement with the experimentally observed IRMPD spectrum. The first structure exhibits four histidine-copper interactions in the same plane and a fifth out-of-plane interaction. The second structure exhibits four histidine-copper interactions in the same plane. The fact that the experimental and computational spectra are found to be in good agreement adds considerable insight into the gas-phase structure of the copper(II) L-histidine complex.


Defective platelet aggregation and increased platelet turnover in patients with myelofibrosis and other myeloproliferative diseases.
In 9 patients with myeloproliferative diseases (MPD) (6 with myelofibrosis, MF, 1 with Ph1 positive chronic granulocytic leukaemia, CGL, 1 with primary eosinophilia, PE, 1 with pre-leukaemia syndrome, preL) collagen, epinephrine, and ADP-induced aggregation, N-ethylmaleimide-induced malondialdehyde (MDA) production, beta-thromboglobulin (beta-TG) plasma levels, and platelet turnover were studied. Collagen-induced aggregation was found to be normal in 7 patients, absent in 1, and reduced in 1. In all but 3 patients, aggregation with ADP was markedly reduced. Epinephrine-induced aggregation was decreased in 7 patients. No difference was found between mean MDA production in MPD (3.21 +/- 0.50 nmol/10(9) PLTs) and in control group of 21 normal subjects (3.04 +/- 0.26 nmol/10(9) PLTs). Mean beta-TG levels were significantly higher (P less than 0.01) in MPD patients (165.00 +/- 28.29 ng/ml) than in healthy controls (81.76 +/- 14.63 ng/ml). Mean platelet production half-time was significantly shorter in MPD (2.48 +/- 0.24 d) than in the control group (3.43 +/- 0.17 d), after adjustment for age by covariance analysis (P less than 0.005). Our data do not indicate an abnormal prostaglandin synthesis and are consistent with the hypothesis that a disseminated intravascular platelet aggregation might take place in MPD patients.


Alpha1-antitrypsin determines the pattern of emphysema and function in tobacco smoke-exposed mice: parallels with human disease.
Cigarette smoking in humans is associated with various patterns of emphysema and functional consequences. We tested the hypothesis that variations in alpha1-antitrypsin expression modulate the pattern of emphysema and functional consequences in cigarette smoke-exposed mice. We compared the effects of up to 6 months of cigarette smoke exposure in C57BL/6J (C57) mice and in low-alpha1-antitrypsin, C57BL/6J pa+/pa+ (pallid) mice. At the end of the experiment, we determined lung mechanical properties, the extent (mean linear intercept) and type of emphysema, and the cellular inflammatory response. After 4 months of cigarette smoking, pallid smoking mice, but not C57 smoking mice, had a significant increase in mean linear intercept. After 6 months of smoke exposure, C57 smoking mice and pallid smoking mice had similar degrees of emphysema. The pattern of emphysema in pallid smoking mice was more diffuse than in C57 smoking mice, affecting all airspaces. Pallid mice, but not C57 mice, developed a T cell inflammation in the alveolar wall after 6 months of smoking (p < 0.01). Although lung compliance was not changed in C57 smoking mice after smoke exposure, it increased significantly in pallid smoking mice over the 6 months of exposure (p < 0.0082). In summary, cigarette smoking induces emphysema in C57 and pallid mice, but the emphysema, inflammatory infiltrate, and resulting physiologic abnormalities were substantially different in the two strains, with the C57 and pallid mice exhibiting features similar to centrilobular and panlobular emphysema, respectively.


Protein unfolding and subsequent refolding: a spectroscopic investigation.
The mechanism by which the protein Bovine Serum Albumin (BSA) undergoes unfolding induced by Guanidine Hydrochloride (GdHCl) and then the subsequent refolding brought in by many-fold dilution was studied by steady-state fluorescence, anisotropy, time resolved measurements and Circular Dichroism (CD) spectroscopy. CD data reveal that the protein attains a degree of extra rigidity at low concentrations of the denaturant, GdHCl, and this observation was correlated with other techniques used in this present work. The unfolding and refolding of BSA appear to proceed through intermediates and both the processes are sequential in nature. The intrinsic fluorescence from the tryptophan amino acid residue of BSA and another external fluorophore Nile Red was made use of in order to investigate the mechanisms of unfolding and refolding and we have conclusively proved that both these processes follow a reversible mechanism.


Improved sintering performance of β-SiAlON-Si3N4 and its osteogenic differentiation ability by adding β-SiAlON.
To improve the sintering performance of silicon nitride bioceramics, we explored the effect of β-SiAlON's Z-value on the physical, chemical, and biological properties of β-SiAlON-Si3N4 composites. Results showed that the phase product was β-Si3N4. As the Z-value increased, the X-ray diffraction peaks gradually shifted to a smaller angle, the material grains were more tightly packed, and the bulk density and compressive strength increased, reaching the highest values (2.71 g/cm3 and 1157 MPa, respectively) at Z = 4. Soaking and ion-release experiments show that in an aqueous environment, a small amount of Al and Si ions were released, and no obvious decomposition occurred on the surface of the material. The biological performance showed that the growth of cultured cells in each group was in good condition, there was no obvious difference in morphology and adhesion, and the materials had good biological performance. An increase in the Z-value promotes the formation of mineralized nodules and osteogenic differentiation of MC3T3-E1 cells, which may be because the release of Si can promote osteogenic differentiation. Therefore, the addition of β-SiAlON could improve the sintering performance of β-Si3N4 without degrading its biological properties. The prepared β-SiAlON-Si3N4 composite ceramic is a latent bioceramic material.


Human Ku70 protein binds hairpin RNA and double stranded DNA through two different sites.
Human protein Ku usually functions in the cell as a complex of two subunits, Ku70 and Ku80. The Ku heterodimer plays a key role in the non-homologous end joining DNA repair pathway by specifically recognizing the DNA ends at the site of the lesion. The binding of the Ku heterodimer to DNA has been well-studied, and its interactions with RNA have been also described. However, Ku70 subunit is known to have independent DNA binding capability, which is less characterized. RNA binding properties of Ku70 have not been yet specially studied. We have prepared recombinant full-length Ku70 and a set of its truncated mutants in E. coli, and studied their interactions with nucleic acids of various structures: linear single- and double-stranded DNA and RNA, as well as closed circular DNA and hairpin RNA. Ku70 has demonstrated a high affinity binding to double stranded DNA and hairpin RNA with a certain structure only. Interestingly, in contrast to the Ku heterodimer, Ku70 is found to interact with closed circular DNA. We also show for the first time that Ku70 employs two different sites for DNA and RNA binding. The double-stranded DNA is recognized by the C-terminal part of Ku70 including SAP domain as it has been earlier demonstrated, whereas hairpin RNA binding is provided by amino acids 251-438.


Examination of Imported Cheeses for Aflatoxin M1.
A total of 118 imported cheeses from 13 countries were analyzed for aflatoxin M1. Six were very hard types that included Parmesan, Romano and Sapsago; 74 were hard types that included Swiss and Cheddar; and 38 were soft or semisoft types, mainly Camembert and cheese spreads. Eight (6.8%) contained aflatoxin M1 at levels of 0.1 to 1.0 ng/g (limit of determination was 0.05 ng/g).


Confocal backscatter laser velocimeter with on-axis sensitivity.
A confocal backscatter laser Doppler velocimeter (LDV) that measures two velocity components has been developed. This device requires only two incident beams polarized normally to one another. Moreover, the velocity components sensed are nearly orthogonal. The velocimeter employs a combined dual-scatter, local oscillator arrangement to obtain the bidirectional sensitivity. Two photodetectors are used, each sensing only one Doppler frequency proportional to one of the very nearly orthogonal velocity components. In addition, a single Bragg cell serves to frequency bias both velocity components in order to eliminate directional ambiguity. A differencing technique has also been incorporated to enhance the dual-scatter Doppler signal corresponding to the transverse velocity.


Photodynamic Diagnosis-Assisted Transurethral Resection Using Oral 5-Aminolevulinic Acid Decreases the Risk of Repeated Recurrence in Non-Muscle-Invasive Bladder Cancer: A Cumulative Incidence Analysis by the Person-Time Method.
Clinical evidence regarding risk reduction of repeated bladder recurrence after initial photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT) is still limited in patients with non-muscle-invasive bladder cancer (NMIBC). We analyzed patients with primary NMIBC undergoing TURBT without any adjuvant treatment to compare the risk of cumulative recurrence between the conventional white-light (WL)-TURBT and PDD-TURBT. Out of 430 patients diagnosed with primary NMIBC from 2010 to 2019, 40 undergoing WL-TURBT and 60 undergoing PDD-TURBT were eligible. Multivariate Cox regression analysis for time to the first recurrence demonstrated that PDD assistance was an independent prognostic factor with better outcome (p = 0.038, hazard ratio = 0.39, and 95% confidence interval 0.16-0.95). While no patient experienced more than one recurrence within 1000 postoperative days in the PDD-TURBT group, five out of 40 patients treated by WL-TURBT experienced repeated recurrence. The comparison of cumulative incidence per 10,000 person-days between the two groups revealed that PDD assistance decreased by 6.6 recurrences per 10,000 person-days (exact p = 0.011; incidence rate ratio 0.37, Clopper-Pearson confidence interval 0.15-0.82). This is the first study addressing PDD assistance-induced risk reduction of repeated bladder recurrence using the person-time method. Our findings could support clinical decision making, especially on adjuvant therapy after TURBT.


Poly-L-lactide surfaces subjected to long-term cell cultures: cell proliferation and polymer degradation.
Short term cell cultures are usually grown in contact with biomaterials to assess cytocompatibility. Depending on the rate of material degradation or corrosion, the time of culture can be a key-point in the method which, if too short, may not show any effect of the released material on the cells. A long term culture was therefore carried out with L929 fibroblast cells in contact with PLLA/PDLA samples for up to eight months. The degradation was measured in terms of shear-strength properties, intrinsic viscosity of the material and its cristallinity. The effect of the material on the cells was evaluated by measuring the growth rate of the cells. A significant decrease in the shear strength of the material was measured after three months. The rate of modification of the intrinsic viscosity was regular and decreased progressively throughout the culture period. Differential scanning calorimetry showed that the samples were initially essentially amorphous and that contact with the cell culture and its medium did not change its crystallinity level. The growth rate of the cells was not modified by the presence of the material when compared to the control. This study showed this material to be cytocompatible for a long period of time, even after detection of modifications of its physico-chemical properties.


[Analysis of phenotypes and genotypes in 66 patients with 21-hydroxylase deficiency identified by neonatal screening].
To analyze the phenotype-genotype correlation of 21-hydroxylase deficiency (21-OHD) patients found by neonatal screening, and to investigate the characteristics of gene frequency of these patients. Clinical and biochemical data of 66 21-OHD patients diagnosed by neonatal screening in department of pediatric endocrinology and genetics and neonatal screening center of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from 2009 to 2014 were retrospectively analyzed. Point mutations of CYP21A2 gene were analyzed by Sanger sequencing, and large gene deletions were detected by multiplex ligation-dependent probe amplification (MLPA). Then the correlation between phenotypes and genotypes of these patients were analyzed. (1) Forty-one out of 66 patients who presented adrenal crisis or other signs of salt loss at age range from 4 days to 2 months were classified as salt-wasting forms. The remaining 25 patients did not present any signs of salt loss at preliminary diagnosis (12 days-2 months). (2) Definite mutations of CYP21A2 gene on two alleles were found in all 66 patients (132 alleles). A total of thirteen types of different point mutations (98/132, 74.2%), large gene deletions (24/132, 18.2%) and clusters of point mutations (10/132, 7.6%) were found. The most frequent point mutations were I2G, p. I173N, p. R357W, p. G111Vfs*21 and p. Q319*, accounting for 65.2% of alleles. (3) Phenotype and genotype correlation analysis was performed in 41 21-OHD patients with salt wasting forms. Predicted phenotypes according to genotypes in 36 (87.8%) of the 41 patients were consistent with their actual phenotypes. In 4 out of the 41 patients, the actual phenotypes were different from predicted phenotypes according to their genotypes. And in one patient, prediction of phenotype could not be made based on genotype as carrying an unknown function mutation on one allele. Adrenal crisis or other signs of salt loss were found in 62% of 21-OHD patients at age range from 4 days to 2 months. In 66 Chinese 21-OHD children, total mutation frequency of I2G, p. I173N, p. R357W, p. G111Vfs*21 and p. Q319* accounted for 65.2% of alleles. In 87.8% of patients with salt wasting forms, predicted phenotypes according to genotypes were consistent with their actual phenotypes.


Measurement of spleen size using gamma camera scintigraphy in essential thrombocythaemia.
By using gamma camera imaging the spleen size was determined in 33 consecutive patients with essential thrombocythaemia (ET) and in 33 consecutive patients with reactive thrombocytosis (RT). All ET patients were newly diagnosed and had not received myelosuppressive treatment prior to study; they all fulfilled the criteria for ET as established by the Polycythemia Vera Study Group. In both posterior and lateral projections, the spleen area in the group of ET patients was significantly larger than in the RT patients. The present study has shown that 39% of ET patients at diagnosis have splenic enlargement. Evaluation of spleen size is therefore a useful diagnostic test in patients presenting with unexplained thrombocytosis.


Cropland redistribution to marginal lands undermines environmental sustainability.
Cropland redistribution to marginal land has been reported worldwide; however, the resulting impacts on environmental sustainability have not been investigated sufficiently. Here we investigated the environmental impacts of cropland redistribution in China. As a result of urbanization-induced loss of high-quality croplands in south China (∼8.5 t ha-1), croplands expanded to marginal lands in northeast (∼4.5 t ha-1) and northwest China (∼2.9 t ha-1) during 1990-2015 to pursue food security. However, the reclamation in these low-yield and ecologically vulnerable zones considerably undermined local environmental sustainability, for example increasing wind erosion (+3.47%), irrigation water consumption (+34.42%), fertilizer use (+20.02%) and decreasing natural habitats (-3.11%). Forecasts show that further reclamation in marginal lands per current policies would exacerbate environmental costs by 2050. The future cropland security risk will be remarkably intensified because of the conflict between food production and environmental sustainability. Our research suggests that globally emerging reclamation of marginal lands should be restricted and crop yield boost should be encouraged for both food security and environmental benefits.


Observation of sperm-head vacuoles and sperm morphology under light microscope.
The presence of sperm-head vacuoles has been suspected to be deleterious to the outcomes of assisted reproductive technology (ART). It is difficult to accurately distinguish morphologically abnormal sperm with vacuoles under a light microscope. This study was performed to analyze the result of the observation of sperm-head vacuoles using Papanicolaou staining under a light microscope and whether the male partner's age affects these vacuoles. Sperm morphology with vacuoles was evaluated using Papanicolaou staining and observed under a light microscope (400×) in 980 men. The normal morphology was divided into three categories (group A, <4% of normal morphology; group B, 4%-14% of normal morphology; and group C, >14% of normal morphology). The criteria for the sperm-head vacuoles were those given in the World Health Organization manual. For the analysis of the age factor, the participants were divided into the following groups: 26-30 years, 31-35 years, 36-40 years, 41-45 years, and 46-50 years. The percentage of sperm-head vacuoles increased with normal sperm morphology (group A vs. groups B, C) (p<0.05). In the case of the age factor, a statistically significant difference was not observed across any of the age groups. A majority of the sperm-head vacuoles showed a statistically significant difference among normal morphology groups. Therefore, we should consider the probability of the percentage of sperm-head vacuoles not increasing with age but with abnormal sperm morphology. A further study is required to clarify the effect of the sperm-head vacuoles on ART outcomes.


Population pharmacokinetics and dosing recommendations for cisplatin during intraperitoneal peroperative administration: development of a limited sampling strategy for toxicity risk assessment.
Ovarian cancer is the leading cause of gynaecological cancer-related death in Western countries. Intraperitoneal (IP) peroperative chemotherapy is an interesting therapeutic option. However, very few data are available regarding pharmacokinetics and especially population pharmacokinetics. Thirty-one patients with advanced epithelial cancer classified as International Federation of Gynecology and Obstetrics stage IIIC were included in the study. Blood and IP samples were taken over a 24-hour period during and after IP treatment. Both total and ultrafiltered (Uf) platinum (Pt) concentrations were analysed using a population approach with nonlinear mixed-effects modelling (NONMEM) software. Improvement of the model with covariates was performed as well as assessment of the model using bootstrap and posterior visual predictive methods. Both IP fluid and serum pharmacokinetics were satisfactorily described with a three-compartment model for both Uf Pt and total Pt concentrations. The covariates were bodyweight for the IP volume of distribution in the Uf Pt model, and both IP and serum protein concentrations for the clearance from the central compartment in the total Pt model. A nomogram, based on the results of the Monte Carlo simulations, displays a dose recommendation regarding both the risk of renal toxicity and the potent efficacy of the treatment. A limited sampling strategy (LSS) allowing the estimation of potential risk of renal toxicity is also described. The pharmacokinetics of cisplatin during peroperative IP chemotherapy could be successfully fitted with the present model, which allowed a dosing strategy accompanied by an LSS to facilitate the follow-up of patients.


Activation of Saccharomyces cerevisiae Mlh1-Pms1 Endonuclease in a Reconstituted Mismatch Repair System.
Previous studies reported the reconstitution of an Mlh1-Pms1-independent 5' nick-directed mismatch repair (MMR) reaction using Saccharomyces cerevisiae proteins. Here we describe the reconstitution of a mispair-dependent Mlh1-Pms1 endonuclease activation reaction requiring Msh2-Msh6 (or Msh2-Msh3), proliferating cell nuclear antigen (PCNA), and replication factor C (RFC) and a reconstituted Mlh1-Pms1-dependent 3' nick-directed MMR reaction requiring Msh2-Msh6 (or Msh2-Msh3), exonuclease 1 (Exo1), replication protein A (RPA), RFC, PCNA, and DNA polymerase δ. Both reactions required Mg(2+) and Mn(2+) for optimal activity. The MMR reaction also required two reaction stages in which the first stage required incubation of Mlh1-Pms1 with substrate DNA, with or without Msh2-Msh6 (or Msh2-Msh3), PCNA, and RFC but did not require nicking of the substrate, followed by a second stage in which other proteins were added. Analysis of different mutant proteins demonstrated that both reactions required a functional Mlh1-Pms1 endonuclease active site, as well as mispair recognition and Mlh1-Pms1 recruitment by Msh2-Msh6 but not sliding clamp formation. Mutant Mlh1-Pms1 and PCNA proteins that were defective for Exo1-independent but not Exo1-dependent MMR in vivo were partially defective in the Mlh1-Pms1 endonuclease and MMR reactions, suggesting that both reactions reflect the activation of Mlh1-Pms1 seen in Exo1-independent MMR in vivo. The availability of this reconstituted MMR reaction should now make it possible to better study both Exo1-independent and Exo1-dependent MMR.


The role of obinutuzumab in the management of follicular lymphoma.
The outcomes for follicular lymphoma (FL) have improved significantly in recent years. This has been driven by an improved understanding of the pathobiology of FL and the development of therapeutic anti-CD20 antibodies. Combining rituximab with chemotherapy, coupled with its use as maintenance therapy, has contributed to significant improvements in disease control and progression-free survival. However, FL remains incurable and almost all patients invariably relapse. Therefore, there remains a need to develop novel therapeutic options and optimize existing regimens. Obinutuzumab (a first-in-class, glycoengineered, humanized type 2 anti-CD20 antibody) has been evaluated in a number of clinical trials. In this review, we will summarize the evaluable results of clinical trials investigating the efficacy of obinutuzumab in the treatment of FL.


Covert orienting in three etiologies of congenital hydrocephalus: the effect of midbrain and posterior fossa dysmorphology.
Covert orienting is related to the integrity of the midbrain, but the specificity of the relation is unclear. We compared covert orienting in three etiologies of congenital hydrocephalus (aqueductal stenosis [AS], Dandy-Walker malformation [DWM], and spina bifida myelomeningocele [SBM]--with and without tectal beaking) to explore the effects of midbrain and posterior fossa malformations. We hypothesized a stepwise order of group performance reflecting the degree of midbrain tectum dysmorphology. Performance on an exogenously cued covert orienting task was compared using repeated measures analysis of covariance, controlling for age. Individuals with SBM and tectal beaking demonstrated the greatest disengagement cost in the vertical plane, whereas individuals with AS performed as well as a typically developing (TD) group. Individuals with SBM but no tectal beaking and individuals with DWM showed greater disengagement costs in the vertical plane relative to the TD group, but better performance relative to the group with SBM and tectal beaking. Individuals with AS, DWM, and SBM and tectal beaking demonstrated poorer inhibition of return than TD individuals. Impairments in attentional disengagement in SBM are not attributable to the general effects of hydrocephalus, but are instead associated with specific midbrain anomalies that are part of the Chiari II malformation.


Unruptured intracranial aneurysms and the assessment of rupture risk based on anatomical and morphological factors: sifting through the sands of data.
Aneurysmal subarachnoid hemorrhage continues to have high rates of morbidity and mortality for patients despite optimal medical and surgical management. Due to the fact that aneurysmal rupture can be such a catastrophic event, preventive treatment is desirable for high-risk lesions. Given the variability of the literature evaluating unruptured aneurysms regarding basic patient population, clinical practice, and aneurysm characteristics studied, such as size, location, aspect ratio, relationship to the surrounding vasculature, and the aneurysm hemodynamics, a meta-analysis is nearly impossible to perform. This review will instead focus on the various anatomical and morphological characteristics of aneurysms reported in the literature with an attempt to draw broad inferences and serve to highlight pressing questions for the future in our continued effort to improve clinical management of unruptured intracranial aneurysms.


An Eight-CpG-based Methylation Classifier for Preoperative Discriminating Early and Advanced-Late Stage of Colorectal Cancer.
To develop and validate a CpG-based classifier for preoperative discrimination of early and advanced-late stage colorectal cancer (CRC). We identified an epigenetic signature based on methylation status of multiple CpG sites (CpGs) from 372 subjects in The Cancer Genome Atlas (TCGA) CRC cohort, and an external cohort (GSE48684) with 64 subjects by LASSO regression algorithm. A classifier derived from the methylation signature was used to establish a multivariable logistic regression model to predict the advanced-late stage of CRC. A nomogram was further developed by incorporating the classifier and some independent clinical risk factors, and its performance was evaluated by discrimination and calibration analysis. The prognostic value of the classifier was determined by survival analysis. Furthermore, the diagnostic performance of several CpGs in the methylation signature was evaluated. The eight-CpG-based methylation signature discriminated early stage from advanced-late stage CRC, with a satisfactory AUC of more than 0.700 in both the training and validation sets. This methylation classifier was identified as an independent predictor for CRC staging. The nomogram showed favorable predictive power for preoperative staging, and the C-index reached 0.817 (95% CI: 0.753-0.881) and 0.817 (95% CI: 0.721-0.913) in another training set and validation set respectively, with good calibration. The patients stratified in the high-risk group by the methylation classifier had significantly worse survival outcome than those in the low-risk group. Combination diagnosis utilizing only four of the eight specific CpGs performed well, even in CRC patients with low CEA level or at early stage. Our classifier is a valuable predictive indicator that can supplement established methods for more accurate preoperative staging and also provides prognostic information for CRC patients. Besides, the combination of multiple CpGs has a high value in the diagnosis of CRC.


Characterization of the Foreign Body Response to Common Surgical Biomaterials in a Murine Model.
Implanted biomaterials are subject to a significant reaction from the host, known as the foreign body response (FBR). We quantified the FBR to five materials following subcutaneous implantation in mice. Polyvinyl alcohol (PVA) and silicone sheets are considered highly biocompatible biomaterials and were cut into 8mm-diameter disks. Expanded PTFE (ePTFE)and polypropylene are also widely used biocompatible biomaterials and were cut into 2cm-long cylinders. Cotton was selected as a negative control material that would invoke an intense FBR, was cut into disks and implanted. The implants were inserted subcutaneously into female C57BL/6 mice. On post-implantation days 14, 30, 60, 90 and 180, implants were retrieved. Cellularity was assessed with DAPI stain, collagen with Masson's trichrome stain. mast cells with toluidine-blue, macrophages with F4/80 immunohistochemical-stain, and capsular thickness and foreign body giant cells with hematoxylin & eosin. DAPI revealed a significantly increased cellularity in both PVA andsilicone, and ePTFE had the lowest cell density. Silicone showed the lowest cellularity at d14 and d90 whereas ePTFE showed the lowest cellularity at days 30, 60, and 180. Masson's trichrome staining demonstrated no apparent difference in collagen. Toluidine blue showed no differences in mast cells. There were, however, fewer macrophages associated with ePTFE. On d14, PVA had highest number of macrophages, whereas polypropylene had the highest number at all time points after d14. Giant cells increased earlier and gradually decreased later. On d90, PVA exhibited a significantly increased number of giant cells compared to polypropylene and silicone. Silicone consistently formed the thinnest capsule throughout all time points. On d14, cotton had formed the thickest capsule. On d30 polypropylenehas formed thickest capsule and on days 60, 90 and 180, PVA had formed thickest capsule. These data reveal differences in capsule thickness and cellular response in an implant-related manor, indicating that fibrotic reactions to biomaterials are implant specific and should be carefully considered when performing studies on fibrosis when biomaterials are being used.


Sustained focal effects of low-dose intramuscular succinylcholine.
We studied low-dose intramuscular succinylcholine in 9 subjects as part as an ongoing investigation of its potential to predict responses to botulinum toxin. We measured compound muscle action potentials (CMAPs) from the extensor digitorum brevis (EDB) muscles in each foot before and after intramuscular injections of 2.5 mg of succinylcholine into the EDB. Succinylcholine reduced mean CMAP amplitudes to 42% of baseline; the maximal reduction occurred at 19 +/- 6 (mean +/- standard deviation) minutes. Recovery to 73% of the baseline CMAP amplitude (approximately 50% recovery from block) occurred at 105 +/- 49 minutes after injection. Repetitive (train-of-four) stimulation at 2 Hz produced mild CMAP decrements (5-25%), but only during the recovery phase. Varying the succinylcholine concentrations (10, 20, or 50 mg/mL) while holding the total drug dose constant did not change the rate of onset or the extent of block. No systemic complications occurred. We conclude that: (1) 2.5 mg intramuscular succinylcholine can safely induce selective muscle weakness with a time course that differs from intravenously administered succinylcholine; and (2) further clinical studies comparing intramuscular succinylcholine and botulinum toxin are warranted.


Acute Management of Iatrogenic Injury to Vertebral Artery With Central Venous Catheter in a Critically Ill Patient.
Vertebral artery (VA) injury during catheterization is quite rare given its anatomical position, but can be catastrophic when it is not discovered early on and managed accordingly. A multidisciplinary approach to the management of such injury has to weigh-in the benefits and risks of open surgery versus endovascular intervention. This can be done after thorough assessment of the patient's condition and accessibility of the injured vessel. We report a case of a 90-year-old female admitted as a case of pneumonia associated with decreased level of consciousness. She acquired an iatrogenic injury due to insertion of central venous catheter (CVC) into her dominant right VA as confirmed via CT angiography (CTA). This case report aims to highlight the role of endovascular intervention in the acute management of VA injury in a critically ill patient.


Vegetative and reproductive phenology of a floodplain tree species Barringtonia acutangula from North East India.
Vegetative and reproductive phenology of Barringtonia acutangula, a floodplain tree species was studied at Chatla floodplain, Assam North East India with the aim to investigate vegetative and reproductive phenology under stressful environment of seasonal submergence and to assess the impact of environmental variables (temperature and precipitation) on tree phenophases. Quantitative assessment was made at 15 day interval for all the phenophases (leaf initiation, leaf-fall, flowering and fruiting) by tagging 40 (forty) trees over aperiod of two years (2012-14).To test seasonal influence on the phenology of Barringtonia acutangula different phenophases were correlated with environmental variables and statistical spearman's rank correlation coefficient was employed. Aridity index was computed that delineate influence of rainfall and temperature together on any phenophases. Leaf initiation showed positively significant correlation with temperature (r(s) = 0.601, p = < .05) during the year 2012-2013 whereas it was significantly correlated with rainfall (r(s) = 0.583, p = < .05) and aridity index (r(s) = 0.583, p = < .05) during the year 2013-2014. Leaf-fall was significant negatively correlated with temperature (r(s) = -0.623, p = < .05), rainfall (r(s) = -0.730, p = < .01) and aridity index (r(s) = -0.730, p = < .01) for both the studied years. Flowering was significantly influenced by temperature (r(s) = 0.639, p = < .05), rainfall (r(s) = 0.890, p = < .01) and aridity index (r(s) = 0.890, p = < .01) while in one month lag flowering was significantly correlated with rainfall (r(s) = 0.678, p = < .01) in 2012-13. Fruiting was also positively significant with temperature (r(s) = 0.795, P < .05), rainfall (r(s) = 0.835, P < .01) and aridity index (r(s) = 0.835, P < .01) for both the years. During one month lag period fruiting was positively correlated with temperature, rainfall and aridity index in both the years. Temperature, rainfall and aridity index were major determinants of the various vegetative and reproductive phenology of B. acutangula and any changes in these variables in future due to climate change, might have profound effect on phenophases of this tree species.


A comparison of demographic and psychosexual characteristics of women with primary versus secondary provoked vestibulodynia.
Provoked vestibulodynia (PVD) is a distressing genital pain condition affecting approximately 12% of premenopausal women. It has been speculated that primary (ie, lifelong) and secondary (ie, acquired) PVD may represent 2 distinct conditions with different etiologies. There is also evidence that primary and secondary PVD subtypes may respond differently to conventional treatments. The goal of this study was to compare the demographic, clinical, and psychosexual characteristics of a large sample of premenopausal women with primary and secondary PVD. A total of 132 premenopausal women (n=42 primary; n=90 secondary) with PVD who sought treatment in a Multidisciplinary Vulvodynia Program completed demographic questions and a battery of validated self-report measures before treatment. Women with primary PVD had a longer duration of PVD as well as more time before diagnosis. Women with secondary PVD reported significantly more clitoral hood pain, higher overall vestibular pain levels, more overall sexual dysfunction and sex-related distress, and proportionately more intercourse occasions that were painful. Women with primary pain stated they had significantly more dysmenorrhea and were more likely to report that their partners were unaware of their PVD symptoms. There were no significant subtype differences on any psychological measure but a trend towards higher magnification of symptoms in women with secondary PVD. Overall the findings suggest some important differences in the characteristics of women with primary versus secondary PVD which may have management-related implications.


Production of the RdxA protein in metronidazole-susceptible and -resistant isolates of Helicobacter pylori cultured from treated mice.
The objective of this study was to use immunoblotting with RdxA antisera to examine the production of the RdxA protein in mouse-derived metronidazole-susceptible and -resistant isolates of Helicobacter pylori. A 24 kDa immunoreactive band corresponding to RdxA was observed in all 15 metronidazole-susceptible and five of 50 metronidazole-resistant isolates. The rdxA gene of these five isolates contained missense mutations and transformation experiments confirmed that these mutations were associated with inactivation of the rdxA gene. No RdxA protein was produced in the other 45 metronidazole-resistant strains, including one in which the nucleotide sequence of the rdxA gene was unchanged. These results demonstrate a high correlation between production of the RdxA protein and susceptibility of H. pylori to metronidazole. Testing for the absence of the RdxA protein identifies the majority of strains that will respond poorly to metronidazole-containing eradication regimens.


Localized amyloidosis of the head and neck and upper aerodigestive and lower respiratory tracts.
Seven cases of localized amyloidosis limited to structures of the head and neck and upper aerodigestive and lower respiratory tracts evaluated and treated at Boston University Hospitals in a recent 7-year period were reviewed. Negative Congo red staining of abdominal adipose aspiration biopsy or rectal biopsy specimens established that the amyloidosis was not systemic. Localized amyloidosis occurred in discrete masses in a variety of sites in the aerodigestive tract including the orbit, nasopharynx, lips, floor of mouth, tongue, larynx, and tracheobronchial tree. Five patients required surgical excision because of significant airway obstruction or organic dysfunction. Amyloid deposits completely excised with the carbon dioxide laser have not recurred, though other amyloid masses may appear elsewhere within the same organ or region. Amyloidosis may occur primarily or secondarily to other disease states. Localized amyloidosis has not been chemically identified but is usually defined by the absence of systemic features. While rare, amyloidosis must be recognized and understood by the otolaryngologist/head and neck surgeon to allow appropriate diagnostic and therapeutic planning.


Roles of epithelial-mesenchymal transition in cancer drug resistance.
Overcoming intrinsic and acquired drug resistance is a major challenge in treating cancer. Poor responses to drug treatment can result in metastasis, cancer dissemination and death. Recently, the epithelial-mesenchymal transition (EMT) has been found to play a critical role in cancer drug resistance, but the nature of this intrinsic link remains unclear. This review summarizes recent advances in the understanding of drug resistance and focuses especially on the association between EMT and drug resistance. We discuss the roles of EMT in regulating drug resistance across different types of cancer, focusing simultaneously on the molecular mechanisms and potential pathways involved in the regulation of drug resistance by EMT. In addition, we discuss potential therapeutic strategies to target EMT to reverse drug resistance.


[The use of spinal analgesia in urology].
The past few years are marked by a renewed interest in regional analgesia application in urological practice. The opinion is set forth that this is attributable to the new technique for spinal analgesia suggested, as well as to the influence exerted by the improved endoscopic electroresection technique. To assay spinal analgesia performed by the new technology, the clinical course of spinal analgesia, level of block, expenditure of analgetics, blood loss and changes in hemodynamics are studies in a series of 202 patients, operated in the Clinical Center of Urology. As shown by the results, the block occurs promptly and last for three hours against the background of stable hemodynamics and blood loss reduction. There are no changes in gas exchange and acid-base balance, nor complaints of post-puncture headache. Proceeding from the aforementioned findings, vindication of the spinal analgesia method in urology is proposed.


Perceived challenges in implementing halal standards by halal certifying bodies in the United States.
Islamic dietary laws inform halal standards, defining which foods are halal (lawful and permissible). Many halal foods are produced in non-Muslim majority countries increasing the likelihood they might be haram (prohibited). Halal certification is one way to operationalize halal standards, hence protecting Muslim consumers. At present there is no unified halal standard guiding halal certification. The aim of this study was to determine the perceived challenges in implementing halal standards in the United States. Semi-structured in-depth interviews were done with a representative from 6 of the 11 halal certifying bodies (HCBs) in the United States. All reported their role was to verify food safety records for compliance with government regulations but not to monitor food safety practices. Two main issues-forged halal certificates and expired halal logos were identified as significant issues. Three HCBs stated there is no problem with having multiple halal standards, but all believed it is necessary to have one universal halal standard with minimum standards followed by everyone. The findings of this study can be beneficial to the U.S. halal industry as it highlights the challenges and issues they face.


Medical education in the USA--adult-friendly?
In the United States of America, the Area Health Education Center (AHEC) system of training residents has allowed high-quality postgraduate education to flourish. This paper describes the evolution of the AHECs in the context of medical education over the past 50 years. The arrangements for programme administration and design, resident assessment and appraisal, training of trainers in educational methods, and the accreditation of training programmes are discussed. The fast-evolving UK postgraduate education scene can learn some useful lessons from the US system.


Peroneal Tubercle Hypertrophy: A Case Report.
The peroneal tubercle is an osseous prominence present on the calcaneus bone at the junction between the middle and the anterior third of its lateral surface. It is a bony septum which divides the tendons of the peroneus brevis and the peroneus longus and offers insertion to the inferior peroneal retinaculum. A hypertrophy of this prominence causes pain in the lateral and the posterior part of the foot while wearing shoes, rarely peroneal tenosynovitis can even cause it to break. In the following pages, we will describe a case of peroneal tubercle hypertrophy, visible even at clinical examination, in a 26-year-old male patient without apparent causes nor previous trauma.


Preoperative risk factors associated with symptomatic pulmonary embolism after total knee arthroplasty.
This retrospective case-control study reviewed 124 consecutive patients undergoing cemented total knee arthroplasty under regional anesthesia for osteoarthritis. Seven (5.6%) patients developed symptomatic pulmonary embolism despite warfarin prophylaxis. Bilateral procedures and preoperative hemoglobin were identified as significant risk factors for the development of symptomatic pulmonary embolism after total knee arthroplasty (hemoglobin > or =14 g/L, odds ratio 2.4, confidence interval [CI] 1.2-4.6, and bilateral cases odds ratio 7.2, CI 1.3-39.6). Additionally, preoperative hemoglobin <14 gm/L was associated with a 98% negative predictive value of developing symptomatic pulmonary embolism with a 14% false-negative rate (sensitivity 85.7%, 95% CI 80-92; specificity 67.9%, 95% CI 60-77; positive predictive value 14%, 95% CI .08-2). These findings indicate preoperative hemoglobin levels should be considered in addition to the usual patient demographics in future thromboembolism studies as a potential risk factor for symptomatic pulmonary embolism.


IL-7 and IL-15 differentially regulate CD8+ T-cell subsets during contraction of the immune response.
Although it is known that interleukin-7 (IL-7) and IL-15 influence the survival and turnover of CD8+ T cells, less is known about how these cytokines affect different subsets during the course of the immune response. We find that IL-7 and IL-15 differentially regulate CD8+ T-cell subsets defined by KLRG1 and CD127 expression during the contraction phase of the immune response. The provision of IL-15, or the related cytokine IL-2, during contraction led to the preferential accumulation of KLRG1(hi)CD127(lo) CD8+ T cells, whereas provision of IL-7 instead favored the accumulation of KLRG1(lo)CD127(hi) cells. While IL-7 and IL-15 both induced proliferation of KLRG1(lo) cells, KLRG1(hi) cells exhibited an extraordinarily high level of resistance to cytokine-driven proliferation in vivo despite their dramatic accumulation upon IL-15 administration. These results suggest that IL-15 and IL-2 greatly improve the survival of KLRG1(hi) CD8+ T cells, which are usually destined to perish during contraction, without inducing proliferation. As the availability of IL-15 and IL-2 is enhanced during periods of extended inflammation, our results suggest a mechanism in which a population of cytokine-dependent KLRG1(hi) CD8+ T cells is temporarily retained for improved immunity. Consideration of these findings may aid in the development of immunotherapeutic strategies against infectious disease and cancer.


p53 inhibits JC virus DNA replication in vivo and interacts with JC virus large T-antigen.
The onset of DNA replication is an important step within the life cycle of the human neurotropic polyomavirus JC. In this report, evidence that both the human and the murine tumor suppressor protein p53 strongly inhibit JCV DNA replication in vivo is presented. This inhibition is dose-dependent and not a secondary effect of a decreased expression of JCV large T-antigen in response to p53. Using deletion mutants of murine p53 and tumor-derived point mutations of human p53, the basis of the suppression of JCV DNA replication by p53 was dissected. Deletion of either the amino- or the carboxy-terminal domain of murine p53 did not interfere with the repression of JCV DNA replication. However, deletion of the highly conserved central region of p53 abolished the inhibitory effect on replication. The tumor-derived human mutant p53(His273) inhibited JCV DNA replication significantly, whereas another tumorigenic mutant, p53(His175), had no inhibitory effect Concomitantly, a direct protein-protein interaction between p53 and JCV large T-antigen was lost in mutants which did not affect JCV DNA replication. These results strongly suggest that p53 inhibits JCV DNA replication by interacting with JCV large T-antigen.


Host density predicts the probability of parasitism by avian brood parasites.
The spatial distribution of hosts can be a determining factor in the reproductive success of parasites. Highly aggregated hosts may offer more opportunities for reproduction but can have better defences than isolated hosts. Here we connect macro- and micro-evolutionary processes to understand the link between host density and parasitism, using avian brood parasites as a model system. We analyse data across more than 200 host species using phylogenetic comparative analyses and quantify parasitism rate and host reproductive success in relation to spatial distribution using field data collected on one host species over 6 years. Our comparative analysis reveals that hosts occurring at intermediate densities are more likely to be parasitized than colonial or widely dispersed hosts. Correspondingly, our intraspecific field data show that individuals living at moderate densities experience higher parasitism rates than individuals at either low or high densities. Moreover, we show for the first time that the effect of host density on host reproductive success varies according to the intensity of parasitism; hosts have greater reproductive success when living at high densities if parasitism rates are high, but fare better at low densities when parasitism rates are low. We provide the first evidence of the trade-off between host density and parasitism at both macro- and micro-evolutionary scales in brood parasites. This article is part of the theme issue 'The coevolutionary biology of brood parasitism: from mechanism to pattern'.


Development and Validation of an LC-MS/MS Method to Quantify Gilteritinib and Its Clinical Application in Patients With FLT3 Mutation-Positive Acute Myelogenous Leukemia.
Gilteritinib, a novel oral tyrosine kinase inhibitor, is used to treat acute myeloid leukemia (AML) with FMS-like tyrosine kinase-3 (FLT3) mutations. Therapeutic drug monitoring (TDM) of gilteritinib is important for improving clinical outcomes and ensuring safety. Therefore, this study aimed to develop a simplified method for quantifying gilteritinib in human plasma using liquid chromatography-tandem mass spectrometry. Liquid chromatography was performed by using an Acquity BEH C18 column (50 mm × 2.1 mm, 1.7 μm) and a gradient elution with 0.1% formic acid in water (A) and acetonitrile (B). Detection was performed by using a Shimadzu tandem mass spectrometer through multiple reaction monitoring in the positive-ion mode. The developed method enabled quantification of gilteritinib in 4 minutes and was validated by evaluating selectivity, calibration curve (10-1000 ng/mL, r 2 > 0.99), a lower limit of quantification (LLOQ), accuracy (overall bias -4.2% to 1.9%), precision (intraday CV ≤ 7.9%; interday CV ≤ 13.6%), carryover, recovery, matrix effect, dilution integrity, and stability according to the US Food and Drug Administration (FDA) guidelines. This method was successfully applied to the TDM of gilteritinib trough concentrations in 3 patients with AML. The developed method fulfilled the FDA guideline criteria and can easily be implemented to facilitate TDM in patients receiving gilteritinib in a clinical setting.


Does loading influence the severity of cartilage degeneration in the canine Groove-model of OA?
Many animal models are used to study osteoarthritis (OA). In these models the role of joint loading in the development of OA is not fully understood. We studied the effect of loading on the development of OA in the canine Groove-model. In ten female beagle dogs OA was induced in one knee according to the Groove-model. The animals were divided in groups with and without forced-loading. Forced-loading was achieved by fixing the contra-lateral limb to the trunk 3 times a week for 4 hours. After 20 weeks joint tissues of all dogs were evaluated. Subjective evaluation revealed less movement with more loading in the forced-loading-group compared to the group without forced-loading. In both groups induction of OA resulted in macroscopical and microscopical OA changes as well as alterations in cartilage metabolism characteristics for OA. Although differences were small, for some parameters they were statistically significant for the forced-loading-group. There were no differences between the contra-lateral healthy joints of both groups. The present study demonstrates that in the Groove-model intensified loading is not a prerequisite for the development of OA, although it adds to some extent to the severity of the OA.


Characterization of autoantibodies and cytokines related to cutaneous lupus erythematosus.
To investigate the profiles of anti-RPLP0, anti-galectin3 antibodies, interferon-α (IFN-α), interferon-λ1(IFN-λ1) and interleukin-17A/F(IL-17A/F) in the subtypes of cutaneous lupus erythematosus (CLE) including acute CLE (ACLE), subacute CLE (SCLE) and discoid lupus erythematosus (DLE). Serum levels of autoantibodies and cytokines were determined by enzyme-linked immunoabsorbent assay (ELISA). Lupus lesions were evaluated by cutaneous lupus erythematosus disease area and severity index (CLASI). Serum anti-RPLP0, anti-galectin3 antibodies and IFN-λ1 were higher in systemic lupus erythematosus (SLE) patients with skin lesions than those without skin lesions, compared to healthy controls. IFN-α, IL-17A and IL-17F was elevated in all patients regardless of skin lesions. The two antibodies, IFN-α and IL-17A were positively correlated with the CLASI score in all patients with CLE. In addition, serum IL-17A was positively correlated to the CLASI score of ACLE, SCLE and DLE, while anti-RPLP0 and anti-galectin3 antibodies were only correlated to the score of SCLE and IL-17F to DLE. Serum anti-RPLP0, anti-galectin3 antibodies, IFN-α, IFN-λ1 and IL-17A/F are associated with the occurrence of lupus skin lesions regardless of the systemic complications, whereas the profiles of these inflammatory mediators vary with the subtypes of lupus skin lesions.


Blue Light Interference in the Phytochrome-controlled Germination of the Spores of Cheilanthes farinosa.
Short exposure of the spores of Cheilanthes farinosa to low intensity red light promotes their germination, which is not reversed by a subsequent exposure to far red light. Germination is, however, inhibited by blue light administered before or after red light. Inhibition of germination by blue light is annulled by exposure to a higher intensity of red light, and germination of the repromoted spores is inhibited by far red light. Mutual photoreversibility of germination is also observed in repromoted spores irradiated successively with far red and red light. Although germination appears to be basically under phytochrome control, it is postulated that the presence of a blue light-absorbing pigment interferes with phytochrome transformations in the spores.


Short communication: breast parenchymal patterns and their changes with age.
In studies on mass screening, it has often been reported that tumours in breasts with dense parenchyma are difficult to detect and may have a more advanced stage at diagnosis. Shorter rescreening intervals have been suggested for these women but, before recommending such a strategy, it is important to investigate how often dense breast parenchyma (P2 and DY patterns according to Wolfe) is actually present in a screening population and to what extent these patterns change with age. The prevalence of dense breast parenchyma (P2 and DY) in our study population was 33% at first examination (n = 2581), which is fairly low compared with other screening populations. Its presence was strongly, inversely age-dependent. Breast patterns of 1177 women, aged 35-85 years, were followed for 12 years. In 39% (182/461) of the women with a P2 or DY pattern at their first examination, regression to a lucent pattern (N1 and P1) occurred over the years. The majority of these women were assumed to have reached menopause in the follow-up period. These findings support the hypothesis that the presence of dense breast parenchyma is related to the reproductive period and indicate that shortening the rescreening intervals would be most effective in pre-menopausal age groups.


A radiomics evaluation of 2D and 3D MRI texture features to classify brain metastases from lung cancer and melanoma.
Brain metastases are occasionally detected before diagnosing their primary site of origin. In these cases, simple visual examination of medical images of the metastases is not enough to identify the primary cancer, so an extensive evaluation is needed. To avoid this procedure, a radiomics approach on magnetic resonance (MR) images of the metastatic lesions is proposed to classify two of the most frequent origins (lung cancer and melanoma). In this study, 50 T1-weighted MR images of brain metastases from 30 patients were analyzed: 27 of lung cancer and 23 of melanoma origin. A total of 43 statistical texture features were extracted from the segmented lesions in 2D and 3D. Five predictive models were evaluated using a nested cross-validation scheme. The best classification results were achieved using 3D texture features for all the models, obtaining an average AUC > 0.9 in all cases and an AUC = 0.947 ± 0.067 when using the best model (naïve Bayes).


Six novel transcripts that remove a huge intron ranging from 250 to 800 kb are produced by alternative splicing of the 5' region of the dystrophin gene in human skeletal muscle.
The dystrophin gene, which is mutated in patients with Duchenne and Becker muscular dystrophies, comprises 79 exons and is thus the largest known human gene. A full spectrum of splicing of dystrophin transcript has not been elucidated yet. In this study, 6 novel alternative splicing reactions were discovered in the 5' region by amplifying the cDNA corresponding to exons M1 through 18. Two of these novel transcripts maintain the translational reading frame and are presumed to produce truncated dystrophin, while the other four have disrupted reading frames. The physical distance between splice donor and acceptor sites ranged from 250 kb to 800 kb. Furthermore, the same six alternative splicing products were obtained from mouse skeletal muscle cDNA. This indicated that these novel alternative splicing events are conserved in humans and mice.


Advising families on AD/HD: a multimodal approach.
Nurses who interact with families having children with attention deficit hyperactivity disorder (AD/HD) are perfectly poised to help them understand optimal AD/HD management. While medication can be important in managing AD/HD symptoms, many times it is not a sufficient treatment. A medical examination and a comprehensive neuropsychological or psycho-educational evaluation are important to establish the diagnosis and identify or rule out competing diagnoses and potential co-morbid conditions. A comprehensive evaluation will also lay the groundwork for planning accommodations in school and supports at home that will best facilitate an individual child's learning and development. Nurses can encourage comprehensive evaluations, educate parents about school advocacy, and assist families in understanding ways in which changes in parenting style and the home environment can benefit a child with AD/HD. Nurses can also educate families about the varied professionals and range of resources helpful in managing AD/HD and improving outcomes.


G9a histone methyltransferase inhibitor BIX01294 promotes expansion of adult cardiac progenitor cells without changing their phenotype or differentiation potential.
As a follow-up to our previous reports showing that the G9a histone methyltransferase-specific inhibitor BIX01294 enhances bone marrow cell cardiac potential, this drug was examined for its effects on cardiomyocytes and mouse cardiac progenitor cells (CPCs). Cardiomyocytes and cardiac explants were cultured ± BIX01294, and examined for changes in cardiac function, protein and gene expression. Additionally, enriched populations of CPCs, contained in the 'phase bright cell' component of explants, were harvested from non-treated and BIX01294-treated cardiac tissue, and assayed for differences in cell phenotype and differentiation potential. Mouse CPCs were cultured with rat cardiomyocytes to allow differentiation of the progenitors to be assayed using species-specific PCR primers. While BIX01294 had no discernible effect on myocyte function and sarcomeric organization, treatment with this drug significantly increased CPC proliferation, as indicated by enhanced MTT metabolization and BrdUrd incorporation (4.1- and 2.0-fold, respectively, P < 0.001) after 48 h labelling, and increased Ki67 expression (4.8-fold, P < 0.001) after 7 days culture. Heart explants exposed to BIX01294 generated 3.6-fold (P < 0.005) greater yields of CPCs by 2 weeks culture. Importantly, CPCs obtained from non-treated and BIX01294-treated cultures did not differ in phenotype or differentiation potential. These data indicate that BIX01294 can expand CPCs without undermining their capacity as cardiac progenitors, and suggest that this drug may have utility for generating large numbers of CPCs for cardiac repair.


A new model for force generation by skeletal muscle, incorporating work-dependent deactivation.
A model is developed to predict the force generated by active skeletal muscle when subjected to imposed patterns of lengthening and shortening, such as those that occur during normal movements. The model is based on data from isolated lamprey muscle and can predict the forces developed during swimming. The model consists of a set of ordinary differential equations, which are solved numerically. The model's first part is a simplified description of the kinetics of Ca(2+) release from sarcoplasmic reticulum and binding to muscle protein filaments, in response to neural activation. The second part is based on A. V. Hill's mechanical model of muscle, consisting of elastic and contractile elements in series, the latter obeying known physiological properties. The parameters of the model are determined by fitting the appropriate mathematical solutions to data recorded from isolated lamprey muscle activated under conditions of constant length or rate of change of length. The model is then used to predict the forces developed under conditions of applied sinusoidal length changes, and the results compared with corresponding data. The most significant advance of this model is the incorporation of work-dependent deactivation, whereby a muscle that has been shortening under load generates less force after the shortening ceases than otherwise expected. In addition, the stiffness in this model is not constant but increases with increasing activation. The model yields a closer prediction to data than has been obtained before, and can thus prove an important component of investigations of the neural-mechanical-environmental interactions that occur during natural movements.


Early pleural fluid dynamics following video-assisted thoracoscopic lobectomy has limited clinical value.
The objective of this study was to evaluate the potential of predicting the pleural fluid output in patients after video-assisted thoracoscopic lobectomy of the lung. Detailed measurements of continuous fluid output were obtained prospectively using an electronic thoracic drainage device (Thopaz+™, Medela AG, Switzerland). Patients were divided into high (≥500 mL) and low (<500 mL) 24-hour fluid output, and detailed flow curves were plotted graphically to identify arithmetic patterns predicting fluid output in the early (≤24 hours) and later (24-48 hours) post-operative phase. Furthermore, multiple logistic regression analysis was used to predict high 24-hour fluid output using baseline data. Data were obtained from 50 patients, where 52% had a fluid output of <500 mL/24 hours. From visual assessment of flow curves, patients were grouped according to fluid output 6 hours postoperatively. An output ≥200 mL/6 hours was predictive of 'high 24-hour fluid output' (P<0.0001). However, 33% of patients with <200 mL/6 hours ended with a 'high 24-hour fluid output'. Baseline data showed no predictive value of fluid production, and 24-hour fluid output had no predictive value of fluid output between 24 and 48 hours. Assessment of initial fluid production may predict high 24-hour fluid output (≥500 mL) but seems to lack clinical value in drain removal criteria.


Mimicking protein-protein electron transfer: voltammetry of Pseudomonas aeruginosa azurin and the Thermus thermophilus Cu(A) domain at omega-derivatized self-assembled-monolayer gold electrodes.
Well-defined voltammetric responses of redox proteins with acidic-to-neutral pI values have been obtained on pure alkanethiol as well as on mixed self-assembled-monolayer (SAM) omega-derivatized alkanethiol/gold bead electrodes. Both azurin (P. aeruginosa) (pI = 5.6) and subunit II (Cu(A) domain) of ba(3)-type cytochrome c oxidase (T. thermophilus) (pI = 6.0) exhibit optimal voltammetric responses on 1:1 mixtures of [H(3)C(CH(2))(n)()SH + HO(CH(2))(n)()SH] SAMs. The electron transfer (ET) rate vs distance behavior of azurin and Cu(A) is independent of the omega-derivatized alkanethiol SAM headgroups. Strikingly, only wild-type azurin and mutants containing Trp48 give voltammetric responses: based on modeling, we suggest that electronic coupling with the SAM headgroup (H(3)C- and/or HO-) occurs at the Asn47 side chain carbonyl oxygen and that an Asn47-Cys112 hydrogen bond promotes intramolecular ET to the copper. Inspection of models also indicates that the Cu(A) domain of ba(3)-type cytochrome c oxidase is coupled to the SAM headgroup (H(3)C- and/or HO-) near the main chain carbonyl oxygen of Cys153 and that Phe88 (analogous to Trp143 in subunit II of cytochrome c oxidase from R. sphaeroides) is not involved in the dominant tunneling pathway. Our work suggests that hydrogen bonds from hydroxyl or other proton-donor groups to carbonyl oxygens potentially can facilitate intermolecular ET between physiological redox partners.


Haploidentical Hematopoietic Cell Transplantation Using Posttransplant Cyclophosphamide for Sézary Syndrome.
Patients with advanced-stage mycosis fungoides (MF) and Sézary syndrome (SS) have a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment option; however, since most patients with MF/SS are elderly, they often have difficulty in finding HLA-matched donors. In recent years, HCT from HLA-haploidentical donors (haplo-HCT) using posttransplant cyclophosphamide (PTCy) as graft-versus-host disease prophylaxis has been conducted for patients without HLA-matched donors. Infectious complications, particularly cutaneous bacterial infections, are common among patients with MF/SS. The lower incidence of severe infectious complications after haplo-HCT than after an unrelated cord blood transplantation could lead to lower transplant-related mortality. Here, we report on a patient with SS who was treated successfully with haplo-HCT with PTCy. The patient has remained in complete remission for more than 24 months.


Metabolic changes associated with anaesthesia and cherry poisoning in a pony.
A case of a pony with severe cyanide intoxication as a result of cherry ingestion is presented. General anaesthesia was performed for colic surgery. Severe metabolic lactate acidosis in combination with a high arterial oxygen partial pressure and clinically good peripheral perfusion parameters were the remarkable signs during anaesthesia. Severe hypothermia was obvious during recovery. Ten hours post-surgery the pony was euthanized as a result of neurological signs. The diagnosis of cyanide intoxication was made post-mortem. Cherry ingestion can lead to lethal cyanide intoxication in horses indicated by severe nonhypoxic lactic acidosis during anaesthesia.


The effects of various cytokines on interleukin-6 and interferon-alpha synthesis in human peripheral blood mononuclear cells.
The effect of various recombinant cytokines on the induction of interleukin-6 (IL-6) synthesis induced in adherent and nonadherent cells of human peripheral blood mononuclear cells (PBMNC) by bacterial lipopolysaccharide (LPS) or concanavalin A (CA) was studied. The results showed that human interferon-(HuIFN)-alpha, -beta, and gamma at a concentration of 100-10,000 IU/ml enhanced the LPS-induced IL-6 production in the adherent cell fraction of PBMNC. However, in nonadherent cells, treatment with HuIFN-alpha or -beta inhibited the CA-stimulated IL-6 production in a dose-dependent manner. Recombinant (r) IL-2 enhanced the IL-6 production of the adherent cells, while rIL-1 alone in the absence of other inducer induced IL-6 production in the nonadherent cell fraction. Other cytokines such as the recombinant tumor necrosis factor-alpha (rTNF-alpha) or rIL-6 itself did not modulate IL-6 production in human PBMNC. TNF and the interleukins studied did not affect the Sendai virus-induced IFN production in the adherent cells. In contrast, the different IFNs exerted a significant priming effect.


Feeding infants with cleft lip, cleft palate, or cleft lip and palate.
In assessing 143 infants with cleft lip and palate, we found feeding problems to vary with the patients' anatomic lesion. Effective feeding techniques were identified by first assessing the infant's ability to generate negative intraoral pressure and to move the tongue against the nipple and then by matching these deficits to appropriate feeding devices.


COVID-19 drugs in aquatic systems: a review.
The outbreak of the human coronavirus disease 2019 (COVID-19) has induced an unprecedented increase in the use of several old and repurposed therapeutic drugs such as veterinary medicines, e.g. ivermectin, nonsteroidal anti-inflammatory drugs, protein and peptide therapeutics, disease-modifying anti-rheumatic drugs and antimalarial drugs, antiretrovirals, analgesics, and supporting agents, e.g. azithromycin and corticosteroids. Excretion of drugs and their metabolites in stools and urine release these drugs into wastewater, and ultimately into surface waters and groundwater systems. Here, we review the sources, behaviour, environmental fate, risks, and remediation of those drugs. We discuss drug transformation in aquatic environments and in wastewater treatment systems. Degradation mechanisms and metabolite toxicity are poorly known. Potential risks include endocrine disruption, acute and chronic toxicity, disruption of ecosystem functions and trophic interactions in aquatic organisms, and the emergence of antimicrobial resistance.


Constrictive pericarditis caused by calcification and organized hematoma 30 years after cardiac surgery.
A 54-year-old man, who had undergone atrial septal defect (ASD) closure 30 years previously, was admitted for exertional dyspnea and chest oppression. He presented with right pleural effusion and hepatomegaly. Hemodynamic characteristics were consistent with constrictive pericarditis caused by multiple cystic lesions anterior to the main pulmonary artery and right ventricle, and severe calcification over the posterior and diaphragmatic sides of the heart. Magnetic resonance imaging was useful for differential diagnosis of the cystic mass and at surgery, it was revealed that the cystic lesions were old hematoma without cells. Pericardiectomy and removal of the calcification were performed safely using an ultrasonic scalpel, without cardiopulmonary bypass, resulting in hemodynamic improvement and relief of his symptoms.


Toward implementing an MRI-based PET attenuation-correction method for neurologic studies on the MR-PET brain prototype.
Several factors have to be considered for implementing an accurate attenuation-correction (AC) method in a combined MR-PET scanner. In this work, some of these challenges were investigated, and an AC method based entirely on the MRI data obtained with a single dedicated sequence was developed and used for neurologic studies performed with the MR-PET human brain scanner prototype. The focus was on the problem of bone-air segmentation, selection of the linear attenuation coefficient for bone, and positioning of the radiofrequency coil. The impact of these factors on PET data quantification was studied in simulations and experimental measurements performed on the combined MR-PET scanner. A novel dual-echo ultrashort echo time (DUTE) MRI sequence was proposed for head imaging. Simultaneous MR-PET data were acquired, and the PET images reconstructed using the proposed DUTE MRI-based AC method were compared with the PET images that had been reconstructed using a CT-based AC method. Our data suggest that incorrectly accounting for the bone tissue attenuation can lead to large underestimations (>20%) of the radiotracer concentration in the cortex. Assigning a linear attenuation coefficient of 0.143 or 0.151 cm(-1) to bone tissue appears to give the best trade-off between bias and variability in the resulting images. Not identifying the internal air cavities introduces large overestimations (>20%) in adjacent structures. On the basis of these results, the segmented CT AC method was established as the silver standard for the segmented MRI-based AC method. For an integrated MR-PET scanner, in particular, ignoring the radiofrequency coil attenuation can cause large underestimations (i.e., <or=50%) in the reconstructed images. Furthermore, the coil location in the PET field of view has to be accurately known. High-quality bone-air segmentation can be performed using the DUTE data. The PET images obtained using the DUTE MRI- and CT-based AC methods compare favorably in most of the brain structures. A DUTE MRI-based AC method considering all these factors was implemented. Preliminary results suggest that this method could potentially be as accurate as the segmented CT method and could be used for quantitative neurologic MR-PET studies.


Adaptor proteins Grb2 and Crk couple Pyk2 with activation of specific mitogen-activated protein kinase cascades.
The protein tyrosine kinase Pyk2 acts as an upstream regulator of mitogen-activated protein (MAP) kinase cascades in response to numerous extracellular signals. The precise molecular mechanisms by which Pyk2 activates distinct MAP kinase pathways are not yet fully understood. In this report, we provide evidence that the protein tyrosine kinase Src and adaptor proteins Grb2, Crk, and p130Cas act as downstream mediators of Pyk2 leading to the activation of extracellular signal-regulated kinase (ERK) and c-Jun amino-terminal kinase (JNK). Pyk2-induced activation of Src is necessary for phosphorylation of Shc and p130Cas and their association with Grb2 and Crk, respectively, and for the activation of ERK and JNK cascades. Expression of a Grb2 mutant with a deletion of the amino-terminal Src homology 3 domain or the carboxyl-terminal tail of Sos strongly reduced Pyk2-induced ERK activation, with no apparent effect on JNK activity. Grb2 with a deleted carboxyl-terminal Src homology 3 domain partially blocked Pyk2-induced ERK and JNK pathways, whereas expression of dominant interfering mutants of p130Cas or Crk specifically inhibited JNK but not ERK activation by Pyk2. Taken together, our data reveal specific pathways that couple Pyk2 with MAP kinases: the Grb2/Sos complex connects Pyk2 to the activation of ERK, whereas adaptor proteins p130Cas and Crk link Pyk2 with the JNK pathway.


A Rapid and Simple HPLC Method for Therapeutic Monitoring of Vancomycin.
Therapeutic monitoring of the antibiotic vancomycin is important to achieve specific plasma concentration and prevent toxic effects. Several assays have been described for vancomycin determination in clinical practice, but high-performance liquid chromatography is still considered the gold standard for the quantification of vancomycin. In this study, we developed a new and rapid high-performance liquid chromatography method requiring 50 μL of plasma for the quantification of vancomycin. Acetonitrile was used for processing plasma by protein precipitation (1:2.5). Isocratic chromatographic analysis was carried out on a C18 silica-based (2.7 μm) column with the mobile phase containing 20 mM ammonium acetate/formic acid buffer (pH 4.0):methanol 88:12 (v/v). A diode array detector was used for UV detection at 240 nm. This method was validated according to the Brazilian Health Surveillance Agency legislation and International Conference on Harmonization guidelines. The measurement range was 1-100 μg/mL, analysis time was 8 min, and intermediate precision was <12%, supporting the present method as a fast, simple, and effective alternative for therapeutic monitoring of vancomycin.


The rise of one-person households and their recent characteristics in Korea.
"This paper explores the rise in the proportion of one-person households [in South Korea] which since 1960 was attributable largely to rural-to-urban migration of young people. The heavy migration of young people from rural to urban cities actually brought about the rural household division which contributed to the fall in household size, and contributed to the increase in one-person households of urban young singles, on the one hand, and the increase in one-person households of rural elderly widows, on the other. The rise in the aggregate propensity to live alone was also evident.... Although the rise in one-person households was evident and by 1990 about one out of every ten households was a one-person household, the findings on the recent characteristics of one-person households do not indicate any big change in the traditional family norms."


Umeclidinium for the treatment of chronic obstructive pulmonary disease.
Umeclidinium is a novel inhaled long-acting muscarinic receptor antagonist (LAMA) approved for treatment of chronic obstructive pulmonary disease (COPD). It provides a bronchodilation of at least 24 h, is well tolerated and has a safe profile. In this article, we describe its pharmacokinetic and pharmacodynamic characteristics. Moreover, we present a meta-analysis of randomized clinical trials carried out in COPD patients, in which the change of forced expiratory volume in 1 s (FEV1) induced by umeclidinium has been compared with that elicited by placebo or the active compound tiotropium. The data generated by the pivotal trials indicate that umeclidinium bromide delivered once-daily via the Ellipta™ inhaler is an effective and well-tolerated treatment for COPD. Therefore, it could to be used as an alternative to LAMAs already in the market, although substantial information is still lacking. It is likely that in the future, umeclidinium will be used frequently, mainly in combination with vilanterol, which is a new once-daily long-acting β2-agonist (LABA).


Differences of Clinicopathological Features between Metaplastic Breast Carcinoma and Nonspecific Invasive Breast Carcinoma and Prognostic Profile of Metaplastic Breast Carcinoma.
Metaplastic breast carcinoma is a rare special type of breast cancer, which has distinguished clinical characteristics. We aimed to evaluate the clinicopathological features of metaplastic breast carcinoma compared with nonspecific invasive breast carcinoma and study the prognosis of metaplastic breast carcinoma. We reviewed metaplastic breast carcinoma cases (n = 37) from January 2000 to December 2021 and nonspecific invasive breast carcinoma cases (n = 433) from January 2019 to December 2020 extracted from our institution retrospectively. The following variables were recorded, including the patients' general information, complications, T stage, expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, Ki-67, molecular subtyping, lymph node status, skin or chest wall involvement, vessel carcinoma embolus, therapy modality (surgical treatments, chemotherapy, and radiotherapy), and survival. Patients with metaplastic breast carcinoma had more advanced disease than patients with nonspecific invasive breast carcinoma (T stage: P=0.0011). A greater proportion of metaplastic breast carcinoma presented with triple-negative breast cancer than nonspecific invasive breast carcinoma (79.41% vs. 12.47%, P ≤ 0.001). Our study showed that the skin or chest wall invasion was more frequent in metaplastic breast carcinoma patients (11.76% vs. 1.62%, P=0.005). The 5-year survival rate for metaplastic breast carcinoma patients was 57.66% (95% CI: 0.3195∼0.7667). No local recurrence was observed while distant metastasis occurred in 33.33% of patients with metaplastic breast carcinoma. Death due to disease occurred in 24.24% of patients with metaplastic breast carcinoma. The majority of metaplastic breast carcinoma patients had more advanced disease and triple-negative disease than nonspecific invasive breast carcinoma patients. Also, metaplastic breast carcinoma patients had frequent skin or chest wall invasion and a high rate of distant metastasis and mortality.


Mutations of p53 in thyroid carcinoma with an insular component.
Thyroid carcinoma with an insular component (TCIC) is considered noteworthy in view of its peculiar histopathological features and clinicopathological behavior. The purpose of the present study was to clarify the rate of mutation in the p53 gene in TCIC as compared with rates in papillary and follicular carcinomas of the thyroid. Formalin-fixed and paraffin-embedded blocks of tissue from 46 cases of TCIC were analyzed. DNA was extracted from tissues and exons 5 through 8 of the p53 gene were amplified by the polymerase chain reaction. Mutations were detected by analysis of single-strand conformation polymorphism. Of the 46 cases of TCIC, 6 had a mutation in exon 5, 2 in exon 7, and 5 in exon 8, while 1 case had mutations in all exons examined. The mutation rate of the p53 gene in TCIC was 38%. Immunostaining revealed overexpression of p53 in nuclei that were mainly in areas of the insular component rather than in surrounding areas of well-differentiated carcinoma. The frequency of positive immunostaining in TCIC was 53%. Considering that TCIC is intermediate between papillary plus follicular carcinoma and anaplastic carcinoma in terms of survival and the rate of mutation of the p53 gene, we can speculate that mutation in the p53 gene might be associated with the insular component and might play an important role in the clinicopathological behavior of thyroid carcinoma.


Systemic itraconazole in the yellow nail syndrome.
Although a number of treatments have been reported to be effective with yellow nail syndrome (YNS), vitamin E at high doses is the only one that has been successfully utilized in a consistent number of patients affected by YNS. Recent data indicate that itraconazole pulse regimen may be effective in this disease. We report our experience with itraconazole treatment in patients affected by YNS. Systemic itraconazole was administered in eight patients (five males and three females; mean age 55.2 years), at a dosage of 400 mg daily for 1 week a month for 6 months. Nail growth was measured every 3 months. Complete cure was achieved in two of eight patients, with mild improvement in two and no improvement in four. The results of our study show that itraconazole cannot be considered effective for YNS, especially if compared with vitamin E, the efficacy and tolerability of which is already proven.


Propulsion of Active Colloids by Self-Induced Field Gradients.
Previously, metallodielectric Janus particles have been shown to travel with their dielectric hemisphere forward under low frequency applied electric fields as a result of asymmetric induced-charge electroosmotic flow. Here, it is demonstrated that at high frequencies, well beyond the charge relaxation time of the electric double layer induced around the particle, rather than the velocity decaying to zero, the Janus particles reverse direction, traveling with their metallic hemisphere forward. It is proposed that such motion is the result of a surface force, arising from localized nonuniform electric field gradients, induced by the dual symmetry-breaking of an asymmetric particle adjacent to a wall, which act on the induced dipole of the particle to drive net motion even in a uniform AC field. Although the field is external, since the driving gradient is induced on the particle level, it may be considered an active colloid. We have thus termed this propulsion mechanism "self-dielectrophoresis", to distinguish from traditional dielectrophoresis where the driving nonuniform field is externally fixed and the particle direction is restricted. It is demonstrated theoretically and experimentally that the critical frequency at which the particle reverses direction can be characterized by a nondimensional parameter which is a function of electrolyte concentration and particle size.


Cobalt-Catalyzed Olefinic C-H Alkenylation/Alkylation Switched by Carbonyl Groups.
The first cobalt-catalyzed cross-couplings between olefins has been demonstrated to provide C(alkenyl)-H alkenylation and alkylation products, using complex [Cp*Co(CO)I2]. While coupling partner acrylates afforded conjugated dienoates, α,β-unsaturated ketones led to γ-alkenyl ketones completely, representing a switchable C-H functionalization controlled by different carbonyl groups.


Effect of lipophilic tail architecture and solvent engineering on the structure of trehalose-based nonionic surfactant reverse micelles.
We use small-angle X-ray scattering and dynamic light scattering to investigate the structural and dynamical properties of trehalose polyisostearate, abbreviated as TQ-n (n = 3, 5, and 7), in different organic solvents, where n represents the number of isosterate chains per surfactant molecule. TQ-n spontaneously assembles into reverse micelles without addition of water at 25 °C. We found that for TQ-5 and TQ-7, steric hindrance of the lipophilic surfactant tail causes significant reduction of the aggregation number, whose scheme is clearly distinguished from the modification of the critical packing parameter. Increasing the hydrocarbon chain length of oils from octane to hexadecane favors one-dimensional micellar growth, leading to the formation of rodlike micelles due to different penetration tendencies of oils into the lipophilic shell of the surfactant. Subtle differences in solvent polarity also plays a crucial role in the micellar size, which is decreased when liquid paraffin is replaced with squalene. A further decrease is attained in more polar mixed triglyceride oils. A rising temperature also results in the same direction. The extrapolated structure factor to the zero scattering vector, S(q → 0), for the TQ-3/decane systems almost exactly follows that predicted for hard spheres, demonstrating that osmotic compressibility of the system is well explained if accounting for the excluded volume. However, we found that the effective diffusion coefficient decreases with surfactant concentration, which is an opposite trend to what is expected for hard spheres. This apparent contradiction is likely to be due to the occurrence of transient interdigitation between the lipophilic tails of neighboring reverse micelles at higher concentration. Our data highlight the relevance of the concept of "tunable reverse micellar geometry" in the novel trehalose-based nonionic surfactant binary mixtures, in which lipophilic tail architecture, solvent engineering, concentration, and temperature act as intrinsic parameters for the structure control of the reverse micelles.


Amino Acid Transport into Cultured Tobacco Cells: II. EFFECT OF CALCIUM.
The effects of calcium ions on lysine transport into cultured Wisconsin-38 tobacco cells were examined. In the presence of calcium, lysine was transported at a relatively low rate for 30 to 40 minutes followed by a period of increasing rates and subsequent stabilization at a higher rate after 2 to 3 hours. In the absence of calcium, transport was uniformly low.Time-dependent stimulation of lysine transport rate was observed after the cells had been preincubated in calcium-containing media. Similar treatments also resulted in the stimulated uptake of a variety of other amino acids, organic compounds, and sulfate. The stimulation of lysine uptake was apparently not due to nutrient starvation.Lysine transport was not stimulated in a time-dependent fashion by K(+), La(3+), Mg(2+), or Mn(2+). Cells with stimulated transport rates continued to exhibit high rates when washed with calcium-containing media followed by transport in calcium-containing media. All other cation wash treatments were inhibitory, although magnesium treatments resulted in partial preservation of stimulated transport rates. Cycloheximide inhibited the calcium/time-dependent stimulation of lysine transport and caused the stimulated rate to decay.The initial experimental treatments or the culture conditions may represent some form of shock that alters the membrane transport mechanism, thus reducing transport. The observed calcium/time-dependent stimulation may require protein synthesis and represents damage repair.


Seroprevalence of Visceral Leishmaniasis in Children up to 12 Years old Among Nomadic Tribes from Rural Areas of Pars Abad, Northwestern Iran: an Observational Study in 2015.
Since Pars Abad district had been known as a focus of visceral leishmaniasis (VL) in Ardabil Province but the prevalence of the disease in nomadic tribes has not been determined, thus, this study was conducted. This descriptive cross-sectional study was conducted on children up to 12yr old of nomadic tribes from Pars Abad County, Ardabil Province, Iran in 2015. For each individual, a questionnaire including age, sex, clinical manifestations, history of disease, and contact with reservoir hosts of VL were completed, separately. To determine VL seroprevalence, blood samples were collected from the children and after centrifugation, the plasma samples were tested using Direct Agglutination Test (DAT) for detection of anti-Leishmania infantum antibodies. Statistical analyses were performed using SPSS16. From 776 children up to 12yr old, 2 (0.25%) showed anti-L. infantum antibodies at titers 1:1600 and only one case (0.13%) showed anti-Leishmania antibodies at titers 1:3200. The child with anti-L. infantum antibodies titers of 1:3200 showed mild fever for more than 2 months period, paleness, weakness and mild splenomegaly. After physical examination and confirmation of VL (kala-azar), the patient was treated with antileishmanial drugs. The findings indicated that L. infantum infection is being circulated with low prevalence in nomadic tribes of Pars Abad but it is necessary that the surveillance system is regularly monitored among physicians and public health managers in the studied areas.


Comparison and Analysis of Gut Microbiota in Children With IgA Vasculitis With Different Clinical Symptoms.
Background: Henoch-Schönlein purpura, now called immunoglobulin A (IgA) vasculitis, is a common autoimmune disease in children, its association with gut microbiota composition remains unknown. Methods: The collected cases were divided into three groups: G1 group of simple skin type, G2 group with no digestive tract expression, G3 group of mixed digestive tract, and C group of healthy children. The fecal samples of each group of children were collected and the sequencing data was processed and analyzed. The dilution curve reflected the reasonableness of the amount of sequencing data. Results: The number of species composition sequences in the G1, G2 and G3 groups was lower than that in the C group, especially for the G2 and G3 groups. The four most abundant bacteria were Bacteroidetes, Firmicutes, Proteobacteria and Actinobacteria. The relative abundance of Proteobacteria in the G2 and G3 groups was significantly higher than that in the G1 and C groups, while the relative abundance of Actinobacteria was significantly reduced, and the relative abundance of Actinobacteria in the G1 group was lower than that in the C group. Principal component analysis of the UPGMA clustering tree and each group of samples showed that the microbial community composition of the same group of samples was similar. Conclusions: The abundance of intestinal microbes in children with IgA vasculitis is lower than in normal children. Bacteroidetes, Firmicutes, Proteobacteria and Actinobacteria are the four most abundant bacteria in the intestinal flora of children. Proteobacteria and Actinobacteria are associated with organ involvement in IgA vasculitis.


[Homeostatic indices in persons subjected to ionizing radiation exposure].
Over the period of 1986-1990 a comprehensive evaluation was carried out in a series of a 5578 subjects exposed to ionizing radiation because of Chernobyl NPP breakdown, using hematologic, immunologic and biochemical methods of investigation. The above series included liquidators of aftermath of the accident, residents of Pripyat' and Kiev. Changes were revealed in all the parameters studied. In view of the abnormal changes in the values for blood, immunologic status and biochemical tests characterizing the functional state of the liver in those subjects having been in the area of abnormal radiation, as well as its potential remote sequelae, it is advisable that the above contingents of the population be under prophylactic management.