Ultrasensitive detection of miRNA based on efficient immobilization of probe and electrochemiluminescent quenching of Ru(bpy)32+ by methylene blue.
A high performance miRNA biosensor based on effective click chemistry assembly of a Ru(bpy)32+ labeled DNA probe and efficient electrochemiluminescence (ECL) quenching of the Ru(bpy)32+/BDEA (BDEA = N-butyldiethanolamine) system by surface-confined electroactive methylene blue (MB) dye is reported. When the target miRNA was present, the ECL signal instantly changed from "light off" to "light on" status. Using the specific miRNA let-7d as the target analyte, this biosensor provided sensitive detection over approximately six orders of magnitude (10 fM-10 nM), with a limit of detection of 10 fM (S/N = 3). Detailed study of the ECL quenching behavior of the Ru(bpy)32+/BDEA system by MB in solution suggested that the ECL quenching involves a combination of photoluminescence dynamic quenching and quenching processes directly associated with the redox reactions, as well as resonance energy transfer. A large binding constant of 4.7 × 1011 M-1 between let-7d and the DNA hairpin was estimated using an ECL-based extended Langmuir isotherm model, suggesting remarkably strong binding of the target to the probe. Furthermore, our biosensor exhibited excellent specificity and reproducibility. Using the developed system, the concentration of the target miRNA extracted from the A549 cell line could be obtained, demonstrating the potential application of the developed biosensor to practical biological sample analysis.


Marked dissociation of photopic and mesopic contrast sensitivity even in normal observers.
Although contrast vision is not routinely tested, it is important: for instance, it predicts traffic incidents better than visual acuity. Mesopic contrast sensitivity (CS) testing approximates low-lighting conditions but entails dark adaptation, which can disrupt clinical routine. In receptor-specific diseases, a dissociation of photopic and mesopic sensitivity would be expected, but can photopic CS act as a surrogate measure for mesopic CS, at least for screening purposes? Photopic and mesopic contrast sensitivities were studied in three groups: 47 normal subjects, 23 subjects with glaucoma, and three subjects with cataract. Twenty-eight of the normal subjects were additionally tested with artificial blur. Photopic contrast sensitivity was assessed with both the Freiburg Acuity and Contrast Test (FrACT) and the Mars Letter Contrast Sensitivity Charts. Mesopic contrast sensitivity, without and with glare, was measured with the Mesoptometer IIb. Coefficients of repeatability and limits of agreement were calculated for all tests. Test-retest limits of agreement were ± 0.17 logCS for Mars, ± 0.21 logCS for FrACT, and ±0.20 logCS / ± 0.14 logCS for Mesoptometer IIb without and with glare, respectively. In terms of inter-test comparison, Mars and FrACT largely agreed, except for ceiling effects in the Mars test. While mesopic and photopic contrast sensitivities correlate significantly (r = 0.51, p < 0.01), only 27 % of the variance is in common. In particular, subjects with high photopic results may be nearly as likely to have low as well as high mesopic results. The photopic contrast sensitivity tests assessed here cannot serve as surrogate measures for current mesopic contrast sensitivity tests. Low photopic CS predicts low mesopic CS, but with normal photopic CS, mesopic CS can be normal or pathologic.


An ultrafast and highly efficient enrichment method for both N-Glycopeptides and N-Glycans by bacterial cellulose.
A powerful and fast glycopeptide/glycan enrichment method is critical for the efficiency and throughput of mass spectrometry (MS)-based glycoproteomic and glycomic analyses, especially for large-scale sample analysis. Here, we report an ultrafast and effective method for both intact N-glycopeptide and N-glycan enrichment and apply it to human serum samples. In this method, a natural hydrophilic material, bacterial cellulose (BC), was adopted and fully optimized for enrichment. This method offers the following advantages: (i) The enrichment material has natural hydrophilicity and is low-cost, biocompatible, biodegradable and easily accessible; (ii) the whole enrichment procedure is remarkably simple and fast. It takes only 10 min for intact glycopeptides/glycans to be easily purified from mixtures; (iii) the specificity of this method is over 94% for both glycan and glycopeptide enrichment; and (iv) the outstanding specificity of this technique enables high isolation efficiency for the enrichment of both intact glycopeptides and glycans. A total of 36 N-glycans and 31 N-glycopeptides were identified from human immunoglobulin G (IgG). The glycan and glycopeptide absorption capacity of BC was as high as 333 μg/mg and 250 μg/mg (IgG/BC) respectively. The selectivity for glycan and glycopeptide enrichment reached 1:100 (IgG/bovine serum albumin (BSA), molar ratio) and 1:200 (maltoheptaose (DP7)/BSA, molar ratio), respectively. Furthermore, a total of 159 N-glycans and 523 N-glycopeptides were identified in human serum by using this method. Overall, the BC-based enrichment method we present here provides an ultrafast and highly efficient method for the enrichment of both N-glycopeptides and N-glycans in complex samples and shows great potential in large-scale glycoproteomic and glycomic analyses.


Schisandra extract ameliorates arthritis pathogenesis by suppressing the NF-κB and MAPK signalling pathways.
Schisandra chinensis is a medicinal plant used to treat various diseases. Extracts from the leaves or fruits of S. chinensis and their components are used in osteoarthritis (OA). The OA inhibitory effect of schisandrol A, one of its components, has been previously confirmed. We aimed to confirm the OA inhibitory effect of Schisandra (including components like schisandrol A) to identify why the inhibitory effect of the Schisandra extract is better. First, we investigated the effects of the Schisandra extract on OA as a potential therapeutic. Experimental OA was induced in a mouse model via destabilized medial meniscus surgery. The animals were orally administered the Schisandra extract; the inhibition of cartilage destruction was confirmed using histological analysis. In vitro analysis showed that the Schisandra extract attenuated osteoarthritic cartilage destruction by regulating IL-1β-induced MMP3 and COX-2 levels. The Schisandra extract inhibited IL-1β-induced degradation of IκB (NF-κB pathway) and IL-1β-induced phosphorylation of p38 and JNK (mitogen-activated protein kinase (MAPK) pathway). RNA-sequencing analysis showed that the Schisandra extract decreased the expression of IL-1β-induced MAPK and NF-κB signalling pathway-related genes more than schisandrol A alone. Therefore, Schisandra extract may be more effective than schisandrol A in preventing OA progression by regulating MAPK and NF-κB signalling.


Fiber-based source of photon pairs at telecom band with high temporal coherence and brightness for quantum information processing.
We experimentally demonstrate a bright pulsed source of correlated photon pairs at the 1550 nm telecom band by pumping 300 m dispersion-shifted fiber with a 4 ps pulse train. We investigate the coherence property of the source by measuring the second-order intensity correlation function g(2) of individual signal (idler) photons. A preliminary Hong-Ou-Mandel-type two-photon interference experiment with two such sources confirms the high temporal and spatial coherence of the source. The source is suitable for multiphoton quantum interference of independent sources, which is required in quantum information processing.


First report of Rhodnius amazonicus Almeida, Santos & Sposina, 1973 (Hemiptera, Reduviidae, Triatominae) invading a dwelling in the state of Amapá, Brazil.
Rhodnius amazonicus has been previously reported in the Brazilian states of Amazonas and Pará, as well as in French Guiana. However, this is the first recorded presence of this species in Amapá, which is situated in the northern region of Brazil. The specimen was collected from a house in the rural area of the municipality of Porto Grande. Other triatomines, such as Panstrongylus geniculatus, Rhodnius pictipes, and Eratyrus mucronatus, were also found in the same locality in different houses. These species are vectors of Trypanosoma cruzi, which causes Chagas disease. Therefore, this report may contribute to understanding transmission in the state of Amapá, where new infections and outbreaks of Chagas disease have been recorded.


Sleep Apnea, Obesity, and Diabetes - an Intertwined Trio.
To synthesize the existing literature regarding the complex interplay between sleep disturbance, obesity, and diabetes. The review emphasizes the three pillars of health being diet, exercise, and sleep, with the notion that if one is ignored, then the other two could suffer. Sleep deprivation is associated with incident obesity, perhaps mediated by dysregulation in leptin and ghrelin - hormones important in regulation of appetite. Sleep apnea is very common particularly among obese people with type 2 diabetes mellitus. Treatment of sleep apnea has clear symptomatic benefits although its impact on long-term cardiometabolic health is less clear. Sleep disturbance may be an important modifiable risk for patients at risk of cardiometabolic disease. An assessment of sleep health may be an important component of the comprehensive care of patients with obesity and diabetes mellitus.


Attributes of a surgical chairperson associated with extramural funding of a department of surgery.
Chairpersons of surgery departments are key stakeholders and role models and leaders of research in academic medical institutions. However, the characteristics of surgical chairpersons are understudied. This study aimed to investigate the association between the personal academic achievement of a surgical chairperson and the National Institutes of Health (NIH) funding of the department. We calculated the Hirsch index (H-index), a measure of research productivity, for chairpersons of surgery of the top 90 research medical schools that were ranked by U.S. News & World Report. Specialty training, y as chairperson, location, and NIH institutional and department funding were analyzed. Nonparametric tests and linear regression methods were used to compare the different groups. Of the 90 chairpersons, 20 positions for chairs (22%) are either recent (<1 y) or unfilled (n = 6). Only 3% of all chairpersons are women, and the median H-index for the chairpersons is 20 (Interquartile range 14-27) with a median 101 publications with 14 cites per publication. Median surgery-specific NIH funding in 2011 was $1.7 million (Interquartile range $721,042-5,085,305). The chairperson's H-index was exponentially associated with department funding in multivariate models adjusting for institution rank, except when the H-index was extreme (<4 or >49) (coefficient 0.32, P = 0.02). The research productivity of a chairperson is the only personal attribute of those studied that is associated with the departmental NIH funding. This suggests the important role an academically productive surgical leader may play as a champion for the academic success of the department.


Cause-specific mortality in insulin-treated diabetic patients: a 20-year follow-up.
Diabetes is one of the most common chronic diseases in Western populations. There have been few large published cohort studies of diabetes with 20 years of follow-up worldwide, and none other than the present one in NZ. To establish cause-specific death rates, by age and sex in insulin-treated diabetic individuals living in Canterbury, NZ. Insulin-treated diabetic subjects on the Canterbury Diabetes Registry were followed over 20 years and vital status determined. Following notification of deaths, age- and sex-specific mortality rates, and sex-specific mortality ratios (SMRs) were calculated. During follow-up 966 diabetic subjects contributed 13,495 person-years and 525 deaths occurred (261 females and 264 males). At all ages mortality rates were considerably higher than expected mortality. Relative mortalities were increased for cardiovascular (SMR women 3.73, 95% CI: 3.16-4.30; men 3.27, 95% CI: 2.76-3.78), renal (SMR women 5.55, 95% CI: 2.53-8.57; men 7.15, 95% CI: 3.40-10.90), respiratory disease (SMR women 3.31, 95% CI: 1.98-4.63; men 2.32, 95% CI: 1.41-3.23) and malignancy (SMR women 4.99, 95% CI: 2.99-6.99; men 2.19, 95% CI: 1.42-2.96) with cardiovascular disease accounting for the single greatest cause of excess death at all ages. Mortality rates for diabetic individuals remain high, resulting in shortened life spans relative to the general population. To reduce these death rates attention must be paid to the early detection and treatment of CVD and associated risk factors.


Opposing effect of EGFRWT on EGFRvIII-mediated NF-κB activation with RIP1 as a cell death switch.
RIP1 is a central mediator of cell death in response to cell stress but can also mediate cell survival by activating NF-κB. Here, we show that RIP1 acts as a switch in EGFR signaling. EGFRvIII is an oncogenic mutant that does not bind ligand and is coexpressed with EGFRWT in glioblastoma multiforme (GBM). EGFRvIII recruits ubiquitin ligases to RIP1, resulting in K63-linked ubiquitination of RIP1. RIP1 binds to TAK1 and NEMO, forming an EGFRvIII-RIP1 signalosome that activates NF-κB. RIP1 is essential for EGFRvIII-mediated oncogenicity and correlates with NF-κB activation in GBM. Surprisingly, activation of EGFRWT with EGF results in a negative regulation of EGFRvIII, with dissociation of the EGFRvIII-RIP1 signalosome, loss of RIP1 ubiquitination and NF-κB activation, and association of RIP1 with FADD and caspase-8. If EGFRWT is overexpressed with EGFRvIII, the addition of EGF leads to a RIP1 kinase-dependent cell death. The EGFRWT-EGFRvIII-RIP1 interplay may regulate oncogenicity and vulnerability to targeted treatment in GBM.


Role of Oceanic and Terrestrial Atmospheric Moisture Sources in Intraseasonal Variability of Indian Summer Monsoon Rainfall.
Summer Monsoon Rainfall over the Indian subcontinent displays a prominent variability at intraseasonal timescales with 10-60 day periods of high and low rainfall, known as active and break periods, respectively. Here, we study moisture transport from the oceanic and terrestrial sources to the Indian landmass at intraseasonal timescales using a dynamic recycling model, based on a Lagrangian trajectory approach applied to the ECMWF-ERA-interim reanalysis data. Intraseasonal variation of monsoon rainfall is associated with both a north-south pattern from the Indian landmass to the Indian Ocean and an east-west pattern from the Core Monsoon Zone (CMZ) to eastern India. We find that the oceanic sources of moisture, namely western and central Indian Oceans (WIO and CIO) contribute to the former, while the major terrestrial source, Ganga basin (GB) contributes to the latter. The formation of the monsoon trough over Indo-Gangetic plain during the active periods results in a high moisture transport from the Bay of Bengal and GB into the CMZ in addition to the existing southwesterly jet from WIO and CIO. Our results indicate the need for the correct representation of both oceanic and terrestrial sources of moisture in models for simulating the intraseasonal variability of the monsoon.


Targeted radio-nuclide therapy of skeletal metastases.
In this review, we will focus on one particular class of stromal targeted therapy, i.e. the bone seeking radiopharmaceuticals (BSRs), but will also highlight selected issues related to the bone stroma as these concepts are new, rapidly evolving, and clearly linked to the underlying BSR mechanisms of targeting and action. Herein we review clinical BSR-trials of significance with randomized trials at center stage. Furthermore, we cover a new class of BSR in late clinical development based on bone-stromal targeted alpha-particle irradiation. Lastly, we discuss potential advances in combining BSR with bisphosphonates and/or chemotherapy and emphasize the feasibility of repeated dosing.


Acute and chronic Chlamydia pneumoniae infection in pregnancy complicated with preeclampsia.
To investigate whether Chlamydia pneumoniae (Cp) infection is more common in women whose current pregnancy is complicated with preeclampsia (PE) as compared to pregnant women without PE. Thirty pregnant women with PE and 30 pregnant women without PE were studied between 29 and 30 weeks of gestation. The presence of an acute or chronic Cp infection was determined by the estimations of serum IgG, IgM, and IgA Cp antibodies. None of the women were diagnosed as having acute Cp infection. Prevalence of chronic Cp infection was 53 and 66% in the PE and control groups, respectively (X(2), p = 0.068). Chronic Cp infection is not more common in women whose pregnancy is complicated with PE as compared to pregnant women without PE. Therefore, no association between Cp infection and PE can be established.


Effect of Recycling and Autoclave Sterilization on the Unloading Forces of NiTi Closed-Coil Springs: An In Vitro Study.
Clinicians use the NiTi coil springs frequently for its appropriate mechanical properties. The aim of this study was to determine the effect of recycling and autoclave sterilization on the unloading forces of NiTi closed coil springs. Fourteen NiTi closed coil spring with the length of 9mm were selected. Each coil was stretched to a peak extension of 12 mm. A universal testing machine was used to acquire load/deflection curve of the coil springs at 25±2°C. The influence of thermocycling (1000 cycles,5-55°C), autoclaving (134°C, 32PSI, 3min) and mechanical strain (9mm extension) which simulated the oral condition, were considered. Data were statistically analyzed by adopting Repeated Measures MANOVA Paired t-Test. Autoclaving in the 1, 4, 6 steps increased the force levels of coil springs about 2-5gf (p< 0.01). Thermocycling reduced their force levels about 4-6gf. Prolonged strain at 3, 5 steps decreased the magnitude of forces levels about 3-4gf. Concerning all the limitations; according to the results of this study; it is possible to recycle Ni-Ti closed-coil springs without significant reduction in their force levels.


[Management of the bladder outlet obstruction associated with BPH in patients with special circumstances and/or complications].
Medical or surgical treatment of lower urinary tract symptoms associated with the bladder obstruction due to BPH must take into account patient's comorbidities and tBPH complication. The objective is to review the different situations in order to optimize the treatment. A review of the literature was conducted in English on the Pubmed website using the following keywords: BPH; diabetes; anticoagulants; antiplatelet agents; renal insufficiency; indwelling catheter; bladder calculus; urinary tract infection; hematuria; chronic bladder retention or diverticulum. The bibliographical sources cited in the European recommendations have been used. Some co-morbidities and complications may affect surgical outcomes: age is associated with increased anesthetic and surgical risks, diabetes with detrusor hypoactivity or overactivity that will not always be improved by surgery, chronic bladder retention with detrusor underactivity risk and anticoagulants and antiaggregants with an additional bleeding risk. Bladder stone should be treated with, in the majority of cases, BPH surgery. Bladder diverticulum is an indication of BPH surgery but not systematically associated with diverticulectomy. Persistent hematuria despite treatment with 5 alpha reductase inhibitor and repeated urinary tract infection are indications for surgery. The presence of co-morbidities or complication related to BPH leads to specifics of care that should not be ignored urologists. 5 consensus d'experts.


Streptococcus agalactiae in pregnancies complicated by preterm prelabor rupture of membranes.
The main aim of this study was to evaluate the presence of Streptococcus agalactiae (S. agalactiae) in the vagina and the amniotic fluid in pregnancies complicated by preterm prelabor rupture of membranes (PPROM). The next aim was to evaluate the incidence of S. agalactiae early onset sepsis in newborns from PPROM pregnancies, with respect to the presence of S. agalactiae in the vagina and the amniotic fluid. Singleton gestations with PPROM between 24 + 0 and 36 + 6 were included. A vaginal swab was obtained, and amniocentesis was performed at admission. The presence of S. agalactiae in the vagina and in the amniotic fluid was assessed by culture and by real-time polymerase chain reaction, respectively. In total, 336 women were included. The presence of S. agalactiae in the vaginal and amniotic fluid was found in 9% (31/336) and 1% (3/336) of women. One woman had S. agalactiae in the amniotic fluid but was negative for the presence of S. agalactiae in the vaginal fluid. Early onset neonatal sepsis developed in one newborn from pregnancies complicated by the presence of S. agalactiae in the amniotic fluid. The presence of S. agalactiae in the vagina and amniotic fluid complicated approximately each 10th and each 100th PPROM pregnancy. Cultivation-negative findings of S. agalactiae in the vagina did not exclude the positivity of the amniotic fluid for S. agalactiae and the development of early onset sepsis in newborns.


Estrogen-responsive finger protein as a new potential biomarker for breast cancer.
Estrogen-responsive finger protein (Efp) is a member of RING finger-B box-Coiled Coil family and is also a downstream target of estrogen receptor alpha. Previously, Efp was shown to mediate estrogen-induced cell growth, which suggests possible involvement in the development of human breast carcinomas. In this study, we examined expression of Efp in breast carcinoma tissues and correlated these findings with various clinicopathologic variables. Thirty frozen specimens of breast carcinomas were used for immunohistochemistry and laser capture microdissection/real-time PCR of Efp. Immunohistochemistry for Efp was also done in 151 breast carcinoma specimens fixed with formalin and embedded in paraffin wax. Efp immunoreactivity was detected in breast carcinoma cells and was significantly associated with the mRNA level (n = 30). Efp immunoreactivity was positively associated with lymph node status or estrogen receptor alpha status and negatively correlated with histologic grade or 14-3-3sigma immunoreactivity (n = 151). Moreover, Efp immunoreactivity was significantly correlated with poor prognosis of breast cancer patients, and multivariate analyses of disease-free survival and overall survival for 151 breast cancer patients showed that Efp immunoreactivity was the independent marker. Our data suggest that Efp immunoreactivity is a significant prognostic factor in breast cancer patients. These findings may account for an oncogenic role of Efp in the tumor progression of breast carcinoma.


Prevalence and Risk Factors for CKD: A Comparison Between the Adult Populations in China and the United States.
Chronic kidney disease (CKD) is an important noncommunicable disease globally. Overall prevalence of CKD and distribution of its stages differ between countries. We postulate that these differences may not only be due to variation in prevalence of risk factors but also their differential impact in different populations or settings. We used nationally representative data on the adult populations from both the United States (US; National Health and Nutrition Examination Survey [NHANES], 2009 to 2010, N = 5557) and China (China National Survey of CKD, 2009 to 2010, N = 46,949). Age, sex, central obesity, cardiovascular disease, diabetes, hypertension, and hyperuricemia were explored as candidate risk factors for CKD. The prevalence of CKD was calculated using survey weights. The prevalence of decreased estimated glomerular filtration rate (eGFR), defined as eGFR < 60 ml/min per 1.73 m2, was 6.5% in the US versus 2.7% in China, whereas the prevalence of albuminuria (defined as urine albumin to creatinine ratio of ≥30 mg/g) was 8.1% in the US versus 9.5% in China. The distribution of eGFR categories differed between the countries (P < 0.001). Stronger associations of diabetes with both indicators were seen in the US participants, whereas stronger associations of male sex with both indicators and of hypertension with albuminuria were observed in the Chinese participants (P < 0.05). After multivariable adjustment, a 65% change in prevalence difference for decreased eGFR was seen between China and the US. People in China and the US share many common risk factors for CKD, but differences in prevalence and the potential impact of these risk factors for CKD were observed.


Dual elicitation for improved production of withaferin A by cell suspension cultures of Withania somnifera.
High yielding transformed callus culture of W. somnifera was established by infecting hypocotyls with Agrobacterium tumefaciens MTCC-2250. Maximum withaferin A content of 0.0875 mg/g dry cell weight and transformation efficiency of 80% were obtained. Confirmation of transformation was done on the basis of the presence of the ags gene by using polymerase chain reaction. Various abiotic elicitors (arachidonic acid, methyl jasmonate, calcium chloride, and copper sulfate) and biotic elicitors (cell extracts and culture filtrates of Alternia alternata, Fusarium solani, and Verticilium dahaliae) were tested at different concentrations to enhance withaferin A production in suspension culture of transformed cells. Maximum enhancements of 5.4 times and 9.7 times, respectively, were obtained when copper sulfate (100 microM) and the cell extract of V. dahaliae (5% v/v) were added separately to suspension cultures. The dual elicitation strategy by the combined addition of these two elicitors resulted in 13.8-fold enhancement of withaferin A content in comparison to control cultures (2.65 mg/L). The present study indicates the potential of this biotechnology-based methodology for the large-scale production of withaferin A.


The use of urologic investigations among patients with traumatic spinal cord injuries.
To assess the use of urologic investigations among traumatic spinal cord injury (TSCI) patients. This is a retrospective cohort study from Ontario, Canada. We included all adult TSCI patients injured between 2002 and 2012. The primary outcome was the frequency of urodynamic testing, renal imaging, and cystoscopy. Primary exposure was the year of injury. The impact of age, sex, comorbidity, socioeconomic status, and lesion level was assessed with Cox regression models. One thousand five hundred and fifty one incident TSCI patients were discharged from a rehabilitation hospital. The median follow-up time of this cohort was 5.0 years (interquartile range =2.9-7.5). At least one urodynamics, renal imaging, or cystoscopy was performed during follow-up for 50%, 80%, and 48% of the cohort, respectively. The overall rate of these tests was 0.22, 0.60, and 0.22 per person-year of follow-up. The proportion of patients who had regular, yearly urodynamics (<2%), renal imaging (6%), or cystoscopy (<2%) was low. There were no significant linear trends in the use of these tests over the 10-year study period. Urodynamics were significantly less likely to be performed in patients over 65 years of age (hazard ratio [HR] =0.63, P<0.01) and those with a higher level of comorbidity (HR =0.72, P<0.01). Patients with quadriplegia were significantly less likely to receive any of the investigations compared to those with paraplegia. Renal imaging is done at least once for the majority of patients with TSCI; however, only half undergo urodynamics or cystoscopy. Few patients have regular urologic testing. The reality of urologic testing after TSCI is very different from urologist's ideals and practice guidelines.


Correction: Molecular subtypes of oropharyngeal cancer show distinct immune microenvironment related with immune checkpoint blockade response.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Aberrant hypermethylation of the CHFR prophase checkpoint gene in human lung cancers.
The CHFR gene, which was recently cloned by Scolnick and Halazonetis in search for a novel mitotic checkpoint gene with fork-head association motifs, has been suggested to play a key role in the mitotic prophase checkpoint. In this study, we demonstrated tumor-specific aberrant hypermethylation of the promoter region of the CHFR gene in a significant fraction of lung cancers in association with loss of detectable levels of CHFR transcripts. Aberrant hypermethylation was observed in seven of 37 primary lung cancer cases. Treatment with the demethylating agent 5-aza-2'-deoxycytidine restored expression of the CHFR gene in lung cancer cell lines exhibiting aberrant hypermethylation and loss of its expression. In contrast, genetic alterations were found to be infrequent in lung cancers. This is the first description of aberrant hypermethylation of the CHFR gene in any type of human cancer, and provides further evidence of the involvement of multiple checkpoint alterations in lung cancer.


Influence of milk feeding levels and calf housing on subsequent performance of Holstein heifers.
The purpose of this study was to investigate the effects of increased milk feeding levels or social housing during the preweaning stage of Holstein dairy heifers on subsequent weight gain, health, and reproductive parameters over time. A total of 210 heifers were grouped by calving date in groups of 10 and randomly assigned to one of 3 treatments: low-milk individual housing (LMI; 4 L of milk/d), high-milk individual housing (HMI; 8 L of milk/d), or low-milk social housing (LMS; 4 L of milk/d). Data collected included passive transfer status, disease events, weight gain at different time periods, age at first calving, calving intervals, and milk yield over the first 3 lactations. Passive transfer was successful in 189 calves, and, overall, disease events were low in this herd. The average daily gain for heifers in the HMI group (0.79 ± 0.05 kg/d) was significantly higher (F 2, 9 = 4.76) during the preweaning treatment period compared with the other groups (LMI: 0.59 ± 0.05 kg/d; LMS: 0.68 ± 0.04 kg/d). Although treatment groups did not differ with respect to age at first calving, the LMS and HMI heifers calved (22 and 15 d, respectively) earlier than the LMI heifers. Milk yield over 3 lactations was similar among the treatment groups. This suggests that both nutrition and social dynamics can influence performance of preweaned calves. Further investigation is needed to understand the mechanisms driving increased weight gain in socially housed calves.


A comparison of mammography and ultrasonography in the evaluation of breast masses.
Aim of the study is to evaluate breast masses using mammography (MG) and ultrasonography (USG) independently and in combination. Our study group consisted of 62 female patients, with breast symptoms such as palpable lumps, pain in the breast and nipple discharge who were examined prospectively over a period of 6 months. All 62 patients were examined by both MG and USG independently. Fine needle aspiration cytology (FNAC) or core cut biopsy was done according to the findings of MG and USG and then the results were correlated with each modality finding. According to this study MG showed an efficiency of 81.8 % compared to 95.5 % for USG in detecting fibrocystic mastitis. However their combined approach resulted in 100 %. In the case of fibroadenomas, MG showed 75 % efficiency and USG only 35 % and the combination resulting in 93.7 %. For carcinomas, MG had an efficiency of 77.8 % and USG 55.6 %, but the combination had an efficiency of 98.1 %. Overall, the histopathological results when correlated with each modality finding showed that MG had an efficiency of only 77.4 % and USG only 69.8 % when used alone in detecting these lesions of the breast compared to an efficiency of 98.1 % obtained by their combined approach. In our study, we showed that there was no significant difference in sensitivity between MG and USG (p = 0.3768) but there was significant difference in MG alone and MG-USG combination (p = 0.0015) and USG alone and USG-MG combination (p = 0.0001). Our study confirmed that combined MG and USG had higher sensitivity rate than the sensitivity rate observed for either single modality. The diagnostic accuracy for carcinomas of the breast appear to improve when MG was combined with USG, even in cases which showed no evidence of microcalcification or other signs of abnormalities. Our study implies that, USG may be the only viable modality in pregnant and lactating women as it does not involve ionizing radiation and also in dense breast tissue, as density is a limiting factor for MG.


[Hypernephroma in native kidney of patient with renal transplant].
The uremic patients, specially in periodic dialysis, may present bilateral kidneys cytes with high frequency. This pathology, known as acquired cyst renal disease, is found associated in its evolution with the emergence renal malignant disease. A patient who undergoing chronic dialysis and renal transplant subsequently developed an asymptomatic renal neoplasm. The epidemiological, clinical, diagnostic aspects and therapeutic of the acquired cysts renal and your association with renal cancer are analyzed.


Localization and role of nitric oxide synthase and endogenous nitric oxide synthase inhibitors in the rabbit lower urinary tract.
We investigated the possible role of endogenous methylarginine derivatives, such as NG-monomethyl-L-arginine (L-NMMA), asymmetrical NG, NG-dimethyl-L-arginine (ADMA) and symmetrical NG, N'G-dimethyl-L-arginine (SDMA), for regulating nitric oxide synthase in the rabbit lower urinary tract. Strips of detrusor, trigone and proximal urethra were processed for the determination of endogenous methylarginines and L-arginine by automated high performance liquid chromatography. We also compared nitric oxide synthase activity and nitric oxide mediated functional responses to electrical field stimulation in the 3 regions. Nitric oxide synthase activity was measured by determining the conversion of [3H] L-arginine to [3H] L-citrulline. L-NMMA, ADMA and SDMA were detectable by high performance liquid chromatography in the detrusor, trigone and proximal urethra. Electrical field stimulation induced nitric oxide mediated prominent relaxation in the trigone and proximal urethra, while no relaxation response was observed in the detrusor. Exogenously applied 1 to 100 microM. L-NMMA and 1 to 100 microM. ADMA but not 100 microM. SDMA dependently inhibited Ca2+ dependent nitric oxide synthase activity in all regions, and electrical field stimulation induced relaxation in the trigone and proximal urethra. Inhibition with L-NMMA and ADMA was blocked in the presence of 3 mM. L-arginine but not by 3 mM. D-arginine. Three methylarginines and nitric oxide synthase are localized throughout the rabbit lower urinary tract. Endogenous L-NMMA and ADMA may be involved in regulating nitric oxide biosynthesis of the micturition reflex in the normal or disease state.


IRIS-HSVD algorithm for automatic quantitation of in vivo 31P MRS.
The rapid development of (31)P magnetic resonance spectroscopy (MRS) has enhanced non-invasive measurement of brain metabolites, which is important for biomedical research. The accuracy and efficiency of data post processing and quantification is paramount for MRS applications. One of the difficulties with in vivo(31)P MRS data quantification is the separation of broad line-width resonances from chemical compounds' resonances under a low signal-to-noise ratio condition. Furthermore, the chemical shift of some compounds caused by pH and Mg(2+) concentration can be troublesome. This work aims to develop an automatic algorithm using a state-space based quantification approach to solve the above mentioned problems. To achieve this aim, we utilized an HSVD based adaptive optimizing prior knowledge algorithm, which uses so called "interference" signals to optimize prior knowledge iteratively for parameter optimization. We termed this algorithm IRIS-HSVD, which stands for Iterative Reduction of Interference Signal HSVD. The Monte Carlo evaluations of the algorithm were conducted with simulated data using in vivo parameters commonly obtained from a 4T scanner. The performance of this algorithm using simulated data was compared to those of other automatic methods including HSVD and HTLS-PK. Examples of in vivo(31)P data obtained from brains of healthy subjects on a 4T MRI scanner were also presented, which demonstrated the superiority of the new method. The results were compared with those using AMARES.


[Treatment with omeprazole, clarithromycin and amoxicillin for one week. Their efficacy and tolerance in eradicating Helicobacter pylori in primary care].
To study the effectiveness and tolerance of the combination of omeprazole, clarithromycin and amoxycillin taken for a week on the eradication of Helicobacter pylori (HP) in patients with peptic ulcer and symptomatic chronic gastritis. Intervention study. Urban health centre. 121 patients, diagnosed by fiber gastroscopy and with an HP infection demonstrated by the urease test, breath test, serology or biopsy, were studied prospectively. 13 suffered from a gastric ulcer, 54 from duodenal ulcer and 54 from chronic gastritis. Two patients stopped treatment because of side-effects, but were included in the study (analysis by treatment intention). The combination of omeprazole (20 mg/12 hours), amoxycillin (1 gr/12 hours) and clarithromycin (500 mg/12 hours) was administered for a week. No medication was prescribed afterwards. Therapeutic compliance (count of tablets and interview) and side-effects were systematically evaluated. Four to eight weeks later patients took a breath test with Urea C14 to confirm eradication. Average age was 47 (SD 14.5); 54% were women. Eradication was confirmed in 80.2% of cases (CI 95%; 73.1-87.3). Side-effects were light or moderate in all cases: the most common were dysgeusia (67%), nausea (18%) and diarrhoea (17%). The triple therapy of omeprazole, amoxycillin and clarithromycin for a week is efficacious in eradicating HP. It is extremely easy to apply, and there are few relevant side-effects.


Physicochemically Tuned Myofibroblasts for Wound Healing Strategy.
Normal healing of skin wounds involves a complex interplay between many different cellular constituents, including keratinocytes, immune cells, fibroblasts, myofibroblasts, as well as extracellular matrices. Especially, fibroblasts play a critical role in regulating the immune response and matrix reconstruction by secreting many cytokines and matrix proteins. Myofibroblasts, which are differentiated form of fibroblasts, feature high cellular contractility and encourage the synthesis of matrix proteins to promote faster closure of the wounds. We focus on the functional characteristics of these myofibroblasts as the healing strategy for severe wounds where the surplus amount of matrix proteins could be beneficial for better regeneration. In this study, we first employed multiple physicochemical cues, namely topographical alignment, TGF-β1, and electrical field (EF), to induce differentiation of dermal fibroblasts into myofibroblasts, and to further activate the differentiated cells. We then used these cells in a mouse wound model to verify their potential as a transplantable substitute for the severe wound. Our results confirmed that physicochemically stimulated myofibroblasts promoted faster healing of the wound compared to the case with non-stimulated myofibroblasts through elevated matrix reconstruction in the mouse model. Conclusively, we propose the utilization of physicochemically tuned myofibroblasts as a novel strategy for promoting better healing of moderate to severe wounds.


The two tempos of nuclear pore complex evolution: highly adapting proteins in an ancient frozen structure.
The origin of the nuclear compartment has been extensively debated, leading to several alternative views on the evolution of the eukaryotic nucleus. Until recently, too little phylogenetic information was available to address this issue by using multiple characters for many lineages. We analyzed 65 proteins integral to or associated with the nuclear pore complex (NPC), including all the identified nucleoporins, the components of their anchoring system and some of their main partners. We used reconstruction of ancestral sequences of these proteins to expand the detection of homologs, and showed that the majority of them, present all over the nuclear pore structure, share homologs in all extant eukaryotic lineages. The anchoring system, by contrast, is analogous between the different eukaryotic lineages and is thus a relatively recent innovation. We also showed the existence of high heterogeneity of evolutionary rates between these proteins, as well as between and within lineages. We show that the ubiquitous genes of the nuclear pore structure are not strongly conserved at the sequence level, and that only their domains are relatively well preserved. We propose that an NPC very similar to the extant one was already present in at least the last common ancestor of all extant eukaryotes and it would not have undergone major changes since its early origin. Importantly, we observe that sequences and structures obey two very different tempos of evolution. We suggest that, despite strong constraints that froze the structural evolution of the nuclear pore, the NPC is still highly adaptive, modern, and flexible at the sequence level.


Species differences determine azido phencyclidine labeling pattern in desensitized nicotinic acetylcholine receptors.
Acetylcholine receptor enriched membranes from Torpedo ocellata, Torpedo marmorata and Torpedo californica were studied using [3H] azido-phencyclidine (AZ-PCP). [3H]-PCP binding to receptors from all three species revealed marked similarities. Photoaffinity labeling by [3H]-AZ-PCP resulted in the tagging of mainly alpha, beta and delta subunits in all species. When carbamylcholine was added, it enhanced the labeling of beta subunits in T. ocellata, delta in T. marmorata and alpha in T. californica, suggesting species differences in the photolabeling pattern. Multiple homologous binding sites for PCP between the receptor subunits would allow small variations in receptor structure to be manifested in labeling by AZ-PCP, with no differences in binding and functional properties of the receptors.


Using a novel patient medication list for ambulatory pediatric patients within a hospital-based complex care program.
Medication errors are common in the pediatric outpatient setting, and children with multiple prescriptions are at increased risk. Little is known about medication reconciliation's application in the ambulatory setting. Caregivers' perceptions of a patient medication list (PML), created for children with complex health needs, were assessed. Caregivers of children followed by a tertiary care hospital ambulatory complex care program from February through December 2009 were enrolled in the study. An electronic PML software was nested within a clinical database. At the clinic visit, the medications were updated in the database by a nurse practitioner, and a PML was created and printed for the caregivers. Caregivers were asked to complete a pre-questionnaire before using the PML and a post-questionnaire 12 weeks later. The pre-questionnaire demonstrated that 19 (68%) of 28 caregivers expected the PML to be very helpful. After a mean of 19.3 weeks, on the post-questionnaire, 14 (50%) of the 28 caregivers reported that the PML was very helpful, 10 (40%) of 25 caregivers used the PML at every follow-up clinic visit, and 18 (67%) of 27 caregivers were satisfied with the PML. Five (18%) of 28 caregivers strongly agreed that the PML increased their knowledge of the child's medications, and 3 (11%) of 28 caregivers strongly agreed that the PML helped them remember to give the child's medications at home. A subset of caregivers in a complex care program reported that a PML was helpful during interactions with their medical team. Yet in general, caregivers did not find the PML helpful in increasing their medication knowledge or reminding them to administer their child's medications.


Assessing the environmental sustainability of different soil disinfestation methods used in solar greenhouse vegetable production systems.
Overuse of fertilizers and irrigation and continuous monocropping is increasingly jeopardizing vegetable production in solar greenhouses as it causes serious soil degradation and the spread of soil-borne diseases. As a countermeasure, the practice of anaerobic soil disinfestation (ASD) has been recently introduced, which is carried out during the summer fallow period. However, ASD may increase N leaching and greenhouse gas (GHG) emissions when large amounts of chicken manure are applied. This study assesses how the use of different amounts of chicken manure (CM) combined with rice shells (RS) or maize straw (MS) affects soil O2 availability, N leaching, and GHG emissions during and following the ASD period. Application of RS or MS alone effectively stimulated long-lasting soil anaerobiosis without major stimulating effects on N2O emissions and N leaching. Seasonal N leaching and N2O emissions were in the ranges of 144-306 and 3-44 kg N ha-1, respectively, and were strongly increasing with increasing rates of manure application. Combining high rates of manure application with the additional incorporation of crop residues further increased N2O emissions by 56 %-90 % as compared to the standard practice of farmers (1200 kg N ha-1 CM). About 56 %-91 % of seasonal N2O emissions occurred during the ASD period, whereas N leaching mainly occurred in the cropping period (75 %-100 %). Our study shows, that for priming ASD incorporation of crop residue is sufficient and that the addition of chicken manure for ASD is not needed and should be reduced or even prohibited as it does not improve yields but stimulates the emission of the strong GHG N2O.


I can't drink what I used to: The interaction between ethanol and the aging brain.
The population of most countries is increasing and the United Nations predicts that by the year 2050 those over the age of 60 years old will increase from 900 million individuals to approximately 2.1 billion individuals (United Nations, 2015). The increase in the number of older individuals will place a strain on many national health care systems making it important to investigate behaviors in the aged that may negatively impact general health in this demographic. Recent work has shown that older adults consume alcohol, often at levels that exceed the legal limit of intoxication. Unfortunately, consumption of high levels of ethanol in the older population is associated with many health consequences and may negatively impact the brain. Given ethical constraints found in many biomedical studies, animal models are needed to investigate the possible negative impact of high ethanol use in aged populations. However, few studies have investigated the effect of ethanol exposure in aged animals compared to ethanol exposure in younger animals and consequently the impact of ethanol in the aged population is not well understood. The current review summarizes initial work establishing the impact of ethanol in aged animals. The reviewed research studies support the working hypothesis that ethanol exposure produces significantly greater effects in aged animals compared to younger animals on many, if not all, behavioral tasks. In addition, the review proposes several initial, promising avenues of research to explore the neurobiological mechanisms that underly greater effects on ethanol-induced ataxia, cognition and sleep time. It is hoped that this effort will not only lead to a better understanding of behaviors impacted by ethanol in aged animals, but also improve the understanding brain mechanisms of the reported increased sensitivity to ethanol in the aged population.


Astrocyte responses to experimental glaucoma in mouse optic nerve head.
To delineate responses of optic nerve head astrocytes to sustained intraocular pressure (IOP) elevation in mice. We elevated IOP for 1 day to 6 weeks by intracameral microbead injection in 4 strains of mice. Astrocyte alterations were studied by transmission electron microscopy (TEM) including immunogold molecular localization, and by laser scanning microscopy (LSM) with immunofluorescence for integrin β1, α-dystroglycan, and glial fibrillary acidic protein (GFAP). Astrocyte proliferation and apoptosis were quantified by Ki67 and TUNEL labeling, respectively. Astrocytes in normal optic nerve head expressed integrin β1 and α-dystroglycan by LSM and TEM immunogold labeling at electron dense junctional complexes that were found only on cell membrane zones bordering their basement membranes (BM) at the peripapillary sclera (PPS) and optic nerve head capillaries. At 1-3 days after IOP elevation, abnormal extracellular spaces appeared between astrocytes near PPS, and axonal vesical and mitochondrial accumulation indicated axonal transport blockade. By 1 week, abnormal spaces increased, new collagen formation occurred, and astrocytes separated from their BM, leaving cell membrane fragments. Electron dense junctional complexes separated or were absent at the BM. Astrocyte proliferation was modest during the first week, while only occasional apoptotic astrocytes were observed by TEM and TUNEL. Astrocytes normally exhibit junctions with their BM which are disrupted by extended IOP elevation. Responses include reorientation of cell processes, new collagen formation, and cell proliferation.


Antibody response elicited by the SARS-CoV-2 vaccine booster in patients with multiple sclerosis: Who gains from it?
Although two doses of COVID-19 vaccine elicited a protective humoral response in most persons with multiple sclerosis (pwMS), a significant group of them treated with immunosuppressive disease-modifying therapies (DMTs) showed less efficient responses. This prospective multicenter observational study evaluates differences in immune response after a third vaccine dose in pwMS. Four hundred seventy-three pwMS were analyzed. Compared to untreated patients, there was a 50-fold decrease (95% confidence interval [CI] = 14.3-100.0, p < 0.001) in serum SARS-CoV-2 antibody levels in those on rituximab, a 20-fold decrease (95% CI = 8.3-50.0, p < 0.001) in those on ocrelizumab, and a 2.3-fold decrease (95% CI = 1.2-4.6, p = 0.015) in those on fingolimod. As compared to the antibody levels after the second vaccine dose, patients on the anti-CD20 drugs rituximab and ocrelizumab showed a 2.3-fold lower gain (95% CI = 1.4-3.8, p = 0.001), whereas those on fingolimod showed a 1.7-fold higher gain (95% CI = 1.1-2.7, p = 0.012), compared to patients treated with other DMTs. All pwMS increased their serum SARS-CoV-2 antibody levels after the third vaccine dose. The mean antibody values of patients treated with ocrelizumab/rituximab remained well below the empirical "protective threshold" for risk of infection identified in the CovaXiMS study (>659 binding antibody units/mL), whereas for patients treated with fingolimod this value was significantly closer to the cutoff.


Fluorine-Containing Covalent Organic Frameworks: Synthesis and Application.
Covalent organic frameworks (COFs) are a type of crystalline porous polymers that possess ordered structures and eternal pores. Because of their unique structural characteristics and diverse functional groups, COFs have been used in various application fields, such as adsorption, catalysis, separation, ion conduction, and energy storage. Among COFs, the fluorine-containing COFs (fCOFs) have been developed for special applications by virtue of special physical and chemical properties resulting from fluorine element, which is a nonmetallic halogen element and possesses strong electronegativity. In the organic chemistry field, introducing fluorine into chemicals enables those chemicals to exhibit many interesting properties, and fluorine chemistry increasingly plays an important role in the history of chemical development. The introduction of fluorine in COFs can enhance the crystallinity, porosity, and stability of COFs, making COFs having superior performances and some new applications. In this review, the synthesis and application of fCOFs are systematically summarized. The application involves photocatalytic production of hydrogen peroxide, photocatalytic water splitting, electrocatalytic CO2 reduction, adsorption for different substances (H2 , pesticides, per-/polyfluoroalkyl substances, polybrominated diphenyl ethers, bisphenols, and positively charged organic dye molecules), oil-water separation, energy storage (e.g., zinc-ion batteries, lithium-sulfur batteries), and proton conduction. Perspectives of remaining challenges and possible directions for fCOFs are also discussed.


Resistance to Millettia molluscicide in Biomphalaria glabrata: a quantitative genetical approach.
This paper demonstrates the use of a quantitative genetical technique to assess genetic variance in molluscicide resistance in a Millettia thonningii-Biomphalaria glabrata system. Results indicated that there were significant genetic variances in both snail size and survival time in 10 p.p.m. molluscicide suspension. The possibility of wider applications of this technique in examining the genetic basis of molluscicide or pesticide resistance in target species is discussed.


Multifocal Endobronchial Fibromas Presenting as Unilobar Emphysema.
Tracheobronchial fibromas are very rare, locally-invasive tumors of the airways. Fewer than 30 cases have been reported within the English-speaking literature. Historically, these neoplasms have been diagnosed as isolated endobronchial masses, with affected patients presenting with wheezing, cough, stridor, hemoptysis, dyspnea, or pneumonia. We report the case of 39-year-old man with multiple, synchronous endobronchial fibromas causing unilobar emphysema. A computed tomographic scan and bronchoscopy with biopsy were performed preoperatively to diagnose these lesions in the orifices of the anterior segment and the lingula within the left upper lobe. The patient underwent successful video-assisted left upper lobectomy, without recurrence at 3 years. This is the first report of a synchronous presentation of multiple pulmonary endobronchial fibromas within the same patient and the first report of endobronchial fibroma presenting as unilobar air trapping. Recognition of the unusual presentation of this uncommon pathology can lead to timely intervention.


On the Incongruence between Psychometric and Psychosocial-Biodemographic Measures of Life History.
In evolutionary psychology, it is customary to measure life-history via psychometric inventories such as the Arizona Life History Battery (ALHB). The validity of this approach has been questioned: it is argued that these measures are not congruent with biological life history events, such as the number of children, age at first birth, or pubertal timing. However, empirical data to test this critique are lacking. We therefore administered the ALHB to a convenience sample of young adults in Serbia (N = 447). We also collected information on psychosocial-biodemographic life history parameters closely related to biological life history traits: pubertal timing, onset of sexual behavior, short- and long-term mating, number of children, timing of reproduction, parenthood values, and environmental harshness. We found that correlations between these two sets of measures were rare, unsystematic, and mostly low in magnitude. Stable patterns of relations emerged only between the indicators of environmental conditions from both sets of measures. Furthermore, some ALHB indicators were found to be positively related with early fertility, which is incongruent with the conceptual foundation of ALHB. Finally, network analysis and factor analysis within each set of measures revealed different structures and that the hypothesis of unidimensionality, on which the ALHB was founded, cannot be applied to psychosocial-biodemographic life history indicators. Our results support the critique of ALHB as a set of measures lacking validity to capture biodemographic life-history parameters. ALHB measures are indeed relevant for understanding life-history variation, but they cannot be used as a substitute for specific life history characteristics. Our findings are a warning to researchers to use direct measures of biological events in order to measure life-history dynamics.


[Antimalarial chemoprophylaxis in children].
In early age, drugs without side effects are required for malaria chemoprophylaxis. Several regimens are available for drug-resistant plasmodium spp in many countries.


Glycoproteomic identification of galectin-3 and -8 ligands in bronchoalveolar lavage of mild asthmatics and healthy subjects.
Galectins, a family of small carbohydrate binding proteins, have been implicated in regulation of inflammatory reactions, including asthma and fibrosis in the lungs. Galectins are found in cells of the airways and in airway secretions, but their glycoprotein ligands there have only been studied to a very limited extent. Bronchoalveolar lavage (BAL) fluid from mild asthmatics and healthy volunteers were fractionated by affinity chromatography on the immobilized galectins. Total (10-30 μg) and galectin bound (~1-10 μg) protein fractions were identified, quantified and compared using shot-gun proteomics and spectral counts. About 175 proteins were identified in unfractionated BAL-fluid, and about 100 bound galectin-3 and 60 bound galectin-8. These included plasma glycoproteins, and typical airway proteins such as SP-A2, PIGR and SP-B. The concentration of galectin-binding proteins was 100-300 times higher than the concentration of galectins in BAL. The low relative concentration of galectins in BAL makes it likely that functional interactions with glycoproteins occur at sites rich in galectin, such as cells of the airways, rather than the extracellular fluid itself. The profile of galectin bound proteins differed between samples from asthma patients and healthy subjects and correlated with the presence of fibroblasts or eosinophils. This included appearance of a specific galectin-8-binding glycoform of haptoglobin, previously shown to be increased in serum in other inflammatory conditions. It is technically feasible to identify galectin-binding glycoproteins in low concentration patient samples such as BAL-fluid, to generate biomedically interesting results. This article is part of a Special Issue entitled Glycoproteomics.


Biglycan modulates osteoblast differentiation and matrix mineralization.
MC3T3-E1 cell-derived clones expressing higher (S) or lower (AS) levels of biglycan were generated and characterized. The processes of cell differentiation and matrix mineralization were accelerated in S but delayed in AS, indicating that BGN modulates osteoblastic cell differentiation. Biglycan (BGN), a member of the small leucine-rich proteoglycan family, is one of the major proteoglycans found in bone and has been implicated in bone formation. In this study, the effects of over- or underexpression of BGN on osteoblastic cell phenotypes and matrix mineralization were studied. MC3T3-E1 cells were transfected with vectors containing the BGN cDNA in a sense or antisense orientation to generate clones expressing higher (S clones) or lower (AS clones) levels of BGN. MC3T3-E1 cells and those transfected with an empty vector (EV) were used as controls. The levels of BGN synthesized by these clones were evaluated by Western blot analysis. Cell growth was analyzed by cell counting and cell differentiation by the gene expression patterns of several osteoblastic markers using quantitative real-time PCR. The abilities of these clones to form mineralized matrices were evaluated by in vitro and in vivo mineralization assays. Furthermore, the clones were treated with BMP-4 and their responsiveness was assessed. The cell growth in these clones was unaffected; however, osteoblast differentiation was significantly accelerated in S clones and suppressed in AS clones. The in vitro matrix mineralization in S clones was significantly enhanced but severely impaired in AS clones. When transplanted into immunodeficient mice, S clone transplants exhibited larger areas of lamellar bonelike matrices, whereas only minute amounts of woven bone-type structure was found in AS transplants. The response to BMP-4 was higher in S clones but poorer in AS clones compared with that of controls. BGN modulates osteoblast differentiation, possibly by regulating BMP signaling, and consequently matrix mineralization.


Effect of curing and heat treatments on the Salmonella survival and physicochemical properties of chicken egg yolk.
Cured egg yolk is a novel gastronomic preparation, which a salt and sugar mixture gradually diffuses into the egg yolk, promoting its solidification from the exterior to the inner parts and greatly concentrates fat and flavor. This study was undertaken to analyze the effect of curing and its association with heat treatments on the Salmonella survival and physicochemical properties of chicken egg yolks. Contaminated egg yolks (8.4 log10 CFU/g) were covered by a mixture of sugar and salt and stored at 4.5 °C for curing, for 2, 24, 72 and 144 h. The cured yolks were subjected to the heat treatments: 62 °C for 30 min in temperature-controlled water circulator or at 80 °C for 3 h in oven. None of the treatments promoted the complete inactivation of Salmonella (detection limit of 100 CFU/g). However, Salmonella populations were significantly reduced (p ≤ 0.05) when heat processes were applied, reaching a maximum reduction of 5.6 log10 CFU/g when the yolks were cured for 2 h and subsequently treated in temperature-controlled water circulator (62 °C for 30 min). This treatment kept the physicochemical properties similar to the ones without heat treatment, while the oven treatment showed considerable changes on texture, water activity and visual color. In conclusion, the use of curing time of 2 h followed by temperature-controlled water circulator process can improve the safety of cured egg yolks made from high quality eggs. However, other methods should be considered and analyzed to promote a complete inactivation of Salmonella.


Severe hypoglycaemia. A one-year prospective survey in Wollongong.
A one-year prospective survey of serious hypoglycaemia has been carried out in the Wollongong area. Of insulin-treated patients attending the diabetes clinic, 3.5% had a hypoglycaemic attack of sufficient severity to be referred to hospital. A further 1% received treatment for attacks of hypoglycaemia at home. It is considered that nearly two-thirds of the attacks of hypoglycaemia may have been preventable. Further reductions may be achieved by the better education of patients about their disease.


Associations between paternal urinary phthalate metabolite concentrations and reproductive outcomes among couples seeking fertility treatment.
Limited evidence suggests that male exposure to ubiquitous environmental phthalates may result in poor reproductive outcomes among female partners. This analysis included male-female couples undergoing in vitro fertilization (IVF) and/or intrauterine insemination (IUI). We evaluated associations between the geometric mean of paternal specific gravity-adjusted urinary phthalate concentrations prior to the female partners' cycle and fertilization, embryo quality, implantation, and live birth using generalized linear mixed models. Two-hundred eighteen couples underwent 211 IVF and 195 IUI cycles. Trends were observed between paternal urinary mono-3-carboxypropyl phthalate (MCPP; P=0.01) and mono(carboxyoctyl) phthalate (MCOP; P=0.01) and decreased odds of implantation. MCPP and MCOP were also associated with decreased odds of live birth following IVF (P=0.01 and P=0.04, respectively), and monobutyl phthalate above the first quartile was significantly associated with decreased odds of live birth following IUI (P=0.04). However, most urinary phthalate metabolites were not associated with these reproductive outcomes. Selected phthalates were associated with decreased odds of implantation and live birth.


Vibrio damsela infection in a stranded leatherback turtle (Dermochelys coriacea).
Necropsy of a stranded adult leatherback turtle (Dermochelys coriacea) determined that the animal died as a result of valvular endocarditis and septicemia. Vibrio damsela was isolated from the endocardial thrombus. The route of entry for infection probably was through the gastrointestinal tract.


Cucumeropsis mannii seed oil ameliorates Bisphenol-A-induced adipokines dysfunctions and dyslipidemia.
This study demonstrated the therapeutic potentials of Cucumeropsis mannii seed oil (CMSO) capable of alleviating BPA-induced dyslipidemia and adipokine dysfunction. In this study, we evaluated the effects of CMSO on adipokine dysfunctions and dyslipidemia in bisphenol-A (BPA)-induced male Wistar rats. Six-week-old 36 albino rats of 100-200 g weight were assigned randomly to six groups, which received varied doses of BPA and/or CMSO. The administration of BPA and CMSO was done at the same time for 42 days by oral intubation. The adipokine levels and lipid profile were measured in adipose tissue and plasma using standard methods. BPA induced significant (p < .05) increases in triglycerides, cholesterol, leptin, LDL-C, and atherogenic and coronary risk indices in adipose tissue and plasma, as well as a decrease in adiponectin and HDL-C levels in Group II animals. BPA administration significantly (p < .05) elevated Leptin levels and reduced adiponectin levels. BPA plus CMSO reduced triglycerides, cholesterol, leptin, LDL-C, and atherogenic and coronary risk indices while increasing adiponectin levels and HDL-C in adipose tissue and plasma (p < .05). The results showed that BPA exposure increased adipose tissue as well as serum levels of the atherogenic index, triglycerides, cholesterol, coronary risk index, LDL-C, leptin, and body weight with decreased adiponectin levels and HDL-C. Treatment with CMSO reduced the toxicities caused by BPA in rats by modulating the body weight, adiponectin/leptin levels, and lipid profiles in serum and adipose tissue. This study has shown that CMSO ameliorates BPA-induced dyslipidemia and adipokine dysfunctions. We suggest for further clinical trial to establish the clinical applications.


Investigating the causal effect of cognition on the self-reported loss of functional dentition using marginal structural models: The Panel on Health and Ageing of Singaporean Elderly study.
To assess the effect of cognition on the loss of functional dentition. We used data from the three waves of the Panel on Health and Ageing of Singaporean Elderly study (n = 4990 at baseline, 774 complete cases analysed) over 6 years (2009-2015). The outcome was the loss of functional dentition (<21 teeth). The exposure was cognitive impairment, while baseline confounders included age, sex, education, and ethnicity. Time-varying confounders included income, living arrangements, smoking, diabetes, depressive symptoms, cardiovascular disease, and body mass index. We used marginal structural mean models with inverse probability treatment weighted. The mean age of the participants was 70.2 years at baseline. The proportion of participants with loss of functional dentition increased from 74.6% to 89.9% over 6 years. Women, ethnic Chinese, less educated, smokers, people with diabetes, and individuals with depression had a higher proportion of loss of functional dentition than their counterparts. Loss of functional dentition was 1.8 times higher (odds ratio 1.80; 95% confidence interval 0.88-3.69) among those with cognitive impairment after taking well-known confounders into account. After accounting for the time-varying exposure and confounding evidence, the association between cognition and functional dentition among the elderly in Singapore remains uncertain.


Spectrum of KIT/PDGFRA/BRAF mutations and Phosphatidylinositol-3-Kinase pathway gene alterations in gastrointestinal stromal tumors (GIST).
Pathogenetic pathways of gastrointestinal stromal tumors (GIST) lacking mutations in KIT and PDGFRA (∼15%) are still poorly studied. Nearly nothing is known about PI3K alterations in GISTs and only a few GISTs with BRAF mutations have been reported. BRAF mutations (V600E) were found in 3/87 tumors (3.5%) concomitantly were wild type for KIT and PDGFRA. No mutations were detected in KRAS, NRAS, and FGFR3. For the first-time we demonstrated a PIK3CA mutation (H1047L) simultaneously occurring with a 15-bp deletion in KIT exon 11 in one tumor. We suggest that BRAF mutations are of pathogenetic significance in wild type GISTs. The PI3K pathway should be assessed in future studies.


Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance.
Since cloning of the ATP-binding cassette (ABC) family member breast cancer resistance protein (BCRP/ABCG2) and its characterization as a multidrug resistance efflux transporter in 1998, BCRP has been the subject of more than two thousand scholarly articles. In normal tissues, BCRP functions as a defense mechanism against toxins and xenobiotics, with expression in the gut, bile canaliculi, placenta, blood-testis and blood-brain barriers facilitating excretion and limiting absorption of potentially toxic substrate molecules, including many cancer chemotherapeutic drugs. BCRP also plays a key role in heme and folate homeostasis, which may help normal cells survive under conditions of hypoxia. BCRP expression appears to be a characteristic of certain normal tissue stem cells termed "side population cells," which are identified on flow cytometric analysis by their ability to exclude Hoechst 33342, a BCRP substrate fluorescent dye. Hence, BCRP expression may contribute to the natural resistance and longevity of these normal stem cells. Malignant tissues can exploit the properties of BCRP to survive hypoxia and to evade exposure to chemotherapeutic drugs. Evidence is mounting that many cancers display subpopulations of stem cells that are responsible for tumor self-renewal. Such stem cells frequently manifest the "side population" phenotype characterized by expression of BCRP and other ABC transporters. Along with other factors, these transporters may contribute to the inherent resistance of these neoplasms and their failure to be cured.


Methylmercury promotes oxidative stress and autophagy in rat cerebral cortex: Involvement of PI3K/AKT/mTOR or AMPK/TSC2/mTOR pathways and attenuation by N-acetyl-L-cysteine.
Methylmercury (MeHg) is a potent neurotoxicant that could induce oxidative stress and autophagy. However, the underlying mechanisms through which MeHg affects the central nervous system have not been fully elucidated, and little has been known of the interaction between oxidative stress and autophagy. Therefore, rats were administrated with different MeHg concentrations to evaluate the neurotoxic effects and autophagy in cerebral cortex. Moreover, we have investigated the neuroprotective role of N-acetyl-L-cysteine (NAC) against MeHg-induced neurotoxicity in order to estimate the regulation effects of oxidative stress on autophagy. A total of 64 rats, 40 of which were randomly divided into control and MeHg-treated (4, 8 and 12 μ mol/kg) groups. The remaining 24 rats were divided into control, NAC control (1 mmol/kg), 12 μ mol/kg MeHg, and NAC pretreatment. Administration of 12 μ mol/kg MeHg significantly increased behavioral and pathological abnormalities, and autophagy levels. In addition, the oxidative stress levels increased, together with abnormal expression of autophagy-related molecules. Pretreatment with NAC significantly prevented MeHg-induced oxidative stress and PI3K/AKT/mTOR or AMPK/TSC2/mTOR-mediated autophagy. In conclusion, the present study suggested that oxidative stress can regulate autophagy through PI3K/AKT/mTOR or AMPK/TSC2/mTOR pathways. This study provides a theoretical basis for the study and treatment of MeHg-induced neurotoxicity.


Causes of death and competing risk analysis of the associated factors for non-small cell lung cancer using the Surveillance, Epidemiology, and End Results database.
To investigate the probability of death (POD) from any causes by time after diagnosis of non-small cell lung cancer (NSCLC) and the factors associated with survival for NSCLC patients. A total of 202,914 patients with NSCLC from 2004 to 2013 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The overall survival (OS) and lung cancer-specific survival (LCSS) were calculated and POD from any causes at different time periods after diagnosis was explored. The predictive factors for OS, LCSS and survival from non-lung cancer deaths were investigated using multivariate analysis with Cox proportional hazards regression and competing risk regression analysis. The 5- and 10-year OS were 20.4% and 11.5%, accordingly that for LCSS were 25.5% and 18.4%, respectively. Lung cancer contributed 88.3% (n = 128,402) of the deaths. The POD from lung cancer decreased with time after diagnosis. In multivariate analysis, advanced age and advanced stage of NSCLC were associated with decreased OS and LCSS. Comparing to no surgery, any kind of resection conferred lower risk of death from lung cancer and higher risk of dying from non-lung cancer conditions except lobectomy or bilobectomy, which was associated with lower risk of death from both lung cancer and non-lung cancer conditions. Most of the patients with NSCLC died from lung cancer. Rational surveillance and treatment policies should be made for them. Early stage and lobectomy or bilobectomy were associated with improved OS and LCSS. It is reasonable to focus on early detection and optimal surgical treatment for NSCLC.


[Multiple subpial transection in surgical treatment of intractable epilepsy].
To increase the effect of epilepsy surgery, we use multiple subpial transection (MST) clinically on the basis of experimental study. We analyzed the seizure type and course of 116 intractable epilepsy patients treated with MST and surgical technique were modified. 100 patients were followed up for 1 to 5 years. Complete control of seizure was obtained in 62 patients (62%), significant reduction (over 75%) in 20 (20%), reduction (over 50%) in 12 (12%), and no change in 6 (6%). The total effective rate was 94%, and the significant effective rate was 82%. No functional defect was found in any patients. MST is a effective in surgical treatment of intractable epilepsy and can replace conventional methods. Combined bilateral frontal lobe MST and anterior callosotomy is a good way to treat intractable generalized epilepsy.


Identification of bio-active food compounds as potential SARS-CoV-2 PLpro inhibitors-modulators via negative image-based screening and computational simulations.
Despite significant studies on the COVID-19 pandemic, scientists around the world are still battling to find a definitive therapy against the ongoing severe global health crisis. In this study, advanced computational approaches have been employed to identify bioactive food constituents as potential SARS-CoV-2 PLpro inhibitors-modulators. As a validated antiviral drug target, PLpro has gained tremendous attention for therapeutics developments. Therefore, targeting the multifunctional SARS-CoV-2 PLpro protein, ∼1039 bioactive dietary compounds have been screened extensively through novel techniques like negative image-based (NIB) screening and molecular docking approaches. In particular, the three different models of NIB screening have been generated and used to re-score the dietary compounds based on the negative image which is created by reversing the shape and electrostatics features of PLpro protein's ligand-binding cavity. Further, 100 ns molecular dynamics simulation has been performed and MM-GBSA based binding free energies have been estimated for the final proposed four dietary compounds (PC000550, PC000361, PC000558, and PC000573) as potential inhibitors/modulators of SARS-CoV-2 PLpro protein. Employed computational study outcome also has been compared with respect to the earlier experimentally investigated compound GRL0617 against SARS-CoV-2 PLpro protein, which suggests much greater interaction potential in terms of binding affinity and other energetic contributions for the proposed dietary compounds. Hence, the present study suggests that proposed dietary compounds can be suitable chemical entities for modulating the activity of PLpro protein or can be further utilized for optimizing or screening of novel chemical surrogates, however also needs experimental evaluation for entry in clinical studies for better assessment.


D-cycloserine, a partial NMDA receptor-associated glycine-B site agonist, enhances reversal learning, but a cholinesterase inhibitor and nicotine has no effect.
The present study examined the efficacy of single and combined treatments with an anticholinesterase, tetrahydroaminoacridine, nicotine and a glycine-B site partial agonist, D-cycloserine, in alleviating the water maze reversal learning defect induced by a medial septal lesion. D-cycloserine (3 and 10 mg/kg) improved reversal learning. Tetrahydroaminoacridine (1 and 3 mg/kg) and nicotine (0.1 and 0.3 mg/kg) had no effect on reversal learning. A combination of tetrahydroaminoacridine 3 mg/kg or nicotine 0.3 mg/kg and D-cycloserine 10 mg/kg was not more effective than D-cycloserine 10 mg/kg alone in improving reversal learning. This suggests that stimulation of NMDA mechanisms may more effectively improve in medial septal-lesioned rats reversal learning processes than stimulation of cholinergic activity.


It's his right, it's her duty: benevolent sexism and the justification of traditional sexual roles.
This study tested the effects on social perceptions of sexual marital rights and duties of ambivalent sexist ideology and information about the benevolent sexist ideology of a husband, portrayed in a hypothetical marital vignette. In addition, the perception of whether hypothetical forced sex between husband and wife is considered rape was explored. For one half of the participants (college students), the husband was presented as high in benevolent sexism (BS); and for the other half, no information about his ideology was given. Results showed that participants in the first group ranked sexual marital rights (for him) and duties (for her) more highly, and regarded forced sex as rape to a lesser extent. Positive relationships were also found between participants' BS and these ratings. Moreover, participants' perceptions of marital rights and duties played a mediating role in the relationship between their BS and their perception of forced penetration as rape. Finally, an interaction was found between participants' and husbands' BS in the perception of marital rights and duties: The influence of participants' BS was higher when the husband was presented as a benevolent sexist man. Results highlight the role of sexist attitudes in the interpretation of marital rape.


Asymptotic Properties of the Number of Matching Coalescent Histories for Caterpillar-Like Families of Species Trees.
Coalescent histories provide lists of species tree branches on which gene tree coalescences can take place, and their enumerative properties assist in understanding the computational complexity of calculations central in the study of gene trees and species trees. Here, we solve an enumerative problem left open by Rosenberg (IEEE/ACM Transactions on Computational Biology and Bioinformatics 10: 1253-1262, 2013) concerning the number of coalescent histories for gene trees and species trees with a matching labeled topology that belongs to a generic caterpillar-like family. By bringing a generating function approach to the study of coalescent histories, we prove that for any caterpillar-like family with seed tree t , the sequence (hn)n ≥ 0 describing the number of matching coalescent histories of the n th tree of the family grows asymptotically as a constant multiple of the Catalan numbers. Thus, hn ∼ βt cn, where the asymptotic constant βt > 0 depends on the shape of the seed tree t. The result extends a claim demonstrated only for seed trees with at most eight taxa to arbitrary seed trees, expanding the set of cases for which detailed enumerative properties of coalescent histories can be determined. We introduce a procedure that computes from t the constant βt as well as the algebraic expression for the generating function of the sequence (hn)n ≥ 0.


Synthesis and HIV-1 integrase inhibitory activities of caffeic acid dimers derived from Salvia officinalis.
The synthesis of two caffeoyl-coumarin conjugates, derived from sagecoumarin, has been accomplished, starting from ferulic acid, isoferulic acid and sesamol. Both compounds exhibited potent inhibitory activities at micromolar concentrations against HIV-1 integrase in 3'-end processing reaction but were less effective against HIV-1 replication in a single-round infection assay of HeLa-beta-gal-CD4+ cells.


Enhancement of humoral immune responses against viral vaccines by a non-pyrogenic 6-O-acylmuramyldipeptide and synthetic low toxicity analogues of lipid A.
6-O-Acyl derivatives of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) and synthetic, low toxicity lipid-A analogues were examined for their ability to enhance the potency of current viral vaccines. 6-O-(2-Tetradecylhexadecanoyl)-MDP (B30-MDP) in non-irritative vehicles such as physiological saline, phosphate-buffered saline (PBS), squalene-PBS emulsion, Intralipid or liposomes, significantly stimulated the primary and secondary antibody production of guinea-pigs against influenza split or subunit vaccine and inactivated the hepatitis B virus surface (HBs) antigen. Mice seemed less responsive to the adjuvanticity of B30-MDP than guinea-pigs. Two low toxicity lipid A analogues, acylated beta(1-6)-D-glucosamine disaccharide bisphosphates (which do not have amide-bound or ester-bound 3-acyloxyacyl groups unlike fully toxic Escherichia coli-type lipid A), caused significantly enhanced antibody responses, primary or secondary, when administered to mice by incorporation into liposomes with inactivated HBs antigen.


Induction of apoptosis by a short-chain neuropeptide analog in small cell lung cancer.
Small cell lung cancer (SCLC) cells express a variety of neuropeptides which act as autocrine growth factors. Although several neuropeptide analogs have been reported to antagonize SCLC proliferation, the development of these compounds has been limited by their low potency and the cytostatic nature of their effects. In the present study we evaluated the cytotoxic activity of four short-chain substance P analogs (NY3460, NY3238[-pHOPA], NY3238[Phe1], NY3238[Lys5]) against a panel of five SCLC cell lines. NY3460 was the most potent compound in all five SCLC cell lines (IC50 = 2.8-3.7 microM) as assessed by a MTT growth inhibitory assay. NY3238[Phe1] was also relatively active in all cell lines (IC50 = 3.5-11.2 microM), while NY3238[Lys5] and NY3238[-pHOPA] were substantially less active. NY3460 was the only agent to induce an increase in the percentage of cells with subdiploid DNA content suggestive of apoptosis by flow cytometric DNA content analysis. The induction of apoptosis was confirmed by fluorescent microscopy in NCI-H69, NCI-H82, NCI-H446, and NCI-H510 cells after exposure to 5.0 microM NY3460 for 48 h. These findings suggest that NY3460 is a relatively potent cytotoxic inhibitor of SCLC growth, and that short-chain neuropeptide analogs deserve further evaluation as anti-SCLC agents.


Chikungunya Virus-Associated Disease.
Chikungunya virus (CHIKV) infection has become increasingly prevalent in the last decade not only across the southern hemisphere but also, because of a recently documented viral mutation, in southern Europe and the USA. With the global spread of CHIKV infection, practitioners should know its epidemiology, pathophysiology and clinical features. The acute phase of CHIKV disease is characterised by a fever-arthralgia-rash syndrome. Chronic rheumatic manifestations can persist for months to years with very variable clinical presentations. Some cases mimic inflammatory rheumatism such as rheumatoid arthritis. Several risk factors for persistent joint pain, notably older age, have been identified in cohort studies. Despite a low mortality rate with CHIKV infection, the rate of disability with chronic joint symptoms is high, and effective treatments are lacking. Current research is focusing on the development of vaccines and antiviral drugs, and data on treatment of CHIKV-induced chronic arthritis are needed.


A novel case of cutaneous myxoid spindle cell neoplasm with FMR1-ALK gene fusion and CD34/S100 co-expression.
A novel class of superficial CD34+ and S100+ cutaneous spindle cell neoplasm harboring ALK rearrangements has recently been described. Morphologically, these neoplasms have been characterized by bland spindled cells organized in whorls and cords against myxoid stroma, eventuating in the designation "superficial ALK-rearranged myxoid spindle cell neoplasm." Here, we report a 78-year-old male with a 3-mm pink papule on the chest, clinically concerning for cutaneous carcinoma. Biopsy of the specimen showed a biphasic tumor with hypercellular and hypocellular zones consisting of epithelioid cells and monomorphic, bland spindled cells. The spindled cells were arranged in perineurial-like concentric whorls and cords embedded in a myxo-collagenous stroma. Neoplastic cells were diffusely positive for CD34, S100, and D5F3-ALK, without SOX10 expression. Negative markers included GLUT1, EMA, factor XIIIa, desmin, actin, and SMA. ALK-rearrangement was identified on fluorescence in situ hybridization break-apart assay. A corresponding novel FMR1-ALK fusion was found by next-generation sequencing (NGS) based RNA sequencing. Identification of this new FMR1-ALK fusion signature adds to the spectrum of diagnostic genomic alterations in this newly described class of tumors.


Cortisone and cortisol break hydrogen-bonding rules to make a drug-prodrug solid solution.
Multidrug products enable more effective therapies and simpler administration regimens, provided that a stable formulation is prepared, with the desired composition. In this view, solid solutions have the advantage of combining the stability of a single crystalline phase with the potential of stoichiometry variation of a mixture. Here a drug-prodrug solid solution of cortisone and cortisol (hydrocortisone) is described. Despite the structural differences of the two components, the new phase is obtained both from solution and by supercritical CO2 assisted spray drying. In particular, to enter the solid solution, hydrocortisone must violate Etter's rules for hydrogen bonding. As a result, its dissolution rate is almost doubled.


Regulation of arterial reactivity by concurrent signaling through the E-prostanoid receptor 3 and angiotensin receptor 1.
Prostaglandin E2 (PGE2), a cyclooxygenase metabolite that generally acts as a systemic vasodepressor, has been shown to have vasopressor effects under certain physiologic conditions. Previous studies have demonstrated that PGE2 receptor signaling modulates angiotensin II (Ang II)-induced hypertension, but the interaction of these two systems in the regulation of vascular reactivity is incompletely characterized. We hypothesized that Ang II, a principal effector of the renin-angiotensin-aldosterone system, potentiates PGE2-mediated vasoconstriction. Here we demonstrate that pre-treatment of arterial rings with 1nM Ang II potentiated PGE2-evoked constriction in a concentration dependent manner (AUC-Ang II 2.778±2.091, AUC+Ang II 22.830±8.560, ***P<0.001). Using genetic deletion models and pharmacological antagonists, we demonstrate that this potentiation effect is mediated via concurrent signaling between the angiotensin II receptor 1 (AT1) and the PGE2 E-prostanoid receptor 3 (EP3) in the mouse femoral artery. EP3 receptor-mediated vasoconstriction is shown to be dependent on extracellular calcium in combination with proline-rich tyrosine kinase 2 (Pyk2) and Rho-kinase. Thus, our findings reveal a novel mechanism through which Ang II and PGE2 regulate peripheral vascular reactivity.


The future of fulvestrant ("Faslodex").
Changes in clinical practice regarding favoured first-line and adjuvant treatments for postmenopausal women with advanced breast cancer (ABC) mean that it is becoming increasingly important to identify agents that are effective following aromatase inhibitor (AI) failure as well as tamoxifen failure. Fulvestrant ("Faslodex") is a new oestrogen receptor (ER) antagonist with no agonist effects that binds, blocks and degrades the ER. Fulvestrant is at least as effective as anastrozole following tamoxifen failure and also shows activity after progression on AIs. Its very good tolerability profile and novel mode of action, might offer potential for the use of fulvestrant in combination regimens, and there is also scope for investigating the use of loading and higher dose regimens in an attempt to further enhance efficacy. Here, the rationale and evidence for the efficacy of fulvestrant following AI failure and its combination with AIs and novel agents such as gefitinib and trastuzumab will be reviewed. The ongoing clinical development programme for fulvestrant will more fully the role of this valuable new agent in the treatment of postmenopausal ABC.


Disseminated adenovirus disease in immunocompromised patient successfully treated with oral ribavirin: a case report.
In patients with immunological disorders, adenovirus infections are associated with significant rates of morbidity and mortality. Only few hematological units use molecular virological methods, such as polymerase chain reaction, for surveillance of adenovirus infection, and treatment strategies have never been evaluated in multicenter clinical trials. This report describes the detection and treatment of human adenovirus (HAdVs) disseminated disease in the case of a 46-year-old immunocompromised female having myelodysplastic syndrome with refractory cytopenia with multilineage dysplasia: International Prognostic Scoring System 1. Serum and urine samples were tested for the presence of adenoviral DNA using the quantitative real-time polymerase chain reaction (PCR) assay. For additional confirmation, sequencing of PCR products was also performed. With real-time PCR, we detected HAdV DNA in both serum and urine samples. The viral level constantly decreased with applied oral ribavirin therapy. As the result of sequencing, HAdVs type 11 was determined. Surveillance of adenovirus by real-time PCR is useful in detecting and monitoring disseminated HAdV infection; it is a potential standard diagnostic approach that could assist clinicians to decide whether antiviral therapy ought to be administered.


Experience of extracorporeal membrane oxygenation as a bridge to lung transplantation in France.
Extracorporeal membrane oxygenation (ECMO) is increasingly used as a bridge to lung transplantation (LTx). However, data concerning this approach remain limited. We retrospectively reviewed the medical records of all patients in France who received ECMO as a bridge to LTx from 2007 to 2011. Post-transplant survival and associated factors were assessed by the Kaplan-Meier method and the Cox model. Included were 36 patients from 11 centers. Indications for LTx were cystic fibrosis (CF) in 20 (56%), pulmonary fibrosis (PF) in 11 (30%), and other diagnoses in 5 (14%). ECMO was venovenous for 27 patients (75%) and venoarterial for 9 (25%). Mean follow-up was 17 months. Bridging to LTx was achieved in 30 patients (83%); however, only 27 patients (75%) survived the LTx procedure, and 20 (56%) were discharged from hospital. From ECMO initiation, 2-year survival rates were 50.4% overall, 71.0% for CF patients, 27.3% for PF patients, and 20.0% for other patients (p < 0.001). From LTx, 2-year survival rates were 60.5% overall, 71.0% for CF patients, 42.9% for PF patients, and 33.0% for other patients (p = 0.04). Our study confirms that the use of ECMO as a bridge to LTx in France could provide a medium-term survival benefit for LTx recipients with critical conditions. Survival differed by underlying respiratory disease. Larger studies are needed to further define the optimal use of ECMO.


GJB2 mutations and additional disabilities in a pediatric cochlear implant population.
Children with severe to profound sensorineural hearing loss due to GJB2 mutations have often been deemed good cochlear implant candidates. Studies on children with GJB2 mutations and cochlear implants have typically excluded children with additional disabilities. To investigate the presence of additional disabilities among children with and without GJB2 mutations in a cochlear implant population. A retrospective chart review was performed of children with non-syndromic sensorineural hearing loss (SNHL) who received a cochlear implant between 1993 and 2004. Among 108 children within the cochlear implant database; 46 patients met the inclusion criteria of idiopathic non-syndromic hearing loss. Sixteen children had GJB2 mutations, 12 were GJB2 negative, and 17 did not receive GJB2 testing but had no other identifiable etiology or risk factor contributing to hearing loss. The proportion of children with additional disabilities that would affect either pre-operative assessments or post-operative results in the GJB2 positive group was 44% compared to 33% of children in the GJB2 negative. Additional disabilities were present in 41% of the children who did not receive GJB2 testing. The disabilities in the GJB2 positive group included specific learning disability, apraxia, epileptiform aphasia, attention deficit disorder, global developmental delay, and gross motor delay. The GJB2 negative and those children not receiving GJB2 testing had motor delays, language delay, autism, specific learning disability, and attention deficit disorder. The proportion of children with at least 6 months CI use who relied on oral communication was 62% in the GJB2 positive group, 66% in the GJB2 negative group, and 38% in the untested group. A majority of the genetic alleles were 35delG (81%) and 10 of 16 (63%) patients with GJB2 mutations were homozygous 35delG. The rate of developmental diagnoses was similar in patients with homozygous GJB2 compared to compound heterozygous genotypes. The presence of biallelic GJB2 mutations does not rule out non-hearing related disorders that can have an effect on speech, language and learning. Forty-four percent of children with GJB2 mutations had other conditions that could directly affect pre-implant evaluation and post-implant performance. This rate is similar to the reported prevalence among the overall population of children with hearing loss. All children should have a comprehensive evaluation of development and behavior regardless of the etiology of hearing loss.


Parallel introgression, not recurrent emergence, explains apparent elevational ecotypes of polyploid Himalayan snowtrout.
The recurrence of similar evolutionary patterns within different habitats often reflects parallel selective pressures acting upon either standing or independently occurring genetic variation to produce a convergence of phenotypes. This interpretation (i.e. parallel divergences within adjacent streams) has been hypothesized for drainage-specific morphological 'ecotypes' observed in polyploid snowtrout (Cyprinidae: Schizothorax). However, parallel patterns of differential introgression during secondary contact are a viable alternative hypothesis. Here, we used ddRADseq (N = 35 319 de novo and N = 10 884 transcriptome-aligned SNPs), as derived from Nepali/Bhutanese samples (N = 48 each), to test these competing hypotheses. We first employed genome-wide allelic depths to derive appropriate ploidy models, then a Bayesian approach to yield genotypes statistically consistent under the inferred expectations. Elevational 'ecotypes' were consistent in geometric morphometric space, but with phylogenetic relationships at the drainage level, sustaining a hypothesis of independent emergence. However, partitioned analyses of phylogeny and admixture identified subsets of loci under selection that retained genealogical concordance with morphology, suggesting instead that apparent patterns of morphological/phylogenetic discordance are driven by widespread genomic homogenization. Here, admixture occurring in secondary contact effectively 'masks' previous isolation. Our results underscore two salient factors: (i) morphological adaptations are retained despite hybridization and (ii) the degree of admixture varies across tributaries, presumably concomitant with underlying environmental or anthropogenic factors.


Autistic disorder and chromosomal mosaicism 46,XY[123]/46,XY,del(20)(pter --> p12.2)[10].
We report on a 3-year-old boy with a moderate to severe mental retardation, autistic behavior patterns, and myoclonic epilepsy of early childhood. The cytogenetic analysis of blood lymphocytes revealed a deletion of chromosome 20pter --> p12.2 occurring as mosaicism in 8% of the analyzed metaphases: 46,XY[123]/46,XY,del(20)(pter --> p12.2)[10]. The deletion was confirmed by the recently developed multicolor banding approach and additionally by region specific fluorescence in situ hybridization (FISH) probes. To the best of our knowledge, this is the first report on a patient with autistic behavior with terminal 20p deletion mosaicism reported up to present.


Antiplatelet therapy for postdischarge medical management of acute coronary syndrome.
Postdischarge management of patients with acute coronary syndrome is often suboptimal, despite their high risk of a subsequent event. Updated American College of Cardiology/American Heart Association guidelines emphasize the need for aggressive modification of risk factors and treatment with antiplatelet, antihypertensive, and lipid-lowering agents commenced in-hospital and continued long-term. Antiplatelet therapy involving aspirin and clopidogrel is the mainstay of secondary risk reduction. Increased adherence to medication and risk factor modification at discharge has been demonstrated with acute care quality improvement initiatives. Extension of these initiatives to postdischarge care will provide data on medication adherence post acute coronary syndrome and functional outcomes in the community setting. Successful secondary prevention of cardiovascular events requires implementation of evidence-based guidelines by physicians, and adherence to pharmacotherapy and lifestyle modifications by patients. Primary care physicians are well placed to influence adherence through their ongoing relationships with patients and can save lives by implementing secondary risk reduction measures after discharge.