Intravascular metabolism of different fatty acids during lipid infusion in man.
The differential intravascular metabolism of individual fatty acids contained in triacylglycerol-rich particles was studied by infusing 6 normal subjects for 5h with a conventional soy-based emulsion and an experimental olive oil-based emulsion. Both emulsions contained similar amounts of palmitate (11%) and stearate (3-4%) but the former was quite rich in linoleate (54%) and alpha-linolenate (7%), while the latter was rich in oleate (69%). During hydrolysis of circulating triacylglycerols by endothelial lipases, the associated rise of non-esterified fatty acids (FFA) in plasma represents the balance between fatty acid release and tissue uptake. Plasma levels of triacylglycerols and FFA increased about 3 fold and total body fat oxidation was raised to similar values with both emulsions. Fatty acid pattern quickly changed in plasma triacylglycerols to resemble the composition of emulsion particles, with an exception for palmitate which increased markedly more, suggesting a high level of hepatic re-esterification and re-appearance in nascent very low density lipoprotein triglycerides (VLDL-TG) secreted into the circulation. In plasma FFA, stearate and palmitate increased more and alpha-linolenate much less than expected from their content in the emulsion, indicating probably low tissue uptake for the former ones but avid removal for the latter.


Evaluation of hyper thermal acid hydrolysis of Kappaphycus alvarezii for enhanced bioethanol production.
Hyper thermal (HT) acid hydrolysis of Kappaphycus alvarezii, a red seaweed, was optimized to 12% (w/v) seaweed slurry content, 180mM H2SO4 at 140°C for 5min. The maximum monosaccharide concentration of 38.3g/L and 66.7% conversion from total fermentable monosaccharides of 57.6g/L with 120gdw/L K. alvarezii slurry were obtained from HT acid hydrolysis and enzymatic saccharification. HT acid hydrolysis at a severity factor of 0.78 efficiently converted the carbohydrates of seaweed to monosaccharides and produced a low concentration of inhibitory compounds. The levels of ethanol production by separate hydrolysis and fermentation with non-adapted and adapted Kluyveromyces marxianus to high concentration of galactose were 6.1g/L with ethanol yield (YEtOH) of 0.19 at 84h and 16.0g/L with YEtOH of 0.42 at 72h, respectively. Development of the HT acid hydrolysis process and adapted yeast could enhance the overall ethanol fermentation yields of K. alvarezii seaweed.


Lack of collagen XVIII accelerates cutaneous wound healing, while overexpression of its endostatin domain leads to delayed healing.
Endostatin, the C-terminal fragment of collagen XVIII, is known to suppress tumour growth and angiogenesis by inhibiting endothelial cell proliferation and migration. We have previously shown that endostatin and its precursor are important for the structural organization of basement membranes (BM). The aim of this study was to investigate cutaneous wound healing in mice overexpressing endostatin in keratinocytes (ES-tg) and in mice lacking collagen XVIII (Col18a1(-/-)). Excisional wounds were made on the dorsal skin of mice, the wound areas were measured and the wounds were collected for further analyses after 3, 6 or 14 days. The healing of the wounds was delayed in the ES-tg mice and accelerated in the Col18a1(-/-) mice, and the vascularisation rate was accelerated in the Col18a1(-/-) mice, but not affected in the ES-tg mice. Abnormal capillaries with swollen endothelial cells and narrowed lumens were observed in the wounds of the ES-tg mice. In these mice also the formation of the epidermal BM was delayed, and the structure of the epidermal and capillary BMs was more disorganised. Moreover, detachment of the epidermis from the granulation tissue was observed in half (n=10) of the 6-day-old ES-tg wounds, but in none of the controls, suggesting an increased fragility of the epidermal-dermal junction in the presence of an excess of endostatin.


Developing a Peer Support Protocol for Improving Veterans' Engagement to Computer-Delivered Cognitive Behavioural Therapy.
Computer-delivered cognitive behavioural therapy (cCBT) is an effective alternative to provider-delivered treatment for depression and anxiety, but high attrition poses a significant challenge to its use. Peer support is a feasible approach to improving cCBT engagement, but less is known about its acceptability among Veterans. To obtain feedback from Veterans (n = 24) with depression and/or anxiety on their preferences for (a) activities of Veterans Administration Peer Support Specialists (VA PSS) in helping Veterans use Moving Forward, a cCBT-based protocol developed by VA, and (b) methods for delivering support to Veterans using this programme. Four focus groups (5-7 Veterans per group) provided feedback to be used in the development of a peer-supported engagement intervention to help Veterans with depression and anxiety use Moving Forward. Content areas included roles that a VA PSS might play in supporting the use of and engagement in Moving Forward, as well as methods of delivering that support. Veteran preferences for PSS activity focused on practical aspects of using Moving Forward, including orientation to the programme, technical support, and monitoring progress. Feedback also suggested that Veterans preferred more personal roles for the PSS, including emotional support, as well as application of Moving Forward to 'real life' problems. The findings extend the literature on online, patient-facing mental health protocols by identifying emotional support and 'real life' skills application as Veteran-preferred components of a peer-support protocol designed to enhance use of and engagement in cCBT for depression and anxiety.


Acceptance and disclosure of HIV status through an integrated community/home-based care program in South Africa.
To report the outcome of a comparative study among people living with HIV/AIDS (PLWHAs) served by an integrated community/home-based care (ICHC) programme and those who are not in any home-based care programme in terms of acceptance and disclosure of the HIV status. One of the major challenges in HIV/AIDS care in developing countries is acceptance and disclosure of a positive HIV status by PLWHAs. Denial and non-disclosure of HIV status hinders prevention efforts as well as access to treatment, care and support for PLWHAs. Quantitative data were collected in 2004 from a group of PLWHAs served by the ICHC programme and a group that was not receiving any community/home-based care. Data were compared between the two groups in terms of acceptance and disclosure of HIV status. The ICHC was effective in improving acceptance and disclosure of the HIV-positive status by PLWHAs in the programme. PLWHAs in the ICHC programme did not find disclosure of their status difficult, and had disclosed their positive HIV status to more people than those who are not in any programme. PLWHAs in the ICHC programme not only disclosed their positive HIV status within their family network and households, but also disclosed to the community in general, sports group, religious groups and other social networks. Community/home-based care programmes can serve as catalysts for acceptance and disclosure of a positive HIV status by PLWHAs.


Estimation of the sensitivity and specificity of four serum ELISA and one fecal PCR for diagnosis of paratuberculosis in adult dairy cattle in New Zealand using Bayesian latent class analysis.
In New Zealand, a new diagnostic approach for the control of paratuberculosis in mixed aged milking cows has been developed using a combination of ELISA and quantitative fecal PCR (f-qPCR). Our analysis was designed to evaluate performance of these individual tests in infected or infectious mixed aged cows across the prevalence of infection typically encountered on NZ dairy farms and calculate test accuracy when used as a screening test of serological ELISAs for four separate antigens read in parallel followed by a confirmatory quantitative f-qPCR test. Data from a cross-sectional study of 20 moderate prevalence herds was combined with existing data from 2 low and 20 high prevalence herds forming a dataset of 3845 paired serum and fecal samples. Incidence of clinical Johne's disease (JD) was used to classify herds into three prevalence categories. High (≥ 3% annual clinical JD for the last three years), moderate (<3 - 1%) and low (<1% incidence for at least the last five years). Positive tests were declared if> 50 ELISA units and f-qPCR at two cut-points (≥1 × 104 genomes/mL or >1 × 103 genomes/mL). Fixed Bayesian latent class models at both f-qPCR cut-points, accounted for conditional independence and paired conditional dependence. Mixed models at both f-qPCR cut-points, using a different mechanism to account for conditional dependencies between tests were also implemented. Models (24 in number) were constructed using OpenBUGS. The aim was to identify Mycobacterium avium subsp. paratuberculosis (MAP) infected cows that met at least one of two criteria: shedding sufficient MAP in feces to be detected by f-qPCR or mounting a detectable MAP antibody response. The best fit to the data was obtained by modelling pairwise dependencies between tests in a fixed model or by accounting for dependencies in a mixed model at a fecal cut-off of ≥1 × 104 genomes/mL. Test performance differed with prevalence, but models were robust to prior assumptions. For the fixed model, at a prevalence of 0.29 (95 % probability interval (PI) = 0.25-0.33), as a screening plus confirmatory f-qPCR, post-test probability for disease in a positive animal was 0.84 (95 %PI = 0.80-0.88) and 0.16 (95 %PI = 0.15-0.18) for disease in a test negative animal. In low prevalence herds (0.01(95 %PI = 0.00-0.04)) the equivalent figures were 0.84 (95 %PI = 0.08-0.92) and 0.00 (95 %PI = 0.00-0.02). These results suggest this is a useful tool to control JD on dairy farms, particularly in herds with higher levels of infection, where the sampling and testing cost per animal is defrayed across more detected animals.


[Mouth diseases and acquired immunodeficiency syndrome].
The purpose of this article is to describe oral manifestations of AIDS, specially opportunistic infections, hairy leukoplakia and Kaposi's sarcoma. Fungal infections, viral infections, salivary glands disturbances and neoplasms are related. Treatment and epidemiology in Argentine are included.


Designing clinical trials based on modern imaging and metastasis-directed treatments in patients with oligometastatic breast cancer: a consensus recommendation from the EORTC Imaging and Breast Cancer Groups.
Breast cancer remains the most common cause of cancer death among women. Despite its considerable histological and molecular heterogeneity, those characteristics are not distinguished in most definitions of oligometastatic disease and clinical trials of oligometastatic breast cancer. After an exhaustive review of the literature covering all aspects of oligometastatic breast cancer, 35 experts from the European Organisation for Research and Treatment of Cancer Imaging and Breast Cancer Groups elaborated a Delphi questionnaire aimed at offering consensus recommendations, including oligometastatic breast cancer definition, optimal diagnostic pathways, and clinical trials required to evaluate the effect of diagnostic imaging strategies and metastasis-directed therapies. The main recommendations are the introduction of modern imaging methods in metastatic screening for an earlier diagnosis of oligometastatic breast cancer and the development of prospective trials also considering the histological and molecular complexity of breast cancer. Strategies for the randomisation of imaging methods and therapeutic approaches in different subsets of patients are also addressed.


An understanding of mitochondria and its role in targeting nanocarriers for diagnosis and treatment of cancer.
Nanotechnology has changed the entire paradigm of drug targeting and has shown tremendous potential in the area of cancer therapy due to its specificity. In cancer, several targets have been explored which could be utilized for the better treatment of disease. Mitochondria, the so-called powerhouse of cell, portrays significant role in the survival and death of cells, and has emerged as potential target for cancer therapy. Direct targeting and nanotechnology based approaches can be tailor-made to target mitochondria and thus improve the survival rate of patients suffering from cancer. With this backdrop, in present review, we have reemphasized the role of mitochondria in cancer progression and inhibition, highlighting the different targets that can be explored for targeting of disease. Moreover, we have also summarized different nanoparticulate systems that have been used for treatment of cancer via mitochondrial targeting.


Meta-analysis of diagnostic accuracy of neutrophil CD64 for neonatal sepsis.
The aim of this study was to systematically evaluate the diagnostic performance of nCD64 for neonatal sepsis. Computer retrieval was conducted for the databases of PubMed, Embase, and Springer databases up to March 18, 2015 to select the relevant studies on nCD64 and neonatal sepsis. Sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and 95 % confidence intervals (CI) for diagnostic efficiency of nCD64 were pooled. In addition, the summary receiver operating characteristic (SROC) curve was also conducted based on the sensitivity and specificity. Seventeen studies including 3478 participants were included in this meta-analysis. The overall pooled sensitivity, specificity, PLR, NLR and DOR were 0.77 (95 % CI: 0.74-0.79), 0.74 (95 % CI: 0.72-0.75), 3.58 (95 % CI: 2.85-4.49), 0.29 (95 % CI: 0.22-0.37) and 15.18 (95 % CI: 9.75-23.62), respectively. In addition, the area under the SROC curve (AUC) was 0.8666, and no threshold effect was found based on the Spearman correlation analysis (P = 0.616). Besides, subgroup analysis showed higher sensitivity, specificity and AUC in term infants and proven infection group than those in preterm infants and clinical infection group, respectively. The n CD64 expression alone is not a satisfactory marker for diagnosing neonatal sepsis with relatively low sensitivity, specificity, PLR and NLR, in spite of relatively high SROC area. Therefore, the n CD64 expression used in diagnosis of neonatal sepsis should be treated with caution.


Practical methods to increase use of advance medical directives.
To compare the effectiveness of two means for increasing the use of advance medical directives: written materials only versus written materials and an educational videotape. Population-based, randomized controlled trial with 3-month follow up. Kaiser Permanente Colorado Region, a not-for-profit group-model health maintenance organization. A population-based sample of all 1,302 members aged 75 years and older who used the Franklin Medical Office, excluding 55 persons who died or disenrolled during the study period or were identified by their physicians as blind or cognitively impaired. All subjects were mailed a 10-page cartoon-illustrated educational pamphlet on patient choices, a selection of Colorado advance medical directive forms, and a guide to their completion; 619 subjects also were mailed a 20-minute videotape on advance directives. Both groups had access to a study nurse for assistance in completing and placing advance medical directives. The main outcome measure is the proportion of subjects who placed a directive in their medical record for the first time. Placement rates increased almost identically, from 21.2% to 35.0% in the written materials-only group and from 18.9% to 32.6% in the group receiving the videotape (95% confidence interval for difference -0.04, 0.04, p =.952). In an elderly population with a substantial baseline placement rate, mailing of written materials substantially increased placement of an advance directive in the medical record, but the addition of a videotape did not. Mailing the video did increase the use of treatment trials and made patients more aware of reasons not to use advance directives.


An 81-year-old woman with chronic illnesses and a strong faith.
Mrs. Smith is an 81-year-old woman who has several medical problems. Despite these problems, however, her faith and spirituality strength give her the strength and determination to move forward in life. She stresses that, "My faith helps me cope with my illnesses." This article describes Mrs. Smith's roller coaster life and how faith, prayer, and hope have allowed her to continue to press forward. She interprets pain and illnesses as challenges, not obstacles. Her physician who has been treating her for about 20 years indicates that she has continued to have multiple chronic health issues and has maintained an incredibly positive spirit, particularly when traditional medicine has failed to make a difference. Spiritual care is being increasingly documented as an important component of whole person medicine. For some, religiosity and spirituality are important aspects of patient-provider relationship. God, faith, and hope are essential factors to Mrs. Smith who uses spirituality and religion daily to cope with her chronic illnesses.


Electron energy-loss spectroscopy of anomalous plutonium behavior in nuclear waste materials.
Plutonium-enriched layer has been observed in corroded spent uranium oxide fuel (CSNF). These Pu-enriched regions were examined with analytical transmission electron microscopy combined with electron energy-loss spectroscopy (EELS). The enriched region also contained U, Am, Ru, Zr, but only minor enrichment of rare earth elements. The Pu, possibly as Pu(V) according to EELS measurements, was dispersed within re-precipitated uranium oxide (identified as U3O8) nano-crystals between U(VI) secondary phases and the CSNF surface. The U, Pu, and Am enrichment was observed in the corrosion products with tests on different nuclear fuels. This may have implications for the long-term behavior of CSNF under storage in a geologic waste repository. Furthermore, there may be an increased potential for the generation of Pu-bearing colloids from this type of weathered CSNF.


Dextran 40-containing infusion fluids and corneal swelling: a specular microscopic study.
We studied the effect of dextran 40 on corneal swelling with a specular microscope. The corneas were stressed by the addition of 10(-5)M ouabain to the infusion fluids for various time intervals. Dextran 40 inhibited swelling of functionally impaired corneas. However, when the dextran 40 was removed from the solution, the corneas swelled rapidly to reach the level of those incubated in ouabain without dextran 40. When the corneas were stressed in ouabain for a short period, dextran 40 had a protective effect that lasted even after its removal from the solution.


SNARK, a novel downstream molecule of EBV latent membrane protein 1, is associated with resistance to cancer cell death.
To investigate the effect of Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) on human cancer cells, we sought to identify and analyse potential target genes that were differentially expressed in the presence and absence of LMP1. LMP1 upregulated the expression of SNARK compared with the empty vector transfected control cells, which was confirmed by reverse-transcription polymerase chain reaction. Cytotoxicity assay showed that SNARK expression increased drug resistance in response to doxorubicin (P = 0.0009), whereas knockdown of SNARK by siRNA (siSNARK) effectively inhibited LMP-1-mediated increase of cell survival (P = 0.0131). The expression of anti-apoptotic genes such as BCL6 and BIRC2 was increased by SNARK, and knockdown of these genes decreased SNARK-mediated increase of cell survival. The associations of SNARK, BCL6, and BIRC2 and the presence of EBV were also observed in T-cell lymphoma cell lines, NKL and HANK-1. These results suggest that SNARK is a downstream cellular target of LMP1 in malignant cells and can be a novel candidate for therapeutic intervention of EBV-associated cancer.


1-(2-Carboxyindol-5-yloxy)propan-2-ones as inhibitors of human cytosolic phospholipase A2alpha: synthesis, biological activity, metabolic stability, and solubility.
Indole-5-carboxylic acids with 3-aryloxy-2-oxopropyl residues in position 1 were previously reported to be potent inhibitors of cytosolic phospholipase A(2)alpha (cPLA(2)alpha) isolated from human platelets. In continuation of our attempts to develop novel cPLA(2)alpha inhibitors, a series of structurally related indole-2-carboxylic acids containing 3-aryloxy-2-oxopropoxy residues in position 5 were synthesized and tested for their cPLA(2)alpha-inhibitory potency. Furthermore, the thermodynamic solubility of these compounds and their metabolic stability against rat liver microsomes were evaluated.


Detection of unconjugated and conjugated steroids in the ovary, eggs, and haemolymph of the decapod crustacean Nephrops norvegicus.
Gas chromatography/mass spectrometry with selected ion monitoring has been employed to examine extracts from the ovary, eggs, and haemolymph of the marine prawn, Nephrops norvegicus, to demonstrate the presence of steroids. Both free and conjugated steroids were isolated by solvent partitioning and chromatography (lipophilic Sephadex, reversed-phase Sep Pak, and normal phase medium-pressure liquid chromatography) and steroidal conjugates were cleaved enzymatically. Steroids were determined as their methyloxime derivatives, trimethylsilyl (TMS) ethers or methyloxime-TMS ethers. All assignments were based on the detection of characteristic ions and cochromatography with the authentic steroid derivatives. 5 alpha-Dihydrotestosterone, testosterone, pregnenolone, and 20 alpha-hydroxypregn-4-en-3-one were detected in unconjugated form in the ovary. The eggs and haemolymph were found to contain unconjugated 17 beta-estradiol. Conjugated 5 alpha-dihydrotestosterone was detected in both the ovary and haemolymph, but no conjugated steroids were found in the eggs.


Phase I/II study protocol to assess safety and efficacy of adoptive cell therapy with anti-PD-1 plus low-dose pegylated-interferon-alpha in patients with metastatic melanoma refractory to standard of care treatments: the ACTME trial.
Treatment with anti-PD-1 immunotherapy does not lead to long-lasting clinical responses in approximately 60% of patients with metastatic melanoma. These refractory patients, however, can still respond to treatment with tumour infiltrating lymphocytes (TIL) and interferon-alpha (IFNa). A combination of TIL, pegylated-interferon-alpha (PEG-IFNa) and anti-PD-1 is expected to provide a safe, feasible and effective therapy for patients with metastatic melanoma, who are refractory to standard of care treatment options. Patients are treated in two phases. In phase I, the safety of the combination TIL and anti-PD-1 is assessed (cohort 1) according to CTCAE 4.03 criteria. Subsequently, the safety of cotreatment with PEG-IFNa is tested in cohort 2. The efficacy will be evaluated in the second phase of the trial. Efficacy is evaluated according to RECIST 1.1 and immune-related response criteria. Clinical and immunological parameters will be evaluated for their relation with clinical responsiveness. Ethical approval of the trial was obtained from the Central Committee on Research Involving Human Subjects in the Netherlands. The trial results will be shared with the scientific community at (inter)national conferences and by publication in a peer-reviewed journal. NCT03638375; Pre-results.


Conceptual and operational understanding of learning for sustainability: a case study of the beef industry in north-eastern Australia.
Extensive attention has been given to understanding learning processes that foster sustainability. Despite this focus there is still limited knowledge of learning processes that create changes in perspectives and practices. This paper aims to increase understanding of learning processes in the context of sustainability and refers to the beef industry in north-eastern Australia. A framework based on adult learning theories was developed and used to analyse the what, why and how of beef producers' learning to improve land condition. Twenty-eight producers were interviewed face-to-face and another 91 participated in a telephone survey. Most beef producers were motivated to learn due to perceived problems with existing practices and described mainly learning new skills and techniques to improve production. Beef producers main learning sources were their own experiences, observing others' practices and sharing experiences with peers and family members. Results showed that organised collective learning, adversity and active experimentation with natural resource management skills and techniques can facilitate critical reflection of practices, questioning of the self, others and cultural norms and an enhanced sense of environmental responsibility.


Familial proximal renal tubular acidosis. A distinct clinical entity.
We have studied a family in which nine members present hyperchloremic acidosis with normal plasma creatinine and good ability to acidify urine. Renal functions, other than bicarbonate wasting, are normal, which identifies the condition as a pure form of proximal renal tubular acidosis. The acidosis persists into adult life and appears to be inherited as an autosomal dominant trait. All affected members are asymptomatic and the only peculiar finding is a decrease in stature. No hypercalciuria was detected, and no evidence of rickets or osteomalacia was found by x-ray studies. We consider these findings characteristic of a familial trait different from that in previously reported cases of renal tubular acidosis.


Multichannel recording and analysis of physiological data using a personal computer.
A flexible data acquisition system was designed for an Apple IIe computer. For implementation, we used a microcomputer capable of recording 4 channels simultaneously with a selectable sample rate; this information was saved on a floppy disc and the recordings could be evaluated later. This evaluation is accomplished by reproducing the analog signals on display and calculating a histogram after deleting artefacts in the signal.


Composition, bioactive substances, extraction technologies and the influences on characteristics of Camellia oleifera oil: A review.
C. oleifera oil is one of the high-quality edible oils recommended by the Food and Agriculture Organization of the United Nations (FAO). Pharmacological studies have shown that C. oleifera oil is the homology of medicine and food, and it possesses extensive beneficial health properties both in vivo and in vitro. C. oleifera oil found its application in the functional food, cosmetic, and pharmaceutical industries. In recent years, the need for high-quality and high-quantity production of C. oleifera oil for human consumption has increased. The present review examines the chemical composition of C. oleifera oil, bioactive substances, extraction technologies, and evidence supporting the health benefits of C. oleifera oil. From the reviewed studies, it appears that C. oleifera oil contains a significant proportion of unsaturated fatty acids (>85%) with oleic acid (>75%) as the major compound, and high contents of squalene, tea polyphenols, tocopherol and phytosterol. Some variations in C. oleifera oil composition can be found depending on the kernel's origin and the extraction method used. Emerging technologies such as aqueous extraction, and supercritical fluid extraction are highly efficient processes, and can achieve higher recovery while reducing solvent and energy consumption. This review provides an in-depth discussion on the various extraction technologies and factors affecting the extraction efficiency of C. oleifera oil using traditional and emerging methods. The influences of different extraction methods on the C. oleifera oil characteristics are also introduced. Furthermore, challenges and future prospects of the extraction of C. oleifera oil have been identified and discussed.


Brazilian green propolis water extract up-regulates the early expression level of HO-1 and accelerates Nrf2 after UVA irradiation.
Exposure to ultraviolet A (UVA) irradiation is the major cause of human skin aging. Suppression of UVA irradiation-induced skin fibroblast cell damage protects the skin against aging. An oxidative stress response transcription factor nuclear factor-(erythroid-derived 2)-related factor 2 (Nrf2) has an important role as a cytoprotective system against oxidative stress in the human skin and other organs. Propolis has been commonly used as a traditional medicine since ancient times. The water extract of propolis (WEP) mainly contains caffeoylquinic acids. In our previous study, we reported that WEP and its major constituents protected immortalized human skin fibroblast cells (NB1-RGB) against UVA irradiation-induced cell death. In this study, we examined the mechanism of WEP-mediated skin protection and the possible involvement of Nrf2/antioxidant response element (ARE) pathways. Brazilian green propolis was used in the present study (Minas Gerais State, Brazil), Baccharis dracunculifolia is its main source. The Baccharis propolis was extracted with water at 50 °C to yield water extract. The NB1-RGB cell cultures were incubated for 23 h. After replenishing the medium, WEP or its constituents were added to the cell cultures. After 1 h, the cells were exposed to 10 J/cm(2) of UVA light (365 nm UVA light source, CL-1000 L UV Closslinkers, Ultraviolet Products Ltd., Cambridge, UK). Heme oxygenase-1 (HO-1) expression levels in NB1-RGB cells were evaluated using western blotting. Nrf2 nuclear translocation changes in NB1-RGB cells were indicated using immunostaining. We demonstrated that WEP pretreatment up-regulated HO-1 expression level after UVA irradiation at earlier time points than vehicle pretreatment did, and three main constituents of WEP showed similar effects. Furthermore, WEP pretreatment also accelerated Nrf2 nuclear translocation after UVA irradiation. Our findings indicated that WEP acts as an early inducer of HO-1 and rapid activator of Nrf2 to protect against UVA-induced oxidative stress.


Remodeling of the focal adhesion complex by hydrogen-peroxide-induced senescence.
Cellular senescence is a phenotype characterized by cessation of cell division, which can be caused by exhaustive replication or environmental stress. It is involved in age-related pathophysiological conditions and affects both the cellular cytoskeleton and the prime cellular mechanosensors, focal adhesion complexes. While the size of focal adhesions increases during senescence, it is unknown if and how this is accompanied by a remodeling of the internal focal adhesion structure. Our study uses metal-induced energy transfer to study the axial dimension of focal adhesion proteins from oxidative-stress-induced senescent cells with nanometer precision, and compares these to unstressed cells. We influenced cytoskeletal tension and the functioning of mechanosensitive ion channels using drugs and studied the combined effect of senescence and drug intervention on the focal adhesion structure. We found that H2O2-induced restructuring of the focal adhesion complex indicates a loss of tension and altered talin complexation. Mass spectroscopy-based proteomics confirmed the differential regulation of several cytoskeletal proteins induced by H2O2 treatment.


Prospective randomized controlled trial of fetal fibronectin on preterm labor management in a tertiary care center.
The purpose of this study was to investigate the effect of the rapid fetal fibronectin on the length of hospital stay and the use of preterm labor interventions in a tertiary care center. Women who were seen in the Labor and Delivery Unit with symptoms of preterm labor were assigned randomly to receive fetal fibronectin (n=46 women) or to preterm labor management without fetal fibronectin (n=51 women). Physicians were not blinded to the result; groups were compared. There was no difference between groups in demographic or obstetric characteristics, the hours spent in labor and delivery, the number of women who were admitted to the antepartum service, the length of stay, or medical interventions. When the results for women with a negative fetal fibronectin test were compared to women with a positive fetal fibronectin test, a significant difference was found in admissions to the antepartum service (P=.032) and the length of stay (P=.008). A negative fetal fibronectin test was associated with fewer admissions to the antepartum ward and a shorter length of stay.


Regional serotonin transporter availability and depression are correlated in Wilson's disease.
In patients with Wilson's disease (WD), depression is a frequent psychiatric symptom. In vivo neuroimaging studies suggest that depression and other neuropsychiatric disorders are associated with central serotonergic deficits. However, in vivo measurements of serotonergic neurotransmission have not until now been performed in patients with this copper deposition disorder. The present prospective study revealed that depressive symptomatology is related to an alteration of presynaptic serotonin transporters (SERT) availability as measured by [123I]-2beta-carbomethoxy-3beta-(iodophenyl)tropane ([123I]beta-CIT) and high-resolution single-photon emission computed tomography (SPECT). SERT imaging with [123I]beta-CIT-SPECT could therefore become a useful tool for diagnosis and therapy monitoring in depressed WD patients.


Rapid kinetic BRET measurements to monitor G protein activation by GPCR and non-GPCR proteins.
Heterotrimeric G proteins are central hubs of signal transduction whose activity is controlled by G protein-coupled receptors (GPCRs) as well as by a complex network of regulatory proteins. Recently, bioluminescence resonance energy transfer (BRET)-based assays have been used to monitor real-time activation of heterotrimeric G proteins in cells. Here we describe the use of a previously established BRET assay to monitor G protein activation upon GPCR stimulation and its adaptation to measure G protein activation by non-GPCR proteins, such as by cytoplasmic guanine nucleotide exchange factors (GEFs) like GIV/Girdin. The BRET assay monitors the release of free Gβγ from Gα-Gβγ heterotrimers as a readout of G protein activation, which is readily observable upon agonist stimulation of GPCRs. To control the signal input for non-GPCR activators, we describe the use of a chemically induced dimerization strategy to promote rapid membrane translocation of proteins containing the Gα-binding and -activating (GBA) motif found in some nonreceptor GEFs. The assay described here allows the kinetic measurement of G protein activation with subsecond temporal resolution and to compare the levels of activation induced by GPCR agonists vs those induced by the membrane recruitment of nonreceptor G protein signaling activators.


Associations of weight cycling with cardiovascular health using American Heart Association's Life's Simple 7 in a diverse sample of women.
Prior research shows that weight cycling is associated with poorer cardiovascular health (CVH). Women experience unique life events (e.g. pregnancy, menopause) which may make them more prone to weight cycling. Examining the influence of weight cycling history (HWC) on CVH, quantified using the American Heart Association's Life's Simple 7 (LS7), may provide novel targets to improve CVH. A cross-sectional sample of 485 women at Columbia University Irving Medical Center (2016-2018) were scored on each LS7 metric (BMI, blood pressure, fasting cholesterol and glucose, physical activity, diet, and smoking): 0 (low), 1 (moderate) or 2 (high). Metric points were summed into a composite LS7 score as a measure of CVH: 0-8 (low), 9-10 (moderate), 11-14 (high). Multivariable-adjusted logistic and linear regression models were used for the associations between HWC and CVH. Most women (73%) reported HWC (range: 0-20); 26% had low CVH and 74% moderate/high CVH. Logistic models showed HWC was associated with higher odds of having poor CVH [OR (95%CI): 2.39 (1.36-4.20)]. Linear models showed each additional weight cycling episode was associated with lower LS7 scores [ß(SE): -0.37 (0.07); p < 0.01]. Associations between HWC and odds of having poor CVH were stronger among pre-menopausal women and those with no pregnancy history (p-interaction = 0.009, 0.004, respectively). In conclusion, HWC was associated with higher odds of poorer CVH with stronger associations seen in pre-menopausal and women with no pregnancy history. These findings suggest that in addition to having a healthy weight, maintaining a consistent weight may be important for achieving optimal CVH, but warrant prospective confirmation.


Consequences of non-fatal electrical injury: findings of community-based national survey in Bangladesh.
This study was designed to document the consequences of electrical injury in Bangladesh. A community-based cross-sectional survey was conducted from January to December 2003. Nationally representative data were collected from 171,366 rural and urban households, comprising a total of 819,429 population. Face-to-face interview was chosen as a data collection method. The overall rate of electrical injury was 73.7 per 100,000 population-year. The rate of permanent disability due to electrical injury in Bangladesh was 0.366 per 100,000 population-year. Among the total 604 non-fatal electrical injuries in the survey, 282 (46.7%) had suffered from temporary disabilities for different durations. A total of 172 students were injured from electrical injury and among them 139 (80.8%) missed school for different durations due to their illness. Mean duration of absence from school was 9.72 days (SD±10.98), ranging from 1 to 45 days. Among the working people average duration of work loss was 10.56 days (SD±14.98), ranging from 1 to 90 days. About 39% of the total patients with electrical injury were contributors to their family income. For each family the expenditure for each seriously injured patient due to electrical injury was USD 271. Electrical Injury is a major cause of morbidity in Bangladesh. It is responsible for significant loss of school days and work days and creating serious health and economic hardship for the inflicted families. A nationwide prevention program needs to be developed to address this problem.


Collective animal migration.
Migratory movement is a strategy employed by a broad range of taxa as a response to temporally and spatially varying environmental conditions. Multiple factors can drive animal migration, including movement to hospitable environments when local conditions become unfavourable (such as to reduce nutritional and thermoregulatory stress), movement to find mates and/or breeding sites, and movement to minimise competition, predation, infection or parasitism. Migrating animals can often be seen to move together (Figure 1), sometimes in vast numbers. Despite this, the social aspects of migration have, to date, received very limited attention. Synchronisation of migratory behaviour among organisms, itself, does not imply that migrants utilise social information: synchrony is inevitable if there are relatively short windows of opportunity in which to move, or there exist sudden environmental changes that must be responded to. However, as will be outlined here, there is there is growing evidence that many migratory animals do utilise social cues, and that collective factors could shape migration in a variety of important ways.


Corrigendum to "Low-Level Laser Irradiation Exerts Antiaggregative Effect on Human Platelets Independently on the Nitric Oxide Metabolism and Release of Platelet Activation Markers".
[This corrects the article DOI: 10.1155/2017/6201797.].


Hemoglobin A1c in Muscat, Oman - A 3 year study.
Glycosylated Hemoglobin (HbA1c) reflects the average blood glucose level during the previous 2-3 months. HbA1c is used as marker for long term blood glucose control in diabetic patients. In this retrospective study, the prevalence of diabetic control was evaluated from HbA1c tests of diabetic patients over a period of 3 years (January 2005-December 2007) from Muscat Region, Sultanate of Oman. Blood samples from a total number of 7442 patients were analysed at Al Nahdha Hospital Laboratory received from different Primary Health Care Centers and Hospitals of Muscat region as this hospital was the referral hospital for HbA1c testing. The method used for the estimation of HbA1c was Turbidimetric inhibition immunoassay and the test was carried out in Hitachi 902 an automated chemistry analyzer. The results show that only 22.8% of patients had good glycemic control and 77.2% had bad glycemic control. Diabetic patients should be informed of the fact that maintaining HbA1c below 7% will minimize their risk of developing the complications.


[MALT Lymphoma of the Conjunctiva in a 13-year old Child--5-Year Relapse-free Follow-up Following Antibiotic Treatment].
In February 2007, a 13-year old boy presented with a livid tumour in the lower conjunctival fornix of the left eye. OPHTHALMOLOGICAL FINDINGS: The tumor was salmon-coloured, bulging and elastic and filled the whole lower conjunctival fornix of the left eye. There was no other pathological finding in the left eye. Uncorrected visual acuity was 20/20. Intraocular pressure was 12 mmHg. The eye was fully motile. Incisional biopsy was performed in February 2007. The tumor was histologically an extranodal MALT lymphoma. DNA testing for Chlamydophila trachomatis and Chlamydophila pneumonia was negative. Systemic treatment was started with doxycycline (200 mg daily). After six weeks, the tumour was slightly smaller. Azithromycin 500 mg once a week was added. 18 months after initiation of the treatment, the tumour had completely regressed. A second sample taking in the former tumor area showed tumor-free conjunctiva and subconjunctival tissue. As a precaution, the combined antibiotic therapy was continued for 10 months and the patient was followed for five more years. The lymphoma did not relapse in the conjunctiva and orbit or in the whole body. We showed that extranodal MALT lymphomas of the conjunctiva can be successfully treated with antibiotics alone. At the start of therapy, the child was 13 years old. To our knowledge, this patient is the first child in Germany and one of the first in the world with ocular adnexal lymphoma who could be successfully treated with combined antibiotic therapy and who could be followed up for 5 years without relapse. Thus, we could avoid radiotherapy or chemotherapy in childhood and eliminate the risk of a therapy-induced secondary malignancy.


Cyclophosphamide enfeebles myocardial isometric contraction force via RIP1/RIP3/MLKL/TRPM7-mediated necroptosis.
This study explores the negative impact of cyclophosphamide (CP) on cardiac contractility by specifically examining its effect on the active and passive tension of the cardiac muscle in-vitro and revealing the mechanism through which CP induces myocardial insult in-vivo. In young male Sprague-Dawley rats, cardiac toxicity was induced by a single intraperitoneal injection of CP (150 mg/kg body weight). Axial heart tissue slices were electrically stimulated, and the total isometric contraction force was measured at varying pretension levels. Blood and tissue biochemical assays, and histological/ immuno-histological assessments were conducted to evaluate the underlying molecular mechanisms. Statistical analysis shows that there is a significant difference between the drugged and the control groups in terms of the active tension values. Moreover, the pre-tension stress significantly affects both the active and passive tension values. CP altered heart, body, and heart-to-body weight, desolated cardiac muscle architecture, surged cardiac enzymes (CK-MB, LDH, and cTn l), augmented myocardial oxidative stressors (MDA), and weakened myocardial antioxidant status (SOD and GSH). Mechanistically, cyclophosphamide prompted the necroptotic trajectory evidenced by the activation of RIPK1, RIPK3, MLKL and TRPM7, the inhibition of caspase 8 and BCL2 and the upregulation of the protein/mRNA expression of TNF-α and TNFR1. This study identifies necroptosis as a key factor in cyclophosphamide-evoked myocardial contractility impairment, highlighting its potential as a target for alleviating antitumor-related myocardial damage. This innovative approach to investigating the underlying mechanisms of CP-induced cardiac toxicity offers valuable insights into the potential of developing new therapies to mitigate cyclophosphamide's negative impact.


Multiple signal classification algorithm for super-resolution fluorescence microscopy.
Single-molecule localization techniques are restricted by long acquisition and computational times, or the need of special fluorophores or biologically toxic photochemical environments. Here we propose a statistical super-resolution technique of wide-field fluorescence microscopy we call the multiple signal classification algorithm which has several advantages. It provides resolution down to at least 50 nm, requires fewer frames and lower excitation power and works even at high fluorophore concentrations. Further, it works with any fluorophore that exhibits blinking on the timescale of the recording. The multiple signal classification algorithm shows comparable or better performance in comparison with single-molecule localization techniques and four contemporary statistical super-resolution methods for experiments of in vitro actin filaments and other independently acquired experimental data sets. We also demonstrate super-resolution at timescales of 245 ms (using 49 frames acquired at 200 frames per second) in samples of live-cell microtubules and live-cell actin filaments imaged without imaging buffers.


Topical treatment for phimosis: time span and other factors behind treatment effectiveness.
To study the factors that may influence the effectiveness of 0.2% betamethasone/hyaluronidase cream in the treatment of phimosis. We treated 427 patients (3-10 years old, mean 6.33) in a prospective, randomized, blind study, with 214 patients on a 4-week and 213 patients on an 8-week course. All patients were seen once monthly at least for 6 months after the end of treatment. The penis was photographed to allow objective evaluation of treatment response. The therapeutic response was graded as total success when there was complete exposure of the glans; partial success when there was exposure of half of the glans, impeded by balanopreputial adherence or ring fibrosis at the prepuce; and therapeutic failure when patients had no or less than 50% glans exposure. After treatment 92.1% of patients showed total or partial success, but during follow up (mean 9.36 months, range 6-13) 29.5% failed to maintain this (22.6% and 37.6% for 8- and 4-week treatment, respectively). During treatment, 13.6% presented side effects or complications: prepuce ardor (6.1%), hyperemia (4.6%), paraphimosis (0.0098%). Intervention or interruption of treatment was unnecessary. The two groups were statistically similar in all parameters, but time of treatment=8 weeks, previous urethral meatal exposure and no previous balanoposthitis increased the chance of total success. Surgery was indicated for failure or relapse in 181 patients (42.38%). Treatment with topical 0.2% betamethasone/hyaluronidase cream for 8 weeks is effective and safe, especially if the urethral meatus is exposed and there is no previous balanoposthitis. Rescue treatment is not recommended, as the results were not encouraging.


The pathogenesis and prognosis of lupus nephritis: information from repeat renal biopsy.
Of an inception cohort of 87 patients with lupus nephritis who underwent a renal biopsy, 42 underwent second biopsies a median of 25 months later. From first to second biopsy, focal and diffuse proliferative nephritis (World Health Organization classes III and IV) became less frequent, and mesangial hypercellularity (class II) and a membranous pattern (class V) increased. The National Institutes of Health activity index and mesangial and subendothelial deposits declined while the chronicity index, a tubulointerstitial index, and subepithelial deposits increased. The biopsy improvement in urinary protein excretion was best explained by decreases in the activity index score and the amount of subendothelial deposits. A decrease in the amount of subendothelial deposits tended to predict an improvement in the serum creatinine level from first to second biopsy. With follow-up from second biopsy in excess of 7 years, the best predictors of long-term outcome were the ultrastructural variables mesangial, subendothelial and subepithelial deposits. When the change in biopsy predictors from first to second biopsy was evaluated, a decrease in the amount of mesangial or subendothelial deposits was best at predicting a lower risk of renal impairment, renal insufficiency, and mortality. The results confirm the importance of immune complex deposition as measured by electron microscopy in the pathogenesis of lupus nephritis and suggest that control of this process may alter renal function and prognosis.


Modelling biological systems from molecules to dynamical networks.
A report of the 5th IEEE International Conference on Systems Biology (IEEE ISB2011), 2-4 September 2011, Zhuhai, China.


NMDA receptor involvement in antidepressant-like effect of pioglitazone in the forced swimming test in mice.
Previously, we showed that pioglitazone exerts its antidepressant-like effect through peroxisome proliferator-activated receptor gamma receptors and demonstrated the possible involvement of calcium-dependent nitric oxide synthase inhibitors. Based upon the in vitro results, pioglitazone reduces N-methyl-D-aspartate (NMDA)-mediated calcium currents in hippocampal neurons. In this study, we evaluated the involvement of the NMDA receptor (NMDAR) on the antidepressant-like effect of pioglitazone in the forced swimming test (FST) in mice. After the assessment of locomotor activity in the open-field test, mice were forced to swim individually and the immobility time of the last 4 min was evaluated. Pioglitazone was administered orally with doses of 5, 10, and 20 mg/kg 4 h before FST. To assess the involvement of NMDARs in the possible antidepressant-like effect of pioglitazone, a selective glutamate receptor agonist, NMDA (75 mg/kg, intraperitoneally [i.p.] or 20 ng/mouse, intracerebroventricularly [i.c.v.]), was administered before pioglitazone (20 mg/kg). To further determine a possible role of NMDARs in this effect, a noncompetitive antagonist of the NMDA, MK-801 (0.05 mg/kg, i.p. or 100 ng/mouse, i.c.v.), was coadministered with pioglitazone (10 mg/kg) 4 h prior to FST. Pioglitazone (20 mg/kg) administered 4 h prior to FST significantly reduced the immobility time. Coadministration of the noneffective doses of pioglitazone and MK-801 revealed an antidepressant-like effect in FST. Moreover, NMDA significantly reversed the antidepressant-like effect of pioglitazone administered 4 h prior to FST. The antidepressant-like effect of pioglitazone in the FST is mediated partly through NMDAR signaling. This study provides a new approach for the treatment of depression.


Discovery of a novel HLA-C*04 null allele, HLA-C*04:279N, in a Singaporean individual.
A nucleotide mutation in codon 75 of HLA-C*04:01:01:01 results in a novel allele HLA-C*04:279N.


Mitochondrial DNA depletion in HIV-infected patients is more pronounced with chronic hepatitis C and enhanced following treatment with pegylated interferon plus ribavirin.
Mitochondrial DNA (mtDNA) damage seems to be responsible for many of the toxicities associated with the long-term use of nucleoside analogues in HIV-infected patients. These adverse effects, mainly lipoatrophy, seem to be even more pronounced in subjects with hepatitis C virus (HCV) co-infection. However, there is no information about a possible additive effect of HCV on mtDNA depletion nor about the impact of ribavirin use in HIV/HCV-coinfected individuals. mtDNA was measured in peripheral blood mononuclear cells (PBMC) collected from 192 individuals classified into 4 groups: HIV-neg/HCV-neg (control group, n = 11), HIV-pos/HCV-neg (56), HIV-neg/HCV-pos (18) and HIV-pos/HCV-pos (107). A duplex real-time NASBA assay was used to quantify mtDNA on maximal platelet-depleted specimens and all experiments were run in duplicate. The mtDNA copy number per cell was estimated taking as reference the nuclear DNA copy number. The mean mtDNA values in the control group was 757 copies/cell, while it was 428, 349 and 296 for HIV-pos, HCV-pos and HIV/HCV-coinfected individuals, respectively (P < 0.001 for all groups relative to the control group). No significant differences were observed when comparing patients with HIV or HCV infections alone, but coinfected individuals showed a lower mtDNA copy number than patients infected with HIV (P < 0.001) or with HCV (P = 0.089). In a subset of 18 patients with HIV/HCV-coinfection, treatment with pegylated interferon plus ribavirin produced a further reduction in mtDNA (mean value, 189 copies/cell; P = 0.009). HIV and HCV may independently cause mtDNA depletion in PBMC. Coinfection may result in more pronounced mtDNA depletion. The administration of interferon plus ribavirin may further enhance mtDNA depletion. These findings may explain the greater risk of lipoatrophy of antiretroviral therapy in HIV-infected patients with HCV coinfection and why anti-HCV therapy may aggravate this effect.


Development of a fluorescent intercalator displacement assay (G4-FID) for establishing quadruplex-DNA affinity and selectivity of putative ligands.
A fluorescent intercalator displacement assay (G4-FID) has been designed based on the displacement of thiazole orange (TO) positioned onto a quadruplex-forming oligonucleotide by putative ligands. This technique was validated by the use of a set of representative and fully characterized G-quadruplex binders (ranging from pyridodicarboxamide to macrocyclic ligands). To further extend its applicability, a comparative version has been developed which allows a rapid and viable determination of quadruplex- over duplex-selectivity.


Comparing an in-person workshop and a postal Delphi survey for involving health service users in health care and health research prioritization.
To involve health service users in health care and health research priority setting, different methods exist. Which method is most suitable under which circumstances is unknown. We compared a postal Delphi survey and an in-person workshop to involve health service users in priority settings for rehabilitative care and research in Germany. One hundred and eighty-four former rehabilitants were randomly assigned to a postal Delphi survey (n = 152) or an in-person workshop (n = 32). Two hundred and seventy-six employees in rehabilitation were also invited to the Delphi Survey. The methodological comparison refers only to the sample of rehabilitants. Within each method, the participants agreed on the top 10 priorities for practice improvement and research in rehabilitative care. The priorities were compared descriptively. Participants' satisfaction was measured with the Public and Patient Engagement Evaluation Tool. The usability of both methods was compared based on the effort, time and material costs required for implementation. Seventy-five former rehabilitants and 41 employees in rehabilitation completed both Delphi survey rounds. Eleven former rehabilitants participated in the in-person workshop. Priorities for practice improvement showed a high degree of overlap between both methods whereas research priorities differed greatly. Participants of the in-person workshop felt significantly better prepared, more listened to and more likely to feel that different views on the topics were discussed. Participants of the Delphi survey expressed difficulties in understanding all survey questions. The Delphi survey was more elaborate in preparation and implementation but caused lower material costs. The differences in research priorities between the two methods could be due to the different samples, differences in the individual interests of participants or differences in the prioritization process. In-person workshops seem to be more appropriate for complex topics, where clarifications of questions and deeper discussions are needed. Delphi surveys seem to be more suitable for easily understandable topics, larger sample sizes and when fewer financial resources are available. The different study phases were supported by employees in rehabilitation and former rehabilitants (e.g., developing study documents, and interpreting results).


T-cell therapies for HIV: Preclinical successes and current clinical strategies.
Although antiretroviral therapy (ART) has been successful in controlling HIV infection, it does not provide a permanent cure, requires lifelong treatment, and HIV-positive individuals are left with social concerns such as stigma. The recent application of T cells to treat cancer and viral reactivations post-transplant offers a potential strategy to control HIV infection. It is known that naturally occurring HIV-specific T cells can inhibit HIV initially, but this response is not sustained in the majority of people living with HIV. Genetically modifying T cells to target HIV, resist infection, and persist in the immunosuppressive environment found in chronically infected HIV-positive individuals might provide a therapeutic solution for HIV. This review focuses on successful preclinical studies and current clinical strategies using T-cell therapy to control HIV infection and mediate a functional cure solution.


Characterization of cancer stem-like cells derived from a side population of a human gallbladder carcinoma cell line, SGC-996.
The cancer stem cell (CSC) hypothesis proposes that CSCs, which can renew themselves proliferate infinitely, and escape chemotherapy, become the root of recurrence and metastasis. Previous studies have verified that side population (SP) cells, characterized by their ability to efflux lipophilic substrate Hoechst 33342, to share many characteristics of CSCs in multiplying solid tumors. The purpose of this study was to sort SP cells from a human gallbladder carcinoma cell line, SGC-996 and to preliminarily identify the biological characteristics of SP cells from the cell line. Using flow cytometry we effectively sorted SP cells from the cell line SGC-996. SP cells not only displayed higher proliferative, stronger clonal-generating, more migratory and more invasive capacities, but showed stronger resistance. Furthermore, our experiments demonstrated that SP cells were more tumorigenic than non-SP counterparts in vivo. Real-time PCR analysis and immunocytochemistry showed that the expression of ATP-binding cassette subfamily G member 2 (ABCG2) was significantly higher in SP cells. Hence, these results collectively suggest that SP cells are progenitor/stem-like cells and ABCG2 might be a candidate marker for SP cells in human gallbladder cancer.


Desensitization of the cAMP system in mouse Leydig cells by hCG, cholera toxin, dibutyryl cAMP and cAMP: localization of the 'lesion' to the guanine nucleotide regulatory protein-adenylate cyclase complex.
The mechanism of hCG-induced desensitization of the cAMP system was studied in Percoll-purified mouse Leydig cells. Pretreatment of Leydig cells with hCG resulted in a time- and dose-dependent decrease in the capacity of hCG-induced cAMP formation. Maximal desensitization (approximately 90%) was induced by only partial prior stimulation. Desensitization, however, was not observed without a prior increase in cAMP or testosterone production. Pretreatment of the cells with N6,O2'-dibutyryl cAMP (DBcAMP) also induced a dose- and time-dependent densensitization. cAMP was only effective in the presence of the phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine (MIX). Cholera toxin desensitized the hormone-induced cAMP response as drastically as hCG. Cholera toxin was unable to reverse the refractory state induced by one of the agonists. hCG-induced desensitization was not associated with a loss in [125I]hCG binding or an increase in maximal phosphodiesterase activity, and appeared not to be dependent on protein synthesis. Membranes from hCG, cholera toxin of DBcAMP-desensitized cells showed an impaired adenylate cyclase activity in response to hCG, hCG plus beta-gamma-imidoguanosine 5'-triphosphate (GPPNP) and NaF. In conclusion, hCG-induced desensitization of the adenylate cyclase system in mouse Leydig cells can be mimicked by cholera toxin, DBcAMP and cAMP, indicating a cAMP-mediated process. The site of the 'lesion' has to be localized to the guanine nucleotide regulatory protein-adenylate cyclase complex rather than to its uncoupling from the hormone receptor.


Sequence evolution, processing, and posttranslational modification of zonadhesin D domains in primates, as inferred from cDNA data.
Zonadhesin is a mammalian transmembrane sperm ligand. Precursor zonadhesin essentially consists of MAM (meprin/A5 antigen/mu receptor tyrosine phosphatase) domains, a mucin-like repeat, and D domains (homologous to von Willebrand D). Recent immunovisualization and binding assays indicate that zonadhesin D domains 1-3 bind postacrosomally to the zona pellucida. This feature has attracted considerable interest in the evolution of zonadhesin and its possible biological and biomedical implications. Previous molecular evolutionary analyses, however, were confined to cDNA sequences of only few distantly related species. Moreover, except for rabbit and pig, little is known about zonadhesin's processing. To delineate the situation in primates including humans, we analyze here the evolution of zonadhesin on the basis of D domain encoding cDNAs of about 4900 base pairs (bp) length from a representative primate sampling (1 Strepsirhini, 3 Cercopithecidae, 3 Platyrrhini, and human; 7 new sequences) plus GenBank data from mouse, rabbit, and pig. Site-specific (CODEML and HyPhy) analysis indicates positive evolution of zonadhesin. Moreover, moving window analysis (CRANN) points to a positive correlation of sequence evolution and sperm-competition. Significant accumulations of positively selected sites across interspecifically variable motifs (identified by PROSITE) suggest that positive selection promotes differences between species by amino acid exchanges and changes in posttranslational modification. In the case of zonadhesin D domains, positive selection might thus contribute to the species-specific binding of zonadhesin and zona pellucida. A high conservation of processing and dimerization motifs of primate zonadhesin in analogy to pig, on the other hand, illustrates that zonadhesin's backbone needs to meet basic requirements in order to retain function.


[Fracture of the separated nickel titanium instruments during ultrasonic removal: an experimental study].
This in vitro study is to evaluate the effect of ultrasonic power settings and cooling methods on fracture behavior of the separated nickel titanium instruments during ultrasonic removal. 40 discarded and 10 new nickel titanium instruments were used to establish the separated instrument removal model. The discarded instruments were divided into four groups according to two ultrasonic power settings(6 or 10) and different cooling methods (using water coolant or without using water coolant), and all the new instruments were put into the group in which ultrasonic vibration was used at a higher power setting (10) without using water coolant. The time required for fracture of the separated instruments was recorded. The time was longer with statistical significance at a lower power setting compared with that at a higher power setting regardless of the use of water coolant. The time was longer with statistical significance by the use of water coolant compared with that without using coolant regardless of power settings (6 or 10). The time required for fracture of the new instruments was longer than that of the discarded instruments with statistical significance. During ultrasonic removal of separated nickel titanium instruments, water coolant could decrease the occurrence of fracture. When removing separated nickel titanium instruments with ultrasonic vibration, an attempt without coolant shouldn't be made at a higher power setting.


Perfluoroalkanes remain on water surface even after volatilization: Affinity analysis of fluorinated solvent with water surface.
Perfluoroalkyl (Rf) compounds are known to have a poor solubility for most solvents except fluorinated solvents, which is known as a fluorous property. In Langmuir (L) film studies of Rf compounds, fluorinated solvents such as perfluoro-n-alkanes are generally used as a good solvent for depositing a sample monolayer on the water surface. On the other hand, a single Rf chain with a short length such as C6F13- is known to exhibit a totally different character from a condensed matter to have a strong affinity to a water molecule on the water surface via the dipole-dipole interaction, which is known as the dipole interactive (DI) property. On considering the DI property, the solvents of perfluoro-n-alkanes would remain on water for a long time, which may disturb the formation of L film on water. In the present study, details of a liquid layer of perfluoro-n-alkanes on water are investigated by using infrared external reflection (IR ER) spectrometry. Although the perfluoro-n-alkanes are highly volatile, the relevant vibration bands did not disappear even after two hours, which means that they remain on the water surface. Fortunately, however, the remained solvent, C6F14, has been found no disturbing factor for preparation of L films.


Appearance of immunoreactive endocrine cells during the development of the rat pancreas, with special reference to polypeptide-secreting cells.
The chronological appearance of PP cells in fetal pancreatic islets was studied using specific anti-PP serum and the direct peroxidase method. The presence of A and B cells was also studied, using the same immunocytochemical technique, as a reference pattern related to data previously reported. Our data confirm that the A cell is the earliest endocrine cell type, appearing on the 12th day of gestation, followed by B cells (14th day) and later on by PP cells (19th day). Primitive islets were identified in the pancreas after the 15th day. However, the spatial cell disposition observed in the adult islet was only recognized at the 20th day of gestation. The data reported provide the necessary information to establish the complete chronology in the rat fetus. Consequently, the development of pancreatic islets in the rat fetus could be employed as a useful model to study the existence of factors that control the sequential appearance of endocrine cells and the possible changes occurring in the islets of animals with genetic diabetes during the fetal period.


Shoulder injury related to vaccine administration following SARS-CoV-2 inoculation: Case series and review of literature.
Shoulder Injuries Related to Vaccine Administration (SIRVA), describes those cases of shoulder severe post-inoculation complications, including pain and prolonged disability. Most of the reported cases have been secondary to influenza vaccination. This study retrospectively describes a series of 18 patients following SARS-CoV-2 inoculation and compares the findings with those previously reported for other vaccines. Inclusion criteria was onset of symptoms within 48 h after injection, symptoms duration of at least seven days, and restricted range of motion in absence of symptoms prior to vaccination. Average age was 59.4 years old (38-76), and 72.2% were women. In many cases (58%) the initial diagnosis was not clear, which lead to incorrect treatment. The most common pathological finding was subacromial-subdeltoid bursitis (66.6%). All patients who received depot corticosteroids followed by a gentle rehabilitation program showed strong clinical improvement but did not completely resolve the symptoms at 7.2 months average final follow-up. Surgical intervention was necessary in one of the patients due to the persistence of symptoms despite conservative treatment. Shoulder injury related to vaccine administration is rare, but when present, its torpid evolution makes it difficult to treat. We have found in our case series a similar pattern to that already described for other vaccines. A high index of suspicion helps to pick up the condition promptly and early treatment can bring satisfactory outcome.


Atezolizumab Treatment Beyond Progression in Advanced NSCLC: Results From the Randomized, Phase III OAK Study.
Cancer immunotherapy may alter tumor biology such that treatment effects can extend beyond radiographic progression. In the randomized, phase III OAK study of atezolizumab (anti-programmed death-ligand 1) versus docetaxel in advanced NSCLC, overall survival (OS) benefit with atezolizumab was observed in the overall patient population, without improvement in objective response rate (ORR) or progression-free survival (PFS). We examine the benefit-risk of atezolizumab treatment beyond progression (TBP). Eight hundred fifty patients included in the OAK primary efficacy analysis were evaluated. Atezolizumab was continued until loss of clinical benefit. Docetaxel was administered until Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) disease progression (PD)/unacceptable toxicity; no crossover to atezolizumab was allowed. ORR, PFS, post-PD OS, target lesion change, and safety were evaluated. In atezolizumab-arm patients, ORR was 16% versus 14% and median PFS was 4.2 versus 2.8 months per immune-modified RECIST versus RECIST v1.1. The median post-PD OS was 12.7 months (95% confidence interval [CI]: 9.3-14.9) in 168 atezolizumab-arm patients continuing TBP, 8.8 months (95% CI: 6.0-12.1) in 94 patients switching to nonprotocol therapy, and 2.2 months (95% CI: 1.9-3.4) in 70 patients receiving no further therapy. Of the atezolizumab TBP patients, 7% achieved a post-progression response in target lesions and 49% had stable target lesions. Atezolizumab TBP was not associated with increased safety risks. Within the limitations of this retrospective analysis, the post-PD efficacy and safety data from OAK are consistent with a positive benefit-risk profile of atezolizumab TBP in patients performing well clinically at the time of PD.


Nosocomial bloodstream infections in ICU and non-ICU patients.
Nosocomial bloodstream infections (BSI) create a serious health problem in hospitals all over the world. The objectives of our study were to explore putative disease markers and potential risk factors with nosocomial BSI in patients in intensive care units (ICU) and non-ICU patients and to determine risk factors associated with increased 28-day mortality rate in patients with nosocomial BSI acquired in combined medical-surgical ICU. However, the major purposes of this report were to identify epidemiologic differences between nosocomial BSI acquired in ICU and non-ICU, as well as analyses outcomes for patients with nosocomial BSI acquired in ICU. A 1-year prospective cohort study was performed to determine the incidence of nosocomial BSI in hospitalized patients. Patient characteristics, risk factors related to health care, and source of infection of patients with BSI acquired in non-ICU were compared with those patient with BSI acquired in ICU. Also, nested case-control study of patients to nosocomial BSI acquired in ICU was performed to evaluate outcome. Patients were identified by active surveillance and positive blood culture during the study period. The incidence of nosocomial BSI was 2.2 per 1000 admission in non-ICU patients and 17.4 per 1000 admission in ICU patients. The 28-day crude mortality rate was 69% in ICU patients. A multivariate model showed that nasogastric tube (RR, 25.1; 95% CI: 3.845-163.85; P=.001), mechanical ventilation (RR, 13.04; 95% CI: 1.974-96.136; P=.008), and H2 blockers (RR, 12.16; 95% CI: 1.748-84.623; P=.012) were more prevalent among patients with BSI acquired in ICU, and aggressive procedures (RR, 8.65; 95% CI: 1.70-44.00; P=.009) were more prevalent among patients with BSI acquired in non-ICU patients. Risk factors independently associated with increased 28-day mortality rate in ICU patients were mechanical ventilation (OR, 8.63; 95% CI: 1.5-49.8; P=.016) and SAPS II >40 (OR, 6.0; 95% CI: 1.0-35.7; P=.049). The most common isolated nosocomial BSI pathogens (in both groups of patients) were coagulase-negative staphylococci (21%), Staphylococcus aureus (14%), and Klebsiella species (13%). Klebsiella species was the only organism independently influencing the poor outcome of nosocomial BSI in ICU patients (OR, 4.3; 95% CI: 1.2-15.3; P=.022). Our results show epidemiologic differences between non-ICU and ICU BSI. Also, this study suggests that severity of underlying host conditions, mechanical ventilation, and microbial agents (Klebsiella species) affect the outcome of NBI in patients in ICU.


Protective effects of diphenyl diselenide in a mouse model of brain toxicity.
Interest in organoselenide chemistry and biochemistry has increased in the past three decades, mainly due to their chemical and biological activities. Here, we investigated the protective effect of the organic selenium compound diphenyl diselenide (PhSe)2 (5 μmol/kg), in a mouse model of methylmercury (MeHg)-induced brain toxicity. Our group has previously demonstrated that the oral and repeated administration (21 days) of MeHg (40 mg/L) induced MeHg brain accumulation at toxic concentrations, and a pattern of severe cortical and cerebellar biochemical and behavioral. In order to assess neurotoxicity, the neurochemical parameters, namely, mitochondrial complexes I, II, II-III and IV, glutathione peroxidase (GPx) and glutathione reductase (GR) activities, the content of thiobarbituric acid-reactive substances (TBA-RS), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and brain-derived neurotrophic factor (BDNF), as well as, metal deposition were investigated in mouse cerebral cortex. Cortical neurotoxicity induced by brain MeHg deposition was characterized by the reduction of complexes I, II, and IV activities, reduction of GPx and increased GR activities, increased TBA-RS and 8-OHdG content, and reduced BDNF levels. The daily treatment with (PhSe)2 was able to counteract the inhibitory effect of MeHg on mitochondrial activities, the increased oxidative stress parameters, TBA-RS and 8-OHdG levels, and the reduction of BDNF content. The observed protective (PhSe)2 effect could be linked to its antioxidant properties and/or its ability to reduce MeHg deposition in brain, which was here histochemically corroborated. Altogether, these data indicate that (PhSe)2 could be consider as a neuroprotectant compound to be tested under neurotoxicity.


Mechanical stretching boosts expansion and regeneration of intestinal organoids through fueling stem cell self-renewal.
Intestinal organoids, derived from intestinal stem cell self-organization, recapitulate the tissue structures and behaviors of the intestinal epithelium, which hold great potential for the study of developmental biology, disease modeling, and regenerative medicine. The intestinal epithelium is exposed to dynamic mechanical forces which exert profound effects on gut development. However, the conventional intestinal organoid culture system neglects the key role of mechanical microenvironments but relies solely on biological factors. Here, we show that adding cyclic stretch to intestinal organoid cultures remarkably up-regulates the signature gene expression and proliferation of intestinal stem cells. Furthermore, mechanical stretching stimulates the expansion of SOX9+ progenitors by activating the Wnt/β-Catenin signaling. These data demonstrate that the incorporation of mechanical stretch boosts the stemness of intestinal stem cells, thus benefiting organoid growth. Our findings have provided a way to optimize an organoid generation system through understanding cross-talk between biological and mechanical factors, paving the way for the application of mechanical forces in organoid-based models.


Revisiting the Links-Species Scaling Relationship in Food Webs.
Predicting the number of interactions among species in a food web is an important task. These trophic interactions underlie many ecological and evolutionary processes, ranging from biomass fluxes, ecosystem stability, resilience to extinction, and resistance against novel species. We investigate and compare several ways to predict the number of interactions in food webs. We conclude that a simple beta-binomial model outperforms other models, with the added desirable property of respecting biological constraints. We show how this simple relationship gives rise to a predicted distribution of several quantities related to link number in food webs, including the scaling of network structure with space and the probability that a network will be stable.


Fliv-1: a surface membrane differentiation antigen of fetal rat hepatocytes.
A monoclonal antibody of IgG1 subclass was raised against 15 day fetal hepatocytes. The antibody appears to recognize a surface membrane-associated fetal hepatocyte antigen. Preliminary experiments suggest that the antibody recognizes a protein epitope. The tissue distribution of the antigen, designated Fliv-1, was studied by immunoperoxidase staining on whole body sections from fetal rats of different gestational ages. In 15 day fetal rats the antigen was detected on Rathke's pouch, brain infundibulum, tongue, liver, pancreatic acini, adrenal gland, vertebral myotome, and some developing muscle tissue. All normal adult tissues that were examined, two rat hepatoma cell lines, and hepatomas induced in rats by a single injection of diethylnitrosamine, were negative for the Fliv-1 antigen. On the basis of its tissue distribution, it seems unlikely that Fliv-1 is a previously described fetal hepatocyte marker.


Cerebrospinal fluid (CSF) extracted immediately after REM sleep deprivation prevents REM rebound and contains vasoactive intestinal peptide (VIP).
Intraventricular administration of cerebrospinal fluid (CSF) obtained from sleep deprived (SD) animals and vasoactive intestinal peptide (VIP) have been shown to increase rapid eye movement (REM) sleep. It has thus been suggested that VIP may accumulate in the CSF as a consequence of waking, and might thus be partly responsible for the subsequent rebound of REM sleep which follows prolonged wakefulness. To this data there are no studies testing this hypothesis. The purpose of this study, therefore, was to determine REM rebound following the extraction of CSF immediately after REMSD and to quantify by radioimmunoassay (RIA) the concentration of VIP in the CSF of progressively increasing REMSD periods. The results showed that REM rebound normally seen following REMSD is reduced by extraction of CSF, and that VIP concentration in such CSF is augmented. The results are discussed in terms of the possibility that waking induces an accumulation of VIP in the CSF, which is in turn involved in the production of REM sleep.


The warming city: the increasing risk of summer fires in Delhi.
Rising temperatures are mainly associated with wildfires, but the incidence of fire may also increase in the urban context. Yet, fire in Delhi, India, as elsewhere in the towns and cities of the Global South, remains largely invisible, despite the nearly 11 million people each year who are burnt severely enough to require medical attention. This paper focuses on whether summer temperatures in Delhi are rising and whether higher temperatures and lower humidity contribute to a greater number of fires in urban areas. The data strongly suggest a relationship between the warming city, a growing number of summer fires, and mounting temperatures around the world. Delhi, however, is only one example of an urban reality that is common to much of the Global South. Similar questions about the incidence of fire and whether the number is increasing need to be asked of other towns and cities that share the same vulnerabilities.


Coupling of SPME with MCC/UV-IMS as a tool for rapid on-site detection of groundwater and surface water contamination.
The combination of headspace solid phase microextraction (HS-SPME) [1] with fast chromatographic pre-separation by means of multi-capillary columns (MCC) coupled to an ion mobility spectrometer equipped with a 10.6 eV photoionisation source was applied to rapid on-site monitoring of ground and surface water contaminations. Under field conditions, water contaminants were directly detectable down to the upper microg/L range. The potential of the developed method is illustrated by measurements of BTEX, naphthalene, chlorinated alkenes and chlorinated benzenes in water. Practical results from investigations of contaminated groundwater at a former gasworks site and groundwater from the site of a metal processing plant, focusing on the key substances benzene, naphthalene and tetrachloroethene, demonstrate the feasibility of the system for field studies.


Identification and characterization of immune complexes in the cerebrospinal fluid of patients with spinal cord schistosomiasis.
The pathogenesis of neuroschistosomiasis is largely unknown. Available evidence suggests that it depends on the presence of parasite eggs in the nervous tissue and on the host's immune response. We investigated the presence of immune complexes (ICs) in the cerebrospinal fluid (CSF) of four patients with spinal cord schistosomiasis (SCS), and performed their characterization. ICs containing soluble egg antigen of Schistosoma mansoni (SEA) were found in the CSF of all the SCS patients. To our knowledge, this is the first evidence of ICs containing schistosomal antigens in the CSF of patients with SCS. Further studies are necessary to confirm our findings and investigate the possible roles of ICs in the pathogenesis of this disease.


Analysis of regenerating hepatic cell replication in vivo by differential chromatid staining.
The cell cycle of mouse hepatic cells was examined in vivo following partial hepatectomy, by differential chromatid staining in the presence of non-inhibitory concentrations of bromodeoxyuridine (BrdU). Using this technique, distribution curves were obtained for the appearance of metaphase cells in successive generations, and mean cell cycle time (11 hr) was determined. Cell cycle times derived with this technique are several-fold faster than previous reports of regenerating liver which used radionucleotide labelling.


[The problem of child abuse and neglect. 1: Analysis of hospital treated pediatric and pediatric surgical patients].
Definitions, legal aspects, epidemiology and the author's experience in 58 relevant cases between 1966 and 1986 are described and recommendations for diagnosis, notification and prevention are given. The author underlines the importance of the early detection of the maltreatment and neglect of children and the conclusions to be drawn.


A novel approach to treatment of unexpected vertebroplasty complication.
We report a novel approach to treatment of an unexpected complication of vertebroplasty. During initial positioning of transpedicular vertebroplasty needles in a 73-year-old woman, we encountered unexpected ease of needle advancement resulting in progression of the needle through the anterior cortex of the thoracic vertebral body. The transpedicular needle advanced into the mediastinum and, presumably, the adventitia of the descending thoracic aorta. Administration of polymethylmethacrylate cement was performed to tamponade bleeding at the time of the procedure and to reduce the risk of potential delayed bleeding complications within the mediastinum. The treatment was successful and the patient had no immediate or delayed complications as a result of the unintended needle advancement.


Gaming in China Before the COVID-19 Pandemic and After the Lifting of Lockdowns: a Nationwide Online Retrospective Survey.
With the lockdown and social distancing during the outbreak of coronavirus disease 2019 (COVID-19), gaming has become a popular leisure activity. This study aimed to explore changes in gaming behavior after the lifting of COVID-19 lockdowns and risk factors for increased gaming behavior. This online retrospective study included 5268 gamers. A total of 5% gamers scored 32 or higher on the 9-item Internet Gaming Disorder Scale-Short-Form (IGDS9-SF), suggesting diagnosis of internet gaming disorder (IGD). Over one-third of gamers reported an increase in time spent on gaming per day after the lockdowns were lifted. Logistic regression analysis revealed that gamers who were female, students, experienced stress, or scored higher on IGDS9-SF were more likely to spend more time on gaming per day after the lifting of lockdowns. These findings highlighted the needs for more effective coping strategies or interventions to prevent excessive gaming, especially for females and students.


[Detection of gamma globulin and Inv markers in vaginal secretions].
The Gm 1, Gm 2, and Inv 1-factors in the vaginal secretion are in accordance with the corresponding serum features to be expected basically. Deviations are possible. They are either caused by interference factors in the vaginal secretion or other factors which are not, however, always detectable in each case. It is important to test in advance the appropriate dilutions for the particular antiserum charges and to examine extracts of the samples to find out whether they have the necessary concentration.


Rapid activation of catalase followed by citrate efflux effectively improves aluminum tolerance in the roots of chick pea (Cicer arietinum).
The present study demonstrates the comparative response of two contrasting genotypes (aluminum (Al) tolerant and Al sensitive) of chick pea (Cicer arietinum) against Al stress. The Al-tolerant genotype (RSG 974) showed lesser inhibition of root growth as well as lower oxidative damages, measured in terms of the accumulation of H2O2 and lipid peroxidation compared to the Al-sensitive genotype (RSG 945). The accumulation of Al by roots of both genotypes was almost equal at 96 and 144 h after Al treatment; however, it was higher in Al-tolerant than Al-sensitive genotype at 48 h after Al treatment. Further, the Al-mediated induction of superoxide dismutase (SOD) activity was significantly higher in Al-tolerant than Al-sensitive genotype. Ascorbate peroxidase (APX) activity was almost similar in both genotypes. Al treatment promptly activated catalase activity in Al-tolerant genotype, and it was remarkably higher than that of Al-sensitive genotype. As another important Al detoxification mechanism, citrate efflux was almost equal in both genotypes except at 1000 μM Al treatment for 96 and 144 h. Further, citrate carrier and anion channel inhibitor experiment confirmed the contribution of citrate efflux in conferring Al tolerance in Al-tolerant genotype. Based on the available data, the present study concludes that rapid activation of catalase (also SOD) activity followed by citrate efflux effectively improves Al tolerance in chick pea.


Changes in physician referral patterns as a result of continuing education.
The evaluation of physician behavior as an outcome of continuing education has been an ellusive quantity of measure. This paper demonstrates one measure that can be used to evaluate the effect of continuing education in terms of physician behavior.


Phase I/II evaluation of pentostatin (2'-deoxycoformycin) in a five day schedule for the treatment of relapsed/refractory B-cell chronic lymphocytic leukaemia.
The purpose of this study was to determine the efficacy and toxicity of pentostatin (2'-deoxycoformycin) administered in a five day schedule every 28 days to patients with B-cell chronic lymphocytic leukaemia (B-CLL) relapsed from or refractory to at least one line of prior chemotherapy. The initial dose level of 2 mg/m2/day was adjusted up or down by 0.5 mg/m2 in subsequent cycles on the basis of haematological and non-haematological toxicities. The five day schedule was selected because published pharmacokinetic studies had indicated that although pentostatin had an elimination half-life of approximately six hours and could inhibit plasma adenosine deaminase activity for 24 hours, recovery of enzyme activity rapidly took place and accumulation of dATP which has a toxic effect on non-replicating lymphoid cells could be increased by repeated dosing. Twenty-nine patients were entered into the study and dose-escalation was possible in nine, while dose reductions were required for five patients. Of the 24 patients evaluable for response, complete responses were achieved in two and partial responses in five for an overall response rate of 29.2%. Toxicity consisted of myelosuppression, infection, nausea and vomiting and hepatotoxicity but was experienced at acceptable levels considering the heavily pre-treated nature of the patient population. Pentostatin in this schedule has salvage activity in previously treated or resistant patients with B-CLL.


Pharmacological characteristics of beta-adrenoceptor binding sites in intact and sympathectomized rat spleen.
[3H]-(--)-Dihydroalprenolol ([3H]-DHA) binds to rat spleen membranes with a dissociation equilibrium constant (KD) of about 0.7 nM and a maximal number of binding sites of 272 fmoles x mg protein-1. Approximately 90% of the sites labelled by 1 nM [3H]-DHA possess classical properties of beta-adrenoceptors. The labelled ligand is stereospecifically displaced by the isomers of propranolol and the order of potency of agonists is: isoprenaline greater than adrenaline greater than noradrenaline. Highly selective beta 1 antagonists such as practolol and atenolol displaced [3H]-DHA from spleen membranes in a biphasic manner indicating the co-existence of beta 1 and beta 2 sites (30--35% beta 1; 65--70% beta 2) in this tissue. Support for this classification was provided by the binding of the beta 2 agonist procaterol to spleen membranes. This drug possessed high affinity only for those sites that have low affinity for the beta 1 selective agents. Chemical sympathectomy induced by chronic 6-hydroxydopamine administration did not alter the number or the pharmacological properties of beta-adrenoceptor binding sites. The results suggest that both beta 1 and beta 2 adrenoceptors are probably postsynaptic in spleen.


A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer.
Here we describe how patterns of gene expression in human tumors have been deconvoluted to reveal a mechanism of action for the cyclin D1 oncogene. Computational analysis of the expression patterns of thousands of genes across hundreds of tumor specimens suggested that a transcription factor, C/EBPbeta/Nf-Il6, participates in the consequences of cyclin D1 overexpression. Functional analyses confirmed the involvement of C/EBPbeta in the regulation of genes affected by cyclin D1 and established this protein as an indispensable effector of a potentially important facet of cyclin D1 biology. This work demonstrates that tumor gene expression databases can be used to study the function of a human oncogene in situ.


Kinetic profiling and functional characterization of 8-phenylxanthine derivatives as A2B adenosine receptor antagonists.
A2B adenosine receptor (A2BAR) antagonists have therapeutic potential in inflammation-related diseases such as asthma, chronic obstructive pulmonary disease and cancer. However, no drug is currently clinically approved, creating a demand for research on novel antagonists. Over the last decade, the study of target binding kinetics, along with affinity and potency, has been proven valuable in early drug discovery stages, as it is associated with improved in vivo drug efficacy and safety. In this study, we report the synthesis and biological evaluation of a series of xanthine derivatives as A2BAR antagonists, including an isothiocyanate derivative designed to bind covalently to the receptor. All 28 final compounds were assessed in radioligand binding experiments, to evaluate their affinity and for those qualifying, kinetic binding parameters. Both structure-affinity and structure-kinetic relationships were derived, providing a clear relationship between affinity and dissociation rate constants. Two structurally similar compounds, 17 and 18, were further evaluated in a label-free assay due to their divergent kinetic profiles. An extended cellular response was associated with long A2BAR residence times. This link between a ligand's A2BAR residence time and its functional effect highlights the importance of binding kinetics as a selection parameter in the early stages of drug discovery.


Twin pregnancy. Management of delivery.
Management of the twin delivery remains controversial, particularly when the second twin in nonvertex and has an estimated fetal weight of 600 to 1500 gm. Management of schemes based on fetal presentation and estimated weights, as well as specific techniques and options for intrapartum care, are discussed.


Histology of normal bone--a computerized study in the iliac crest.
The application of an electronic digitizer and a computerized program for the quantitative assessment of bone morphology is reported. The method was used to measure bone surfaces and areas in undecalcified sections of iliac crest in 50 control subjects at necropsy.


Sex-Specific associations between hip muscle strength and foot progression angle.
The foot progression angle (FPA) influences knee loading during gait, but its determinants are unclear. The purpose of this study was to compare FPA between males and females and also examine the association between lower extremity kinematics during gait, hip strength, and the FPA. 25 males and 25 females completed 5 gait trials while FPA and frontal and transverse plane hip and knee angles were calculated from the dominant limb during the foot flat portion of stance. Hip extensor/flexor, abductor/adductor, and internal/external rotator strength were evaluated using maximum voluntary isometric contractions. One-way MANOVAs compared gait and strength outcomes. Stepwise regression assessed the association between FPA, and MVIC and kinematics after accounting for speed in males and females. There was no difference in FPA between sexes (p > 0.05), but females had greater frontal and transverse plane hip angles compared with males (all p < 0.05). Greater hip abduction (p = 0.02) strength was associated with greater FPA, but only in males. In males, greater hip abductor strength may contribute to a more neutral position of the foot during gait, which could help maintain an equal knee loading distribution. Our results suggest that there are sex specific control strategies to achieve a similar FPA during gait.


Correction: DCE-MRI-Derived Parameters in Evaluating Abraxane-Induced Early Vascular Response and the Effectiveness of Its Synergistic Interaction with Cisplatin.
[This corrects the article DOI: 10.1371/journal.pone.0162601.].


Carbazole- and thiophene-containing conjugated microporous polymers with different planarity for enhanced photocatalytic hydrogen evolution.
We report the synthesis of two carbazole-thiophene-based conjugated microporous polymers (Cz-3Th and Cz-4Th CMPs) with different degrees of planarity for photocatalytic hydrogen evolution from water. Depending upon the building linker's planarity, we found that the porous structure, hydrogen-evolution rate, and photocatalytic stability of the resultant CMPs varied.


[Femoral hypoplasia-unusual facies syndrome: A case report].
Femoral hypoplasia-unusual facies syndrome is a rare disease with variable expressivity, although cases have been reported with an autosomal dominant pattern. It particularly affects the structures of the face associated with hypoplasia of the femur. Its aetiology is relatively unknown. However, this syndrome has been associated with maternal diabetes, drug exposure, viral infections, radiation, and oligohydramnios. The case of a newborn with this syndrome is presented. Newborn of 41 weeks gestation with small nose, thin upper lip, micrognathia, long philtrum, low set ears, epicanthal folds, dysplastic hips showing flexion, and adduction of the right leg, and shortening at the expense of the thigh. X-ray images revealed femoral hypoplasia and dysplastic acetabular roof. Different physicians from other specialties who excluded other associated malformations performed a complete evaluation. Surgical bone lengthening of lower limb is scheduled at 5 months of age, with the purpose that she walks with her own feet; at the same time she began management with kinesiotherapy. Femoral hypoplasia-unusual facies syndrome is a rare condition. A multidisciplinary health care team must treat individuals with femoral hypoplasia-unusual facies syndrome.


Capillaric field effect transistors.
Controlling fluid flow in capillaric circuits is a key requirement to increase their uptake for assay applications. Capillary action off-valves provide such functionality by pushing an occluding bubble into the channel using a difference in capillary pressure. Previously, we utilized the binary switching mode of this structure to develop a powerful set of fundamental fluidic valving operations. In this work, we study the transistor-like qualities of the off-valve and provide evidence that these structures are in fact functionally complementary to electronic junction field effect transistors. In view of this, we propose the new term capillaric field effect transistor to describe these types of valves. To support this conclusion, we present a theoretical description, experimental characterization, and practical application of analog flow resistance control. In addition, we demonstrate that the valves can also be reopened. We show modulation of the flow resistance from fully open to pinch-off, determine the flow rate-trigger channel volume relationship and demonstrate that the latter can be modeled using Shockley's equation for electronic transistors. Finally, we provide a first example of how the valves can be opened and closed repeatedly.