In vivo evaluation of the penetration of topically applied drugs into human skin by spectroscopic methods.
Spectroscopic techniques are reported on which allow to study in vivo the penetration behaviour of topically applied light-absorbing drugs into human skin. Remittance spectroscopy, a purely optical method, provides a good tool in both, skin adaptation by use of a remote viewing head coupled to the spectrometer via optical fibres, and adequate sensitivity for the detection of small amounts of the applied drugs. The measuring depth in the skin is determined by the wavelength-dependent optical penetration depth, which itself depends on light absorption and light scattering. In the UV-spectral region the optical penetration depth is of the order of the thickness of the stratum corneum (UV-A) or of only a superficial part of it (UV-B, UV-C). Fluorescence spectroscopy, another optical method, offers two kinds of drug detection, a direct one in case of self-fluorescent drugs or an indirect one being based on the light absorption of the drug, which may give rise to a screening of the self-fluorescence of the skin itself or of an applied marker. The measuring depth is comparable to that achieved with remittance spectroscopy. A third method is photothermal spectroscopy which is determined by thermal properties of the skin in addition to optical properties. Photothermal spectroscopy is unique in that it allows depth profiles of drug concentration to be measured non-invasively, as the photothermal measuring depth can be changed by varying the modulation frequency of the intensity-modulated incident light. Results of measurements demonstrating the potentials of these spectroscopic methods are presented.


Fish Skin Microbiomes Are Highly Variable Among Individuals and Populations but Not Within Individuals.
Fish skin-associated microbial communities are highly variable among populations and species and can impact host fitness. Still, the sources of variation in microbiome composition, and particularly how they vary among and within host individuals, have rarely been investigated. To tackle this issue, we explored patterns of variation in fish skin microbiomes across different spatial scales. We conducted replicate sampling of dorsal and ventral body sites of perch (Perca fluviatilis) from two populations and characterized the variation of fish skin-associated microbial communities with 16S rRNA gene metabarcoding. Results showed a high similarity of microbiome samples taken from the left and right side of the same fish individuals, suggesting that fish skin microbiomes can be reliably assessed and characterized even using a single sample from a specific body site. The microbiome composition of fish skin differed markedly from the bacterioplankton communities in the surrounding water and was highly variable among individuals. No ASV was present in all samples, and the most prevalent phyla, Actinobacteria, Bacteroidetes, and Proteobacteria, varied in relative abundance among fish hosts. Microbiome composition was both individual- and population specific, with most of the variation explained by individual host. At the individual level, we found no diversification in microbiome composition between dorsal and ventral body sites, but the degree of intra-individual heterogeneity varied among individuals. To identify how genetic and phenotypic characteristics of fish hosts impact the rate and nature of intra-individual temporal dynamics of the skin microbiome, and thereby contribute to the host-specific patterns documented here, remains an important task for future research.


[Neurofibromatosis type 2].
Neurofibromatosis 2 (NF2) is a rare autosomal dominant disease whose hallmark is the development of bilateral vestibular schwannomas. Other features of NF2 include schwannomas, meningiomas, ependymomas, localized along the central nervous system, schwannomas of the peripheral nerves, cutaneous and ophthalmological manifestations. NF2 can be diagnosed in patients without bilateral vestibular schwannoma with sets of diagnostic criteria. Disease phenotype is variable among patients. Main negative prognostic factors are a young age at onset of symptoms and a high number of tumors at diagnosis. NF2 tumor suppressor gene encodes Merlin/Schwannomin, and is also involved in most sporadic schwannomas and meningiomas. Its functions remains largely unknown. Treatment and follow of NF2 patients up require oto-neurosurgical teams experienced in NF2. Yearly and life time surveillance is mandatory. A clinical screening protocol is suggested. Classically, only symptomatic lesions are to be treated. Some authors advocate an early proactive strategy against vestibular schwannoma in order to preserve hearing. When a treatment is advisable, surgery remains the treatment of choice for tumors. Auditory brainstem implant must be taken into account in hearing rehabilitation.


Current trends in managing the anophthalmic socket after primary enucleation and evisceration.
To evaluate current trends in the management of the anophthalmic socket after primary enucleation and evisceration. The active membership of the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS) was surveyed regarding primary enucleations and eviscerations performed between January and December 2002. Survey questions included practice demographics, orbital implant use, wrapping materials, placement of a motility peg, reasons for implant choice, and complications encountered. A total of 2,779 primary orbital implants were reported, comprising 1,919 (69.1%) enucleations and 860 (30.9%) eviscerations. The high-density porous polyethylene implant was used most frequently for enucleations (42.7%), followed by coralline hydroxyapatite (27.3%) and nonporous alloplastic implants (19.9%). For eviscerations, the high-density porous polyethylene implant was the most commonly used implant (42.3%), followed by hydroxyapatite (25.9%) and nonporous alloplastic implants (25.7%). The top 3 reasons for implant choice were outcome (69.3%), cost (43.6%), and experience (39.5%). Most implants were either not wrapped (59.8%) or were wrapped in donor sclera (25.2%) or polyglactin mesh (7.2%). Pegs were used in 8.1% of all implants reported. The most frequent complications encountered for unpegged implants were exposure (3.2%) and infection (0.4%). For pegged implants, the most common complications reported were pyogenic granuloma (13.7%), exposure (5.7%), and discharge (5.7%). In managing the anophthalmic socket, ASOPRS survey respondents preferred to use the porous polyethylene implant after primary enucleation and evisceration. Most orbital implants were not wrapped, and most surgeons preferred not to place a motility post or peg in the implant.


Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death.
Ninety-two AIDS patients with Pneumocystis carinii pneumonia (PCP) were randomized to receive folinic acid or matching placebo in conjunction with trimethoprim-sulfamethoxazole in a prospective, double-blind trial. Neither frequency of dose-limiting toxicity (26% vs. 37%; P = .4) nor time to occurrence (P = .7) was associated with folinic acid use. Although incidence of neutropenia was lower in patients receiving folinic acid (23% vs. 47%; P = .03), time to occurrence of neutropenia did not differ (P = .4). Seven (7.6%) of 92 patients with confirmed PCP met criteria for therapeutic failure, and 5 (6%) died during therapy. Surprisingly, folinic acid use was associated with a higher rate of both therapeutic failure (15% vs. 0; P = .01) and death (11% vs. 0; P = .06). Time to therapeutic failure was shorter and probability of death greater in patients receiving folinic acid (P = .005, P = .02, respectively), even when adjusted for baseline arterial oxygen pressure, serum lactate dehydrogenase, respiratory rate, CD4 cell count, and peak serum level of trimethoprim or sulfamethoxazole.


[Drug-induced changes in adrenal cortex function].
Glucocorticoids, commonly used in the treatment of various disorders, particularly if administered at high doses, may lead to the development of iatrogenic Cushing's syndrome, being by far the most common iatrogenic disorder of the adrenal gland. In some cases, however, adrenal cortex function may be affected by other drugs and risk of the development of various clinical entities is dependent on the drug, its dose, as well as on the duration of the treatment. This risk is also related to the baseline function of this gland. Because little is known about the influence of non-hormonal drugs on adrenal cortex function, many physicians are unaware of the existence of these disorders, which, if not detected in the early stages, can pose serious health risk. Although distinguishing endogenous from exogenous adrenal cortex disorders is usually straightforward and based on the patient's history, in rare cases the investigation and differentiation of iatrogenic adrenal cortex disorders may be diagnostically challenging. This article raises awareness of the association between drugs other than adrenal cortex hormones and the function of this gland, and provide the reader with recommendations concerning the diagnosis and treatment of iatrogenic adrenal cortex disorders.


Starting learning in medical practice: an evaluation of a new Introductory Clerkship.
The transition from undergraduate medical education to learning in clinical clerkships can be difficult for students. Learning in clinical practice requires awareness of learning opportunities and goals, active elaboration and reflection. Staff should provide students with guidance to learn from their experiences. A new Introductory Clerkship was designed to facilitate the start of goal-oriented, active and reflective work-based learning. This four-week clerkship is a result of the cooperation of six major specialties in the university hospital. The innovations included explicitly formulated goals, a description of the student's activities in daily practice and of the staff's role, group meetings, a logbook, a halfway formative interview and a final summative interview. The aim of this study was to investigate to what extent the innovations of the new Introductory Clerkship were implemented and how students and residents valued them. Two questionnaires were constructed: one was administered to students (n = 54) and the other to residents (n = 27). Students considered participation in daily practice very instructive, although more observations of history taking and physical examination are wanted. The interviews and group meetings promote students' learning. Use of the logbook needs improvement. Residents perceived a shortage of time and would appreciate more participation of staff members, as well as a better preparation for supervising tasks. Overall, the study demonstrates that it is possible to introduce innovations in clinical clerkships to improve the learning environment of work-based learning.


The messenger between worlds: the regulation of innate and adaptive type-2 immunity by innate lymphoid cells.
Although type-2 immune responses evolved primarily to defend against extracellular helminths, in part through the co-opting of tissue repair and remodeling mechanisms, they are often inappropriately directed towards relatively innocuous allergens resulting in conditions including asthma, allergic rhinitis, food allergy, and atopic dermatitis. The recent discovery of group 2 innate lymphoid cells (ILC2) has increased our understanding of the initiation of these responses and the roles played by CD4(+) T helper (Th) 2 cells in their modulation. This review focuses on the important messenger role of ILC2 in translating epithelial-derived alarmins into downstream adaptive type-2 responses via dendritic cells and T cells, with special emphasis on their roles in allergic disease.


Characteristics of eosinophilic inclusions within Schistosoma japonicum eggs.
Although eosinophilic bar- or droplet-like inclusions are frequently detectable inside eggs deposited in the livers of Schistosoma japonicum-infected animals, little is known of their exact nature. In the livers of mice implanted with freshly laid eggs, inclusion-positive eggs were found in 28.7 and 46.2% of deposited eggs at 2 and 4 weeks, respectively, after implantation, but in 4.3% at 5 weeks when most of the eggs had already degenerated. When the extent of granuloma formation was investigated, granulomas around inclusion-positive eggs were smaller than those around negative eggs. Host factors associated with the formation of inclusion were sought using in vivo and in vitro studies. Following the administration of anti-egg antigen serum into egg-implanted mice, no increase in occurrence of inclusion-positive eggs was seen. In a co-culture of mature eggs with infected rabbit or mouse serum, inclusions were rarely found. In contrast, they were found in 17.9% of eggs in the presence of splenic cells. The present study is the first to show that there is decreased granuloma formation in the presence of eosinophilic inclusions inside eggs and our in vitro study suggests that host cell-egg interaction is responsible for the formation of inclusions.


An Outcomes Review of 330 Sternal Wound Reconstructions: Timing of Closure Does Make a Difference.
Sternal wound infection and dehiscence following cardiac surgery remain difficult clinical problems with high morbidity. Older classification systems regarding timing to reconstruction do not take into account recent improvements in critical care, wound vacuum-assisted closure use, or next-generation antibiotic therapies, which may prolong time to reconstruction. Records of patients undergoing sternal wound reconstruction performed by the senior author (J.A.A.) from 1996 to 2018 at a high-volume cardiac surgery center were reviewed. Indications included sternal wound infection or dehiscence. All patients underwent single-stage removal of hardware, débridement, and flap closure. Patients were divided into two groups based on timing of wound closure after cardiac surgery: less than 30 days or greater than or equal to 30 days. Of the 505 patients identified during the study period, 330 had sufficient data for analysis. Mean time to sternal wound surgery was 15.7 days in the early group compared to 64.4 days (p < 0.01) beyond 30 days. Postdébridement cultures were positive in 72 percent versus 62.5 percent of patients (p = 0.11), whereas rates of postoperative infection were significantly higher in the delayed group: 1.9 percent versus 9.5 percent (p < 0.01). Partial wound dehiscence rates were also higher after 30 days (1.9 percent versus 11.3 percent; p < 0.01), whereas total length of stay was decreased. Use of wound vacuum-assisted closure was significantly associated with reconstruction beyond 30 days (p < 0.01). Although performing sternal wound reconstruction more than 30 days after initial cardiac surgery was associated with a shorter overall hospital length of stay and higher extubation rates in the operating room, these patients also had elevated postoperative infection and wound complication rates. The authors thus recommend not delaying definitive surgical reconstruction when possible. Therapeutic, III.


[Correlations of Methylenetetrahydrofolate Reductase Gene Polymorphism and Genomic DNA Hypomethylation Level with Ankylosing Spondylitis].
Objective To investigate the relationship of both DNA methylation level and methylenetrahydrofolate reductase(MTHFR)gene polymorphism with ankylosing spondylitis(AS). Methods Totally 200 Chinese AS patients with HLA-B27(+)and 120 healthy controls were included from Hunan Province.All the cases were diagnosed according to the 1984 modified New York criteria for AS.The DNA methylation was examined by cytosine extension method,while the MTHFR gene C677T polymorphism was analyzed by the polymerase chain reaction(PCR)and restriction fragment length polymorphism(RFLP).The plasma homocysteine(Hcy)level was examined by enzyme-linked immunosorbent assay(ELISA),while the red blood folate level was analyzed by the specific immunoassays. Results The ratio of the T/T genotype mutation in the AS group was significantly higher than in the control group(17.0% vs. 5.0%;χ2=9.874, P=0.002).The plasma homocysteine concentration of AS group was(18.71 ± 2.42)μmol/L,which was significantly higher than that in normal control group [(10.97 ± 2.93)μmol/L](t=24.402, P<0.001).The plasma Hcy concentration of the T/T genotype [(21.70±1.80)μmol/L] was significantly higher than that of the C/C genotype[(18.31±1.94)μmol/L](q=12.088, P=0.01)and the C/T genotype [(17.80±2.18)μmol/L](q=6.496, P=0.01)in the AS group.The DNA methylation level of the T/T genotype in AS group was significantly lower than that in normal control group(t=5.655, P<0.001)and also significantly lower than those of the C/C genotype(t=11.514, P<0.001)and the C/T genotype in AS group(t=10.287, P<0.001). Conclusions In the Han population in Hunan Province,the C677T polymorphism of the MTHFR gene is associated with the onset of AS.The T/T mutation at position 677 of the MTHFR gene is an important influencing factor for hyperhcyemia in the AS patients.The T/T mutation at position 677 of the MTHFR gene is associated with genomic DNA hypomethylation.Thus,hypomethylation of DNA may be one of the pathogenic mechanisms of AS.


Clinics in diagnostic imaging (106). Viable left tubal twin ectopic pregnancy.
Live twin ectopic gestations are extremely rare. There are more than 100 reported twin tubal pregnancies but less than ten have foetal cardiac motions demonstrated in both embryos. We describe an additional patient with live twin ectopic gestation. A 32-year-old woman presented with increasing left-sided abdominal pains. She had a high beta-hCG level and a significant history of subfertility with previous surgical intervention. Transvaginal ultrasonography showed viable left tubal twin ectopic pregnancy. The diagnosis was confirmed at surgery. Factors that contribute to the risk of ectopic pregnancy, diagnosis and the management of this condition are described.


Model-free scoring system for risk prediction with application to hepatocellular carcinoma study.
There is an increasing need to construct a risk-prediction scoring system for survival data and identify important risk factors (e.g., biomarkers) for patient screening and treatment recommendation. However, most existing methodologies either rely on strong model assumptions (e.g., proportional hazards) or only handle binary outcomes. In this article, we propose a flexible method that simultaneously selects important risk factors and identifies the optimal linear combination of risk factors by maximizing a pseudo-likelihood function based on the time-dependent area under the receiver operating characteristic curve. Our method is particularly useful for risk evaluation and recommendation of optimal subsequent treatments. We show that the proposed method has desirable theoretical properties, including asymptotic normality and the oracle property after variable selection. Numerical performance is evaluated on several simulation data sets and an application to hepatocellular carcinoma data.


TCOMs as a screening tool for hyperbaric oxygen therapy.
Transcutaneous oximetry (TcPO2), often referred to as TCOM, is a noninvasive measurement of oxygen tension in the tissue via a heated electrode. TCOMs can be used prior to beginning hyperbaric oxygen (HBO) treatment to determine if the patient has adequate blood flow to the wounded area to benefit from HBO. A case study of how it can be used in a problematic wound is presented.


Quality of life after therapy for localized prostate cancer.
Given the lack of unequivocal survival data clearly favoring one treatment over another for localized prostate cancer, patients strongly consider quality-of-life effects when choosing treatment for this common malignancy. In the past 15 years, a sizeable body of literature assessing health-related quality-of-life (HRQOL) outcomes in localized prostate cancer has emerged. The goal of this article is to review the quality-of-life experience after treatment for localized prostate cancer. Specifically, I will briefly discuss how quality of life is measured and then review the quality of life effects of each of the commonly used treatment strategies in localized prostate cancer. Finally, I attempt to directly compare the quality-of-life effects of the various treatments to assist clinicians in advising patients with newly diagnosed localized prostate cancer.


Making an impact: FEBS Open Bio celebrates its 3rd anniversary.
As FEBS celebrates its 50th anniversary, it also marks the launch 3 years ago of its newest journal, FEBS Open Bio. This online-only open access journal is now indexed in Web of Science. Papers originally submitted to The FEBS Journal can be transferred to FEBS Open Bio together with any reviewer reports, offering authors a fast-track alternative for publication of their work.


Case Report: Mitral Valve Involvement and First-Degree Atrial-Ventricular Block in Two Patients With Multisystem Inflammatory Syndrome in Children.
COVID-19 seems to be less frequent and severe in children compared to adults. Despite the very few symptoms usually found in children, great attention was recorded when in April 2020 a hyperinflammatory process in children with fever and multiorgan involvement after a paucisymptomatic COVID infection was reported. The United States Centers for Disease Control and the World Health Organization recognized and defined this syndrome as "Multisystem Inflammatory Syndrome in Children (MIS-C)." We describe two cases of MIS-C presenting with fever, cutaneous rash, and a mild cardiac involvement expressed with a transient mitral valve involvement and a first-degree atrioventricular block. Acute treatment was managed with intravenous immunoglobulin, oral aspirin, and intravenous corticosteroids reaching consequent good outcome. Clinical characteristics, treatment management, follow-up, and long-term evolution of children with MIS-C are still poorly defined. Further research is needed to better understand the pathogenesis of this newly described condition, to validate a high-level recommended therapy and a specific therapy tapering timings.


Conformational Asymmetry and Quasicrystal Approximants in Linear Diblock Copolymers.
Small angle x-ray scattering experiments on three model low molar mass diblock copolymer systems containing minority polylactide and majority hydrocarbon blocks demonstrate that conformational asymmetry stabilizes the Frank-Kasper σ phase. Differences in block flexibility compete with space filling at constant density inducing the formation of polyhedral shaped particles that assemble into this low symmetry ordered state with local tetrahedral coordination. These results confirm predictions from self-consistent field theory that establish the origins of symmetry breaking in the ordering of block polymer melts subjected to compositional and conformational asymmetry.


Phase II trial of oral cyclophosphamide, prednisone, and diethylstilbestrol for androgen-independent prostate carcinoma.
The authors evaluated the combination of oral cyclophosphamide, oral prednisone, and diethylstilbestrol (DES) in patients with androgen-independent prostate carcinoma (AIPC). Thirty-seven patients with prostate carcinoma refractory to androgen ablation who had undergone antiandrogen withdrawal (if previously treated with an antiandrogen) were enrolled in the current study. They were treated with oral cyclophosphamide 100 mg per day on Days 1-20, prednisone 10 mg per day continuously, and DES 1 mg continuously, on a 30-day cycle. Warfarin 1 mg per day was given as prophylaxis for thrombosis. Patient levels of prostate-specific antigen (PSA) were monitored on a monthly basis, with imaging studies every 3 months. Patients continued to receive therapy until disease progression or the occurrence of significant toxicity. The effect of therapy on the patient's quality of life was assessed using the Functional Assessment of Cancer Therapy-Prostate. Thirty-six patients were evaluable for response. Of the 36 patients, 15 (42%) had a 50% or greater decline in PSA levels from pretreatment levels and 1 patient (6%) with measurable disease had a partial response to therapy. The median duration of response was 4.5 months (range, 4-18 months). The overall median survival period was 16.4 months. The treatment was well tolerated, with only three patients removed from the study for toxicities associated with treatment. One patient, who had been treated for more than 24 months, developed acute leukemia. Quality of life evaluation in 17 patients showed a significant improvement in responders, whereas nonresponders had no deterioration while receiving therapy. Cyclophosphamide, prednisone, and DES represent a well tolerated, low-cost combination therapy with significant activity in the treatment of patients with AIPC.


The impact of peppermint oil on the irritable bowel syndrome: a meta-analysis of the pooled clinical data.
Peppermint oil (PO) has intrinsic properties that may benefit patients with irritable bowel syndrome (IBS) symptoms. The study objective was to determine the effect of peppermint oil in the treatment of the IBS. We systematically searched MEDLINE (PubMed), Cochrane Central Register of Controlled Trials (Cochrane CENTRAL), ClinicalTrials.gov, EMBASE (Ovid), and Web of Science for randomized controlled trials (RCTs) of PO for IBS. We appraised the eligible studies by the Cochrane risk of bias tool. We performed random-effects meta-analysis on primary outcomes including global improvement in IBS symptoms and abdominal pain. A PRISMA-compliant study protocol is registered in PROSPERO Register [2016, CRD42016050917]. Twelve randomized trials with 835 patients were included. For global symptom improvement, the risk ratio (RR) from seven RCTs for the effect of PO (n = 253) versus placebo (n = 254) on global symptoms was 2.39 [95% confidence interval (CI): 1.93, 2.97], I2 = 0%, z = 7.93 (p < 0.00001). Regarding abdominal pain, the RR from six RCTs for the effect of PO (n = 278) versus placebo (n = 278) was 1.78 [95% CI: 1.43, 2.20], I2 = 0%, z = 5.23 (p < 0.00001). Overall, there were no differences in the reported adverse effects: PO (32 events, 344 total, 9.3%) versus placebo (20 events, 327 total, 6.1%) for eight RCTs; RR 1.40 [95% CI: 0.87, 2.26] I2 = 0%, z = 1.39 (p = 0.16). The number needed to treat with PO to prevent one patient from having persistent symptoms was three for global symptoms and four for abdominal pain. In the most comprehensive meta-analysis to date, PO was shown to be a safe and effective therapy for pain and global symptoms in adults with IBS.


More severe toxicity of genetic polymorphisms on MTHFR activity in osteosarcoma patients treated with high-dose methotrexate.
5,10-Methylenetrahydrofolate reductase (MTHFR), a key enzyme for folate metabolism, catalyses the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is located at the end of the short arm (1p36.3). Two common non-synonymous variants, the C677T (Ala222Val) and A1298C (Glu429Ala), were mainly described with decreased enzymatic activity and an alteration of intracellular folate distribution. Osteosarcomas are currently treated with high dose of methotrexate (MTX). The decreased enzyme activity of MTHFR theoretically could increase the drug action of MTX and at the same time increase toxic and side effect. Germline variants of C677T and A1298C were studied in 59 osteosarcoma patients, with whom the A1298C is detected with particularly low rate of mutant genotype (N = 1, 0.8%) and could not proceed with statistical calculations. 15 patients were wild type of C677T (CC, 25.4%), 20 were heterozygous mutant genotype (CT, 33.9%) and 24 were homozygous mutant genotype (TT, 40.7%). Patients harboring the TT/CT genotype had the same progression-free survival and tumor necrosis rate in comparison with patients having the CC genotype (P = 0.349 and P = 0.465 respectively). And the C677T polymorphisms had no significant correlation with MTX initial plasma concentration (P = 0.867; r = 0.024) and delayed elimination (P = 0.305; r = -0.136). However patients with mutant genotype of C677T were associated with higher degree of liver toxicity (P = 0.043) and fever reaction of MTX (P = 0.050) while G3/G4 hematologic toxicity were more likely to be noticed with TT than CT/CC (P = 0.095). The study suggests that genetic polymorphism of MTHFR C677T in the MTX metabolic pathway seems to be associated with the trend for more side effects statistically, but has no obvious effect on histologic response and survival.


Tiron Inhibits UVB-Induced AP-1 Binding Sites Transcriptional Activation on MMP-1 and MMP-3 Promoters by MAPK Signaling Pathway in Human Dermal Fibroblasts.
Recent research found that Tiron was an effective antioxidant that could act as the intracellular reactive oxygen species (ROS) scavenger or alleviate the acute toxic metal overload in vivo. In this study, we investigated the inhibitory effect of Tiron on matrix metalloproteinase (MMP)-1 and MMP-3 expression in human dermal fibroblast cells. Western blot and ELISA analysis revealed that Tiron inhibited ultraviolet B (UVB)-induced protein expression of MMP-1 and MMP-3. Real-time quantitative PCR confirmed that Tiron could inhibit UVB-induced mRNA expression of MMP-1 and MMP-3. Furthermore, Tiron significantly blocked UVB-induced activation of the MAPK signaling pathway and activator protein (AP)-1 in the downstream of this transduction pathway in fibroblasts. Through the AP-1 binding site mutation, it was found that Tiron could inhibit AP-1-induced upregulation of MMP-1 and MMP-3 expression through blocking AP-1 binding to the AP-1 binding sites in the MMP-1 and MMP-3 promoter region. In conclusion, Tiron may be a novel antioxidant for preventing and treating skin photoaging UV-induced.


Design of a new optical system for Alcator C-Mod motional Stark effect diagnostic.
The motional Stark effect (MSE) diagnostic on Alcator C-Mod uses an in-vessel optical system (five lenses and three mirrors) to relay polarized light to an external polarimeter because port access limitations on Alcator C-Mod preclude a direct view of the diagnostic beam. The system experiences unacceptable, spurious drifts of order several degrees in measured pitch angle over the course of a run day. Recent experiments illuminated the MSE diagnostic with polarized light of fixed orientation as heat was applied to various optical elements. A large change in measured angle was observed as two particular lenses were heated, indicating that thermal-stress-induced birefringence is a likely cause of the spurious variability. Several new optical designs have been evaluated to eliminate the affected in-vessel lenses and to replace the focusing they provide with curved mirrors; however, ray tracing calculations imply that this method is not feasible. A new approach is under consideration that utilizes in situ calibrations with in-vessel reference polarized light sources.


Ca2+ influx is an essential component of the positive-feedback loop that maintains leading-edge structure and activity in macrophages.
In migrating eukaryotic cells, phosphatidylinositol 3-kinase (PI3K), filamentous actin (F-actin), and monomeric Rho GTPases are key components of a complex positive-feedback system that maintains and amplifies a phosphatidylinositol-3,4,5-trisphosphate signal at the leading edge of the cell. This lipid signal is required for cell polarization and movement. In leukocytes and Dictyostelium, activation or inhibition of any one of these components leads to the activation or inhibition, respectively, of the others via undefined feedback interactions. The role of Ca(2+) signals in migrating leukocytes is controversial, and there has been no indication that Ca(2+) participates in positive feedback. Here, we demonstrate that an extracellular Ca(2+) influx is required for positive feedback at the leading edge of spontaneously polarized macrophages. Inhibition of extracellular Ca(2+) influx leads to loss of leading-edge PI3K activity, disassembly of F-actin, cessation of ruffling, and decay of chemoattractant signals. Conversely, increasing cytosolic Ca(2+) enhances membrane ruffling, PI3K activity, and F-actin accumulation. Overall, these findings demonstrate that an extracellular Ca(2+) influx is an essential component, together with PI3K and F-actin, of the positive-feedback cycle that maintains leading-edge structure and ruffling activity and that supports the chemoattractant response. Strikingly, the Ca(2+)-sensitive enzyme protein kinase Calpha (PKCalpha) is enriched at the leading edge, and its enrichment is sensitive to blockade of Ca(2+) influx, to inhibition of PI3K activity, and to F-actin depolymerization. These findings support the working hypothesis that a local, leading-edge Ca(2+) signal recruits PKCalpha as a central player in the positive-feedback loop.


Combined EphB2 receptor knockdown with radiation decreases cell viability and invasion in medulloblastoma.
Medulloblastoma is one of the most common types of pediatric brain tumor characterized by the subpopulation of cells that exhibit high invasive potential and radioresistant properties. In addition, dysregulated function and signaling by Eph family of receptors have been shown to impart pro-tumorigenic characteristics in this brain malignancy. In the current study, we investigated whether EphB2 knockdown in combination with radiation can alter invasiveness and decrease medulloblastoma tumor growth or viability in vitro. The expression of EphB2 receptor was analyzed by immunohistochemistry and Western blotting. Microarray analysis and mRNA analysis was performed on medulloblastoma patient datasets and compared to the normal cerebellum. The radiosensitization effect following EphB2 knockdown was determined by clonogenic assay in human medulloblastoma cells. Effects of EphB2-siRNA in absence or presence of radiation on cell cycle distribution, cell viability, and invasion were analyzed by flow cytometry, MTT assay, trypan blue exclusion assay, xcelligence system, and Western blotting. We observed that EphB2 is expressed in both medulloblastoma cell lines and patient samples and its downregulation sensitized these cells to radiation as evident by decreased clonogenic survival fractions. EphB2 expression was also high across different medulloblastoma subgroups compared to normal cerebellum. The radiosensitization effect observed following EphB2 knockdown was in part mediated by enhanced G2/M cell cycle arrest. We also found that the combined approach of EphB2 knockdown and radiation exposure significantly reduced overall cell viability in medulloblastoma cells compared to control groups. Similar results were obtained in the xcelligence-based invasion assay. Western blot analysis also demonstrated changes in the protein expression of cell proliferation, cell survival, and invasion molecules in the combination group versus others. Overall, our findings indicate that specific targeting of EphB2 receptor in combination with radiation may serve as an effective therapeutic strategy in medulloblastoma. Future studies are warranted to test the efficacy of this approach in in vivo preclinical models.


Spatio-temporal dynamics of kind versus hostile intentions in the human brain: An electrical neuroimaging study.
Neuroscience research suggests that inferring neutral intentions of other people recruits a specific brain network within the inferior fronto-parietal action observation network as well as a putative social network including brain areas subserving theory of mind, such as the posterior superior temporal sulcus (pSTS), the temporo-parietal junction (TPJ), and also the anterior cingulate cortex (ACC). Recent studies on harmful intentions have refined this network by showing the specific involvement of the ACC, amygdala, and ventromedial prefrontal cortex (vmPFC) in early stages (within 200 ms) of information processing. However, the functional dynamics for kind intentions within and among these networks remains unclear. To address this question, we measured electrical brain activity from 18 healthy adult participants while they were performing an intention inference task with three different types of intentions: kind, hostile and non-interactive. Electrophysiological results revealed that kind intentions were characterized by significantly larger peak amplitudes of N2 over the frontal sites than those for hostile and non-interactive intentions. On the other hand, there were no significant differences between hostile and non-interactive intentions at N2. The source analysis suggested that the vicinity of the left cingulate gyrus contributed to the N2 effect by subtracting the kindness condition from the non-interactive condition within 250-350 ms. At a later stage (i.e., during the 270-500 ms epoch), the peak amplitude of the P3 over the parietal sites and the right hemisphere was significantly larger for hostile intentions compared to the kind and non-interactive intentions. No significant differences were observed at P3 between kind and non-interactive intentions. The source analysis showed that the vicinity of the left anterior cingulate cortex contributed to the P3 effect by subtracting the hostility condition from the non-interactive condition within 450-550 ms. The present study provides preliminary evidence of the spatio-temporal dynamics sustaining the dissociation between the understandings of different types of social intentions.


Breast metastasis from medullary thyroid carcinoma: a report of a case.
Metastasis to the breast is rare. We herein report a patient with metastatic medullary thyroid carcinoma to the breast for whom measuring the calcitonin level was an important clue to the correct diagnosis. A 54-year-old woman visited our hospital for the treatment of recurrent metastatic medullary thyroid carcinoma due to multiple endocrine neoplasia 2A and breast cancer. Positron emission tomography performed before the operation for metastatic medullary thyroid carcinoma recurrence in the neck showed the accumulation of 18F-fluorodeoxyglucose in the bilateral breast at sites other than the disease in the neck. Ultrasonography revealed multiple tumors in both breasts. A core needle biopsy of three breast tumors was performed. Microscopically, the tumor cells showed solid growth and did not show a tubular structure. She was diagnosed with triple-negative invasive ductal carcinoma. Post-operative positron emission tomography was performed as the serum calcitonin level increased after the operation. The accumulation of 18F-fluorodeoxyglucose in the bilateral breast tumors and lymph nodes in the neck was noted. The possibility of the breast tumors being metastasis of metastatic medullary thyroid carcinoma was considered. Needle aspiration was performed for three breast tumors. The calcitonin level of the washout fluid was measured and found to be ≥ 17,500 pg/mL. Immunohistochemistry showed that the tumor cells were calcitonin-positive and gross cystic disease fluid protein-15-negative. Vandetanib was started as recurrent metastatic medullary thyroid carcinoma with breast metastasis was finally diagnosed. The serum calcitonin level decreased after 1 month. Although breast metastasis of medullary thyroid carcinoma is rare, a correct diagnosis is indispensable for appropriate treatment. When a breast tumor shows atypical morphological features for breast cancer according to the histopathology in a patient with a history of cancer, metastasis to the breast should be considered. Calcitonin measurement of the needle washout fluid was useful for confirming metastatic medullary thyroid carcinoma.


[Biosynthesis and significance of acute phase proteins].
Acute phase proteins (APP) increase by the chemical receptors of macrophage via stimulations of either Fc or complement or other chemical receptors. No differences of APP pattern were observed by the different stimulants, because the effects of stimulation are changed by many processing steps in the macrophage as well as in the liver cell thereafter. Whether the APP increase results in good prognosis for original sickness or not are examined by multiple regression analysis in 38 cases of maxillary and 51 cases of laryngeal cancer with the observation for over five years. Alpha 1X contributes positively with length of their life, whereas alpha 1AG and ceruloplasmin contribute negatively. We could say that not all components of APP increase are advantageous for the diseases.


INPP4B and RAD50 have an interactive effect on survival after breast cancer.
Genes sharing similar genomic landscape have the potential to interactively orchestrate certain clinicopathological features of a disease. Deletion of the RAD50 gene is a common event particularly in basal-like breast cancer, and often occurs together with deletions of BRCA1, RB1, TP53, PTEN, and INPP4B. In this study, we investigate whether these co-deleted genes have interactive effects on survival in breast cancer. Using publicly available TCGA data, we employed Cox's proportional hazards models to test whether genomic deletions of these genes, or reduced protein or transcript levels associate with breast cancer patient survival in an interactive manner. Further validation was obtained at the transcriptional level by including 1,596 additional cases from 13 publicly available gene expression data sets from the KM-plotter database. Our results indicate that RAD50 and INPP4B associate interactively with breast cancer survival at the transcriptional, translational, and genomic levels in the TCGA data set (p (interaction) < 0.05). While neither of the genes was independently prognostic on its own, low INPP4B levels in combination with above median RAD50 abundance associated with increased hazard, both at the mRNA (HR 2.39, 95 % CI 1.20-4.76) and protein (HR 2.92, 95 % CI 1.42-6.00) levels, whereas concomitant deletion or low expression of both genes associated with unexpectedly improved survival. A similar pattern was observed in the KM-plotter data set (p (interaction) = 0.0067). We find that RAD50 and INPP4B expression levels have a synergistic influence on breast cancer survival, possibly through their effects on treatment response.


[Study on the expression, purification and the anti-endotoxin activity of human endotoxin binding peptide and its mutant].
To express endotoxin binding peptide and its mutant in E coli DH5alpha and detect the antiendotoxin activity of the purified peptides. (1 ) E coli DH5at containing pinpointXa3-EBP and pinpointXa3-mEBP was activated by IPTG to express biotin fusion protein. The fusion proteins were purified, and then digested by factor Xa for isolation of EBP and mEBP. The target peptide was purified with affinity chromatography and reversed-phase HPLC. Sequences of 10 amino acids at N-terminal were used for identification of mEBP. (2) PBMCs were isolated from blood of normal people, and they were stimulated with 5 mg/L FITC-LPS plus 2.0,5. 0 and 12. 5 mg/L EBP or mEBP. Then the mean fluorescent intensity was detected. PBMC was also stimulated with 1 mg/L LPS plus 2.0, 5.0 and 12.5 mg/L EBP or mEBP for 5 hours for the detection of the TNF-alpha and IL-6 level in the supernatant. (3) Thirty-five Kunming mice were randomized into normal control ( n = 5, with intraperitoneal injection of 0. 2 ml isotonic saline) , model group(n = 5, with intraperitoneal injection of LPS and 20% TBSA full-thickness burns), and treatment group (n = 15, with intraperitoneal injection of 5 mg/kg PMB or 10 mg/kg EBP or mEBP after burns). The serum contents of TNF-a and IL-6, and TNF-alpha mRNA level in hepatic tissue in each group were determined 6 hours after treatment. ( 1 ) EBP and mEBP were obtained after Xa digestion of biotin fusion protein, with purity reaching above 98% . The sequence of 10 amino acid at N-terminal was in accord with what expected. (2) The fluorescent intensity was decreased followed by an increase in mEBP or EBP concentration. Compared with normal PMBC, IL-6 and TNF-alpha level in the supernatant were obviously lowered in 1 mg/L LPS + 12.5 mg/L EBP group and I mg/L LPS +2. O0 , 5. 0, 12. 5 mg/L mEBP groups ( P < 0.01). (3) The serum level of IL-6 and TNF-ca in the therapeutic groups were obviously lower than that in model group ( P < 0.01 ) , and the levels of these cytokines were significantly lower in 10 mg/kg mEBP group than that in 10 mg/kg EBP group ( P <0. 01) , but they were similar to that in 5 mg/kg PMB treatment group ( P >0.05). (4) Relative optical density of TNF-alpha. mRNA in control, model, 10 mg/kg mEBP, 10 mg/kg EBP and 5 mg/kg PMB groups was 0.25, 0.93, 0.51 , 0.77 and 0.43, respectively. Endotoxin binding peptides can be obtained by procaryon expression. Both EBP and mEBP have anti-LPS activity, but mEBP is more effective.


Molecular bases of adhesion of Candida albicans.
The purpose of this review is to focus on the location and the adhesion activity of the protein (peptide) and the mannan moieties of the mannoprotein in the outer surface of the Candida albicans cell wall. A macromolecule of the mannoprotein located on the outermost surface is undoubtedly a strong adhesin comprising several adhesion molecules including protein and mannan. Mannoproteins can be divided into two classes, higher molecular weight peptidomannans (260 kDa) and lower molecular weight mannoproteins (50-66 kDa), both of which consist of similar mannans and disparate proteins or peptides which have distinct adhesion specificities. The protein moiety of mannoprotein can be divided functionally into two groups, lectin-like proteins and proteins recognizing arginine-glycine-aspartic acid (RGD) ligands. The latter proteins are further subdivided into two groups, CR2/CR3-like proteins and proteins binding extracellular matrix (ECM) proteins. Hydrophobicity of the cell surface of C. albicans influences adhesion of the organisms to epithelial cells. Degree of glycosylation of cell surface mannoproteins that affect yeast cell surface hydrophobicity affects adhesion of C. albicans to epithelial cells. The hydrophobic proteins may have low levels of glycosylation, and changes in glycosylation may determine exposure of hydrophobic protein regions at the cell surface. The serotype A-specific oligosaccharide of antigen 6 (pentaose or hexaose of mannan moiety) has been shown to exhibit marked adhesion ability for epithelial cells, and mannotetraose related to antigenic factor 5 which is present in both serotypes A and B showed adhesive activity for tissue macrophages. Proteinoceous adhesins of C. albicans are expressed preferably on the mycelial form. It is suggested that several of the adhesion molecules of C. albicans described above appear to complementarily utilize multiple adhesion mechanisms.


Harnessing graphene-hBN hyperstructure for single-photon sources.
One of the key challenges to move single-photon sources into practical applications is the ability to efficiently extract light from a single quantum emitter while maintaining efficient photon emission. Here, we propose to harness the optical topological transitions of graphene-hBN hyperstructure to engineer the emission from quantum emitters and achieve preferential power extraction. We have designed a hyperstructure, which possesses tunability of spontaneous emission and enhancement of extraction during optical topological transitions from the closed (ellipsoid) isofrequency surface to an open (hyperboloid) isofrequency surface by tuning the chemical potential of graphene. Such an interesting feature relies exclusively on the hyperbolic properties of hBN and tunable behavior of graphene, which is confirmed by detailed calculations and simulations. Remarkably, single-photon sources based on the hyperstructure do not require overmuch microfabrication and they are capable of working at tunable frequency.


The odyssey of nontoxic nodular goiter (NTNG) in Greece under suppression therapy, and after improvement of iodine deficiency.
Nontoxic nodular goiter (NTNG) is common in endemic goiter regions. Thyroxine (T4) is often used to treat NTNG. There is little information regarding T4 treatment in regions that have recently become iodine sufficient. We studied the effect of T4 treatment on thyroid function tests in southwestern Greece (SWG), a recently iodine-sufficient area. We studied 827 residents of SWG (group A) to determine goiter prevalence, thyroid function, and urinary iodine concentration (UIC). Group B: 385 consecutive patients with thyroid dysfunction. Of these, 89 had NTNG and followed for 10 years on T4 treatment, and 296 had hyperthyroidism. Group C: 29 patients with NTNG, treated with triiodothyronine (T3) 50 mug/day and followed for 6 months. Measurements included serum T4 and 24-hour radioactive iodine uptake (RAIU) before and at the end of T3 administration. The median UIC in group A was 114 microg/L. In group B (89 patients), the incidence of newly diagnosed hyperthyroidism was 5-7% per year with a cumulative percentage of 33% at the 10th year. The initial thyrotropin (TSH) was lower (0.78 +/- 0.51 mIU/L) in those who developed thyrotoxicosis compared to those who remained euthyroid (1.17 +/- 0.74 mIU/L) (p < 0.05). In 296 thyrotoxic patients, the incidence of autoimmune hyperthyroidism and toxic multi-nodular goiter (TMNG) was similar. In group C, 10/29 patients remained euthyroid and the 24-hour RAIU decreased by 49% during T3 treatment. Similarly, serum T4 decreased by 49%. In the remaining patients who developed hyperthyroidism, 24-hour RAIU and T4 were decreased by 19% and 22%, respectively. In SWG, a recently iodine-sufficient region, the risk of developing hyperthyroidism in patients with NTNG after administration of 100-150 microg T4 is relatively high in those whose serum TSH before T4 treatment is in the lower normal range. Therefore, T4 treatment should be avoided in these patients.


[The health care setting and professional confidentiality].
Professional secrecy must be treated with extra vigilance at a time when the dissemination of information and new communication technologies is developing. Hospitals are not excluded from this trend.This change in work practices is an advantage for child care, but also poses risks. In this context, the health framework plays a key role.


Telomerase Induction in HPV Infection and Oncogenesis.
Telomerase extends the repetitive DNA at the ends of linear chromosomes, and it is normally active in stem cells. When expressed in somatic diploid cells, it can lead to cellular immortalization. Human papillomaviruses (HPVs) are associated with and high-risk for cancer activate telomerase through the catalytic subunit of telomerase, human telomerase reverse transcriptase (hTERT). The expression of hTERT is affected by both high-risk HPVs, E6 and E7. Seminal studies over the last two decades have identified the transcriptional, epigenetic, and post-transcriptional roles high-risk E6 and E7 have in telomerase induction. This review will summarize these findings during infection and highlight the importance of telomerase activation as an oncogenic pathway in HPV-associated cancer development and progression.


Cynoglossum officinale toxicity in calves.
Six calves were given dried, ground Cynoglossum officinale daily in a dose which provided 15 (two calves) or 60 (four calves) mg per kg per day of total pyrrolizidine alkaloids. Those calves given 60 mg per kg of total pyrrolizidine alkaloids per day died following a single dose of plant material. These calves had a marked elevation of serum gamma-glutamyltransferase (GGT) and aspartate transaminase (AST) activities and serum bile acid and total bilirubin (TBili) concentrations. These four calves all had massive hepatocellular necrosis and haemorrhage of the liver. Of the two calves that were given 15 mg per kg of total pyrrolizidine alkaloids per day, one died on day 34 and the other survived until day 35 when it was painlessly killed. There were significant elevations in serum AST and GGT activities in these calves. The histological lesions of the calf surviving until 35 days were compatible with pyrrolizidine alkaloid toxicity, that is megalocytosis, karyomegaly and necrosis of hepatocytes with karyomegaly of biliary epithelium. The pyrrolizidine base present in Cynoglossum officinale (heliotridine) and its esters have a similar type of toxicity to the highly toxic and more familiar macrocyclic diester pyrrolizidine alkaloids of the pyrrolizidine base (retronecine), present in Senecio or Crotolaria species.


Multiple-dose tolerability and pharmacokinetics of tirilazad mesylate at doses of up to 10 mg/kg/day administered over 5-10 days in healthy volunteers.
Multiple dose pharmacokinetics and tolerability of tirilazad mesylate were assessed at the maximum dosage and duration expected for tirilazad mesylate therapy of subarachnoid hemorrhage and head injury. Healthy male subjects (47) received either 1 mg/kg/day, 3 mg/kg/day, 6 mg/kg/day, or 10 mg/kg/day tirilazad mesylate, given as 10 minute i.v. infusions every 6 hours for 21 (at the highest dose) or 41 doses. Plasma tirilazad mesylate and U-89678, an active metabolite, were quantified by HPLC. Thirty-nine subjects completed the study. Tirilazad mesylate was generally well tolerated; injection site irritation was the primary adverse effect. Sporadic, dose unrelated elevations in liver enzymes were observed. All medical events were reversible. No clinically significant effects on vital signs, cardiac telemetry, or other laboratory values were seen. Both tirilazad and U-89678 accumulated on multiple dosing, and steady-state plasma levels were approximated by day 11 of dosing. U-89678 average steady-state concentrations approached 58% of those of the parent compound in the 6.0 mg/kg/day dose group. Following the last dose, mean half-lives for tirilazad ranged from 61.2-123 hours; mean U-89678 half-lives ranged from 60.5-111 hours. Tirilazad mesylate pharmacokinetics exhibited slight nonlinearity, AUC0-6 values for the 6 mg/kg/day were 33% higher than those predicted based on data from the 1.0 mg/kg dose group. Neither the long half-lives of U-89678 and tirilazad nor slight nonlinearity of tirilazad pharmacokinetics are likely to have significant clinical impact during short-term treatment of acute neurological injury.


Monitoring Sodium Content in Processed Foods in Argentina 2017-2018: Compliance with National Legislation and Regional Targets.
Sodium intake in Argentina has been estimated to be at least double the dose of 2000 mg/day recommended by WHO, mostly coming from processed foods. Argentina is one of the few countries in the world that have regulated sodium content in certain food products. This study presents an assessment of sodium content in a selection of food groups and categories as reported in the nutrient information panels. We surveyed 3674 food products, and the sodium content of 864 and 1375 of them was compared to the maximum levels according to the Argentinean law and the regional targets, respectively. All food categories presented high variability of sodium content. Over 90% of the products included in the national sodium reduction law were found to be compliant. Food groups with high median sodium, such as condiments, sauces and spreads, and fish and fish products, are not included in the national law. In turn, comparisons with the lower regional targets indicated that almost 50% of the products analyzed had sodium contents above the recommended values. This evidence suggests that enhancing sodium reduction in processed foods may be a necessity for public health objectives and it is also technically feasible in Argentina.


Chronic inositol treatment reduces depression-like immobility of Flinders Sensitive Line rats in the forced swim test.
Inositol, a precursor of the PIP cycle that was reported to have therapeutic effects in depressive patients and to be effective in two animal models of depression, was evaluated in the forced swim test using the genetic Flinders Sensitive Line (FSL) rats model of depression. Groups of rats were tested in a 2 x 2 design with Strain (FSL or Control) as one factor and Drug (Inositol or Placebo) as the second factor. Rats received chronic treatment (daily for 14 days) with inositol (1.2 g/kg) or placebo (1:2 glucose/mannitol solution). On day 14 rats were exposed to the forced swim test for 5 min and their behavior videotaped. Tapes were analyzed for three levels of activity: immobility, swimming, and vigorous struggle. Inositol countered the exaggerated immobility of FSL rats in the forced swim test, without affecting control animals. Data support our previous suggestion of inositol as a potential antidepressant.


Evaluation of the effectiveness of CT-guided infiltration in the treatment of Arnold's neuralgia.
The aim of this study was to evaluate the effectiveness of computed tomography (CT)-guided infiltration in the treatment of Arnold's neuralgia. A retrospective study included 31 patients suffering from Arnold's neuralgia and having undergone a total of 45 CT-guided infiltrations of the greater occipital nerve (GON), in a proximal site (emergence of the GON, technique 1, n = 24) or in two proximal sites (emergence of the GON and at the site of the first bend of the GON drawn by the GON, technique 2, n = 21). Infiltration was considered to be effective when pain relief was equal to or greater than 50% for at least 1 month. There was no significant difference between the two techniques regarding immediate pain relief effect (53.3% for technique 1 vs. 60.5% for technique 2, p = 0.5), but technique 2 yielded better persistence of pain relief effect (p = 0.01), leading to a significantly higher percentage of effective infiltrations with technique 2 (p = 0.03). Infiltrations carried out in a single site yield results that are comparable to those previously published. Infiltrations in two sites provide significantly better results and should now be preferred to other single-site techniques in order to reduce the rate of failure or recurrence of Arnold's neuralgia.


Heine's method and A n to A m transformation formulas.
We apply Heine's method-the key idea Heine used in 1846 to derive his famous transformation formula for 2 ϕ 1 series-to multiple basic series over the root system of type A. In the classical case, this leads to a bibasic extension of Heine's formula, which was implicit in a paper of Andrews which he wrote in 1966. As special cases, we recover extensions of many of Ramanujan's 2 ϕ 1 transformations. In addition, we extend previous work of the author regarding a bibasic extension of Andrews' q-Lauricella function, and show how to obtain very general transformation formulas of this type. The results obtained include transformations of an n-fold sum into an m-fold sum.


Examination of the nitric oxide production-suppressing component in Tinospora tuberculata.
The component of aqueous Tinospora tuberculata extract that inhibits nitric oxide (NO) production was examined using macrophages activated by the addition of lipopolysaccharide. The aqueous extract was partitioned with ethyl acetate. The aqueous layer was fractionated with a Diaion column. The residue of the aqueous extract was extracted with methanol, and partitioned with ethyl acetate. The ethyl acetate layer was found to be associated with a distinct decrease in the NO level and inducible NO synthase. On further fractionation, the subfraction of E-3 showed high anti-NO activity. N-trans-Feruloyltyramine isolated from E-3 was identified as exhibiting strong anti-NO activity. This compound is the most active component of Tinospora tuberculata with respect to the suppression of NO production.


Water pollution and administrative division adjustments: A quasi-natural experiment in Chaohu Lake, China.
Administrative division adjustments, such as agglomerations, upgrading, and revocation, introduce a series of uncertain impacts on the social and economic development in administrative regions. Previous studies have focused more on the economic effects of administrative division adjustments, but in this paper, we also consider the environmental effects of such adjustments. In 2011, with the approval of the State Council, the prefecture-level Chaohu city was officially revoked, resulting in a county-level Chaohu city. One district and four counties under the jurisdiction of the original Chaohu city were placed under the jurisdiction of Hefei, Wuhu, and Ma'anshan. This adjustment made Chaohu Lake an inner lake of Hefei city. The administrative division adjustment of Chaohu Lake, China, is used as a quasi-natural experiment to explore the influence of such an adjustment on pollution control. The synthetic control method (SCM) is used in this study to evaluate the effect of the administrative division adjustment on the water quality indicators of Chaohu Lake. The following conclusions are drawn. First, after the administrative division adjustment, some water quality indicators, such as ammonia nitrogen, improved; however, other major pollution indicators, such as chemical oxygen demand (COD) and dissolved oxygen (DO), worsened to varying degrees. Second, the results reveal that improper development ideas, excessive industrial expansion, and the shift in economic growth and environmental goals were problems after the adjustment. Returning to the original intention of the administrative division adjustment, rationalizing the Chaohu Lake management system and designing a sound and feasible accountability mechanism are fundamental measures for reducing pollution.


Examining life-course influences on chronic disease: the importance of birth cohort studies from low- and middle- income countries. An overview.
The objectives of this overview are to describe the past and potential contributions of birth cohorts to understanding chronic disease aetiology; advance a justification for the maintenance of birth cohorts from low- and middle-income countries (LMIC); provide an audit of birth cohorts from LMIC; and, finally, offer possible future directions for this sphere of research. While the contribution of birth cohorts from affluent societies to understanding disease aetiology has been considerable, we describe several reasons to anticipate why the results from such studies might not be directly applied to LMIC. More than any other developing country, Brazil has a tradition of establishing, maintaining and exploiting birth cohort studies. The clear need for a broader geographical representation may be precipitated by a greater collaboration worldwide in the sharing of ideas, fieldwork experience, and cross-country cohort data comparisons in order to carry out the best science in the most efficient manner. This requires the involvement of a central overseeing body--such as the World Health Organization--that has the respect of all countries and the capacity to develop strategic plans for 'global' life-course epidemiology while addressing such issues as data-sharing. For rapid progress to be made, however, there must be minimal bureaucratic entanglements.


[International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia 2012].
Kidney tumours form a broad spectrum of distinguished histopathological and molecular genetic entities. The last WHO classification is dated to 2004. Current classification has been published in October 2013 by ISUP (International Society of Urological Pathology). There were 5 new epithelials tumours: tubulocystic renal cell carcinoma (RCC), acquired cystic disease-associated RCC, clear cell (tubulo-)papillary RCC, the MiT family translocation RCCs (in particular t(6;11) RCC), and hereditary leiomyomatosis RCC syndrome-associated RCC. Another 3 subtypes of RCC were added as "provisional" entities: thyroid-like follicular RCC; succinate dehydrogenase B deficiency-associated RCC; and ALK translocation RCC. Modifications were performed in already existing entities: multicystic clear cell RCC (formerly multilocular cystic RCC) is newly included as a subcategory of clear cell RCC with low malignant potential. Oncocytic papillary RCC (PRCC) has not been recognized as a distinctive subcategory of PRCC yet. Hybrid oncocytic-chromophobe tumour was placed within the chromophobe RCC category. Recent advances related to collecting duct carcinoma, renal medullary carcinoma, and mucinous spindle cell and tubular RCC were elucidated. Outside of the epithelial category, current approach to our understanding of angiomyolipoma, including the epithelioid variant and angiomyolipoma with epithelial cysts was clarified. Cystic nephroma and mixed epithelial and stromal tumour were considered as a spectrum of one entity. Synovial sarcoma was placed within the sarcoma group. The new classification is to be referred to as the International Society of Urological Pathology Vancouver Classification of Renal Neoplasia.


'Greater good' versus civil liberties in the United States: Tuberculosis and Seattle's Firland Sanatorium.
As far back as the late 1700s, peoples in the United States were developing ways to control infectious disease without infringing on Constitutional rights. Despite acknowledgement that an infected person has certain civil liberties, the history of public health law shows that, in many instances, infectious disease isolation and quarantine proved to be scientifically questionable at best. I examine an historical example of such questionable relationship between public health and civil liberties: the locked ward at Firland Sanatorium in Seattle, Washington. Mandatory quarantine at Firland began in the late 1940s and lasted until the facility closed in the early 1970s. Can examining this history enhance understanding of the relationship between "the greater good" and an individual's civil liberties?


Prevalence of intron gain over intron loss in the evolution of paralogous gene families.
The mechanisms and evolutionary dynamics of intron insertion and loss in eukaryotic genes remain poorly understood. Reconstruction of parsimonious scenarios of gene structure evolution in paralogous gene families in animals and plants revealed numerous gains and losses of introns. In all analyzed lineages, the number of acquired new introns was substantially greater than the number of lost ancestral introns. This trend held even for lineages in which vertical evolution of genes involved more intron losses than gains, suggesting that gene duplication boosts intron insertion. However, dating gene duplications and the associated intron gains and losses based on the molecular clock assumption showed that very few, if any, introns were gained during the last approximately 100 million years of animal and plant evolution, in agreement with previous conclusions reached through analysis of orthologous gene sets. These results are generally compatible with the emerging notion of intensive insertion and loss of introns during transitional epochs in contrast to the relative quiet of the intervening evolutionary spans.


Arsenite reduces insulin secretion in rat pancreatic beta-cells by decreasing the calcium-dependent calpain-10 proteolysis of SNAP-25.
An increase in the prevalence of type 2 diabetes has been consistently observed among residents of high arsenic exposure areas. We have previously shown that in rat pancreatic beta-cells, low arsenite doses impair the secretion of insulin without altering its synthesis. To further study the mechanism by which arsenite reduces insulin secretion, we evaluated the effects of arsenite on the calcium-calpain pathway that triggers insulin exocytosis in RINm5F cells. Cell cycle and proliferation analysis were also performed to complement the characterization. Free [Ca2+]i oscillations needed for glucose-stimulated insulin secretion were abated in the presence of subchronic low arsenite doses (0.5-2 microM). The global activity of calpains increased with 2 microM arsenite. However, during the secretion of insulin stimulated with glucose (15.6 mM), 1 microM arsenite decreased the activity of calpain-10, measured as SNAP-25 proteolysis. Both proteins are needed to fuse insulin granules with the membrane to produce insulin exocytosis. Arsenite also induced a slowdown in the beta cell line proliferation in a dose-dependent manner, reflected by a reduction of dividing cells and in their arrest in G2/M. Data obtained showed that one of the mechanisms by which arsenite impairs insulin secretion is by decreasing the oscillations of free [Ca(2+)]i, thus reducing calcium-dependent calpain-10 partial proteolysis of SNAP-25. The effects in cell division and proliferation observed with arsenite exposure can be an indirect consequence of the decrease in insulin secretion.


The origin of ovarian teratomas.
Chromosome and enzyme markers have been studied in 21 benign ovarian teratomas from 14 patients. Markers heterozygous in the patient were completely homozygous in 52% of the teratomas and completely heterozygous in 19%. The remainder showed a mixture of the two, 10% having homozygous centromeres with some heterozygous enzyme markers and 19% having heterozygous centromeres and some homozygous enzyme markers. These results suggest that benign ovarian teratomas in the present series arise from germ cells in a number of different ways. Those with heterozygous centromeres probably arise by failure of meiosis I. Some tumours with homozygous centromeres must arise by failure of meiosis II, but because of the low level of heterozygous enzyme markers in this group a substantial number are thought to arise by duplication of a mature ovum to give an entirely homozygous genotype, genetically the female equivalent of the complete hydatidiform mole.


Influence of Solid-State Packing of Dipolar Merocyanine Dyes on Transistor and Solar Cell Performances.
A series of nine dipolar merocyanine dyes has been studied as organic semiconductors in transistors and solar cells. These dyes exhibited single-crystal packing motifs with different dimensional ordering, which can be correlated to the performance of the studied devices. Hereby, the long-range ordering of the dyes in staircase-like slipped stacks with J-type excitonic coupling favors charge transport and improves solar cell performance. The different morphologies of transistor thin films and solar cell active layers were investigated by UV-vis, AFM, and XRD experiments. Selenium-containing donor-acceptor (D-A) dimethine dye 4 showed the highest hole mobility of 0.08 cm(2) V(-1) s(-1). BHJ solar cells based on dye 4 were optimized by taking advantage of the high crystallinity of the donor material and afforded a PCE of up to 6.2%.


Palladium-catalyzed, modular synthesis of highly functionalized indoles and tryptophans by direct annulation of substituted o-haloanilines and aldehydes.
One-pot synthesis of indoles by a palladium-catalyzed annulation of ortho-haloanilines and aldehydes has been developed. Coupling of ortho-iodoaniline with aldehyde is realized under mild ligandless conditions [Pd(OAc)2, DABCO, DMF, 85 degrees C], whereas X-Phos is found to be the ligand of choice for coupling reactions involving ortho-chloroanilines/ortho-bromoanilines and aldehydes. A variety of ortho-haloanilines with different electronic properties are suitable substrates, and aldehydes including chiral ones participated in this reaction without racemization. Coupling of (S)-2-N,N-di-tert-butoxycarbonyl-5-oxopentanoate, derived from L-glutamic acid, with ortho-haloanilines provides a rapid access to the ring-A-substituted tryptophans in good to excellent yields.


Fluctuation-induced dispersion forces on thin DNA films.
In this work, the calculation of Casimir forces across thin DNA films is carried out based on the Lifshitz theory. The variations of Casimir forces due to the DNA thicknesses, volume fractions of containing water, covering media, and substrates are investigated. For a DNA film suspended in air or water, the Casimir force is attractive, and its magnitude increases with decreasing thickness of DNA films and the water volume fraction. For DNA films deposited on a dielectric (silica) substrate, the Casimir force is attractive for the air environment. However, the Casimir force shows unusual features in a water environment. Under specific conditions, switching sign of the Casimir force from attractive to repulsive can be achieved by increasing the DNA-film thickness. Finally, the Casimir force for DNA films deposited on a metallic substrate is investigated. The Casimir force is dominated by the repulsive interactions at a small DNA-film thickness for both the air and water environments. In a water environment, the Casimir force turns out to be attractive for a large DNA-film thickness, and a stable Casimir equilibrium can be found. The influences of electrolyte screening on the Casimir pressure of DNA films are also discussed at the end. In addition to the adhesion stability, our finding could be applicable to the problems of condensation and decondensation of DNA, due to fluctuation-induced dispersion forces.


Efforts Toward Elimination of Infectious Agents in Blood Products.
The US blood supply has never been safer. This level of safety depends on a multifaceted approach including blood donor screening, sensitive infectious disease testing, and good manufacturing practice. However, risks remain for transfusion-transmitted infections due to bacterial contamination of platelets and emerging diseases. Thus, ongoing improvements in screening and testing are required. Newer pathogen reduction technologies have shown promise in further ameliorating the safety of the blood supply.


Epitaxial Growth of a Thin Layer of Putative Cancer Cells under Limited Resources and in the Presence of an Alkylating Agent.
The dynamics of the Eden cluster in a 32x32 lattice is implemented using a stochastic model. A single-type of cells solid tumor is assumed. Duplication is probabilistic, and occurs when there is room in the immediate surroundings of a cell, otherwise the cell is inhibited by contact. The growth is epitaxial, the shape of the cluster is disk-like; the ratio between the numbers of perimeter cells; and bulk cells decreases as the cluster grows. Percolation is flagged by an inflection in the rate of growth. We assume that the inflection point actually flags a shortage of nutrients, thereafter the rate of growth decreases to zero. Cancer cells in culture, when deprived of nutrients, actually exhibit a similar behavior. Under the logistic hypothesis, the lattice contains nutrients to sustain the growth up to 1024 cells. The model is expanded to include a drug that pollutes the environment. The drug is an alkylating agent that hinders duplication, eventually causing the death of the cell. The logistic equation accounts for drug consumption. The probability of duplication with the drug decreases as the drug is consumed, eventually leading to relapse. Relapses and survival times are investigated as a function of the dose injected.


Feasibility and Accuracy of Digitizing Edentulous Maxillectomy Defects: A Comparative Study.
The aim of this study was to evaluate the feasibility and accuracy of using an intraoral scanner to digitize edentulous maxillectomy defects. A total of 20 maxillectomy models with two defect types were digitized using cone beam computed tomography. Conventional and digital impressions were made using silicone impression material and a laboratory optical scanner as well as a chairside intraoral scanner. The 3D datasets were analyzed using 3D evaluation software. Two-way analysis of variance revealed no interaction between defect types and impression methods, and the accuracy of the impression methods was significantly different (P = .0374). Digitizing edentulous maxillectomy defect models using a chairside intraoral scanner appears to be feasible and accurate.


[Effect of androgen replacement therapy on mixed dry eye in a rabbit model].
Objective: To explore the effect of androgen replacement therapy in a rabbit dry eye model characterized by androgen deficiency and meibomian gland dysfunction (MGD). Methods: Thirty 6-month-old male Chinchilla rabbits were randomly divided into the treatment group, model group and control group, with 10 rabbits in each group. In the treatment and model groups, 2/3 of the meibomian gland openings were closed by cauterization with electric coagulation pen, and bilateral testes were removed. One gram gel containing 1% testosterone was applied for 28 days on the skin of rabbits in the treatment group since day 28 after the surgery. The model group and control group received transdermal petrolatum instead. Tear secretion, tear breakup time (TBUT), corneal fluorescein staining, and serum free testosterone level were monitored throughout the study period. The globes and eyelids were collected for hematoxylin-eosin staining and periodic acid-Schiff staining. Conjunctival tissue was tested for the expression of miRNA-744-5p and interleukin-6. Meibum was collected for fatty acid analysis. Results: Animals presented with typical dry eye signs and androgen deficiency. After 28-day androgen replacement therapy, compared with the model group, the treatment group had a significantly higher tear secretion rate [(14.7±5.2) vs (10.3±3.6) mm, P=0.001], higher TBUT [(15.0±4.2) vs (10.2±3.6) s, P=0.003], lower fluorescein staining score [0 (0, 1) vs 2 (1, 4), P<0.001], and higher goblet cell density at conjunctival fornix (27.2±7.6 vs 10.7±4.8, P<0.001). Additionally, compared with the model group, the conjunctiva of the treatment group expressed a significantly lower level of miRNA-744-5p (1.67±0.24 vs 2.63±0.58, P<0.001) and interleukin-6 [2.38 (1.84, 4.61) vs 4.82 (3.99, 6.36), P=0.022]. Meanwhile, the treatment group showed significantly increased level of 16∶1, Δ9 fatty acid [(10.31±1.00)% vs (3.87±0.45)%, P<0.001] and iso-18∶0 fatty acid [(7.09±0.93)% vs (2.44±0.70)%, P<0.001], but decreased level of iso-26∶0 fatty acid [(5.72±1.07)% vs (8.02±0.65)%, P<0.001] in the meibum compared with the model group. Conclusion: Androgen replacement therapy can alleviate dry eye signs in rabbits presented with combined androgen deficiency and MGD.


Use of panitumumab-IRDye800 to image microscopic head and neck cancer in an orthotopic surgical model.
Fluorescence imaging hardware (SPY) has recently been developed for intraoperative assessment of blood flow via detection of probes emitting in the near-infrared (NIR) spectrum. This study sought to determine if this imaging system was capable of detecting micrometastatic head and neck squamous cell carcinoma (HNSCC) in preclinical models. A NIR fluorescent probe (IRDye800CW) was covalently linked to a monoclonal antibody targeting epidermal growth factor receptor (EGFR; panitumumab) or nonspecific IgG. HNSCC flank (SCC-1) and orthotopic (FADU and OSC19) xenografts were imaged 48-96 h after systemic injection of labeled panitumumab or IgG. The primary tumor and regional lymph nodes were dissected using fluorescence guidance with the SPY system and grossly assessed with a charge-coupled NIR system (Pearl). Histologic slides were also imaged with a NIR charged-coupled device (Odyssey) and fluorescence intensity was correlated with pathologic confirmation of disease. Orthotopic tongue tumors were clearly delineated from normal tissue with tumor-to-background ratios of 2.9 (Pearl) and 2.3 (SPY). Disease detection was significantly improved with panitumumab-IRDye compared to IgG-IRDye800 (P < 0.05). Tissue biopsy samples (average size 3.7 mm) positive for fluorescence were confirmed for pathologic disease by histology and immunohistochemistry (n = 25 of 25). Biopsy samples of nonfluorescent tissue were proven to be negative for malignancy (n = 28 of 28). The SPY was able to detect regional lymph node metastasis (<1.0 mm) and microscopic areas of disease. Standard histological assessment in both frozen and paraffin-embedded histologic specimens was augmented using the Odyssey. Panitumumab-IRDye800 may have clinical utility in detection and removal of microscopic HNSCC using existing intraoperative optical imaging hardware and may augment analysis of frozen and permanent pathology.


Structural and functional characterization of a ubiquitin variant engineered for tight and specific binding to an alpha-helical ubiquitin interacting motif.
Ubiquitin interacting motifs (UIMs) are short α-helices found in a number of eukaryotic proteins. UIMs interact weakly but specifically with ubiquitin conjugated to other proteins, and in so doing, mediate specific cellular signals. Here we used phage display to generate ubiquitin variants (UbVs) targeting the N-terminal UIM of the yeast Vps27 protein. Selections yielded UbV.v27.1, which recognized the cognate UIM with high specificity relative to other yeast UIMs and bound with an affinity more than two orders of magnitude higher than that of ubiquitin. Structural and mutational studies of the UbV.v27.1-UIM complex revealed the molecular details for the enhanced affinity and specificity of UbV.v27.1, and underscored the importance of changes at the binding interface as well as at positions that do not contact the UIM. Our study highlights the power of the phage display approach for selecting UbVs with unprecedented affinity and high selectivity for particular α-helical UIM domains within proteomes, and it establishes a general approach for the development of inhibitors targeting interactions of this type.


Cryptophthalmos: a report on three sibling cases.
Three siblings, two females and one male, with the rare disease, cryptophthalmos, are reported on. Cryptophthalmos is usually familiar, inherited as an autosomal recessive trait. The clinical manifestations indicate that the eyeball is present but disorganised; the lid muscles, extraocular muscles, and the nerve elements controlling ocular movements in the brain are developed. Treatment is of no avail, but in unilateral cases the partial lid coloboma, anterior symblepharon, and corneal opacification of the opposite eye may be somewhat improved by surgery.


Parental perceptions of their child's weight and future concern: the Pacific Islands Families Study.
Little is known about the perception of overweight, expressed as a level of concern, of Pacific parents and its relevance to children's weight. The aim of this study was to analyse data collected at birth and four and six years in the Pacific Island Families Study (PIFS) to investigate the relationship between parental perceptions of child weight status and actual weight status. A total of 569 parent child dyads (299 boys (52.5%), 270 girls (47.5%); 47.1% Samoan, 20.9% Tongan, 18.6% Cook Island, 4.9% Niue, 8.4% other Pacific) were examined in this Parental Perception of Overweight Obesity Study (PPOS). At four and six years the question was asked of the parent "How concerned are you about your child becoming overweight?" A 5-point Likert scale was used, with possible answers ranging from "unconcerned" through increasing levels of concern to "very concerned". At four and six years weight and height were also measured and body mass index (BMI) derived and classified using international standards. Potential factors associated with parental perception were examined in a multivariate model using logistic regression. The majority of parents were unconcerned at four and six years (62% and 69.1%) about the future overweight status of their child. Using the international BMI classifications, at four years 40.1% of the children were classified as normal weight, 34.1% as overweight, and 25.8% as obese. At six years the proportions were similar; i.e., normal 41.3%, overweight 31.1%, and obese 27.6%. At four and six years the proportion of parents who were concerned about their child's future weight status was related to the child weight status e.g., at 6 years 20% of parents of normal children, 28% percent of parents of overweight and 51% of parents of obese children were concerned (p trend < 0.0001). Ethnicity and parity were significantly related to parental perceptions (p < 0.0001); identification with Tongan ethnicity was related to a higher proportion of concerned parents and an increased number of children in the family were related to a smaller proportion of concerned parents. While the level of concern was low and the prevalence of overweight and obesity high, the context of the socio economic and demographic environments must be taken into account in the formulation of interventions. Overweight and obese Pacific children may benefit from interventions that target the awareness of parents, making them more conscious of the relationship of obesity with food and activity patterns and give practical support to change the environment. These findings raise the concern that there is a normalisation of overweight and obesity in Pacific parents and/or children. Interventions firstly should address the socio economic demographic environment of a Pacific family making healthier choices the easier choices.


Systolic hypertension: an increasing clinical challenge in Asia.
Systolic hypertension, the predominant form of hypertension in patients aged over 50-60 years, is a growing health issue as the Asian population ages. Elevated systolic blood pressure is mainly caused by arterial stiffening, resulting from age-related vascular changes. Elevated systolic pressure increases the risk of cardiovascular disease, mortality and renal function decline, and this risk may increase at lower systolic pressure levels in Asian than Western subjects. Hence, effective systolic pressure lowering is particularly important in Asians yet blood pressure control remains inadequate despite the availability of numerous antihypertensive medications. Reasons for poor blood pressure control include low awareness of hypertension among health-care professionals and patients, under-treatment, and tolerability problems with antihypertensive drugs. Current antihypertensive treatments also lack effects on the underlying vascular pathology of systolic hypertension, so novel drugs that address the pathophysiology of arterial stiffening are needed for optimal management of systolic hypertension and its cardiovascular complications.


Size Effect of Ordered Mesoporous Carbon Nanospheres for Anodes in Li-Ion Battery.
The present work demonstrates the application of various sizes of ordered mesoporous carbon nanospheres (OMCS) with diameters of 46-130 nm as an active anode material for Li-ion batteries (LIB). The physical and chemical properties of OMCS have been evaluated by performing scanning electron microscopy (SEM), transmission electron microscopy (TEM), N₂ adsorption-desorption analysis; small-angle scattering system (SAXS) and X-ray diffraction (XRD). The electrochemical analysis of using various sizes of OMCS as anode materials showed high capacity and rate capability with the specific capacity up to 560 mA·h·g-1 at 0.1 C after 85 cycles. In terms of performance at high current rate compared to other amorphous carbonaceous materials; a stable and extremely high specific capacity of 240 mA·h·g-1 at 5 C after 15 cycles was achieved. Such excellent performance is mainly attributed to the suitable particle size distribution of OMCS and intimate contact between OMCS and conductive additives; which can be supported from the TEM images. Results obtained from this study clearly indicate the excellence of size distribution of highly integrated mesoporous structure of carbon nanospheres for LIB application.


Association of pre-diagnosis physical activity with recurrence and mortality among women with breast cancer.
Evidence is emerging that physical activity (PA) may improve overall survival after breast cancer diagnosis. However, the effect of PA on breast cancer recurrence and on cause-specific mortality is less investigated. We assessed the association of pre-diagnosis PA with recurrence, overall and cause-specific survival in a prospective cohort study in Germany including 3,393 non-metastatic breast cancer patients aged 50-74 years. Cox proportional hazards models were calculated adjusted for relevant prognostic factors. During a median follow-up of 5.6 years, 367 patients deceased. Overall mortality was significantly inversely associated with pre-diagnosis recreational PA. However, this effect was mainly attributed to deaths due to causes other than breast cancer. Multiple fractional polynomial analyses yielded a nonlinear association with markedly increased non-breast cancer mortality for women who did not engage in any sports or cycling in the years before the breast cancer diagnosis with a hazard ratio (HR, none vs. any) of 1.71, 95% confidence interval (1.16, 2.52). There were no further risk reductions with increasing activity levels. The association with breast cancer-specific mortality showed a similar dose-response but was far less pronounced with HR (none vs. any) = 1.22 (0.91, 1.64). In contrast, regarding cancer recurrence the dose-response was linear. However, this association was restricted to estrogen/progesterone receptor-negative (ER-/PR-) cases (p interaction = 0.033) with HR (highest vs. no recreational PA) = 0.53 (0.24, 1.16), p trend = 0.0045. Thus, breast cancer patients with a physically inactive lifestyle pre-diagnosis may decease prematurely irrespective of their cancer prognosis. Higher levels of exercise may reduce the risk of recurrence of ER-/PR- breast tumors.


CT colonography: where have we been and where are we going?
Over the past decade, computed tomographic (CT) colonography (also known as virtual colonoscopy) has been used to investigate the colon for colorectal neoplasia. Numerous clinical and technical advances have allowed CT colonography to advance slowly from a research tool to a viable option for colorectal cancer screening. However, substantial controversy remains among radiologists, gastroenterologists, and other clinicians with regard to the current role of CT colonography in clinical practice. On the one hand, all agree there is much excitement about a noninvasive imaging examination that can reliably depict clinically important colorectal lesions. However, this is tempered by results from several recent studies that show the sensitivity of CT colonography may not be as great when performed and the images interpreted by radiologists without expertise and training. The potential to miss important lesions exists; moreover, if polyps cannot be differentiated from folds and residual fecal matter, unnecessary colonoscopy will be performed. In this review, current issues will be discussed regarding colon cancer and the established and reimbursed strategies to screen for it and the past, current, and potential future role of CT colonography.


trans-10,cis-12 conjugated linoleic acid inhibits the G1-S cell cycle progression in DU145 human prostate carcinoma cells.
Conjugated linoleic acid (CLA) is a group of positional and geometric isomers of linoleic acid, and has evidenced anti-cancer activities in experimental animal cancer models and in vitro studies. The two predominant isomers of CLA are cis-9,trans-11 CLA (c9t11) and trans-10,cis-12 CLA (t10c12). The present study was performed to study the effect of the individual CLA isomers on DU145 cell growth. The cells were incubated in serum-free medium with different concentrations of the fatty acids. Treatment of cells with t10c12 (at 2.5-10 micromol/L) resulted in a dose-dependent reduction in the numbers of viable cells, whereas c9t11 CLA at a concentration of 5 micromol/L slightly increased viable cell numbers at 3 days (P < .05). DNA flow cytometric analysis revealed that the treatment of DU145 cells with t10c12 for 24 hours induced a small but significant increase in the number of cells in the G1 phase, accompanied by a complementary decrease in cells in the S phase. c9t, however, had no effect on cell cycle progression. To determine the molecular mechanisms underlying t10c12-induced G1 arrest, the levels of cell cycle regulatory proteins were estimated by western blot analyses. t10c12 induced a marked increase in p21(CIP1/WAF1) protein levels in a dose-dependent manner. p27(KIP1) was not affected by t10c12. t10c12 moderately decreased cyclin A and cyclin D1 protein levels (P > .05). However, t10c12 did not affect the expression of cyclin-dependent kinase (CDK) 2, CDK4, or cyclin E. t10c12 increased p21(CIP1/WAF1) bound to CDK2 and attenuated CDK2 activity. These results indicate that t10c12-induced p21(CIP1/WAF1) binds to CDK, and inhibits the activity of this enzyme, which results in the observed decrease in the G1-S progression in DU145 cells.


Cross border semantic interoperability for learning health systems: The EHR4CR semantic resources and services.
With the development of platforms enabling the integration and use of phenome, genome, and exposome data in the context of international research, data management challenges are increasing, and scalable solutions for cross border and cross domain semantic interoperability need to be developed. Reusing routinely collected clinical data, especially, requires computable portable phenotype algorithms running across different electronic health record (EHR) products and healthcare systems. We propose a framework for describing and comparing mediation platforms enabling cross border phenotype identification within federated EHRs. This framework was used to describe the experience gained during the EHR4CR project and the evaluation of the platform developed for accessing semantically equivalent data elements across 11 European participating EHR systems from 5 countries. Developers of semantic interoperability platforms are beginning to address a core set of requirements in order to reach the goal of developing cross border semantic integration of data.


Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy. INCAS Study Group.
Current antiretroviral treatment can induce significant and sustained virological and immunological responses in HIV-1-infected persons over at least the short- to mid-term. In this study, long-term immune reconstitution was investigated during highly active antiretroviral therapy. Patients enrolled in the INCAS study in The Netherlands were treated for 102 weeks (range 52-144 weeks) with nevirapine (NVP) + zidovudine (ZDV) (n = 9), didanosine (ddl) + ZDV (n = 10), or NVP + ddl + ZDV (n = 10). Memory and naïve CD4+ and CD8+ T cells were measured using CD45RA and CD27 monoclonal antibodies (mAb), T-cell function was assayed by CD3 + CD28 mAb stimulation, and plasma HIV-1 RNA load was measured by ultra-direct assay (cut-off < 20 copies/ml). Compared to both double combination regimens the triple combination regimen resulted in the most sustained increase in CD4+ T cells (change in CD4+, + 253 x 10(6) cells/l; standard error, 79 x 10(6) cells/l) and reduction of plasma HIV-1 RNA. In nine patients (31%) (ddl + ZDV, n = 2; NVP + ddl + ZDV, n = 7) plasma HIV-1 RNA levels remained below cut-off for at least 2 years. On average, these long-term virological responders demonstrated a significantly higher increase of naïve and memory CD4+ T cells (P = 0.01 and 0.02, respectively) as compared with patients with a virological failure, and showed improved T-cell function and normalization of the naïve; memory CD8+ T-cell ratio. However, individual virological success or failure did not predict the degree of immunological response. T-cell patterns were independent of baseline CD4+ T-cell count, T-cell function, HIV-1 RNA load or age. Low numbers of naïve CD4+ T cells at baseline resulted in modest long-term naïve T-cell recovery. Patients with prolonged undetectable plasma HIV-1 RNA levels during antiretroviral therapy do not invariably show immune restoration. Naïve T-cell recovery in the setting of complete viral suppression is a gradual process, similar to that reported for immune recovery in adults after chemotherapy and bone marrow transplantation.


Reversible Colorimetric Sensor for Moisture Detection in Organic Solvents and Application in Inkless Writing.
Colorimetric sensors based on Sudan-III (1) and Alizarin red S (2) have been developed for the detection of a trace amount of water in organic solvents such as THF, acetone, acetonitrile, and DMSO. The deprotonated (anionic) forms of 1 and 2 namely 1.F and 2.F are reprotonated by using a trace amount of water. Deprotonation of 1 and 2 was obtained by using fluoride anion. Test papers of 1.F and 2.F in organic solvents with and without moisture showed dramatic changes in color. Receptor 1.F exhibits high sensitivity for water in acetone and THF with the detection limit as low as 0.0042 and 0.0058 wt %. Remarkably, probes 1.F and 2.F are reversible in nature both in solution and in test strips. 1.F and 2.F are reversible and reusable for sensing moisture in the organic solvents with high selectivity, high sensitivity, and fast response. The reversible moisture sensor 1.F has also been used for application in inkless writing.


Cellular and noncellular bloodborne biomarkers in asthma.
To provide an overview of studied cellular and noncellular blood-derived asthma biomarkers. PubMed literature review. Articles discussing cellular and noncellular bloodborne asthma biomarkers. Discussed asthma biomarkers include peripheral blood cell counts of T cells, fibrocytes, or granulocytes, as well as levels of cytokines, periostin, IgE, and lipid mediators with or without stimulation. Moreover, this article summarizes the association of various blood biomarkers with the type of airway inflammation, presence of atopy, and dominance of specific T-cell subsets and associated pathways in asthma. Furthermore, biomarkers are here listed according to their proposed clinical use, such as diagnosis, disease phenotyping, classification of severity, assessment of disease control, and monitoring of and predicting treatment response. Further research on asthma biomarkers may improve asthma endotyping and ultimately lead to personalized treatment.