The effect of digestion and dewatering on sudden increases and regrowth of indicator bacteria after dewatering.
Several investigators have reported higher densities of indicator bacteria after dewatering of anaerobically digested biosolids. The increases appear to occur at two points in the biosolids process: the first, referred to as "sudden increase", occurs immediately after dewatering; the second, "regrowth", occurs during storage over longer periods. The objectives of this study were to examine the effect of digestion and dewatering processes on sudden increase and regrowth of fecal coliform and E. coli. Samples were collected from five thermophilic and five mesophilic digestion processes, with either centrifuge or belt filter press dewatering. Sudden increase typically was observed in the thermophilic processes with centrifuge dewatering and was not observed in the mesophilic processes with either centrifuge or belt filter press dewatering. Regrowth was observed in both thermophilic and mesophilic processes with centrifuge dewatering but not belt filter press dewatering.


Quality of reporting of neonatal and infant trials in high-impact journals.
To perform a systematic review of the quality of reporting for randomized controlled trials (RCTs) with infants and neonates that were published in high-impact journals and to identify RCT characteristics associated with quality of reporting. RCTs that enrolled infants younger than 12 months and were published in 2005-2009 in 6 pediatric or general medical journals were reviewed. Eligible RCTs were evaluated for the presence of 11 quality criteria selected from the Consolidated Standards of Reporting Trials guidelines. The relationships between quality of reporting and key study characteristics were tested with nonparametric statistics. Two reviewers had very good agreement regarding the eligibility of studies (κ = 0.85) and the presence of quality criteria (κ = 0.82). Among 179 eligible RCTs, reporting of the individual quality criteria varied widely. Only 50% included a flow diagram, but 99% reported the number of study participants. Higher quality of reporting was associated with greater numbers of study participants, publication in a general medical journal, and greater numbers of centers (P < .0001 for each comparison). Geographic region and positive study outcomes were not associated with reporting quality. The quality of reporting of infant and neonatal RCTs is inconsistent, particularly in pediatric journals. Therefore, readers cannot assess accurately the validity of many RCT results. Strict adherence to the Consolidated Standards of Reporting Trials guidelines should lead to improved reporting.


The Manifesto of Pharmacoenosis: Merging HIV Pharmacology into Pathocoenosis and Syndemics in Developing Countries.
Pathocoenosis and syndemics theories have emerged in the last decades meeting the frequent need of better understanding interconnections and reciprocal influences that coexistent communicable and non-communicable diseases play in a specific population. Nevertheless, the attention to pharmacokinetic and pharmacodynamics interactions of co-administered drugs for co-present diseases is to date limitedly paid to alert against detrimental pharmacological combos. Low and middle-income countries are plagued by the highest burden of HIV, tuberculosis, malaria, and helminthiasis, and they are experiencing an alarming rise in non-communicable disorders. In these settings, co-infections and comorbidities are common, but no tailored prescribing nor clinical trials are used to assess and exploit existing opportunities for the simultaneous and potentially synergistic treatment of intertwined diseases. Pharmacoenosis is the set of interactions that take place within a host as well as within a population due to the compresence of two or more diseases and their respective treatments. This framework should pilot integrated health programmes and routine clinical practice to face drug-drug interaction issues, avoiding negative co-administrations but also exploiting potential favourable ones to make the best out of the worst situations; still, to date, guiding data on the latter possibility is limited. Therefore, in this narrative review, we have briefly described both detrimental and favourable physiopathological interactions between HIV and other common co-occurring pathologies (malaria, tuberculosis, helminths, and cardiovascular disorders), and we have presented examples of advantageous potential pharmacological interactions among the drugs prescribed for these diseases from a pharmacokinetics, pharmacodynamics, and pharmacogenetics standpoint.


Conformational behavior and self-assembly of disjoint semi-flexible ring polymers adsorbed on solid substrates.
The conformational behavior and spatial organization of self-avoiding semi-flexible ring polymers, that are fully adsorbed on solid substrates, are investigated via systematic coarse-grained molecular dynamics simulations. Our results show that both conformations and spatial organization of the polymers depend strongly on their bending stiffness, κ, and on their areal number density, ρ. For ρ < ρ*, where ρ* is the overlap density, and for low values of κ, thermal fluctuations lead to weakly anisotropic instantaneous conformations of the polymers. The interplay between thermal fluctuations and polymer stiffness leads to a non-monotonic dependence of the polymers elongation on κ with a maximum elongation at some intermediate κ. Regardless of κ, the polymers elongation is almost independent of ρ for ρ ⪅ ρ*, then increases with ρ. At ρ ≈ ρ* and high κ, the almost circularly-shaped polymers self-assemble into a triangular lattice with quasi-long range order. For ρ above ρ* and high κ, crowding of the polymers leads to their self-assembly into liquid-crystalline phases. In particular, for ρ moderately above ρ* and high κ, the polymer conformations are obround and self-assemble into domains with smectic-A-like order. At higher densities, the polymer have a biconcave geometry and self-assemble into domains with smectic-C-like order.


Work-system risk factors for permanent work disability among home-care workers: a case-control study.
There is a growing need for home-care services in western societies. As home-care workers show high levels of absence related to poor health it is important that we broaden our knowledge about what factors in the work system contribute to this. The aim of this study was to explore and estimate the impact of the work system on permanent work disability and its relative importance compared with home-life risks among home-care workers. The cases (617 subjects) were all home-care workers in Sweden, whose disability pension was approved in 1997 or 1998. The controls (771 subjects) were home-care workers still working. We used a questionnaire to gain situation-specific information on working life and home life 5 and 15 years before disability pension entitlement. The most important risk factors in the work system were poor ergonomic/lifting conditions, time pressure and lack of professional caring technique. Fifteen years prior to disability pension entitlement, insufficient management (odds ratio (OR) 95%, CI 2.6[1.6;4.2]) and relational problems at work were also risk factors. Five years before disability pension entitlement, poor organisational support (4.1 [2.5;6.7]), opportunities for co-working and working climate (3.5 [2.4;5.2]) were also strongly related to a persisting work ability. The magnitude of exposure to a number of risk factors had an increased effect (highest 13.8 [5.6-33.8]). The strongest risk factor in home life was little opportunity to rest from work (4.9 [3.0;8.0]). The risk factors in working life were robust to the inclusion of the grouped risk factors of home life. The conclusion was that risk factors related to the work system are, alone, strongly related to permanent work disability among home-care workers. Also, exposure to several of the risk factors constitutes a notably strong risk for permanent work disability.


Incidence and characteristics of vascular trauma at a level 2 trauma center.
Despite the significant number of trauma patients treated at level 2 trauma centers (L2TCs) in the United States, most of the literature describing vascular trauma is from level 1 trauma centers (L1TCs). Currently, trauma center designation criteria do not require vascular surgery as a necessary component service. A retrospective chart review was performed for all trauma patients with a vascular surgery consultation seen at our L2TC between 2013 and 2018. Patient demographics, injury characteristics, and outcomes were collected and analyzed with descriptive statistics. Of the 3062 trauma patients evaluated at our L2TC, 110 (3.6%) had a vascular surgery consultation. Operative intervention was performed in 35.2% of consults, and 1.0% of all trauma patients had a vascular intervention. Average age was 57 years, and the majority were male (n = 75; 68.2%). Mean Injury Severity Score was 12.0 ± 9.6, and blunt injury (n = 77; 87.5%) was more common than penetrating (n = 11; 12.5%). The most common location of injury was the lower extremity (n = 23; 74.2%), followed by upper extremity (n = 3; 9.7%), chest (n = 2; 6.5%), neck (n = 2; 6.5%), and pelvis (n = 1; 3.2%). Endovascular interventions were performed by the vascular surgery service in 67.7% (n = 21) of all injuries. There was one amputation (3.2%) and one postoperative mortality (3.2%). At our L2TC, postoperative morbidity and mortality rates at 30 days were substantially lower compared with previously reported data. However, mean injury severity score and the incidence of penetrating and polytrauma were also lower at our institution. Most patients were managed nonoperatively, but when they did require an operation, endovascular therapies were more commonly implemented. Vascular surgery should be considered an integral service in trauma level designation, and there is a need for further investigation of these outcomes in L2TCs.


Serum patterns of mir-23a and mir-181b in irritable bowel syndrome and colorectal cancer - A pilot study.
Emerging evidence demonstrates that microRNAs (miRNAs) could serve as reliable biomarkers of inflammation and oncogenesis. The aim of this study was to determine whether miR-23a and miR-181b were suitable as biomarkers of irritable bowel syndrome (IBS) and colorectal cancer (CRC). Forty patients with IBS (29 females, 11 males), 33 with CRC (14 females, 19 males), and 33 healthy controls (17 females, 16 males) were prospectively included. Serum levels of miRNAs were evaluated by quantitative real-time PCR. The serum levels of miR-23a and miR-181b were significantly higher in the IBS group (p = 0.0009 and 0.004, respectively) and CRC group (p = 0.002 and 0.029, respectively) than in the control group. Serum levels of miR-23a and miR-181b were upregulated in CRC vs. IBS, but the differences did not reach statistical significance (p = 0.169 and 0.179, respectively). The miRNet and Reactome databases identified phosphatase and tensin homolog as a major common pathway, indicating inflammation as a central hallmark. Although miRNAs could serve as reliable biomarkers in clinical practice, future studies are needed to establish appropriate cut-off limits.


The impact of diet switching on resource allocation to reproduction and longevity in Mediterranean fruitflies.
Understanding the factors that determine the allocation and utilization of organism resources may provide an insight into the mechanisms of adaptation, ageing and reproduction. Resource allocation, which is regarded as a method of adaptation, increases fitness and is genetically controlled. Experiments with variable diet feeding of female Mediterranean fruitflies (Ceratitis capitata) demonstrated that the feeding regime dramatically influences lifespan, mortality and the reproduction of flies. An analysis of experimental data and numerical experiments reveals that resource allocation could explain lifespan increase when females are switched from a sugar-only to a protein-containing diet. The heterogeneity of the initial female cohort in terms of the total amount of resources and its allocation to the processes of maintenance and reproduction plays a significant role in this.


Methodological challenges of symptom management research in recurrent cancer.
Completion of first-line treatment is an important milestone for adults newly diagnosed with cancer. However, for many adults, the cancer experience of the 21st century does not end with the completion of initial treatment. Decreased functional status, distressing symptoms, and residual effects of treatment impact the daily lives of cancer survivors. Cancer has evolved into a chronic illness, in which a disease-free period may be followed by recurrent cancer. Researchers face challenges in the design and analysis of symptom management studies in recurrent disease. Residual effects can preclude a true "baseline" measurement of the symptom(s) of interest to the researcher. In addition, as cancer survivors age, they are more likely to have comorbid conditions that increase the likelihood of developing toxicities and residual symptoms that are specific to cancer treatments. Research studies of cancer-related symptoms in adults with recurrent disease pose many methodological challenges. Selection of appropriate study design, sample inclusion and exclusion criteria, measures of comorbidity and symptoms, and advanced analysis techniques are among the strategies proposed to address these methodological challenges.


DNA demethylation is directly related to tumour progression: evidence in normal, pre-malignant and malignant cells from uterine cervix samples.
A computer-assisted assay based on the quantitative analysis of DNA methylation in individual interphase nuclei by indirect immunolabelling with anti-5-methylcytosine antibodies was recently developed in our laboratory. In situ analyses were performed on individual nuclei from normal and experimentally hypo- or hypermethylated cultured cells as well as on human peripheral blood B-lymphocytes from normal and chronic lymphoid leukemia (CLL) samples. We present the results obtained on cells from patients affected by different degrees of preneoplastic or neoplastic changes of the uterine cervix as compared to normal controls. The analysis of DNA methylation in individual cells from cytofuge samples was performed as follows: within each nucleus the eu- and heterochromatin methylation levels were quantified in the grey scale range by dedicated software in terms of numbers, areas and optical densities (ODs) of the immunolabeled dense heterochromatic regions ("spots"), and of the optical density of nuclear background, i.e., of nuclear euchromatin. Analogously, in randomly chosen microscope fields of tissue sections from paraffin-embedded samples, progressive tissue demethylation was observed in dysplastic and cancer cells as compared to normal ones. Both methods showed significant and progressive DNA hypomethylation in dysplastic and cancer cells as compared to control specimens.


Hot topics from the Assemblies.
Tissue-resident alveolar macrophages (TR-AM) are depleted from the lung during the early stages of bleomycin-induced lung injury and fibrosis. The recovery of the population of macrophages after bleomycin could be completely attributable to the recruitment and differentiation of monocyte-derived alveolar macrophages (Mo-AM). The authors used multiple lineage-trace mouse models where they selectively depleted TR-AM or Mo-AM and induced fibrosis with bleomycin. Deletion of TR-AM had no effect on the severity of the fibrotic phenotype. However, when Mo-AM were depleted animals showed attenuated fibrosis as evidenced by normalised collagen levels and recovered lung compliance.


[Secondary prevention of stroke with antiplatelet drugs].
Patients suffering from a transient ischemic attack (TIA) or ischemic stroke are at high risk of a recurrent stroke. The risk is between 10% and 15% in the 1st year after the event and highest in the immediate period following the index event. In patients without cardiac source of embolism, the risk of stroke can be reduced by acetylsalicylic acid (ASA). The relative risk reduction for recurrent vascular events (myocardial infarction, stroke, vascular death) with aspirin is 18% and the risk reduction for stroke 13%. Clopidogrel is superior to ASA in patients with high risk of recurrence due to concomitant vascular disease or multiple risk factors. Clinical trials for secondary stroke prevention at present focus on combination antiplatelet therapy. Large clinical trials such as MATCH, CARESS, CHARISMA, and PRoFESS will investigate whether combination antiplatelet therapy is superior to monotherapy and whether the combination of dipyridamole plus ASA is comparable to clopidogrel plus ASA in terms of efficacy and safety.


Three-Dimensional Optical Mapping of Nanoparticle Distribution in Intact Tissues.
The role of tissue architecture in mediating nanoparticle transport, targeting, and biological effects is unknown due to the lack of tools for imaging nanomaterials in whole organs. Here, we developed a rapid optical mapping technique to image nanomaterials in intact organs ex vivo and in three-dimensions (3D). We engineered a high-throughput electrophoretic flow device to simultaneously transform up to 48 tissues into optically transparent structures, allowing subcellular imaging of nanomaterials more than 1 mm deep into tissues which is 25-fold greater than current techniques. A key finding is that nanomaterials can be retained in the processed tissue by chemical cross-linking of surface adsorbed serum proteins to the tissue matrix, which enables nanomaterials to be imaged with respect to cells, blood vessels, and other structures. We developed a computational algorithm to analyze and quantitatively map nanomaterial distribution. This method can be universally applied to visualize the distribution and interactions of materials in whole tissues and animals including such applications as the imaging of nanomaterials, tissue engineered constructs, and biosensors within their intact biological environment.


A cephalometric evaluation of pretreatment and post-treatment outcome using Tetragon analysis: a retrospective study.
Few cephalometric analyses have been put forward to assess the treatment outcome after orthodontic treatment. However, these analyses are somewhat complicated and time consuming. The Tetragon analysis is introduced with measurement of treatment outcome as one of its objectives. The study was undertaken to evaluate the treatment outcome by checking the skeletal and dental changes using pretreatment and post-treatment radiographs and to evaluate the efficiency of treatment in the Department of Orthodontics, College of Dental Sciences, Davangere, using the Tetragon analysis. Records of 35 finished patients with fixed orthodontic therapy using preadjusted edgewise appliance were selected. The samples were analyzed separately for the skeletal parameters consisting of skeletal class I, II and III using Tetragon analysis. The post-treatment reduction of upper incisor palatal plane angle was found to be statistically significant in skeletal class I (p < 0.01) and skeletal class II patients (p < 0.05). The post-treatment increase in interincisal angle was found to be statistically significant in skeletal class I (p < 0.01) class II patients (p < 0.05). Fixed appliance therapy reduced the proclination of upper incisors and increased the interincisal angle in skeletal class I and II cases but not in skeletal class III cases. The lower incisal angulation and the maxilla-mandibular plane angle did change significantly and so were the angles of the Trigon. The Tetragon analysis proved easy to measure the treatment outcome.


The nuclear chloride ion channel NCC27 is involved in regulation of the cell cycle.
NCC27 is a nuclear chloride ion channel, identified in the PMA-activated U937 human monocyte cell line. NCC27 mRNA is expressed in virtually all cells and tissues and the gene encoding NCC27 is also highly conserved. Because of these factors, we have examined the hypothesis that NCC27 is involved in cell cycle regulation. Electrophysiological studies in Chinese hamster ovary (CHO-K1) cells indicated that NCC27 chloride conductance varied according to the stage of the cell cycle, being expressed only on the plasma membrane of cells in G2/M phase. We also demonstrate that Cl- ion channel blockers known to block NCC27 led to arrest of CHO-K1 cells in the G2/M stage of the cell cycle, the same stage at which this ion channel is selectively expressed on the plasma membrane. These data strongly support the hypothesis that NCC27 is involved, in some as yet undetermined manner, in regulation of the cell cycle.


The use of immunohistologic analysis in differentiating cutaneous T-cell lymphoma from psoriasis and dermatitis.
--Many investigators have applied immunohistologic analysis to skin biopsy specimens to distinguish cutaneous T-cell lymphoma (CTCL) from benign inflammatory diseases, such as psoriasis and dermatitis, which can clinically mimic early-stage CTCL. We studied the number and distribution of epidermal cells labeled with various monoclonal antibodies in normal skin and in psoriatic, dermatitic, and CTCL lesions by the immunoperoxidase technique. --Extensive staining of keratinocytes (KCs) with HLA-DR was seen in 27 of 41 patients with CTCL, but in only one of 14 patients with psoriasis and zero of 10 patients with dermatitis. CD2+ and CD3+ cells were present in the middle and upper epidermis of CTCL lesions in much greater numbers than in normal, dermatitic, and psoriatic skin. The percent epidermal area covered by CD1+ cells in psoriatic lesions (1.13%) and dermatitic lesions (1.65%) was significantly lower than that found in CTCL lesions (3.60%). --Epidermal immunohistologic patterns using anti-CD1, anti-CD2, anti-CD3, and anti-HLA-DR antibodies have the potential to distinguish CTCL from psoriasis and dermatitis in clinically ambiguous cases.


An exploration of applicant perceptions of asynchronous video MMIs in medical selection.
This article was migrated. The article was marked as recommended. Over the last two decades, technological advancements internationally have meant that the Internet has become an important medium for recruitment and selection. Consequently, there is an increased need for research that examines the effectiveness of newer technology-mediated selection methods. This exploratory research study qualitatively explored applicant perceptions of fairness of asynchronous video interviews used in medical selection. Ten undergraduate medical students participated in a pilot asynchronous multiple-mini interview and were invited to share their experiences and perceptions in a follow-up interview. The data was transcribed verbatim and analysed using template analysis, with Gilliland's (1993) organisational justice theory guiding the original template. Many of the original themes from Gilliland's model were uncovered during analysis. Additionally, some significant themes were identified that did not form part of the original template and were therefore added to the final coding template - these were specifically relating to technology, including acceptability in a medical context; technical issues and adverse impact. Overall, results suggested that participants perceived asynchronous video interviews to be a fair method of selection. However, participants thought asynchronous interviews should only be used as part of an extensive selection process and furthermore, should not replace face-to-face interviews. Findings are discussed in line with existing research of fairness perceptions and justice theory in selection ( Gilliland, 1993) and implications for research and practice are presented.


Solid-state time-gated luminescence microscope with ultraviolet light-emitting diode excitation and electron-multiplying charge-coupled device detection.
Many naturally occurring materials are autofluorescent, a property that can reduce the discriminative ability of fluorescence methods, sometimes to the point where they cannot be usefully applied. Shifting from the spectral to the temporal domain, it is possible to discriminate fluorophores on the basis of their fluorescence decay lifetime. Luminophores with sufficiently long lifetimes can be discriminated from short-lived autofluorescence using time-gated luminescence (TGL). This technique relies upon the application of a brief excitation pulse followed by a resolving period to permit short-lived autofluorescence to decay, after which detection is enabled to capture persistent emission. In our studies, a high-power UV LED was mounted in the filter capsule of an Olympus BX51 microscope to serve as the excitation source. The microscope was fitted with an Andor DV885 electron-multiplying CCD (EM-CCD) camera with the trigger input synchronized to UV LED operation. Giardia lamblia cysts labeled with the europium chelate BHHST were analyzed against an autofluorescent background with the TGL microscope. The EM-CCD camera captured useful TGL images in real time with a single exposure cycle. With 4x frame averaging, images acquired in TGL mode showed a 30-fold improvement in SNR compared with conventional fluorescence microscopy.


Ascorbic acid attenuates the pressor response to voluntary apnea in postmenopausal women.
We recently demonstrated that postmenopausal women have an augmented blood pressure response to voluntary apnea compared to premenopausal women. Both obstructive sleep apnea (OSA) and healthy aging are associated with increased oxidative stress, which may impair cardiovascular function. Restoring physiological responses could have clinical relevance since transient surges in blood pressure are thought to be an important stimulus for end-organ damage in aging and disease. We tested the hypothesis that acute antioxidant infusion improves physiological responses to voluntary apnea in healthy postmenopausal women (n = 8, 64 ± 2 year). We measured beat-by-beat mean arterial pressure (MAP), heart rate (HR), and brachial artery blood flow velocity (BBFV, Doppler ultrasound) following intravenous infusion of normal saline and ascorbic acid (~3500 mg). Subjects performed maximal voluntary end-expiratory apneas and changes (Δ) from baseline were compared between infusions. The breath hold duration and oxygen saturation nadir were similar between saline (29 ± 6 sec, 94 ± 1%) and ascorbic acid (29 ± 5 sec, 94 ± 1%). Ascorbic acid attenuated the pressor response to voluntary apnea (ΔMAP: 6 ± 2 mmHg) as compared to saline (ΔMAP: 12 ± 2 mmHg, P = 0.034) and also attenuated forearm vasoconstriction (ΔBBFV: 4 ± 9 vs. -12 ± 7%, P = 0.049) but did not affect ΔHR. We conclude that ascorbic acid lowers the blood pressure response to voluntary apnea in postmenopausal women by inhibiting vasoconstriction in the limb vasculature. Whether ascorbic acid has similar effects in OSA patients remains to be prospectively tested.


Use of Virtual Reality Feedback for Patients with Chronic Neck Pain and Kinesiophobia.
This study examined how individuals with and without neck pain performed exercises under the influence of altered visual feedback in virtual reality. Chronic neck pain (n=9) and asymptomatic (n=10) individuals were recruited for this cross-sectional study. Participants performed head rotations while receiving programmatically manipulated visual feedback from a head-mounted virtual reality display. The main outcome measure was the control-display gain (ratio between actual head rotation angle and visual rotation angle displayed) recorded at the just-noticeable difference. Actual head rotation angles were measured for different gains. Detection of the manipulated visual feedback was affected by gain. The just-noticeable gain for asymptomatic individuals, below and above unity gain, was 0.903 and 1.159, respectively. Head rotation angle decreased or increased 5.45° for every 0.1 increase or decrease in gain, respectively. The just-noticeable gain for chronic pain individuals, below unity gain, was 0.950. The head rotation angle increased 4.29° for every 0.1 decrease in gain. On average, chronic pain individuals reported that neck rotation was feasible for 84% of the unity gain trials, 66% of the individual just-noticeable difference trials, and 50% of the "nudged" just-noticeable difference trials. This research demonstrated that virtual reality may be useful for promoting the desired outcome of increased range of motion in neck rehabilitation exercises by altering visual feedback.


The rate of internalization of different receptor-ligand complexes in alveolar macrophages is receptor-specific.
To probe the mechanisms of endocytosis in alveolar macrophages, we examined the internalization rates of three different receptors. Initial rates of internalization for mannosylated BSA, diferric transferrin and alpha-macroglobulin-proteinase complexes were all different. Although the absolute rates of internalization varied depending on the cell preparation, transferrin was internalized at 10-20% and alpha-macroglobulin-proteinase complex at 40-60% of the rate of manosylated-BSA. Incubation of cells with transferrin did not affect the rate of internalization of mannosylated BSA or alpha-macroglobulin-proteinase complexes, and the rates of internalization were independent of receptor occupancy. These different internalization rates could not be ascribed to different rates of diacytosis. Altering the distribution of unoccupied surface receptors by either trypsin treatment of cells at 0 degree C or exposure to hyperosmotic solutions resulted in the absolute internalization rates being affected by the experimental condition, but the hierarchy in receptor internalization rates was maintained. The fact that a variety of conditions affect receptor internalization rates to the same degree implies the existence of co-ordinate regulation at a single rate-limiting step. Based on these results, we suggest that differences in internalization rate reflect the ability of ligand-receptor complexes to be captured by coated pits.


Early physiological responses of Pinus pinea L. seedlings infected by Heterobasidion sp.pl. in an ozone-enriched atmospheric environment.
The presence of the American root-rot disease fungus Heterobasidion irregulare Garbel. & Otrosina was detected in Italian coastal pine forests (Pinus pinea L.) in addition to the common native species Heterobasidion annosum (Fries) Brefeld. High levels of tropospheric ozone (O3) as an atmospheric pollutant are usually experienced in Mediterranean pine forests. To explore the effect of interaction between the two Heterobasidion species and ozone pollution on P. pinea, an open-top chamber (OTC) experiment was carried out. Five-year-old P. pinea seedlings were inoculated with the fungal species considered (H. irregulare, H. annosum and mock-inoculation as control), and then exposed in charcoal-filtered open-top chambers (CF-OTC) and non-filtered ozone-enriched chambers (NF+) from July to the first week of August 2010 at the experimental facilities of Curno (North Italy). Fungal inoculation effects in an ozone-enriched environment were assessed as: (i) the length of the inoculation lesion; (ii) chlorophyll a fluorescence (ChlF) responses; and (iii) analysis of resin terpenes. Results showed no differences on lesion length between fungal and ozone treatments, whereas the short-term effects of the two stress factors on ChlF indicate an increased photosynthetic efficiency, thus suggesting the triggering of compensation/repair processes. The total amount of resin terpenes is enhanced by fungal infection of both species, but depressed by ozone to the levels observed in mock-inoculated plants. Variations in terpene profiles were also induced by stem base inoculations and ozone treatment. Ozone might negatively affect terpene defences making plants more susceptible to pathogens and insects.


Multifunctional PVCL nanogels with redox-responsiveness enable enhanced MR imaging and ultrasound-promoted tumor chemotherapy.
Development of versatile nanoplatforms that simultaneously integrate therapeutic and diagnostic features for stimuli-responsive delivery to tumors remains a great challenge. In this work, we report a novel intelligent redox-responsive hybrid nanosystem composed of MnO2 nanoparticles (NPs) and doxorubicin (DOX) co-loaded within poly(N-vinylcaprolactam) nanogels (PVCL NGs) for magnetic resonance (MR) imaging-guided and ultrasound-targeted microbubble destruction (UTMD)-promoted tumor chemotherapy. Methods: PVCL NGs were first synthesized via a precipitation polymerization method, decorated with amines using ethylenediamine, and loaded with MnO2 NPs through oxidation with permanganate and DOX via physical encapsulation and Mn-N coordination bonding. The as-prepared DOX/MnO2@PVCL NGs were well characterized. UTMD-promoted cellular uptake and therapeutic efficacy of the hybrid NGs were assessed in vitro, and a xenografted tumor model was used to test the NGs for MR imaging and UTMD-promoted tumor therapy in vivo.Results: The as-prepared DOX/MnO2@PVCL NGs with a size of 106.8 nm display excellent colloidal stability, favorable biocompatibility, and redox-responsiveness to the reductive intracellular environment and tumor tissues having a relatively high glutathione (GSH) concentration that can trigger the synchronous release of Mn2+ for enhanced T1-weighted MR imaging and DOX for enhanced cancer chemotherapy. Moreover, the DOX/MnO2@PVCL NGs upon the UTMD-promotion exhibit a significantly enhanced tumor growth inhibition effect toward subcutaneous B16 melanoma owing to the UTMD-improved cellular internalization and tumor penetration. Conclusion: Our work thereby proposes a promising theranostic nanoplatform for stimuli-responsive T1-weighted MR imaging-guided tumor chemotherapy.


Comprehensive modeling of cell culture profile using Raman spectroscopy and machine learning.
Chinese hamster ovary (CHO) cells are widely utilized in the production of antibody drugs. To ensure the production of large quantities of antibodies that meet the required specifications, it is crucial to monitor and control the levels of metabolites comprehensively during CHO cell culture. In recent years, continuous analysis methods employing on-line/in-line techniques using Raman spectroscopy have attracted attention. While these analytical methods can nondestructively monitor culture data, constructing a highly accurate measurement model for numerous components is time-consuming, making it challenging to implement in the rapid research and development of pharmaceutical manufacturing processes. In this study, we developed a comprehensive, simple, and automated method for constructing a Raman model of various components measured by LC-MS and other techniques using machine learning with Python. Preprocessing and spectral-range optimization of data for model construction (partial least square (PLS) regression) were automated and accelerated using Bayes optimization. Subsequently, models were constructed for each component using various model construction techniques, including linear regression, ridge regression, XGBoost, and neural network. This enabled the model accuracy to be improved compared with PLS regression. This automated approach allows continuous monitoring of various parameters for over 100 components, facilitating process optimization and process monitoring of CHO cells.


Skeletal Muscle Function Is Altered in Male Mice on Low-Dose Androgen Receptor Antagonist or Estrogen Receptor Agonist.
In males, skeletal muscle function may be altered by shifts in either circulating testosterone or estrogen. We examined the effect of acute (2-week) exposures to 17α-ethinyl estradiol (EE2), an estrogen receptor (ER) agonist, or flutamide, an androgen receptor (AR) antagonist, on the contractile function of individual skeletal muscle fibers from slow-contracting soleus and fast-contracting extensor digitorum longus muscles from adult male mice. Single fiber specific tension (force divided by cross-sectional area) was decreased with flutamide treatment in all myosin heavy chain (MHC) fiber types examined (I, IIA, and IIB); similar effects were observed with EE2 treatment but only in the fastest-contracting MHC IIB fibers. The decreases in maximally Ca2+-activated specific tension were primarily a result of fewer strongly bound myosin-actin cross-bridges, with flutamide treatment also showing lower myofilament lattice stiffness. Myosin-actin cross-bridge kinetics were slower in MHC IIA fibers in flutamide-treated mice, but faster in EE2-treated mice, indicating that contractile velocity may be affected differently in this fiber type, which is commonly expressed in human skeletal muscle. Importantly, these effects were observed in the absence of outcomes previously used to evaluate ER agonists or AR antagonists in rodents including weight of reproductive organs or mammary gland morphology. Our findings indicate that substantial shifts in skeletal muscle function occur in male mice following acute exposures to low doses of a pharmacological ER agonist and an AR antagonist. These results suggest that countermeasures to maintain physical function may be needed early in situations that induce similar ER agonist and AR antagonist conditions.


Histone deacetylase inhibitor BG45-mediated HO-1 expression induces apoptosis of multiple myeloma cells by the JAK2/STAT3 pathway.
Multiple myeloma (MM) is a hematological malignancy that is characterized by the clonal expansion of plasma cells in the bone marrow. Histone deacetylases (HDACs) represent a new type of molecular targeted therapy for different types of cancers and promising targets for myeloma therapy. We showed that HDAC3 mRNA and protein levels of CD138 mononuclear cells from MM patients were higher than those in healthy donors. Therefore, we investigated the effects of a novel class I HDAC inhibitor BG45 on MM cells in vitro. BG45 downmodulated heme oxygenase 1 (HO-1) when class I HDACs decreased in MM cells. HO-1 is a target for the treatment of MM. Moreover, BG45 induced hyperacetylation of histone H3 and inhibited the growth, especially the apoptosis of MM cell lines. Treatment with BG45 induced apoptosis by downregulating bcl-2 and Bcl-xl, upregulating Bax and other antiapoptotic proteins and activating poly(ADP-ribose)polymerase, and decreasing protein levels of p-JAK2 and p-STAT3. These effects were partly blocked by HO-1. Correspondingly, BG45 led to an accumulation in the G0/G1 phase, accompanied by decreased levels of CDK4 and phospho-retinoblastoma protein, an increased level of p21, and a moderately reduced level of CDK2. Clinical use of single agents was limited because of toxic side effects and drug resistance. However, combining BG45 with lenalidomide exerted synergistic effects. In conclusion, we verified the potent antimyeloma activity of this novel HDAC inhibitor and that the combination of BG45 and lenalidomide is a new method for MM treatment. Thus, BG45 may be applicable to the treatment of MM and other hematological malignancies.


Histopathological evaluation of infertility: Lessons from laboratory rodents.
Infertility is a growing challenge globally with emerging risk factors. There are effective laboratory tests to evaluate infertility in humans, nevertheless, some measures, especially histopathological evaluations, are invasive due to the pain inflicted when accessing the reproductive organs and obtaining samples; hence, their relevance may be limited in humans. However, these histopathological evaluations provide essential information on the etiopathogenesis of infertility and the likely mechanisms of action of potential therapeutic candidates. Also, non-invasive methods are available, such as the assay of testosterone in the blood and semen analysis, both of which are predictors of testicular functions. This review provides detailed information on the available histopathological investigations of infertility, such as qualitative and quantitative histopathological assessments of gonadal tissues, specific cell counts, and sperm morphology characterization, with a focus on the procedures, interpretation, and pathophysiological basis. Data from the literature revealed that histopathological examinations of the reproductive organs, as well as spermatozoa, are useful in understanding the pathogenesis of incident infertility. Histopathological evaluation may range from basic hematoxylin and eosin stains to some special stains. Also, histopathological findings (such as spermatogenic cells and planimetric variables, like seminiferous tubule diameter and theca cell and corpus luteum thickness) may be quantified and analyzed for comparison. Some skill is required for these investigations, which may be a limiting factor; however, they are important tools in translational medicine.


[A functional gene map is required to adapt therapy of metastatic neuroblastoma].
Neuroblastoma is a very common solid tumor which arises in childhood and shows an extreme heterogeneity at the clinical, histological and genetic levels. Besides age and stage, N-myc amplification and 1p deletion are prognostic factors of the disease: in Europe, these genetic markers are used to conduct therapy. In France, N-myc amplification is a factor of bad prognosis which leads, in all forms of the disease including localised forms and metastatic forms of children aged of less than 1 year, to a myeloablative treatment with autologous hematopoietic stem cells transplantation. By contrast, N-myc amplification has no impact on the survival of children aged of more than 1 year with a poor prognosis (30% overall survival, 5 years) but this genetic abnormality is taken into account to treat primary tumor of these patients. In an attempt to find out prognostic factors of these aggressive forms of the disease, various pathways (apoptosis, differentiation angiogenesis, detoxication, immune response) have been recently surveyed, but studies have been carried out on a limited number of genes. Moreover, experimental models of human metastatic neuroblastoma have been obtained in which variations of genes transcript levels involved in these pathways, are observed. The current break-through of cDNA microarrays allows to develop a dynamic transcriptomic scanning of these models as well as of tumors and bone marrows from patients upon conventional chemotherapy. This technology will enable: i) to define molecular entities of the metastatic disease; ii) to apply adapted treatment; iii) to develop new therapeutic strategies.


Prevalence of chronic kidney disease in the Japanese general population.
We previously estimated the prevalence of chronic kidney disease (CKD) stages 3-5 at 19.1 million based on data from the Japanese annual health check program for 2000-2004 using the Modification of Diet in Renal Disease (MDRD) equation multiplied by the coefficient 0.881 for the Japanese population. However, this equation underestimates the GFR, particularly for glomerular filtration rates (GFRs) of over 60 ml/min/1.73 m(2). We did not classify the participants as CKD stages 1 and 2 because we did not obtain proteinuria data for all of the participants. We re-estimated the prevalence of CKD by measuring proteinuria using a dipstick test and by calculating the GFR using a new equation that estimates GFR based on data from the Japanese annual health check program in 2005. Data were obtained for 574,024 (male 240,594, female 333,430) participants over 20 years old taken from the general adult population, who were from 11 different prefectures in Japan (Hokkaido, Yamagata, Fukushima, Tochigi, Ibaraki, Tokyo, Kanazawa, Osaka, Fukuoka, Miyazaki and Okinawa) and took part in the annual health check program in 2005. The glomerular filtration rate (GFR) of each participant was computed from the serum creatinine value using a new equation: GFR (ml/min/1.73 m(2)) = 194 x Age(-0.287) x S-Cr(-1.094) (if female x 0.739). The CKD population nationwide was calculated using census data from 2005. We also recalculated the prevalence of CKD in Japan assuming that the age composition of the population was same as that in the USA. The prevalence of CKD stages 1, 2, 3, and 4 + 5 were 0.6, 1.7, 10.4 and 0.2% in the study population, which resulted in predictions of 0.6, 1.7, 10.7 and 0.2 million patients, respectively, nationwide. The prevalence of low GFR was significantly higher in the hypertensive and proteinuric populations than it was in the populations without proteinuria or hypertension. The prevalence rate of CKD in Japan was similar to that in the USA when the Japanese general population was age adjusted to the US 2005 population estimate. About 13% of the Japanese adult population-approximately 13.3 million people-were predicted to have CKD in 2005.


Stretchable, curvilinear electronics based on inorganic materials.
All commercial forms of electronic/optoelectronic technologies use planar, rigid substrates. Device possibilities that exploit bio-inspired designs or require intimate integration with the human body demand curvilinear shapes and/or elastic responses to large strain deformations. This article reviews progress in research designed to accomplish these outcomes with established, high-performance inorganic electronic materials and modest modifications to conventional, planar processing techniques. We outline the most well developed strategies and illustrate their use in demonstrator devices that exploit unique combinations of shape, mechanical properties and electronic performance. We conclude with an outlook on the challenges and opportunities for this emerging area of materials science and engineering.


Simulations of supercooled water under passive or active stimuli.
We use molecular dynamics simulations to study the behavior of supercooled water subject to different stimuli from a diluted azobenzene hydrophobic probe. When the molecular motor does not fold, it acts as a passive probe, modifying the structure of water around it, while when the motor is active, it induces elementary diffusion processes inside the medium acting mainly on the dynamics. We study two particular densities, the density of ambient water and a lower density around the ambient pressure ice density, chosen to favor high density liquid and low density liquid (LDL) water, respectively. We find that the passive probe induces ever an acceleration or a slowing down of the diffusion process around it depending on the density of water, while the active probe induces acceleration only. We find a crossover between the diffusion coefficients for the two densities near the passive probe, around T = 215 K. This dynamical crossover is associated with a modification of the structure of water near the probe. Structure calculations show a crossover of the proportion of LDL water around the same temperature, suggesting that it induces the observed dynamical crossover. In opposition with these results, the active stimuli increase diffusion for both densities and decrease the proportion of LDL water at low temperatures. However, we also find for the active stimuli a crossover of the LDL proportion between the two densities of study, showing remarkable similarities between active and passive stimulus results.


Community leadership and participation in the Saradidi, Kenya, rural health development programme.
Community participation and leadership in initiating and implementing a health development programme in Saradidi, Kenya were examined. Organization of the area into villages had to be sensitive to existing community organizational structures such as geography, religion, kinship and administrative boundaries. The lowest level government leaders did not always have the support of the community. Some groups such as women and those who were not wealthy were not always included in leadership positions; these people, however, were often most aware of certain village problems. In Saradidi, women's groups were important for community development; they supported the volunteer community health workers and carried out many village health activities. Many village health committees did not function effectively. Village health workers were supported principally by the programme centre. Village income-generating activities were not very successful. Group involvement in income raising ventures proved to be inefficient; many ended up as income draining activities. Village group income projects must be well selected relative to the skills and resources available and the ability of the product to be marketed; only exceptional ones should be encouraged. Those based at the programme's centre were more successful perhaps because of a greater investment in skills, money and marketing. Age was an important factor in accepted leadership roles in Saradidi; most effective leaders were more than 45 years of age. Village health helpers volunteered a significant proportion of their time despite poor support by village health committees and no financial remuneration. The central project structure and the training they received compensated for the lack of guidance by village health committees.


Rhesus immune responses to SIV Gag expressed by recombinant BCG vectors are independent from pre-existing mycobacterial immunity.
A recombinant Mycobacterium bovis BCG (rBCG) vector expressing HIV transgenes is an attractive candidate as a dual vaccine against HIV and TB. However, pre-existing immune responses to mycobacteria may influence immune responses to rBCG. We analyzed data from a rhesus rBCG trial to determine the effect of pre-existing mycobacterial immune responses on the vaccine-induced responses to the vector and expressed transgene. Indian-origin rhesus macaques were primed with rBCG expressing simian immunodeficiency virus (SIV) Gag and boosted with attenuated vaccinia NYVAC gag-pol. Mycobacteria responses were measured by Mycobacterium tuberculosis (Mtb) purified protein derivative (PPD) interferon-γ ELISpot and Mtb whole cell lysate (WCL) ELISA. SIV Gag responses were measured by SIV Gag ELISpot and by p11C tetramer binding. Baseline Mtb PPD ELISpot responses and Mtb WCL antibody responses in rhesus macaques overlapped those in human populations. Cellular and antibody responses boosted sharply 4 weeks after rBCG vaccination. Mtb WCL antibody titers at 4 weeks correlated with baseline titers. Primates vaccinated with rBCG developed strong SIV Gag ELISpot and p11C tetramer responses after rBCG prime and NYVAC boost. There were no correlations between the pre-existing mycobacterial immune responses and the SIV Gag T cell responses after vaccination. Rhesus immune responses to SIV Gag expressed by rBCG vectors were independent from pre-existing anti-mycobacterial immunity. Rhesus macaques may serve as a surrogate for investigations of pre-existing anti-mycobacterial immunity in humans.


Divergent vascular mechanisms downstream of Sry establish the arterial system in the XY gonad.
Although the primitive vasculature is identical in XX and XY genital ridges until 11.5 days postcoitum (dpc), by 12.5 dpc the XY gonad develops a distinct vasculature. This male-specific vasculature, which includes the development of a large coelomic vessel, develops coincident with expression of Sry and formation of testis cords. We show that similar levels of proliferation and vasculogenesis expand the primary vasculature in XX and XY gonads. However, soon after Sry expression begins, the XY gonad recruits a large number of endothelial cells from the adjacent mesonephros, a mechanism totally absent in XX gonads. These migrating cells do not contribute to venous or lymphatic development. Instead, these cells contribute to the arterial system, as indicated by expression of ephrinB2 and by elements of the Notch signaling pathway. This newly formed arterial system establishes a new pattern of blood flow in the XY gonad, which we speculate may have an important role in export of testosterone to masculinize the XY embryo.


Dementia Risk and Protective Factors Differ in the Context of Memory Trajectory Groups.
Previous research has identified multiple risk and protective factors for late onset Alzheimer's disease (LOAD). However, it is not known whether these risk and protective factors differ for individuals who are cognitively stable versus those already experiencing declines. This study examined how dementia risk factors differ across subgroups of older adults defined by memory trajectory. This line of research may lead to more individualized risk profiles. Risk factors for incident LOAD were compared across previously-validated groups of older adults exhibiting different memory trajectories ("Stable-High," "Stable-Low," "Decliner," "Rapid Decliner") using stratified Cox regressions. Participants included 2,593 racially/ethnically diverse older adults (mean age of 76 at study entry) in the Washington Heights-Inwood Columbia Aging Project. Predictors of incident dementia differed across trajectory groups: older age only incurred independent risk in stable groups, education did not incur independent protection in the rapidly declining group, depression only incurred independent risk in the stable-low group, stroke incurred independent risk in the two extreme groups, and APOE-ɛ4 only incurred independent risk in the rapidly declining group. The finding that different risk factors for LOAD were associated with specific memory trajectories may reflect the existence of resilience or vulnerability factors that modify the individual influences of risk/protective factors. This study highlights the utility of considering interactions between dementia risk factors and a patient's unique cognitive history.


Alterations in lung volume and pulmonary function in relation to hemodynamic changes in acute myocardial infarction.
To characterize the changes in lung volumes after acute myocardial infarction (AMI), and the relationship of these changes to other alterations in lung function which correlate with the severity of pulmonary vascular congestion, we made measurements of pulmonary hemodynamics, lung volume, closing volume, frequency dependence of total pulmonary resistance to forced oscillation, and arterial PO2 in 18 subjects with AMI. The most consistent finding was reduced lung volume which correlated with the severity of pulmonary diastolic hypertension. Frequency dependence of resistance showed a small but significant correlation with pulmonary hemodynamics. Closing volume measurements by the resident gas method in nine subjects was not related to hemodynamics. Follow-up studies at the time of hospital discharge revealed a significant return toward normal for arterial PO2, all lung volumes, and total pulmonary resistance at 9 Hz. Based on measurements in healthy subjects, the reduced lung volume after AMI may explain the changes in resistance. In acute and follow-up studies the degree of lung volume reduction and the severity of hypoxemia were strongly correlated.


The Regulation of Cbf1 by PAS Kinase Is a Pivotal Control Point for Lipogenesis vs. Respiration in Saccharomyces cerevisiae.
PAS kinase 1 (Psk1) is a key regulator of respiration in Saccharomyces cerevisiae Herein the molecular mechanisms of this regulation are explored through the characterization of its substrate, Centromere binding factor 1 (Cbf1). CBF1-deficient yeast displayed a significant decrease in cellular respiration, while PAS kinase-deficient yeast, or yeast harboring a Cbf1 phosphosite mutant (T211A) displayed a significant increase. Transmission electron micrographs showed an increased number of mitochondria in PAS kinase-deficient yeast consistent with the increase in respiration. Although the CBF1-deficient yeast did not appear to have an altered number of mitochondria, a mitochondrial proteomics study revealed significant differences in the mitochondrial composition of CBF1-deficient yeast including altered Atp3 levels, a subunit of the mitochondrial F1-ATP synthase complex. Both beta-galactosidase reporter assays and western blot analysis confirmed direct transcriptional control of ATP3 by Cbf1 In addition, we confirmed the regulation of yeast lipid genes LAC1 and LAG1 by Cbf1 The human homolog of Cbf1, Upstream transcription factor 1 (USF1), is also known to be involved in lipid biogenesis. Herein, we provide the first evidence for a role of USF1 in respiration since it appeared to complement Cbf1 in vivo as determined by respiration phenotypes. In addition, we confirmed USF1 as a substrate of human PAS kinase (hPASK) in vitro Combined, our data supports a model in which Cbf1/USF1 functions to partition glucose toward respiration and away from lipid biogenesis, while PAS kinase inhibits respiration in part through the inhibition of Cbf1/USF1.


Geophysical signatures of soil AFFF contamination from spectral induced polarization and low field nuclear magnetic resonance methods.
Few field methods are available for characterizing source zones impacted with aqueous film forming foam (AFFF). Non-invasive geophysical characterization of AFFF source zone contamination in situ could assist with the delineation and characterization of these sites, allowing for more informed sampling regimes aimed at quantifying subsurface poly- and perfluoroalkyl substances (PFAS) contamination. We present initial results from the investigation of the sensitivity of two existing surface and borehole-deployable geophysical technologies, spectral induced polarization (SIP), and low field nuclear magnetic resonance (NMR), to soils impacted with AFFF. To investigate the sensitivity of these methods to AFFF-impacted soil, bench-scale column experiments were conducted on samples consisting of natural and synthetic soils and groundwater. While our findings do not show strong evidence of NMR sensitivity to soil PFAS contamination, we do find evidence that SIP has sufficient sensitivity to detect sorption of AFFF constituents (including PFAS) to soils. This finding is based on evidence that AFFF constituents associated with the pore surface produce a measurable polarization response in both freshly impacted synthetic soils and in soils historically impacted with AFFF. Our findings encourage further exploration of the SIP method as a technology for characterizing contaminant concentrations across AFFF source zones.


IRE1α Disruption in Triple-Negative Breast Cancer Cooperates with Antiangiogenic Therapy by Reversing ER Stress Adaptation and Remodeling the Tumor Microenvironment.
Cancer cells exploit the unfolded protein response (UPR) to mitigate endoplasmic reticulum (ER) stress caused by cellular oncogene activation and a hostile tumor microenvironment (TME). The key UPR sensor IRE1α resides in the ER and deploys a cytoplasmic kinase-endoribonuclease module to activate the transcription factor XBP1s, which facilitates ER-mediated protein folding. Studies of triple-negative breast cancer (TNBC)-a highly aggressive malignancy with a dismal posttreatment prognosis-implicate XBP1s in promoting tumor vascularization and progression. However, it remains unknown whether IRE1α adapts the ER in TNBC cells and modulates their TME, and whether IRE1α inhibition can enhance antiangiogenic therapy-previously found to be ineffective in patients with TNBC. To gauge IRE1α function, we defined an XBP1s-dependent gene signature, which revealed significant IRE1α pathway activation in multiple solid cancers, including TNBC. IRE1α knockout in TNBC cells markedly reversed substantial ultrastructural expansion of their ER upon growth in vivo. IRE1α disruption also led to significant remodeling of the cellular TME, increasing pericyte numbers while decreasing cancer-associated fibroblasts and myeloid-derived suppressor cells. Pharmacologic IRE1α kinase inhibition strongly attenuated growth of cell line-based and patient-derived TNBC xenografts in mice and synergized with anti-VEGFA treatment to cause tumor stasis or regression. Thus, TNBC cells critically rely on IRE1α to adapt their ER to in vivo stress and to adjust the TME to facilitate malignant growth. TNBC reliance on IRE1α is an important vulnerability that can be uniquely exploited in combination with antiangiogenic therapy as a promising new biologic approach to combat this lethal disease. SIGNIFICANCE: Pharmacologic IRE1α kinase inhibition reverses ultrastructural distension of the ER, normalizes the tumor vasculature, and remodels the cellular TME, attenuating TNBC growth in mice.


Assessment of Fixation of Mandibular Interforaminal Fractures by Using a Single Second-Generation Headless Compression Screw: A Pilot Study.
The aim of this article is to evaluate the efficacy of a single second-generation headless compression screw along with a lower arch bar in the fixation of interforaminal mandible fractures. A total of seven patients were included in the study. An open approach was used either intraorally or extraorally. A second-generation 3.0 HCS (headless compression screw), 24 to 32 mm in length, diameter at the head of 3.5 mm, smooth shaft with 2.0 mm and at the leading edge 3.0 mm (Synthes, Paoli, PA) was used for the fixation along with a lower arch bar. Postoperative clinical and radiographic follow-up was performed at 3 weeks, 3 months, 6 months, and 1 year. A single, cannulated HCS was found to be effective in fixation of interforaminal mandible fractures except in one case where a miniplate had to be applied subapically. Clinical and radiographic follow-up revealed accurate reduction and fixation in all cases and no postoperative occlusal disturbances. A single, second-generation HCS along with a lower arch bar provides good results when used for the fixation of interforaminal mandible fractures. Headless compression screw fixation of interforaminal mandible fracture is a simple, quick, economic, and efficient method of rigid fixation with minimum complications.


Protection of dystrophic muscle cells using Idebenone correlates with the interplay between calcium, oxidative stress and inflammation.
There is strong cross-talk between abnormal intracellular calcium concentration, high levels of reactive oxygen species (ROS) and an exacerbated inflammatory process in the dystrophic muscles of mdx mice, the experimental model of Duchenne muscular dystrophy (DMD). In this study, we investigated effects of Idebenone, a potent anti-oxidant, on oxidative stress markers, the anti-oxidant defence system, intracellular calcium concentrations and the inflammatory process in primary dystrophic muscle cells from mdx mice. Dystrophic muscle cells were treated with Idebenone (0.05 μM) for 24 h. The untreated mdx muscle cells were used as controls. The MTT assay showed that Idebenone did not have a cytotoxic effect on the dystrophic muscle cells. The Idebenone treatment was able to reduce the levels of oxidative stress markers, such as H2 O2 and 4-HNE, as well as decreasing intracellular calcium influx in the dystrophic muscle cells. Regarding Idebenone effects on the anti-oxidant defence system, an up-regulation of catalase levels, glutathione reductase (GR), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity was observed in the dystrophic muscle cells. In addition, the Idebenone treatment was also associated with reduction in inflammatory molecules, such as nuclear factor kappa-B (NF-κB) and tumour necrosis factor (TNF) in mdx muscle cells. These outcomes supported the use of Idebenone as a protective agent against oxidative stress and related signalling mechanisms involved in dystrophinopathies, such as DMD.


Therapeutic Potential of Minor Cannabinoids in Dermatological Diseases-A Synthetic Review.
Dermatological diseases pose a significant burden on the quality of life of individuals and can be challenging to treat effectively. In this aspect, cannabinoids are gaining increasing importance due to their therapeutic potential in various disease entities including skin diseases. In this synthetic review, we comprehensively analyzed the existing literature in the field of potential dermatological applications of a lesser-known subgroup of cannabinoids, the so-called minor cannabinoids, such as cannabidivarin (CBDV), cannabidiforol (CBDP), cannabichromene (CBC), tetrahydrocannabivarin (THCV), cannabigerolic acid (CBGA), cannabigerol (CBG), cannabielsoin (CBE), cannabimovone (CBM) or cannabinol (CBN), while drawing attention to their unique pharmacological properties. We systematically searched the available databases for relevant studies and analyzed the data to provide an overview of current thematic knowledge. We looked through the full-text, bibliographic and factographic databases, especially Scopus, Web of Science, PubMed, Polish Scientific Journals Database, and selected the most relevant papers. Our review highlights that minor cannabinoids exhibit diverse pharmacological activities, including anti-inflammatory, analgesic, antimicrobial, and anti-itch properties. Several studies have reported their efficacy in mitigating symptoms associated with dermatological diseases such as psoriasis, eczema, acne, and pruritus. Furthermore, minor cannabinoids have shown potential in regulating sebum production, a crucial factor in acne pathogenesis. The findings of this review suggest that minor cannabinoids hold therapeutic promise in the management of dermatological diseases. Further preclinical and clinical investigations are warranted to elucidate their mechanisms of action, determine optimal dosage regimens, and assess long-term safety profiles. Incorporating minor cannabinoids into dermatological therapies could potentially offer novel treatment options of patients and improve their overall well-being.


Effectiveness of off-the-shelf footwear in reducing foot pain in Australian Department of Veterans' Affairs recipients not eligible for medical grade footwear: study protocol for a randomized controlled trial.
Foot pain is highly prevalent in older people, and in many cases is associated with wearing inadequate footwear. In Australia, the Department of Veterans' Affairs (DVA) covers the costs of medical grade footwear for veterans who have severe foot deformity. However, there is a high demand for footwear by veterans with foot pain who do not meet this eligibility criterion. Therefore, this article describes the design of a randomized controlled trial to evaluate the effectiveness of low cost, off-the-shelf footwear in reducing foot pain in DVA recipients who are currently not eligible for medical grade footwear. One hundred and twenty DVA clients with disabling foot pain residing in Melbourne, Australia, who are not eligible for medical grade footwear will be recruited from the DVA database, and will be randomly allocated to an intervention group or a 'usual care' control group. The intervention group will continue to receive their usual DVA-subsidized podiatry care in addition to being provided with low-cost, supportive footwear (Dr Comfort®, Vasyli Medical, Labrador, Queensland, Australia). The control group will also continue to receive DVA-subsidized podiatry care, but will not be provided with the footwear until the completion of the study. The primary outcome measure will be pain subscale on the Foot Health Status Questionnaire (FHSQ), measured at baseline and 4, 8, 12 and 16 weeks. Secondary outcome measures measured at baseline and 16 weeks will include the function subscale of the FHSQ, the Manchester Foot Pain and Disability Index, the number of DVA podiatry treatments required during the study period, general health-related quality of life (using the Short Form 12® Version 2.0), the number of falls experienced during the follow-up period, the Timed Up and Go test, the presence of hyperkeratotic lesions (corns and calluses), the number of participants using co-interventions to relieve foot pain, and participants' perception of overall treatment effect. Data will be analyzed using the intention-to-treat principle. This study is the first randomized controlled trial to evaluate the effectiveness of off-the-shelf footwear in reducing foot pain in DVA recipients. The intervention has been pragmatically designed to ensure that the study findings can be implemented into policy and clinical practice if found to be effective. Australian New Zealand Clinical Trials Registry: ACTRN12612000322831.


Methotrexate inhibition of inducible nitric oxide synthase in murine lung epithelial cells in vitro.
Nitric oxide (NO) is produced in lung epithelial cells by nitric oxide synthases (NOSs), which can enhance inflammation and edema formation. The inducible NOS (iNOS, type II NOS) has been shown to be increased in lung disorders such as asthma. Therapy for asthma includes antiinflammatory agents such as corticosteroids and antineoplastic agents such as methotrexate (MTX). We hypothesized that NO production by epithelial cells in vitro would be attenuated by MTX, and that this effect would be additive with corticosteroids. In order to test this hypothesis, cells from the murine lung epithelial-cell line LA-4 were cultured to confluence and stimulated to express iNOS and produce NO by cytomix, a combination of human tumor necrosis factor-alpha (TNF-alpha), human interleukin-1beta (IL-1beta) and murine interferon-gamma (IFN-gamma). Nitrite and nitrite + nitrate were measured in the culture supernatant fluids as an index of NO production. MTX caused a dose- and time-dependent inhibition of nitrite and nitrite + nitrate (P < 0.05, all comparisons). Importantly, the inhibition of NO production by MTX (10(-3) M) was additive with dexamethasone (10(-5) to 10(-9) M), but cyclophosphamide, bleomycin, and cytosine-beta-D-arabinofuranoside (Ara-C), other antineoplastic agents, caused no inhibition of NO production. To investigate the mechanism of NO inhibition with MTX, we added tetrahydrobiopterin, which reversed the inhibition. MTX had no effect on the expression of iNOS on Western blotting or iNOS mRNA on Northern blotting. These data show that MTX inhibits NO production by iNOS in murine lung epithelial cells in vitro and that MTX produces added inhibition with corticosteroids, and suggest a potential strategy for reducing NO production in vivo.


Screening methods for influenza antiviral drug discovery.
Influenza antiviral high-throughput screens have been extensive, and yet no approved influenza antivirals have been identified through high-throughput screening. This underscores the idea that development of successful screens should focus on the exploitation of the underrepresented viral targets and novel, therapeutic host targets. The authors review conventional screening applications and emerging technologies with the potential to enhance influenza antiviral discovery. Real-world examples from the authors' work in biocontained environments are also provided. Future innovations are discussed, including the use of targeted libraries, multiplexed assays, proximity-based endpoint methods, non-laboratory-adapted virus strains, and primary cells, for immediate physiological relevance and translational applications. The lack of successful anti-influenza drug discovery using high-throughput screening should not deter future efforts. Increased understanding of the functions of viral targets and host-pathogen interactions has broadened the target reservoir. Future screening efforts should focus on identifying new drugs against unexploited viral and host targets using currently developed assays, and on the development of novel, innovative assays to discover new drugs with novel mechanisms. Innovative screens must be designed to identify compounds that specifically inhibit protein-protein or protein-RNA interactions or other virus/host factor interactions that are crucial for viral replication. Finally, the use of recent viral isolates, increased biocontainment (for highly-pathogenic strains), primary cell lines, and targeted compound libraries must converge in efficient high-throughput primary screens to generate high-content, physiologically-relevant data on compounds with robust antiviral activity.


[What may be expected from endorectal ultrasonography and magnetic resonance imaging in the assessment of local extension of cancer of the prostate?].
30 patients presenting with a clinical stage A or B cancer underwent TRUS and MRI with a body coil prior to radical prostatectomy. Imaging and pathology were correlated to assess the limits of TRUS and MRI in pre-operative staging of prostatic carcinoma. Results showed that TRUS and MRI had a sensitivity of 42 and 66% and a specificity of 89 and 94% respectively, for the diagnosis of macroscopic capsular effraction. Seminal vesicle invasion was diagnosed by TRUS with a sensitivity of 16% and a specificity of 81%. With MRI, the sensitivity and the specificity were 85 and 94% if only gross infiltration was considered. Sensitivity dropped to 45% if microscopic invasion was included. We conclude that: (1) postero-lateral venous plexus are more easily delineated by MRI, permitting a more accurate diagnosis of capsular penetration. (2) Seminal vesicle invasion cannot be diagnosed by TRUS as the echostructure of the cancer and the caudal junction of the seminal vesicles and vas deferens are similar. (3) A normal caudal junction on TRUS or a normal bilateral hypersignal of the seminal vesicles on MRI are associated with seminal vesicle invasion in less than 5% of cases. (4) A normal caudal junction on TRUS eliminates false positive cases of MRI related to non tumoral hyposignals of the seminal vesicles.


Environmental and chemical carcinogenesis.
People are continuously exposed exogenously to varying amounts of chemicals that have been shown to have carcinogenic or mutagenic properties in experimental systems. Exposure can occur exogenously when these agents are present in food, air or water, and also endogenously when they are products of metabolism or pathophysiologic states such as inflammation. It has been estimated that exposure to environmental chemical carcinogens may contribute significantly to the causation of a sizable fraction, perhaps a majority, of human cancers, when exposures are related to "life-style" factors such as diet, tobacco use, etc. This chapter summarizes several aspects of environmental chemical carcinogenesis that have been extensively studied and illustrates the power of mechanistic investigation combined with molecular epidemiologic approaches in establishing causative linkages between environmental exposures and increased cancer risks. A causative relationship between exposure to aflatoxin, a strongly carcinogenic mold-produced contaminant of dietary staples in Asia and Africa, and elevated risk for primary liver cancer has been demonstrated through the application of well-validated biomarkers in molecular epidemiology. These studies have also identified a striking synergistic interaction between aflatoxin and hepatitis B virus infection in elevating liver cancer risk. Use of tobacco products provides a clear example of cancer causation by a life-style factor involving carcinogen exposure. Tobacco carcinogens and their DNA adducts are central to cancer induction by tobacco products, and the contribution of specific tobacco carcinogens (e.g. PAH and NNK) to tobacco-induced lung cancer, can be evaluated by a weight of evidence approach. Factors considered include presence in tobacco products, carcinogenicity in laboratory animals, human uptake, metabolism and adduct formation, possible role in causing molecular changes in oncogenes or suppressor genes, and other relevant data. This approach can be applied to evaluation of other environmental carcinogens, and the evaluations would be markedly facilitated by prospective epidemiologic studies incorporating phenotypic carcinogen-specific biomarkers. Heterocyclic amines represent an important class of carcinogens in foods. They are mutagens and carcinogens at numerous organ sites in experimental animals, are produced when meats are heated above 180 degrees C for long periods. Four of these compounds can consistently be identified in well-done meat products from the North American diet, and although a causal linkage has not been established, a majority of epidemiology studies have linked consumption of well-done meat products to cancer of the colon, breast and stomach. Studies employing molecular biomarkers suggest that individuals may differ in their susceptibility to these carcinogens, and genetic polymorphisms may contribute to this variability. Heterocyclic amines, like most other chemical carcinogens, are not carcinogenic per se but must be metabolized by a family of cytochrome P450 enzymes to chemically reactive electrophiles prior to reacting with DNA to initiate a carcinogenic response. These same cytochrome P450 enzymes--as well as enzymes that act on the metabolic products of the cytochromes P450 (e.g. glucuronyl transferase, glutathione S-transferase and others)--also metabolize chemicals by inactivation pathways, and the relative amounts of activation and detoxification will determine whether a chemical is carcinogenic. Because both genetic and environmental factors influence the levels of enzymes that metabolically activate and detoxify chemicals, they can also influence carcinogenic risk. Many of the phenotypes of cancer cells can be the result of mutations, i.e., changes in the nucleotide sequence of DNA that accumulate as tumors progress. These can arise as a result of DNA damage or by the incorporation of non-complementary nucleotides during DNA synthetic processes. Based upon the disparity between the infrequency of spontaneous mutations and the large numbers of mutations reported in human tumors, it has been postulated that cancers must exhibit a mutator phenotype, which would represent an early event in cancer progression. A mutator phenotype could be generated by mutations in genes that normally function to guarantee genetic stability. These mutations presumably arise via DNA damage by environmental or endogenous agents, but it remains to be determined whether the acquisition of a mutator phenotype is a necessary event during tumor progression.


The effect of calcitonin on the prechordal mesoderm, neural plate and neural crest of Xenopus embryos.
Developing Xenopus embryos treated during gastrulation with 22 micrograms/l of salmar calcitonin in the ambient water develop into larvae exhibiting a decrease in interocular distance. In view of the hypocalcaemic properties of calcitonin and the importance of calcium ions in cell aggregation, this phenomenon has been attributed to an alteration in cell adhesion which results in faulty cell migration during gastrulation with consequent abnormalities of the prechordal region of the archenteron roof and the overlying neural plate. Histological examination of affected specimens shows that the principal defect arising from the prechordal mesoderm and prechordal plate is aglossia and a severely reduced oral cavity. This results in narrowing of the head and consequent decrease in interocular distance. Accompanying this effect is distortion of the diencephalon and third ventricle, which may indicate faulty induction of the neural plate by the perturbed subjacent prechordal region.


Assessment of pain in women randomly allocated to speculum or digital insertion of the Foley catheter for induction of labor.
The primary aim was to assess pain subjectively and objectively in women during insertion of a Foley catheter for induction of labor. A secondary aim was to assess pain during cervical ripening and to evaluate maternal satisfaction. Randomized controlled trial. University hospital, Sweden. Forty-two women undergoing induction of labor and cervical ripening with a Foley catheter. Women were randomly allocated to digital (n=21) or to speculum (n=21) placement of a Foley catheter. A visual analogue scale (VAS) was used for subjective assessment of pain and, for objective measurements, a skin conductance algesimeter was used and the area under the curve (AUC) was calculated (μSs). Maternal satisfaction was evaluated in a questionnaire. Pain sensation during placement of the Foley catheter. There was a significant difference between groups in pain measurements during insertion of the Foley catheter. The speculum group had higher median pain scores than the digital group, VAS=5 vs. = 3 (p=0.03) and greater median AUC measurements: 1840 vs. 823 μSs (p=0.04). There was no difference in pain assessments during cervical ripening. Overall satisfaction scores were high and comparable between groups. Digital placement of the Foley catheter is subjectively and objectively less painful compared to the use of a speculum. Digital placement should therefore be considered as an alternative in the management of these patients. Ripening of the cervix with the Foley catheter is well tolerated and the overall satisfaction rate among patients induced with this method is high.


What factors influence concordance with medications? Findings from the U.K. Asian Diabetes study.
To investigate concordance with medication, as assessed at baseline and at 1- and 2-year follow-up, and to examine factors associated with non-concordance in a UK-resident South-Asian population. Data from the UK Asian Diabetes Study were analysed. Concordance with medications was assessed and recorded at three time points during the study. Multiple logistic regression was used to investigate the factors associated with non-concordance; the associations of baseline factors with year 1 concordance and baseline plus year 1 factors with year 2 concordance. Data for 403 patients from seven practices participating in the UK Asian Diabetes Study were analysed. The numbers of patients who were non-concordant were: 63 (16%) at baseline; 101 (25%) at year 1; and 122 (30%) at year 2. The baseline-measured variables that were significantly associated with year 1 non-concordance included diabetes duration, history of cardiovascular disease, components of the EuroQol quality of life questionnaire, the EQ-5D score, and number of medications prescribed. In multivariable analyses, the most important determinant of year 1 non-concordance was baseline non-concordance: odds ratio 13.6 (95% confidence limits 4.7, 39.9). Number of medications prescribed for blood pressure control was also significant: odds ratio 1.8 (95% confidence limits 1.4, 2.4). Similar results were observed for year 2 non-concordance. Non-concordance with medications was common and more likely in people prescribed more medications. The current target-driven management of risk factor levels may lead to increasing numbers and doses of medications. Considering the high cost of medications and the implications of poor health behaviours on morbidity and mortality, further investigation of prescribing behaviours and the factors affecting patient concordance are required.


[Carboxymethylcellulose hydrogel-filled breast implants. Our experience in 15 years].
The author reports 15 years of laboratory and surgical experience with the use of breast implants pre-filled with carboxy-methyl-cellulose gel which he has used since 1984. Laboratory tests and results are presented. The author has undertaken a retrospective analysis of 380 clinical cases since 1984. He concludes that there is a future role for breast implants containing a non-toxic, visco-elastic and biodegradable filling gel in conjunction with the manufacture of increasingly reliable implant linings.


Effects of Two Years of Calorie Restriction on Aerobic Capacity and Muscle Strength.
Calorie restriction (CR) improves health span and delays age-related diseases in many species. The multicenter Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) study was the first randomized controlled trial of CR in nonobese humans. The aim of this investigation was to determine the effects of CR on V˙O2max and muscle strength in the CALERIE trial. Healthy, normal-weight, and mildly overweight women and men (n = 218, mean ± SE age = 37.9 ± 0.5 yr) were randomized to 25% CR or an ad libitum (AL) control condition in a 2:1 allocation (143 CR, 75 AL). V˙O2max was determined with an incremental treadmill test; the strength of the knee flexors and extensors was assessed by dynamometry at baseline, 1 yr, and 2 yr. The CR group achieved an average 11.9% ± 0.7% CR during the 2-yr intervention. Body weight decreased in CR (-7.7 ± 0.4 kg), but not AL (+0.2 ± 0.5 kg). Absolute V˙O2max (L·min) decreased at 1 and 2 yr with CR, whereas V˙O2max expressed relative to body mass increased at both time points (1 yr: +2.2 ± 0.4; 2 yr: +1.9 ± 0.5 mL·kg·min) and relative to AL. The CR group increased their treadmill test time and workload at 1 and 2 yr. Strength results in CR were similar, with decreases in absolute flexor and extensor strength, but increases when expressed relative to body mass. No changes were observed for V˙O2max expressed relative to lean body mass or leg lean mass. Two years of modest CR without a structured exercise component did not appear to compromise aerobic capacity in healthy nonobese adults. The clinical implications of the observed changes in V˙O2max and muscle strength will be important to explore in future studies.


Comfort and adaptation to silicone hydrogel lenses for daily wear.
To investigate initial comfort and adaptation of currently successful low oxygen transmissibility soft lens wearers refitted with silicone hydrogel (SH) lenses for daily wear. Fifty-five subjects were enrolled in a subject-masked 5-month clinical trial in which they wore 5 SH lenses in a randomized, crossover design. Comfort, burning, and dryness were rated on scales of 0 to 100 immediately on insertion and the time for lens settling was recorded. Symptoms were then rated at various times, using BlackBerry wireless communication devices (Research in Motion, Waterloo, Canada), during the day for 2 cycles of 2 weeks wear for each lens type. Comfort immediately on insertion varied between lens types (P=0.002). All lens types were reported by the subjects to have settled within 30 to 45 sec of insertion (P=0.14) and "settled" comfort was greater than comfort immediately on insertion (P<0.001). Comfort within the first hour of wear also varied between lens types (P=0.02). Comfort during the day decreased significantly for all lenses (P=0.001), but there was no difference between lenses (P=0.19) and no effect of lens age (P=0.15). The wearing times were greater with the SH lenses than the habitual lenses worn before study commencement (P=0.001). Overall performance of the lenses after 4 weeks was high, with no difference between lenses (P=0.45). Initial comfort and adaptation to all SH lenses were good and no differences in the overall ratings were found between the 5 SH lenses investigated. Decreased comfort was noted later in the day with all lens types, but longer wearing times were reported with the SH lenses than previous hydroxyethyl methacrylate-based lenses.


[The smooth endoplasmic reticulum develops in mesophyll cells of early-spring ephemerals].
A study was made of the mesophyll cell ultrastructure of early-spring ephemerals Scilla sibirica, Crocus vernus, Galanthus caucasicus, G. plicatus, Leucojum vernum, Muscari szovitsianum, Ornithogalum balansae of summer-vegetating. Scilla scilloides and of S. sibirica growing in greenhouse. The highly developed smooth endoplasmic reticulum (SER) was a distinctive feature of the early-spring ephemeral mesophyll cell during leaf growth (cell expansion). Direct connections of SER-compartments with the tonoplast were found (SER and vacuole cavities were continuous). On running through the cytosol the SER tubules were in close contact with the plasma membrane. SER was not found during the same period of cell expansion in summer-vegetating Scilla scilloides and S. sibirica growing in greenhouse, as well as in mature cells of all investigated plants. The role of SER in the adaptation of early-spring ephemerals to drastic temperature fluctuations is discussed.


The effect of thermal preslaughter stress on the susceptibility of broiler chickens differing with respect to growth rate, age at slaughter, blood parameters, and ascites mortality, to hemorrhages in muscles.
In this study we investigated the occurrence of hemorrhages in four groups of electrically stunned broilers, differing with respect to growth rate, age at slaughter, hemodynamic parameters, and ascites mortality. In addition, the effect of three thermal preslaughter conditions on hemorrhage occurrence in thigh and breast muscles was studied. Broilers were either reared at a thermoneutral or low temperature regimen, and were either restricted in their feed consumption or consumed feed ad libitum. Prior to slaughter the broilers were exposed for 2 +/- 0.5 h to either cold (4 +/- 2 C, RH 100%), moderate (19 +/- 2 C, RH: 70 to 80%), or warm (30 +/- 2 C, RH: 60 to 70%) conditions. There was no effect of rearing group, nor was there an interaction between rearing group and preslaughter condition on hemorrhage scores in the thighs or breasts. Preslaughter conditions only affected hemorrhage scores in the left thigh. Scores were highest in broilers exposed to moderate preslaughter conditions. These data indicate that the cause of hemorrhages in muscles is multifactorial. Hemorrhage severity was not diminished in broilers retarded in growth. Pathological hemodynamic adaptations to low rearing temperatures, leading to ascites, did not increase hemorrhage severity, neither upon exposure to moderate nor to cold or warm preslaughter conditions.


Multi-scale problem in the model of RNA virus evolution.
A mathematical or computational model in evolutionary biology should necessary combine several comparatively fast processes, which actually drive natural selection and evolution, with a very slow process of evolution. As a result, several very different time scales are simultaneously present in the model; this makes its analytical study an extremely difficult task. However, the significant difference of the time scales implies the existence of a possibility of the model order reduction through a process of time separation. In this paper we conduct the procedure of model order reduction for a reasonably simple model of RNA virus evolution reducing the original system of three integro-partial derivative equations to a single equation. Computations confirm that there is a good fit between the results for the original and reduced models.


Liver FoxO1 overexpression is positively associated with the degree of liver injury in cirrhotic patients.
Chronic liver disease and related complications, cirrhosis and hepatocellular carcinoma, are associated with high mortality. Curative treatments, partial hepatectomy or liver transplantation, have limited applicability in patients with cirrhosis due to the poor liver regenerative capacity. Thus, we need to find new diagnostic and therapeutic alternatives, to block the disease progression and to improve the survival of patients. In this context, preclinical studies have demonstrated the key role of the protein kinase B (Akt) in liver dysfunction, but the status of Akt and its targets in patients with chronic hepatopathy remains unknown. Aims: To determine the activation status of the Akt pathway and their association with liver functionality in cirrhotic patients. This retrospective study includes liver tissue samples from 36 hepatectomized patients with (n=27) and without (n=9) cirrhosis. Multiplex analysis of proteins involved in the Akt/mTOR pathway was performed using a Luminex panel and Western blot. Conventional liver function tests were determined in serum before resection surgery. Akt and forkhead box protein O1 (FoxO1) are overexpressed in the liver of cirrhotic patients: (2.1 vs. 1.0 densitometric relative units (DRU); p<0.01, and 9.5 vs. 4.4 DRU; p<0.01, respectively). FoxO1 showed the best correlation with markers of liver injury (aspartate aminotransferase (ASAT): r=0.51, p<0.05; alanine aminotransferase (ALAT): r=0.49, p<0.05), and was the only enzyme in the Akt pathway identified as an independent predictor of ASAT and ALAT levels. The intrahepatic expression of FoxO1 could have clinical utility as a potential prognostic marker for patients with advanced liver disease.


Virulence of mixed fungal infections in honey bee brood.
Honey bees, Apis mellifera, have a diverse community of pathogens. Previous research has mostly focused on bacterial brood diseases of high virulence, but milder diseases caused by fungal pathogens have recently attracted more attention. This interest has been triggered by partial evidence that co-infection with multiple pathogens has the potential to accelerate honey bee mortality. In the present study we tested whether co-infection with closely related fungal brood-pathogen species that are either specialists or non-specialist results in higher host mortality than infections with a single specialist. We used a specially designed laboratory assay to expose honey bee larvae to controlled infections with spores of three Ascosphaera species: A. apis, the specialist pathogen that causes chalkbrood disease in honey bees, A. proliperda, a specialist pathogen that causes chalkbrood disease in solitary bees, and A. atra, a saprophytic fungus growing typically on pollen brood-provision masses of solitary bees. We show for the first time that single infection with a pollen fungus A. atra may induce some mortality and that co-infection with A. atra and A. apis resulted in higher mortality of honey bees compared to single infections with A. apis. However, similar single and mixed infections with A. proliperda did not increase brood mortality. Our results show that co-infection with a closely related fungal species can either increase or have no effect on host mortality, depending on the identity of the second species. Together with other studies suggesting that multiple interacting pathogens may be contributing to worldwide honey bee health declines, our results highlight the importance of studying effects of multiple infections, even when all interacting species are not known to be specialist pathogens.


Evaluation of pain and catheter-related bladder discomfort relative to balloon volumes of indwelling urinary catheters: A prospective study.
To evaluate patients' tolerance to indwelling urinary catheters (IUCs) before and after reducing their balloon volumes. IUCs are a source of discomfort or pain. All consecutive patients hospitalized in our department with IUCs were included during the study period with some exclusion. Each patient was his/her own control before and two hours after reduction of the balloon volume (RBV) by half using two types of assessments, a visual analog scale for pain and a catheter-related bladder discomfort (CRBD) symptom questionnaire. Forty-nine patients were included in our study that completed the assessments. The mean scores for pain before and after RBVs were 2.80 and 2.02, respectively. The difference was significant (p<0.05). The mean grades of the CRBD before and after RBVs were 1.02 and 0.75, respectively. The difference was significant (p<0.05). A 50% RBV has shown a significant amelioration in tolerating the catheter.


Bronchodilation by pituitary adenylate cyclase-activating peptide and related peptides.
Pituitary adenylate cyclase-activating peptide (PACAP) is present in nerves in the vicinity of bronchial and vascular smooth muscle in the airways. At least one endogenous form of PACAP, PACAP 1-27, has high affinity binding sites in the lung, probably including cholinergic nerve terminals, bronchial smooth muscle, epithelial and mononuclear inflammatory cells. The mechanism of action for PACAP 1-27 and 1-38 in vivo involves endogenous catecholamines, peptidases and nitric oxide, depending on tissue type. Intracellularly, cyclic adenosine monophosphate (cAMP) as well as calcium and sodium mobilization is probably involved. PACAP 1-27 and 1-38 inhibit airway smooth muscle tone in vitro and in vivo. The inhibitory effect of PACAP 1-38 is more sustained than that of PACAP 1-27, in vitro as well as in vivo. PACAP 1-38 also causes more sustained inhibition of bronchoconstriction after inhalation in vivo, than does vasoactive intestinal peptide (VIP). PACAP 1-27 given intravenously virtually abolishes allergen-induced bronchoconstriction in vivo. Novel synthetic analogues of PACAP 1-27 cause more sustained inhibition of airway smooth muscle tone in vitro and in vivo than do PACAP 1-27 or 1-38. Both PACAP 1-27 and 1-38 inhibit arterial smooth muscle tone but, administration of PACAP 1-27, 1-38 or a structural analogue of PACAP 1-27 in the airways, induces no cardiovascular side effects at doses inhibiting bronchoconstriction. PACAP 1-38 enhances phagocytosis in macrophages and inhibits the release of the pro-inflammatory cytokine interleukin-2 in lymphocytes, suggesting antiinflammatory effects. It is concluded that pituitary adenylate cyclase-activating peptide 1-27 and 1-38, or structurally related molecules, may be useful as bronchodilators but their effect on human bronchial smooth muscle and on human inflammatory cells is in need of evaluation.