Long-term blood pressure outcomes of laparoscopic adrenalectomy in trHTN patients.
Treatment resistant hypertension (trHTN) is a common clinical problem faced by many clinicians. Laparoscopic adrenalectomy effectively trims blood pressure (BP) elevation secondary to various functional adrenal disorders. However, the impact of adrenalectomy on BP within trHTN patients has never been reported. Our present study aims to investigate the effect of adrenalectomy on BP management within trHTN patients, and to explore clinical predictors for postoperative BP normalization. In our current study, 117 patients diagnosed with trHTN and performed with unilateral adrenalectomy were consecutively enrolled, demographic and medical information were documented for baseline data collection. BP was measured with a standard electronic sphygmomanometer twice a day. Long-term periodical interview was conducted and 109 (93.2%) enrolled patients were successfully followed-up at an averaged 36.2 months. At follow-up, 27/109 (25%) trHTN patients acquired BP normalization and 68/109 (62%) patients acquired BP improvement. Mean taking anti-hypertensive agents reduced from presurgical 4.24 to present 1.21 (P < 0.01), along with 7.2 mmHg reduction in SBP (P < 0.01). Image macro-adenoma and hypokalemia history were found to be the two strongest predictors for postoperative BP normalization. (χ2= 28.032, P < 0.01). The incidence of adverse postoperative events was quite small. In summary, this current study implicates that adrenalectomy is an efficacious and safe surgical strategy for BP management in trHTN patients. Patients with both unilateral macro-adenoma and hypokalemia are more prone to acquire postoperative BP normalization.


A high dietary calcium intake is needed for a positive effect on bone density in Swedish postmenopausal women.
The importance of dietary calcium for bone health is unclear, partly since most investigations have dealt only with a fairly narrow range of calcium intake. In the present population-based observational study with longitudinal dietary assessment, we investigated women with a mean age of 60 years and with a consistently high (range 1417-2417, mean 1645 mg, n = 40), intermediate (800-1200, mean 1006 mg, n = 35) or low (400-550, mean 465 mg, n = 40) estimated daily consumption of calcium. Measurements of bone mineral density (BMD) of the lumbar spine, femoral neck and total body were performed by dual-energy X-ray absorptiometry, as well as ultrasound of the heel. In a multivariate analysis, with adjustment for energy intake the risk factors for osteoporosis (age, body mass index, physical activity, menopausal age, use of estrogens, smoking and former athletic activity), the group with the highest calcium intake had higher values for BMD than the others at all measured sites. The average mean difference compared with the low and the intermediate calcium group was 11% for the femoral neck, 8-11% for the lumbar spine and 5-6% for total body BMDs. In univariate analyses and multivariate models which did not include energy intake, the differences between the groups were less pronounced. The women in the intermediate calcium group had approximately the same mean BMD values as those in the low calcium group. These findings support the view that only a high calcium intake (3% highest percentiles in the studied population) protects against osteoporosis in Swedish postmenopausal women.


Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo.
Sundry mevalonate-derived constituents (isoprenoids) of fruits, vegetables and cereal grains suppress the growth of tumors. This study estimated the concentrations of structurally diverse isoprenoids required to inhibit the increase in a population of murine B16(F10) melanoma cells during a 48-h incubation by 50% (IC50 value). The IC50 values for d-limonene and perillyl alcohol, the monoterpenes in Phase I trials, were 450 and 250 micromol/L, respectively; related cyclic monoterpenes (perillaldehyde, carvacrol and thymol), an acyclic monoterpene (geraniol) and the end ring analog of beta-carotene (beta-ionone) had IC50 values in the range of 120-150 micromol/L. The IC50 value estimated for farnesol, the side-chain analog of the tocotrienols (50 micromol/L) fell midway between that of alpha-tocotrienol (110 micromol/L) and those estimated for gamma- (20 micromol/L) and delta- (10 micromol/L) tocotrienol. A novel tocotrienol lacking methyl groups on the tocol ring proved to be extremely potent (IC50, 0.9 micromol/L). In the first of two diet studies, experimental diets were fed to weanling C57BL female mice for 10 d prior to and 28 d following the implantation of the aggressively growing and highly metastatic B16(F10) melanoma. The isomolar (116 micromol/kg diet) and the Vitamin E-equivalent (928 micromol/kg diet) substitution of d-gamma-tocotrienol for dl-alpha-tocopherol in the AIN-76A diet produced 36 and 50% retardations, respectively, in tumor growth (P < 0.05). In the second study, melanomas were established before mice were fed experimental diets formulated with 2 mmol/kg d-gamma-tocotrienol, beta-ionone individually and in combination. Each treatment increased (P < 0.03) the duration of host survival. Our finding that the effects of individual isoprenoids were additive suggests the possibility that one component of the anticarcinogenic action of plant-based diets is the tumor growth-suppressive action of the diverse isoprenoid constituents of fruits, vegetables and cereal grains.


Computed tomography in the assessment of diffuse lung disease.
Computed tomography (CT) has a significant impact on the evaluation of patients suspected of having diffuse lung disease. The technique is based on thin-section scans and high-resolution reconstruction. CT interpretation is based on a recognition of the main pattern, associated findings, and distribution of the lesions assessed at the regional level as well as the level of the secondary pulmonary lobule. CT may demonstrate clinically suspected abnormalities undetected on the radiographs. It may have characteristic pictures in patients with non specific findings on the radiograph. It can be used to limit the differential diagnosis to a few possibilities. In selected cases, in the presence of the appropriate clinical setting, CT appearances can be diagnostic or so strongly suggestive that lung biopsy can be avoided. When a lung biopsy is indicated, CT has a considerable value in determining the most appropriate site for the biopsy. To a certain extent, CT may also provide information on disease activity and prognosis, particularly in the differentiation between inflammatory changes, potentially treatable or reversible, and irreversible lung fibrosis.


Pre-Menopausal Women With Breast Cancers Having High AR/ER Ratios in the Context of Higher Circulating Testosterone Tend to Have Poorer Outcomes.
Women with breast tumors with higher expression of AR are in general known to have better survival outcomes while a high AR/ER ratio is associated with poor outcomes in hormone receptor positive breast cancers mostly in post menopausal women. We have evaluated the AR/ER ratio in the context of circulating androgens specifically in patients younger than 50 years most of whom are pre-menopausal and hence have a high estrogenic hormonal milieu. Tumor samples from patients 50 years or younger at first diagnosis were chosen from a larger cohort of 270 patients with median follow-up of 72 months. Expression levels of ER and AR proteins were detected by immunohistochemistry (IHC) and the transcript levels by quantitative PCR. Ciculating levels of total testosterone were estimated from serum samples. A ratio of AR/ER was derived using the transcript levels, and tumors were dichotomized into high and low ratio groups based on the third quartile value. Survival and the prognostic significance of the ratio was compared between the low and high ratio groups in all tumors and also within ER positive tumors. Results were further validated in external datasets (TCGA and METABRIC). Eighty-eight (32%) patients were ≤50 years, with 22 having high AR/ER ratio calculated using the transcript levels. Circulating levels of total testosterone were higher in women whose tumors had a high AR/ER ratio (p = 0.02). Tumors with high AR/ER ratio had significantly poorer disease-free survival than those with low AR/ER ratio [HR-2.6 (95% CI-1.02-6.59) p = 0.04]. Evaluation of tumors with high AR/ER ratio within ER positive tumors alone reconfirmed the prognostic relevance of the high AR/ER ratio with a significant hazard ratio of 4.6 (95% CI-1.35-15.37, p = 0.01). Similar trends were observed in the TCGA and METABRIC dataset. Our data in pre-menopausal women with breast cancer suggest that it is not merely the presence or absence of AR expression but the relative activity of ER, as well as the hormonal milieu of the patient that determine clinical outcomes, indicating that both context and interactions ultimately influence tumor behavior.


Synthesis of Hollow Biomineralized CaCO3-Polydopamine Nanoparticles for Multimodal Imaging-Guided Cancer Photodynamic Therapy with Reduced Skin Photosensitivity.
The development of activatable nanoplatforms to simultaneously improve diagnostic and therapeutic performances while reducing side effects is highly attractive for precision cancer medicine. Herein, we develop a one-pot, dopamine-mediated biomineralization method using a gas diffusion procedure to prepare calcium carbonate-polydopamine (CaCO3-PDA) composite hollow nanoparticles as a multifunctional theranostic nanoplatform. Because of the high sensitivity of such nanoparticles to pH, with rapid degradation under a slightly acidic environment, the photoactivity of the loaded photosensitizer, i.e., chlorin e6 (Ce6), which is quenched by PDA, is therefore increased within the tumor under reduced pH, showing recovered fluorescence and enhanced singlet oxygen generation. In addition, due to the strong affinity between metal ions and PDA, our nanoparticles can bind with various types of metal ions, conferring them with multimodal imaging capability. By utilizing pH-responsive multifunctional nanocarriers, effective in vivo antitumor photodynamic therapy (PDT) can be realized under the precise guidance of multimodal imaging. Interestingly, at normal physiological pH, our nanoparticles are quenched and show much lower phototoxicity to normal tissues, thus effectively reducing skin damage during PDT. Therefore, our work presents a unique type of biomineralized theranostic nanoparticles with inherent biocompatibility, multimodal imaging functionality, high antitumor PDT efficacy, and reduced skin phototoxicity.


Prismatic analyser concept for neutron spectrometers.
Developments in modern neutron spectroscopy have led to typical sample sizes decreasing from few cm to several mm in diameter samples. We demonstrate how small samples together with the right choice of analyser and detector components makes distance collimation an important concept in crystal analyser spectrometers. We further show that this opens new possibilities where neutrons with different energies are reflected by the same analyser but counted in different detectors, thus improving both energy resolution and total count rate compared to conventional spectrometers. The technique can readily be combined with advanced focussing geometries and with multiplexing instrument designs. We present a combination of simulations and data showing three different energies simultaneously reflected from one analyser. Experiments were performed on a cold triple axis instrument and on a prototype inverse geometry Time-of-flight spectrometer installed at PSI, Switzerland, and shows excellent agreement with the predictions. Typical improvements will be 2.0 times finer resolution and a factor of 1.9 in flux gain compared to a focussing Rowland geometry, or of 3.3 times finer resolution and a factor of 2.4 in flux gain compared to a single flat analyser slab.


Intensive care utilisation following attempted suicide through self-poisoning.
To evaluate intensive care utilisation following attempted suicide through self-poisoning. Retrospective analysis of clinical records. Intensive Care Unit, Teaching Hospital, Peradeniya. All patients admitted over the period 1991-1995. 292 patients were admitted after a suicide attempt by ingestion of a poisonous substance or drug in overdose. 52% were mechanically ventilated. The mean stay was 6 days. Daily intensive care cost averaged Rs. 8000 for a ventilated patient. Fifty three patients died. The 292 patients constituted 10.2% of the total admissions to the unit. Suicide as a medical emergency imposes pressure on the limited resources and facilities available in intensive care units. Concrete preventive measures are mandatory to prevent loss of life and health care resources.


Producing and imaging a thin line of He*₂ molecular tracers in helium-4.
Cryogenic helium-4 has long been recognized as a useful material in fluids research. The unique properties of helium-4 in the gaseous phase and the normal liquid phase allow for the generation of turbulent flows with exceptionally high Reynolds and Rayleigh numbers. In the superfluid phase, helium-4 exhibits two-fluid hydrodynamics and possesses fascinating properties due to its quantum nature. However, studying the flows in helium-4 has been very challenging largely due to the lack of effective visualization and velocimetry techniques. In this article, we discuss the development of novel instrumentation for flow-visualization in helium based on the generation and imaging of thin lines of metastable He*₂ tracer molecules. These molecular tracers are created via femtosecond-laser field-ionization of helium atoms and can be imaged using a laser-induced fluorescence technique. By observing the displacement and distortion of the tracer lines in helium, quantitative information about the flow field can be extracted. We present experimental results in the study of thermal counterflow in superfluid helium that validate the concept of this technique. We also discuss anticipated future developments of this powerful visualization technique.


Spontaneous calf hematoma in a patient with diabetic nephropathy receiving maintenance hemodialysis: A case report and review of the literature.
We report the outcome of a 52-year-old patient with diabetic nephropathy and receiving maintenance hemodialysis (HD) using low molecular weight heparin (LMWH) as an anticoagulant for 2 years. He presented right lower limb pain accompanied with difficulty in walking for 2 months, and had no history of bleeding tendency or trauma. Physical examination revealed marked swelling and tenderness on his right lower limb. By ultrasound and magnetic resonance imaging (MRI) diagnoses, the calf hematoma was diagnosed and identified with venous thrombosis. Following treatment with heparin-free HD, the swelling regressed and pain subsided, and a follow-up MRI showed complete dissolution of hematoma. However, similar symptoms recurred in the right upper limb after 2 months without any predisposition, he was just placed on HD with LMWH, and symptoms regressed following the aforementioned therapy. This suggests that HD patients, especially with diabetic nephropathy having extremity hematoma, should be watched for the development of spontaneous hemorrhage that can be differentially diagnosed by imaging tests, such as MRI, and can be effectively treated with heparin-free HD.


Inclusion and Quality of Life for Older Adults: Nurses Advocating for Policy Change.
Social inclusion and social determinants of health (SDH) are key to healthy aging, and a failure to adequately address these influences can lead to negative health consequences such as the development and worsening of chronic conditions. Health policy is needed that prioritizes aging well in place as an "upstream" approach to address SDH and thereby improve health outcomes and promote quality of life. Globally, nurses are well positioned to advocate for such policy, given their commitment to fostering social inclusion and quality of life for older adults. This article presents a policy submission, made by nurses enrolled in a graduate health policy course, to Canada's Standing Committee on Human Resources and Social Development and the Status of Persons with Disabilities, for the Committee's report on Advancing Inclusion of and Quality of Life for Seniors ().


Gas phase deposition of well-defined bimetallic gold-silver clusters for photocatalytic applications.
Cluster beam deposition is employed for fabricating well-defined bimetallic plasmonic photocatalysts to enhance their activity while facilitating a more fundamental understanding of their properties. AuxAg1-x clusters with compositions (x = 0, 0.1, 0.3, 0.5, 0.7, 0.9 and 1) spanning the metals' miscibility range were produced in the gas-phase and soft-landed on TiO2 P25-coated silicon wafers with an optimal coverage of 4 atomic monolayer equivalents. Electron microscopy images show that at this coverage most clusters remain well dispersed whereas EXAFS data are in agreement with the finding that the deposited clusters have an average size of ca. 5 nm and feature the same composition as the ablated alloy targets. A composition-dependant electron transfer from Au to Ag that is likely to impart chemical stability to the bimetallic clusters and protect Ag atoms against oxidation is additionally evidenced by XPS and XANES. Under simulated solar light, AuxAg1-x clusters show a remarkable composition-dependent volcano-type enhancement of their photocatalytic activity towards degradation of stearic acid, a model compound for organic fouling on surfaces. The Formal Quantum Efficiency (FQE) is peaking at the Au0.3Ag0.7 composition with a value that is twice as high as that of the pristine TiO2 P25 under solar simulator. Under UV the FQE of all compositions remains similar to that of pristine TiO2. A classical electromagnetic simulation study confirms that among all compositions Au0.3Ag0.7 features the largest near-field enhancement in the wavelength range of maximal solar light intensity, as well as sufficient individual photon energy resulting in a better photocatalytic self-cleaning activity. This allows ascribing the mechanism for photocatalysis mostly to the plasmonic effect of the bimetallic clusters through direct electron injection and near-field enhancement from the resonant cluster towards the conduction band of TiO2. These results not only demonstrate the added value of using well-defined bimetallic nanocatalysts to enhance their photocatalytic activity but also highlights the potential of the cluster beam deposition to design tailored noble metal modified photocatalytic surfaces with controlled compositions and sizes without involving potentially hazardous chemical agents.


A cluster of occupational mental illness in an NHS trust.
A cluster of clinical cases of occupational mental illness has not previously been reported. A prospective cross-sectional study of patients referred for examination and advice about rehabilitation was undertaken to ascertain a variety of employer's rates of occupational mental illness. A background rate of referral for occupational mental illness of 3.1/1,000 employees per year was found apart from in one NHS trust where the rate was 25.6/1,000. Most patients were nurses and diagnoses were anxiety and/or depression with a median length of time off work of four months. There was no evidence that patients from this employer were vulnerable to mental illness. The high rate of occupational mental illness was associated with organisational change and a hostile working climate. This study shows that NHS trusts may be associated with unhealthy working practices. A cluster of occupational mental illness should be statutorily reportable to the Health and Safety Executive for further investigation.


The time-limited influence of sentential context on function word identification.
Sentential context effects on the identification of the Dutch function words te (to) and de (the) were examined. In Experiment 1, listeners labeled words on a [t inverted e]-[d inverted e] continuum more often as te when the context waste biased (Ik probeer [? inverted e] schieten [I try to/the shoot]) than when it was de biased (Ik probeer [? inverted e] schoenen [I try to/the shoes]). The effect was weaker in slower responses. In Experiment 2, disambiguation began later, in the second word after [? inverted e]. There was a weak context effect only in the slower responses. In Experiments 3 and 4, disambiguation occurred on the word before [? inverted e]: There was no context effect when one set of sentences was used, but there was an effect (larger in the faster responses) when more sentences were used. Syntactic processing affects word identification only within a limited time frame. It appears to do so not by influencing lexical access processes through feedback but, instead, by biasing decision making.


Enhanced anticancer activity of a combination of docetaxel and Aneustat (OMN54) in a patient-derived, advanced prostate cancer tissue xenograft model.
The current first-line treatment for advanced metastatic prostate cancer, i.e. docetaxel-based therapy, is only marginally effective. The aim of the present study was to determine whether such therapy can be improved by combining docetaxel with Aneustat (OMN54), a multivalent botanical drug candidate shown to have anti-prostate cancer activity in preliminary in vitro experiments, which is currently undergoing a Phase-I Clinical Trial. Human metastatic, androgen-independent C4-2 prostate cancer cells and NOD-SCID mice bearing PTEN-deficient, metastatic and PSA-secreting, patient-derived subrenal capsule LTL-313H prostate cancer tissue xenografts were treated with docetaxel and Aneustat, alone and in combination. In vitro, Aneustat markedly inhibited C4-2 cell replication in a dose-dependent manner. When Aneustat was combined with docetaxel, the growth inhibitions of the drugs were essentially additive. In vivo, however, the combination of docetaxel and Aneustat enhanced anti-tumor activity synergistically and very markedly, without inducing major host toxicity. Complete growth inhibition and shrinkage of the xenografts could be obtained with the combined drugs as distinct from the drugs on their own. Analysis of the gene expression of the xenografts using microarray indicated that docetaxel + Aneustat led to expanded anticancer activity, in particular to targeting of cancer hallmarks that were not affected by the single drugs. Our findings, obtained with a highly clinically relevant prostate cancer model, suggest, for the first time, that docetaxel-based therapy of advanced human prostate cancer may be improved by combining docetaxel with Aneustat.


Hydrodynamic delivery of interleukin 15 gene promotes resistance to high fat diet-induced obesity, fatty liver and improves glucose homeostasis.
The objective of this study is to examine the effect of hydrodynamic delivery of plasmid containing Il-15 gene on high fat diet-induced obesity and obesity-associated metabolic disorders. We demonstrate that Il-15 gene transfer results in multiple beneficial effects, including blockade of weight gain, alleviation of fatty liver and improvement in glucose homeostasis in mice. These effects are accompanied by suppressed expression of genes involved in lipogenesis and gluconeogenesis including Scd-1, Fas, Pdk4, Pepck and G6p, and enhanced expression of genes responsible for lipolysis and glucose metabolism such as Cpt1-α, Cpt1-β, Acadm, Acadl and Glut-4. Collectively, our results suggest that Il-15 gene transfer is an effective approach in preventing diet-induced obesity and obesity-associated complications.


Distinguishing chromophore structures of photocycle intermediates of the photoreceptor PYP by transient fluorescence and energy transfer.
The cinnamoyl chromophore is the light-activated switch of the photoreceptor photoactive yellow protein (PYP) and isomerizes during the functional cycle. The fluorescence of W119, the only tryptophan of PYP, is quenched by energy transfer to the chromophore. This depends on the chromophore's transition dipole moment orientation and spectrum, both of which change during the photocycle. The transient fluorescence of W119 thus serves as a sensitive kinetic monitor of the chromophore's structure and orientation and was used for the first time to investigate the photocycle kinetics. From these data and measurements of the ps-fluorescence decay with background illumination (470 nm) we determined the fluorescence lifetimes of W119 in the I(1) and I (1') intermediates. Two coexisting distinct chromophore structures were proposed for the I(1) photointermediate from time-resolved X-ray diffraction ( Ihee, H., et al. Proc. Natl. Acad. Sci. U.S.A., 2005, 102, 7145 ): one with two hydrogen bonds to E46 and Y42, and a second with only one H-bond to Y42 and a different orientation. Only for the first of these is the calculated fluorescence lifetime of 0.22 ns in good agreement with the observed one of 0.26 ns. The second structure has a predicted lifetime of 0.71 ns. Thus, we conclude that in solution only the first I(1) structure occurs. The high resolution structure of the I(1') intermediate, the decay product of I(1) at alkaline pH, is still unknown. We predict from the observed lifetime of 1.3 ns that the chromophore structure of I(1') is quite similar to that of the I(2) intermediate, and I(1') should thus be considered as the alkaline (deprotonated) form of I(2).


Possible common biological and immunological properties for detecting encapsulated strains of Staphylococcus epidermidis.
Twenty strains of capsular type II Staphylococcus epidermidis, determined by the method of Ichiman, were obtained from clinical specimens. Among them, 5, 5, and 10 strains were 4+, 3+, and 2+ in the intensities of their reactions against fluorescent antibody, respectively. Strains exhibiting 4+ and 3+ intensities were mouse virulent and phage nontypable, while 2+ strains were mouse avirulent and phage typable. When three strains randomly selected from each of the mouse-virulent and mouse-avirulent strains were compared in terms of their cell volume indices, all mouse-virulent strains had significantly higher indices (average, 1.86 times) than the mouse-avirulent strains. With intraperitoneal injection of the strains into mice, strains with higher cell volume indices resisted ingestion by peritoneal cells, while strains with low cell volume indices were sensitive to phagocytosis. When the capacity to absorb a definite amount of passive protective activity in rabbit antiserum prepared with capsular type II strains was compared among these strains, 10 to 20 mg of mouse-virulent strains was capable of completely absorbing the passive protective activity, whereas more than 80 mg of the cells was required for similar absorption by mouse-avirulent strains. In ultra-thin sections of three mouse-virulent strains stained with ferritin-conjugated rabbit antiserum, well-defined capsules were detected around cell walls; however, no capsule was seen around the walls of three mouse-avirulent strains.


Iliac crest free flap in oromandibular reconstruction. 13 cases study.
Oromandibular reconstruction following oncological resection is particularly challenging. In this past decade, great improvements have been made, in functional and aesthetic terms, following the introduction of composite free flaps. By means of this reconstructive technique, it is, in fact, possible to restore mandibular continuity, and, consequently, the morphology of the lower third of the face; rehabilitate mastication through osteointegrated implants, and optimise the reconstruction of soft tissue, employing the fascio-cutaneous or muscular portion of these flaps. Between January 1995 and January 2001, 70 oromandibular reconstructions employing osseous free flaps were performed in the Department of Maxillo-Facial Surgery of the Ospedale Maggiore in Parma, and in 13 of these the iliac crest free flap was used. Personal experience is described regarding the indications and use of this flap.


Unconventional aspects of electronic transport in delafossite oxides.
The electronic transport properties of the delafossite oxides [Formula: see text] are usually understood in terms of two well-separated entities, namely the triangular [Formula: see text] and ([Formula: see text] layers. Here, we review several cases among this extensive family of materials where the transport depends on the interlayer coupling and displays unconventional properties. We review the doped thermoelectrics based on [Formula: see text] and [Formula: see text], which show a high-temperature recovery of Fermi-liquid transport exponents, as well as the highly anisotropic metals [Formula: see text], [Formula: see text], and [Formula: see text], where the sheer simplicity of the Fermi surface leads to unconventional transport. We present some of the theoretical tools that have been used to investigate these transport properties and review what can and cannot be learned from the extensive set of electronic structure calculations that have been performed.


Factors related to musculoskeletal disorders in quality control palm workers at palm purchasing establishments in Sichon District, Nakhon Si Thammarat, Thailand.
The palm quality selection process has risks of problems in ergonomics. The aim of this research is to study the factors related to musculoskeletal disorders in quality control palm workers at palm purchasing establishments in Sichon District, Nakhon Si Thammarat, Thailand. A cross-sectional study was conducted with 50 workers with musculoskeletal disorders, as assessed by the Bureau of Occupational and Environmental Disease, Ministry of Public Health, Thailand. Ergonomic risk assessment was performed using the Rapid Entire Body Assessment (REBA), and the data studied with the help of descriptive statistics and chi-square analyses. All data were analyzed using SPSS version 19. The sample included 96% of males with an average age of 34.2 years (SD=11.09). The participants used pickup trucks to transport palm oil from the plantation. 72% of the workers had worked at the plantation for 4.9±4.9 years; 54% did not work overtime. The average amount of palm oil collection for palm quality control was 23.5±11.3 tons/day. Quality control palm workers using sidecars (28%) were found to be moderately at risk, and those using trucks (72%) were at a high level of risk. The prevalence of musculoskeletal disorders after one year at work was 78%. The amount of palm oil controlled per day, working overtime, car type used for transport, and ergonomics risk level, were significantly related to musculoskeletal disorders in quality control palm workers (p-value <0.05). The results indicate a need for the top management and health-related personnel to promote occupational health and safety measures for quality control palm workers.


Evaluation of genetic variants in miRNAs in patients with colorectal cancer.
Aberrant expression and structural alteration of miRNAs are considered to participate in cancer development. It has been suggested that common single-nucleotide polymorphisms (SNPs) in miRNAs are associated with susceptibility to several human diseases including colorectal cancer (CRC). A case-control study at 157 CRC patients and 299 healthy controls of Greek origin was undertaken in order to investigate the association between the genotype and allelic frequencies of three common SNPs (rs2910164, rs11614913 and rs3746444) in pre-miRNAs, miR-146a, miR-196a2 and miR-499. The risk for CRC was significantly higher at the carriers of miR-146a rs2910164 CC genotype and C allele (p=0.02 and p< 0.001, respectively). None of the other performed analysis showed any statistically significant results. Our findings suggest that the rs2910164 polymorphism in pre-miRNA, miR-146a may be associated with the risk of CRC.


Effect of cigarette smoking on serum anti-Mullerian hormone and antral follicle count in women seeking fertility treatment: a prospective cross-sectional study.
The relationship between smoking and ovarian reserve markers is inconclusive. The primary objective of our study was to assess the effect of cigarette smoking on the quantitative ovarian reserve parameters, serum anti-Mullerian hormone (AMH) and antral follicle count (AFC) as relevant to prediction of fertility outcomes in women seeking fertility treatment. Our secondary aims were to validate self-reported smoking behaviour using biomarkers and evaluate the association between biomarkers of ovarian reserve (serum AMH and AFC) with biomarkers of smoking exposure (breath carbon monoxide (CO) and urine cotinine levels). Prospective, cross-sectional study. Single tertiary care fertility centre. Women ≤35 years seeking fertility treatment. Serum AMH and AFC. Significant differences were found among current smokers, ex-smokers and never smokers for breath CO (F(2,97)=33.32, p<0.0001) and urine cotinine levels (p<0.001). However, no significant differences were found either for serum AMH (F(2,91)=1.19, p=0.309) or total AFC (F(2,81)=0.403, p=0.670) among the three groups. There was no significant correlation between pack years of smoking and serum AMH (r=-0.212, n=23, p=0.166) or total AFC (r=-0.276, n=19, p=0.126). No significant correlation was demonstrated between breath CO and serum AMH (r=0.082, n=94, p=0.216) or total AFC (r=0.096, n=83, p=0.195). Similarly, no significant correlation was demonstrated between urine cotinine levels and serum AMH (r=0.146, n=83, p=0.095) or total AFC (r=-0.027, n=77, p=0.386). We did not find a statistically significant difference in quantitative ovarian reserve markers between current smokers, ex-smokers and never smokers which would be clinically meaningful in our study population. We confirmed that self-reported smoking correlates well with quantitatively measured biomarkers of smoking. This validated the self-reported comparison groups to ensure a valid comparison of outcome measures. There was no significant association between biomarkers of smoking and biomarkers of ovarian reserve. We were also unable to demonstrate a correlation between the lifetime smoking exposure and ovarian reserve.


Electron cryo-crystallography of a recombinant cardiac gap junction channel.
Gap junctions in the heart play an important functional role by electrically coupling cells, thereby organizing the pattern of current flow to allow co-ordinated muscle contraction. Cardiac gap junctions are therefore intimately involved in normal conduction as well as the genesis of potentially lethal arrhythmias. We recently utilized electron cryo-microscopy and image analysis to examine frozen-hydrated 2D crystals of a recombinant, C-terminal truncated form of connexin 43 (Cx43; alpha 1), the principal cardiac gap junction protein. The projection map at 7 A resolution revealed that each 30 kDa connexin subunit has a transmembrane alpha-helix that lines the aqueous pore and a second alpha-helix in close contact with the membrane lipids. The distribution of densities allowed us to propose a model in which the two apposing connexons that form the channel are staggered by approximately 30 degrees. We are now recording images of tilted, frozen-hydrated 2D crystals, and a preliminary 3D map has been computed at an in-plane resolution of approximately 7.5 A and a vertical resolution of approximately 25 A. As predicted by our model, the two apposing connexons that form the channel are staggered with respect to each other for certain connexin molecular boundaries within the hexamer. Within the membrane interior each connexin subunit displays four rods of density, which are consistent with an alpha-helical conformation for the four transmembrane domains. Preliminary studies of BHK hamster cells that express the truncated Cx43 designated alpha 1 Cx263T demonstrate that oleamide, a sleep inducing lipid, blocks in vivo dye transfer, suggesting that oleamide causes closure of alpha 1 Cx263T channels. The comparison of the 3D structures in the presence and absence of oleamide may provide an opportunity to explore the conformational changes that are associated with oleamide-induced blockage of dye transfer. The structural details revealed by our analysis will be essential for delineating the molecular basis for intercellular current flow in the heart, as well as the general molecular design and functional properties of this important class of channel proteins.


The influence of environmental factors and education on tobacco smoking among students of the Faculty of Nursing, Medical University of Lublin.
Tobacco smoking among medical personnel is a problem concerning not only our country. Nurses and midwives in their work have a close contact with patients allowing influence on their health behaviours. Positive own example is indispensable in this field. Formation of proper attitudes and healthy behaviours should be one of the main goals of academic education of nurses and midwives. The aim of the study was an attempt at analysing the problem of tobacco smoking among the students of the Faculty of Nursing, Medical University of Lublin. The material consisted of 152 anonymous questionnaires filled in by the students in the academic year 2001/2002. There was applied the method of standardized interview using an interview questionnaire. The material was analysed by means of descriptive statistics methods. Women were more prevalent among the respondents (143 persons out of 152), the mean age equalled 29.4 years. The majority were students of nursing (109 persons) and 43 represented midwifery. Twenty-seven percent of all students declared tobacco smoking, 13% quitted the habit and 60% never smoked. The studies proved that medical education and knowledge of harmfulness of tobacco smoking are the main reasons of non-smoking habits of the analysed group of students. The decision about taking up smoking is mostly influenced by smoking peers. This testifies to the need of further educational actions during nursing studies that would promote proper health behaviours in this field.


Cornea as a tissue reservoir of Trypanosoma cruzi.
Trypanosoma cruzi causal agent of Chagas' disease is a paninfective parasite of mammals transmitted through skin fecal contamination by Triatominae vectors. Studies of alternative routes for infection are scarce; therefore, eye infection should be important, because of the eye's high blood irrigation and brain proximity, as port of entry of the parasite. Trypanosoma cruzi parasites and/or their genetic material in ocular and adjacent muscle tissues were studied in batches of six NMRI mice (15 g) and Trichomys apereoides, an ancient caviomorph (250 g) inoculated with T. cruzi metacyclics from Brazilian (2) and Venezuelan (3) isolates genetically typified as T. cruzi I and II. Two animals/batch in the acute or chronic phase were killed and necropsies of cardiac and skeletal muscles, eyeball, and surrounding ocular muscle were processed for hematoxylin-eosine staining. Tissue parasitism was determined. DNA of the digested sections of the eyeball (5-10 mum) was extracted for T. cruzi k-DNA amplification by PCR, with S35 and S36 primers. The PCR products were analyzed. The average of maximum values of parasitemia of all infected animals was of 10(5) trypomastigotes/ml blood. Skeletal muscle and heart were colonized in patent infection for all isolates. Amastigote nests were found in corneal tissue of 2/3 of the used isolates and adjacent ocular muscle and connective tissue were parasitized. Trypanosoma cruzi k-DNA (330-bp band) was observed in ocular tissue of 4/6 of the isolates studied in both animal models. Investigations concerning infection of the eye globe tissues by T. cruzi are extremely scarce. The presence of stages of T. cruzi and/or its genetic products in ocular tissues indicate a broad colonization from a systemic infection. The results show the ocular environment as a possible appropriate microniche for T. cruzi and emphasize the risk of transmitting T. cruzi by ocular fluids and by parasitized cornea through transplants.


Bioactive Glass Modified with Zirconium Incorporation for Dental Implant Applications: Fabrication, Structural, Electrical, and Biological Analysis.
Implantology is crucial for restoring aesthetics and masticatory function in oral rehabilitation. Despite its advantages, certain issues, such as bacterial infection, may still arise that hinder osseointegration and result in implant rejection. This work aims to address these challenges by developing a biomaterial for dental implant coating based on 45S5 Bioglass® modified by zirconium insertion. The structural characterization of the glasses, by XRD, showed that the introduction of zirconium in the Bioglass network at a concentration higher than 2 mol% promotes phase separation, with crystal phase formation. Impedance spectroscopy was used, in the frequency range of 102-106 Hz and the temperature range of 200-400 K, to investigate the electrical properties of these Bioglasses, due to their ability to store electrical charges and therefore enhance the osseointegration capacity. The electrical study showed that the presence of crystal phases, in the glass ceramic with 8 mol% of zirconium, led to a significant increase in conductivity. In terms of biological properties, the Bioglasses exhibited an antibacterial effect against Gram-positive and Gram-negative bacteria and did not show cytotoxicity for the Saos-2 cell line at extract concentrations up to 25 mg/mL. Furthermore, the results of the bioactivity test revealed that within 24 h, a CaP-rich layer began to form on the surface of all the samples. According to our results, the incorporation of 2 mol% of ZrO2 into the Bioglass significantly improves its potential as a coating material for dental implants, enhancing both its antibacterial and osteointegration properties.


Altered connectivity of the dorsal and ventral visual regions in dyslexic children: a resting-state fMRI study.
While there is emerging evidence from behavioral studies that visual attention skills are impaired in dyslexia, the corresponding neural mechanism (i.e., deficits in the dorsal visual region) needs further investigation. We used resting-state fMRI to explore the functional connectivity (FC) patterns of the left intraparietal sulcus (IPS) and the visual word form area (VWFA) in dyslexic children (N = 21, age mean = 12) and age-matched controls (N = 26, age mean = 12). The results showed that the left IPS and the VWFA were functionally connected to each other in both groups and that both were functionally connected to left middle frontal gyrus (MFG). Importantly, we observed significant group differences in FC between the left IPS and the left MFG and between the VWFA and the left MFG. In addition, the strengths of the identified FCs were significantly correlated with the score of fluent reading, which required obvious eye movement and visual attention processing, but not with the lexical decision score. We conclude that dyslexics have deficits in the network composed of the prefrontal, dorsal visual and ventral visual regions and may have a lack of modulation from the left MFG to the dorsal and ventral visual regions.


A regio- and diastereoselective intramolecular nitrone cycloaddition for practical 3- and 2,3-disubstituted piperidine synthesis from gamma-butyrolactone.
A fast and efficient route for diversity-oriented synthesis of 3- and 2,3-disubstituted piperidines, featuring an intramolecular nitrone cycloaddition with high regio- and diastereoselectivity, was achieved in six steps and 36-66% overall yield from commercially available gamma-butyrolactone or 1,4-butanediol. A new N-alkenyl nitrone enoate was used in this intramolecular nitrone cycloaddition, and the regioselectivity, diastereoselectivity, and reversibility of this cycloaddition were investigated.


Terahertz liquid crystal programmable metasurface based on resonance switching.
A programmable metasurface based on liquid crystal is of great significance to versatile dynamic wave manipulation such as beamforming and beam steering. One of the biggest obstacles currently is the lack of a simple way to multi-bit programming scheme for massive electrically addressable arrays, which limits its application and magnifies drawbacks like unavoidable symmetrical beam diffraction. Here, we put forward the concept of a liquid crystal metasurface based on a resonance switching mechanism for quasi-2-bit coding control, which is established upon interdigital structure electrodes. This enables a more elaborate control of meta-unit and a quasi-2-bit modulation based on a universal binary coding system to be realized. Our design could suppress unwanted -1 diffraction order with a maximum single-beam scanning angle of ± 21° under active beam manipulation. This concept paves the way for a feasible and robust multi-bit coding scheme of a liquid crystal metasurface, which is promising for THz applications such as spatial light modulators and wireless communication.


Caspase recruitment domains for protein interactions in cellular signaling (Review).
The caspase recruitment domain (CARD), a well‑known protein interaction module, belongs to the death domain (DD) superfamily, which includes DDs, death effector domains, and pyrin domains. The DD superfamily mediates the protein interactions necessary for apoptosis and immune cell signaling pathways. Among these domains, the CARD has been studied extensively as it mediates important cellular signaling events that are associated with various human diseases including cancer, neuro‑degenerative diseases and immune disorders. Homo‑type and hetero‑type CARD‑CARD interactions mediate the formation of large signaling complexes, including caspase‑activating complexes and downstream signaling complexes. The present review summarizes and discusses the results of structural studies of various CARDs and their complexes. These studies shed light on the mechanisms that control the assembly and disassembly of signaling complexes and provide an improved understanding of cellular signaling processes.


A unique scenario for coronary atherectomy.
Despite several attempts, balloon angioplasty of a slightly eccentric stenotic lesion in the proximal right coronary artery failed to result in any increase of luminal diameter. Following disruption and partial removal of a fibrous atherosclerotic cap using directional atherectomy, subsequent balloon angioplasty was highly successful.


Clinical potential of implantable wireless sensors for orthopedic treatments.
Implantable wireless sensors have been used for real-time monitoring of chemicals and physical conditions of bones, tendons and muscles to diagnose and study orthopedic diseases and injuries. Due to the importance of these sensors in orthopedic care, a critical review, which not only analyzes the underlying technologies but also their clinical implementations and challenges, will provide a landscape view on their current state and their future clinical role. By conducting an extensive literature search and following the leaders of orthopedic implantable wireless sensors, this review covers the battery-powered and battery-free wireless implantable sensor technologies, and describes their implementation for hips, knees, spine, and shoulder stress/strain monitoring. Their advantages, limitations, and clinical challenges are also described. Currently, implantable wireless sensors are mostly limited for scientific investigations and demonstrative experiments. Although rapid advancement in sensors and wireless technologies will push the reliability and practicality of these sensors for clinical realization, regulatory constraints and financial viability in medical device industry may curtail their continuous adoption for clinical orthopedic applications. In the next five years, these sensors are expected to gain increased interest from researchers, but wide clinical adoption is still unlikely.


Inactivation of the ribonucleoside triphosphate reductase from Lactobacillus leichmannii by 2'-chloro-2'-deoxyuridine 5'-triphosphate: a 3'-2' hydrogen transfer during the formation of 3'-keto-2'-deoxyuridine 5'-triphosphate.
The ribonucleoside triphosphate reductase of Lactobacillus leichmannii converts the substrate analogue 2'-chloro-2'-deoxyuridine 5'-triphosphate (ClUTP) into a mixture of 2'-deoxyuridine triphosphate (dUTP) and the unstable product 3'-keto-2'-deoxyuridine triphosphate (3'-keto-dUTP). This ketone can be trapped by reduction with NaBH4, producing a 4:1 mixture of xylo-dUTP and dUTP. When [3'-3H]ClUTP is treated with enzyme in the presence of NaBH4, the isomeric deoxyuridines isolated after alkaline phosphatase treatment retained 15% of the 3H in ClUTP. Degradation of these isomeric nucleosides has established the location of the 3H in 3'-keto-dUTP as predominantly 2'(S). The xylo-dU had 98.6% of its label at the 2'(S) position and 1.5% at 2'(R). The isolated dU had 89.6% of its label at 2'(S) and 1.4% at 2'(R), with the remaining 9% label inferred to be at the 3'-carbon, this resulting from the direct enzymic production of dUTP. These results are consistent with enzymic production of a 1:1000 mixture of dUTP and 3'-keto-dUTP, where the 3'-hydrogen of ClUTP is retained at 3' during production of dUTP and is transferred to 2'(S) during production of 3'-keto-dUTP. The implications of these results and the unique role of the cofactor adenosylcobalamin (Ashley et al., 1986) are discussed in terms of reductase being a model for the B12-dependent rearrangement reactions.


Associations for BCO2, PCSK9, and TR1B1 Polymorphism and Lifestyle Factors with Ischemic Stroke: A Nested Case-Control Study.
To investigate associations for polymorphisms in β-carotene 9',10'-oxygenase (BCO2, rs10431036 and rs11214109), proprotein convertase subtilisin kexin type 9 (PCSK9, rs11583680), and tribbles pseudokinase 1 (TRIB1, rs17321515 and rs2954029), as well as lifestyle factors, with ischemic stroke (IS). This nested case-control study included 161 patients with IS and 483 matched control individuals. We collected medical reports, lifestyle details, and blood samples from individuals and used the PCR-ligase detection reaction method to genotype single nucleotide polymorphisms (SNPs). The GA+AA genotype of rs10431036 (p<0.001) and rs17321515 (p=0.003), the CT+TT genotype of rs11214109 (p=0.005), and the TA+AA genotype of rs2954029 (p=0.006) in dominant models increased the risk of IS. In additive models, the GG genotype of rs17321515 (p=0.005) and the TT genotype of rs2954029 (p=0.008) increased the risk of IS. Adequate intake of fruits/vegetables reduced the risk of IS (p=0.005). Although there was no interaction between genes and fruits/vegetables, people with inadequate intake of fruits/vegetables who carried a risk genotype had a higher risk of IS than those only having inadequate fruits/vegetables intake or those only carrying a risk genotype. Also, the haplotypes AC, AT, and GT (comprising rs10431036 and rs11214109) and GT (comprising rs2954029 and rs17321515) were found to be associated with an increased risk of IS (p<0.05). Polymorphisms in BCO2 and TRIB1 and fruits/vegetables intake were associated with IS. These results provide the theoretical basis for gene screening to prevent chronic cerebrovascular diseases.


NK Cell Responses in Zika Virus Infection Are Biased towards Cytokine-Mediated Effector Functions.
Zika virus (ZIKV) is a mosquito-borne flavivirus that has emerged as a global concern because of its impact on human health. ZIKV infection during pregnancy can cause microcephaly and other severe brain defects in the developing fetus and there have been reports of the occurrence of Guillain-Barré syndrome in areas affected by ZIKV. NK cells are activated during acute viral infections and their activity contributes to a first line of defense because of their ability to rapidly recognize and kill virus-infected cells. To provide insight into NK cell function during ZIKV infection, we have profiled, using mass cytometry, the NK cell receptor-ligand repertoire in a cohort of acute ZIKV-infected female patients. Freshly isolated NK cells from these patients contained distinct, activated, and terminally differentiated, subsets expressing higher levels of CD57, NKG2C, and KIR3DL1 as compared with those from healthy donors. Moreover, KIR3DL1+ NK cells from these patients produced high levels of IFN-γ and TNF-α, in the absence of direct cytotoxicity, in response to in vitro stimulation with autologous, ZIKV-infected, monocyte-derived dendritic cells. In ZIKV-infected patients, overproduction of IFN-γ correlated with STAT-5 activation (r = 0.6643; p = 0.0085) and was mediated following the recognition of MHC class 1-related chain A and chain B molecules expressed by ZIKV-infected monocyte-derived dendritic cells, in synergy with IL-12 production by the latter cells. Together, these findings suggest that NK cells contribute to the generation of an efficacious adaptive anti-ZIKV immune response that could potentially affect the outcome of the disease and/or the development of persistent symptoms.


[Evaluation of bone density in women after thyroid cancer surgery and treatment with suppressive doses of L-thyroxine].
The aim of this work was to evaluate the degree of bone resorption and incidence of osteoporosis in female postmenopausal patients with differentiated thyroid cancer treated with suppressive doses of thyroxine. During the regular follow-up of women with differentiated thyroid cancer, densitometry of lumbar spine (L2-L4) and femoral head were performed. urine concentration of deoxypyridinoline and calcium-phosphate metabolism were also evaluated. Osteoporosis was diagnosed in 11% of patients, all without hormone replacement therapy (HRT). Mean bone density was significantly higher in patients treated with HRT. A decrease in bone mass was related to the duration of thyroxine therapy. The best results of bone mass density were obtained in patients on HRT and with short duration of thyroxine therapy. Deoxypiridinoline estimation did not exhibit significant differences between groups, however it was useful in the individual evaluation of bone resorption.


Structure and Biosynthesis of Crocagins: Polycyclic Posttranslationally Modified Ribosomal Peptides from Chondromyces crocatus.
Secondary metabolome mining efforts in the myxobacterial multiproducer of natural products, Chondromyces crocatus Cm c5, resulted in the isolation and structure elucidation of crocagins, which are novel polycyclic peptides containing a tetrahydropyrrolo[2,3-b]indole core. The gene cluster was identified through an approach combining genome analysis, targeted gene inactivation in the producer, and in vitro experiments. Based on our findings, we developed a biosynthetic scheme for crocagin biosynthesis. These natural products are formed from the three C-terminal amino acids of a precursor peptide and thus belong to a novel class of ribosomally synthesized and post-translationally modified peptides (RiPPs). We demonstrate that crocagin A binds to the carbon storage regulator protein CsrA, thereby inhibiting the ability of CsrA to bind to its cognate RNA target.


Late complications of tracheostomy.
Tracheostomy may be associated with numerous acute, perioperative complications, some of which continue to be relevant well after the placement of the tracheostomy. A number of clinically important unique late complications have been recognized as well, including the formation of granulation tissue, tracheal stenosis, tracheomalacia, tracheoinnominate-artery fistula, tracheoesophageal fistula, ventilator-associated pneumonia, and aspiration. The clinical relevance of these complications is considerable, as their manifestations range from minimally symptomatic to failure to wean from the ventilator (tracheal stenosis) to life-threatening hemorrhage (tracheoinnominate fistula). Treatment modalities vary depending upon the nature of the complication. For the most frequent complication, tracheal stenosis, a multidisciplinary approach utilizing bronchoscopy, laser, airway stents, and tracheal surgery is most effective.


An emphasis on molecular mechanisms of anti-inflammatory effects and glucocorticoid resistance.
Glucocorticoids (GC) are universally accepted agents for the treatment of anti-inflammatory and immunosuppressive disorders. They are used in the treatment of rheumatic diseases and various inflammatory diseases such as allergy, asthma and sepsis. They bind with GC receptor (GR) and form GC-GR complex with the receptor and exert their actions. On activation the GC-GR complex up-regulates the expression of nucleus anti-inflammatory proteins called as transactivation and down-regulates the expression of cytoplasmic pro-inflammatory proteins called as transrepression. It has been observed that transactivation mechanisms are notorious for side effects and transrepressive mechanisms are identified for beneficial anti-inflammatory effects of GC therapy. GC hampers the function of numerous inflammatory mediators such as cytokines, chemokines, adhesion molecules, arachidonic acid metabolites, release of platelet-activating factor (PAF), inflammatory peptides and enzyme modulation involved in the process of inflammation. The GC resistance is a serious therapeutic problem and limits the therapeutic response of GC in chronic inflammatory patients. It has been observed that the GC resistance can be attributed to cellular microenvironment changes, as a consequence of chronic inflammation. Various other factors responsible for resistance have been identified, including alterations in both GR-dependent and GR-independent signaling pathways of cytokine action, hypoxia, oxidative stress, allergen exposure and serum-derived factors. The present review enumerates various aspects of inflammation such as use of GC for treatment of inflammation and its mechanism of action. Molecular mechanisms of anti-inflammatory action of GC and GC resistance, alternative anti-inflammatory treatments and new strategy for reversing the GC resistance have also been discussed.


[Antiplatelet therapy in secondary stroke prevention].
New studies have refined the role of antiplatelet therapy in secondary prevention after noncardioembolic strokes. The first line antiplatelet therapy remains Aspirin. Clopidogrel and the combination aspirine plus dipyridamole are suitable alternatives with a slightly better protection. Ticagrelor, a reversible P2Y12 receptor inhibitor used in cardiology, has not demonstrated its superiority to Aspirin. Early after stroke, a double antiplatelet therapy combining Aspirin and clopidogrel is increasingly administered as a recent study demonstrated a decrease in the incidence of cerebrovascular events after a minor stroke or high-risk TIA. This benefit is particularly high in patients with severe atherosclerotic disease. The duration of the double antiplatelet therapy should not exceed three months to reduce the haemorrhagic risk.


Age in antiretroviral therapy programmes in South Africa: a retrospective, multicentre, observational cohort study.
As access to antiretroviral therapy (ART) expands, increasing numbers of older patients will start treatment and need specialised long-term care. However, the effect of age in ART programmes in resource-constrained settings is poorly understood. The HIV epidemic is ageing rapidly and South Africa has one of the highest HIV population prevalences worldwide. We explored the effect of age on mortality of patients on ART in South Africa and whether this effect is mediated by baseline immunological status. In this retrospective cohort analysis, we studied HIV-positive patients aged 16-80 years who started ART for the first time in six large South African cohorts of the International Epidemiologic Databases to Evaluate AIDS-Southern Africa collaboration, in KwaZulu-Natal, Gauteng, and Western Cape (two primary care clinics, three hospitals, and a large rural cohort). The primary outcome was mortality. We ascertained patients' vital status through linkage to the National Population Register. We used inverse probability weighting to correct mortality for loss to follow-up. We estimated mortality using Cox's proportional hazards and competing risks regression. We tested the interaction between baseline CD4 cell count and age. Between Jan 1, 2004, and Dec 31, 2013, 84,078 eligible adults started ART. Of these, we followed up 83,566 patients for 174,640 patient-years. 8% (1817 of 23,258) of patients aged 16-29 years died compared with 19% (93 of 492) of patients aged 65 years or older. The age adjusted mortality hazard ratio was 2·52 (95% CI 2·01-3·17) for people aged 65 years or older compared with those 16-29 years of age. In patients starting ART with a CD4 count of less than 50 cells per μL, the adjusted mortality hazard ratio was 2·52 (2·04-3·11) for people aged 50 years or older compared with those 16-39 years old. Mortality was highest in patients with CD4 counts of less than 50 cells per μL, and 15% (1103 of 7295) of all patients aged 50 years or older starting ART were in this group. The proportion of patients aged 50 years or older enrolling in ART increased with successive years, from 6% (290 of 4999) in 2004 to 10% (961 of 9657) in 2012-13, comprising 9% of total enrolment (7295 of 83 566). At the end of the study, 6304 (14%) of 44,909 patients still alive and in care were aged 50 years or older. Health services need reorientation towards HIV diagnosis and starting of ART in older individuals. Policies are needed for long-term care of older people with HIV. National Institutes of Health (National Institute of Allergy and Infectious Diseases), US Agency for International Development, and South African Centre for Epidemiological Modelling and Analysis.


Genetic evidence substantiates transmission of Trichinella spiralis from one swine farm to another.
Trichinella spiralis ranks seventh in the risk posed by foodborne parasites. It causes most human cases of trichinellosis and is the most frequent cause of Trichinella outbreaks on pig farms and in wild boar, worldwide. Veterinary inspectors seek the source of outbreaks in hopes of limiting the spread. Established molecular tools are inadequate for distinguishing among potential T. spiralis infection sources because genetic variability in these zoonotic pathogens is limited in Europe. Microsatellite markers proved successful in tracing an outbreak of T. britovi, a related parasite harboring much more genetic variation. Here, we successfully employed microsatellite markers to determine the genetic structure of T. spiralis isolates from two pig outbreaks, discovering notable uniformity among parasites within each farm and discovering an epidemiological link between these two outbreaks. The individual larvae from five isolates of T. spiralis from two pig farms and from ten wild boars were genotyped using nine microsatellite markers to examine their genetic structure. Notably uniform parasite populations constituted each farm outbreak, and the parasites from the first and second outbreaks resembled each other to a notable degree, indicating an epidemiological link between them. Wild boar harbored more genetically variable larval cohorts, distinguishing them from parasites isolated from domestic pigs. Microsatellite markers succeeded in distinguishing isolates of the highly homogeneous T. spiralis, aiding efforts to track transmission. Each outbreak was composed of a homogenous group of parasites, suggesting a point source of contamination.


A technique for the prevention of automatic implantable cardioverter defibrillator generator migration.
In order to prevent AICD generator migration in nine patients and correct chronic painful generator migration in three patients, we placed the AICD generator in an absorbable microfibrillar collagen pouch at the time of implant to facilitate fibrous capsule formation. Over a mean follow-up period of 14 +/- 2 months for the new implants, there have been no episodes of generator erosion, migration or infection. The three patients who suffered from generator migration have been symptom free for 12 +/- 2 months. We conclude that use of a microfibrillar collagen pouch at the time of AICD implant is a safe, inexpensive, and effective method for preventing generator migration.


Serum levels of miR-29, miR-122, miR-155 and miR-192 are elevated in patients with cholangiocarcinoma.
Cholangiocarcinoma (CCA) represents the second most common primary hepatic malignancy. Despite tremendous research activities, the prognosis for the majority of patients is still poor. Only in case of early diagnosis, liver resection might potentially lead to long-term survival. However, it is still unclear which patients benefit most from extensive liver surgery, highlighting the need for new diagnostic and prognostic stratification strategies. Serum concentrations of a 4 miRNA panel (miR-122, miR-192, miR-29b and miR-155) were analyzed using semi-quantitative reverse-transcriptase PCR in serum samples from 94 patients with cholangiocarcinoma undergoing tumour resection and 40 healthy controls. Results were correlated with clinical data. Serum concentrations of miR-122, miR-192, miR-29b and miR-155 were significantly elevated in patients with CCA compared to healthy controls or patients with primary sclerosing cholangitis without malignant transformation. Although preoperative levels of these miRNAs were unsuitable as a prognostic marker of survival, a strong postoperative decline of miR-122 serum levels was significantly associated with a favorable patients' prognosis. Analysis of circulating miRNAs represents a promising tool for the diagnosis of even early stage CCA. A postoperative decline in miRNA serum concentrations might be indicative for a favorable patients' outcome and helpful to identify patients with a good prognosis after extended liver surgery.


Expression of MS4A and TMEM176 Genes in Human B Lymphocytes.
The MS4A gene family in humans includes CD20 and at least 15 other genes. CD20 exists as homo-oligomers in the plasma membrane, however different MS4A proteins expressed in the same cell may hetero-oligomerize. Given the importance of CD20 in B-cell function and as a therapeutic target, we sought to explore the potential for CD20 hetero-oligomerization with other MS4A proteins. We investigated expression in primary human B-cells of the four MS4A genes previously shown to be expressed in human B-cell lines (MS4A4A, MS4A6A, MS4A7, MS4A8B), as well as two genes comprising the closely related TMEM176 gene family, with a view to identifying candidates for future investigation at the protein level. TMEM176A and TMEM176B transcripts were either not detected, or were detected at relatively low levels in a minority of donor B-cell samples. MS4A4A and MS4A8B transcripts were not detected in any normal B-cell sample. MS4A6A and MS4A7 transcripts were detected at low levels in most samples, however the corresponding proteins were not at the plasma membrane when expressed as GFP conjugates in BJAB cells. We also examined expression of these genes in chronic lymphocytic leukemia (CLL), and found that it was similar to normal B-cells with two exceptions. First, whereas MS4A4A expression was undetected in normal B-cells, it was expressed in 1/14 CLL samples. Second, compared to expression levels in normal B-cells, MS4A6A transcripts were elevated in 4/14 CLL samples. In summary, none of the MS4A/TMEM176 genes tested was expressed at high levels in normal or in most CLL B-cells. MS4A6A and MS4A7 were expressed at low levels in most B-cell samples, however the corresponding proteins may not be positioned at the plasma membrane. Altogether, these data suggest that CD20 normally does not form hetero-oligomers with other MS4A proteins and that there are unlikely to be other MS4A proteins in CLL that might provide useful alternate therapeutic targets.


Biomimetic seleninates and selenonates.
The synthesis of a variety of pyranose-, nucleoside-, (amino acid)-, and polyhydric-based seleninic and selenonic acids by DMDO oxidation of the corresponding selenoesters is reported, as well as some unusual coupling reactions of the seleninate and selenonate functionality with biological nucleophilic groups (sulfhydryl, indole, phenol, imidazole, carboxamide) that are found in proteins and enzyme active sites.


Morphological variations of intra-testicular arterial vasculature in bovine testis--a corrosion casting study.
Proper blood supply is necessary for the physiological function of every internal organ. The article offers the first classification of the bovine intra-testicular arteries. A corrosive study focused on the intra-testicular arterial vasculature was performed on 40 bovine testes. The vessels were analyzed accurately using MultiScanBase v.18.02 software. A corrosive study focused on the intra-testicular arteries was performed on 40 bovine testes. The vessels were analyzed accurately using MultiScanBase v.18.02 software. In bulls, the centripetal arteries tended to run straight to the mediastinal region, where they form knot-like vascular structures. Those structures are the origin for centrifugal recurrent branches, running peripherally. However, three basic types of intra-testicular arterial vasculature were noted. Type I had centrifugal, recurrent branches, running peripherally towards the surface of the testis but did not reach the tunica albuginea. Type II exhibited centrifugal, recurrent branches running more horizontally than type I. Type III is the most heterogeneous type, composed of other variform types of arteries not classified as type I or type II. Type II was most commonly observed as a vascular conglomerate of intra-testicular arteries within the arterial network of the mediastinum testis. In type III, artery diameter was significantly smaller than observed in types I and II (p < 0.01). Types I and II did not differ between each other regarding artery diameter (p > 0.05). Variations of the intra-testicular arterial vasculature in bovine testis may suggest that particular types of vessels play different physiological roles. The most common type of intra-testicular artery comprising the arterial network of the mediastinum testis was type II.


Ionic changes induced by excitatory amino acids in the rat cerebral cortex.
The ionic mechanisms underlying the action of excitatory amino acids were investigated in the rat motor cortex. Ion-selective microelectrodes were attached to micropipettes such that their tips were very close and local changes in extracellular concentration of sodium, calcium, and potassium ions elicited through ionophoretic applications of glutamate (Glu) and of its agonists N-methyl-D-aspartate (NMDA), quisqualate (Quis), and kainate (Ka) were measured. These agents produced moderate increases in [K+]o (up to 13 mM) but, in contrast, substantial tetrodotoxin-insensitive decreases in [Na+]o (maximally of 60 mM). NMDA-induced sodium responses could be blocked by manganese, while the Quis- and Ka-induced responses were not. Quis and Ka produced increases in [Ca2+]o or biphasic responses while NMDA, even with small doses, induced each time drastic decreases in [Ca2+]o (maximally of 1.15 mM), which could be attenuated or blocked by manganese but not by organic calcium channel blockers. NMDA responses could be abolished by reduced doses of 2-amino-phosphonovalerate. The largest Glu- and NMDA-induced calcium responses were observed in the superficial cortical layers, but such maxima disappeared after selective degeneration of pyramidal tract neurons. All amino acids produced sizeable reductions in the extracellular space volume. The following can be concluded. (i) All the excitatory amino acids tested induce an increased permeability to sodium and potassium ions. (ii) In addition, the NMDA-operated channels have specifically a large permeability for calcium, although calcium ions contribute only by less than 10% to the NMDA-induced inward currents.(ABSTRACT TRUNCATED AT 250 WORDS)


Induction of cachexia in mice by systemically administered myostatin.
Mice and cattle with genetic deficiencies in myostatin exhibit dramatic increases in skeletal muscle mass, suggesting that myostatin normally suppresses muscle growth. Whether this increased muscling results from prenatal or postnatal lack of myostatin activity is unknown. Here we show that myostatin circulates in the blood of adult mice in a latent form that can be activated by acid treatment. Systemic overexpression of myostatin in adult mice was found to induce profound muscle and fat loss analogous to that seen in human cachexia syndromes. These data indicate that myostatin acts systemically in adult animals and may be a useful pharmacologic target in clinical settings such as cachexia, where muscle growth is desired.


Comparison of Olfactory Function before and After Endoscopic Sinus Surgery.
Olfactory loss in patients with chronic rhinosinusitis has been measured by different methods. However, the results have been variable, and it is not clear whether endoscopic sinus surgery significantly improves olfactory function. This study was performed to evaluate the influence of endoscopic sinus surgery on olfactory function in patients with chronic rhinosinusitis. In this prospective analytic study, 73 patients (mean age, 39.63±12.94 years) with a diagnosis of polyps and sinusitis during 2011 were studied. The olfaction test was performed with three solutions; one with no odor (water) and two with phenylethyl alcohol (50% and 90% dilution, respectively). The patients' olfaction state were graded as no olfaction, or low, moderate or good olfaction before and 1 and 3 months after surgery, and was given scores between 0 and 3 and evaluated quantitatively. Right-side olfaction was improved in 68.5% and left side in 67.1% of patients. Mean olfaction score on the right and left side was significantly improved after surgery in comparison with basic scores (before and after on the right side: 0.95±0.88 and 2.02±1.04; before and after on the left side: 1.02±0.84 and 2.00±1.21; both P<0.001). Improvement after surgery in cases with left- and right-side anosmia was 66.7% and 61.9%, in low olfaction was 82.3% and 72.7% and in moderate olfaction was 66.7% and 80%. In patients with rhinosinusitis, endoscopic sinus surgery has considerable effect in improving olfactory function.


Mass-ablation-rate measurements in direct-drive cryogenic implosions using x-ray self-emission images.
A technique to measure the mass ablation rate in direct-drive inertial confinement fusion implosions using a pinhole x-ray framing camera is presented. In target designs consisting of two layers of different materials, two x-ray self-emission peaks from the coronal plasma were measured once the laser burned through the higher-Z outer layer. The location of the inner peak is related to the position of the ablation front and the location of the outer peak corresponds to the position of the interface of the two layers in the plasma. The emergence of the second peak was used to measure the burnthrough time of the outer layer, giving the average mass ablation rate of the material and instantaneous mass remaining. By varying the thickness of the outer layer, the mass ablation rate can be obtained as a function of time. Simulations were used to validate the methods and verify that the measurement techniques are not sensitive to perturbation growth at the ablation surface.


A parental requirement for dual-specificity phosphatase 6 in zebrafish.
Signaling cascades, such as the extracellular signal-regulated kinase (ERK) pathway, play vital roles in early vertebrate development. Signals through these pathways are initiated by a growth factor or hormone, are transduced through a kinase cascade, and result in the expression of specific downstream genes that promote cellular proliferation, growth, or differentiation. Tight regulation of these signals is provided by positive or negative modulators at varying levels in the pathway, and is required for proper development and function. Two members of the dual-specificity phosphatase (Dusp) family, dusp6 and dusp2, are believed to be negative regulators of the ERK pathway and are expressed in both embryonic and adult zebrafish, but their specific roles in embryogenesis remain to be fully understood. Using CRISPR/Cas9 genome editing technology, we generated zebrafish lines harboring germ line deletions in dusp6 and dusp2. We do not detect any overt defects in dusp2 mutants, but we find that approximately 50% of offspring from homozygous dusp6 mutants do not proceed through embryonic development. These embryos are fertilized, but are unable to proceed past the first zygotic mitosis and stall at the 1-cell stage for several hours before dying by 10 h post fertilization. We demonstrate that dusp6 is expressed in gonads of both male and female zebrafish, suggesting that loss of dusp6 causes defects in germ cell production. Notably, the 50% of homozygous dusp6 mutants that complete the first cell division appear to progress through embryogenesis normally and give rise to fertile adults. The fact that offspring of homozygous dusp6 mutants stall prior to activation of the zygotic genome, suggests that loss of dusp6 affects gametogenesis and/or parentally-directed early development. Further, since only approximately 50% of homozygous dusp6 mutants are affected, we postulate that ERK signaling is tightly regulated and that dusp6 is required to keep ERK signaling within a range that is permissive for proper embryogenesis. Lastly, since dusp6 is expressed throughout zebrafish embryogenesis, but dusp6 mutants do not exhibit defects after the first cell division, it is possible that other regulators of the ERK pathway compensate for loss of dusp6 at later stages.


Predictors of Detected Organophosphorus Pesticides Among Orang Asli Children Living in Malaysia.
Increasing use of pesticides in agriculture to control pest may result in permanent damage to the environment and consequently cause harmful health problems especially among infant and children. Due to pesticide's natural toxicity and its widespread use, it causes a serious threat to public health especially to this vulnerable group. The purpose of this study was to determine the organophosphorus pesticide urinary metabolite levels and its predictors among Orang Asli children of the Mah Meri tribe living in an agricultural island in Kuala Langat, Selangor. Data collection was carried out at an island in Kuala Langat, Selangor, where a total of 180 Orang Asli children of the Mah Meri tribe voluntarily participated in the study. Data were collected via a validated, modified questionnaire. Urinary organophosphate metabolites, namely dimethylphosphate, diethylphosphate, dimethylthiophosphate, dimethyldithiophosphate, diethylthiophosphate, and diethyldithiophosphate were measured to assess organophosphate pesticide exposure in children. Eighty-four (46.7%) of the respondents were positive for urine dialkyl phosphate metabolites. In multivariable analysis, children who frequently consumed apples had 4 times higher risk of pesticide detection than those who consumed apple less frequently. In addition, those who frequently ate cucumbers had 4 times higher risk for pesticide detection than those who ate cucumbers less frequently. Children with a father whose occupation involved high exposure to pesticides (agriculture) had 3 times higher risk of pesticide detection than those with a father in a low-risk occupation (nonagriculture). Almost half of the children (46.7%) in the study area tested positive for urinary dialkyl phosphate metabolite levels. Most of the metabolite levels were equal to or higher than that reported in other previous studies. Major factors associated with pesticide detection in children in this study were frequent intake of apple and cucumber and fathers who are working in an agricultural area.


The effects of pressure on valence tautomeric transitions of dinuclear cobalt complexes.
The effects of pressure on valence trautomeric transition behavior of two complexes, [{Co(tpa)}2(dhbq)].(PF6)3 (.(PF6)3) and [{Co(dpqa)}2(dhbq)](PF6)3 (II x (PF6)3) (tpa = tris(2-pyridylmethyl)amine, dpqa = di(2-pyridylmethyl)-N-(quinolin-2-ylmethyl)amine and dhbq = deprotonated 2,5-dihydroxy-1,4-benzoquinone), in the light of changes of magnetic susceptibilities were investigated; the results show that external pressure makes the SC + ET transition process of the two complexes into a general SC process only.


Influence of Tibial Component Position on Altered Kinematics Following Total Ankle Arthroplasty During Simulated Gait.
Ankle and hindfoot kinematics following total ankle arthroplasty (TAA) are poorly understood and it is unclear whether patients can replicate physiologic motion after TAA. Furthermore, the effect of implant position on TAA kinematics is unknown. The objective of this study was to compare ankle and hindfoot kinematics pre- and post-TAA during simulated gait and determine to what degree tibial component position correlated with variations in ankle kinematics. Eight midtibia cadaveric specimens were utilized in this institutional review board-approved study. The stance phase of gait was simulated both pre- and post-TAA in each specimen using a 6 degrees of freedom robotic platform. Ankle and hindfoot kinematics were measured from reflective markers attached to bones via surgical pins. The effect of tibial component position on absolute differences in ankle kinematics was assessed using linear regression. No differences were observed in ankle sagittal and coronal plane motion between the intact and TAA conditions. Differences in ankle joint kinematics were identified in the transverse plane, where internal talar rotation was significantly increased following TAA compared with the native condition. The medial-lateral position of the tibial component was found to correlate with the altered transverse plane motion observed after TAA (β = 1.861 degrees/mm, R2 = 0.72, P = .008). No significant differences in subtalar and talonavicular joint kinematics in any plane were observed comparing the pre- and post-TAA condition. This study demonstrated an increased internal rotation of the ankle in the transverse plane following TAA. This increase was correlated with the medial-lateral position of the tibial implant. This finding could have clinical implications for how tibial components are positioned during the operative procedure, and how implant design and position may affect ankle kinematics following TAA.


Spontaneous arterial hemorrhage as a complication of dengue.
Bleeding complications of dengue hemorrhagic fever such as epistaxis, gum bleeding, gastrointestinal bleeding, hypermenorrhea, hematuria, and thrombocytopenia have been documented. A 49-year-old female presented with complaints of intermittent high-grade fever for the past 4 days, lower abdominal pain and altered sensorium for 1 day. Laboratory investigations revealed severe anemia, mild thrombocytopenia, hypofibrinogenemia, and positive dengue serology. Emergency ultrasound examination of the abdomen revealed a possible rapidly expanding hematoma from the inferior epigastric artery and suggested urgent computed tomography (CT) angiogram for confirmation of the same. CT angiogram was confirmatory, and patient underwent emergency embolization of the right inferior epigastric artery. We report the first case of inferior epigastric hemorrhage and rectus sheath hematoma as a consequence of dengue.


MIR-27a regulates the TGF-β signaling pathway by targeting SMAD2 and SMAD4 in lung cancer.
The transforming growth factor-β (TGF-β) signaling pathway is associated with carcinogenesis and various biological processes. SMAD2 and SMAD4, which are putative tumor suppressors, have an important role in TGF-β signaling. The aberrant expression of these genes is implicated in some cancers. However, the mechanisms of SMAD2 and SMAD4 dysregulation are poorly understood. In this study, we observed that miR-27a was upregulated in lung cancer cell lines and patients. In addition, SMAD2 and SMAD4 genes were identified as targets of miR-27a by several target prediction databases and experimental validation. Functional studies revealed that miR-27a overexpression decreased SMAD2 and SMAD4 mRNA and protein levels. Furthermore, miR-27a contributed to cell proliferation and invasion by inhibiting TGF-β-induced cell cycle arrest. These results suggest that miR-27a may function as an oncogene by regulating SMAD2 and SMAD4 in lung cancer. Thus, miR-27a may be a potential target for cancer therapy.


Creative, Person Centered Narrative Psychopharmacotherapy (CP-CNP): From Theory to Clinical Practice.
Modern psychopharmacotherapy is a hot and controversial topic, glorified by some and vilified by others within the field of psychiatry that is by itself deeply divided and stigmatized. Mental disorders are multifactorial and polygenic phenomena with polymorphic clinical manifestations and poorly defined endophenotypes. They are characterized with high rate of morbidity, comorbidity, disability, mortality, and treatment failures. These relentless and commonly tragic disorders represent heavy burden on patients, their families and society and there is an urgent need to improve treatment successfulness in psychiatry. The best treatments are those that utilize and integrate multiple modalities. The time is ripe for psychiatry to find its transdisciplinary integrative soul and increase treatment effectiveness. Creation and fostering hope, meaning, personal responsibility, spirit of optimism and commitment can significantly contribute to overall positive response to pharmacotherapy, but in the other way round drug treatment can contribute to creation and fostering hope, meaning, personal responsibility, spirit of optimism and commitment. This paper addresses the concept of creative person-centered narrative psychopharmacotherapy (CP-CNP) as a transdisciplinary integrative strategy for improvement of the therapeutic effectiveness in patients with mental disorders. CP-NCP represents a set of tools that can allow higher effectiveness and efficiency in treatment of major mental disorders in a systemic way.


Oxidative stress and the role of novel thiol compounds at fertilization.
A new class of thiols, the 1-methyl-4-mercaptohistidines, has been found in high concentrations in invertebrate eggs. This family, called the ovothiols, has unusual redox properties, including the ability to confer a CN- -resistant NAD(P)H oxidase activity on ovoperoxidase, the enzyme that catalyzes the physiological crosslinking of the fertilization envelope with dityrosine residues. Ovothiol has a redox potential of 44 mV positive to glutathione and thus is maintained in the reduced state in eggs by reduced glutathione, without the need for an ovothiol reductase. We propose that high concentrations of reduced ovothiol are present in eggs to protect them from the oxidative stress caused by the respiratory burst of fertilization.


Targeting HIV protease: from peptidomimetics to non-peptide inhibitors.
The identification of HIV-1 protease as a target for therapeutic intervention against AIDS, soon followed by the resolution of its three-dimensional structure, has had a major impact on drug-design methodologies. The possible HIV-1 protease inhibitors that have been synthesized number in the thousands and exhibit amazing chemical diversity, but only a few happen to be useful for human therapy. This review covers the development of some of these inhibitors, the reasons for this limited success, current therapeutic problems and challenges remaining ahead.


Microhomology-mediated circular DNA formation from oligonucleosomal fragments during spermatogenesis.
The landscape of extrachromosomal circular DNA (eccDNA) during mammalian spermatogenesis, as well as the biogenesis mechanism, remains to be explored. Here, we revealed widespread eccDNA formation in human sperms and mouse spermatogenesis. We noted that germline eccDNAs are derived from oligonucleosomal DNA fragmentation in cells likely undergoing cell death, providing a potential new way for quality assessment of human sperms. Interestingly, small-sized eccDNAs are associated with euchromatin, while large-sized ones are preferentially generated from heterochromatin. By comparing sperm eccDNAs with meiotic recombination hotspots and structural variations, we found that they are barely associated with de novo germline deletions. We further developed a bioinformatics pipeline to achieve nucleotide-resolution eccDNA detection even with the presence of microhomologous sequences that interfere with precise breakpoint identification. Empowered by our method, we provided strong evidence to show that microhomology-mediated end joining is the major eccDNA biogenesis mechanism. Together, our results shed light on eccDNA biogenesis mechanism in mammalian germline cells.


cRGD-installed docetaxel-loaded mertansine prodrug micelles: redox-triggered ratiometric dual drug release and targeted synergistic treatment of B16F10 melanoma.
Combinatorial chemotherapy, which has emerged as a promising treatment modality for intractable cancers, is challenged by a lack of tumor-targeting, robust and ratiometric dual drug release systems. Here, docetaxel-loaded cRGD peptide-decorated redox-activable micellar mertansine prodrug (DTX-cRGD-MMP) was developed for targeted and synergistic treatment of B16F10 melanoma-bearing C57BL/6 mice. DTX-cRGD-MMP exhibited a small size of ca. 49 nm, high DTX and DM1 loading, low drug leakage under physiological conditions, with rapid release of both DTX and DM1 under a cytoplasmic reductive environment. Notably, MTT and flow cytometry assays showed that DTX-cRGD-MMP brought about a synergistic antitumor effect to B16F10 cancer cells, with a combination index of 0.37 and an IC50 over 3- and 13-fold lower than cRGD-MMP (w/o DTX) and DTX-cRGD-Ms (w/o DM1) controls, respectively. In vivo studies revealed that DTX-cRGD-MMP had a long circulation time and a markedly improved accumulation in the B16F10 tumor compared with the non-targeting DTX-MMP control (9.15 versus 3.13% ID/g at 12 h post-injection). Interestingly, mice treated with DTX-cRGD-MMP showed almost complete growth inhibition of B16F10 melanoma, with tumor inhibition efficacy following an order of DTX-cRGD-MMP > DTX-MMP (w/o cRGD) > cRGD-MMP (w/o DTX) > DTX-cRGD-Ms (w/o DM1) > free DTX. Consequently, DTX-cRGD-MMP significantly improved the survival rates of B16F10 melanoma-bearing mice. Importantly, DTX-cRGD-MMP caused little adverse effects as revealed by mice body weights and histological analyses. The combination of two mitotic inhibitors, DTX and DM1, appears to be an interesting approach for effective cancer therapy.


alpha-D-Glucopyranosyl fluoride as a D-glucopyranosyl donor for a glycosyltransferase complex from Streptococcus mutans FA1.
alpha-D-glucopyranosyl fluoride can serve as the D-glucopyranosyl donor for the glycosyltransferase from Streptococcus mutans. The products of the reaction are a D-glucan of high molecular weight and fluoride ion. The rate of reaction was measured by an electrode specific for the fluoride ion. The reaction was inhibited by the substrate at concentrations greater than 30 mM, but was not affected by fluoride ion. There was little inhibition of the reaction by a series of monosaccharides, except for 2-amino-2-deoxy-D-glucose, D-mannitol, and 3-deoxy-D-ribo-hexose. Maltose, isomaltose, isomaltotriose, and D-fructose all stimulated the release of fluoride from alpha-D-glucopyranosyl fluoride.


Sensitive Monitoring of Enterobacterial Contamination of Food Using Self-Propelled Janus Microsensors.
Food poisoning caused by bacteria is a major cause of disease and death worldwide. Herein we describe the use of Janus micromotors as mobile sensors for the detection of toxins released by enterobacteria as indicators of food contamination. The micromotors are prepared by a Pickering emulsion approach and rely on the simultaneous encapsulation of platinum nanoparticles for enhanced bubble-propulsion and receptor-functionalized quantum dots (QDs) for selective binding with the 3-deoxy-d-manno-oct-2-ulosonic acid target in the endotoxin molecule. Lipopolysaccharides (LPS) from Salmonella enterica were used as target endotoxins, which upon interaction with the QDs induce a rapid quenching of the native fluorescence of the micromotors in a concentration-dependent manner. The micromotor assay can readily detect concentrations as low as 0.07 ng mL-1 of endotoxin, which is far below the level considered toxic to humans (275 μg mL-1). Micromotors have been successfully applied for the detection of Salmonella toxin in food samples in 15 min compared with several hours required by the existing Gold Standard method. Such ultrafast and reliable approach holds considerable promise for food contamination screening while awaiting the results of bacterial cultures in a myriad of food safety and security defense applications.


Tracheal expression of Osiris gene family in Drosophila.
The Drosophila trachea is a premier genetic system to investigate the fundamental mechanisms of tubular organ formation. Development of the trachea consists of the well understood early branch specification and migration processes, and the less clear later branch maturation process including the apical membrane expansion, cytoskeleton rearrangement, luminal matrix clearance, and air-filling. We identified seven members of the Osiris (Osi) gene family with obvious tracheal expression in Drosophila. In addition, HA-tagged Osi proteins are highly concentrated in vesicle-like structures at and near the apical membrane. Osi proteins are predicted to contain endocytic signals and transmembrane domains. The localization of Osi proteins is consistent with these predictions. Interestingly, the Drosophila tracheal tube maturation process also occurs at the apical membrane. Taken together, the localization of Osi proteins suggest that these proteins are likely involved in tube maturation through vesicular trafficking or interacting with other apical membrane proteins.


Drinking games and college students. Part 2: Nursing implications.
In Part 1 of this article, published in the February 2010 issue, the problem of drinking game participation by U.S. college students was described. College students may play these games for reasons of peer acceptance and social interaction. Unfortunately, approximately two thirds of U.S. college students participate in this risky binge drinking behavior, from which serious consequences and harms can result. In this article, implications for community and mental health nurses are discussed. Nurses in a variety of settings have unique opportunities to educate, counsel, treat, and refer these students regarding the risks and protections of this behavior.


The Role of Interchain Force and/or Chain Entanglement in the Melt Strength and Ductility of PLA-Based Materials.
As an eco-friendly material, PLA was a desirable alternative to polyethylene and polypropylene films due to its biodegradability. The preferable melt strength of PLA-based materials was a key factor in ensuring its processing using extrusion blow. This paper focuses on the influence of interchain force and/or chain entanglement on the melt strength and ductility of PLA-based materials in recent years. In addition, the preparation of PLA-based materials via physical blending or reactive processing was also summarized. The blending of PLA with a flexible heteropolymer, driven by the interchain force and/or chain entanglements, were characterized as a practicable method for toughening PLA-based materials. Also, the restructuring of PLA chains, by branching based on chain entanglement, was suitable for increasing chain entanglements in PLA matrix, yielding satisfactory melt strength and ductility. This review aims to elucidate the relationship between interchain forces and/or entanglement with the melt strength and ductility of PLA-based materials. An essential and systematic understanding of the tailoring melt strength and rheological properties of PLA by interchain forces and/or entanglement was apt to improve and perfect the processing technology of the extrusion blow, and consequently improve the tensile strength and toughness of PLA films.


People with dementia as peer workers, challenges, and benefits: a thematic analysis and nominal groups study.
There are national initiatives to involve service users in service delivery. However, programs employing people with dementia as peer support workers (PSWs) in memory services are in their infancy. This study is the first to explore the challenges and benefits to staff and peers involved in such a program. Focus groups, structured based on nominal groups (NG) methodology were run with PSWs and clinical staff from two memory services. In total, there were 12 participants, with three focus groups: PSWs alone (n = 3); staff members alone (n = 6); and PSWs and staff members combined (n = 6). Data were analyzed through thematic analysis of recorded session content and the ranking of themes inherent in an NG approach. Perceived benefits of the PSW program were similar for staff and PSWs and included personal benefits for PSWS and stereotype reduction for staff. More challenges were reported by staff than PSWs, but both groups agreed that role definition and dealing with the cognitive deterioration inherent in dementia were key issues. The PSW program does have benefits for involved staff and PSWs. However, the challenges identified highlight the need for careful and consensual setup and consideration of power dynamics, with agreed roles and clear guidelines to deal with cognitive deterioration.


[A case of neonatal galactosemia].
The paper describes a rare case of hereditary thesaurismosis, galactosemia, in a full-term neonate girl aged 12 days with morphologically verified fetal giant-cell cholestatic hepatitis with the development of ascitis and jaundice.