Evaluation of liver perfusion in diabetic patients using 99mTc-sestamibi.
The liver is an important organ for various aspects of glucose metabolism, including glucose uptake, storage, and synthesis. It is a major organ in the metabolic process with perfusion provided by both the portal vein and hepatic artery. In diabetic patients organ perfusion is reduced and this is linked to atherosclerosis, and as a result complications occur. In this study, we aimed to evaluate liver perfusion by scintigraphic methods in diabetic patients. We retrospectively investigated 1,100 myocardial perfusion scintigraphies taken between January 2011 and December 2012 at Canakkale Onsekiz Mart University Medical Faculty Nuclear Medicine Department. A total of 66 patients who were diagnosed with diabetes mellitus and had myocardial perfusion scintigraphies were included in the study. The control subjects included 127 patients without diabetes mellitus who were chosen at random. Patients with chronic liver disease were not included in the study. The values from liver regions of interest (liver-ROI) rates and heart regions of interest (heart-ROI) rates were compared between the patients and controls. Patients were grouped according to the presence of diabetes. In the diabetes mellitus group, the liver-ROI average was lower (p = 0.66) than in the controls. In the control group, the average liver-ROI/heart-ROI ratios were higher than the ratio in the diabetes mellitus group (p = 0.019). Multivariate variance analysis showed that the diabetes mellitus liver-ROI/heart-ROI ratio was independent of other risk factors (p = 0.003; F: 9.6). Powered by Editorial Manager(®) and ProduXion Manager(®) from Aries Systems Corporation. This study shows that liver perfusion in diabetic patients is reduced compared with those without diabetes. Prospective studies with larger patient groups are required.


Step brightness changes of distant mountain ridges and their perception.
When successive ridges of distant mountains are seen, observers often report that, near the ridge where the brightness changes abruptly, the upper part of the nearer ridge appears darker than at its lower portions. Similarly, they report that the base of the more distant mountain seems brighter adjacent to the nearer ridge than on its upper portions. The explanation of this phenomenon, known as the step contrast effect, is a special case of Mach bands. It is usually attributed to a visual illusion involving lateral inhibition in the eye, which is most apparent in the vicinity of step brightness changes. Using analytic techniques and numerical integrations to simulate the airlight-induced brightness distributions of such scenes, we show that in many cases the perceived brightness distribution is qualitatively similar to the true brightness distribution and thus is not a visual illusion.


Contralateral prophylactic mastectomy for unilateral breast cancer in women at average risk: Systematic review of patient reported outcomes.
The rate of contralateral prophylactic mastectomy (CPM) in women with early, unilateral cancer is relatively high and is increasing around the world a previous study. Women choose this option for many reasons other than reducing their risk of future cancer, including symmetry, reasons related to breast reconstruction and attempting to manage fear of recurrence. This systematic review evaluated patient-reported quality of life outcomes following CPM. A literature search of MEDLINE, PubMed and PsycINFO was performed to February 2019. Abstracts and full-text articles were assessed for eligibility according to pre-determined criteria. Data were extracted into evidence tables for analysis. A total of 19 articles met eligibility criteria and were included in analysis. These included patient-reported data from 6088 women undergoing CPM. They reported high levels of satisfaction with the decision for surgery, low levels of decisional regret and high satisfaction with cosmesis and reconstruction. Breast-specific and general quality of life was high overall but was even better in women choosing breast reconstruction after surgery. Fear of cancer recurrence was high after CPM. Depression, distress and a negative impact on body image were evident; however, levels were high in both CPM and non-CPM groups. This study provides information that can be used by surgeons and psychologists when counselling women about the potential benefits and harms of CPM. This process must include discussion about the trade-offs such as body image issues and ongoing fear of recurrence in addition to the positive aspect of cancer risk reduction. Women are unlikely to regret their decision for CPM.


A randomized study of cisplatin and 5-FU hepatic arterial infusion chemotherapy with or without adriamycin for advanced hepatocellular carcinoma.
This multicenter, randomized, open-labeled, clinical trial evaluated the efficacy and safety of cisplatin/5-fluorouracil (5-FU) hepatic arterial infusion chemotherapy (CF-HAIC) versus adriamycin adding to CF-HAIC (ACF-HAIC) in advanced HCC patients. Fifty-six patients with advanced HCC were randomized to two treatment groups: (1) CF-HAIC group [n = 29, 5-FU, 500 mg/m(2) on days 1-3, and cisplatin, 60 mg/m(2) on day 2] and (2) ACF-HAIC group [n = 27, adriamycin, 50 mg/m(2) on day 1, 5-FU, 500 mg/m(2) on days 1-3, and cisplatin, 60 mg/m(2) on day 2] every 4 weeks via an implantable port system. Primary efficacy endpoint was overall survival (OS). Treatment response and time to progression were secondary endpoints. Treatment response rates did not differ significantly between the two treatment groups. Time to progression (5.4 vs. 5.8 months, P = 0.863) and OS (11.1 vs. 8.8 months, P = 0.448) were not significantly different. When the factors affecting patient OS were analyzed, disease control rate [P < 0.001, HR 6.437 (95% CI 2.580-16.064)] was independently associated with OS. Age (≥60 years) and serum AFP level (≥200 ng/dL) also were significant factors for OS [P = 0.007, HR 4.945 (95% CI 1.543-15.850), P = 0.048, HR 2.677 (95% CI 1.010-7.095), respectively]. Grade 4 treatment-related toxicity and mortality was not observed in both groups. Although both HAIC regimens are safe and effective in patients with advanced HCC, HAIC adding adriamycin did not show delayed tumor progression and survival benefit compared to CF-HAIC in advanced HCC.


Clinically-staged T3N0 rectal cancer: is preoperative chemoradiotherapy the optimal treatment?
Preoperative chemoradiotherapy has been widely adopted as the standard of care for stage II-III rectal cancers. However, patients with T3N0 lesions had been shown to have a better prognosis than other categories of locally advanced tumor. Thus, neoadjuvant chemoradiation is likely to be overtreatment in this subgroup of patients. Nevertheless, the low accuracy rate of preoperative staging techniques for detection of node-negative tumors does not allow to check this hypothesis. We analyzed a group of patients with cT3N0 low rectal cancer who underwent neoadjuvant chemoradiotherapy with the purpose of evaluating the incidence of metastatic nodes in the resected specimens. Between January 2002 and February 2008, 100 patients with low rectal cancer underwent clinical staging by means of endorectal ultrasound, computed tomography, positron emission tomography, and magnetic resonance imaging. All patients received preoperative 5-fluorouracil-based chemoradiotherapy and surgical resection with curative aim. Of 100 patients with locally advanced rectal cancer, 32 were clinically staged as T3N0M0. Pathological analysis showed the presence of lymph node metastases in nine patients (28%) (node-positive group). In the remaining 23 cases, clinical N stage was confirmed at pathology (node-negative group). Node-positive and node-negative groups differ only in the number of ypT3 tumors (P < .01). Our results indicate that immediate surgery for patients with cT3N0 rectal cancer represents an undertreatment risk in at least 28% of cases, making necessary the use of postoperative chemoradiotherapy. Preoperative chemoradiotherapy should be the therapy of choice on the grounds of the principle that overtreatment is less hazardous than undertreatment for cT3N0 rectal cancers.


Structural and electronic properties of CuSbS2 and CuBiS2: potential absorber materials for thin-film solar cells.
As the demand for photovoltaics rapidly increases, there is a pressing need for the identification of new visible light absorbing materials for thin-film solar cells that offer similar performance to the current technologies based on CdTe and Cu(In,Ga)Se(2). Metal sulphides are the ideal candidate materials, but their band gaps are usually too large to absorb significant fractions of visible light. However, by combining Cu(+) (low binding energy d(10) band) and Sb(3+)/Bi(3+) (low binding energy s(2) band), the ternary sulphides CuSbS(2) and CuBiS(2) are formed, which have been gathering recent interest for solar cell applications. Using a hybrid density functional theory approach, we calculate the structural and electronic properties of these two materials. Our results highlight the stereochemical activity of the Sb and Bi lone pair electrons, and predict that the formation of hole carriers will occur in the Cu d(10) band and hence will involve oxidation of Cu(I).


Regulation of transmembrane electrical potential gradient in rat hepatocytes in situ.
The transmembrane electrical potential gradient (Em) has been measured in hepatocytes from intact anesthetized rats using conventional intracellular microelectrodes under a variety of conditions. Em measurements in control animals were normally distributed around a mean of -35.5 +/- 4.6 mV (SD) with a coefficient of variation (CV) of 13.1% and a range of -26 to -54 mV. In individual livers, however, measurements of Em at a given point in time exhibited little cell-to-cell variation (cv of 4.5%). The Em was noted to fluctuate spontaneously over time and to change consistently in response to a variety of physiological stimuli including fasting (depolarization to -28.5 +/- 3.8 mV) and infusion of glucagon in physiological amounts (hyperpolarization to -45.0 +/- 1.8 mV). Hepatocyte Em abruptly depolarized (2-5 mV) after an intravenous bolus of taurocholate (3 mumol) or alanine (45 mumol), suggesting that both solutes exhibit electrogenic uptake. The Em returned to or below preinfusion values within 5 min. Continued infusion of alanine (10.8 mumol/min), but not taurocholate (810 nmol/min), caused a sustained and unexpected hyperpolarization of Em of 8.2 +/- 3.1 mV that lasted at least 60 min. In separate studies, alanine administration did not alter the biliary excretion of a taurocholate load. Taken together, these observations demonstrate that rat hepatocytes in situ are tightly coupled electrically and that physiological stimuli, including fasting, glucagon, and sodium-coupled solute uptake can change Em considerably over time. The late hyperpolarization of Em caused by alanine appears to offset the rise in intracellular Na+ associated with alanine uptake and preserve the Na+ electrochemical gradient such that Na+-coupled taurocholate transport is maintained.


Distance-dependent plasmon resonant coupling between a gold nanoparticle and gold film.
We present an experimental analysis of the plasmonic scattering properties of gold nanoparticles controllably placed nanometers away from a gold metal film. We show that the spectral response of this system results from the interplay between the localized plasmon resonance of the nanoparticle and the surface plasmon polaritons of the gold film, as previously predicted by theoretical studies. In addition, we report that the metal film induces a polarization to the single nanoparticle light scattering, resulting in a doughnut-shaped point spread function when imaged in the far-field. Both the spectral response and the polarization effects are highly sensitive to the nanoparticle-film separation distance. Such a system shows promise in potential biometrology and diagnostic devices.


Impact of seasonal variation in meteorological conditions on dry eye severity.
To compare dry eye (DE) diagnosis patterns by season in Miami vis-a-vis the US and examine differences in DE symptoms and signs by season in Miami. US veteran affairs (VA) patient visits with ICD-9 codes for DE (375.15) and routine medical examination (V70.0) from 2010 to 2013 were retrospectively analyzed to evaluate the seasonal pattern of DE diagnosis. A total of 365 patients with normal ocular anatomy were prospectively recruited from the Miami VA eye clinic from 2014 to 2016 for the assessment of symptoms and signs. While DE visit prevalence in Miami was about 10% lower than that of the rest of the country (22.5% vs 33.7%), Miami had roughly four times higher variability in DE visit prevalence throughout the year than the US. Peak values for DE symptoms in the Miami cohort aligned with peak DE prevalence seen in the retrospective sample, occurring in spring and fall. A similar, but less dramatic, pattern was noted with DE signs. The seasonal pattern in DE symptoms remained even after controlling for confounders including demographics and medication use. DE symptoms, and to a lesser degree signs, varied by month, with the highest severity of symptoms occurring in spring and fall, which corresponded with peak allergy season and weather fluctuations, respectively. These findings have important implications for season-specific diagnosis, treatment, and management of DE.


Connexin-43 upregulation in micrometastases and tumor vasculature and its role in tumor cell attachment to pulmonary endothelium.
The modulation of gap junctional communication between tumor cells and between tumor and vascular endothelial cells during tumorigenesis and metastasis is complex. The notion of a role for loss of gap junctional intercellular communication in tumorigenesis and metastasis has been controversial. While some of the stages of tumorigenesis and metastasis, such as uncontrolled cell division and cellular detachment, would necessitate the loss of intercellular junctions, other stages, such as intravasation, endothelial attachment, and vascularization, likely require increased cell-cell contact. We hypothesized that, in this multi-stage scheme, connexin-43 is centrally involved as a cell adhesion molecule mediating metastatic tumor attachment to the pulmonary endothelium. Tumor cell attachment to pulmonary vasculature, tumor growth, and connexin-43 expression was studied in metastatic lung tumor sections obtained after tail-vein injection into nude mice of syngeneic breast cancer cell lines, overexpressing wild type connexin-43 or dominant-negatively mutated connexin-43 proteins. High-resolution immunofluorescence microscopy and Western blot analysis was performed using a connexin-43 monoclonal antibody. Calcein Orange Red AM dye transfer by fluorescence imaging was used to evaluate the gap junction function. Adhesion of breast cancer cells to the pulmonary endothelium increased with cancer cells overexpressing connexin-43 and markedly decreased with cells expressing dominant-negative connexin-43. Upregulation of connexin-43 was observed in tumor cell-endothelial cell contact areas in vitro and in vivo, and in areas of intratumor blood vessels and in micrometastatic foci. Connexin-43 facilitates metastatic 'homing' by increasing adhesion of cancer cells to the lung endothelial cells. The marked upregulation of connexin-43 in tumor cell-endothelial cell contact areas, whether in preexisting 'homing' vessels or in newly formed tumor vessels, suggests that connexin-43 can serve as a potential marker of micrometastases and tumor vasculature and that it may play a role in the early incorporation of endothelial cells into small tumors as seeds for vasculogenesis.


Formononetin, a methoxy isoflavone, enhances bone regeneration in a mouse model of cortical bone defect.
The bone regeneration and healing effect of formononetin was evaluated in a cortical bone defect model that predominantly heals by intramembranous ossification. For this study, female Balb/c mice were ovariectomised (OVx) and a drill-hole injury was generated in the midfemoral bones of all animals. Treatment with formononetin commenced the day after and continued for 21 d. Parathyroid hormone (PTH1-34) was used as a reference standard. Animals were killed at days 10 and 21. Femur bones were collected at the injury site for histomorphometry studies using microcomputed tomography (μCT) and confocal microscopy. RNA and protein were harvested from the region surrounding the drill-hole injury. For immunohistochemistry, 5 µm sections of decalcified femur bone adjoining the drill-hole site were cut. μCT analysis showed that formononetin promoted bone healing at days 10 and 21 and the healing effect observed was significantly better than in Ovx mice and equal to PTH treatment in many aspects. Formononetin also significantly enhanced bone regeneration as assessed by calcein-labelling studies. In addition, formononetin enhanced the expression of osteogenic markers at the injury site in a manner similar to PTH. Formononetin treatment also led to predominant runt-related transcription factor 2 and osteocalcin localisation at the injury site. These results support the potential of formononetin to be a bone-healing agent and are suggestive of its promising role in the fracture-repair process.


Ubiquitin-dependent regulation of translesion polymerases.
In response to DNA damage, TLS (translesion synthesis) allows replicative bypass of various DNA lesions, which stall normal replication. TLS is achieved by low-fidelity polymerases harbouring less stringent active sites. In humans, Y-family polymerases together with Pol zeta (polymerase zeta) are responsible for TLS across different types of damage. Protein-protein interaction contributes significantly to the regulation of TLS. REV1 plays a central role in TLS because it interacts with all other Y-family members and Pol zeta. Ubiquitin-dependent regulatory mechanisms also play important roles in TLS. Ubiquitin-binding domains have been found in TLS polymerases and they might be required for TLS activity. Mono-ubiquitination of PCNA (proliferating-cell nuclear antigen), the central scaffold of TLS polymerases, is thought to promote TLS. In addition, both non-proteolytic and proteolytic polyubiquitination of PCNA and TLS polymerases has been demonstrated. Owing to their low fidelity, the recruitment of TLS polymerases is strictly restricted to stalled replication forks.


Completeness of main outcomes across randomized trials in entire discipline: survey of chronic lung disease outcomes in preterm infants.
To map the availability of information on a major clinical outcome--chronic lung disease--across the randomized controlled trials in systematic reviews of an entire specialty, specifically interventions in preterm infants. Survey of systematic reviews. Cochrane Database of Systematic Reviews. All Cochrane systematic reviews (as of November 2013) that had evaluated interventions in preterm infants. We identified how many of those systematic reviews had looked for information on chronic lung disease, how many reported on chronic lung disease, and how many of the randomized controlled trials included in the systematic reviews reported on chronic lung disease. We also randomly selected 10 systematic reviews that did not report on chronic lung disease and 10 that reported on any such outcomes and identified whether any information on chronic lung disease appeared in the primary reports of the randomized controlled trials but not in the systematic reviews. Whether availability of chronic lung disease outcomes differed by type of population and intervention and whether additional non-extracted data might have been available in trial reports. 174 systematic reviews with 1041 trials exclusively concerned preterm infants. Of those, 105 reviews looked for chronic lung disease outcomes, and 79 reported on these outcomes. Of the 1041 included trials, 202 reported on chronic lung disease at 28 days and 200 at 36 weeks postmenstrual; 320 reported on chronic lung disease with any definition. The proportion of systematic reviews that looked for or reported on chronic lung disease and the proportion of trials that reported on chronic lung disease was larger in preterm infants with respiratory distress or support than others (P<0.001) and differed across interventions (P<0.001). Even for trials on children with ventilation interventions, only 56% (48/86) reported on chronic lung disease. In the random sample, 45 of 84 trials (54%) had no outcomes on chronic lung disease in the systematic reviews, and only 9/45 (20%) had such information in the primary trial reports. Most trials included in systematic reviews of interventions on preterm infants are missing information on one of the most common serious outcomes in this population. Use of standardized clinical outcomes that would have to be collected and reported by default in all trials in a given specialty should be considered.


Genetic analysis of spermidine synthase from Leishmania donovani.
The polyamine biosynthetic pathway of protozoan parasites has been validated as a target in antiparasitic chemotherapy. To investigate this pathway at the biochemical and genetic level in a model parasite, the gene encoding spermidine synthase (SPDSYN), a key polyamine biosynthetic enzyme, has been cloned and sequenced from Leishmania donovani. The L. donovani SPDSYN gene encodes a polypeptide of 300 amino acids that exhibits 56% amino acid identity with the human counterpart. SPDSYN is present as a single copy gene in the leishmanial genome and encodes a 1.6 kb transcript. Employing SPDSYN flanking sequences to construct drug resistance cassettes, a Deltaspdsyn knockout strain of L. donovani was created by double targeted gene replacement. This Deltaspdsyn line could not convert putrescine to spermidine and was auxotrophic for polyamines. The polyamine auxotrophy could be circumvented by exogenous spermidine but not by putrescine (1,4-diaminobutane), cadaverine (1,5-diaminopentane), 1,3-diaminopropane, or spermine. Incubation of the null mutant in polyamine-deficient medium resulted in a rapid depletion in the intracellular spermidine level with a concomitant elevation of the putrescine pool. In addition, the level of trypanothione, a spermidine-containing thiol, was reduced, whereas the glutathione pool increased 3-4-fold. These data establish that SPDSYN is an essential enzyme in L. donovani promastigotes. The molecular and cellular reagents created in this investigation provide a foundation for subsequent structure-function and inhibitor design studies on this key polyamine biosynthetic enzyme.


GnRH and its receptor (GnRH-R) are expressed in the canine placenta and uterus.
In reproductive tissues, GnRH participates in the regulation of cell growth and proliferation by direct binding to the GnRH-R, which is essential for embryo implantation. However, there is no study on the expression and cellular localization of GnRH and GnRH-R in the canine uterus and placenta. Therefore, bitches were ovariohysterectomized 10 to 12 days after mating (vaginal cytology and progesterone measurement), the uteri were flushed, and if embryos were detectable, bitches were allocated to the embryo positive group (E-pos.; preimplantation, n = 5). Other bitches were operated at later stages and, dependent on the gestational age, either allotted to the post-implantation group (Day 18-25 after mating, n = 9), or the mid-gestation group (Day 30-40 after mating, n = 3). Dogs negative in embryo flushing served as controls (E-neg.; controls, n = 5). Samples of the entire uterine wall were taken from the middle of the horn in E-neg. and E-pos. groups, and from placental and interplacental uterine sites in post-implantation and mid-gestation groups. GnRH-R expression was localized at the mRNA and protein levels by immunohistochemistry and in situ hybridization. The expression of GnRH and GnRH-R mRNA was assessed by semiquantitative polymerase chain reaction. Additionally, both GnRH and GnRH-R mRNA were expressed in all tissues examined until mid-gestation. Relative expression of GnRH was higher than that of GnRH-R (P < 0.05). During the post-implantation stage, GnRH-R expression was significantly higher in uteroplacental than in interplacental tissues. In the uterus, GnRH-R stained strongly in the surface and glandular epithelial cells, and seemed to be weaker in myometrium and stroma. Placental signals were predominantly localized in fetal trophoblast cells and to a lesser extent in maternal decidual cells. These findings suggest a local regulatory function of GnRH during early canine pregnancy.


Growing-season temperature and precipitation are independent drivers of global variation in xylem hydraulic conductivity.
Stem xylem-specific hydraulic conductivity (KS ) represents the potential for plant water transport normalized by xylem cross section, length, and driving force. Variation in KS has implications for plant transpiration and photosynthesis, growth and survival, and also the geographic distribution of species. Clarifying the global-scale patterns of KS and its major drivers is needed to achieve a better understanding of how plants adapt to different environmental conditions, particularly under climate change scenarios. Here, we compiled a xylem hydraulics dataset with 1,186 species-at-site combinations (975 woody species representing 146 families, from 199 sites worldwide), and investigated how KS varied with climatic variables, plant functional types, and biomes. Growing-season temperature and growing-season precipitation drove global variation in KS independently. Both the mean and the variation in KS were highest in the warm and wet tropical regions, and lower in cold and dry regions, such as tundra and desert biomes. Our results suggest that future warming and redistribution of seasonal precipitation may have a significant impact on species functional diversity, and is likely to be particularly important in regions becoming warmer or drier, such as high latitudes. This highlights an important role for KS in predicting shifts in community composition in the face of climate change.


Giant piezoelectricity of Sm-doped Pb(Mg1/3Nb2/3)O3-PbTiO3 single crystals.
High-performance piezoelectrics benefit transducers and sensors in a variety of electromechanical applications. The materials with the highest piezoelectric charge coefficients (d 33) are relaxor-PbTiO3 crystals, which were discovered two decades ago. We successfully grew Sm-doped Pb(Mg1/3Nb2/3)O3-PbTiO3 (Sm-PMN-PT) single crystals with even higher d 33 values ranging from 3400 to 4100 picocoulombs per newton, with variation below 20% over the as-grown crystal boule, exhibiting good property uniformity. We characterized the Sm-PMN-PT on the atomic scale with scanning transmission electron microscopy and made first-principles calculations to determine that the giant piezoelectric properties arise from the enhanced local structural heterogeneity introduced by Sm3+ dopants. Rare-earth doping is thus identified as a general strategy for introducing local structural heterogeneity in order to enhance the piezoelectricity of relaxor ferroelectric crystals.


Tumor necrosis factor and immune interferon synergistically induce cytochrome b-245 heavy-chain gene expression and nicotinamide-adenine dinucleotide phosphate hydrogenase oxidase in human leukemic myeloid cells.
Recombinant tumor necrosis factor (rTNF) and rIFN-gamma induce in the human leukemia cell lines HL-60, ML3, and U937 the accumulation of transcripts of the X chromosome-linked chronic granulomatous disease (X-CGD) gene, encoding the 91-kD heavy chain of cytochrome b-245, a component of the NADPH oxidase of phagocytic cells. The gene is induced within 6 h by either cytokine, and its accumulation is observed upon induction with rIFN-gamma up to 5 d. The combined effect of the two cytokines is more than additive. rIFN-gamma also induces accumulation of X-CGD mRNA in immature myeloid cells from peripheral blood of chronic myeloid leukemia (CML) patients, whereas rTNF has almost no effect. The cells from CML patients constitutively express TNF mRNA, suggesting that endogenously produced TNF may play a role in the effect of rIFN-gamma on these cells. rTNF induces X-CGD gene expression in the myeloid cell lines acting, at least in part, at the transcriptional level, as shown in nuclear run-on experiments. The gene encoding the 22-kD light chain of cytochrome b-245 is constitutively expressed in the human myeloid cell lines and the accumulation of its transcripts is affected by neither rTNF nor rIFN-gamma, rTNF and rIFN-gamma synergistically to induce the cell lines to express the cytochrome b-245 heterodimer (as evaluated by its visible spectrum), and to produce NADPH oxidase activity and H2O2 upon stimulation with phorbol diesters.


Application of microbial indices to assess the performance of a sequencing batch reactor and membrane bioreactor treating municipal wastewater.
Microbial indexes of filamentous bacterial density were evaluated for their potential to act as indicators of sludge settling characteristics for sequencing batch reactor (SBR) and membrane bioreactor (MBR) treatment options. These options were operated using settled sewage over a range of aerated loading rates from 0.05 to 0.4/d and the evolution of protozoan and metazoan populations analysed. A filament density score ranging between 0 and 5, which has previously been applied to conventional activated sludge processes, was shown also to be a useful tool for the SBR and MBR, and was correlated to the settleability of the mixed liquor from both reactors. Due to the hydrodynamics of both systems and the subsequent differences in mixed liquors, optimum performance for each bioreactor was obtained under different operating conditions. Although there was no correlation between the numbers of any given protozoan species and plant operating conditions, there was a clear dependence between operating conditions and protozoan diversity. The highest diversity was found when operating conditions were optimum for both the SBR and MBR.


The importance of the stem cell marker prominin-1/CD133 in the uptake of transferrin and in iron metabolism in human colon cancer Caco-2 cells.
As the pentaspan stem cell marker CD133 was shown to bind cholesterol and to localize in plasma membrane protrusions, we investigated a possible function for CD133 in endocytosis. Using the CD133 siRNA knockdown strategy and non-differentiated human colon cancer Caco-2 cells that constitutively over-expressed CD133, we provide for the first time direct evidence for a role of CD133 in the intracellular accumulation of fluorescently labeled extracellular compounds. Assessed using AC133 monoclonal antibody, CD133 knockdown was shown to improve Alexa488-transferrin (Tf) uptake in Caco-2 cells but had no impact on FITC-dextran or FITC-cholera-toxin. Absence of effect of the CD133 knockdown on Tf recycling established a role for CD133 in inhibiting Tf endocytosis rather than in stimulating Tf exocytosis. Use of previously identified inhibitors of known endocytic pathways and the positive impact of CD133 knockdown on cellular uptake of clathrin-endocytosed synthetic lipid nanocapsules supported that CD133 impact on endocytosis was primarily ascribed to the clathrin pathway. Also, cholesterol extraction with methyl-β-cyclodextrine up regulated Tf uptake at greater intensity in the CD133(high) situation than in the CD133(low) situation, thus suggesting a role for cholesterol in the inhibitory effect of CD133 on endocytosis. Interestingly, cell treatment with the AC133 antibody down regulated Tf uptake, thus demonstrating that direct extracellular binding to CD133 could affect endocytosis. Moreover, flow cytometry and confocal microscopy established that down regulation of CD133 improved the accessibility to the TfR from the extracellular space, providing a mechanism by which CD133 inhibited Tf uptake. As Tf is involved in supplying iron to the cell, effects of iron supplementation and deprivation on CD133/AC133 expression were investigated. Both demonstrated a dose-dependent down regulation here discussed to the light of transcriptional and post-transciptional effects. Taken together, these data extend our knowledge of the function of CD133 and underline the interest of further exploring the CD133-Tf-iron network.


Nalidixic acid: an antibacterial paradox.
Nalidixic acid was found to be most bactericidal against various species of gram-negative bacteria at 50 to 200 mug/ml. With all species tested, increases in the concentration of nalidixic acid above this range reduced, rather than increased, its bactericidal effect so that, at levels in the region of 400 mug/ml, the drug was relatively bacteriostatic. Therefore, the mode of action of nalidixic acid at various concentrations was investigated. It was found that at the most bactericidal concentration deoxyribonucleic acid synthesis, but no ribonucleic acid (RNA) or protein synthesis, was inhibited. However at higher concentrations, where the drug is least bactericidal, both RNA and protein synthesis were found to be inhibited. Results are presented which suggest that the protein synthesis inhibition is a secondary manifestation of the ability of the drug to inhibit RNA synthesis, and that of RNA synthesis is most likely the second target site for the action of the drug when bacteria are exposed to it in high concentrations. The clinical implications of these findings are discussed.


HIV type 1 mother-to-child transmission facilitated by distinctive glycosylation sites in the gp120 envelope glycoprotein.
The human immunodeficiency virus type 1 (HIV-1) characteristics associated with mother-to-child transmission (MTCT) are still poorly understood. We studied a cohort of 30 mothers from Rwanda infected with HIV-1 subtype A or C viruses of whom seven infected their children either during gestation or soon after birth. CD4 counts and viral load did not significantly differ between nontransmitting mother (NTM) versus transmitting mother (TM) groups. In contrast to earlier studies we not only analyzed and compared the genotypic characteristics of the V1-V5 region of the gp120 envelope of viruses found in TM and their infected children, but also included data from the NTM. No differences were found with respect to length and number of potential N-glycosylation sites (PNGS) in the V1-V2 and the V1-V5 region. We identified that viruses with a PNGS on positions AA234 and AA339 were preferably transmitted and that viruses with PNGS-N295 showed a disadvantage in transmission. We also showed that the frequency of PNGS-N339 in the viruses of TM and infected children was significantly higher than the frequency in NTM in our cohort and in viruses undergoing sexual transmission while the frequency of PNGS-N295 in children was significantly lower than the frequency in TM and acute horizontal infections. Collectively, our results provide evidence that the presence of the PNGS-N339 site and absence of the PNGS-N295 site in the gp120 envelope confers an advantage to HIV-1 when considering MTCT.


Extremely low birth weight children and their peers: a comparison of preschool performance.
Though not well studied, extremely low birth weight (ELBW; < 1000 g) appears to be a major risk factor for developmental disability, with most affected children experiencing school problems (40% to 64%) rather than severe handicap (25%). This study marks the first published US attempt to document prospectively the developmental/educational progress of a cohort of predominantly white, middle-class ELBW children with randomly selected and matched heavier birth weight (1500 through 2500 g and > 2500 g) peer comparison groups. Sixty ELBW children and 60 peers were administered a test battery at age 4 years, including the McCarthy Scales of Children's Abilities, Peabody Picture Vocabulary Test, and Beery Test of Visual-Motor Integration. The ELBW group mean scores were significantly lower than those of the peer groups on every measure, although generally still within 1 SD of the test mean. Twenty-three percent were clearly disabled; 26% had optimal development, having attained at least average scores on all measures; and 51% attained borderline scores globally or had an average cognitive score, but specifically poor performance in one or more areas. Comparison groups were 2 1/2 times more likely to have optimal development and had mean cognitive scores 15 to 18 points higher than the ELBW group. In summary, weaker performance on all measures exists prior to school entry among nondisabled ELBW children compared with their peers. It is unclear whether these data portend emerging school-based disabilities or describe a continuing recovery process to be completed in middle childhood. Continued follow-up of this cohort at 7 and 10 years of age will address these questions.


Genome-wide evolutionary dynamics of influenza B viruses on a global scale.
The global-scale epidemiology and genome-wide evolutionary dynamics of influenza B remain poorly understood compared with influenza A viruses. We compiled a spatio-temporally comprehensive dataset of influenza B viruses, comprising over 2,500 genomes sampled worldwide between 1987 and 2015, including 382 newly-sequenced genomes that fill substantial gaps in previous molecular surveillance studies. Our contributed data increase the number of available influenza B virus genomes in Europe, Africa and Central Asia, improving the global context to study influenza B viruses. We reveal Yamagata-lineage diversity results from co-circulation of two antigenically-distinct groups that also segregate genetically across the entire genome, without evidence of intra-lineage reassortment. In contrast, Victoria-lineage diversity stems from geographic segregation of different genetic clades, with variability in the degree of geographic spread among clades. Differences between the lineages are reflected in their antigenic dynamics, as Yamagata-lineage viruses show alternating dominance between antigenic groups, while Victoria-lineage viruses show antigenic drift of a single lineage. Structural mapping of amino acid substitutions on trunk branches of influenza B gene phylogenies further supports these antigenic differences and highlights two potential mechanisms of adaptation for polymerase activity. Our study provides new insights into the epidemiological and molecular processes shaping influenza B virus evolution globally.


Cognitive loss and recovery in long-term alcohol abusers.
The nature of the memory and visuospatial defects associated with chronic alcoholism, and the recovery of these functions, were investigated in a large group of alcoholic men and well-matched nonalcoholic controls. Both young and old alcoholics displayed significant impairments on tasks requiring the learning of novel associations and the holding of information in memory over longer delay intervals. The recovery of cognitive skills was found to depend on the length of abstinence and the particular behavioral functions examined. Whereas psychomotor skills and short-term memory improved significantly with prolonged abstinence, long-term memory was impaired even after seven years of continuous sobriety. We propose that recovery of short-term memory reflects reestablishment of cortical functioning, while the persistent long-term memory defect indicates more permanent damage to diencephalic structures.


Multiple mouse-protective antibodies directed against group B streptococci. Special reference to antibodies effective against protein antigens.
The data presented in this paper establish the finding that multiple specific protective antibodies exist in rabbits in response to immunization with Group B streptococci. The summary in Table I indicates the serological types into which Group B streptococci have been divided on the basis of their antigenic composition. This classification is dependent upon passive protection of mice with antibodies directed against the specific antigens, and types are defined in these terms. Heretofore, it was thought that type-specific polysaccharides accounted for all such protection in Group B streptococci. Certain exceptions of cross-protection between types due to minor polysaccharide determinants soon appeared; cross-protection reactions based on protein determinants in at least two types were also discovered. The present experiments show that specific antibodies directed to either polysaccharide or protein antigens of a single strain can be protective against infection with streptococci containing these antigens.


Down-regulation of the orphan nuclear receptor ROR gamma t is essential for T lymphocyte maturation.
Thymocyte development is a tightly regulated process. CD4+CD8+ double-positive (DP) immature thymocytes exhibit distinct phenotypic features from mature T cells; they express only 10% of surface TCR that are found on mature T cells and do not proliferate and produce IL-2 in response to stimulation. In this report we show that transgenic expression of the orphan nuclear receptor ROR gamma t in mature T cells down-regulates their surface TCR expression. The ROR gamma t transgene inhibits IL-2 production by mature T cells, and this inhibition may be partially due to the inhibitory effect of ROR gamma t on c-Rel transcription. Furthermore, ectopic expression of ROR gamma t inhibits the proliferation of mature and immature T cells. These results, together with its predominant expression in DP thymocytes, suggest that ROR gamma t controls these distinct phenotypic features of DP thymocytes. Our data suggest that down-regulation of ROR gamma t expression in thymocytes is essential for their maturation.


The T lymphocyte glycoprotein CD2 binds the cell surface ligand LFA-3.
CD2 (known also as T11 (ref. 1), LFA-2 (ref. 2) and the erythrocyte rosette receptor (ref. 3] is a functionally important T lymphocyte surface glycoprotein of relative molecular mass 50,000 to 58,000 (Mr 50-58 K) which appears early in thymocyte ontogeny and is present on all mature T cells. Monoclonal antibodies to CD2 inhibit cytotoxic T-lymphocyte (CTL)-mediated killing by binding to the T lymphocyte and blocking adhesion to the target cell. Such antibodies also inhibit T helper cell responses including antigen-stimulated proliferation, interleukin-2 (IL-2) secretion, and IL-2 receptor expression. Certain combinations of monoclonal antibodies to CD2 epitopes trigger proliferation of peripheral blood T lymphocytes, cytotoxic effector function and expression of IL-2 receptors by thymocytes, resulting in thymocyte proliferation in the presence of exogenous IL-2 (ref. 11). These findings suggest that CD2 can function in signalling as well as being an adhesion molecule. To understand the role of CD2 in T-cell adhesion and activation, it is essential to define its natural ligand. Our previous observation that purified CD2 inhibits rosetting of T lymphocytes with sheep erythrocytes and can be absorbed by sheep erythrocytes suggested it also might bind with detectable affinity to human cells. We now report that CD2 binds to a cell-surface antigen known as lymphocyte function-associated antigen-3 (LFA-3) with high affinity, and can mediate adhesion of lymphoid cells via interaction with LFA-3.


Recent trends in the treatment of cerebral aneurysms: analysis of a nationwide inpatient database.
The most appropriate treatment for cerebral aneurysms, both ruptured and unruptured, is currently under debate, and updated guidelines have yet to be defined. The authors attempted to identify trends in therapy for cerebral aneurysms in the US as well as outcomes. The authors retrospectively reviewed data from the Nationwide Inpatient Sample hospital discharge database (Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality) for the period 1993-2003. Multiple variables were categorized and subjected to statistical analysis for International Classification of Diseases, 9th Revision, Clinical Modification codes related to subarachnoid hemorrhage (SAH), unruptured aneurysm, and clipping and endovascular treatment of cerebral aneurysm. During the study period, the numbers of discharges remained stable for SAH but doubled for unruptured aneurysms. Concomitantly, the number of aneurysms treated with clip placement remained stable, and the number treated by means of endovascular procedures doubled. By the study's end, the mortality rates had decreased 20% for SAH and 50% for unruptured aneurysms. Increasing age was associated with increased mortality rates, mean length of hospital stay (LOS), and mean charges (p < 0.01). Endovascular treatment was used more often in older patients (p < 0.01). Teaching status and larger hospital size were associated with higher charges and longer hospital stays (although the association was not statistically significant) and with better outcomes (p < 0.05) and lower mortality rates (p < 0.05), especially in patients who underwent aneurysm clipping (p < 0.01). Endovascular treatment was associated with significantly higher mortality rates in small hospitals (p < 0.001) and steadily increasing morbidity rates (45%). Morbidity rates, mean LOS, and mean charges were higher for aneurysm clipping (p < 0.01). From 1993 to 2003, endovascular techniques for aneurysm occlusion have been increasingly used, while the use of surgical clipping procedures has remained stable. Toward the end of the study period, better overall outcomes were observed in the treatment of cerebral aneurysms, both ruptured and unruptured. Large academic centers were associated with better results, particularly for surgical clip placement.


Identification and quantitation of flavanols and proanthocyanidins in foods: how good are the datas?
Evidence suggesting that dietary polyphenols, flavanols, and proanthocyanidins in particular offer significant cardiovascular health benefits is rapidly increasing. Accordingly, reliable and accurate methods are needed to provide qualitative and quantitative food composition data necessary for high quality epidemiological and clinical research. Measurements for flavonoids and proanthocyanidins have employed a range of analytical techniques, with various colorimetric assays still being popular for estimating total polyphenolic content in foods and other biological samples despite advances made with more sophisticated analyses. More crudely, estimations of polyphenol content as well as antioxidant activity are also reported with values relating to radical scavenging activity. High-performance liquid chromatography (HPLC) is the method of choice for quantitative analysis of individual polyphenols such as flavanols and proanthocyanidins. Qualitative information regarding proanthocyanidin structure has been determined by chemical methods such as thiolysis and by HPLC-mass spectrometry (MS) techniques at present. The lack of appropriate standards is the single most important factor that limits the aforementioned analyses. However, with ever expanding research in the arena of flavanols, proanthocyanidins, and health and the importance of their future inclusion in food composition databases, the need for standards becomes more critical. At present, sufficiently well-characterized standard material is available for selective flavanols and proanthocyanidins, and construction of at least a limited food composition database is feasible.


Cellular senescence: a hitchhiker's guide.
Since its first description over 50 years ago, cellular senescence has gained increasing attention. The number of research publications on cellular senescence last year alone is more than the number of publications in the decade in 1990s. Laboratories solely studying senescence, scientific conferences and organisations dedicated to field of cellular senescence are also on the rise. These not only indicate the growing interest in this field but also highlight the importance of cellular senescence in cell biology from yeast to human. Cellular senescence is implicated in normal ageing, tumour suppression, tumourigenesis, chronic diseases and more recently, in embryogenesis. Thus, understanding senescence is crucial for the understanding of organismal biology. In addition, understanding of cellular senescence will be invaluable in the development of therapeutic targets in the fight against age-related comorbidities, cancer and chronic disease progression.


CHIVA to treat saphenous vein insufficiency in chronic venous disease: characteristics and results.
There is considerable debate in the literature with relation to the best method to treat patients with chronic venous disease (CVD). CHIVA is an office-based treatment for varicose veins performed under local anesthesia. The aim of the technique is to lower transmural pressure in the superficial venous system and avoid destruction of veins. Recurrence of varicosities, nerve damage, bruising and suboptimal aesthetic results are common to all treatments for the disease. This paper evaluates and discusses the characteristics and results of the CHIVA technique. We conclude that CHIVA is a viable alternative to common procedures that is associated with less bruising, nerve damage, and recurrence than stripping saphenectomy. The main advantages are preservation of the saphenous vein, local anesthesia, low recurrence rates, low cost, low pain, and no nerve damage. The major disadvantages are the learning curve and the need to train the team in venous hemodynamics.


Intrahemispheric and interhemispheric spread of cerebral cortical myoclonic activity and its relevance to epilepsy.
Nine patients with cortical myoclonus (due to various pathologies), in whom movement of one limb induced bilateral limb jerks, were investigated. Three of these patients also had bilateral cortical reflex myoclonus when one limb was subjected to an electrical stimulus. The relative latencies to onset of electromyogram (EMG) activity in various ipsilateral and contralateral muscles in action and reflex jerks were studied. Bilateral reflex and action jerks induced by unilateral electrical stimuli or limb movement were not synchronous. EMG activity was usually recorded in the muscles of the stimulated or moved limb, before being recorded in the homologous muscles of the contralateral limb. It is proposed that this difference in relative latency between homologous muscles represents the interhemispheric delay due to the transcallosal spread of excitation from one sensorimotor cortex to the opposite cerebral cortex. The relative latencies of muscles on the same side of the body reflected not only the differences in efferent delays from the motor cortex via spinal cord and peripheral nerves, but also delays due to the spread of myoclonic activity within the sensorimotor cortex itself. This intrahemispheric spread followed a grossly somatotopic pattern. It is suggested that this spread involves cortico-cortical pathways. The additional delay due to spread of activity from hand to leg area of the sensorimotor cortex was about 10 ms in the first active hemisphere, in both generalized reflex and action jerks. The delays due to somatotopic spread of activity in the opposite later activated hemisphere were shorter. The tendency for spread of excitation through callosal and cortico-cortical pathways is an additional pathophysiological abnormality in some patients with cortical myoclonus, and may be important in the generalization of seizures seen in these patients.


Modeling breast cancer-associated c-Src and EGFR overexpression in human MECs: c-Src and EGFR cooperatively promote aberrant three-dimensional acinar structure and invasive behavior.
Epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, is overexpressed in as many as 60% cases of breast and other cancers. EGFR overexpression is a characteristic of highly aggressive molecular subtypes of breast cancer with basal-like and BRCA1 mutant phenotypes distinct from ErbB2-overexpressing breast cancers. Yet, EGFR is substantially weaker compared with ErbB2 in promoting the oncogenic transformation of nontumorigenic human mammary epithelial cells (human MEC), suggesting a role for cooperating oncogenes. Here, we have modeled the co-overexpression of EGFR and a biologically and clinically relevant potential modifier c-Src in two distinct immortal but nontumorigenic human MECs. Using a combination of morphologic analysis and confocal imaging of polarity markers in three-dimensional Matrigel culture together with functional analyses of early oncogenic traits, we show for the first time that EGFR and c-Src co-overexpression but not EGFR or c-Src overexpression alone unleashes an oncogenic signaling program that leads to hyperproliferation and loss of polarity in three-dimensional acinar cultures, marked enhancement of migratory and invasive behavior, and anchorage-independent growth. Our results establish that EGFR overexpression in an appropriate context (modeled here using c-Src overexpression) can initiate oncogenic transformation of nontumorigenic human MECs and provide a suitable in vitro model to interrogate human breast cancer-relevant oncogenic signaling pathways initiated by overexpressed EGFR and to identify modifiers of EGFR-mediated breast oncogenesis.


Tantalum oxide nanoparticles as versatile contrast agents for X-ray computed tomography.
Here, we describe the synthesis, characterization and in vitro and in vivo performance of a series of tantalum oxide (TaOx) based nanoparticles (NPs) for computed tomography (CT). Five distinct versions of 9-12 nm diameter silane coated TaOx nanocrystals (NCs) were fabricated by a sol-gel method with varying degrees of hydrophilicity and with or without fluorescence, with the highest reported Ta content to date (78%). Highly hydrophilic NCs were left bare and were evaluated in vivo in mice for micro-CT of full body vasculature, where following intravenous injection, TaOx NCs demonstrate high vascular CT contrast, circulation in blood for ∼3 h, and eventual accumulation in RES organs; and following injection locally in the mammary gland, where the full ductal tree structure can be clearly delineated. Partially hydrophilic NCs were encapsulated within mesoporous silica nanoparticles (MSNPs; TaOx@MSNPs) and hydrophobic NCs were encapsulated within poly(lactic-co-glycolic acid) (PLGA; TaOx@PLGA) NPs, serving as potential CT-imagable drug delivery vehicles. Bolus intramuscular injections of TaOx@PLGA NPs and TaOx@MSNPs to mimic the accumulation of NPs at a tumor site produce high signal enhancement in mice. In vitro studies on bare NCs and formulated NPs demonstrate high cytocompatibility and low dissolution of TaOx. This work solidifies that TaOx-based NPs are versatile contrast agents for CT.


Secukinumab in the treatment of psoriatic arthritis: efficacy and safety results through 3 years from the year 1 extension of the randomised phase III FUTURE 1 trial.
To assess the long-term (3 year) efficacy and safety of secukinumab in patients with active psoriatic arthritis (PsA) in the extension phase of the FUTURE 1 study (NCT01892436). Following the 2-year core trial, eligible patients receiving subcutaneous secukinumab 150 or 75 mg entered a 3-year extension phase. Results are presented for key efficacy and safety endpoints at week 156. In total, 460 patients entered the extension study; 308 patients originally randomised to secukinumab were assessed for efficacy. Sustained improvements in all efficacy endpoints were achieved with secukinumab through week 156. Overall, 76.8%/54.9% (secukinumab 150 mg) and 65.2%/39.0% (secukinumab 75 mg) of patients achieved an American College of Rheumatology (ACR) 20/50 response (multiple imputation data); ACR20 responses were sustained irrespective of previous anti-tumour necrosis factor exposure. Improvements in quality of life and physical function were also sustained through week 156. Radiographic results (observed data; van der Heijde modified total Sharp score (mTSS)) showed that 78.1% (secukinumab 150 mg) and 74.8% (secukinumab 75 mg) of patients had no radiographic progression (≤0.5 increase in mTSS) through week 156. Exposure-adjusted incidence rates for selected adverse events per 100 patient-years (secukinumab 150/75 mg) were serious infections (1.7/1.6), Candida infections (1.4/0.7), Crohn's disease (0/0.3), ulcerative colitis (0/0.3) and major adverse cardiac events (0.3/0.8). Subcutaneous secukinumab provided sustained improvements in the signs and symptoms, quality of life and physical function of patients with active PsA with low rate of radiographic disease progression through 3 years. Secukinumab was well tolerated with no new safety signals.


Glycotherapy: new advances inspire a reemergence of glycans in medicine.
The beginning of the 20(th) century marked the dawn of modern medicine with glycan-based therapies at the forefront. However, glycans quickly became overshadowed as DNA- and protein-focused treatments became readily accessible. The recent development of new tools and techniques to study and produce structurally defined carbohydrates has spurred renewed interest in the therapeutic applications of glycans. This review focuses on advances within the past decade that are bringing glycan-based treatments back to the forefront of medicine and the technologies that are driving these efforts. These include the use of glycans themselves as therapeutic molecules as well as engineering protein and cell surface glycans to suit clinical applications. Glycan therapeutics offer a rich and promising frontier for developments in the academic, biopharmaceutical, and medical fields.


Evaluation of a web-based intervention to reduce antibiotic prescribing for LRTI in six European countries: quantitative process analysis of the GRACE/INTRO randomised controlled trial.
To reduce the spread of antibiotic resistance, there is a pressing need for worldwide implementation of effective interventions to promote more prudent prescribing of antibiotics for acute LRTI. This study is a process analysis of the GRACE/INTRO trial of a multifactorial intervention that reduced antibiotic prescribing for acute LRTI in six European countries. The aim was to understand how the interventions were implemented and to examine effects of the interventions on general practitioners' (GPs') and patients' attitudes. GPs were cluster randomised to one of three intervention groups or a control group. The intervention groups received web-based training in either use of the C-reactive protein (CRP) test, communication skills and use of a patient booklet, or training in both. GP attitudes were measured before and after the intervention using constructs from the Theory of Planned Behaviour and a Website Satisfaction Questionnaire. Effects of the interventions on patients were assessed by a post-intervention questionnaire assessing patient enablement, satisfaction with the consultation, and beliefs about the risks and need for antibiotics. GPs in all countries and intervention groups had very positive perceptions of the intervention and the web-based training, and felt that taking part had helped them to reduce prescribing. All GPs perceived reducing prescribing as more important and less risky following the intervention, and GPs in the communication groups reported increased confidence to reduce prescribing. Patients in the communication groups who received the booklet reported the highest levels of enablement and satisfaction and had greater awareness that antibiotics could be unnecessary and harmful. Our findings suggest that the interventions should be broadly acceptable to both GPs and patients, as well as feasible to roll out more widely across Europe. There are also some indications that they could help to engender changes in GP and patient attitudes that will be helpful in the longer-term, such as increased awareness of the potential disadvantages of antibiotics and increased confidence to manage LRTI without them. Given the positive effects of the booklet on patient beliefs and attitudes, it seems logical to extend the use of the patient booklet to all patients.


Functional impact of sarcopenia in respiratory muscles.
The risk for respiratory complications and infections is substantially increased in old age, which may be due, in part, to sarcopenia (aging-related weakness and atrophy) of the diaphragm muscle (DIAm), reducing its force generating capacity and impairing the ability to perform expulsive non-ventilatory motor behaviors critical for airway clearance. The aging-related reduction in DIAm force generating capacity is due to selective atrophy of higher force generating type IIx and/or IIb muscle fibers, whereas lower force generating type I and IIa muscle fiber sizes are preserved. Fiber type specific DIAm atrophy is also seen following unilateral phrenic nerve denervation and in other neurodegenerative disorders. Accordingly, the effect of aging on DIAm function resembles that of neurodegeneration and suggests possible common mechanisms, such as the involvement of several neurotrophic factors in mediating DIAm sarcopenia. This review will focus on changes in two neurotrophic signaling pathways that represent potential mechanisms underlying the aging-related fiber type specific DIAm atrophy.


Concurrent effects of age class and food distribution on immigration success and population dynamics in a small mammal.
During the settlement stage of dispersal, the outcome of conflicts between residents and immigrants should depend on the social organization of resident populations as well as on individual traits of immigrants, such as their age class, body mass and/or behaviour. We have previously shown that spatial distribution of food influences the social organization of female bank voles (Myodes glareolus). Here, we aimed to determine the relative impact of food distribution and immigrant age class on the success and demographic consequences of female bank vole immigration. We manipulated the spatial distribution of food within populations having either clumped or dispersed food. After a pre-experimental period, we released either adult immigrants or juvenile immigrants, for which we scored sociability and aggressiveness prior to introduction. We found that immigrant females survived less well and moved more between populations than resident females, which suggest settlement costs. However, settled juvenile immigrants had a higher probability to reproduce than field-born juveniles. Food distribution had little effects on the settlement success of immigrant females. Survival and settlement probabilities of immigrants were influenced by adult female density in opposite ways for adult and juvenile immigrants, suggesting a strong adult-adult competition. Moreover, females of higher body mass at release had a lower probability to survive, and the breeding probability of settled immigrants increased with their aggressiveness and decreased with their sociability. Prior to the introduction of immigrants, resident females were more aggregated in the clumped food treatment than in the dispersed food treatment, but immigration reversed this relationship. In addition, differences in growth trajectories were seen during the breeding season, with populations reaching higher densities when adult immigrants were introduced in a plot with dispersed food, or when juvenile immigrants were introduced in a plot with clumped food. These results indicate the relative importance of intrinsic and extrinsic factors on immigration success and demographic consequences of dispersal and are of relevance to conservation actions, such as reinforcement of small populations.


Linking environmental nutrient enrichment and disease emergence in humans and wildlife.
Worldwide increases in human and wildlife diseases have challenged ecologists to understand how large-scale environmental changes affect host-parasite interactions. One of the most profound changes to Earth's ecosystems is the alteration of global nutrient cycles, including those of phosphorus (P) and especially nitrogen (N). Along with the obvious direct benefits of nutrient application for food production, anthropogenic inputs of N and P can indirectly affect the abundance of infectious and noninfectious pathogens. The mechanisms underpinning observed correlations, however, and how such patterns vary with disease type, have long remained conjectural. Here, we highlight recent experimental advances to critically evaluate the relationship between environmental nutrient enrichment and disease. Given the interrelated nature of human and wildlife disease emergence, we include a broad range of human and wildlife examples from terrestrial, marine, and freshwater ecosystems. We examine the consequences of nutrient pollution on directly transmitted, vector-borne, complex life cycle, and noninfectious pathogens, including West Nile virus, malaria, harmful algal blooms, coral reef diseases, and amphibian malformations. Our synthetic examination suggests that the effects of environmental nutrient enrichment on disease are complex and multifaceted, varying with the type of pathogen, host species and condition, attributes of the ecosystem, and the degree of enrichment; some pathogens increase in abundance whereas others decline or disappear. Nevertheless, available evidence indicates that ecological changes associated with nutrient enrichment often exacerbate infection and disease caused by generalist parasites with direct or simple life cycles. Observed mechanisms include changes in host/vector density, host distribution, infection resistance, pathogen virulence or toxicity, and the direct supplementation of pathogens. Collectively, these pathogens may be particularly dangerous because they can continue to cause mortality even as their hosts decline, potentially leading to sustained epidemics or chronic pathology. We suggest that interactions between nutrient enrichment and disease will become increasingly important in tropical and subtropical regions, where forecasted increases in nutrient application will occur in an environment rich with infectious pathogens. We emphasize the importance of careful disease management in conjunction with continued intensification of global nutrient cycles.


Atomic-scale coupling of photons to single-molecule junctions.
Spatial resolution at the atomic scale has been achieved in the coupling of light to single molecules adsorbed on a surface. Electron transfer to a single molecule induced by green to near-infrared light in the junction of a scanning tunneling microscope (STM) exhibited spatially varying probability that is confined within the molecule. The mechanism involves photo-induced resonant tunneling in which a photoexcited electron in the STM tip is transferred to the molecule. The coupling of photons to the tunneling process provides a pathway to explore molecular dynamics with the combined capabilities of lasers and the STM.


Development of a prototype lateral flow immunoassay (LFI) for the rapid diagnosis of melioidosis.
Burkholderia pseudomallei is a soil-dwelling bacterium and the causative agent of melioidosis. Isolation of B. pseudomallei from clinical samples is the "gold standard" for the diagnosis of melioidosis; results can take 3-7 days to produce. Alternatively, antibody-based tests have low specificity due to a high percentage of seropositive individuals in endemic areas. There is a clear need to develop a rapid point-of-care antigen detection assay for the diagnosis of melioidosis. Previously, we employed In vivo Microbial Antigen Discovery (InMAD) to identify potential B. pseudomallei diagnostic biomarkers. The B. pseudomallei capsular polysaccharide (CPS) and numerous protein antigens were identified as potential candidates. Here, we describe the development of a diagnostic immunoassay based on the detection of CPS. Following production of a CPS-specific monoclonal antibody (mAb), an antigen-capture immunoassay was developed to determine the concentration of CPS within a panel of melioidosis patient serum and urine samples. The same mAb was used to produce a prototype Active Melioidosis Detect Lateral Flow Immunoassay (AMD LFI); the limit of detection of the LFI for CPS is comparable to the antigen-capture immunoassay (∼0.2 ng/ml). The analytical reactivity (inclusivity) of the AMD LFI was 98.7% (76/77) when tested against a large panel of B. pseudomallei isolates. Analytical specificity (cross-reactivity) testing determined that 97.2% of B. pseudomallei near neighbor species (35/36) were not reactive. The non-reactive B. pseudomallei strain and the reactive near neighbor strain can be explained through genetic sequence analysis. Importantly, we show the AMD LFI is capable of detecting CPS in a variety of patient samples. The LFI is currently being evaluated in Thailand and Australia; the focus is to optimize and validate testing procedures on melioidosis patient samples prior to initiation of a large, multisite pre-clinical evaluation.


Image simulation for biological microscopy: microlith.
Image simulation remains under-exploited for the most widely used biological phase microscopy methods, because of difficulties in simulating partially coherent illumination. We describe an open-source toolbox, microlith (https://code.google.com/p/microlith), which accurately predicts three-dimensional images of a thin specimen observed with any partially coherent imaging system, as well as images of coherently illuminated and self-luminous incoherent specimens. Its accuracy is demonstrated by comparing simulated and experimental bright-field and dark-field images of well-characterized amplitude and phase targets, respectively. The comparison provides new insights about the sensitivity of the dark-field microscope to mass distributions in isolated or periodic specimens at the length-scale of 10nm. Based on predictions using microlith, we propose a novel approach for detecting nanoscale structural changes in a beating axoneme using a dark-field microscope.


The relationship between cumulative unfair treatment and intima media thickness and adventitial diameter: The moderating role of race in the study of women's health across the nation.
Unfair treatment may have a detrimental effect on cardiovascular health. However, little research on chronic health outcomes uses cumulative measures of unfair treatment. We tested whether cumulative unfair treatment was associated with greater subclinical cardiovascular disease in a diverse sample of African-American, Caucasian, Chinese, and Hispanic women. We also examined whether this relationship varied by race. The Study of Women's Health Across the Nation is a longitudinal study of midlife women. Cumulative unfair treatment was calculated as the average of unfair treatment assessed over 10 years at 6 time points. Subclinical cardiovascular disease, specifically carotid intima media thickness and adventitial diameter, was assessed via carotid ultrasound conducted at study year 12 in 1,056 women. We tested whether cumulative unfair treatment was related to subclinical cardiovascular disease via linear regression, controlling for demographic factors including socioeconomic status and cardiovascular risk factors. The relation between unfair treatment and subclinical cardiovascular disease significantly varied by race (ps < .05), with unfair treatment related to higher intima media thickness (B = .03, SE = .01, p = .009) and adventitial diameter (B = .02, SE = .009, p = .013) only among Caucasian women. No significant relations between unfair treatment and subclinical cardiovascular disease outcomes were observed for African-American, Hispanic, and Chinese women. Our findings indicate that cumulative unfair treatment is related to worse subclinical cardiovascular disease among Caucasian women. These findings add to the growing literature showing that Caucasian women's experience of unfair treatment may have detrimental health implications. (PsycINFO Database Record


GAPDH is conformationally and functionally altered in association with oxidative stress in mouse models of amyotrophic lateral sclerosis.
It is proposed that conformational changes induced in proteins by oxidation can lead to loss of activity or protein aggregation through exposure of hydrophobic residues and alteration in surface hydrophobicity. Because increased oxidative stress and protein aggregation are consistently observed in amyotrophic lateral sclerosis (ALS), we used a 4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid (BisANS) photolabeling approach to monitor changes in protein unfolding in vivo in skeletal muscle proteins in ALS mice. We find two major proteins, creatine kinase (CK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), conformationally affected in the ALS G93A mouse model concordant with a 43% and 41% reduction in enzyme activity, respectively. This correlated with changes in conformation and activity that were detected in CK and GAPDH with in vitro oxidation. Interestingly, we found that GAPDH, but not CK, is conformationally and functionally affected in a longer-lived ALS model (H46R/H48Q), exhibiting a 22% reduction in enzyme activity. We proposed a reaction mechanism for BisANS with nucleophilic amino acids such as lysine, serine, threonine, and tyrosine, and BisANS was found to be primarily incorporated to lysine residues in GAPDH. We identified the specific BisANS incorporation sites on GAPDH in nontransgenic (NTg), G93A, and H46R/H48Q mice using liquid chromatography-tandem mass spectrometry analysis. Four BisANS-containing sites (K52, K104, K212, and K248) were found in NTg GAPDH, while three out of four of these sites were lost in either G93A or H46R/H48Q GAPDH. Conversely, eight new sites (K2, K63, K69, K114, K183, K251, S330, and K331) were found on GAPDH for G93A, including one common site (K114) for H46R/H48Q, which is not found on GAPDH from NTg mice. These data show that GAPDH is differentially affected structurally and functionally in vivo in accordance with the degree of oxidative stress associated with these two models of ALS.


Using Convolutional Neural Networks to Support Insertion of New Concepts into SNOMED CT.
Many major medical ontologies go through a regular (bi-annual, monthly, etc.) release cycle. A new release will contain corrections to the previous release, as well as genuinely new concepts that are the result of either user requests or new developments in the domain. New concepts need to be placed at the correct place in the ontology hierarchy. Traditionally, this is done by an expert modeling a new concept and running a classifier algorithm. We propose an alternative approach that is based on providing only the name of a new concept and using a Convolutional Neural Network-based machine learning method. We first tested this approach within one version of SNOMED CT and achieved an average 88.5% precision and an F1 score of 0.793. In comparing the July 2017 release with the January 2018 release, limiting ourselves to predicting one out of two or more parents, our average F1 score was 0.701.


Effect of suramin on squamous differentiation and apoptosis in three human non-small-cell lung cancer cell lines.
Non-small cell lung cancer (NSCLC) is fatal in approximately 90% of all cases due to the failure of systemic therapy, secondary to resistance to chemotherapy. In such malignancies new therapeutic paradigms are needed. One such approach takes advantage of normal physiologic growth regulatory mechanisms, such as terminal cellular differentiation or apoptosis. Suramin, as an antineoplastic drug, has shown efficacy in the treatment of prostate cancer and is capable of promoting differentiation in several human cancer cell lines. Little is known about the differentiating effects of suramin in lung cancer. In the present investigation we evaluated the ability of suramin to induce cross-linked envelope (CLE) formation, as a common marker for squamous differentiation and apoptosis, in three representative human non-small cell lung cancer cell lines: NCI-H226 (squamous), NCI-H358 (bronchoalveolar [adenocarcinoma]), and NCI-H596 (adenosquamous). Among agents that we have tested, suramin demonstrated the unique ability to induce spontaneous CLE formation in the two cell lines with squamous features, NCI-H226 and NCI-H596. Suramin induced CLE formation was accompanied by DNA fragmentation, a marker for apoptosis, in NCI-H596 and NCI-H358, but not in NCI-H226. Stimulation of CLE formation by suramin correlated with the rapid induction of both type II transglutaminase (TG) activity and involucrin expression. These parameters were protein synthesis independent, suggesting posttranslational mechanisms of suramin activity. Induction of differentiation/apoptosis markers by suramin did not correlate with its effect on growth. Modulation of signal transduction is a likely candidate mechanism for suramin activity in lung cancer. The relationship between growth, squamous differentiation, and apoptosis is considered.


Complex folding pathways in a simple beta-hairpin.
The determination of the folding mechanisms of proteins is critical to understand the topological change that can propagate Alzheimer and Creutzfeld-Jakobs diseases, among others. The computational community has paid considerable attention to this problem; however, the associated time scale, typically on the order of milliseconds or more, represents a formidable challenge. Ab initio protein folding from long molecular dynamics simulations or ensemble dynamics is not feasible with ordinary computing facilities and new techniques must be introduced. Here we present a detailed study of the folding of a 16-residue beta-hairpin, described by a generic energy model and using the activation-relaxation technique. From a total of 90 trajectories at 300 K, three folding pathways emerge. All involve a simultaneous optimization of the complete hydrophobic and hydrogen bonding interactions. The first two pathways follow closely those observed by previous theoretical studies (folding starting at the turn or by interactions between the termini). The third pathway, never observed by previous all-atom folding, unfolding, and equilibrium simulations, can be described as a reptation move of one strand of the beta-sheet with respect to the other. This reptation move indicates that non-native interactions can play a dominant role in the folding of secondary structures. Furthermore, such a mechanism mediated by non-native hydrogen bonds is not available for study by unfolding and Gō model simulations. The exact folding path followed by a given beta-hairpin is likely to be influenced by its sequence and the solvent conditions. Taken together, these results point to a more complex folding picture than expected for a simple beta-hairpin.


Combined use of alveolar distraction osteogenesis and segmental osteotomy in anterior vertical ridge augmentation.
Vertical defects of the anterioral veolar ridge are challenging cases in implant dentistry. Various techniques, such as onlay bone grafting, segmental osteotomy (SO) oral veolar distraction osteogenesis (ADO), have been suggested to manage those situations. ADO has an advantage of being capable of enhancing both hard and soft tissue simultaneously. One of the possible complications of ADO is rotation ortilting the transport segment (TS). In this report, we present a 30-year old woman who had a severe anterior vertical deficiency. ADO was started to manage the case, but advancement of the TS lagged on the left side and the segment rotated. A SO was planned and the lagged side was corrected. Two years after the surgery, hard and soft tissue gains were found to be preserved. Vertical alveolar bone deficiencies are challenging cases for dental implantology. Alveolar DO promotes soft tissue along with hard tissue, and the bone regeneration process and shows lower infection rates and greater stability over the long term. However, the technique has some disadvantages and can lead to complications, such as breaking of the distraction device, nerve injury or paresthesia, fracture of transport bone, hematoma, wound dehiscence, severe bleeding, and even jaw fractures. Deviation of the TS from the distraction path is another undesired situation. The rigidity of the device, the width of the mucosa, the volume of the transport and anchor segments, and the amount of augmentation can affect vector deviation. We suggest that SO can be used in similar cases in which TS could not be distracted on a straight vector line.


Anabolic steroids: a review for the clinician.
The number of athletes self-administering ergogenic pharmacological agents to increase their competitive edge continues to be a problem. Most athletes using anabolic steroids (AS) have acquired a crude pharmacological database regarding these drugs. Their opinions regarding steroids have been derived from their subjective experiences and anecdotal information. For this reason, traditional warnings regarding the lack of efficacy and potential dangers of steroid misuse are disregarded. A common widely held opinion among bodybuilders is that the anabolic steroid experts are the athletic gurus who for years have utilised themselves as the experimental participants and then dispensed their empirical findings. This review will address the common anabolic steroid misconceptions held by many of today's athletes by providing an evaluation of the scientific literature related to AS in athletic performance.


Human hepatic microsomal thiol methyltransferase. Assay conditions, biochemical properties, and correlation studies.
Thiol methyltransferase (TMT) catalyzes the S-methylation of aliphatic sulfhydryl drugs and xenobiotic compounds. As a first step in the determination of whether genetic control of TMT activity in an easily accessible human cell, the red blood cell (RBC), might reflect the regulation of TMT in the human liver, we determined optimal conditions for the assay of human hepatic microsomal TMT activity. We then used those assay conditions to study the biochemical properties and regulation of TMT in the human liver for comparison with the properties of TMT in the human RBC. Substrate kinetic studies of hepatic microsomes performed with 2-mercaptoethanol (2-ME) revealed biphasic kinetics similar to those found in the human RBC, with apparent "high-" and "low"-affinity forms of TMT activity. The high-affinity form had an optimal pH of 7.2-7.6 and apparent KM values of 9.0 microM for 2-ME and 7.5 microM for S-adenosyl-L-methionine. The low-affinity form had an optimal pH of 8.8 and apparent KM values of 20 mM for 2-ME and 44 microM for S-adenosyl-L-methionine. Both forms were inhibited by compounds that also inhibited human RBC membrane TMT. The two kinetic forms of hepatic microsomal TMT activity were inactivated approximately 50% by heating for 15 min at 53 degrees C and, as was found with RBC TMT, had very similar thermal stability profiles.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats.
Hypothalamic melanocortins are among several neuropeptides strongly implicated in the control of food intake. Agonists for melanocortin 4 (MC-4) receptors such as alpha-melanocyte-stimulating hormone (alpha-MSH), a product of proopiomelanocortin (POMC), reduce food intake, whereas hypothalamic agouti-related protein (AgRP) is a MC-4 receptor antagonist that increases food intake. To investigate whether reduced melanocortin signaling contributes to hyperphagia induced by uncontrolled diabetes, male Sprague-Dawley rats were studied 7 days after administration of streptozotocin (STZ) or vehicle. In addition, we wished to determine the effect of diabetes on muscle uncoupling protein 3 (UCP-3), a potential regulator of muscle energy metabolism. STZ diabetic rats were markedly hyperglycemic (31.3 +/- 1.0 mmol/l; P < 0.005) compared with nondiabetic controls (9.3 +/- 0.2 mmol/l). Insulin treatment partially corrected the hyperglycemia (18.8 +/- 2.5 mol/l; P < 0.005). Plasma leptin was markedly reduced in STZ diabetic rats (0.4 +/- 0.1 ng/ml; P < 0.005) compared with controls (3.0 +/- 0.4 ng/ml), an effect that was also partially reversed by insulin treatment (1.8 +/- 0.3 ng/ml). Untreated diabetic rats were hyperphagic, consuming 40% more food (48 +/- 1 g/day; P < 0.005) than controls (34 +/- 1 g/day). Hyperphagia was prevented by insulin treatment (32 +/- 2 g/day). In untreated diabetic rats, hypothalamic POMC mRNA expression (measured by in situ hybridization) was reduced by 80% (P < 0.005), whereas AgRP mRNA levels were increased by 60% (P < 0.01), suggesting a marked decrease of hypothalamic melanocortin signaling. The change in POMC, but not in AgRP, mRNA levels was partially reversed by insulin treatment. By comparison, the effects of diabetes to increase hypothalamic neuropeptide Y (NPY) expression and to decrease corticotropin-releasing hormone (CRH) expression were normalized by insulin treatment, whereas the expression of mRNA encoding the long form of the leptin receptor in the arcuate nucleus was unaltered by diabetes or insulin treatment. UCP-3 mRNA expression in gastrocnemius muscle from diabetic rats was increased fourfold (P < 0.005), and the increase was prevented by insulin treatment. The effect of uncontrolled diabetes to decrease POMC, while increasing AgRP gene expression, suggests that reduced hypothalamic melanocortin signaling, along with increased NPY and decreased CRH signaling, could contribute to diabetic hyperphagia. These responses, in concert with increased muscle UCP-3 expression, may also contribute to the catabolic effects of uncontrolled diabetes on fuel metabolism in peripheral tissues.


Evaluation of the analytical performance of a portable ion-selective electrode meter for measuring whole-blood, plasma, milk, abomasal-fluid, and urine sodium concentrations in cattle.
A portable ion-selective electrode (ISE) meter (LAQUAtwin B-722; Horiba Instruments Inc., Irvine, CA) is available for measuring the sodium ion concentration ([Na]) in biological fluids. The objective of this study was to characterize the analytical performance of the ISE meter in measuring [Na] in whole-blood, plasma, milk, abomasal fluid, and urine samples from cattle. Method comparison studies were performed using whole-blood and plasma samples from 106 sick calves and 11 sick cows admitted to a veterinary teaching hospital, 80 milk and 206 urine samples from 16 lactating Holstein-Friesian cows with experimentally induced free water, electrolyte, and acid-base imbalances, and 67 abomasal fluid samples from 7 healthy male Holstein-Friesian calves fed fresh milk with or without an oral electrolyte solution. Deming regression and Bland-Altman plots were used to determine the accuracy of the meter against reference methods. The meter used in direct mode on undiluted samples measured whole-blood [Na] 9.7 mmol/L (7.3%) lower than a direct ISE reference method and plasma [Na] 16.7 mmol/L (12.7%) lower than an indirect ISE reference method. The meter run in direct mode measured milk [Na] 3.1 mmol/L lower and abomasal fluid [Na] 9.0% lower than indirect ISE reference methods. The meter run in indirect mode on diluted samples accurately measured urine [Na] compared with an indirect ISE reference method. We conclude that, after adjustment for the bias determined from Bland-Altman plots, the LAQUAtwin ISE meter provides a clinically useful and low-cost cow-side instrument for measuring [Na] in whole blood, plasma, milk, and abomasal fluid.


An extended role for the nucleoid structuring protein H-NS in the virulence gene regulatory cascade of Shigella flexneri.
The H-NS nucleoid structuring protein has been shown previously to play a negative role in controlling virulence gene expression in Shigella flexneri by repressing transcription of the virF and virB regulatory genes and the VirF-dependent icsA structural gene under non-permissive growth conditions. Here, we show that H-NS also acts at the promoters of the VirB-dependent structural genes in the regulatory cascade. H-NS protein binds to the promoter regions in vivo and in vitro. The promoters were shown physically and by in silico analysis to contain regions of DNA curvature, a feature of H-NS binding sites. H-NS binding sites were determined by DNase I footprinting at the icsB and the virA promoters. The locations of these sites were consistent with a role for H-NS as a transcription repressor. The VirB-dependent structural gene promoters were found to respond directly to the H-NS repressor, revealing a level of control that is additional to that exerted by the H-NS-dependent virB activator gene. Moreover, the promoters were sensitive to the level of VirB protein in the cell, requiring a threshold level of VirB to be reached before becoming active. A model is discussed in which the levels of expression of the structural genes reflect the outcome of competition between the countervailing regulatory activities of the H-NS and VirB proteins.


One-stage circumferential buccal mucosa graft urethroplasty for bulbous stricture repair.
A one-stage onlay urethroplasty, using a buccal mucosa graft, is presented for patients with bulbous strictures in whom the urethral mucosa is seriously involved in the disease. Of 40 patients who underwent a dorsal buccal mucosa graft urethroplasty for bulbous urethral strictures, 5 required complete removal of the urethral mucosa and its replacement by a buccal mucosa graft. All these patients had undergone previous urethrotomy with a false passage inside the bulbous urethra and had a suprapubic tube in place. The goal of removal and replacement of the urethral mucosa in each case was to create a new, wide urethral mucosal bed to promote successful one-stage reconstruction. All patients voided spontaneously without problems after removal of the catheter. After 4 months, the mean peak flow was 21 mL/s. After 6 months, urethroscopy did not show any stricture recurrence. None of the patients required instrumentation or dilation. In patients with bulbous urethral strictures and false passage into the mucosa and spongiosum tissues, the complete removal and replacement of the urethral mucosa using a circumferential buccal mucosa graft promotes successful one-stage urethral reconstruction.


Micronutrient intake adequacy and depression risk in the SUN cohort study.
The aim of the study was to prospectively assess the association between micronutrient intake adequacy and risk of depression. This dynamic cohort study involves Spanish university graduates (SUN Project). Dietary intake was assessed at baseline and after 10 years of follow-up with a semi-quantitative food frequency questionnaire. Micronutrient intake adequacy for vitamins B1, B2, B3, B6, B12, C, A, D, E, folic acid, zinc, iodine, selenium, iron, calcium, potassium, phosphorus, magnesium and chrome was estimated. Inadequate intake for each nutrient was defined when the intake of the nutrient was below the estimated average requirements (EAR) if available or the adequate intake levels, if EARs were not available. We compared participants with inadequate intake for ≥4 nutrients vs. those with one nutrient. Participants were classified as having incident depression if they had no previous history of depression or antidepressants use at baseline, but they reported during follow-up a new clinical diagnosis of depression by a physician, use of antidepressant drugs, or both. Time-dependent multivariable Cox regression models were fitted. After a median follow-up of 8.5 years, 953 new cases of depression were observed among 13,983 participants. Participants with inadequate intake for ≥4 nutrients showed a significantly higher risk of depression [multivariable hazard ratio (HR) = 1.37; 95% confidence interval (CI) 1.01-1.85]. When the analyses were updated with repeated assessments of intakes, the association was attenuated and it was no longer statistically significant (Multivariable HR = 1.11; 95% CI 0.82-1.51). Micronutrient inadequacy in four or more micronutrients could exert a moderate role in the development of depression.


Spermatogonial stem cells alone are not sufficient to re-initiate spermatogenesis in the rat testis following adjudin-induced infertility.
The blood-testis barrier (BTB) is a unique ultrastructure in the testis, which creates a specialized microenvironment in the seminiferous epithelium known as the apical (or adluminal) compartment for post-meiotic germ-cell development and for maintenance of an immunological barrier. In this study, we have demonstrated unequivocally that a functional and intact BTB is crucial for the initiation of spermatogenesis, in particular, the differentiation of spermatogonial stem cells (SSCs). It was shown that adult rats (∼300 g body weight, b.w.) treated with adjudin at 50 (low-dose) or 250 (high-dose) mg/kg b.w. by gavage led to germ-cell depletion from the seminiferous tubules and that >98% of the tubules were devoid of germ cells by ∼2 week and rats became infertile in both groups after the sperm reserve in the epididymis was exhausted. While the population of SSC/spermatogonia in the seminiferous tubules from both groups was similar to that of normal rats, only rats from the low-dose group were capable of re-initiating spermatogenesis; and by 20 weeks, greater than 75% of the tubules displayed normal spermatogenesis and the fertility of these rats rebounded. Detailed analysis by dual-labelled immunofluorescence analysis and a functional BTB integrity assay revealed that in both treatment groups, the BTB was disrupted from week 6 to week 12. However, the disrupted BTB 'resealed' in the low-dose group, but not in the high-dose group. Our findings illustrate that SSC/spermatogonia failed to differentiate into spermatocytes beyond A(aligned) spermatogonia in the high-dose group with a disrupted BTB. In short, these findings illustrate the critical significance of the BTB for re-initiation of spermatogenesis besides SSC and spermatogonia.


[From garbage production to residue transformation].
This research has a starting point the promising articulation between recyclable waste materials pickers and visual artists. Their intersection point is the way they reshape the remnants of the consumption society: waste pickers give new uses to objects bringing dignity to cast out materials, while visual artists reshape these subjectively refused objects into art, giving them new social value. This study tries to locate the continuity gap we created in regard to waste materials processing - what may they tell about us? Where do they stand at our social scale of values? Thus it becomes clear how waste objects aren't just technical realities but renewed values. Approaching waste objects with a logic that merely envisages their technical side would leave behind something they had as an essential part.


Month 2 culture status and treatment duration as predictors of recurrence in pulmonary tuberculosis: model validation and update.
New regimens capable of shortening tuberculosis treatment without increasing the risk of recurrence are urgently needed. A 2013 meta-regression analysis, using data from trials published from 1973 to 1997 involving 7793 patients, identified 2-month sputum culture status and treatment duration as independent predictors of recurrence. The resulting model predicted that if a new 4-month regimen reduced the proportion of patients positive at month 2 to 1%, it would reduce to 10% the risk of a relapse rate >10% in a trial with 680 subjects per arm. The 1% target was far lower than anticipated. Data from the 8 arms of 3 recent unsuccessful phase 3 treatment-shortening trials of fluoroquinolone-substituted regimens (REMox, OFLOTUB, and RIFAQUIN) were used to assess and refine the accuracy of the 2013 meta-regression model. The updated model was then tested using data from a treatment shortening trial reported in 2009 by Johnson et al. The proportions of patients with recurrence as predicted by the 2013 model were highly correlated with observed proportions as reported in the literature (R2 = 0.86). Using the previously proposed threshold of 10% recurrences as the maximum likely considered acceptable by tuberculosis control programs, the original model correctly identified all 4 six-month regimens as satisfactory, and 3 of 4 four-month regimens as unsatisfactory (sensitivity = 100%, specificity = 75%, PPV = 80%, and NPV = 100%). A revision of the regression model based on the full dataset of 66 regimens and 11181 patients resulted in only minimal changes to its predictions. A test of the revised model using data from the treatment shortening trial of Johnson et al found the reported relapse rates in both arms to be consistent with predictions. Meta-regression modeling of recurrence based on month 2 culture status and regimen duration can inform the design of future phase 3 tuberculosis clinical trials.


Spatial modeling of multiple sclerosis for disease subtype prediction.
Magnetic resonance imaging (MRI) has become an essential tool in the diagnosis and managing of Multiple Sclerosis (MS). Currently, the assessment of MS is based on a combination of clinical scores and subjective rating of lesion images by clinicians. In this work we present an objective 5-way classification of MS disease subtype as well as a comparison between three different approaches. First we propose two spatially informed models, a Bayesian Spatial Generalized Linear Mixed Model (BSGLMM) and a Log Gaussian Cox Process (LGCP). The BSGLMM accounts for the binary nature of lesion maps and the spatial dependence between neighboring voxels, and the LGCP accounts for the random spatial variation in lesion location. Both improve upon mass univariate analyses that ignore spatial dependence and rely on some level of arbitrarily defined smoothing of the data. As a comparison, we consider a machine learning approach based on multi-class support vector machine (SVM). For the SVM classification scheme, unlike previous work, we use a large number of quantitative features derived from three MRI sequences in addition to traditional demographic and clinical measures. We show that the spatial models outperform standard approaches with average prediction accuracies of up to 85%.