Functional outcomes after disc excision in deep endometriosis of the rectum using transanal staplers: a series of 111 consecutive patients.
To assess the postoperative outcomes of patients with rectal endometriosis managed by disc excision using transanal staplers. Prospective study using data recorded in the CIRENDO database (NCT02294825). University tertiary referral center. A total of 111 consecutive patients managed between June 2009 and June 2016. We performed rectal disc excision using two different transanal staplers: [1] the Contour Transtar stapler (the Rouen technique); and [2] the end to end anastomosis circular transanal stapler. Pre- and postoperative digestive function was assessed using standardized gastrointestinal questionnaires: the Gastrointestinal Quality of Life Index and the Knowles-Eccersley-Scott Symptom Questionnaire. The two staplers were used in 42 (37.8%) and 69 patients (62.2%), respectively. The largest diameter of specimens achieved was significantly higher using the Rouen technique (mean ± SD, 59 ± 11 mm vs. 36 ± 7 mm), which was used to remove nodules located lower in the rectum (5.5 ± 1.3 cm vs. 9.7 ± 2.5 cm) infiltrating more frequently the adjacent posterior vaginal wall (83.3% vs. 49.3%). Associated nodules involving sigmoid colon were managed by distinct procedures, either disc excision (2.7%) or segmental resection of sigmoid colon (9.9%). Postoperative values for the Gastrointestinal Quality of Life Index increased 1 and 3 years after the surgery, but improvement in constipation was not significant. The probability of pregnancy at 1 year after the arrest of medical treatment was 73.3% (95% confidence interval 54.9%-88.9%), with a majority of spontaneous conceptions. Disc excision using transanal staplers is a valuable alternative to colorectal resection in selected patients presenting with rectal endometriosis, allowing for good preservation of rectal function.


Mutations of N-terminal regions render the retinoblastoma protein insufficient for functions in development and tumor suppression.
To assess biological roles of the retinoblastoma protein (RB), four independent transgenic mouse lines expressing human RB with different deletions in the N-terminal region (RBdeltaN) were generated and compared with mice expressing identically regulated, full-length RB. Expression of both RB and RBdeltaN caused developmental growth retardation, but the wild-type protein was more potent. In contrast to wild-type RB, the RBdeltaN proteins were unable to rescue Rb-/- mice completely from embryonic lethality. Embryos survived until gestational day 18.5 but displayed defects in the terminal differentiation of erythrocytes, neurons, and skeletal muscle. In Rb+/- mice, expression of the RBdeltaN transgenes failed to prevent pituitary melanotroph tumors but delayed tumor formation or progression. These results strongly suggest that N-terminal regions are crucial for embryonic and postnatal development, tumor suppression, and the functional integrity of the entire RB protein. Furthermore, these transgenic mice provide models that may begin to explain human families with low-penetrance retinoblastoma and mutations in N-terminal regions of RB.


A guide for writing anti-racist tenure and promotion letters.
In a two-page tenure letter, senior faculty can make or break a career. This power has an outsized impact on Black academics and other scholars with marginalized identities, who are awarded tenure at lower rates than their white colleagues. We suggest that this difference in tenure rates is due to an implicit, overly narrow definition of academic excellence that does not recognize all the contributions that Black scholars make to their departments, institutions and academia in general. These unrecognized contributions include the (often invisible) burdens of mentoring and representation that these scholars bear disproportionately. Here we propose a set of practical steps for writing inclusive, anti-racist tenure letters, including what to do before writing the letter, what to include (and not include) in the letter itself, and what to do after writing the letter to further support the candidate seeking tenure. We are a group of mostly non-Black academics in science, technology, engineering and mathematics (STEM) based in the United States who are learning about and working toward Black liberation in academia; we hope these recommendations will help ongoing efforts to move toward an inclusive academia that appreciates and rewards diverse ways of doing, learning and knowing.


MR urography: Anatomical and quantitative information on congenital malformations in children.
Magnetic resonance urography (MRU) is considered to be the next step in uroradiology. This technique combines superb anatomical images and functional information in a single test. In this article, we aim to present the topic of MRU in children and how it has been implemented in Northern Greece so far. The purpose of this study is to demonstrate the potential of MRU in clinical practice. We focus both on the anatomical and the quantitative information this technique can offer. MRU was applied in 25 children (ages from 3 to 11 years) diagnosed with different types of congenital malformations. T1 and T2 images were obtained for all patients. Dynamic, contrast-enhanced data were processed and signal intensity versus time curves were created for all patients from regions of interest (ROIs) selected around the kidneys in order to yield quantitative information regarding the kidneys function. From the slopes of these curves we were able to evaluate which kidneys were functional and from the corticomedullary cross-over point to determine whether the renal system was obstructed or not. In all 25 cases MRU was sufficient, if not superior to other imaging modalities, to establish a complete diagnosis.


Oxidative Stress Induces Senescence in Cultured RPE Cells.
The aim of this research is to determine whether oxidative stress induces cellular senescence in human retinal pigment epithelial cells. Cultured ARPE19 cells were subjected to different concentrations of hydrogen peroxide to induce oxidative stress. Cells were seeded into 24-well plates with hydrogen peroxide added to cell medium and incubated at 37°C + 5% CO2 for a 90-minute period [at 0, 300, 400 and 800 micromolar (MCM) hydrogen peroxide]. The number of viable ARPE19 cells were recorded using the Trypan Blue Dye Exclusion Method and cell senescence was measured by positive staining for senescence-associated beta-galactosidase (SA-beta-Gal) protein. Without hydrogen peroxide treatment, the number of viable ARPE19 cells increased significantly from 50,000 cells/well to 197,000 within 72 hours. Treatment with hydrogen peroxide reduced this level of cell proliferation significantly (to 52,167 cells at 400 MCM; to 49,263 cells at 800 MCM). Meanwhile, cells with a high level of positive senescence-indicator SA-Beta-Gal-positive staining was induced by hydrogen peroxide treatment (from a baseline level of 12% to 80% at 400 MCM and at 800 MCM). Our data suggests that oxidative stress from hydrogen peroxide treatment inhibited ARPE19 cell proliferation and induced cellular senescence.


Involvement of TRPM7 Channel on the Induction of Diabetic Neuropathic Pain in Mice: Protective Role of Selenium and Curcumin.
Excessive levels of the mitochondrial reactive oxygen radical (mitSOX) and Ca2+ influx were found to cause neuropathic pain in patients with diabetes mellitus (DM). Naltriben (NLT) and mitSOX activate the transient receptor (TRP) melastatin 7 (TRPM7) channel, but antioxidants and carvacrol inhibit it. Selenium (Se) and curcumin (CRC) have been thoroughly studied for their modulator effects on streptozotocin (STZ)-induced neuropathic pain, apoptosis, and oxidative stress through the blockage of TRP channels in dorsal root ganglion (DRG) neurons. It has not yet been fully understood how Se and CRC protect against STZ-induced neuropathic pain by modulating TRPM7. Here, we assessed how Se and CRC affected the Ca2+ influx, mitSOX-mediated oxidative damage, and apoptosis in the DRGs of mice through modifying TRPM7 activity. Seven groups (control, Se, CRC, STZ, STZ + Se, STZ + CRC, and STZ + Se + CRC) were induced from the 56 male mice. We observed that the STZ-induced stimulation of TRPM7 increased mechanical neuropathic pain (von Frey), thermal neuropathic pain (hot plate), cytosolic Ca2+, TRPM7 current density, TRPM7 expression, lipid peroxidation, mitSOX, cytosolic ROS, apoptosis, caspase-3, caspase-8, and caspase-9 concentrations, whereas Se and CRC therapies diminished the alterations. The STZ-mediated decreases of DRG viability, brain glutathione, glutathione peroxidase, vitamin A, and vitamin E concentrations were also upregulated in the treatment groups by the therapies. These findings collectively imply that an imbalance of neuropathic pain, oxidative neurotoxicity, and apoptosis in the mice is caused by the STZ-mediated activation of TRPM7. However, the downregulation of TRPM7 activity caused by the injections of Se and CRC reduced the neurotoxicity and apoptosis.


Fate of zinc oxide and silver nanoparticles in a pilot wastewater treatment plant and in processed biosolids.
Chemical transformations of silver nanoparticles (Ag NPs) and zinc oxide nanoparticles (ZnO NPs) during wastewater treatment and sludge treatment must be characterized to accurately assess the risks that these nanomaterials pose from land application of biosolids. Here, X-ray absorption spectroscopy (XAS) and supporting characterization methods are used to determine the chemical speciation of Ag and Zn in sludge from a pilot wastewater treatment plant (WWTP) that had received PVP coated 50 nm Ag NPs and 30 nm ZnO NPs, dissolved metal ions, or no added metal. The effects of composting and lime and heat treatment on metal speciation in the resulting biosolids were also examined. All added Ag was converted to Ag2S, regardless of the form of Ag added (NP vs ionic). Zn was transformed to three Zn-containing species, ZnS, Zn3(PO4)2, and Zn associated Fe oxy/hydroxides, also regardless of the form of Zn added. Zn speciation was the same in the unamended control sludge. Ag2S persisted in all sludge treatments. Zn3(PO4)2 persisted in sludge and biosolids, but the ratio of ZnS and Zn associated with Fe oxy/hydroxide depended on the redox state and water content of the biosolids. Limited differences in Zn and Ag speciation among NP-dosed, ion-dosed, and control biosolids indicate that these nanoparticles are transformed to similar chemical forms as bulk metals already entering the WWTP.


Autologous double-barrel vascularized fibula bone graft for arthrodesis of the shoulder after tumor resection.
Arthrodesis of the shoulder is a straightforward and established alternative to reconstruct the shoulder function after tumor resection of the proximal humerus. In most cases, some kind of intercalary bone graft is used to bridge the bony defect. However, due to low stability of a single fibula autograft and disadvantages of exogenous graft material when performing combined allo- and autograft reconstruction, efforts to develop new surgical techniques, with the intention to lower the complication rates, are ongoing. We present a detailed description of the surgical technique and the outcome of three patients with osteosarcomas of the proximal humerus, which were treated with tumor resection and autologous double-barrel vascularized fibula bone graft for arthrodesis of the shoulder. The construct was stabilized using a 4.5-mm pelvic reconstruction plate positioned on the scapular spine and the lateral aspect of the humerus. A wide surgical margin was achieved in all patients. Two of them could be reintegrated and are able to work with excellent shoulder function. In one patient, who developed metastasis, a deep infection under chemotherapy 16 months after index surgery complicated the postoperative course. The fibula's unique dual endosteal and periosteal blood supply makes it effective as a double-barrel bone graft for major long bone defects, which requires extra bone volume to prevent fractures until bone hypertrophy occurs. Additional bone and scar formation between the two struts are believed to provide a stable and long lasting construct, as seen in our patients.


Evolutionarily derived networks to inform disease pathways.
Methods to identify genes or pathways associated with complex diseases are often inadequate to elucidate most risk because they make implicit and oversimplified assumptions about underlying models of disease etiology. These can lead to incomplete or inadequate conclusions. To address this, we previously developed human phenotype networks (HPN), linking phenotypes based on shared biology. However, such visualization alone is often uninterpretable, and requires additional filtering. Here, we expand the HPN to include another method, evolutionary triangulation (ET). ET utilizes the hypothesis that alleles affecting disease risk in multiple populations are distributed consistently with differences in disease prevalence and compares allele frequencies among populations and their relationship to phenotype prevalence. We hypothesized that combining these methods will increase our ability to detect genetic patterns of association in complex diseases. We combined HPN and ET to identify network patterns associated with type 2 diabetes mellitus (T2DM), a leading cause of death worldwide. Fasting glucose, a continuous trait, was used as a proxy for T2DM and differs significantly among continental populations. The combined method identified several diabetes-related traits and several phenotypes related to cardiovascular diseases, for which diabetes is a major risk factor. ET-HPN found more phenotypes related to our target and related phenotypes than the application of either method alone. Not only could we detect phenotype connections related to T2DM, but we also identified phenotypes that are distributed in parallel to it, e.g., amyotrophic lateral sclerosis. Our analyses showed that ET-filtered HPN provides information that neither technique can individually.


Aspirin's effect on kinetic parameters of cells contributes to its role in reducing incidence of advanced colorectal adenomas, shown by a multiscale computational study.
Aspirin intake has been shown to lead to significant protection against colorectal cancer, for example with an up to twofold reduction in colorectal adenoma incidence rates at higher doses. The mechanisms contributing to protection are not yet fully understood. While aspirin is an anti-inflammatory drug and can thus influence the tumor microenvironment, in vitro and in vivo experiments have recently shown that aspirin can also have a direct effect on cellular kinetics and fitness. It reduces the rate of tumor cell division and increases the rate of cell death. The question arises whether such changes in cellular fitness are sufficient to significantly contribute to the epidemiologically observed protection. To investigate this, we constructed a class of mathematical models of in vivo evolution of advanced adenomas, parameterized it with available estimates, and calculated population level incidence. Fitting the predictions to age incidence data revealed that only a model that included colonic crypt competition can account for the observed age-incidence curve. This model was then used to predict modified incidence patterns if cellular kinetics were altered as a result of aspirin treatment. We found that changes in cellular fitness that were within the experimentally observed ranges could reduce advanced adenoma incidence by a sufficient amount to account for age incidence data in aspirin-treated patient cohorts. While the mechanisms that contribute to the protective effect of aspirin are likely complex and multi-factorial, our study demonstrates that direct aspirin-induced changes of tumor cell fitness can significantly contribute to epidemiologically observed reduced incidence patterns.


Successful treatment of hairy cell leukemia with beta-ser interferon.
Twelve patients with hairy cell leukemia underwent treatment with beta-ser interferon, a type I interferon with potent antiproliferative activity. Ten of the 12 patients had had prior therapy and the median time from diagnosis to initiation of treatment was 8.5 months (range 1 month to 18 years). Bone marrow involvement ranged from 90-100% hairy cells. Beta-ser interferon was administered as an intravenous injection of 90 million units per dose, three times weekly. Dose reductions were by dose and by frequency in individual patients. Ten of 12 patients (83%) responded, including 7 complete (CR) and 3 partial (PR) responses. The median time to at least PR was 6 months and the median time to CR was 12 months. The median duration of overall response (PR + CR or PR) is 31+ months (range 26(+)-40+ months). Of the 6 patients who underwent dose reductions due to toxicity or poor tolerance, 4 CR patients reverted to PR, and 2 PR patients have increased the number of hairy cells in the marrow, while maintaining normal peripheral blood counts. One each of these has regained CR and PR status after an increase in dose.


Does Increasing Treatment Frequency Address Suboptimal Responses to Ivermectin for the Control and Elimination of River Blindness?
Several African countries have adopted a biannual ivermectin distribution strategy in some foci to control and eliminate onchocerciasis. In 2010, the Ghana Health Service started biannual distribution to combat transmission hotspots and suboptimal responses to treatment. We assessed the epidemiological impact of the first 3 years of this strategy and quantified responses to ivermectin over 2 consecutive rounds of treatment in 10 sentinel communities. We evaluated Onchocerca volvulus community microfilarial intensity and prevalence in persons aged ≥20 years before the first, second, and fifth (or sixth) biannual treatment rounds using skin snip data from 956 participants. We used longitudinal regression modeling to estimate rates of microfilarial repopulation of the skin in a cohort of 217 participants who were followed up over the first 2 rounds of biannual treatment. Biannual treatment has had a positive impact, with substantial reductions in infection intensity after 4 or 5 rounds in most communities. We identified 3 communities-all having been previously recognized as responding suboptimally to ivermectin-with statistically significantly high microfilarial repopulation rates. We did not find any clear association between microfilarial repopulation rate and the number of years of prior intervention, coverage, or the community level of infection. The strategy of biannual ivermectin treatment in Ghana has reduced O. volvulus microfilarial intensity and prevalence, but suboptimal responses to treatment remain evident in a number of previously and consistently implicated communities. Whether increasing the frequency of treatment will be sufficient to meet the World Health Organization's 2020 elimination goals remains uncertain.


Opportunities and Challenges in HIV Treatment as Prevention Research: Results from the ANRS 12249 Cluster-Randomized Trial and Associated Population Cohort.
The ANRS 12249 treatment as prevention (TasP) trial investigated the impact of a universal test and treat (UTT) approach on reducing HIV incidence in one of the regions of the world most severely affected by the HIV epidemic-KwaZulu-Natal, South Africa. We summarize key findings from this trial as well as recent findings from controlled studies conducted in the linked population cohort quantifying the long-term effects of expanding ART on directly measured HIV incidence (2004-2017). The ANRS TasP trial did not-and could not-demonstrate a reduction in HIV incidence, because the offer of UTT in the intervention communities did not increase ART coverage and population viral suppression compared to the standard of care in the control communities. Ten controlled studies from the linked population cohort-including several quasi-experimental study designs-exploit heterogeneity in ART exposure to show a consistent and substantial impact of expanding provision of ART and population viral suppression on reduction in HIV incidence at the couple, household, community, and population levels. In this setting, all of the evidence from large, population-based studies (inclusive of the ANRS TasP trial) is remarkably coherent and consistent-i.e., higher ART coverage and population viral suppression were repeatedly associated with clear, measurable decreases in HIV incidence. Thus, the expanded provision of ART has plausibly contributed in a major way toward the dramatic 43% decline in population-level HIV incidence in this typical rural African population. The outcome of the ANRS TasP trial constitutes a powerful null finding with important insights for overcoming implementation challenges in the population delivery of ART. This finding does not imply lack of ART effectiveness in blocking onward transmission of HIV nor its inability to reduce HIV incidence. Rather, it demonstrates that large increases in ART coverage over current levels will require health systems innovations to attract people living with HIV in early stages of the disease to participate in HIV treatment. Such innovations and new approaches are required for the true potential of UTT to be realized.


Practice variability in management of acute respiratory distress syndrome: bringing evidence and clinician education to the bedside using a web-based teaching tool.
Clinical practice often lags behind publication of evidence-based research and national consensus guidelines. To assess practice variability in the clinical management of acute respiratory distress syndrome (ARDS) and test an evidence-based, online clinician-education tool designed to improve intensive-care clinicians' understanding of current evidence about ARDS management. We surveyed 117 intensive care clinicians (16 critical care physician specialists, 28 resident physicians, 50 critical care nurses, and 23 respiratory therapists) with an online questionnaire in our tertiary academic institution. Fifty of the original respondents (12 residents, 26 critical care nurses, and 12 respiratory therapists) also responded to a repeat survey that included context-sensitive hypertext links to a summary of critically appraised primary articles regarding ARDS management, to determine if the responses changed after the clinicians had read the evidence-based summary information. Critical care physician specialists were most likely to choose the low-tidal-volume (low-VT) ventilation strategy and protocol-based ventilator weaning and were least likely to choose neuromuscular blockade or parenteral nutrition (p < 0.05). In a paired comparison, individual respondents were more likely to choose treatment options that are based on stronger evidence (low-VT, daily interruption in sedation, and protocol weaning [p < 0.01]). We also reviewed the medical records of 100 patients who were mechanically ventilated for > 48 h, during the 6 months before and after the survey, from which we identified 45 ARDS patients. Following the clinician-education intervention, ARDS patients were less likely to receive potentially injurious high-VT ventilation (mean day-3 VT 10.3 +/- 2.3 mL/kg before vs 8.9 +/- 1.7 mL/kg after, p = 0.02). Web-based teaching tools are useful to educate intensive-care practitioners and to promote evidence-based practice.


FLEET velocimetry for combustion and flow diagnostics.
We report the use of femtosecond laser electronic excitation tagging (FLEET) for velocimetry at a 100-kHz imaging rate. Sequential, single-shot, quantitative velocity profiles of an underexpanded supersonic nitrogen jet were captured at a 100-kHz rate. The signal and lifetime characteristics of the FLEET emission were investigated in a methane flame above a Hencken burner at varying equivalence ratios, and room temperature gas mixtures involving air, methane, and nitrogen. In the post-flame region of the Hencken burner, the emission lifetime was measured as two orders of magnitude lower than lab air conditions. Increasing the equivalence ratio above 1.1 leads to a change in behavior, with a doubled lifetime. By measuring the emission in a cold methane flow, a short-lived signal was measured that decayed after the first microsecond. As a proof of concept for velocimetry in a reacting environment, the exhaust of a pulsed detonator was measured by FLEET. Quantitative velocity information was obtained that corresponded to a maximum centerline velocity of 1800 m/s for the detonation wave. Extension of FLEET to larger scale, complex flow environments is now a viable option.


Loss of prolyl carboxypeptidase in two-kidney, one-clip goldblatt hypertensive mice.
It is well documented that angiotensin (Ang) II contributes to kidney disease progression. The protease prolyl carboxypeptidase (PRCP) is highly expressed in the kidney and may be renoprotective by degrading Ang II to Ang-(1-7). The aim of the study was to investigate whether renal PRCP protein expression and activity are altered in two-kidney, one-clip (2K1C) Goldblatt hypertensive mice. Left renal artery was constricted by using 0.12 mm silver clips. Blood pressure was measured using telemetry over the eleven weeks of study period and revealed an immediate increase in 2K1C animals during the first week of clip placement which was followed by a gradual decrease to baseline blood pressure. Similarly, urinary albumin excretion was significantly increased one week after 2K1C and returned to baseline levels during the following weeks. At 2 weeks and at the end of the study, renal pathologies were exacerbated in the 2K1C model as revealed by a significant increase in mesangial expansion and renal fibrosis. Renal PRCP expression and activity were significantly reduced in clipped kidneys. Immunofluorescence revealed the loss of renal tubular PRCP but not glomerular PRCP. In contrast, expression of prolyl endopeptidase, another enzyme capable of converting Ang II into Ang-(1-7), was not affected, while angiotensin converting enzyme was elevated in unclipped kidneys and renin was increased in clipped kidneys. Results suggest that PRCP is suppressed in 2K1C and that this downregulation may attenuate renoprotective effects via impaired Ang II degradation by PRCP.


Preferential expression of a Mr 155,000 milk-fat-globule membrane glycoprotein on luminal epithelium of lobules in human breast.
An integral membrane glycoprotein with an apparent molecular weight of 155,000 and isoelectric points ranging from 7.2 to 7.6 has been found to be predominantly expressed on the apical plasma membrane of luminal epithelial cell lining the lobules and terminal ducts in breast. The glycoprotein was purified to homogeneity from human milk-fat-globule membrane and was termed MFGM-gp 155. Polyclonal antibodies were raised which specifically reacted to a single component that electrophoretically comigrated with this glycoprotein in immunoblotting experiments. These antibodies appear to recognize epitopes which are expressed on the protein segment of the glycoprotein. Using an indirect immunohistological method, the glycoprotein was localized predominantly on the apical plasma membrane of luminal epithelial cells lining the alveoli of normal breasts. The expression of the antigen was maintained in both morphologically well- and poorly differentiated lobular carcinoma cells. The antigen was weakly detectable on normal epithelial cells lining the terminal ducts and malignant cells of infiltrating ductal and medullary carcinomas. Expression of the glycoprotein is not organ specific as it is detectable in normal epithelial cells of kidney, pancreas, salivary gland, and stomach and in malignant cells of colon and stomach. The antibodies did not react with large ductal, myoepithelial, stromal, endothelial, epidermal squamous epithelial cells, melanocytes, eccrine sweat glands and ducts, sebaceous glands, erythrocytes, and lymphocytes in breast and skin tissues. Thus, antibodies to this glycoprotein appear to be useful phenotype markers to study differentiation of mammary epithelial cells and the pathogenesis of different histological types of mammary carcinomas, including Paget's disease and signet-ring cell carcinoma of mammary gland.


Local and serum IgE in vasomotor rhinitis.
Total and specific IgE in serum and nasal secretions were measured in twenty five subjects with vasomotor rhinitis without asthma (21 perennial vasomotor allergic rhinitis and 4 seasonal vasomotor allergic rhinitis) after Carbacholine nasal challenge-test. The level of total and specific IgE was lower in the pure, non diluted nasal secretions than in the serum. The diagnostic usefullness of these measurements and the concept of "localized allergy" are discussed.


Elevated retinol binding protein 4 contributes to insulin resistance in spontaneously hypertensive rats.
Retinol binding protein 4 (RBP4) is an adipokine secreted by adipose tissue and liver and contributes to insulin resistance (IR) in animals. Although several human studies indicated that RBP4 is positively correlated with blood pressure and is elevated in untreated hypertensive subjects, the role of RBP4 in IR of hypertensive animals still remains obscure. In this study, spontaneously hypertensive rats (SHR) were used to investigate the relationship between RBP4 levels and IR. We found that at 7 weeks old, SHR had significantly increased plasma RBP4 levels and RBP4 expression in liver and epididymal adipose tissue accompanied by worsening of IR as compared with Wistar-Kyoto (WKY) control rats. Administration of fenretinide in SHR to increase urinary RBP4 excretion significantly decreased plasma RBP4 levels and improved IR. Moreover, treatment with valsartan markedly reduced blood pressure, circulating RBP4 and adiponectin levels, and IR in SHR. Valsartan also reversed the increase of hepatic gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and the decrease of type 4 glucose transporter (GLUT4) in adipose tissue. In conclusion, these results suggest that RBP4 contributes, at least partly, to the pathogenesis of IR in SHR. Furthermore, the decrease of blood pressure caused by valsartan not only decreased RBP4 levels, but also improved IR in SHR.


Trimodal cancer treatment: beneficial effects of combined antiangiogenesis, radiation, and chemotherapy.
It has been suggested that chemotherapy and radiotherapy could favorably be combined with antiangiogenesis in dual anticancer strategy combinations. Here we investigate the effects of a trimodal strategy consisting of all three therapy approaches administered concurrently. We found that in vitro and in vivo, the antiendothelial and antitumor effects of the triple therapy combination consisting of SU11657 (a multitargeted small molecule inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases), Pemetrexed (a multitargeted folate antimetabolite), and ionizing radiation were superior to all single and dual combinations. The superior effects in human umbilical vein endothelial cells and tumor cells (A431) were evident in cell proliferation, migration, tube formation, clonogenic survival, and apoptosis assays (sub-G1 and caspase-3 assessment). Exploring potential effects on cell survival signaling, we found that radiation and chemotherapy induced endothelial cell Akt phosphorylation, but SU11657 could attenuate this process in vitro and in vivo in A431 human tumor xenografts growing s.c. on BALB/c nu/nu mice. Triple therapy further decreased tumor cell proliferation (Ki-67 index) and vessel count (CD31 staining), and induced greater tumor growth delay versus all other therapy regimens without increasing apparent toxicity. When testing different treatment schedules for the A431 tumor, we found that the regimen with radiotherapy (7.5 Gy single dose), given after the institution of SU11657 treatment, was more effective than radiotherapy preceding SU11657 treatment. Accordingly, we found that SU11657 markedly reduced intratumoral interstitial fluid pressure from 8.8 +/- 2.6 to 4.2 +/- 1.5 mm Hg after 1 day. Likewise, quantitative T2-weighed magnetic resonance imaging measurements showed that SU11657-treated mice had reduced intratumoral edema. Our data indicates that inhibition of Akt signaling by antiangiogenic treatment with SU11657 may result in: (a) normalization of tumor blood vessels that cause prerequisite physiologic conditions for subsequent radio/chemotherapy, and (b) direct resensitization of endothelial cells to radio/chemotherapy. We conclude that trimodal cancer therapy combining antiangiogenesis, chemotherapy, and radiotherapy has beneficial molecular and physiologic effects to emerge as a clinically relevant antitumor strategy.


Critical care outcomes: linking structures, processes, and organizational and clinical outcomes.
Organizational structure and process are thought to affect patient care outcomes beyond the effects of expert clinical care. To test the hypothesis that a discretionary pattern of organizational structure and process factors is predictive of critical care unit performance, ie, desirable patient and organizational outcomes. Quality-of-care patient and organizational outcomes were evaluated in 25 critical care units. A single value representing each critical care unit's euclidian distance from a theoretically ideal pattern of discretionary function was determined and correlated with unit-level measures of outcomes (standardized mortality ratio, severity-adjusted length of stay, patient satisfaction, quality of nursing care, and nursing retention). Distance from the ideal-type discretionary pattern predicted organizational but not clinical outcomes. Units closer to the ideal-type pattern had higher RN retention, and were viewed as better places to work, with higher-quality care by both nurses and physicians. Objectively measured quality of care, patient satisfaction, severity-adjusted mortality, and length of stay were not consistently related to better-structured units. With experienced critical care practitioners, unit-level structure and process factors were better predictors of organizational outcomes than of clinical outcomes.


Developmental Changes in Locating Voice and Sound in Space.
We know little about how infants locate voice and sound in a complex multi-modal space. Using a naturalistic laboratory experiment the present study tested 35 infants at 3 ages: 4 months (15 infants), 5 months (12 infants), and 7 months (8 infants). While they were engaged frontally with one experimenter, infants were presented with (a) a second experimenter's voice and (b) castanet sounds from three different locations (left, right, and behind). There were clear increases with age in the successful localization of sounds from all directions, and a decrease in the number of repetitions required for success. Nonetheless even at 4 months two-thirds of the infants attempted to search for the voice or sound. At all ages localizing sounds from behind was more difficult and was clearly present only at 7 months. Perseverative errors (looking at the last location) were present at all ages and appeared to be task specific (only present in the 7 month-olds for the behind location). Spontaneous attention shifts by the infants between the two experimenters, evident at 7 months, suggest early evidence for infant initiation of triadic attentional engagements. There was no advantage found for voice over castanet sounds in this study. Auditory localization is a complex and contextual process emerging gradually in the first half of the first year.


Staging Science: Authoritativeness and Fragility of Models and Measurement in the COVID-19 Crisis.
In the COVID-19 crisis, society pins its hopes on science to play an authoritative role in reducing uncertainty and ambiguity. But is science up to the task? This is far from self-evident. The demands on science in times of crisis run counter to the values of good, normal science. Crisis science needs to be fast, univocal, personalized, and direct, while normal science is slow, contentious, collective, and sensitive to complexity. Science can only play its atypical role if it is staged in the public arena. Some patterns of staging stand out: personalization, visualization, and connection to lived experiences. So far, the staging of science has been successful, but it is fragile. The COVID-19 crisis shows the potential of well-staged forms of alliance between science and policy, but when the general assumption is that scientists will "solve" societal "problems," the staging of science has gone too far.


ProBNP for stratifying patients with heart failure.
To verify whether the serum levels of N-Terminal ProBNP fraction (ProBNP) allow us to identify with accuracy the clinical functional status of patients with heart failure (HF), because the clinical diagnosis of this syndrome is based basically on clinical data when the complementary tests have lower specificity. Sixty-nine patients with a history of HF were studied. Their mean age of was 53.5 years and 78.3% were males. All underwent clinical and echocardiographic evaluations and a test to determine the serum dosage of ProBNP. According to clinical manifestation, patients were in the following functional classes (FC), 14% FC I, 40.6% FC II, 28.1% FC III, and 23.4% FC IV. The mean ejection fraction (EF) was 0.28. ProBNP did not differ according to age, sex, and cause of cardiopathy. No correlation existed between EF and the ProBNP serum level. ProBNP levels were significantly lower in patients in FC I than those in FC II (42 vs 326.7 pmol/L; P=0.0001), and in FC II than those in FC III (P=0.01). ProBNP levels did not differ statically between FC III and IV patients (888.1 vs 1082.8 pmol/L; P=0.25). ProBNP values greater than 100 pmol/L identify patients with decompensated HF with a sensitivity of 98%. ProBNP values over 100 pmol/L were indicative of HF, and patients with advanced HF had values over 270 pmol/L. A ProBNP dosage test was an excellent auxiliary in the clinical characterization of patients with HF.


The Development and Evaluation of an Analytical Framework to Explore Student Nurses' Cultural Beliefs of Dementia.
People diagnosed with dementia need culturally sensitive, person-centered care to promote their health and well-being. Therefore, healthcare professionals should be able to provide culturally competent care, of which an element is the understanding of their own cultural heritage and how this impacts on their beliefs regarding dementia, as cultural norms and values provide meanings and understanding of chronic conditions such as dementia. This study used focus groups to explore the cultural beliefs of student nurses regarding dementia, generating a large set of qualitative data that required structure and a framework to analyze. One purpose of this article was to present the methodological analysis, which encompasses the analytical framework. The second purpose was to apply the framework to elicit the cultural beliefs regarding dementia among student nurses from multiple national backgrounds. Focus groups with student nurses from five higher education institutes in England, the Philippines, Slovenia, and New Zealand were conducted, audiotaped, and transcribed verbatim. The qualitative data were analyzed using the framework method of analysis. Data from the focus groups conducted at the two higher education institutes in England were analyzed by encompassed synthesizing, refining, and agreeing on the codes, categories, and themes that were established separately by four researchers. The developed analytical framework was then tested on the qualitative data obtained from the focus groups conducted in Slovenia, the Philippines, and New Zealand. The results were presented in three parts: the cultural analytical framework, the process of developing the initial categories/themes, and the final themes that emerged from the data obtained from the focus groups. An analytical framework was developed and applied to understand student nurses' cultural values and beliefs of dementia.


Impact of surgeon annual volume on short-term maternal outcome in cesarean delivery.
The annual procedure volume is an accepted marker for quality of care and has been documented in various medical fields. Surgeon volume has been shown to correlate with morbidity and mortality rates in surgical and high-risk medical procedures. Although cesarean delivery is 1 of the most common surgical procedures in the United States, the link between a surgeon's annual cesarean delivery volume and maternal outcome has never been tested. The purpose of this study was to evaluate the impact of a surgeon's annual volume on short-term maternal outcome in cesarean deliveries. We performed a retrospective cohort study in a single tertiary center between 2006 and 2013. Cesarean deliveries were categorized into 2 groups based on the annual volume of cesarean delivery of the attending obstetrician. The "low" group included obstetricians with a low annual volume, whose annual volume of cesarean delivery was lower than median. The "high" group comprised obstetricians with a high annual volume whose annual volume was at median and above. Further analyses were done for quartiles and for 4 clinical relevant groups according to the annual number of cesarean deliveries that were performed/supervised by the attending obstetrician (≤20, 21-60, 61-120, and >120). The primary outcome was a composite adverse maternal outcome that included ≥1 of the following outcomes: urinary or gastrointestinal tract injuries, hemoglobin drop >3 g/dL, blood transfusion, relaparotomy, puerperal fever, prolonged maternal hospitalization, and readmission. Secondary outcomes were operative times (skin incision to delivery and overall). A total of 11,954 cesarean deliveries were included; the median annual number of cesarean deliveries that were performed/supervised by 1 obstetrician was 48. Unadjusted analysis suggested that the patients in the high group had fewer urinary and gastrointestinal injuries (18/9278 [0.2%] vs 16/2676 [0.6%] injuries; P < .001), less blood loss as measured by hemoglobin drop >3 g/dL (1053/9278 [11.5%] vs 366/2676 [13.8%]; P < .001), and fewer cases of prolonged maternal hospitalization (80/9278 [0.9%] vs 39/2676 [1.5%]; P = .006). The rate of blood transfusion, relaparotomy, puerperal febrile morbidity, and readmission to hospital did not differ between groups. Multivariable regression analysis showed that cesarean delivery performed/supervised by the high group resulted in a significantly lower composite adverse maternal outcome (15.8% vs 18.9%; odds ratio, 0.86; 95% confidence interval, 0.78-0.95; P = .004). This was related primarily to a decreased frequency of urinary and gastrointestinal injuries, lower likelihood of hemoglobin drop >3 g/dL, and lower incidence of prolonged maternal hospitalization. Operative times were significantly shorter for the high group. Composite adverse maternal outcome ranged from 21.8% in the lowest quartile to 17.9% in quartile 2, to 17.4% in quartile 3, and 15.6% in quartile 4. quartile 4 served as the reference; quartile 3 had an odds ratio of 1.14 (95% confidence interval, 1.01-1.29; P = .029); quartile 2 had an odds ratio of 1.18 (95% confidence interval, 1.02-1.36; P = .021, and quartile 1 had an odds ratio of 1.51 (95% confidence interval, 1.14-1.99; P = .004) for composite adverse maternal outcome. Composite adverse maternal outcome ranged from 21.5% in clinical group 1 to 17.5% in clinical group 2, to 17.9% in clinical group 3, and 15.2% in clinical group 4 (P = .001). Cesarean delivery performed/supervised by clinical groups 2, 3, and 4 in comparison with clinical group 1 were associated with a statistically significant risk reduction, (23%, 25%, and 34% respectively). Maternal composite morbidity is decreased as the volume of cesarean deliveries that are performed or supervised by obstetricians increases.


Mortality due to coronary heart disease and kidney disease among middle-aged and elderly men and women with gout in the Singapore Chinese Health Study.
Whether the link between gout and mortality is causal or confounded by lifestyle factors or comorbidities remains unclear. Studies in Asia are warranted due to the rapid modernisation of the locale and ageing of the population. The association between gout and mortality was examined in a prospective cohort, the Singapore Chinese Health Study, comprising 63 257 Singapore Chinese individuals, aged 45-74 years during the enrolment period of 1993-8. All enrollees were interviewed in person on lifestyle factors, current diet and medical histories. All surviving cohort members were contacted by telephone during 1999-2004 to update selected exposure and medical histories (follow-up I interview), including the history of physician-diagnosed gout. Cause-specific mortality in the cohort was identified via record linkage with the nationwide death registry, up to 31 December 2009. Out of 52 322 participants in the follow-up I interview, 2117 (4.1%) self-reported a history of physician-diagnosed gout, with a mean age at diagnosis of 54.7 years. After a mean follow-up period of 8.1 years, there were 6660 deaths. Relative to non-gout subjects, subjects with gout had a higher risk of death (HR 1.18; 95% CI 1.06 to 1.32), and specifically from death due to coronary heart disease (CHD) (HR 1.38, 95% CI 1.10 to 1.73) and kidney disease (HR 5.81, 95% CI 3.61 to 9.37). All gout-mortality risk associations were present in both genders but the risk estimates appeared higher for women. Gout is an independent risk factor for mortality, and specifically for death due to CHD and kidney disease.


Sarcoidosis and the Th1 chemokine MIG.
Sarcoidosis is a systemic inflammatory disease, affecting any organ, and that can be discovered by accident in approximately 5% of cases. High levels of the type-1 helper (Th1)-dependent chemokine, monokine induced by interferon (IFN)-γ (MIG)/chemokine (C-X-C motif) ligand (CXCL)9, and its receptor CXCR3 have been reported in bronchoalveolar lavage and biopsy samples of patients with sarcoidosis. These elevated levels are related with the amount of CD4+ lymphocytes and total lymphocytes. Alveolar macrophages resulted stained positive for all CXCR3 ligands and produced elevated levels of these chemokines. It has been shown that the epithelioid and giant cells of the sarcoid lungs were stained positive for MIG, IFN-inducible T-cell α chemoattractant (I-TAC) and IFN-γ-inducible protein 10 (IP-10), suggesting that MIG plays an important role in the accumulation of Th1 lymphocytes in sarcoid lungs. In addition, serum levels of MIG were related with the severity of the disease, and a correlation between the serial measurements of MIG and the clinical course of the disease was shown, indicating MIG as a potentially useful biomarker of sarcoidosis and its severity.


Unravelling animal exposure profiles of human Q fever cases in Queensland, Australia, using natural language processing.
Q fever, caused by the zoonotic bacterium Coxiella burnetii, is a globally distributed emerging infectious disease. Livestock are the most important zoonotic transmission sources, yet infection in people without livestock exposure is common. Identifying potential exposure pathways is necessary to design effective interventions and aid outbreak prevention. We used natural language processing and graphical network methods to provide insights into how Q fever notifications are associated with variation in patient occupations or lifestyles. Using an 18-year time-series of Q fever notifications in Queensland, Australia, we used topic models to test whether compositions of patient answers to follow-up exposure questionnaires varied between demographic groups or across geographical areas. To determine heterogeneity in possible zoonotic exposures, we explored patterns of livestock and game animal co-exposures using Markov Random Fields models. Finally, to identify possible correlates of Q fever case severity, we modelled patient probabilities of being hospitalized as a function of particular exposures. Different demographic groups consistently reported distinct sets of exposure terms and were concentrated in different areas of the state, suggesting the presence of multiple transmission pathways. Macropod exposure was commonly reported among Q fever cases, even when exposure to cattle, sheep or goats was absent. Males, older patients and those that reported macropod exposure were more likely to be hospitalized due to Q fever infection. Our study indicates that follow-up surveillance combined with text modelling is useful for unravelling exposure pathways in the battle to reduce Q fever incidence and associated morbidity.


Vocational rehabilitation of the older worker.
Work is an important social role. A disability can interfere with a person's work abilities and opportunities at any age. Unfortunately, the older population has received disproportionately little attention in rehabilitation, particularly in vocational rehabilitation. This is true, in spite of the fact that there is a growing population of older persons, with a high prevalence of disability. When returning an older disabled person to work, consideration of his or her particular physical, psychological, and social characteristics is required. This paper discusses the involvement of occupational therapists in the returning of older persons to work.


Distress Screening: Evaluating a Protocol for Gynecologic Cancer Survivors .
A gynecologic cancer diagnosis and subsequent treatment may cause significant morbidity, leading to increased distress levels and poorer quality of life (QOL) for survivors. Clinicians have explored opportunities to integrate comprehensive distress management protocols into clinical settings using existing supportive care resources. . The aims were to improve multidisciplinary management of distress using a clinical pathway for gynecologic cancer survivors and to improve patient satisfaction with distress management. . This study is phase II of a quality improvement initiative to assess distress using the National Comprehensive Cancer Network Distress Thermometer and Patient Related Outcome Measures Information Systems QOL tool and to evaluate the use of a clinical pathway to identify and link gynecologic cancer survivors to multidisciplinary supportive care resources. The data were compared to results from phase I of this study with data triangulation that included medical record audits. . Thirty-five percent of survivors reported distress scores of 5 or greater. The use of a clinical pathway model for universal distress screening increased referrals to multidisciplinary service teams from 19 to 34, with a 32% increase in social work referrals. Patients appreciated the comprehensive approach the healthcare team used to treat cancer and help improve QOL.


Rates and risk factors for persistent opioid use after cardiothoracic surgery: A cohort study.
This study's aim was to estimate potential risk factors for persistent opioid use after cardiothoracic surgery. This study included participants in the McGill University Health Centre clinical trial (2014 to 2016). Provincial medical services, prescription claims, and medical charts data were linked. Persistent opioid use was defined as an initial peri-operative opioid dispensation followed by an opioid dispensation between 91 and 180 days postdischarge. Multivariable Cox Proportional Hazards models were used to assess factors associated with persistent opioid use. A cohort of 815 patients (mean age: 68.9 [standard deviation = 8.9]) was assembled, of which 8.2% became persistent opioid users. Factors such as higher Charlson Comorbidity Index (adjusted hazard ratio: 3.4, 95% confidence interval: 1.1-10.6), history of diabetes (adjusted hazard ratio: 2.1, 95% confidence interval: 1.3-3.4), substance and alcohol abuse (adjusted hazard ratio: 16.3, 95% confidence interval: 5.3-49.5), and radiotherapy (adjusted hazard ratio: 2.4, 95% confidence interval: 1.5-4.1) were associated with a higher hazard of persistent opioid use. Previous opioid use (adjusted hazard ratio: 1.7, 95% CI: 1.0-2.8), daily peri-operative opioid dose (adjusted hazard ratio: 2.3, 95% confidence interval: 1.5-3.7), having an opioid dispensation 30 days pre-admission (adjusted hazard ratio: 1.7, 95% confidence interval: 1.0-2.8), and pre-admission analgesic use (adjusted hazard ratio: 1.7, 95% confidence interval: 1.0-2.8), were also associated with an increased hazard of persistent use. Being prescribed multimodal analgesia at discharge (adjusted hazard ratio: 0.54, 95% confidence interval: 0.32-0.92) was associated with a 46% decreased hazard of developing persistent opioid use. Multiple patient- and medication-related characteristics were associated with an increased hazard of persistent opioid use.


COVID-19 infection produces subarachnoid hemorrhage; acting now to understand its cause: A short communication.
In the medical literature, some case reports on the association of the COVID-19 infection and occurrence of spontaneous subarachnoid hemorrhage (SAH)have been reported Aim of the present paper is to search the causes of this association The diagnosis of COVID-19 was based on the real-time reverse-transcription polymerase chain reaction (PCR) test and computed tomography (CT) of the chest. There were four patients, whose median ages were 46,758, ranged 36-54 years). In conclusion, Spontaneous SAH can occur in the early and late course of COVID-19 infection. Its early recognition of the patient with spontaneous SAH is imperative.


Sources of toxoplasma infection in pregnant women: European multicentre case-control study. European Research Network on Congenital Toxoplasmosis.
To determine the odds ratio and population attributable fraction associated with food and environmental risk factors for acute toxoplasmosis in pregnancy. Case-control study. Six large European cities. Pregnant women with acute infection (cases) detected by seroconversion or positive for anti-Toxoplasma gondii IgM were compared with pregnant women seronegative for toxoplasma (controls). Odds ratios for acute infection adjusted for confounding variables; the population attributable fraction for risk factors. Risk factors most strongly predictive of acute infection in pregnant women were eating undercooked lamb, beef, or game, contact with soil, and travel outside Europe and the United States and Canada. Contact with cats was not a risk factor. Between 30% and 63% of infections in different centres were attributed to consumption of undercooked or cured meat products and 6% to 17% to soil contact. Inadequately cooked or cured meat is the main risk factor for infection with toxoplasma in all centres. Preventive strategies should aim to reduce prevalence of infection in meat, improve labelling of meat according to farming and processing methods, and improve the quality and consistency of health information given to pregnant women.


Trachoma control: the SAFE strategy.
As a contagious bacterial infection that affects the conjunctival covering of the eye, the cornea and the eyelids, trachoma is controlled by an endorsed integrated strategy consisting of surgery for trichiasis, antibiotic therapy, facial cleanliness and environmental improvement, namely, the SAFE strategy developed by World Health Organization. Developed based on evidence from previous field trials and constantly modified in practice, SAFE strategy has greatly boosted the progress in trachoma control. Regardless of the fact that there are still many pending questions, national program coordinators are convinced that trachoma control initiative based on SAFE strategy would be effective.


Effects of lead and natriuretic hormone on kinetics of sodium-potassium-activated adenosine triphosphatase: possible relevance to hypertension.
Inhibition of vascular smooth muscle sodium-potassium-activated adenosine triphosphatase (Na-K-ATPase) has been postulated as a central mechanism in enhancing vascular contractility. In the present study, kinetics of inhibition of Na-K-ATPase by lead, ouabain, and natriuretic hormone (NH) was studied in a purified hog cerebral cortex enzyme preparation. Determination of I50 values for lead, ouabain, and NH revealed that NH is the most potent inhibitor of the enzyme system (0.8 x 10(-6) M ouabain equivalents). Kinetic analyses indicated that lead and NH exhibited different inhibitory mechanisms. The inhibition by lead was noncompetitive with respect to potassium and competitive with respect to sodium and MgATP. Natriuretic hormone was noncompetitive with respect to potassium, uncompetitive with respect to MgATP, and exhibited no inhibitory effect with respect to sodium. Synergism between lead and NH in the inhibition of Na-K-ATPase raises the possibility that lead may be a contributory factor in hypertension via this mechanism.


[Problem of homologization of the cerebral neocortex in cetaceans].
Homologization of the cerebeal neocortex of the cetaceans was performed by comparison of macro- and micro-signs of the structural organization of the cerebral cortex of cetaceanson the one hand and comparison with the same data on the cerebral cortex of ungulates, carnivores and primates. The degree of homology of main fissures and convolutions of the brain of the cetaceans was shown to differ very markedly from the brain of carnivores and priimates. Besides, the complex of macroscopic and cytoarchitectonic characteristics as compared with earlier data on the structural organization of the new cortex of the dolphin (1969,1970) permitted identification of a new type of the cortex which is characteristic only of cetaceans andnot of the ground mammals.


A feedback mechanism to control apoptosis occurs in the digestive gland of the oyster crassostrea gigas exposed to the paralytic shellfish toxins producer Alexandrium catenella.
To better understand the effect of Paralytic Shellfish Toxins (PSTs) accumulation in the digestive gland of the Pacific oyster, Crassostrea gigas, we experimentally exposed individual oysters for 48 h to a PSTs producer, the dinoflagellate Alexandrium catenella. In comparison to the effect of the non-toxic Alexandrium tamarense, on the eight apoptotic related genes tested, Bax and BI.1 were significantly upregulated in oysters exposed 48 h to A. catenella. Among the five detoxification related genes tested, the expression of cytochrome P450 (CYP1A) was shown to be correlated with toxin concentration in the digestive gland of oysters exposed to the toxic dinoflagellate. Beside this, we observed a significant increase in ROS production, a decrease in caspase-3/7 activity and normal percentage of apoptotic cells in this tissue. Taken together, these results suggest a feedback mechanism, which may occur in the digestive gland where BI.1 could play a key role in preventing the induction of apoptosis by PSTs. Moreover, the expression of CYP1A, Bax and BI.1 were found to be significantly correlated to the occurrence of natural toxic events, suggesting that the expression of these genes together could be used as biomarker to assess the biological responses of oysters to stress caused by PSTs.


Superior mesenteric artery syndrome.
Superior mesenteric artery syndrome is a rare and controversial form of upper intestinal obstruction in which the third part of the duodenum is compressed by the overlying superior mesenteric artery. Any disease process decreasing the angle between the superior mesenteric artery and the abdominal aorta can result in the external compression of the duodenum and subsequent intestinal obstruction. The aetiology, presentation, investigation and management of this unusual condition are discussed.


Supplemental norgestomet, progesterone, or melengestrol acetate increases pregnancy rates in suckled beef cows after timed inseminations.
In Exp. 1, 187 lactating beef cows were treated with injections of GnRH 7 d before and 48 h after prostaglandin F2alpha (PGF2alpha; Cosynch) or with Cosynch plus a 7-d treatment with an intravaginal progesterone (P4)-releasing insert (CIDR-B; Cosynch + CIDR). In Exp. 2, 183 lactating beef cows were treated with the Cosynch protocol or with Cosynch plus a 7-d treatment with norgestomet (Cosynch + NORG). In Exp. 1 and 2, blood samples for later P4 analyses were collected on d -17, -7 (first GnRH injection), 0 (PGF2alpha injection), and at timed artificial insemination (TAI; 48 h after PGF2alpha). In Exp. 3, 609 lactating beef cows were treated with the Cosynch + CIDR protocol or were fed 0.5 mg of melengestrol acetate (MGA) per day for 14 d before initiating the Cosynch protocol 12 d after the 14th d of MGA feeding (MGA + Cosynch). Blood samples were collected as in Exp. 1 and 2, plus additional samples on d -33 and -19 before PGF2alpha. In Exp. 4, 360 lactating beef cows were treated with a Cosynch + CIDR protocol, with TAI occurring at either 48 or 60 h after PGF2alpha, while receiving either GnRH or saline to form four treatments. Blood samples were collected as in Exp. 1 and 2. In Exp. 1, addition of P4 reduced the ability of the first GnRH injection to induce ovulation in anestrous cows with low P4 before PGF2alpha but improved (P = 0.06) pregnancy rates (61 vs 66%). In Exp. 2, the addition of NORG mimicked P4 by likewise increasing (P < 0.01) pregnancy rates (31 vs 51%) beyond those after Cosynch. In Exp. 3, the Cosynch + CIDR protocol increased (P < 0.001) pregnancy rates from 46 to 55% compared to the MGA + Cosynch protocol. In Exp. 4, administration of GnRH at TAI improved (P < 0.05) pregnancy outcomes (50 vs 42%), whereas timing of TAI had limited effects. We conclude that a progestin treatment concurrent with the Cosynch protocol improved pregnancy outcomes in all experiments, but pretreatment of cows with MGA was not as effective as the CIDR insert or NORG implants in this Cosynch-TAI model. Most of the improvement in pregnancy rates was associated with the increase in pregnancy rates of anestrous cows, regardless of whether ovulation was successfully induced in response to GnRH 7 d before PGF2alpha. Injection of GnRH at TAI following the Cosynch + CIDR protocol increased pregnancy rates in cycling cows with high P4 before the PGF2alpha injection and in anestrous cows with low P4 before PGF2alpha injection.


Force-generating domain of myosin motor.
To understand the underlying mechanism of force generation by myosin motor, it is crucial to know which part of the molecule is essential for the process. Recent structure determination of myosin motor domain at atomic resolution has revealed that the domain comprises two smaller domains, the "ATPase domain" consisting of only an N-terminal segment of the heavy chain and the "neck domain" consisting of a long alpha-helix of the heavy chain and two light chains. This atomic structure begs the question of whether both domains are required for force generation. To answer it, we genetically truncated the head to generate a recombinant fragment composed of the "ATPase domain" alone. The truncated head drove sliding movement of actin filaments and generated force in a novel in vitro assay system, which allows us to hold a specific site of the head on a glass surface. These results indicate that the compact ATPase domain functions as a force-generating machinery of the myosin motor.


Determination of the self-association residues within a homomeric and a heteromeric AAA+ enhancer binding protein.
The σ(54)-dependent transcription in bacteria requires specific activator proteins, bacterial enhancer binding protein (bEBP), members of the AAA+ (ATPases Associated with various cellular Activities) protein family. The bEBPs usually form oligomers in order to hydrolyze ATP and make open promoter complexes. The bEBP formed by HrpR and HrpS activates transcription from the σ(54)-dependent hrpL promoter responsible for triggering the Type Three Secretion System in Pseudomonas syringae pathovars. Unlike other bEBPs that usually act as homohexamers, HrpR and HrpS operate as a highly co-dependent heterohexameric complex. To understand the organization of the HrpRS complex and the HrpR and HrpS strict co-dependence, we have analyzed the interface between subunits using the random and directed mutagenesis and available crystal structures of several closely related bEBPs. We identified key residues required for the self-association of HrpR (D32, E202 and K235) with HrpS (D32, E200 and K233), showed that the HrpR D32 and HrpS K233 residues form interacting pairs directly involved in an HrpR-HrpS association and that the change in side-chain length at position 233 in HrpS affects self-association and interaction with the HrpR and demonstrated that the HrpS D32, E200 and K233 are not involved in negative regulation imposed by HrpV. We established that the equivalent residues K30, E200 and E234 in a homo-oligomeric bEBP, PspF, are required for the subunit communication and formation of an oligomeric lock that cooperates with the ATP γ-phosphate sensing PspF residue R227, providing insights into their roles in the heteromeric HrpRS co-complex.


Multivariate Cutoff Level Analysis (MultiCoLA) of large community data sets.
High-throughput sequencing techniques are becoming attractive to molecular biologists and ecologists as they provide a time- and cost-effective way to explore diversity patterns in environmental samples at an unprecedented resolution. An issue common to many studies is the definition of what fractions of a data set should be considered as rare or dominant. Yet this question has neither been satisfactorily addressed, nor is the impact of such definition on data set structure and interpretation been fully evaluated. Here we propose a strategy, MultiCoLA (Multivariate Cutoff Level Analysis), to systematically assess the impact of various abundance or rarity cutoff levels on the resulting data set structure and on the consistency of the further ecological interpretation. We applied MultiCoLA to a 454 massively parallel tag sequencing data set of V6 ribosomal sequences from marine microbes in temperate coastal sands. Consistent ecological patterns were maintained after removing up to 35-40% rare sequences and similar patterns of beta diversity were observed after denoising the data set by using a preclustering algorithm of 454 flowgrams. This example validates the importance of exploring the impact of the definition of rarity in large community data sets. Future applications can be foreseen for data sets from different types of habitats, e.g. other marine environments, soil and human microbiota.


Effect of carotenoid β-cryptoxanthin on cellular and humoral immune response in rabbit.
Beta-cryptoxanthin (b-Cr) is a pro-vitamin A and one of the major carotenoids that can be commonly found in mammalian serum and tissues. Foods rich in certain fatty acids are known to be effective to gain a healthy immune system. In the present study, we evaluated the effect of b-Cr on rabbit humoral and cellular immune responses to have a better vision about the mechanism of effect of carotenoids on immune system. Twenty rabbits were randomly divided into five groups (4 per group): Groups consisted of: 1) control group (normal saline; 2) b-Cr (control); 3) vaccine control; 4) 5 mg/kg b-Cr o.p. + vaccine; 5) 10 mg/kg b-Cr o.p. + vaccine. Blood samples were obtained from the marginal ear artery at three time points: days 0, 14 and 21 of the study. Blood CD4+ and CD8+ lymphocytes and Serum Immunoglobulin and Cytokines content were evaluated. Results show that b-Cr administration increased the blood CD4+ lymphocytes count (P > 0.01). Serum IgG, IgM and IgA levels increased (P > 0.05) following b-Cr administration. b-Cr treatment increased serum IL-4 levels (P > 0.05). According to presented results, b-Cr may increase the humoral immunity in mammals. So, it would possible has a potentially beneficial effect on health and on prevention of the immunity related diseases.


Monoclonal antibody specific for T cell-derived human IgE binding factors.
A B cell hybridoma secreting monoclonal antibody against human IgE binding factors was obtained by immunization of BALB/c mice with partially purified IgE binding factors, and fusion of their spleen cells with SP-2/0-AG14 cells. The monoclonal antibody bound all of the 60,000, 30,000, and 15,000 dalton IgE binding factors from two T cell hybridomas and those from activated T cells of a normal individual. The antibody bound both IgE-potentiating factors, which had affinity for lentil lectin, and IgE-suppressive factors, which had affinity for peanut agglutinin. However, the monoclonal anti-IgE-binding factor bound neither Fc epsilon R on RPMI 8866 cells nor IgE binding factors from the B lymphoblastoid cells. A monoclonal antibody against Fc epsilon R on B cells (H107) bound the 60,000 and 30,000 dalton IgE binding factors from both T cell hybridomas and RPMI 8866 cells but did not bind the 15,000 dalton IgE binding factors from either T cells or B cells. The results indicate that T cell-derived IgE binding factors have a unique antigenic determinant that is lacking in both Fc epsilon R on B cells and B cell-derived IgE binding factors. The anti-IgE binding factor and anti-Fc epsilon R monoclonal antibodies both failed to stain cell surface components of IgE binding factor-producing T cell hybridomas. However, both antibodies induced the T cell hybridoma to form IgE binding factors. The results suggest that the T cell hybridomas bear low numbers of Fc epsilon R that share antigenic determinants with IgE binding factors secreted from the cells.


Comparison between bioactive and immunoactive luteinizing hormone (LH) in ovariectomized streptozotocin-induced diabetic rats: response to LH-releasing hormone.
The effect of streptozotocin-induced diabetes on circulating levels of immunoactive LH (I-LH) and bioactive LH (B-LH) was investigated. LH was measured in adult ovariectomized (OVX) rats before and after acute LHRH administration, with or without estradiol benzoate (Eb) treatment (10 micrograms, 48 and 24 h before experiments). I-LH and B-LH were measured in the same samples by RIA and the rat interstitial cell testosterone assay, respectively. OVX diabetic animals showed a significant reduction in both I-LH (63%) and B-LH (73%). Treatment with Eb induced a decrease in basal I-LH and B-LH levels in all experimental groups (50%). These values were normalized after insulin therapy. No alterations in the pituitary responsiveness to LHRH were detected when I-LH levels were determined. However, B-LH levels assayed after LHRH stimulation were significantly decreased in diabetic animals. Insulin treatment was unable to restore this response. The effect of Eb treatment on these parameters was also tested. In these conditions LHRH injections induced similar increases in serum I-LH and B-LH in both diabetic and control rats. These results indicate that, in diabetic OVX rats, basal and LHRH-induced LH has a reduced bioactivity, but this reduction is reversed by Eb treatment. This might indicate that the major defect lies in the ovary rather than at the pituitary level, supporting the notion of an important role of the steroid milieu on the B-LH modulation.


Effectiveness of a motionless ultrasonic toothbrush in reducing plaque and gingival inflammation in patients with fixed orthodontic appliances.
To compare the effectiveness of a motionless ultrasonic toothbrush to a manual toothbrush in reducing dental plaque, gingival inflammation, and mutans streptococci in patients with fixed orthodontic appliances. Twenty-five orthodontic patients were recruited to this crossover study. The patients were randomized into two groups starting with manual or motionless ultrasonic toothbrushes for 30 days. After a 30-day washout period, the patients switched to the other toothbrush type for 30 days. Plaque and gingival indices were evaluated by two calibrated-blinded examiners before and after each 30-day period of brushing. Salivary samples were also collected for quantification of mutans streptococci. On the bracket side, the motionless ultrasonic toothbrush showed a significantly higher mean plaque index bracket score after 30-day usage than baseline (P = .049), while the manual toothbrush group showed no difference between the before and after brushing periods (P = .10). The changes in plaque index bracket score were significantly more favorable in the manual toothbrush group than in the ultrasonic toothbrush group (P = .04). In contrast, no difference was observed on the nonbracket side. There was no significant difference in the changes of gingival index or the numbers of mutans streptococci between the two groups. Manual toothbrushing performed better than brushing with the motionless ultrasonic toothbrush in plaque removal on the bracket side in orthodontic patients. However, no difference was observed in terms of gingival status and the numbers of mutans streptococci.


Combination of transient 2D-IR experiments and ab initio computations sheds light on the formation of the charge-transfer state in photoexcited carbonyl carotenoids.
The excited state dynamics of carbonyl carotenoids is very complex because of the coupling of single- and doubly excited states and the possible involvement of intramolecular charge-transfer (ICT) states. In this contribution we employ ultrafast infrared spectroscopy and theoretical computations to investigate the relaxation dynamics of trans-8'-apo-β-carotenal occurring on the picosecond time scale, after excitation in the S2 state. In a (slightly) polar solvent like chloroform, one-dimensional (T1D-IR) and two-dimensional (T2D-IR) transient infrared spectroscopy reveal spectral components with characteristic frequencies and lifetimes that are not observed in nonpolar solvents (cyclohexane). Combining experimental evidence with an analysis of CASPT2//CASSCF ground and excited state minima and energy profiles, complemented with TDDFT calculations in gas phase and in solvent, we propose a photochemical decay mechanism for this system where only the bright single-excited 1Bu(+) and the dark double-excited 2Ag(-) states are involved. Specifically, the initially populated 1Bu(+) relaxes toward 2Ag(-) in 200 fs. In a nonpolar solvent 2Ag(-) decays to the ground state (GS) in 25 ps. In polar solvents, distortions along twisting modes of the chain promote a repopulation of the 1Bu(+) state which then quickly relaxes to the GS (18 ps in chloroform). The 1Bu(+) state has a high electric dipole and is the main contributor to the charge-transfer state involved in the dynamics in polar solvents. The 2Ag(-) → 1Bu(+) population transfer is evidenced by a cross peak on the T2D-IR map revealing that the motions along the same stretching of the conjugated chain on the 2Ag(-) and 1Bu(+) states are coupled.


First Dutch guidelines on lipedema using the international classification of functioning, disability and health.
Introduction Lipedema is a chronic, progressive condition that can result in considerable disability. In 2011, the Dutch Society of Dermatology and Venereology organized a task force to create guidelines on lipedema, using the International Classification of Functioning, Disability and Health of the World Health Organization. Guideline development Clinical questions on significant issues in lipedema care were proposed, involving (1) making the diagnosis of lipedema; (2) clinimetric measurements for early detection and adequate follow-up; and (3) treatment. A systematic review of literature published up to June 2013 was conducted. Based on available evidence and experience of the task force, answers were formed and recommendations were stated. The guidelines define criteria to make a medical diagnosis of lipedema, a minimum data set of (repeated) clinical measurements that should be used to ensure early detection and an individually outlined follow-up plan, pillars on which conservative treatment should be based and recommendations on surgical treatment options. Conclusions Little consistent information concerning either diagnostics or therapy can be found in the literature. It is likely that lipedema is frequently misdiagnosed or wrongly diagnosed as only an aesthetic problem and therefore under- or mis-treated. Treatment is divided into conservative and chirurgic treatment. The only available technique to correct the abnormal adipose tissue is surgery. Recommendations To ensure early detection and an individually outlined follow-up, the committee advises the use of a minimum data set of (repeated) measurements of waist circumference, circumference of involved limbs, body mass index and scoring of the level of daily practice and psychosocial distress. Promotion of a healthy lifestyle with individually adjusted weight control measures, graded activity training programs, edema reduction, and other supportive measures are pillars of conservative therapy. Tumescent liposuction is the treatment of choice for patients with a suitable health profile and/or inadequate response to conservative and supportive measures.


Maintained barostatic regulation of heart rate in digesting snakes (Boa constrictor).
When snakes digest large meals, heart rate is accelerated by withdrawal of vagal tone and an increased non-adrenergic-non-cholinergic tone that seems to stem from circulating blood-borne factors exerting positive chronotropic effects. To investigate whether this tonic elevation of heart rate impairs the ability for autonomic regulation of heart during digestion, we characterised heart rate responses to pharmacological manipulation of blood pressure in the snake Boa constrictor through serial injections of sodium nitroprusside and phenylephrine. Both fasting and digesting snakes responded with a robust tachycardia to hypotension induced by sodium nitroprusside, with digesting snakes attaining higher maximal heart rates than fasting snakes. Both fasting and digesting snakes exhibited small reductions of the cardiac chronotropic response to hypertension, induced by injection of phenylephrine. All heart rate changes were abolished by autonomic blockade with the combination of atropine and propranolol. The digesting snakes retained the capacity for compensatory heart rate responses to hypotension, despite their higher resting values, and the upward shift of the barostatic response curve enables snakes to maintain the cardiac limb of barostatic regulation for blood pressure regulation.


Integrating osteoimmunology and nanoparticle-based drug delivery systems for enhanced fracture healing.
Fracture healing is a complex interplay of molecular and cellular mechanisms lasting from days to weeks. The inflammatory phase is the first stage of fracture healing and is critical in setting the stage for successful healing. There has been growing interest in exploring the role of the immune system and novel therapeutic strategies, such as nanoparticle drug delivery systems in enhancing fracture healing. Advancements in nanotechnology have revolutionized drug delivery systems to the extent that they can modulate immune response during fracture healing by leveraging unique physiochemical properties. Therefore, understanding the intricate interactions between nanoparticle-based drug delivery systems and the immune response, specifically macrophages, is essential for therapeutic efficacy. This review provides a comprehensive overview of the relationship between the immune system and nanoparticles during fracture healing. Specifically, we highlight the influence of nanoparticle characteristics, such as size, surface properties, and composition, on macrophage activation, polarization, and subsequent immune responses. IMPACT STATEMENT: This review provides valuable insights into the interplay between fracture healing, the immune system, and nanoparticle-based drug delivery systems. Understanding nanoparticle-macrophage interactions can advance the development of innovative therapeutic approaches to enhance fracture healing, improve patient outcomes, and pave the way for advancements in regenerative medicine.


Dietary intake of Aboriginal Australian children aged 6-36 months in a remote community: a cross-sectional study.
Scarce literature comprehensively captures the transition to solid foods for children in remote Aboriginal Australian communities, a population expected to be especially vulnerable to nutritional inadequacy for largely socio-economic reasons. This study describes the dietary intake of children aged 6-36 months in a remote Aboriginal community during the years of solids introduction and establishment. Specifically, we aimed to explore milk feeding practices, major sources of nutrition and traditional food consumption, dietary patterns and nutrient and food group intakes, and compare these to national and international recommendations. This dietary assessment was conducted as part of an observational, cross-sectional Child Health and Nutrition study. Three 24-h dietary recalls were completed with the parent/care-giver of each participant over 2-4 weeks, capturing a pay-week, non-pay-week and weekend day from October 2017-February 2018. Additional information collected included sociodemographic data, food security status, usual cooking practices, and attendance at playgroup. Diet histories for 40 children were included in the analysis (~ 40% of the population). Breast feeding rates were high (85%), with mothers exclusively feeding on demand. Very few participants met recommended intakes for wholegrains (n = 4, 10%), vegetables (n = 7, 18%), dairy (n = 5, 18%) and fruit (n = 13, 33%), while more children met the guidelines for meat (n = 19, 48%) and discretionary food intake (n = 28, 70%). Traditional foods were always nutritionally dense and consumed frequently (n = 22, 55% of children). Statistically significant pay-cycle differences in intakes of all macro-, and numerous micro-nutrients were observed. Many positive early feeding practices are currently enacted in remote Aboriginal communities including responsive and long duration breastfeeding, and nutrient-dense traditional food consumption from earliest solids introduction. However, the non-pay-week/pay-week cycle is impacting the quality and quantity of children's diets at a time of rapid growth and development.


Incidence, predictors and mortality risk of new heart failure in patients hospitalised with atrial fibrillation.
To determine the incidence, risk predictors and relative mortality risk of incident heart failure (HF) in patients following atrial fibrillation (AF) hospitalisation. The Western Australian Hospitalisation Morbidity Data Collection was used to identify patients aged 25-94 years with index (first-in-period) AF hospitalisation, but without a prior HF admission, between 2000 and 2013. We evaluated the risk of incident HF hospitalisation within 3 years after AF admission, and the impact of HF hospitalisation on all-cause mortality. The cohort comprised 52 447 patients, 57.5% men, with a median age of 73.1 (IQR 63.2-80.8) years. At 3 years after AF discharge, the cumulative incidence of HF (n=6153) was 11.7% (95% CI 11.5% to 12.0%) and all-cause death (n=9702) was 18.5% (95% CI 18.2% to 18.8%). Independent predictors of incident HF included advancing age, any history of myocardial infarction (MI), peripheral vascular disease, valvular heart disease, chronic kidney disease, chronic obstructive pulmonary disease, hypertension, diabetes, obesity and excessive alcohol use (all p<0.001). Patients hospitalised for first-ever HF compared with those without HF hospitalisation had an adjusted HR of 3.3 (95% CI 3.1 to 3.4) for all-cause mortality (p<0.001). Independent predictors of HF were also shared with those for mortality, with the exception of hypertension. Hospitalisation for new HF is common in patients with AF and independently associated with a 3-fold hazard for death. The clinical predictors of incident HF emphasise the importance of integrated management of common comorbid conditions and lifestyle risk factors in patients with AF to reduce their morbidity and mortality.


Characterization of two molluscan crystal-modulating biomineralization proteins and identification of putative mineral binding domains.
Ethylenediamine-tetraacetic acid extracted water-soluble matrix proteins in molluscan shells secreted from the mantle epithelia are believed to control crystal nucleation, morphology, orientation, and phase of the deposited mineral. Previously, atomic force microscopy demonstrated that abalone nacre proteins bind to growing step edges and to specific crystallographic faces of calcite, suggesting that inhibition of calcite growth may be one of the molecular processes required for growth of the less thermodynamically stable aragonite phase. Previous experiments were done with protein mixtures. To elucidate the role of single proteins, we have characterized two proteins isolated from the aragonitic component of nacre of the red abalone, Haliotis rufescens. These proteins, purified by hydrophobic interaction chromatography, are designated AP7 and AP24 (aragonitic protein of molecular weight 7 kDa and 24 kDa, respectively). Degenerate oligonucleotide primers corresponding to N-terminal and internal peptide sequences were used to amplify cDNA clones by a polymerase chain reaction from a mantle cDNA library; the deduced primary amino acid sequences are presented. Preliminary crystal growth experiments demonstrate that protein fractions enriched in AP7 and AP24 produced CaCO(3) crystals with morphology distinct from crystals grown in the presence of the total mixture of soluble aragonite-specific proteins. Peptides corresponding to the first 30 residues of the N-terminal sequences of both AP7 and AP24 were generated. The synthetic peptides frustrate the progression of step edges of a growing calcite surface, indicating that sequence features within the N-termini of AP7 and AP24 include domains that interact with CaCO(3). CD analyses demonstrate that the N-terminal peptide sequences do not possess significant percentages of alpha-helix or beta-strand secondary structure in solution. Instead, in both the presence and absence of Ca(II), the peptides retain unfolded conformations that may facilitate protein-mineral interaction.


[The role of oxygen radicals in the physiology and pathology of human sperm].
Reactive oxygen species in low doses are necessary compound of sperm capacitation and hyperactivation. Superoxide anion, hydroxyl radical and hydrogen peroxide initiate sperm capacitation. The edding of antioxidant enzymes inhibits the spontaneous and induced sperm hyperactivation. The process of capacitation is accompanied with the superoxide anion production output by spermatozoa. High doses of reactive oxygen species block the sperm motility through the inhibition of ATP synthesis by the mitochondrial enzymes and cell membrane compounds injury.


Phosphorylated and other modified forms of eukaryotic ribosomal protein S3 analysed by two-dimensional gel electrophoresis.
Proteins were isolated from the 40S ribosomal subunits of baby-hamster kidney fibroblasts and subjected to two-dimensional gel electrophoresis. When the cells were pretreated with cyclic AMP or 2-deoxyglucose a more basic derivative of ribosomal protein S3 or S3a was often observed, apparently similar to that previously reported to occur early in liver generation. This derivative was not a dephosphorylated form of protein S3, which protein does not appear to be phosphorylated in normal cells; nor did it correspond to the proteolytic fragment, S3b. It appears to be an oxidation product of protein S3 or S3a, as it can be eliminated by thorough reduction of the ribosomal protein before electrophoresis. In contrast with previous results with Krebs II ascites cells, starvation of baby-hamster kidney fibroblasts of glucose did not cause extensive phosphorylation of ribosomal protein S3.


Collagenase specificity in chondrosarcoma metastasis.
The treatment of some mesenchymal malignancies has made significant gains over the past few decades with the development of effective systemic therapies. In contrast, the treatment of chondrosarcoma has been limited to surgical resection, with the most significant prognostic indicators being surgical margins and histologic grade. We have reported that MMP-1/TIMP-1 gene expression serves to prognosticate for tumor recurrence in this group of patients. This led to the hypothesis that collagenase activity facilitates cell egression from the cartilaginous matrix. In the current study we examine the specificity of collagenase gene expression in archival human chondrosarcoma samples using semi-quantitative PCR. Messenger RNA was affinity extracted and subject to reverse transcription. The subsequent cDNA was amplified using novel primers and quantitated by densitometry. Ratios of gene expression were constructed and compared to disease-free survival. The data demonstrate that the significance of the MMP-1/TIMP-1 ratio as a predictor of recurrence is confirmed with a larger number of patients. Neutrophil collagenase or MMP-8 was observed in only 5 of 29 samples. Collagenase-3 or MMP-13 was observed in all samples but the level did not correlate with disease-free survival. Since the collagenases have similar activity for fibrillar collagens and cleave the peptide in the same location, post-transcriptional regulatory mechanisms may account for the observed specificity. The determination of the MMP-1/TIMP-1 gene expression ratio not only serves to identify those patients at risk for recurrence but may also serve as a novel therapeutic avenue as an adjunct to surgical resection.


Strategies to Reduce Salt Content and Its Effect on Food Characteristics and Acceptance: A Review.
Sodium is a necessary nutrient for regulating extracellular fluid and transferring molecules around cell membranes with essential functions. However, the prevalence of some diseases is related to unnecessary sodium intake. As a result, a particular problem for the food industry remains a matter of sodium content in foods. It is considered that customer acceptance is associated with salt perception dynamics related to the evolution of food production. It is a significant challenge and technique to minimize the salt content of various foods and provide replacement products with substantial reductions in salt levels. This review summarizes salt reduction strategies related to health problems based on traditional review methodology, with practical and methodological screening performed to determine the appropriate reference sources. Various technological (salt replacement, food reformulation, size and structural modifications, alternative processing, and crossmodal odor interaction) and behavioral strategies (memory process, gradual salt reduction, and swap) are identified in this work, including a deeper understanding of the principles for reducing sodium content in foods and their effect on food characteristics and potential opportunities for the food industry. Thereby, the food industry needs to find the proper combination of each strategy's advantages and disadvantages to reduce salt consumption while maintaining product quality.


Intraspecific Differences in Biogeochemical Responses to Thermal Change in the Coccolithophore Emiliania huxleyi.
The species concept in marine phytoplankton is defined based on genomic, morphological, and functional properties. Reports of intraspecific diversity are widespread across major phytoplankton groups but the impacts of this variation on ecological and biogeochemical processes are often overlooked. Intraspecific diversity is well known within coccolithophores, which play an important role in the marine carbon cycle via production of particulate inorganic carbon. In this study, we investigated strain-specific responses to temperature in terms of morphology, carbon production, and carbonate mineralogy using a combination of microscopy, elemental analysis, flow cytometry, and nuclear magnetic resonance. Two strains of the cosmopolitan coccolithophore E. huxleyi isolated from different regions (subtropical, CCMP371; temperate, CCMP3266) were cultured under a range of temperature conditions (10°C, 15°C, and 20°C) using batch cultures and sampled during both exponential and stationary growth. Results for both strains showed that growth rates decreased at lower temperatures while coccosphere size increased. Between 15°C and 20°C, both strains produced similar amounts of total carbon, but differed in allocation of that carbon between particulate inorganic carbon (PIC) and particulate organic carbon (POC), though temperature effects were not detected. Between 10°C and 20°C, temperature effects on daily production of PIC and POC, as well as the cellular quota of POC were detected in CCMP3266. Strain-specific differences in coccolith shedding rates were found during exponential growth. In addition, daily shedding rates were negatively related to temperature in CCMP371 but not in CCMP3266. Despite differences in rates of particulate inorganic carbon production, both strains were found to produce coccoliths composed entirely of pure calcite, as established by solid-state 13C and 43Ca NMR and X-ray diffraction measurements. These results highlight the limitations of the species concept and the need for a trait-based system to better quantify diversity within marine phytoplankton communities.


International stem cell registries.
Rapid advances in stem cell research have led to the derivation of hundreds of human embryonic stem (hES) cell lines in centers throughout the world, as well as the development of new technologies for producing pluripotent stem cells. These cell lines have unique characteristics and were derived using a variety of ethical guidelines. Stem cell registries have been developed in order to collect, organize, and disseminate cell line-specific information. In this review, we describe the current state of the field by providing an overview of the unique qualities and mandates of the three major stem cell registries: the European hES Cell Registry, the Registry of hES Cell Line Provenance developed by the International Society for Stem Cell Research, and the International Stem Cell Registry of hES and induced pluripotent stem cell lines established at the University of Massachusetts Medical School. While each registry has its own unique mandate and features, there is some overlap in the goals and information provided. This review discusses the challenges and prospects for an integrated approach in which all three registries effectively collaborate to minimize duplication and facilitate information exchange within the stem cell community.


Factors associated with kidney disease progression and mortality in a referred CKD population.
Knowing how kidney disease progresses is important for decision making in patients with chronic kidney disease (CKD) and for designing clinical services. Prospective cohort study. We examined renal function trajectories in CRISIS (Chronic Renal Insufficiency Standards Implementation Study), in which 1,325 patients with CKD stages 3-5 and mean age of 65.1 years were followed up prospectively for a median of 26 months after referral to a regional nephrology center in the United Kingdom. By protocol, estimated glomerular filtration rate was determined every 12 months. CKD stage defined as estimated glomerular filtration rate ≥ 45 (stage 3a), 30-44 (3b), 15-29 (4), and < 15 (5) mL/min/1.73 m². Onset of renal replacement therapy (RRT), death, the composite end point of RRT or death, or decreasing CKD stage. During a median follow-up of 26 months, 13% reached the end point of RRT (5.1 events/100 patient-years), 20% died (9.6 deaths/100 patient-years), and 33% reached the combined end point of RRT or death (14.7 events/100 patient-years). For stage 3a, baseline prevalence and annual probabilities of decreasing CKD stage, RRT, and death were 18.0%, 0.41, 0.01, and 0.02, respectively. Corresponding values for stage 3b were 32.5%, 0.22, < 0.01, and 0.06; for stage 4, 36.5%, 0.17, 0.03, and 0.10; and for stage 5, 13.2%, zero (by definition), 0.31, and 0.08, respectively. Markov model projections suggested a steady decrease for proportions with stages 3a, 3b, and 4; a steady increase for death and RRT; and a biphasic pattern for (non-RRT) stage 5, with a plateau in the first 2 years followed by a steady decrease. Single-center observational study. This study suggests that death and RRT are the dominant outcomes in patients referred for management of CKD and that most patients spend comparatively little time in late stages without RRT.


Ligand capture and activation of human platelets at monolayer modified gold surfaces.
Blood platelet adhesion is crucial in dictating haemocompatibility of medical implants and in platelet capture in diagnostics. Understanding the role of platelet activation in dictating platelet adhesion at chemically modified interfaces is important but relatively unexplored. Using scanning electron microscopy and confocal fluorescence microscopy a quantitative assessment of capture of blood platelets at self-assembled monolayers and mixed monolayers (SAMs) on gold as a function of the activation status of the platelets was conducted. Single and mixed monolayers were prepared using thiol-functionalized arginine-glycine-aspartic acid (RGD), C-Ahx-GRGDS (Ahx = aminohexanoic acid linker), thiolated poly(ethylene)glycol (PEG-COOH) and 1-octanethiol. When incubated with suspensions of resting platelets, RGD promoted platelet adhesion compared to bare or alkanethiol modified gold. Increasing the alkanethiol ratio in the deposition solution decreased the extent of platelet adhesion. Platelet adhesion increased approximately 3 fold at PEG-COO- modified surfaces compared to RGD-alone. Platelets adhered to RGD or mixed RGD : alkane SAM surfaces were found to be captured in their resting state. In contrast, platelets captured at PEG-COO- SAM surfaces were activated by these substrates. The effect of treating platelets with the chemical activators, Mn2+ or DTT or the physiological activator, thrombin, on the capture efficiency and activation at RGD modified surfaces was also investigated. Mn2+ treated platelets presented similar adhesion to untreated platelets, while surprisingly DTT yielded a very significant decrease in platelet adhesion. And, any platelets that were captured, were in a resting state. Thrombin activated platelets were captured with similar efficiencies as untreated platelets. However, the platelets captured were fully activated. The distinction between capture of chemically and physiologically activated platelet is interesting and likely to originate from differences in the conformation of the integrin induced by each process. Finally, platelet adhesion to each surface could be reversed by incubation with a solution of linear or cyclical RGD or PEG-COO- for the RGD and PEGCOO- surfaces respectively. The specificity of platelet removal confirmed that platelet adhesion at RGD surfaces is occurring through integrin-RGD interactions.