Influence of extracellular magnesium on capillary endothelial cell proliferation and migration.
We investigated the role of extracellular magnesium on capillary endothelial cell migration and proliferation, components of endothelial cell function that play an important role in angiogenesis and wound healing. Cell migration and proliferation were tested in six different MgSO4 concentrations and in various culture conditions. The Boyden chamber procedure was used to evaluate migration of bovine adrenal cortex capillary endothelial cells. We found that low magnesium concentration inhibited cell migration, but a dose-dependent increase in migration was observed when magnesium level was increased beyond the normal serum concentration (up to 2.4 mM magnesium; p less than 0.0001). Cell proliferation was also inhibited by very low magnesium concentration, an effect observed under all conditions studied. When cell proliferation was stimulated by acidic or basic fibroblast growth factors, it appeared that a ceiling was reached, an increasing magnesium concentration had no additional stimulatory effect. However, a dose-dependent increase in proliferation (p less than 0.005) was observed when magnesium concentration was increased above the normal serum level (0.8 mM) in culture conditions that did not cause marked cell proliferation. Thus, magnesium has an important role in endothelial cell migration and proliferation: very low extracellular magnesium concentrations inhibit and supranormal levels enhance both migration and proliferation. These results suggest that magnesium deficiency might adversely influence the healing and reendothelialization of vascular injuries and the healing of myocardial infarction and might also result in delayed or inadequate angiogenesis, effects potentially leading to infarct expansion and inadequate collateral development.


Comparison of antithyroid drug metabolism in the rat and guinea pig.
The thyroid accumulation, metabolism and urine excretion of (35S) propylthiouracil was compared in the guinea pig and the rat. Per gram thyroid tissue, the guinea pig thyroid took up much less drug than the rat, metabolised it faster and had a shorter t 1/2 for total 35S and free (35S) propylthiouracil. Liver metabolism, clearance of the drug from the serum and excretion in the urine were also considerably faster in the guinea pig. It is likely that a much larger dose of propylthiouracil would need to be administered to induce goitre in the guinea pig than is necessary in the rat.


Prognostic factors in critically ill surgical patients requiring continuous renal replacement therapy.
Acute mortality of unselected critically ill patients has improved during the last 15 years. Whether these benefits also affect long-term survival of critically ill surgical patients with severe acute renal failure is unclear, as are the prognostic factors relevant for survival time or mortality. We performed a retrospective analysis of data collected prospectively from March 1993, through February 2005. Data from a cohort of 170 consecutive postoperative patients without preceding kidney diseases but requiring continuous renal replacement therapy (CRRT) during intensive care unit (ICU) stay were analyzed. Six-month survival rate after ICU admission was 20.6%. In patients surviving more than 6 months, 5-year survival was 71.6%. After adjustment for relevant covariates, older age, disease severity at ICU admission, peritonitis and a large number of red cell units transfused during ICU stay were associated with worse 6-month prognosis. Duration of CRRT, and the origin and type of kidney failure were unimportant for prognosis, as was ICU admission date. Six-month prognosis of critically ill surgical patients with severe acute renal failure is poor and mostly determined by the disease severity at ICU admission and by the frequency of surgical complications. Outcome had not improved over the study period, but after successful surgical and intensive care therapy, long-term survival appears to be reasonably good.


Testing not-so-obvious models of healthcare quality.
The purpose of this paper is to show that, although there has been some research to identify the dimensions on which healthcare quality and in-patient satisfaction should be measured, the confirmation of constructs and indicators that constitute an overall care quality and satisfaction remains unclear. The objective is to present several models of service quality and satisfaction in healthcare for discharged patients; and to test those models in a sample of discharged patients in public hospitals in the United Arab Emirates. A detailed in-patient survey (using interviews) was used. Data were collected with questionnaires from adult discharges (n = 244) in public hospitals in the UAE. Several structures are proposed and tested. Confirmatory Factor Analysis (CFA) and LISREL SIMPLIS using maximum likelihood estimation were used to estimate and test the parameters of the hypothesized models derived deductively from the previous literature. Several models (with one, two, three and four constructs) with different structures were tested using CFA. The final recommended model is based on three constructs--quality of care, process and administration, and information. The goodness-of-fit statistics supported the basic solution of the healthcare quality-satisfaction model. The model has been found to capture attributes that characterize healthcare quality in a developing country such as the UAE and could represent other modern healthcare systems. It can be used as a basis for evaluation in healthcare practices from discharges (in-patients) point of view. The study highlights the importance of patients' satisfaction with care as predictors of quality of care. The results also confirm the construct validity of the previously discussed healthcare quality scales.


An integrated protein localization and interaction map for Potato yellow dwarf virus, type species of the genus Nucleorhabdovirus.
The genome of Potato yellow dwarf virus (PYDV; Nucleorhabdovirus type species) was determined to be 12,875 nucleotides (nt). The antigenome is organized into seven open reading frames (ORFs) ordered 3'-N-X-P-Y-M-G-L-5', which likely encode the nucleocapsid, phospho, movement, matrix, glyco and RNA-dependent RNA polymerase proteins, respectively, except for X, which is of unknown function. The ORFs are flanked by a 3' leader RNA of 149 nt and a 5' trailer RNA of 97 nt, and are separated by conserved intergenic junctions. Phylogenetic analyses indicated that PYDV is closely related to other leafhopper-transmitted rhabdoviruses. Functional protein assays were used to determine the subcellular localization of PYDV proteins. Surprisingly, the M protein was able to induce the intranuclear accumulation of the inner nuclear membrane in the absence of any other viral protein. Finally, bimolecular fluorescence complementation was used to generate the most comprehensive protein interaction map for a plant-adapted rhabdovirus to date.


Genetics of obesity.
The prevalence and cost of overweight and obesity are projected to continue to rise in our current sedentary, energy-rich environment. The heritability of obesity is reported to be 40-80%. The objectives of this article are to review recent genetic discoveries about the basis of human obesity; describe familial or syndromic obesity, which is rare but presents early and should, if suspected, be referred for full specialist diagnosis of the underlying genetic disorder; and summarise immediate implications for general practice. Increasingly, specialised genetic studies are helping to unravel the complex physiology underlying the regulation and control of body fatness. Rare but serious syndromic obesity can now be identified early in life. Possible targets for future drug treatment are currently being found and tested, offering hope for the future. Understanding the heritable nature of obesity should also help to relieve the blame and guilt from the professional's approach to current weight management.


Gastric Electrical Pacing Reduces Apoptosis of Interstitial Cells of Cajal via Antioxidative Stress Effect Attributing to Phenotypic Polarization of M2 Macrophages in Diabetic Rats.
Gastric electrical pacing (GEP) could restore interstitial cells of Cajal in diabetic rats. M2 macrophages contribute to the repair of interstitial cells of Cajal injury though secreting heme oxygenase-1 (HO-1). The aim of the study is to investigate the effects and mechanisms of gastric electrical pacing on M2 macrophages in diabetic models. Sixty male Sprague-Dawley rats were randomized into control, diabetic (DM), diabetic with the sham GEP (DM+SGEP), diabetic with GEP1 (5.5 cpm, 100 ms, 4 mA) (DM+GEP1), diabetic with GEP2 (5.5 cpm, 300 ms, 4 mA) (DM+GEP2), and diabetic with GEP3 (5.5 cpm, 550 ms, 4 mA) (DM+GEP3) groups. The apoptosis of interstitial cells of Cajal and the expression of macrophages were detected by immunofluorescence technique. The expression levels of the Nrf2/HO-1 and NF-κB pathway were evaluated using western blot analysis or immunohistochemical method. Malonaldehyde, superoxide dismutase, and reactive oxygen species were tested to reflect the level of oxidative stress. Apoptosis of interstitial cells of Cajal was increased in the DM group but significantly decreased in the DM+GEP groups. The total number of macrophages was almost the same in each group. In the DM group, M1 macrophages were increased and M2 macrophages were decreased. However, M2 macrophages were dramatically increased and M1 macrophages were reduced in the DM+GEP groups. Gastric electrical pacing improved the Nrf2/HO-1 pathway and downregulated the phosphorylation of NF-κB. In the DM group, the levels of malonaldehyde and reactive oxygen species were elevated and superoxide dismutase was lowered, while gastric electrical pacing reduced the levels of malonaldehyde and reactive oxygen species and improved superoxide dismutase. Gastric electrical pacing reduces apoptosis of interstitial cells of Cajal though promoting M2 macrophages polarization to play an antioxidative stress effect in diabetic rats, which associates with the activated Nrf2/HO-1 pathway and the phosphorylation of NF-κB pathway.


Combining Virtual Touch Tissue Imaging and BI-RADS May Improve Solid Breast Lesion Evaluation.
Ultrasound elastography (UE) is a novel imaging method. The purpose of this study was to determine the utility of Virtual Touch tissue imaging in the evaluation of solid breast lesions. 209 breast solid lesions in 192 patients that had been evaluated using ultrasound (US) and UE were reviewed and analyzed. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for UE, US, and US plus UE in the differentiation of malignant from benign breast lesions were 80.8, 75.6, 77.9, 73.1, and 82.8% for UE, 87.2, 86.1, 86.6, 83.7, and 89.2% for US, and 92.5, 86.9, 89.5, 85.3, and 93.4% for US plus UE. There were significant differences between UE and US plus UE (all p < 0.05). Except for accuracy, there were no significant differences between UE and US or US and US plus UE (all p > 0.05). The area under the curve obtained from the ROC curve for UE, US, and US plus UE in differentiating malignant from benign lesions was 0.845, 0.884, and 0.922, respectively. The UE scoring system is not superior to BI-RADS in the sonographic evaluation of solid breast lesions. Combined use may improve the performance.


Twenty-week exposures to the drinking water disinfection by-product dibromoacetic acid: reproductive cyclicity and steroid concentrations in the female Sprague-Dawley rat.
Elevated gavage exposures to the drinking water disinfection by-product dibromoacetic acid (DBA) have been found to disrupt estrous cyclicity in the rat and induce increases in estradiol concentrations in both cycling (day of estrus) and ovariectomized/estradiol-implanted females. The present study was designed to investigate both effects in Sprague-Dawley rats following an extended 20-week treatment with lower dosages of DBA administered in the drinking water (calculated mean intake concentrations of 5, 16, and 33 mg/kg/d). No treatment-related effects on cyclicity were present, although elevations in serum estradiol on the day of vaginal estrus were noted in regularly cycling rats when assessed at the 3rd and 11th weeks of exposure. By the 19th week, this effect was no longer present in cycling animals, but its absence was attributable to a marked increase in control estradiol concentrations, which may be associated with endocrine alterations that precede a disruption in estrous cyclicity in middle-aged females. In the 20th week, diestrous estrone levels were elevated at all dosages without effects on serum androstenedione or progesterone. Uterine and pituitary weights were unchanged at this time, although there were modest increases in liver weights at the two highest dosages. A small number of rats in persistent estrus (PE) did show a general increase in pituitary weight associated with DBA exposure, possibly reflecting an added layering of treatment on the PE-associated rise in estradiol normally seen in these females. The results indicate that increases in circulating estradiol from drinking water exposures to DBA were not linked to a premature disruption of estrous cyclicity in this moderately estrogen-sensitive rat strain.


Pedal branch arterial bypass for limb salvage.
In patients with critical lower extremity ischemia and occlusion of the distal tibial and pedal arteries bypasses to pedal artery branches may offer the only alternative to primary amputation. The results of 22 pedal branch arterial bypasses are reported, and a review of the literature is offered. The charts of 22 patients undergoing pedal branch arterial bypass during a 12-year period were retrospectively reviewed. The results of six additional reports of this technique were also evaluated. In the present series the cumulative primary graft patency rate was 72 per cent after 2 years. The cumulative limb salvage rate during this interval was 82 per cent. Similar graft patency and limb salvage rates were obtained with the approximately 200 other bypasses of this nature as reported in six other series. Pedal branch arterial bypass offers limb salvage results that are comparable to perimalleolar and pedal artery bypasses. In patients with critical limb ischemia and occlusion of distal tibial and pedal arteries, pedal artery branches should be sought as potential outflow sites. Bypasses to these arteries result in good long-term limb salvage, improved survival, and good functional ability for amputation. Pedal artery branch bypasses are a superior alternative to primary amputation.


Giant aneurysm of basilar artery.
In the article we showed the patient, a woman with unruptured giant aneurysm of basilar artery, we showed the done examinations, and therapy dilemmas about what to do in the given case. We found in literature a number of examples which suggest operation treatment, but of embolisation too, some suggest conservative treatment.


Bone construction surgery: A case report using recombinant human platelet-derived growth factor-BB.
The position and condition of bone largely sets the stage for functional and esthetic implant success. In bone construction surgery, creating a sustainable functional matrix is complex, but necessary, to enable long-term mechanotransduction and maintenance of soft tissue support. A patient with a severe peri-implantitis ridge defect in the anterior maxilla underwent bone construction surgery simultaneous with implant removal using a composite bone graft (mineralized freeze dried bone allograft + xenograft) enhanced with recombinant human platelet-derived growth factor (rhPDGF-BB). Space maintenance for bone construct immobility and unimpeded wound healing was ensured via a nonresorbable titanium reinforced polytetrafluoroethylene membrane and an absorbable porcine collagen membrane. Primary closure was maintained throughout the 6 month healing process at which time implant diagnostics commenced for prosthetically directed implant placement using dynamic navigation and involving soft tissue augmentation. Uncovery was performed 3 months thereafter leading to provisionalization and prosthetic phase completion. This case report highlights a severe maxillary anterior ridge defect secondary to advanced peri-implantitis in a systemically healthy Caucasian male patient. The surgical outcome success, both clinically and radiographically, underscores the complexities of complete regional anatomy rehabilitation after suffering catastrophic and debilitating bone loss from inflammatory peri-implantitis. Further, it demonstrates the importance of incorporating optimized angiogenetic therapeutics to help establish a vascularized functional bone matrix for implant success.


Fingolimod effects in neuroinflammation: Regulation of astroglial glutamate transporters?
Fingolimod is an oral sphingosine-1-phosphate-receptor modulator which reduces the recirculation of immune cells and may also directly target glial cells. Here we investigate effects of fingolimod on expression of astroglial glutamate transporters under pro-inflammatory conditions. In astrocyte cell culture, the addition of pro-inflammatory cytokines led to a significant downregulation of glutamate transporters glutamate transporter-1 (slc1a2/SLC1A2) and glutamate aspartate transporter (slc1a3/SLC1A3) expression on the mRNA or protein level. In this setting, the direct application of fingolimod-1 phosphate (F1P) on astrocytes did not change expression levels of slc1a2 and slc1a3 mRNA. The analysis of both transporters on the protein level by Western Blot and immunocytochemistry did also not reveal any effect of F1P. On a functional level, the addition of conditioned supernatants from F1P treated astrocytes to neuronal cell culture did not result in increased neurite growth. In experimental autoimmune encephalomyelitis as a model of multiple sclerosis, fingolimod treatment reduced T cell and macrophages/microglia mediated inflammation and also diminished astrocyte activation. At the same time, fingolimod restored the reduced expression of slc1a2 and slc1a3 in the inflamed spinal cord on the mRNA level and of SLC1A2 and SLC1A3 on the protein level, presumably via indirect, anti-inflammatory mechanisms. These findings provide further evidence for a predominantly peripheral effect of the compound in neuroinflammation.


Cytogenetic engineering in vivo: restoration of biologic complement activity to C5-deficient mice by intravenous inoculation of hybrid cells.
Splenic macrophages were identified as at least one source of C5 elaboration in normal mice. Hybrid cells were formed from splenic macrophages from C5-deficient mice and either kidney cells from mice with normal amounts of C5 or chicken erythrocytes. These hybrids elaborated C5 in vitro. C5-Deficient mice inoculated with these hybrid cells developed, in their serum, antigenically active mouse C5, as well as both hemolytic and biologic complement activity. These studies demonstrate the feasibility of genetic "repair" in mammals.


Normal protein diet for episodic hepatic encephalopathy: results of a randomized study.
Protein-restricted diets are usually prescribed for cirrhotic patients with hepatic encephalopathy. However, protein restriction may worsen the nutritional status without resulting in an improvement of hepatic encephalopathy. We designed a study to assess the effects of the amount of protein in the diet on the evolution of episodic hepatic encephalopathy. Cirrhotics admitted to the hospital because of an episode of encephalopathy (n=30) were randomized to receive a low-protein diet with progressive increments or a normal protein diet for 14 days, in addition to standard measures to treat hepatic encephalopathy. Protein synthesis and breakdown were studied at day 2 and day 14 with the glycine-N(15) infusion method. The outcome of hepatic encephalopathy was not significantly different between both groups of treatment. Protein synthesis was similar for low and normal protein diet, but those of the low-protein diet group showed higher protein breakdown. Diets with a normal content of protein, which are metabolically more adequate, can be administered safely to cirrhotic patients with episodic hepatic encephalopathy. Restriction of the content of protein of the diet does not appear to have any beneficial effect for cirrhotic patients during an episode of encephalopathy.


Bogota bag in the treatment of abdominal wound dehiscence.
A patient who underwent emergency laparotomy for rectal prolapse developed repeated abdominal wound dehiscence and subsequently an enteric fistula. The management of abdominal wound dehiscence is discussed, specifically with regards to the Bogota bag. Use of Bogota bag has been reported worldwide but this may be the first report here.


Deriving uniform semiclassical approximations for one-dimensional fermionic systems.
A complete derivation is provided of the uniform semiclassical approximations to the particle and kinetic energy densities of N noninteracting bounded fermions in one dimension. The employed methodology allows the inclusion of non-perturbative quantum effects, including tunneling and quantum oscillations, via an infinite resummation of the Poisson summation formula. We explore the analytic behavior, physical meaning, and the relationship between the semiclassical uniform approximations for the fermionic kinetic energy and particle densities.


Accelerated learning by active example selection.
Much previous work on training multilayer neural networks has attempted to speed up the backpropagation algorithm using more sophisticated weight modification rules, whereby all the given training examples are used in a random or predetermined sequence. In this paper we investigate an alternative approach in which the learning proceeds on an increasing number of selected training examples, starting with a small training set. We derive a measure of criticality of examples and present an incremental learning algorithm that uses this measure to select a critical subset of given examples for solving the particular task. Our experimental results suggest that the method can significantly improve training speed and generalization performance in many real applications of neural networks. This method can be used in conjunction with other variations of gradient descent algorithms.


The CYCLOIDEA-RADIALIS module regulates petal shape and pigmentation, leading to bilateral corolla symmetry in Torenia fournieri (Linderniaceae).
The diverse pigmentation patterns of flower corollas probably result from pollinator-mediated selection. Previous studies demonstrated that R2R3-MYB factors may have been recruited in the regulation of corolla pigmentation. However, how R2R3-MYBs became so diverse in their regulation of different pigmentation patterns remains unclear. Here, we studied a Lamiales species, Torenia fournieri, which has elaborate zygomorphic flowers with dorsal-ventral asymmetries in corolla pigmentation. We found recent gene duplication events in CYCLOIDEA-like (CYC-like) and RADIALIS-like (RAD-like) genes, and functionally analyzed three dorsal-specific expression factors: TfCYC1, TfCYC2, and TfRAD1. We found that the CYC-RAD module coordinates petal shape and corolla pigmentation, as ectopic expression of TfCYC2 or TfRAD1 disrupted the asymmetric corolla pigmentation pattern and produced strongly dorsalized flowers. Dorsal petal identity was lost when TfCYC2 was down-regulated or when TfRAD1 was knocked out. In T. fournieri, the diversified CYC and RAD genes have evolved regulatory loops, and TfCYC2 binds directly to the regulatory regions of an R2R3-MYB factor gene, TfMYB1, which might lead to its asymmetric expression and ultimately establish the asymmetric pigmentation pattern. These findings support the existence of a regulatory module that integrates dorsal-ventral patterning and asymmetric corolla pigmentation in T. fournieri.


Health Insurance Literacy and Medical Care Avoidance Among International Students: A Case Study.
Objectives: This research examines the health insurance literacy and healthcare utilization of international students attending a university in the US Midwest. Methods: One hundred and forty-three undergraduate and graduate students attending a midsize metropolitan university in the Midwest completed an online survey in early 2022. Results: Many students surveyed could not identify the definitions of basic terms, such as copay. Furthermore, about 80% of students surveyed could not determine their financial responsibilities in two medical settings. Regression results show that the continent they are from and the length of their stay in the United States significantly predict their understanding of key health insurance terms. More than half of the international students surveyed indicated they often feel confused about their health insurance (57.34%). Only about 20% have delayed or skipped care due to unfamiliarity with the health insurance system. Conclusion: The health insurance literacy of most international students at the midwestern university we surveyed is not ideal. This and possibly other universities in the United States should take more initiatives to help their international students understand the health insurance system.


Comparison of the AcT 5 diff autoloader hematology analyzer to the Abbott Cell-Dyn 3200 analyzer at Charlevoix Area Hospital.
The Coulter AcT 5 diff autoloader (AL) hematology analyzer (Beckman Coulter, Fullerton, CA, USA) was evaluated at the Charlevoix Area Hospital, a small rural community hospital. The analyzer was compared to the laboratory's current instrument, a Cell-Dyn 3200 (Abbott Laboratories, Abbott Park, IL, USA). The study included comparisons of precision, efficiency and productivity, and reliability. The 5-part white blood cell differentials on both instruments were compared, and the clinical utility and flagging performance of both analyzers were confirmed by manual differential counts. The AcT 5 diff AL was shown to have excellent precision and accuracy. The addition of the autoloader to the AcT 5 diff provides a low-volume system with the added benefits of a "load and leave" analyzer normally available only to larger laboratories.


Biopsychosocial health disparities among young women enrolled in cardiac rehabilitation.
Our aim was to compare the biopsychosocial characteristics of young women with those of older women who were enrolled in cardiac rehabilitation (CR). The baseline characteristics of women who prematurely terminated CR participation were also explored. Baseline physiological and psychosocial indices of women ≤ 55 years compared with older women eligible for CR were evaluated 1 week before enrolling in either a traditional CR or a gender-specific, motivationally enhanced CR. A greater proportion of young women (n = 65) compared with their older counterparts (n = 187) were diagnosed with acute myocardial infarction during their index hospitalization. They demonstrated lower high-density lipoprotein cholesterol, higher total cholesterol/high-density lipoprotein cholesterol ratios, and greater body weight compared with older women and were more likely to be active smokers. Young women compared with older women reported significantly worse health perceptions, quality of life, optimism, hope, social support, and stress and significantly more symptoms of depression and anxiety. Women who prematurely terminated CR participation were younger, more obese, with worse quality of life, and greater symptoms of depression and anxiety compared with women completing CR. Notable differences in physiological and psychosocial profiles of young women compared with older women enrolled in CR were evident, placing them at high risk for nonadherence to secondary prevention interventions as well as increased risk for disease progression and subsequent cardiac adverse events. Continued existence of these health differentials represents an important public health problem and warrants further research to address these age-related and sex-specific health disparities among women with coronary heart disease.


How goblet cells respond to dry eye: adaptive and pathological roles of voltage-gated calcium channels and P2X7 purinoceptors.
Dry eye is a common sight-impairing, painful disorder characterized by disruption of the preocular tear film, whose integrity is required for ~70% of the eye's refractive power. A universal feature of clinical dry eye is hyperosmolarity of the tears resulting from their accelerated evaporation due to dysfunction of tear- and oil-producing ocular glands. A key adaptive response to dryness/hyperosmolarity is release of tear-stabilizing mucin by conjunctival goblet cells. Yet the mechanisms mediating this response to hyperosmolarity remain poorly understood. In this study of freshly excised rat conjunctiva, perforated-patch recordings revealed that during sustained hyperosmolarity, the development of a nonspecific cation (NSC) conductance depolarizes the goblet cells to a near-optimal voltage for the tonic activation of their voltage-gated calcium channels (VGCCs). In turn, as demonstrated by high-resolution membrane capacitance measurements, VGCC activation boosts the exocytotic response of conjunctival goblet cells to neural input. However, over time, VGCC activation also increases the vulnerability of these cells to the lethality of hyperosmolarity. Viability assays further revealed that hyperosmotic-induced goblet cell death is critically dependent on P2X7 receptor channels. Similar to the yin-yang impact of VGCCs on goblet cell physiology and pathobiology, P2X7 activation not only compromises goblet cell viability but also enhances exocytotic activity. Thus, the NSC/VGCC and P2X7 purinoceptor pathways are components of a previously unappreciated high-gain/high-risk adaptive strategy to combat ocular dryness. These pathways boost release of tear-stabilizing mucin at the risk of jeopardizing the viability of the conjunctival goblet cells, whose loss is a histopathological hallmark of irreversible mucin-deficient dry eye.


Pulmonary hypertension phenotypes in patients with systemic sclerosis.
Pulmonary hypertension (PH) commonly affects patients with systemic sclerosis (SSc) and is associated with significant morbidity and increased mortality. PH is a heterogenous condition and several different forms can be associated with SSc, including pulmonary arterial hypertension (PAH) resulting from a pulmonary arterial vasculopathy, PH due to left heart disease and PH due to interstitial lung disease. The incidence of pulmonary veno-occlusive disease is also increased. Accurate and early diagnosis to allow optimal treatment is, therefore, essential. Recent changes to diagnostic haemodynamic criteria at the 6th World Symposium on Pulmonary Hypertension have resulted in therapeutic uncertainty regarding patients with borderline pulmonary haemodynamics. Furthermore, the optimal pulmonary vascular resistance threshold for diagnosing PAH and the role of exercise in identifying early disease require further elucidation. In this article we review the epidemiology, diagnosis, outcomes and treatment of the spectrum of pulmonary vascular phenotypes associated with SSc.


Chaotic mimic robots.
In this paper, chaos is applied to the control of moving robots in order to generate random-like trajectories needed in tasks such as exploration, scanning natural terrains or mapping of unknown environments. Synchronization between the robots of a team is achieved by exploiting the paradigm of mirror neurons, i.e. a neural structure playing a key role in the process of imitation and behaviour understanding. The experimental results discussed in the paper demonstrate that the introduced approach can be successfully applied to implement an efficient learning system for mobile robots.


Stereoisomers of calcium antagonists distinguish a myocardial and vascular mode of protection against cardiac ischemic injury.
Concentration-dependent effects of the enantiomers of the calcium antagonists, gallopamil, diltiazem, and bepridil have been studied in the Langendorff-perfused rat heart, subjected to 30 min of global ischemia. It is shown that the time course, as well as the height of the energy deprivation-induced left ventricular diastolic contracture that develops during ischemia, can be selectively inhibited by negative inotropic concentrations of the calcium antagonist enantiomers. The time needed for recovery from the diastolic contracture during the reperfusion phase can be shortened significantly by lower, vasodilating concentrations of the drugs. In normoxically perfused hearts, stereoselectivity factors (sf) of the enantiomers of the compounds amounted to 63, 10, and 2 for the negative inotropic and 12.6, 79, and 4 for the vasodilating activities of gallopamil, cis-diltiazem, and bepridil, respectively. The sf values of negative inotropism proved to be remarkably similar to sf values of 50 and 7.9 for gallopamil and cis-diltiazem in the protection of the ischemic contracture during ischemia, whereas the sf values of coronary flow increase closely paralleled the values of 7.9, 63, and 2.5 for gallopamil, cis-diltiazem, and bepridil, respectively, in protection during the reperfusion phase. The results strongly suggest that at reperfusion the vasoselective enantiomers of calcium antagonists provide protection related to improved tissue perfusion, and thereby possibly restoring the distorted ionic and energetic homeostasis, whereas the other enantiomers are more involved in a direct energy-saving activity, resulting in protection during the ischemic period.


Association of the neutrophil-to-lymphocyte ratio and prostate cancer detection rates in patients via contemporary multi-core prostate biopsy.
The aim of this study was to determine whether the neutrophil-to-lymphocyte ratio (NLR), a measure of the systemic inflammatory response is associated with the overall prostate cancer detection rate in men who underwent contemporary multi (≥12)-core transrectal ultrasound (TRUS) biopsy. We reviewed the records of 3913 patients with initial prostate-specific antigen (PSA) levels ranging from 4 to 10 ng ml-1 who underwent TRUS-guided prostate biopsy between April 2006 and May 2014. NLR was calculated by prebiopsy neutrophil and lymphocyte counts. We excluded patients who had evidence of acute prostatitis, a history of prostate surgery, and any systemic inflammatory disease. A multivariate logistic regression model was used to analyze prostate cancer detection. After adjusting for confounding factors, predictive values were determined according to the receiver operating characteristic-derived area under the curve, both including and excluding the NLR variable. In univariate analyses, NLR was a significant predictor of prostate cancer detection (P < 0.001). In multivariate analyses, a higher NLR was significantly associated with prostate cancer detection after adjusting for other factors (OR = 1.372, P= 0.038). The addition of NLR increased the accuracy from 0.712 to 0.725 (P = 0.005) in the multivariate model for prostate cancer detection. NLR may be a potentially useful clinical marker in the detection of prostate cancer among men with a PSA level in the 4-10 ng ml-1 range. These findings are derived from a retrospective analysis and should be validated in larger populations through prospective studies.


8-Nitroguanine as a potential biomarker for progression of malignant fibrous histiocytoma, a model of inflammation-related cancer.
Chronic inflammation is a critical component of carcinogenesis and tumor progression. Reactive nitrogen and oxygen species generated by inflammatory cells form mutagenic DNA lesions, such as 8-nitroguanine, which may play an integral role in inflammation-related carcinogenesis. Hypoxia-inducible factor (HIF)-1alpha has been established as a prognostic biomarker in various tumors, including malignant fibrous histiocytoma (MFH). The aim of this study was to evaluate the impact of 8-nitroguanine formation and HIF-1alpha expression on the prognosis of patients with inflammation-related cancer. Immunohistochemical analyses were employed to examine the distribution of 8-nitroguanine and HIF-1alpha, using clinical specimens from 36 patients with MFH as a model of inflammation-related cancer. 8-Nitroguanine formation was predominantly observed in the nuclei of tumor cells and inflammatory cells in tumor tissues, while HIF-1alpha was expressed in the cytoplasm and nuclei of tumor cells. Little or no immunoreactivity of 8-nitroguanine and HIF-1alpha was observed in adjacent non-tumor tissues. Significantly higher levels of both 8-nitroguanine and HIF-1alpha were observed in the tissue specimens of deceased patients than in those of living subjects. Survival curves analyzed by the Kaplan-Meier method differed significantly between the high- and low-staining groups of 8-nitroguanine (p=0.00003) as well as HIF-1alpha (p=0.01104). These results suggest a significant role of the pathway of iNOS-dependent 8-nitroguanine formation via HIF-1alpha and NF-kappaB on the progression of inflammation-related cancer. In conclusion, 8-nitroguanine is an excellent candidate prognostic and predictive biomarker together with HIF-1alpha in inflammation-related tumor progression.


[Trigeminal neuralgia and other facial pain--diagnosis and therapy].
The hallmark of trigeminal neuralgia is the abrupt onset of short pains in the face or in a part of the face, described as stabbing, lightning or electric shocks. Attacks are often triggered by cutaneous stimuli to the face or the oral cavity, which may be such minor activities as talking, chewing, brushing the teeth, or even wind blowing on the face. As a result, facial hygiene as well as a good diet may be neglected. Although 1% of the patients may eventually develop the disorder bilaterally, pain does not cross the midline during any single episode. The clinical course is characterized by exacerbations and remissions, but as the disorder progresses, remissions become shorter and exacerbations more severe. Carbamazepine is the most powerful drug for this condition, but side effects may occur. Neurosurgical treatment may then be considered; the different techniques and approaches are mentioned. Other pain conditions in the face will be reviewed. If the trigeminal neuralgia may be considered as a nerve irritation, like the glossopharyngeal neuralgia and the nasociliary neuralgia, nerve lesion may elicit neurogenic or neuropathic pain, characterized by chronic burning pain; post-zoster pain, iatrogenic and posttraumatic pain illustrate this condition. Cluster headache (Horton neuralgia), Sluder's neuralgia and auriculotemporal neuralgia may be related to a dysfunction of the autonomous nervous system. Finally, lesion in the mandibular joint may cause unilateral facial pain.


POSTPRANDIAL DOSING OF BOLUS INSULIN IN PATIENTS WITH TYPE 1 DIABETES: A CROSS-SECTIONAL STUDY USING DATA FROM THE T1D EXCHANGE REGISTRY.
To assess the prevalence and characteristics of patients with type 1 diabetes (T1D) who dose bolus insulin postprandial (PostP) versus preprandial (PreP). Data for this cross-sectional study were obtained from 21,533 participants in the T1D Exchange Registry. Data were drawn from the enrollment questionnaire. Patients who dosed 'immediately before meal' or 'several minutes before meal' were classified as PreP. Patients who dosed 'during meal' or 'after meal' were classified as PostP. Data reported (PostP vs. PreP) are mean ± SD and percentage, as appropriate. After exclusion of patients who did not answer the dose-timing question or who selected 'not given regularly' or 'depends on glucose level prior to meal,' (4,229 of 25,762), 21,533 patients were included in the study. Ninety-nine percent of patients used rapid-acting insulin analogues; 32% dosed insulin PostP. Compared to PreP, children <18 years of age dosing PostP were characterized by higher glycated hemoglobin (HbA1c) (8.7 ± 1.5% [72 ± 16.4 mmol/mol] vs. 8.4 ± 1.7% [68 ± 18.6 mmol/mol]), larger insulin dose (1.2 ± 0.7 IU/kg/day vs. 1.1 ± 0.7 IU/kg/day), greater prevalence of history of hypoglycemia, and diabetic ketoacidosis. Adults who dosed PostP were characterized by younger age (33.0 ± 15.3 years vs. 39.5 ± 16.6 years), higher HbA1c (8.3 ± 1.5% [67 ± 16.4 mmol/mol] vs. 7.8 ± 1.5% [62 ± 16.4 mmol/mol]), and larger insulin dose (1.0 ± 0.6 IU/kg/day vs. 0.9 ± 0.5 IU/kg/day) than PreP. This study reveals that a large proportion of patients dose bolus insulin PostP. Despite the use of current rapid-acting insulin analogues, patients who dose PostP are characterized by poorer glycemic control in all patients and a greater prevalence of history of severe hypoglycemia and diabetic ketoacidosis in children. BMI = body mass index; CGM = continuous glucose monitoring; DKA = diabetic ketoacidosis; HbA1c = glycated hemoglobin; PostP = postprandial; PreP = preprandial; SMBG = self-monitored blood glucose; T1D = type 1 diabetes.


Fractones: extracellular matrix niche controlling stem cell fate and growth factor activity in the brain in health and disease.
The stem cell niche refers to a specific microenvironment where stem cells proliferate and differentiate to produce new specialized cells throughout an organism's adulthood. Growth factors are crucial signaling molecules that diffuse through the extracellular space, reach the stem cell niche, and ultimately promote stem cell proliferation and differentiation. However, it is not well known how multiple growth factors, often with antagonistic activities, work together in the stem cell niche to select target stem cell populations and determine stem cell fate. There is accumulating evidence suggesting that extracellular matrix (ECM) molecules play an important role in promoting growth factor access and activity in the stem cell niche. In the adult brain neurogenic zone, where neural stem cells (NSCs) reside, there exist specialized ECM structures, which we have named fractones. The processes of NSC allow them to come into contact with fractones and interact with its individual components, which include heparan sulfate proteoglycans (HSPGs) and laminins. We have demonstrated that fractone-associated HSPGs bind growth factors and regulate NSC proliferation in the neurogenic zone. Moreover, emerging results show that fractones are structurally altered in animal models with autism and adult hydrocephalus, as demonstrated by changes in fractone size, quantity, or HSPG content. Interestingly, ECM structures similar to fractones have been found throughout β-amyloid plaques in the brain of patients with Alzheimer's disease. Pathological fractones may cause imbalances in growth factor activity and impair neurogenesis, leading to inflammation and disorder. Generally speaking, these stem cell niche structures play a potentially vital role in controlling growth factor activity during both health and disease.


Evaluation of Ultrafast Wave-Controlled Aliasing in Parallel Imaging 3D-FLAIR in the Visualization and Volumetric Estimation of Cerebral White Matter Lesions.
Our aim was to evaluate an ultrafast 3D-FLAIR sequence using Wave-controlled aliasing in parallel imaging encoding (Wave-FLAIR) compared with standard 3D-FLAIR in the visualization and volumetric estimation of cerebral white matter lesions in a clinical setting. Forty-two consecutive patients underwent 3T brain MR imaging, including standard 3D-FLAIR (acceleration factor = 2, scan time = 7 minutes 50 seconds) and resolution-matched ultrafast Wave-FLAIR sequences (acceleration factor = 6, scan time = 2 minutes 45 seconds for the 20-channel coil; acceleration factor = 9, scan time = 1 minute 50 seconds for the 32-channel coil) as part of clinical evaluation for demyelinating disease. Automated segmentation of cerebral white matter lesions was performed using the Lesion Segmentation Tool in SPM. Student t tests, intraclass correlation coefficients, relative lesion volume difference, and Dice similarity coefficients were used to compare volumetric measurements among sequences. Two blinded neuroradiologists evaluated the visualization of white matter lesions, artifacts, and overall diagnostic quality using a predefined 5-point scale. Standard and Wave-FLAIR sequences showed excellent agreement of lesion volumes with an intraclass correlation coefficient of 0.99 and mean Dice similarity coefficient of 0.97 (SD, 0.05) (range, 0.84-0.99). Wave-FLAIR was noninferior to standard FLAIR for visualization of lesions and motion. The diagnostic quality for Wave-FLAIR was slightly greater than for standard FLAIR for infratentorial lesions (P < .001), and there were fewer pulsation artifacts on Wave-FLAIR compared with standard FLAIR (P < .001). Ultrafast Wave-FLAIR provides superior visualization of infratentorial lesions while preserving overall diagnostic quality and yields white matter lesion volumes comparable with those estimated using standard FLAIR. The availability of ultrafast Wave-FLAIR may facilitate the greater use of 3D-FLAIR sequences in the evaluation of patients with suspected demyelinating disease.


[Erythrocyte antigen for the rapid intravital diagnosis of fowl typhoid and pullorum disease].
A stable erythrocyte antigen was obtained for the rapid diagnosis of typhoid and pullorum disease in birds, which was tested under laboratory and field conditions. It was found that with the use of whole blood or serum taken from birds that had been either experimentally infected or had died of spontaneous infection of Salmonella gallinarum and Salmonella enteritidis the erythrocyte antigen was substantially superior to the routinely used colour ordinary test-antigen in terms of time consumed, intensity, and number of reacting birds. Discussed is the effect of its quick adoption into practice on the basis of its higher epizootiologic, epidemiologic, and economic value.


Report on the 4-h rule and National Emergency Access Target (NEAT) in Australia: time to review.
Objective The aim of the present study was to provide a summary of a systematic review of literature reporting benefits and limitations of implementing National Emergency Access Target (NEAT), a target stipulating that a certain proportion of patients presenting to hospital emergency departments are admitted or discharged within 4h of presentation. Methods A systematic review of published literature using specific search terms, snowballing techniques applied to retrieved references and Google searches was performed. Results are presented as a narrative synthesis given the heterogeneity of included studies. Results Benefits of a time-based target for emergency care are improved timeliness of emergency care and reduced in-hospital mortality for emergency admissions to hospital. Limitations centre on using a process measure (time) alone devoid of any monitoring of patient outcomes, the threshold nature of a time target and the fact that currently NEAT combines the measurement of clinical management of two very different patient cohorts seeking emergency care: less acute patients discharged home and more acute patients admitted to hospital. Conclusions Time-based access targets for emergency presentations are associated with significant improvements in in-hospital mortality for emergency admissions. However, other patient-important outcomes are deserving of attention, choice of targets needs to be validated by empirical evidence of patient benefit and single targets need to be partitioned into separate targets pertaining to admitted and discharged patients. What is known about the topic? Time targets for emergency care originated in the UK. The introduction of NEAT in Australia has been controversial. NEAT directs that a certain proportion of patients will be admitted or discharged from an emergency department (ED) within 4h. Recent dissolution of the Australian National Partnership Agreement (which provided hospitals with financial incentives for achieving NEAT compliance) has prompted a re-examination of the 4-h rule, the evidence underpinning its introduction and its benefits and risks to patients What does this paper add? This paper is executive summary of key findings from a systematic literature review on the benefits and limitations of NEAT (the 4-h rule) commissioned by the Queensland Clinical Senate to inform future policy and targets. What are the implications for practitioners? There is evidence that a time-based target has been associated with a reduction in in-hospital mortality for emergency admissions to Australian hospitals. Concerns remain regarding a time-based target alone being used to drive redesign efforts at improving access to emergency care. A time-based target should be coupled with close monitoring of patient outcomes of emergency care. Target thresholds need to be evidence based and separate targets should be reported for admitted, discharged and all patients presenting to the ED.


Application of Physiologically Based Pharmacokinetic Modeling to Predict Drug Exposure and Support Dosing Recommendations for Potential Drug-Drug Interactions or in Special Populations: An Example Using Tofacitinib.
Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. It is eliminated via multiple pathways including oxidative metabolism (∼70%) and renal excretion (29%). This study aimed to predict the impact of drug-drug interactions and renal or hepatic impairment on tofacitinib pharmacokinetics using a physiologically based pharmacokinetic (PBPK) model. The model was developed using Simcyp based on the physicochemical properties and in vitro and in vivo pharmacokinetics data for tofacitinib. The model was verified by comparing the predicted pharmacokinetic profiles with those observed in available clinical studies after single or multiple doses of tofacitinib, as well as with tofacitinib as a victim of drug-drug interactions (because of inhibition of cytochrome P450 [CYP450] 3A4, CYP450 2C19, or CYP450 induction). In general, good agreement was observed between Simcyp predictions and clinical data. The results from this study provide confidence in using the PBPK modeling and simulation approach to predict the pharmacokinetics of tofacitinib under intrinsic (eg, renal or hepatic impairment) or extrinsic (eg, inhibition of CYP450 enzymes and/or renal transporters) conditions. This approach may also be useful in predicting pharmacokinetics under untested or complex situations (eg, when a combination of intrinsic and extrinsic factors may impact pharmacokinetics) when conducting clinical studies may be difficult, in response to health authority questions regarding dosing in special populations, or for labeling discussions.


A Donation After Circulatory Death Program Has the Potential to Increase the Number of Donors After Brain Death.
Donation after circulatory death has been responsible for 75% of the increase in the numbers of deceased organ donors in the United Kingdom. There has been concern that the success of the donation after circulatory death program has been at the expense of donation after brain death. The objective of the study was to ascertain the impact of the donation after circulatory death program on donation after brain death in the United Kingdom. Retrospective cohort study. A national organ procurement organization. Patients referred and assessed as donation after circulatory death donors in the United Kingdom between October and December 2013. None. A total of 257 patients were assessed for donation after circulatory death. Of these, 193 were eligible donors. Three patients were deemed medically unsuitable following surgical inspection, 56 patients did not proceed due to asystole, and 134 proceeded to donation. Four donors had insufficient data available for analysis. Therefore, 186 cases were analyzed in total. Organ donation would not have been possible in 79 of the 130 actual donors if donation after circulatory death was not available. Thirty-six donation after circulatory death donors (28% of actual donors) were judged to have the potential to progress to brain death if withdrawal of life-sustaining treatment had been delayed by up to a further 36 hours. A further 15 donation after circulatory death donors had brain death confirmed or had clinical indications of brain death with clear mitigating circumstances in all but three cases. We determined that the maximum potential donation after brain death to donation after circulatory death substitution rate observed was 8%; however due to mitigating circumstances, only three patients (2%) could have undergone brain death testing. The development of a national donation after circulatory death program has had minimal impact on the number of donation after brain death donors. The number of donation after brain death donors could increase with changes in end-of-life care practices to allow the evolution of brain death and increasing the availability of ancillary testing.


LABVIEW graphical user interface for precision multichannel alignment of Raman lidar at Jet Propulsion Laboratory, Table Mountain Facility.
The Jet Propulsion Laboratory operates lidar systems at Table Mountain Facility (TMF), California (34.4 degrees N, 117.7 degrees W) and Mauna Loa Observatory, Hawaii (19.5 degrees N, 155.6 degrees W) under the framework of the Network for the Detection of Atmospheric Composition Change. To complement these systems a new Raman lidar has been developed at TMF with particular attention given to optimizing water vapor profile measurements up to the tropopause and lower stratosphere. The lidar has been designed for accuracies of 5% up to 12 km in the free troposphere and a detection capability of <5 ppmv. One important feature of the lidar is a precision alignment system using range resolved data from eight Licel transient recorders, allowing fully configurable alignment via a LABVIEW/C++ graphical user interface (GUI). This allows the lidar to be aligned on any channel while simultaneously displaying signals from other channels at configurable altitude/bin combinations. The general lidar instrumental setup and the details of the alignment control system, data acquisition, and GUI alignment software are described. Preliminary validation results using radiosonde and lidar intercomparisons are briefly presented.


Anisotropic Electron Tail Generation during Tearing Mode Magnetic Reconnection.
The first experimental evidence of anisotropic electron energization during magnetic reconnection that favors a direction perpendicular to the guide magnetic field in a toroidal, magnetically confined plasma is reported in this Letter. Magnetic reconnection plays an important role in particle heating, energization, and transport in space and laboratory plasmas. In toroidal devices like the Madison Symmetric Torus, discrete magnetic reconnection events release large amounts of energy from the equilibrium magnetic field. Fast x-ray measurements imply a non-Maxwellian, anisotropic energetic electron tail is formed at the time of reconnection. The tail is well described by a power-law energy dependence. The expected bremsstrahlung from an electron distribution with an anisotropic energetic tail (v_{⊥}>v_{∥}) spatially localized in the core region is consistent with x-ray emission measurements. A turbulent process related to tearing fluctuations is the most likely cause for the energetic electron tail formation.


Notes on Two Rare Species of Brachyuran Crabs (Families Matutidae and Parthenopidae) From Indonesian Waters with New Distribution Records.
Several species of brachyuran crabs in Indonesian waters have not been reported since almost 100 years ago. This research reports a brachyuran crab that is rarely found and one new record in Indonesian waters. This study was conducted in the waters of southern Aru Island and the Malacca Strait using trawls during a cruise held by the Research Institute for Marine Fisheries, Ministry of Marine Affairs and Fisheries, Indonesia.. Our findings were Izanami reticulata, a new record (family Matutidae) from southern Aru Island, and Cryptopadia fornicata (family Parthenopidae) from the Malacca Strait. The two locations are close to where the species were found in previous studies: the Arafura Sea, which is adjacent to the Aru Islands, and the Malacca Strait, which is adjacent to Borneo. It is suspected that the presence of these two species in Indonesia is due to their distribution through sea currents during the pelagic larval stage. This article also provides the specific habitat for both species in Indonesia, which was previously unknown. In addition, this article contributes to strengthening Indonesia as a mega-biodiversity country with an initial compilation of a database of Brachyura in its waters.


Pharmacokinetics of doripenem during high volume hemodiafiltration in patients with septic shock.
Pharmacokinetics (PK) of doripenem was determined during high volume hemodiafiltration (HVHDF) in patients with septic shock. A single 500 mg dose of doripenem was administered as a 1 hour infusion during HVHDF to 9 patients. Arterial blood samples were collected before and at 30 or 60 minute intervals over 8 hours (12 samples) after study drug administration. Doripenem concentrations were determined by ultrahigh performance liquid chromatography-tandem mass spectrometry. Population PK analysis and Monte Carlo simulation of 1,000 subjects were performed. The median convective volume of HVHDF was 10.3 L/h and urine output during the sampling period was 70 mL. The population mean total doripenem clearance on HVHDF was 6.82 L/h, volume of distribution of central compartment 10.8 L, and of peripheral compartment 12.1 L. Doses of 500 mg every 8 hours resulted in 88.5% probability of attaining the target of 50% time over MIC for bacteria with MIC = 2 µg/mL at 48 hours, when doubling of MIC during that time was assumed. Significant elimination of doripenem occurs during HVHDF. Doses of 500 mg every 8 hours are necessary for treatment of infections caused by susceptible bacteria during extended HVHDF.


The peptide-chain size dependence of positive dissociation energy effect in metallized and protonated polydentate oligoglycine peptides.
The dependence of the positive dissociation energy (PDE) on the size of both protonated and various metal cationized (M+/2+=Na+, K+, Mg2+, and Ca2+) oligoglycines GnHM (G=glycine; n=1-5, and including 6 for GnHK) in the gas phase has been first determined at the B3LYP level with different basis sets. Results show that these PDEs become negative ones when n>or=5 for GnHNa, n>or=6 for GnHK, n>or=2 for GnHMg, and n>or=3 for GnHCa. Moreover, the PDE effect decreases gradually along the increase of oligoglycine size for all these PDE systems. More charge transfer to the ambient ligand and large electrostatic effect of the two divalent cation (Mg2+ and Ca2+) involved systems make them lose the PDE effect more rapidly, and hold more compact and oblate shapes than the monovalent ones. Differently, polydentate GnHK prefers a spherical to oblate shape along with the increase of oligoglycine size.


A systematic review of the health literacy of adults with lifelong communication disability: Looking beyond accessing and understanding information.
To determine the a) extent to which people with lifelong communication disability are included in health literacy research, b) level of health literacy of people with lifelong communication disability, c) methods applied to measure the health literacy of people with lifelong communication disability, d) barriers and facilitators mediating the health literacy of people with lifelong communication disability, and e) outcomes of health literacy interventions for people with lifelong communication disability. We searched for studies relating to health literacy, people with lifelong communication disability, and key areas of the Sørensen et al. (2012) health literacy model (i.e., accessing, understanding, appraising, applying health information, personal/environmental/systemic barriers and facilitators). Analysis of 60 studies demonstrated that this population is not well represented. Insufficient research exists to inform statements on level of health literacy or methods used to measure health literacy of this population. Barriers and facilitators appear consistent with those applicable to the general population. Health literacy intervention outcomes were variable. Significant gaps exist in the research which has primarily focused on people with intellectual disability accessing and understanding health information. Findings can inform policies, practice, and future research on health literacy and people with lifelong communication disability.


Combined Dual-Energy and Single-Energy Metal Artifact Reduction Techniques Versus Single-Energy Techniques Alone for Lesion Detection Near an Arthroplasty.
OBJECTIVE. The purpose of this study was to compare a combined dual-energy CT (DECT) and single-energy CT (SECT) metal artifact reduction technique with a SECT metal artifact reduction technique for detecting lesions near an arthroplasty in a phantom model. MATERIALS AND METHODS. Two CT phantoms with a cobalt chromium sphere attached to a titanium rod, simulating an arthroplasty, within a background of soft-tissue attenuation containing spherical lesions (range, 10-20 mm) around the head and stem of different attenuations from the background (range of attenuation, 10-70 HU) were scanned with a single CT scanner individually (unilateral) and together (bilateral) with the following three dose-equivalent techniques: the currently used clinical protocol (140 kVp, 300 Reference mAs); 100 kVp; and DECT (100 kVp and 150 kVp with a tin filter). Three radiologists reviewed the datasets to identify lesions. Nonparametric AUC was estimated for each reader with each technique. Multireader ANOVA was performed to compare AUCs. Multiple-variable logistic regression analysis was used to identify factors affecting sensitivity and specificity. RESULTS. Accuracy was lower (p < 0.001) for the DECT 130-keV technique than for the 100-, 70-, and 140-kVp techniques. Sensitivity was higher with unilateral arthroplasties (p = 0.037), with greater contrast differences from background (p < 0.001), and with the SECT 100-kVp technique versus other techniques (p < 0.001). The difference in specificities of modalities was not statistically significant (p = 0.148). CONCLUSION. Combining DECT and SECT techniques does not provide additional benefits for lesion detection as opposed to using SECT alone.


Indomethacin delays gastric restitution: association with the inhibition of focal adhesion kinase and tensin phosphorylation and reduced actin stress fibers.
Repair of superficial gastric mucosal injury is accomplished by the process of restitution-migration of epithelial cells to restore continuity of the mucosal surface. Actin filaments, focal adhesions, and focal adhesion kinase (FAK) play crucial roles in cell motility essential for restitution. We studied whether epidermal growth factor (EGF) and/or indomethacin (IND) affect cell migration, actin stress fiber formation, and/or phosphorylation of FAK and tensin in wounded gastric monolayers. Human gastric epithelial monolayers (MKN 28 cells) were wounded and treated with either vehicle or 0.5 mM IND for 16 hr followed by EGF. EGF treatment significantly stimulated cell migration and actin stress fiber formation, and increased FAK localization to focal adhesions, and phosphorylation of FAK and tensin, whereas IND inhibited all these at the baseline and EGF-stimulated conditions. IND-induced inhibition of FAK phosphorylation preceded changes in actin polymerization, indicating that actin depolymerization might be the consequence of decreased FAK activity. In in vivo experiments, rats received either vehicle or IND (5 mg/kg i.g.), and 3 min later, they received water or 5% hypertonic NaCl; gastric mucosa was obtained at 1, 4, and 8 hr after injury. Four and 8 hr after hypertonic injury, FAK phosphorylation was induced in gastric mucosa compared with controls. IND pretreatment significantly delayed epithelial restitution in vivo, and reduced FAK phosphorylation and recruitment to adhesion points, as well as actin stress fiber formation in migrating surface epithelial cells. Our study indicates that FAK, tensin, and actin stress fibers are likely mediators of EGF-stimulated cell migration in wounded human gastric monolayers and potential targets for IND-induced inhibition of restitution.


Development and validation of a prognostic model based on immune variables to early predict severe cases of SARS-CoV-2 Omicron variant infection.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has prevailed globally since November 2021. The extremely high transmissibility and occult manifestations were notable, but the severity and mortality associated with the Omicron variant and subvariants cannot be ignored, especially for immunocompromised populations. However, no prognostic model for specially predicting the severity of the Omicron variant infection is available yet. In this study, we aim to develop and validate a prognostic model based on immune variables to early recognize potentially severe cases of Omicron variant-infected patients. This was a single-center prognostic study involving patients with SARS-CoV-2 Omicron variant infection. Eligible patients were randomly divided into the training and validation cohorts. Variables were collected immediately after admission. Candidate variables were selected by three variable-selecting methods and were used to construct Cox regression as the prognostic model. Discrimination, calibration, and net benefit of the model were evaluated in both training and validation cohorts. Six hundred eighty-nine of the involved 2,645 patients were eligible, consisting of 630 non-ICU cases and 59 ICU cases. Six predictors were finally selected to establish the prognostic model: age, neutrophils, lymphocytes, procalcitonin, IL-2, and IL-10. For discrimination, concordance indexes in the training and validation cohorts were 0.822 (95% CI: 0.748-0.896) and 0.853 (95% CI: 0.769-0.942). For calibration, predicted probabilities and observed proportions displayed high agreements. In the 21-day decision curve analysis, the threshold probability ranges with positive net benefit were 0~1 and nearly 0~0.75 in the training and validation cohorts, correspondingly. This model had satisfactory high discrimination, calibration, and net benefit. It can be used to early recognize potentially severe cases of Omicron variant-infected patients so that they can be treated timely and rationally to reduce the severity and mortality of Omicron variant infection.


Development of sequence characterized DNA markers linked to a dominant verticillium wilt resistance gene in tomato.
Sequences were determined for codominant RAPD markers closely linked to the Ve locus, a dominant verticillium wilt resistance gene in tomato. Analysis of the sequences linked to Ve and ve revealed a perfectly homologous sequence with a central polymorphic region comprising 79 nucleotide substitutions, insertions, and deletions. Codominant and allele-specific SCARs were developed using conserved and polymorphic sequences linked to the Ve locus. High resolution linkage analysis using F2 progeny segregating for resistance and marker-assisted selection indicated that linkage between the genetic markers and the Ve locus is less than 0.67 +/- 0.49 cM. Sequences were useful in determining the molecular structure of a polymorphic genomic region closely linked to the Ve locus and in developing genetic markers that facilitated marker-assisted selection of the resistant, susceptible, heterozygous, and homozygous genotypes.


Use of CAD/CAM in Second-Stage Implant Surgery to Achieve Improved Final Restoration Esthetics, Natural Gingival Appearance.
To achieve a predictable esthetic outcome when using an implant-supported crown for rehabilitation of an edentulous space, computer-aided design/computer-aided manufacturing (CAD/CAM) technology can be utilized in the second stage of implant surgery to scan, mill, and restore the implant site all in one office visit. In this case report, an implant for a first molar was restored with a CAM-fabricated hybrid ceramic crown, designed using CEREC® 4.4 software. A 3-dimensional scan was taken chairside at the time of uncovering the implant using powder-free intraoral scanning. Specific design features were implemented to control peri-implant soft-tissue growth to meet the patient's esthetic expectations and achieve an outstanding clinical outcome. This report emphasizes the value of using a CAD/CAM-milled crown in achieving an emergence profile in second-stage surgery, describes a polymer-infiltrated-ceramic-network material as a potential biomaterial for implant restoration, and discusses the importance of taking a digital impression to capture details for improved restoration esthetics and longevity.


Ocular Injury in Cosmetic Laser Treatments of the Face.
BACKGROUND: The eye is a vulnerable and commonly injured organ in cosmetic laser procedures of the face. Treatment of the eyelids and periorbital areas increases this risk, especially when ocular protection devices are not used or are removed during the procedure. A study has shown that injury from laser epilation of the periocular areas is one of the most common causes of litigation in cutaneous laser surgery. OBJECTIVE: The goal of this review is to determine the causes of ocular injury in cosmetic laser procedures and derive lessons on critical safety elements to prevent future injury. METHODS: We conducted a review of the current literature through a PubMed search on case reports of ocular injury in cosmetic laser treatments of the face. Twenty-one cases are examined. RESULTS: In more than 62 percent of cases, ocular protection was not used or protection was used but removed during the procedure to treat areas close to the eye. However, despite the proper use of intraocular corneal shields and wavelength-specific goggles, accidents occurred in 33 percent of cases. CONCLUSION: Ocular protection devices are essential to prevent most cases of laser-induced eye injury. Use of high fluence and long wavelength lasers increases the risk of ocular injury due to deeper penetration of the organ by radiation. Inadequate cooling between pulses also predisposes to injury by cosmetic lasers.


Modified distributed Bragg reflector for protecting organic light-emitting diode displays against ultraviolet light.
Sunlight/UV (ultraviolet)-induced degradation is still a critical issue for outdoor applications of organic light-emitting diode (OLED) displays. Therefore, effective UV-blocking structures that can prevent OLED displays from sunlight/UV degradation and still keep the OLED panels' display performance is necessary. In this report, modified distributed Bragg reflector (DBR) structures having UV-absorbing dielectric materials and adjusted layer/pair thicknesses were developed to realize effective UV blocking properties (nearly 0% transmittance below 400 nm), constantly high transmittance like glass in the visible range (∼92%) required for display applications, and sharp transition in transmission between the UV and the visible ranges. Furthermore, under the rigorous IEC 60068-2-5 solar test condition, it was verified that the developed modified, UV-blocking DBR can effectively enhance the OLED panel's resistance against UV/solar-induced degradation, effectively reducing voltage shifts of OLED devices after repeated solar test cycles.


Generation of longer 3' cDNA fragments from massively parallel signature sequencing tags.
Massively Parallel Signature Sequencing (MPSS) is a powerful technique for genome-wide gene expression analysis, which, similar to SAGE, relies on the production of short tags proximal to the 3'end of transcripts. A single MPSS experiment can generate over 10(7) tags, providing a 10-fold coverage of the transcripts expressed in a human cell. A significant fraction of MPSS tags cannot be assigned to known transcripts (orphan tags) and are likely to be derived from transcripts expressed at very low levels (approximately 1 copy per cell). In order to explore the potential of MPSS for the characterization of the human transcriptome, we have adapted the GLGI protocol (Generation of Longer cDNA fragments from SAGE tags for Gene Identification) to convert MPSS tags into their corresponding 3' cDNA fragments. GLGI-MPSS was applied to 83 orphan tags and 41 cDNA fragments were obtained. The analysis of these 41 fragments allowed the identification of novel transcripts, alternative tags generated from polymorphic and alternatively spliced transcripts, as well as the detection of artefactual MPSS tags. A systematic large-scale analysis of the genome by MPSS, in combination with the use of GLGI-MPSS protocol, will certainly provide a complementary approach to generate the complete catalog of human transcripts.


Inhibitory effect of 1-benzyl-5[(C)-2,6-dimethyl-1,5-heptadienyl] imidazole (KK-42) on desert locust, Schistocerca gregaria forsk.
Imidazole compound KK-42 was tested for its inhibitory effect on Schistocerca gregaria. The compound caused 80% mortality after 19 days of treatment with 100 microg of KK-42/insect. It also caused the production of deformed adults at even lower doses. Ecdysteroid content, when estimated by RIA, declined due to KK-42 treatment in both haemolymph and ovaries of the insect. Reduction in ecdysteroid titer was maximum at 100 microg of KK-42/insect. The value estimated by RIA was 0.34 ng/pL haemolymph as compared to 0.97 ng/microL in case of controls. Similarly,ecdysteroid content of ovaries detected was 0.48 ng/mg in treated ones as compared to 0.61 ng/mg in controls. Histological studies, however, revealed no alteration in the ovarian tissues due to KK-42 treatment.


Simultaneous thickness and group index measurement with a single arm low-coherence interferometer.
We present a single arm low-coherence interferometer to directly measure the physical thickness and group refractive index of optically transparent samples having flat and parallel surfaces. The optical arrangement, resembling a common-path interferometer, is more compact and stable than the usual dual-arm low-coherence interferometer. It has been used to measure samples of Herasil 102 fused silica, Schott B270 Superwhite crown glass and borosilicate cover glass. The results obtained indicate uncertainties in the third decimal place for index values and thicknesses accurate to within 2 μm.


Laparoendoscopic single-site surgery (LESS) for excision of a seminal vesicle cyst associated with ipsilateral renal agenesis.
We report a case of laparoendoscopic single-site surgery (LESS) for a symptomatic left seminal vesicular cyst and ipsilateral renal agenesis. A 49-year-old man presented with a 1-year history of severe irritation upon voiding and intractable, recurrent hematospermia. A computed tomography scan showed a 68×41×38 mm sized left seminal vesicular cyst with ipsilateral renal agenesis. LESS was performed successfully to treat the seminal vesicle cyst. The total operative time was 125 minutes, and blood loss was minimal. The patient was discharged from the hospital on the second postoperative day.


Lesional expression of RhoA and RhoB following traumatic brain injury in humans.
Inhibition of the small GTPase Rho or of its downstream target Rho-associated kinase (ROCK) has been shown to promote axon regeneration and to improve functional recovery following traumatic CNS lesions in the adult rat. In order to determine the expression pattern of RhoA and RhoB following human traumatic brain injury (TBI) and to assess whether Rho is a possible target for pharmacological intervention in humans, we investigated expression patterns of RhoA and RhoB in brain specimens from 25 patients who died after closed TBI in comparison to brain tissue derived from four neuropathologically unaffected control patients by immunohistochemistry. A highly significant lesional upregulation of both RhoA and RhoB was observed beginning several hours after the traumatic event and continuing for months after TBI. The cellular sources of both molecules included polymorphonuclear granulocytes, monocytes/macrophages, and reactive astrocytes. Additionally, expression of RhoA was also detected in neuronal cells in some of the cases. From our data, we conclude that inhibition of Rho is a promising mechanism for the development of new pharmacological interventions in human TBI. As the observed upregulation of RhoA and RhoB was still detectable months after TBI, we speculate that even delayed treatment with Rho inhibitors might be a therapeutic option.


The Interplay of English as a Foreign Language Learners' Interest, Self-Efficacy, and Involvement.
Founded on the advent of Positive Psychology in recent decades, the learners' involvement has been a critical issue since the origin of teaching and learning despite it being quickly developed in previous decades. The enhancement of motivational aspects like self-efficacy and interest appears to have a high impact on learners' success and achievement. Although both constructs are extensively investigated in various subjects, their association between and the learners' involvement in the process of language learning have not been taken into account so far. This review intended to scrutinize the association among students' self-efficacy, their academic interest, and their involvement. It is significant to pinpoint that the current review can help educational administrations, professional improvement centers, and policymakers to consider the above-mentioned issues in the progression of language education to develop their involvement.


The expression and localization of β-endorphin and µ,δ-opioid receptors in synovial tissues in patient with rheumatoid arthritis and osteoarthritis.
Abstract An examination of the localization and distribution of β-endorphin and opioid receptors in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Immunohistochemical staining, reverse transcription polymerase chain reaction (RT-PCR) analysis, and in situ hybridization were performed using synovial tissues obtained from RA and OA patients. Immunohistochemical staining showed that β-endorphin was strongly expressed in synovial lining cells and in a few lymphocytes and macrophages surrounding the vessels, whereas µ- and δ-opioid receptors were expressed in lymphocytes and macrophages. However, we detected the weak expression of these opioid peptides in synovial tissues of OA patients. RT-PCR analysis showed that preproopiomelanocortin (POMC) mRNA, a precursor of β-endorphin, was strongly expressed in synovial tissues of RA patients, but these PCR products of synovial tissues obtained from OA patients were weakly detected compared with those from RA patients. POMC mRNA was also expressed in synovial tissues in RA patients. In in situ hybridization, the expression of POMC mRNA was detected in macrophages, synovial lining cells, and fibroblasts in synovial tissues of RA patients as well as β-endorphin. In RA patients, β-endorphin and µ- and δ-opioid receptors are synthesized and located in synovial lining cells, lymphocytes, and macrophages surrounding the vessels in synovial tissues, and may play a role in the regulation and modulation of inflammation.


Non-specific protection from respiratory tract infections in cattle generated by intranasal administration of an innate immune stimulant.
Alternatives to antibiotics for prevention of respiratory tract infections in cattle are urgently needed given the increasing public and regulatory pressure to reduce overall antibiotic usage. Activation of local innate immune defenses in the upper respiratory tract is one strategy to induce non-specific protection against infection with the diverse array of viral and bacterial pathogens associated with bovine respiratory disease complex (BRDC), while avoiding the use of antibiotics. Our prior studies in rodent models demonstrated that intranasal administration of liposome-TLR complexes (LTC) as a non-specific immune stimulant generated high levels of protection against lethal bacterial and viral pathogens. Therefore, we conducted studies to assess LTC induction of local immune responses and protective immunity to BRDC in cattle. In vitro, LTC were shown to activate peripheral blood mononuclear cells in cattle, which was associated with secretion of INFγ and IL-6. Macrophage activation with LTC triggered intracellular killing of Mannheimia hemolytica and several other bacterial pathogens. In studies in cattle, intranasal administration of LTC demonstrated dose-dependent activation of local innate immune responses in the nasopharynx, including recruitment of monocytes and prolonged upregulation (at least 2 weeks) of innate immune cytokine gene expression by nasopharyngeal mucosal cells. In a BRDC challenge study, intranasal administration of LTC prior to pathogen exposure resulted in significant reduction in both clinical signs of infection and disease-associated euthanasia rates. These findings indicate that intranasal administration of a non-specific innate immune stimulant can be an effective method of rapidly generating generalized protection from mixed viral and bacterial respiratory tract infections in cattle.


Lormetazepam (Lorámet): a multicentre assessment of its efficacy and acceptability as a hypnotic in out-patients with sleep disturbances.
In an open, multicentre study, the short-acting benzodiazepine hypnotic lormetazepam (Loramet) was administered nightly (1-2 mg p.o.) for a period of 7 nights to 665 out-patients with various types of sleep disturbances. The patients assessed the efficacy and acceptability of lormetazepam with the aid of a simple diary card and a set of visual analogue scales. The results showed that about 75% of the patients reported a significant improvement in their sleep pattern. The time to onset of sleep was decreased, the number of nocturnal wakings was reduced and the patients reported waking in the morning more refreshed and co-ordinated. The effects were significant after the first night and there were further significant improvements by the seventh night on the drug. In patients who had prior experience of other hypnotics, twice as many preferred lormetazepam to temazepam and three times as many preferred lormetazepam to nitrazepam. Nine patients withdrew from the study due to lack of efficacy and only fifteen patients dropped out following the occurrence of side-effects, mainly drowsiness and light-headedness. It was concluded that lormetazepam is an effective and highly acceptable hypnotic in patients with sleep disturbances.


Current understanding and approach to well differentiated lung neuroendocrine tumors: an update on classification and management.
Neuroendocrine tumors (NETs) are rare neoplasms that can arise from any tissue. They are classified based on embryonic gut derivative (i.e. foregut, midgut and hindgut) with midgut tumors being the most common (e.g. gastrointestinal NET). The second most common category of NETs is that which arises from the lung. In fact, 25% of primary lung cancers are NETs, including small cell lung cancer (SCLC), which comprises 20% of all lung cancers. The remaining 5% are large cell neuroendocrine cancer (LCNEC, 3%), typical carcinoids (TCs, 1.8%), and atypical carcinoids (ACs, 0.2%). The less common TCs/ACs are well differentiated lung NETs. Their incidence has been increasing in more recent years and although these tumors are slow growing, advanced disease is associated with poor survival. There have been advances in classification of lung NETs that have allowed for more appropriate management upfront. They are cured by surgical resection when disease is limited. However, advanced and metastatic disease requires medical therapy that is ever changing and expanding. In this review, the aim is to summarize the current understanding and classification of well differentiated lung NETs (i.e. TCs and ACs), and focus on recent updates in medical management of advanced disease, along with a brief discussion on potential future discoveries.


Probiotic use in an infectious disease setting.
The lethality of infectious diseases and deep concern over growing antimicrobial resistance make it essential that alternative or adjunct therapies be developed. Areas covered: Using papers published in PubMed, a case is presented to consider beneficial microbes as a means to improve management of infectious diseases. Clinical evidence is mounting that certain probiotic microbes can contribute to this armamentarium. These could have an immediate effect against necrotizing enterocolitis, pre- and post-surgical procedures, antibiotic-associated infections, urogenital infections in women and for reducing the severity and duration of respiratory infections. While further studies will always be warranted irrespective of the intervention, and quality assurance and patient safety must remain a priority, the main barrier to implementation may well be unwarranted hesitation amongst physicians, healthcare administrators and regulators. Meanwhile, patients are already taking things into their own hands at a time when their knowledge of product selection is poor and clinical guidance is invariably missing. Expert commentary: Until vaccines and other alternatives emerge, it would be foolhardy to not use best practices to bring probiotics into mainstream infectious disease management. Our ability to manipulate microbial-host interactions offers hope before the last antibiotic stops being effective.


A Stress-Responsive NAC Transcription Factor from Tiger Lily (LlNAC2) Interacts with LlDREB1 and LlZHFD4 and Enhances Various Abiotic Stress Tolerance in Arabidopsis.
Our previous studies have indicated that a partial NAC domain protein gene is strongly up-regulated by cold stress (4 °C) in tiger lily (Lilium lancifolium). In this study, we cloned the full-length of this NAC gene, LlNAC2, to further investigate the function of LlNAC2 in response to various abiotic stresses and the possible involvement in stress tolerance of the tiger lily plant. LlNAC2 was noticeably induced by cold, drought, salt stresses, and abscisic acid (ABA) treatment. Promoter analysis showed that various stress-related cis-acting regulatory elements were located in the promoter of LlNAC2; and the promoter was sufficient to enhance activity of GUS protein under cold, salt stresses and ABA treatment. DREB1 (dehydration-responsive binding protein1) from tiger lily (LlDREB1) was proved to be able to bind to the promoter of LlNAC2 by yeast one-hybrid (Y1H) assay. LlNAC2 was shown to physically interact with LlDREB1 and zinc finger-homeodomain ZFHD4 from the tiger lily (LlZFHD4) by bimolecular fluorescence complementation (BiFC) assay. Overexpressing LlNAC2 in Arabidopsis thaliana showed ABA hypersensitivity and enhanced tolerance to cold, drought, and salt stresses. These findings indicated LlNAC2 is involved in both DREB/CBF-COR and ABA signaling pathways to regulate stress tolerance of the tiger lily.


Environmental surface asepsis.
Environmental surface disinfection is easily accomplished with precleaning and disinfection techniques, and prepared surfaces or difficult-to-clean items can be covered with impermeable barriers. When carried out effectively, both practitioners and patients are protected from exposure to microorganisms that transmit disease and cause illness.


Ion cyclotron emission diagnostic system on the experimental advanced superconducting tokamak and first detection of energetic-particle-driven radiation.
A passive and noninvasive diagnostic system based on high-frequency B-dot probes (HFBs) has been designed and developed for the measurement and identification of ion cyclotron emission (ICE) in the Experimental Advanced Superconducting Tokamak (EAST). Details of the hardware components of this system including HFBs, direct current blockers, radio frequency splitters, filters, and power detectors as well as data acquisition systems are presented. A spectrum analyzer is used in addition to the ordinary speed acquisition card for data registration and analysis. The reliability of a HFB based diagnostic system has been well validated during the 2018 spring experiments on the EAST. ICE signals corresponding to fundamental cyclotron frequency of hydrogen ions and harmonics of deuterium ions were observed in experiments where deuterium plasmas were heated with deuterium neutral beams. The field dependence of ICE has been verified by recent experiments with three different background magnetic fields. The observed ratio of the ICE frequency is consistent with the ratio of the magnetic field intensity within measurement errors of a few percent.


Human amniotic fluid promotes retinal pigmented epithelial cells' trans-differentiation into rod photoreceptors and retinal ganglion cells.
To evaluate the effect of human amniotic fluid (HAF) on retinal pigmented epithelial cells growth and trans-differentiation into retinal neurons, retinal pigmented epithelium (RPE) cells were isolated from neonatal human cadaver eye globes and cultured in Dulbecco's modified Eagle's medium-F12 supplemented with 10% fetal bovine serum (FBS). Confluent monolayer cultures were trypsinized and passaged using FBS-containing or HAF-containing media. Amniotic fluid samples were received from pregnant women in the first trimester of gestation. Cell proliferation and death enzyme-linked immunosorbent assays were performed to assess the effect of HAF on RPE cell growth. Trans-differentiation into rod photoreceptors and retinal ganglion cells was also studied using immunocytochemistry and real-time polymerase chain reaction techniques. Primary cultures of RPE cells were successfully established under FBS-containing or HAF-containing media leading to rapid cell growth and proliferation. When RPE cells were moved to in vitro culture system, they began to lose their differentiation markers such as pigmentation and RPE65 marker and trans-differentiated neural-like cells followed by spheroid colonies pertaining to stem/progenitor cells were morphologically detected. Immunocytochemistry (ICC) analysis of HAF-treated cultures showed a considerable expression of Rhodopsin gene (30% Rhodopsin-positive cells) indicating trans-differentiation of RPE cells to rod photoreceptors. Real-time polymerase chain reaction revealed an HAF-dose-dependant expression of Thy-1 gene (RGC marker) and significant promoting effect of HAF on RGCs generation. The data presented here suggest that HAF possesses invaluable stimulatory effect on RPE cells growth and trans-differentiation into retinal neurons. It can be regarded as a newly introduced enriched supplement in serum-free kinds of media used in neuro-retinal regeneration studies.


Discal attachments of the human temporomandibular joint.
Despite its clinical significance, the anatomy of the human temporomandibular joint (TMJ) and its relationship to the lateral pterygoid muscle remains poorly described and often misrepresented in standard texts. The aim of this study was to describe how the anterior and posterior attachments of the TMJ disc vary between lateral, central and medial regions of the joint. Ten left TMJs were removed en bloc from cadavers and serial sections were made at 3-4mm intervals. Observations were made to ascertain the anterior and posterior attachments of the disc and the joint structures were traced from standardized photographs. Laterally, the capsule and lateral discal ligament merged prior to their attachment at the condylar pole. Medially, muscle fibres, capsule and the disc converged on the medial pole of the condyle. There was no evidence that fibres of the upper head of the lateral pterygoid muscle inserted directly into the disc. The upper head inserted into the condyle either directly at the pterygoid fovea or via a central tendon or indirectly via the capsule. Posteriorly, the superior part of the posterior attachment of the disc attached to the cartilaginous meatus and tympanic part of the temporal bone. The inferior part of the posterior attachment of the disc attached to the posterior surface of the condyle. In four joints, this attachment was folded beneath the posterior band of the disc, creating a wedge-shaped flap that ran medio-laterally. This study is in broad agreement with other anatomical TMJ studies but there are two main points of difference. Firstly, a true muscle insertion of the superior head of the lateral pterygoid muscle to the disc was not observed. Secondly, a wedge-shaped flap of retrodiscal tissue was identified between the condyle and the disc.


Identifying fish diversity hot-spots in data-poor situations.
One of the more challenging tasks in Marine Spatial Planning (MSP) is identifying critical areas for management and conservation of fish stocks. However, this objective is difficult to achieve in data-poor situations with different sources of uncertainty. In the present study we propose a combination of hierarchical Bayesian spatial models and remotely sensed estimates of environmental variables to be used as flexible and reliable statistical tools to identify and map fish species richness and abundance hot-spots. Results show higher species aggregates in areas with higher sea floor rugosity and habitat complexity, and identify clear richness hot-spots. Our findings identify sensitive habitats through essential and easy-to-use interpretation tools, such as predictive maps, which can contribute to improving management and operability of the studied data-poor situations.


Secondary metabolite genes encoded by potato rhizosphere microbiomes in the Andean highlands are diverse and vary with sampling site and vegetation stage.
Potato (Solanum tuberosum) is an important staple crop worldwide, it has been cultivated in the Andean Altiplano under low-input farming practices at high altitudes and under harsh environment for centuries. We analyzed secondary metabolite (SM) gene diversity encoded in the potato rhizosphere microbiome during plant growth at three distinct sites located in the Andes at high altitudes by 454-pyrosequencing of non-ribosomal peptide and polyketide biosynthetic genes. Phylogenetic analysis indicated that the majority of rhizosphere SM-encoding sequences differed from previously known sequences and may have distinct ancestors. In particular, actinobacterial methyl-malonyl-CoA transferase and acyl carrier protein from Firmicutes, both involved in the synthesis of SMs, showed widespread distribution of clades which were clearly distinct from sequences deposited in public databases, and only 11% of these sequences could be linked to the production of specific classes of SMs. Although the same cultivar was analyzed, SM gene composition radically differed among plant growth stages and across sites, suggesting a distinct repertoire of SM genes that likely encode diverse SM structures. Also, great diversity of non-ribosomal peptide and polyketide biosynthetic pathways in potato-associated microbiomes in the Andean highlands may represent a rich source of novel natural products.


Reaction Phenotyping of Low-Turnover Compounds in Long-Term Hepatocyte Cultures Through Persistent Selective Inhibition of Cytochromes P450.
Recognizing the challenges of determining the relative contribution of different drug metabolizing enzymes to the metabolism of slowly metabolized compounds, a cytochrome P450 reaction phenotyping (CRP) method using cocultured human hepatocytes (HEPATOPAC) has been established. In this study, the emphasis on the relative contribution of different cytochrome P450 (P450) isoforms was assessed by persistently inhibiting P450 isoforms over 7 days with human HEPATOPAC. P450 isoform-selective inhibition was achieved with the chemical inhibitors furafylline (CYP1A2), tienilic acid (CYP2C9), (+)-N-3-benzylnirvanol (CYP2C19), paroxetine (CYP2D6), azamulin (CYP3A), and a combination of 1-aminobenzotriazole and tienilic acid (broad spectrum inhibition of P450s). We executed this CRP method using HEPATOPAC by optimizing for the choice of P450 inhibitors, their selectivity, and the temporal effect of inhibitor concentrations on maintaining selectivity of inhibition. In general, the established CRP method using potent and selective chemical inhibitors allows to measure the relative contribution of P450s and to calculate the fraction of metabolism (f m) of low-turnover compounds. Several low-turnover compounds were used to validate this CRP method by determining their hepatic intrinsic clearance and f m, with comparison with literature values. We established the foundation of a robust CRP for low-turnover compound test system which can be expanded to include inhibition of other drug metabolizing enzymes. This generic CRP assay, using human long-term hepatocyte cultures, will be an essential tool in drug development for new chemical entities in the quantitative assessment of the risk as a victim of drug-drug interactions. SIGNIFICANCE STATEMENT: An ongoing trend is to develop drug candidates which have limited metabolic clearance. The current studies report a generic approach to conducting reaction phenotyping studies with human HEPATOPAC, focusing on P450 metabolism of low-turnover compounds. Potent and selective chemical inhibitors were used to assess the relative contribution of the major human P450s. Validation was achieved by confirming hepatic intrinsic clearance and fraction of metabolism for previously reported low-turnover compounds. This approach is adaptable for assessment of all drug metabolizing enzymes.