Cost analysis of osteoporosis related to untreated menopause.
Menopausal osteoporosis has many consequences for women over 50. Its complications incur high treatment costs both for society and the patients themselves. Collection of the epidemiological data required for a cost analysis of menopause-related osteoporosis is not easy, but we have calculated the direct (i.e. purely medical) costs as follows: hip fractures: approximate number per annum in women over 50: 55,000, minimum hospital costs (treatment and rehabilitation): 3.5 bn FF; forearm fractures: approximate number per annum: 35,000, cost of out-patient treatment: 200 m FF; vertebral fractures: common, but generally unrecorded: estimated number 40,000-65,000 cost: unevaluated. The relative benefit of hormone therapy versus nontreatment may be used to calculate the cost of osteoporosis due to non treated menopause. In France, where currently only 5% women over 50 are treated, this cost is 2.2 bn FF. If 50% of women were treated, the savings from hormone therapy (in terms of osteoporosis treatment costs) could be 1.2 bn FF, a figure which must be weighed against a cost analysis of oestrogen therapy.


Quinones and halogenated monoterpenes of algal origin show anti-proliferative effects against breast cancer cells in vitro.
Red and brown algae have been shown to produce a variety of compounds with chemotherapeutic potential. A recent report described the isolation of a range of novel polyhalogenated monoterpene compounds from the red algae Plocamium corallorhiza and Plocamium cornutum collected off the coast of South Africa, together with the previously described tetraprenylquinone, sargaquinoic acid (SQA), from the brown algae Sargassum heterophyllum. In our study, the algal compounds were screened for anti-proliferative activity against metastatic MDA-MB-231 breast cancer cells revealing that a number of compounds displayed anti-cancer activity with IC(50) values in the micromolar range. A subset of the compounds was tested for differential toxicity in the MCF-7/MCF12A system and five of these, including sargaquinoic acid, were found to be at least three times more toxic to the breast cancer than the non-malignant cell line. SQA was further analysed in terms of its mechanism of cytotoxicity in MDA-MB-231 cells. The ability to initiate apoptosis was distinguished from the induction of an inflammatory necrotic response via flow cytometry with propidium iodide and Hoescht staining, confocal microscopy with Annexin V and propidium iodide staining as well as the PARP cleavage assay. We report that SQA induced apoptosis while a polyhalogenated monoterpene RU015 induced necrosis in metastatic breast cancer cells in vitro. Furthermore, we demonstrated that apoptosis induction by SQA occurs via caspase-3, -6, -8, -9 and -13 and was associated with down-regulation of Bcl-2. In addition, cell cycle analyses revealed that the compound causes G(1) arrest in MDA-MB-231 cells.


Protective effect of oxytocin on LPS-induced acute lung injury in mice.
Oxytocin (OT), a neurohypophyseal hormone synthesized in the paraventricular and supraoptic nuclei of the hypothalamus, has been reported to have an anti- inflammatory effect. However, its role in acute lung injury (ALI) has never been investigated. The aim of this study was to explore the therapeutic effects and potential mechanism action of OT on lipopolysaccharide (LPS)-induced ALI. Mice were treated with OT 30 min before the intraperitoneal injection of LPS. After 2 h, the effects of OT on lung histopathological changes, lung wet/dry (W/D) ratio, myeloperoxidase (MPO) activity, levels of inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), and expression of inflammation proteins were detected. The results showed that OT significantly reduced LPS-induced pathological injury, W/D ratio, MPO activity, and the levels of interleukin (IL)-1β, IL-18 and IL-6. Further, OT also inhibited LPS-induced Toll-like receptor 4 expression and NLR family pyrin domain containing 3 inflammasome activation. OT receptor antagonist (L-368,899) was given 90 min before injecting OT to further demonstrate the role of OT in LPS-induced ALI. The results showed OT could not alleviate the aforementioned inflammatory reactions after administering L-368,899. In conclusion, the present results indicated that OT could reduce inflammatory responses of LPS-induced ALI.


Influence of underlying coronary artery disease on the natural history and prognosis of exercise-induced left bundle branch block.
The long-term prognosis of exercise-induced left bundle branch block (BBB) in patients with and without underlying coronary artery disease (CAD) was examined by following 15 patients (7 with normal coronary arteries and 8 with CAD) for an average of 6.6 years (range 2.2 to 11.2). Over the follow-up interval, permanent left BBB developed in 8 of the 15 patients. Seven of these 8 had underlying CAD, compared to 0 of 6 patients with normal coronary arteries and normal left ventricular function (p less than 0.002). In 1 patient with normal coronary arteries and a left ventricular ejection fraction of 0.34, permanent left BBB developed. During follow-up, 4 patients died; 3 had significant CAD and 1 had depressed left ventricular function. In no patient did high-grade atrioventricular block develop and no patient required pacing. Thus, development of permanent left BBB in patients with exercise-induced left BBB is related to presence or absence of underlying CAD or myocardial disease. When left BBB is found in the absence of underlying heart disease, there does not tend to be progression of the conduction disturbance and the prognosis is excellent.


Polarization-resolved spectroscopy imaging of grain boundaries and optical excitations in crystalline organic thin films.
Exploration of optical properties of organic crystalline semiconductors thin films is challenging due to submicron grain sizes and the presence of numerous structural defects, disorder and grain boundaries. Here we report on the results of combined linear dichroism (LD)/ polarization-resolved photoluminescence (PL) scanning microscopy experiments that simultaneously probe the excitonic radiative recombination and the molecular ordering in solution-processed metal-free phthalocyanine crystalline thin films with macroscopic grain sizes. LD/PL images reveal the relative orientation of the singlet exciton transition dipoles at the grain boundaries and the presence of a localized electronic state that acts like a barrier for exciton diffusion across the grain boundary. We also show how this energy barrier can be entirely eliminated through the optimization of deposition parameters that results in films with large grain sizes and small-angle boundaries. These studies open an avenue for exploring the influence of long-range order on exciton diffusion and carrier transport.


The wrinkle severity rating scale: a validation study.
Patient satisfaction is the most important outcome in facial aesthetic surgery. However, the need for evidence-based evaluation of aesthetic procedures dictates the use of more objective and quantitative measures of treatment outcome. The present study was undertaken to validate a new clinical outcome instrument, the Wrinkle Severity Rating Scale. Five clinical investigators were presented with 30 photographic images of the lower face and asked to rate nasolabial fold severity on each side using the 5-grade Wrinkle Severity Rating Scale (WSRS). Standardized definitions of the five grades were provided to the investigators in visual (photographic) and descriptive formats. To take into account possible facial asymmetry, nasolabial folds on the left and right sides of the face were rated separately. Assessments were conducted independently and were repeated after >or=2 weeks. Intra-observer (test-retest) agreement was 68.7% (left side) and 72.7% (right side); weighted kappa coefficients for the left and right sides were 0.77 and 0.81, respectively. Mean inter-observer agreement (internal consistency) was 67.7% (left side) and 72.3% (right side); weighted kappa coefficients for the left and right sides were 0.75 (95% CI 0.70-0.79) and 0.78 (95% CI 0.72-0.83), respectively. The WSRS is a valid and reliable instrument for quantitative assessment of facial skin folds, with good inter- and intra-observer consistency. By allowing objective and reproducible grading of data, the WSRS should prove a useful clinical tool for assessing the effectiveness of soft-tissue augmentation and other facial contouring procedures.


[Isolation of gastric cancer stem cells based on colony morphology and detection of their sensitivity to 5-fluorouracil].
To investigate the sensitivity of gastric cancer stem cells (GCSCs) to 5-fluorouracil (5-FU), and to explore the cytological mechanism of drug-resistance of gastric cancer. Immunohistochemical staining was employed to examine expression of stem cell marker CD44 and drug-resistance protein thymidylate synthase (TS) in 71 cases with gastric cancer. Based on morphology of cell colonies derived from AGS gastric cell line, colonies consisting of GCSCs were isolated, and expression of CD44 and TS, as well as self-renewal capacity of GCSCs were detected. Sensitivity of GCSCs to 5-FU was examined through CCK-8 assay. The positive rates of CD44 and TS were 59.2% (42/71) and 56.3% (40/71) in gastric cancer, and expression of CD44 was associated with that of TS (χ(2)=12.76, P<0.01; Kappa=0.41). Serial sections indicated that CD44+ cancer cells simultaneously expressed TS. AGS developed morphologically diverse colonies, and the GCSCs colonies exhibited a tight and regular shape, which were called holoclone. Holoclones expressed CD44 and TS strongly, possessing capacity of robust self-renewal and forming a lot of second passage clones after incubation. Subclones expressed CD44 and TS weakly, forming less second passage clones. Paraclones almost did not express CD44 and TS, forming no second passage clone after incubation. Affected by 5-Fu, three holoclones showed less growth inhibition compared with another colony type and wild-type AGS cells. Furthermore, IC50 of 5-FU for three holoclones was (113.43±5.81), (272.68±25.75) and (118.14±17.75) μmol/L respectively, which were significantly higher than that of one subcolony type [(16.97±1.01) μmol/L] and AGS cells [(27.52±0.59) μmol/L] (all P<0.05). GCSCs possess lower sensitivity to 5-FU, and may play a critical role in drug-resistance of gastric cancer.


Application of DIAGNOdent as a guide for removing carious dentin with Er:YAG laser.
The purpose of this study was to investigate the DIAGNOdent values applicable as a guide for removal of outer layer of carious dentin with Er:YAG laser. Carious dentin of human extracted molars was removed by bur with Caries Detector (Group 1: red stained dentin was left, Group 2: light pink stained dentin was left) and by Er:YAG laser with DIAGNOdent value as a guide (30>Group 3>21, 20>Group 4>11, 10>Group 5). The cavity floor dentin after removing carious dentin was examined using microradiograms, EPMA and SEM. The cavity floor dentin of group 1,3 showed the decreases in the degree of X-ray absorption. In group 2,4 and 5, decrease of Ca, P were not observed. The decrease of Mg was observed on the more superficial part of the cavity floor for group 3 than for group 4. When carious dentin was removed using Er:YAG laser, the carious dentin outer layer was ideally removed with DIAGNOdent values: 11-20. DIAGNOdent values: 11-20, could indicate the completion of outer layer removal of carious dentin with Er:YAG laser, but there are some problems that must be addressed before the clinical application.


The Aging Epigenome.
During aging, the mechanisms that normally maintain health and stress resistance strikingly decline, resulting in decrepitude, frailty, and ultimately death. Exactly when and how this decline occurs is unknown. Changes in transcriptional networks and chromatin state lie at the heart of age-dependent decline. These epigenomic changes are not only observed during aging but also profoundly affect cellular function and stress resistance, thereby contributing to the progression of aging. We propose that the dysregulation of transcriptional and chromatin networks is a crucial component of aging. Understanding age-dependent epigenomic changes will yield key insights into how aging begins and progresses and should lead to the development of new therapeutics that delay or even reverse aging and age-related diseases.


Pregnancy outcomes after cerclage placement in nulliparous women with a short cervix on transvaginal ultrasonography.
Little is known about pregnancy outcomes associated with a short cervix and cerclage placement in nulliparous women. An electronic query of our ultrasound database was used to identify patients whose cervical length measured < 25 mm between 16-24 weeks of gestation. Any nulliparous women, with no prior pregnancy lasting beyond 13 weeks 6 d gestational age, were included in the analysis. The primary outcome was the interval of time from the diagnosis of a short cervix (<25 mm) to the time of delivery. Our query identified 70 patients for analysis. The interval of time from diagnosis of a short cervix to delivery was observed to be 85 d (12.1 weeks) in the cerclage group and 116 d (16.6 weeks) in the expectantly managed group (p = 0.02). In those women receiving a cerclage, there was a statistically significant risk of spontaneous preterm birth <32 weeks gestational age (R.R. 6.7 [95% CI 1.45-30.6]). The impact of a short cervix is largely unknown in patients with an uncomplicated obstetrical history. Our investigation would suggest that in this subset of patients, cerclage would not be beneficial in preventing preterm delivery.


Health and school outcomes during children's transition into adolescence.
Normative biopsychosocial stressors that occur during entry into adolescence can affect school performance.As a set of resources for adapting to life's challenges, good health may buffer a child from these potentially harmful stressors. This study examined the associations between health (measured as well-being, functioning, symptoms, and chronic conditions) and school outcomes among children aged 9-13 years in 4th-8th grades. We conducted a prospective cohort study of 1,479 children from 34 schools followed from 2006 to 2008. Survey data were obtained from children and their parents, and school records were abstracted. Measures of child self-reported health were dichotomized to indicate presence of a health asset. Outcomes included attendance, grade point average, state achievement test scores, and child-reported school engagement and teacher connectedness. Both the transition into middle school and puberty had independent negative influences on school outcomes. Chronic health conditions that affected children's functional status were associated with poorer academic achievement. The number of health assets that a child possessed was positively associated with school outcomes. Low levels of negative stress experiences and high physical comfort had positive effects on teacher connectedness, school engagement, and academic achievement, whereas bullying and bully victimization negatively affected these outcomes. Children with high life satisfaction were more connected with teachers, more engaged in schoolwork, and earned higher grades than those who were less satisfied. As children enter adolescence, good health may buffer them from the potentially negative effects of school and pubertal transitions on academic success.


Extending decision support: preparation and implementation.
The shift towards patient-centered care requires innovative, flexible decision-making models. Current decision aids provide information and help patients clarify values. By focusing almost exclusively on these two components, the aids miss some necessary elements that can improve decision quality. We discuss two such elements in this paper. First is avoiding the tendency to move into providing information about options and outcomes before adequate preparation. The second is the tendency to neglect to provide adequate implementation support.


Serotonin immunoreactive nerve fibers and terminals in the rat pituitary--light- and electron-microscopic studies.
Serotonin-immunoreactive nerve fibers were demonstrated to form a plexus in the intermediate lobe of rat pituitary. Such fibers were sporadic in the posterior lobe where they occurred exclusively in the zone adjacent to the intermediate lobe, and in the anterior lobe. With the aid of electron-microscopic immunocytochemistry, labeled fibers were shown to constitute the majority of neuronal processes found in the intercellular region of the intermediate lobe. They were frequently seen to establish synaptoid contacts with endocrine cells.


Electrophysiological patterning of the heart.
In the adult heart, electrophysiological heterogeneity is present to guide activation and contraction. A change in electrophysiological heterogeneity, for example, during disease, can contribute to arrhythmogenesis. During development, spatial and temporal patterns of transcriptional activity regulate the localized expression of ion channels that cause electrophysiological heterogeneity throughout the heart. If we gain insight into the regulating processes that generate the electrophysiological characteristics and factors involved during development, we can use this knowledge in the search for new therapeutic targets. In this review, we discuss which factors guide the electrical patterning of atrioventricular conduction system and ventricles and how this patterning relates to arrhythmogenic disease in patients.


Accessory cells reduce lipoprotein suppression of lymphocyte activation.
Plasma lipoproteins of d less than or equal to 1.063 g/ml suppress lymphocyte activation triggered in vitro by polyclonal T cell mitogens. The extent of suppression decreases as the number of accessory cells per culture increases. Accessory cells isolated by glass adherence and by counter-flow centrifugation reduce lipoprotein suppression to the same extent. Modulation of lipoprotein suppression by accessory cells is independent of the amount and type of polyclonal activator. Reduction of lipoprotein suppression requires viable accessory cells and that they be present with lymphocytes, mitogen and lipoproteins during the initial 24-h culture period. It is within this same time period that lipoproteins exert their suppressive effect. Accessory cells isolated from a patient with the homozygous form (receptor-defective) of familial hypercholesterolemia also reduce the extent of lipoprotein suppression, suggesting that modulation is not mediated by the classic low density lipoprotein receptor. There appear to be at least two mechanisms by which accessory cells may alter lipoprotein suppression of T lymphocyte activation: by secretion of a soluble factor, probably not interleukin 1, that decreases the extent of suppression and by direct modification of the population of suppressive lipoproteins. Neither mechanism accounts for the lipoprotein-enhanced activation that occurs when cultures contain approximately equal numbers of T lymphocytes and accessory cells.


High-performance liquid chromatographic-fluorescence determination of human faecal bile acids.
A high-performance liquid chromatographic method with fluorescence detection has been developed for the determination of human faecal bile acids, especially free faecal bile acids. Faecal bile acids were extracted using an Amberlite XAD-2 column and then fractionated into four groups (free, glycine-conjugated, taurine-conjugated and sulphated bile acids) on a piperidinohydroxypropyl Sephadex LH-20 column. The free bile acid fraction and free bile acids obtained after enzymatic hydrolysis and/or solvolysis of the three other fractions were derivatized with 1-bromoacetylpyrene and dicyclohexyl-18-crown-6-ether. The derivatized bile acids were separated stepwise on a Shim-pack CLC-ODS column using acetonitrilemethanol-water (100:50:30) (A), (100:50:20) (B), and (100:50:0) (C) as mobile phases with changing automatically from A to C using a solvent changer. Calibration curves of bile acid standards were linear in the range between 20 and 400 pmole, when monitored at 370 nm (excitation) and 440 nm (emission). Percent recoveries of bile acids from human faecal samples were between 80 to 95%. The method is applicable to clinical use and is sensitive, reliable, and useful for the detailed determination of human faecal bile acids, especially of free faecal bile acids.


Recent advances on postharvest technologies of bell pepper: A review.
The bell pepper (Capsicum annuum L.) is a commercially important horticultural crop grown in tropical and sub-tropical areas across the world. Despite this importance, it is a perishable vegetable with a limited shelf life and high disease susceptibility. Bell pepper output has expanded significantly in recent years. However, this crop is still experiencing close to 40% postharvest losses annually. Chemical fumigation for postharvest disease control of bell pepper has been shown to be efficient against fungal infections, but environmental impact and consumption hazards limit its full use. Recently, non-chemical techniques including biological and botanical methods, non-destructive technologies and Artificial intelligence have been demonstrated to be effective as postharvest management of bell pepper. The paper provides exciting information on recent and emerging techniques for curtailing these losses in bell pepper, alongside their mechanism and existing benefits. The current limitations of these techniques as well as recommendations for potential applications are also addressed.


Educational crisis of Rohingya refugee children in Bangladesh: Access, obstacles, and prospects to formal and non-formal education.
The article discusses the contemporary educational crisis of Rohingya children in Bangladesh. It aims to identify the challenges of formal and non-formal education faced by Rohingya children and their prospects. In this scholarship, the author attempts to answer the questions-what are the current formal and non-formal educational services in the Rohingya refugee camps and how and to what extent do the existing educational services intensify the other crisis in their lives, and what are the prospects for them going forwards. ology: This study is primarily based on secondary sources of data. It focuses on the available educational services and key obstacles that affect Rohingya children's formal and non-formal educational opportunities in Bangladesh and their prospects in Myanmar. The study found the absence of formal and non-formal education for Rohingya children in refugee camps has a significant impact on their ability to become an active member of society. Although refugee children and their parents express a willingness to formal education under the Myanmar curriculum, limited educational services and various structural and legal barriers hinder their progress. Finally, the study explores the prospects of formal and non-formal education for Rohingya children in Bangladesh and concludes with recommendations to improve their educational opportunities. The study results can differ in other contexts and countries hosting refugees. Findings of the study may be helpful for policymakers and practitioners.


A comparison of the efficacy and tolerability of dorzolamide and acetazolamide as adjunctive therapy to timolol. Oral to Topical CAI Study Group.
To compare the efficacy and tolerability of dorzolamide to acetazolamide. Following a timolol and acetazolamide run-in, 105 patients with elevated intraocular pressure (IOP) were randomized to dorzolamide or acetazolamide, in addition to timolol, for 12 weeks. More patients receiving acetazolamide discontinued due to clinical adverse experiences than patients receiving dorzolamide; 13 (25%) vs. 1 (2%); p<0.001. The prevalence of systemic adverse experiences for the dorzolamide group dropped by 50% by Week 12, but remained unchanged for the acetazolamide group, as compared to baseline; p<0.001. Ocular burning/stinging was more common in the dorzolamide group (21% vs. 0%; p<0.001). The mean trough IOP at Day 1 and Week 12 were 20.5 mmHg and 21.8 mmHg for the dorzolamide group, and 20.4 mmHg and 20.5 mmHg for the acetazolamide group. The mean peak IOP at Dayl and Week 12 were 18.9 mmHg and 20.0 mmHg for the dorzolamide group, and 18.7 mmHg and 18.6 mmHg for the acetazolamide group. Mean IOP was slightly lower (by approximately 1 mmHg) with acetazolamide, while dorzolamide demonstrated much better tolerability.


Exploring predictors of first appointment attendance at a pain management service.
Individual characteristics such as gender, employment and age have been shown to predict attendance at pain management services (PMS). The characteristics of those who drop out of pain management programmes have also been explored, but as yet no studies have analysed the characteristics of those who do not attend the service following referral. To explore the characteristics and predictors of those who attend and those who do not attend their first appointment with a PMS. Predictive factors in the two groups - attenders (n = 425) and non-attenders (n = 69) - were explored using logistic regression. Non-attendance was significantly predicted by the patient being a smoker and the appointment being in the morning. Non-attenders also scored higher on the Modified Somatic Perception Questionnaire, indicating higher levels of somatic pain. Predictors of non-attendance were different from those for individuals who drop out of pain services. Implications and recommendations are made for PMS.


Inhibitory substances produced by Lactobacilli isolated from sourdoughs--a review.
Several sourdough lactic acid bacteria (LAB) produce inhibitory substances other than organic acids. Bacteriocins (bavaricin A, and plantaricin ST31), a bacteriocin-like inhibitory substance (BLIS C57), and a new antibiotic (reutericyclin) have been discovered. Maximum antimicrobial production was found in the pH range 4.0-6.0. Temperature optima vary strongly. The substances are resistant to heat and acidity, and inactivated by proteolytic enzymes, except for reutericyclin. Bavaricin A and plantaricin ST31 have been purified to homogeneity. Bavaricin A is classified as a class IIa bacteriocin. Reutericyclin is a new tetramic acid. The mode of action of bavaricin A, BLIS C57, and reutericyclin is bactericidal. Some of these substances are active towards some Bacilli, Staphylococci and Listeria strains. Up to now, only the application potential of purified bavaricin A has been examined. More research should be done to study the production, the activity, and the stability of these inhibitory substances in food systems as these often differ from the broths mostly used in this kind of studies. Furthermore, an extensive screening of the sourdough microflora must be performed, in particular towards Bacilli and fungi. This could lead to the discovery of additional inhibitory substances, although it seems that the frequency of isolating bacteriocin-producing sourdough LAB is low. However, potent antimicrobials towards Bacilli as well as antifungal substances will have to be found using rational screening strategies and novel purification and analytical techniques.


Rendezvous procedure to establish ureteral continuity from a delayed ureteral leak following pelvic surgery. A case report.
Iatrogenic damage to the ureter as a result of an abdominal or pelvic surgical procedure is unusual. However, it does occur and the surgeon must be prepared to deal knowledgeably with the injury. Leaks that are recognized within the operating theater are managed, for the most part, at the same surgical procedure oftentimes with urologic consultation. A delayed leak presents unique problems in that direct access to the site of the leak is not possible except by a reoperative procedure. Delayed leaks present a clinical situation involving the urologist, interventional radiologist, as well as the surgeon. A patient who developed delayed urine leakage following a partial sacrectomy to remove recurrent mucinous appendiceal malignancy was studied. The leakage was controlled using a nephroureteral stent. Placement of the nephroureteral stent was made possible by the rendezvous procedure. The sequence of procedures to reestablish ureteral continuity following a delayed leak are important in the successful placement of a nephroureteral stent. After establishing the site of the injury a percutaneous nephrostomy must be placed. Then, through the nephrostomy, a guidewire is placed in the ureter to be recovered and advanced into the bladder using a ureteroscope and grasping forceps. A nephroureteral stent is placed over the guidewire to bridge the gap and stent the ureteral defect. The rendezvous procedure can be successful a large percentage of the time with a delayed ureteral leakage. Successful recovery of a guidewire in the ureter by ureteroscopy requires a combined interventional radiology and urologic procedure.


SERCA2 regulates proinsulin processing and processing enzyme maturation in pancreatic beta cells.
Increased circulating levels of incompletely processed insulin (i.e. proinsulin) are observed clinically in type 1 and type 2 diabetes. Previous studies have suggested that Ca2+ signalling within beta cells regulates insulin processing and secretion; however, the mechanisms that link impaired Ca2+ signalling with defective insulin maturation remain incompletely understood. We generated mice with beta cell-specific sarcoendoplasmic reticulum Ca2+ ATPase-2 (SERCA2) deletion (βS2KO mice) and used an INS-1 cell line model of SERCA2 deficiency. Whole-body metabolic phenotyping, Ca2+ imaging, RNA-seq and protein processing assays were used to determine how loss of SERCA2 impacts beta cell function. To test key findings in human model systems, cadaveric islets were treated with diabetogenic stressors and prohormone convertase expression patterns were characterised. βS2KO mice exhibited age-dependent glucose intolerance and increased plasma and pancreatic levels of proinsulin, while endoplasmic reticulum (ER) Ca2+ levels and glucose-stimulated Ca2+ synchronicity were reduced in βS2KO islets. Islets isolated from βS2KO mice and SERCA2-deficient INS-1 cells showed decreased expression of the active forms of the proinsulin processing enzymes PC1/3 and PC2. Additionally, immunofluorescence staining revealed mis-location and abnormal accumulation of proinsulin and proPC2 in the intermediate region between the ER and the Golgi (i.e. the ERGIC) and in the cis-Golgi in beta cells of βS2KO mice. Treatment of islets from human donors without diabetes with high glucose and palmitate concentrations led to reduced expression of the active forms of the proinsulin processing enzymes, thus phenocopying the findings observed in βS2KO islets and SERCA2-deficient INS-1 cells. Similar findings were observed in wild-type mouse islets treated with brefeldin A, a compound that perturbs ER-to-Golgi trafficking. Taken together, these data highlight an important link between ER Ca2+ homeostasis and proinsulin processing in beta cells. Our findings suggest a model whereby chronic ER Ca2+ depletion due to SERCA2 deficiency impairs the spatial regulation of prohormone trafficking, processing and maturation within the secretory pathway. RNA-seq data have been deposited in the Gene Expression Omnibus (GEO; accession no.: GSE207498).


Identification of a radical SAM enzyme involved in the synthesis of archaeosine.
Archaeosine (G+), 7-formamidino-7-deazaguanosine, is an archaea-specific modified nucleoside found at the 15th position of tRNAs. In Euryarchaeota, 7-cyano-7-deazaguanine (preQ0)-containing tRNA (q0N-tRNA), synthesized by archaeal tRNA-guanine transglycosylase (ArcTGT), has been believed to be converted to G+-containing tRNA (G+-tRNA) by the paralog of ArcTGT, ArcS. However, we found that several euryarchaeal ArcSs have lysine transfer activity to q0N-tRNA to form q0kN-tRNA, which has a preQ0 lysine adduct as a base. Through comparative genomics and biochemical experiments, we found that ArcS forms a robust complex with a radical S-adenosylmethionine (SAM) enzyme named RaSEA. The ArcS-RaSEA complex anaerobically converted q0N-tRNA to G+-tRNA in the presence of SAM and lysine via q0kN-tRNA. We propose that ArcS and RaSEA should be considered an archaeosine synthase α-subunit (lysine transferase) and β-subunit (q0kN-tRNA lyase), respectively.


'Hidden lamination' in the dorsal lateral geniculate nucleus: the functional organization of this thalamic region in the rat.
The cyto-and myeloarchitecture of the rat's dorsal lateral geniculate nucleus (dLGN) display none of the laminar features characteristic of this thalamic region in carnivores and primates. Despite this, the rodent's nucleus contains a segregation of functionally and ocularly distinct afferents--organizational properties manifested in the prominent lamination of these other mammalian forms. The rat's dLGN can be divided into two main regions: an inner core and an outer shell. The inner core contains two ocular laminae receiving direct retinotopic projections from the contralateral nasal and ipsilateral temporal retinae, mapping the contralateral visual hemifield. The outer shell receives a retinotopic projection from the complete contralateral retina only, the representation of the ipsilateral hemifield being extremely compressed at the medial edge of this lamina. The retinotopic maps in these three ocular laminae (contra, ipsi, contra) are in conjugate register, so that lines of projection course rostro-ventro-medially from the optic tract at the thalamic surface through these laminae. Three morphologically distinct retinal ganglion cell types project to the dLGN, and the axons of these ganglion cells are partially segregated within the optic tract in anticipation of their segregation within the nucleus, where they terminate at distinct locations along the lines of projection. Type I and III cells terminate in the inner core of the nucleus, while type II and III cells terminate in the outer shell. The outer shell also receives a direct projection from the superior colliculus. These characteristics of the afferent termination within the rat's dLGN support the view of a general mammalian plan for the organization of this thalamic region, and provide a basis for further experimentation to test speculations about potentially homologous subdivisions of this nucleus. Conclusions regarding functionally analogous pathways are proposed with less confidence, due to the paucity of definitive evidence for physiologically distinct cell classes. The type I cells in the rat's retina are the likely homologues of the cat's alpha-cell. Geniculocortical relay cells driven by them have properties similar to the cat's Y-cell. The inner core of the nucleus then may transmit information of a Y-like nature onto striate cortex. The outer shell of the rat's nucleus, a portion of which receives collicular as well as retinal innervation, may convey W-like information onto striate cortex. The rat's retinogeniculate projection appears to be lacking a beta-cell-like pathway that may subserve X-cell function altogether.


Atypical chondrodysplasia: a further variant of multiple enchondromatosis with vertebral involvement?
We report the case of a child with asymmetrical enchondromatosis and vertebral involvement, who presented in utero, and postulate its relationship to similar rarely reported cases.


DPP-4 inhibitor sitagliptin prevents inflammation and oxidative stress of heart and kidney in two kidney and one clip (2K1C) rats.
Hyperglycemia and insulin resistance often develop cardiovascular and nephrological dysfunction in diabetic patients. Sitagliptin is used to treat diabetes and showed potential benefit in lowering increased blood glucose level in diabetes. This investigation reports the effect of sitagliptin treatment on oxidative stress in kidney and heart of 2K1C rats. Male Long Evans rats underwent unilateral surgical stenosis of the renal artery [2-kidney-1-clip (2K1C) method]. These animals entered a 4-weeks dosing period with sitagliptin. Blood and urine sampling and organ harvesting were finally performed. Blood plasma, heart, kidney tissues and urine were tested for the assessment of inflammation and oxidative stress in kidney and heart of 2K1C rats after 4 weeks of surgery. 2K1C rats showed cardiac hypertrophy, increased left ventricular wet weight compared to sham which was not significantly altered by sitagliptin treatment. Uric acid and creatinin concentrations were also increased in 2K1C rats. Sitagliptin significantly prevented the elevation of uric acid and creatinin concentration in plasma and urine in this rat model. Oxidative stress markers in plasma such as malondialdehyde (MDA), nitric oxide (NO), and advanced protein oxidation product (APOP) concentrations were increased in the 2K1C rats as compared to sham-operated animals. Increased concentrations of these oxidative stress markers were also normalized by sitagliptin treatment. 2K1C rats also showed increased level of uric acid and creatinine both in plasma and urine; which are also reduced to normal level in sitagliptin treated rats. Moreover, 2K1C surgery initiated inflammatory cell infiltration, increased MPO activity and fibrosis in both heart and kidneys which were further ameliorated by sitagliptin treatment. Our study suggests that sitagliptin treatment in 2K1C rats prevented inflammation and fibrosis of heart and kidney by ameliorating elevated oxidative stress in heart and kidney tissues.


Mutations in EDM2 selectively affect silencing states of transposons and induce plant developmental plasticity.
We previously reported on the A. thaliana gene EDM2, which is required for several developmental processes and race-specific immunity. Although EDM2 encodes a nuclear protein with features commonly observed in epigenetic factors, its role in chromatin silencing remains unknown. Here we demonstrate that silencing states of several transposons in edm2 mutants are altered. Levels of their transcripts anti-correlate with those of the repressive epigenetic marks H3K27me1, H3K9me2, and DNA-methylation at CHG sites. In addition, double mutant analysis revealed epistasis between EDM2 and the major histone H3K9-methyltransferase gene KRYPTONITE/SUVH4 in the control of H3K9me2 and CHG methylation. Moreover, we found that the expressivity of several mutant edm2 phenotypes exhibits stochastic variation reminiscent of mutants of known epigenetic modifiers. We propose that EDM2 affects the expression of transposons and developmentally important genes by modulating levels of repressive chromatin marks in a locus dependent manner.


Relation of Atrial Fibrillation to Angiographic Characteristics and Coronary Artery Disease Severity in Patients Undergoing Percutaneous Coronary Intervention.
Patients with atrial fibrillation (AF) have an increased risk of coronary artery disease (CAD) compared to patients without. Angiographic characteristics, clinical presentation and severity of CAD according to the presence of AF have been poorly described. We performed a retrospective study of 303 consecutive patients (mean age 69.6 ± 10.8 years; 23.1% women) with and without AF undergoing percutaneous coronary intervention. Data on (1) type of CAD presentation, (2) coronary involvement, and (3) number of diseased coronary vessels (≥70%/luminal narrowing) were collected. CHA2DS2-VASc and 2 major adverse cardiac event (MACE) scores were calculated. Presentation of CAD was ST-segment elevation myocardial infarction (STEMI) in 37.6% of patients, non-STEMI- unstable angina in 55.1%, and other in 7.3%. Non-STEMI-unstable angina was more common in AF (69.6% vs 46.6%, p <0.001), while STEMI was more in the non-AF (22.3% vs 46.6%, p <0.001) group. Left anterior descending artery (LAD) was the most common diseased vessel (70.6%) followed by right coronary artery (RCA, 56.4%) and obtuse marginal artery (36.6%). Patients with AF had a significantly lower RCA involvement (47.3% vs 61.8%, p = 0.016), with a trend for LAD (64.3% vs 74.3%, p = 0.069). At multivariable logistic regression analysis, AF remained inversely associated with RCA involvement (odds ratio [OR] 0.541, 95% confidence interval [CI] 0.335 to 0.874, p = 0.012) and with ≥3 vessel CAD (OR 0.470, 95% CI 0.272 to 0.810, p = 0.007). The 2MACE score was associated with diseased LAD (OR 1.301, 95% CI 1.103 to 1.535, p = 0.002) and with ≥3 vessel CAD (OR 1.330, 95% CI 1.330 to 1.140, p <0.001). In conclusion, patients with AF show lower RCA involvement and generally less severe CAD compared to non-AF ones. The 2MACE score was higher in LAD obstruction and identified patients with severe CAD.


Risk factors associated with inhibitor development in Chinese patients with haemophilia B.
Inhibitor development is a severe complication of factor IX substitution treatment for haemophilia B (HB). Current research examined the association between inhibitor development and F9 genotypes and polymorphisms in immune response genes in Chinese HB patients. 11 inhibitor-positive HB patients and 41 inhibitor-negative HB patients were enrolled. Direct sequencing, copy number variation (CNV) detection and fragment length analysis were applied to identify F9 genotypes and 15 polymorphisms in immune response genes. 7 patients developed high titer inhibitors, with 5 of them having histories of consecutive exposure to FIX products on demand for at least 5 days. Allergic reactions/anaphylaxis to prothrombin complex concentrates (PCC) occurred in 3 patients before inhibitors were detected. Five nonsense mutations (E54X, R75X, Q185X, R298X and R379X), two large deletions (E1~6del and E1~8del) and one missense mutation (S411G) were identified in patients with inhibitors. Missense mutations had a low odds ratio for FIX inhibitors development (IOR) of 0.078 (P = 0.02), while nonsense mutation presented a high IOR of 8.500 (P = 0.0044). The frequency of allele T in CD44(95102) (A/T) was significantly higher in inhibitor-negative patients, with OR of 0.324 (P = 0.04). Nonsense mutations conferred a higher risk for while allele T in CD44(95102) (A/T) might play a protective role against inhibitor development in Chinese HB patients.


Reverse genetics for proteomics: from proteomic discovery to scientific content.
Proteomic strategies generally result in rather descriptive outcomes. Although proteomic patterns may lead to understanding of cellular function or failure, they do not provide insights into cellular mechanisms of normal physiology or molecular mechanisms of disease. The integration of single events or patterns into complex biological processes and signaling networks must be functionally validated by studying these processes in a dynamic physiological context. Effective methodologies, applied at the level of intact cells and model organisms that monitor their function, topology and interaction of proteins are necessary and essential. Reverse genetic strategies can greatly advance the understanding of patterns identified through proteomic analysis. RNAi as an accessible method for routine functional analysis of cells and whole model organisms represents a quantum leap in revolutionizing reverse genetics. This paper aims at describing an integrated workflow linking proteome-based discovery to molecular analysis of single genes and proteins by RNAi, potentially contributing to the advanced understanding of molecular mechanisms in neurodegenerative disease, including Parkinson's disease.


CAR-T Engager proteins optimize anti-CD19 CAR-T cell therapies for lymphoma.
B cell lymphoma therapy has been transformed by CD19-targeting cellular therapeutics that induce high clinical response rates and impressive remissions in relapsed and refractory patients. However, approximately half of all patients who respond to CD19-directed cell therapy relapse, the majority within 6 months. One characteristic of relapse is loss or reduction of CD19 expression on malignant B cells. We designed a unique therapeutic to prevent and reverse relapses due to lost or reduced CD19 expression. This novel biologic, a CAR T Engager, binds CD20 and displays the CD19 extracellular domain. This approach increases the apparent CD19 antigen density on CD19-positive/CD20-positive lymphoma cells, and prevents antigen-loss induced relapse, as CD19 bound to CD20 remains present on the cell surface. We demonstrate that this novel therapeutic prevents and reverses lymphoma relapse in vitro and prevents CD19-negative lymphoma growth and relapse in vivo.


Stress and the aging immune system.
Immune functioning decreases with normal aging and with stress. Social and psychological stressors are a part of daily life and the source of life changing events. Across the lifespan, individuals encounter numerous stressors with effects that accrue at sundry rates due to differential stress exposure, differential stress buffering, differential stress reactivity, differential stress duration (recovery), and differential restorative processes. Research on stress in older adults provides evidence that these processes contribute to effects that mimic, exacerbate, and possibly accelerate the effects of aging on immunity.


Hydrothermal Synthesis of β-Nb2ZnO6 Nanoparticles for Photocatalytic Degradation of Methyl Orange and Cytotoxicity Study.
β-Nb2ZnO6 nanoparticles were synthesized by a hydrothermal process and calcined at two temperatures, 500 °C and 700 °C, and assigned as A and B, respectively. X-ray diffraction, together with transmission electron microscopy, revealed that the β-Nb2ZnO6 nanoparticles calcined at 700 °C (B) were more crystalline than the β-Nb2ZnO6 calcined at 500 °C (A) with both types of nanoparticles having an average size of approximately 100 nm. The physiochemical, photocatalytic, and cytotoxic activities of both types of β-Nb2ZnO6 nanoparticles (A and B) were examined. Interestingly, the photodegradation of methyl orange, used as a standard for environmental pollutants, was faster in the presence of the β-Nb2ZnO6 nanoparticles calcined at 500 °C (A) than in the presence of those calcined at 700 °C (B). Moreover, the cytotoxicity was evaluated against different types of cancer cells and the results indicated that both types of β-Nb2ZnO6 nanoparticles (A and B) exhibited high cytotoxicity against MCF-7 and HCT116 cells but low cytotoxicity against HeLa cells after 24 and 48 h of treatment. Overall, both products expressed similar EC50 values on tested cell lines and high cytotoxicity after 72 h of treatment. As a photocatalyst, β-Nb2ZnO6 nanoparticles (A) could be utilized in different applications including the purification of the environment and water from specific pollutants. Further biological studies are required to determine the other potential impacts of utilizing β-Nb2ZnO6 nanoparticles in the biomedical application field.


Interrater and intrarater reliability of ventilatory thresholds determined in individuals with spinal cord injury.
Cross-sectional. Individualized training regimes are often based on ventilatory thresholds (VTs). The objectives were to study: (1) whether VTs during arm ergometry could be determined in individuals with spinal cord injury (SCI), (2) the intrarater and interrater reliability of VT determination. University research laboratory. Thirty graded arm crank ergometry exercise tests with 1-min increments of recreationally active individuals (tetraplegia (N = 11), paraplegia (N = 19)) were assessed. Two sports physicians assessed all tests blinded, randomly, in two sessions, for VT1 and VT2, resulting in 240 possible VTs. Power output (PO), heart rate (HR), and oxygen uptake (VO2) at each VT were compared between sessions or raters using paired samples t-tests, Wilcoxon signed-rank tests, intraclass correlation coefficients (ICC, relative agreement), and Bland-Altman plots (random error, absolute agreement). Of the 240 VTs, 217 (90%) could be determined. Of the 23 undetermined VTs, 2 (9%) were VT1 and 21 (91%) were VT2; 7 (30%) among individuals with paraplegia, and 16 (70%) among individuals with tetraplegia. For the successfully determined VTs, there were no systematic differences between sessions or raters. Intrarater and interrater ICCs for PO, HR, and VO2 at each VT were high to very high (0.82-1.00). Random error was small to large within raters, and large between raters. For VTs that could be determined, relative agreement was high to very high, absolute agreement varied. For some individuals, often with tetraplegia, VT determination was not possible, thus other methods should be considered to prescribe exercise intensity.


Gamma hydroxybutirate use for sexual assault.
The use of gamma hydroxybutyrate (GHB) as a recreational drug has quickly spread among European young people during the past decade. Although it has been claimed that GHB can be potentially used to facilitate sexual assault, no case reports have been previously described. A case is described in which GHB was used with that criminal purpose and a review of previous literature is undertaken.


Intraarterial Chemotherapy for Liver Metastases.
Colorectal cancer (CRC) is one of the leading cancers globally in terms of both incidence and cancer-related mortality. Liver metastatic disease is the main prognostic driver for patients with CRC. The management options for liver metastatic CRC continue to evolve, particularly with the incorporation of locoregional therapies into the treatment paradigm. Hepatic arterial infusion (HAI) chemotherapy is one such liver directed approach used with the goal of converting patients to liver resection, reducing the risk of recurrence, treating recurrent disease, and most importantly improving overall survival. This article summarizes the role of HAI chemotherapy in the treatment of liver metastatic CRC.


Analysis of the phase shifting effects of gastrin releasing peptide when microinjected into the suprachiasmatic region.
The role of gastrin releasing peptide (GRP) in phase shifting circadian rhythms was investigated. Microinjection of GRP into the suprachiasmatic region (SCN) region produced only small changes in the phase of free-running circadian activity rhythms in hamsters housed in constant darkness. However, co-administration of GRP with vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI) produced significantly larger phase delays than GRP alone. These data support the hypothesis that GRP interacts with VIP and PHI within the SCN to induce phase shifts of circadian rhythms.


Synthesis of well-defined poly(N-isopropylacrylamide)-b-poly(L-glutamic acid) by a versatile approach and micellization.
A novel Fmoc-protected chain transfer agent (CTA) was synthesized and applied in the reversible addition-fragmentation chain transfer (RAFT) polymerization of N-isopropylacrylamide (NIPAAm), resulting in well-defined Fmoc-protected PNIPAAm and the amino-end capped PNIPAAm by the subsequent hydrolysis. Poly(N-isopropylacrylamide)-b-poly(l-glutamic acid) (PNIPAAm-b-PLGA) with controlled molecular weight and narrow molecular weight distribution was synthesized successfully via ring-opening polymerization (ROP) of alpha-amino acid N-carboxyanhydrides (NCAs) by using PNIPAAm-NH2 as the macroinitiator. Both pH- and thermo-responsive micellization behaviors of the block copolymer PNIPAAm55-b-PLGA35 in dilute aqueous solution were investigated by means of the pyrene fluorescence, circular dichroism, 1H NMR, transmission electron microscopy and dynamic and static light scattering. Spherical PLGA-core and rod-like PNIPAAm-core micelles are formed in response to pH and temperature. The reversible transition between the PLGA-core and PNIPAAm-core micelles was observed. This work provides a versatile approach for synthesizing well-defined stimuli-responsive polypeptide-based double hydrophilic diblock copolymers (DHBCs), and is of great potential for generating useful stimuli-responsive materials in biomedical applications.


[The effect of formaldehyde modification on the physicochemical properties and specific activity of an allergen from Dermatophagoides farinae mites].
D. farinae allergen has been modified with formaldehyde and its properties have been studied. This study has demonstrated that the formolation of D. farinae ticks allergen causes changes in isoelectric points of proteins and a shift of protein fraction to acidic pH values: 3.0-4.85; an insignificant decrease in the volume of gel filtration output on a column packed with Sephacryl S-300; a decrease in the esterase activity from 10.5 to 1.8 microM tosylarginine methyl ester/min. per mg of protein. As revealed with the use of microdot enzyme immunoassay, the modified allergen loses its capacity to bind with human specific IgE antibodies in vitro.


Chemotaxis in Dictyostelium discoideum: effect of concanavalin A on chemoattractant mediated cyclic gmp accumulation anlight scattering decrease.
In cells of the cellular slime mold Dictyostelium discoideum concanavalin A (Con A), at a concentration of 100 microgram per ml, inhibits folic acid and cyclic AMP induced decrease in light scattering. Con A has no effect on folic acid mediated cyclic GMP accumulation and increases cyclic AMP mediated cyclic GMP accumulation two-fold. At a lower Con A concentration, 10 microgram per ml, changes in light scattering induced by folic acid are normal and cyclic AMP induces a monophasic instead of a biphasic response. The stimulatory effect of Con A on cyclic AMP mediated cyclic GMP accumulation is still observable at 10 microgram Con A per ml. When cells are repeatedly stimulated with cyclic AMP, a decrease in light scattering without being accompanied by changes in cyclic GMP concentration is observed. Based on these results a model for chemotaxis is proposed.


Secondary Education and Health Outcomes in Young People from the Cape Area Panel Study (CAPS).
Education is one of the strongest social determinants of health, yet previous literature has focused on primary education. We examined whether there are additional benefits to completing upper secondary compared to lower secondary education in a middle-income country. We performed a longitudinal analysis of the Cape Area Panel Study, a survey of adolescents living in South Africa. We undertook causal modeling using structural marginal models to examine the association between level of education and various health outcomes, using inverse probability weighting to control for sex, age, ethnicity, home language, income, whether employed in past year, region of birth, maternal educational status, marital status, whether currently pregnant and cognitive ability. Educational attainment was defined as primary (grades 1-7), lower secondary (grades 8-9) or upper secondary (grades 10-12). Of 3,432 participants, 165 (4.8%) had completed primary education, 646 (18.8%) lower secondary and 2,621 (76.3%) upper secondary. Compared to those completing lower secondary, males completing upper secondary education were less likely to have a health problem (OR 0.49; 95%CI 0.27-0.88; p = 0.02); describe their health as poor (0.52; 0.29-0.95; p = 0.03) or report that health interferes with daily life (0.54; 0.29-0.99; p = 0.047). Females were less likely to have been pregnant (0.45; 0.33-0.61; p<0.001) or pregnant under 18 (0.32; 0.22-0.46; p<0.001); and having had sex under 16 was also less likely (males 0.63; 0.44-0.91; p = 0.01; females 0.39; 0.26-0.58; p<0.001). Cigarette smoking was less likely (males 0.52; 0.38-0.70; p = <0.001; females 0.56; 0.41-0.76; p<0.001), as was taking illicit drugs in males (0.6; 0.38-0.96; p = 0.03). No associations were found between education and alcohol use, psychological distress, obesity, increased waist circumference or hypertension. Completing upper secondary education was associated with improved health outcomes compared with lower secondary education. Expanding upper secondary education offers middle-income countries an effective way of improving adolescent health.


Superoxidase dismutase (SOD) topical use in oncologic patients: treatment of acute cutaneous toxicity secondary to radiotherapy.
The objective of this study is to evaluate the efficiency of SOD applied topically in oncologic patients affected by acute radiodermatitis. This study includes 57 patients who showed a dermatitis grade 2 or superior; they were administered SOD ointment b.i.d. (40 mg, weekly) and follow-up continued for 12 weeks. At the end of radiotherapy, 77.1% of the patients ameliorated completely or partially, and at the end of the 12-week period 100% of patients were free of toxicity. No acute toxicity relapses were reported. Response time reduced during radiotherapy, as well as the treatment time at the end of it. The employment of SOD topically is efficient in the treatment of radiodermatitis, which is an acute side effect of radiotherapy.


Comment on "Estimate of the vibrational frequencies of spherical virus particles".
This Comment corrects some errors which appeared in the calculation of an elastic sphere eigenenergies. As a result, the symmetry of the mode having the lowest frequency is changed. Also a direction for calculating the damping of these modes for embedded elastic spheres is given.


Comparison of amyloid deposition in human kidney biopsies as predictor of poor patient outcome.
Amyloidosis leads to deposition of abnormal protein with beta-pleated sheet structure in specific compartments of the affected organs. The histological localization of these amyloid deposits determines the overall survival of the patient. In this study we have assessed the histological localization and severity of amyloid deposition in 35 patients with biopsy-proven renal amyloidosis and have compared those to clinical parameters, histo-pathological injury criteria and respective patient outcome. Comparisons were statistically analyzed using thus comparison between the different study groups, which was done using Student t-test and analysis of variance. We find that the glomerulus is by far the most commonly and most severely affected renal compartment and patients with severe glomerular amyloidosis advance faster towards end stage renal disease (ESRD) and death, compared to those patients without glomerular amyloid deposits. Patients with severe glomerular amyloidosis showed higher serum creatinine and urine protein levels, while patients with severe vascular amyloidosis showed higher levels of interstitial inflammatory infiltrate. In kidneys affected by amyloidosis, the amyloid proteins are predominantly deposited along vessels, especially the small vessels including glomerular capillary loops. The severity of glomerular amyloid deposition enhances the risk of developing ESRD and increases the risk for premature death.


A wave of WNT signaling balanced by secreted inhibitors controls primitive streak formation in micropattern colonies of human embryonic stem cells.
Long-range signaling by morphogens and their inhibitors define embryonic patterning yet quantitative data and models are rare, especially in humans. Here, we use a human embryonic stem cell micropattern system to model formation of the primitive streak (PS) by WNT. In the pluripotent state, E-cadherin (E-CAD) transduces boundary forces to focus WNT signaling to the colony border. Following application of WNT ligand, E-CAD mediates a front or wave of epithelial-to-mesenchymal (EMT) conversion analogous to PS extension in an embryo. By knocking out the secreted WNT inhibitors active in our system, we show that DKK1 alone controls the extent and duration of patterning. The NODAL inhibitor cerberus 1 acts downstream of WNT to refine the endoderm versus mesoderm fate choice. Our EMT wave is a generic property of a bistable system with diffusion and we present a single quantitative model that describes both the wave and our knockout data.


Recent developments in the analysis of musty odour compounds in water and wine: A review.
One of the most common taints in foods is a musty or earthy odour, which is commonly associated with the activity of microorganisms. Liquid foods, particularly wine and water, can be affected by this defect due to the presence of certain aromatic organic compounds at very low concentrations (ng/L) consistent with human threshold perception levels. The volatile compounds responsible for a mouldy off-aroma include approximately 20 compounds, namely, haloanisoles, geosmin, 2-methylisoborneol, several alkyl-methoxypyrazines, 1-octen-3-ol, 1-octen-3-one, trans-octenol, 3-octanone, fenchol and fenchone. Methods for determining these very low concentrations of odour compounds must be extremely sensitive and selective with efficient preconcentration treatments. A number of extraction techniques based on LLME (liquid-liquid microextraction), SPME (solid-phase microextraction) or SBSE (stir-bar sorptive extraction) can be applied and should be selected on a case-by-case basis. Moreover, recent developments in GC instrumentation coupled to different detection systems can effectively increase the selectivity and sensitivity of the analysis of target compounds.


Pre-medication with Gabapentin is associated with significant reductions in nausea and vomiting after shoulder arthroscopy: A meta-analysis.
Arthroscopic shoulder surgery is increasingly performed as a day case procedure. Nausea, vomiting and inadequate pain control are the most frequent reasons for reattendance or failed discharge. Gabapentin is advocated as an adjunct to mitigate these symptoms and its use in shoulder arthroscopy may provide improved post-operative symptom control. The aim of this study was to perform a meta-analysis of studies evaluating the role of gabapentin in the peri-operative management of shoulder arthroscopy. Gabapentin is associated with significant improvements in post-operative nausea, vomiting and pain control after shoulder arthroscopy. A systematic review using Medline was conducted in accordance with the PRISMA guidelines. Randomised controlled trials studies reporting on patients >15 years old receiving either preoperative gabapentin or placebo before any shoulder arthroscopic surgery were considered for eligibility. Studies were appraised against the Consolidated Standards of Reporting Trials (CONSORT) checklist. A meta-analysis was performed using Review Manager 5.3. Four randomized controlled trials were identified for inclusion (n=227). Meta-analysis demonstrated a beneficial effect of gabapentin in preventing nausea and vomiting in the postoperative period (Odds Ratio 0.30, p=0.04). However, pooled data analysis did not show significant advantage in using gabapentin for postoperative pain control (p=0.11), although one study demonstrated a significant reduction in opioid consumption after gabapentin. No significant difference was reported in post-operative dizziness or sedation between the groups. Gabapentin did not show any significant benefit in postoperative pain control but is associated with significant reductions in post-operative nausea and vomiting after shoulder arthroscopy. I, meta-analysis.


Verteporfin-mediated on/off photoswitching functions synergistically to treat choroidal vascular diseases.
Choroidal vascular diseases, such as age-related macular degeneration, are the leading cause of vision impairment and are characterized by pathological angiogenesis. Verteporfin-mediated photodynamic therapy is a current strategy that selectively occludes choroidal neovasculature. However, the clinically used large-dose systemic administration increases the risk of systemic adverse events, such as phototoxicity to superficial tissues. In this study, we developed an in situ verteporfin delivery system with a photoswitching synergistic function that disassembles in response to intraocular inflammatory enzymes. Under light-on conditions, verteporfin-mediated photodynamic therapy effectively occurs and this leads to vascular occlusion. Under light-off conditions, non-photoactive verteporfin negatively regulates vascular endothelial growth factor-induced angiogenesis as a yes-associated protein inhibitor. Taken together, our system serves as an intraocular verteporfin reservoir to improve the bioavailability of verteporfin by innovatively exploiting its photochemical and biological functions. This work provides a promising strategy with synergistic antiangiogenic effects for the treatment of choroidal vascular diseases.


[Intra-abdominal hemorrhage as rare complication of a Meckel's diverticulum. A case report].
A case report of hemoperitoneum following perforation of Meckel's diverticulum as a rare complication is presented. Symptoms and diagnostic problems are discussed.


Blocking of acid-fixed nuclear binding of Epstein-Barr virus nuclear antigen (EBNA) by different DNA species.
Treatment of Epstein-Barr virus-determined nuclear antigen (EBNA) with DNA resulted in blocking of its ability to convert acid-fixed EBNA-negative cell nuclei to an EBNA-positive form. Epstein-Barr virus (EBV) DNA, herpes simplex virus type 2 (HSV-2) DNA and DNA isolated from three lymphoblastoid cell lines differed in their potency to block this reaction. EBV DNA was found to be about three times more effective than cellular DNAs in abolishing the ability of DNA-cellulose-purified EBNA to convert acid-fixed nuclei to the EBNA-positive form; the effect of HSV-2 DNA was of intermediate character. No difference was found between the blocking potency of DNAs isolated from EBV-genome-negative Ramos cells and EBV-genome-positive Raji and P3HR-1 cells.


Does training in a virtual reality simulator improve surgical performance?
The development of computerized surgical simulators in a virtual reality environment demands models for proper validation. Recent investigations have shown that a virtual reality simulator (MIST-VR) is a reliable tool for the assessment of laparoscopic psychomotor skills and that it improves the automation of the so-called fulcrum effect. Therefore, we set out to determine whether training with the MIST-VR would improve the surgical performance of surgically inexperienced medical students and to see if results obtained in the simulator would correlate with surgical performance. A total of 29 medical students were randomized into two groups. One group received preoperative MIST-VR training. Both groups then performed a simulated laparoscopic appendectomy in a pig. The operations were videotaped and examined by three independent observers. There was no significant difference in performance between the two groups. The performance with the MIST-VR correlated with the results in surgery. A method that can measure surgical skill, based on the scoring of independent observers who view videotaped performances, seems to be reliable. MIST-VR did not improve the surgical skills of the subjects, but the results with MIST-VR did predict surgical outcome.


How thick is the lithosphere?
A rapid decrease in shear velocity in the suboceanic mantle is used to infer the thickness of the lithosphere. It is proposed that new and highly precise group velocity data constrain the solutions and imply a thickness near 70 km.


Intrinsic Functional Connectivity is Organized as Three Interdependent Gradients.
The intrinsic functional architecture of the brain supports moment-to-moment maintenance of an internal model of the world. We hypothesized and found three interdependent architectural gradients underlying the organization of intrinsic functional connectivity within the human cerebral cortex. We used resting state fMRI data from two samples of healthy young adults (N's = 280 and 270) to generate functional connectivity maps of 109 seeds culled from published research, estimated their pairwise similarities, and multidimensionally scaled the resulting similarity matrix. We discovered an optimal three-dimensional solution, accounting for 98% of the variance within the similarity matrix. The three dimensions corresponded to three gradients, which spatially correlate with two functional features (external vs. internal sources of information; content representation vs. attentional modulation) and one structural feature (anatomically central vs. peripheral) of the brain. Remapping the three dimensions into coordinate space revealed that the connectivity maps were organized in a circumplex structure, indicating that the organization of intrinsic connectivity is jointly guided by graded changes along all three dimensions. Our findings emphasize coordination between multiple, continuous functional and anatomical gradients, and are consistent with the emerging predictive coding perspective.


Visualization of the corticospinal tract pathway using magnetic resonance axonography and magnetoencephalography for stereotactic irradiation planning of arteriovenous malformations.
Corticospinal tract (CST) information using anisotropic diffusion-weighted imaging and magnetoencephalography were integrated into radiosurgical planning for two patients with deeply seated arteriovenous malformation. The volume of CST receiving >10 Gy, >15 Gy, and maximum dose of CST could be reduced when plans were created with the aid of CST information compared with plans without the information. The results indicate that the use of CST information might reduce the risk of post-radiosurgical motor disturbance resulting from radiation necrosis.


Diabetes mellitus in newborns and infants.
Diabetes mellitus is uncommon in infancy and newborn period. The two common forms seen are the transient and permanent forms of diabetes mellitus of the newborn. They have to be differentiated from the transient hyperglycemic states (Blood sugar > 125 mg/dl) seen in newborns who receive parenteral glucose infusions and in those with septicemia and CNS disorders. Transient diabetes mellitus of the newborn (TDNB) is defined as hyperglycemia occurring within the first month of life lasting at least 2 weeks and requiring insulin therapy. Most of these cases resolve spontaneously by 4 months. It has a reported incidence of 1 in 45,000 to 60,000 live births. The most likely etiology is a maturational delay of cAMP mediated insulin release. The clinical features include small for datedness, proneness for birth asphyxia, open-eye alert facies, dehydration, emaciation, polyuria and poydipsia. These children are prone to septicemia and urinary tract infections. They have hyperglycemia, glucosuria, absent or mild ketonuria, low basal insulin, C-peptide and IGF-1 levels. Treatment consists of hydration and judicious administration of insulin with close monitoring. Thirty percent of these children are likely to develop permanent neonatal diabetes. Compared to transient form, permanent diabetes mellitus is uncommon. It is usually due to pancreatic dysgenesis often associated with other malformations and rarely due to type 1 diabetes mellitus. The diagnosis is based on the demonstration of both exocrine and endocrine pancreatic dysfunction. These children are managed as type 1 diabetes mellitus. They are prone to develop the vascular complications of diabetes at an earlier date.


[Use and value of common European lactation-promoting medicinal plants (galactagogues)].
Plant galactagogues can successfully help to stimulate lactation. A survey on the drugs most commonly used in Europe is presented, and their role in folk medicine as well as their efficiency in clinical tests are discussed. Recommendations for galactagogous teas to support breast-feeding are made.


Differential adherence of M line Biomphalaria glabrata hemocytes to Schistosoma mansoni and Echinostoma paraensei larvae, and experimental manipulation of hemocyte binding.
The ability of M line strain Biomphalaria glabrata hemocytes to adhere to mother sporocysts (MS) of PR1 Schistosoma mansoni or to MS or daughter rediae (DR) of Echinostoma paraensei was studied using an in vitro hemocyte adherence assay. Hemocytes were significantly more likely to bind to S. mansoni MS than to E. paraensei MS or DR. Hemocyte adherence to E. paraensei MS or DR was significantly increased if glutaraldehyde-fixed larvae were used as targets. Also, E. paraensei MS pretreated with the lectin concanavalin A (Con A) were more likely to be bound by hemocytes than MS pretreated with Con A in the presence of the competing sugar, alpha-methyl mannoside. Pretreatment of hemocytes with Con A increased their ability to bind E. paraensei sporocysts, but the effect was small compared to that achieved by pretreatment of MS with Con A. The lectin probably did not function as a bridging molecule between hemocytes and MS but, rather, altered the MS surface in a way that facilitated adherence. Similarly, adherence to E. paraensei MS was significantly increased if the MS were pretreated with cell-free M line plasma prior to use in adherence assays. Our results indicate that the two parasites provoke fundamentally different responses from M line hemocytes in vitro and that the living tegument can be modified by host humoral factors and by lectins such that hemocyte binding is significantly increased.


A novel mutation outside homeodomain of HOXD13 causes synpolydactyly in a Chinese family.
Human synpolydactyly (SPD), belonging to syndactyly (SD) II, is caused by mutations in homeobox d13 (HOXD13). Here, we describe the study of a two-generation Chinese family with a variant form of synpolydactyly. The sequence of the HOXD13 gene was analyzed. Luciferase assays were conducted to determine whether the mutation affected the function of the HOXD13 protein. We identified a novel c.659G>C (p.Gly220Ala) mutation outside the HOXD13 homeodomain responsible for the disease in this family. This mutation was not found in any of the unaffected family members and healthy control. Luciferase assays demonstrated that this mutation affected the transcriptional activation ability of HOXD13 (only approximately 84.7% of wild type, p<0.05). Phenotypes displayed by individuals carrying the novel mutation present additional features, such as the fifth finger clinodactyly, which is not always associated with canonical SPD. This finding enhances our understanding about the phenotypic spectrum associated with HOXD13 mutations and advances our understanding of human limb development.


Endovascular treatment for elderly patients with ruptured aneurysm.
We report our results of endovascular treatment for elderly patients with ruptured aneurysm and discuss the indication for treatment. One hundred and thirty four consecutive patients with ruptured aneurysm treated in our institute during the last 4 years were retrospectively evaluated. Fifty eight patients were included in group A (over 70 years old), and 76 patients in group B (under 69 years old). In both groups, the outcome was strongly related to the preoperative Hunt & Kosnik grade. However, significant risk factors (i.e. pneumonia, rupture of extracranial aneurysm) which make prognosis poor were more common in group A. Group A showed poor outcome in grade III patients, although there were no outcome differences between the two groups in patients of other grades. Endovascular treatment for elderly patients with ruptured aneurysms seemed to be useful. Their outcome was strongly related to their preoperative condition. General risk factors should be evaluated before treatment, especially in elderly patients. Patients with low Hunt & Kosnik grade seem to be most suitable for endovascular treatment. On the other hand, outcome of patients with poor preoperative grade was worse despite the less invasive nature of endovascular treatment. An improvement of outcome in grade III patients is desirable.


Trabecular bone score as a skeletal fragility index in acromegaly patients.
Lumbar spine trabecular bone score (TBS) was significantly decreased in active acromegaly patients. TBS may be useful to assess the skeletal fragility in acromegaly in which bone mineral density (BMD) is not sufficient to represent bone strength and explain the high incidence of fragility fractures in acromegaly patients. Although the data on BMD are controversial, patients with acromegaly have an increased risk of fragility fracture. We examined the lumbar spine TBS to explain the skeletal deterioration in acromegaly patients. We included 14 men and 19 women acromegaly patients who underwent dual-energy X-ray absorptiometry at the time of diagnosis from 2000 to 2014 at Seoul National University Hospital. Ninety-nine age-, sex- and body mass index-matched controls were recruited. Biochemical parameters, lumbar spine TBS, and BMD at all sites were measured. Gonadal status was evaluated at diagnosis. Lumbar spine TBS was lower in acromegaly patients than in controls in both genders (1.345 ± 0.121 vs. 1.427 ± 0.087, P = 0.005 in men; 1.356 ± 0.082 vs. 1.431 ± 0.071, P = 0.001 in women). In contrast, BMD at all sites did not differ between the two groups. Hypogonadal acromegaly patients (men, n = 9; women, n = 12) had lower TBS values compared with controls both in men and women (all P < 0.05), although BMD at all sites were similar for the two groups. In eugonadal acromegaly patients, lumbar spine TBS was lower than in women controls only (P = 0.041). Skeletal microarchitecture was deteriorated in acromegaly patients as assessed by TBS, which seems to be a consequence of growth hormone excess as well as hypogonadism, especially in women.


Comparison between anterior approaches and posterior approaches for the treatment of multilevel cervical spondylotic myelopathy: A meta-analysis.
We aimed to compare the clinical outcomes of anterior approaches (anterior cervical corpectomy with fusion, cervical discectomy with fusion) and posterior approaches (laminectomy, laminoplasty) in multilevel cervical spondylotic myelopathy (MCSM) patients using a systematic meta-analysis. PubMed, Embase, Scopus, and the Cochrane library were searched for literatures up to March 27, 2015 without language restriction. The reference lists of selected articles were also screened. Heterogeneity was identified using Q test and I(2) statistic. A fixed effect model was used for homogeneous data and a random effects model for heterogeneous data. Weighted mean difference (WMD) or odds ratio (OR) with 95% confidence intervals (CIs) were calculated. Subgroup analysis was conducted according to the cause of MCSM. Seventeen articles were selected. Higher post-Japanese Orthopedic Association (JOA, P=0.002) and shorter length of stay (P=0.004) were found in anterior approaches group compared with posterior approaches. Moreover, operation time was shorter (P<0.00001) and neurological recovery rate was higher (P=0.005) in ossification of posterior longitudinal ligament patients underwent posterior approaches. Complication rate of posterior approaches was lower in spinal stenosis subgroup (P<0.0001). MCSM patients performed anterior approaches showed superior post-JOA and shorten length of stay. However, the outcomes such as operation time and complication rate are associated with the cause of MCSM. Therefore, the favorable surgical strategy for MCSM still needs more studies.


The effects of oncogene transfection on growth and antibody production of human-mouse heterohybridomas.
Human-mouse heterohybridomas producing human monoclonal antibodies show slower growth rates and lower peak cell densities than murine hybridomas. In order to improve the growth properties we transfected a heterohybridoma cell line with expression plasmids containing the oncogenes v-src, c-Ha-ras and SV40largeT. The plasmids were transferred by electroporation. Growth promoting activities of the plasmids were proven in NIH3T3 cells whereby a doubling of the maximum cell densities of this cell type was observed. The oncogene products were analyzed by means of northern blotting and immunofluorescence. After transfection of c-src and c-ras, a heterohybridoma cell line was derived which showed improved growth characteristics compared to the original cell line. Although specific antibody production was lower, antibody concentrations which accumulated in batch culture were higher due to increased maximum cell densities.


The restraint stress-induced decrease of the nocturnal prolactin surge and the physiology of pseudopregnancy and pregnancy in the rat.
Experiments were performed to determine whether the restraint stress-induced decrease of the nocturnal prolactin (PRL) surge affected the length of pseudopregnancy (PSP) and/or the outcome of pregnancy in rats. Vaginal cycles were monitored daily and animals were electro-mechanically cervically stimulated on the morning of metestrus to induce PSP. Animals were restraint stressed by tying the hind legs together with plastic coated bell wire beginning on day 1 of PSP from 0100-0700h with reapplication of stress at 0400h for 6-9 days and then blood sampled for PRL and progesterone plasma levels. Restraint stress significantly decreased plasma PRL (P less than 0.001) and progesterone (P less than 0.05) levels. The length of PSP was significantly decreased (P less than 0.01) for restraint animals and for control animals that were blood sampled compared to control animals that were not sampled. In the pregnancy experiment, animals were mated upon arrival into the laboratory and assigned to one of four groups. For the restraint group, stress was initiated on day 1 of pregnancy as indicated by the presence of sperm in the vaginal lavage. Animals were stressed for 6-9 days for 6 hours during the nocturnal PRL surge as described above. One control group had no treatment; a second control group was sampled only, and a third control group was injected daily with pimozide, a dopamine antagonist, and stressed for 6-9 days. The group which received no treatment had significantly greater (P less than 0.05) incidence of successful pregnancy compared to the other 3 groups; there were no differences (P greater than 0.05) between the sampled, restraint and restraint + pimozide groups in the incidence of successful pregnancy. We conclude that restraint stress during the nocturnal PRL surge minimally affects the length of PSP and that the effect of stress on the outcome of pregnancy is not due to the decrease in nocturnal PRL surge.


Effect of In Utero Non-Steroidal Anti-Inflammatory Drug Therapy for Severe Ebstein Anomaly or Tricuspid Valve Dysplasia (NSAID Therapy for Fetal Ebstein anomaly).
Ebstein anomaly (EA) and tricuspid valve dysplasia (TVD) are rare congenital malformations associated with nearly 50% mortality when diagnosed in utero. The diseases often produce severe tricuspid regurgitation (TR) in the fetus and in some cases, pulmonary regurgitation (PR) and circular shunting ensue. Since the ductus arteriosus (DA) plays a critical role in the circular shunt and may be constricted by transplacental nonsteroidal anti-inflammatory drugs (NSAIDs), we sought to assess the effect of NSAIDs on fetuses with EA/TVD. We reviewed mothers of singleton fetuses with EA/TVD and PR, indicative of circular shunting, who were offered NSAIDs at multiple centers from 2010 to 2018. Initial dosing consisted of indomethacin, followed by ibuprofen in most cases. Twenty-one patients at 10 centers were offered therapy at a median gestational age (GA) of 30.0 weeks (range: 20.9 to 34.9). Most (15/21 = 71%) mothers received NSAIDs, and 12 of 15 (80%) achieved DA constriction after a median of 2.0 days (1.0 to 6.0). All fetuses with DA constriction had improved PR; 92% had improved Doppler patterns. Median GA at pregnancy outcome (live-birth or fetal demise) was 36.1 weeks (30.7 to 39.0) in fetuses with DA constriction versus 33 weeks (23.3 to 37.3) in fetuses who did not receive NSAIDs or achieve DA constriction (p = 0.040). Eleven of 12 patients (92%) with DA constriction survived to live-birth, whereas 4 of 9 patients (44%) who did not receive NSAIDs or achieve DA constriction survived (p = 0.046). In conclusion, our findings demonstrate the proof of concept that NSAIDs mitigate circular shunt physiology by DA constriction and improve PR among fetuses with severe EA/TVD. Although the early results are encouraging, further investigation is necessary to determine safety and efficacy.


3-Methyl-5-(4-methyl-phen-oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde.
In the title compound, C18H16N2O2, the phenyl and pyrazole rings subtend a dihedral angle of 22.68 (8)°. The packing of the title compound features aromatic π-π stacking and weak C-H⋯π inter-actions.


Lower serum endocan levels are associated with the development of acute lung injury after major trauma.
Endocan is a proteoglycan expressed by endothelial cells in the lung that may inhibit leukocyte recruitment and thus prevent the development of acute lung injury (ALI). We tested the association of serum endocan levels with subsequent development of ALI after major trauma. This was a single-center nested case-control study within a prospective cohort study of major trauma patients. Using an enzyme-linked immunosorbent assay test, we measured endocan levels from admission serum in 24 controls (no ALI) and 24 cases (ALI within 5 days of trauma). Multivariable logistic regression was used to test the association of admission serum endocan levels with subsequent ALI. Patients who developed ALI had lower levels of endocan on admission (mean, 3.5 ± 1.4 ng/mL vs 4.9 ± 2.6 ng/mL in controls; P = .02). For each 1-unit increase in serum endocan level, the odds ratio for ALI development decreased (0.69; 95% confidence interval, 0.49-0.97; P = .03). Lower endocan levels remained associated with a higher incidence of ALI after adjustment for age and illness severity. Lower levels of serum endocan on admission are associated with subsequent development of ALI in trauma patients. These observations may be explained by endocan-mediated blockade of leukocyte recruitment in the lung.


Pre-cancerous breast lesions: implications for breast cancer prevention trials.
The relationship between benign breast disease and breast cancer has become the focus of increased clinical attention as breast cancer prevention becomes a clinical reality. In this setting an understanding of the magnitude of the increase in risk conferred by the various types of benign breast disease assumes increasing importance. When benign breast disease is considered as an aggregate, estimates of the relative risk of breast cancer development range from 0.8 to 4.5. This article describes the risk associated with proliferative and non-proliferative benign breast disease, as well as the rationale for considering lobular carcinoma in situ and ductal carcinoma in situ (in some cases) as risk factors for breast carcinoma rather than actual malignant lesions. Mathematical models can provide a more precise estimate of breast cancer risk, but these efforts may be confounded by the lack of uniformity in the pathologic definition of borderline benign breast lesions. The breast cancer prevention trials offer a unique opportunity to improve our database on the natural history of high risk benign breast lesions, while attempting to reduce the 44,000 deaths occurring annually from breast cancer.


Future psychiatric services in Italy: lesson from the COVID-19 pandemic.
During the COVID-19 epidemic, home care and remote working showed important technological innovations, leading to review all public mental health policies. In this article, some considerations based on the Italian COVID-19 experience in order to plan post-COVID psychiatric interventions are reported.


Effectiveness of neuromuscular electrical stimulation for endometriosis-related pain: A protocol of systematic review and meta-analysis.
This study will assess the effectiveness and safety of neuromuscular electrical stimulation (NMES) for endometriosis-related pain (ERP). Seven electronic databases of Cochrane Library, PUBMED, EMBASE, WANGFANG, VIP, CBM, and CNKI will be searched. We will search all electronic databases related the randomized controlled trials (RCTs) on the effectiveness and safety of NMES for ERP up to the March 31, 2020 without restrictions of language. RevMan 5.3 software will be used for risk of bias assessment, related data analysis and meta-analysis. This systematic review and meta-analysis will summarize current high-quality RCTs on the effectiveness and safety of NMES for ERP. Results of this study will provide the basis for both clinician and further research. This study will investigate whether NMES is effective and safety for the treatment of ERP. INPLASY202040191.


T1a breast carcinoma and the role of axillary dissection.
Axillary dissection (AD) does not affect recurrence or survival in T1a breast cancer. Cohort study comparing patients who underwent AD and those who did not. Provincial cancer agency. Six hundred ninety-one women with pathologically diagnosed T1a tumors. Rates of axillary metastases stratified according to grade and lymphovascular and/or neural invasion, rates of relapse, and disease-specific survival. Grade 1, 2, and 3 tumors without lymphovascular and/or neural invasion had axillary nodal involvement rates of 0.7%, 7%, and 7.8% of patients, respectively; with lymphovascular and/or neural invasion, axillary nodes were involved in 9.1%, 39.3%, and 44.4%, respectively. No statistically significant differences were found between the cohorts in relapse rates (P =.70) or survival (P =.84). Higher tumor grade and lymphovascular and/or neural invasion increased the rate of nodal metastases in T1a tumors, but AD did not improve relapse rates or breast cancer-specific survival.


Developing precision medicine using scarless genome editing of human pluripotent stem cells.
Many avenues exist for human pluripotent stem cells (hPSCs) to impact medical care, but they may have their greatest impact on the development of precision medicine. Recent advances in genome editing and stem cell technology have enabled construction of clinically-relevant, genotype-specific "disease-in-a-dish" models. In this review, we outline the use of genome-edited hPSCs in precision disease modeling and drug screening as well as describe methodological advances in scarless genome editing. Scarless genome-editing approaches are attractive for genotype-specific disease modeling as only the intended DNA base-pair edits are incorporated without additional genomic modification. Emerging evidentiary standards for development and approval of precision therapies are likely to increase application of disease models derived from genome-edited hPSCs.


The correlation between the roentgenographic appearance and operative findings at the bone-cement junction of the socket in Charnley low friction arthroplasties.
In a series of 200 Charnley low friction arthroplasties revised for various reasons, the preoperative anteroposterior roentgenograms were categorized in terms of demarcation at the bone-cement interface of the socket and compared with the operative findings of movement at the bone-cement junction. All sockets showing no demarcation were found to be fixed soundly. Seven percent of the sockets showing demarcation of the outer one-third only were loose, and when two-thirds of the sockets were demarcated, 71% were loose. Ninety-four percent of the sockets with complete demarcation and all sockets that had migrated were found to be loose at revision. There is a definite correlation between roentgenographic demarcation and socket loosening. The more extensive the demarcation, the more likely it is that the socket is loose. Radiographic demarcation of the cemented socket is a prognostic sign for eventual failure.


Anthropogenic waste indicators (AWIs), particularly PAHs and LABs, in Malaysian sediments: Application of aquatic environment for identifying anthropogenic pollution.
Polycyclic aromatic hydrocarbons (PAHs) and linear alkylbenzenes (LABs) were used as anthropogenic markers of organic chemical pollution of sediments in the Selangor River, Peninsular Malaysia. This study was conducted on sediment samples from the beginning of the estuary to the upstream river during dry and rainy seasons. The concentrations of ƩPAHs and ƩLABs ranged from 203 to 964 and from 23 to 113 ng g(-1) dry weight (dw), respectively. In particular, the Selangor River was found to have higher sedimentary levels of PAHs and LABs during the wet season than in the dry season, which was primarily associated with the intensity of domestic wastewater discharge and high amounts of urban runoff washing the pollutants from the surrounding area. The concentrations of the toxic contaminants were determined according to the Sediment Quality Guidelines (SQGs). The PAH levels in the Selangor River did not exceed the SQGs, for example, the effects range low (ERL) value, indicating that they cannot exert adverse biological effects.


Metronidazole treatment of acute diarrhea in dogs: A randomized double blinded placebo-controlled clinical trial.
Metronidazole is commonly administered to dogs with acute diarrhea, but there is limited evidence to support this practice. To investigate the effects of metronidazole administration on dogs with acute nonspecific diarrhea. Thirty-one dogs, including 14 test population dogs and 17 controls. Randomized controlled clinical trial. Dogs with acute diarrhea in which causation was not determined by routine fecal diagnostic testing were randomly assigned to metronidazole treatment (10-15 mg/kg PO q12h for 7 days) or placebo. Fecal cultures and characterization of Clostridium perfringens isolates also were performed. Owners maintained medication and fecal scoring logs, and fecal diagnostic tests were repeated on day 7. The mean ± SD time to resolution of diarrhea for test population dogs (2.1 ± 1.6 days) was less than that for controls (3.6 ± 2.1 days, P = .04). Potential relationships of C. perfringens with acute diarrhea pathogenesis were not investigated, but only 3 of 13 (23.1%) test population dogs had persistent C. perfringens carriage at day 7, which was less than the 11 of 14 (78.6%) controls with persistent growth (P = .007). Our results suggest that metronidazole treatment can shorten duration of diarrhea and decrease fecal culture detection of C. perfringens in some dogs with acute nonspecific diarrhea. Additional studies are needed to assess the benefits and risks of routine use of metronidazole for this purpose because most dogs achieve resolution of diarrhea within several days regardless of treatment.


A descriptive study of high resolution total colonic intracavitary manometry and colonic transit test in the diagnostic efficacy of functional constipation in Chinese patients.
This study was to observe the diagnostic efficacy of high resolution total colonic intracavitary manometry (HRCM) vs colonic transit test (CTT) in the assessment of functional constipation (FC) in Chinese patients. Seventy-nine cases of patients with severe FC who were admitted and received colon resection between July 2016 and July 2019 at the Tianjin Union Medical Center were retrospectively reviewed. Before operation, all patients received CTT at outpatient service, followed by HRCM at ward. The resected tissues were subject to histological observation, which was used to determine the diagnostic efficacy of HRCM vs CTT. The accuracy of CTT for the FC diagnosis was 69.6% (55/79), and the false negative ratio was 30.4%. The accuracy of HRCM for the FC diagnosis was 81.0% (64/79), and the false negative ratio was 19.0% (15/79). Twelve patients showed normal characteristics after CTT but abnormal after HRCM. In contrast, only 4 showed normal after HRCM but abnormal after CTT. In addition, among the 79 patients 12 were detected normal by both CTT and HRCM. HRCM can be more suitable to assess FC compared with CTT, while CTT is still indispensable for HRCM to diagnose FC.


The use of inter-professional education (IPE) healthcare law and ethics scenario based learning sessions amongst nursing, midwifery and law students: A qualitative investigation.
The Nursing and Midwifery Council (NMC, 2018) require registrants to practice ethically and lawfully. Nevertheless, in 2019-2020, the NMC received 5704 referrals regarding registrants' fitness to practice, many of these referrals related to registrants' criminality, clinical competence, and misconduct. Additionally, litigation within healthcare remains a concern. NHS Resolution (2020) reported costs of payments relating to clinical negligence schemes of £2324.2 million in 2019/20. This paper discusses a qualitative investigation of healthcare law and ethics teaching and learning within undergraduate midwifery and nursing curricula and the use of scenario based (inter-professional education) IPE sessions amongst nursing, midwifery and law students. Two scenario based IPE sessions attended by nursing, midwifery and law students were delivered in addition to existing curricula. Scenarios were based on real life cases. Students collaborated to identify means of managing legal and ethical issues arising from the scenarios. Sessions were facilitated by lecturers from the schools of law, midwifery and nursing. Semi structured interviews were completed with IPE session participants and academics with an interest in healthcare law and ethics (students n = 3, academic staff n = 3). Thematic content analysis was applied to interview data. Findings Scenario based IPE sessions are valued by participants who claim they are effective in enabling the development of knowledge and understanding of healthcare law and ethics while providing insight into the application of theory in practice. Participants claimed that healthcare law and ethics was a fundamental part of caring professions and essential to nursing and midwifery curricula. Substantial numbers of nurses and midwives are called to account by their professional body and in law for issues related to their practice, with significant financial and personal costs. Healthcare law and ethics remains fundamental to professional practice with IPE scenario based sessions offering a means to develop knowledge and enable students to consider ethical, legal and professional issues.