Glaucocalyxin a protect liver function via inhibiting platelet over-activation during sepsis.
Rabdosia japonica (Burm. f.) var. glaucocalyx (Maxim.) is a perennial herb, and is traditionally used as folk medicine for treating inflammatory diseases and cancer. Gaucocalyxin A (GLA) is an ent‑kaurane diterpenoid that is isolated from the aerial parts of R. japonica (Burm. f.) var. glaucocalyx (Maxim.). In a recent study, we found that GLA protects against acute liver dysfunction induced by Escherichia coli, which is likely related to its anti-inflammatory effects. However, the mechanism by which GLA protects liver injury during sepsis is unknown. To evaluate the anti-inflammatory function of GLA and its regulatory effect on platelet function. An in vivo model of sepsis was established by inoculating mice with E. coli. Live function and platelet activation were evaluated through standard assays. The levels of pro-inflammatory factors were measured through ELISA and qRT-PCR. GLA alleviated liver dysfunction in the mouse model of sepsis. GLA-treated mice displayed lower complement activation and liver dysfunction after E. coli infection. GLA alleviated the decrease in peripheral platelet counts by inhibiting their clearance by Kupffer cells in liver. Furthermore, GLA inhibited platelet activation through the RIP1/RIP3/AKT pathway and downregulated C3aR expression on the platelets, thereby inhibiting liver injury and dysfunction due to excessive complement activation. GLA can inhibit platelet activation by reducing surface expression of C3aR, which protect the liver from injury induced by excessive complement activation. GLA is a novel therapeutic agent for controlling sepsis-related liver dysfunction.


A phase II trial of dose-reduced nab-paclitaxel for patients with previously treated, advanced or recurrent gastric cancer (OGSG 1302).
For unresectable or recurrent advanced gastric adenocarcinoma (AGC), tri-weekly administration of nanoparticle albumin-bound paclitaxel (nab-PTX) at 260 mg/m2 achieved a response rate of 27.8% in a phase II trial in Japan. However, frequent neutropenia and peripheral neuropathy limit its use in clinical settings. We, thus, conducted a single-arm phase II trial to investigate the efficacy and safety of a reduced dose (220 mg/m2) of tri-weekly nab-PTX. Eligible patients included those with AGC and ECOG performance status of 0-2 who had received one or more prior chemotherapy containing fluoropyrimidine regimens. A reduced dose of nab-PTX (220 mg/m2) was administered tri-weekly. The primary endpoint was response rate (RR). Secondary endpoints were overall survival (OS), progression-free survival (PFS), disease-control rate (DCR), incidence of adverse events, relative dose intensity (RDI) and proportion of patients receiving subsequent chemotherapy. Among 33 patients enrolled, 32 were treated with protocol therapy. RR was 3.1% [95% confidence interval (CI), 0-16.2%], which did not reach the protocol-specified threshold (p = 0.966). DCR was 37.5% (95% CI, 21.1-56.3%). Median OS and PFS were 6.3 (95% CI, 4.4-14.2) and 2.2 (95% CI, 1.8-3.1) months, respectively. RDI was 97.8%. Twenty (62.5%) patients received subsequent chemotherapy. Toxicity was relatively mild with the most common grade ≥ 3 adverse events being neutropenia (38%), anemia (13%), fatigue (19%), anorexia (16%), and peripheral neuropathy (13%). Tri-weekly nab-PTX with a reduced dose (220 mg/m2) is not recommended for AGC in a second-line or later setting, despite demonstrating less toxicity than at 260 mg/m2. Clinical trial registration The OGSG1302 trial was registered with UMIN-CTR as UMIN000000714.


Bidirectional immunomodulatory activities of polysaccharides purified from Pleurotus nebrodensis.
A novel Pleurotus nebrodensis polysaccharide (PN50G) was purified, characterized, and cultured with RAW264.7 macrophages to evaluate its bidirectional immunostimulating characteristics. PN50G was purified by using Sepharose 4B gel filtration; the molecular weight of PN50G was distributed at 2,000 kDa. The total protein and carbohydrate constituent ratios in PN50G were 2.6 ± 0.9 % and 92.4 ± 6.1 % (w/w), respectively, which suggests that PN50G may be a major proteo-polysaccharide component. The phagocytosis of macrophages was improved significantly, and remarkable changes were observed in the morphology of PN50G-treated cells. Compared with the control group, the productions of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), and inducible nitric oxide synthase (iNOS) in the macrophages as well as the messenger RNA expressions were strongly induced by PN50G. Pro-/anti-inflammatory (IL-6/IL-10, TNF-α/IL-10, NO/IL-10) cytokine secretion ratios by lipopolysaccharide-stimulated RAW264.7 macrophages were significantly decreased by PN50G treatments in a dose-dependent manner under an excessive immune experimental model. This study suggests that purified PN50G can improve immunity and suppress immune overactivity in LPS-induced macrophages in a preventive manner to coordinate innate immunity and inflammatory responses.


Improvement of the catalytic performance of hybrid nanocomposite based on phosphate-benzimidazole in Knoevenagel condensation.
In this work, we have developed a simple and very effective experimental strategy for the reaction of Knoevenagel via the condensation of aromatic aldehydes substituted with active methylene compounds in the presence of hybrid nanocomposites xMCl2-yNaPO3 (MCl2 = 2,2'-dibenzimidazolyl butane dichlorhydrates), under ecological conditions. The Phosphate-Benzimidazole hybrid nanocomposite as heterogeneous catalysts has demonstrated a high catalytic activity for the Knoevenagel condensation in ethanol as an ecological solvent. It has several advantages such as light reaction conditions, a simple and ecological working procedure. Meanwhile, xMCl2-yNaPO3 can be recovered by simple filtration and this catalytic system having an interesting lifetime (five cycles) with no decrease in activity.


Schistosoma haematobium infection in Mauritania: two years of follow-up after a targeted chemotherapy--a life-table approach of the risk of reinfection.
Reinfection pattern among 6- to 20-year-old subjects was studied over 24 months in two Mauritanian villages of intense Schistosoma haematobium infection after a targeted chemotherapy with praziquantel involving the whole community. Subjects received treatment according to the presence of haematuria/proteinuria and this indirect screening technique was able to identify 98-100% of the heavily infected subjects (50 + eggs/10 ml). The two villages differed with respect to their characteristics, quality of follow-up and reinfection pattern. The post-treatment 6-month cumulative incidence during the two transmission periods following the chemotherapy, estimated from a subset of 116 subjects, was 18.0% and 20.5%. Reinfection rates were higher among males (Cox-Mantel: P = 0.0015), among children 6-10 years of age than older (P = 0.0078) and among subjects with more than 50 eggs/10 ml of urine before treatment than subjects with a lower egg output (P = 0.009). A Cox proportional hazard regression model was fitted and confirmed that gender, age and pretreatment level of infection were predictors of the rate of reinfection but that there was no interaction between these predictors.


Comparative proteomic profiling of mammalian cell lysates using phosphopeptide microarrays.
A library of 176 human phosphotyrosine-containing peptides was used to establish cell lysate binding profiles in a two colour microarray format. The resulting hits led to the pull-down and identification of biomarkers associated with cancer states.


Receptor-mediated endocytosis of tissue-type plasminogen activator (t-PA) by liver cells.
Tissue-type plasminogen activator (t-PA) has a short half-life in the circulation because the enzyme is rapidly cleared by the liver. This short review summarizes recent literature concerning mechanisms of uptake and degradation of t-PA in the liver. In vivo studies in rats show that degradation takes place via a lysosomal pathway. Saturation of the uptake system at high t-PA concentrations suggests a receptor-mediated mechanism. Competition experiments with various glycoproteins indicate that the asialoglycoprotein receptor is not involved, but they point to a role for the mannose receptor, which recognizes t-PA via its high mannose-type oligosaccharide on the first kringle domain. Both in vivo and in vitro studies with isolated liver cells demonstrate that parenchymal cells, as well as liver endothelial cells, are involved in the clearance of t-PA. Parenchymal cells, as the hepatoma cell line Hep G2, endocytose t-PA via a still unknown, possibly t-PA specific receptor, while liver endothelial cells catabolize t-PA via the mannose receptor.


On-line glucose monitoring by near infrared spectroscopy during the scale up steps of mammalian cell cultivation process development.
NIR spectroscopy is a non-destructive tool for in-situ, on-line bioprocess monitoring. One of its most frequent applications is the determination of metabolites during cultivation, especially glucose. Previous studies have usually investigated the applicability of Near Infrared (NIR) spectroscopy at one bioreactor scale but the effect of scale up was not explored. In this study, the complete scale up from shake flask (1 L) through 20 L, 100 L and 1000 L up to 5000 L bioreactor volume level was monitored with on-line NIR spectroscopy. The differences between runs and scales were examined using principal component analysis. The bioreactor runs were relatively similar regardless of scales but the shake flasks differed strongly from bioreactor runs. The glucose concentration throughout five 5000 L scale bioreactor runs were predicted by partial least squares regression models that were based on pre-processed spectra of bioreactor runs and combinations of them. The model that produced the lowest error of prediction (4.18 mM on a 29 mM concentration range) for all five runs in the prediction set was based on the combination of 20 L and 100 L data. This result demonstrated the capabilities and the limitations of an NIR system for glucose monitoring in mammalian cell cultivations.


Normal versus alpha-amanitin induced cellular dynamics of the midgut epithelium in female Aedes aegypti L. (Insecta, Diptera) in response to blood feeding.
In midgut epithelial cells (stomach) of untreated female A. aegypti an increase in the surface area of the rough endoplasmic reticulum (rer) and in the ratio of membrane-bound to free ribosomes is morphometrically measured during digestion of the first blood meal. This can be correlated with the synthesis and release of digestive proteases. The dynamics of the ribosomes in A. aegypti are similar to those in A. stephensi. 3 ng alpha-amanitin per mosquito prevent normal blood digestion, the proliferation of the rer and the increase in the ratio of bound to free ribosomes. On the other hand, some synthesis of new ribosomes takes place.


Pharmacological evaluation of ifosfamide and its enantiomers in laboratory animals.
Some pharmacological properties of commercial racemic ifosfamide (Holoxan) and its D- and L-enantiomers were compared in experiments on mice and rats. Although values of acute toxicity and some results of subchronic treatment revealed better parameters of L-form in comparison to racemic mixture, distinct hepatotoxic effects and thrombocytopenia noted in the course of prolonged treatment seem to be the important factors limiting therapeutic usefulness of levorotatory form.


Predictive value of sphingosine kinase 1 expression in neoadjuvant treatment of breast cancer.
Sphingolipids play important roles in apoptosis and cell proliferation. Sphingosine kinase 1 (SphK1) expression has a prognostic impact in primary breast cancer, but its predictive value is currently unknown. A total of 112 breast cancer specimens from a prospective neoadjuvant chemotherapy trial (GeparDuo) were studied. Using tissue microarrays of pre-treatment core cut biopsies, we determined the expression of SphK1 by immunohistochemistry. The upper quartile of the cohort according to an immune reactive score of SphK1 was used as cutoff for high expression. We observed a larger number of samples with high SphK1 expression among ER-negative cancers (36.8 vs. 20.5 % among ER-positive cancers; Fisher test p = 0.073). Eighteen of the 112 patients demonstrated a pathological complete response. A significant predictive value for pathological complete response was observed for ER negativity (p = 0.003), young age (p = 0.037), and high tumor grade (p = 0.049). An increased pCR rate was observed in tumors with high SphK1 expression within the luminal subtype (26.7 vs. 5.8 %; Fisher test p = 0.040). No significant difference in survival was detected according to SphK1 expression. Our results suggest that SphK1 may be a predictive factor for pCR after neoadjuvant treatment in luminal type breast cancers and warrants further investigation.


[Nail psoriasis--an ignored disorder. Pathogenesis, diagnosis and therapy].
Approximately 50% of all patients with psoriasis develop characteristic nail changes as a clinical correlate of psoriatic inflammation of the nail matrix and/or nail bed. The most frequent signs of nail psoriasis are pitting and distal onycholysis. The most commonly used score to assess the severity of nail involvement at present is the Nail Psoriasis Severity Index (NAPSI). Although more than half of affected patients experience a significant physical and mental impairment, this index does not include patient-reported symptoms. There is a striking association between nail psoriasis and a higher risk of psoriatic arthritis with a prevalence of nail involvement among patients with psoriatic arthritis as high as 70%. A possible explanation is the close anatomical link between the nail apparatus and the distal interphalangeal joint; enthesitis of the latter is carried by fibers to the nail and becomes clinically visible as nail psoriasis. Nail involvement is not adequately reflected in current concepts of disease management. There is limited evidence for the efficacy of topical therapies in nail psoriasis. A number of large studies document an improvement of nail psoriasis in response to biologics and, more recently, also to methotrexate.


Carotid Body-Mediated Chemoreflex Function in Aging and the Role of Receptor-Interacting Protein Kinase.
Ventilatory impairment during aging has been linked to carotid body (CB) dysfunction. Anatomical/morphological studies evidenced CB degeneration and reductions in the number of CB chemoreceptor cells during aging. The mechanism(s) related to CB degeneration in aging remains elusive. Programmed cell death encompasses both apoptosis and necroptosis. Interestingly, necroptosis can be driven by molecular pathways related to low-grade inflammation, one hallmark of the aging process. Accordingly, we hypothesized that necrotic cell death dependent on receptor-interacting protein kinase-3 (RIPK3) may contribute, at least in part, to impair CB function during aging. Adult (3 months) and aged (24 months) wild type (WT) and RIPK3-/- mice were used to study chemoreflex function. Aging results in significant reductions in both the hypoxic (HVR) and hypercapnic ventilatory responses (HCVR). Adult RIPK3-/- mice showed normal HVR and HCVR compared to adult WT mice. Remarkable, aged RIPK3-/- mice displayed no reductions in HVR nor in HCVR. Indeed, chemoreflex responses obtained in aged RIPK3-/- KO mice were undistinguishable from the ones obtained in adult WT mice. Lastly, we found high prevalence of breathing disorders during aging and this was absent in aged RIPK3-/- mice. Together our results support a role for RIPK3-mediated necroptosis in CB dysfunction during aging.


Bottom-up fabrication of photoluminescent carbon dots with uniform morphology via a soft-hard template approach.
A novel soft-hard template approach for preparing photoluminescent carbon dots (CDs) with tunable sizes, compositions, crystalline degrees and photoluminescence properties has been developed using four different precursors as carbon sources. The results offer a new strategy for fabrication of monodispersed CDs with well-defined morphology.


Dairy Consumption, Blood Pressure, and Risk of Hypertension: An Evidence-Based Review of Recent Literature.
Hypertension is a major risk factor for development of stroke, coronary heart disease, heart failure, and end-stage renal disease. In a systematic review of the evidence published from 2004 to 2009, the 2010 Dietary Guidelines Advisory Committee (DGAC) concluded there was moderate evidence of an inverse relationship between the intake of milk and milk products (dairy) and blood pressure. This review synthesizes results from studies published over the past year on the relationship between dairy intake, blood pressure, and hypertension risk. The influence of dairy micronutrients including calcium, vitamin D, potassium, and phosphorous on blood pressure and incident hypertension is examined. Emerging research on bioactive dairy peptides is also reviewed. Lastly, recent evidence on effects of dairy fat content on blood pressure and hypertension risk, and the impact of inclusion of low-fat dairy in dietary patterns is also investigated.


Soft Tissue Necrosis in Head and Neck Cancer Patients After Transoral Robotic Surgery or Wide Excision With Primary Closure Followed by Radiation Therapy.
Risk factors were evaluated for surgical bed soft tissue necrosis (STN) in head and neck cancer patients treated with postoperative radiation therapy (PORT) after transoral robotic surgery (TORS) or wide excision with primary closure. Sixty-seven patients were evaluated. STN was defined as ulceration and necrosis of the surgical bed or persistently unhealed high-grade acute mucositis with pain after PORT. The median RT dose of primary site was 63.6 Gy (range, 45-67.15 Gy) with 2 Gy/fx (range 1.8-2.2 Gy/fx). Total 41 patients (61.2%) were treated with concurrent chemoradiotherapy. The median follow-up period was 26 months. STN was diagnosed in 13 patients (19.4%). Most of the patients were treated with oral steroids, antibiotics, and analgesics and the lesions were eventually improved (median of 6 months after PORT). STN did not influence local control. A depth of invasion (DOI > 1.4 cm, odds ratio [OR] 14.04, p = 0.004) and maximum dose/fraction (CTVpmax/fx > 2.3 Gy, OR 6.344, p = 0.043) and grade 3 acute mucositis (OR 6.090, p = 0.054) were related to STN. The 12 (23.5%) of 51 oropharyngeal cancer patients presented STN, and the risk factors were DOI > 1.2 cm (OR 21.499, P = 0.005), CTVpmax/fx > 2.3 Gy (OR 12.972, P = 0.021) and grade 3 acute mucositis (OR 10.537, P = 0.052). Patients treated with TORS or WE with primary closure followed by PORT had a high risk of surgical bed STN. STN risk factors included DOI (>1.2-1.4 cm) and CTVpmax/fx (>2.3 Gy). Radiation therapy after TORS must be carefully designed to prevent STN.


Results of stereotactic radiosurgery for patients with imaging defined cavernous sinus meningiomas.
The purpose of this study was to evaluate the efficacy and safety of stereotactic radiosurgery as primary management for patients with imaging defined cavernous sinus meningiomas. Between 1992 and 2001, 49 patients had radiosurgery for dural-based masses of the cavernous sinus presumed to be meningiomas. The mean patient age was 55.5 years. The mean tumor volume was 10.2 mL; the mean tumor margin dose was 15.9 Gy. The mean follow-up was 58 months (range, 16-144 months). No tumor enlarged after radiosurgery. Twelve of 38 patients (26%) with preexisting diplopia or facial numbness/pain had improvement in cranial nerve function. Five patients (10%) had new (n = 3) or worsened (n = 2) trigeminal dysfunction; 2 of these patients (4%) underwent surgery at 20 and 25 months after radiosurgery despite no evidence of tumor progression. Neither patient improved after partial tumor resection. One patient (2%) developed an oculomotor nerve injury. One patient (2%) had an ischemic stroke related to occlusion of the cavernous segment of the internal carotid artery. Event-free survival was 98%, 85%, and 80% at 1, 3, and 7 years after radiosurgery, respectively. Univariate analysis of patient and dosimetric factors found no analyzed factor correlated with postradiosurgical morbidity. Radiosurgery was an effective primary management strategy for patients with an imaging defined cavernous sinus meningioma. Except in situations of symptomatic mass effect, unusual clinical presentation, or atypical imaging features, surgery to confirm the histologic diagnosis is unlikely to provide clinical benefit.


Information seeking and retrieval skills of nurses: Nurses readiness for evidence based practice in hospitals of a medical university in Iran.
With the explosion of medical information, and emergence of evidence-based practice (EBP) in healthcare system, searching, retrieving and selecting information for clinical decision-making are becoming required skills for nurses. The aims of this study were to examine the use of different medical information resources by nurses and their information searching and retrieving skills in the context of EBP. A descriptive, cross-sectional study was conducted in four teaching hospitals in Iran. Data were collected from 182 nurses using a questionnaire in 2014. The nurses indicated that they use more human and printed resources than electronic resources to seek information (mean=2.83, SD=1.5; mean=2.77, SD=1.07; and mean=2.13, SD=0.88, respectively). To search online resources, the nurses use quick/basic search features more frequently (mean=2.45, SD=1.15) than other search features such as advanced search, index browsing and MeSH term searching. (1.74≤mean≤2.30, SD=1.01). At least 80% of the nurses were not aware of the purpose or function of search operators such as Boolean and proximity operators. In response to the question measuring skills of the nurses in developing an effective search statement by using Boolean operators, only 20% of them selected the more appropriate statement, using some synonyms of the concepts in a given subject. The study showed that the information seeking and retrieval skills of the nurses were poor and there were clear deficits in the use of updated information resources. To compensate their EBP incompetency, nurses may resort to human resources. In order to use the latest up to date evidence independently, nurses need to improve their information literacy. To reach this goal, clinical librarians, health information specialists, nursing faculties, and clinical nurse educators and mentors can play key roles by providing educational programs. Providing access to online resources in clinical wards can also encourage nurses to learn and use these resources.


Multiplicity of glucocorticoid action in inhibiting allograft rejection.
Glucocorticoids (GCs) are used as immunosuppressive and antiinflammatory agents in organ transplantation and in treating autoimmune diseases and inflammatory disorders. GCs were shown to exert their antiproliferative effects directly through blockade of certain elements of an early membrane-associated signal transduction pathway, modulation of the expression of select adhesion molecules, and by suppression of cytokine synthesis and action. GCs may act indirectly by inducing lipocortin synthesis, which in turn, inhibits arachidonic acid release from membrane-bound stores, and also by inducing transforming growth factor (TGF)-beta expression that subsequently blocks cytokine synthesis and T cell activation. Furthermore, by preferentially inhibiting the production of Th1 cytokines, GCs may enhance Th2 cell activity and, hence, precipitate a long-lasting state of tolerance through a preferential promotion of a Th2 cytokine-secreting profile. In exerting their antiproliferative effects, GCs influence both transcriptional and posttranscriptional events by binding their cytosolic receptor (GR), which subsequently binds the promoter region of cytokine genes on select DNA sites compatible with the GCs responsible elements (GRE) motif. In addition to direct DNA binding, GCs may also directly bind to, and hence antagonize, nuclear factors required for efficient gene expression, thereby markedly reducing transcriptional rate. The pleiotrophy of the GCs action, coupled with the diverse experimental conditions employed in assessing the GCs effects, indicate that GCs may utilize more than one mechanism in inhibiting T cell activation, and warrant careful scrutiny in assigning a mechanism by which GCs exert their antiproliferative effects.


Perioperative polyphenon E- and siliphos-inhibited colorectal tumor growth and metastases without impairment of gastric or abdominal wound healing in mouse models.
Perioperative anticancer therapy that does not impair wound healing is needed to counter the persistent proangiogenic plasma compositional changes that occur after colorectal resection. Polyphenon E (PolyE), a green tea derivative (main component EGCG), and Siliphos (main component silibinin), from the milk thistle plant, both have antitumor effects. This study assessed the impact of PolyE/Siliphos (PES) on wound healing and the growth of CT-26 colon cancer in several murine models. One wound healing and three tumor studies were performed. Tumor Study (TS)1 assessed the impact of PES on subcutaneous tumor growth, whereas TS2 assessed PES's impact on subcutaneous growth when given pre- and post-CO(2) pneumoperitoneum (pneumo), sham laparotomy, or anesthesia alone. TS3 determined the ability of PES to limit hepatic metastases (mets) after portal venous injection of tumor cells. In the final study, laparotomy and gastrotomy wound healing were assessed several ways. BALB/c mice were used for all studies. The drugs were given via drinking water (PolyE) and gavage (Siliphos), daily, for 7-9 days preprocedure and for 7-21 days postoperatively. Tumor mass, number/size of hepatic mets, and proliferation and apoptosis rates were assessed. The abdominal breaking strength and energy to failure were measured postmortem as was gastric bursting pressures. PES significantly inhibited subcutaneous growth in the nonoperative setting. PES also significantly decreased the number/size of liver mets when given perioperatively. Abdominal wound breaking strength, energy to wound failure, and collagen content were not altered by PES; gastrotomy bursting strength also was not affected by PES. Neither drug alone had a significant impact on tumor growth. The PES combination inhibited subcutaneous and hepatic tumor growth yet did not impair wound healing. PES holds promise as a perioperative anticancer therapy.


The experimental study of cardiac allograft vasculopathy and myocardial fibrosis in rats.
We sought to analyze the development of myocardial fibrosis and cardiac allograft vasculopathy (CAV) as a theoretical basis for the prevention and treatment of rejection. Heterotopic cardiac transplantation was performed from Wistar rats to Sprague-Dawley rats. The recipients pretreated with donor splenocyte (SPC) infusion followed by cyclophosphamide (CP) were divided into 3 groups: Control animals without immunosuppression (Group 1; n = 10); Group 2, CsA treatment (n = 10) with euthanasia 2-3 months posttransplantation; and Group 3 (n = 20), CP plus SPC treatment with 10 recipients euthanized at 2 weeks posttransplantation and 10 animals monitored for at least 1 year posttransplantation. Histological studies were performed to evaluate myocardial fibrosis and CAV; 2-3 days after transplantation, there was abundant infiltration of collagenous fibers in the adventitia and intima of the coronary arteries in Group 1 allografts. Group 2 allografts demonstrated abundant infiltration of collagenous fibers in the adventitia and intima of arteries and arterioles resulting in significant luminal stenosis. In contrast, pretreatment of animals with SPC and CP induced long-term allograft survival; myocardial fibrosis and CAV were dramatically reduced in Group 3 compared with Groups 1 and 2. The infiltration of collagenous fibers in coronary arteries was one of the major causes of CAV. Preconditioning of recipients with SPC followed by CP not only induced immune tolerance but also alleviated myocardial fibrosis and CAV in allografts.


Emerging roles of RETINOBLASTOMA-RELATED proteins in evolution and plant development.
RETINOBLASTOMA-RELATED (RBR) proteins are plant homologs of the human tumor suppressor pRB. Similar to their animal counterparts they have roles in cell cycle regulation and differentiation. We discuss recent findings of the evolution of RBR functions ranging from a molecular ruler and metabolic integrator in algae to a coordinator of differentiation in gametophytes. Genetic analysis and manipulation of protein levels during gametophytic and post-embryonic plant development are now providing new insights into the function of RBR in stem cell maintenance, cell specification and differentiation. We briefly explain interactions of RBR with chromatin-modifying complexes that appear to be a central underlying molecular mechanism during developmental transitions.


Redirected perforant and commissural of connections of eutopic and ectopic neurons in the hippocampus of methylazoxymethanol-acetate treated rats.
In an earlier study, it was reported that clusters of ectopic neurons developed postnatally in the hippocampus of rats which were exposed to Methylazoxymethanol acetate (MAMac) during fetal development (Singh, 1977b). This paper describes the perforant tract and commissural connections of hippocampal eutopic and ectopic neurons. These connections were traced with a reduced-silver method (Eager, 1970). Two observations of significance were made: (i) Ectopic neurons misplaced in stratum radiatum received terminals from axons in the perforant tract. The upper boundary for these redirected fibers was stratum pyramidale--approximately 350 mu outside the normal boundary which is situated near the hippocampal fissure. (ii) Ectopic neurons received a dramatically reduced commissural projection, compared with eutopic pyramidal neurons in Ammon's horn. Eutopic neurons in the hippocampus were found to receive afferent perforant tract and commissural fibers in the same way--i.e., density and distribution, as in control rats.


The effect of small-scale environmental changes on disease incidence and severity in a natural plant-pathogen interaction.
The incidence and severity of Rhynchosporium secalis infections were assessed in a large population of Hordeum leporinum. Transects were set out in four directions from five trees to determine the effect of shading. Under the tree canopy 60.3% of H. leporinum plants were infected while only 11.2% were infected away from the canopy. Disease severity, on those plants which were infected, was higher under the canopy (mean 12.4% and 13.0% leaf area diseased for the flag and first leaves, respectively) than away from the canopy (means of 7.8% and 5.0% for the flag and first leaves respectively). Plants under the tree canopy contained on average 23% more nitrogen, raising the possibility that the susceptibility of the host changed in response to nitrogen levels. However, the observed pattern is also consistent with the hypothesis that shade-associated changes in the environment enhanced the ability of the pathogen to infect and develop on the host. The data clearly demonstrate the importance of small-scale environmental factors on natural host-pathogen interactions. These environmental factors may cause differential selection for disease resistance within a host population, which may ultimately lead to the formation of sub-populations with differing levels of resistance.


Biodegradability of wastewater determines microbial assembly mechanisms in full-scale wastewater treatment plants.
Wastewater treatment plants (WWTPs) are critical for maintaining sustainable development in modern societies, wherein microbial populations residing in activated sludge (AS) are responsible for the removal of pollutants from wastewater. The biodegradability [biological oxygen demand/chemical oxygen demand (B/C ratio)] of influent, as a measure of the degree of available energy and toxicity to microorganisms in AS, has been hypothesized to drive AS microbial community assembly. However, the validity of this hypothesis has not been tested in full-scale WWTPs. In this study, we assessed the pollutant removal loads, the microbial community diversity, the relative importance of deterministic and stochastic assembly processes, and bio-interactions within the communities by analyzing 195 AS samples comprising nearly 5 000 000 16S rRNA sequences. Our results indicate that the effects of B/C ratio on pollutant removal loads can be perfectly reflected through biological properties, implying that B/C ratio determined WWTPs performance through affecting microbial community. Very low and/or very high B/C ratios result in low microbial diversity, strong stochastic processes, and large, complex networks, leading to low pollutant removal load of treatment. A B/C ratio of around 0.5 was optimal for system stability and efficiency. Based on the results of this study, the authors propose using the B/C ratio as an indispensable index to assess system performance and to provide an indicator of an impending process upset before function deteriorates significantly. This study provides a specific measure that can be used to evaluate strategies for process optimization and operation of WWTPs.


Effects of hydrodynamics processes on phosphorus fluxes from sediment in large, shallow Taihu Lake.
The turnover of phosphorus (P) in lake sediments, a major cause of eutrophication and subsequent deterioration of water quality, is in need of deep understanding. In this study, effects of resuspension on P release were studied in cylindrical microcosms with Y-shape apparatus. The results indicated that there was a positive correlation between flux of suspended substance across sediment-water interface (F(SS)) and the wind speed, and an increasing F(SS) during each wind process followed by a steady state. The maximal F(SS) under light, moderate, and strong wind conditions were 299.9 +/- 41.1, 573.4 +/- 61.7, and 2093.8 +/- 215.7 g/m2, respectively. However, flux of P across sediment-water interface (F(P)) did not follow a similar pattern as F(SS) responding to wind intensity, which increased and reached the maximum in initial 120 min for light wind, then decreased gradually, with maximal flux of 9.4 +/- 1.9 mg/m2. A rapid increase of F(P) at the first 30 min was observed under moderate wind, with maximal flux of 11.2 +/- 0.6 mg/m2. Surprisingly, strong wind caused less F(P) than under light and moderate wind conditions with maximal flux of 3.5 +/- 0.9 mg/m2. F(SS) in water column declined obviously during the sedimentation process after winds, but F(P) varied with wind regime. No obvious difference was detected on F(P) after 8 h sedimentation process, compared with the initial value, which means little redundant P left in the water column after winds.


Pattern generation in the lobster (Panulirus) stomatogastric ganglion. II. Pyloric network simulation.
1. Results from the companion paper were incorporated into a physiologically realistic computer model of the three principal cell types (PD/AB, LP, PY) of the pyloric network in the stomatogastric ganglion. Parameters for the model were mostly calculated (sometimes estimated) from experimental data rather than fitting the model to observed output patterns. 2. The initial run was successful in predicting several features of the pyloric pattern: the observed gap between PD and LP bursts, the appropriate sequence of the activity periods (PD, LP, PY), and a substantial PY burst not properly simulated by an earlier model. 3. The major discrepancy between model and observed patterns was the too-early occurrence of the PY burst, which resulted in a much shortened LP burst. Motivated by this discrepancy, additional investigations were made of PY properties. A hyperpolarization-enabled depolarization-activated hyperpolarizing conductance change was discovered which may make an important contribution to the late phase of PY activity in the normal burst cycle. Addition of this effect to the model brought its predictions more in line with observed patterns. 4. Other discrepancies between model and observation were instructive and are discussed. The findings force a substantial revision in previously held ideas on pattern production in the pyloric system. More weight must be given to functional properties of individual neurons and less to properties arising purely from network interactions. This shift in emphasis may be necessary in more complicated systems as well. 5. An example has been provided of the value quantitative modeling can be to network physiology. Only through rigorous quantitative testing can qualitative theories of how the nervous system operates be substantiated.


Disruption of Striatal-Enriched Protein Tyrosine Phosphatase Signaling Might Contribute to Memory Impairment in a Mouse Model of Sepsis-Associated Encephalopathy.
Sepsis-associated encephalopathy (SAE) is a potentially irreversible acute cognitive dysfunction with unclear mechanism. Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase which normally opposes synaptic strengthening by regulating key signaling molecules involved in synaptic plasticity and neuronal function. Thus, we hypothesized that abnormal STEP signaling pathway was involved in sepsis-induced cognitive impairment evoked by lipopolysaccharides (LPS) injection. The levels of STEP, phosphorylation of GluN2B (pGluN2B), the kinases extracellular signal-regulated kinase 1/2 (pERK), cAMP-response element binding protein (CREB), synaptophysin, brain derived neurotrophic factor (BDNF), and post-synaptic density protein 95 (PSD95) in the hippocampus, prefrontal cortex, and striatum were determined at the indicated time points. In the present study, we found that STEP levels were significantly increased in the hippocampus, prefrontal cortex, and striatum following LPS injection, which might resulted from the disruption of the ubiquitin-proteasome system. Notably, a STEP inhibitor TC-2153 treatment alleviated sepsis-induced memory impairment by increasing phosphorylation of GluN2B and ERK1/2, CREB/BDNF, and PSD95. In summary, our results support the key role of STEP in sepsis-induced memory impairment in a mouse model of SAE, whereas inhibition of STEP may provide a novel therapeutic approach for this disorder and possible other neurodegenerative diseases.


Race Differences in the Associations between Menstrual Cycle Characteristics and Epithelial Ovarian Cancer.
Menstrual cycle characteristics-including age at menarche and cycle length- have been associated with ovarian cancer risk in White women. However, the associations between menstrual cycle characteristics and ovarian cancer risk among Black women have been sparsely studied. Using the Ovarian Cancer in Women of African Ancestry (OCWAA) Consortium that includes 1,024 Black and 2,910 White women diagnosed with epithelial ovarian cancer (EOC) and 2,325 Black and 7,549 White matched controls, we investigated associations between menstrual cycle characteristics (age at menarche, age at menstrual regularity, cycle length, and ever missing three periods) and EOC risk by race and menopausal status. Multivariable logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Black women were more likely to be <11 years at menarche than White women (controls: 9.9% vs. 6.0%). Compared with ≥15 years at menarche, <11 years was associated with increased EOC risk for White (OR = 1.25; 95% CI, 0.99-1.57) but not Black women (OR = 1.10; 95% CI, 0.80-1.55). Among White women only, the association was greater for premenopausal (OR = 2.20; 95% CI, 1.31-3.68) than postmenopausal women (OR = 1.06; 95% CI, 0.82-1.38). Irregular cycle length was inversely associated with risk for White (OR = 0.78; 95% CI, 0.62-0.99) but not Black women (OR = 1.06; 95% CI, 0.68-1.66). Earlier age at menarche and cycle irregularity are associated with increased EOC risk for White but not Black women. Associations between menstrual cycle characteristics and EOC risk were not uniform by race.


Modular construction of plasmids by parallel assembly of linear vector components.
Construction of plasmids is the basic and pivotal technology in molecular biology. The common method for constructing plasmids is to cut DNA fragments by restriction enzymes and then join the resulting fragments using ligase. We present here a modified Golden Gate cloning method for modular construction of plasmids. Unlike the original Golden Gate cloning system for cloning from entry vector to expression vector, this method can be used to construct plasmids immediately from linear DNA fragments. After polymerase chain reaction (PCR) amplification for flanking with BsaI sites, multiple linear DNA components (modules) can be parallel assembled into a circle plasmid by a single restriction-ligation reaction using the method. This method is flexible to construct different types of plasmids because the modules can be freely selected and assembled in any combination. This method was applied successfully to construct a prokaryotic expression plasmid from four modules and a plant expression plasmid from five modules (fragments). The results suggest that this method provides a simple and flexible platform for modular construction of plasmids.


Telescoping of drinking-related behaviors: gender, racial/ethnic, and age comparisons.
To examine demographic differences in alcohol telescoping-the rate of self-reported movement from regular alcohol consumption to the onset of regular heavy drinking-as well as differences in ages of initiation of regular alcohol use and alcohol use to intoxication. The present study compared the retrospective reports of 2037 clients (1252 males, 785 females) enrolled in substance user treatment facilities around the country in 1998 and 1999. Overall, the findings support previous research, indicating that women generally move more rapidly than men from initiation of regular alcohol use to problem use (telescoping). The findings also indicate that African-Americans generally begin regular alcohol use later than their Anglo counterparts and move more rapidly from initiation of regular alcohol use to problem use (telescoping). Examining the sample by older vs. younger age groups demonstrates that gender and racial/ethnic differences in the age of initiation of regular alcohol use and in telescoping may be limited by age group, as these patterns appear in the older but not the younger cohort. These findings suggest that self-reported regular alcohol use, alcohol abuse, and telescoping differences vary dramatically by gender, race/ethnicity, and age cohort. Furthermore, the pattern of findings suggests that these differences are more likely the result of sociocultural than biological differences between the groups under study.


Organization-based self-development prescriptive model for the promotion of professional development of Iranian clinical nurses.
Professional development is reiterated in the new definition of modern organizations as a serious undertaking of organizations. This article aims to present and describe a prescriptive model to increase the quality of professional development of Iranian nurses within an organization-based framework. This article is an outcome of the results of a study based on grounded theory describing how Iranian nurses develop. The present study adopted purposive sampling and the initial participants were experienced clinical nurses. Then, the study continued by theoretical sampling. The present study involved 21 participants. Data were mainly collected through interviews. Analysis began with open coding and continued with axial coding and selective coding. Trustworthiness was ensured by applying Lincoln and Guba criteria such as credibility, dependability, and conformability. Based on the data gathered in the study and a thorough review of related literature, a prescriptive model has been designed by use of the methodology of Walker and Avant (2005). In this model, the first main component is a three-part structure: Reformation to establish a value-assigning structure, a position for human resource management, and a job redesigning. The second component is certain of opportunities for organization-oriented development. These strategies are as follows: Raising the sensitivity of the organization toward development, goal setting and planning the development of human resources, and improving management practices. Through this model, clinical nurses' professional development can transform the profession from an individual, randomized activity into more planned and systematized services. This model can lead to a better quality of care.


Replacing and safeguarding pancreatic β cells for diabetes.
Pluripotent stem cells are a scalable source of pancreatic cells for transplantation into patients with diabetes. Here, we describe how the field is gaining momentum toward a β cell replacement therapy.


10p- syndrome associated with multiple chromosomal abnormalities.
A karyotype with six de novo autosomal abnormalities in chromosomes 2,4,9,10,12, and 13 was identified in a 7-year-old boy with mental retardation and other minor malformations. The G- and C-banding techniques revealed an equilibrated translocation between autosomes 2 and 4 and between autosomes 9 and 13. One chromosome 10 has lost genetic material from its short arms, probably because of an interstitial deletion. An unidentified chromosomal fragment has become inserted in the long arms of an autosome 12. The G bands demonstrate that genetic material inserted in the autosome 12 is not the genetic material deleted from the autosome 10. The propositus presents clinical features similar to the reported cases with 10p- syndrome. Nevertheless it is not possible to establish the influence of the genetic material inserted in autosome 12 on the propositus' phenotype.


Synergistic inhibition of replication of human immunodeficiency virus type 1, including that of a zidovudine-resistant isolate, by zidovudine and 2',3'-dideoxycytidine in vitro.
The combination of zidovudine (AZT) and 2',3'-dideoxycytidine synergistically inhibits human immunodeficiency virus type 1 (HIV-1) replication in vitro with AZT-sensitive and AZT-resistant clinical isolates and HIV-1IIIB. Synergy was determined by the median-effect principle and isobologram techniques. Cytotoxicity of the agents was not observed. Clinical trials are ongoing to define the combination's role in HIV-1 therapy.


Congenital coronary anomalies present with a frequency of 0.7% in the general population. Most coronary anomalies are benign, but some may be linked to ischaemia and sudden cardiac death. In this case report, we describe the findings of a middle-aged man who was seen for unspecific cardiac symptoms. Echocardiography revealed a vascular abnormality recently recognised as an indicator of coronary anomaly, the retroaortic anomalous coronary sign. With this case, we wish to spread awareness of this sign to highlight what it indicates and what its potential implications are.


Subdivision of the Escherichia coli K-12 genome for sequencing: manipulation and DNA sequence of transposable elements introducing unique restriction sites.
A transposon-based method of introducing unique restriction sites was used for subdivision of the Escherichia coli genome into a contiguous series of large non-overlapping segments spanning 2.5Mb. The segments, sizes ranging from 150 to 250kb, were isolated from the chromosome using the inserted restriction sites and shotgun cloned into an M13 vector for DNA sequencing. These shotgun sizes proved easily manageable, allowing the genomic sequence of E. coli to be completed more efficiently and rapidly than was possible by previously available methods. The 9bp duplication generated during transposition was used as a tag for accurate splicing of the segments; no further sequence redundancy at the junction sites was needed. The system is applicable to larger genomes even if they are not already well-characterized. We present the technology for segment sequencing, results of applying this method to E. coli, and the sequences of the transposon cassettes.


Investigation of the Radiographic Imaging Volume and Occupational Dose of Radiologic Technologists before and during the COVID-19 Pandemic.
This study aimed to assess occupational radiation doses for radiologic technologists (RTs) in Saudi Arabia shortly before and during the COVID-19 pandemic, considering changes in imaging volume during that time. This retrospective study included the imaging volume data and the RTs' occupational dose records from a central hospital for 2019 and 2020. The occupational dose-in terms of annual and quarterly mean effective doses (AMEDs and QMEDs)-was estimated for 115 RTs using thermoluminescent dosimeter records. There was a 22% increase in the AMED in 2020 compared with 2019, though the overall imaging volume decreased by 9% in 2020. The percentage changes in AMEDs between 2019 and 2020 for general radiography (GR), computed tomography (CT), interventional radiology (IR), nuclear medicine (NM), and mammography (MG) were 45%, 56%, 9%, 18% and -2%, respectively. The highest contribution to AMEDs in 2020 for modalities was due to GR and CT procedures, accounting for 0.50 mSv and 0.58 mSv, respectively. The percentage change in imaging volumes between 2019 and 2020 depicted a slight decrease in Q2 (-1%) and a substantial decrease in Q1 (-10%), Q3 (-12%), and Q4 (-11%) for 2020. The overall percentage changes in imaging volumes in 2020 for GR (conventional and mobile), CT, IR, NM, and MG were -7% (-19% and 48%), -11%, 13%, -26%, and -46%, respectively. Investigating the changes in 2020 by comparing Q1 of 2020 (before the pandemic restrictions) with Q2 (during the pandemic restrictions and changes in workflow) revealed that the QMED during Q2 increased by 5% with a 17.4% decrease in the imaging volume. However, CT procedures were increased by 11.1% during the pandemic restrictions in Q2 of 2020, with an increase in the corresponding QMED of 66%. Moreover, mobile GR procedures increased by 21% in Q2 of 2020 compared to Q1. This study indicated the impact of the COVID-19 pandemic on imaging volume and occupational dose. Overall, the study observed a decrease in the imaging volume and an increase in RTs' effective doses by 2020. However, there was an increase in mobile GR and CT examinations during the COVID-19 pandemic restrictions in 2020. This study suggested that the increased mobile GR and CT examinations contributed to greater effective doses for RTs in 2020.


Use of the transverse colon conduit for vesicovaginal fistula in late-stage carcinoma of the cervix.
Fifty-five patients with advanced carcinoma of the cervix and vesicovaginal fistula were managed by urinary diversion using the transverse colon as a conduit. The surgical technique is described and this form of urinary diversion is recommended for these patients.


True Aneurysm of Ovarian and Uterine Arteries:a Comprehensive Review.
Gonadal artery aneurysm represents an extremely rare condition often unrecognized until rupture. A literature review was undertaken on Pubmed from 1990 to 2020 to identify reported cases of ovarian and uterine artery aneurysms, including the index case presented here. Data about the clinical presentation, diagnostic approach, and treatment were collected. Twenty-one articles reporting on data about 22 patients, including the index case, were included. The patients's median age was 46.7 years (range 30-80) and aneurysm maximal diameter 2.6 cm (range 0.75-5 cm). Except for one asymptomatic patient, the aneurysm's clinical presentation was abdominal/back pain in the majority of cases (n = 20, 90.9%). Rupture with retroperitoneal hematoma occurred in 16 cases (72.7%) and hemorrhagic shock in one case (4.5%). No history of vaginal bleeding was reported in any case. The majority of the aneurysms were diagnosed in women of childbearing age: in 50% (n = 11) of cases during the peripartum period and in 22.7% (n = 5) of cases during the postmenstruation period. The remaining cases (n = 6, 27.3%) were detected during the postmenopausal period. The majority of patients (n = 15, 68.2%) were emergently treated with an endovascular approach by embolization, achieving the total exclusion of the aneurysm in 86.7% of cases (13 patients). In 7 cases (31.8%), surgical ligation was performed, of which 2 (9.1%) were for the failure of a primarily attempted coils embolization. The spontaneous thrombosis of the uterine aneurysm was noted 3 months after the initial diagnosis in one patient. The Gonadal artery aneurysms are unrecognized entities until an acute rupture occurs. Endovascular treatment by embolization is progressively becoming the first-line treatment with satisfactory results.


Risk of drug use during pregnancy: master protocol for living systematic reviews and meta-analyses performed in the metaPreg project.
Knowledge about the risks of drugs during pregnancy is continuously evolving due to the frequent publication of a large number of epidemiological studies. Systematic reviews and meta-analyses therefore need to be regularly updated to reflect these advances. To improve dissemination of this updated information, we developed an initiative of real-time full-scale living meta-analyses relying on an open online dissemination platform ( www.metapreg.org ). All living meta-analyses performed in this project will be conducted in accordance with this master protocol after adaptation of the search strategy. A systematic literature search of PubMed and Embase will be performed. All analytical studies (e.g., cohort, case-control, randomized studies) reporting original empirical findings on the association between in utero exposure to drugs and adverse pregnancy outcomes will be included. Study screening and data extraction will be performed in a semi-automation way supervised by a biocurator. A risk of bias will be assessed using the ROBINS-I tools. All clinically relevant pregnancy adverse outcomes (malformations, stillbirths, neuro-developmental disorders, pre-eclampsia, etc.) available in the included studies will be pooled through random-effects meta-analysis. Heterogeneity will be evaluated by I2 statistics. Our living systematic reviews and subsequent updates will inform the medical, regulatory, and health policy communities as the news results evolve to guide decisions on the proper use of drugs during the pregnancy. Open Science Framework (OSF) registries.


Home parenteral nutrition in patients with systemic sclerosis: a retrospective review of 12 cases.
To evaluate the effect of home total parenteral nutrition (HTPN) on the nutritional and functional status of patients with systemic sclerosis (SSc). Retrospective review of SSc patients from the HTPN database at the University Health Network, Toronto, Canada, from 1998 to 2010. In total 12 subjects (9 females, 3 males) with SSc were identified. At initiation of HTPN, the age was 48.75 ± 3.94 years and the median body mass index was 16.8 kg/m(2) (range 12.3-21.3). This significantly increased to 18.3 kg/m(2) (17.0-21.7) at 6 months and to 19.7 kg/m(2) (17.0-24.6) at 12 months. The mean Karnofsky score at baseline was 58.00 ± 3.27, and the score at 12 months of 39.00 ± 13.29 did not change significantly. HTPN improved the nutritional status of these patients with SSc but it did not improve their functional status.


Collagen arrangements in ureter.
The collagen fibres of rabbit and human ureter were exposed by digestion with trypsin and hyaluronidase. The fibre structure was examined using an SEM and examples of the inner and outer fibre structures are shown together with the effects of different types of mechanical strain. An interesting difference between the arrangements of the inner fibres of human and rabbit was seen where the human ureter had a cross-ply structure while in the rabbit it was helical.


Psychosocial and health stressors during the COVID-19 pandemic and their association with sleep quality.
We investigated how psychosocial and health stressors and related cognitive-affective factors were differentially associated with sleep quality during the early months of the COVID-19 pandemic. Adults living in Florida (n = 2,152) completed a Qualtrics survey in April-May 2020 (Wave 1). Participants (n = 831) were reassessed one month later (Wave 2; May-June 2020). At Wave 1, participants reported their level of physical contact with someone they care about, presence of a pre-existing chronic disease, employment status, loneliness, health worry, and financial distress. At Wave 2, participants rated their quality of sleep and insomnia symptoms. Loneliness, but not health worry or financial distress, directly predicted worse sleep quality. Lack of physical contact was indirectly associated with worse sleep quality via greater levels of loneliness. Further, results showed the presence of a pre-existing chronic disease was associated with both greater health worry and worse sleep quality. Loneliness was the sole cognitive-affective predictor of worse sleep quality when controlling for other psychosocial factors. As expected, adults living with a chronic disease reported impaired sleep quality. Understanding the processes influencing sleep quality during a significant time of stress is important for identifying risk factors, informing treatment, and improving sleep health beyond the pandemic.


Screening strategies for atrial fibrillation in the elderly population: a systematic review and network meta-analysis.
Opportunistic screening for atrial fibrillation (AF) is currently recommended for patients aged 65 years and older. However, this has recently been called into question by two studies that report that opportunistic screening is no more effective than usual care. Furthermore, there seems to be no consensus on which is the most effective screening strategy (opportunistic or systematic). Thus, we aimed to compare the different AF detection strategies with each other using the methodology of systematic review with network meta-analysis. An electronic database search of MEDLINE, CENTRAL, and EMBASE was performed. In addition, we also searched OpenGrey, experts' knowledge and screened the reference list of included studies or other relevant publications. The search was performed on the 2nd of November of 2020 and updated on the 20th of September of 2021. We performed a random-effects pairwise meta-analysis and a random-effects network meta-analysis within a frequentist framework in an intention to screen analysis. We reported the results as relative risk (RR) with 95% confidence intervals (CI). We assessed the confidence in the evidence using the GRADE framework. Nine studies were included, enrolling 80,665 participants. Pooled effect sizes suggested that systematic screening was effective when compared with usual care (RR 2.11; 95% CI 1.48-3.02; high GRADE confidence) and when compared with opportunistic screening (RR 1.86; CI 1.23-2.82; high GRADE confidence) but no significant difference was found between opportunistic screening and usual care (RR 1.13; 95% CI 0.79-1.63; low GRADE confidence). Systematic screening was the most effective strategy for detecting atrial fibrillation in individuals aged 65 years or older. Opportunistic screening was no more effective than usual care, but the results were weakened by a low quality of evidence due to risk of bias of the included studies and imprecision in the results. PROSPERO registration number: CRD42020218672.


United States Population Disparities in Ophthalmic Care: Blindness and Visual Impairment in the IRIS® Registry (Intelligent Research in Sight).
To evaluate associations of patient characteristics with United States eye care use and likelihood of blindness. Retrospective observational study. Patients (19 546 016) with 2018 visual acuity (VA) records in the American Academy of Ophthalmology's IRIS® Registry (Intelligent Research in Sight). Legal blindness (20/200 or worse) and visual impairment (VI; worse than 20/40) were identified from corrected distance acuity in the better-seeing eye and stratified by patient characteristics. Multivariable logistic regressions evaluated associations with blindness and VI. Blindness was mapped by state and compared with population characteristics. Eye care use was analyzed by comparing population demographics with United States Census estimates and proportional demographic representation among blind patients versus a nationally representative US population sample (National Health and Nutritional Examination Survey [NHANES]). Prevalence and odds ratios for VI and blindness; proportional representation in the IRIS® Registry, Census, and NHANES by patient demographics. Visual impairment was present in 6.98% (n = 1 364 935) and blindness in 0.98% (n = 190 817) of IRIS patients. Adjusted odds of blindness were highest among patients ≥ 85 years old (odds ratio [OR], 11.85; 95% confidence interval [CI], 10.33-13.59 vs. those 0-17 years old). Blindness also was associated positively with rural location and Medicaid, Medicare, or no insurance vs. commercial insurance. Hispanic (OR, 1.59; 95% CI, 1.46-1.74) and Black (OR, 1.73; 95% CI, 1.63-1.84) patients showed a higher odds of blindness versus White non-Hispanic patients. Proportional representation in IRIS Registry relative to the Census was higher for White than Hispanic (2- to 4-fold) or Black (11%-85%) patients (P < 0.001). Blindness overall was less prevalent in NHANES than IRIS Registry; however, prevalence in adults aged 60+ was lowest among Black participants in the NHANES (0.54%) and second highest among comparable Black adults in IRIS (1.57%). Legal blindness from low VA was present in 0.98% of IRIS patients and associated with rural location, public or no insurance, and older age. Compared with US Census estimates, minorities may be underrepresented among ophthalmology patients, and compared with NHANES population estimates, Black individuals may be overrepresented among blind IRIS Registry patients. These findings provide a snapshot of US ophthalmic care and highlight the need for initiatives to address disparities in use and blindness. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.


A prospective radiological anatomical study of the variations of the position of the colon in the left pararenal space.
Percutaneous puncture of the kidney allows direct access to the pyelocalicial cavities. The posterior approach of this retroperitoneal organ can be complicated of transcolic punctures due to the postrenal position of the colon. A prospective radiological anatomical study of the relationship between the left kidney and the descending colon was undertaken. One hundred computed tomograms of adult subjects were obtained from which the anatomy of the left perirenal area was determined: the descending colon is more frequently behind the kidney in the young females. Two main factors determinants of this situation are: 1) colon ontogenesis in relation to the attachment of the primitive mesocolon, permitting a 'fixed' left colon, or 'moving' left colon at the end of a long mesocolon, allowing it to pass behind the kidney; 2) a mechanical factor whereby the accumulation of perirenal fat with increasing age may be a limiting factor in lateral displacement of the colon.


Considering new methodologies in strategies for safety assessment of foods and food ingredients.
Toxicology and safety assessment are changing and require new strategies for evaluating risk that are less depending on apical toxicity endpoints in animal models and relying more on knowledge of the mechanism of toxicity. This manuscript describes a number of developments that could contribute to this change and implement this in a stepwise roadmap that can be applied for the evaluation of food and food ingredients. The roadmap was evaluated in four case studies by using literature and existing data. This preliminary evaluation was shown to be useful. However, this experience should be extended by including examples where experimental work needs to be included. To further implement these new insights in toxicology and safety assessment for the area of food and food ingredients, the recommendation is that stakeholders take action in addressing gaps in our knowledge, e.g. with regard to the applicability of the roadmap for mixtures and food matrices. Further development of the threshold of toxicological concern is needed, as well as cooperation with other sectors where similar schemes are under development. Moreover, a more comprehensive evaluation of the roadmap, also including the identification of the need for in vitro experimental work is recommended.


Antifertility, antibacterial, antifungal and percent disease incidence aspects of macrocyclic complexes of manganese(II).
Macrocyclic complexes of Mn(II) were synthesized by template condensation using 2,6-diaminopyridine and diethylenetriamine with malonic, succinic, glutaric and adipic acids. The reaction proceeded smoothly to completion. These 16- to 24-membered N(6), but behaving as tetradentate, macrocyclic complexes were characterized by elemental analyses, molecular weight determinations, infrared, electronic, mass and X-ray spectral analyses. The elemental analyses are consistent with the formation of complexes [Mn(N(6)L(n))Cl(2)]. All the complexes are stable and monomeric in nature, as indicated by the molecular weight determinations. The spectral studies confirmed the proposed framework of the new macrocyclic complexes and indicated an octahedral geometry around the central metal atom. The complexes were screened in vitro against a number of pathogenic fungi and bacteria to assess their growth-inhibiting potential. The testicular sperm density, sperm morphology, sperm motility, density of cauda epididymis, spermatozoa and fertility in mating trials and the biochemical parameters of the reproductive organs of the rat were examined and are discussed.


Lipoprotein-mediated inhibition of endothelial cell production of platelet-derived growth factor-like protein depends on free radical lipid peroxidation.
Cultured vascular endothelial cells produce several mitogens including a platelet-derived growth factor-like protein (PDGF-c). We previously reported that acetylated low density lipoprotein (acetyl-LDL) caused accumulation of cholesterol and specific inhibition of PDGF-c production by bovine aortic endothelial cells (Fox, P. L., and DiCorleto, P. E. (1986) Proc. Natl. Acad. Sci. U. S. A. 83, 4774-4778). We have now examined the role of cholesterol and other lipids on the inhibition of production of PDGF-c. Incubation of endothelial cells with free cholesterol/albumin complexes resulted in a large increase in cellular cholesterol content but did not inhibit PDGF-c production, demonstrating that cholesterol itself is not inhibitory. Involvement of lipid peroxides in the suppression of PDGF-c production was indicated by three observations. LDL modified in vitro by free radical lipid peroxidation quantitatively inhibited PDGF-c production. The inhibition was dependent on the level of LDL oxidation (as measured by thiobarbituric acid reactivity) and was specific since total protein synthesis was not affected. Inhibition of PDGF-c production by acetyl-LDL was also dependent on peroxidation. A lipid extract from oxidized LDL, but not from native LDL, specifically inhibited PDGF-c production. Chloroquine, monensin, and NH4Cl, inhibitors of lysosomal hydrolytic activity, did not prevent acetyl-LDL-mediated inhibition of PDGF-c production, indicating that cellular metabolism of the lipoprotein was not required for the inhibition. Furthermore, acetyl-LDL suppressed PDGF-c production by endothelial cells even in the presence of butylated hydroxytoluene, an inhibitor of lipid peroxidation, suggesting that cellular propagation of free radicals was not required for the inhibition. Finally, inhibition of PDGF-c production may be regulated at the post-transcriptional level since Northern blot analysis using a v-sis probe showed that the PDGF B-chain mRNA amounts were unaffected by oxidized or acetylated LDL. In summary, levels of an oxidized lipoprotein that have no effect on endothelial cell viability or protein synthetic rates can completely suppress production of a growth factor which may act as a paracrine mitogen in normal and pathological vascular processes.


[ST-segment elevation myocardial infarction due to anaphylactic shock triggered by contrast medium].
We present a case of a 57 year-old patient who developed inferior wall myocardial infarction as a consequence of anaphylactic shock, which occurred as a reaction to contrast medium. The patient was discharged home fully recovered after 14 days with recommendation of further allergology diagnostics.


Beneficial effect of enteral feeding.
The last 4 decades have seen an explosion in nutritional research investigating both clinical and laboratory issues occurring in diverse groups of patients who cannot maintain a normal oral diet. Over the past 25 years, researchers have investigated how the administration of macro- and micronutrients via the gastrointestinal tract provides additional benefit over parenteral administration of similar nutrients. The administration of enteral feeding provides effects that are far beyond those of merely administering macro- and micronutrients. Rather, the processing of nutrients via the gastrointestinal tract stimulates a complex response that has implications for body composition and for immunologic integrity. Route and type of nutrition are important aspects of successful patient recovery.


A simple screening assay for receptor switching of avian influenza viruses.
Adaptation of the receptor-binding preference from alpha2,3- to alpha2,6-linked sialic acid is an essential step for an avian influenza virus to transmit efficiently in human population and become a pandemic virus. The currently available assays for receptor-binding preference are complex and not widely available. A simple high-throughput screening assay will facilitate early detection of a potential pandemic virus, which is crucial for the prevention and control of the possible pandemic. We wanted to develop a simple assay to differentiate influenza viruses with alpha2,3- or alpha2,6-linked receptor-binding preference. The assay employs a specific sialidase (from Salmonella thyphimurium) that can eliminate alpha2,3-linked sialic acid from red blood cells. A reduction of hemagglutination titer indicates alpha2,3-linked receptor preference in this assay. Using a panel of H5N1 avian influenza isolates and H1/H3 human influenza isolates, as well as mutated H5 reverse genetics virus, the assay could accurately differentiate the viruses according to their receptor-binding preference. Furthermore, the assay was sufficiently sensitive to detect a minor variant with alpha2,6-linkage-specificity in a background of alpha2,3-linkage-specific virus. We have developed a simple screening assay capable of detecting avian influenza viruses that have switched their receptor-binding preference.


Further mitigating carbon footprint pressure in urban agglomeration by enhancing the spatial clustering.
The increasing environmental pressure of anthropogenic CO2 emissions is impeding the sustainability of urban agglomerations (UAs). Recent research has shown that the spatial clustering of UA elements reduces CO2 emissions but underestimates its impact on vegetation carbon sequestration. Using an extended IPAT equation analysis framework and the Logarithmic Mean Divisia Index decomposition approach, this study revealed the positive effects of the economy and population spatial clustering on carbon footprint pressure (CFP) mitigation. Specifically, improving economic spatial clustering mitigated the rise in UA's CFP caused by affluence and population growth. Furthermore, population clustering in core cities effectively mitigated CFP in neighboring cities. Additionally, we found that the efficiency improvement, i.e., the decrease in the ratio of carbon emissions and gross domestic product, should be the dominant driver of CFP mitigation, followed by improved vegetation carbon sequestration. However, these drivers have limited future potential. We believe that by improving UA's spatial clustering of the economy and population, future urban environmental pressures and climate risks will be mitigated.


Non-HLA autoimmunity genetic factors contributing to Autoimmune Polyglandular Syndrome type II in Tunisian patients.
Autoimmune Polyglandular Syndrome Type II (APSII) is characterized by the co-occurrence of clinical insufficiency of at least two endocrine glands. Although, HLA determinants of APSII predisposition have been identified, little attention has been paid to non-HLA genes. Here, we used SNP genotyping in a Sequenom platform and genetic association tests to study a cohort of 60 APSII Tunisian patients presenting highly frequent co-occurrence of Autoimmune Thyroid Disease (AITD) and Type 1 Diabetes (T1D) and lower frequency of Addison's disease (AD). We tested the high a priori possibility that well-established non-HLA autoimmunity loci were involved in APSII and confirmed five association signals to APSII, namely: (1) two T1D-associated SNPs, in CTLA4 and IL2RA, suggest their involvement in T1D pathogenesis in this cohort; (2) two SNPs in STAT4 and IL15 not previously associated to endocrinopathies, are possibly involved in co-occurrence of organ autoimmunity in APSII, and; (3) one SNP in TNF alpha showed association to APSII irrespective of AD. While this work was performed in a relatively small cohort, these results support the notion that the non-HLA genetic component of APSII include genetic factors specific of particular autoimmune manifestations as well as genetic factors that promote the co-occurrence of multiple autoimmune endocrinopathies.


Spatial variations in the associations of surface water quality with roads and traffic across an urbanization gradient in northern Georgia, USA.
Roads and traffic are important elements of urbanization, but their spatial associations with surface water quality in watersheds have been seldom studied. In this study, the spatially varying associations of three urbanization indicators, including road density, traffic density, and percentages of urban land, with twenty water quality indicators, including dissolved oxygen (DO), specific conductance (SC), dissolved solids (DS), suspended solids (SS), biochemical oxygen demand (BOD), dissolved nutrients, dissolved ions, heavy metals, and coliform bacteria, across the watersheds in the northern part of the state of Georgia, USA, have been examined by a conventional statistical method, ordinary least squares regression (OLS), and a spatial statistical method, geographically weighted regression (GWR). The results from OLS show that the urbanization indicators all have significant positive associations with the majority of the studied water pollutants, indicating that water pollution is significantly contributed by human activities related to urbanization in northern Georgia. In contrast, GWR results show that the associations vary across the watersheds affected by their urbanization levels. Significant positive associations are found between each urbanization indicator and each of the studied water pollutants, but not in all watersheds. The associations of suspended solids, nitrogen nutrients, and coliform bacteria with all three urbanization indicators are more significant in less-urbanized watersheds, while the associations of dissolved ions, BOD, and orthophosphate (PO4) with road density and traffic density are more significant than those with urban land in more-urbanized watersheds, indicating that those water pollutants are more contributed by human activities associated with roads and traffic than other activities in more-urbanized areas. As a pilot study to explore how and why the associations of surface water quality with roads and traffic change across watersheds with different urbanization levels, its findings suggest that the policies of watershed management, land-use planning, and transportation planning should be tailored in local areas based on the locally important water pollutants and their associated urbanization indicators.


Psychosocial concerns of Nigerian women with breast and cervical cancer.
Cancer has the potential to provoke worries which should be assessed in order to adequately respond to patients' problems. We highlight in this paper the problems that concerned 30 women with cervical cancer (mean age 51.2) and 76 with breast cancer (mean age 44.9), how these concerns affected their emotional lives, and the factors associated with these worries. They were interviewed with the 33-item modified version of a German questionnaire rating psychosocial concerns (FBS) by Sullwold, and Goldberg's General Health Questionnaire (GHQ-12) for psychopathological symptoms. Cervical cancer patients had significantly higher FBS and GHQ-12 scores than breast cancer. Breast cancer cases had FBS scores similar to those of women with sickle cell disease and insulin-dependent diabetes mellitus. The commonest recurrent worries in both groups were depression about their condition (45%), thoughts of death (37%), insomnia (33.3%), bodily odour (30%), impairment of work efficiency (30%) terrifying dreams (27%) and fear of illness being life-long (25%). Over 90% denied experience of worries indicating social stigma. FBS scores were significantly correlated with GHQ scores and both were negatively associated with adequacy of social contacts. These data suggest the need for psychosocial intervention in such cases in Nigeria.


Does right lateral decubitus position change retroperitoneal oblique corridor? A radiographic evaluation from L1 to L5.
To determine if the retroperitoneal oblique corridor will be affected by right lateral decubitus position. Forty volunteers were randomly enrolled and MRI scan was performed from L1 to L5 in supine and right lateral decubitus positions, respectively. In images across the center of each disc, O was defined as the center of a disc and A (supine) or A' (right lateral decubitus) was located in left lateral border of the aorta or the iliac artery; B (supine) or B' (right lateral decubitus) was on the anterior medial border of the psoas. The distance of AB and A'B' (Recorded as A-Ps and A-Pr, respectively) at each level was recorded and compared to each other. The relationships between A-Pr, sex, BMI and relative psoas cross-sectional area (PCSA) at each level were also evaluated. A-Pr was significantly smaller than A-Ps at L1/2, L2/3 and L3/4 (All p < 0.05); there was no significantly difference of A-Pr between all levels (p = 0.105), but L1/2 seemed to be larger than L3/4, followed by L2/3 and L4/5; A-Pr at each level was not affected by sex (All p > 0.05); linear relationships were found between A-Pr, BMI and PCSA at L1/2 and L3/4. ROC at L1/2, L2/3 and L3/4 will significantly decrease from supine to right lateral decubitus position and the reason may be due to the relaxed psoas deformation. Using MRI images in supine position for pre-operatively ROC evaluation is not accurate. Spine surgeon should also be more cautious when OLIF is performed at L4/5 where ROC is the smallest. Patients from Asia and those with strong psoas major at L1/2 and L3/4 are also associated with relatively narrow ROC.


Sustained elevation of neutrophils in rats induced by lentivirus-mediated G-CSF delivery.
Patients with severe chronic and cyclic neutropenia, characterized by neutrophil numbers <500 cells/microl, are treated daily with recombinant granulocyte colony-stimulating factor (G-CSF). As an alternative delivery approach we investigated the ability of lentivirus vectors to provide sustained G-CSF expression. Fischer rats were injected intramuscularly (IM) with vesicular stomatitis virus G (VSV-G)-pseudotyped lentivirus pRRL-CMV-G-CSF-SIN that encoded rat G-CSF cDNA regulated by the human cytomegalovirus (CMV) promoter and incorporated a self-inactivating (SIN) construct in the 3' long terminal repeat (LTR). Control rats received normal saline or lentivirus encoding the enhanced green fluorescent protein (eGFP). Rats were serially monitored for blood cell production and tissues assayed for provirus distribution. Rats receiving a single IM injection of lentivirus exhibited elevated neutrophil counts for 14 months. Virus administration of 6 x 10(7) infectious units induced sustained levels of neutrophil production having a mean +/- standard deviation (SD) of 5650 +/- 900 cells/microl and rats that received a 10-fold lower dose of virus showed mean neutrophil counts of 3340 +/- 740 cells/microl. These were significantly higher than the mean of control animals receiving saline or control lentivirus (1,760 +/- 540 cells/microl, P < 0.0001). White blood cell (WBC) counts were significantly elevated in treated over control animals (P < 0.0001). Hematocrits (P > 0.3), lymphocytes (P > 0.2) and platelets (P > 0.1) were not significantly different between control and treated animals. Genomic DNA from muscle at the injection sites was positive for provirus, whereas lung, spleen, liver, kidney and non-injected muscle samples were all negative, suggesting lack of virus spread. These studies indicate that lentivirus vectors administered IM provide sustained, therapeutic levels of neutrophils and suggest this approach to treat patients with severe and cyclic neutropenia.


Comparison of Three Suture Materials in Capsular Closure Closure Time and Wound Complications Following Knee Arthroplasty.
Watertight capsular closure in knee arthro- plasty is desirable in order to achieve a good functional outcome. Barbed knotless sutures are being increasingly used in wound closure following knee arthroplasty. The prior studies have compared barbed sutures with either VICRYL® or Ethibond for closure, while none had compared all the three in a single setting in terms of closure time, needle stick injuries, postoperative complications, and functional outcome. One hundred and forty-three subjects of unilateral knee arthroplasty were screened for eligibility in the prospective randomized controlled trial. One hundred and twenty patients fulfilled the inclusion criteria and were randomized into three groups to undergo capsular closure with barbed sutures, VICRYL, or Ethibond. The wound closure was fastest with barbed su- tures followed by VICRYL and Ethibond (10.4 ± 4.1; 15.4 ± 4.7; 17.2 ± 3.8 minutes; p < 0.001). There were seven needle stick injuries in the Ethibond group followed by three in the VICRYL group and none in the barbed suture group. The Knee Society Scores and wound related complications were comparable in all the three groups. Barbed suture, VICRYL, and Ethibond are equally good in the capsular closure following knee arthro- plasty. The faster wound closure time achieved may not be clinically relevant in the short term.


Carcinoma of the colon after ureterosigmoidostomy and trigonosigmoidostomy for exstrophy of the bladder.
Two cases of adenocarcinoma of the colon developing 28 and 33 years after ureterosigmoidostomy and trigonosigmoidostomy are described. The mechanisms of neoplastic transformation and the clinical implications are discussed.


Structural stability, S-O rotational barrier and vibrational analyses of monomeric non-planar halosulfonic acids X-SO2-OH (X=F, Cl and Br).
The structural stability of halosulfonic acids X-SO2-OH (X=F, Cl and Br) were investigated by DFT-B3LYP/6-311+G** and ab initio MP2/6-311+G** calculations. The potential energy curve for the XSOH internal rotation around S-O bond was consistent with one minimum that corresponds to non-linear structure with XSOH torsional angle of about 80 degrees . The vibrational frequencies were computed at DFT-B3LYP level for the stable non-planar structure of the three molecules. Normal coordinate calculations were then carried out and the potential energy distributions (PED) were calculated for the molecules. On the basis of PED values and comparison with experimental data reliable assignments were provided for normal modes of fluoro-, chloro- and bromosulfonic acids.


The Role of Repeat Administration of Adventitial Delivery of Lentivirus-shRNA-Vegf-A in Arteriovenous Fistula to Prevent Venous Stenosis Formation.
To determine if a second dose of a lentivirus mediated small hairpin RNA that inhibits Vegf-A gene expression (LV-shRNA-Vegf-A) can improve lumen vessel area (LVA) of the outflow vein of an arteriovenous fistula (AVF) and decrease venous neointimal hyperplasia. Chronic kidney disease was created in C57BL/6 mice; 28 days later, an AVF was created by connecting the right carotid artery to the ipsilateral jugular vein. Immediately after AVF creation, 5 × 10(6) plaque-forming units of LV-shRNA-Vegf-A or control shRNA was administered to the adventitia of the outflow vein, and a second dose of the same treatment was administered 14 days later. Animals were sacrificed at 21 days, 28 days, and 42 days after AVF creation for reverse transcription polymerase chain reaction and histomorphometric analyses. By day 21, there was a 125% increase in the average LVA (day 21, P = .11), with a decrease in cell proliferation (day 21, P = .0079; day 28, P = .28; day 42, P = .5), decrease in α-smooth muscle cell actin staining (day 21, P < .0001; day 28, P < .05; day 42, P = .59), and decrease in hypoxic stress (day 21, P < .001; day 28, P = .28; day 42, P = .46) in LV versus control shRNA vessels. A second dose of LV-shRNA-Vegf-A administration results in a moderate improvement in LVA at day 21.


The effects of preoperative radiation on healing of rat colonic anastomoses.
The effect of delaying surgery, after a nominal standard dose of 4500 rad was administered to the abdomen of rats, on the healing of colonic anastomoses was evaluated. Healing, as determined by bursting pressure of colonic segments, was significantly depressed (p less than 0.05) at five days after surgery in groups irradiated five or 15 days prior to surgery as compared with groups receiving either no radiotherapy or irradiation ten days prior to surgery. Five-day healing was not significantly depressed in the group irradiated ten days prior to operation as compared with the group receiving no irradiation. No significant (p less than 0.05) differences were noted at ten or 15 days after surgery between groups that were and were not irradiated. At ten days after surgery all groups had higher bursting pressures than the control group at five days after surgery. Thus, there appears to be an optimal time interval between radiation and surgery to ensure maximal colonic healing.


Phagocytized beads reduce the α5β1 integrin facilitated invasiveness of cancer cells by regulating cellular stiffness.
Cell invasion through the extracellular matrix (ECM) of connective tissue is an important biomechanical process, which plays a prominent role in tumor progression. The malignancy of tumors depends mainly on the capacity of cancer cells to migrate and metastasize. A prerequisite for metastasis is the invasion of cancer cells through connective tissue to targeted organs. Cellular stiffness and cytoskeletal remodeling dynamics have been proposed to affect the invasiveness of cancer cells. Here, this study investigated whether highly invasive cancer cells are capable of invading into dense 3D-ECMs with an average pore-size of 1.3 or 3.0 μm when phagocytized beads (2.7 and 4.5 μm diameter) increased their cellular stiffness and reduced their cytoskeletal remodeling dynamics compared to weakly invasive cancer cells. The phagocytized beads decreased the invasiveness of the α5β1(high) cancer cells into 3D-ECMs, whereas the invasiveness of the α5β1(low) cancer cells was not affected. The effect of phagocytized beads on the highly invasive α5β1(high) cells was abolished by specific knock-down of the α5 integrin subunit or addition of an anti-α5 integrin blocking antibody. Furthermore, the reduction of contractile forces using MLCK and ROCK inhibitors abolished the effect of phagocytized beads on the invasiveness of α5β1(high) cells. In addition, the cellular stiffness of α5β1(high) cells was increased after bead phagocytosis, whereas the bead phagocytosis did not alter the stiffness of α5β1(low) cells. Taken together, the α5β1 integrin dependent invasiveness was reduced after bead phagocytosis by altered biomechanical properties, suggesting that the α5β1(high) cells need an appropriate intermediate cellular stiffness to overcome the steric hindrance of 3D-ECMs, whereas the α5β1(low) cells were not affected by phagocytized beads.


Association of sequence alterations in the putative promoter of RAB7L1 with a reduced parkinson disease risk.
To examine whether PARK16, which was recently identified as a protective locus for Parkinson disease (PD) in Asian, white, and South American populations, is also associated with PD in the genetically homogeneous Ashkenazi Jewish population. Case-control study. A medical center affiliated with a university. Subjects Five single-nucleotide polymorphisms (SNPs) located between RAB7L1 and SLC41A1 were analyzed in 720 patients with PD and 642 controls, all of Ashkenazi Jewish origin. Haplotypes were defined and risk estimates were determined for each SNP and haplotype. Bioinformatic analysis defined the putative promoter region of RAB7L1 and the transcription factor binding sites that are potentially affected by 2 of the tested SNPs. All tested SNPs were significantly associated with PD (odds ratios = 0.64-0.76; P = .0002-.014). Two of them, rs1572931 and rs823144, were localized to the putative promoter region of RAB7L1 and their sequence variations altered the predicted transcription factor binding sites of CdxA, p300, GATA-1, Sp1, and c-Ets-1. Only 0.4% of patients were homozygous for the protective rs1572931 genotype (T/T), compared with 3.0% among controls (P = 5 × 10(-5)). This SNP was included in a haplotype that reduced the risk for PD by 10- to 12-fold (P = .002-.01) in all patients with PD and in a subgroup of patients who do not carry the Ashkenazi founder mutations in the GBA or LRRK2 genes. Our data demonstrate that specific SNP variations and haplotypes in the PARK16 locus are associated with reduced risk for PD in Ashkenazim. Although it is possible that alterations in the putative promoter of RAB7L1 are associated with this effect, the role of other genes in this locus cannot be ruled out.


Nuclear envelope breakdown may deliver an inhibitor of protein phosphatase 1 which triggers cyclin B translation in starfish oocytes.
In vertebrates, enhanced translation of mRNAs in oocytes and early embryos entering M-phase is thought to occur through polyadenylation, involving binding, hyperphosphorylation and proteolytic degradation of Aurora-activated CPEB. In starfish, an unknown component of the oocyte nucleus is required for cyclin B synthesis following the release of G2/prophase block by hormonal stimulation. We have found that CPEB cannot be hyperphosphorylated following hormonal stimulation in starfish oocytes from which the nucleus has been removed. Activation of Aurora kinase, known to interact with protein phosphatase 1 and its specific inhibitor Inh-2, is also prevented. The microinjection of Inh-2 restores Aurora activation, CPEB hyperphosphorylation and cyclin B translation in enucleated oocytes. Nevertheless, we provide evidence that CPEB is in fact hyperphosphorylated by cdc2, without apparent involvement of Aurora or MAP kinase, and that cyclin B synthesis can be stimulated without previous degradation of phosphorylated CPEB. Thus, the regulation of cyclin B synthesis necessary for progression through meiosis can be explained by an equilibrium between CPEB phosphorylation and dephosphorylation, and both aspects of this control may rely on the sole activation of Cdc2 and subsequent nuclear breakdown.


The insensitivity of Vinca rosea to vinblastine.
Root tip mitosis in both Vinca rosea and the chosen control Lepidium sativum is susceptible to the effects of colchicine at and above 5X10(-4)M.--Root tip mitosis in L. sativum is susceptible to the effects of vinblastine at concentrations equal to and greater than 10(-4)M, while root tip mitosis in V. rosea, the plant which is the source of vinblastine, is unaffected by exogenously-applied VBL at concentrations up to and including 10(-2)M.--The possible mechanisms by which the resistance of V. rosea to vinblastine might be conferred are discussed.


Cost-effectiveness of HARNESS-MRI protocol in focal drug-resistant epilepsy in a limited-resources country: An Egyptian study.
The international league against epilepsy (ILAE) recommended the harmonized neuroimaging of epilepsy structural sequences (HARNESS-MRI) to improve the detection of epileptogenic lesions in patients with focal drug-resistant epilepsy (DRE). The application of this protocol is still limited in low-resource countries, mainly due to apparent high costs. We aimed to evaluate the cost-effectiveness of the HARNESS-MRI protocol in Egypt and highlighted our experience. Patients diagnosed with focal DRE at Cairo University epilepsy clinic underwent both conventional MRI (c-MRI) and HARNESS-MRI. Electro-clinical data were collected and analyzed. After the radiologists' initial diagnosis, a multidisciplinary team re-evaluated the MRI. Lesion detection rate and cost for detecting an extra lesion by HARNESS-MRI protocol were calculated. The study included 230 patients with focal DRE (146, 62% males and 91, 38% females), with a mean age of 20.5 years. Epileptogenic lesions detected by c-MRI and HARNESS-MRI before and after the board meeting were 40, 106, and 131 lesions, respectively (P < 0.001). Sixty-nine percent of the lesions detected by HARNESS-MRI were missed on c-MRI; most commonly were mesial temporal sclerosis (MTS) and Malformations of cortical development (MCDs). Thirty-seven MTS and 32 MCDs were detected with HARNESS-MRI, compared to only 6 and 3, respectively, detected on c-MRI (P < 0.001). HARNESS-MR protocol is more cost-effective than c-MRI in detecting MRI lesions; it can save about 42$ for detecting an extra lesion in MRI. The HARNESS-MRI protocol was cost-effective and highly recommended even in limited-resource countries for patients with focal DRE.


A century of influence: Part 1. Orthodontic pioneers.
The story of orthodontics during the first 100 years of Journal publication can be told through the people who lived it. As part of the American Journal of Orthodontics and Dentofacial Orthopedics' Centennial Celebration, we present 100 people who most influenced the specialty during the last 100 years. Part 1 describes the orthodontic pioneers who were born in the 1800 s. They were broadly educated in the sciences, and most studied orthodontics with Angle, Dewey, or Lischer. They were innovators and inventors, and they laid the foundation of the specialty during the early years of the 20th century.


Transcriptional control of Drosophila bicoid by Serendipity delta: cooperative binding sites, promoter context, and co-evolution.
Concentration of maternal BICOID (BCD) establishes the anterior pattern in the Drosophila embryo. Successive deletions in the bcd promoter allowed us to localize an enhancer sequence in the 5'-UTR and a down-regulating element downstream of the ATG initiator codon, and identify a 49 bp region sufficient to drive transcription of a reporter gene specifically in nurse cells. This fragment contains two binding sites for the Serendipity (Sry) d zinc finger activator, that mediate its cooperative binding. Both sites (sdbs) are essential for bcd expression. Further analysis showed that the bcd promoter configuration is decisive for Sry d activating function. Replacement of sdbs by binding sites for Sry b, the Sry d paralog, restores bcd transcription in sry d mutant ovaries, demonstrating that the functional divergence between these two proteins during evolution was mainly driven by changes in their DNA-specific recognition properties, resulting in the control of separate developmental pathways.


Platelet-derived growth factor receptor beta signaling is required for efficient epicardial cell migration and development of two distinct coronary vascular smooth muscle cell populations.
The epicardium plays an essential role in coronary artery formation and myocardial development, but signals controlling the development and differentiation of this tissue are not well understood. To investigate the role of platelet-derived growth factor receptor (PDGFR)beta in development of epicardial-derived vascular smooth muscle cells (VSMCs), we examined PDGFRbeta(-/-) and PDGFRbeta epicardial mutant hearts. We found that PDGFRbeta(-/-) hearts failed to form dominant coronary vessels on the ventral heart surface, had a thinned myocardium, and completely lacked coronary VSMCs (cVSMCs). This constellation of defects was consistent with a primary defect in the epicardium. To verify that these defects were specific to epicardial derivatives, we generated mice with an epicardial deletion of PDGFRbeta that resulted in reduced cVSMCs distal to the aorta. The regional absence of cVSMCs suggested that cVSMCs could arise from 2 sources, epicardial and nonepicardial, and that both were dependent on PDGFRbeta. In the absence of PDGFRbeta signaling, epicardial cells adopted an irregular actin cytoskeleton, leading to aberrant migration of epicardial cells into the myocardium in vivo. In addition, PDGF receptor stimulation promoted epicardial cell migration, and PDGFRbeta-driven phosphoinositide 3'-kinase signaling was critical for this process. Our data demonstrate that PDGFRbeta is required for the formation of 2 distinct cVSMC populations and that loss of PDGFRbeta-PI3K signaling disrupts epicardial cell migration.