Plasmalemma vesicle-associated protein promotes angiogenesis in cholangiocarcinoma via the DKK1/CKAP4/PI3K signaling pathway.
Cholangiocarcinoma (CCA) is aggressive and has poor clinical outcomes because of typically delayed diagnosis and a lack of effective non-surgical therapeutic options. Recent studies have shown that plasmalemma vesicle-associated protein (PLVAP) is related to angiogenesis in various tumors, and in vivo PLVAP targeting therapy has been proven effective against hepatocellular carcinoma and pancreatic cancer. The goal of this study was to determine the potential therapeutic utility of targeting PLVAP and thus angiogenesis in CCA and explore the underlying molecular mechanisms. We found that the PLVAP expression levels were significantly higher in CCA tissues when compared with matched adjacent non-tumor tissues obtained from a total of 90 CCA patients; higher expression levels of PLVAP were associated with shorter overall survival of patients. In addition, overexpression of PLVAP was associated with higher micro-vessel density in CCA tissues. In a PLVAP overexpressing CCA patient-derived xenograft model, a novel humanized anti-PLVAP antibody in combination with Gemcitabine plus Cisplatin was significantly inhibited tumor growth. Molecular analysis of CCA cells co-cultured with human umbilical vascular endothelial cells or human hepatic sinusoidal endothelial cells showed that Dickkopf-related protein 1 (DKK1) secreted by CCA cells activated the PI3K/Akt pathway after binding to its receptor, cytoskeleton-associated protein 4 (CKAP4), resulting in the upregulation of PLVAP. Thus, CCA cells increased the angiogenic potency of endothelial cells in a paracrine fashion. Consistently, patients bearing CKAP4 and PLVAP overexpressing tumors had a poor prognosis. In conclusion, the DKK1/CKAP4/PI3K/PLVAP pathway increases angiogenesis in CCA and is therefore a potential anti-angiogenic target.


Neuroprotective and neurotrophic actions of the mood stabilizer lithium: can it be used to treat neurodegenerative diseases?
The mood stabilizing drug lithium has emerged as a robust neuroprotective agent in preventing apoptosis of neurons. Long-term treatment with lithium effectively protects primary cultures of rat brain neurons from glutamate-induced, NMDA receptor-mediated excitotoxicity. This neuroprotection is accompanied by an inhibition of NMDA-receptor-mediated calcium influx, upregulation of anti-apoptotic Bcl-2, downregulation of pro-apoptotic p53 and Bax, and activation of cell survival factors. Lithium treatment antagonizes glutamate-induced activation of c-Jun-N-terminal kinase (JNK), p38 kinase, and AP-1 binding, which has a major role in cytotoxicity, and suppresses glutamate-induced loss of phosphorylated cAMP responsive element binding protein (CREB). Lithium also induces the expression of brain-derived neurotrophic factor (BDNF) and subsequent activation TrkB, the receptor for BDNF, in cortical neurons. The activation of BDNF/TrkB signaling is essential for the neuroprotective effects of this drug. In addition, lithium stimulates the proliferation of neuroblasts in primary cultures of CNS neurons. Lithium also shows neuroprotective effects in rodent models of diseases. In a rat model of stroke, post-insult treatment with lithium or valproate, another mood stabilizer, at therapeutic doses markedly reduces brain infarction and neurological deficits. This neuroprotection is associated with suppression of caspase-3 activation and induction of chaperone proteins such as heat shock protein 70. In a rat model of Huntington's disease (HD) in which an excitotoxin is unilaterally infused into the striatum, both long- and short-term pretreatment with lithium reduces DNA damage, caspase-3 activation, and loss of striatal neurons. This neuroprotection is associated with upregulation of Bcl-2. Lithium also induces cell proliferation near the injury site with a concomitant loss of proliferating cells in the subventricular zone. Some of these proliferating cells display neuronal or astroglial phenotypes. These results corroborate our findings obtained in primary neuronal cultures. The neuroprotective and neurotrophic actions of lithium have profound clinical implications. In addition to its present use in bipolar patients, lithium could be used to treat acute brain injuries such as stroke and chronic progressive neurodegenerative diseases.


Oral Bilateral Collagenous Fibroma: A previously unreported case and literature review.
Collagenous fibroma, also known as desmoplastic fibroblastoma, is a rare benign slow growing tumor particularly uncommon in the oral cavity. The aim of this study was to analyze the clinical and histopathological features of an oral collagenous fibroma as well as to compare this data with those reported in an English-literature review. The thirteenth case of collagenous fibroma in the oral cavity and the first to present clinically as a bilateral mass was described. A 48-years-old female patient was referred to a School of Dentistry, complaining about an asymptomatic swelling on the hard palate, lasting around ten years. The intraoral examination revealed two well-defined mass, bilaterally in the hard palate. An excisional biopsy was performed. Microscopically, the connective tissue consisted of dense collagen bundles in which were seen scarcely distributed spindle-shaped to stellate fibroblastic cells. Blood vessels were few, as well as inflammatory cells. Immunohistochemical staining was positive for vimentin, α-smooth muscle actin and factor XIIIa and negative for S-100, CD68, CD34, HHF35, desmin and AE1/AE3. The patient remains disease-free 24 months after excision. In conclusion, oral collagenous fibroma should be included in the differential diagnosis of bilateral sessile nodules in the oral cavity. Key words:Connective tissue, mouth diseases, mouth neoplasms, oral diagnosis, oral pathology.


Dynamics of charge-transfer-to-solvent precursor states in I- (water)n (n = 3-10) clusters studied with photoelectron imaging.
The dynamics of charge-transfer-to-solvent states are studied in I- (H2O)(n=3-10) clusters and their deuterated counterparts using time-resolved photoelectron imaging. The photoelectron spectra for clusters with n > or = 5 reveal multiple time scales for dynamics after their electronic excitation. An increase in the vertical detachment energy (VDE) by several hundred millielectronvolts on a time scale of approximately 1 ps is attributed to stabilization of the excess electron, primarily through rearrangement of the solvent molecules, but a contribution to this stabilization from motion of the I atom cannot be ruled out. The VDE drops by approximately 50 meV on a time scale of tens of picoseconds; this is attributed to loss of the neutral iodine atom. Finally, the pump-probe signal decays with a time constant of 60 ps-3 ns, increasing with cluster size. This decay is commensurate with the growth of very slow electrons and is attributed to autodetachment. Smaller clusters (n = 3, 4) display simpler dynamics. Anisotropy parameters are reported for clusters n = 4-9.


Recent Advances in Elongational Flow Dominated Polymer Processing Technologies.
The continuous development of plasticizing conveying methods and devices has been carried out to meet the needs of the polymer processing industry. As compared to the conventional shear-flow-dominated plasticizing and conveying techniques, a new method for processing polymers based on elongational flow was proposed. This new method and the related devices such as vane extruders, eccentric rotor extruders and so on, exhibited multiple advantages including shorter processing time, higher mixing effectiveness, improved product performance and better adaptability to various material systems. The development of new techniques in the field of polymer material processing has opened up a broad space for the development of new plastic products, improved product performance and reduced processing costs. In this review, recent advances concerning the processing techniques based on elongational flow are summarized, and the broad applications in polymer processing as well as some future opportunities and challenges in this vibrant area are elucidated in detail.


New insight into the pathogenesis of nail psoriasis and overview of treatment strategies.
Psoriasis is a chronic inflammatory disease affecting up to 3% of the general population. The prevalence of nail involvement in psoriasis patients varies between 15% and 79%. While the nails represent a small portion of the body surface area, psoriasis in these areas can have a disproportionate influence on a patient's physical and psychosocial activities. Differential diagnosis between an onychomycosis and a psoriatic nail could be challenging; nevertheless, coexistence of onychomycosis and nail psoriasis also occurs and both are common disorders in the general population. Nail psoriasis can be difficult to treat. Treatment of nail psoriasis should consider the body surface area of skin disease, psoriatic arthritis, severity of nail disease, and the impairment in the quality of life. All patients should be tested for onychomycosis before starting a therapy. This recommendation is underlined by the fact that nail psoriasis is mostly treated by immunosuppressive drugs, like steroids, methotrexate, or biologics, which may aggravate mycotic nail infections. Conventional systemic therapy, such as use of steroids, cyclosporine, methotrexate, and retinoid in the long term, can cause organ toxicities. Currently, use of apremilast and tofacitinib favors an early healing of nail psoriasis because they act directly on the pathogenic targets, distressing the inflammatory signals associated with the initiation and maintenance of the disease activity, and as with several conventional synthetic disease modifying antirheumatic drugs, they are characterized by the convenience of oral administration. The number of treatment options has increased considerably in recent years; however, given the heterogeneity of the disease, the therapy should be personalized to individual cases.


A systematic review and meta-analysis of the effects of cardiac rehabilitation interventions on cognitive impairment following stroke.
The cardiac rehabilitation model has potential as an approach to providing rehabilitation following stroke. This review aims to identify evidence for the participation of stroke patients in cardiac/cardiovascular rehabilitation programs internationally, whether or not such programs offer a cognitive intervention as part of treatment, and the impact of rehabilitation on post-stroke cognitive function. Five electronic databases were searched from inception to 1 May 2019, namely: MEDLINE, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature, the Cochrane Central Register of Controlled Trials, and the Web of Science. Eligible studies included both randomized and non-randomized studies of cardiac rehabilitation-type interventions which measured cognitive function in patients with transient ischemic attack (TIA) or stroke. Of 14,153 records reviewed, nine studies which delivered cardiac rehabilitation-type interventions to stroke patients were finally included. Only three of these studies delivered cognitive rehabilitation as part of the intervention. Cardiac rehabilitation had no statistically significant effect on cognitive function in five randomized controlled trials (standardized mean difference= 0.28, 95% CI= -0.16 to 0.73) or in three one group pre-post studies (standardized mean difference= 0.15, 95% CI= -0.03 to 0.33). This review highlights that there are very few studies of delivery of cardiac rehabilitation to stroke patients and that the inclusion of cognitive interventions is even less common, despite the high prevalence of post-stroke cognitive impairment.IMPLICATIONS FOR REHABILITATIONThe cardiac rehabilitation model has the potential to be expanded to include patients post-stroke given the commonality of secondary prevention needs, thereby becoming a cardiovascular rehabilitation model.Up to half of patients experience cognitive impairment after stroke; suggesting that a post-stroke cardiovascular rehabilitation model should incorporate specific cognitive strategies for patients.This systematic review identified three cardiovascular rehabilitation programmes which delivered cognitive rehabilitation as part of treatment; however, evidence for efficacy is weak.


Growth hormone therapy in children after cranial/craniospinal radiation therapy: sexually dimorphic outcomes.
Radiation therapy (RT) to the craniospinal region in childhood affects final height. The use of GH treatment (GHRx) in children after cranial or craniospinal RT results in variable improvement in final height. Nineteen children (12 males and 7 females) with tumors of the head, treated with cranial or craniospinal RT and subsequently with GHRx, were assessed for final height. Two outcome measures of efficacy of GHRx were used: Y1 = final height SD score (SDS) corrected for genetic potential, using midparental sex-adjusted target height (SATH) SDS, and Y2 = change in height SDS from predicted final height SDS pre-GHRx to actual final height SDS post-GHRx. The median age at diagnosis was 5.4 yr, the median RT to the hypothalamic-pituitary axis was 40 Gy, the median spinal RT dose in 13 of 19 of the subjects treated was 36 Gy, and the median years post-RT to GHRx was 4.8 yr. Adjuvant chemotherapy was used in 12 of 19 patients. All but one (optic glioma) had a lesion anatomically distant from the suprasellar region. The effects of age at diagnosis, sex, L-T4 or GnRH agonist use, conventional vs. hyperfractionated RT, spinal RT, dose of spinal or cranial RT, chemotherapy, peak stimulated GH, dose and duration of GHRx, age at GHRx, time interval between RT and GHRx initiation, bone age, and height SDS at the start of GHRx were also assessed. Y1girls best correlated with younger age at diagnosis and im vs. sc GHRx. Y2girls best correlated with delayed bone age and younger age at diagnosis [Y1girls = -9.95 + 0.38 (age in years at diagnosis) + 3.11[GH method (1 = i.m.; 2 = s.c.)]; r2 = 0.898; P = 0.02; Y2girls = -3.54 + 1.8 (bone age - age in years) + 0.334 (age at diagnosis in years); r2= 0.956; P = 0.02]. Both Y1boys and Y2boys were strongly associated with spinal RT and younger age at diagnosis or treatment [Y1boys = -11.22 + 4.65 [spinal RT (1 = yes; 2 = no)] + 0.396 (age in years at diagnosis); r2= 0.64, P = 0.01; Y2boys = -6.32 + 0.23 (age in years at GH start) + 1.75 [spinal RT (1 = yes; 2 = no)]; r2= 0.646; P < 0.01]. This small historical cohort underscores that final stature is significantly reduced when immature bones are exposed to ionizing radiation. Intramuscular vs. sc use of GHRx is likely to be simply a surrogate marker for earlier methods of treatment. Of note, spinal RT did not significantly impact girls' final heights, whereas in boys, spinal RT strongly predicted ultimate short stature and a reduced response to GHRx. This sexually dichotomous response may be due in part to the greater percentage of spinal growth remaining for boys vs. girls throughout childhood.


Rollover injury in vehicles with high-strength-to-weight ratio (SWR) roofs, curtain and side airbags, and other safety improvements.
This study investigated trends in severe injury and ejection in rollover crashes involving lap-shoulder-belted drivers and right-front passengers. It was conducted because of changes in 2009 to consumer information programs and regulations related to rollover protection. The data are presented by model year (MY) of the vehicle in groups from 1995 to 2016. NASS-CDS cases with 2010-2016 MY vehicles were also evaluated to determine the crash circumstances and causes for severe injury of belted occupants in vehicles with a high strength-to-weight (SWR) roof, curtain, and side airbags and other safety improvements. 1997-2015 NASS-CDS data were evaluated for severe injury and ejection of lap-shoulder-belted front outboard occupants in light vehicles. Crashes were grouped by front, side, rear, and rollover. The injury and ejection data were grouped by vehicle MY: 1995-1999, 2000-2004, 2005-2009, and 2010-2016. Only drivers and right-front passengers were included if they were lap-shoulder belted and 15+ years old. Severely injured occupants were defined as those with Maximum Abbreviated Injury Scale (MAIS) 4-6 or fatality (MAIS 4 + F). National estimates were made with weighted data using the ratio weight in NASS-CDS. All NASS-CDS electronic cases were evaluated for belted occupants with MAIS 4 + F injury in rollovers involving 2010-2016 MY vehicles. The crash circumstances and injuries were studied. These vehicles had high-SWR roofs to meet Insurance Institute for Highway Safety (IIHS) ratings and FMVSS 216. The 1997-2015 NASS-CDS included 2,083,776 belted front occupants in rollover crashes with 24,466 (1.17%) MAIS 4 + F injuries. The frequency of rollover crashes has decreased with modern vehicles (P < .0001). The 1995-1999 MY vehicles involved in a rollover accounted for 7.03% of all crashes (756,228/10,760,000). The corresponding proportion was 3.57% with 2010-2016 MY vehicles (81,406 vs. 2,282,062). The risk for MAIS 4 + F was 1.325 ± 0.347% in rollover crashes with 1995-1999 MY vehicles. It was 27.2% lower in 2010-2016 MY vehicles at 0.964 ± 0.331% (P < .001). There were 42,567 (2.002%) ejections of belted occupants in rollover crashes, irrespective of injury outcome. The risk for ejection was 3.042 ± 1.44% in rollover crashes with 1995-1999 MY vehicles. It was 43.6% lower in 2004-2009 MY vehicle at 1.715 ± 0.660% (P < .001) and 83.4% lower in 2010-2016 MY vehicle at 0.505 ± 0.336% (P < .001). There were 17 rollovers with MAIS 4 + F in 2010-2016 MY vehicles in NASS-CDS. Their roof strength was SWR =4.15 ± 1.05 based on 15 vehicles. Many of the collisions involved front or side impacts and then a rollover. Four cases involved 16- to 30-year-old drivers in extremely high-speed loss-of-control crashes resulting in >10-cm vertical roof deformation or substantial roof deformation based on photos. The roof strength (SWR) of 4.20 ± 1.0 was not sufficient to prevent roof deformation in these crashes. This study found a reduction in severe injury and ejection risk with modern vehicles. It indicates that vehicle safety has improved in response to IIHS and NHTSA efforts to expand the array of safety requirements and increase performance so that newer models are safer than earlier ones. There has been an incremental improvement in safety due to these advances.


Cogan's syndrome with pyoderma gangrenosum: management of two uncommon disorders with aggressive presentation in a patient.
Pyoderma gangrenosum (PG) coexisting with Cogan's syndrome (CS) is uncommon, although cutaneous manifestations are known to develop in CS. A middle-aged white female patient had chronic relapsing PG requiring ciclosporin and prednisolone. Despite receiving optimal doses of ciclosporin and prednisolone, she developed acute vestibulo-auditory symptoms as a result of CS. Ciclosporin was switched to methotrexate and prednisolone was increased. However, she continued to develop acute scleritis, requiring methylprednisolone pulses, and still had further flares of PG. Her methotrexate was held off when she developed severe pneumonia and she then received a trial of intravenous immunoglobulins (IVIG) for her recurrent leg ulcers. Unfortunately, she failed to respond to IVIG. Her ulcers eventually responded to six doses of monthly intravenous cyclophosphamide induction. Although CS is not an antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, we used pulse cyclophosphamide, based on the experience of cyclophosphamide efficacy in severe ANCA-associated vasculitis (AAV). Following induction, both diseases currently remain under control with azathioprine as maintenance treatment.


The Drosophila NFAT homolog is involved in salt stress tolerance.
The NFAT gene encodes the only homolog in Drosophila of the five human Nuclear Factors of Activated T-cells, NFAT1-5. Its rel homology domain is most similar to that of NFAT5, and like the latter it lacks conserved AP1 and calcineurin binding sites. Two promoters give rise to alternative transcripts that are ubiquitously expressed in several different tissues. We generated mutants for each transcript, as well as a mutant that lacks all functional NFAT expression. Only the null mutant generated a visible phenotype, indicating that the two transcripts are redundant. The mutants are sensitive to high salt diet and have enlarged anal pads in hypotonic solution, suggesting that NFAT, like mammalian NFAT5, is regulating the osmotic balance. A phylogenetic reconstruction puts the Drosophila gene near the root of the NFAT tree, indicating that regulation of tonicity may be an ancestral function of the NFAT family.


A unique case of spontaneous regression of metastatic papillary renal cell carcinoma: a case report.
Spontaneous regression of cancer is a rare, but well documented, phenomenon. We present a unique case of an 82 year old Chinese male who experienced spontaneous regression of histologically-verified metastatic type II papillary renal cell carcinoma in the absence of intervening systemic therapy or surgery. This is the first reported case of spontaneous regression of papillary renal cell carcinoma. The mechanism of spontaneous regression remains unknown, and represents a challenge for existing oncology paradigms.


Substance Use and Healthcare Utilization Across the Pre-Exposure Prophylaxis (PrEP) Care Cascade among Black and Latino Men Who Have Sex with Men.
Background: Despite the documented efficacy of pre-exposure prophylaxis (PrEP) for HIV prevention, large disparities in uptake and adherence exist among Black and Latino/Hispanic men who have sex with men (BLMSM). Limited data exists among BLMSM on the impact of substance use at different stages of the PrEP Care Cascade. We examined the ways substance (alcohol, cannabis, other drug) use is related to PrEP experiences across the PrEP Care Cascade (PrEP aware/no use; PrEP use/discontinuation; PrEP use/adherent).Methods: We utilized data from a national sample of 908 BLMSM (Mage = 25.17, range: 18-29), collected between February and October 2020.Results: We found that heavier alcohol use, more other drug (e.g., cocaine) use, more participant healthcare utilization, and higher number of partners across all measures of substance use were separately associated with a lower likelihood of being aware of PrEP. These same factors were also associated with a higher likelihood of PrEP adherence. Conversely, only cannabis use was associated with discontinuation of PrEP use.Conclusions: While we confirm some earlier findings (i.e., alcohol use is associated with both PrEP discontinuation and PrEP use), we newly identify cannabis as a barrier to the adherence of PrEP. Our findings highlight the need for improved PrEP interventions to increase awareness among BLMSM with substance use who are among the most at-risk for HIV infection.


Disseminated tuberculosis presenting as acute coronary syndrome.
Tuberculosis is a major public health problem in Bangladesh. Though tuberculosis is common but acute myopericarditis can rarely be caused by tuberculosis infection. A case of disseminated tuberculosis presenting with features of acute coronary syndrome is presenting here. A 26 years old man was admitted for severe central chest pain for 2 days and fever for 2 months. His ECG showed ST segment elevation in chest leads, V1 to V4 with elevated Troponin I and high ESR. Chest X-Ray depicted an enlarged cardiac shadow. Echocardiography demonstrated multiple dynamic cavitary lesions involving interventricular septum as well as anterior wall of the left ventricle within myocardium with moderate pericardial effusion with trivial mitral regurgitation. A CT scan of chest with contrast revealed multiple calcific communicating cavities within endocardium and myocardium involving interventricular septum and anterior wall of the left ventricle of heart and multiple cavitary lesions in the mid zone of left lung with bilateral mild pleural effusion. The patient made an excellent recovery on management of acute coronary syndrome and on antitubercular therapy.


Can we combine symptom scales for collaborative research projects?
Collaborative research projects have the potential to answer important research questions, which may otherwise require huge resources, funding, and time to complete. There are several scales for measuring psychotic symptoms in schizophrenia and other psychotic disorders, with the Scale for Assessment of Positive Symptoms (SAPS), Scale for Assessment of Negative Symptoms (SANS), Positive and Negative Symptom Scale (PANSS), and the Brief Psychiatric Rating Scale (BPRS) being among the most commonly used. High quality research efforts have used these three scales in different projects, and in order to merge study efforts, some means of combining data from these scales may be necessary. We reviewed correlations in published studies for these three scales, finding them to be highly correlated, however on comparison of the three scales there were considerable clinical differences between them. The paper discusses potential methods for combining the scales in collaborative research, including use of the recently developed standardised remission criteria for schizophrenia.


The role of RPA2 phosphorylation in homologous recombination in response to replication arrest.
Failure to reactivate stalled or collapsed DNA replication forks is a potential source of genomic instability. Homologous recombination (HR) is a major mechanism for repairing the DNA damage resulting from replication arrest. The single-strand DNA (ssDNA)-binding protein, replication protein A (RPA), plays a major role in multiple processes of DNA metabolism. However, the role of RPA2 hyperphosphorylation, which occurs in response to DNA damage, had been unclear. Here, we show that hyperphosphorylated RPA2 associates with ssDNA and recombinase protein Rad51 in response to replication arrest by hydroxyurea (HU) treatment. In addition, RPA2 hyperphosphorylation is critical for Rad51 recruitment and HR-mediated repair following HU. However, RPA2 hyperphosphorylation is not essential for both ionizing radiation (IR)-induced Rad51 foci formation and I-Sce-I endonuclease-stimulated HR. Moreover, we show that expression of a phosphorylation-deficient mutant of RPA2 leads to increased chromosomal aberrations following HU treatment but not after exposure to IR. Finally, we demonstrate that loss of RPA2 hyperphosphorylation results in a loss of viability when cells are confronted with replication stress whereas cells expressing hyperphosphorylation-defective RPA2 or wild-type RPA2 have a similar sensitivity to IR. Thus, our data suggest that RPA2 hyperphosphorylation plays a critical role in maintenance of genomic stability and cell survival after a DNA replication block via promotion of HR.


Difference in expression of two neurokinin-1 receptors in adenoma and carcinoma from patients that underwent radical surgery for colorectal carcinoma.
Mechanisms underlying tumor progression remain a main problem in the diagnosis and treatment of patients with tumors. The present study compared the expression of full-length neurokinin-1 receptors (fl-NK-1R) and truncated neurokinin-1 receptors (tr-NK-1R) in adenoma and carcinoma from patients with colorectal carcinoma, to explore their possible contributions in adenoma-carcinoma progression. Samples were collected immediately following colorectal carcinoma surgery. Using reverse transcription-quantitative polymerase chain reaction and immunohistochemical staining, the relative mRNA and protein levels of tr-NK-1R and fl-NK-1R were compared in adenoma and carcinoma. tr-NK-1R mRNA was significantly upregulated (1.7 fold; P=0.026) in carcinoma tissues compared with adenoma tissues, while the fl-NK-1R transcription level showed no difference (P=0.438). No significant change was observed in the fl-NK-1R protein level in adenoma, carcinoma and peri-carcinoma tissues (P=0.244). However, total neurokinin-1 receptor (NK-1R) protein levels in adenoma and carcinoma tissues were significantly increased compared to peri-carcinoma tissue (P=0.026 and P=0.007, respectively). The outcomes suggested that the increase in total NK-1R protein in adenoma and carcinoma tissues is the result of the increase in tr-NK-1R levels. The present findings indicate that tr-NK-1R serves an important role in colorectal adenoma progression, with a possible role in adenoma-carcinoma progression. Thus, tr-NK-1R may be used as a marker for diagnosing and treating patients with colorectal adenomas.


Parvovirus dark matter in the cloaca of wild birds.
With the development of viral metagenomics and next-generation sequencing technology, more and more novel parvoviruses have been identified in recent years, including even entirely new lineages. The Parvoviridae family includes a different group of viruses that can infect a wide variety of animals. In this study, systematic analysis was performed to identify the "dark matter" (datasets that cannot be easily attributed to known viruses) of parvoviruses and to explore their genetic diversity from wild birds' cloacal swab samples. We have tentatively defined this parvovirus "dark matter" as a highly divergent lineage in the Parvoviridae family. All parvoviruses showed several characteristics, including 2 major protein-coding genes and similar genome lengths. Moreover, we observed that the novel parvo-like viruses share similar genome organizations to most viruses in Parvoviridae but could not clustered with the established subfamilies in phylogenetic analysis. We also found some new members associated with the Bidnaviridae family, which may be derived from parvovirus. This suggests that systematic analysis of domestic and wild animal samples is necessary to explore the genetic diversity of parvoviruses and to mine for more of this potential dark matter.


A novel derivative of valepotriate inhibits the PI3K/AKT pathway and causes Noxa-dependent apoptosis in human pancreatic cancer cells.
Natural compound valepotriate exhibits inhibitory activity against a number of cancers, but the effect of valepotriate against pancreatic cancer is unclear, and the structure-activity relationship of valepotriate has not been characterized. In this study, we performed a structure-based similarity search and found 16 hit compounds. Among the 16 hits, (1S,6S,7R)-6-(acetyloxy)-1-[(3-methylbutanoyl)oxy]-4a,5,6,7a-tetrahydro-1H-spiro[cyclopenta[c]pyran-7,2'-oxiran]-4-ylmethyl 3-methylbutanoate (denoted as Amcp) exhibited superior anticancer activity against human pancreatic cancer BxPC-3 and SW1990 cells. The anti-proliferation activity of Amcp was validated in human pancreatic cancer BxPC-3 and SW1990 cells in vitro. Amcp more effectively induced apoptosis in BxPC-3 and SW1990 cells than gemcitabine. At a concentration of 15 μM, Amcp significantly suppressed the PI3K/AKT pathway and disrupted the mitochondrial membrane equilibrium through modulation of Noxa and Mcl-1 balance in both cell lines. Meanwhile, knockdown of Noxa substantially attenuated Amcp-induced reduction of cell viability and anti-apoptotic protein Mcl-1 level in BxPC-3 cells. In addition, Amcp showed synergistic anticancer effects when combined with gemcitabine in BxPC-3 cells. To conclude, this work not only suggests that Amcp possesses a dual-inhibitory activity towards PI3K/AKT pathway and Mcl-1, but also enlightens further development of bioactive valepotriate derivatives.


[A case of thrombosed St. Jude Medical valve 16 years after initial mitral valve replacement].
We report successful surgery for a thrombosed St. Jude Medical (SJM) valve 16 years after the initial mitral valve replacement even under conditions of satisfactory anticoagulation therapy. A 61-year-old-female had intermittent claudication and was admitted to our hospital for examination. The prosthetic valve sounds were normal to auscultation and the left ankle-pressure index was decreased to 0.6. Transthoracic echocardiography revealed no mitral regurgitation and a mean mitral valve gradient of 6-7 mmHg. Furthermore, transesophageal echocardiography revealed that one of the leaflets of the prosthetic valve was entirely immobilized at the closing position and a mobile soft tissue mass, 5 mm in diameter, was detected at the atrial side of the obstructed leaflet. Although 96,0000 IU of urokinase was administered intravenously for a week, we could not confirm any change in leaflet mobility. At the time of surgery, the posterior leaflet of the SJM valve, which was implanted at an anatomical orientation, was obstructed at the closing position with old and fresh thrombi. We decided upon replacement with a CarboMedics 29 M prosthetic valve. Postoperative medication consisted of warfarin plus low-dose aspirin. Generally, valve thrombosis occurs within 5 years after valve replacement. However, valve thrombosis is possible even in a reliable SJM valve and as long as 16 years after replacement. Therefore, the implantation of an SJM valve at an anti-anatomical orientation might lower the incidence of valve thrombosis in addition to life-long anticoagulation therapy.


Acute intraoperative effect of intravenous amiodarone on right ventricular function in patients undergoing valvular surgery.
Amiodarone is commonly used in the acute care setting. However the acute hemodynamic and echocardiographic effect of intravenous amiodarone administered intraoperatively on right ventricular (RV) systolic and diastolic function using transesophageal echocardiography (TEE) has not been described. The study design was a randomized controlled trial in elective cardiac surgical patients undergoing valvular surgery. Patients received an intravenous loading dose of 300 mg of either amiodarone or placebo in the operating room, followed by an infusion of 15 mg/kg for two days. Hemodynamic profiles, echocardiographic measurement of RV and left ventricular (LV) dimensions, Doppler interrogation of tricuspid and mitral valve, hepatic and pulmonary venous flow combined with tissue Doppler imaging of the tricuspid and mitral valve annulus were obtained before and after bolus. Although more patients in the placebo group had chronic obstructive lung disease (14 vs 6, p=0.05) and diabetes (14 vs 5; p=0.0244), there was no difference in terms of baseline hemodynamic, 2D and Doppler variables. After bolus, a significant increase in pulmonary artery pressure, central venous pressure and pulmonary vascular resistance index (p<0.05) was observed in the amiodarone group with reduction in systolic to diastolic (S/D) ratio of the hepatic (p=0.0247) and pulmonary venous (p=0.0052) velocity. Acute administration of amiodarone is associated with alteration in RV diastolic properties and has minimal negative inotropic effect on RV systolic function in cardiac surgical patients with valvular disease.


Physiological effects of invasive ventilation with neurally adjusted ventilatory assist (NAVA) in a crossover study.
Neurally Adjusted Ventilatory Assist (NAVA) is a mode of assisted mechanical ventilation that delivers inspiratory pressure proportionally to the electrical activity of the diaphragm. To date, no pediatric study has focused on the effects of NAVA on hemodynamic parameters. This physiologic study with a randomized cross-over design compared hemodynamic parameters when NAVA or conventional ventilation (CV) was applied. After a baseline period, infants received NAVA and CV in a randomized order during two consecutive 30-min periods. During the last 10 min of each period, respiratory and hemodynamic parameters were collected. No changes in PEEP, FiO2, sedation or inotropic doses were allowed during these two periods. The challenge was to keep minute volumes constant, with no changes in blood CO2 levels and in pH that may affect the results. Six infants who had undergone cardiac surgery (mean age 7.8 ± 4.1 months) were studied after parental consent. Four of them had low central venous oxygen saturation (ScvO2 < 65 %). The ventilatory settings resulted in similar minute volumes (1.7 ± 0.4 vs. 1.6 ± 0.6 ml/kg, P = 0.67) and in similar tidal volumes respectively with NAVA and with CV. There were no statistically significant differences on blood pH levels between the two modes of ventilation (7.32 ± 0.02 vs. 7.32 ± 0.04, P = 0.34). Ventilation with NAVA delivered lower peak inspiratory pressures than with CV: -32.7 % (95 % CI: -48.2 to -17.1 %, P = 0.04). With regard to hemodynamics, systolic arterial pressures were higher using NAVA: +8.4 % (95 % CI: +3.3 to +13.6 %, P = 0.03). There were no statistically significant differences on cardiac index between the two modes of ventilation. However, all children with a low baseline ScvO2 (<65 %) tended to increase their cardiac index with NAVA compared to CV: 2.03 ± 0.30 vs. 1.91 ± 0.39 L/min.m2 (median ± interquartile, P = 0.07). This pilot study raises the hypothesis that NAVA could have beneficial effects on hemodynamics in children when compared to a conventional ventilatory mode that delivered identical PEEP and similar minute volumes. ClinicalTrials.gov Identifier: NCT01490710 . Date of registration: December 7, 2011.


Rab escort protein-1 is a multifunctional protein that accompanies newly prenylated rab proteins to their target membranes.
Rab proteins comprise a family of small GTPases that serve a regulatory role in vesicular membrane traffic. Geranylgeranylation of these proteins on C-terminal cysteine motifs is crucial for their membrane association and function. This post-translational modification is catalysed by rab geranylgeranyl transferase (Rab-GGTase), a multisubunit enzyme consisting of a catalytic heterodimer and an accessory component, named rab escort protein (REP)-1. Previous in vitro studies have suggested that REP-1 presents newly synthesized rab proteins to the catalytic component of the enzyme, and forms a stable complex with the prenylated proteins following the transfer reaction. According to this model, a cellular factor would be required to dissociate the rab protein from REP-1 and to allow it to recycle in the prenylation reaction. RabGDP dissociation inhibitor (RabGDI) was considered an ideal candidate for this role, given its established function in mediating membrane association of prenylated rab proteins. Here we demonstrate that dissociation from REP-1 and binding of rab proteins to the membrane do not require RabGDI or other cytosolic factors. The mechanism of REP-1-mediated membrane association of rab5 appears to be very similar to that mediated by RabGDI. Furthermore, REP-1 and RabGDI share several other functional properties, the ability to inhibit the release of GDP and to remove rab proteins from membranes; however, RabGDI cannot assist in the prenylation reaction. These data suggest that REP-1 is per se sufficient to chaperone newly prenylated rab proteins to their target membranes.


Research utilization and attitudes towards research among learning disability nurses in Northern Ireland.
Research utilization and attitudes towards research among learning disability nurses in Northern Ireland The current emphasis on evidence-based practice has focused attention once again on the research activities of health professionals in general and their research utilization in particular. While there has been a limited number of studies on research utilization in the United Kingdom, these have tended to concentrate on general nurses and midwives. Little is known about the research activities, research utilization and the attitudes to research of learning disability nurses. This paper reports on data from a survey of a convenience sample of 87 nurses from three learning disability hospitals in Northern Ireland. The results show that while these nurses generally held positive attitudes to research, a substantial minority (18.3%) believed that 'research is not relevant to the day to day work in nursing'. Only a quarter of the sample reported using research 'frequently/all the time' in their practice. The extent of research utilization among these disability nurses must be considerably improved if evidence-based practice is to become a reality in their field of nursing.


[Effect of macrolides on biofilm of mucoid Pseudomonas aeruginosa].
To observe the effect of macrolides with different structures on biofilm of mucoid Pseudomonas aeruginosa so as to provide a theoretical basis for treatment of bacterial biofilm diseases. Modified plate culture method was used to establish in vitro bacterial biofilm model, which was identified by silver nitrate staining. After the biofilm was treated by gatifloxacin and/or macrolides with different structures and of different concentrations, the number of viable bacteria was measured by MTT method and bacterial adherence was measured by crystal violet staining. Clarithromycin and azithromycin of 1/4 and 1/16 MIC combined with gatifloxacin significantly inhibited the adherence of mucoid Pseudomonas aeruginosa (P < 0.05) and reduced the number of viable mucoid Pseudomonas aeruginosa compared with gatifloxacin alone (P < 0.05), while such effects could not be seen for rovamycin. Inhibiting the adherence of mucoid Pseudomonas aeruginosa may be one of the mechanisms by which macrolides such as clarithromycin and azithromycin enhance the antibacterial activity of gatifloxacin against mucoid Pseudomonas aeruginosa.


Outcomes in day surgery.
To summarize and examine the updated published results on the outcome measures that can be used to assess the quality of ambulatory surgery and anesthesia. Major morbidity and mortality following ambulatory surgery is exceedingly low. Cancellations and delays may have a negative impact on the patients, healthcare personnel and the organizations. Minor cardiovascular adverse events are the most common intraoperatively and are associated with preexisting cardiovascular diseases and elderly patients. Respiratory events postoperatively are associated with obesity, smoking and asthma. Also, pain is a common cause for longer postoperative stay, unanticipated admission and readmission. Postoperative nausea and vomiting occurs in 30% of patients and strongly affects patient satisfaction. Furthermore, prolonged stays are mainly caused by surgical factors, or minor symptoms like pain or nausea. Surgical factors are also the main causes of unanticipated hospital admission. The type of surgery and the 24 h postoperative symptoms may affect the degree of return to daily living function. Also, patient satisfaction affects the outcome of healthcare and the use of healthcare services. Ambulatory surgery, as currently practiced, provides quality care that is cost-effective. Minor adverse events such as pain and postoperative nausea and vomiting are still common, and improvement could be targeted in these areas.


X-ray structure of an asymmetrical trimeric ferredoxin-photosystem I complex.
Photosystem I (PSI), a large protein complex located in the thylakoid membrane, mediates the final step in light-driven electron transfer to the stromal electron carrier protein ferredoxin (Fd). Here, we report the first structural description of the PSI-Fd complex from Thermosynechococcus elongatus. The trimeric PSI complex binds three Fds in a non-equivalent manner. While each is recognized by a PSI protomer in a similar orientation, the distances between Fds and the PSI redox centres differ. Fd binding thus entails loss of the exact three-fold symmetry of the PSI's soluble subunits, inducing structural perturbations which are transferred to the lumen through PsaF. Affinity chromatography and nuclear magnetic resonance analyses of PSI-Fd complexes support the existence of two different Fd-binding states, with one Fd being more tightly bound than the others. We propose a dynamic structural basis for productive complex formation, which supports fast electron transfer between PSI and Fd.


Study of neurontin: titrate to effect, profile of safety (STEPS) trial: a narrative account of a gabapentin seeding trial.
Seeding trials, clinical studies conducted by pharmaceutical companies for marketing purposes, have rarely been described in detail. We examined all documents relating to the clinical trial Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) produced during the Neurontin marketing, sales practices, and product liability litigation, including company internal and external correspondence, reports, and presentations, as well as depositions elicited in legal proceedings of Harden Manufacturing vs Pfizer and Franklin vs Warner-Lambert, most which were created between 1990 and 2009. Using a systematic search strategy, we identified and reviewed all documents related to the STEPS trial in order to identify key themes related to the trial's conduct and determine the extent of marketing involvement in its planning and implementation. Documents demonstrated that STEPS was a seeding trial posing as a legitimate scientific study. Documents consistently described the trial itself, not trial results, to be a marketing tactic in the company's marketing plans. Documents demonstrated that at least 2 external sources questioned the validity of the study before execution, and that data quality during the study was often compromised. Furthermore, documents described company analyses examining the impact of participating as a STEPS investigator on rates and dosages of gabapentin prescribing, finding a positive association. None of these findings were reported in 2 published articles. The STEPS trial was a seeding trial, used to promote gabapentin and increase prescribing among investigators, and marketing was extensively involved in its planning and implementation.


Size, Shape, and Protein Corona Determine Cellular Uptake and Removal Mechanisms of Gold Nanoparticles.
Size, shape, and protein corona play a key role in cellular uptake and removal mechanisms of gold nanoparticles (Au NPs). The 15 nm nanoparticles (NP1), the 45 nm nanoparticles (NP2), and the rod-shaped nanoparticles (NR) enter into cells via a receptor-mediated endocytosis (RME) pathway. The star-shaped nanoparticles (NS) adopt not only clathrin-mediated, but also caveolin-mediated endocytosis pathways. However, the 80 nm nanoparitcles (NP3) mainly enter into the cells by macropinocytosis pathway due to the big size. Furthermore, the results indicate that the presence of protein corona can change the uptake mechanisms of Au NPs. The endocytosis pathway of NP1, NP2, and NS changes from RME to macropinocytosis pathway and NR changes from RME to clathrin and caveolin-independent pathway under the non-fetal bovine serun (FBS)-coated condition. Both FBS-coated and non-FBS-coated of five types of Au NPs are released out through the lysosomal exocytosis pathway. The size, shape, and protein corona have an effect on the exocytosis ratio and amount, but do not change the exocytosis mechanism. The systematic study of the endocytosis and exocytosis mechanism of Au NPs with different sizes and shapes will benefit the toxicology evaluation and nanomedicine application of Au NPs.


The Slope Safety, Heavy Metal Leaching, and Pollutant Diffusion Prediction Properties under the Influence of Unclassified Cemented Paste Backfill in an Open Pit.
Open-pit unclassified cemented paste backfilling (OPUCPB) methods have not only addressed the disposal problems of tailings but also eliminated geological hazards of high and steep open pit slopes and created conditions for ecological restoration of the open pit in the future. In this paper, slope safety simulations, heavy metal leaching, groundwater monitoring, and pollutant diffusion predictions were examined to evaluate the slope safety pattern and environmental protection enabled by OPUCPB. The results showed that: (1) The safety factor of the open pit slope was proportional to the height of OPUCPB operation. Under the condition of seismic force and seepage field, the safety factor of slope B was increased from 1.188 to 1.574 by OPUCPB. (2) The toxic and harmful components in tailings were significantly stabilized by the OPUCPB. Under the conditions of acid leaching and water leaching, the quality of the leaching solution met the requirements of the class III limit of groundwater (GB/T14848-2017). (3) The monitoring results of groundwater quality around the open pit showed that the OPUCPB had no effect on groundwater, and the water quality met the requirements of the class III limit of groundwater (GB/T14848-2017). (4) Considering the diffusion prediction of pollutants and groundwater under extreme conditions, it was found that the pollution process is slow, and the shortest time required for pollutants to reach the standard limit is 232 d at a distance of 50 m from the leakage point. Therefore, the influence of OPUCPB can be controlled, and this method can achieve improved reclamation of open pits and safety treatment of tailings. It was worth popularizing and applying in mining enterprises.


Supported employment for Irish adults with intellectual disability: the OPEN ROAD experience.
Supported employment is an approach to ensuring the vocational and social integration of persons with intellectual and other disabilities by placing and then training them to carry out real jobs in the regular workplace, supported by staff members or co-workers. This article focuses on the actual employment outcomes for participants in OPEN ROAD, a three-year innovative project which introduced adults with moderate and severe levels of intellectual disability in Dublin, Ireland to ordinary jobs. Supported workers (n = 24) were men and women aged between 19 and 49 years who obtained part-time jobs chiefly within the financial and food service and retail sectors of an economy marked by high rates of long-term unemployment. Effective job-finding and support strategies as well as individual outcomes are described. Priorities for those at national and agency levels planning for meaningful, sustainable employment for persons in this population are suggested.


Self-reported physical health among older surrogate parents to children orphaned and affected by HIV disease.
Around the globe, older relatives, largely grandparents, have become the surrogate parents to children and adolescents orphaned by parental death from HIV/AIDS and to those whose infected parents are too ill to serve as their primary caregivers. Largely invisible to research, programme and policy initiatives, these older surrogate parents face compounded stress and the risk of neglected and compromised health. An exploratory study of third- and fourth-generation relatives (n=20, mean of 59 years) found an average of 3.3 chronic health conditions. Fifty-five per cent rated their own health as "fair" or "poor" and 70% reported having insufficient time to attend to their own health. Supportive services are needed to address the health needs of these "hidden patients".


Antilipoprotein autoimmune hyperlipidemia. The Ig-Lp test.
In the antilipoprotein type of autoimmune hyperlipidemia (AIH), the immunoglobulins (Ig) are bound to lipoproteins by their antibody site and circulate as immune Ig-Lp complexes. In the earlier studies, the specific antibody activities were demonstrated in vitro by specific but rather sophisticated methods which were not suitable for the screening of antilipoprotein AIH in large populations. In the Ig-Lp test described here, the immunoglobulins bound to the low density lipoproteins (Ig-Lp) are detected by floating the complexes at D 1.10 in the ultracentrifuge in a physiological saline sucrose density gradient; delipidating them by ether in the presence of 0.2 M urea, and assaying the protein by radial immunodiffusion and laser immunonephelometry with antisera specific for IgG, IgA, IgM, low density lipoproteins and albumin. Radial immunodioffusion and immunonephelometry gave similar results. This Ig-Lp test was positive in 5 myelomas associated with hyperlipidemia, which were previously classified as AIH with specific methods. And the test was specific for the Ig type of the monoclonal antibody involved in each case (3 IgA, 1 IgG and 1 IgM). It was negative in 6 normolipidemic myelomas and also in 40 sera from healthy blood donors and one normal serum taken 4 hours after a fat meal. Although the Ig-Lp test is not specific for antilipoprotein antibodies, the results of this study allow to use if for the screening for AIH.


Stereotactic radiation therapy of intracranial arteriovenous malformations.
Twenty-six patients with large intracranial arteriovenous malformations (AVM), not suited for open surgery or radiosurgery, have been treated by fractionated stereotactic radiation therapy using a linear accelerator. The preliminary results are based on follow-up angiography one and a half years after treatment, and in 5 cases also 5 years after treatment. In 2 cases a complete obliteration of the AVMs has occurred, and in the majority of the remaining cases a reduction of the size of the lesion has been obtained. Further development of the method is needed in order to improve the results. Today treatment with this technique is only recommended in cases which cannot be treated with other methods.


The ellagitannin trimer rugosin G inhibits recombinant human histidine decarboxylase.
Rugosin G, an ellagitannin trimer, was isolated from the water-soluble fraction of red rose petals, and its inhibitory activity against recombinant human histidine decarboxylase was investigated. Rugosin G showed potent inhibition compared to ellagitannin monomers and a dimer with macrocyclic structure (oenothein B), suggesting the potent inhibition of rugosin G was attributed to its linear oligomeric conformation. Abbreviations: HDC, histidine decarboxylase; Me2CO, acetone; EtOAc, ethyl acetate.


Hexavalent Chromium Exposure Induces Intestinal Barrier Damage via Activation of the NF-κB Signaling Pathway and NLRP3 Inflammasome in Ducks.
Hexavalent chromium [Cr(VI)] is a dangerous heavy metal which can impair the gastrointestinal system in various species; however, the processes behind Cr(VI)-induced intestinal barrier damage are unknown. Forty-eight healthy 1-day-old ducks were stochastically assigned to four groups and fed a basal ration containing various Cr(VI) dosages for 49 days. Results of the study suggested that Cr(VI) exposure could significantly increase the content of Cr(VI) in the jejunum, increase the level of diamine oxidase (DAO) in serum, affect the production performance, cause histological abnormalities (shortening of the intestinal villi, deepening of the crypt depth, reduction and fragmentation of microvilli) and significantly reduced the mRNA levels of intestinal barrier-related genes (ZO-1, occludin, claudin-1, and MUC2) and protein levels of ZO-1, occludin, cand laudin-1, resulting in intestinal barrier damage. Furthermore, Cr(VI) intake could increase the contents of hydrogen peroxide (H2O2) and malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-18 (IL-18) but decrease the activities of total superoxide dismutase (T-SOD), catalase (CAT), and glutathione reductase (GR), as well as up-regulate the mRNA levels of TLR4, MyD88, NF-κB, TNFα, IL-6, NLRP3, caspase-1, ASC, IL-1β, and IL-18 and protein levels of TLR4, MyD88, NF-κB, NLRP3, caspase-1, ASC, IL-1β, and IL-18 in the jejunum. In conclusion, Cr(VI) could cause intestinal oxidative damage and inflammation in duck jejunum by activating the NF-κB signaling pathway and the NLRP3 inflammasome.


[Sexual disorder from an evolutionary perspective].
Evolutionary-psychology hypothesizes how character traits, emotions and behavioral patterns present in modern-day humans, have evolved to contribute to the survival and procreation of our ancestors. Stevens and Price (2000) wrote, "Darwinian paradigm is the bedrock on which allã biological sciences are now based, and no psychological explanation can hope to survive if it is incompatible with it". The present paper hypothesizes how sexual disorders, for males and females, contributed to survival and procreation of our ancestors and ways to incorporate that knowledge during psychotherapy.


Constitutive CaMKII activity regulates Na+ channel in rat ventricular myocytes.
The cardiac voltage-gated Na(+) channel controls the upstroke of action potential and membrane excitability. The Na(+) channel associates with Ca(2+)/CaM-dependent protein kinase (CaMKII), but the role of CaMKII on Na(+) channel activity in the resting state is not clear. In this report, we investigated whether CaMKII constitutively regulates Na(+) currents (I(Na)), independent of Ca(2+) influx in rat ventricular myocytes using patch clamp technique. CaMKII inhibition (by KN93 or autocamtide-related inhibitory peptide) caused a negative shift in I(Na) steady-state inactivation and delayed recovery from slow inactivation, limiting channel availability. The reduction of I(Na) was 29.47+/-3.01% at a holding potential (V(h)) of -120 mV and it increased to 77.70+/-7.92% when V(h) was -70 mV, suggesting that near the resting membrane potential, three-quarters of I(Na) depends on CaMKII action. CaMKII inhibition also enhanced intermediate inactivation, as well as delayed recovery from fast inactivation, and decreased late I(Na). KN92, an inactive analog of KN93, had no effect on I(Na). Using an antibody against phosphorylated (activated) CaMKII, we found that constitutively active CaMKII co-immunoprecipitated with Na(+) channels under resting conditions. CaMKII inhibitors reduced the level of phosphorylated CaMKII, which correlated with the degree of reduction in channel availability. These data suggest that CaMKII in an active form contributes to regulating I(Na). Finally, we observed a drastic reduction in the upstroke velocity of action potentials upon CaMKII inhibition. In conclusion, CaMKII constitutively regulates cardiac Na(+) channel and this regulatory mechanism is important for the maintenance of Na(+) channel characteristics under physiological conditions.


Muscle strength, power and adaptations to resistance training in older people.
Muscle strength and, to a greater extent, power inexorably decline with ageing. Quantitative loss of muscle mass, referred to as "sarcopenia", is the most important factor underlying this phenomenon. However, qualitative changes of muscle fibres and tendons, such as selective atrophy of fast-twitch fibres and reduced tendon stiffness, and neural changes, such as lower activation of the agonist muscles and higher coactivation of the antagonist muscles, also account for the age-related decline in muscle function. The selective atrophy of fast-twitch fibres has been ascribed to the progressive loss of motoneurons in the spinal cord with initial denervation of fast-twitch fibres, which is often accompanied by reinnervation of these fibres by axonal sprouting from adjacent slow-twitch motor units (MUs). In addition, single fibres of older muscles containing myosin heavy chains of both type I and II show lower tension and shortening velocity with respect to the fibres of young muscles. Changes in central activation capacity are still controversial. At the peripheral level, the rate of decline in parameters of the surface-electromyogram power spectrum and in the action-potential conduction velocity has been shown to be lower in older muscle. Therefore, the older muscle seems to be more resistant to isometric fatigue (fatigue-paradox), which can be ascribed to the selective atrophy of fast-twitch fibres, slowing in the contractile properties and lower MU firing rates. Finally, specific training programmes can dramatically improve the muscle strength, power and functional abilities of older individuals, which will be examined in the second part of this review.


NHL Pathological Image Classification Based on Hierarchical Local Information and GoogLeNet-Based Representations.
Accurate classification for different non-Hodgkin lymphomas (NHL) is one of the main challenges in clinical pathological diagnosis due to its intrinsic complexity. Therefore, this paper proposes an effective classification model for three types of NHL pathological images, including mantle cell lymphoma (MCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL). There are three main parts with respect to our model. First, NHL pathological images stained by hematoxylin and eosin (H&E) are transferred into blue ratio (BR) and Lab spaces, respectively. Then specific patch-level textural and statistical features are extracted from BR images and color features are obtained from Lab images both using a hierarchical way, yielding a set of hand-crafted representations corresponding to different image spaces. A random forest classifier is subsequently trained for patch-level classification. Second, H&E images are cropped and fed into a pretrained google inception net (GoogLeNet) for learning high-level representations and a softmax classifier is used for patch-level classification. Finally, three image-level classification strategies based on patch-level results are discussed including a novel method for calculating the weighted sum of patch results. Different classification results are fused at both feature 1 and image levels to obtain a more satisfactory result. The proposed model is evaluated on a public IICBU Malignant Lymphoma Dataset and achieves an improved overall accuracy of 0.991 and area under the receiver operating characteristic curve of 0.998. The experimentations demonstrate the significantly increased classification performance of the proposed model, indicating that it is a suitable classification approach for NHL pathological images.


Deep Multi-Feature Transfer Network for Fourier Ptychographic Microscopy Imaging Reconstruction.
Fourier ptychographic microscopy (FPM) is a potential imaging technique, which is used to achieve wide field-of-view (FOV), high-resolution and quantitative phase information. The LED array is used to irradiate the samples from different angles to obtain the corresponding low-resolution intensity images. However, the performance of reconstruction still suffers from noise and image data redundancy, which needs to be considered. In this paper, we present a novel Fourier ptychographic microscopy imaging reconstruction method based on a deep multi-feature transfer network, which can achieve good anti-noise performance and realize high-resolution reconstruction with reduced image data. First, in this paper, the image features are deeply extracted through transfer learning ResNet50, Xception and DenseNet121 networks, and utilize the complementarity of deep multiple features and adopt cascaded feature fusion strategy for channel merging to improve the quality of image reconstruction; then the pre-upsampling is used to reconstruct the network to improve the texture details of the high-resolution reconstructed image. We validate the performance of the reported method via both simulation and experiment. The model has good robustness to noise and blurred images. Better reconstruction results are obtained under the conditions of short time and low resolution. We hope that the end-to-end mapping method of neural network can provide a neural-network perspective to solve the FPM reconstruction.


Using farmers' local knowledge of tree provision of ecosystem services to strengthen the emergence of coffee-agroforestry landscapes in southwest China.
Intensive monoculture coffee farms quickly expanded in Yunnan Province in the 1990's and 2000's. In 2012, local authorities in Pu'er and Xishuangbanna Prefectures, the main coffee producing centre in the province, initiated a large-scale conversion program of these farms towards coffee-agroforestry systems to promote "ecologically-friendly coffee". Shade tree inventories and household interviews were conducted in these two prefectures to characterize coffee farms and the Local Ecological Knowledge (LEK) of farmers on the provision of ecosystem services by associated tree species. This study on newly emerging coffee farming systems revealed a high level of tree species diversity at both farm and landscape levels despite the previous dominance of intensive coffee monoculture and the large-scale distribution of a limited number of shade tree species by the government. 162 tree species were encountered during farm inventories, out of which the community of coffee farmers was able to rank 30 against 9 ecosystem services and disservices. This study reveals that this LEK is a type of hybrid knowledge that still relies mostly on traditional knowledge of tree species combined with experience acquired from newly-implemented coffee-agroforestry practices. This study also pointed out knowledge gaps regarding the impact of mature trees on coffee yield, coffee quality and pest control. The participatory approach resulted in the identification of non-promoted species with a high potential to provide locally relevant ecosystem services in coffee-agroforestry systems. These results lead to the upgrade of an online tool (www.shadetreeadvice.org) which allows extension services generating lists of recommended shade tree species tailored to the local ecological context and individual farmers' needs. This tool will benefit farmers' livelihood, support landscape health and contribute to the sustainability of the emerging Yunnan coffee agriculture sector.


Being a mentor in the digital era: An exploratory study of the benefits undergraduate student mentors derived from providing virtual mentoring to youth.
The purpose of the study was to understand mentors' perceptions of the benefits they derived from providing virtual mentoring to youth at risk of school failure and justice system involvement in an alternative school-based mentoring program. Using data collected from 38 university student mentors, we used a qualitative case study design focused on generating highly credible descriptions of mentors' perceptions of how they were affected by their experiences providing virtual mentoring. The three conceptual themes that emerged in our analysis were that virtual mentors described experiencing the following outcomes: (1) the reduction of biases and development of cultural humility, (2) the development of communication and leadership skills, and (3) a cultivation of civic responsibility and a sense of empowerment to make a difference. These findings suggest that providing virtual mentoring to youth may be one important tool for building competencies for undergraduate students.


Enhancement of β-amyloid oligomer accumulation after intracerebroventricular injection of streptozotocin, which involves central insulin signaling in a transgenic mouse model.
The β-amyloid (Aβ) oligomer rather than fibrillar Aβ has become the important focus of recent studies on the pathogenesis of Alzheimer's disease (AD). Insulin signaling plays important roles in cognitive disease, such as AD. However, in-vivo evidence for the link between central insulin signaling and the Aβ oligomer are lacking, and the mechanisms underlying the effect of central insulin signaling on AD are still elusive. Our team has established the Presenilin-1 Val97Leu mutant transgenic (PS1V97L) AD mouse model with the intraneuronal Aβ oligomer as the potential initiator for other pathologies, but without extracellular amyloid plaque formation. Using this model, we investigated the roles of disturbed central insulin signaling induced by intracerebroventricular injection of streptozotocin (STZ) in the progression of AD. We observed that PS1V97L mice after intracerebroventricular injection of STZ showed increased Aβ oligomer accumulation and aggravated spatial learning and memory deficit in the absence of diabetes symptoms. Furthermore, STZ administration inhibited the activation of the insulin receptor and enhanced the activation of c-Jun NH2-terminal kinase, which was accompanied by increased production of carboxy-terminal fragments from the amyloid precursor protein, in the brain of PS1V97L mice. Overall, our study provided in-vivo evidence for a role of central insulin signaling in AD progression.


Next-Generation Human Liver Models for Antimalarial Drug Assays.
Advances in malaria prevention and treatment have significantly reduced the related morbidity and mortality worldwide, however, malaria continues to be a major threat to global public health. Because Plasmodium parasites reside in the liver prior to the appearance of clinical manifestations caused by intraerythrocytic development, the Plasmodium liver stage represents a vulnerable therapeutic target to prevent progression. Currently, a small number of drugs targeting liver-stage parasites are available, but all cause lethal side effects in glucose-6-phosphate dehydrogenase-deficient individuals, emphasizing the necessity for new drug development. Nevertheless, a longstanding hurdle to developing new drugs is the availability of appropriate in vitro cultures, the crucial conventional platform for evaluating the efficacy and toxicity of drugs in the preclinical phase. Most current cell culture systems rely primarily on growing immortalized or cancerous cells in the form of a two-dimensional monolayer, which is not very physiologically relevant to the complex cellular architecture of the human body. Although primary human cells are more relevant to human physiology, they are mainly hindered by batch-to-batch variation, limited supplies, and ethical issues. Advances in stem cell technologies and multidimensional culture have allowed the modelling of human infectious diseases. Here, current in vitro hepatic models and toolboxes for assaying the antimalarial drug activity are summarized. Given the physiological potential of pluripotent and adult stem cells to model liver-stage malaria, the opportunities and challenges in drug development against liver-stage malaria is highlighted, paving the way to assess the efficacy of hepatic plasmodicidal activity.


Role of Omega-3 Fatty Acids as Non-Photic Zeitgebers and Circadian Clock Synchronizers.
Omega-3 fatty acids (ω-3 FAs) are well-known for their actions on immune/inflammatory and neurological pathways, functions that are also under circadian clock regulation. The daily photoperiod represents the primary circadian synchronizer ('zeitgeber'), although diverse studies have pointed towards an influence of dietary FAs on the biological clock. A comprehensive literature review was conducted following predefined selection criteria with the aim of updating the evidence on the molecular mechanisms behind circadian rhythm regulation by ω-3 FAs. We collected preclinical and clinical studies, systematic reviews, and metanalyses focused on the effect of ω-3 FAs on circadian rhythms. Twenty animal (conducted on rodents and piglets) and human trials and one observational study providing evidence on the regulation of neurological, inflammatory/immune, metabolic, reproductive, cardiovascular, and biochemical processes by ω-3 FAs via clock genes were discussed. The evidence suggests that ω-3 FAs may serve as non-photic zeitgebers and prove therapeutically beneficial for circadian disruption-related pathologies. Future work should focus on the role of clock genes as a target for the therapeutic use of ω-3 FAs in inflammatory and neurological disorders, as well as on the bidirectional association between the molecular clock and ω-3 FAs.


Diblock-type supramacromolecule via biocomplementary hydrogen bonding.
Control of nanostructure formation by a diblock-type supramacromolecule via biocomplementary hydrogen bonding has been achieved. Two different homopolymers, poly(4-trimethylsilylstyrene) and poly(styrene-d8), that are end-decorated with complementary oligonucleotides, i.e., thymidine phosphates and deoxyadenosine phosphates, were prepared by using the phosphoramidite method and blended successively. Association behavior in a blend solution was examined with NMR, and a cast bulk film obtained from the solution has been confirmed to show a nanophase-separated structure by transmission electron microscopy and X-ray scattering. Suppression of this nanostructure formation of a block-type supramacromolecule was also attained by adding a smaller agent as an inhibitor.


Periodontitis in patients with systemic lupus erythematosus: A nationwide study of 1,990 patients.
The aim of this study was to examine the association between systemic lupus erythematosus (SLE) and periodontitis in Norway during a 10-year period from 2008 through 2017. In this population-based study, 1,990 patients were included in the SLE-cohort based on diagnostic codes registered in the Norwegian Patient Registry. The control group (n = 170,332) comprised patients registered with diagnostic codes for non-osteoporotic fractures or hip or knee replacement because of osteoarthritis. The outcome was periodontitis, defined by procedure codes registered in the Control and Payment of Health Refunds database. Logistic regression analyses were performed to estimate odds ratio for periodontitis in patients versus controls adjusted for potential covariates. Periodontitis was significantly more common in SLE patients compared to controls (OR 1.78, 95% CI 1.47-2.14) and the difference was highest in SLE-patients 20 to 30 years of age (OR 3.24, 95% CI 1.23 - 8.52). The periodontitis rate in SLE patients was in the same range as for patients with diabetes mellitus type 2. Patients with SLE had an almost doubled risk of periodontitis compared with the control population, and the difference was most accentuated in the young patients. These findings warrant an increased focus on dental health in SLE-patients.


Late-Onset Sepsis as a Risk Factor for Bronchopulmonary Dysplasia in Extremely Low Birth Weight Infants: A Nationwide Cohort Study.
This study aimed to determine the effect of late-onset sepsis (LOS) on the development of bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants. A prospective cohort study was performed using data collected from 64 centres registered in the Korean national registry. LOS was defined as a positive blood culture and antibiotics treatment after 72 hours of life and prior to 36 weeks postmenstrual age (PMA). Data on the causative organisms were collected and analysed for respiratory outcomes. Among the 1,434 ELBW infants who survived to 36 weeks PMA, 481 (34%) developed LOS caused by bacteria (n = 405), fungi (n = 28), or both (n = 48). The incidence of BPD was significantly associated with LOS in both the entire cohort and the propensity score-matched cohort. Two or more LOS episodes were a risk factor for BPD. The impact of multiple episodes of LOS on BPD was prominent in infants who received mechanical ventilation for two weeks or less. The estimated odds ratios for BPD and severe BPD were greater with fungal LOS than with bacterial LOS. In conclusion, LOS, particularly complicated by multiple episodes and/or fungi, was a risk factor for BPD in ELBW infants.


Resveratrol-induced limitation of dysfunction of mitochondria isolated from rat brain in an anoxia-reoxygenation model.
Resveratrol protection on the main functions of purified rat brain mitochondria submitted to anoxia-reoxygenation was investigated. Resveratrol (<0.1 microM) reversed partly (23.3%) the respiratory control ratio (RCR) decrease by protecting both states 3 and 4. This effect was both observed when resveratrol was added before anoxia or reoxygenation. Resveratrol fully inhibited the release of cytochrome c in a concentration-dependent manner and significantly decreased the superoxide anion (O2(0-)) production at a concentration of 1 nM. The mitochondrial membranes damaged after the anoxia-reoxygenation were partly protected (about 70%) by resveratrol at 0.1 microM. The oxygen consumption of mitochondria in presence of NADH and cytochrome c was significantly inhibited by resveratrol with a low EC50 of 18.34 pM. Resveratrol inhibited the CCCP-induced uncoupling from about 20%. The effects of resveratrol on oxidative phosphorylation parameters were also investigated in rats after pretreatment (0.4, 2 and 10 mg/kg/day) for one week. After the isolation of brain mitochondria, the RCR was significantly less decreased in the resveratrol group compared to the control group. These results showed that resveratrol could preserve the mitochondrial functions with at least three mechanisms: antioxidant properties, action on complex III and a membrane stabilizing effect.


Sex-dependent Differences in the Bioenergetics of Liver and Muscle Mitochondria from Mice Containing a Deletion for glutaredoxin-2.
Our group recently published a study demonstrating that deleting the gene encoding the matrix thiol oxidoreductase, glutaredoxin-2 (GRX2), alters the bioenergetics of mitochondria isolated from male C57BL/6N mice. Here, we conducted a similar study, examining H2O2 production and respiration in mitochondria isolated from female mice heterozygous (GRX2+/-) or homozygous (GRX2-/-) for glutaredoxin-2. First, we observed that deleting the Grx2 gene does not alter the rate of H2O2 production in liver and muscle mitochondria oxidizing pyruvate, α-ketoglutarate, or succinate. Examination of the rates of H2O2 release from liver mitochondria isolated from male and female mice revealed that (1) sex has an impact on the rate of ROS production by liver and muscle mitochondria and (2) loss of GRX2 only altered ROS release in mitochondria collected from male mice. Assessment of the bioenergetics of these mitochondria revealed that loss of GRX2 increased proton leak-dependent and phosphorylating respiration in liver mitochondria isolated from female mice but did not alter rates of respiration in liver mitochondria from male mice. Furthermore, we found that deleting the Grx2 gene did not alter rates of respiration in muscle mitochondria collected from female mice. This contrasts with male mice where loss of GRX2 substantially augmented proton leaks and ADP-stimulated respiration. Our findings indicate that some fundamental sexual dimorphisms exist between GRX2-deficient male and female rodents.


Contribution of selenocysteine to the peroxidase activity of selenoprotein S.
Selenoprotein S (SelS, VIMP) is an intrinsically disordered enzyme that utilizes selenocysteine to catalyze the reduction of disulfide bonds and peroxides. Here it is demonstrated that selenocysteine is the residue oxidized by the peroxide substrate. It is possible to trap the reaction intermediate selenenic acid when the resolving cysteine is mutated. The selenocysteine allows SelS to rapidly re-form its selenenylsulfide bond following its reduction, and to resist inactivation by H2O2. We propose that SelS's peroxidase mechanism is similar to that of atypical 2-Cys peroxiredoxin and that selenocysteine allows SelS to sustain activity under oxidative stress.


[Use of the immunoautoradiographic method for determining HBsAg in the blood of serum hepatitis patients].
The use of immunoautoradiography for HBsAg detection increased its primary detection rate in the blood of patients with acute serum hepatitis to 70% (by 12--15% more than in the gel precipitation test). Antigenemia in patients with acute serum hepatitis has been shown to last much longer than could be determined by gel precipitation. As a result of this, over 60% of the patients with HBs-antigenemia in the acute period are discharged from the hospital still containing the antigen. A correlation between the duration of antigenemia in the GP test and the speed of antigen disappearance from the blood according to the IAR test was established. The IAR method was found to be highly sensitive and specific; its application helps solving some theoretical and practical problems.


Comparative effects of the addition of meat from beef, chicken, mullet and hake to a bean seed ragout on iron metabolism and iron status in growing rats.
The objective was to study the comparative effects of the addition of meat from beef, chicken, mullet and hake to a bean seed ragout (BSR) on iron metabolism and iron status in growing rats. The iron metabolism and the iron status were investigated through the exploration of the total iron in the blood and the reserve of iron stored in the liver, spleen, intestine, heart and tibia. Our findings showed that the iron concentration in total blood significantly increased only in the BSR + beef group by 23% (p < 0.006) as compared to the control group (BSR). However, it significantly decreased in the BSR + chicken group by 19.3% (p < 0.002). The reserve of iron stored in the liver significantly increased in the BSR + beef and the BSR + hake groups by 69.5% (p < 0.003) and 160% (p < 2.5.10(-7)) respectively, as compared to the control group. The effect of hake was more pronounced than beef. However, in the BSR + chicken and the BSR + mullet groups, the reserve of iron stored in the liver did not significantly differ from the control group. The reserve of iron stored in the spleen increased significantly in all groups. The increase has reached 370% in the BSR + hake group (p < 1.10(-7)). In the intestine, the reserve of iron was significantly enhanced only in the group fed BSR + beef by 120% (p < 0.01). In contrast, this reserve was lower in the rats fed BSR + mullet than in the other groups, a reduction of 64% (p < 1.10(-5)) as compared to the control group. In the heart, iron concentration significantly increased between 36.5 and 50%, as compared to the control group. The iron stored in the tibia significantly increased only in the beef and the hake groups by 88% (p < 0.05) and 57.4% (p < 0.02) respectively. Our findings demonstrated that beef, chicken, mullet and hake did not have the same effect on iron metabolism and iron status in growing rats fed BSR diets. The rats fed BSR + beef have a better iron status than those fed BSR + hake, BSR + chicken or BSR + mullet in descending order.


Restriction of rRNA synthesis by VHL maintains energy equilibrium under hypoxia.
Biological evolution abides by an unbending rule obligating organisms to maintain energy equilibrium. Hypoxia reduces cellular energy supply and is thus thought to be deleterious. We report that cells have evolved pH-sensitive mechanisms to maintain energy equilibrium by lowering energy demand. We found that fermentation-induced acidosis allows hypoxic cells to maintain energy equilibrium and viability under hypoxia by restricting ribosomal biogenesis, the most energy-demanding cellular process. Acidosis triggers nucleolar condensation, decreases precursor rRNA synthesis, reduces the dynamic profile of the RNA polymerase I preinitiation factor UBF1 and its interaction with the promoter of rRNA genes (rDNA). These changes require the pH-dependent interaction of the statically detained von Hippel-Lindau tumor suppressor protein (VHL) with rDNA. This phenomenon is promoted by, but does not require, activation of the hypoxia-inducible factor (HIF), a transcription factor implicated in extracellular acidification, energy production and oxygen homeostasis. Abrogating this program by silencing VHL expression, competing rDNA-VHL interaction or preventing environmental acidification triggers energy starvation and cell death under hypoxia. Our data suggest that oxygen-starved cells maintain energy equilibrium by gauging the environmental concentration of H(+) to statically detain VHL to nucleolar rDNA and restrict ribosome production. These findings also provide an explanation for the protective effect of acidosis in ischemic settings such as development, stroke and cancer.


A method for machine learning generation of realistic synthetic datasets for validating healthcare applications.
Digital health applications can improve quality and effectiveness of healthcare, by offering a number of new tools to users, which are often considered a medical device. Assuring their safe operation requires, amongst others, clinical validation, needing large datasets to test them in realistic clinical scenarios. Access to datasets is challenging, due to patient privacy concerns. Development of synthetic datasets is seen as a potential alternative. The objective of the paper is the development of a method for the generation of realistic synthetic datasets, statistically equivalent to real clinical datasets, and demonstrate that the Generative Adversarial Network (GAN) based approach is fit for purpose. A generative adversarial network was implemented and trained, in a series of six experiments, using numerical and categorical variables, including ICD-9 and laboratory codes, from three clinically relevant datasets. A number of contextual steps provided the success criteria for the synthetic dataset. A synthetic dataset that exhibits very similar statistical characteristics with the real dataset was generated. Pairwise association of variables is very similar. A high degree of Jaccard similarity and a successful K-S test further support this. The proof of concept of generating realistic synthetic datasets was successful, with the approach showing promise for further work.


Splenic injury during percutaneous nephrolithotomy: a case report with novel management technique.
We describe a case of a splenic injury caused by a transsplenic percutaneous nephrostomy tract. The case was completed without incident and the nephrostomy tube was noted to traverse the spleen on routine postoperative imaging. This rare complication was managed by deposition of Gelfoam((R)) pledgets along the transsplenic nephrostomy tract and placement of a ureteral stent. This novel management technique has not been previously described in the literature and was successful in the conservative treatment of the uncommon complication of splenic injury during percutaneous nephrolithotomy.


ATRA attenuate proteinuria via downregulation of TRPC6 in glomerulosclerosis rats induced by adriamycin.
In this research, we explored the molecular mechanism of proteinuria in glomerulosclerosis rats and the protective effects of ATRA. This research set up three groups: SHO group, GS group, and ATRA group (15 mg/(kg d), Sigma, St. Louis, MO). The serum creatinine (Scr), urea nitrogen (BUN), and 24-h proteinuria were detected 12 weeks after administration of ATRA. The pathological and ultrastructure changes were observed under light microscope and transmission electron microscope. The protein expression of TGF-β1 and Col-IV in glomerulus was detected by immunohitochemistry method. The mRNA and the protein expression of glomerular TRPC6 were detected by RT-PCR and Western blot. In the rat model of GS, the expressions of TRPC6 were significantly elevated compared with the normal rat group; however, the use of ATRA down-regulated the expression of TRPC6 in the glomeruli and attenuated glomerulosclerosis and proteinuria. Scr and BUN were also improved by the treatment of ATRA. Our results demonstrated that ATRA could ameliorate glomerulosclerosis and proteinuria in GS, which may be related to suppressed expression of TRPC6.


Sequence-dependent binding of bis-amidine carbazole dications to DNA.
The conventional wisdom argues that DNA intercalators possess a condensed polyaromatic ring whereas DNA minor groove binders generally contain unfused aromatic heterocycles, frequently separated by amide bonds. Recently, this view has been challenged with the discovery of powerful intercalating agents formed by unfused aromatic molecules and groove binders containing a polyaromatic nucleus. Bis-amidinocarbazoles belong to this later category of drugs having a planar chromophore and capable of reading the genetic information accessible within the minor groove of AT-rich sequences [Tanious, F.A., Ding, D., Patrick, D.A., Bailly, C., Tidwell, R.R. & Wilson, W.D. (2000) Biochemistry 39, 12091-12101]. But in addition to the tight binding to AT sites, we show here that bis-amidinocarbazoles can also interact with GC sites. The extent and mode of binding of 2,7 and 3,6 substituted amidinocarbazoles to AT and GC sequences were investigated by complementary biochemical and biophysical methods. Absorption, fluorescence, melting temperature and surface plasmon resonance (SPR) measurements indicate that the position of the two amidine groups on the carbazole ring influences significantly the drug-DNA interaction. SPR and DNase I footprinting data confirm the AT-preference of the compounds and provide useful information on their additional interaction with GC sequences. The 3,6-carbazole binds approximately twice as strongly to the GC-containing hairpin oligomer than the 2,7-regioisomer. The high tendency of the 3,6 compound to intercalate into different types of DNA containing G.C base pairs is shown by electric linear dichroism. This work completes our understanding of the sequence-dependent DNA binding properties of carbazole dications.


Unusual Intramural Coronary Artery With Vertical Course Complicating an Arterial Switch Operation.
Intramural coronary arteries in patients with d-transposition of the great arteries (d-TGA) usually arise from the opposite sinus of Valsalva and traverse horizontally across the posterior/facing commissure before emerging externally from the appropriate sinus of Valsalva. Failure to make appropriate technical modifications during coronary transfer can result in an important risk of posttransfer ischemia. We report a case with an unusual course of an intramural left anterior descending (LAD) coronary artery in a patient with d-TGA, with origin at the mid ascending aorta and a vertical intramural course, increasing the susceptibility to injury during an arterial switch operation (ASO).


Using two models of workplace facilitation to create conditions for development of a person-centred culture: A participatory action research study.
To examine facilitation in workplace learning where nurses are focused on creating person-centred cultures; to provide a framework for novice and proficient facilitators/practitioners to learn in and from their own workplaces and practices; and to provide the conditions where practitioners can gain an understanding of the culture and context within their own workplace. Evidence suggests that person-centred cultures depend on purposeful, facilitated practice-based learning activities. For person-centredness to become more meaningful to nursing leaders in their daily work, focus must be placed on their acquisition and use of facilitation skills. The facilitation framework "Critical Companionship" remains an exemplar in the development of expert facilitation skills. Two sequential facilitation models were developed as "steps" towards Critical Companionship, as a framework for novice and proficient facilitators and practitioners to learn in and from their own workplaces and practices. This research, situated in a critical social science paradigm, drew on participatory action research to devise, explore and refine two facilitation models: Critical Allies and Critical Friends. The researcher adopted an insider approach to work with five nursing leaders, which was subsequently reported using the EQUATOR guidelines on best practice in reporting of participatory action research. The results show the complexity of enabling facilitation within the workplace. Four themes and twelve subthemes emerged from the data that describe the attributes needed to facilitate workplace learning and reveal that managers can have an active role in enabling person-centred culture development. This research adds to the body of knowledge on developing person-centred culture. It offers practical stepping stones for novice and proficient facilitators to enable embodiment of the skills necessary to facilitate learning in person-centred cultures. The models offer a workplace-friendly pathway with practical methods and further contribute to our understanding of how we create person-centred cultures. Facilitation of practice development and workplace learning remains the most effective methods to develop person-centred cultures. This research introduces a pathway for clinical leaders/managers to become facilitators with their own teams, maximising the impact on the culture where care is delivered.


Telomeres and Telomerase in the Control of Stem Cells.
Stem cells serve as a source of cellular material in embryogenesis and postnatal growth and regeneration. This requires significant proliferative potential ensured by sufficient telomere length. Telomere attrition in the stem cells and their niche cells can result in the exhaustion of the regenerative potential of high-turnover organs, causing or contributing to the onset of age-related diseases. In this review, stem cells are examined in the context of the current telomere-centric theory of cell aging, which assumes that telomere shortening depends not just on the number of cell doublings (mitotic clock) but also on the influence of various internal and external factors. The influence of the telomerase and telomere length on the functional activity of different stem cell types, as well as on their aging and prospects of use in cell therapy applications, is discussed.


Aspartic Acid Stabilized Iron Oxide Nanoparticles for Biomedical Applications.
Aspartic acid stabilized iron oxide nanoparticles (A-IONPs) with globular shape and narrow size distribution were prepared by the co-precipitation method in aqueous medium. A quantum-mechanical approach to aspartic acid optimized structure displayed negative charged sites, relatively high dipole moment, and hydrophilicity, which recommended it for interaction with iron cations and surrounding water electrical dipoles. A-IONPs were characterized by TEM, XRD, ATR-FTIR, EDS, DSC, TG, DLS, NTA, and VSM techniques. Theoretical study carried out by applying Hartree-Fock and density functional algorithms suggested that some aspartic acid properties related to the interaction can develop with nanoparticles and water molecules. The results of experimental investigation showed that the mean value of particle physical diameters was 9.17 ± 2.2 nm according to TEM image analysis, the crystallite size was about 8.9 nm according to XRD data, while the magnetic diameter was about 8.8 nm, as was determined from VSM data interpretation with Langevin's theory. The A-IONP suspension was characterized by zeta-potential of about -11.7 mV, while the NTA investigation revealed a hydrodynamic diameter of 153.9 nm. These results recommend the A-IONP suspension for biomedical applications.


Development of a measurement instrument for nursing documentation in the patient record.
To develop, validate and test the reliability of a measurement instrument that measures the extent to which records describe essential aspects of nursing care such as the admission report, nursing diagnoses, interventions, and progress and outcome evaluations. A measurement instrument was developed based on the Cat-ch-Ing instrument and the Scale for Degrees of Accuracy in Nursing Diagnoses. A record screening was conducted in 7 hospitals in the Netherlands. Content validity was tested by using two Delphi panels. Each of the 250 records was assessed by two reviewers independently. The reliability of the instrument was tested by calculating Cohen's weighted Kappa inter-rater reliability coefficient of 250 records and 12 reviewers. Internal consistency was calculated by using Cronbach's alpha. The new measurement instrument, named D-Catch, consists of six items. Quantity and quality variables were used to judge the accuracy of the nursing documentation. Internal consistency: Cronbach's Alpha 0.722. The inter-rater reliability coefficients were between 0.397-1.000. The D-Catch instrument was estimated to be a valid and reliable measurement instrument for nursing records in hospitals in the Netherlands. An adverse effect on the inter-rater reliability may have been that, specifically in long stay situations, documentation forms with diagnoses, interventions and outcomes were often unstructured and found to be repetitious.


Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus.
We have investigated the functional significance of conserved sequences within the 9p21.3 risk locus for coronary artery disease (CAD) and determined the relationship of 9p21.3 to expression of ANRIL and to whole genome gene expression. We demonstrate that a conserved sequence within the 9p21.3 locus has enhancer activity and that the risk variant significantly increases reporter gene expression in primary aortic smooth muscle cells. Whole blood RNA expression of the short variants of ANRIL was increased by 2.2-fold whereas expression of the long ANRIL variant was decreased by 1.2-fold in healthy subjects homozygous for the risk allele. Expression levels of the long and short ANRIL variants were positively correlated with that of the cyclin-dependent kinase inhibitor, CDKN2B (p15) and TDGF1 (Cripto), respectively. Relevant to atherosclerosis, genome-wide expression profiling demonstrated upregulation of gene sets modulating cellular proliferation in carriers of the risk allele. These findings are consistent with the hypothesis that the 9p21.3 risk allele contains a functional enhancer, the activity of which is altered in carriers of the risk allele. 9p21.3 may promote atherosclerosis by regulating expression of ANRIL, which in turn is associated with altered expression of genes controlling cellular proliferation pathways.


Non-Transfusional Hemocomponents: From Biology to the Clinic-A Literature Review.
Non-transfusional hemocomponents for surgical use are autogenous products prepared through the centrifugation of a blood sample from a patient. Their potential beneficial outcomes include hard and soft tissue regeneration, local hemostasis, and the acceleration of wound healing. Therefore, they are suitable for application in different medical fields as therapeutic options and in surgical practices that require tissue regeneration.