Dual PI3K/mTOR inhibition is required to effectively impair microenvironment survival signals in mantle cell lymphoma.
Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. Antitumor activity has been observed with mTOR inhibitors. However, they have shown limited clinical efficacy in relation to drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we have performed a comparative analysis of the mTOR inhibitor everolimus, the pan-PI3K inhibitor NVP-BKM120 and the dual PI3K/mTOR inhibitor NVP-BEZ235 in primary MCL cells. We found NVP-BEZ235 to be more powerful than everolimus or NVP-BKM120 in PI3K/Akt/mTOR signaling inhibition, indicating that targeting the PI3K/Akt/mTOR pathway at multiple levels is likely to be a more effective strategy for the treatment of MCL than single inhibition of these kinases. Among the three drugs, NVP-BEZ235 induced the highest change in gene expression profile. Functional validation demonstrated that NVP-BEZ235 inhibited angiogenesis, migration and tumor invasiveness in MCL cells. NVP-BEZ235 was the only drug able to block IL4 and IL6/STAT3 signaling which compromise the therapeutic effect of chemotherapy in MCL. Our findings support the use of the dual PI3K/mTOR inhibitor NVP-BEZ235 as a promising approach to interfere with the microenvironment-related processes in MCL.


Respite care for caregivers and people with severe mental illness: literature review.
The aim of this study was to review research literature over the past 10 years on respite care for people affected by severe mental illness; and identify key implications for nursing practice in provision of respite care for family caregivers of people with severe mental illness. Family caregivers play an important role in health care, but need regular breaks to maintain their own health and well-being. Respite care is one of the few services available with a primary focus on supporting family caregivers. In most developed countries the notion of respite care as an extension of the health care service has been embraced, evidenced by a growing body of literature in health and health-related disciplines. An initial literature search was undertaken using the key words "respite", "short-term care", "shared care" and "day care" in major electronic databases for nursing, psychiatry, psychology and sociology literature between 1967 and 2002, identifying 704 articles. Closer examination of the literature from 1993 to 2002 on gaps and trends in respite care for people affected by severe mental illness was conducted. This is discussed in the context of the broader literature, particularly on dementia, where the mainstream research on respite care is found. The majority of family caregiving studies identified a need for greater quality, quantity, variety and flexibility in respite provision, and the literature has remained largely silent in relation to those affected by severe mental illness. There are contradictory findings on outcomes of respite care services and a lack of controlled empirical studies and evaluative research on effectiveness. Respite care is beneficial for caregivers, there is significant unmet need in provision of services for the mentally ill, and greater flexibility and the needs of caregivers should be recognised and addressed.


Intensity fluctuations in laser links between the ground and a satellite.
Laser-beam-intensity fluctuations between an uplink (ground to satellite) and a downlink (satellite to ground) are described. The dependence of the beam radius on log-intensity variance in the uplink and the dependence of receiving-aperture diameter on the log-intensity variance in the downlink using a known theory were calculated. Statistical analysis of the experimental data on the laser links was performed, and high correlation coefficients of 0.94 between the normalized intensity variances of the uplink and those of the stellar scintillation were obtained. The beam-pointing error in the satelliteborne laser transmitter chiefly caused fluctuations in the downlink.


Lysophosphatidic acid induces cell migration through the selective activation of Akt1.
Akt plays pivotal roles in many physiological responses including growth, proliferation, survival, metabolism, and migration. In the current studies, we have evaluated the isoform-specific role of akt in lysophosphatidic acid (LPA)-induced cell migration. Ascites from ovarian cancer patients (AOCP) induced mouse embryo fibroblast (MEF) cell migration in a dose-dependent manner. On the other hand, ascites from liver cirrhosis patients (ALCP) did not induce MEF cell migration. AOCP-induced MEF cell migration was completely blocked by pre-treatment of cells with LPA receptor antagonist, Ki16425. Both LPA- and AOCP-induced MEF cell migration was completely attenuated by PI3K inhibitor, LY294002. Furthermore, cells lacking Akt1 displayed defect in LPA-induced cell migration. Re-expression of Akt1 in DKO (Akt1-/-Akt2-/-) cells restored LPA-induced cell migration, whereas re-expression of Akt2 in DKO cells could not restore the LPA-induced cell migration. Finally, Akt1 was selectively phosphorylated by LPA and AOCP stimulation. These results suggest that LPA is a major factor responsible for AOCP-induced cell migration and signaling specificity of Akt1 may dictate LPA-induced cell migration.


Single-Cell Acoustic Force Spectroscopy: Resolving Kinetics and Strength of T Cell Adhesion to Fibronectin.
Assessing the strength and kinetics of molecular interactions of cells with the extracellular matrix is fundamental to understand cell adhesion processes. Given the relevance of these processes, there is a strong need for physical methods to quantitatively assess the mechanism of cell adhesion at the single-cell level, allowing discrimination of cells with different behaviors. Here we introduce single-cell acoustic force spectroscopy (scAFS), an approach that makes use of acoustic waves to exert controlled forces, up to 1 nN, to hundreds of individual cells in parallel. We demonstrate the potential of scAFS by measuring adhesion forces and kinetics of CD4+ T lymphocytes (CD4) to fibronectin. We determined that CD4 adhesion is accelerated by interleukin-7, their main regulatory cytokine, whereas CD4 binding strength remains the same. Activation of these cells likely increases their chance to bind to the vessel wall in the blood flow to infiltrate inflamed tissues and locally coordinate the immune response.


Stochastic Tunneling of Two Mutations in a Population of Cancer Cells.
Cancer initiation, progression, and the emergence of drug resistance are driven by specific genetic and/or epigenetic alterations such as point mutations, structural alterations, DNA methylation and histone modification changes. These alterations may confer advantageous, deleterious or neutral effects to mutated cells. Previous studies showed that cells harboring two particular alterations may arise in a fixed-size population even in the absence of an intermediate state in which cells harboring only the first alteration take over the population; this phenomenon is called stochastic tunneling. Here, we investigated a stochastic Moran model in which two alterations emerge in a cell population of fixed size. We developed a novel approach to comprehensively describe the evolutionary dynamics of stochastic tunneling of two mutations. We considered the scenarios of large mutation rates and various fitness values and validated the accuracy of the mathematical predictions with exact stochastic computer simulations. Our theory is applicable to situations in which two alterations are accumulated in a fixed-size population of binary dividing cells.


Combined intraarterial carboplatin, intraarterial etoposide phosphate, and IV Cytoxan chemotherapy for progressive optic-hypothalamic gliomas in young children.
Optic pathway and/or hypothalamic astrocytomas in children are often quiescent, but in some cases, more aggressive tumors may cause progressive visual, endocrine, and neurologic deterioration. The initial treatment of these gliomas includes surgery and IV chemotherapy. Radiotherapy is not recommended in young children because of its severe adverse effects on cognitive and neuroendocrine function. This report suggests a new approach using combined intraarterial and IV carboplatin-based chemotherapy for patients for whom first line treatment has already failed. Six children (mean age, 57 months) with the diagnosis of optic pathway hypothalamic gliomas, who had tumor progression after surgery and underwent IV chemotherapy, were treated monthly with intraarterially administered carboplatin, intraarterially administered etoposide phosphate, and IV administered Cytoxan. Four of the children had histologically verified pilocytic astrocytomas, and in two cases, diagnosis was made on the basis of clinical findings. Administration of the intraarterial chemotherapy required catheter placement in both internal carotid arteries at the level of C2-C3 and into one of the vertebral arteries at the level of C6-C7, with the patient under general anesthesia. Four of six patients had partial radiographic response, one had stable disease, and one had progressive disease after one cycle. Three patients showed clinical improvement. There were no serious complications associated with the angiographic procedures. Toxicities included bronchospasm that resolved after 3 to 4 minutes in one patient. One patient showed mild ototoxicity, and four patients needed platelet transfusion because of hematologic toxicity of drugs. These results suggest that this modality of chemotherapy (administered after failure of systemic [ie, IV] chemotherapy), of progressive optic-hypothalamic astrocytomas in young children may be an effective treatment prior to radiotherapy.


Intestinal epithelial vitamin D receptor deletion leads to defective autophagy in colitis.
Vitamin D and the vitamin D receptor (VDR) appear to be important immunological regulators of inflammatory bowel diseases (IBD). Defective autophagy has also been implicated in IBD, where interestingly, polymorphisms of genes such as ATG16L1 have been associated with increased risk. Although vitamin D, the microbiome and autophagy are all involved in pathogenesis of IBD, it remains unclear whether these processes are related or function independently. We investigated the effects and mechanisms of intestinal epithelial VDR in healthy and inflamed states using cell culture models, a conditional VDR knockout mouse model (VDR(ΔIEC)), colitis models and human samples. Absence of intestinal epithelial VDR affects microbial assemblage and increases susceptibility to dextran sulfate sodium-induced colitis. Intestinal epithelial VDR downregulates expressions of ATG16L1 and lysozyme, and impairs antimicrobial function of Paneth cells. Gain and loss-of-function assays showed that VDR levels regulate ATG16L1 and lysozyme at the transcriptional and translational levels. Moreover, low levels of intestinal epithelial VDR correlated with reduced ATG16L1 and representation by intestinal Bacteroides in patients with IBD. Administration of the butyrate (a fermentation product of gut microbes) increases intestinal VDR expression and suppresses inflammation in a colitis model. Our study demonstrates fundamental relationship between VDR, autophagy and gut microbial assemblage that is essential for maintaining intestinal homeostasis, but also in contributing to the pathophysiology of IBD. These insights can be leveraged to define therapeutic targets for restoring VDR expression and function.


Wound emergencies: the importance of assessment, documentation, and early treatment using a wound electronic medical record.
Chronic wounds such as diabetic foot ulcers, venous ulcers, and pressure ulcers are a major source of morbidity and mortality. To describe wound characteristics associated with a wound emergency, the Wound Electronic Medical Records (WEMR) of 200 consecutive admissions (139 patients, average number of admissions 1.4) to a dedicated inpatient wound healing unit over a period of 5 months were retrospectively reviewed. Patient mean age was 62 +/- 16 years, 59% were men, 27% had a foot ulcer and diabetes mellitus, and 29% had venous ulcers. Presenting signs and symptoms included wound pain, cellulitis, nonpurulent drainage, and undermining, but few presented with classic local clinical signs of infection. Treatment consisted of sharp debridement with deep tissue culture and pathology from the wound base and/or systemic antibiotics. Twenty-percent (20%) of patients had pathology-confirmed and 38% had pathology- or radiology-confirmed osteomyelitis on admission, supporting that new or increasing wound pain, cellulitis, and/or nonpurulent drainage or presence of significant undermining may be indicative of an invasive infection and that patients presenting with these signs and symptoms require an immediate treatment plan and consideration of hospital admission. Use of an objective documentation system such as the WEMR may help alert clinicians to subtle wound changes that require aggressive treatment; thereby, avoiding emergency room visits and hospital admissions. Future research is needed utilizing the WEMR across multiple medical centers to further define criteria for a chronic wound emergency.


Impact of microsatellite status in early-onset colonic cancer.
The molecular profile of early-onset colonic cancer is undefined. This study evaluated clinicopathological features and oncological outcomes of young patients with colonic cancer according to microsatellite status. Anonymized data from an international collaboration were analysed. Criteria for inclusion were patients younger than 50 years diagnosed with stage I-III colonic cancer that was surgically resected. Clinicopathological features, microsatellite status, and disease-specific outcomes were evaluated. A total of 650 patients fulfilled the criteria for inclusion. Microsatellite instability (MSI) was identified in 170 (26.2 per cent), whereas 480 had microsatellite-stable (MSS) tumours (relative risk of MSI 2.5 compared with older patients). MSI was associated with a family history of colorectal cancer and lesions in the proximal colon. The proportions with pathological node-positive disease (45.9 versus 45.6 per cent; P = 1.000) and tumour budding (20.3 versus 20.5 per cent; P = 1.000) were similar in the two groups. Patients with MSI tumours were more likely to have BRAF (22.5 versus 6.9 per cent; P < 0.001) and KRAS (40.0 versus 24.2 per cent; P = 0.006) mutations, and a hereditary cancer syndrome (30.0 versus 5.0 per cent; P < 0.001; relative risk 6). Five-year disease-free survival rates in the MSI group were 95.0, 92.0, and 80.0 per cent for patients with stage I, II, and III tumours, compared with 88.0, 88.0, and 65.0 per cent in the MSS group (P = 0.753, P = 0.487, and P = 0.105 respectively). Patients with early-onset colonic cancer have a high risk of MSI and defined genetic conditions. Those with MSI tumours have more adverse pathology (budding, KRAS/BRAF mutations, and nodal metastases) than older patients with MSI cancers.


Colonoscopy in the elderly: low risk, low yield in asymptomatic patients.
Current colonoscopy guidelines do not address the issue of when to stop performing screening and surveillance colonoscopy in the elderly. We reviewed our experience and results of colonoscopy in patients aged 80 years and older to assess the risks and diagnostic yield in this population. We reviewed retrospectively the endoscopic and pathologic reports from consecutive colonoscopies performed on patients aged 80 years and older at a single, high-volume endoscopy center between August 1999 and May 2003. Patient characteristics, indications for examination, findings at colonoscopy, and complications were recorded and analyzed. A total of1,199 colonoscopic examinations were performed on 1,112 patients. Average age was 83.1 (range, 80-100) years. Male:female distribution was 1:1.7. Leading exclusive indications for colonoscopy included: polyp surveillance, 227 (19 percent); altered bowel habits, 168 (14 percent); iron-deficiency anemia, 132 (11 percent); and cancer follow-up, 108 (9 percent). Eighty-six examinations (7 percent) were performed solely for an indication of colorectal cancer screening. Twenty-two percent of patients had more than one indication for colonoscopy. Forty-five malignancies were found (3.7 percent). No cancers were found in the screening group, and two malignancies (0.7 percent) were detected in patients undergoing colonoscopy for polyp surveillance. There were eight (0.6 percent) reported major complications. Colonoscopy can be performed safely in patients aged 80 years and older. However, the diagnostic yield is low, particularly in patients undergoing routine screening or surveillance examinations. Colonoscopy should for the most part be limited to elderly patients with symptoms or specific clinical findings.


Sequence analysis of heparan sulphate indicates defined location of N-sulphated glucosamine and iduronate 2-sulphate residues proximal to the protein-linkage region.
A strategy that we originally used to identify an N-acetylated domain adjacent to the protein-linkage sequence of heparan sulphate proteoglycan (HSPG) [Lyon, Steward, Hampson & Gallagher (1987) Biochem. J. 242, 493-498] has been adapted for analysis of the location of GlcNSO3-HexA and GlcNSO3(+/- 6S)-IdoA(2S) units most proximal to the core protein. [3H]Glucosamine-labelled HSPG from human skin fibroblasts was depolymerized by using HNO2 or heparinase under conditions that allowed cleavage of all susceptible linkages. The degraded PG was coupled to Sepharose beads through the protein component, enabling specific recovery of protein-linked resistant oligosaccharides. These were released by treatment with alkaline borohydride and analysed by gel filtration and gradient PAGE. This strategy allowed investigation of the sequence of sugar residues along the chain relative to a common reference point (i.e. the reducing end of the chain). HNO2 scission confirmed the presence of a well-defined N-acetylated sequence predominantly 9-12 disaccharide units in length proximal to the core protein. Heparinase scission produced two classes of oligosaccharides (Mr approx. 7000 and 15,000) with the general formula: IdoA(2S)-GlcNSO3-[HexA-GlcNR]n-HexA-GlcNSO3-[Hex A-GlcNAc]9 12-GlcA-Gal-Gal-Xyl in which the average value for n is 1-2 for the 7000-Mr species and approx. 22 for the 15,000-Mr species. The latter oligosaccharides extend to about one-third of the total length of the HS chains (Mr approx. 45,000). HNO2 scission of these oligosaccharides enabled hypothetical models for their sequence to be proposed. The general arrangement of N-sulphated and N-acetylated disaccharides between the proximal GlcNSO3 and terminal IdoA(2S) residues of the 15,000-Mr fragment was similar to that in the original polysaccharide, suggesting the possibility of a tandemly repeating pattern in the sequence of HS.


Lymphogranuloma venereum in Europe, 2003-2008.
Lymphogranuloma venereum, caused by the L serovars of Chlamydia trachomatis, emerged in Europe in 2003 and a series of outbreaks were reported in different countries. The infection presents as a severe proctitis in men who have sex with men, many of whom are co-infected with HIV and other sexually transmitted infections. This paper reviews the number of cases reported over a five year period, from 2003 to 2008, from countries that were part of the European Surveillance of Sexually Transmitted Infections (ESSTI) network. Reports were received from Belgium, Denmark, France, Germany, the Netherlands, Portugal, Spain, Sweden, and the United Kingdom. It appears that after five years the characteristics of the patients infected has overall remained unchanged, although the total number of cases has increased and more countries in Europe have now identified cases of LGV.


Identification of the lipid-binding site of phosphatidylcholine-transfer protein with phosphatidylcholine analogs containing photoactivable carbene precursors.
The lipid binding site of the phosphatidylcholine transfer protein from bovine liver has been investigated by use of phosphatidylcholine analogs which carry a diazirinophenoxy group linked to the omega-carbon of either the sn-2-[1-14C]hexanoyl (PC I) or sn-2-[1-14C]undecanoyl chain (PC II). Photolysis of the PC I(PC II)-transfer protein complex resulted in a covalent coupling of 30-40% of the label to the protein as shown by sodium dodecyl sulfate/polyacrylamide gel electrophoresis. Upon mild alkaline treatment of the photolysed complex the protein containing covalently coupled 14C-label was separated from the noncoupled 14C-label by gel permeation chromatography. The 14C-labeled protein was degraded with protease from Staphylococcus aureus, trypsin and cyanogen bromide and specific 14C-labeled peptides were sequenced by automated Edman degradation. Major sites of coupling shown by release of radioactivity were identified as Tyr54 and the peptide segment Val171-Phe-Met-Tyr-Tyr-Phe-Asp177. Both PC I and PC II coupled extensively to Tyr54 (90% and 50% of total labeling, respectively). The remainder of the radioactivity was released from the peptide Val171-Asp177 with a distinct difference in in the pattern of release depending on whether PC I or PC II were used. Thus, coupling occurred preferentially to Tyr175 and Asp177 with PC I while Val171 and Met173 were labeled preferentially with PC II. This shift in coupling is compatible with an increase of 0.6 nm for the sn-2-fatty-acyl chains of PC I and II, assuming that the peptide Val171-Asp177 has adopted the strongly predicted beta-strand configuration. These data have been interpreted in terms of the localization of phosphatidylcholine in the phosphatidylcholine transfer protein.


Intraoperative imaging of the distal radioulnar joint using a modified skyline view.
Nonanatomic reduction of the sigmoid notch in distal radius fractures may lead to limited motion, instability, or pain with pronation and supination. Standard radiological projections only poorly capture the sigmoid notch contours in the axial plane. The purpose of this study was to find an intraoperatively feasible radiological projection that will facilitate an axial view of the distal radioulnar joint. We modified a previously described radiographic projection termed the skyline view for evaluating the distal radius axially. We created intra-articular steps at the sigmoid notch in solid foam forearm models to identify the best of 12 projections using an image intensifier. Four observers scored each projection based on the clarity of the sigmoid notch contour and indicated the presence and location of an intra-articular stepoff. The sigmoid notch was best visualized in the modified skyline view with the wrist in extension and 10° to 15° of dorsal forearm angulation relative to the x-ray path. All observers correctly recognized the presence and location of intra-articular steps at the sigmoid notch with this view. The same forearm angulation with the wrist in flexion did not reach equally good visibility of the sigmoid notch. Arm position (wrist flexion, forearm rotation, or forearm angulation) and intra-articular stepoff (none, palmar, or dorsal) were dependent determinates. Elimination of the variable forearm rotation had minimal effect, indicating that forearm rotation is not important for visualization of the sigmoid notch. The modified skyline view for visualization of the distal radioulnar joint in an axial plane allows good visibility of the sigmoid notch and reliable identification of stepoffs. Further cadaver and in vivo studies are required to verify the validity of this method.


Reactive oxygen species modulator-1 (Romo1) predicts unfavorable prognosis in colorectal cancer patients.
Reactive oxygen species modulator-1 (Romo1) is a novel protein that has been reported to be crucial for cancer cell proliferation and invasion. However, its clinical implications in colorectal cancer patients are not well-known. For the first time, we investigated the association between Romo1 and the clinical outcomes of colorectal cancer patients. We examined Romo1 expression in resected tumor tissues immunohistochemically and assessed it with histological scores. We conducted survival analyses for patients who had curative resection (n = 190) in accordance with clinical parameters including level of Romo1 expression, and we examined the association between Romo1 expression and cell invasion using Matrigel invasion assay in colorectal cancer cells. We observed significantly longer mean disease-free survival in the low Romo1 group compared with the high Romo1 group (161 vs 127.6 months, p = 0.035), and the median overall survival of the low Romo1 group was significantly longer than that of the high Romo1 group (196.9 vs 171.3 months, p = 0.036). Cell invasiveness decreased in the Romo1 knockdown colorectal cancer cells in contrast to the controlled cells. Romo1 overexpression in tumor tissue was associated with a high lymph node ratio between the metastatic and examined lymph nodes (p = 0.025). Romo1 overexpression in tumor tissue was significantly associated with survival in curatively resected colorectal cancer patients, suggesting Romo1 expression as a potential adverse prognostic marker. Increased Romo1 expression was found to be associated with high lymph node ratio. Cancer invasiveness appeared to be a key reason for the poor survival related to highly expressed Romo1.


The murine DNA glycosylase NEIL2 (mNEIL2) and human DNA polymerase beta bind microtubules in situ and in vitro.
8-oxoguanine DNA glycosylase (OGG1), a major DNA repair enzyme in mammalian cells and a component of the base excision repair (BER) pathway, was recently shown to be associated with the microtubule network and the centriole at interphase and the spindle assembly at mitosis. In this study, we determined whether other participants in the BER pathway also bind microtubules in situ and in vitro. Purified recombinant human DNA polymerase beta (DNA Pol beta) and purified recombinant mNEIL2 were chemically conjugated to fluorochromes and photosensitive dyes and used in in situ localization and binding experiments. Results from in situ localization, microtubule co-precipitation and site-directed photochemical experiments showed that recombinant human DNA Pol beta and recombinant mNEIL2 associated with microtubules in situ and in vitro in a manner similar to that shown earlier for another BER pathway component, OGG1. Observations reported in this study suggest that these BER pathway components are microtubule-associated proteins (MAPs) themselves or utilize yet to be identified MAPs to bind microtubules in order to regulate their intracellular trafficking and activities during the cell cycle.


Automated Insulin Delivery Systems: Hopes and Expectations of Family Members.
This study examines the hopes and expectations that children, adolescents, and adults with type 1 diabetes and their families have for new automated insulin delivery systems. The study also aims to examine how the automated insulin delivery system may impact family functioning and individual members' psychosocial adjustment. Forty-eight semistructured focus groups (n = 195) and 89 individual interviews were conducted with children, adolescents, and adults with type 1 diabetes and parents and partners. Coders reviewed results in key themes most likely to contain references to the family system. Clusters were analyzed using thematic analysis to identify participants' salient hopes and expectations of how new technology may impact family relationships and individual psychosocial functioning. Three main themes emerged for participants' hopes and expectations for implementation of the automated insulin delivery system. First, there is an expectation that this diabetes technology will alleviate diabetes-specific worry and burden for the people with diabetes and other family members. Second, there is also hope that this system may reduce day-to-day stress and, third, improve family relationships. The unique perspective of a broad age group provides insight into how individuals and families creatively address the multiple tasks required in daily diabetes management. Study findings elucidate the very high hopes and expectations held by those managing type 1 diabetes and the impact this new technology may have on family relationships. Awareness of these hopes and expectations is important for developers and clinicians in addressing potential challenges to uptake and to ensure that expectations are set appropriately.


Frog secretions and hunting magic in the upper Amazon: identification of a peptide that interacts with an adenosine receptor.
A frog used for "hunting magic" by several groups of Panoan-speaking Indians in the borderline between Brazil and Peru is identified as Phyllomedusa bicolor. This frog's skin secretion, which the Indians introduce into the body through fresh burns, is rich in peptides. These include vasoactive peptides, opioid peptides, and a peptide that we have named adenoregulin, with the sequence GLWSKIKEVGKEAAKAAAKAAGKAALGAVSEAV as determined from mass spectrometry and Edman degradation. The natural peptide may contain a D amino acid residue, since it is not identical in chromatographic properties to the synthetic peptide. Adenoregulin enhances binding of agonists to A1 adenosine receptors; it is accompanied in the skin secretion by peptides that inhibit binding. The vasoactive peptide sauvagine, the opioid peptides, and adenoregulin and related peptides affect behavior in mice and presumably contribute to the behavioral sequelae observed in humans.


CDNA cloning of p112, the largest regulatory subunit of the human 26s proteasome, and functional analysis of its yeast homologue, sen3p.
The 26S proteasome is a large multisubunit protease complex, the largest regulatory subunit of which is a component named p112. Molecular cloning of cDNA encoding human p112 revealed a polypeptide predicted to have 953 amino acid residues and a molecular mass of 105,865. The human p112 gene was mapped to the q37.1-q37.2 region of chromosome 2. Computer analysis showed that p112 has strong similarity to the Saccharomyces cerevisiae Sen3p, which has been listed in a gene bank as a factor affecting tRNA splicing endonuclease. The SEN3 also was identified in a synthetic lethal screen with the nin1-1 mutant, a temperature-sensitive mutant of NIN1. NIN1 encodes p31, another regulatory subunit of the 26S proteasome, which is necessary for activation of Cdc28p kinase. Disruption of the SEN3 did not affect cell viability, but led to temperature-sensitive growth. The human p112 cDNA suppressed the growth defect at high temperature in a SEN3 disruptant, indicating that p112 is a functional homologue of the yeast Sen3p. Maintenance of SEN3 disruptant cells at the restrictive temperature resulted in a variety of cellular dysfunctions, including defects in proteolysis mediated by the ubiquitin pathway, in the N-end rule system, in the stress response upon cadmium exposure, and in nuclear protein transportation. The functional abnormality induced by SEN3 disruption differs considerably from various phenotypes shown by the nin1-1 mutation, suggesting that these two regulatory subunits of the 26S proteasome play distinct roles in the various processes mediated by the 26S proteasome.


The use of composite resins in combination with anchorage posts as core material in endodontically treated teeth: clinical aspects of the technique.
In vitro tests and a clinical examination of 51 patients who were treated over a period of 12 years have demonstrated that a composite resin core that is surrounded by a gold crown may provide the same function and strength as a conventional gold core. However, the method demands a thorough knowledge of the materials and a careful and detailed technique. The importance of an initially effective dentinal bond to the chosen hybrid composite resin is stressed. Zinc phosphate cements and the technique of cementing are also discussed. In most cases, a damaged root will have to be reinforced with a post, and the author recommends the use of a threaded titanium post that fits well and is bound to the root with a so-called passive cementation technique. The author has also had positive experiences with composite resin crowns, which can be expected to have a functional life of at least 10 years.


Gene dysregulation by histone variant H2A.Z in bladder cancer.
The incorporation of histone variants into nucleosomes is one of the main strategies that the cell uses to regulate the structure and function of chromatin. Histone H2A.Z is an evolutionarily conserved histone H2A variant that is preferentially localized within nucleosomes at the transcriptional start site (TSS). H2A.Z reorganizes the local chromatin structure and recruits the transcriptional machinery for gene activation. High expression of H2A.Z has been reported in several types of cancers and is causally linked to genomic instability and tumorigenesis. However, it is not entirely clear how H2A.Z overexpression in cancer cells establishes aberrant chromatin states and promotes gene expression. Through integration of genome-wide H2A.Z ChIP-seq data with microarray data, we demonstrate that H2A.Z is enriched around the TSS of cell cycle regulatory genes in bladder cancer cells, and this enrichment is correlated with the elevated expression of cancer-promoting genes. RNAi-mediated knockdown of H2A.Z in the cancer cells causes transcriptional suppression of multiple cell cycle regulatory genes with a distinct decrease in cell proliferation. H2A.Z nucleosomes around the TSS have higher levels of H3K4me2/me3, which coincides with the recruitment of two chromatin factors, WDR5 and BPTF. The observed recruitment is functional, as the active states of H2A.Z target genes are largely erased by suppressing the expression of WDR5 or BPTF, effects resembling H2A.Z knockdown. We conclude that H2A.Z is overexpressed in bladder cancer cells and contributes to cancer-related transcription pathways. We also provide evidence in support of the engagement of H3K4me2/me3 and WDR5/BPTF in H2A.Z-induced cancer pathogenesis. Further studies are warranted to understand how H2A.Z overexpression contributes to the recruitment of the full repertoire of transcription machinery to target genes in bladder cancer cells.


Motor mechanism for protein threading through Hsp104.
The protein-remodeling machine Hsp104 dissolves amorphous aggregates as well as ordered amyloid assemblies such as yeast prions. Force generation originates from a tandem AAA+ (ATPases associated with various cellular activities) cassette, but the mechanism and allostery of this action remain to be established. Our cryoelectron microscopy maps of Hsp104 hexamers reveal substantial domain movements upon ATP binding and hydrolysis in the first nucleotide-binding domain (NBD1). Fitting atomic models of Hsp104 domains to the EM density maps plus supporting biochemical measurements show how the domain movements displace sites bearing the substrate-binding tyrosine loops. This provides the structural basis for N- to C-terminal substrate threading through the central cavity, enabling a clockwise handover of substrate in the NBD1 ring and coordinated substrate binding between NBD1 and NBD2. Asymmetric reconstructions of Hsp104 in the presence of ATPgammaS or ATP support sequential rather than concerted ATP hydrolysis in the NBD1 ring.


[The assistance of the ventilated infant: role of the nurse in the management of the endotracheal tube].
One of the principal duties of a staff nurse working in a NICU is the assistance of the ventilated infants. The management of the endotracheal tube is a key moment in the neonatal care and it is fundamental to prevent the ventilator induced lung injury and the change in the perfusion (especially in the brain) that may determine an impairment of gas exchange. Therefore, the role of the staff nurse is to guarantee that the tube remains correctly placed and firmly fixed in order to avoid tubes displacement and accidental extubations. High production of bronchial secretion may lead to a tube obstruction, partial or complete, that can cause formation of atelectasic areas as consequence of impaired ventilation. Tracheal suction may reduce this adverse event, but it is associated with hypoxic events, cardiocirculatory instability and can determine an increase in the endocranial pressure. Actually the scientific literature is poor in guidelines about the frequency, the duration, the level of pressure and the material to use in tracheal suctioning. The tracheal suction is a complicated intervention; to be well performed, it needs the nurse having a good observation capacity, a knowledge of the infant's pulmonary disease and, moreover, it requires that the nurse is acknowledged of the modality of the respiratory assistance of the infant. Therefore, this procedure is specifically patient-oriented. In this review we analyze the scientific literature about the nurse management of the ventilated infant, and we report our personal experience about the strategy in reducing adverse effects as the loosing of end expiration lung volume and the accidental extubations.


Spatial and temporal trends of bat-borne rabies in Chile.
In Chile, while dog rabies has decreased markedly over the last 30 years, bat rabies is still reported frequently. In order to shed new light on the spatiotemporal trends of these reports, we analysed active and passive data from years 1985 and 2012, which included 61 076 samples from 289 counties of Chile. We found that from 1994 to 2012, more than 15 000 bat samples were submitted for diagnostics through passive surveillance, 9·5% of which tested positive for rabies. By contrast, the prevalence of infection was only ~0·4% among the nearly 12 000 bat samples submitted through active surveillance. We found that the prevalence of dog rabies dropped steadily over the same period, with just a single confirmed case since 1998. None of the 928 samples from wild animals, other than bats, were positive for rabies. Although there has been only one confirmed case of human rabies in Chile since 1985, and a single confirmed case in a dog since 1998, bats remain a reservoir for rabies viruses. While active surveillance indicates that rabies prevalence is low in bat colonies, the high proportion of positive bats submitted through passive surveillance is a concern. To prevent human rabies, local public health agencies should increase research on the basic ecology of bats and the role of stray dogs and cats as potential rabies amplifiers.


Preferential vitrification of water in small alginate microcapsules significantly augments cell cryopreservation by vitrification.
The morphological changes of small (approximately 100 microm) alginate microcapsules and the biophysical alterations of water in the microcapsules during cryopreservation were studied using cryomicroscopy and scanning calorimetry. It was found that water in the small microcapsules can be preferentially vitrified over water in the bulk solution in the presence of 10% (v/v) or more dimethylsulfoxide (DMSO, a cryoprotectant), which resulted in an intact morphology of the microcapsules post cryopreservation with a cooling rate of 100 degrees Celsius/min. A small amount of Ca(2+) (up to 0.15 M) was also found to help maintain the microcapsule integrity during cryopreservation, which is attributed to the enhancement of the alginate matrix strength by Ca(2+) rather than promoting vitrification of water in the microcapsules. The preferential vitrification of water in small microcapsules was further found to significantly augment cell cryopreservation by vitrification at a low concentration of cryoprotectants (i.e., 10% (v/v)) using a small quartz microcapillary (400 microm in diameter). Therefore, the small alginate microcapsule could be a great system for protecting living cells that are highly sensitive to stresses due to freezing (i.e., ice formation) and high concentration of cryoprotectants from injury during cryopreservation.


N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function.
This report provides a historical overview of research concerning the endogenous hallucinogen N, N-dimethyltryptamine (DMT), focusing on data regarding its biosynthesis and metabolism in the brain and peripheral tissues, methods and results for DMT detection in body fluids and brain, new sites of action for DMT, and new data regarding its possible physiological and therapeutic roles. Research that further elaborates its consideration as a putative neurotransmitter is also addressed. Taking these studies together, the report proposes several new directions and experiments to ascertain the role of DMT in the brain, including brain mapping of enzymes responsible for the biosynthesis of DMT, further studies to elaborate its presence and role in the pineal gland, a reconsideration of binding site data, and new administration and imaging studies. The need to resolve the "natural" role of an endogenous hallucinogen from the effects observed from peripheral administration are also emphasized.


The origins of C4 grasslands: integrating evolutionary and ecosystem science.
The evolution of grasses using C4 photosynthesis and their sudden rise to ecological dominance 3 to 8 million years ago is among the most dramatic examples of biome assembly in the geological record. A growing body of work suggests that the patterns and drivers of C4 grassland expansion were considerably more complex than originally assumed. Previous research has benefited substantially from dialog between geologists and ecologists, but current research must now integrate fully with phylogenetics. A synthesis of grass evolutionary biology with grassland ecosystem science will further our knowledge of the evolution of traits that promote dominance in grassland systems and will provide a new context in which to evaluate the relative importance of C4 photosynthesis in transforming ecosystems across large regions of Earth.


Medication errors in a pediatric emergency department.
To initiate investigation into the medication errors that occur in a pediatric emergency department. These errors have the potential for significant morbidity and mortality, as well as costly litigation. We conducted a retrospective chart review of all medication and intravenous fluid errors identified in a pediatric emergency department through incident reports filed over a 5-year period. An attempt was made to determine who was involved with the errors and what caused the errors. The patient outcomes were noted and classified according to clinical significance using previously published criteria. Thirty-three incident reports involving medication or intravenous fluid errors were analyzed. Most errors occurred on the evening and night shifts. Nurses were involved in 39% of reported errors; the nurse and emergency physician were jointly involved in 36%. The most common error was an incorrect dose of medication (35%) or incorrect medication given (30%). In one third of the cases, the family was not made aware of the error. In 12%, patients required additional treatment, and one was admitted to the hospital because of the error. There were no deaths. Incorrect recording of patient weights leading to an incorrect medication dose and failure to note drug allergy are common causes for medication errors in the pediatric emergency department. Incorrect drugs and i.v. fluids are given because of similar names and packaging. Many of the errors in the ED seem to be preventable.


Genetic diversity and population structure of domestic and wild reindeer (Rangifer tarandus L. 1758): A novel approach using BovineHD BeadChip.
Reindeer (Rangifer tarandus L. 1758) are an essential element of the Russian Far North, providing a significant source of nutrition for the representatives of 18 ethnicities. The species has wild and domestic forms, which are in constant interaction. The aim of our study was to characterize the genetic structure of domestic and wild reindeer populations, using a genome-wide bovine genotyping array (BovineHD BeadChip). The wild reindeer samples were obtained from the western Taymyr Peninsula population and from the taiga and tundra populations in the Sakha Republic (Yakutia). The domestic populations included the Evenk, Even, and Chukotka-Khargin breeds of Yakutia and the Nenets breed from the Nenets Autonomous district and Murmansk region. The level of genetic diversity was higher for the wild population. Analyzing Neighbor-Net tree, multidimensional scaling, and Structure results, we observed strong genetic population structure and clear differentiation between domestic and wild populations. All regional populations of domestic reindeer were clearly separated, while wild reindeer showed similar genetic backgrounds. Nevertheless, we found contrasting patterns in the genetic structure of the tundra and taiga reindeer, in accordance with their morphological and ecological differences. Thus, our study revealed a clear genetic differentiation between domestic and wild reindeer populations. It provides novel insights into the genetic diversity and structure of reindeer populations, to support resource utilization and aid in the development of genetic improvement strategies and conservation programs for this species.


Netrin-1 expression is an independent prognostic factor for poor patient survival in brain metastases.
The multifunctional molecule netrin-1 is upregulated in various malignancies and has recently been presented as a major general player in tumorigenesis leading to tumor progression and maintenance in various animal models. However, there is still a lack of clinico-epidemiological data related to netrin-1 expression. Therefore, the aim of our study was to elucidate the association of netrin-1 expression and patient survival in brain metastases since those constitute one of the most limiting factors for patient prognosis. We investigated 104 brain metastases cases for netrin-1 expression using in-situ hybridization and immunohistochemistry with regard to clinical parameters such as patient survival and MRI data. Our data show that netrin-1 is strongly upregulated in most cancer subtypes. Univariate analyses revealed netrin-1 expression as a significant factor associated with poor patient survival in the total cohort of brain metastasis patients and in sub-entities such as non-small cell lung carcinomas. Interestingly, many cancer samples showed a strong nuclear netrin-1 signal which was recently linked to a truncated netrin-1 variant that enhances tumor growth. Nuclear netrin-1 expression was associated with poor patient survival in univariate as well as in multivariate analyses. Our data indicate both total and nuclear netrin-1 expression as prognostic factors in brain metastases patients in contrast to other prognostic markers in oncology such as patient age, number of brain metastases or Ki67 proliferation index. Therefore, nuclear netrin-1 expression constitutes one of the first reported molecular biomarkers for patient survival in brain metastases. Furthermore, netrin-1 may constitute a promising target for future anti-cancer treatment approaches in brain metastases.


Aberrations of anamorphic optical systems. II. Primary aberration theory for cylindrical anamorphic systems.
By applying a new method for aberration derivation to anamorphic systems made from cylindrical surfaces, we obtain a complete set of primary aberration coefficients. This set is in a form similar to the well-known Seidel aberrations for rotationally symmetrical optical systems (RSOS). The aberration coefficients include first-order quantities only. By tracing four nonskew paraxial marginal and chief rays in the two associated RSOS of the anamorphic system, the aberration coefficients can be derived.


The effect of vitamin D3 on CD34 progenitor cells in vitamin D deficiency rickets.
Vitamin D metabolites have multiple functions not only in calcium homeostasis, but also in hematopoiesis. To detect the effect of vitamin D on hematopoiesis with a surface glycoprotein marker, the proportions of the CD34+ cells were measured in bone marrow, peripheral blood and spleen prior to and after vitamin D3 treatment in an infant with severe rickets, myelofibrosis and myeloid metaplasia. CD34+ cells measured 0.4% in bone marrow, 8.0% in peripheral blood and 8.7% in splenic aspirate. The detection of a high and comparable level of CD34+ cells in both peripheral blood and splenic aspirate on admission and the decline in the level of CD34+ cells (2%) following treatment support that CD34+ cells were from extramedullary hematopoiesis in spleen. The improvement of rickets and hematological findings with treatment at the same time raises the possibility of vitamin D3 acting directly upon the same target or upon different targets at the same time or of the presence of interaction between two targets. Our findings may also show a relation between vitamin D3 and its metabolites to bone marrow stem cells.


[Application of optical flow dynamic texture in land use/cover change detection].
In the present study, a novel change detection approach for high resolution remote sensing images is proposed based on the optical flow dynamic texture (OFDT), which could achieve the land use & land cover change information automatically with a dynamic description of ground-object changes. This paper describes the ground-object gradual change process from the principle using optical flow theory, which breaks the ground-object sudden change hypothesis in remote sensing change detection methods in the past. As the steps of this method are simple, it could be integrated in the systems and software such as Land Resource Management and Urban Planning software that needs to find ground-object changes. This method takes into account the temporal dimension feature between remote sensing images, which provides a richer set of information for remote sensing change detection, thereby improving the status that most of the change detection methods are mainly dependent on the spatial dimension information. In this article, optical flow dynamic texture is the basic reflection of changes, and it is used in high resolution remote sensing image support vector machine post-classification change detection, combined with spectral information. The texture in the temporal dimension which is considered in this article has a smaller amount of data than most of the textures in the spatial dimensions. The highly automated texture computing has only one parameter to set, which could relax the onerous manual evaluation present status. The effectiveness of the proposed approach is evaluated with the 2011 and 2012 QuickBird datasets covering Duerbert Mongolian Autonomous County of Daqing City, China. Then, the effects of different optical flow smooth coefficient and the impact on the description of the ground-object changes in the method are deeply analyzed: The experiment result is satisfactory, with an 87.29% overall accuracy and an 0.850 7 Kappa index, and the method achieves better performance than the post-classification change detection methods using spectral information only.


Psychosocial interventions for the management of chronic orofacial pain.
Psychosocial factors have a role in the onset of chronic orofacial pain. However, current management involves invasive therapies like occlusal adjustments and splints which lack an evidence base. To determine the efficacy of non-pharmacologic psychosocial interventions for chronic orofacial pain. The following electronic databases were searched: the Cochrane Oral Health Group Trials Register (to 25 October 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 4), MEDLINE via OVID (1950 to 25 October 2010), EMBASE via OVID (1980 to 25 October 2010) and PsycINFO via OVID (1950 to 25 October 2010). There were no restrictions regarding language or date of publication. Randomised controlled trials which included non-pharmacological psychosocial interventions for adults with chronic orofacial pain compared with any other form of treatment (e.g. usual care like intraoral splints, pharmacological treatment and/or physiotherapy). Data were independently extracted in duplicate. Trial authors were contacted for details of randomisation and loss to follow-up, and also to provide means and standard deviations for outcome measures where these were not available. Risk of bias was assessed and disagreements between review authors were discussed and another review author involved where necessary. Seventeen trials were eligible for inclusion into the review. Psychosocial interventions improved long-term pain intensity (standardised mean difference (SMD) -0.34, 95% confidence interval (CI) -0.50 to -0.18) and depression (SMD -0.35, 95% CI -0.54 to -0.16). However, the risk of bias was high for almost all studies. A subgroup analysis revealed that cognitive behavioural therapy (CBT) either alone or in combination with biofeedback improved long-term pain intensity, activity interference and depression. However the studies pooled had high risk of bias and were few in number. The pooled trials were all related to temporomandibular disorder (TMD). There is weak evidence to support the use of psychosocial interventions for chronic orofacial pain. Although significant effects were observed for outcome measures where pooling was possible, the studies were few in number and had high risk of bias. However, given the non-invasive nature of such interventions they should be used in preference to other invasive and irreversible treatments which also have limited or no efficacy. Further high quality trials are needed to explore the effects of psychosocial interventions on chronic orofacial pain.


Association between temperature, humidity and ebolavirus disease outbreaks in Africa, 1976 to 2014.
Ebolavirus disease (EVD) outbreaks have been occurring sporadically in Central Africa since 1976. In 2014, the first outbreak in West Africa was reported in Guinea. Subsequent outbreaks then appeared in Liberia, Sierra Leone and Nigeria. The study of environmental factors underlying EVD epidemiology may provide useful insights into when and where EVD outbreaks are more likely to occur. In this paper, we aimed to investigate the association between climatic factors and onset of EVD outbreaks in humans. Our results suggest lower temperature and higher absolute humidity are associated with EVD outbreak onset in the previous EVD outbreaks in Africa during 1976 to 2014. Potential mechanisms through which climate may have an influence on ebolavirus infection in the natural host, intermediate hosts and humans are discussed. Current and future surveillance efforts should be supported to further understand ebolavirus transmission events between and within species.


Diagnosis and management of 528 abdominal aortic aneurysms.
Between 1960 and 1979 528 patients with abdominal aortic aneurysms presented to the university department of surgery. Of these, 222 (42%) were elective cases, 72 acute (14%), 174 had ruptured (33%), and four had had a spontaneous aortoduodenal fistula (1%). In all these patients resections were undertaken, but in another 56 patients (11%) the aneurysm was not resected. A review of these cases showed that 91% had symptoms at their first presentation; abdominal pain and backache being most common. The diagnosis could be established in 91% by the presence of pulsatile abdominal mass on clinical examination. The operative mortality for elective resection was 8%, for acute 19%, for ruptured cases 42%, and for spontaneous aortoduodenal fistula 50%. After successful resection the overall five-year survival was 65% by the life table method, and there was no significant difference between elective, acute, and ruptured cases. This five-year survival after resection compares favourably with the expected 76% survival of a similar normal population, and was considerably better than that for conservatively treated patients. As most cases have symptoms, and diagnosis may be established easily by routine physical examination in 91%, the prognosis for this condition could be considerably improved by increased awareness of its existence and early referral for treatment as an elective surgical procedure.


Nucleotide sequence, chromosomal localization and developmental expression of the mouse int-1-related gene.
cDNA clones encoding the murine int-1-related protein (m-irp) were isolated from an 8.5-day mouse embryo library. m-irp and its human counterpart, h-irp, share extensive nucleotide homology in coding (92%) and 3' untranslated (69%) regions. At the amino acid level, m-irp and h-irp share 97% of amino acids including all 24 cysteine residues, which are highly conserved among members of the int-1 family. However, in contrast to h-irp and int-1, the predicted m-irp protein sequence did not contain a signal peptide sequence. Analysis of polymerase chain reaction, amplified cDNA, and genomic sequences strongly suggests that a single-base substitution has created a new 5' splice site 17 bp 5' of a highly conserved splice site. Splicing at this new site generates a mRNA-encoding an amino-terminal truncated protein. Splicing at the conserved splice site generates a mRNA species encoding a protein with a signal peptide sequence similar to h-irp. Close linkage between m-irp and the met oncogene maps m-irp sequences to proximal mouse chromosome 6. Adult and fetal expression of m-irp was examined by RNA blot analysis. Adult expression of m-irp is restricted to lungs and heart, and fetal expression, to placental tissue and to all stages of fetal development examined. In situ hybridization localized early fetal m-irp expression to the pericardium of the heart, to the umbilicus and associated allantoic mesoderm, and to the ventral lateral mesenchyme tissue surrounding the umbilical vein in the fetus. These results suggest a role for m-irp in the development of fetal allantoic communication.


Machine-learning approach for local classification of crystalline structures in multiphase systems.
Machine learning is one of the most popular fields in computer science and has a vast number of applications. In this work we will propose a method that will use a neural network to locally identify crystal structures in a mixed phase Yukawa system consisting of fcc, hcp, and bcc clusters and disordered particles similar to plasma crystals. We compare our approach to already used methods and show that the quality of identification increases significantly. The technique works very well for highly disturbed lattices and shows a flexible and robust way to classify crystalline structures that can be used by only providing particle positions. This leads to insights into highly disturbed crystalline structures.


Novel membrane-based electrochemical sensor for real-time bio-applications.
This article presents a novel membrane-based sensor for real-time electrochemical investigations of cellular- or tissue cultures. The membrane sensor enables recording of electrical signals from a cell culture without any signal dilution, thus avoiding loss of sensitivity. Moreover, the porosity of the membrane provides optimal culturing conditions similar to existing culturing techniques allowing more efficient nutrient uptake and molecule release. The patterned sensor electrodes were fabricated on a porous membrane by electron-beam evaporation. The electrochemical performance of the membrane electrodes was characterized by cyclic voltammetry and chronoamperometry, and the detection of synthetic dopamine was demonstrated down to a concentration of 3.1 pM. Furthermore, to present the membrane-sensor functionality the dopamine release from cultured PC12 cells was successfully measured. The PC12 cells culturing experiments showed that the membrane-sensor was suitable as a cell culturing substrate for bio-applications. Real-time measurements of dopamine exocytosis in cell cultures were performed, where the transmitter release was recorded at the point of release. The developed membrane-sensor provides a new functionality to the standard culturing methods, enabling sensitive continuous in vitro monitoring and closely mimicking the in vivo conditions.


A Comparison of Social Dominance Theory and System Justification: The Role of Social Status in 19 Nations.
This study tests specific competing hypotheses from social dominance theory/realistic conflict theory (RCT) versus system justification theory about the role of social status. In particular, it examines whether system justification belief and effects are stronger among people with low socioeconomic status, and in less socially developed and unequal nations than among better-off people and countries. A cross-national survey was carried out in 19 nations from the Americas, Western and Eastern Europe, Asia, and Oceania using representative online samples ( N = 14,936, 50.15% women, Mage = 41.61 years). At the individual level, system justification beliefs, right-wing authoritarianism, social dominance orientation, national identification, sociopolitical conservatism, sex, age, and social status were measured. At the national level, the human development index and the Gini index were used. Multilevel analyses performed indicated that results fit better with the social dominance/RCT approach, as system justification was higher in high-status and developed nations; further, associations between legitimizing ideologies and system justification were stronger among high-status people.


Scaling rules for transverse magnetic waves propagating in nonlinear thin-film optical waveguides.
For TM-polarized waves, a mode power measure is applied to characterize nonlinear thin-film optical waveguides in an approach analogous to that we recently proposed for TE-polarized waves. For design conditions in which all the guided waves are induced by the nonlinearity of the film, we study how the power level threshold needed for wave propagation differs between the TE and the TM modes of polarization. Since our description is based on universal parameters, our results are applicable to different geometries of waveguides through simple scaling rules.


Extracellular matrix formation enhances the ability of Streptococcus pneumoniae to cause invasive disease.
During infection, pneumococci exist mainly in sessile biofilms rather than in planktonic form, except during sepsis. However, relatively little is known about how biofilms contribute to pneumococcal pathogenesis. Here, we carried out a biofilm assay on opaque and transparent variants of a clinical serotype 19F strain WCH159. After 4 days incubation, scanning electron microscopy revealed that opaque biofilm bacteria produced an extracellular matrix, whereas the transparent variant did not. The opaque biofilm-derived bacteria translocated from the nasopharynx to the lungs and brain of mice, and showed 100-fold greater in vitro adherence to A549 cells than transparent bacteria. Microarray analysis of planktonic and sessile bacteria from transparent and opaque variants showed differential gene expression in two operons: the lic operon, which is involved in choline uptake, and in the two-component system, ciaRH. Mutants of these genes did not form an extracellular matrix, could not translocate from the nasopharynx to the lungs or the brain, and adhered poorly to A549 cells. We conclude that only the opaque phenotype is able to form extracellular matrix, and that the lic operon and ciaRH contribute to this process. We propose that during infection, extracellular matrix formation enhances the ability of pneumococci to cause invasive disease.


An extract of the medicinal plant Artemisia annua modulates production of inflammatory markers in activated neutrophils.
To investigate the ability of a commercial extract from the medicinal plant Artemisia annua to modulate production of the cytokine, tumor necrosis factor-alpha (TNF-α), and the cyclooxygenase (COX) inflammatory marker, prostaglandin E2 (PGE2) in activated neutrophils. Neutrophils were harvested from rat whole blood and cultured in the presence of plant extract or control samples. Neutrophils, except unactivated control cells, were activated with 10 μg/mL lipopolysaccharide (LPS). The cells were cultured with a range of different concentrations of the A. annua extracts (400-1 μg/mL) and artemisinin (200 and 100 μg/mL) and the supernatants were then tested by enzyme-linked immunosorbent assay (ELISA) for the concentrations of TNF-α and PGE2. Each sample was assayed in triplicate. Positive controls with an inhibitor were assayed in triplicate: chloroquine 2.58 and 5.16 μg/mL for TNF-α, and ibuprofen 400 μg/mL for PGE2. An unsupplemented group was also assessed in triplicate as a baseline control. Neutrophils were stimulated to an inflammatory state by the addition of LPS. A. annua extract significantly inhibited TNF-α production by activated neutrophils in a dose-dependent manner. There was complete inhibition by the A. annua extract at 200, 100, and 50 μg/mL (all P≤0.0003). At A. annua extract concentrations of 25, 10, and 5 μg/mL, TNF-α production was inhibited by 89% (P<0.0001), 54% (P=0.0002), and 38% (P=0.0014), respectively. A. annua 1 μg/mL did not significantly inhibit TNF-α production (8.8%; P>0.05). Concentrations of 400, 200, and 100 μg/mL A. annua extract significantly inhibited PGE2 production by 87% (P=0.0128), 91% (P=0.0017), and 93% (P=0.0114), respectively. An extract of A. annua was shown to be a potent inhibitor of TNF-α and a strong inhibitor of PGE2 production in activated neutrophils at the concentrations tested. Further studies are warranted with this promising plant extract.


Design of clinical trials in AKI: a report from an NIDDK workshop. Trials of patients with sepsis and in selected hospital settings.
AKI remains an important clinical problem, with a high mortality rate, increasing incidence, and no Food and Drug Administration-approved therapeutics. Advances in addressing this clinical need require approaches for rapid diagnosis and stratification of injury, development of therapeutic agents based on precise understanding of key pathophysiological events, and implementation of well designed clinical trials. In the near future, AKI biomarkers may facilitate trial design. To address these issues, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a meeting, "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers," in December of 2010 that brought together academic investigators, industry partners, and representatives from the National Institutes of Health and the Food and Drug Administration. Important issues in the design of clinical trials for interventions in AKI in patients with sepsis or AKI in the setting of critical illness after surgery or trauma were discussed. The sepsis working group discussed use of severity of illness scores and focus on patients with specific etiologies to enhance homogeneity of trial participants. The group also discussed endpoints congruent with those endpoints used in critical care studies. The second workgroup emphasized difficulties in obtaining consent before admission and collaboration among interdisciplinary healthcare groups. Despite the difficult trial design issues, these clinical situations represent a clinical opportunity because of the high event rates, severity of AKI, and poor outcomes. The groups considered trial design issues and discussed advantages and disadvantages of several short- and long-term primary endpoints in these patients.


[Use of physical therapy measures in the rehabilitation of patients having undergone radical mastectomy].
Low-frequency electrotherapy, magnetotherapy, massage, exercise therapy and drugs were used in 90 patients who after radical treatment for breast cancer suffered pain and limited mobility in the shoulder joint. These procedures were intended to treat said complications, to normalize reflexes and to cut down the period of rehabilitative therapy. The treatment proved effective. No untoward effects on the course of the disease were observed within the first 3-5 years.


Expression of STAT5, COX-2 and PIAS3 in correlation with NSCLC histhopathological features.
Signal transducers and activators of transcription (STATs), their inhibitors and cyclooxygenase-2 (COX-2) participate in transformations of many various types of cancers. The aim of the present study was to evaluate the relationship between STAT5A/B, COX-2, and PIAS3 mRNA expression and tumor staging, metastasis status, and histopathological subtype in 71 patients with confirmed non-small cell lung cancer (NSCLC) diagnosis. Total RNA was isolated from NSCLC tissue samples and the expression of the studied genes was assessed using TaqMan probes in real-time PCR assay. The expression levels of STAT5A, STAT5B, and COX-2 genes were increased in 69%, 79%, and 71% NSCLC samples respectively, while PIAS3 expression was decreased in the majority (69%) of the studied tissues. Statistically significant differences were observed between STAT5 isoforms (P = 0.0008), with higher expression of STAT5B. We found statistically significant positive correlation between STAT5B and COX-2 (rho = 0.045), and significant negative correlation between STAT5B and PIAS3 (rho = -0.049). The negative correlation between STAT5B and PIAS3 (rho = -0.43) was also observed in T2a+T2b tumor group. Additionally, STAT5B and COX-2 expression levels were significantly different between T1a+T1b and T2a+T2b tumors (P = 0.002 and P = 0.041, respectively), with higher expression of both genes in T2 tumor stage. PIAS3 expression was significantly lower in NSCC subtype as compared with SCC subtype (P = 0.017). Also, STAT5A and STAT5B immunoexpression was assessed, and the results indicated significantly higher protein levels in NSCLC patients as compared with controls (P = 0.048 and P = 0.034, respectively). High STAT5B immunoexpression was positively correlated with STAT5B gene expression in tumors (rho = 0.755). STAT5B protein level was also significantly higher in T2a+T2b tumors, reflecting high STAT5B gene expression in this group. There was no statistically significant association between mRNA and protein expression levels of the studied genes and patients' characteristics: age, gender, smoking. The obtained results highlight the importance of the genes STAT5B and COX-2 in lung cancer progression.


Fat infiltration on magnetic resonance imaging of the sacroiliac joints has limited diagnostic utility in nonradiographic axial spondyloarthritis.
To explore whether morphological features of fat infiltration (FI) on sacroiliac joint (SIJ) magnetic resonance imaging (MRI) contribute to diagnostic utility in 2 inception cohorts of patients with nonradiographic axial spondyloarthritis (nr-axSpA). Four blinded readers assessed SIJ MRI in 2 cohorts (A/B) of 157 consecutive patients with back pain who were ≤ 50 years old, and in 20 healthy controls. Patients were classified according to clinical examination and pelvic radiography as having nr-axSpA (n = 51), ankylosing spondylitis (n = 34), or nonspecific back pain (n = 72). Readers recorded FI, bone marrow edema (BME), and erosion, predefined morphological features of FI (distinct border, homogeneity, subchondral location), and anatomical distribution of SIJ FI. The proportion of SIJ quadrants affected by FI and frequencies of various SIJ FI features were analyzed descriptively. We calculated positive/negative likelihood ratios (LR) to estimate the diagnostic utility of various features of FI, with and without associated BME, and erosion. Of the patients with nr-axSpA in cohorts A/B, 45.0%/48.4% had FI in ≥ 2 SIJ quadrants. Of those, 25.0%/22.6% and 20.0%/25.8% showed FI with distinct border or homogeneous pattern, respectively, and 50% to 100% of those patients displayed concomitant BME or erosion. FI per se in ≥ 2 SIJ quadrants had no diagnostic utility (LR+ 1.62/1.91). FI with distinct border (LR+ 8.29/2.13) or homogeneity (LR+ 6.24/3.78) demonstrated small to moderate diagnostic utility. SIJ FI per se was not of clinical utility in recognition of nr-axSpA. Distinct border or homogeneity of FI on SIJ MRI showed small to moderate diagnostic utility in nr-axSpA, but were strongly associated with concomitant BME or erosion, highlighting the contextual interpretation of SIJ MRI.


Securing genome stability by orchestrating DNA repair: removal of radiation-induced clustered lesions in DNA.
In addition to double- and single-strand DNA breaks and isolated base modifications, ionizing radiation induces clustered DNA damage, which contains two or more lesions closely spaced within about two helical turns on opposite DNA strands. Post-irradiation repair of single-base lesions is routinely performed by base excision repair and a DNA strand break is involved as an intermediate. Simultaneous processing of lesions on opposite DNA strands may generate double-strand DNA breaks and enhance nonhomologous end joining, which frequently results in the formation of deletions. Recent studies support the possibility that the mechanism of base excision repair contributes to genome stability by diminishing the formation of double-strand DNA breaks during processing of clustered lesions.


MOR is not enough: identification of novel mu-opioid receptor interacting proteins using traditional and modified membrane yeast two-hybrid screens.
The mu-opioid receptor (MOR) is the G-protein coupled receptor primarily responsible for mediating the analgesic and rewarding properties of opioid agonist drugs such as morphine, fentanyl, and heroin. We have utilized a combination of traditional and modified membrane yeast two-hybrid screening methods to identify a cohort of novel MOR interacting proteins (MORIPs). The interaction between the MOR and a subset of MORIPs was validated in pulldown, co-immunoprecipitation, and co-localization studies using HEK293 cells stably expressing the MOR as well as rodent brain. Additionally, a subset of MORIPs was found capable of interaction with the delta and kappa opioid receptors, suggesting that they may represent general opioid receptor interacting proteins (ORIPS). Expression of several MORIPs was altered in specific mouse brain regions after chronic treatment with morphine, suggesting that these proteins may play a role in response to opioid agonist drugs. Based on the known function of these newly identified MORIPs, the interactions forming the MOR signalplex are hypothesized to be important for MOR signaling and intracellular trafficking. Understanding the molecular complexity of MOR/MORIP interactions provides a conceptual framework for defining the cellular mechanisms of MOR signaling in brain and may be critical for determining the physiological basis of opioid tolerance and addiction.


Fit for Duty: Lessons Learned from Outpatient and Homebound Hematopoietic Cell Transplantation to Prepare Family Caregivers for Home-Based Care.
In the past decade, the demand for home-based care has been amplified by the Coronavirus disease 2019 pandemic. Home-based care has significant benefits for patients, their families, and healthcare systems, but it relies on the often-invisible workforce of family and friend caregivers who shoulder essential health care responsibilities, frequently with inadequate training and support. Hematopoietic cell transplantation (HCT), a potentially curative but intensive treatment for many patients with blood disorders, is being increasingly offered in home-based care settings and necessitates the involvement of family caregivers for significant patient care responsibilities. However, guidelines for supporting and preparing HCT caregivers to effectively care for their loved ones at home have not yet been established. Here, informed by the literature and our collective experience as clinicians and researchers who care for diverse patients with hematologic malignancies undergoing HCT, we provide considerations and recommendations to better support and prepare family caregivers in home-based HCT and, by extension, family caregivers supporting patients with other serious illnesses at home. We suggest tangible ways to screen family caregivers for distress and care delivery challenges, educate and train them to prepare for their caregiving role, and create an infrastructure of support for family caregivers within this emerging care delivery model.


Sexual Behavior Among Young Carers in the Context of a Kenyan Empowerment Program Combining Cash-Transfer, Psychosocial Support, and Entrepreneurship.
This study examined associations between sexual initiation, unprotected sex, and having multiple sex partners in the past year with participation in a three-year empowerment program targeting orphan and vulnerable children (OVC). The Kenya-based program combines community-conditioned cash transfer, psychosocial empowerment, health education, and microenterprise development. Program participants (n = 1,060) were interviewed in a cross-sectional design. Analyses used gender-stratified hierarchical logit models to assess program participation and other potential predictors. Significant predictors of increased female sexual activity included less program exposure, higher age, younger age at most recent parental death, fewer years of schooling, higher food consumption, higher psychological resilience, and lower general self-efficacy. Significant predictors of increased male sexual activity included more program exposure, higher age, better food consumption, not having a living father, and literacy. Findings support a nuanced view of current cash transfer programs, where female sexual activity may be reduced through improved financial status but male sexual activity may increase. Targeting of OVC sexual risk behaviors would likely benefit from being tailored according to associations found in this study. Data suggest involving fathers in sexual education, targeting women who lost a parent at a younger age, and providing social support for female OVC may decrease risk of human immunodeficiency virus (HIV) transmission.


Conjugal transfer of plasmid-borne multiple antibiotic resistance in Streptococcus faecalis var. zymogenes.
A strain of Streptococcus faecalis var. zymogenes, designated JH1, had high-level resistance to the antibiotics streptomycin, kanamycin, neomycin, erythromycin, and tetracycline. These resistances were lost en bloc from approximately 0.1% of cells grown in nutrient broth at 45 C. The frequency of resistance loss was not increased by growth in the presence of the "curing" agents acriflavine or acridine orange, but after prolonged storage in nutrient agar 17% of cells became antibiotic sensitive. Covalently closed circular deoxyribonucleic acid (DNA) molecules were isolated from the parental strain and from antibiotic-sensitive segregants by using cesium chloride-ethidium bromide gradients. DNA molecular species were identified by using neutral sucrose gradients. Strain JH1 contained two covalently closed circular DNA species of molecular weights 50 x 10(6) and 38 x 10(6). An antibiotic-sensitive segregant, strain JH1-9, had lost the larger molecular species. A second sensitive segregant, strain JH1-5, had also lost the larger molecular species but a new molecular species of approximate molecular weight 6 x 10(6) was present. The antibiotic resistances that were curable from the parental strain were transferred to antibiotic-sensitive strains of S. faecalis and to strain JH1-9, during mixed incubation in nutrient broth at 37 C. Data to be described are interpreted to suggest that the transfer is by a conjugal mechanism. Analysis of the plasmid species in recipient clones showed that all had received the plasmid of molecular weight 50 x 10(6). Strain JH1-5 was not a good recipient. Analysis of one successful recipient clone of JH1-5 revealed that it had gained the 50 x 10(6) molecular weight plasmid but lost the 6 x 10(6) molecular weight species. These data are interpreted to mean that the multiple antibiotic resistance is borne by a transferable plasmid of 50 x 10(6) molecular weight, and that in clone JH1-5 this plasmid suffered a large deletion leaving only a 6 x 10(6) remnant which was incompatible with the complete replicon.


Application of Clinical Aging Indicators for the Assessment of Neurological Health via Screening Among Residents of the Almaty Region.
Life expectancy at birth is considered to be a primary indicator of public health success. However, an increase in life expectancy is meaningless if it is not accompanied by an equivalent increase in the number of life years without disability such as physical, cognitive, and psychological abilities. The main consequences of disease leading to neurological dysfunction are directly related to issues such as the inability to walk, talk, learn, live in society, or take care of oneself. The objective of the study was to conduct a medical examination of elderly people as a part of the scientific program "Development of a model (program) of anti-aging to provide active longevity of elderly people of Kazakhstan." As part of a pilot study, we assessed the presence of the following clinical indicators of aging: cognitive impairment (MMSE test), pyramidal symptoms, and ataxia. We conducted medical examination (screening) among 150 elderly persons in Almaty City Polyclinic #8 and 287 elderly persons in Central Regional Clinic of Rayimbek Area, Almaty region aged 45 and above. The results show that the intensity of changes is directly dependent on the age of the study groups. The cognitive function is the most affected and depends on the age of examinees. The changes are more expressed among residents of Almaty region. The average MMSE score in Almaty was 28.2 (age group of 45-49 years) and 25.8 (age group of 80 and above), and 27.3 and 24.0 respectively in Almaty region. The various symptoms among residents of Almaty tend to stabilize after 65 years, however, the frequency of ataxia continues to grow and increases significantly after 75 years. Considering that important risk factors of neurological disorders are cerebrovascular diseases of various origins (primarily hypertension, atherosclerosis, and diabetes), an adequate treatment of these diseases will increase a healthy lifespan. Furthermore, it is necessary to conduct additional research for possible methods of reducing existing morbidities so that healthy aging can be achieved.


Saccular or dissecting aneurysms involving the basilar trunk: Endovascular treatment and clinical outcome.
Objectives: Basilar artery trunk aneurysms (BTAs) are a rare pathology and difficult to treat. We present our experience regarding angiographic results and clinical outcomes for 16 BTAs treated by reconstructive endovascular treatment (EVT) using stent or balloon. Methods: Between January 2003 and December 2014, 15 patients (mean age, 58.6 years; 11 males) with 16 BTAs were enrolled. Clinical manifestation, outcomes and procedural complications were evaluated retrospectively, and follow-up angiography was performed 12 and 24 months after procedure. Results: Subarachnoid hemorrhage (SAH) developed in seven aneurysms and nine were found incidentally. In one case, SAH followed by acute infarction on pons. The location of the aneurysms was the pure basilar artery (BA) trunk in 13 and the junction of the BA and the superior cerebellar artery in 3. Reconstructive EVT was technically successful in 15 aneurysms (93.8%) and failed in one due to the difficulty of vascular access. Stent/balloon-assisted coiling was performed in 13 aneurysms and sole stent therapy in two aneurysms. One patient had periprocedural complication of acute in-stent thrombosis. All treated patients had no symptoms with the usual activities except three patients, who died from myocardial infarction, aneurysmal rebleeding, and cerebellar infarction. Angiographic follow-up was performed in nine aneurysms; three aneurysms were recanalized (33.3%) and six aneurysms had no interval change (66.7%). There was no significant event during the follow-up period (mean, 23.5 months). Conclusion: In the treatment of BTAs, reconstructive EVT may provide a feasible and safe option to microsurgery.


Biofuels: balancing risks and rewards.
This paper describes a framework that can be used to evaluate the environmental risks and benefits associated with biofuel production. It uses the example of biodiesel produced from Argentinean soy to show how such a framework can be used to conceptualize trade-offs between different environmental, social and economic impacts of biofuel production. Results showing the greenhouse-gas savings and overall life-cycle impact of different 'soy-biodiesel' production methods are presented. These impacts and the significance of uncertainty in overall assessments of key parameters, such as greenhouse-gas savings, are discussed. It is shown that, even where sufficient knowledge exists to be able to quantify these impacts, the sustainability of supply of a particular biofuel is inextricably linked to values and ethical judgements. However, tailoring certification efforts to the issues that are most likely to make a significant difference to the overall sustainability could improve the effectiveness of certification efforts. The potential for a framework to guide and focus certification efforts is discussed and future research and policy priorities suggested.


Cultural transmission results in convergence towards colour term universals.
As in biological evolution, multiple forces are involved in cultural evolution. One force is analogous to selection, and acts on differences in the fitness of aspects of culture by influencing who people choose to learn from. Another force is analogous to mutation, and influences how culture changes over time owing to errors in learning and the effects of cognitive biases. Which of these forces need to be appealed to in explaining any particular aspect of human cultures is an open question. We present a study that explores this question empirically, examining the role that the cognitive biases that influence cultural transmission might play in universals of colour naming. In a large-scale laboratory experiment, participants were shown labelled examples from novel artificial systems of colour terms and were asked to classify other colours on the basis of those examples. The responses of each participant were used to generate the examples seen by subsequent participants. By simulating cultural transmission in the laboratory, we were able to isolate a single evolutionary force-the effects of cognitive biases, analogous to mutation-and examine its consequences. Our results show that this process produces convergence towards systems of colour terms similar to those seen across human languages, providing support for the conclusion that the effects of cognitive biases, brought out through cultural transmission, can account for universals in colour naming.


Garlic for hypertension: A systematic review and meta-analysis of randomized controlled trials.
In the past decade, garlic has become one of the most popular complementary therapies for blood pressure (BP) control used by hypertensive patients. Numerous clinical studies have focused on the BP-lowering effect of garlic, but results have been inconsistent. Overall, there is a dearth of information available to guide the clinical community on the efficacy of garlic in hypertensive patients. To systematically review the medical literature to investigate the current evidence of garlic for the treatment of hypertension. PubMed, the Cochrane Library and EMBASE were searched for appropriate articles from their respective inceptions until August 2014. Randomized, placebo-controlled trials comparing garlic vs. a placebo in patients with hypertension were considered. Papers were independently reviewed by two reviewers and were analyzed using Cochrane software Revman 5.2. A total of seven randomized, placebo-controlled trials were identified. Compared with the placebo, this meta-analysis revealed a significant lowering effect of garlic on both systolic BP (WMD: -6.71 mmHg; 95% CI: -12.44 to -0.99; P = 0.02) and diastolic BP (WMD: -4.79 mmHg; 95% CI: -6.60 to -2.99; P < 0.00001). No serious adverse events were reported in any of the trials. The present review suggests that garlic is an effective and safe approach for hypertension. However, more rigorously designed randomized controlled trials focusing on primary endpoints with long-term follow-up are still warranted before garlic can be recommended to treat hypertensive patients.


Variation and molecular evolution of HmbR, the Neisseria meningitidis haemoglobin receptor.
Meningococcal disease caused by serogroup B Neisseria meningitidis remains an important health problem in many parts of the world, and there are currently no comprehensive vaccines. Poor immunogenicity, combined with immunological identity to human sialic acids, have hindered the development of a serogroup B conjugate vaccine, resulting in the development of alternative vaccine candidates, including many outer-membrane protein (OMP)-based formulations. However, the design of protein-based meningococcal vaccines is complicated by the high level of genetic and antigenic diversity of the meningococcus. Knowledge of the extent and structuring of this diversity can have implications for the use of particular proteins as potential vaccine candidates. With this in mind, the diversity of the meningococcal OMP HmbR was investigated among N. meningitidis isolates representative of major hyper-invasive lineages. In common with other meningococcal antigens, the genetic diversity of hmbR resulted from a combination of intraspecies horizontal genetic exchange and de novo mutation. Furthermore, genealogical analysis showed an association of hmbR genes with clonal complexes and the occurrence of two hmbR families, A and B. Three variable regions (VR1-VR3), located in loops 2, 3 and 4, were observed with clonal complex structuring of VR types. A minority of codons (3.9 %), located within putative surface-exposed loop regions of a 2D model, were under diversifying selection, indicating regions of the protein likely to be subject to immune attack.


Fast internal marker tracking algorithm for onboard MV and kV imaging systems.
Intrafraction organ motion can limit the advantage of highly conformal dose techniques such as intensity modulated radiation therapy (IMRT) due to target position uncertainty. To ensure high accuracy in beam targeting, real-time knowledge of the target location is highly desired throughout the beam delivery process. This knowledge can be gained through imaging of internally implanted radio-opaque markers with fluoroscopic or electronic portal imaging devices (EPID). In the case of MV based images, marker detection can be problematic due to the significantly lower contrast between different materials in comparison to their kV-based counterparts. This work presents a fully automated algorithm capable of detecting implanted metallic markers in both kV and MV images with high consistency. Using prior CT information, the algorithm predefines the volumetric search space without manual region-of-interest (ROI) selection by the user. Depending on the template selected, both spherical and cylindrical markers can be detected. Multiple markers can be simultaneously tracked without indexing confusion. Phantom studies show detection success rates of 100% for both kV and MV image data. In addition, application of the algorithm to real patient image data results in successful detection of all implanted markers for MV images. Near real-time operational speeds of approximately 10 frames/sec for the detection of five markers in a 1024 x 768 image are accomplished using an ordinary PC workstation.


Eculizumab treatment alters the proteometabolome beyond the inhibition of complement.
Therapeutic strategies targeting complement have revolutionized the treatment of myasthenia gravis (MG). However, a deeper understanding of complement modulation in the human system is required to improve treatment responses and identify off-target effects shaping long-term outcomes. For this reason, we studied a cohort of patients with MG treated with either eculizumab or azathioprine as well as treatment-naive patients using a combined proteomics and metabolomics approach. This strategy validated known effects of eculizumab on the terminal complement cascade. Beyond that, eculizumab modulated the serum proteometabolome as distinct pathways were altered in eculizumab-treated patients, including the oxidative stress response, mitogen-activated protein kinase signaling, and lipid metabolism with particular emphasis on arachidonic acid signaling. We detected reduced levels of arachidonate 5-lipoxygenase (ALOX5) and leukotriene A4 in eculizumab-treated patients. Mechanistically, ligation of the C5a receptor (C5aR) is needed for ALOX5 metabolism and generation of downstream leukotrienes. As eculizumab prevents cleavage of C5 into C5a, decreased engagement of C5aR may inhibit ALOX5-mediated synthesis of pro-inflammatory leukotrienes. These findings indicate distinct off-target effects induced by eculizumab, illuminating potential mechanisms of action that may be harnessed to improve treatment outcomes.


The structural isomerism in gold nanoclusters.
The isomerism in thiolate-protected gold (Au) nanoclusters is important for the understanding of structure-property correlations and the design of Au nanoclusters with specific structures and properties. Although recent studies have identified stereoisomerism, the understanding of structural isomerism is still lacking. Herein, we identified three distinct mechanisms of structural isomerism (i.e., core isomerism, staple isomerism, and complex isomerism) based on the crystallized isomers of thiolate-protected Au nanoclusters, and these mechanisms can be viewed as analogous to those of the structural isomerism in organic molecules (i.e., chain isomerism, point isomerism, and functional isomerism). Using the discovered core isomerism and staple isomerism, two Au28(SR)20 isomers are predicted and their synthesis feasibilities are illuminated. These new insights into the structural isomerism can facilitate rational design of new isomers of thiolate-protected Au nanoclusters and guide future experimental synthesis.


Reaching movements may reveal the distorted topography of spatial representations after neglect.
It has been proposed that patients with spatial neglect fail to respond appropriately toward stimuli opposite their brain lesion because they have an impairment of directing attention. However, a disorder of 'intention' - or movement initiation - has also been demonstrated in this condition. Recently, the paths of neglect patients' reaches have been shown to be abnormally curved, but it is unclear whether this impairment is visual or motor. Here, we show for the first time that reaches to and from identical positions executed by three patients recovering from neglect are significantly more curved to visually defined targets compared to when the same targets are defined proprioceptively. These findings indicate that abnormal hand paths in neglect result from an impairment in the visual representation of space used to guide reaches but without any general failure of spatial representation of target position. Furthermore, the curved hand paths reveal how the topography of that representation is distorted in spatial neglect.


Characterizing brain anatomical connections using diffusion weighted MRI and graph theory.
A new methodology based on Diffusion Weighted Magnetic Resonance Imaging (DW-MRI) and Graph Theory is presented for characterizing the anatomical connections between brain gray matter areas. In a first step, brain voxels are modeled as nodes of a non-directed graph in which the weight of an arc linking two neighbor nodes is assumed to be proportional to the probability of being connected by nervous fibers. This probability is estimated by means of probabilistic tissue segmentation and intravoxel white matter orientational distribution function, obtained from anatomical MRI and DW-MRI, respectively. A new tractography algorithm for finding white matter routes is also introduced. This algorithm solves the most probable path problem between any two nodes, leading to the assessment of probabilistic brain anatomical connection maps. In a second step, for assessing anatomical connectivity between K gray matter structures, the previous graph is redefined as a K+1 partite graph by partitioning the initial nodes set in K non-overlapped gray matter subsets and one subset clustering the remaining nodes. Three different measures are proposed for quantifying anatomical connections between any pair of gray matter subsets: Anatomical Connection Strength (ACS), Anatomical Connection Density (ACD) and Anatomical Connection Probability (ACP). This methodology was applied to both artificial and actual human data. Results show that nervous fiber pathways between some regions of interest were reconstructed correctly. Additionally, mean connectivity maps of ACS, ACD and ACP between 71 gray matter structures for five healthy subjects are presented.


Microglial ablation and lipopolysaccharide preconditioning affects pilocarpine-induced seizures in mice.
Activated microglia have been associated with neurodegeneration in patients and in animal models of Temporal Lobe Epilepsy (TLE), however their precise functions as neurotoxic or neuroprotective is a topic of significant investigation. To explore this, we examined the effects of pilocarpine-induced seizures in transgenic mice where microglia/macrophages were conditionally ablated. We found that unilateral ablation of microglia from the dorsal hippocampus did not alter acute seizure sensitivity. However, when this procedure was coupled with lipopolysaccharide (LPS) preconditioning (1 mg/kg given 24 h prior to acute seizure), we observed a significant pro-convulsant phenomenon. This effect was associated with lower metabolic activation in the ipsilateral hippocampus during acute seizures, and could be attributed to activity in the mossy fiber pathway. These findings reveal that preconditioning with LPS 24 h prior to seizure induction may have a protective effect which is abolished by unilateral hippocampal microglia/macrophage ablation.