Balancing professional obligations and risks to providers in learning healthcare systems.
Clinicians and administrators have a professional obligation to contribute (OTC) to improvement of healthcare quality. At the same time, participation in embedded research poses risks to healthcare institutions. Disclosure of an institution's sensitive information could endanger relationships with patients and undermine its reputation. The existing ethical framework (EF) for learning healthcare systems (LHSs) does not address the conflict between the OTC and institutional interests. Ethical guidance and policy regulation are needed to create a safe environment for embedded research. In this article we analyse the EF for LHSs and the concept of professionalism. We suggest that the EF should be supplemented with an obligation to protect provider's legitimate interests. We define legitimate interests as those that enable providers to discharge their primary duties. We argue that both the OTC and the obligation to protect legitimate interests are grounded in the concept of medical professionalism and can be understood as a matter of contract between a democratic society and medical professionals. The proposed supplemented EF can be implemented into a regulatory system in three different ways: the self-regulating: where providers decide themselves how to balance the ethical claims, the centralised: where a governmental institution decides the right balance between providers' interests and interests of a health system; and the mediating: where medical professionals, the state and patients negotiate their interests. Our article contributes to the discussion on ethical relevance of providers' interests and the regulatory model for weighing opposite interests in LHSs.


An improved understanding of cancer genomics through massively parallel sequencing.
DNA sequencing technology advances have enabled genetic investigation of more samples in a shorter time than has previously been possible. Furthermore, the ability to analyze and understand large sequencing datasets has improved due to concurrent advances in sequence data analysis methods and software tools. Constant improvements to both technology and analytic approaches in this fast moving field are evidenced by many recent publications of computational methods, as well as biological results linking genetic events to human disease. Cancer in particular has been the subject of intense investigation, owing to the genetic underpinnings of this complex collection of diseases. New massively-parallel sequencing (MPS) technologies have enabled the investigation of thousands of samples, divided across tens of different tumor types, resulting in new driver gene identification, mutagenic pattern characterization, and other newly uncovered features of tumor biology. This review will focus both on methods and recent results: current analytical approaches to DNA and RNA sequencing will be presented followed by a review of recent pan-cancer sequencing studies. This overview of methods and results will not only highlight the recent advances in cancer genomics, but also the methods and tools used to accomplish these advancements in a constantly and rapidly improving field.


Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP).
Ninety patients with progressive recurrent lymphoma were treated with a combination of cisplatin 100 mg/m2 intravenously (IV) by continuous infusion over 24 hours, followed by cytosine arabinoside in two pulses each at a dose of 2 g/m2 given 12 hours apart. Dexamethasone, 40 mg orally or IV, was given on days 1 through 4. Vigorous hydration was reinforced by routine use of mannitol. Treatments were repeated at 3- to 4-week intervals for six to ten courses. Most patients had not achieved complete remission (CR) with prior therapies, which included Adriamycin (all patients) and methotrexate and VP-16 (58 patients). Median patient age was 55 years. Intermediate-grade lymphoma was the most frequent pathologic diagnosis. Seven patients died within two weeks of therapy; of the remaining 83 patients, 28 (34%) or 31% if all patients are considered, achieved CR, and 22 (26.5%) achieved partial remission (PR). Response was evident after the first two cycles of chemotherapy and appeared to be independent of the histopathologic type of lymphoma. To date, only eight of the complete responders have relapsed at a median follow-up of 11 months. The overall 2-year survival in 25%. Further analysis showed that patients with low tumor burden and normal lactic acid dehydrogenase (LDH) had a high CR response rate (67%) and a survival rate of 61% at 2 years. In contrast, patients with both high tumor burden and elevated serum LDH levels had a negligible CR rate, and only 5% are surviving at 1 year. Patients with either high tumor burden with normal LDH or low tumor burden with elevated LDH had an intermediate survival. Myelosuppression-related infection was the most frequent serious complication of this regimen (31%) and the cause of death of ten patients. Acute lysis syndrome was also observed in five patients with high tumor burden and was the cause of death in three of these patients. DHAP has proven to be an effective non-crossresistant regimen for patients with relapsing or refractory lymphoma, particularly for patients who have favorable prognostic characteristics.


Association of a Human FABP1 Gene Promoter Region Polymorphism with Altered Serum Triglyceride Levels.
Liver fatty acid-binding protein (L-FABP), also known as fatty acid-binding protein 1 (FABP1), is a key regulator of hepatic lipid metabolism. Elevated FABP1 levels are associated with an increased risk of cardiovascular disease (CVD) and metabolic syndromes. In this study, we examine the association of FABP1 gene promoter variants with serum FABP1 and lipid levels in a Chinese population. Four promoter single-nucleotide polymorphisms (SNPs) of FABP1 gene were genotyped in a cross-sectional survey of healthy volunteers (n = 1,182) from Fuzhou city of China. Results showed that only the rs2919872 G>A variant was significantly associated with serum TG concentration(P = 0.032).Compared with the rs2919872 G allele, rs2919872 A allele contributed significantly to reduced serum TG concentration, and this allele dramatically decreased the FABP1 promoter activity(P < 0.05). The rs2919872 A allele carriers had considerably lower serum FABP1 levels than G allele carriers (P < 0.01). In the multivariable linear regression analysis, the rs2919872 A allele was negatively associated with serum FABP1 levels (β = -0.320, P = 0.003), while serum TG levels were positively associated with serum FABP1 levels (β = 0.487, P = 0.014). Our data suggest that compared with the rs2919872 G allele, the rs2919872 A allele reduces the transcriptional activity of FABP1 promoter, and thereby may link FABP1 gene variation to TG level in humans.


Lauric acid and myristic acid from Allium sativum inhibit the growth of Mycobacterium tuberculosis H37Ra: in silico analysis reveals possible binding to protein kinase B.
The bulb of Allium sativum Linn (Alliaceae) has numerous medicinal values. Though the petroleum ether extract of the bulb has shown to exhibit antimycobacterial activity, the phytochemical(s) responsible for this inhibitory activity is not known. To characterize the bioactive compounds in the petroleum ether extract of Allium sativum (garlic) that inhibit the growth of Mycobacterium tuberculosis H37Ra. Bioactivity-guided fractionation was employed to isolate the bioactive compounds. Antimycobacterial activity was evaluated by well-diffusion method and microplate alamar blue assay (MABA). Infrared spectroscopy, mass spectrometry and nuclear magnetic resonance spectroscopy were used to characterize the bioactive compounds. Autodock was used to obtain information on molecular recognition, and molecular dynamics simulation was performed using GROMACS. The bioactive compounds that inhibited the growth of M. tuberculosis H37Ra were found to be lauric acid (LA) and myristic acid (MA). The minimal inhibitory concentration of LA and MA was found to be 22.2 and 66.7 μg/mL, respectively. In silico analysis revealed that these fatty acids could bind at the cleft between the N-terminal and C-terminal lobes of the cytosolic domain of serine/threonine protein kinase B (PknB). The inhibition activity was dependent on the alkyl chain length of the fatty acid, and the amino acid residues involved in binding to fatty acid was found to be conserved across the Pkn family of proteins. The study indicates the possibility of using fatty acid derivatives, involving Pkn family of proteins, to inhibit the signal transduction processes in M. tuberculosis.


Olfaction in birds: differential embryonic expression of nine putative odorant receptor genes in the avian olfactory system.
We have isolated nine putative odorant receptor genes from the chick, named COR1 to COR9, that belong to the large multigene family of olfactory G protein-coupled receptors found in the fish, rat, mouse, dog, and human. By combining genomic DNA blot analysis, low stringency library screenings, and several PCR analyses, we were able to detect approximately 20 COR genes in the chick genome highly related to COR1-9. By in situ hybridization of newborn and adult, COR expression was detected only in the olfactory epithelium, and exhibited a random spatial distribution. During development, COR expression was observed as early as embryonic stage E5. Different levels of gene expression were observed for the COR1-9 genes: at E5, COR1-6 expression was high compared to the expression of COR7, COR8, and COR9. Surprisingly, at E5, a row of COR1-6 positive cells probably associated with the olfactory nerve extended outside the olfactory placode, reaching the anterior pole of the developing forebrain. These results suggest that, in addition to their role as putative odorant receptors, some COR may play a role in the development of the avian olfactory system.


30,000-year-old wild flax fibers.
A unique finding of wild flax fibers from a series of Upper Paleolithic layers at Dzudzuana Cave, located in the foothills of the Caucasus, Georgia, indicates that prehistoric hunter-gatherers were making cords for hafting stone tools, weaving baskets, or sewing garments. Radiocarbon dates demonstrate that the cave was inhabited intermittently during several periods dated to 32 to 26 thousand years before the present (kyr B.P.), 23 to 19 kyr B.P., and 13 to 11 kyr B.P. Spun, dyed, and knotted flax fibers are common. Apparently, climatic fluctuations recorded in the cave's deposits did not affect the growth of the plants because a certain level of humidity was sustained.


Histone H3 tail positioning and acetylation by the c-Myb but not the v-Myb DNA-binding SANT domain.
The c-Myb transcription factor coordinates proliferation and differentiation of hematopoietic precursor cells. Myb has three consecutive N-terminal SANT-type repeat domains (R1, R2, R3), two of which (R2, R3) form the DNA-binding domain (DBD). Three amino acid substitutions in R2 alter the way Myb regulates genes and determine the leukemogenicity of the retrovirally transduced v-Myb oncogene. The molecular mechanism of how these mutations unleash the leukemogenic potential of Myb is unknown. Here we demonstrate that the c-Myb-DBD binds to the N-terminal histone tails of H3 and H3.3. C-Myb binding facilitates histone tail acetylation, which is mandatory during activation of prevalent differentiation genes in conjunction with CCAAT enhancer-binding proteins (C/EBP). Leukemogenic mutations in v-Myb eliminate the interaction with H3 and acetylation of H3 tails and abolish activation of endogenous differentiation genes. In primary v-myb-transformed myeloblasts, pharmacologic enhancement of H3 acetylation restored activation of differentiation genes and induced cell differentiation. Our data link a novel chromatin function of c-Myb with lineage-specific expression of differentiation genes and relate the loss of this function with the leukemic conversion of Myb.


Amplitude-only, passive, broadband, optical spatial cloaking of very large objects.
We demonstrate three amplitude cloaks that can hide very large spatial objects over the entire visible spectrum using only passive, off-the-shelf optics. The cloaked region for all of the devices exceeds 10⁶ mm³, with the largest exceeding 10⁸ mm³. Although unidirectional, these cloaks can hide the cloaked object, even if the object is transversely illuminated or self-illuminated. Due to the small usable solid angle, but simple scaling, these cloaks may be of value in hiding small field-of-view objects such as mid- to high-earth orbit satellites from earth-based observation. Active phase front manipulation can also make these cloaks invisible to some forms of image homodyning.


Root-Knot Disease Caused by Meloidogyne arenaria and M. javanica in Teak in São Paulo State, Brazil.
Teak (Tectona grandis Linn. F.) is one of the most important forest crops in Brazil, occupying areas in different regions, such as Goiás, Mato Grosso, Paraná, and São Paulo states. Teak wood is used for many purposes such as shipbuilding, rolling and plywood, firewood, and charcoal. In May 2011, teak symptomatic feeder root samples, exhibiting inconspicuous, small galls, were collected in the municipality of Piracicaba, São Paulo State, Brazil (22°41'46.90″S, 47°38'36.84″W). Specimens were identified through perineal patterns and esterase phenotypes of 20 adult females (1,2). Perineal patterns and esterase phenotypes were consistent with those described for Meloidogyne arenaria (Neal, 1889) Chitwood, 1949 and M. javanica (Treub, 1885) Chitwood, 1949. Perineal patterns of M. arenaria showed a low dorsal arch, compressed dorsolaterally, with lateral field marked by some forked and broken striae; no punctate markings between anus and tail terminus were observed. Perineal patterns of M. javanica were rounded, with low dorsal arch, striae smooth, lateral field distinct, clearly demarcated from striae by parallel lines. From the esterase electrophoresis we obtained A2 (Rm:1.2;1.3) and J3 (Rm:1.0;1.25;1.4) phenotypes, typical from M. arenaria and M. javanica, respectively. To our knowledge, this is the first report of M. arenaria parasitizing teak roots in Brazil and elsewhere (new host) and the first report of M. javanica infecting teak in the State of São Paulo. Previously, M. javanica was reported to be infecting teak-growing areas in the State of Mato Grosso (3). This finding has a great importance, not only by the inclusion of these parasites in teak pathological scenario, but also for predicting possible damage in plant species used in teak-based intercropping systems. References: (1) P. R. Esbenshade and A. C. Triantaphyllou. J. Nematol. 22:10, 1990. (2) K. M. Hartman and J. N. Sasser. 1985. Page 115 in: An Advanced Treatise on Meloidogyne. Volume II, Methodology. K. R. Barker et al., eds. North Carolina State University Graphics, Raleigh,1985. (3) R. A. Silva et al. Nematol. Bras. 27:261, 2003.


C1 posterior arch screw as an auxiliary anchor in posterior reconstruction for atlantoaxial dislocation associated with type II odontoid fracture: a case report and review of the literature.
Although pedicle or lateral mass screws are usually chosen to fix atlantoaxial (C1-C2) instability, there is an increased risk for vertebral artery (VA) injury when used in patients with bone or arterial anomalies or osteoporotic bone. Here we report the C1 posterior arch screw as a new technique for upper cervical fixation. A 90-year-old man complained of upper cervical pain after falling in his house. The initial computed tomography (CT) scan showed C1-C2 posterior dislocation with a type II odontoid fracture. The patient underwent C2 fracture reduction and posterior C1-C2 fixation. On the right side of C1, because lateral mass screw placement could cause injury to the dominant VA considering a risk in oldest-old osteoporotic patients, a posterior arch screw was chosen instead as an auxiliary anchor. An intralaminar screw was placed on the right side of C2 because a high-riding VA was observed. A lateral mass screw and a pars interarticularis screw were placed on the left side of C1 and C2, respectively. Ten months later, the odontoid fracture had healed, with normal anatomical alignment. Although the patient experienced slight weakness when spreading his bilateral fingers, his overall condition was good. We have presented a novel technique using C1 posterior arch screws for the fixation of a C1-C2 dislocation. Such a screw is an alternative to the C1 lateral mass screw in patients who are at risk for a VA injury because of anomalous bone and arterial structures or poor bone quality. Although there have been few comparable studies, and the long-term outcome is unknown, fixation with a posterior arch screw could be a beneficial choice for surgeries involving the upper cervical region.


Role of NFkappaB in antigen presentation and development of regulatory T cells elucidated by treatment of dendritic cells with the proteasome inhibitor PSI.
Dendritic cells (DC) are the most potent antigen-presenting cells for naive T cells, due to their high expression of MHC and costimulatory molecules, but relatively little is known about the biochemical pathways that regulate this function. We used the proteasome inhibitor N-benzyloxycarbonyl-Ile-Glu(O-tert-butyl)-Ala-leucinal (PSI) to demonstrate that DC antigen presentation is NFkappaB dependent. As PSI is not a specific inhibitor of NFkappaB, we reproduced this finding using a very specific approach, namely adenoviral gene transfer of IkappaBalpha, the naturally occurring inhibitor of NFkappaB. The mechanism for this inhibition of DC antigen presentation involves at least three aspects of antigen presenting function: down-regulation of HLA class II, down-regulation of CD86, and inhibition of the immunostimulatory cytokines IL-12 and TNF-alpha. In the light of the marked down-regulation of antigen-presentation cell function, it was of interest to investigate what effects exposure to PSI-treated DC might have on T cell function. It was found that immunological tolerance was induced, as challenge of T cells previously exposed to PSI-treated DC, with normal DC from the same donor did not restore their response, despite the presence of viable T cells. There were also changes in T cell surface markers, with down-regulation of CD3 and CD25 expression, and inhibition of the production of Th1 cytokines like IL-2 and IFN-gamma. These results demonstrates that NFkappaB is an effective target for blocking DC antigen presentation and inhibiting T cell-dependent immune responses, and this has implications for the development of therapeutic agents for use in multiple conditions, including transplantation, allergy and autoimmune diseases.


Apoptotic and mitotic indices predict survival rates in lymph node-negative colon carcinomas.
An imbalance between apoptosis and mitosis is believed to underlie colon cancer development and progression. These processes regulate the growth of normal and neoplastic epithelia, and in tumors, may confer prognostic information. To test this hypothesis, we determined apoptotic and mitotic indices (AI, MI) by morphology in H&E sections of 154 lymph node-negative, sporadic colon carcinomas. The relationship of these indices to genetic (p53 and Bcl-2) and biological features (DNA ploidy and cell kinetics) and patient survival rates was determined. Tumor features were compared in proximal and distal tumors, given postulated differences in their pathogenesis. Bcl-2 and p53 proteins were examined using immunohistochemistry and DNA ploidy and proliferative indices (PIs) by flow cytometry. Tumor features were dichotomized for analysis of relapse-free survival and overall survival (OS) rates using a Cox proportional hazards model. Median patient follow-up was 8.8 years. The median AI and MI were 1.2% (0-7.6) and 0.40% (0-1.8), respectively, and did not differ by tumor site. AI correlated with histological grade (P = 0.03); MI correlated with PI (P = 0.02) and inversely with Bcl-2 in distal tumors (P = 0.02). p53 and Bcl-2 expression were detected in 52 and 53% of tumors, respectively. Distal tumor site was associated with aneuploidy (P = 0.001), p53 (P = 0.001), and PI > 15% (P = 0.002). In a univariate analysis, colon cancers with high MIs (>0.5%) had a poor prognosis (P = 0.04). Bcl-2 overexpression (>20% + tumor cells) was associated with more favorable OS (P = 0.04). The association of ploidy and PI with outcome was of borderline significance for all tumors; however, diploidy predicted better survival in proximal cancers. In distal cancers, low AIs (< or = 0.25%) and high MIs (>0.5%) were adverse prognostic markers. After adjustment for other variables, an increased MI predicted shorter OS with a hazard ratio (HR) for death of 2.70; 95% confidence interval (CI) was 1.23-5.91 (P = 0.01). Expression of Bcl-2 was associated with more favorable OS (HR, 0.46; 95% CI, 0.21-1.0; P = 0.06). In proximal cancers, Bcl-2 expression was the most important predictor of OS (HR, 0.17; 95% CI, 0.03-0.85; P = 0.03). In distal tumors, low AIs (HR, 3.33; 95% CI, 1.27-9.09; P = 0.01) and high MIs predicted poor survival. In conclusion, increased mitosis and low or absent Bcl-2 expression are significant risk factors for death in node-negative colon cancers, as are low rates of apoptosis in distal tumors. If validated prospectively, our results may identify patient subsets than can benefit from adjuvant chemotherapy.


Tannin-binding salivary proteins in three captive rhinoceros species.
Tannin-binding salivary proteins (TBSP) are considered to be counter-defences acquired in the course of evolution by animals whose natural forage contains such tannins. As tannins mostly occur in browse material but not in grasses, it is assumed that grazers do not have a need for TBSP. Whereas it has been shown in several non-ungulate species that TBSP can be induced by dietary tannins, their presence or absence in ungulates has, so far, been shown to be a species-specific characteristic independent of dietary manipulations. We investigated saliva from three rhinoceros species from zoological gardens fed comparable, conventional zoo diets. As expected, saliva from white rhinoceroses (Ceratotherum simum, grazer) had lower tannin-binding capacities than that from black rhinoceroses (Diceros bicornis, browser). Surprisingly, however, Indian rhinoceroses (Rhinoceros unicornis), commonly regarded as grazers as well, displayed the highest tannin-binding capacities of the three species investigated. It is speculated that this discrepancy might be a result of an evolutionarily recent switch to a grass-dominated diet in Indian rhinoceroses, and that the black rhinoceros, which is closer related to the white rhinoceros than the Indian species, has evolved an inducible mechanism of TBSP production. In separate trials during which the tannin content of the diets of black rhinoceroses was increased by the addition of either tannic acid or quebracho, the tannin-binding capacity of black rhinoceros saliva was increased to levels within the same range as that of Indian rhinoceroses on the conventional diets. While induction trials in white and Indian rhinoceroses remain to be performed for a full understanding of salivary anti-tannin defence in rhinoceroses, these results are the first report of an induced salivary response to increased dietary tannin levels in an ungulate species.


CD8+ T-Cell responses to Trypanosoma cruzi are highly focused on strain-variant trans-sialidase epitopes.
CD8+ T cells are crucial for control of a number of medically important protozoan parasites, including Trypanosoma cruzi, the agent of human Chagas disease. Yet, in contrast to the wealth of information from viral and bacterial infections, little is known about the antigen specificity or the general development of effector and memory T-cell responses in hosts infected with protozoans. In this study we report on a wide-scale screen for the dominant parasite peptides recognized by CD8+ T cells in T. cruzi-infected mice and humans. This analysis demonstrates that in both hosts the CD8+ T-cell response is highly focused on epitopes encoded by members of the large trans-sialidase family of genes. Responses to a restricted set of immunodominant peptides were especially pronounced in T. cruzi-infected mice, with more than 30% of the CD8+ T-cell response at the peak of infection specific for two major groups of trans-sialidase peptides. Experimental models also demonstrated that the dominance patterns vary depending on the infective strain of T. cruzi, suggesting that immune evasion may be occurring at a population rather than single-parasite level.


[CT findings of pulmonary hypertension].
For the treatment for pulmonary hypertension (PH), the differential diagnosis of its causal diseases is essential. To determine whether X-ray CT is useful for differentiating PH, we reviewed CT findings of 53 patients (18 men and 35 women, mean age of 44.9) given a diagnosis of PH, consisting of 25 with primary pulmonary hypertension (PPH), 18 with chronic pulmonary embolism (cPE), 6 with Eisenmenger syndrome, 5 cases of collagen diseases, 2 of acute PE, and 1 of cor pulmonale. The intrapulmonary distribution of CT findings (ground glass opacity [GGO], mosaic attenuation, striation and/or infiltration, and interlobular septal thickening) were reviewed and scored on a 4-point scale (grade 0: no findings, 1: involving one third of the lung, 2: involving one-two thirds, and 3: diffuse distribution) by two radiologists who reached a consensus. PPH showed preferentially diffuse distribution of GGO as compared with cPE (p<0.05). However, there was no apparent relationship between the pulmonary vascular resistance and the distribution of GGO in PPH cases. The mosaic attenuation pattern was more frequent in cPE (43%) than PPH (12% ; p<0.05). Striation and/or infiltration was observed in 36% of cPE, but only 4% of PPH. Interlobular septal thickening was seen in 16% of PPH, and 0% in cPE. Evaluation of CT findings is useful to differentiate PH.


[Are psychiatric patients likely to benefit from DSM-5?].
The diagnosis plays a central role in medicine. If the validity of a diagnosis is in doubt, there will be doubt with regard to the existence of illness, the legitimacy of illness-behavior in the patient and the necessity of medical treatment. In this paper we discuss the changes made in DSM-5, testing whether they will contribute to a better position of our patients and of psychiatry. Critical appraisal of the changes made in DSM-5 and their potential impact on the position of our patients and of psychiatry. Critical discussion. DSM-5 has seen improvements in a series of essential areas, which will indeed benefit our patients. However, the most fundamental problems inherent in a system that aims to classify symptoms, disregarding their etiology, have not been solved. Given our infrastructure, we are well positioned to further develop and standardise appropriate medical specialty psychiatric diagnosis. This is more fruitful than ongoing criticism of DSM.


Determination of protein carbonyls in plasma, cell extracts, tissue homogenates, isolated proteins: Focus on sample preparation and derivatization conditions.
Protein oxidation is involved in regulatory physiological events as well as in damage to tissues and is thought to play a key role in the pathophysiology of diseases and in the aging process. Protein-bound carbonyls represent a marker of global protein oxidation, as they are generated by multiple different reactive oxygen species in blood, tissues and cells. Sample preparation and stabilization are key steps in the accurate quantification of oxidation-related products and examination of physiological/pathological processes. This review therefore focuses on the sample preparation processes used in the most relevant methods to detect protein carbonyls after derivatization with 2,4-dinitrophenylhydrazine with an emphasis on measurement in plasma, cells, organ homogenates, isolated proteins and organelles. Sample preparation, derivatization conditions and protein handling are presented for the spectrophotometric and HPLC method as well as for immunoblotting and ELISA. An extensive overview covering these methods in previously published articles is given for researchers who plan to measure protein carbonyls in different samples.


A multiscale computational model predicts distribution of anti-angiogenic isoform VEGF165b in peripheral arterial disease in human and mouse.
Angiogenesis is the growth of new blood vessels from pre-existing microvessels. Peripheral arterial disease (PAD) is caused by atherosclerosis that results in ischemia mostly in the lower extremities. Clinical trials including VEGF-A administration for therapeutic angiogenesis have not been successful. The existence of anti-angiogenic isoform (VEGF165b) in PAD muscle tissues is a potential cause for the failure of therapeutic angiogenesis. Experimental measurements show that in PAD human muscle biopsies the VEGF165b isoform is at least as abundant if not greater than the VEGF165a isoform. We constructed three-compartment models describing VEGF isoforms and receptors, in human and mouse, to make predictions on the secretion rate of VEGF165b and the distribution of various isoforms throughout the body based on the experimental data. The computational results are consistent with the data showing that in PAD calf muscles secrete mostly VEGF165b over total VEGF. In the PAD calf compartment of human and mouse models, most VEGF165a and VEGF165b are bound to the extracellular matrix. VEGF receptors VEGFR1, VEGFR2 and Neuropilin-1 (NRP1) are mostly in 'Free State'. This study provides a computational model of VEGF165b in PAD supported by experimental measurements of VEGF165b in human and mouse, which gives insight of VEGF165b in therapeutic angiogenesis and VEGF distribution in human and mouse PAD model.


Sexually dimorphic expression of gonadotropin subunits in the pituitary of protogynous honeycomb grouper (Epinephelus merra): evidence that follicle-stimulating hormone (FSH) induces gonadal sex change.
Recent studies have suggested that the hypothalamic-pituitary-gonadal axis is involved in gonadal sex change in sex-changing teleosts. However, its underlying mechanism remains largely unknown. In this study, we focused on the distinct roles of two gonadotropins (GTHs), follicle-stimulating hormone (FSH) and luteinizing hormone (LH), in the protogynous hermaphrodite teleost, honeycomb grouper (Epinephelus merra). First, we investigated the expression pattern of mRNAs for GTH subunits (cga, fshb, and lhb) in the pituitaries from fish at the different sexual phases. Real-time RT-PCR analyses showed that fhsb mRNA levels in the female pituitary were low. However, fshb transcripts increased dramatically in association with testis development. In contrast, levels of cga and lhb mRNAs did not significantly vary during sex change. In addition, immunohistochemical observations of Fshb- and Lhb-producing cells in the pituitary, through the use of specific antibodies for detections of teleost GTH subunits, were consistent with sexually dimorphic expression of Fshb. In order to identify the role of GTH in gonad of honeycomb grouper, we treated females with bovine FSH (50 or 500 ng/fish) or LH (500 ng/fish) in vivo. After 3 wk, FSH treatments induced female-to-male sex change and up-regulated endogenous androgen levels and fshb transcripts, whereas LH treatment had no effect on sex change. These results suggest that FSH may trigger the female-to-male sex change in honeycomb grouper.


Human Brat ortholog TRIM3 is a tumor suppressor that regulates asymmetric cell division in glioblastoma.
Cancer stem cells, capable of self-renewal and multipotent differentiation, influence tumor behavior through a complex balance of symmetric and asymmetric cell divisions. Mechanisms regulating the dynamics of stem cells and their progeny in human cancer are poorly understood. In Drosophila, mutation of brain tumor (brat) leads to loss of normal asymmetric cell division by developing neural cells and results in a massively enlarged brain composed of neuroblasts with neoplastic properties. Brat promotes asymmetric cell division and directs neural differentiation at least partially through its suppression on Myc. We identified TRIM3 (11p15.5) as a human ortholog of Drosophila brat and demonstrate its regulation of asymmetric cell division and stem cell properties of glioblastoma (GBM), a highly malignant human brain tumor. TRIM3 gene expression is markedly reduced in human GBM samples, neurosphere cultures, and cell lines and its reconstitution impairs growth properties in vitro and in vivo. TRIM3 expression attenuates stem-like qualities of primary GBM cultures, including neurosphere formation and the expression of stem cell markers CD133, Nestin, and Nanog. In GBM stem cells, TRIM3 expression leads to a greater percentage dividing asymmetrically rather than symmetrically. As with Brat in Drosophila, TRIM3 suppresses c-Myc expression and activity in human glioma cell lines. We also demonstrate a strong regulation of Musashi-Notch signaling by TRIM3 in GBM neurospheres and neural stem cells that may better explain its effect on stem cell dynamics. We conclude that TRIM3 acts as a tumor suppressor in GBM by restoring asymmetric cell division.


Steroidogenic factor 1 (NR5A1) maintains centrosome homeostasis in steroidogenic cells by restricting centrosomal DNA-dependent protein kinase activation.
Steroidogenic factor 1 (SF-1 or NR5A1) is a nuclear receptor that controls adrenogenital cell growth and differentiation. Adrenogenital primordial cells from SF-1 knockout mice die of apoptosis, but the mechanism by which SF-1 regulates cell survival is not entirely clear. Besides functioning in the nucleus, SF-1 also resides in the centrosome and controls centrosome homeostasis. Here, we show that SF-1 restricts centrosome overduplication by inhibiting aberrant activation of DNA-dependent protein kinase (DNA-PK) in the centrosome. SF-1 was found to be associated with Ku70/Ku80 only in the centrosome, sequestering them from the catalytic subunit of DNA-PK (DNA-PKcs). In the absence of SF-1, DNA-PKcs was recruited to the centrosome and activated, causing aberrant activation of centrosomal Akt and cyclin-dependent kinase 2 (CDK2)/cyclin A and leading to centrosome overduplication. Centrosome overduplication caused by SF-1 depletion was averted by the elimination of DNA-PKcs, Ku70/80, or cyclin A or by the inhibition of CDK2 or Akt. In the nucleus, SF-1 did not interact with Ku70/80, and SF-1 depletion did not activate a nuclear DNA damage response. Centriole biogenesis was also unaffected. Thus, centrosomal DNA-PK signaling triggers centrosome overduplication, and this centrosomal event, but not the nuclear DNA damage response, is controlled by SF-1.


Patient characteristics, practice activities, and one-month outcomes for chronic, recurrent low-back pain treated by chiropractors and family medicine physicians: a practice-based feasibility study.
Chronic low-back pain is a significant public health problem for which few therapies are supported by predictable outcomes. In this report, practice activities and 1-month outcomes data are presented for 93 chiropractic patients and 45 medical patients with chronic, recurrent low-back pain. A prospective, observational, community-based feasibility study involving chiropractors and family medicine physicians. Forty private chiropractic clinics, the outpatient clinic of the Department of Family Medicine at Oregon Health Sciences University, and 5 other Portland area family medicine clinics. The main outcome measures were pain severity, functional disability, sensory and affective pain quality at 1 month, and patient satisfaction assessed at 7 to 10 days and at 1 month. Although differences were noted in age, sex, education, and employment, the patients were closely matched at baseline with respect to frequency, severity, and type of low-back pain and the psychosocial dimensions of general health. The treatment of choice for chiropractors was spinal manipulation and physical therapy modalities; for medical physicians antiinflammatory agents were most frequently used. Chiropractic patients averaged 4 visits, and medical patients averaged 1 visit. On average, chiropractic patients showed improvement across all outcomes: 31% change in pain severity, 29% in functional disability, 36% in sensory pain quality, and 57% in affective pain quality. Medical patients showed minimal improvement in pain severity (6%) and functional disability (1%) and showed deterioration in the sensory (29%) and affective (26%) dimensions of pain quality. Satisfaction scores were higher for chiropractic patients. Outcomes for medical patients were heavily dependent on psychosocial status at baseline. Patients with chronic low-back pain treated by chiropractors show greater improvement and satisfaction at 1 month than patients treated by family physicians. Nonclinical factors may play an important role in patient progress. Findings from the Health Resources and Services Administration-funded project will include a report on the influence of practice activities, including more frequent visits by chiropractic patients, on the clinical course of low-back pain and patient outcomes. (J Manipulative Physiol Ther 2000;23:239-45).


Investigation of intrathecal transport of NPT002, a prospective therapeutic based on phage M13, in nonhuman primates.
Presently, there are no effective treatments for conditions characterized by protein misfolding, such as Alzheimer's, Parkinson's, and other diseases involving CNS. Since misfolding occurs at the earliest stage of the disease, it is likely to be involved in subsequent pathological developments. It has been found that NPT002 (bacteriophage M13) directly dissociates aggregates of misfolded proteins that form amyloid, including amyloid-β, tau and α-synuclein. For CNS applications, NPT002 requires delivery to the brain parenchyma, the target tissue. NPT002 is an elongated ~950 nm particle that cannot penetrate into the brain from the blood. Furthermore, phage particles, due to their size, cannot be effectively transported in vivo by diffusion. Considering the physiology of the leptomeningeal space, intrathecal administration appears to be a promising convection-driven avenue for NPT002 delivery. In this paper, we use positron emission tomography to investigate the transport of NPT002 in Macaca fascicularis. The data suggest that approximately 50 % of the administered dose can reach the cerebral leptomeningeal space after a single lumbar intrathecal injection. A biologically significant fraction of the phage then enters the brain, resulting in potentially therapeutic cortical and subcortical exposure.


Toward the Standardization of Biochar Analysis: The COST Action TD1107 Interlaboratory Comparison.
Biochar produced by pyrolysis of organic residues is increasingly used for soil amendment and many other applications. However, analytical methods for its physical and chemical characterization are yet far from being specifically adapted, optimized, and standardized. Therefore, COST Action TD1107 conducted an interlaboratory comparison in which 22 laboratories from 12 countries analyzed three different types of biochar for 38 physical-chemical parameters (macro- and microelements, heavy metals, polycyclic aromatic hydrocarbons, pH, electrical conductivity, and specific surface area) with their preferential methods. The data were evaluated in detail using professional interlaboratory testing software. Whereas intralaboratory repeatability was generally good or at least acceptable, interlaboratory reproducibility was mostly not (20% < mean reproducibility standard deviation < 460%). This paper contributes to better comparability of biochar data published already and provides recommendations to improve and harmonize specific methods for biochar analysis in the future.


Systems analysis and improvement to optimize pMTCT (SAIA): a cluster randomized trial.
Despite significant increases in global health investment and the availability of low-cost, efficacious interventions to prevent mother-to-child HIV transmission (pMTCT) in low- and middle-income countries with high HIV burden, the translation of scientific advances into effective delivery strategies has been slow, uneven and incomplete. As a result, pediatric HIV infection remains largely uncontrolled. A five-step, facility-level systems analysis and improvement intervention (SAIA) was designed to maximize effectiveness of pMTCT service provision by improving understanding of inefficiencies (step one: cascade analysis), guiding identification and prioritization of low-cost workflow modifications (step two: value stream mapping), and iteratively testing and redesigning these modifications (steps three through five). This protocol describes the SAIA intervention and methods to evaluate the intervention's impact on reducing drop-offs along the pMTCT cascade. This study employs a two-arm, longitudinal cluster randomized trial design. The unit of randomization is the health facility. A total of 90 facilities were identified in Côte d'Ivoire, Kenya and Mozambique (30 per country). A subset was randomly selected and assigned to intervention and comparison arms, stratified by country and service volume, resulting in 18 intervention and 18 comparison facilities across all three countries, with six intervention and six comparison facilities per country. The SAIA intervention will be implemented for six months in the 18 intervention facilities. Primary trial outcomes are designed to assess improvements in the pMTCT service cascade, and include the percentage of pregnant women being tested for HIV at the first antenatal care visit, the percentage of HIV-infected pregnant women receiving adequate prophylaxis or combination antiretroviral therapy in pregnancy, and the percentage of newborns exposed to HIV in pregnancy receiving an HIV diagnosis eight weeks postpartum. The Consolidated Framework for Implementation Research (CFIR) will guide collection and analysis of qualitative data on implementation process. This study is a pragmatic trial that has the potential benefit of improving maternal and infant outcomes by reducing drop-offs along the pMTCT cascade. The SAIA intervention is designed to provide simple tools to guide decision-making for pMTCT program staff at the facility level, and to identify low cost, contextually appropriate pMTCT improvement strategies. ClinicalTrials.gov NCT02023658.


Phylogenetic analysis of microbial communities in different regions of the gastrointestinal tract in Panaque nigrolineatus, a wood-eating fish.
The Neotropical detritivorous catfish Panaque nigrolineatus imbibes large quantities of wood as part of its diet. Due to the interest in cellulose, hemi-cellulose and lignin degradation pathways, this organism provides an interesting model system for the detection of novel microbial catabolism. In this study, we characterize the microbial community present in different regions of the alimentary tract of P. nigrolineatus fed a mixed diet of date palm and palm wood in laboratory aquaria. Analysis was performed on 16S rRNA gene clone libraries derived from anterior and posterior regions of the alimentary tract and the auxiliary lobe (AL), an uncharacterized organ that is vascularly attached to the midgut. Sequence analysis and phylogenetic reconstruction revealed distinct microbial communities in each tissue region. The foregut community shared many phylotypes in common with aquarium tank water and included Legionella and Hyphomicrobium spp. As the analysis moved further into the gastrointestinal tract, phylotypes with high levels of 16S rRNA sequence similarity to nitrogen-fixing Rhizobium and Agrobacterium spp. and Clostridium xylanovorans and Clostridium saccharolyticum, dominated midgut and AL communities. However, the hindgut was dominated almost exclusively by phylotypes with the highest 16S rRNA sequence similarity to the Cytophaga-Flavobacterium-Bacteroides phylum. Species richness was highest in the foregut (Chao(1) = 26.72), decreased distally through the midgut (Chao(1) = 25.38) and hindgut (Chao(1) = 20.60), with the lowest diversity detected in the AL (Chao(1) = 18.04), indicating the presence of a specialized microbial community. Using 16S rRNA gene phylogeny, we report that the P. nigrolineatus gastrointestinal tract possesses a microbial community closely related to microorganisms capable of cellulose degradation and nitrogen fixation. Further studies are underway to determine the role of this resident microbial community in Panaque nigrolineatus.


Comorbid Dementia and Cancer in Residents of Nursing Homes: Secondary Analyses of a Cross-Sectional Study.
Life expectancy is increasing continuously, which increases the likelihood of developing dementia or cancer. Both dementia and cancer are serious conditions that give manifold symptoms. The interaction of these conditions is however complex and less explored. The aim of this study was to identify the prevalence of cancer and differences regarding neuropsychiatric symptoms (NPS) and medication among nursing home (NH) patients with and without dementia and cancer. This is a cross-sectional study of Norwegian NH patients (N = 1825). Participants were categorized according to degree of dementia (Clinical Dementia Rating > 1) and cancer diagnoses. Differences in NPS and other symptoms, as well as the use of medication, were explored. Eighty-four percent of NH patients had dementia, and 5.5% had comorbid dementia and cancer. Patients with comorbid dementia and cancer received significantly more analgesics compared with patients without cancer but with dementia (P < .05). Compared with patients without dementia but with cancer, patients with comorbid dementia and cancer had significantly more NPS, including sleep disturbances and agitation. Patients with comorbid dementia and cancer receive more analgesics than patients with dementia but still display more agitation and sleep disturbances than patients with cancer and patients with neither dementia nor cancer, suggesting that symptoms may not be treated adequately. The results indicate a considerable strain for patients with comorbid dementia and cancer and highlight essential challenges for the clinician who is responsible for treatment and care. Nurses should pay attention to agitation and sleep disturbances among patients with comorbid dementia and cancer.


Advance care planning for adults with CKD: a systematic integrative review.
Recent clinical practice guidelines have highlighted the importance of advance care planning (ACP) for improving end-of-life care for people with chronic kidney disease (CKD). We conducted a systematic integrative review of the literature to inform future ACP practice and research in CKD, searching electronic databases in April 2013. Synthesis used narrative methods. We focused on adults with a primary diagnosis of CKD in any setting. We included studies of any design, quantitative or qualitative. ACP was defined as any formal means taken to ensure that health professionals and family members are aware of patients' wishes for care in the event they become too unwell to speak for themselves. Measures of all kinds were considered of interest. 55 articles met criteria reporting on 51 discrete samples. All patient samples included people with CKD stage 5; 2 also included patients with stage 4. Seven interventions were tested; all were narrowly focused and none was evaluated by comparing wishes for end-of-life care with care received. One intervention demonstrated effects on patient and family outcomes in the form of improved well-being and anxiety following sessions with a peer mentor. Insights from qualitative studies that have not been used to inform interventions include the importance of instilling patient confidence that their advance directives will be enacted and discussing decisions about (dis)continuing dialysis therapy separately from "aggressive" life-sustaining treatments (eg, ventilation). Although quantitative and qualitative findings were integrated according to best practice, methods for this are in their infancy. Research on ACP in patients with CKD is limited, especially intervention studies. Interventions in CKD should attend to barriers and facilitators at the levels of patient, caregiver, health professional, and system. Intervention studies should measure impact on compliance with patient wishes for end-of-life care.


History and development of trauma care in the United States.
Until recently the development of systems for trauma care in the United States has been inextricably linked to wars. During the Revolutionary War trauma care was based on European trauma principles particularly those espoused by the Hunter brothers. Surgical procedures were limited mostly to soft tissue injuries and amputations. The American Civil War was remarkable because of the contributions that were made to the development of systems for trauma care. The shear magnitude of casualties required extensive infrastructure to support the surgeons at the battlefield and to care for the wounded. For the first time in an armed conflict, anaesthetics were used on a routine basis. Despite these major contributions, hospital gangrene was a terrible problem and was the cause of many mortalities. World War I and World War II were noteworthy because of the contributions made by surgeons in the use of blood. One of the major lessons of World War II was the reemphasis of how frequently lessons have to be relearned regarding the treatment and care of wounds. Between the Korean Conflict and the Vietnam War the discovery was made of the tremendous fluid shifts into the cell after severe hemorrhagic shock. As a consequence, the treatment of patients with shock was altered during the Vietnam Conflict, which resulted in better outcomes and less renal failure. The first trauma centers for civilians were started in the United States in 1966. Since 1988 the number of states with mature trauma systems has expanded from two to 35. During the same period, many studies have documented the efficacy of trauma systems in reducing unnecessary mortality and disability.


EDTA chelation reappraisal following new clinical trials and regular use in millions of patients: review of preliminary findings and risk/benefit assessment.
EDTA chelation therapy is regularly used in thousands of patients worldwide. An FDA approval of more than 50 years ago for heavy metal detoxification prompted many physicians to use EDTA as an alternative medicine for many categories of patients. Recently, NIH initiated the so-called Trial to Assess Chelation Therapy (TACT), which has been designed to evaluate whether EDTA and high dose oral vitamins and mineral therapy could offer clinical, quality of life, and economic benefits for patients with a previous myocardial infraction. A 50% reduction of urinary Pb and improvement of systolic blood pressure was observed in 33 cardiovascular patients following 20 iv administrations. In another study involving 15 patients of different categories, EDTA also has been shown to be an effective and nontoxic chelator for the removal of xenobiotic metals such as Pb, Cd, Ni and Al. Administration of iv EDTA on weekly basis appears to be a sufficient and nontoxic protocol for treating patients with suspected overload and toxicity of xenobiotic metals especially Pb and Cd. The causative effect of xenobiotic metals in cancer, cardiovascular, neurodegenerative, renal and other diseases needs further investigation. Similarly, the use of EDTA chelation therapy in other conditions, which are not related to xenobiotic metal toxicity needs further investigation and confirmation of therapeutic use from controlled randomized clinical trials. Metal balance and drug interaction studies are required to clarify the risk/benefit assessment for the long term use of EDTA in patients with excess xenobiotic metal toxicity and in other conditions.


Logical Observation Identifiers Names and Codes (LOINC®) Applied to Microbiology: A National Laboratory Mapping Experience in Taiwan.
Logical Observation Identifiers Names and Codes (LOINC) is a universal standard for identifying laboratory tests and clinical observations. It facilitates a smooth information exchange between hospitals, locally and internationally. Although it offers immense benefits for patient care, LOINC coding is complex, resource-intensive, and requires substantial domain expertise. Our objective was to provide training and evaluate the performance of LOINC mapping of 20 pathogens from 53 hospitals participating in the National Notifiable Disease Surveillance System (NNDSS). Complete mapping codes for 20 pathogens (nine bacteria and 11 viruses) were requested from all participating hospitals to review between January 2014 and December 2016. Participating hospitals mapped those pathogens to LOINC terminology, utilizing the Regenstrief LOINC mapping assistant (RELMA) and reported to the NNDSS, beginning in January 2014. The mapping problems were identified by expert panels that classified frequently asked questionnaires (FAQs) into seven LOINC categories. Finally, proper and meaningful suggestions were provided based on the error pattern in the FAQs. A general meeting was organized if the error pattern proved to be difficult to resolve. If the experts did not conclude the local issue's error pattern, a request was sent to the LOINC committee for resolution. A total of 53 hospitals participated in our study. Of these, 26 (49.05%) used homegrown and 27 (50.95%) used outsourced LOINC mapping. Hospitals who participated in 2015 had a greater improvement in LOINC mapping than those of 2016 (26.5% vs. 3.9%). Most FAQs were related to notification principles (47%), LOINC system (42%), and LOINC property (26%) in 2014, 2015, and 2016, respectively. The findings of our study show that multiple stage approaches improved LOINC mapping by up to 26.5%.


Tumor suppressor BTG1 limits activation of BCL6 expression downstream of ETV6-RUNX1.
Translocation t(12;21) (p13;q22), giving rise to the ETV6-RUNX1 fusion gene, is the most common genetic abnormality in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This translocation usually arises in utero, but its expression is insufficient to induce leukemia and requires other cooperating genetic lesions for BCP-ALL to develop. Deletions affecting the transcriptional coregulator BTG1 are frequently observed in ETV6-RUNX1-positive leukemia. Here we report that Btg1 deficiency enhances the self-renewal capacity of ETV6-RUNX1-positive mouse fetal liver-derived hematopoietic progenitors (FL-HPCs). Combined expression of the fusion protein and a loss of BTG1 drive upregulation of the proto-oncogene Bcl6 and downregulation of BCL6 target genes, such as p19Arf and Tp53. Similarly, ectopic expression of BCL6 promotes the self-renewal and clonogenic replating capacity of FL-HPCs, by suppressing the expression of p19Arf and Tp53. Together these results identify BCL6 as a potential driver of ETV6-RUNX1-mediated leukemogenesis, which could involve loss of BTG1-dependent suppression of ETV6-RUNX1 function.


Understanding the psychology of bullying: Moving toward a social-ecological diathesis-stress model.
With growing recognition that bullying is a complex phenomenon, influenced by multiple factors, research findings to date have been understood within a social-ecological framework. Consistent with this model, we review research on the known correlates and contributing factors in bullying/victimization within the individual, family, peer group, school and community. Recognizing the fluid and dynamic nature of involvement in bullying, we then expand on this model and consider research on the consequences of bullying involvement, as either victim or bully or both, and propose a social-ecological, diathesis-stress model for understanding the bullying dynamic and its impact. Specifically, we frame involvement in bullying as a stressful life event for both children who bully and those who are victimized, serving as a catalyst for a diathesis-stress connection between bullying, victimization, and psychosocial difficulties. Against this backdrop, we suggest that effective bullying prevention and intervention efforts must take into account the complexities of the human experience, addressing both individual characteristics and history of involvement in bullying, risk and protective factors, and the contexts in which bullying occurs, in order to promote healthier social relationships.


Pediatric Hospital Medicine: A Proposed New Subspecialty.
Over the past 20 years, hospitalists have emerged as a distinct group of pediatric practitioners. In August of 2014, the American Board of Pediatrics (ABP) received a petition to consider recommending that pediatric hospital medicine (PHM) be recognized as a distinct new subspecialty. PHM as a formal subspecialty raises important considerations related to: (1) quality, cost, and access to pediatric health care; (2) current pediatric residency training; (3) the evolving body of knowledge in pediatrics; and (4) the impact on both primary care generalists and existing subspecialists. After a comprehensive and iterative review process, the ABP recommended that the American Board of Medical Specialties approve PHM as a new subspecialty. This article describes the broad array of challenges and certain unique opportunities that were considered by the ABP in supporting PHM as a new pediatric subspecialty.


Photoacoustic-Enabled Self-Guidance in Magnetic-Hyperthermia Fe@Fe3 O4 Nanoparticles for Theranostics In Vivo.
Magnetic nanoparticles have gained much interest for theranostics benefited from their intrinsic integration of imaging and therapeutic abilities. Herein, c(RGDyK) peptide PEGylated Fe@Fe3 O4 nanoparticles (RGD-PEG-MNPs) are developed for photoacoustic (PA)-enabled self-guidance in tumor-targeting magnetic hyperthermia therapy in vivo. In the αv β3 -positive U87MG glioblastoma xenograft model, the PA signal of RGD-PEG-MNPs reaches its maximum in the tumor at 6 h after intravenous administration. This signal is enhanced by 2.2-folds compared to that of the preinjection and is also 2.2 times higher than that in the blocking group. It demonstrates the excellent targeting property of RGD-PEG-MNPs. With the guidance of the PA, an effective magnetic hyperthermia to tumor is achieved using RGD-PEG-MNPs.


Crystal structures of acetylcholinesterase in complex with HI-6, Ortho-7 and obidoxime: structural basis for differences in the ability to reactivate tabun conjugates.
Inhibition of acetylcholinesterase (AChE) by organophosphorus compounds (OPs) such as pesticides and nerve agents causes acute toxicity or death of the intoxicated individual. The inhibited AChE may be reactivated by certain oximes as antidotes for clinical treatment of OP-intoxications. Crystal structures of the oximes HI-6, Ortho-7 and obidoxime in complex with Mus musculus acetylcholinesterase (mAChE) reveal different roles of the peripheral anionic site (PAS) in the binding of the oximes. A limited structural change of the side chains of Trp286 and Asp74 facilitates the intercalation of the 4-carboxylamide pyridinium ring of HI-6 between the side chains of Tyr124 and Trp286. The 2-carboxyimino pyridinium ring of HI-6 is accommodated at the entrance of the catalytic site with the oximate forming a hydrogen bond to the main-chain nitrogen atom of Phe295. In contrast to HI-6, the coordination of Ortho-7 and obidoxime within the PAS is facilitated by an extended structural change of Trp286 that allows one of the carboxyimino pyridinium rings to form a cation-pi interaction with the aromatic groups of Tyr72 and Trp286. The central chain of Ortho-7 and obidoxime is loosely coordinated in the active-site gorge, whereas the second carboxyimino pyridinium ring is accommodated in the vicinity of the phenol ring of Tyr337. The structural data clearly show analogous coordination of Ortho-7 and obidoxime within the active-site gorge of AChE. Different ability to reactivate AChE inhibited by tabun is shown in end-point reactivation experiments where HI-6, Ortho-7 and obidoxime showed an efficiency of 1, 45 and 38%, respectively. The low efficiency of HI-6 and the significantly higher efficiency of Ortho-7 and obidoxime may be explained by the differential binding of the oximes in the PAS and active-site gorge of AChE.


Feasibility of a porcine oral mucosa equivalent: a preclinical study.
Oral tissue engineering aims to treat and fill tissue deficits caused by congenital defects, facial trauma, or malignant lesion surgery, as well as to study the biology of oral mucosa. The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) require a large animal model to evaluate cell-based devices, including tissue-engineered oral mucosa, prior to initiating human clinical studies. Porcine oral mucosa is non-keratinized and resembles that of humans more closely than any other animal in terms of structure and composition; however, there have not been any reports on the reconstruction of a porcine oral mucosa equivalent, probably due to the difficulty to culture porcine fibroblasts. In this study, we demonstrate the feasibility of a 3D porcine oral mucosa equivalent based on a collagen-GAG-chitosan scaffold, as well as reconstructed porcine epithelium by using an amniotic membrane as support, or without any support in form of epithelial cell sheets by using thermoresponsive culture plates. Explants technique was used for the isolation of the porcine fibroblasts and a modified fibroblast medium containing 20% fetal calf serum was used for their culture. The histological and transmission electron microscopic analyses of the resulting porcine oral mucosa models showed the presence of non-keratinized epithelia expressing keratin 13, the major differentiation marker of non-keratinized oral mucosa, in all models, and the presence of newly synthesized collagen fibers in the lamina propria equivalent of the full-thickness model, indicating the functionality of porcine fibroblasts.


Removing atmospheric turbulence via space-invariant deconvolution.
To correct geometric distortion and reduce space and time-varying blur, a new approach is proposed in this paper capable of restoring a single high-quality image from a given image sequence distorted by atmospheric turbulence. This approach reduces the space and time-varying deblurring problem to a shift invariant one. It first registers each frame to suppress geometric deformation through B-spline-based nonrigid registration. Next, a temporal regression process is carried out to produce an image from the registered frames, which can be viewed as being convolved with a space invariant near-diffraction-limited blur. Finally, a blind deconvolution algorithm is implemented to deblur the fused image, generating a final output. Experiments using real data illustrate that this approach can effectively alleviate blur and distortions, recover details of the scene, and significantly improve visual quality.


The case against memory consolidation in REM sleep.
We present evidence disputing the hypothesis that memories are processed or consolidated in REM sleep. A review of REM deprivation (REMD) studies in animals shows these reports to be about equally divided in showing that REMD does, or does not, disrupt learning/memory. The studies supporting a relationship between REM sleep and memory have been strongly criticized for the confounding effects of very stressful REM deprivation techniques. The three major classes of antidepressant drugs, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), and selective serotonin reuptake inhibitors (SSRIs), profoundly suppress REM sleep. The MAOIs virtually abolish REM sleep, and the TCAs and SSRIs have been shown to produce immediate (40-85%) and sustained (30-50%) reductions in REM sleep. Despite marked suppression of REM sleep, these classes of antidepressants on the whole do not disrupt learning/memory. There have been a few reports of patients who have survived bilateral lesions of the pons with few lingering complications. Although these lesions essentially abolished REM sleep, the patients reportedly led normal lives. Recent functional imaging studies in humans have revealed patterns of brain activity in REM sleep that are consistent with dream processes but not with memory consolidation. We propose that the primary function of REM sleep is to provide periodic endogenous stimulation to the brain which serves to maintain requisite levels of central nervous system (CNS) activity throughout sleep. REM is the mechanism used by the brain to promote recovery from sleep. We believe that the cumulative evidence indicates that REM sleep serves no role in the processing or consolidation of memory.


A supramolecular hydrogel for spatial-temporal release of auxin to promote plant root growth.
Short peptide-based hydrogels have attracted extensive research interests in drug delivery because of their responsive properties. So far, most drug molecules have been conjugated with short peptides via an amide bond, restricting the release of the native drug molecules. In this study, we demonstrated the effectiveness of an auxin-based hydrogelator linked by a hydrolysable ester bond. Hydrogel I, formed by the gelator (NAA-G'FFY) linked with an ester bond, was able to release 1-naphthaleneacetic acid (NAA), whereas hydrogel II, formed by the gelator without an ester bond (NAA-GFFY), was not. By mixing NAA-G'FFY with Fmoc-GFFY to form a two-component hydrogel, the spatial and temporal release of NAA was achieved, promoting on-site auxin responses including primary root elongation and lateral root formation in the model plant Arabidopsis thaliana. The strategy of using a hydrolysable ester bond to connect drug molecules and self-assembling peptides could lead to the development of supramolecular hydrogels with more controllable drug release profiles.


A national study of AIDS and residency training: experiences, concerns, and consequences.
To examine residents' experiences in the care of patients with the acquired immunodeficiency syndrome (AIDS), and to examine factors that may influence their attitudes about such care. Cross-sectional, self-administered questionnaire survey conducted in 1989. All senior internal medicine and family medicine residents in ten geographically representative states who were identified through the 1986 National Residency Matching Program. Seventy-four percent of residents reported that patients with AIDS accounted for 5% or more of general medicine admissions, and 50% of residents reported that they were currently following one or more human immunodeficiency virus (HIV)-infected patients in their continuity clinics. Among residents who had provided ambulatory care to patients with AIDS, 77% felt that it was an excellent educational experience, and among those who planned to do general primary care in their future practices, 74% planned on providing primary care to patients with AIDS. However, 61% expressed concerns about the adequacy of their training in AIDS ambulatory care. A greater amount of contact with outpatients who had AIDS, but not with inpatients who had AIDS, was associated with residents' intending to provide AIDS primary care in their future practices. Among all residents, 23% reported that, if given a choice, they would not provide care to any patients with AIDS, and 23% reported that they would not work in an area with a high prevalence of AIDS because of concern about contracting the syndrome. Nine percent of residents reported that they had been exposed to a blood-contaminated needlestick from an HIV-seropositive patient. Although most residents have substantial contact with inpatients and outpatients with AIDS, most still find their education in AIDS ambulatory care to be deficient. A minority of residents would prefer not to care for patients with AIDS. Residency curricula should include training and experience in ambulatory AIDS care, explicitly address negative attitudes toward caring for patients with AIDS, and include programs to reduce needlestick exposures.


Infrared liquid crystal polymer micropolarizer.
The ability to create arbitrary patterned linear and circular infrared (IR) liquid crystal polymer (LCP) polarizers is demonstrated. The operating wavelength of the thin-film polarizer ranges from 700 to 4200 nm. The linear micropolarizer is fabricated using IR dichroic dye as a guest in LCP host with feature size as small as 4 μm. The circular micropolarizer is fabricated using cholesteric LCPs with feature size as small as 6.2 μm.


A Framework for Assessing Uncertainty Associated with Human Health Risks from MSW Landfill Leachate Contamination.
Landfilling is a cost-effective method, which makes it a widely used practice around the world, especially in developing countries. However, because of the improper management of landfills, high leachate leakage can have adverse impacts on soils, plants, groundwater, aquatic organisms, and, subsequently, human health. A comprehensive survey of the literature finds that the probabilistic quantification of uncertainty based on estimations of the human health risks due to landfill leachate contamination has rarely been reported. Hence, in the present study, the uncertainty about the human health risks from municipal solid waste landfill leachate contamination to children and adults was quantified to investigate its long-term risks by using a Monte Carlo simulation framework for selected heavy metals. The Turbhe sanitary landfill of Navi Mumbai, India, which was commissioned in the recent past, was selected to understand the fate and transport of heavy metals in leachate. A large residential area is located near the site, which makes the risk assessment problem both crucial and challenging. In this article, an integral approach in the form of a framework has been proposed to quantify the uncertainty that is intrinsic to human health risk estimation. A set of nonparametric cubic splines was fitted to identify the nonlinear seasonal trend in leachate quality parameters. LandSim 2.5, a landfill simulator, was used to simulate the landfill activities for various time slices, and further uncertainty in noncarcinogenic human health risk was estimated using a Monte Carlo simulation followed by univariate and multivariate sensitivity analyses.


Using data-driven rules to predict mortality in severe community acquired pneumonia.
Prediction of patient-centered outcomes in hospitals is useful for performance benchmarking, resource allocation, and guidance regarding active treatment and withdrawal of care. Yet, their use by clinicians is limited by the complexity of available tools and amount of data required. We propose to use Disjunctive Normal Forms as a novel approach to predict hospital and 90-day mortality from instance-based patient data, comprising demographic, genetic, and physiologic information in a large cohort of patients admitted with severe community acquired pneumonia. We develop two algorithms to efficiently learn Disjunctive Normal Forms, which yield easy-to-interpret rules that explicitly map data to the outcome of interest. Disjunctive Normal Forms achieve higher prediction performance quality compared to a set of state-of-the-art machine learning models, and unveils insights unavailable with standard methods. Disjunctive Normal Forms constitute an intuitive set of prediction rules that could be easily implemented to predict outcomes and guide criteria-based clinical decision making and clinical trial execution, and thus of greater practical usefulness than currently available prediction tools. The Java implementation of the tool JavaDNF will be publicly available.


Gluteus Medius Insertion Damage: A Comparison of Reconstruction and Hip Fracture Nails.
This study assessed damage to the gluteus medius tendon insertion when performing trochanteric nailing with either a reconstruction nail or a cephalomedullary nail. Ten cadavers were randomized to receive proximal reaming for either a reconstruction nail or cephalomedullary nail; the contralateral hip served as an internal control. One specimen was found to have a displaced femoral neck fracture and was excluded from data analysis. Reconstruction nailing led to tendon damage in 4 of 9 hips, compared to 8 of 9 with hip fracture nailing (p = 0.29). In the reconstruction nail group, the average amount of tendon damaged was 3% (range 0-10%), while in the hip fracture nail group, the average was 15% (range 0-20.3%) (p = 0.0003). Open reaming for placement of a reconstruction nail caused less gluteus medius tendon damage when compared to open reaming for placement of a hip fracture nail. (Journal of Surgical Orthopaedic Advances 29(2):77-80, 2020).


Diffusion-weighted and perfusion-weighted magnetic resonance imaging of the prostate gland of healthy adult dogs.
To describe diffusion and perfusion characteristics of the prostate gland of healthy sexually intact adult dogs as determined by use of diffusion-weighted and perfusion-weighted MRI. 12 healthy sexually intact adult Beagles. Ultrasonography of the prostate gland was performed. Subsequently, each dog was anesthetized, and morphological, diffusion-weighted, and perfusion-weighted MRI of the caudal aspect of the abdomen was performed. The apparent diffusion coefficient was calculated for the prostate gland parenchyma in diffusion-weighted MRI images in the central ventral and peripheral dorsal areas. Perfusion variables were examined in multiple regions of interest (ROIs) in the ventral and dorsal areas of the prostate gland and in the gluteal musculature. Signal intensity was determined, and a time-intensity curve was generated for each ROI. Results of ultrasonographic examination of the prostate gland revealed no abnormalities for any dog. Median apparent diffusion coefficient of the prostate gland was 1.51 × 10-3 mm2/s (range, 1.04 × 10-3 mm2/s to 1.86 × 10-3 mm2/s). Perfusion-weighted MRI variables for the ROIs differed between the prostate gland parenchyma and gluteal musculature. Results provided baseline information about diffusion and perfusion characteristics of the prostate gland in healthy sexually intact adult dogs. Additional studies with dogs of various ages and breeds, with and without abnormalities of the prostate gland, will be necessary to validate these findings and investigate clinical applications.


Quantitative Measurements of Breast Density Using Magnetic Resonance Imaging: A Systematic Review and Meta-Analysis.
Breast density, a measure of dense fibroglandular tissue relative to non-dense fatty tissue, is confirmed as an independent risk factor of breast cancer. Although there has been an increasing interest in the quantitative assessment of breast density, no research has investigated the optimal technical approach of breast MRI in this aspect. Therefore, we performed a systematic review and meta-analysis to analyze the current studies on quantitative assessment of breast density using MRI and to determine the most appropriate technical/operational protocol. Databases (PubMed, EMBASE, ScienceDirect, and Web of Science) were searched systematically for eligible studies. Single arm meta-analysis was conducted to determine quantitative values of MRI in breast density assessments. Combined means with their 95% confidence interval (CI) were calculated using a fixed-effect model. In addition, subgroup meta-analyses were performed with stratification by breast density segmentation/measurement method. Furthermore, alternative groupings based on statistical similarities were identified via a cluster analysis employing study means and standard deviations in a Nearest Neighbor/Single Linkage. A total of 38 studies matched the inclusion criteria for this systematic review. Twenty-one of these studies were judged to be eligible for meta-analysis. The results indicated, generally, high levels of heterogeneity between study means within groups and high levels of heterogeneity between study variances within groups. The studies in two main clusters identified by the cluster analysis were also subjected to meta-analyses. The review confirmed high levels of heterogeneity within the breast density studies, considered to be due mainly to the applications of MR breast-imaging protocols and the use of breast density segmentation/measurement methods. Further research should be performed to determine the most appropriate protocol and method for quantifying breast density using MRI.


Applications of vibrational tags in biological imaging by Raman microscopy.
As a superb tool to visualize and study the spatial-temporal distribution of chemicals, Raman microscopy has made a big impact in many disciplines of science. While label-free imaging has been the prevailing strategy in Raman microscopy, recent development and applications of vibrational/Raman tags, particularly when coupled with stimulated Raman scattering (SRS) microscopy, have generated intense excitement in biomedical imaging. SRS imaging of vibrational tags has enabled researchers to study a wide range of small biomolecules with high specificity, sensitivity and multiplex capability, at a single live cell level, tissue level or even in vivo. As reviewed in this article, this platform has facilitated imaging distribution and dynamics of small molecules such as glucose, lipids, amino acids, nucleic acids, and drugs that are otherwise difficult to monitor with other means. As both the vibrational tags and Raman instrumental development progress rapidly and synergistically, we anticipate that this technique will shed light onto an even broader spectrum of biomedical problems.


Editor's Highlight: Mode of Action Analysis for Rat Hepatocellular Tumors Produced by the Synthetic Pyrethroid Momfluorothrin: Evidence for Activation of the Constitutive Androstane Receptor and Mitogenicity in Rat Hepatocytes.
High dietary levels of momfluorothrin, a nongenotoxic synthetic pyrethroid, induced hepatocellular tumors in male and female Wistar rats in a 2-year bioassay. The mode of action (MOA) for rat hepatocellular tumors was postulated to occur via activation of the constitutive androstane receptor (CAR), as momfluorothrin is a close structural analogue of the pyrethroid metofluthrin, which is known to produce rat liver tumors through a CAR-mediated MOA. To elucidate the MOA for rat hepatocellular tumor formation by momfluorothrin, this study was conducted to examine effects on key and associative events of the CAR-mediated MOA for phenobarbital based on the International Programme on Chemical Safety framework. A 2-week in vivo study in Wistar rats revealed that momfluorothrin induced CYP2B activities, increased liver weights, produced hepatocyte hypertrophy and increased hepatocyte replicative DNA synthesis. These effects correlated with the dose-response relationship for liver tumor formation and also showed reversibility upon cessation of treatment. Moreover, momfluorothrin did not increase CYP2B1/2 mRNA expression and hepatocyte replicative DNA synthesis in CAR knockout rats. Using cultured Wistar rat hepatocytes and the RNA interference technique, knockdown of CAR resulted in a suppression of induction of CYP2B1/2 mRNA levels by momfluorothrin. Alternative MOAs for liver tumor formation were excluded. A global gene expression profile analysis of the liver of male Wistar rats treated with momfluorothrin for 2 weeks also showed similarity to the prototypic CAR activator phenobarbital. Overall, these data strongly support that the postulated MOA for momfluorothrin-induced rat hepatocellular tumors as being mediated by CAR activation.


ATP activation of DNA polymerase III holoenzyme from Escherichia coli. II. Initiation complex: stoichiometry and reactivity.
DNA polymerase III holoenzyme (holenzyme) has an ATPase activity elicited only by a primed DNA template. Reaction of preformed ATP.holoenzyme complex with a primed template results in hydrolysis of the ATP bound to the holoenzyme, release of ADP and Pi, and formation of an initiation complex between holoenzyme and the primed template. Approximately two ATP molecules are hydrolyzed for each initiation complex formed, a value in keeping with the number bound in the ATP.holoenzyme complex. The possibility that the latter and the initiation complex contain two holoenzyme molecules is supported by the presence of two beta monomers in the initiation complex. Holoenzyme action in the absence of ATP resembles that of pol III (the holoenzyme core) or DNA polymerase III (holoenzyme lacking the beta subunit), with or without ATP, in sensitivity to salt and in processivity of elongation. The initiation complex formed by ATP-activated holoenzyme resists a level of KCl (150 mM) that completely inhibits nonactivated holoenzyme and the incomplete forms of the holoenzyme, and displays a processivity at least 20 times greater. Upon completing replication of available template, holoenzyme can dissociate and form an initiation complex with another primed template, provided ATP is available to reactivate the holoenzyme. By inference, no essential subunits are lost in the cycle of initiation, elongation and dissociation.


Perceived likelihood of using HIV pre-exposure prophylaxis medications among young men who have sex with men.
Pre-exposure prophylaxis (PrEP) is a new strategy for reducing the risk of HIV infection; however, questions about the likelihood of use remain. As part of an ongoing longitudinal study of YMSM, interest in PrEP use under various conditions of side-effects, dosing, and effectiveness were assessed. Participants aged 16-20 living in Chicago and the surrounding areas were recruited beginning December 2009, using a modified form of respondent driven sampling. A cross-sectional sample of 171 HIV negative YMSM interviewed approximately 6 months after initial enrollment was analyzed. This sample was somewhat interested in adopting PrEP as an HIV prevention strategy, particularly if the dosing and side-effects burden was low and the perceived benefits were high. PrEP interest was unrelated with drug use and number of sexual partners, but negatively correlated with number of unprotected anal sex acts. The scale was positively associated with intentions for use in specific risk situations.


Exposure of the thyroid to radiation during routine orthopaedic procedures.
The availability and usage of portable image intensifiers has revolutionised routine orthopaedic practice. Extensive use of fluoroscopy however may result into significant radiation exposure to operating staff. An accumulated dose of 65 microSv per procedure over long exposure has been reported to increase the risk of thyroid cancer. The present prospective study aimed at measuring the scattered dose to the thyroid using an Unfors EDD dosimeter during DHS/IMHS for fractures of the neck of the femur and IM nailing for long bone fractures. In 32 procedures, the dose of 65 microSv was exceeded 13 times; 8 times during DHS/IMHS and 5 times during IMN. The average thyroid dose was 142 microSv during IMN and 55 microSv during DHS. Only 9 of the total 223 (4%) theatre personnel were using a thyroid shield in spite of its availability. These results suggest that the thyroid is frequently exposed to potentially harmful radiation during these procedures. Strict inclusion of a thyroid shield as a part of routine radiation protection is recommended.


Cooked starchy food in hearths ca. 120 kya and 65 kya (MIS 5e and MIS 4) from Klasies River Cave, South Africa.
Plant carbohydrates currently constitute 55-80% of the modern human diet (FAO and WHO, 1997) and some of today's key global health issues are associated with excessive carbohydrate consumption. However, starch carbohydrate is still a poorly understood element of modern human diet and our past starch diet may provide insights for future research. Despite an archaeological narrative that links our early hominin ancestors to a diet that is rich in roots and tubers, there is little deep time archaeological evidence of human plant starch consumption. Geneticists hypothesise that the duplication of starch digestion genes in early Homo sapiens (∼300 kya), is an adaptive response to an increased starch diet. Here we offer the earliest evidence of identified fragments of charred starch plant tissue (parenchyma) from cave and rock shelter hearths dated to Marine Isotope Stage (MIS) 5e and MIS 4, from the Middle Stone Age (MSA) site of Klasies River main site, South Africa (34.06°S, 24.24°E).


Laboratory Mice Are Frequently Colonized with Staphylococcus aureus and Mount a Systemic Immune Response-Note of Caution for In vivo Infection Experiments.
Whether mice are an appropriate model for S. aureus infection and vaccination studies is a matter of debate, because they are not considered as natural hosts of S. aureus. We previously identified a mouse-adapted S. aureus strain, which caused infections in laboratory mice. This raised the question whether laboratory mice are commonly colonized with S. aureus and whether this might impact on infection experiments. Publicly available health reports from commercial vendors revealed that S. aureus colonization is rather frequent, with rates as high as 21% among specific-pathogen-free mice. In animal facilities, S. aureus was readily transmitted from parents to offspring, which became persistently colonized. Among 99 murine S. aureus isolates from Charles River Laboratories half belonged to the lineage CC88 (54.5%), followed by CC15, CC5, CC188, and CC8. A comparison of human and murine S. aureus isolates revealed features of host adaptation. In detail, murine strains lacked hlb-converting phages and superantigen-encoding mobile genetic elements, and were frequently ampicillin-sensitive. Moreover, murine CC88 isolates coagulated mouse plasma faster than human CC88 isolates. Importantly, S. aureus colonization clearly primed the murine immune system, inducing a systemic IgG response specific for numerous S. aureus proteins, including several vaccine candidates. Phospholipase C emerged as a promising test antigen for monitoring S. aureus colonization in laboratory mice. In conclusion, laboratory mice are natural hosts of S. aureus and therefore, could provide better infection models than previously assumed. Pre-exposure to the bacteria is a possible confounder in S. aureus infection and vaccination studies and should be monitored.


Sub-nanometer drift correction for super-resolution imaging.
Spatial resolution of conventional far-field fluorescence microscopy is limited by diffraction of light. Single-molecule localization microscopy (SMLM), such as (direct) stochastic optical reconstruction microscopy (dSTORM/STORM), and (fluorescence) photoactivation localization microscopy (fPALM/PALM), can break this barrier by localizing single emitters and reconstructing super-resolution image with much higher precision. Nevertheless, a SMLM measurement needs to record a large number of image frames and takes considerable recording time. In this process, sample drift becomes a critical problem and cannot be neglected. In this Letter, we present a sub-nanometer precision, low-cost sample drift correction method based on minimizing normalized root-mean-square error (NRMSE) between bright field images. Two optical configurations are suggested for recording bright field and fluorescence images simultaneously or alternately. The method was demonstrated on simulated data, and better than 0.3 nm drift correction precision was achieved. It was also applied on dSTORM imaging of F-actins of 3T3 cell, and the quality of reconstructed super-resolution image was improved observably. This method does not require special hardware, extra labelling or markers, and no precision decline due to photobleaching. It can be applied as an add-on for SMLM setups and achieves sub-nanometer precision drift correction for post-measurement or real time drift compensation.


Cheminformatics Analysis of Natural Product Scaffolds: Comparison of Scaffolds Produced by Animals, Plants, Fungi and Bacteria.
Natural products (NPs) have evolved over a very long natural selection process to form optimal interactions with biologically relevant macromolecules. NPs are therefore a very useful source of inspiration for the design of new drugs. In the present study we report the results of a cheminformatics analysis of a large database of NP structures focusing on their scaffolds. First, general differences between NP scaffolds and scaffolds from synthetic molecules are discussed, followed by a comparison of the properties of scaffolds produced by different types of organisms. Scaffolds produced by plants are the most complex and those produced by bacteria differ in many structural features from scaffolds produced by other organisms. The results presented here may be used as a guidance in selection of scaffolds for the design of novel NP-like bioactive structures or NP-inspired libraries.


Histopathology of the gut in rheumatic diseases.
The gastrointestinal tract regulates the trafficking of macromolecules between the environment and the host through an epithelial barrier mechanism and is an important part of the immune system controlling the equilibrium between tolerance and immunity to non-self-antigens. Various evidence indicates that intestinal inflammation occurs in patients with rheumatic diseases. In many rheumatic diseases intestinal inflammation appears to be linked to dysbiosis and possibly represents the common denominator in the pathogenesis of different rheumatic diseases. The continuative interaction between dysbiosis and the intestinal immune system may lead to the aberrant activation of immune cells that can re-circulate from the gut to the sites of extraintestinal inflammation as observed in patients with ankylosing spondylitis. The exact contribution of genetic factors in the development of intestinal inflammation in rheumatic diseases needs to be clarified.


Ocular surface squamous neoplasia among HIV-infected patients in Botswana.
Ocular surface squamous neoplasia (OSSN) is a group of ocular tumours that has been rising in incidence among HIV-infected individuals in sub-Saharan Africa. Surgical excision is the mainstay of treatment for OSSN in this region. This retrospective cohort study examined the clinical characteristics and treatment modalities used for 468 patients with OSSN from a large tertiary referral center in Gaborone, Botswana, over a 10-year period from 1998 to 2008. The estimated annual incidence of OSSN in Botswana reached a peak of 7.0 cases per 100 000 persons per year in 2004. The mean age of the patients in the study was 38 years (interquartile range 30 - 44), and 53.9% were women. Of the patients, 48.5% were known to be HIV-infected, 1.5% were HIV-uninfected, and 50.0% had unknown HIV status. Among HIV-infected patients with CD4 counts, the median CD4 count was 192 cells/µL. As initial OSSN treatment, 20.7% of patients received simple surgical excision, 70.9% received surgical excision with adjunctive beta radiation, 0.9% received evisceration, 1.3% received enucleation, and 6.2% underwent surgical removal of unknown type. The overall rate of known recurrence was 7.1%; however, among those with at least 6 months of follow-up, the recurrence rate was 24.2%. Rates of known recurrence after simple surgical excision and surgical excision with adjunctive beta-radiation were 10.3% and 5.4%, respectively. This study confirms the high incidence of OSSN among young individuals in Botswana. Further investigation is warranted to determine the most effective treatment modalities to prevent recurrence of OSSN among patients in sub-Saharan Africa.


Mapping of tyrosine hydroxylase in the alpaca (Lama pacos) brainstem and colocalization with CGRP.
The distribution of tyrosine hydroxylase (TH) in the brainstem of alpaca (Lama pacos) has been analysed using immunohistochemical methods. The following catecholaminergic cell nuclei have been detected: A1, C1, A2, C2 and area postrema in the medulla oblongata; A5, A6d, A7sc and A7d in the pons; as have several mesencephalic groups: A8, A9l, A9m, A9v, A9pc, A10, A10c, A10d and A10dc. This nuclear parcellation differs from that found in rodents, but agrees with the results reported in other members of the Artiodactyla order, such as giraffe or pig, and with the catecholaminergic distribution detected in species of other mammalian orders. Thus, these findings support the hypothesis that the animals included in the same order show the same nuclear complement in the neuromodulatory systems. In addition, it seems that other species share the same catecholaminergic groups as the alpaca, suggesting that a specific nuclear disposition was important and worth maintaining throughout evolution. Moreover, the distribution of TH has been compared with that of CGRP by double immunohistochemistry. Double-labelled neurons were very isolated and observed only in a few catecholaminergic groups: A1 and C2 in the medulla oblongata, A6d, A7sc and A7d in the pons, and A9l in the mesencephalon. However, interaction between TH and CGRP may be possible in more brainstem regions, particularly the area postrema. This interaction may prove important in the regulation of the specific cardiovascular control of alpacas given their morphological characteristics.


Genomic and metatranscriptomic analyses of Weissella koreensis reveal its metabolic and fermentative features during kimchi fermentation.
The genomic and metabolic features of Weissella koreensis, one of the major lactic acid bacteria in kimchi, were investigated through genomic, metabolic, and transcriptomic analyses for the genomes of strains KCTC 3621T, KACC 15510, and WiKim0080. W. koreensis strains were intrinsically vancomycin-resistant and harbored potential hemolysin genes that were actively transcribed although no hemolysin activity was detected. KEGG and reconstructed fermentative metabolic pathways displayed that W. koreensis strains commonly employ the heterolactic pathway to produce d-lactate, ethanol, acetate, CO2, d-sorbitol, thiamine, and folate from various carbohydrates including d-glucose, d-mannose, d-lactose, l-malate, d-xylose, l-arabinose, d-ribose, N-acetyl-glucosamine, and gluconate, and strains KCTC 3621T and WiKim0080 additionally have metabolic pathways of d-galacturonate and d-glucoronate. Phenotypic analyses showed that all strains did not ferment d-galactose, probably due to the lack of d-galactose transporting system, and strains KCTC 3621T and WiKim0080 fermented d-fructose, indicating the presence of d-fructose transporting system. Fermentative features of W. koreensis were investigated through kimchi transcriptional analysis, suggesting that W. koreensis is mainly responsible for kimchi fermentation with the production of various fermentative metabolites during late fermentation period. This was the first study to investigate the genomic and metabolic features of W. koreensis, which may provide better understandings on kimchi fermentation.


Triglycerides are negatively correlated with cognitive function in nondemented aging adults.
Vascular risk factors like hyperlipidemia may adversely affect brain function. We hypothesized that increased serum triglycerides are associated with decreased executive function and memory in nondemented elderly subjects. We also researched possible vascular mediators and white matter microstructure as assessed with diffusion tensor imaging (DTI). Participants were 251 nondemented elderly adults (54% male) with a mean age of 78 (SD = 6.4; range: 62-94) years and a mean education of 15.6 (SD = 2.9; range: 8-23) years. Fasting blood samples were used to detect serum triglyceride and low-density lipoprotein (LDL) levels along with ApoE4 status. DTI was used to determine whole brain fractional anisotropy (FA). Composite executive and memory scores were derived from item response theory. Clinical Dementia Rating (CDR) scores provided informant-based measures of daily functioning. Triglyceride levels were inversely correlated with executive function, but there was no relationship with memory. Controlling for age, gender, and education did not affect this correlation. This relationship persisted after controlling for vascular risk factors like LDL, total cholesterol, CDR and ApoE4 status. Lastly, adding whole-brain FA to the model did not affect the correlation between triglycerides and executive function. Triglyceride levels are inversely correlated with executive function in nondemented elderly adults after controlling for age, education, gender, total cholesterol, LDL, ApoE4 status, CDR, and white-matter microstructure. The fact that the effect of triglycerides on cognition was not clearly mediated by vascular risks or cerebrovascular injury raises questions about widely held assumptions of how triglycerides might impact cognition function. (PsycINFO Database Record


The potential to identify South Asians using a computerised algorithm to classify names.
Ethnic studies are limited by the lack of information on ethnic origin in data sources. This paper examines a computerised approach to identify South Asians by names. Computerised analysis of names is not an ideal solution, but it helps to solve the methodological difficulty of identifying South Asians, particularly in historical administrative datasets where self-assessed ethnicity is not possible and visual inspection is too time consuming and prone to errors. This approach, though useful, is limited to groups easily distinguishable by name and the collection of information on ethnicity should remain the aim in the long-term.


Rheumatoid arthritis associated with expanded populations of granular lymphocytes.
Two patients with classic rheumatoid arthritis developed severe neutropenia and increased numbers of large granular lymphocytes in the blood and bone marrow. These lymphocytes exhibited homogeneous surface membrane immunophenotypes of Leu5+, Leu11-, Leu4+, Leu3-, Leu2-, Leu7+ and Leu5+, Leu11+, Leu4+, Leu3-, Leu2+, Leu7-, respectively. In both patients, neutropenia was initially corrected with corticosteroid therapy; long-term improvement followed low-dose oral cyclophosphamide and methotrexate therapies. In these 2 patients and 12 previous patients with rheumatoid arthritis associated with expanded populations of immunophenotypically homogeneous large granular lymphocytes, neutropenia occurred in all 14, thrombocytopenia in 6, anemia in 7, and mild or moderate splenomegaly in 12. In contrast to Felty's syndrome, granular lymphocyte expansions in rheumatoid arthritis usually occur in older patients, may appear simultaneously with arthritis, and are usually associated with normal or elevated blood leukocyte counts. Mild hemocytopenias in these patients can often be managed with observation. Therapy with corticosteroids or immunosuppressive-cytotoxic drugs may be beneficial in more severe cases, but splenectomy is not recommended.