Backbone resonance assignments for G protein α(i3) subunit in the GDP-bound state.
Guanine-nucleotide binding proteins (G proteins) serve as molecular switches in signaling pathways, by coupling the activation of G protein-coupled receptors (GPCRs) at the cell surface to intracellular responses. In the resting state, G protein forms a heterotrimer, consisting of the G protein α subunit with GDP (Gα·GDP) and the G protein βγ subunit (Gβγ). Ligand binding to GPCRs promotes the GDP-GTP exchange on Gα, leading to the dissociation of the GTP-bound form of Gα (Gα·GTP) and Gβγ. Then, Gα·GTP and Gβγ bind to their downstream effector enzymes or ion channels and regulate their activities, leading to a variety of cellular responses. Finally, Gα hydrolyzes the bound GTP to GDP and returns to the resting state by re-associating with Gβγ. The G proteins are classified with four major families based on the amino acid sequences of Gα: i/o, s, q/11, and 12/13. Here, we established the backbone resonance assignments of human Gαi3, a member of the i/o family with a molecular weight of 41 K, in complex with GDP. The chemical shifts were compared with those of Gα(i3) in complex with a GTP-analogue, GTPγS, which we recently reported, indicating that the residues with significant chemical shift differences are mostly consistent with the regions with the structural differences between the GDP- and GTPγS-bound states, as indicated in the crystal structures. The assignments of Gα(i3)·GDP would be useful for the analyses of the dynamics of Gα(i3) and its interactions with various target molecules.


Impacts of Community-Based Natural Resource Management on Wealth, Food Security and Child Health in Tanzania.
Community-based natural resource management (CBNRM) is a major global strategy for enhancing conservation outcomes while also seeking to improve rural livelihoods; however, little evidence of socioeconomic outcomes exists. We present a national-level analysis that empirically estimates socioeconomic impacts of CBNRM across Tanzania, while systematically controlling for potential sources of bias. Specifically, we apply a difference-in-differences model to national-scale, cross-sectional data to estimate the impact of three different CBNRM governance regimes on wealth, food security and child health, considering differential impacts of CBNRM on wealthy and poor populations. We also explore whether or not longer-standing CBNRM efforts provide more benefits than recently-established CBNRM areas. Our results show significant improvements in household food security in CBNRM areas compared with non-CBNRM areas, but household wealth and health outcomes in children are generally not significantly different. No one CBNRM governance regime demonstrates consistently different welfare outcomes than the others. Wealthy households benefit more from CBNRM than poor households and CBNRM benefits appear to increase with longer periods of implementation. Perhaps evidence of CBNRM benefits is limited because CBNRM hasn't been around long enough to yield demonstrable outcomes. Nonetheless, achieving demonstrable benefits to rural populations will be crucial for CBNRM's future success in Tanzania.


Association of high resting end tidal CO2 with carotid artery thickness in women, but not men.
A previous study found high resting end tidal CO2 (PetCO2) to be an independent determinant of systolic blood pressure in women, but not men. The present study investigates the association of PetCO2 with the common carotid artery intima-media thickness (IMT) and wall-to-lumen (W/L) ratio in a sample of normotensive men and women. Resting PetCO2 of 188 healthy volunteers, including 88 men and 100 women, in the Baltimore Longitudinal Study on Aging was monitored continuously for 25 min via a respiratory gas monitor. At another session, carotid artery IMT was determined via high-resolution B-mode carotid ultrasonography. The ratio of IMT to carotid artery diameter was calculated as W/L ratio. Resting blood pressure was determined oscillometrically every 5 min for 20 min during each session. Univariate associations of PetCO2 with systolic blood pressure (SBP) (P< 001), IMT (P< 001) and W/L ratio (P< 001) were significant in women, but not men. Multiple regression analyses showed that high resting PetCO2 was a predictor of SBP (P < 01), IMT (P< 01) and W/L ratio (P< 01) in women, independent of age, body mass index and SBP. For men, age (P < 001) and SBP (P < 01) were independent predictors of carotid IMT, while age (P< 001) was the only independent predictor of W/L ratio in men. This study indicates that PetCO2 can play a role in cardiovascular structure, as well as function, in women, and that the relationship is independent of the association of PetCO2 with blood pressure.


Alteration of hormone levels in transgenic tobacco plants overexpressing the rice homeobox gene OSH1.
The rice (Oryza sativa L.) homeobox gene OSH1 causes morphological alterations when ectopically expressed in transgenic rice, Arabidopsis thaliana, and tobacco (Nicotiana tabacum L.) and is therefore believed to function as a morphological regulator gene. To determine the relationship between OSH1 expression and morphological alterations, we analyzed the changes in hormone levels in transgenic tobacco plants exhibiting abnormal morphology. Levels of the plant hormones indole-3-acetic acid, abscisic acid, gibberellin (GA), and cytokinin (zeatin and trans-zeatin [Z]) were measured in leaves of OSH1-transformed and wild-type tobacco. Altered plant morphology was found to correlate with changes in hormone levels. The more severe the alteration in phenotype of transgenic tobacco, the greater were the changes in endogenous hormone levels. Overall, GA1 and GA4 levels decreased and abscisic acid levels increased compared with wild-type plants. Moreover, in the transformants, Z (active form of cytokinin) levels were higher and the ratio of Z to Z riboside (inactive form) also increased. When GA3 was supplied to the shoot apex of transformants, internode extension was restored and normal leaf morphology was also partially restored. However, such GA3-treated plants still exhibited some morphological abnormalities compared with wild-type plants. Based on these data, we propose the hypothesis that OSH1 affects plant hormone metabolism either directly or indirectly and thereby causes changes in plant development.


[Aging through P300 in a Mexican population].
Research on aging processes have involved the study of evoked potentials. The last decades have witnessed increases in the study of the relationship between event related potentials and the brain's information processes. P300 has been widely studied to assess the neurophysiologic bases that underlie changes which take place during normal and physiologic aging settings. This study was aimed to establish normative data on the P300 component (latency and amplitude) in a Mexican population. One hundred and six (106) neurologically intact subjects, with ages ranging from 20 to 100 years were divided into seven groups. An electrophysiologic assessment using the classical paradigm to generate P300 was used. Monopolar registries referring to the auricular lobules and short circuiting in the Fz, Cz y Pz derivations while monitoring eye movements were used. ANOVA was used for analyzing the effects of age in the latency and the amplitude of both the N100 and P300 components for each one of the derivations. This analysis revealed statistically significant differences (p < 0.05) among the seven groups. The linear regression analysis showed an increase for each aging year in the 0.38 ms latency (r = 0.3804, p < 0.001) and a decrease in the 0.20 mV amplitude (r = 0.2036, p < 0.03). The normative data of the P300 component in the Mexican population studied yielded an objective reference for differential diagnosis and early detection of dementia disorders in patients belonging to a normal aging population.


Hamstring graft motion in the femoral bone tunnel when using titanium button/polyester tape fixation.
The objective of this study was to determine the relative motion of a quadruple hamstring graft within the femoral bone tunnel (graft-tunnel motion) under tensile loading. Six graft constructs were prepared from the semitendinosus and gracilis tendons of human cadavers and were fixed with a titanium button and polyester tape within a bone tunnel in a cadaveric femur. Three different lengths of polyester tape (15, 25, and 35 mm loops) were evaluated. The femur was held stationary and uniaxial tensile loads were applied to the distal end of the graft using a materials testing machine. Each construct was subjected to loading for ten cycles with upper limits of 50 N, 100 N, 200 N and 300 N. Graft-tunnel motion was then determined using the distances between reflective tape markers placed on the hamstring graft and at the entrance to the femoral bone tunnel, which were tracked with a high-resolution video system. Graft-tunnel motion was found to range from 0.7 +/- 0.2 mm to 3.3 +/- 0.2 mm, and significant increases in graft-tunnel motion were observed with increasing tensile loads (P < 0.05). Shorter tape length (15 mm) resulted in significantly less motion when compared to longer tape length (35 mm) (P < 0.05). We conclude that graft-tunnel motion is significant and should be considered when using this fixation technique. Early stress on the graft, as seen in postoperative rehabilitation exercises and athletic activities, may cause large graft-tunnel motion before graft incorporation is complete. A shorter distance between the tendon tissue and the titanium button is recommended to minimize the amount of graft-tunnel motion. Alternative fixation materials to polyester tape, or different fixation techniques, need to be developed such that graft-tunnel motion can be reduced. Further studies are needed to evaluate the effect of graft-tunnel motion on graft incorporation in the bone tunnel.


Developing and assessing cardiovascular biomarkers.
Atherosclerosis is a slow process that over time can lead to fatal events. Early identification and prediction of future risk can allow for preventive strategies to be instituted. There is an increasing interest in utilizing novel biomarkers in cardiovascular disease screening and management. These novel biomarkers may help in cardiovascular disease risk assessment and treatment monitoring, and some may be treatment targets. To be useful for risk prediction, novel biomarkers need to show a significant association with cardiovascular disease events and bring additional value in risk stratification when added to known risk prediction models. Biomarkers used for treatment monitoring need to show that they can serve as good surrogates of cardiovascular disease status. In this article, we present 3 biomarkers that are currently approved by the U.S. Food and Drug Administration for use in cardiovascular disease management and risk assessment: C-reactive protein, lipoprotein-associated phospholipase A2, and myeloperoxidase. Other new biomarkers have also been shown recently to help in cardiovascular disease risk prediction and management. In this article, we will review 2 of these new biomarkers: cardiac troponin T measured by a highly sensitive assay and brain natriuretic peptide.


Music and Tactile Stimuli during Daily Milking Affect the Welfare and Productivity of Dairy Cows.
The objective of this study was to evaluate the effects of tactile stimuli and music during daily milking on the productive, physiological, well-being, and health parameters of dairy cows. The experiment, which lasted 39 days, was conducted on a commercial farm with forty crossbred cows (age: 36 to 42 months; weight: 350 to 400 kg) distributed in a completely randomized design (2 × 2) via the following treatments: (Con)-cows not exposed to stimuli, (Tac)-cows exposed to tactile stimuli before milking, (Mus)-cows exposed to music during milking, (Tac+Mus)-cows exposed to both stimuli. In this study, classical music with a slow (75 to 107 BPM) and moderate tempo (90 to 100 BPM) was played, and tactile stimuli was provided manually using a flexible stick in the posterior region and udders of the cows. Cows not exposed to any of the stimuli had up to 41% higher residual milk quantity compared to those exposed to one of or both of the stimuli. The sound stimulus promoted an increase in milk letdown before the start of milking. Cows exposed to stimuli showed higher serotonin levels, indicating a beneficial effect on animal well-being. However, cows exposed to pre-milking tactile stimuli showed an increase in somatic cell count. Combining both techniques may have positive effects on milk productivity and well-being. However, using music alone may be more recommendable as it does not pose health risks.


Identification of a dicer homologue gene (DCL2) in Nicotiana tabacum.
Eukaryotes possess a mechanism that generates small interfering RNA (siRNA) and microRNA (miRNA) and use these to regulate gene expression at the transcriptional or post-transcriptional level. These small RNAs (21-24nt) are processed from long double-stranded RNA precursors by type III RNase enzymes, referred to as DICER or DICER-LIKE proteins (DCLs). In Arabidopsis, there are four DCL genes and their role in small RNA biogenesis and silencing has been the subject of intense study. DCL2 is less well studied than the other DCL proteins although it is known to play a role in formation of natural antisense siRNA and may be involved in transitive silencing of transgene transcripts. This study provides basic genomic information on DCL2 in the Nicotiana tabacum (NtDCL2) gene family and its probable roles in plant growth and development.


Extrachromosomal DNA in chloramphenicol resistant myxococcus strains.
The presence of extrachromosomal DNA in strains of Myxococcus xanthus and M fulvus was examined by rate-zonal centrifugation of radioactively-labelled DNA in 'cleared lysates'. All the strains examined contained extrachromosomal DNA, with the exception of M. xanthus FBt. Chloramphenicol resistance is inducible in M. xanthus FBt. A peak of extrachromosomal DNA, containing covalently closed molecules, was found in one of the induced strains, implying that induction of chloramphenicol resistance is associated with the production of a plasmid. By incubating R+ strains of Escherichia coli with myxococci, R factor-mediated chloramphenicol resistance can be introduced into the latter. Evidence of extra chromosomal DNA in a derivative of M. xanthus with chloramphenicol resistance from R factor RI. 19 unique to the chloramphenicol strain, was obtained. By using a double-labelling technique, several chloramphenicol-resistant strains of M. fulvus M were examined. Evidence for a peak, unique for the chloramphenicol-resistant strain, was found in a strain with resistance derived from the R factor, S-a, but not from comparable strains with resistance derived from R factors R57b, R1. 19 and R478.


Acute changes in serum calcium and parathyroid hormone circulating levels induced by the oral intake of five currently available calcium salts in healthy male volunteers.
Several calcium supplements are currently available and many of them are marketed without proper comparison of the bioavailability of the actual preparations. The aim of the present trial was to evaluate and compare the acute changes in serum calcium (Ca) and parathyroid hormone (PTH) levels following the oral administration of a vehicle and of five calcium salts currently prescribed in Western Europe. No significant changes in serum Ca or PTH levels were observed after administration of the vehicle. All calcium salts induced significant increases in serum Ca and decreases in serum PTH compared to baseline values. Comparison of the six response curves revealed a significantly greater increase in serum Ca and a greater decrease in serum PTH after each of the calcium salts than observed after the vehicle. However, no statistically significant differences were observed between the different calcium salts for serum Ca increments. The decrease in serum PTH observed after administration of an ossein-hydroxyapatite complex was significantly less important than after the four other calcium salts, even if statistically different than after vehicle. When assessing the area under the curve (AUC) of PTH values, we observed that calcium carbonate and citrate induce a significantly greater decrease in serum PTH than the other calcium salts which are, however, statistically more active than the vehicle. Serum PTH is decreased under the lower limit of the normal range (10 pg/ml), between t60 and t120 for calcium carbonate and citrate and between t60 and t90 for calcium gluconolactate while the mean PTH values remain within the normal range throughout the study with calcium pidolate, the ossein-hydroxyapatite complex and the vehicle. In conclusion, all calcium preparations significantly increase serum calcium and decrease serum parathormone, compared to what is observed after oral intake of a vehicle. However, significant differences in suppression of parathormone are observed between the different calcium preparations and might be of importance for their clinical use.


[Bilateral facial paralysis and diabetes: report of a case].
The author presents the case of a 68-year-old white woman who presented bilateral facial paralysis in the course of an undiagnosed diabetes mellitus. The paralysis remained stable for four years and as soon as the diabetes was treated, her symptoms improved.


The immune checkpoint B7-H3 (CD276) regulates adipocyte progenitor metabolism and obesity development.
The immune checkpoint B7-H3 (CD276) is a member of the B7 family that has been studied in the tumor microenvironment and immunotherapy, but its potential role in metabolism remains largely unknown. Here, we show that B7-H3 is highly expressed in mouse and human adipose tissue at steady state, with the highest levels in adipocyte progenitor cells. B7-H3 is rapidly down-regulated upon the initiation of adipocyte differentiation. Combined RNA sequencing and metabolic studies reveal that B7-H3 stimulates glycolytic and mitochondrial activity of adipocyte progenitors. Loss of B7-H3 in progenitors results in impaired oxidative metabolism program and increased lipid accumulation in derived adipocytes. Consistent with these observations, mice knocked out for B7-H3 develop spontaneous obesity, metabolic dysfunction, and adipose tissue inflammation. Our results reveal an unexpected metabolic role for B7-H3 in adipose tissue and open potential new avenues for the treatment of metabolic diseases by targeting the B7-H3 pathway.


B-cell chronic lymphocytic leukemia: a bird of a different feather.
To review the recent major advances in the molecular and cell biology of B-cell chronic lymphocytic leukemia (B-CLL). We analyzed the nature of malignant B-CLL B cells and their interactions with the microenvironment. B-CLL is a malignancy of a mantle zone-based subpopulation of anergic, self-reactive, activated CD5+ B cells devoted to the production of polyreactive natural autoantibodies. It is the quintessential example of a human malignancy that primarily involves defects in the induction of programmed cell death. An abnormal karyotype is observed in about 50% of patients with B-CLL. Patients with 13q14 abnormalities show heavy somatic mutation and have a benign disease. Trisomy 12 is associated with unmutated VH genes, atypical cellular morphology, and progressive disease. Extended cell survival is further shielded by a kinetic refractoriness likely promoted by abnormalities of the B-cell antigen receptor complex and favored by some cytokines that highlight a reciprocal dialog between malignant B and T cells. Because the tumor cells act as the major accessory cells, the accumulating malignant B-cell population per se is a hurdle to the production of normal antibodies and leads to a progressive and severe hypogammaglobulinemia. Conceivably, in the presence of certain immunoglobulin genes and when the T-cell control becomes deficient, activated malignant B cells may become able to present self-antigens and drive residual normal B cells to produce polyclonal autoantibodies restricted to self-antigens expressed only by blood cells and cause autoimmune cytopenias. The distinctiveness of B-CLL B cells explains why B-CLL is different from other B-cell tumors and accounts for the development of immune deficiency and autoimmunity.


Progesterone inhibits endometrial cancer invasiveness by inhibiting the TGFβ pathway.
Increased expression of TGFβ isoforms in human endometrial cancer correlates with decreased survival and poor prognosis. Progesterone has been shown to exert a chemoprotective effect against endometrial cancer, and previous animal models have suggested that these effects are accompanied by changes in TGFβ. The goal of this study was to characterize the effect of progesterone on TGFβ signaling pathway components and on TGFβ-induced protumorigenic activities in endometrial cancer cell lines. Progesterone significantly decreased expression of three TGFβ isoforms at 72 hours after treatment except for TGFβ2 in HEC-1B and TGFβ3 in Ishikawa cells. Progesterone treatment for 120 hours attenuated expression of the three isoforms in all cell lines. Progesterone exposure for 72 hours reduced expression of TGFβ receptors in HEC-1B cells and all but TGFβR1 in Ishikawa cells. Progesterone reduced TGFβR3 expression in RL-95 cells at 72 hours, but TGFβR1 and βR2 expression levels were not affected by progesterone at any time point. SMAD2/3 and pSMAD2/3 were substantially reduced at 72 hours in all cell lines. SMAD4 expression was reduced in RL-95 cells at 24 hours and in HEC-1B and Ishikawa cells at 72 hours following progesterone treatment. Furthermore, progesterone effectively inhibited basal and TGFβ1-induced cancer cell viability and invasion, which was accompanied by increased E-cadherin and decreased vimentin expression. An inhibitor of TGFβRI blocked TGFβ1-induced effects on cell viability and invasion and attenuated antitumor effects of progesterone. These results suggest that downregulation of TGFβ signaling is a key mechanism underlying progesterone inhibition of endometrial cancer growth.


XOmiVAE: an interpretable deep learning model for cancer classification using high-dimensional omics data.
The lack of explainability is one of the most prominent disadvantages of deep learning applications in omics. This 'black box' problem can undermine the credibility and limit the practical implementation of biomedical deep learning models. Here we present XOmiVAE, a variational autoencoder (VAE)-based interpretable deep learning model for cancer classification using high-dimensional omics data. XOmiVAE is capable of revealing the contribution of each gene and latent dimension for each classification prediction and the correlation between each gene and each latent dimension. It is also demonstrated that XOmiVAE can explain not only the supervised classification but also the unsupervised clustering results from the deep learning network. To the best of our knowledge, XOmiVAE is one of the first activation level-based interpretable deep learning models explaining novel clusters generated by VAE. The explainable results generated by XOmiVAE were validated by both the performance of downstream tasks and the biomedical knowledge. In our experiments, XOmiVAE explanations of deep learning-based cancer classification and clustering aligned with current domain knowledge including biological annotation and academic literature, which shows great potential for novel biomedical knowledge discovery from deep learning models.


Steroid-dependent states and adrenal insufficiency. Fluid and electrolyte disturbances.
Patients on steroid hormone therapy for chronic adrenal insufficiency experience stable fluid and electrolyte balance. The patient with acute adrenal insufficiency, however, experiences a fluid and electrolyte balance crisis that develops over a few short hours. Nurses in all health care settings need to be alert for patients at risk for crisis and the characteristic symptoms of acute adrenal insufficiency. Nursing interventions aimed at correcting fluid and electrolyte imbalance and providing patient education for prevention of further crisis is critical.


Long peripheral catheters in neonates: filling the gap between short peripheral catheters and epicutaneous-caval catheters?
Non-critically ill neonates at times require venous access to provide peripherally compatible infusions for a limited period (more than 3 days). In such a situation, short peripheral cannulas are not appropriate as their average duration is about 2 days, while-on the other hand-epicutaneous-caval catheters may be too invasive. In these patients, insertion of long peripheral cannulas may be an effective option. In this observational retrospective study, we revised all "long" peripheral catheters (4 and 6 cm long) inserted by direct Seldinger technique in our neonatal intensive care unit when peripheral venous access was required for more than 3 days. We inserted 52 2Fr polyurethane catheters, either 4 cm long (n = 25) or 6 cm long (n = 27) in 52 patients. Mean dwelling time was 4.17 days (range 1-12). Most devices were inserted in the cephalic vein (n = 18, 35%), and the rest in the saphenous vein (n = 11, 21%) and other superficial veins. There was no significant correlation between the duration of the device and type of infusion (p = 0.40). The main complications were infiltration (n = 16, 31%) and phlebitis (n = 8, 15%). The rate of removal due to complications was significantly higher (p < 0.01) in neonates with bodyweight <2000 g at the time of insertion. In our experience, 2 Fr 4-6 cm long peripheral catheters may be a valid option for neonates requiring peripherally compatible infusions for more than 3 days. The limits of this study are the necessity of training in the technique of insertion and the small size of our sample. The longest dwell was observed in neonates weighing >2000 g at the time of LPC insertion.


Acute thanol effect on chemotaxis and other components of host defense.
The effect of alcohol on granulocyte chemotaxis was studies with a radioactive assaysystem. Chemotaxis was inhibited in vitro by concentrations of alcohol above 400 mg. per cent when present during all steps in the assay, but levels above 800 mg. per cent required for inhibition when alcohol was present only during the granulocyte incubation. No inhibition of chemotactic factor generation was found with alcohol concentration up to 1,500 mg. per cent. Cells and serum exposed to alcohol in vivo by acute intxication of donors demonstrated normal in vitro chemotactic performance, even when the assay itself was carried out in medium containing 200 mg. of alcohol. Thestudies do not exclude alcohol's in vivo induction of an inhibitor which must remain present during chemotaxis for inhibition; nor would they have detected an impairment of chemotaxis occurring after the peak blood alcohol concentration. The intoxicated volunteer subjects were also evaluated for changes in delayed hypersensitivity, serum complement concentration, granulocyte hexose monophosphate shunt activity, and circulating whiteblood cell counts; no consistent changes were seen.


New resources for the Drosophila 4th chromosome: FRT101F enabled mitotic clones and Bloom syndrome helicase enabled meiotic recombination.
Genes on the long arm of the Drosophila melanogaster 4th chromosome are difficult to study because the chromosome lacks mitotic and meiotic recombination. Without recombination numerous standard methods of genetic analysis are impossible. Here, we report new resources for the 4th. For mitotic recombination, we generated a chromosome with an FRT very near the centromere in 101F and a derivative that carries FRT101F with a distal ubiquitously expressed GAL80 transgene. This pair of chromosomes enables both unmarked and MARCM clones. For meiotic recombination, we demonstrate that a Bloom syndrome helicase and recombination defective double mutant genotype can create recombinant 4th chromosomes via female meiosis. All strains will be available to the community via the Bloomington Drosophila Stock Center. Additional resources for studies of the 4th are in preparation and will also be made available. The goal of the 4th Chromosome Resource Project is to accelerate the genetic analysis of protein-coding genes on the 4th, including the 44 genes with no demonstrated function. Studies of these previously inaccessible but largely conserved genes will close longstanding gaps in our knowledge of metazoan development and physiology.


Combination therapy with intra-articular injection of mesenchymal stem cells and articulated joint distraction for repair of a chronic osteochondral defect in the rabbit.
The present study investigated intra-articular injection of bone-marrow-derived mesenchymal stem cells (MSCs) combined with articulated joint distraction as treatment for osteochondral defects. Large osteochondral defects were created in the weight-bearing area of the medial femoral condyle in rabbit knees. Four weeks after defect creation, rabbits were divided into six groups: control group, MSC group, distraction group, distraction + MSC group, temporary distraction group, and temporary distraction + MSC group. Groups with MSC received intra-articular injection of MSCs. Groups with distraction underwent articulated distraction arthroplasty. Groups with temporary distraction discontinued the distraction after 4 weeks. The rabbits were euthanized at 4, 8, and 12 weeks after treatment except temporary distraction groups which were euthanized at only 12 weeks. Histological scores in the distraction + MSC group were significantly better than in the control, MSC group or distraction group at 4 and 8 weeks, but showed no further improvement. At 12 weeks, the temporary distraction + MSC group showed the best results, demonstrating hyaline cartilage repair with regeneration of the osteochondral junction. In conclusion, joint distraction with intra-articular injection of MSCs promotes early cartilage repair, and compressive loading of the repair tissue after temporary distraction stimulates articular cartilage regeneration.


The politics of engagement between Islam and the secular state: ambivalences of 'civil society'.
The paper reveals contemporary transformations of the interaction between Islam and secular states from opposition to engagement. In-depth ethnographic evidence challenges the predominant juxtaposition of Islam against the secular state. Following micro-sites of interaction between the Gülen movement and the state from Turkey to Kazakhstan, my fieldwork revealed a continuum of engagements between them. The paper analyses the engagements ranging from contestation and negotiation to co-operation. The case illustrates the extent to which scholarly interest in opposition and clash has left a wide-ranging variety of state-Islam interaction understudied with regard to civil society. It also reveals the conditions under which effective Islamic horizontal organizations have provided the platforms of vertical engagements with the secular states. The major argument of the paper is that both civil and uncivil outcomes in the Muslim world are primarily shaped by the nature of state-Islam interaction. The evidence suggests that the key to understanding the relationship between Islam and civil society is the state.


Glycosaminoglycan sulfation determines the biochemical properties of prion protein aggregates.
Prion diseases are transmissible neurodegenerative disorders associated with the conversion of the cellular prion protein, PrP(C), to a misfolded isoform called PrP(Sc). Although PrP(Sc) is a necessary component of the infectious prion, additional factors, or cofactors, have been shown to contribute to the efficient formation of transmissible PrP(Sc). Glycosaminoglycans (GAGs) are attractive cofactor candidates as they can be found associated with PrP(Sc) deposits, have been shown to enhance PrP misfolding in vitro, are found in the same cellular compartments as PrP(C) and have been shown to be disease modifying in vivo. Here we investigated the effects of the sulfated GAGs, heparin and heparan sulfate (HS), on disease associated misfolding of full-length recombinant PrP. More specifically, the degree of sulfation of these molecules was investigated for its role in modulating the disease-associated characteristics of PrP. Both heparin and HS induced a β-sheet conformation in recombinant PrP that was associated with the formation of aggregated species; however, the biochemical properties of the aggregates formed in the presence of heparin or HS varied in solubility and protease resistance. Furthermore, these properties could be modified by changes in GAG sulfation, indicating that subtle changes in the properties of prion disease cofactors could initiate disease associated misfolding.


A microbial fuel cell equipped with a biocathode for organic removal and denitrification.
Microbial fuel cells (MFCs) are a promising anaerobic technology but they are limited by the high cost of the catalyst used at the cathode (typically platinum). In this study, we designed a novel type of two-chambered MFC wherein an autoheterotrophic denitrifying biofilm replaced the costly catalyst on the cathode surface. Micro-organisms performed denitrification by using electrons supplied by bacteria oxidizing domestic wastewater and acetate as substrates in the anode chamber. This two-chambered MFC equipped with a biocathode generated during more than 1.5 month up to 9.4 mW m(-2) of anode surface or 0.19 W m(-3) of anode chamber volume, while removing over 65% of COD, 84% of total nitrogen and nearly 30% of suspended solids with domestic wastewater as a substrate, and nearly 95% of acetate in the subsequent experiments.


Inter-observer Variability Analysis of Automatic Lung Delineation in Normal and Disease Patients.
Human interaction has become almost mandatory for an automated medical system wishing to be accepted by clinical regulatory agencies such as Food and Drug Administration. Since this interaction causes variability in the gathered data, the inter-observer and intra-observer variability must be analyzed in order to validate the accuracy of the system. This study focuses on the variability from different observers that interact with an automated lung delineation system that relies on human interaction in the form of delineation of the lung borders. The database consists of High Resolution Computed Tomography (HRCT): 15 normal and 81 diseased patients' images taken retrospectively at five levels per patient. Three observers manually delineated the lungs borders independently and using software called ImgTracer™ (AtheroPoint™, Roseville, CA, USA) to delineate the lung boundaries in all five levels of 3-D lung volume. The three observers consisted of Observer-1: lesser experienced novice tracer who is a resident in radiology under the guidance of radiologist, whereas Observer-2 and Observer-3 are lung image scientists trained by lung radiologist and biomedical imaging scientist and experts. The inter-observer variability can be shown by comparing each observer's tracings to the automated delineation and also by comparing each manual tracing of the observers with one another. The normality of the tracings was tested using D'Agostino-Pearson test and all observers tracings showed a normal P-value higher than 0.05. The analysis of variance (ANOVA) test between three observers and automated showed a P-value higher than 0.89 and 0.81 for the right lung (RL) and left lung (LL), respectively. The performance of the automated system was evaluated using Dice Similarity Coefficient (DSC), Jaccard Index (JI) and Hausdorff (HD) Distance measures. Although, Observer-1 has lesser experience compared to Obsever-2 and Obsever-3, the Observer Deterioration Factor (ODF) shows that Observer-1 has less than 10% difference compared to the other two, which is under acceptable range as per our analysis. To compare between observers, this study used regression plots, Bland-Altman plots, two tailed T-test, Mann-Whiney, Chi-Squared tests which showed the following P-values for RL and LL: (i) Observer-1 and Observer-3 were: 0.55, 0.48, 0.29 for RL and 0.55, 0.59, 0.29 for LL; (ii) Observer-1 and Observer-2 were: 0.57, 0.50, 0.29 for RL and 0.54, 0.59, 0.29 for LL; (iii) Observer-2 and Observer-3 were: 0.98, 0.99, 0.29 for RL and 0.99, 0.99, 0.29 for LL. Further, CC and R-squared coefficients were computed between observers which came out to be 0.9 for RL and LL. All three observers however manage to show the feature that diseased lungs are smaller than normal lungs in terms of area.


A novel hypothesis for COVID-19 pathogenesis: Retinol depletion and retinoid signaling disorder.
The SARS-CoV-2 virus has caused a worldwide COVID-19 pandemic. In less than a year and a half, more than 200 million people have been infected and more than four million have died. Despite some improvement in the treatment strategies, no definitive treatment protocol has been developed. The pathogenesis of the disease has not been clearly elucidated yet. A clear understanding of its pathogenesis will help develop effective vaccines and drugs. The immunopathogenesis of COVID-19 is characteristic with acute respiratory distress syndrome and multiorgan involvement with impaired Type I interferon response and hyperinflammation. The destructive systemic effects of COVID-19 cannot be explained simply by the viral tropism through the ACE2 and TMPRSS2 receptors. In addition, the recently identified mutations cannot fully explain the defect in all cases of Type I interferon synthesis. We hypothesize that retinol depletion and resulting impaired retinoid signaling play a central role in the COVID-19 pathogenesis that is characteristic for dysregulated immune system, defect in Type I interferon synthesis, severe inflammatory process, and destructive systemic multiorgan involvement. Viral RNA recognition mechanism through RIG-I receptors can quickly consume a large amount of the body's retinoid reserve, which causes the retinol levels to fall below the normal serum levels. This causes retinoid insufficiency and impaired retinoid signaling, which leads to interruption in Type I interferon synthesis and an excessive inflammation. Therefore, reconstitution of the retinoid signaling may prove to be a valid strategy for management of COVID-19 as well for some other chronic, degenerative, inflammatory, and autoimmune diseases.


The molecular basis of the prevention of Alzheimer's disease through healthy nutrition.
The Alzheimer's disease (AD) brain shows numerous pathological phenomena, including amyloid plaques, neurofibrillary tangles, elevated levels of advanced glycation endproducts and their receptor, oxidative damage and inflammation, all of which contribute to neurodegeneration. In this review, we consider these neuropathologies associated with AD and propose that inflammation and oxidative stress play major pathogenic roles throughout disease progression. It is believed that oxidative stress and inflammation not only play major roles early in the disease, but that they act in a reinforcing cycle, amplifying their damaging effects. Therefore, epidemiological studies indicate that anti-inflammatory, antioxidant and neuroprotective agents including those from medicinal plants and health promoting foods may protect against AD, possibly through scavenging of reactive oxygen species, cytokine downregulation and strengthening the neurons antioxidant defense. This concept is further supported by evidence that certain diets (such as a Mediterranean diet) have been associated with a lower incidence of AD. This review highlights specific foods and diets thought to lower the risk of developing AD and discusses the potential of healthy nutrition in disease prevention.


In silico characterization of resonance energy transfer for disk-shaped membrane domains.
Förster resonance energy transfer (FRET) has become an important tool to study the submicrometer distribution of proteins and lipids in membranes. Although resolving the two-dimensional distribution of fluorophores from FRET is generally underdetermined, a forward approach can be used to determine characteristic FRET "signatures" for interesting classes of microdomain organizations. As a first step toward this goal, we use a stochastic Monte Carlo approach to characterize FRET in the case of molecules randomly distributed within disk-shaped domains. We find that when donors and acceptors are confined within domains, FRET depends very generally on the density of acceptors within domains. An implication of this result is that two domain populations with the same acceptor density cannot be distinguished by this FRET approach even if the domains have different diameters or different numbers of molecules. In contrast, both the domain diameter and molecule number can be resolved by combining this approach with a segregation approach that measures FRET between donors confined in domains and acceptors localized outside domains. These findings delimit where the inverse problem is tractable for this class of distributions and reframe ways FRET can be used to characterize the structure of microdomains such as lipid rafts.


Predictive value of CD4 lymphocyte numbers for the development of opportunistic infections and malignancies in HIV-infected persons.
Infection with the human immunodeficiency virus (HIV) results in progressive depletion of the CD4 subset T-lymphocytes and the development of opportunistic infections and certain malignancies. Charts were reviewed for 185 HIV-infected individuals with 265 AIDS-defining illnesses (ADIs) who had T-lymphocyte subset analyses performed within 2 months prior to or 1 month following the diagnosis. Also included were 22 HIV-infected patients with oral candidiasis and 20 with asymptomatic infection. Significant differences in CD4 lymphocyte numbers were observed between the 12 ADIs, oral candidiasis, and asymptomatic infection, allowing them to be grouped into five general categories, based on mean CD4 count: (a) asymptomatic infection, CD4 greater than 500/mm3; (b) oral candidiasis and tuberculosis, range 250-500/mm3; (c) Kaposi's sarcoma, lymphoma, and cryptosporidiosis, range 150-200/mm3; (d) Pneumocystis carinii pneumonitis, disseminated Mycobacterium avium complex, herpes simplex ulceration, toxoplasmosis, cryptococcosis, and esophageal candidiasis, range 75-125/mm3; (e) cytomegalovirus retinitis, less than 50/mm3. Our data concur with clinical impressions and provide a basis for interim treatment and prophylaxis recommendations.


The foxtail millet (Setaria italica) terpene synthase gene family.
Terpenoid metabolism plays vital roles in stress defense and the environmental adaptation of monocot crops. Here, we describe the identification of the terpene synthase (TPS) gene family of the panicoid food and bioenergy model crop foxtail millet (Setaria italica). The diploid S. italica genome contains 32 TPS genes, 17 of which were biochemically characterized in this study. Unlike other thus far investigated grasses, S. italica contains TPSs producing all three ent-, (+)- and syn-copalyl pyrophosphate stereoisomers that naturally occur as central building blocks in the biosynthesis of distinct monocot diterpenoids. Conversion of these intermediates by the promiscuous TPS SiTPS8 yielded different diterpenoid scaffolds. Additionally, a cytochrome P450 monooxygenase (CYP99A17), which genomically clustered with SiTPS8, catalyzes the C19 hydroxylation of SiTPS8 products to generate the corresponding diterpene alcohols. The presence of syntenic orthologs to about 19% of the S. italica TPSs in related grasses supports a common ancestry of selected pathway branches. Among the identified enzyme products, abietadien-19-ol, syn-pimara-7,15-dien-19-ol and germacrene-d-4-ol were detectable in planta, and gene expression analysis of the biosynthetic TPSs showed distinct and, albeit moderately, inducible expression patterns in response to biotic and abiotic stress. In vitro growth-inhibiting activity of abietadien-19-ol and syn-pimara-7,15-dien-19-ol against Fusarium verticillioides and Fusarium subglutinans may indicate pathogen defensive functions, whereas the low antifungal efficacy of tested sesquiterpenoids supports other bioactivities. Together, these findings expand the known chemical space of monocot terpenoid metabolism to enable further investigations of terpenoid-mediated stress resilience in these agriculturally important species.


Targeted gene silencing by RNA interference in Chlamydomonas.
Small RNA-guided gene silencing is an evolutionarily conserved process that operates by a variety of molecular mechanisms and plays an essential role in developmental pathways and defense responses against genomic parasites in eukaryotes. Double-stranded RNA (dsRNA) triggered posttranscriptional gene silencing, termed RNA interference (RNAi), is also becoming a powerful tool for reverse genetics studies. Stable RNAi, induced by the expression of long dsRNAs or duplex small RNAs from genome-integrated transgenes, has been achieved in multiple organisms, including the green alga Chlamydomonas reinhardtii. However, the level of gene repression is often quite variable, depending on the type of construct, transgene copy number, site of integration, and target gene. Moreover, unintended transcripts partly complementary to a trigger dsRNA can also be silenced, making difficult the interpretation of observed phenotypes. To obviate some of these problems we have developed a tandem inverted repeat system that consistently induces cosilencing of a gene with a selectable RNAi-induced phenotype (encoding tryptophan synthase beta-subunit) and any other (nonessential) gene of interest. In addition, to circumvent off-target effects, for each tested gene, RNAi lines are generated with at least two transgenes, homologous to distinct and nonoverlapping sequences of the target transcript. A common phenotype among these independent RNAi strains is expected to result from suppression of expression of the gene of interest. We demonstrate this approach for the characterization of a gene of unknown function in Chlamydomonas, encoding a predicted exoribonuclease with weak similarity to 3'hExo/ERI-1.


One-pot solution synthesis of shape-controlled copper selenide nanostructures and their potential applications in photocatalysis and photothermal therapy.
Developing a facile and reliable method for the fabrication of transition metal chalcogenides is a vital and endless pursuit of scientific and technological disciplines. In this work, we develop a one-pot solution approach to obtain copper selenide nanostructures with different morphologies and crystal structures (Cu2Se nanoparticles, CuSe nanoplates and CuSe2 nanosheets). In comparison to previously reported methods, our method did not use expensive and very toxic raw materials. After detailed studies of reaction conditions, including temperature, reaction time, and feeding amount of surfactants and precursors, we found that the feeding ratio of precursors played a key role in the crystal structures and morphologies of the final products. Moreover, as a proof-of-concept study, the potential applications of the as-prepared copper selenide nanostructures in the photocatalytic discoloration of aqueous methylene blue (MB) under visible light irradiation and near-infrared (NIR) light induced photothermal therapy for cancer treatment were investigated. Encouraged by their strong photocatalytic activities and high photothermal conversion efficiencies (calculated to be 51.0%, 49.5% and 48.9% for Cu2Se nanoparticles, CuSe nanoplates and CuSe2 nanosheets, respectively), we believe that copper selenide nanostructures fabricated from the one-pot solution approach developed in this work would be promising candidates for a wide variety of emerging applications.


Assessment of knowledge of oral pathologists and postgraduate students on safe laboratory practices during the COVID-19 pandemic.
Oral pathologists are involved in laboratory diagnosis and receive specimens of biopsy, oral cytologic smears and samples for hematology, biochemistry and microbiology and thus are at a risk for laboratory-acquired infections, which may occur inadvertently and can be considered as an occupational hazard. This study was conducted during the coronavirus disease (COVID-19) pandemic to assess the knowledge of oral pathologists and oral pathology postgraduate students regarding the safe laboratory practices, procedures and guidelines. The study was a cross-sectional online questionnaire-based study. Questions were framed to evaluate the knowledge on specimen/sample collection, its handling, disposal and protective measures for laboratory personnel. The study population comprised oral pathologists and oral pathology postgraduate students of various dental colleges in India. A Google Doc format was used to create an effective computerized questionnaire system, and the link was forwarded to around 500 participants. The survey was fielded online between August 29, 2020, and September 5, 2020. Three hundred and twelve responses were received, which were downloaded as spreadsheets for subsequent data analysis. Mean value of right answers for the oral pathologists was 8.11 ± 2.02 and for postgraduate students was 7.38 ± 1.75. When the knowledge score between the two groups was compared, a statistically significant difference was found. This article compares and highlights the knowledge lacunae among the oral pathologists and oral pathologists postgraduate students in relation to guidelines to be followed for safety in the laboratory. Adhering to these biosafety regulations reduces occupational health hazards and enhances a safe working environment in the laboratory.


Appropriate and Inappropriate Implantable Cardioverter Defibrillators Therapies in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia Patients.
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiomyopathy characterized histologically by the replacement of ventricular myocardium with fibrous and fatty tissue, and clinically by ventricular tachycardia arrhythmias primarily of right ventricular (RV) origin. Implantable cardioverter defibrillator (ICD) is the only proven therapy to reduce mortality in ARVC/D patients. However, it has the risk of inappropriate anti-tachycardia pacing (ATP) or shocks. This study aimed to assess the occurrence of appropriate and inappropriate ICD therapies in ARVC/D patients who underwent ICD implantation in a single Cardiac Centre. Retrospective analysis of the data of patients with the diagnosis of ARVC/D based on the 2010 revised Task Force Criteria, who underwent ICD implantation in the Heart Centre, at King Faisal Specialist Hospital and Research Center (KFSH&RC), Riyadh between January 1997 and May 2016. The clinical data and information about appropriate and inappropriate ICD therapies were obtained from medical records with the review of the available intra-cardiac electrograms (EGMs). Twenty-two ARVC/D patients with ICD implantation (20 males (91%), mean age at ICD implantation: 32 ± 14 years). ICD was implanted for secondary prevention of sudden cardiac death (SCD) in 15 patients (68.2%), and for primary prevention in 7 patients (31.8%). At mean follow-up of 9.4 ± 4.8 years, 11 patients (50%) had appropriate ICD therapies, and five patients (22.7%) had inappropriate ICD therapies. Out of 950 ICD therapies, 865 (91%) were appropriate (586 episodes of VT/VF treated with ATP (61.3%), and 279 episodes treated with shocks (29.37%)) and 85 (9.4%) were inappropriate (45 episodes treated with ATP (4.73%), and 40 treated with shocks (4.21%)). ARVC/D patients are at risk of VT/VF arrhythmias. ICD therapy is the only proven life-saving therapy in those patients. Most of ICD therapies in our patient's population are appropriate, and ATP therapy is effective in terminating most of VT episodes. Although we do not have any patient with subcutaneous ICD, the high success rate of ATP suggests that transvenous ICD would be more appropriate in ARVC/D patients.


Knowledge, opinions and attitudes of Italian mothers towards HPV vaccination and Pap test.
This study evaluated the knowledge and attitudes of Italian mothers - whose daughters had been vaccinated in 2012 - towards primary (anti-HPV vaccination) and secondary (Pap test screening) cervical cancer prevention, as well as sources of information and mother-daughter communication on health issues. The survey - part of a multicenter study carried out in 4 Italian cities (Ferrara, Rome, Cassino and Palermo) - was conducted through self-administered questionnaires. The first univariate analysis evaluated differences between mothers of under-18s and over-18s relative to knowledge and attitudes on HPV vaccination and Pap test. The second univariate analysis evaluated differences between the 2 groups of mothers and possible geographical variations regarding the sources of information on HPV and Pap test. The sample proved knowledgeable about the correlation between HPV and cervical cancer (>85%) but less aware of other HPV-related diseases. HPV vaccination should be administered before first sexual intercourse according to mothers of over-18s, and to 14- to 17-year-olds according to mothers of under-18s. Up to 88% of mothers of under-18s and 80% of mothers of over-18s declared that the vaccine should be given free of charge. More mothers of under-18s consulted a general practitioner (GP) or gynecologist before deciding to vaccinate their daughters. Mothers of under-18s received information on HPV vaccination mainly from GPs and gynecologists, while mothers of over-18s were informed through TV and books/journals. Over 80% of the sample declared satisfaction with the information received from their gynecologist during the Pap test. The findings provide useful information for the development of effective public health interventions that may help improve acceptance of HPV vaccination among mothers.


The energetics of lymph formation.
A very important unanswered problem is the source of the energy required for formation of lymph. The most widely held theory has been that fluid filters from the capillaries, flows through the tissues, and then enters the lymphatic as a result of a continuous positive pressure gradient from the blood capillary to the lymphatic capillary. However, this fails to account for the negative pressures that have been measured by implanted perforated capsules and by the wick technique, both of which suggest that the interstitial free fluid pressure is negative. Furthermore, because the fluid in the tissue gel is in equilibrium with the free fluid, it has a chemical potential equivalent to the negative pressure of the free fluid. At present, the only probable source of energy that could create the negative hydrostatic pressure in the free fluid and the equivalent negative chemical potential in the intragel fluid is a lymphatic suction pump. Unfortunately, the existence of this has not yet been proved, but mechanisms by which the terminal lymphatic system could act as a suction pump have been proposed.


Providing linguistically appropriate services to persons with limited English proficiency: a needs and resources investigation.
Increasing numbers of persons in the United States cannot speak, read, write, or understand the English language at a level that permits them to interact effectively. These limitations can hamper encounters between patients and healthcare providers, often leading to misunderstandings as to diagnosis and treatment, which in turn may result in poor patient compliance, unsatisfactory outcomes, and increased costs. A questionnaire was developed and distributed to clinical practice managers at the University of Maryland School of Medicine to assess the needs for language interpretation services and resources among clinical faculty providing healthcare to persons with limited English proficiency (LEP). Literature review, search of key Web sites, and consultation with national experts on issues pertaining to language access, health services, and reimbursement strategies also were done. Then, recommendations regarding the costs and benefits of language interpretation in healthcare settings were developed. Because recipients of federal financial assistance from the Department of Health and Human Services must provide meaningful access to persons with LEP at no cost to the client, there are clear benefits to providing language interpretation. Providers and managers should be made aware of interpretation service options and cost-saving strategies.


Improved methods for thermal rearrangement of alicyclic α-hydroxyimines to α-aminoketones: synthesis of ketamine analogues as antisepsis candidates.
Ketamine is an analgesic/anesthetic drug, which, in combination with other drugs, has been used as anesthetic for over 40 years. Ketamine induces its analgesic activities by blocking the N-methyl-D-aspartate (NMDA) receptor in the central nervous system (CNS). We have reported that low doses of ketamine administrated to patients before incision significantly reduced post-operative inflammation as reflected by reduced interleukin-6 (IL-6) sera-levels. Our data demonstrated in a rat model of Gram-negative bacterial-sepsis that if we inject a low dose of ketamine following bacterial inoculation we reduce mortality from approximately 75% to 25%. Similar to what we have observed in operated patients, the levels of TNF-α and IL-6 in ketamine-treated rats were significantly lower than in septic animals not treated with ketamine. On the base of these results, we have designed and synthesized series of new analogues of ketamine applying a thermal rearrangement of alicyclic α-hydroxyimines to a-aminoketones in parallel arrays. One of the analogues (compound 6e) displayed high activity in down-regulating the levels of IL-6 and TNF-α in vivo as compared to ketamine.


Imputation strategies for genomic prediction using nanopore sequencing.
Genomic prediction describes the use of SNP genotypes to predict complex traits and has been widely applied in humans and agricultural species. Genotyping-by-sequencing, a method which uses low-coverage sequence data paired with genotype imputation, is becoming an increasingly popular SNP genotyping method for genomic prediction. The development of Oxford Nanopore Technologies' (ONT) MinION sequencer has now made genotyping-by-sequencing portable and rapid. Here we evaluate the speed and accuracy of genomic predictions using low-coverage ONT sequence data in a population of cattle using four imputation approaches. We also investigate the effect of SNP reference panel size on imputation performance. SNP array genotypes and ONT sequence data for 62 beef heifers were used to calculate genomic estimated breeding values (GEBVs) from 641 k SNP for four traits. GEBV accuracy was much higher when genome-wide flanking SNP from sequence data were used to help impute the 641 k panel used for genomic predictions. Using the imputation package QUILT, correlations between ONT and low-density SNP array genomic breeding values were greater than 0.91 and up to 0.97 for sequencing coverages as low as 0.1 × using a reference panel of 48 million SNP. Imputation time was significantly reduced by decreasing the number of flanking sequence SNP used in imputation for all methods. When compared to high-density SNP arrays, genotyping accuracy and genomic breeding value correlations at 0.5 × coverage were also found to be higher than those imputed from low-density arrays. Here we demonstrated accurate genomic prediction is possible with ONT sequence data from sequencing coverages as low as 0.1 × , and imputation time can be as short as 10 min per sample. We also demonstrate that in this population, genotyping-by-sequencing at 0.1 × coverage can be more accurate than imputation from low-density SNP arrays.


[Oligosymptomatic celiac disease--axis correction of extreme genu valgum with a gliadin-free diet].
We report on a girl who suffered from a severe left-sided Genu valgum. As there was a remarkable deterioration despite a conservative orthopedic therapy on osteotomy was planned. However, preoperative investigations revealed a malabsorption syndrome with osteomalacia due to coeliac disease. This gliadin-sensitive enteropathy had already been diagnosed and treated in infancy but had been ignored, since no abdominal symptoms had occurred after re-introduction of normal food. Four years after start of gliadin-free diet the false position of the left leg had disappeared and an operative correction had not to be performed.


From managed care to cooperative care.
The difficulties manifested between managed care and its practitioners are formidable but not inevitable. A change in the perception of practitioners toward managed care will need a concerted effort on the part of both the provider and the industry, realizing there is more to gain by working together. The author reports two examples of cooperative care. These did not happen on their own. Rather, perceptions were changed in the only way perceptions are really changed: through results. This article is optimistic that, by persons of vision on both sides, there can be a move from managed to cooperative care.


Challenges and barriers in mental healthcare systems and their impact on the family: A systematic integrative review.
The aim of this systematic integrative review is to analyse the challenges and barriers found in mental healthcare systems and the impact they have on the family. Searches were made of the Web of Science, Scopus, Medline and Cochrane databases using terms relating to mental health, family care and healthcare systems. We included and critically evaluated studies published in English between 2015 and 2019 that directly or indirectly analysed public mental health policies and the consequences they have for the family. We analysed our findings following the inductive content analysis approach. A total of 32 articles that met quality indicators were identified. Very closely related structural, cultural, economic and healthcare barriers were found that contribute to the treatment gap in mental health. The family covers the care systems' deficiencies and weaknesses, and this leads to overload and a diminishing quality of life for caregivers. It is acknowledged that people with mental illness and their families should be able to participate in the development of policies and thus contribute to strengthening mental healthcare systems worldwide.


Isolated Scaphoid Dislocation From Low-Energy Wrist Trauma.
Isolated scaphoid dislocation is an extremely rare injury typically caused by high-energy trauma. We present the first observed case of isolated scaphoid dislocation resulting from a non-traumatic injury of the wrist in power-grip tension in a patient with a questionable history of Marfan Syndrome. A 20-year-old right-hand dominant man presented to the emergency department with right wrist pain and deformation after carrying a table. The patient reported a possible history of Marfan Syndrome, but it had never been definitively diagnosed. Imaging revealed radial dislocation of the scaphoid. Bedside closed reduction was performed followed by outpatient ligament reconstruction with return to normal activities at 6 months. Early diagnosis and management lead to an improved prognosis for isolated scaphoid dislocation. Regardless of patient history or mechanism of injury, treatment options include closed reduction, percutaneous fixation, and/or open reduction with internal fixation and ligamentous reconstruction.


Identification of IQ motif-containing GTPase-activating protein 1 as a regulator of long-term ketosis.
IQ motif-containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffolding protein that integrates multiple cellular processes, including motility, adhesion, and proliferation, but its role in metabolism is unknown. Here, we show that IQGAP1 is induced upon fasting and regulates β-oxidation of fatty acids and synthesis of ketone bodies in the liver. IQGAP1-null (Iqgap1-/-) mice exhibit reduced hepatic PPARα transcriptional activity, as evidenced during fasting, after ketogenic diet, and upon pharmacological activation. Conversely, we found that the activity of fed-state sensor mTORC1 is enhanced in Iqgap1-/- livers, but acute inhibition of mTOR in Iqgap1-/- mice was unable to rescue the defect in ketone body synthesis. However, reexpressing IQGAP1 in the livers of Iqgap1-/- mice was sufficient to promote ketone body synthesis, increase PPARα signaling, and suppress mTORC1 activity. Taken together, we uncover what we believe to be a previously unidentified role for IQGAP1 in regulating PPARα activity and ketogenesis.


AtFH16, [corrected] an Arabidopsis type II formin, binds and bundles both microfilaments and microtubules, and preferentially binds to microtubules.
Formins are well-known regulators that participate in the organization of the actin cytoskeleton in organisms. The Arabidopsis thaliana L. genome encodes 21 formins, which can be divided into two distinct subfamilies. However, type II formins have to date been less well characterized. Here, we cloned a type II formin, AtFH16, and characterized its biochemical activities on actin and microtubule dynamics. The results show that the FH1FH2 structure of AtFH16 cannot nucleate actin polymerization efficiently, but can bind and bundle microfilaments. AtFH16 FH1FH2 is also able to bind and bundle microtubules, and preferentially binds microtubules over microfilaments in vitro. In addition, AtFH16 FH1FH2 co-localizes with microtubules in onion epidermal cells, indicating a higher binding affinity of AtFH16 FH1FH2 for microtubules rather than microfilaments in vivo. In conclusion, AtFH16 is able to interact with both microfilaments and microtubules, suggesting that AtFH16 probably functions as a bifunctional protein, and may thus participate in plant cellular processes.


[Separation of the virotoxins of the mushroom Amanita virosa and comparative study of their interaction on actin in vitro].
Cyclic peptides have been extracted with methanol from Amanita virosa and separated by preparative HPLC. Six peptides were obtained: phalloidin and five new peptides recently identified by Faulstich as virotoxins. We have compared the interaction of these six peptides with actin in vitro. They increased the rate of polymerization of actin and protected F-actin against several denaturating agents: proteases, heat, chaotropic ions, cytochalasin B, and DNAse I. The five virotoxins have therefore the same biological properties as phalloidin. However, the differential spectra of interaction between actin and the five virotoxins are different than the differential spectra between actin and phalloidin, thus it appears that the molecular interaction of actin with virotoxins is different than with phalloidin. The five virotoxins have the same activity. Although these virotoxins have different functional groups on amino acids 1 and 7, it is concluded that these two amino acids are of minor importance in the interaction of these peptides with actin.


Foods and beverages and colorectal cancer risk: a systematic review and meta-analysis of cohort studies, an update of the evidence of the WCRF-AICR Continuous Update Project.
As part of the World Cancer Research Fund International Continuous Update Project, we updated the systematic review and meta-analysis of prospective studies to quantify the dose-response between foods and beverages intake and colorectal cancer risk. PubMed and several databases up to 31 May 2015. Prospective studies reporting adjusted relative risk estimates for the association of specific food groups and beverages and risk of colorectal, colon and rectal cancer. Dose-response meta-analyses using random effect models to estimate summary relative risks (RRs). About 400 individual study estimates from 111 unique cohort studies were included. Overall, the risk increase of colorectal cancer is 12% for each 100 g/day increase of red and processed meat intake (95% CI = 4-21%, I2=70%, pheterogeneity (ph)<0.01) and 7% for 10 g/day increase of ethanol intake in alcoholic drinks (95% CI = 5-9%, I2=25%, ph = 0.21). Colorectal cancer risk decrease in 17% for each 90g/day increase of whole grains (95% CI = 11-21%, I2 = 0%, ph = 0.30, 6 studies) and 13% for each 400 g/day increase of dairy products intake (95% CI = 10-17%, I2 = 18%, ph = 0.27, 10 studies). Inverse associations were also observed for vegetables intake (RR per 100 g/day =0.98 (95% CI = 0.96-0.99, I2=0%, ph = 0.48, 11 studies) and for fish intake (RR for 100 g/day = 0.89 (95% CI = 0.80-0.99, I2=0%, ph = 0.52, 11 studies), that were weak for vegetables and driven by one study for fish. Intakes of fruits, coffee, tea, cheese, poultry and legumes were not associated with colorectal cancer risk. Our results reinforce the evidence that high intake of red and processed meat and alcohol increase the risk of colorectal cancer. Milk and whole grains may have a protective role against colorectal cancer. The evidence for vegetables and fish was less convincing.


Chemical tests as alternatives to animal tests in research on late symptoms in diabetes.
Glycation reactions, such as those seen in late diabetes, can be mimicked in purely chemical systems. The glycation is time-dependent, and in in vitro systems it can continue for days. Ascorbate seems to enhance the reactions. The reactions are associated with free-radical formation through transformation of an Amadori product to (deoxy-)glycoson, catalysed by heavy metals. Ascorbate enhances the reaction by a factor of 5-10 compared with in vitro systems without ascorbate. In vitro systems containing bovine serum albumin retard the formation of free-radicals, because of the formation of advanced glycation products.


QTc interval in patients with multiple sclerosis: an inference from the insula of Reil?
The aim of this study was to investigate the correlation between the duration of the QTc interval and the brain lesion load at the level of the structures involved in superior autonomic control (insula, cingulate cortex and amygdala-hippocampus) in multiple sclerosis (MS) patients. Thirty-one consecutive patients with relapsing-remitting MS were recruited. The QT interval was measured manually in all 12 leads by a single blinded observer, with the longest QT value adjusted for heart rate by using the Bazett's formula. All patients performed a brain magnetic resonance imaging (MRI) scan including three-dimensional double inversion recovery and three volumetric fast-field echo sequences. The following MRI measures were obtained: (i) global and regional cortical thickness (CTh); (ii) white matter lesion load volume; (iii) cortical damage blindly assessed by a trained observer who assigned, on the basis of the number of cortical lesions, a score from 0 to 5 for each of the brain areas analysed. In all, 16% of the patients had an increased QTc interval. The QTc interval was correlated with disease duration, cortical insular lesion volume and grey matter lesion volume in the three examined areas and inversely correlated with global and insular CTh. An increased QTc interval in patients with MS may have a cerebral origin possibly driven by involvement of the insular cortex. With the recent introduction in clinical practice of treatments with potential cardiac effects such as fingolimod, the recognition of a long QTc interval could be clinically crucial and should encourage appropriate electrocardiographic monitoring in order to prevent the risk of malignant ventricular pro-arrhythmia and iatrogenic sudden death.


Endoplasmic reticulum aminopeptidase-1 functions regulate key aspects of the innate immune response.
Endoplasmic reticulum aminopeptidase-1 (ERAP1) is a multifunctional, ubiquitously expressed enzyme whose peptide-trimming role during antigen processing for presentation by MHC I molecules is well established, however, a role for ERAP1 in modulating global innate immune responses has not been described to date. Here we demonstrate that, relative to wild type mice, mice lacking ERAP1 exhibit exaggerated innate immune responses early during pathogen recognition, as characterized by increased activation of splenic and hepatic NK and NKT cells and enhanced production of pro-inflammatory cytokines such as IL12 and MCP1. Our data also revealed that ERAP1 is playing a critical role in NK cell development and function. We observed higher frequencies of terminally matured NK cells, as well as higher frequencies of licensed NK cells (expressing the Ly49C and Ly49I receptors) in ERAP1-KO mice, results that positively correlated with an enhanced NK activation and IFNγ production by ERAP1-KO mice challenged with pro-inflammatory stimuli. Furthermore, during pathogen recognition, ERAP1 regulates IL12 production by CD11c(+) DCs specifically, with increases in IL12 production positively correlated with an increased phagocytic activity of splenic DCs and macrophages. Collectively, our results demonstrate a previously unrecognized, more central role for the ERAP1 protein in modulating several aspects of both the development of the innate immune system, and its responses during the initial stages of pathogen recognition. Such a role may explain why ERAP1 has been implicated by GWAS in the pathogenesis of autoimmune diseases that may be precipitated by aberrant responses to pathogen encounters.


Arginine-stimulated acute phase of insulin and glucagon secretion. I. in normal man.
To document and characterize the immediate phase of glucogen secretion as detected in peripheral blood in man, we have given pulses of L-arginine (0.1 gm. to 10.0 gm.) intravenously over twenty to thirty seconds to twenty-three healthy young men. Peak glucagon and insulin levels averaging four and five times basal levels respectively were reached two to five minutes after arginine administration and had returned to baseline levels by fifteen to thirty minutes. Computing the area above basal for the initial ten minutes after arginine stimulation established a dose-response relationship for the acute phases of glucagon and insulin secretion. A maximal glucagon response was elicited by doses of arginine of 5.0 gm. or greater, whereas for insulin, the plateau was reached at 2.5 gm. of arginine. Sequential 5.0-gm. pulses of arginine administered every thirty minutes showed that there was no augmentation or attenuation of the timing, magnitude (area 0-10 minutes) or absolute peak values reached for either the glucogon or insulin responses. The effect of induced hyperglycemia on the acute phase of insulin and glucagon secretion was assessed by administering the arginine during marked elevation of ambient glucose concentration achieved by the intravenous administration of glucose. This resulted in marked suppression of the acute glucagon response and dramatic accentuation of the insulin response.


Epigenome-Wide Association of Infant Feeding and Changes in DNA Methylation from Birth to 10 Years.
Epigenetic factors have been suggested as mediators of early-life nutrition to future health. Prior studies focused on breastfeeding effects on DNA methylation (DNAm), ignoring other feeding modes. In this analysis of the Isle of Wight birth cohort, feeding modes were categorized as exclusive breastfeeding (EBF), exclusive formula feeding (EFF), and mixed feeding based on whether the respective feeding mode lasted for at least 3 months. In addition, in the past, infant feeding modes were assessed using DNAm at one time point in childhood, not changes of DNAm. In this paper, methylation differences (delta DNAm) were calculated by subtracting residual methylation values at birth from age 10 years (adjusting for cell types and season of blood collection at both ages). These deltas were estimated for all methylation sites where cytosine was followed by guanine (cytosine guanine dinucleotide (CpG) sites). Then, we performed an epigenome-wide association study contrasting EBF, EFF, and mixed feeding with delta DNAm that represents changes in methylation from birth to 10 years. A total of 87 CpGs (EBF: 27 CpGs, EFF: 48 CpGs, mixed: 12 CpGs) were identified using separate linear regression models adjusting for confounders and multiple testing. The sum of all changes in methylation from birth to age 10 years was significantly lower in the EFF group. Correspondingly, the number of CpGs with a methylation decline was 4.7% higher reflecting 13,683 CpGs. Lower methylation related to exclusive formula feeding and its adverse potential for the child's development needs future research to reduce adverse health effects.


Absolute lymphocyte count: a cost-effective method of monitoring HIV-infected individuals.
Depletion of CD4 cell count is a hallmark of disease progression in AIDS. CD4 cell count is essential for physicians to decide about the timing of initiation of antiretroviral therapy (ART) and for prophylaxis of opportunistic infections. WHO has recommended that, absolute lymphocyte count (ALC) of ≤1200/μL can substitute CD4 cell count of ≤200/μL in resource-constrained countries throughout the world. This study was undertaken to know whether there is a correlation between CD4 cell count and ALC in HIV-infected individuals. A single sample of blood was withdrawn for ALC and CD4 cell count. The samples received from December 1, 2004 to December 31, 2005 were analyzed. A total of 196 samples were collected from 185 patients. After exclusion, a total of 182 samples were analyzed. Results revealed that male:female ratio was 126:56 and their age ranged from 13 to 67 years. The median ALC was 1747 cells/μL, whereas the CD4 cell count ranged from 5 to 2848. The correlation coefficient between ALC and CD4 cell count was significant (0.714). There were 49 patients with an ALC of ≤1200/μL of whom 77.6% patients had CD4 cell count ≤ 200/μL (true positive) and 22.4% had CD4 cell count > 200/μL (false positive). There were 133 patients with an ALC of >1200/μL of whom 84.2% had CD4 cell count > 200/μL (true negative) and 15.8% had CD4 cell count ≤ 200/μL (false negative). Taking ALC of ≤1200/μL as a predictor of CD4 cell count ≤ 200/μL ,the sensitivity of the test was 64.4% and specificity was 91.1%. The positive predictive value was 77.6%, negative predictive value was 84.2%, and accuracy was 82.4%. We found that an ALC of ≤ 1520/μL has higher sensitivity (78%) for a CD4 cell count of ≤ 200/μL. The ALC was found to be significantly cost-effective in our setup but chances of missing out patients requiring ART was 1 in 5 using the WHO guidelines.


Vitamin E suppresses telomerase activity in ovarian cancer cells.
Dietary factors influence tumor formation and progression. Vitamin E is a dietary anti-oxidant capable of eliminating free radical damage, inducing apoptosis and decreasing oncogene expression. Therefore, Vitamin E may be a strong candidate for cancer prevention and/or chemotherapeutic intervention. Since telomerase, a ribonucleoprotein uniquely expressed in over 95% of cancers, plays an important role in cellular immortalization, cell growth and tumor progression, the present study investigated the effects of Vitamin E on telomerase activity in human ovarian cancer. Normal and malignant ovarian surface epithelial (OSE) cells were cultured with and without D-alpha tocopheryl acetate (Vitamin E). MTS and Western immunoblot assays were used to examine the effect of Vitamin E on cell growth, survival and cytotoxicity. PCR-ELISA, RT-PCR and luciferase reporter assays were performed to determine the effect of Vitamin E on telomerase activity. Vitamin E suppressed endogenous telomerase activity in ovarian cancer cells, but had no similar effects in telomerase-negative normal OSE cells. Vitamin E also reduced hTERT-mRNA transcript levels and reduced hTERT promoter activity maximally targeting the -976 to -578bp promoter regions. In addition, Vitamin E improved cisplatin-mediated cytotoxicity as evidenced by reduced cancer cell growth and increased cleaved caspase 3 activity. In contrast, Vitamin E protected telomerase-negative OSE cells from cisplatin-mediated cytotoxicity as evidenced by decreased cleaved caspase 3 activity. Our data suggest that, by suppressing telomerase activity, Vitamin E may be an important protective agent against ovarian cancer cell growth as well as a potentially effective therapeutic adjuvant.


Changes in bleeding patterns in von Willebrand disease after institution of long-term replacement therapy: results from the von Willebrand Disease Prophylaxis Network.
Clinically, the leading symptom in von Willebrand disease (VWD) is bleeding, chiefly of mucosal type, for example, epistaxis, gingival, or gastrointestinal bleeding, and menorrhagia. In severe forms of VWD with secondary deficiency of factor VIII, spontaneous joint bleeding, resembling that observed in severe haemophilia A, may also be observed. The bleeding patterns of VWD can affect quality of life, and may be life-threatening. The von Willebrand Disease Prophylaxis Network is an international study group formed with the goal of investigating the role of prophylaxis in clinically severe VWD. The objective of the present study is to investigate the response to prophylaxis focusing primarily on epistaxis, joint bleeding, gastrointestinal bleeding, and heavy bleeding associated with menses. Data from 105 subjects, 10 enrolled in a prospective study and 95 in a retrospective study between 2008 and 2013, were available for analysis. The median annualized rate reductions in bleeding were significant for epistaxis (P < 0.0001), gastrointestinal bleeding (P = 0.0003), joint bleeding (P < 0.0001), and menorrhagia (P = 0.008). Doses on a group level were approximately the same prior to and during prophylaxis, but more patients with gastrointestinal bleeding had prophylaxis three or more times per week as well as higher dosages. Our study, which primarily used retrospective data, indicates that prospective studies are needed to better delineate the doses and dose intervals that should be used for prophylactic treatment of VWD.


Study of the Etiological Spectrum of Spontaneous Bacterial Peritonitis in a Group of Patients Suffering from Liver Cirrhosis.
Spontaneous bacterial peritonitis (SBP) represents the most severe and common infectious complication in patients suffering from liver cirrhosis. The objectives of the study were the evaluation of the risk factors responsible for the occurrence of the spontaneous bacterial peritonitis in a group of patients suffering from liver cirrhosis, the identification of the bacterial spectrum and assessing the response to antibiotic therapy. Material and method - The studied group included 64 patients suffering from liver cirrhosis, with an episode of SBP, who were admitted to the IInd Medical Clinic of the County Hospital of Craiova, within a period of 24 months. The control group included 61 patients with liver cirrhosis with an episode of decompensation of liver disease. The diagnosis of liver cirrhosis was established by using clinical, biological and imagistic criteria, and the SBP's diagnosis was based on cytological and bacteriological analysis of the ascites fluid. Patients suffering from hepatocellular carcinoma, portal vein thrombosis and other infectious conditions were excluded. The anamnesis, the duration of the disease, the alcohol intake, the complete clinical examination, the clinical, biological and imagistic evaluation were monitored. Results and conclusions - The most frequent etiology of SBP is represented in 67% of the cases by Gram negative germs, and thus, the antibiotic therapy will be orientated against this etiological segment. In what antibiotic sensitivity is concerned, most of the germs were sensitive to third generation cephalosporins, quinolones, carbapenems and vancomycin.


Pharmacokinetics, covalent binding and subcellular distribution of [3H]doxorubicin after intravenous administration in the mouse.
Some aspects of the in vivo disposition of [3H]doxorubicin were investigated in mice in the first 6 hr after a 5 mg/kg i.v. dose. The disappearance of radioactivity from plasma and erythrocytes was consistent with biphasic kinetics. Highest peak radioactivity was found in lung, liver and kidney. Retention half-lives of radioactivity in heart, lung, kidney and small intestine were between 4.5 to 6.5 hr, while in liver, adrenal gland and spleen they were 7 to 13 hr and in skeletal muscle and bone marrow were 17 and 35 hr, respectively. Radioactivity in pancreas and epididymal fat had not equilibrated by 6 hr, and brain and testicle contained little radioactivity. Exhaustive methanol-ether extraction of acid-precipitated homogenates showed covalent binding of radioactivity to lung, liver, kidney and spleen at 40 to 100 pmol/mg of protein, while binding in plasma, small intestine and pancreas ranged from 4 to 30 pmol/mg of protein; heart and skeletal muscle showed 0 to 1.4 pmol/mg of protein at all times examined. Differential centrifugation revealed no site of subcellular accumulation within liver, kidney or most notably heart, other than the nuclear fraction. Specific levels of drug were highest in nuclei of liver, requiring 45 min to reach peak amounts; the lowest quantity per milligram of nuclear protein was found in the heart, and had already peaked by 10 min. These results suggest that the cardiotoxicity of doxorubicin may not be due to concentration or retention of drug within heart tissue as a whole or any non-nuclear subcellular fraction of it nor to the covalent binding of drug to heart protein, but may follow directly from the interaction of doxorubicin with the cardiac nuclei.


A myoelectrically controlled shoulder-elbow orthosis for unrecovered brachial plexus injury.
Two myoelectrically controlled battery powered shoulder-elbow orthoses manufactured individually for two traumatic unilateral brachial plexus injury cases are reported. The first case was 24 years old and the other was 6 years old. Both patients had undergone unsuccessful microsurgical nerve repair procedures leaving them with elbow and shoulder paralysis and some residual hand motion. Manufactured orthoses were made of lightweight thermoplastic polyethylene. They stabilised the affected shoulder joint in the neutral position. Elbow extension and flexion were activated by a myoelectrically controlled battery powered orthosis, and the active range of motion of the elbow was between 60 and 140 degrees. These orthoses achieved elbow motions at a speed of 16 degrees per second. The rehabilitation time was 3 months in both patients. The older patient was rehabilitated using a 1 kg mass, and the younger one with 0.5 kg mass, throughout the full range of active elbow motions. After 21 months it was found, in both cases, that the orthotic treatment had been successful and that the patients had been given the ability to engage in two-handed activities of daily living.


Predicting the risk of variceal rehemorrhage in cirrhotic patients with portal vein thrombosis: A two-center retrospective study.
Although portal vein thrombosis (PVT) was thought to deteriorate portal hypertension and contribute to poor prognosis, risk stratification remains unclear. This study aimed to evaluate its effect on the risk of variceal rehemorrhage and to develop a competitive risk model in cirrhotic patients with PVT. Cirrhotic patients with and without PVT admitted for acute variceal hemorrhage were retrospectively included after matching (1:1) for age, gender and etiology of cirrhosis from two tertiary centers with 1-year follow-up. Those with PVT were subsequently divided into the training and validation cohorts. Cox regression analysis was performed to identify risk factors and develop a competitive risk model, of which the predictive performance and optimal decision threshold were evaluated by C-index, competitive risk curves, calibration curves and decision curve analysis. Among 398 patients, PVT significantly increased the variceal rehemorrhage risk. Multivariate Cox regression analysis identified that the Child-Turcotte-Pugh score (P = 0.013), chronic PVT (P = 0.025), C-reactive protein (P < 0.001), and aspartate aminotransferase (P = 0.039) were independently associated with variceal rehemorrhage, which were incorporated into the competitive risk model, with high C-index (0.804 and 0.742 of the training and validation cohorts, respectively), risk stratification ability, and consistency. The optimal decision range of the threshold probability was 0.2-1.0. We confirmed the adverse effect of PVT on variceal rehemorrhage and developed a competitive risk model for variceal rehemorrhage in cirrhotic patients with PVT, which might be conveniently used for clinical decision-making.


Studies on the interaction of achiral cationic pseudoisocyanine with chiral metal complexes.
The effect of chiral metal complexes ([Co(en)(3)]I(3)·H(2)O, cis-[CoBr(NH(3))(en)(2)]Br(2), K[Co(edta)]·2H(2)O and [Ru(phen)(3)](PF(6))(2)) on the polymer-bound J-aggregates in aqueous mixtures of pesudoisocyanine (PIC) iodine and poly(acrylic acid, sodium)(PAAS) have been studied by UV-vis absorption, circular dichroism (CD) and fluorescence spectra. At low concentration, the PIC monomers could self-assemble to form supermolecules by binding to each of the COO(-) groups on the polymer chains through electrostatic interactions. After the addition of chiral metal complexes to the formed PIC-PAAS J-aggregates, we found that only the chiral multiple π-conjugated phenanthroline metal complexes could transfer their metal-centered chiral information to the formed J-aggregates. The chiral J-aggregates showed a characteristic induced circular dichroism (ICD) in the visible region of J-band chromophore, and the ICD signals depend on the absolute configuration, concentration of the chiral multiple π-conjugated metal complexes, as well as temperature. More interestingly, the supramolecular chirality of the polymer supported PIC J-aggregates could be memorized even after the addition of an excess opposite chiral complex enantiomers. This is in sharp contrast to the behavior in the high concentrated NaCl induced PIC-J aggregates, in which the optical rotation of a mixture of two enantiomers varies linearly with their ratio.


[Prevention of adverse reactions of antituberculous drugs in pulmonary tuberculosis in patients with different genetic background].
To study genetic predisposition to adverse reactions caused by drugs, 367 patients with pulmonary tuberculosis were examined. As a genetic marker, the phenotype of haptoglobin (Hp) carriage, the type of HINC inactivation, the activity of the enzyme G-6-PDHG were determined. Adverse reactions were noted in 60.2% of the patients. If there was an unfavourable combination of genetic markers, adverse reactions developed in 100% of the patients, with a relatively unfavourable combination, adverse reactions did in a slightly smaller proportion (78%). With a relatively favourable combination, they were noted only in 38%. A new technology is proposed for the prevention of adverse reactions in pulmonary tuberculosis by using nontraditional treatments, phytotherapy and its combination with ultrasound autoblood radiation. The use of this technology has been shown to reduce the incidence of adverse reactions, to diminish the severity and clinical manifestations of disease.


BRCA mutation-negative women from hereditary breast and ovarian cancer families: a qualitative study of the BRCA-negative experience.
When women from families with a known BRCA1 or BRCA2 mutation test negative for the family mutation, it is assumed that they will transition their personal cancer risk perception from high to average risk. However, there are scant data regarding the experience of mutation-negative women after genetic testing disclosure, particularly related to the shift of risk perception from assumed mutation-positive to actual mutation-negative. This study was designed to explore cancer risk perception and the experience of being a mutation-negative woman within a known BRCA1/2 mutation-positive family. We employed a qualitative descriptive design and convened a sample of 13 women who contributed in-depth, semi-structured telephone interviews (audio-recorded and transcribed verbatim) and performed qualitative content analysis with NVivo 2.0 software. Six major content areas emerged from interview data: (i) rationale for initial involvement in the breast imaging study, (ii) rationale for continued participation, (iii) experience of living in a multiple-case family, (iv) risk perception: the personal meaning of mutation-negative status, (v) opinions regarding cancer aetiology and (vi) communication patterns between mutation-negative and mutation-positive family members. Living in a hereditary breast and ovarian cancer family is a complex experience that affects cognitive, emotional and social functioning. Our findings indicate that mutation-negative women may have unmet psychosocial needs that must be addressed by health-care professionals, particularly in the primary-care setting following genetic disclosure of a potentially reassuring result regarding their lack of the very high cancer risks associated with BRCA1/2 mutations.


Neurological regulation of body weight.
We have now come full circle, from a consideration of the factors influencing the control of BW regulation to a review of the human disorders in which these control mechanisms no longer function appropriately. Experimental observation in both animals and man has led to the inescapable conclusion that FI, BW regulation, and thermogenesis are controlled in large part by the CNS. In man, the fairly stable regulation of BW within reasonably close bounds strongly suggests that BW is monitored in some way, and that FI and energy expenditure are regulated in response to this afferent set of signals. Certainly, the number of factors are legion which can influence the central integration and the effector mechanisms by which FI and energy expenditure are regulated by the CNS. The most striking observation is the relative precision with which the overall system works and how few are the number of pathological conditions which severely alter the regulation of BW. The most prominent challenges in this field are the identification of both the sensors of the nutritional status, composition and weight of the organism, and of the actual effectors of thermogenesis in mammals. A more complete understanding of these factors should enable us to better control perturbations of BW under pathological conditions.


De Sedibus et Causis Morborum: is Essential Tremor a Primary Disease of the Cerebellum?
Morgagni's 1761 publication of De sedibus et causis morborum (i.e., of the Seats and Causes of Diseases) represented a paradigmatic moment in the history of medicine. The book ushered in a new way of conceptualizing human disease, shattering old dogma, and linking constellations of symptoms and signs (i.e., clinical disease) with anatomic pathology in specific organs (i.e., organ disease). This was the anatomical-clinical method, and it attempted to unveil "the seat" of each disease in a specific organ. Essential tremor (ET) is among the most common neurological diseases. There is little debate that the origin of ET lies in the brain, but if one tries to delve more deeply than this, things become murky. The dogma for the past 40 years has been that the seat of ET is the inferior olivary nucleus. Closer scrutiny of this model, however, has revealed its many flaws, and the model, based on little if any empiric evidence, has increasingly lost favor. Arising from a wealth of research in recent years is a growing body of knowledge that links ET to a disarrangement of the cerebellum. Data from a variety of sources reviewed in this issue (clinical, neuroimaging, neurochemical, animal model, physiological, and pathological) link ET to the cerebellum. That the cerebellum is involved in an abnormal brain loop that is responsible for ET is not debated. The tantalizing question is whether an abnormality in the cerebellum is the prime mover, and whether the cerebellum is the seat of this particular disease.


NADP-MALIC ENZYME 1 Affects Germination after Seed Storage in Arabidopsis thaliana.
Aging decreases the quality of seeds and results in agricultural and economic losses. The damage that occurs at the biochemical level can alter the seed physiological status. Although loss of viability has been investigated frequently, little information exists on the molecular and biochemical factors involved in seed deterioration and loss of viability. Oxidative stress has been implicated as a major contributor to seed deterioration, and several pathways are involved in protection against this. In this study, we show that seeds of Arabidopsis thaliana lacking a functional NADP-MALIC ENZYME 1 (NADP-ME1) have reduced seed viability relative to the wild type. Seeds of the NADP-ME1 loss-of-function mutant display higher levels of protein carbonylation than those of the wild type. NADP-ME1 catalyzes the oxidative decarboxylation of malate to pyruvate with the simultaneous production of CO2 and NADPH. Upon seed imbibition, malate and amino acids accumulate in embryos of aged seeds of the NADP-ME1 loss-of-function mutant compared with those of the wild type. NADP-ME1 expression is increased in imbibed aged as compared with non-aged seeds. NADP-ME1 activity at testa rupture promotes normal germination of aged seeds. In seedlings of aged seeds, NADP-ME1 is specifically active in the root meristematic zone. We propose that NADP-ME1 activity is required for protecting seeds against oxidation during seed dry storage.