The molecular basis of β-thalassemia.
The β-thalassemias are characterized by a quantitative deficiency of β-globin chains underlaid by a striking heterogeneity of molecular defects. Although most of the molecular lesions involve the structural β gene directly, some down-regulate the gene through distal cis effects, and rare trans-acting mutations have also been identified. Most β-thalassemias are inherited in a Mendelian recessive fashion but there is a subgroup of β-thalassemia alleles that behave as dominant negatives. Unraveling the molecular basis of β-thalassemia has provided a paradigm for understanding of much of human genetics.


Commissural Gain Control Enhances the Midbrain Representation of Sound Location.
Accurate localization of sound sources is essential for survival behavior in many species. The inferior colliculi (ICs) are the first point in the auditory pathway where cues used to locate sounds, ie, interaural time differences (ITDs), interaural level differences (ILDs), and pinna spectral cues, are all represented in the same location. These cues are first extracted separately on each side of the midline in brainstem nuclei that project to the ICs. Because of this segregation, each IC predominantly represents stimuli in the contralateral hemifield. We tested the hypothesis that commissural connections between the ICs mediate gain control that enhances sound localization acuity. We recorded IC neurons sensitive to either ITDs or ILDs in anesthetized guinea pig, before, during, and following recovery from deactivation of the contralateral IC by cryoloop cooling or microdialysis of procaine. During deactivation, responses were rescaled by divisive gain change and additive shifts, which reduced the dynamic range of ITD and ILD response functions and the ability of neurons to signal changes in sound location. These data suggest that each IC exerts multiplicative gain control and subtractive shifts over the other IC that enhances the neural representation of sound location. Furthermore, this gain control operates in a similar manner on both ITD- and ILD-sensitive neurons, suggesting a shared mechanism operates across localization cues. Our findings reveal a novel dependence of sound localization on commissural processing. Sound localization, a fundamental process in hearing, is dependent on bilateral computations in the brainstem. How this information is transmitted from the brainstem to the auditory cortex, through several stages of processing, without loss of signal fidelity, is not clear. We show that the ability of neurons in the auditory midbrain to encode azimuthal sound location is dependent on gain control mediated by the commissure of the inferior colliculi. This finding demonstrates that commissural processing between homologous auditory nuclei, on either side of the midline, enhances the precision of sound localization.


The Organization of Pericentromeric Heterochromatin in Polytene Chromosome 3 of the Drosophilamelanogaster Line with the Rif11; SuURES Su(var)3-906 Mutations Suppressing Underreplication.
Although heterochromatin makes up 40% of the Drosophila melanogaster genome, its organization remains little explored, especially in polytene chromosomes, as it is virtually not represented in them due to underreplication. Two all-new approaches were used in this work: (i) with the use of a newly synthesized Drosophila line that carries three mutations, Rif11, SuURES and Su(var)3-906, suppressing the underreplication of heterochromatic regions, we obtained their fullest representation in polytene chromosomes and described their structure; (ii) 20 DNA fragments with known positions on the physical map as well as molecular genetic features of the genome (gene density, histone marks, heterochromatin proteins, origin recognition complex proteins, replication timing sites and satellite DNAs) were mapped in the newly polytenized heterochromatin using FISH and bioinformatics data. The borders of the heterochromatic regions and variations in their positions on arm 3L have been determined for the first time. The newly polytenized heterochromatic material exhibits two main types of morphology: a banding pattern (locations of genes and short satellites) and reticular chromatin (locations of large blocks of satellite DNA). The locations of the banding and reticular polytene heterochromatin was determined on the physical map.


Protein kinase D is sufficient to suppress EGF-induced c-Jun Ser 63 phosphorylation.
Phosphorylation of c-Jun at Ser 63/73 by the c-Jun N-terminal kinase (JNK) potentiates the transactivation function of c-Jun. Protein kinase D (PKD), a downstream effector of protein kinase C (PKC), has been implicated in the attenuation of epidermal growth factor (EGF)-induced activation of JNK. In order to determine whether activated PKD is sufficient to modulate the EGF-JNK-c-Jun pathway, we have developed a cellular model system, utilizing human embryonic kidney cells (HEK 293), in which stably transfected, constitutively active or kinase dead mutants of PKD can be inducibly expressed by the insect hormone, ecdysone. Induced expression of constitutively active, but not kinase dead PKD, suppressed EGF stimulated c-Jun phosphorylation at Ser 63, demonstrating that activated PKD is sufficient to suppress c-Jun phosphorylation. This is the first demonstration that PKD modulates phosphorylation of the proto-oncogene c-Jun at a site critical for its ability to mediate cell proliferation and differentiation.


Decellularized cartilage-derived matrix as substrate for endochondral bone regeneration.
Following an endochondral approach to bone regeneration, multipotent stromal cells (MSCs) can be cultured on a scaffold to create a cartilaginous callus that is subsequently remodeled into bone. An attractive scaffold material for cartilage regeneration that has recently regained attention is decellularized cartilage-derived matrix (CDM). Since this material has shown potential for cartilage regeneration, we hypothesized that CDM could be a potent material for endochondral bone regeneration. In addition, since decellularized matrices are known to harbor bioactive cues for tissue formation, we evaluated the need for seeded MSCs in CDM scaffolds. In this study, ectopic bone formation in rats was evaluated for CDM scaffolds seeded with human MSCs and compared with unseeded controls. The MSC-seeded samples were preconditioned in chondrogenic medium for 37 days. After 8 weeks of subcutaneous implantation, the extent of mineralization was significantly higher in the MSC-seeded constructs versus unseeded controls. The mineralized areas corresponded to bone formation with bone marrow cavities. In addition, rat-specific bone formation was confirmed by collagen type I immunohistochemistry. Finally, fluorochrome incorporation at 3 and 6 weeks revealed that the bone formation had an inwardly directed progression. Taken together, our results show that decellularized CDM is a promising biomaterial for endochondral bone regeneration when combined with MSCs at ectopic locations. Modification of current decellularization protocols may lead to enhanced functionality of CDM scaffolds, potentially offering the prospect of generation of cell-free off-the-shelf bone regenerative substitutes.


Platforms for antibiotic discovery.
The spread of resistant bacteria, leading to untreatable infections, is a major public health threat but the pace of antibiotic discovery to combat these pathogens has slowed down. Most antibiotics were originally isolated by screening soil-derived actinomycetes during the golden era of antibiotic discovery in the 1940s to 1960s. However, diminishing returns from this discovery platform led to its collapse, and efforts to create a new platform based on target-focused screening of large libraries of synthetic compounds failed, in part owing to the lack of penetration of such compounds through the bacterial envelope. This article considers strategies to re-establish viable platforms for antibiotic discovery. These include investigating untapped natural product sources such as uncultured bacteria, establishing rules of compound penetration to enable the development of synthetic antibiotics, developing species-specific antibiotics and identifying prodrugs that have the potential to eradicate dormant persisters, which are often responsible for hard-to-treat infections.


[Pseudolithiasis caused by ceftriaxone in children: a case report].
Recently, there are in literature some reports concerning the sonographic observation of transient gallbladder precipitates in children and adults during ceftriaxone treatment. The condition is defined as ceftriaxone-reversible "pseudolithiasis" and the gallbladder precipitates resolve spontaneously after cessation of therapy. We present a case of a 1 year old children treated with ceftriaxone who presented asymptomatic pseudolithiasis that resolved partially two weeks after cessation of treatment. The sonographic observation performed four months after cessation of therapy show a normally gallbladder, without precipitates or sludge.


Modulation of the antioxidant defense system in liver, kidney, and pancreas tissues of alloxan-induced diabetic rats by camphor.
Excess production of reactive oxygen species and the loss of antioxidant efficiency systems play an important role in the development of diabetes. Thus, using antioxidant compounds is an important strategy to reduce these complications. This study aimed to investigate the possible effect of camphor on the serum biochemical parameters and oxidative parameters in the pancreas, liver, and kidney tissues of alloxan-induced diabetic rats. In this study, 40 male Wistar rats were divided into five groups, including normal group, diabetic group, the diabetic group treated with glibenclamide, the diabetic group treated with 30 mg/kg camphor, and the diabetic group receiving the camphor solvent. Intragastric administration of camphor and glibenclamide, as the control drug, to diabetic rats for 21 days lowered their blood glucose, total cholesterol, triglyceride, and LDL-cholesterol, while the blood high-density lipoprotein -cholesterol level was increased. In addition, our results indicated that treatment of diabetic rats with camphor increased the activity of glutathione peroxidase, catalase, and superoxide dismutase enzymes as well as reduced glutathione content in the liver, pancreas, and kidney tissues as compared to the diabetic rats. Based on our data, it can be concluded that camphor has a hypoglycemic activity, and this effect may be attributed, in part, to its antioxidant ability. PRACTICAL APPLICATIONS: Camphor is a terpenoid natural compound derived from the wood present in the camphor laurel's stem and roots (Cinnamomum camphora L.) trees. The synthetic form of camphor is currently being produced for medical, health, and industrial applications. In addition, this compound is present in Rosmarinus officinalis, Cinnamomum zeylanicum, Salvia officinalis, Artemisia Annua, and Ocimum basilicum. Numerous researches have shown its beneficial effects on various diseases. In this study, it has been shown that camphor possesses antidiabetic effects in alloxan-induced diabetic rats. Treatment of diabetic rats with camphor increased the antioxidant capacity and reduces the oxidative stress markers in the liver, pancreas, and kidney tissues as compared to the diabetic rats. Given the favorable effect of camphor on some oxidative parameters in diabetic rats in our study, its antihyperglycemic property is probably due to its antioxidant effects.


Ce Filling Limit and Its Influence on Thermoelectric Performance of Fe3CoSb12-Based Skutterudite Grown by a Temperature Gradient Zone Melting Method.
CoSb3-based skutterudite is a promising mid-temperature thermoelectric material. However, the high lattice thermal conductivity limits its further application. Filling is one of the most effective methods to reduce the lattice thermal conductivity. In this study, we investigate the Ce filling limit and its influence on thermoelectric properties of p-type Fe3CoSb12-based skutterudites grown by a temperature gradient zone melting (TGZM) method. Crystal structure and composition characterization suggests that a maximum filling fraction of Ce reaches 0.73 in a composition of Ce0.73Fe2.73Co1.18Sb12 prepared by the TGZM method. The Ce filling reduces the carrier concentration to 1.03 × 1020 cm-3 in the Ce1.25Fe3CoSb12, leading to an increased Seebeck coefficient. Density functional theory (DFT) calculation indicates that the Ce-filling introduces an impurity level near the Fermi level. Moreover, the rattling effect of the Ce fillers strengthens the short-wavelength phonon scattering and reduces the lattice thermal conductivity to 0.91 W m-1 K-1. These effects induce a maximum Seebeck coefficient of 168 μV K-1 and a lowest κ of 1.52 W m-1 K-1 at 693 K in the Ce1.25Fe3CoSb12, leading to a peak zT value of 0.65, which is 9 times higher than that of the unfilled Fe3CoSb12.


[Research on bacteria microecology in root rot rhizosphere soil of Coptis chinensis produced in Shizhu city].
Illumina Hiseq 2500 high-throughput sequencing platform was used to study the bacteria richness and diversity, the soil enzyme activities, nutrients in unplanted soil, root-rot and healthy rhizophere soil of Coptis chinensis for deeply discussing the mechanism of the root-rot of C. chinensis. The high-throughput sequencing result showed that the artificial cultivation effected the bacteria community richness and diversity. The bacteria community richness in healthy and diseased rhizosphere soil showed significant lower than that of in unplanted soil (P<0.05) and declined bacteria diversity. The bacteria community richness in root-rot rhizosphere soil increased significantly than that of health and unplanted soil and the diversity was lower significant than that of unplanted soil (P<0.05). The results of soil nutrients and enzyme activities detected that the pH value, available phosphorus and urease activity decreased and the sucrase activity increased significantly (P<0.05). The content of organic carbon and alkaline hydrolysis nitrogen the catalase and urease activity in root rot soil samples was significantly lower than that of healthy soil samples (P<0.05). However, the contents of available phosphorus and available potassium were significantly in root-rot sample higher than that of healthy soil samples (P<0.05). Comprehensive analysis showed that the artificial cultivation declined the bacteria community richness and diversity. The bacteria community richness decreased significantly and the decreased diversity may be the cause of the root-rot. Meanwhile, the decrease of carbon and the catalase activity may be another cause of the root-rot in C. chinensis produced in Shizhu city, Chongqing province.


Maspin is an intracellular serpin that partitions into secretory vesicles and is present at the cell surface.
The tumor suppressor maspin (mammary serpin) was originally identified as a component of human mammary epithelial cells that is downregulated as mammary tumor cells progress from the benign to the invasive and metastatic states. Maspin inhibits cellular invasion, motility, and proliferation, but its mechanism of action is currently unknown. Because the cellular machinery responsible for these processes is cytoplasmic, we have reexamined the tissue distribution and subcellular localization of maspin. We find that maspin, or a maspin-like protein, is present in many human organs, in which it localizes to epithelia. In cultured human mammary myoepithelial cells, maspin is predominantly a soluble cytoplasmic protein that associates with secretory vesicles and is present at the cell surface. In vitro assays show that the vesicle association is due to the existence of an uncleaved facultative secretion signal that allows small amounts of maspin to partition into the endoplasmic reticulum. These results demonstrate that maspin is more widespread than previously believed. The subcellular localization studies indicate that soluble intracellular and vesicle-associated maspin probably play an important role in controlling the invasion, motility, and proliferation of cells expressing it, whereas extracellular maspin may also regulate these processes in adjacent cells.


Allergy in the World Health Organization's International Classification of Diseases (ICD)-11.
The International Classification of Diseases (ICD) provides a common language for use worldwide as a diagnostic and classification tool for epidemiology, clinical purposes, and health management. The change in the hierarchy in ICD-11 permitted the construction of the pioneer section addressed to allergic and hypersensitivity conditions (A/H), which may result in more accurate mortality and morbidity statistics, including more accurate accounting for mortality due to anaphylaxis, strengthen classification, terminology, and definitions. The ICD-11 was presented and adopted by the 72nd World Health Assembly in May 2019, and the implementation is ongoing worldwide. The Montpellier World Health Organization (WHO) Collaborating Centre on Classification Scientific Support was designated in 2018 and is responsible for supporting the WHO through representing A/H in the international classifications and quality care of patients from the public health perspective.


Bayesian Phase I/II Biomarker-based Dose Finding for Precision Medicine with Molecularly Targeted Agents.
The optimal dose for treating patients with a molecularly targeted agent may differ according to the patient's individual characteristics, such as biomarker status. In this article, we propose a Bayesian phase I/II dose-finding design to find the optimal dose that is personalized for each patient according to his/her biomarker status. To overcome the curse of dimensionality caused by the relatively large number of biomarkers and their interactions with the dose, we employ canonical partial least squares (CPLS) to extract a small number of components from the covariate matrix containing the dose, biomarkers, and dose-by-biomarker interactions. Using these components as the covariates, we model the ordinal toxicity and efficacy using the latent-variable approach. Our model accounts for important features of molecularly targeted agents. We quantify the desirability of the dose using a utility function and propose a two-stage dose-finding algorithm to find the personalized optimal dose according to each patient's individual biomarker profile. Simulation studies show that our proposed design has good operating characteristics, with a high probability of identifying the personalized optimal dose.


Heart rate as a risk factor in hypertensive individuals. The Italian TensioPulse Study.
The predictive role of heart rate as a new, independent risk factor for the development of high blood pressure and cardiovascular diseases (CVD) has been investigated in recent years and many studies have demonstrated a significant and independent association between heart rate, blood pressure and cardiovascular (CV) endpoints. Various pathogenic pathways can be postulated to explain this association and the role of heart rate as a plausible risk factor. Previous studies have been limited to the examination of small samples of general populations. By contrast, our study is based on a large cohort (38,145) of hypertensive patients. The Italian TensioPulse Study is a detailed investigation of the relation between heart rate (HR) and other CV risk factors in a large cohort of hypertensives. A strong, positive relationship was found between heart rate and both systolic and diastolic blood pressure: r = 0.21 for SBP in both sexes, and r = 0.21 and r = 0.24 for DBP in men and women respectively. Smoking and drinking habits seem to be associated with higher heart rate, SBP and DBP values. These findings and the observation that more than one out of three hypertensives had a relatively high heart rate could assist in the organisation of prevention programmes. Correction of certain lifestyle factors must precede the decision to use drugs to reduce the global CVD risk.


Enhanced B2 transcription in simian virus 40-transformed cells is mediated through the formation of RNA polymerase III transcription complexes on previously inactive genes.
RNA polymerase III (pol III) transcribes the highly repeated murine B2 elements. We showed previously that the B2 RNAs are induced 4-fold in normal growing cells and 20-fold in simian virus 40-transformed cells relative to the levels in normal confluent cells. By employing chromatin as a template in a partially purified pol III transcription system, we now demonstrate that the augmented expression results from the formation of pol III transcription complexes on previously inactive B2 genes. Extracts prepared from normal growing cells and transformed cells transcribed cloned pol III templates 5-fold more efficiently than extracts from normal confluent cells. This increase was attributed to 5-fold greater levels of factor IIIC; the levels of pol III and factor IIIB were the same in all extracts. We discuss how the levels of IIIC and differing accessibility of this factor to repressed B2 genes mediate the formation of pol III transcription complexes in normal growing and transformed cells.


The interaction of proline-rich ligands with profilin probed with an enzyme-linked immunosorbent assay.
To detect interactions of different proline-rich ligands with profilins, the authors developed a simple analytical antibody-based screening method. Profilin I or profilin IIa was coated in microplates, and ligand binding was monitored via antibody detection. Using purified components, the authors show that the assay is very sensitive as nanomolar concentrations of recombinant profilin ligands can be used. They further apply this technique to detect interaction of profilin with various proline-rich partners, either endogenously present or ectopically expressed as tagged fusions, using lysates. With this assay, the authors identify Shootin1 as a novel profilin IIa partner. In addition, they demonstrate that this assay can be used for studying competition or ternary complex formation. In conclusion, they developed a sensitive, easy-to-use, and versatile method for the study of the interaction between profilin and different ligands.


Prevalence, distribution and risk of sessile serrated adenomas/polyps at a center with a high adenoma detection rate and experienced pathologists.
Sessile serrated adenomas/polyps (SSA/Ps) are the precursors of 15 % - 30 % of colorectal cancers (CRC). We aimed to determine the prevalence and distribution of SSA/Ps and to evaluate the association between SSA/Ps and the risk of synchronous advanced neoplasia at a high quality colonoscopy center. Data from all colonoscopies performed within one dedicated colonoscopy center between 2011 and 2015 were prospectively retrieved using an automated reporting system. All lesions were assessed by an experienced gastrointestinal pathologist. Multiple logistic regression was used to evaluate influence of age, gender, and colonoscopy indication on prevalence of SSA/Ps, and to assess the association between SSA/Ps and synchronous advanced neoplasia. In total 4251 histologically confirmed polyps were resected in 3364 patients; 399 polyps were SSA/Ps (9.4 %). The prevalence of SSA/Ps was 8.2 % overall, increasing to 9.0 % for individuals older than 50 years. SSA/P detection rate varied between 2.5 % and 13.6 % among endoscopists. Increased SSA/P prevalence was associated with colonoscopy indications "familial CRC risk" (odds ratio [OR] 1.52, 95 % confidence interval [95 %CI] 1.05 - 2.22; P = 0.03) and "surveillance" (OR 1.73, 95 %CI 1.20 - 2.49; P < 0.01), when compared with the indication "symptoms." The presence of synchronous advanced neoplasia was associated with SSA/Ps overall (OR 1.71, 95 %CI 1.25 - 2.34; P = 0.001), as well as with high risk SSA/Ps (defined as ≥ 10 mm and/or with dysplasia) (OR 2.70, 95 %CI 1.56 - 4.67; P < 0.001) CONCLUSION: SSA/Ps are more common than previously reported and are associated with the presence of synchronous advanced neoplasia. Endoscopists should be assiduous in identifying SSA/Ps in daily practice and should carefully look for synchronous advanced neoplasia when an SSA/P has been recognized. RESULTS from this study can guide detection standards in general colonoscopy practice adapted to the type of patient that may predominate in an individual department.


Amyloid precursor proteins are protective in Drosophila models of progressive neurodegeneration.
The processing of Amyloid Precursor Proteins (APPs) results in several fragments, including soluble N-terminal ectodomains (sAPPs) and C-terminal intracellular domains (AICD). sAPPs have been ascribed neurotrophic or neuroprotective functions in cell culture, although β-cleaved sAPPs can have deleterious effects and trigger neuronal cell death. Here we describe a neuroproprotective function of APP and fly APPL (Amyloid Precursor Protein-like) in vivo in several Drosophila mutants with progressive neurodegeneration. We show that expression of the N-terminal ectodomain is sufficient to suppress the progressive degeneration in these mutants and that the secretion of the ectodomain is required for this function. In addition, a protective effect is achieved by expressing kuzbanian (which has α-secretase activity) whereas expression of fly and human BACE aggravates the phenotypes, suggesting that the protective function is specifically mediated by the α-cleaved ectodomain. Furthermore, genetic and molecular studies suggest that the N-terminal fragments interact with full-length APPL activating a downstream signaling pathway via the AICD. Because we show protective effects in mutants that affect different genes (AMP-activated protein kinase, MAP1b, rasGAP), we propose that the protective effect is not due to a genetic interaction between APPL and these genes but a more general aspect of APP proteins. The result that APP proteins and specifically their soluble α-cleaved ectodomains can protect against progressive neurodegeneration in vivo provides support for the hypothesis that a disruption of the physiological function of APP could play a role in the pathogenesis of Alzheimer's Disease.


Photon budget analysis for fluorescence lifetime imaging microscopy.
We have constructed a mathematical model to analyze the photon efficiency of frequency-domain fluorescence lifetime imaging microscopy (FLIM). The power of the light source needed for illumination in a FLIM system and the signal-to-noise ratio of the detector have led us to a photon "budget." These measures are relevant to many fluorescence microscope users and the results are not restricted to FLIM but applicable to widefield fluorescence microscopy in general. Limitations in photon numbers, however, are more of an issue with FLIM compared to other less quantitative types of imaging. By modeling a typical experimental configuration, examples are given for fluorophores whose absorption peaks span the visible spectrum from Fura-2 to Cy5. We have performed experiments to validate the assumptions and parameters used in our mathematical model. The influence of fluorophore concentration on the intensity of the fluorescence emission light and the Poisson distribution assumption of the detected fluorescence emission light have been validated. The experimental results agree well with the mathematical model. This photon budget is important in order to characterize the constraints involved in current fluorescent microscope systems that are used for lifetime as well as intensity measurements and to design and fabricate new systems.


Induction of calmodulin kinase IV by the thyroid hormone during the development of rat brain.
This communication reports the specific induction of calmodulin kinase IV by the thyroid hormone 3,3',5-triiodo-L-thyronine (T3) in a time- and concentration-dependent manner at a very early stage of brain differentiation using a fetal rat telencephalon primary cell culture system, which can grow and differentiate under chemically defined conditions. The induction of the enzyme that can be observed both on the mRNA and on the protein level is T3-specific, i.e. it cannot be induced by retinoic acid or reverse T3, and can be inhibited on both the transcriptional and the translational level by adding to the culture medium actinomycin D or cycloheximide, respectively. The earliest detection of calmodulin kinase IV in the fetal brain tissue of the rat is at days E16/E17, both on the mRNA as well as on the protein level. This is the first report in which a second messenger-dependent kinase involved in the control of cell regulatory processes is itself controlled by a primary messenger, the thyroid hormone.


Planetary surface photometry and imaging: progress and perspectives.
Spacecraft have visited and returned many thousands of images and spectra of all of the planets, many of their moons, several asteroids, and a few comet nuclei during the golden age of planetary exploration. The signal in each pixel of each image or spectral channel is a measurement of the radiance of scattered sunlight into a specific direction. The information on the structure and composition of the surface that is contained in variation of the radiance with scattering geometry and wavelength, including polarization state, has only just begun to be exploited and is the topic of this review. The uppermost surfaces of these bodies are mainly composed of particles that are continuously generated by impacts of micrometeoroids and larger impactors. Models of light scattering by distributions of sizes and irregular shapes of particles and by closely packed particles within a surface are challenging. These are active topics of research where considerable progress has recently been made. We focus on the surfaces of bodies lacking atmospheres.These surfaces are diverse and their morphologies give evidence of their evolution by impacts and resurfacing by a variety of processes including down slope movement and electrostatic transport of particles, gravitational accumulation of debris, volatile outgassing and migration, and magnetospheric interactions. Sampling of scattering geometries and spatial resolution is constrained by spacecraft trajectories. However, the large number of archived images and spectra demand more quantitative interpretation. The scattering geometry dependence of the radiance is underutilized and promises constraints on the compositions and structure of the surface for materials that lack diagnostic wavelength dependence. The general problem is considered in terms of the lunar regolith for which samples have been returned to Earth.


Interleukin 23 is elevated in the serum of patients with SLE.
Aim: Interleukin-23 (IL-23) is a cytokine that promotes the differentiation of T cells into pro-inflammatory Th17. We have previously shown that IL-23 is upregulated in systemic lupus erythematosus (SLE) patients and lupus prone mice. As SLE is highly heterogeneous, we asked whether IL-23 production correlates with different manifestations of the disease.Methods: We recruited 56 subjects who fulfilled the ACR criteria for SLE. Interleukin-23 was measured in the serum by ELISA.Results: IL-23 levels were positively correlated with the overall SLE disease activity as measured with the SLEDAI. Moreover, IL-23 correlated with the skin, renal domains of SLEDAI and arthritis but not with cytopenias or serositis. IL-23 did also correlate with anti-dsDNA antibody positivity and inversely correlated with C3 levels. We found no relationship between patients' demographics, prior disease manifestations, medications, or autoantibody profile and IL-23 levels. No immunomodulatory medication seemed to be affecting IL-23 levels suggesting that current medications used in SLE are not as effective in shutting down the IL-23/IL-17 axis. Conclusions: IL-23 levels track SLE disease activity mostly in the renal, skin and musculoskeletal domains. Our data suggest that IL-23 inhibitors may be helpful in combination with current standard of care in alleviating arthritis, renal and cutaneous manifestations of the disease.


DiGeorge syndrome with truncus arteriosus: report of one case.
DiGeorge syndrome is a rare disorder characterized by a spectrum of thymic and parathyroid gland abnormalities, conotruncal cardiac defects, and typical facial dysmorphism. We report a male infant with partial DiGeorge syndrome characterized by truncus arteriosus, typical facial dysmorphism, hypocalcemia, lymphocytopenia with T-cell deficiency, and chromosome 22q11.2 deletion. Transient lymphocytopenia was noted for 5 days after birth and hypocalcemia was corrected with calcium gluconate administration. Surgical correction of the truncus arteriosus was performed at the age of 3 months. Unfortunately, the patient subsequently had an unwitnessed cardiac arrest, and despite resuscitation, died at the age of 4 months.


Personalized medicine in advanced urothelial cancer: when to treat, how to treat and who to treat.
The past decade has provided an improved understanding of the molecular mechanism of bladder cancer by defining distinct pathways in tumorigenesis and progression. Advances in technologies, such as high-throughput transcript profiling, microarrays and proteomics, offer a systematic approach to identifying targets for bladder cancer diagnostics and drug discovery. This review presents a select outline of the advances in the development of bio-markers and targets for patient prognosis and therapy selection. This paper describes a representative cohort of recent studies that have the potential to significantly impact the management of muscle invasive and metastatic urothelial carcinoma of the bladder. Space constraints do not permit this review to be comprehensive and we apologize to the authors whose work we do not cite.


[Breast-conserving surgery without radiotherapy in the Cancer Institute Hospital, Tokyo].
We began performing breast-conserving surgery (BCS) in 1986 to achieve complete resection of breast cancer and omit postoperative radiotherapy (RT) if serial and detailed pathologic examination of the resected specimen within a 5-mm width showed that the of margin was cancer free. At of the end of 1998, 1,233 sides of the breast had been conserved, of which 827 sides were shown to have cancer-free margins. As of the end of 2001, with a mean observation period of 79 months, ipsilateral breast tumor recurrence was recognized on 46 sides (19 recurrences, 27 multiple cancers), for a recurrence rate 5.6% and an annual recurrence rate of 0.85%. This rate is slightly better than those reported by eminent institutions in the USA and Europe which all perform RT, confirming the accuracy and safety of our BCS.


Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death.
Nitric oxide produced by cytokine-inducible nitric oxide synthase (iNOS) is thought to be important in the pathogenesis of septic shock. To further our understanding of the role of iNOS in normal biology and in a variety of inflammatory disorders, including septic shock, we have used gene targeting to generate a mouse strain that lacks iNOS. Mice lacking iNOS were indistinguishable from wild-type mice in appearance and histology. Upon treatment with lipopolysaccharide and interferon gamma, peritoneal macrophages from the mutant mice did not produce nitric oxide measured as nitrite in the culture medium. In addition, lysates of these cells did not contain iNOS protein by immunoblot analysis or iNOS enzyme activity. In a Northern analysis of total RNA, no iNOS transcript of the correct size was detected. No increases in serum nitrite plus nitrate levels were observed in homozygous mutant mice treated with a lethal dose of lipopolysaccharide, but the mutant mice exhibited no significant survival advantage over wild-type mice. These results show that lack of iNOS activity does not prevent mortality in this murine model for septic shock.


Rapid activation of Na+/H+ exchange by aldosterone in renal epithelial cells requires Ca2+ and stimulation of a plasma membrane proton conductance.
There is increasing evidence for an additional acute, nongenomic action of the mineralocorticoid hormone aldosterone on renal epithelial cells, leading to a two-step model of mineralocorticoid action on electrolyte excretion. We investigated the acute effect of aldosterone on intracellular free Ca2+ and on intracellular pH in an aldosterone-sensitive Madin-Darby canine kidney cell clone. Within seconds of application of aldosterone, but not of the glucocorticoid hydrocortisone, there was a 3-fold sustained increase of intracellular Ca2+ at a half-maximal concentration of 10(-10) mol/liter. Omission of extracellular Ca2+ prevented this hormone response. In the presence of extracellular Ca2+ aldosterone led to intracellular alkalinization. The Na+/H+ exchange inhibitor ethyl-isopropanol-amiloride (EIPA) prevented the aldosterone-induced alkalinization but not the aldosterone-induced increase of intracellular Ca2+. Omission of extracellular Ca2+ also prevented aldosterone-induced alkalinization. Instead, aldosterone led to a Zn(2+)-dependent intracellular acidification in the presence of EIPA, indicative of an increase of plasma membrane proton conductance. Under control conditions, Zn2+ prevented the aldosterone-induced alkalinization completely. We conclude that aldosterone stimulated net-entry of Ca2+ from the extracellular compartment and a plasma membrane H+ conductance as prerequisites for the stimulation of plasma membrane Na+/H+ exchange which in turn modulates K+ channel acitivity. It is probable that the aldosterone-sensitive H+ conductance maintains Na+/H+ exchange activity by providing an acidic environment in the vicinity of the exchanger. Thus, genomic action of aldosterone determines cellular transport equipment, whereas the nongenomic action regulates transporter activity that requires responses within seconds or minutes, which explains the rapid effects on electrolyte excretion.


Duration of infection and antigen display have minimal influence on the kinetics of the CD4+ T cell response to Listeria monocytogenes infection.
The T cell response to infection consists of clonal expansion of effector cells, followed by contraction to memory levels. It was previously thought that the duration of infection determines the magnitude and kinetics of the T cell response. However, recent analysis revealed that transition between the expansion and contraction phases of the Ag-specific CD8+ T cell response is not affected by experimental manipulation in the duration of infection or Ag display. We studied whether the duration of infection and Ag display influenced the kinetics of the Ag-specific CD4+ T cell response to Listeria monocytogenes (LM) infection. We found that truncating infection and Ag display with antibiotic treatment as early as 24 h postinfection had minimal impact on the expansion or contraction of CD4+ T cells; however, the magnitudes of the Ag-specific CD4+ and CD8+ T cell responses were differentially affected by the timing of antibiotic treatment. Treatment of LM-infected mice with antibiotics at 24 h postinfection did not prevent generation of detectable CD4+ and CD8+ memory T cells at 28 days after infection, vigorous secondary expansion of these memory T cells, or protection against a subsequent LM challenge. These results demonstrate that events within the first few days of infection stimulate CD4+ and CD8+ T cell responses that are capable of carrying out the full program of expansion and contraction to functional memory, independently of prolonged infection or Ag display.


Health care use by Medicare's disabled enrollees.
Three million persons under age 65 are entitled to Medicare because of disability. This study examines their Medicare use and mortality. Disabled enrollees had higher health care use and mortality than comparison groups of Medicare's aged enrollees or of the general population under age 65. One type of disabled enrollee, adults disabled as children (over one-half of whom are mentally retarded) show lower use rates than the other types of enrollees--workers and widows. High mortality of the disabled during the 2-year waiting period for Medicare suggests the need to investigate how they pay for care during this period.


Unbiased diffeomorphic atlas construction for computational anatomy.
Construction of population atlases is a key issue in medical image analysis, and particularly in brain mapping. Large sets of images are mapped into a common coordinate system to study intra-population variability and inter-population differences, to provide voxel-wise mapping of functional sites, and help tissue and object segmentation via registration of anatomical labels. Common techniques often include the choice of a template image, which inherently introduces a bias. This paper describes a new method for unbiased construction of atlases in the large deformation diffeomorphic setting. A child neuroimaging autism study serves as a driving application. There is lack of normative data that explains average brain shape and variability at this early stage of development. We present work in progress toward constructing an unbiased MRI atlas of 2 years of children and the building of a probabilistic atlas of anatomical structures, here the caudate nucleus. Further, we demonstrate the segmentation of new subjects via atlas mapping. Validation of the methodology is performed by comparing the deformed probabilistic atlas with existing manual segmentations.


Effect of synthetic peptides belonging to E2 envelope protein of GB virus C on human immunodeficiency virus type 1 infection.
The use of synthetic peptides as HIV-1 inhibitors has been subject to research over recent years. Although the initial therapeutic attempts focused on HIV-coded enzymes, structural HIV proteins and, more specifically, the mechanisms that the virus uses to infect and replicate are now also considered therapeutic targets. The interest for viral fusion and entry inhibitors is growing significantly, given that they are applicable in combined therapies or when resistance to other antiretroviral drugs is seen and that they act before the virus enters the cell. The 124 synthetic sequences of the GBV-C E2 envelope protein have been obtained by SPPS. The interaction of certain GBV-C peptide sequences with the HIV-1 fusion peptide has been proven through the use of biophysical techniques. We also show how GBV-C E2 domains notably decrease cellular membrane fusion and interfere with the HIV-1 infectivity in a dose-dependent manner, highlighting their potential utility in future anti-HIV-1 therapies.


Combined preoperative chemotherapy and radiotherapy in patients with locally advanced esophageal cancer. Interim analysis of a phase II trial.
The prognosis of patients with locally advanced esophageal cancer (LAEC) remains poor when treated with local modalities. An intensive preoperative program with chemoradiotherapy was used to evaluate the curative resection rate, pathologic response, and survival of patients with LAEC. Ninety patients with LAEC were treated preoperatively with chemotherapy (three courses of fluorouracil, leucovorin, etoposide, and cisplatin [FLEP]) followed by concurrent chemoradiotherapy (one course of cisplatin plus etoposide in combination with 40 Gy of radiation). Transthoracic esophagectomy was performed 4 weeks after the end of radiation. Seventy-two patients were included in this evaluation. Forty-four (61%) underwent a complete tumor resection, and 16 (22%) had no tumor in the resected specimen (pathologic complete response [PCR]). The operative mortality rate was 15%. At a median follow-up time of 22 months (range, 12 to 41), the median survival duration of all 72 patients was 17 months (range, 1 to 41+). The calculated survival rates at 3 years were 33%, 42%, and 68% for all patients, patients after complete resection, and patients with PCR, respectively. This combined treatment modality is active in LAEC, with a PCR in 33% of the patients undergoing surgery. The results appear improved compared with those reported with surgery alone, by approximately doubling the 3-year survival rate. The high efficacy of preoperative chemoradiation warrants evaluation of the role of surgery in LAEC.


Meningococcal serogroup A, C, W, and Y serum bactericidal antibody profiles in Hajj pilgrims.
The religious seasons of Hajj and Umra in the Kingdom of Saudi Arabia (KSA) have historically been associated with epidemics of meningococcal disease. Due to the effective preventive measures taken in recent years, including vaccination, no meningococcal outbreaks have been reported during Hajj or were Hajj-associated. However, little is known about the immunological profile of pilgrims. The aim of this study was to assess the immunological profile of pilgrims on arrival in KSA against the four meningococcal serogroups, A, C, W, and Y, contained within the quadrivalent vaccine. Following consent, socio-demographic factors and health-related information was collected from pilgrims arriving at King Abdul Aziz International Airport and a blood sample taken. Antibodies were quantified by serum bactericidal antibody assay using baby rabbit complement (rSBA) against the four meningococcal serogroups, A, C, W, and Y. Serum samples were collected from 796 pilgrims; rSBA results were obtained for all four serogroups for 741 of these samples. A total of 48 (6.5%) Hajjis had previously attended Hajj, ranging from 1 to 14 times (median 2 times); 98.2% had received meningococcal quadrivalent vaccine in the last 3 years. Of the 13 who had not, all originated from Bangladesh, with four reporting no previous meningococcal vaccination and nine reporting having received the vaccination more than 3 years ago. For serogroup A, only one pilgrim from Indonesia had an rSBA titre <8. For serogroups C, W, and Y, the percentages of pilgrims with rSBA titres <8 were 9.9%, 17.4%, and 9.4%, respectively. Of note was the high prevalence of non-complement-mediated lysis in pilgrims originating from Nigeria (28/47; 59.6%) and Afghanistan (21/47; 44.7%), but not the other countries. This may be a reflection of the type and pattern of antibiotic usage among these communities. The vast majority of pilgrims are vaccinated and protected against meningococcal serogroups A, C, W, and Y.


The impact of uterine adenomyosis on the histopathological risk factors and survival in patients with endometrial adenocarcinoma.
A retrospective cohort study was performed on patients diagnosed with endometrial adenocarcinoma (EC) during a 9-year period to investigate the impact of co-existing adenomyosis on patients with EC. Group A included women with EC and adenomyosis and Group B EC cases without the presence of adenomyosis. Group A was more likely to have early-stage disease, tumours without deep myometrial invasion, low-grade tumours and tumours with negative lymphovascular space invasion when compared to Group B (p = 0.012, p = 0.004, p < 0.001, p = 0.02). There were no statistically significant difference between Group A and Group B for lymph node metastasis (p = 0.064). There was no significant relation between the adenomyosis and survival outcomes in the multivariant analysis (p = 0.437). As a conclusion, patients with adenomyosis were more likely to accompany good histopathologic prognostic factors. Multivariate analysis showed no significant effect of adenomyosis on recurrence and survival parameters.IMPACT STATEMENTWhat is already known on this subject? Adenomyosis is one of the most common accompanying benign histopathological findings of type 1 endometrial carcinomas (EC). Adenomyosis comprises some characteristics similar to malignant tumours, such as invasion, abnormal tissue growth and angiogenesis. Despite concerns have arisen due to both their high incidence and similar molecular links, the possible relation between EC and adenomyosis is still not well grounded.What the results of this study add? We presented a 9-year period retrospective cohort of a tertiary referring single centre and evaluated the prognostic effect of adenomyosis in patients with EC as well as the survival outcomes of these patients. The co-occurrence of adenomyosis was more likely to accompany early-stage (stages 1-2) disease, low-grade tumours (grades 1-2) and tumours with negative LVSI in patients with EC. However, multivariate and survival analysis showed no significant effect of adenomyosis on recurrence and survival parameters.What the implications are of these findings for clinical practice and/or further research? Based on these findings, we suggest that the presence of adenomyosis should not be considered as a prognostic factor in EC. Our results support the overriding opinion about the prognostic value of co-occurrence of adenomyosis and EC. However, further studies exploring the molecular and genomic markers in these two groups are needed to uncover the exact relation of adenomyosis on the prognosis of EC.


Homocysteine Induces Collagen I Expression by Downregulating Histone Methyltransferase G9a.
Hyperhomocysteinemia (HHcy) leads to several clinical manifestations including hepatic fibrosis. Excess deposition of extracellular matrix (ECM) components including collagen is the eponymous lesion of liver fibrosis. In this study, we demonstrated that elevated concentration of Hcy induced the expression of collagen type I in cultured human liver cells as well as in liver tissue of HHcy mice. Meanwhile, Hcy inhibited the expression of histone methyltransferase G9a. Mechanistically, silencing endogenous G9a by siRNA enhanced the promoter activity of COL1A1 in LO2 cells. Conversely, overexpressing G9a inhibited the promoter activity of COL1A1. CHIP assay demonstrated that G9a binds to the neuron-restrictive silencer element (NRSE) on the promoter of COL1A1. Hcy treatment decreased the binding of G9a on NRSE, which in turn decreased the level of H3K9me2 on the promoter of COL1A1, led to upregulation of COL1A1. Taken together, these results provide a novel mechanism on explaining how HHcy promotes ECM production.


The Impact of Alcohol Consumption on Cardiovascular Health: Myths and Measures.
Over the past several decades, the prevalence of cardiovascular disease (CVD) has nearly doubled, and alcohol has played a major role in the incidence of much of it. Alcohol has also been attributed in deaths due to infectious diseases, intentional and unintentional injuries, digestive diseases, and several other non-communicable diseases, including cancer. The economic costs of alcohol-associated health outcomes are significant at the individual as well as the country level. Risks due to alcohol consumption increase for most cardiovascular diseases, including hypertensive heart disease, cardiomyopathy, atrial fibrillation and flutter, and stroke. The widespread message for over 30 years has been to promote the myth that alcohol prolongs life, chiefly by reducing the risk of coronary heart disease (CHD). Lack of universal advice and stringent policy measures have contributed towards increased uptake and easy availability of alcohol. The WHO has called for a 10% relative reduction in the harmful use of alcohol between 2013-2025. However, lack of investment in proven alcohol control strategies, as well as persistence of misinformation and industry interference, have hindered the efforts of public health professionals to make sufficient progress in reducing alcohol related harms and death.


Impact of Renal Denervation on Patients With Obstructive Sleep Apnea and Resistant Hypertension - Insights From the SYMPLICITY HTN-3 Trial.
Obstructive sleep apnea (OSA) is associated with activation of the sympathetic nervous system, and patients with this condition often experience elevated blood pressure (BP), increased BP variability, and nocturnal BP surges. The SYMPLICITY HTN-3 trial was a large prospective, randomized, blinded, sham-controlled trial of renal denervation for treatment of uncontrolled, apparently treatment-resistant hypertension. In a post hoc analysis, we examined the effect of renal denervation vs. sham control on office and ambulatory (including nocturnal) systolic BP in patients with and without OSA. 26% (94/364) of renal denervation subjects and 32% (54/171) of sham control subjects had OSA. Baseline office and nighttime systolic BP values were similar in both arms, including in subjects with and without OSA. Compared with sham control, renal denervation reduced the 6-month office systolic BP in subjects with (-17.0±22.4 vs. -6.3±26.1 mmHg, P=0.01) but not in subjects without OSA (-14.7±24.5 vs. -13.4±26.4 mmHg, P=0.64), P=0.07 for the interaction between treatment arm and OSA status. In those with sleep apnea, renal denervation was also associated with a reduction in maximum (-4.8±21.8 vs. 4.5±24.6 mmHg, P=0.03) and average peak (-5.6±20.4 vs. 3.2±22.4 mmHg, P=0.02) nighttime systolic BP. OSA subjects appeared to be responsive to renal denervation therapy. However, this hypothesis requires prospective testing. (Circ J 2016; 80: 1404-1412).


Access to abortion services: the impact of the European convention on human rights in Ireland.
Abortion is unlawful in Ireland except where it is necessary to save the life of the mother. The right to life of the unborn child is safeguarded under Article 40.3.3 degrees of Bunreacht na hEireann (the Irish Constitution). In 2003 the European Convention on Human Rights was incorporated into Irish domestic legislation, subject to the provisions of the Irish Constitution. The aim of this paper is to consider the potential impact of the ECHR on access to abortion services within the State. This paper commences with discussion of the statutory prohibition on abortion and the Constitutional provisions concerning the protection afforded to the unborn child. It will then be necessary to examine the implications for Ireland of recent European Court of Human Rights' decisions, in particular the recent judgment in A, B & C v Ireland, regarding the right to legal abortions given the unique nature of the legal status of the ECHR and its relationship with the Irish Constitution.


High density lipoproteins--modulators of the calcium channel?
It has recently been shown that human red blood cells possess a voltage-independent calcium channel which can be influenced by in vitro modification of the membraneous cholesterol content. To determine whether there is also a link between plasma lipids and the calcium influx through this channel under in vivo conditions, the calcium influx was measured in red blood cells from 51 male donors (aged 41 +/- 5 years). The influx through the channel was defined as the nitrendipine (15 mumol/l)-inhibitable part of 45Ca2+ influx. The Ca(2+)-ejecting ATPase was inhibited by vanadate. The results demonstrate a strong inverse relationship (r = -0.81; P < 0.001) between the plasma concentration of high density lipoproteins (HDL) and 45Ca2+ influx. No significant correlation was found between 45Ca2+ influx and triglycerides, low density lipoproteins (LDL), very low density lipoproteins (VLDL), total plasma cholesterol or extracellular electrolytes (K+, Na+, Ca2+, Mg2+). The results indicate that HDL are involved in the modulation of the calcium channel and provide a link between the cellular cholesterol turnover and the calcium influx in the pathogenesis of atherosclerosis and hypertension.


A concept analysis of remission within the domain of cancer survivorship.
This concept analysis aims to formulate a unique theoretical definition of the term remission as used in cancer survivorship. Inadequate communication between healthcare providers and cancer survivors is a shared burden affecting survivor well-being. Healthcare providers regularly use the term remission in cancer prognosis, treatment, and long-term cancer management; yet, how healthcare providers and cancer survivors define and interpret the concept of remission is less understood. The Walker and Avant method of concept analysis was applied to define the term remission within the domain of cancer survivorship. DATA SOURCE: Three health sciences databases were chosen for the literature search, including PubMed, the Cumulative Index to Nursing and Allied Health Literature, and Ovid Medline. REVIEW METHODS: Included research articles were evaluated to define the antecedents, attributes, consequences, and empirical referents of the term remission. A cancer diagnosis is the most commonly cited antecedent to cancer remission. During remission, most cancer patients are free of measurable or symptomatic disease; however, the remission milestone is complemented by multiple physical and psychological symptoms. More specific cancer remission attributes include anxiety, recurrence fears, self-perseverance, and loss of social support. Both positive and negative outcomes accompany cancer remission, including acceptance of the treatment journey, appreciation for life, hope, persistent anxiety, personal relief, and triggered memories. This concept analysis reviewed numerous publications to understand remission in the context of cancer survivorship. Advanced practice and registered nurses have a continued opportunity to improve the communication methods of patient-centered teaching and care planning for cancer patients in remission.


Outcome of primary percutaneous coronary intervention at public sector tertiary care hospital in Pakistan.
To determine the outcome of Primary Precutaneous Coronary Intervention (PCI) in our setup and compare the results with the west. This study was conducted at a tertiary care teaching Hospital (National Institute of Cardiovascular Diseases Karachi, Pakistan) during January 1st, 2008 to December 31st, 2008. A total of 113 patients were enrolled who came with STEMI and agreed to go for Primary PCI. We excluded the patients who had history of Thrombolytic therapy within 24 hours, presented with Non ST-elevation Myocardial Infarction (NSTEMI) and coronary angiogram revealed significant left Main or equivalent disease. All Patients received Aspirin, Clopidogrel and Platelet Glycoprotein IIB IIIA Inhibitor. After Primary PCI patients were planned to follow at one month, 3 months and 6 months. Primary end point was to document death, MI, CABG and rehospitalization. Out of 113 cases, 102 (90.3%) were male and 11 (9.7%) were female, Mean age was 51.2 +/- 11.7 years, 54 (47.8%) patients had Hypertension, 28 (24.8%) were Diabetics and 44 (38.9%) were Smokers. Immediate success was achieved in 111 (98.2%) cases. In hospital mortality was 5.3% (3.5% in cardiogenic shock, 1.7% in non-shock patients). Mean Door to Balloon time remained 98.4 minutes. Twelve patients were lost to follow up. Therefore at 6 months, out of 101 patients, 8 (7.9%) died, 5 (4.9%) underwent Coronary Artery Bypass Graft (CABG) surgery and 5 (4.9 %) had been re-hospitalized either for recurrent myocardial infarction or heart failure. Optimal results of primary percutaneous coronary intervention can be achieved for acute STEMI in a developing country at a tertiary care public sector hospital. The results are comparable and nearly similar to the west.


Prophylactic antibiotics for manual removal of retained placenta in vaginal birth.
Retained placenta is a potentially life-threatening condition because of its association with postpartum hemorrhage. Manual removal of placenta increases the likelihood of bacterial contamination in the uterine cavity. To compare the effectiveness and side-effects of routine antibiotic use for manual removal of placenta in vaginal birth in women who received antibiotic prophylaxis and those who did not and to identify the appropriate regimen of antibiotic prophylaxis for this procedure. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2014). All randomized controlled trials comparing antibiotic prophylaxis and placebo or non antibiotic use to prevent endometritis after manual removal of placenta in vaginal birth. There are no included trials. In future updates, if we identify eligible trials, two review authors will independently assess trial quality and extract data No studies that met the inclusion criteria were identified. There are no randomized controlled trials to evaluate the effectiveness of antibiotic prophylaxis to prevent endometritis after manual removal of placenta in vaginal birth.


Reovirus and the Host Integrated Stress Response: On the Frontlines of the Battle to Survive.
Cells are continually exposed to stressful events, which are overcome by the activation of a number of genetic pathways. The integrated stress response (ISR) is a large component of the overall cellular response to stress, which ultimately functions through the phosphorylation of the alpha subunit of eukaryotic initiation factor-2 (eIF2α) to inhibit the energy-taxing process of translation. This response is instrumental in the inhibition of viral infection and contributes to evolution in viruses. Mammalian orthoreovirus (MRV), an oncolytic virus that has shown promise in over 30 phase I-III clinical trials, has been shown to induce multiple arms within the ISR pathway, but it successfully evades, modulates, or subverts each cellular attempt to inhibit viral translation. MRV has not yet received Food and Drug Administration (FDA) approval for general use in the clinic; therefore, researchers continue to study virus interactions with host cells to identify circumstances where MRV effectiveness in tumor killing can be improved. In this review, we will discuss the ISR, MRV modulation of the ISR, and discuss ways in which MRV interaction with the ISR may increase the effectiveness of cancer therapeutics whose modes of action are altered by the ISR.


In Vivo and In Vitro Toxicity Profiles of Hexane Extract of Alpinia malaccensis Rhizome in Rat and Cell Line Models.
The objective of the study was to evaluate the potential toxicity of crude n-hexane extract of Alpinia malaccensis rhizome. The in vivo acute oral toxicity was evaluated by administering a single oral dose of the extract at 0, 300, or 2000 mg/kg body weight to female Wistar rats according to modified OECD Test Guideline 423. For the in vitro cytotoxicity study, A549, HepG2, 3T3, and COS-7 cell lines were exposed to different doses of A. malaccensis extract and cell viability was assessed adopting MTT assay followed by AO/EB staining, Hoechst staining, and comet assay with a view to compare the cellular and molecular mechanisms underlying the toxicity, if any. It was found that administration of 2000 mg/kg bw dose in in vivo oral acute toxicity study did not produce significant toxicity or mortality. No significant (p < 0.05) differences were observed for body weight and hematological and biochemical parameters compared to control after 14 days of treatment. No changes in behavior, body weight, hematological and biochemical parameters, and aspects of histopathology were observed when compared to the control. Thus, the possible oral lethal dose for A. malaccensis extract is above 2000 mg/kg body weight. The in vitro cytotoxicity analysis showed nontoxicity concentrations of the extract to be 2, 1.4, 30, and 1.4 µg/mL for A549, HepG2, 3T3, and COS-7 cells, respectively, where no apoptotic/necrotic cell death and DNA damage were observed. In conclusion, the extract of rhizome of A. malaccensis did not produce apparent cytotoxicity or acute oral toxicity, confirming the scope to use A. malaccensis as a safe food preservative and a natural therapeutic product after further subacute and chronic toxicity studies.


Bowel preparation for colonoscopy: what is best and necessary for quality?
Colonoscopy is recognizably, the best colon cancer prevention test, provided the quality of the preparation is adequate for detection of precancerous polyps but also allowing for accurate identification of margins, thereby facilitating complete endoscopic resection. As there are many aspects effecting colon prep outcomes, it is timely to review new standards for optimizing outcomes, including product selection based on patient demographics. New national guidelines have set a minimum quality threshold for adequacy and also defined a split day delivery for oral options as the "standard of care". Several new prep options have been recently released and these data are discussed. Optimizing the quality of colon preps has major implications for clinical practice. Clinicians must recognize new targets for standard of care, providing the best approach for each individual patient, considering variable factors which may otherwise compromise success.


Folate, vitamin B12, homocysteine status and chromosome damage rate in lymphocytes of older men.
Deficient levels of folic acid and vitamin B12 are associated with elevated chromosome damage rate and high concentrations of homocysteine in the blood. We have therefore performed a study to determine the prevalence of folate deficiency, vitamin B12 deficiency and hyperhomocysteinemia in 64 healthy men aged between 50 and 70 years, and evaluate the relationship of these micronutrient levels in the blood with the micronucleus frequency in peripheral blood lymphocytes. We also performed a placebo-controlled, double-blind intervention study to determine whether supplementation of the diet with a daily dose of 0.7 mg (as a supplement in cereal) or 2.0 mg (in a tablet) over a period of 4 months resulted in a significant alteration of folate status, homocysteine status and the micronucleus index. Twenty-three per cent of the men were serum folate deficient (<6.8 nmol/l), 16% were red blood cell folate deficient (<317 nmol/l), 4.7% were vitamin B12 deficient (<150 pmol/l) and 37% has plasma homocysteine levels >10 micromol/l. In total, 56% of the men had one or more abnormal blood values for folate, vitamin B12 or homocysteine. The micronucleus index of these men (n = 34) in cytokinesis-blocked binucleated cells (19.2 +/- 1.1) was significantly elevated (P = 0.02) when compared to the micronucleus index of the rest of the men who had normal levels of folate, vitamin B12 and homocysteine (16.3 +/- 1.3, n = 30). Interestingly, the micronucleus index in men with normal folate and vitamin B12, but homocysteine levels >10 micromol/l (19.4 +/- 1.7, n = 15) was also significantly higher (P = 0.05) when compared to those with normal folate, vitamin B12 and homocysteine. This novel result was also supported by the observation that the micronucleus index and plasma homocysteine were significantly (P = 0.0086) and positively correlated (r2 = 0.172) in those subjects who were not deficient in folate or vitamin B12. The micronucleus index was not significantly correlated with folate indices, but there was a significant (P = 0.013) negative correlation with serum vitamin B12 (r2 = 0.099). Daily supplementation of the diet with 0.7 mg free folic acid in cereal for 2 months followed by 2.0 mg free folic acid via a tablet produced a 4-fold increase in plasma folate, a 2.6-fold increase in red blood cell folate and a 11% reduction in plasma homocysteine; however, these changes were not accompanied by a reduction in the micronucleus index. In conclusion, it is apparent that elevated homocysteine status, in the absence of vitamin deficiency and low, but not deficient, vitamin B12 status are important risk factors for increased chromosome damage in lymphocytes.


Discontinued in 2013: oncology drugs.
Introduction: Attrition in clinical development is widely recognised as a key factor negatively impacting overall R&D efficiency. Gaining an understanding of the reasons for candidate failure may lead to improvements in success rates and return on R&D investment. Areas covered: This report provides an analysis of reasons for discontinuation of development of 40 drugs dropped from the global oncology pipeline in 2013 - the largest number of terminations reported since this annual analysis began in 2005. The article also provides discussion on the observations in the context of contemporary views of anticancer drug development. Expert opinion: Twelve drugs (30% of the 2013 discontinuations) failed in Phase III development. None of the pivotal trials investigating these agents incorporated molecular biomarkers for patient stratification. The largest number of drug terminations (20 out of 40) occurred in Phase I development with reasons for termination commonly reported as strategic or undisclosed. Raising the bar in terms of requirements for progression from preclinical development, including the identification of robust pharmacodynamic biomarkers and biomarkers potentially predictive of clinical benefit may lead to an increase in success rates in clinical development and of overall R&D efficiency.


Two EST-derived marker systems for cultivar identification in tree peony.
Tree peony (Paeonia suffruticosa Andrews), a woody deciduous shrub, belongs to the section Moutan DC. in the genus of Paeonia of the Paeoniaceae family. To increase the efficiency of breeding, two EST-derived marker systems were developed based on a tree peony expressed sequence tag (EST) database. Using target region amplification polymorphism (TRAP), 19 of 39 primer pairs showed good amplification for 56 accessions with amplicons ranging from 120 to 3,000 bp long, among which 99.3% were polymorphic. In contrast, 7 of 21 primer pairs demonstrated adequate amplification with clear bands for simple sequence repeats (SSRs) developed from ESTs, and a total of 33 alleles were found in 56 accessions. The similarity matrices generated by TRAP and EST-SSR markers were compared, and the Mantel test (r = 0.57778, P = 0.0020) showed a moderate correlation between the two types of molecular markers. TRAP markers were suitable for DNA fingerprinting and EST-SSR markers were more appropriate for discriminating synonyms (the same cultivars with different names due to limited information exchanged among different geographic areas). The two sets of EST-derived markers will be used further for genetic linkage map construction and quantitative trait locus detection in tree peony.


Meniscal allograft transplantation: a review of the current literature.
Patients who have previously undergone meniscectomy are known to potentially suffer subsequent knee problems including degenerative changes. Meniscal transplantation has been proposed as a possible solution to these problems. This article aims to review the current literature to consolidate the evidence surrounding the use of human meniscal allograft transplantation. Three databases (PubMed, Embase and Medline) were searched to find English language articles pertaining to meniscal allograft transplantation. Each article was critiqued by two authors using a structured appraisal tool, and stratified according to the level of evidence. No Level I or II studies were identified. Many studies had small study groups with limited follow-up and patient selection and description of patient factors varied greatly. This made comparing data difficult. There were also very few papers concentrating on isolated meniscal transplantation. Four types of graft are used--fresh, fresh-frozen, cryopreserved and freeze-dried (lyophilised) graft. Cryopreserved and fresh-frozen allografts are deemed most suitable. Most authors advocate the use of non-irradiated grafts from screened donors to reduce transmission of infection. Best results occur when using bony anchors to fix the graft, although this requires accurate graft positioning. Patients have an improved outcome if they have less severe degenerative changes within the knee prior to transplantation. No statistically significant studies looking at isolated meniscal transplantations have been found. The evidence suggests that meniscal allograft transplantation provides improvement of pain and function in the short and intermediate term. The effect on future joint degeneration is still unknown. The ideal patient group includes patients less than 40 years of age with knee pain, proven meniscal injury and a normally aligned, stable joint without severe degenerative changes.


Plant community data from a statewide survey of paired serpentine and non-serpentine soils in California, USA.
Soils derived from ultramafic parent materials (hereafter serpentine) provide habitat for unique plant communities containing species with adaptations to the low nutrient levels, high magnesium : calcium ratios, and high metal content (Ni, Zn) that characterize serpentine. Plants on serpentine have long been studied in evolution and ecology, and plants adapted to serpentine contribute disproportionately to plant diversity in many parts of the world. In 2000-2003, serpentine plant communities were sampled at 107 locations representing the full range of occurrence of serpentine in California, USA, spanning large gradients in climate. In 2009-2010, plant communities were similarly sampled at 97 locations on nonserpentine soil, near to and paired with 97 of the serpentine sampling locations. (Some serpentine locations were revisited in 2009-2010 to assess the degree of change since 2000-2003, which was minimal.) At each serpentine or nonserpentine location, a north- and a south-facing 50 × 10 m plot were sampled. This design produced 97 "sites" each consisting of four "plots" (north-south exposure, serpentine-nonserpentine soil). All plots were initially visited three or more times over two years to record plant diversity and cover, and a subset were revisited in 2014 to examine community change after a drought. The original question guiding the study was how plant diversity is shaped by the spatially patchy nature of the serpentine habitat. Subsequently, we investigated how climate drives plant diversity at multiple scales (within locations, between locations on the same and different soil types, and across entire regions) and at different levels of organization (taxonomic, functional, and phylogenetic). There are no copyright restrictions and users should cite this data paper in publications that result from use of the data.


PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent synaptic plasticity.
Homozygous or compound heterozygous mutations in the phosphatase and tensin homolog-induced putative kinase 1 (PINK1) gene are causative of autosomal recessive, early onset Parkinson's disease. Single heterozygous mutations have been detected repeatedly both in a subset of patients and in unaffected individuals, and the significance of these mutations has long been debated. Several neurophysiological studies from non-manifesting PINK1 heterozygotes have demonstrated the existence of neural plasticity abnormalities, indicating the presence of specific endophenotypic traits in the heterozygous state. We performed a functional analysis of corticostriatal synaptic plasticity in heterozygous PINK1 knockout (PINK1(+/-) ) mice using a multidisciplinary approach and observed that, despite normal motor behavior, repetitive activation of cortical inputs to striatal neurons failed to induce long-term potentiation (LTP), whereas long-term depression was normal. Although nigral dopaminergic neurons exhibited normal morphological and electrophysiological properties with normal responses to dopamine receptor activation, a significantly lower dopamine release was measured in the striatum of PINK1(+/-) mice compared with control mice, suggesting that a decrease in stimulus-evoked dopamine overflow acts as a major determinant for the LTP deficit. Accordingly, pharmacological agents capable of increasing the availability of dopamine in the synaptic cleft restored normal LTP in heterozygous mice. Moreover, monoamine oxidase B inhibitors rescued physiological LTP and normal dopamine release. Our results provide novel evidence for striatal plasticity abnormalities, even in the heterozygous disease state. These alterations might be considered an endophenotype to this monogenic form of Parkinson's disease and a valid tool with which to characterize early disease stage and design possible disease-modifying therapies.


Use of genetic suppressor elements to dissect distinct biological effects of separate p53 domains.
p53 is a multifunctional tumor suppressor protein involved in the negative control of cell growth. Mutations in p53 cause alterations in cellular phenotype, including immortalization, neoplastic transformation, and resistance to DNA-damaging drugs. To help dissect distinct functions of p53, a set of genetic suppressor elements (GSEs) capable of inducing different p53-related phenotypes in rodent embryo fibroblasts was isolated from a retroviral library of random rat p53 cDNA fragments. All the GSEs were 100-300 nucleotides long and were in the sense orientation. They fell into four classes, corresponding to the transactivator (class I), DNA-binding (class II), and C-terminal (class III) domains of the protein and the 3'-untranslated region of the mRNA (class IV). GSEs in all four classes promoted immortalization of primary cells, but only members of classes I and III cooperated with activated ras to transform cells, and only members of class III conferred resistance to etoposide and strongly inhibited transcriptional transactivation by p53. These observations suggest that processes related to control of senescence, response to DNA damage, and transformation involve different functions of the p53 protein and furthermore indicate a regulatory role for the 3'-untranslated region of p53 mRNA.


[Tibial lengthening by transepiphyseal distraction of the proximal growth plate. An experimental study in the rabbit (author's transl)].
Lengthening by transepiphyseal distraction has been used in man by several authors, but experimental results are variable. In this study twenty young rabbits have been submitted to elongation, half with circumferential metaphyseal release, half without. Lengthening obtained at the end of the growing period has been poor or negative in case with periosteal release, a little better without this incision.


Seed predators exert selection on the subindividual variation of seed size.
Subindividual variation among repeated organs in plants constitutes an overlooked level of variation in phenotypic selection studies, despite being a major component of phenotypic variation. Animals that interact with plants could be selective agents on subindividual variation. This study examines selective pressures exerted during post-dispersal seed predation and germination on the subindividual variation of seed size in hawthorn (Crataegus monogyna). With a seed offering experiment and a germination test, we estimated phenotypic selection differentials for average and subindividual variation of seed size due to seed predation and germination. Seed size affects germination, growth rate and the probability of an individual seed of escaping predation. Longer seeds showed higher germination rates, but this did not result in significant selection on phenotypes of the maternal trees. On the other hand, seed predators avoided wider seeds, and by doing so exerted phenotypic selection on adult average and subindividual variation of seed size. The detected selection on subindividual variation suggests that the levels of phenotypic variation within individual plants may be, at least partly, the adaptive consequence of animal-mediated selection.


Effect of defatted rice bran supplementation on metabolic parameters and inflammatory status in overweight/obese adults with hypercholesterolemia: a randomized, placebo-controlled intervention.
Defatted rice bran (DRB) is a byproduct of rice bran oil production rich in fiber, protein, and antioxidant compounds that may confer beneficial effects on metabolic profiles in humans. The current study aimed to investigate the effects of DRB supplementation on anthropometric and blood biochemical indices, dietary intake, and inflammatory status in overweight/obese subjects with hypercholesterolemia. In a 12-week-randomized placebo-controlled trial, 61 overweight/obese participants with a total cholesterol level > 200 mg/dL were randomly assigned either to 30 g/d DRB (n = 30) or to 10 g/d maltodextrin (n = 31). DRB intervention significantly reduced systolic and diastolic blood pressure by 4.27 and 4.50%, respectively (126.20 ± 13.63 to 120.60 ± 13.72 mmHg, p = 0.0003 and 80.87 ± 7.38 to 77.17 ± 9.83 mmHg, p = 0.0035). HbA1c also decreased significantly by 3.59% (5.89% ± 0.76% to 5.66% ± 0.62%, p = 0.0001) after DRB supplementation. Total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels also decreased insignificantly by 3.12, 1.32, and 1.53%, respectively, after DRB supplementation. Insignificant differences in fasting blood glucose, insulin, homeostatic model assessment of insulin resistance, quantitative insulin sensitivity check index, hs-CRP and homocysteine levels were also observed after DRB intervention. Reduction in caloric and fat intake were reported in DRB groups. DRB supplementation improved blood pressure and HbA1c levels. It also lowered blood cholesterol, albeit insignificantly. Caloric and fat intake were also significantly lower after DRB supplementation. Further study is needed to evaluate the mechanisms by which DRB improves these metabolic indices. Thai Clinical Trial Registration ( https://www.thaiclinicaltrials.org/. ) Thai Clinical Trial Registration number: TCTR20191020003. Registered 20 October 2019.


Paediatric post-concussive symptoms: symptom clusters and clinical phenotypes.
To assess the co-occurrence and clustering of post-concussive symptoms in children, and to identify distinct patient phenotypes based on symptom type and severity. We performed a secondary analysis of the prospective, multicentre Predicting and Preventing Post-concussive Problems in Pediatrics (5P) cohort study, evaluating children 5-17 years of age presenting within 48 hours of an acute concussion. Our primary outcome was the simultaneous occurrence of two or more persistent post-concussive symptoms on the Post-Concussion Symptom Inventory at 28 days post-injury. Analyses of symptom and patient clusters were performed using hierarchical cluster analyses of symptom severity ratings. 3063 patients from the parent 5P study were included. Median age was 12.1 years (IQR: 9.2-14.6 years), and 1857 (60.6%) were male. Fatigue was the most common persistent symptom (21.7%), with headache the most commonly reported co-occurring symptom among patients with fatigue (55%; 363/662). Headache was common in children reporting any of the 12 other symptoms (range: 54%-72%). Physical symptoms occurred in two distinct clusters: vestibular-ocular and headache. Emotional and cognitive symptoms occurred together more frequently and with higher severity than physical symptoms. Fatigue was more strongly associated with cognitive and emotional symptoms than physical symptoms. We identified five patient groups (resolved/minimal, mild, moderate, severe and profound) based on symptom type and severity. Post-concussive symptoms in children occur in distinct clusters, facilitating the identification of distinct patient phenotypes based on symptom type and severity. Care of children post-concussion must be comprehensive, with systems designed to identify and treat distinct post-concussion phenotypes.


Additive solutions for better blood preservation.
For several decades the standard blood preservative solution consisted of citrate, dextrose, and, later, phosphate (ACD and CPD). In 1978 a new solution containing adenine (CPDA-1) was introduced to permit extension of red cell shelf life from 21 to 35 days. The success of CPDA-1 and the high percentage of blood units processed into components (estimated 87% in 1983) have stimulated a burst of research and development activity to develop improved red cell preservation systems. Most of these systems have taken the form of "additive solutions" in which the blood is drawn in CPD or CP2D and processed into components. Then the packed red cells are stored by addition of a solution customized for their preservation. This review evaluates these additive solutions in detail. Innovative systems for pH control (buffers and resins) have also been explored. Our review concludes with discussion of the safety aspects of new preservative solutions and the methodological problems of evaluating these solutions.


Systematic Evaluation of Chiral Fungicide Imazalil and Its Major Metabolite R14821 (Imazalil-M): Stability of Enantiomers, Enantioselective Bioactivity, Aquatic Toxicity, and Dissipation in Greenhouse Vegetables and Soil.
Chiral pesticides are often produced and applied without distinguishing the difference of enantiomers, which sometimes leads to overuse and inaccurate risk assessment. Imazalil is a widely used chiral fungicide; its parent and major metabolite R14821 (imazalil-M) are usually detected in environmental and plant samples. The enantioselective bioactivity of imazalil enantiomers to seven typical pathogens (e.g., Fulvia fulva) was explored. S-(+)-Imazalil showed 3.00-6.59 times higher bioactivity than its antipode for selected pathogens. Molecular docking partly explained the mechanism of enantioselectivity in bioactivity. S-(+)-Imazalil had a stronger hydrophobic interaction and lower energy conformation with binding sites than R-(-)-imazalil. The acute toxicity of S-(+)-imazalil was 1.23-fold and 2.25-fold more than R-(-)-imazalil to P. subcapitata and D. magna, respectively. And, S-(+)-imazalil-M had 2.21-fold and 1.70-fold higher toxicity than R-(-)-imazalil-M to P. subcapitata and D. magna, respectively. However, R-(-)-imazalil was 1.21 times more toxic than S-(+)-imazalil to D. rerio. The enantioselective dissipation of imazalil and imazalil-M was explored under greenhouse conditions. High-effective S-(+)-imazalil preferentially enriched in leaf and fruit of tomato and cucumber, and no enantioselective degradation was found in soil. Imazalil-M enantiomers formed in cucumber, leaf of cucumber, and tomato, and the EF values fluctuated between 0.332 and 0.499. The results could provide information for more accurate assessment of imazalil; they implicated that using S-(+)-imazalil could reduce pesticide input and the risk to D. rerio.


[Juvenile polyposis coli. The usefulness of a genetic study and the role of surgical treatment].
We report two cases of familial juvenile polyposis coli. SMAD4 gene mutation was found in our two patients, leading to the definite diagnosis. Colonic cancer occurred in the first patient. Long-term outcome was favorable after colectomy. In the second patient, prophylactic total colectomy was performed. Rectal bleeding, diarrhea, stomach obstruction and vomiting developed during the follow-up. Proctectomy, distal partial gastrectomy and total gastrectomy were successively performed.


[Genetic diversity of Polygonum capitatum from Guizhou populations by ISSR markers].
To detect genetic diversity of 48 population of Polygonum capitatum in Guizhou province. The genetic diversity of 48 representational populations of P. capitatum including 240 individuals had been investigated by ISSR marker technique. The genetic diversity had been revealed as follow: A total of 8 293 bands were produced in 240 individuals, of which 7 962 bands were common in the 48 population. The value of the average percentage of polymorphic bands (PPB) was 79.09%, Nei's genetic diversity index (H(e)) was 0.245 8, Shannon's information index (I) was 0.396 2, and genetic differentiation index (G(st)) was 0.238 0 at population level, respectively. The genetic differentiation index (G(st)) was 0.072 2, genetic differentiation coefficient by Shannon's diversity (I(st)) was 0.044 2 within the population levels. Groups cluster analysis based on the UPGMA method indicated that although the 48 populations could be divided into 3 groups and the P. capitatum seed sources. The groups cluster showed that a cross clustering of P. capitatum between the southwest and southeast populations in Guizhou province, and no significant correlation was found between geographical and genetic distance among them. The genetic diversity of P. capitatum is relatively high at the population levels, while low within the population levels, a significant degree of genetic differentiation occurs among the populations. The groups cluster analysis indicated they has not apparent genetic variation in regional pattern between the place of origin populations and the migrate populations.


The putative mechanism of thrombosis in antiphospholipid syndrome: impairment of the protein C and the fibrinolytic systems by monoclonal anticardiolipin antibodies.
The mechanism of thrombosis in patients with antiphospholipid syndrome is not clear. To investigate it, we examined the effect of monoclonal anticardiolipin (aCL) antibodies and beta2-glycoprotein I (beta2-GPI), which is required for formation of the aCL epitopes, on activated protein C (APC) and on fibrinolytic activity. First, APC activities were measured in the presence and absence of beta2-GPI or gamma M immunoglobulin (IgM) monoclonal aCLs (EY1C8 and EY2C9), or both, established from peripheral blood lymphocytes obtained from a patient with aCL. beta2-GPI exhibited a procoagulant activity by inhibiting APC activity as well as an anticoagulant activity by inhibiting thrombin generation. Any further inhibition of APC activity was caused by monoclonal aCL, and then only in the presence of beta2-GPI. The remaining tissue plasminogen activator (t-PA) of the sample consisting of beta2-GPI, two-chain recombinant t-PA, and plasminogen activator inhibitor (PAI)-1 was measured by a chromogenic assay using the synthetic substrate S-2251, Glu-plasminogen, and soluble fibrin monomer. beta2-GPI protected t-PA activity from inhibition by PAI-1. However, monoclonal aCLs (EY1C8 and EY2C9) inhibited the effect of beta2-GPI on fibrinolytic activity; that is, monoclonal aCLs inhibited fibrinolytic activity by elevating PAI-1 activity. Thrombosis in patients with aCL can be explained in part by both the inhibition of APC anticoagulant activity and the impairment of fibrinolytic activity by aCL.


Electric-field-induced spin spiral state in bilayer zigzag graphene nanoribbons.
We investigated the emergence of spin spiral ground state induced by the electric field in the bilayer zigzag graphene nanoribbons for the ferromagnetic edge states. To do that, we employed the generalized Bloch theorem to create flat spiral alignments for all the magnetic moments of carbon atoms at the edges within a constraint scheme approach. While the small ribbon width can preserve the ferromagnetic ground state, the large one shows the spiral ground state starting from a certain value of the electric field. We also pointed out that the spiral ground state is caused by the reduction of spin stiffness. In this case, the energy scale exhibits a subtle nature that can only be considered at the low temperature. For the last discussion, we also revealed that the spin spiral ground state appears more rapidly when the thickness increases. Therefore, we justify that the large ribbon width and large thickness can generate many spiral states induced by the electric field.


Presenilin 1 mutations increase amyloid precursor protein production and proteolysis in Xenopus laevis oocytes.
Recent findings suggest that Presenilin 1 (PS1) mutations play a major role in the development of Alzheimer's disease (AD) by increasing the production of the beta amyloid peptide (A beta). The exact mechanism whereby mutations in PS1 lead to this effect is not clear. To examine the question of how PS1 might be involved in amyloid precursor protein (APP) processing, we constructed a chimera of human APP695 fused at the C-terminal to enhanced green fluorescent protein (EGFP). This construct was injected into Xenopus laevis oocytes in the presence of wild type PS1 or one of three PS1 mutations associated with AD. The cellular location of the APP695-EGFP construct was examined by fluorescent confocal microscopy. In addition, membrane fractions of oocytes expressing APP695-EGFP in the presence or absence of wild type or mutant forms of PS1 were evaluated by Western blot analysis. The results show that APP695-EGFP is primarily expressed on the cell surface and undergoes limited cleavage. Specifically, APP695 was cleaved in the A beta domain to generate three distinct C-terminal fragments that correspond in length to stubs expected after cleavage with alpha-, beta- and gamma-secretase, respectively. The presence of wild type PS1 not only increased the production of proteolytic C-terminal fragments of APP, but the production of APP itself. These findings were even more pronounced in the presence of all three PS1 mutations, suggesting that PS1 mutations may lead to over-expression of APP not just increased gamma-secretase activity.


Short report: one case of nasal human myiasis caused by third stage instar larvae of Oestrus ovis.
This is a report of a case of human nasal myiasis caused by third instar larvae of the sheep nasal bot fly, Oestrus ovis. Female flies rarely deposit first instar larvae in the eye, nostrils, and external auditory canal of humans, where they usually survive only a few days without further development. One human infestation by third instar larvae of O. ovis has been recorded in an patient infected with human immunodeficiency virus (HIV) in the United Kingdom. Our report describes a new case of nasal myiasis caused by the third instar larvae of the sheep bot fly in a patient without HIV or signs of any other disease.


Enhanced T cell suppression is directed toward sensitive circulating B cells in multiple myeloma.
Multiple myeloma, a disorder typically accompanied by monoclonal immunoglobulin excess and hypogammaglobulinemia was evaluated to delineate the status of T cell regulation on malignant B cell proliferation. Intact T cells and T cell subsets previously noted by us to be suppressor (T gamma) and helper (T non-gamma) were isolated from 10 controls and 10 myeloma patients. Various concentrations of control and patient T cell subsets were mixed with control and patient B cells and stimulated with PWM. T cell effect on B cell proliferation as measured by [3H]thymidine incorporation was then determined. Myeloma T gamma cells were more effective than control T gamma cells in suppressing control or myeloma B cell [3H]thymidine incorporation. Interestingly, myeloma B cells, when added to myeloma T gamma cells, were suppressed to a greater extent than were control B cells when mixed with a similar concentration of myeloma T gamma cells. These in vitro studies suggest a complexity of B and T cell abnormalities in multiple myeloma; first, the myeloma B cells are extremely sensitive to T gamma cell suppression, and second, myeloma T gamma cells have excessive suppressor capacity. It is yet unclear whether these results are associated with an immunoregulatory response to this malignancy or represent part of the basic disease process.


Comparison of patients with ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA) from a single rheumatology clinic in New Delhi.
Comparison of ankylosing spondylitis (AS) with non-radiographic axial spondyloarthritis (nr-axSpA) classified with the recent ASsessment of spondyloArthritis International Society (ASAS) criteria. This study included 288 patients clinically diagnosed as having spondyloarthritis (SpA) where a satisfactory radiograph of sacroiliac (S-I) joints was available. The AS and the nr-axSpA groups were compared for the various SpA-related variables. Of 288 axSpA patients, there were 187 with AS. Of the remaining 101 patients without radiographic sacroiliitis, S-I joint magnetic resonance imaging (MRI) was available in 72; 54 of them showed active sacroiliitis thus classified as nr-axSpA according to the ASAS criteria. The remaining 18 patients with normal MRI and the other 29 patients without MRI of the S-I joints (total 47 patients), were classified as nr-axSpA using the 'clinical arm' of the ASAS criteria. On comparing the 187 AS with 101 patients in the nr-axSpA group, the AS group showed significantly more males, longer disease duration, more axial symptoms at disease onset, higher Bath Ankylosing Spondylitis Metrology Index and more syndesmophytes. Biologicals were offered significantly more often to the AS group but methotrexate as monotherapy or in combination with other disease-modifying anti-rheumatic drugs was offered more often in nr-axSpA group. There was no statistically significant difference between AS and nr-axSpA in other SpA parameters. The differences brought out between AS and nr-axSpA groups show that they may not be the same disease. A prospective long-term follow-up of large cohorts may help in clarifying if nr-axSpA is simply an early stage in the spectrum of SpA evolving into AS over time or is there inherent difference between them.


Conventional Tumor Markers in Cerebralspinal Fluid in Patients with Elevated Serum Tumor Markers and without Central Nervous System Malignant Diseases.
Objective To explore the diffusion pattern of tumor markers (TM) from serum to cerebrospinal fluid (CSF) via the blood-brain barrier in patients with elevated serum tumor markers (TM).Methods Inpatients receiving lumbar puncture during hospitalization in our center from January 1, 2013 to December 31, 2015 were divided into study group (n=181) and control group (n=251). The study group consisted of patients with elevated serum TMs but without malignant central nervous system diseases. The control group consisted of patients with normal serum TM levels and without malignant diseases. TMs measured in the study group included elevated serum alpha-fetoprotein (AFP) (n=0), carcinoembryonic antigen (CEA) (n=26), carcinomic antigen(CA)125 (n=39), CA15- 3 (n=3),CA19- 9 (n=19), CA724 (n=47), CYFRA21- 1 (n=49), and SCC (n=17).Levels of TMs in the CSF of study group was compared with that of control group.Results Median CEA (U=0.00,P=0.00),CA19- 9 (U=0.00,P=0.00),CA15- 3 (U=0.00,P=0.04),SCC (U=0.00,P=0.00),CA125 (U=0.00,P=0.00),CA72- 4 (U=3.00,P=0.00)),and CYFRA21- 1 (U=0.00,P=0.00) in CSF were significantly lower than the corresponding serum TM levels in the study group.There was no significant difference between study group and control group for the CSF level of CEA (U=3091.00,P=0.18),CA19- 9 (U=1897.00,P=0.14), CA15- 3 (U=373.50,P=0.91)and SCC (U=1925.50,P=0.76). CSF CA125 (U=2188.00,P=0.00) and CA724 (U=1279.00,P=0.00) levels in the study group were lower than those in control group. CSF level of CYFRA21- 1 (U=1826.50,P=0.00) in study group was higher than that in control group;however, it was still lower than the upper limit of reference value. Conclusion In patients with elevated serum CEA, CA19- 9, CA15- 3, SCC, CA125, and CA72- 4 levels, transblood-brain-barrier diffusion of TMs from serum to CSF is highly unlikely.