Biochar ageing improves soil properties, growth and yield of red radish (Raphanus sativus) in a Haplic Cambisol.
The use of biochar as a soil ameliorant has recently gained momentum. However, its application has been reported to have some adverse effects soon after the pyrolysis process. This study aimed to determine the effect of different biochar ageing methods and fertiliser applications on selected soil properties, growth, and yield of red radish (Raphanus sativus L.). A 2 x 3 factorial arrangement was used in a complete randomised design (CRD) with three replications. The factors were (1) biochar ageing at three levels, i.e., naturally aged biochar (NB), artificially aged biochar (AB), and fresh biochar (FB), and (2) fertiliser at two levels viz fertilised (F) and non-fertilised (NF). A control treatment (without biochar) was also included. Irrespective of the ageing method used, biochar application significantly increased soil pH, while fertiliser application significantly reduced soil pH throughout the experiment. Similarly, biochar application significantly increased soil hydraulic conductivity compared to the control. However, after ten weeks, significantly higher soil hydraulic conductivity was reported in treatments with AB biochar compared to both NB and FB. The application of fertiliser in biochar-amended soils improves the soil's hydraulic properties and increases radish growth. The study concludes that AB biochar + fertiliser application improves soil properties and growth of radish.


Network architecture associated with the highly specialized hindlimb of frogs.
Network analyses have been increasingly used in the context of comparative vertebrate morphology. The structural units of the vertebrate body are treated as discrete elements (nodes) of a network, whose interactions at their physical contacts (links) determine the phenotypic modules. Here, we use the network approach to study the organization of the locomotor system underlying the hindlimb of frogs. Nodes correspond to fibrous knots, skeletal and muscular units. Edges encode the ligamentous and monoaxial tendinous connections in addition to joints. Our main hypotheses are that: (1) the higher centrality scores (measured as betweenness) are recorded for fibrous elements belonging to the connective system, (2) the organization of the musculoskeletal network belongs to a non-trivial modular architecture and (3) the modules in the hindlimb reflect functional and/or developmental constraints. We confirm all our hypotheses except for the first one, since bones overpass the fibrous knots in terms of centrality. Functionally, there is a correlation between the proximal-to-distal succession of modules and the progressive recruitment of elements involved with the motion of joints during jumping. From a developmental perspective, there is a correspondence between the order of the betweenness scores and the ontogenetic chronology of hindlimbs in tetrapods. Modular architecture seems to be a successful organization, providing of the building blocks on which evolution forges the many different functional specializations that organisms exploit.


A novel late-onset axial myopathy associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene.
Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of inherited neuromuscular disorders and have been associated with a wide clinical spectrum, ranging from various congenital myopathies to the malignant hyperthermia susceptibility (MHS) trait without any associated weakness. RYR1-related myopathies are usually of early-childhood onset. Here we present 11 patients from 8 families with a late-onset axial myopathy associated with RYR1 variants. Patients presented between the third and seventh decade of life to neuromuscular centres in Norway, the Netherlands and the United Kingdom with predominant axial muscle involvement, comprising variable degrees of lumbar hyperlordosis, scapular winging and/or camptocormia. Marked myalgia was commonly associated. Serum creatine kinase levels were normal or moderately elevated. Muscle imaging showed consistent involvement of the lower paravertebral muscles and the posterior thigh. Muscle biopsy findings were often discrete, featuring variability in fibre size, increased internal nuclei and unevenness of oxidative enzyme staining, but only rarely overt cores. RYR1 sequencing revealed heterozygous missense variants, either previously associated with the MHS trait or localizing to known MHS mutational hotspots. These findings indicate that MHS-related RYR1 mutations may present later in life with prominent axial weakness but not always typical histopathological features. We propose a combined effect of RyR1 dysfunction, aging and particular vulnerability of axial muscle groups as a possible pathogenic mechanism. RYR1 is a candidate for cases with "idiopathic" camptocormia or bent spine syndrome (BSS).


Opportunities for Data Science in the Pharmaceutical Industry: The Use of Data to Find Efficiencies in Drug Development Can?t Come Too Soon.
By the numbers, 2016 was not a good year for the U.S. pharmaceutical industry. As of early December, only 19 new drugs had been approved by the Food and Drug Administration (FDA), fewer than half of those approved in 2015 and the lowest number since 2007. Further, the FDA approved only 61% of submissions in 2016, compared to 95% in 2015 [1]. And, among the largest companies, the return on investment for research and development (R&D) fell to 3.7% [2].


The relationship between indicators of socioeconomic status and cesarean section in public hospitals.
To assess the relationship between indicators of socioeconomic status and cesarean section in public hospitals that adopt standardized protocols of obstetrical care. This was a prospective cohort study conducted between May 2005 and January 2006 with 831 pregnant women recruited from 10 public primary care clinics in São Paulo, Brazil. Demographic and clinical characteristics were collected during pregnancy. The three main exposures were schooling, monthly family income per capita, and residential crowding. The main outcome was cesarean section at three public hospitals located in the area. Crude and adjusted risk ratios (RR), with 95% confidence intervals were calculated using Poisson regression with robust variance. We examined the effects of each exposure variable on cesarean section accounting for potential confounders by using four different models: crude, adjusted by mother's characteristics, by obstetrical complications, and by the other two indicators of socioeconomic status. Among the 757 deliveries performed in the public hospitals, 215 (28.4%) were by cesarean section. In the bivariate analysis, cesarean section was associated with higher family income per capita, higher education, lower residential crowding, pregnancy planning, white skin color, having a partner, and advanced maternal age. In the multivariate analysis, after adjustment for covariates, none of the socioeconomic status variables remained associated with cesarean section. In this group, the chance of women undergoing cesarean section was not associated with indicators of socioeconomic status only, but was defined in accordance with major obstetric and clinical conditions.


The utility of cerebral perfusion SPECT analysis using SPM8, eZIS and vbSEE for the diagnosis of multiple system atrophy-parkinsonism.
Although a correct diagnosis is important for appropriate management, accurately differentiating between multiple system atrophy with predominant parkinsonism (MSA-P) and Parkinson's disease (PD) is often difficult because of similarities in the early-stage symptoms. The aim of this study was to evaluate the diagnostic value of cerebral perfusion single photon emission computed tomography (SPECT) and voxel-based analysis for diagnosing MSA-P patients. Thirty-eight subjects (9 with early-stage MSA-P, 11 with PD, and 18 controls) were included in this study. Z-scores suggestive of hypoperfusion were calculated between patients and controls using statistical parametric mapping (SPM) 8 and easy Z-score imaging system (eZIS) programs. A voxel-based stereotactic extraction estimation (vbSEE) program was performed to determine the target volumes of interest (VOIs) in the putamen, pons, and cerebellum, and quantify Z-scores as "extent" (the rate of voxels with a Z-score >2.0 in these VOIs) and "severity" (average Z-scores in these VOIs). These parameters were used as the determinant in receiver operating characteristic (ROC) analyses. The extent and severity of the cerebellar VOIs were higher in MSA-P patients than in PD patients. In ROC analyses, the extent and severity of the cerebellar VOI exhibited the highest areas under the curves of 0.86 and 0.84, and accuracies of 90 and 90 %, respectively. The diagnostic value of significant cerebellar hypoperfusion was the highest for differentiating MSA-P from PD. This voxel-based analysis of cerebral perfusion SPECT using the SPM8, eZIS, and vbSEE programs is useful for clinically diagnosing MSA-P.


Diabetic neuropathy and painful diabetic neuropathy: Cinderella complications in South East Asia.
The most common and debilitating microvascular complication of diabetes is diabetic peripheral neuropathy (DPN), affecting 50-90% of people with diabetes. The major manifestations of DPN are painful (pDPN) and painless diabetic peripheral neuropathy. Painful symptoms, occur in the feet and are worse at night and whilst they alert both the patient and physician, are often misdiagnosed and mismanaged. The devastating presentation of painless neuropathy with loss of sensation is foot ulceration and Charcot foot. The explosion of diabetes, especially in the South East Asian (SEA) region will result in an increasing prevalence of both painful and painless diabetic peripheral neuropathy. PubMed, EMBASE, Medline and Google Scholar databases were searched between 1990 and 2017. This highlights the widely varying prevalence of DPN and pDPN in the World Health Organization (WHO) defined SEA countries and the dearth of published studies, especially in pDPN. We believe this will provide new direction for future research on DPN in the SEA region.


[The problem in the reactivation of microorganisms on evaluating the efficacy of water disinfectants].
The investigation deals with the topical problem of whether bacterial viability and properties may be restored after the achieved bacteriostatic effect of water disinfection, which reduces the reliability of the control and adequate assessment of its epidemic safety. The objective of the investigation was to study whether bacteria might be reactivated in the estimation of water disinfection with guanidine-containing agents as an alternative to chlorine. Experiments were carried out on the waters from model water reservoirs, by simulating water contamination with residential waste waters and on the natural water from the Moscow River, by reproducing the purification conditions: coagulation, filtration, disinfection with a binary mixture of polyhexamethyleneguanidine hydrochloride and quaternary ammonium compound. The experimental studies of the efficacy of the binary agent against indicator, opportunistic, and pathogenic bacteria indicated that the viability of bacterial cells might be reactivated and restored after water disinfection and cell multiplication upon further exposure. Microorganisms that had the greatest capacity for reactivation after use of the binary agent, as evidenced by the group values of the total number of saprophytes (microbial number) at 37 degrees C, coliform bacteria, and Pseudomonas aeruginosa, were identified. The findings show it necessary to consider reactivation processes in the evaluation of novel disinfectants, which requires a supplemented procedure for obligatorily estimating their exposure 24 hours after use of a reagent.


Fungal ornithine esterases: relationship to iron transport.
Extracts of Fusarium roseum (ATCC 12822) contain an enzyme which hydrolyzes the ornithine ester bonds of fusarinine C, a cyclic trihydroxamic acid produced by this organism. The methyl ester of Ndelta-dinitrophenyl-L-ornithine is also a substrate for the enzyme, and an assay was devised using this substrate. The enzyme exhibits a sharp maximum of activity at pH 7.5 and is extremely temperature sensitive. It is strongly inhibited by HgCl2 and p-chloromercuribenzoate, and it is competitively inhibited by Ndelta-dinitrophenyl-D-ornithine methyl ester (Ki = 0.3mM). Methyl esters of glycine, L-alanine, dinitrophenyl-L-alanine, dinitrophenyl-beta-alanine, and Ndelta-dinitrophenyl-Nalpha-acetyl-L-ornithine are not substrates, although Nepsilon-dinitrophenyl-L-lysine methyl ester is as effective as the ornithine derivative. Nonspecific lipases do not hydrolyze ornithine esters, nor does trypsin. The three ester bonds of fusarinine C are progressively hydrolyzed by the enzyme to eventually yield the monomer, fusarinine. The ferric chelate of fusarinine C is not hydrolyzed. An enzyme from Penicillium sp. was isolated with identical properties toward Nbeta-dinitro-phenyl-L-ornithine methyl ester as substrate. It also hydrolyzes N,N',N"-triacetylfusarinine C, a cyclic trihydroxamate containing Nalpha-acetylornithine ester bonds, which is produced by this organism. This substrate is hydrolyzed to Nalpha-acetylfusarine. In contrast to the Fusarium enzyme, this enzyme is fully active toward the ferric trihydroxamate chelate. However, replacement of iron by aluminum leads to a completely inactive substrate. Production of the enzyme is severely suppressed by iron in the growth medium. It is proposed that these specific ornithylesterases provide a mechanism of cellular iron release by hydrolysis of the ferric ionophores, and that an iron-exchange step occurs prior to, and is a prerequisite for, hydrolysis of the ester bonds.


On-line screening of conformationally constrained nicotines and anabasines for agonist activity at the alpha3beta4- and alpha4beta2-nicotinic acetylcholine receptors using immobilized receptor-based liquid chromatographic stationary phases.
Liquid chromatography columns containing stationary phases based upon immobilized nicotinic acetylcholine receptors (nAChRs) were used to screen a series of conformationally constrained nicotine and anabasine derivatives for agonist activity. The alpha3beta4 nAChR and alpha4beta2 nAChR subtypes were used to prepare the chromatographic columns and [(3)H] epibatidine dihydrochloride ([(3)H] EB) was used as the marker ligand. Single displacement experiments were conducted with the test ligands and with nicotine and carbachol. Nicotine was used as an internal control for compounds with agonist activity and carbachol was used as an internal control for compounds with very weak agonistic activity (K(d) > 4700 nM for alpha3beta4). The displacement of [(3)H] EB by each of the test compounds and internal controls was calculated and expressed as Deltaml. Functional studies were then conducted using a stably transfected cell line that expresses the alpha3beta4 nAChR and EC(50) values were determined for the test compounds and the internal controls. A comparison of the Deltaml and EC(50) values indicated that 9/11 compounds had been correctly identified as agonists or non-agonists of the alpha3beta4 nAChR. A similar comparison could not be made for the alpha4beta2 nAChR, since the intact cell line was not available for testing. The results of the study suggest that the immobilized nAChR columns can be used for the rapid on-line screening of compounds for their relative affinities for the immobilized receptor and as an initial determination of qualitative functional activities.


Serum Lipids and Proliferative Diabetic Retinopathy and Macular Edema in Persons With Long-term Type 1 Diabetes Mellitus: The Wisconsin Epidemiologic Study of Diabetic Retinopathy.
Total serum and high-density lipoprotein cholesterol have been considered risk factors for severe vascular outcomes in persons with type 1 diabetes mellitus. To examine the long-term relationships between these 2 serum lipids and the incidence and prevalence of proliferative diabetic retinopathy and macular edema. Nine-hundred three persons with younger-onset type 1 diabetes mellitus who participated in the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Serum total and high-density cholesterol and history of statin use during the course of 5 visits spanning approximately 30 years (April 10, 1984, to February 13, 2014). Prevalence and incidence of proliferative diabetic retinopathy and macular edema. A modest association was found for higher levels of high-density lipoprotein cholesterol and decreased prevalence of proliferative diabetic retinopathy (odds ratio per 10 mg/dL, 0.87; 95% CI, 0.82-0.93), adjusting for duration of diabetes mellitus, glycosylated hemoglobin A1c, statin use, and end-stage renal disease. While adjusting for covariates, no associations of serum total or high-density lipoprotein cholesterol and incident proliferative diabetic retinopathy or macular edema, nor of statin use with decreased incidence of proliferative diabetic retinopathy or macular edema, were identified. In the course of long-duration diabetes mellitus during a time of changing medical care, there appeared to be little effect of serum lipids or statins on the incidence of proliferative diabetic retinopathy and macular edema.


Funding for teratology information services: up, down, and all around.
Funding for Teratology Information Services has been an ongoing struggle over the 25 years of its existence. Traditional and novel funding mechanisms have been explored with varying success. The importance of providing teratology risk assessment and counseling to all women of reproductive age is now an established health care objective. Sufficient and stable funding for these services is essential.


Chain termination and inhibition of Saccharomyces cerevisiae poly(A) polymerase by C-8-modified ATP analogs.
The nucleotide substrate specificity of yeast poly(A) polymerase (yPAP) toward various C-2- and C-8-modified ATP analogs was examined. 32P-Radiolabeled RNA oligonucleotide primers were incubated with yPAP in the absence of ATP to assay polyadenylation using unnatural ATP substrates. The C-2-modified ATP analogs 2-amino-ATP and 2-chloro (Cl)-ATP were excellent substrates for yPAP. 8-Amino-ATP, 8-azido-ATP, and 8-aza-ATP all produced chain termination of polyadenylation, and no primer extension was observed with the C-8-halogenated derivatives 8-Br-ATP and 8-Cl-ATP. The effects of modified ATP analogs on ATP-dependent poly(A) tail synthesis by yPAP were also examined. Whereas C-2 substitution (2-amino-ATP and 2-Cl-ATP) had little effect on poly(A) tail length, C-8 substitution produced moderate (8-amino-ATP, 8-azido-ATP, and 8-aza-ATP) to substantial (8-Br-ATP and 8-Cl-ATP) reduction in poly(A) tail length. To model the biochemical consequences of 8-Cl-Ado incorporation into RNA primers, a synthetic RNA primer containing a 3'-terminal 8-Cl-AMP residue was prepared. Polyadenylation of this modified RNA primer by yPAP in the presence of ATP was blocked completely. To probe potential mechanisms of inhibition, two-dimensional NMR spectroscopy experiments were used to examine the conformation of two C-8-modified AMP nucleotides, 8-Cl-AMP and 8-amino-AMP. C-8 substitution in adenosine analogs shifted the ribose sugar pucker equilibrium to favor the DNA-like C-2'-endo form over the C-3'-endo (RNA-like) conformation, which suggests a potential mechanism for polyadenylation inhibition and chain termination. Base-modified ATP analogs may exert their biological effects through polyadenylation inhibition and thus may provide useful tools for investigating polyadenylation biochemistry within cells.


Acute deep vein thrombosis cases in the real world.
Practicing interventional radiologists (IRs) are routinely faced with challenging decisions that pertain to the management of patients with acute deep vein thrombosis (DVT). In this article, we describe five questions that are commonly posed by interventionalists and discuss both the indirect published evidence as well as our own experience in dealing with these issues. Our aim is to address procedural and, perhaps more importantly, nonprocedural-related knowledge domains with which the IR physician is less familiar and are often not directly addressed by published data or evidence-based clinical practice guidelines. This discussion is meant to facilitate a stronger understanding of the published literature as it pertains to the justifiable indications for endovascular thrombolytic therapy, the optimal use of anticoagulant therapy, and the reasonable use of adjuncts such as inferior vena cava filters and elastic compression stockings. Our goal is to provide a framework for practicing IRs to help them make the best clinical decisions for their individual patients and, ultimately, achieve optimal DVT treatment outcomes.


Arctigenin exhibits hepatoprotective activity in Toxoplasma gondii-infected host through HMGB1/TLR4/NF-κB pathway.
Toxoplasmosis is a parasitic zoonosis with the highest incidence in humans. Severe lesions due to acute toxoplasmosis have been recorded in the visceral organs including the liver, where hepatocytes and Kupffer cells are important innate immune cells. Arctigenin (AG) is a bioactive ingredient of Arctium lappa L. and increasing evidence suggests that AG exhibits anti-oxidant, anti-inflammatory and anti-Toxoplasma gondii (T. gondii) effects. However, the role of AG in acute liver damage induced by T. gondii infection remains unclear. In this study, we analyzed the effects of AG against T. gondii-induced liver damage by establishing an in vitro infection model using a murine liver cell line (NCTC-1469 cells) and an in vivo mouse model with acute T. gondii infection of virulent RH strain. In the current study, AG effectively attenuated hepatocytes apoptosis and inhibited the reproduction of T. gondii. The results of in vitro and in vivo studies showed that AG significantly reduced alanine aminotransferase/aspartate aminotransferase activities and lessened pathological damage of liver. Moreover, AG suppressed T. gondii-induced inducible nitric oxide synthase production. AG also attenuated liver inflammation by inhibiting T. gondii-induced activation of the high-mobility group box1/toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-κB) signaling pathway. These findings demonstrated that AG exhibited prominent hepatoprotective activities in toxoplasmic liver injury with anti-inflammatory effects by inhibiting the HMGB1/TLR4/NF-κB signaling axis. Thus, this study provides the basis for the development of new drugs to treat toxoplasmic hepatitis.


Stage T3a renal cell carcinoma: staging accuracy of CT for sinus fat, perinephric fat or renal vein invasion.
To study the accuracy of CT for staging T3a (TNM 2009) renal cell carcinoma (RCC). Unenhanced and nephrographic phase CT studies of 117 patients (male:female = 82:35; age range, 21-86 years) with T1-T3a RCC were independently reviewed by 2 readers. The presence of sinus or perinephric fat, or renal vein invasion and tumour characteristics were noted. Median (range) tumour size was 5.5 (0.9-19.0) cm; and 46 (39%), 16 (14%) and 55 (47%) tumours were pT1, pT2 and pT3a RCC, respectively. The sensitivity/specificity for sinus fat, perinephric fat and renal vein invasion were 71/79%, 83/76% and 59/93% (Reader 1) and 88/71%, 68/72% and 69/91% (Reader 2) with κ = 0.41, 0.43 and 0.61, respectively. Sinus fat invasion was seen in 47/55 (85%) cases with T3a RCC vs 16/55 (29%) and 33/55 (60%) for perinephric fat and renal vein invasion. Tumour necrosis, irregularity of tumour edge and direct tumour contact with perirenal fascia or sinus fat increased the odds of local invasion [odds ratio (OR), 2.5-3.7; p < 0.05; κ = 0.42-0.61]. Stage T3a tumours were centrally located (OR, 3.9; p = 0.0009). Stage T3a RCC was identified with a sensitivity of 59-88% and specificity of 71-93% (κ = 0.41-0.61). Sinus fat invasion was the most common invasive feature. Centrally situated renal tumours with an irregular tumour edge, inseparable from sinus structures or the perirenal fascia and CT features of tumour necrosis should alert the reader to the possibility of Stage T3a RCC (OR, 2.5-3.9).


Relevance of the immunohistochemical expression of cytokeratin 8/18 for the diagnosis and classification of breast cancer.
The aim of our study was to characterize and describe the different immunohistochemical expression patterns of cytokeratin 8/18 (CK8/18) in breast tumors and to make a correlation between histopathology, immunohistochemistry for CK8/18 and its possible diagnostic value of this pair of keratins for molecular classification of breast cancers. Forty cases of breast tumors immunostained with monoclonal antibodies against CK8/18 using a polymer based detection system and diaminobenzidine as chromogen were microscopically evaluated in normal and tumor breast tissue concerning the intensity, distribution and density of positive cells. Association with histopathology and nuclear grade were also studied. Three different models of positive reaction were found: (1) normal cytoplasmic with intense and diffuse pattern, (2) aberrant membrane pattern and (3) aberrant cytoplasmic granular pattern associated with membranous positive reaction. Normal expression of CK8/18 was found in 23 cases of breast cancer, aberrant membranous in nine cases and aberrant with granular pattern in four cases. Further studies will be needed to elucidate these differences and possible correlation with other molecular markers.


Relaxation versus decoherence: spin and current dynamics in the anisotropic Kondo model at finite bias and magnetic field.
Using a nonequilibrium renormalization group method we study the real-time evolution of spin and current in the anisotropic Kondo model (both antiferromagnetic and ferromagnetic) at a finite magnetic field h(0) and bias voltage V. We derive analytic expressions for all times in the weak-coupling regime max{V, h(0),1/t} >> T(c) (T(c) is the strong-coupling scale). We find that all observables decay both with the spin relaxation and decoherence rates Gamma(1/2). Various V-dependent logarithmic, oscillatory, and power-law contributions are predicted. The low-energy cutoff of logarithmic terms is generically identified by the difference of transport decay rates. For small times t << max{V, h(0)}(-1), we obtain universal dynamics for spin and current.


Altered localization and activity of canalicular Mrp2 in estradiol-17beta-D-glucuronide-induced cholestasis.
Estradiol-17beta-D-glucuronide (E(2)17G), an endogenous metabolite of estradiol, induces a potent dose-dependent and reversible inhibition of bile flow in the rat. We analyzed the effect of a single dose of E(2)17G (15 micromol/kg, intravenously) to female rats on bile flow and the endocytic retrieval and function of the canalicular multidrug resistance-associated protein 2 (Mrp2) and the effect of pretreatment with dibutyryl-cyclic AMP (DBcAMP; 20 micromol/kg) on these measures. Bile flow was maximally inhibited by 85% within 10 minutes of E(2)17G and returned to 50% and 100% of control levels within 75 and 120 minutes, respectively. Western analysis of total homogenates and mixed plasma and intracellular membranes suggested partial internalization of Mrp2 during the acute phase of cholestasis at 20 minutes and during the period of recovery from cholestasis at 75 minutes, which returned to control levels by 180 minutes after E(2)17G. Confocal analysis confirmed Western studies and demonstrated endocytic retrieval of Mrp2 from the canalicular membrane into pericanalicular and intracellular domains. The biliary concentration and excretion of the model Mrp2 substrate, dinitrophenyl-S-glutathione (DNP-SG), was impaired in parallel with the extent of Mrp2 retrieval. Pretreatment with DBcAMP partially protected against maximal E(2)17G cholestasis and the endocytic retrieval and decreased function of Mrp2 at 20 minutes and significantly accelerated the exocytic insertion of Mrp2 into the canalicular membrane and the recovery of bile flow and biliary excretion of DNP-SG. In conclusion, these data indicate that E(2)17G induces endocytic internalization of Mrp2, which occurs in parallel with decreased bile flow and Mrp2 transport activity.


Effects of happy and sad facial expressions on the perception of time in Parkinson's disease patients with mild cognitive impairment.
Parkinson's disease (PD) is a movement disorder caused by deterioration of the dopaminergic system. Previous studies have demonstrated temporal as well as emotional facial recognition impairment in PD patients. Moreover, it has been demonstrated that emotional facial expressions alter temporal judgments. In the present study, we investigate the magnitude of temporal distortions caused by the presentation of emotional facial expressions (happiness, sadness, and neutral) in PD patients with mild cognitive impairment (PD-MCI) and controls. Seventeen older adults with PD-MCI and 22 healthy older adults took part in the present study. Participants were tested with a time bisection task with standard intervals lasting 400 ms and 1600 ms. Moreover, a complete neuropsychological evaluation was conducted to characterize the sample. Differences between groups were observed indicating a general underestimation of time in PD-MCI patients. Temporal impairments in PD-MCI patients seem to be caused mainly by a dysfunction at the level of reference memory. The effect of emotional facial expressions on time perception was evident in both PD patients and controls, with an overestimation of perceived duration when happiness was presented and an underestimation when sadness was presented. Overall, our results indicate that reduced cognitive abilities might be responsible for the lower temporal ability observed in PD-MCI patients. Moreover, similar effects of emotional stimuli were observed in both PD-MCI patients and controls.


Isolation of Toxoplasma gondii from capybaras (Hydrochaeris hydrochaeris) from São Paulo State, Brazil.
The capybara (Hydrochaeris hydrochaeris) is a large rodent used for human consumption in certain areas of South America. In the present study, viable Toxoplasma gondii was isolated for the first time from this host. Antibodies to T. gondii were assayed in the sera of 64 capybaras from 6 counties of São Paulo State, Brazil, using the modified agglutination test (MAT, > or =1:25 dilution) and the indirect fluorescent antibody test (IFAT, > or =1:16 dilution), and antibodies were found in 48 (75%) by MAT, and 49 (76.6%) by IFAT. Samples of brain, heart, and tongue of 40 seropositive capybaras were pooled, digested in pepsin, and bioassayed in mice. Toxoplasma gondii was isolated from tissue homogenates of 36 capybaras, and the isolates were designated TgCyBrl-36. Most isolates were lethal to mice; 17 of the 36 isolates killed 100% of infected mice, 11 isolates caused mortality in 25-90% of infected mice, and 8 isolates were nonpathogenic to mice. Results indicate that asymptomatic capybaras can harbor mouse-virulent T. gondii, and hence they can serve as a source of infection for humans.


[Diagnostic imaging of headache].
The diagnosis of headache is based on the subjective symptom, and it is generally classified into the primary headaches, which have intracranially no abnormality, and the secondary headaches, which have organic abnormality. Neuroimaging examinations, computed tomography (CT) scan, and magnetic resonance imaging (MRI) are useful for differential diagnosis and can perform to rule out vascular malformation, brain tumor, and other pathologies, and to confirm the diagnosis. There are cases of the secondary headaches resembling the primary headaches and patients complaint of pain by complex of them, in those cases, it is necessary to perform more detailed neuroimaging(three dimensional MRA, helical CT and so on). These neuroimaging could contribute to make diagnosis and treatments for the patients.


Transcriptomic analysis reveals metabolic switches and surface remodeling as key processes for stage transition in Trypanosoma cruzi.
American trypanosomiasis is a chronic and endemic disease which affects millions of people. Trypanosoma cruzi, its causative agent, has a life cycle that involves complex morphological and functional transitions, as well as a variety of environmental conditions. This requires a tight regulation of gene expression, which is achieved mainly by post-transcriptional regulation. In this work we conducted an RNAseq analysis of the three major life cycle stages of T. cruzi: amastigotes, epimastigotes and trypomastigotes. This analysis allowed us to delineate specific transcriptomic profiling for each stage, and also to identify those biological processes of major relevance in each state. Stage specific expression profiling evidenced the plasticity of T. cruzi to adapt quickly to different conditions, with particular focus on membrane remodeling and metabolic shifts along the life cycle. Epimastigotes, which replicate in the gut of insect vectors, showed higher expression of genes related to energy metabolism, mainly Krebs cycle, respiratory chain and oxidative phosphorylation related genes, and anabolism related genes associated to nucleotide and steroid biosynthesis; also, a general down-regulation of surface glycoprotein coding genes was seen at this stage. Trypomastigotes, living extracellularly in the bloodstream of mammals, express a plethora of surface proteins and signaling genes involved in invasion and evasion of immune response. Amastigotes mostly express membrane transporters and genes involved in regulation of cell cycle, and also express a specific subset of surface glycoprotein coding genes. In addition, these results allowed us to improve the annotation of the Dm28c genome, identifying new ORFs and set the stage for construction of networks of co-expression, which can give clues about coded proteins of unknown functions.


Isoforms of a dynorphin B converting enzyme isolated by column electrophoresis in agarose suspension.
A dynorphin B converting enzyme previously purified from bovine spinal cord was subjected to column electrophoresis in agarose suspension. By this technique combined with HPLC gel filtration it was possible to resolve and recover several isoforms of the proteinase. All these isoenzymes were associated with a similar molecular size but apparently they differed with regard to their net charges. No significant difference between their inhibitory profiles or their Km values for the release of Leu-enkephalin-Arg6 from dynorphin B was observed.


Knowledge of epidemiology and statistics for an ophthalmic practitioner.
Ophthalmologists are frequently confronted with treatment options that claim to be better than those currently in use. Statistically significant P values are invariably provided by way of proof. For many ophthalmologists a simple look at this revered P value is enough evidence that a statistically significant result has indeed been obtained. Unfortunately, traditional interpretation of a study based on the P value at an arbitrary cut-off (P<0.05 or any other value) limits the ability to fully appreciate clinical implications. In this article the authors introduce the reader to and illustrate the use of "confidence intervals" as opposed to P values in examining the applicability of study results. Further, what is statistically significant may not necessarily be clinically significant; perhaps not enough for the practitioner to change from the currently preferred method of treatment. To resolve this, the authors have also used common ophthalmic examples to introduce the "number needed to treat", as a simple clinical approach for the practising ophthalmologist wishing to assess the clinical significance of treatment options.


[Severe oropharyngeal angioedema caused by ACE inhibitor. A case report].
Inhibitors of angiotensin converting enzyme (ACE) are suspected of inducing angioedemas in up to 0.2% of all patients. These angioedemas are mainly localized in the upper airways and therefore can cause severe airway obstruction and even death due to suffocation. We report the case of a 64-year-old man, who underwent emergency tracheotomy because of severe angioedema of the larynx, which was refractory to pharmacological treatment. We conclude that patients with ACE inhibitor-induced angioedemas should be observed by monitoring in an intensive care unit to ensure the possibility of early intubation, because conventional antiallergic-antiedematous therapy by histamine-receptor antagonists and corticosteroids is an insufficient, unreliable form of therapy in severe cases. Especially otolaryngologists should know about this uncommon potentially life-threatening side-effect of ACE inhibitors.


The influence of message framing, intention to quit smoking, and nicotine dependence on the persuasiveness of smoking cessation messages.
This study explores the combined effect of message framing, intention to quit smoking, and nicotine dependence on the persuasiveness of smoking cessation messages. Pre- and post-message measures of quit intention, attitude toward smoking cessation, and perceived behavioral control were taken in two separate waves from current cigarette smokers with varying levels of nicotine dependence (N=151). In the second wave, participants were randomly assigned to one of two groups. In the first group, participants read a smoking cessation message which emphasized the benefits of quitting (positive frame). In the second group participants read a message which emphasized the costs of not quitting (negative frame). Results show that smokers' intentions to quit smoking and their level of nicotine dependence jointly influence the persuasiveness of positive and negative message frames. When nicotine dependence and quitting intention are both high, a negative frame works best. Conversely, a positive frame is preferable when nicotine dependence or quitting intention is low. Smokers' level of processing is proposed as the underlying mechanism explaining the different effects of message frames.


Vessels' morphology in SMAD4 and BMPR1A-related juvenile polyposis.
Juvenile polyposis syndrome is a hamartomatous intestinal polyposis associated with malignant changes in 20% of patients at an early age. Germline mutations mostly involve two genes, SMAD4 and BMPR1, with no strong evidence of phenotype-genotype correlation, which could be predictive of the specific long-term evolution. In contrast, PTEN mutations are more commonly associated with Cowden and related diseases. Forty-two unrelated patients affected by juvenile polyposis syndrome were analyzed for germline alterations in the BMPR1A and SMAD4 genes, and for clinical and histological features. Deleterious mutations were found in 14/42 (33%) patients: 5 in BMPR1A and 9 in SMAD4. Low-grade adenomas were present in both SMAD4 and BMPR1A mutation carriers; only patients with SMAD4 mutations harbored carcinoma lesions (5/9). Malformative vessels were present in all SMAD4 related polyps when the mutation involved codons prior to position 423. No gastric polyps were observed in BMPR1A mutation carriers. SMAD4 germline mutations are responsible for a more aggressive digestive phenotype in patients with juvenile polyposis. The presence of malformative vessels within the stromal component might be a useful tool to drive the subsequent genetic and clinical management.


Multiplex polymerase chain reaction for rapid detection of atypical mycobacteria and Mycobacterium tuberculosis complex.
A three-step polymerase chain reaction (PCR) method was developed for the detection and typing of mycobacterial DNA in clinical samples and fixed tissue specimens. The first step was to rule out or prove the presence of DNA of Mycobacterium tuberculosis complex. An amplified fragment from the insertion sequence (IS) 6110 was used for this purpose. Patients negative for IS 6110 were evaluated for a fragment of the 65 kDa-antigen, present in all mycobacteria. In positive patients, a multiplex PCR was performed for M. gordonae, M. avium, M. kansasii, M. fortuitum, and M. malmoense, combined in one PCR run. As another control, to prove mycobacterial DNA, PCR was used for the gene coding for the 16S ribosomal RNA also found in all mycobacteria. Appropriate negative controls were included. Different clinical samples were compared for an efficient amplification of these different mycobacterial DNA fragments. Different mycobacteria can be identified within one day in either unfixed cytologic and bacteriologic samples, or formalin-fixed paraffin-embedded tissue samples. Therefore, this method is a quick, cost efficient, and reliable tool to identify mycobacteria other than the tuberculosis complex.


Inhibition of osteoclast differentiation by gold nanoparticles functionalized with cyclodextrin curcumin complexes.
Gold nanoparticles (GNPs) have been previously reported to inhibit osteoclast (OC) formation. However, previous research only confirmed the osteoclastogenesis inhibitory effect under in vitro conditions. The aim of this study was to develop a therapeutic agent for osteoporosis based on the utilization of GNPs and confirm their effect both in vitro and in vivo. We prepared β-cyclodextrin (CD) conjugated GNPs (CGNPs), which can form inclusion complexes with curcumin (CUR-CGNPs), and used these to investigate their inhibitory effects on receptor activator of nuclear factor-κb ligand (RANKL)-induced osteoclastogenesis in bone marrow-derived macrophages (BMMs). The CUR-CGNPs significantly inhibited the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells in BMMs without inducing cytotoxicity. The mRNA expressions of genetic markers of OC differentiation including c-Fos, nuclear factor of activated T cells 1 (NFATc1), TRAP, and osteoclast associated receptor (OSCAR) were significantly decreased in the presence of CUR-CGNPs. In addition, the CUR-CGNPs inhibited OC differentiation of BMMs through suppression of the RANKL-induced signaling pathway. Additionally, CUR-CGNPs caused a decrease in RANKL-induced actin ring formation, which is an essential morphological characteristic of OC formation allowing them to carry out bone resorption activity. Furthermore, the in vivo results of an ovariectomy (OVX)-induced osteoporosis model showed that CUR-CGNPs significantly improved bone density and prevented bone loss. Therefore, CUR-CGNPs may prove to be useful as therapeutic agents for preventing and treating osteoporosis.


Modulation of cell adhesion by tyrosine kinases and phosphatases inhibitors.
Integrin-mediated activation of monocytes is an important aspect involved in the increase of proinflammatory cytokine messages. Tyrosine phosphorylation of proteins is one of the earliest events involved in these processes: Therefore, we selected two inhibitors, one for tyrosine kinases (quercitin) and another for tyrosine phosphatases (sodium orthovanadate) and we studied their capacity to modulate monocyte adhesion to fibronectin. Our results showed that quercitin strongly inhibits both tyrosine phosphorylation and cell adhesion. Sodium orthovanadate induces a modest increase of tyrosine phosphorylation and a weak enhancement of cell adhesion. When a combination of the two inhibitors was used, the tyrosine phosphorylation level displayed a strong enhancement. In contrast, cell adhesion was inhibited, but to the same degree. These observations indicate that tyrosine kinases may be more important than tyrosine phosphatases in the modulation of cell adhesion by flavonoid compounds.


Synthesis and characterization of water-soluble and photostable L-DOPA dendrimers.
A small drug molecule, L-DOPA, was converted into well-defined dendritic macromolecules. Their monodisperse nature was shown by NMR, MALDI-TOF-MS, and PAGE. A third-generation L-Dopa dendrimer contained 30 L-Dopa residues, which made up its core, branches, and periphery. Individual L-Dopa moieties in the dendrimer were connected to one another via hydrolyzable diester linkages. These Dopa dendrimers showed a 20-fold increase in aqueous solubility and enhanced photostability in solutions over L-Dopa under identical conditions.


Immature tumor angiogenesis in high-grade and high-stage renal cell carcinoma.
To investigate the correlation between pathologic findings and maturation of the tumor neovasculature of renal cell carcinoma by immunohistochemical studies. Formalin-fixed and paraffin-embedded specimens from 25 randomly selected patients with renal cell carcinoma were stained with mouse monoclonal antibodies, anti-human CD31, anti-alpha smooth muscle actin (alphaSMA), and anti-human calponin by the indirect immunoperoxidase method. The microvessels were counted in six areas with the higher number of microvessels in each patient at 200x magnification (0.255 mm2 per area). The number of CD31-positive microvessels in grade 3 tumors was significantly lower than those in grade 1 or 2 tumors (P = 0.003222 and P = 0.043217, respectively). The CD31-positive microvessel counts of those of higher stage, tumor size greater than 4.5 cm, or non-clear cell type were significantly lower than tumors of lower stage, size less than 4.6 cm, or clear cell type. In the grade 3 tumors, the expression ratio of the number of alphaSMA-positive microvessels to the number of CD31-positive microvessels was significantly decreased compared with grade 1 or 2 tumors (P = 0.000011 and P = 0.000000, respectively). The expression of calponin in the tumor neovasculature was not observed. The expression ratios of the number of alphaSMA-positive microvessels to the number of CD31-positive microvessels in higher stages, larger tumor sizes, or non-clear cell types were significantly decreased. The tumor neovasculature of high-grade and high-stage tumors was immature. These results imply that high-grade tumors of renal cell carcinomas may be susceptible to antiangiogenesis therapy inducing apoptosis of immature tumor vessels.


The effect of analyte and analyte concentration upon precision estimates in clinical chemistry.
A significant statistical relationship between concentration and precision is shown for 11 of 14 clinical chemistry analytes, and quantitative expressions of these relationships are given. The relationships are not necessarily the same for automated and manual methods for a given analyte. Automated precision is not significantly better than manual precision for triglyceride, cholesterol and sodium. For 11 other analytes, automated precision is superior at some or all concentrations. State of the art precision is compared with criteria of medical significance. Only calcium shows significantly poorer precision than that required by medical goals.


Vitreoretinal ablation with the 193-nm excimer laser in fluid media.
To ablate retina and vitreous membranes using the 193-nm argon fluoride excimer laser in a fluid medium. A special delivery system for the 193-nm excimer laser was developed that enabled the delivery of the laser into high-absorption liquid environments. The system was tested on the retina in an in vitro cup preparation of cow's eyes, and also in vivo on retina and vitreous membranes of rabbit eyes. The depth of cut as a function of laser energy was determined for an ablating needle with a 0.25-mm exit diameter. Gentle cutting of retinal tissue and of vitreous membranes was obtained in an energy range of 0.075 to 0.25 mJ/pulse. At the energy level of 0.075 mJ/pulse, four pulses were required for full-depth cut formation in rabbit retina, whereas at energy levels greater than 0.17 mJ/pulse, one pulse was sufficient for full-depth cut formation. The maximal rate of cutting achieved for the bovine retina was 2 mm/sec at a 20-Hz repetition rate of the laser. Ablation occurred only when the tip was held in contact with the tissue. The technology described herein appears to be advantageous and applicable to a variety of vitreoretinal surgical procedures.


Multi-material Ceramic-Based Components - Additive Manufacturing of Black-and-white Zirconia Components by Thermoplastic 3D-Printing (CerAM - T3DP).
To combine the benefits of Additive Manufacturing (AM) with the benefits of Functionally Graded Materials (FGM) to ceramic-based 4D components (three dimensions for the geometry and one degree of freedom concerning the material properties at each position) the Thermoplastic 3D-Printing (CerAM - T3DP) was developed. It is a direct AM technology which allows the AM of multi-material components. To demonstrate the advantages of this technology black-and-white zirconia components were additively manufactured and co-sintered defect-free. Two different pairs of black and white zirconia powders were used to prepare different thermoplastic suspensions. Appropriate dispensing parameters were investigated to manufacture single-material test components and adjusted for the additive manufacturing of multi-color zirconia components.


[Adenovirus vector expressing MDA-7/IL-24 selectively induces growth arrests and apoptosis in human hepatocellular carcinoma cell lines independent of the state of p53 gene].
To investigate the effect of melanoma differentiation associated gene-7/interleukin 24 (MDA/IL-24) on human hepatocellular carcinoma cell lines HepG2, MHCC97L and Hep3B and normal liver cell line L02 with a different p53 state. The MDA-7/IL-24 gene was transfected into human hepatocellular carcinoma cell lines HepG2, MHCC97L and Hep3B and hepatocyte line L02 with a replication-incompetent adenovirus vector. The mRNA expression of MDA7/IL-24 in HepG2, MHCC97L, Hep3B and L02 cells was confirmed using RT-PCR. Protein expression was confirmed using ELISA assay. MTT assay and flow cytometry were used to study tumor cell proliferation and cell cycle in vitro. Hoechst and flow cytometry assay after annexin-V and PI staining were performed to indicate the apoptosis effect. Exogenous MDA-7/IL-24 gene was expressed in HepG2, MHCC97L, Hep3B and L02 cells. The protein product of MDA-7/IL-24 was confirmed in the supernatant. MTT assay and apoptosis test indicated MDA-7/IL-24 could induce growth suppression and apoptosis of HepG2, MHCC97L and Hep3B but could not in L02. Cell cycle test revealed MDA-7/IL-24 could block those cancer cells in G2/M but not in the normal cell L02. MDA-7/IL-24 selectively induces growth suppression and apoptosis in hepatocellular carcinoma lines HepG2, MHCC97L and Hep3B in vitro independent of the state of p53 gene but not in normal liver cell L02. This indicates MDA-7/IL-24 can be a perfect gene for gene therapy in hepatocellular carcinoma.


Biomarkers of xenobiotic exposures.
Direct measurement of xenobiotic (foreign) chemicals is not always feasible as an exposure assessment,--owing to rapid metabolism, sequestration into fatty tissues, or lack of suitable assay methods. Furthermore, suspect exposures often involve complex mixtures of organics. In these circumstances, indirect biomarkers of exposure can be most helpful. This paper reviews four urinary parameters that hold promise as biomarkers of exposure in occupational and environmental settings: glucaric acid (end-product of the glucuronidation pathway), thioethers (end-product of glutathione reaction with electrophilic or alkylating agents), porphyrin pattern (altered with disruption in heme biosynthesis), and the Ames mutagenicity test.


The promiscuous enzyme medium-chain 3-keto-acyl-CoA thiolase triggers a vicious cycle in fatty-acid beta-oxidation.
Mitochondrial fatty-acid beta-oxidation (mFAO) plays a central role in mammalian energy metabolism. Multiple severe diseases are associated with defects in this pathway. Its kinetic structure is characterized by a complex wiring of which the functional implications have hardly been explored. Repetitive cycles of reversible reactions, each cycle shortening the fatty acid by two carbon atoms, evoke competition between intermediates of different chain lengths for a common set of 'promiscuous' enzymes (enzymes with activity towards multiple substrates). In our validated kinetic model of the pathway, substrate overload causes a steep and detrimental flux decline. Here, we unravel the underlying mechanism and the role of enzyme promiscuity in it. Comparison of alternative model versions elucidated the role of promiscuity of individual enzymes. Promiscuity of the last enzyme of the pathway, medium-chain ketoacyl-CoA thiolase (MCKAT), was both necessary and sufficient to elicit the flux decline. Subsequently, Metabolic Control Analysis revealed that MCKAT had insufficient capacity to cope with high substrate influx. Next, we quantified the internal metabolic regulation, revealing a vicious cycle around MCKAT. Upon substrate overload, MCKAT's ketoacyl-CoA substrates started to accumulate. The unfavourable equilibrium constant of the preceding enzyme, medium/short-chain hydroxyacyl-CoA dehydrogenase, worked as an amplifier, leading to accumulation of upstream CoA esters, including acyl-CoA esters. These acyl-CoA esters are at the same time products of MCKAT and inhibited its already low activity further. Finally, the accumulation of CoA esters led to a sequestration of free CoA. CoA being a cofactor for MCKAT, its sequestration limited the MCKAT activity even further, thus completing the vicious cycle. Since CoA is also a substrate for distant enzymes, it efficiently communicated the 'traffic jam' at MCKAT to the entire pathway. This novel mechanism provides a basis to explore the role of mFAO in disease and elucidate similar principles in other pathways of lipid metabolism.


Separation and aquatic toxicity of enantiomers of synthetic pyrethroid insecticides.
Synthetic pyrethroid insecticides are chiral compounds with multiple asymmetric positions. In this study, isomers of four commonly used pyrethroids were separated at the enantiomeric level by enantioselective high-performance liquid chromatography (HPLC), and differences between enantiomers in aquatic toxicity were characterized using individual isomers. Isomers of cis-bifenthrin and permethrin were completely resolved on a Sumichiral OA-2500-I column. All eight isomers of cypermethrin and cyfluthrin were completely separated on two chained Chirex 00G-3019-DO columns. Great differences were found between enantiomers in the acute toxicity to aquatic invertebrates Ceriodaphnia dubia or Daphnia magna. In cis-bifenthrin (cis-BF) and cis-permethrin (cis-PM), the 1R-cis isomer was 15-38 times more active than the 1S-cis enantiomer, while in trans-PM, the 1R-trans isomer was substantially more toxic than the 1S-trans enantiomer. In cypermethrin or cyfluthrin, two of the eight isomers, 1R-cis-alphaS and 1R-trans-alphaS, contributed for almost all the toxicity in the racemate, while the other six enantiomers were inactive. These results suggest that significant enantioselectivity occurs for pyrethroids in aquatic toxicity, and such enantiomeric differences must be considered when evaluating ecological effects of pyrethroid insecticides.


Challenges of caring for older patients with multimorbidity including cancer.
As the population is ageing, the number of older patients with multimorbidity including cancer continues to increase. To improve care for these patients, the European Union-funded project "Streamlined Geriatric and Oncological evaluation based on IC Technology" (GERONTE) was initiated to develop a new, patient-centred, holistic care pathway. The aim of this paper is to analyse what challenges are encountered in everyday clinical practice according to patients, their informal caregivers, and healthcare professionals as a starting point for the development of the care pathway. An expert panel of cancer and geriatrics specialists participated in an online survey to answer what challenges they experience in caring for older patients with multimorbidity including cancer and what treatment outcomes could be improved. Furthermore, in-depth interviews with older patients and their informal caregivers were organised to assess what challenges they experience. Healthcare professionals (n = 36) most frequently mentioned the challenge of choosing the best treatment in light of the lack of evidence in this population and how to handle interactions between the (cancer) treatment and multimorbidities. Twelve patients and caregivers participated, and they most frequently mentioned challenges related to treatment outcomes, such as how to deal with symptoms of disease or treatment and how to maintain quality of life. From the challenges, five main themes emerged that should be taken into account when developing a new care pathway for older patients with multimorbidity including cancer. Two themes focus on decision making aspects such as personalized treatment recommendations and inclusion of non-oncologic information, two focus on patient support and monitoring to maintain quality of life and functioning, and one overarching theme addresses care coordination to prevent fragmentation of care. In conclusion, the management of older patients with multimorbidity including cancer is complex and although progress has been made on improving aspects of their care, challenges remain and patients are at risk of receiving inappropriate, unnecessary, and potentially harmful treatment. A patient-centred care pathway that integrates solutions to the five main themes and that moves away from a single-disease centred approach is needed.


Investigation of mutations in the synaptonemal complex protein 3 (SYCP3) gene among azoospermic infertile male patients in the Turkish population.
To investigate possible mutations and/or single nucleotide polymorphisms in the synaptonemal complex protein 3 (SYCP3) gene among nonobstructive azoospermic infertile males in a Turkish population, 75 nonobstructive azoospermic infertile male patients were included in the study. These patients were unrelated to each other and had 46,XY chromosome structure without Y microdeletion. In addition, 75 individuals whose fertility was proven by reproduction were enrolled in the study as controls. Nine exon deep intronic primers belonging to the SYCP3 gene were designed and amplified by PCR, and the nucleotide sequences were identified by DNA sequence analysis. DNA sequence analysis was used to detect mutations and/or single nucleotide polymorphisms in the SYCP3 gene. No mutations were detected in the 9 exons of SYCP3. A total of eleven variations, however, were detected: seven have been identified in the NCBI SNP database, whereas four have not. On the basis of the results, we agree with the idea that SYCP3 mutations are not associated with the genetic susceptibility for meiotic arrest in infertile male patients with nonobstructive azoospermia in the Turkish population and that further studies investigating the other components of the synaptonemal complex protein (SYCP1, SYCP2) should be conducted.


The incidence of transfusion and associated risk factors in pelvic reconstructive surgery.
Almost 400,000 female pelvic reconstructive operations were performed in 2010 for urinary incontinence and pelvic organ prolapse in the United States, and it is likely that this will continue to increase each year. There is a lack of population-based data evaluating the risk of blood transfusion after urogynecologic procedures. We sought to assess the incidence of blood transfusion related to pelvic reconstructive surgery in a large national surgical quality database and to identify transfusion-associated risk factors. This retrospective cohort study was performed using the National Surgical Quality Improvement Program database from the years 2010 through 2014. All women undergoing surgery for pelvic floor disorders were identified by Current Procedural Terminology code. Demographic and clinical variables were abstracted. The incidence of blood transfusion was determined. A multivariate logistic regression analysis was performed to identify clinical factors independently associated with blood transfusion. A total of 54,387 women underwent pelvic reconstructive surgery from 2010 through 2014 in the National Surgical Quality Improvement Program database. Of these subjects, 686 (1.26%) received a blood transfusion. The median age was 57 (range 28-89) years. Of the population, 0.81% was underweight (body mass index <18.5), 27.0% was normal weight (body mass index 18.5-24.9), 35.6% was overweight (body mass index 25-29.9), and 36.7% was obese (body mass index ≥30). The majority of subjects in the study cohort were Caucasian (91.4%) followed by African Americans (4.6%); the remainder included Asian, American Indian/Alaska Native, and Native Hawaiian/Pacific Islander. Hispanic ethnicity was reported in 9.3% of the population. American Society of Anesthesiologists class 1 and 2 represented a majority of the sample (76.5%). Concomitant hysterectomy was performed in 20,735 (38.1%) of the population. In the multivariate analysis, preoperative hematocrit <30% (odds ratio, 13.68; 95% confidence interval, 10.65-17.59), history of coagulopathy (odds ratio, 3.74; 95% confidence interval, 2.50-5.60), and concomitant hysterectomy (odds ratio, 1.77; 95% confidence interval, 1.49-2.12) were factors independently associated with receiving blood transfusion (all P < .05). When compared to American Society of Anesthesiologists class 1, patients who were class 3 (odds ratio, 2.82, P < .01; 95% confidence interval, 2.02-3.93) or class 4 (odds ratio, 6.56, P < .01; 95% confidence interval, 3.65-11.78) were more likely to require a transfusion. When compared to Caucasians, African Americans (odds ratio, 1.73, P < .01; 95% confidence interval, 1.27-2.36) and Hispanics (odds ratio, 1.92, P < .01; 95% confidence interval, 1.54-2.40) were more likely to require a transfusion. In this cohort, overweight (odds ratio, 0.75; 95% confidence interval, 0.62-0.93) and obese (odds ratio, 0.61; 95% confidence interval, 0.49-0.75) subjects were less likely to receive a transfusion. When compared to a vaginal approach, patients who had a minimally invasive approach (odds ratio, 0.63; 95% confidence interval, 0.49-0.83) were less likely to receive a transfusion, while those with an open approach were more likely to receive a transfusion (odds ratio, 5.43; 95% confidence interval, 4.49-6.56). Age was not a risk factor for transfusion. Transfusion after pelvic reconstructive surgery is uncommon. The variables associated with transfusion are preoperative hematocrit <30%, American Society of Anesthesiologists class, bleeding disorders, nonwhite race, Hispanic ethnicity, and concomitant hysterectomy. Recognition of these factors can help guide preoperative counseling regarding transfusion risk after pelvic reconstructive surgery and individualize preoperative preparation.


Dermoscopy of syringocystadenoma papilliferum.
Syringocystadenoma papilliferum is a benign adnexal neoplasm frequently seen in association with other adnexal tumours. We report the dermoscopic features of three cases of syringocystadenoma papilliferum developing in naevus sebaceus. Clinically the lesions were characterised by exophytic papillary structures. Dermoscopically, polymorphous vessels were the prevalent feature.


[Functional significance of MeCP2 mutations in patients with Rett syndrome].
Mutations in the MeCP2 gene cause Rett syndrome and are observed in approximately 80% of Rett syndrome patients. To investigate the functional significance of these mutations, we established two functional assays using transient expression systems. Transcriptional repressive activities of MeCP2 mutants were analyzed by the reporter assay in Drosophila cells. The influences of mutations on methyl-CpG-binding activities were indirectly assessed by examining the affinity of fluorescent labelled mutant proteins to mouse heterochromatins, where approximately one half of all methyl-CpG-base pairs are located. These functional assays are useful in evaluating mutations in the methyl-CpG-binding domain of MeCP2 and will provide insight into the relationship between the genotype and the phenotype of Rett syndrome.


Clinical integration of billing for a pediatric nephrology and transplant program.
To develop and implement a billing process that fully integrates all activities of a pediatric nephrology and transplant program, by facilitating and coordinating data from patients, physicians, hospitals, and third-party billing services to maximize revenues. Financial operations were analyzed via a randomized audit of patient charts that focused on office procedures and revenue collection. Results based on monthly reports documenting revenue received and outstanding, procedures billed, and patient registration accuracy. The combination of improvements in patient registration, chart documentation, new billing sheets with procedure and diagnosis codes, physician in-service education, upgraded charges, and the recredentialing of all practice physicians realized an increase in revenue collections from 18% in 2000 to 89% in 2001. The need to integrate and coordinate information is vital for both billing accuracy and revenue collections. Integration of clinical services and billing procedures has maximized performance, profitability, and accuracy while decreasing administrative time and costs.


PEAK SHIFTS AND POLYMORPHISM DURING PHASE THREE OF WRIGHT'S SHIFTING-BALANCE PROCESS.
The third phase of Wright's shifting-balance theory involves the export of adaptive gene combinations from one subpopulation to another. Previous results have demonstrated that this can occur at very low migration rates, but it has been argued that this simply reflects the ability of migration to overcome selection and fix any (even deleterious) alleles. Here, previous analyses are extended by concentrating on the critical balance between forward and reverse migration rates that still allows phase III to proceed. It is shown that selective advantage, dominance, recombination rate, and the number of loci all affect the ability of a genotype to invade and become fixed in a new subpopulation, but it is unlikely that phase III will occur in the absence of differential migration unless the invading genotype consists of a few dominant loci with a large selection advantage, spreading into a few populations of lower fitness. Therefore, as was envisioned by Wright, differential migration from more to less fit populations will be necessary for phase III to occur under most circumstances.


Use of autologous serum in corneal epithelial defects post-lamellar surgery.
To evaluate the efficacy of an autologous serum treatment of post-LASIK (laser in situ keratomileusis) corneal epithelial defects in a rabbit model. Five milliliters blood samples from 10 New Zealand rabbits were obtained by venepuncture. The serum was aseptically separated and diluted with saline solution to 20%. The final preparation was placed into 3-mL bottles with ultraviolet protection and maintained at 4 degrees C. Corneas were de-epithelialized using a 7-mm optical zone marker. A 160-microm thick flap was created in both eyes of all rabbits using an automatic corneal shaper microkeratome. Right eyes were treated with serum drops 6 times per day. Left eyes were treated with preservative-free artificial tears. Vital staining of the ocular surface and the area of corneal epithelial defect was measured daily for 1 week. Rabbits were humanely euthanized at postoperative day 7, and corneas were fixed and sectioned. Hematoxylin and eosin staining and immunohistochemical analysis were performed. Corneas treated with autologous serum had a statistically significant increase in the epithelial healing rate compared with those treated with artificial tears. Serum-treated corneas showed significantly less terminal transferase-mediated dUTP nick-end labeling (TUNEL) staining in the interface, minimal inflammatory cell infiltration, and less induced synthesis of stromal chondroitin sulfate than did corneas treated with preservative-free artificial tears. Treatment with autologous serum could be an efficient way to provide essential components to the ocular surface in the treatment of post-LASIK epithelial defects. Autologous serum induces faster epithelial healing than do artificial tears, leading to (1) a decrease in keratocyte apoptosis and migration of fibroblasts and myofibroblasts in the wound site, (2) a decrease in the migration of inflammatory cells, and (3) a consequent inhibition of cytokine release. This treatment could improve long-term refractive results post-LASIK.


Management of major colonic haemorrhage.
Major colonic haemorrhage remains a difficult diagnostic and therapeutic problem. We propose that those patients who continue to bleed after resuscitation are best served by immediate laparotomy. High flow antegrade irrigation and intra-operative colonoscopy can then be used to localize the site of bleeding and allow appropriate excisional surgery rather than blind colonic resection.


Patient- and Physician-Reported Outcome of Combined Fractional CO2 and Pulse Dye Laser Treatment for Hypertrophic Scars in Children.
Hypertrophic scars are commonly seen in children and associated with pruritus, pain, functional impairment, and aesthetic disfigurement. Ablative fractional CO2 and pulse dye laser are emerging techniques to improve scar quality. Only limited data are available on children, nonburn scars, and patient-reported outcome. We aimed to investigate safety and outcome of repeated laser therapy for hypertrophic scars originating from burns and other conditions by means of patient- and physician-reported outcome measures. This was a retrospective before-after analysis of laser treatments in children with hypertrophic scars. Outcome was measured using Patient and Observer Scar Assessment Scale, Vancouver Scar Scale and Itch Man Scale. With respect to safety, laser- and anesthesia-related complications were analyzed. Seventeen patients, aged 11.37 ± 4.82 years with 27 scars, underwent 102 distinct laser treatments, mainly combined CO2 and pulse dye laser (94%), with few CO2 only (6%). Vancouver Scar Scale total score before the first and after the first session decreased significantly from 7.65 ± 2.12 to 4.88 ± 1.73; Patient and Observer Scar Assessment Scale observer overall opinion also dropped from 5.88 ± 1.57 to 4.25 ± 1.70. Pruritus improved significantly. Patient age and timing of laser intervention did not have an impact on treatment response. Complications related to laser treatment were seen in 2% (wound infection, n = 2) and to anesthesia in 4% (insignificant n = 2, minor n = 1). Combined laser therapy significantly improves quality, pain, and pruritus of hypertrophic scars in children. When provided by experienced laser and anesthesia teams, it is safe with a low rate of complications.


Long-term Outcomes in Patients with Membranous Nephropathy: A Retrospective Cohort Study in Iran.
Membranous nephropathy (MN) has variable clinical outcomes, ranging from spontaneous remission to slow progression to kidney failure. Since the clinical outcomes of MN have not been studied in a large sample size in Iran, this study was designed to evaluate the outcome of patients diagnosed with MN at Hasheminejad Kidney Center (HKC), Tehran. In this retrospective cohort study, 1086 patients with a diagnosis of MN who were biopsied between 1998 and 2018 in HKC were evaluated through a review of medical records for baseline clinical and laboratory characteristics at the time of biopsy and through a review of follow-up charts and phone calls for the evaluation of clinical outcomes. Of these patients, 551 could be followed for clinical outcomes. The composite outcome included kidney loss (hemodialysis, transplantation, or death). The effect of demographic, clinical, laboratory, and pathological variables on kidney survival was determined by the Cox-regression model using SPSS-16 software at a significance level of .05. Sex (P < .05), higher weight (P < .05), older age (P < .001), hypertension (P < .001), higher baseline proteinuria and lower glomerular filtration rate (GFR) at the onset of the disease were associated with kidney failure (P < .001). A higher percentage of interstitial fibrosis, tubular atrophy, global sclerosis, and a higher pathological class of membranous nephropathy were significantly associated with disease outcome in the univariate Cox-regression analysis (P < .001). Kidney survival rates at 5, 10, and 15 years were 86%, 74%, and 56%; respectively. Our study suggests that baseline demographic, clinical and laboratory factors affect kidney outcomes. Patients who are considered high-risk based on the criteria listed above may need to be candidates for more aggressive therapy. DOI: 10.52547/ijkd.7373.


Dynamic Characteristics of Guanosine-5'-monophosphate Reductase Complexes Revealed by High-Resolution 31P Field-Cycling NMR Relaxometry.
The ability of enzymes to modulate the dynamics of bound substrates and cofactors is a critical feature of catalysis, but the role of dynamics has largely been approached from the perspective of the protein. Here, we use an underappreciated NMR technique, subtesla high-resolution field-cycling 31P NMR relaxometry, to interrogate the dynamics of enzyme bound substrates and cofactors in guanosine-5'-monophosphate reductase (GMPR). These experiments reveal distinct binding modes and dynamic profiles associated with the 31P nuclei in the Michaelis complexes for the deamination and hydride transfer steps of the catalytic cycle. Importantly, the substrate is constrained and the cofactor is more dynamic in the deamination complex E·GMP·NADP+, whereas the substrate is more dynamic and the cofactor is constrained in the hydride transfer complex E·IMP·NADP+. The presence of D2O perturbed the relaxation of the 31P nuclei in E·IMP·NADP+ but not in E·GMP·NADP+, providing further evidence of distinct binding modes with different dynamic properties. dIMP and dGMP are poor substrates, and the dynamics of the cofactor complexes of dGMP/dIMP are disregulated relative to GMP/IMP. The substrate 2'-OH interacts with Asp219, and mutation of Asp219 to Ala decreases the value of Vmax by a factor of 30. Counterintuitively, loss of Asp219 makes both substrates and cofactors less dynamic. These observations suggest that the interactions between the substrate 2'-OH and Asp219 coordinate the dynamic properties of the Michaelis complexes, and these dynamics are important for progression through the catalytic cycle.


Members of Gammaproteobacteria as indicator species of healthy banana plants on Fusarium wilt-infested fields in Central America.
Culminating in the 1950's, bananas, the world's most extensive perennial monoculture, suffered one of the most devastating disease epidemics in history. In Latin America and the Caribbean, Fusarium wilt (FW) caused by the soil-borne fungus Fusarium oxysporum f. sp. cubense (FOC), forced the abandonment of the Gros Michel-based export banana industry. Comparative microbiome analyses performed between healthy and diseased Gros Michel plants on FW-infested farms in Nicaragua and Costa Rica revealed significant shifts in the gammaproteobacterial microbiome. Although we found substantial differences in the banana microbiome between both countries and a higher impact of FOC on farms in Costa Rica than in Nicaragua, the composition especially in the endophytic microhabitats was similar and the general microbiome response to FW followed similar rules. Gammaproteobacterial diversity and community members were identified as potential health indicators. Healthy plants revealed an increase in potentially plant-beneficial Pseudomonas and Stenotrophomonas, while diseased plants showed a preferential occurrence of Enterobacteriaceae known for their plant-degrading capacity. Significantly higher microbial rhizosphere diversity found in healthy plants could be indicative of pathogen suppression events preventing or minimizing disease expression. This first study examining banana microbiome shifts caused by FW under natural field conditions opens new perspectives for its biological control.


Surgical Treatment of Thoracic Spinal Cord Herniation.
Thoracic spinal cord herniation (TSCH) is an unusual condition characterized by central displacement of the spinal cord through a dural defect, resulting in neurological impairment due to compression and vascular compromise. Different surgical techniques have been described to treat symptomatic patients with TSCH such as closure of the defect by primary sutures after reducing the spinal cord, widening the dural defect to prevent cord strangulation, or reducing the spinal cord and using a dural patch. Through a case presentation of a 62-year-old woman with TSCH, we describe step-by-step, a surgical technique for repair by reducing the spinal cord and using a dural patch. In our experience surgical reduction of the hernia will frequently improve the patient's symptoms and signs even in patients with longstanding deficits. The final objective of this surgical technique is to prevent recurrent herniation and progressive deficit.


Identification of novel antiplasmodial compound by hierarquical virtual screening and in vitro assays.
Malaria is an infectious disease caused by protozoa of the genus Plasmodium spp. with approximately 219 million cases in 2017. P. falciparum is main responsible for the most severe form of the disease, cerebral malaria. Despite of public health impacts, chemotherapy against malaria is still limited due to the emergence of drug resistance cases used in monotherapy and combination therapies. Thus, the development of new antimalarial drugs becomes emergency. One way of achieve this goal is to explore essential and/or unique therapeutic targets of the parasite, or at least sufficiently different to ensure selective inhibition. Enoil-ACP reductase (ENR) is a NADH-dependent enzyme responsible for the limiting step of the type II fatty acid biosynthetic pathway (FAS II). Thus, pharmacophore and docking based virtual screening were applied to prioritize molecules for in vitro assays against P. falciparum W2 strain. The application of successive filters at OOCC database (n = 618) resulted in the identification of one molecule (13) (EC50 = 0.098 ± 0.021 μM) with similar biological activity to artemether. The molecule 13 is a typical drug repurposing case due to previous other approved therapeutic uses on Chinese medicine as a non-specific cholinergic antagonist, thus it could be accelerated the drug development process. Additionally, molecular dynamics studies were used to confirm stability of the molecular interactions identified by molecular docking. Thus, representative structures of P. falciparum ENR can be used in a study to propose new derivatives for evaluation of biological activity in vitro and in vivo. Communicated by Ramaswamy H. Sarma.


Effect of cold stratification on seed germination in Solidago × niederederi (Asteraceae) and its parental species.
In this study, we investigated the influence of cold stratification on seed germination in S. × niederederi, a hybrid between the North American S. canadensis and the European S. virgaurea, using fruit samples collected in 2016 in Poland. We aimed to test the hypothesis that the low temperature exposure decreases the final percentage and speed of seed germination in the hybrid and its parental species. For each species, sets of 100 achenes in three replications were mixed with dry sand and stored in Petri dishes in darkness for 12 weeks, at -18 °C and + 4 °C, and + 25 °C. The seeds were incubated for 21 d at room temperature (+25 °C), under the 12 h photoperiod (630 lx). We showed a lack of significant differences in: (i) the final percentage of germinated seeds of studied species stored at the same conditions, (ii) the final percentage of germinated seeds between the applied stratification conditions in the hybrid and its parental species, and (iii) the mean values of Timson's index, mean germination time, and coefficient of velocity of germination between the stratification conditions in each species. The statistically significant inter-specific differences in the mean germination time parameter after the +25 °C treatment suggest that the seeds of S. × niederederi are able to germinate faster than the seeds of its parental species. However, to improve our knowledge of naturalization and invasion abilities of S. × niederederi by sexual reproduction, the seed germination and seedling survival of the hybrid should be tested in the field.


Golfer exposure to chlorpyrifos and carbaryl following application to turfgrass.
Exposure of golfers to pesticides following their application to turfgrass is of concern to regulators, turfgrass professionals, and consumers. Multipathway exposures were evaluated for golfers on turfgrass treated with chlorpyrifos and carbaryl. Air concentrations and transferable foliar residues (TFRs) were measured to assess potential respiratory and dermal exposures, respectively. At the same time, exposure to individuals simulating the play of golf was determined by dosimetry and urinary biomonitoring. Individual golfer exposure was determined in 76 rounds of golf following eight applications of chlorpyrifos and two applications of carbaryl. Estimated exposures to golfers following full course and full rate applications of chlorpyrifos and carbaryl were 19-68 times below current U.S. EPA acute reference dose (Rfd) values, indicating safe exposures under U.S. EPA hazard quotient criteria. Dermal exposure was determined to be the dominant exposure pathway to golfers, accounting for approximately 60% of the chlorpyrifos absorbed dose and 100% of the carbaryl absorbed dose. This study also provides a set of transfer factors (TFs) that may be used to determine dermal exposure of golfers to pesticides using transferable residue data.


Black tea dressings - a rapidly effective treatment for facial dermatitis.
Background: Facial dermatitis is a common dermatologic condition. It is usually treated with either topical corticosteroids or calcineurin inhibitors. However, the use of these drugs is limited by side effects, including skin atrophy, local immunosuppression and possible oncogenicity. Objective: The aim of the study was to evaluate the use of wet dressings with black tea for treating facial dermatitis. Methods: We performed a prospective, open, uncontrolled before-after study enrolling 22 patients with atopic or contact facial dermatitis who were treated with black tea dressings and an emollient cream over 6 days. Disease severity was assessed using the (1) Facial Eczema Area and Severity Index, (2) Visual analog scale for pruritus, (3) Investigator`s Global Assessment score, and (4) Patient's Self-Assessment score. The study was registered at www.ClinicalTrials.gov as NCT02941432. Results: A dramatic and highly significant reduction of all four disease activity scores occurred within the first 3 days of treatment and the patients continued to improve between days 3 and 6. No side effects were observed. Conclusion: Black tea dressings represent an effective treatment option for facial dermatitis. Its advantages include lack of side effects, low cost, and easy availability.


Prevalence of multiple sclerosis in a residential area bordering an oil refinery.
Community concerns about a potential excess of multiple sclerosis (MS) prompted this study. To determine the period prevalence of MS in a community bordering a closed oil refinery and a control community. Cases seen by a neurologist during 1998 to 2001 were obtained from area neurologists and hospital discharge data. Population data were obtained from the year 2000 US Census. Patient data were abstracted by a trained abstractor onto a standardized report form. A consulting neurologist reviewed the form and made a final diagnosis using the Poser criteria plus the category of presumed. Age-adjusted prevalence rates and rates of agreement were calculated. The direct age-adjusted period prevalence for both sexes and all races for the entire study area was 113 per 100,000 (95% CI = 93 to 136). For white subjects only, the prevalence was 123 per 100,000 (95% CI = 102 to 147). With use of an indirect method of age adjustment, the number of observed cases in the community bordering the refinery was similar to the number of cases expected (standardized morbidity ratio = 130.8, 95% CI = 62.3 to 199.3), based on rates from the comparison area. The agreement between the treating neurologist (for definite plus probable cases) and the consulting neurologist (for definite plus probable plus presumed cases) was good (kappa = 0.5733). The prevalence of multiple sclerosis (MS) for this area was generally consistent with prevalence estimates calculated in previous studies in other areas. No significant excess was seen in the exposed area. MS was more prevalent in females than in males. The overall agreement between the consulting and treating neurologist was good.


Partnerships between Black Women and Behaviorally Bisexual Men: Implications for HIV Risk and Prevention.
Although an estimated 87% of new HIV infections in Black/African American women are attributed to sex with men, many women are unaware of their male partners' HIV risk factors. Research on women who are aware of a high-risk male partner may inform HIV prevention. We analyzed transcripts from semi-structured interviews with 20 Black women who reported sex with at least one man who had sex with men and women (MSMW) in the prior 5 years. We applied Choice and Sexual Network theories to the interpretation. The majority described their partnerships as committed and involving emotional or instrumental support. Substance abuse was a common component of the relationships and very few involved consistent condom use. Although nearly all respondents described it as alarming to learn of their partners' involvement with other men and several ended the relationships, many continued the relationships without protective changes in their sex behavior. These narratives indicate that although many leave, many other women remain in relationships after learning of a male partners' high-risk activity. Substance abuse, financial instability, and a desire to remain in intimate partnerships may discourage preventive actions in these women.


High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections.
Better understanding of complications and outcomes of adults hospitalized with respiratory syncytial virus (RSV) infection is necessary. A retrospective cohort study was conducted on all adults (≥ 18 years) admitted to 3 acute care general hospitals in Hong Kong with virologically confirmed RSV infection during 2009-2011 (N = 607). Adults hospitalized for seasonal influenza during the period were used for comparison (n = 547). Both infections were prospectively diagnosed following a standard protocol. Independent reviews of chest radiographs were performed by radiologists. Main outcome measures were all-cause death, respiratory failure requiring ventilatory support, and hospitalization duration. Cox proportional hazards models were used for analyses. The mean age of RSV patients was 75 (SD, 16) years; 87% had underlying conditions. Lower respiratory and cardiovascular complications were diagnosed in 71.9% (pneumonia, 42.3%; acute bronchitis, 21.9%; chronic obstructive pulmonary disease/asthma exacerbation, 27.3%) and 14.3% of patients, respectively; 12.5% had bacterial superinfections. Supplemental oxygen and ventilatory support were required in 67.9% and 11.1%, respectively. Crude all-cause mortality was 9.1% and 11.9% within 30 days and 60 days, respectively; mean length of stay of survivors was 12 (SD, 13) days. Advanced age, radiographic pneumonia, requirement for ventilation, bacterial superinfection, and elevated urea level and white blood cell count were independently associated with poorer survival. Systemic corticosteroid use was associated with longer hospitalization and secondary infections. The overall outcomes of survival and length of stay were not significantly different from those in influenza. RSV can cause severe lower respiratory complications in older adults, resulting in respiratory failure, prolonged hospitalization, and high mortality similar to seasonal influenza. Corticosteroids did not seem to improve outcomes. The unmet need for antiviral therapy and vaccination against RSV in adults should be promptly addressed.


The GADD45A (1506T>C) Polymorphism Is Associated with Ovarian Cancer Susceptibility and Prognosis.
GADD45A (growth arrest and DNA damage 45 A) is the first stress-inducible gene identified to be a target of p53. However, no studies to date have assessed variants of the GADD45 gene and their potential relationship to tumor susceptibility. We investigated the association of the GADD45A (1506T>C) polymorphism with ovarian cancer development in 258 ovarian cancer patients and 332 age-matched healthy women as controls using sequence analysis. We found a statistically significant difference in the GADD45A (1506T>C) genotype distributions between the case and control groups (TT vs. TC vs. CC, P = 0.0021) and found that variant 1506T>C was significantly associated with an increased risk of ovarian cancer (P<0.001, OR = 1.71, 95% CI [1.28-2.29]). We observed a statistically significant effect between tumor histology (P = 0.032) and CA125 status (P = 0.021). Carrying the C allele (TC+CC) was associated with an increased risk of positive CA125 (OR = 3.20, 95% CI [1.15-8.71). Carrying the T allele (TT+TC) showed a significant correlation with both higher GADD45A mRNA expression and longer ovarian cancer RFS (relapse-free survival) and OS (overall survival). We are the first group to demonstrate that the GADD45A (1506T>C) polymorphism is associated with ovarian cancer susceptibility and prognosis. These data suggest that GADD45A (1506T>C) is a new tumor susceptibility gene and could be a useful molecular marker for assessing ovarian cancer risk and for predicting ovarian cancer patient prognosis.


Chronic cerebral arterial spasm. The role of intracranial pressure.
The author used isolated rabbit common carotid and femoral arteries perfused at a constant pressure of 90 mm Hg to examine the variation of flow (F) with transmural pressure (TMP). When the TMP was reduced below 50 to 60 mm Hg in arteries with normal smooth muscle tone, arterial resistance increased significantly causing a reduction in flow. It is suggested that the diffuse arterial narrowing that occurs in patients with severe intracranial hypertension may be the result of a similar reduction in TMP. In the presence of active vasoconstriction, any increase in extraluminal (intracranial) pressure (ICP) resulted in a substantial increase in arterial resistance and subsequent reduction of flow. This F-TMP relationship depended only on the initial degree of constriction and was independent of the vasoconstrictor used to achieve this constriction and of the artery in which this constriction was produced. A review of the literature suggests that human cerebral arteries normally exhibit only mild constrictions in response to subarachnoid blood during the chronic phase of spasm. In the present study, a mild constriction in the absence of increased ICP or a moderate increase in ICP (45 mm Hg) in the absence of constriction produced minor reductions in arterial diameter and an average flow reduction of only 5% to 10%. However, when ICP was increased to 45 mm Hg in the presence of a mild constriction, severe arterial narrowing resulted and flow was reduced by 50%. Therefore, it is suggested that chronic arterial spasm is the result of a mild constriction which is amplified by the simultaneous occurrence of increased ICP. Phenoxybenzamine was found to be effective in reversing and preventing these contractions. The improvement in flow produced by phenoxybenzamine decreased as the TMP was reduced below 60 mm Hg. The effects of both diffuse and local spasm on cerebral blood flow are discussed.


Characterization of gastrointestinal tumor-associated carcinoembryonic antigen-related antigens defined by monoclonal antibodies.
Four major carcinoembryonic antigen-related glycopeptides (Mr 180,000, 160,000, 50,000, and 40,000) were detected in SW948 colon carcinoma cells and in colon adenocarcinoma tissue using a monoclonal antibody (C(4)20-32) generated by immunizing mice with SW1222 human colon carcinoma cells. Only the Mr 50,000 polypeptide was immunoprecipitated from normal colon mucosa by this antibody. Binding studies using other monoclonal antibodies and lectins indicated the different epitopes and carbohydrate attachment sites on each of the four polypeptides. Only monoclonal antibody C(4)20-32 recognized a common determinant on all four polypeptides which was revealed by its reactivity with each affinity-purified component.


Folate levels among various populations in central Iran.
Serum folic acid levels (Lactobacillus casei assay) were determined in 467 subjects representing various socioeconomic classes from rural and urban central Iran. Of the subjects 170 were pregnant females in different trimesters. The mean serum folate levels of the various groups studied ranged from 7.5 to 11.1 ng/ml and are within the normal reported range of 5.9 to 21.0 ng/ml. Only two subjects had serum folate levels below 3.0 to 5.9 ng/ml. In anemic subjects (hematocrit is less than 37%), red blood cell folate levels were also determined and were significantly higher than nonanemic controls (558 +/- 56 versus 346 +/- 35 ng/ml of packed red blood cells, P is less than 0.01). This difference may be related to underutilization of folate in patients with iron deficiency (a common metal deficiency in this area). A probable explanation for the well maintained serum folate levels in late pregnancy as well as in other populations studied in this report may be the high dietary intake of Iranian bread made from wheat flour of high extraction rate.


Rabbit lung after acute smoke inhalation. Cellular responses and scanning electron microscopy.
The cellular responses in the lungs of rabbits and the morphologic features of the tracheobronchial tree by scanning electron microscopy were examined 24 hours following acute inhalation of Douglas fir wood smoke. Thermal injury to the upper airway was excluded. Injury to proximal tracheal lining cells was severe and consisted of loss of the epithelium. The changes of the epithelial barrier in the proximal major bronchi were less severe in nature. However, the alterations observed by scanning electron microscopy suggested dysfunction of the mucociliary blanket. Both cell counts of bronchoalveolar lavage fluid and morphologic findings reflected an increase in alveolar macrophage response. Smoke-exposed alveolar macrophages showed significant changes in the surface features. These findings may explain the tracheobronchitis seen clinically, and the propensity of patients to lung infection following smoke inhalation.


Nanoengineering of Advanced Carbon Materials for Sodium-Ion Batteries.
Recent research shows that the continuing importance of carbon anode materials plays an important role in the development of sodium-ion batteries. Nevertheless, the practical deployment of sodium-ion batteries still faces many challenges such as mediocre sodium storage capability and short cycle life. Therefore, it is imperative to explore improvement methods to boost their competitiveness. Herein, various nanoengineering strategies, including nanostructure design, defect and heteroatom doping, and nanocomposite optimization, are proposed as reliable and effective approaches to improve electrochemical performances and structural stability of carbon-based anode materials for sodium-ion batteries (SIBs). The feasibility of nanoengineering is highlighted as a promising approach to develop next-generation carbon materials for sodium-ion batteries.


Pediatric drugs--a review of commercially available oral formulations.
Pediatric oral formulations can be quite scientifically challenging to develop and the prerequisites for both a measurable dosage form to administer based upon bodyweight, and also taste-masking are two of the challenges unique for pediatric oral formulations. The physicochemical and organoleptic properties of the active drug substance such as solubility, chemical stability, and taste along with the intended dose can determine which formulations are feasible to develop. Oral pediatric formulations are available in 17 different varieties and can be either a ready-to-use formulation such as a solution, syrup, suspension, tablet, scored tablet, chewable tablet, orally disintegrating tablet, or thin strip, or can also be a formulation that requires manipulation such as a powder for constitution to a suspension, tablet for constitution to a suspension, powder for constitution to a solution, drops for reconstitution to a suspension, concentrated solution for dilution, effervescent tablet, bulk oral granules, bulk oral powder, or solid in a capsule to mix with food or drink. Recently there has been an increase in pediatric formulation development inspired by increased regulatory incentives. The intent of this review is to educate the reader on the various types of formulations administered orally to pediatrics, the rationale in deciding which type of formulation to develop, the excipients used, development challenges, the in-use handling of oral pediatric formulations, and the regulatory incentives.


Epidemiological description of cystic ovarian disease in argentine dairy herds: risk factors and effects on the reproductive performance of lactating cows.
To describe the epidemiology of cystic ovarian disease (COD), to find possible risk factors associated with the incidence of cysts and to analyse the impact of COD on the reproductive performance of dairy cows, databases from 22 dairy herds from the main dairy region in Argentina were retrospectively evaluated throughout a 3-year period (2009-2011). A total of 248 COD cases over 9156 parturitions were recorded, resulting in a cumulative incidence rate of 2.7%. Cystic ovarian disease incidence density was lower during the first 100 days post-partum (DPP) than during later stages of lactation. Seasonality had a significant influence on the disease presentation with higher incidence rates during winter and spring. Cows with a previous diagnosis of clinical mastitis showed 2.72 times more chances of developing ovarian cysts. Cystic cows had longer calving to first service and calving to conception intervals and lower conception rate than controls.