Metabolism of androgens in the seminal vesicles and the different lobes of the prostate in young mature rats.
Oxidation and reduction of 4-androstene-3,17-dione (androstenedione), 17 beta-hydroxy-4-androsten-3-one (testosterone), 17 beta-hydroxy-5 alpha-androstan-3-one (DHT), 5 alpha-androstan-3 alpha,17 beta-diol (3 alpha-A'diol) and 5 alpha-androstane-3 beta,17 beta-diol (3 beta-A'diol) were measured in homogenates from ventral (VP), dorsal (DP) and lateral prostate (LP), the coagulating gland (CG) and seminal vesicle (SV) of the intact sexually mature rat using NAD(H) or NADP(H) as cofactors. The specific activity of the various enzymes varied significantly between the different organs. 5 alpha-Reductase activity was highest in the DP and the CG, and undetectable in the LP. 17 beta-Hydroxysteroid oxidoreductase (17 beta-HSOR) activity was mainly confined to the LP. 3 alpha-Hydroxysteroid oxidoreductase (3 alpha-HSOR) activity was also highest in the LP. In the VP the highest 3 alpha-HSOR activity was recorded using NAD(H) as cofactor. In the other organs, similar or higher enzymatic activities were measured using NADP(H) as added cofactor. 3 beta-Hydroxysteroid oxidoreductase (3 beta-HSOR) activity was high in the LP and low or undetectable in the other tissues. Our results indicate that isoenzymes of 3 alpha-HSOR, 3 beta-HSOR and 17 beta-HSOR are present in the accessory sex organs of the rat.


Clonal isolation of populations of gamma-glutamyl transpeptidase-positive and -negative cells from rat liver epithelial cells chemically transformed in vitro.
In a population of cultured rat liver epithelial cells transformed by 11 brief treatments with N-methyl-N'-nitro-N-nitrosoguanidine, 9% of the cells stained intensely for gamma-glutamyl transpeptidase (GGT). We have isolated from this phenotypically heterogeneous tumorigenic cell population 11 GGT-positive and 7 GGT-negative clonal subpopulations (from single cells) and have analyzed the ploidy and selected biochemical, histochemical, and growth properties of the cells in these clonal sublines. As compared to the GGT-negative strains and normal diploid rat liver epithelial cells, cells of the GGT-positive strains are larger in size, have greater DNA content, proliferate more slowly in culture, and have higher specific activities of NADH diaphorase, glucose-6-phosphate dehydrogenase, pyruvate kinase, and lactate dehydrogenase. The GGT-positive strains also show greater alteration and heterogeneity than do the GGT-negative strains in their ability to store glycogen and in their expression of lactate dehydrogenase isozymes. The results indicate that enzymatic changes commonly observed in "altered" hepatocytes in rat livers exposed to chemical carcinogens in vivo can also be produced in vitro in cultured hepatic epithelial cells by treatment with carcinogens. Moreover, treatment of a cell line with a chemical carcinogen generates a population of cells vastly heterogeneous in both their phenotypes and genotypes. Isolation of clonal subpopulations from the resulting cell line allows critical examination of the linkage and mechanistic relationship between tumorigenicity and many paratumorigenic phenotypes.


Pharmacological causes of hyperprolactinemia.
Hyperprolactinemia is a common endocrinological disorder that may be caused by several physiological and pathological conditions. Several drugs may determine a significant increase in prolactin serum concentration that is frequently associated with symptoms. The so-called typical antipsychotics are frequently responsible for drug-related hyperprolactinemia. Risperidone is one of the atypical neuroleptics most likely to induce hyperprolactinemia, while other atypical drugs are unfrequenlty and only transiently associated with increase of prolactin levels. Women are more sensitive than men to the hyperprolactinemic effect of antipsychotics. Classical and risperidone-induced hyperprolactinemia may be revert when a gradual antipsychotic drug discontinuation is combined with olanzapine or clozapine initiation. Antidepressant drugs with serotoninergic activity, including selective serotonin reuptake inhibitors (SSRI), monoamine oxidase inhibitors (MAO-I) and some tricyclics, can cause hyperprolactinemia. A long list of other compounds may determine an increase in prolactin levels, including prokinetics, opiates, estrogens, anti-androgens, anti-hypertensive drugs, H2-receptor antagonists, anti-convulsivants and cholinomimetics. Finally, hyperprolactinemia has also been documented during conditioning and after autologous blood stem-cell transplantation and during chemotherapy, even though disturbances of prolactin seem to occur less frequently than impairments of the hypothalamus-pituitary-gonad/thyroid axis after intensive treatment and blood marrow transplantation.


[The evolutionary characteristics of the hypereosinophilic syndrome].
The case here described is a young male aged 21 years who met all diagnostic criteria for HES: (1) persistent eosinophilia of over 1500/cubic millimeter (19.904-26.070/cubic millimeter) for longer than 6 month (12 month in our patient); (2) lack of evidence of other known causes of secondary hypereosinophilia (SH); (3) multiple organ involvement. The peculiar aspects found in our case are related to organ involvement: occurrence 2 months after HES onset of chronic myocardial infarction in four locations (apical, anteroseptal and posteroseptal, inferior, left ventricular) demonstrated by electrocardiographic and scintigraphic studies; early global cardiac insufficiency (6 months after the onset); acute renal failure (since HES onset) followed by chronic renal failure. The multiple and severe involvement of the nervous system (up to coma) were not a life threat. It is suggested that a possible explanation for the multiple organ involvement could be the chronic disseminated intravascular coagulation.


SMART (SiMulAtion and ReconsTruction) PET: an efficient PET simulation-reconstruction tool.
Positron-emission tomography (PET) simulators are frequently used for development and performance evaluation of segmentation methods or quantitative uptake metrics. To date, most PET simulation tools are based on Monte Carlo simulations, which are computationally demanding. Other analytical simulation tools lack the implementation of time of flight (TOF) or resolution modelling (RM). In this study, a fast and easy-to-use PET simulation-reconstruction package, SiMulAtion and ReconsTruction (SMART)-PET, is developed and validated, which includes both TOF and RM. SMART-PET, its documentation and instructions to calibrate the tool to a specific PET/CT system are available on Zenodo. SMART-PET allows the fast generation of 3D PET images. As input, it requires one image representing the activity distribution and one representing the corresponding CT image/attenuation map. It allows the user to adjust different parameters, such as reconstruction settings (TOF/RM), noise level or scan duration. Furthermore, a random spatial shift can be included, representing patient repositioning. To evaluate the tool, simulated images were compared with real scan data of the NEMA NU 2 image quality phantom. The scan was acquired as a 60-min list-mode scan and reconstructed with and without TOF and/or RM. For every reconstruction setting, ten statistically equivalent images, representing 30, 60, 120 and 300 s scan duration, were generated. Simulated and real-scan data were compared regarding coefficient of variation in the phantom background and activity recovery coefficients (RCs) of the spheres. Furthermore, standard deviation images of each of the ten statistically equivalent images were compared. SMART-PET produces images comparable to actual phantom data. The image characteristics of simulated and real PET images varied in similar ways as function of reconstruction protocols and noise levels. The change in image noise with variation of simulated TOF settings followed the theoretically expected behaviour. RC as function of sphere size agreed within 0.3-11% between simulated and actual phantom data. SMART-PET allows for rapid and easy simulation of PET data. The user can change various acquisition and reconstruction settings (including RM and TOF) and noise levels. The images obtained show similar image characteristics as those seen in actual phantom data.


Conversion of failed laparoscopic adjustable gastric banding: sleeve gastrectomy or Roux-en-Y gastric bypass?
In the literature, late complications and treatment failures in laparoscopic adjustable gastric banding (LAGB) have been reported. When the patient presents with failure of LAGB, surgeons have the option to convert it to a different procedure. The aim of our study is to evaluate and compare the safety and efficacy of converting LAGB to laparoscopic sleeve gastrectomy (LSG) versus laparoscopic Roux-en-Y gastric bypass (LRYGB). Between March 2008 and October 2012, a total of 54 patients underwent conversion of LAGB at our institution. Of these patients, 41 (75.9%) were converted to LRYGB, and 13 (24.1%) patients were converted to LSG. A retrospective review of a prospectively collected database was performed, noting the outcomes and complications of the procedure. Mean body mass index at the time of conversion was 41.8±6.5 kg/m(2) in LRYGB and 39.0±6.6 kg/m(2) in LSG. Mean percentage of excess weight loss was 57.4%±17.0% and 62.4%±19.6% in LRYGB, and it was 47.7%±4.2% and 65.6%±34.5% in LSG at 12 months (P>.34) and 24 months (P>.79) after conversion. Of LRYGB patients, 7 (17.5%) were readmitted as a result of abdominal pain, dehydration, and nausea/vomiting, and 4 (10.0%) patients required reoperation. One LSG patient (8.3%) was readmitted for new-onset severe reflux and underwent hiatal hernia repair. She was converted to LRYGB 32 months after the LSG procedure. Readmission rate (P>.61) and reoperation rate (P>.63) did not show statistical difference between the 2 procedures. Converting LAGB to LSG and LRYGB both seem feasible and resulted in substantial further weight loss.


Comparative evaluation of resin infiltration and fluoride varnish treatment for moderate to high caries risk adults: A randomized controlled trial.
To evaluate the arresting effect of micro-invasive (resin infiltration) and non-invasive (fluoride varnish) treatment options on non-cavitated proximal lesions in individuals with moderate to high risk of caries. In addition, the study evaluated the effect of repeated dental examinations and oral hygiene motivation on daily flossing, brushing frequency, dietary habits, and gingival status. The study was a randomized, controlled, prospective, and parallel-designed clinical trial. 60 adults were enrolled and randomly allocated in a 1:1 ratio to the treatment groups. Cariogram was used to assess the caries risk. The advising instruction for daily habits and oral hygiene by individual risk illustration was given to all participants. Two experienced examiners visually evaluated the severity and activity of the lesions by using the International Caries Detection and Assessment System and Nyvad Activity Assessment respectively. Radiographic scoring of the lesions was performed on bite-wing radiographs by the same examiners. The gingival index was used to check the gingival status of the patients at the initial and control sessions. After examination, resin infiltration (Icon) was applied to 30 subjects, while the other 30 received fluoride varnish (Clinpro White Varnish). The follow-up time was 18 months with 6-month intervals. According to the Pearson Chi-Square test, there was no difference in the arresting effect of resin infiltration and fluoride varnish (P= 0.491). Both treatment groups exhibited a notable arresting effect on non-cavitated lesions, achieving a success rate of 98% (55 out of 56) during the 18-month evaluation period. However, one lesion of a subject who received resin infiltration was observed to progress from an E2 score to cavitation. Furthermore, at the end of 18 months, the subjects' motivation for oral hygiene had increased, and gingival index score decreased from 2 to 1 in 15% of the subjects. Both resin infiltration and fluoride varnish yielded satisfactory results in the treatment of non-cavitated proximal lesions in individuals with moderate to high risk of caries. Repeated motivational instructions were beneficial for patients in maintaining their daily oral hygiene habits and gingival health.


ES-62, a filarial nematode-derived immunomodulator with anti-inflammatory potential.
Arthropod-transmitted filarial nematodes can survive for in excess of a decade via modulation of the vertebrate host immune system. Although human infection can result in very severe pathology, most infected individuals show remarkably little evidence of this. Analysis of the anti-nematode response indicates that apparently pathology-free individuals have an anti-inflammatory immunological phenotype and it has been suggested that this favours maintenance of host good health. It is considered that parasite-derived molecular secretions contribute to the anti-inflammatory phenotype and we have thus investigated the properties of a filarial nematode glycoprotein secreted in some abundance, ES-62. This molecule shows a plethora of immunomodulatory activities that can be classified as anti-inflammatory. It has been observed in a number of studies that several autoimmune disorders including rheumatoid arthritis (RA) exhibit reduced incidence and severity in geographic regions in which filarial nematodes are transmitted to humans. Furthermore, it has been speculated that these two observations are linked although molecular explanations for such an association have not been forthcoming. Although the aetiology of RA remains unknown a majority of data are consistent with it being mediated via excess pro-inflammatory cytokine production. Given that ES-62 is anti-inflammatory, we hypothesised that it might be able to counter the pathology associated with diseases like RA. Indeed, we found that exposure to ES-62 prevented initiation of collagen-induced arthritis (CIA) in a murine model and also suppressed progression of established disease. Ex vivo analyses demonstrated that these effects correlated with inhibition of TNF-alpha production and inhibition of collagen-specific TH-1 responses. The nematode product was also able to suppress pro-inflammatory cytokine release in vitro in synovial cells derived from RA patients. ES-62 thus constitutes a pathogen-derived immunomodulator with significant therapeutic potential.


Discovery of G Protein-Biased Antagonists against 5-HT7R.
5-HT7R belongs to a family of G protein-coupled receptors and is associated with a variety of physiological processes in the central nervous system via the activation of the neurotransmitter serotonin (5-HT). To develop selective and biased 5-HT7R ligands, we designed and synthesized a series of pyrazolyl-diazepanes 2 and pyrazolyl-piperazines 3, which were evaluated for binding affinities to 5-HTR subtypes and functional selectivity for G protein and β-arrestin signaling pathways of 5-HT7R. Among them, 1-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)-1,4-diazepane 2c showed the best binding affinity for 5-HT7R and selectivity over other 5-HTR subtypes. It was also revealed as a G protein-biased antagonist. The self-grooming behavior test was performed with 2c in vivo with Shank3-/- transgenic (TG) mice, wherein 2c significantly reduced self-grooming duration time to the level of wild-type mice. The results suggest that 5-HT7R could be a potential therapeutic target for treating autism spectrum disorder stereotypy.


Unicompartmental Knee Arthroplasty Provides Superior Clinical and Radiological Outcomes Compared to High Tibial Osteotomy at a Follow-Up of 5-8 Years.
Knee Osteoarthritis (OA) is a debilitating disease. Initially, the medial compartments are affected in most cases. For this pathology, joint preservation is preferable. Two surgical procedures aim to meet this goal: high-tibial osteotomy (HTO) and unicompartmental knee arthroplasty (UKA). The aim was to compare clinical and radiological outcomes of HTO versus UKA in patients with unicompartmental, medial OA. Retrospective case series. A total of 86 (61 UKA, 25 HTO) patients that received either treatment at a single, specialized center were assessed pre-operatively and at a single follow-up examination at 77.13 months (±8.170). The Knee Society Score (KSS), range of motion (ROM), SF36 questionnaire and the Tegner score were used. The Kellgren-Lawrence score was assessed pre- and post-surgically. Survivorship with the endpoint "revision" was assessed. The UKA group showed significantly better improvements in KSS scores for pain (p < 0.006) and function (p < 0.001). OA progression (p < 0.02) and survivorship (p < 0.018) differed, significantly favoring UKA. ROM, SF36 and Tegner score did not differ significantly. The presented mid-to long-term data suggest that UKA provides superior results in selected outcomes. Nevertheless, significant differences in the demographics of treatments indicate the challenge of comparing these two treatments.


Molecular thermodynamic modeling of specific ion effects on micellization of ionic surfactants.
Specific ion effects are ubiquitous in biological and colloidal systems. The addition of electrolytes to ionic surfactant solutions has pronounced effects on micellar properties, such as critical micelle concentration (cmc), micellar size, and shape. Ions play an important role in colloid stability and aggregation behavior of ionic surfactant solutions. Despite extensive experimental data, there is no well established molecular theory on specific ion effects. Published molecular thermodynamic theories for ionic surfactants do not properly account for ion-specific effects such as the inversion of the lyotropic series for the cmc of alkyl sulfates and carboxylates. In this work, we present a molecular thermodynamic theory for ionic surfactant solutions to take into account the headgroup-counterion specificity and address ion-specific effects on the cmc and aggregation number. We assume that the charged headgroup and the counterion at the Stern layer form solvent-shared ion pair with different degrees of cosphere overlap. The thickness of the Stern layer is estimated from molecular structures of hydrated surfactant heads and hydrated counterions, and from the knowledge of the qualitative strength of headgroup-counterion interaction in line with Collins' concept of matching water affinities. Our proposed thermodynamic model properly predicts the cmc of both anionic and cationic surfactants of various counterions, and the effect of different inorganic salts on micellization of ionic surfactants.


Cell-free DNA analysis for trisomy risk assessment in first-trimester twin pregnancies.
To examine the clinical implementation of chromosome-selective sequencing of cell-free DNA (cfDNA) in maternal blood and an algorithm that relies on the lower fetal fraction contribution of the 2 fetuses in the assessment of risk for trisomies in twin pregnancies. Risk for trisomies 21, 18 and 13 by cfDNA testing were estimated in stored plasma samples obtained at 11-13 weeks' gestation from 207 pregnancies with known outcome and prospectively in 68 twin pregnancies undergoing screening at 10-13 weeks. Risk scores for trisomies were provided for 192 (92.8%) of stored plasma and for 63 (92.6%) of the prospective cases. In the retrospective study, 10 of 11 trisomic pregnancies were correctly identified with no false positive results. In the prospective study, 3 trisomic pregnancies were correctly identified with no false positive results. The median of the lower fetal fraction in the prospective study of twins was 7.4% (IQR range 5.9-10.0%), which was lower than in our previous study in singletons (median 10.0%, IQR 7.8-13.0%). cfDNA testing in twins is feasible but the reporting rate of results is lower than in singletons due to a lower fetal fraction.


Prolonged preconditioning with natural honey against myocardial infarction injuries.
Potential protective effects of prolonged preconditioning with natural honey against myocardial infarction were investigated. Male Wistar rats were pre-treated with honey (1%, 2% and 4%) for 45 days then their hearts were isolated and mounted on a Langendorff apparatus and perfused with a modified Krebs-Henseleit solution during 30 min regional ischemia fallowed by 120 min reperfusion. Two important indexes of ischemia-induced damage (infarction size and arrhythmias) were determined by computerized planimetry and ECG analysis, respectively. Honey (1% and 2%) reduced infarct size from 23±3.1% (control) to 9.7±2.4 and 9.5±2.3%, respectively (P<0.001). At the ischemia, honey (1%) significantly reduced (P<0.05) the number and duration of ventricular tachycardia (VT). Honey (1% and 2%) also significantly decreased number of ventricular ectopic beats (VEBs). In addition, incidence and duration of reversible ventricular fibrillation (Rev VF) were lowered by honey 2% (P<0.05). During reperfusion, honey produced significant reduction in the incidences of VT, total and Rev VF, duration and number of VT. The results showed cardioprotective effects of prolonged pre-treatment of rats with honey following myocardial infarction. Maybe, the existence of antioxidants and energy sources (glucose and fructose) in honey composition and improvement of hemodynamic functions may involve in those protective effects.


Liquid junctions and isolated proximal tubule transepithelial potentials.
Accurate evaluation of the unavoidable liquid junction potentials (LJP) involved whenever bath (B) and perfusate (P) solutions differ in ionic composition is of fundamental importance in the determination of proximal convoluted tubule (PCT) transepithelial potential, psi T, and its active and diffusion components, psi A and psi D. Therefore, a precise method of measuring these LJP, using Ag/AgCl electrodes, has been developed and successfully tested. The measured LJP, psi B-P, between artificial bath serum containing 6 g/100 ml albumin and ultrafiltrate-like perfusate is +2.6 mV. The average measured potential difference (PD) in rabbit PCT with these solutions was -3.0 mV, psi T thus being only -0.4 mV. Three maneuvers known to abolish psi A (hypothermia, 10(-4) ouabain, or K-free bath) brought the PD close to the reference potential, indicating that psi A congruent to PD and that psi D congruent to psi B-P. From dilution potentials, after correction for LJP (4.3 in the absence and 6.2 mV in the presence of proteins), PNa/PCl was calculated to be 0.9 for midcortical and 1.1 for juxtamedullary PCT in the absence of proteins and slightly lower in their presence. These values of LJP obtained with Ag/AgCl electrodes are between 30 and 100% larger than the ones measured using a saturated KCl bridge or the ones in previous studies, indicating that in these studies psi T as well as PNa/PCl has been overestimated.


Biomarkers in respiratory tract infections: diagnostic guides to antibiotic prescription, prognostic markers and mediators.
Used appropriately, biomarkers improve the assessment of respiratory tract infections and sepsis. Most prominently, circulating procalcitonin levels increase by a factor of several tens of thousands during sepsis. Using a sensitive assay, procalcitonin safely and markedly reduces antibiotic usage in respiratory tract infections and nonbacterial meningitis. Procalcitonin is the protopye of hormokine mediators. The term "hormokine" encompasses the cytokine-like behaviour of hormones during inflammation and infections. The concept is based on a ubiquitous expression of calcitonin peptides during sepsis. Adrenomedullin, another member of the calcitonin peptide superfamily, was shown to complement and improve the current prognostic assessment in lower respiratory tract infections. Other peptides share some features of hormokines, e.g. natriuretic peptide and copeptin. Hormokines are not only biomarkers of infection but are also pivotal inflammatory mediators. Like all mediators, their role during systemic infections is basically beneficial, possibly to combat invading microbes. However, at increased levels they can become harmful for their host. Multiple mechanisms of action were proposed. In several animal models the modulation and neutralisation of hormokines during infection was shown to improve survival, and thus might open new treatment options for severe infections, especially of the respiratory tract.


Incidentally discovered adrenal tumors: endocrine and scintigraphic correlates.
Hormonal and morphological data were investigated in 202 consecutive patients with adrenal incidentalomas (171 unilateral and 31 bilateral) in an attempt to assess subclinical hyperfunction or malignancy. In addition to the classical evaluation, scintiscan was carried out in a large number of these patients. In unilateral incidentalomas, 83% showed normal hormonal function, whereas 17% had biochemical signs of adrenal overactivity (hyperaldosteronism in 3, hypercortisolism in 17, medullary hyperfunction in 9). [75Se]Methylnorcholesterol scintigraphy depicted malignant, space-occupying lesions as decreased or absent radiotracer uptake by the mass, and cortical adenomas as increased or normal uptake. In cortical adenomas a relationship between radiocholesterol uptake and degree of functional autonomy was demonstrated. [123I]Metaiodobenzilguanidine scintiscan visualized 7 of 8 pheochromocytomas. In bilateral incidentalomas, abnormal adrenal function was more frequent, accounting for 29% of cases (hyperaldosteronism in 3, hypercortisolism in 3, adrenal insufficiency in 2, and congenital adrenal hyperplasia in 1). Malignant lesions were not scintigraphically visualized. [75Se]Methylnorcholesterol scan also provided functional information in the case of a cortisol-secreting adenoma and an aldosteronoma with a concomitant contralateral nonhypersecreting adenoma, showing the greatest uptake in the hyperfunctioning adenomas. In both unilateral and bilateral lesions, endocrine testing failed to differentiate benign from malignant tumors. Although hormonal assessment is mandatory to clarify the functional patterns, only morphofunctional examination by scintiscan seems to provide more data about the likelihood of malignancy.


Frequency of Left Ventricular Hypertrophy in Non-Valvular Atrial Fibrillation.
Left ventricular hypertrophy (LVH) is significantly related to adverse clinical outcomes in patients at high risk of cardiovascular events. In patients with atrial fibrillation (AF), data on LVH, that is, prevalence and determinants, are inconsistent mainly because of different definitions and heterogeneity of study populations. We determined echocardiographic-based LVH prevalence and clinical factors independently associated with its development in a prospective cohort of patients with non-valvular (NV) AF. From the "Atrial Fibrillation Registry for Ankle-brachial Index Prevalence Assessment: Collaborative Italian Study" (ARAPACIS) population, 1,184 patients with NVAF (mean age 72 ± 11 years; 56% men) with complete data to define LVH were selected. ARAPACIS is a multicenter, observational, prospective, longitudinal on-going study designed to estimate prevalence of peripheral artery disease in patients with NVAF. We found a high prevalence of LVH (52%) in patients with NVAF. Compared to those without LVH, patients with AF with LVH were older and had a higher prevalence of hypertension, diabetes, and previous myocardial infarction (MI). A higher prevalence of ankle-brachial index ≤0.90 was seen in patients with LVH (22 vs 17%, p = 0.0392). Patients with LVH were at significantly higher thromboembolic risk, with CHA2DS2-VASc ≥2 seen in 93% of LVH and in 73% of patients without LVH (p <0.05). Women with LVH had a higher prevalence of concentric hypertrophy than men (46% vs 29%, p = 0.0003). Logistic regression analysis demonstrated that female gender (odds ratio [OR] 2.80, p <0.0001), age (OR 1.03 per year, p <0.001), hypertension (OR 2.30, p <0.001), diabetes (OR 1.62, p = 0.004), and previous MI (OR 1.96, p = 0.001) were independently associated with LVH. In conclusion, patients with NVAF have a high prevalence of LVH, which is related to female gender, older age, hypertension, and previous MI. These patients are at high thromboembolic risk and deserve a holistic approach to cardiovascular prevention.


Aluminium ions inhibit the formation of diacylglycerol generated by phosphatidylcholine-hydrolysing phospholipase C in tobacco cells.
• Aluminium ions (Al) have been recognized as a major toxic factor for crop production in acidic soils. This study aimed to assess the impact of Al on the activity of phosphatidylcholine-hydrolysing phospholipase C (PC-PLC), a new member of the plant phospholipase family. • We labelled the tobacco cell line BY-2 and pollen tubes with a fluorescent derivative of phosphatidylcholine and assayed for patterns of fluorescently labelled products. Growth of pollen tubes was analysed. • We observed a significant decrease of labelled diacylglycerol (DAG) in cells treated with AlCl(3). Investigation of possible metabolic pathways that control DAG generation and consumption during the response to Al showed that DAG originated from the reaction catalysed by PC-PLC. The growth of pollen tubes was retarded in the presence of Al and this effect was accompanied by the decrease of labelled DAG similar to the case of the BY-2 cell line. The growth of pollen tubes arrested by Al was rescued by externally added DAG. • Our observation strongly supports the role of DAG generated by PC-PLC in the response of tobacco cells to Al.


A primitive therizinosauroid dinosaur from the Early Cretaceous of Utah.
Therizinosauroids are an enigmatic group of dinosaurs known mostly from the Cretaceous period of Asia, whose derived members are characterized by elongate necks, laterally expanded pelves, small, leaf-shaped teeth, edentulous rostra and mandibular symphyses that probably bore keratinized beaks. Although more than a dozen therizinosauroid taxa are known, their relationships within Dinosauria have remained controversial because of fragmentary remains and an unusual suite of characters. The recently discovered 'feathered' therizinosauroid Beipiaosaurus from the Early Cretaceous of China helped to clarify the theropod affinities of the group. However, Beipiaosaurus is also poorly represented. Here we describe a new, primitive therizinosauroid from an extensive paucispecific bonebed at the base of the Cedar Mountain Formation (Early Cretaceous) of east-central Utah. This new taxon represents the most complete and most basal therizinosauroid yet discovered. Phylogenetic analysis of coelurosaurian theropods incorporating this taxon places it at the base of the clade Therizinosauroiden, indicating that this species documents the earliest known stage in the poorly understood transition from carnivory to herbivory within Therizinosauroidea. The taxon provides the first documentation, to our knowledge, of therizinosauroids in North America during the Early Cretaceous.


Immunohistochemical demonstration of hepatitis B core and surface antigens in paraffin sections.
An immunohistochemical staining to demonstrate the hepatitis B core and surface antigens (HBc&sAg) on formalin-fixed, paraffin-embedded liver tissue was investigated. The staining is believed to be valid for the reasons that: (1) HBc&s AG-positive and control tissues were properly selected. (2) The immunospecificities of the antisera to HBc Ag or HBs Ag were verified by immunoelectron microscopy and by conducting the neutralization controls in the staining procedure. (3) The staining results were identical with those shown on unfixed frozen sections from the same cases. The immunoreactive sites of HBc&s Ag are shown to be preserved in the formalin-fixed, paraffin-embedded tissue, and they can be demonstrated by either direct or indirect immunofluorescent and immunoperoxidase methods. The pronase digestion of the tissue sections quenches the nonspecific background staining and thus facilitates the microscopic examination. The indirect immunofluorescent method is more sensitive than the direct. The localization of HBs Ag in liver cells shown by immunohistochemical method is identical with that demonstrated by orcein histochemical stain. The described method demonstrating the HBc Ag in paraffin tissue may offer an additional means in making a specific etiologic diagnosis of hepatitis B viral disease.


Mediation analysis of the associations between neighbourhood walkability and greenness, accelerometer-measured physical activity, and health-related fitness in urban dwelling Canadians.
To estimate sex-specific associations (total, direct, and indirect effects) between objectively measured neighbourhood walkability and greenness and objectively measured physical activity and health-related fitness including cardiorespiratory and muscular fitness in Canadian adults. Neighbourhood walkability (Canadian Active Living Environment) and greenness (Normalized Difference Vegetation Index; NDVI) data were linked to cardiorespiratory (i.e., submaximal step test estimated V̇O2 max) and muscular fitness (i.e., handgrip strength) and accelerometer measured physical activity; Canadian Health Measures Survey). Covariate-adjusted sex-stratified path analyses was conducted to assess if physical activity (light: LPA; moderate: MPA, and; vigorous: VPA) mediated the associations between neighbourhood walkability, NDVI and health-related fitness. Model sample sizes ranged from 987 to 2796 for males and 989 to 2835 for females. Among males, we found indirect effects between neighbourhood walkability and cardiorespiratory fitness via LPA (negative) and VPA (positive). We also found a total effect (negative) between neighbourhood walkability and grip strength and indirect effects between neighbourhood walkability and handgrip strength via LPA (negative) and MPA (negative). Among females, we found a total effect (positive) and direct effect (positive) between neighbourhood walkability and cardiorespiratory fitness, and an indirect effect for neighbourhood walkability and cardiorespiratory fitness via LPA. We found no significant effects related to neighbourhood greenness. Residing in a neighbourhood with higher walkability may positively affect cardiorespiratory fitness but negatively affect muscular strength. The negative associations between neighbourhood walkability and LPA may offset potential positive associations between neighbourhood walkability and MPA and VPA and their subsequent influence on health-related fitness.


[Five-year survival and prognostic factors in a cohort of breast cancer patients treated in Juiz de Fora, Minas Gerais State, Brazil].
The purpose of this study was to analyze five-year survival and the main prognostic factors among women with invasive breast cancer diagnosed from 1998 to 2000 that had undergone surgical treatment in the city of Juiz de Fora, Minas Gerais State, Brazil. Study variables were: age, skin color, place of residence, tumor-related variables, and treatment-related variables. Survival functions were calculated by the Kaplan-Meier method, and multivariate analysis was performed using the Cox proportional hazard model. Disease-specific survival was 81.8%. Tumor size and lymph node involvement were the main independent prognostic factors in the study population, with increased risk of death for women with tumor size greater than 2.0 cm (HR = 1.97; 95%CI: 1.26-3.07) and positive axillary lymph nodes (HR = 4.04; 95%CI: 2.55-6.39). The results emphasize the need for earlier diagnosis and treatment. Access to screening at different levels of care, mainly for women at high risk, should be a key priority for the Unified National Health System in Brazil.


Comparison of cholinesterase inhibitor utilization patterns and associated health care costs in Alzheimer's disease.
Sustained treatment with a cholinesterase inhibitor (ChEI) is used in the management of the symptoms of Alzheimer's disease (AD). However, the characteristic declines in learning and memory seen in AD may erode the patient's ability to adhere to medication regimens with or without caregiver support. To examine differences by type of ChEI in (1) monthly prevalence of use, (2) nonpersistence, (3) switching from the index drug to another ChEI, (4) number of days on therapy, (5) medication possession ratio (MPR), and (6) an estimate of the relationship of these characteristics to total annual health care expenditures. Data were from the MarketScan Medicare Supplemental and Coordination of Benefits 2001-2003 database, which comprised 1.47 million Medicare beneficiaries during this 3-year time period. Inclusion criteria were: (1) aged 65 years or older; (2) at least 1 claim with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 331.0 for AD in any of 15 diagnosis fields on outpatient claims or any of 2 diagnosis fields on inpatient claims at any time during 18 months of observation; (3) at least 1 pharmacy claim for donepezil, galantamine, or rivastigmine preceded by a 6-month period without a ChEI claim; and (4) at least 12 months of follow-up data, for a minimum 18 months continuous enrollment. Multivariate analyses, including logistic regression and exponential conditional mean models, tested for cohort differences in ChEI utilization, controlling for demographics, region of the country, type of insurer, and the Charlson Comorbidity Index (comorbid diagnoses). Using exponential conditional mean models, we also examined the relationship between utilization characteristics and all-cause (i.e., not specific to AD) health care expenditures for a 12-month period, including inpatient and outpatient (physician) care, laboratory and radiology services, emergency room (ER) use, prescription drugs, and long-term care services (e.g., nursing home care, home health visits) paid by Medicare or private insurance, but excluding long-term care services paid by Medicaid. Expenditure was defined as allowed charge (i.e., the total payment received by the service provider including plan and patient paid amounts.) More than 70% of the patients who received ChEI therapy and who otherwise met the inclusion criteria were excluded from this study due to the absence of at least 1 claim with a diagnosis for AD. Of the 3,177 patients included in the study, the index ChEI was donepezil for 62.8% of the patients (n=1,994); 17.2% received galantamine (n=546) and 20.1% received rivastigmine (n=637). The total number of days of index therapy dispensed was greater for those starting on donepezil (mean [median, SD] days=226 [263, 115]) compared with rivastigmine (206 [233, 120], P<0.001), but was not significantly different compared with galantamine (216 [250, 119], P=0.085). Monthly prevalence of use was similar for the 3 drugs until month 5 when a smaller proportion of rivastigmine patients had index medication on hand (65.9%) compared with 72.1% of donepezil patients (P=0.003) and 72.7% of galantamine patients (P=0.012). At 12 months, the likelihood of receiving the index ChEI was higher for donepezil (61.1%) than for either rivastigmine (50.1%, P<0.001) or galantamine (56.4%, P=0.048) and was higher for galantamine than for rivastigmine (P=0.030). The rate of switching for donepezil patients was significantly lower (14.5%) than the switch rate for rivastigmine patients (21.5%, P<0.001) and was similar to the switch rate for galantamine patients (15.0%, P=0.781 for donepezil vs. galantamine; P=0.004 for galantamine vs. rivastigmine). Rates of nonpersistence, measured as having at least 1 gap in therapy of 30 days or more during the 1-year follow-up, were 63.5% for donepezil, 63.7% for galantamine (P=0.933 for donepezil vs. galantamine), and 68.0% for rivastigmine (P=0.042 for donepezil vs. rivastigmine). MPRs and total days supply of any ChEI did not significantly differ among the 3 drugs. Results of multivariate models showed that, controlling for index ChEI drug, each additional month of ChEI treatment was associated with a reduction of 1% in total all-cause health care costs. The mean (SD) total all-cause 1-year health care costs for patients initiated on the 3 ChEIs were not significantly different: $12,112 ($16,437) for donepezil, $12,137 ($19,154) for galantamine (P=0.978), and $12,853 ($14,543) for rivastigmine (P=0.278). During the first year following initiation of ChEI therapy, patients initiated on donepezil had a greater days supply of the index medication than did patients initiated on rivastigmine. At 12 months following treatment initiation, the proportion of patients in therapy was higher for donepezil than for either rivastigmine or galantamine and was higher for galantamine than for rivastigmine. Patients treated with either donepezil or galantamine were less likely to switch from the index drug to another ChEI than were patients treated with rivastigmine. All-cause 1-year health care costs for patients initiated on the 3 ChEIs were not significantly different.


Insecticidal and growth inhibitory potential of Streptomyces hydrogenans DH16 on major pest of India, Spodoptera litura (Fab.) (Lepidoptera: Noctuidae).
Destructive impacts of insecticides on non targeted populations necessitate the development of an eco friendly pest control method. Streptomyces spp. are rich source of bioactive secondary metabolites which may provide valuable alternatives to chemical insect-control agents as they can be less toxic and readily biodegradable. Because of its potent biocontrol attributes, ethyl acetate extract of Streptomyces hydrogenans DH16, a soil isolate, was tested to assess its anti-insect potential against polyphagous noctuid, Spodoptera litura. The secondary metabolites in the ethyl acetate extract of S. hydrogenans DH16 exhibited larvicidal and growth inhibitory activities. The results indicated that highest concentration of 1600 μg/ml was significantly effective as 70% larval, 66.66% prepupal and 100% pupal mortality was noticed. The metabolites also prolonged the larval developmental period. The LC50 and LC90 values were 1337.384 and 2070.516 μg/ml, respectively for the insect. Negative effects of S. hydrogenans were also observed on development of the insect. Significant decline in adult emergence, adult longevity, fecundity and % hatching was recorded at higher concentrations along with morphological abnormalities as compared to control. Significant decrease in relative growth and consumption rate, efficiency of ingested and digested food and increase in approximate digestibility in larvae reared on diet supplemented with ethyl acetate extract accounts for the toxic as well as anti-nutritive nature of extract. Secondary metabolites in the fermentation broth from S. hydrogenans were toxic to the larvae at higher concentrations whereas lower concentrations significantly reduced the reproductive potential of S. litura. Therefore, these metabolites show considerable potential for incorporation in pest management programmes as new biopesticidal formulation.


Evolutionary history of the NAM-B1 gene in wild and domesticated tetraploid wheat.
The NAM-B1 gene in wheat has for almost three decades been extensively studied and utilized in breeding programs because of its significant impact on grain protein and mineral content and pleiotropic effects on senescence rate and grain size. First detected in wild emmer wheat, the wild-type allele of the gene has been introgressed into durum and bread wheat. Later studies have, however, also found the presence of the wild-type allele in some domesticated subspecies. In this study we trace the evolutionary history of the NAM-B1 in tetraploid wheat species and evaluate it as a putative domestication gene. Genotyping of wild and landrace tetraploid accessions showed presence of only null alleles in durum. Domesticated emmer wheats contained both null alleles and the wild-type allele while wild emmers, with one exception, only carried the wild-type allele. One of the null alleles consists of a deletion that covers several 100 kb. The other null-allele, a one-basepair frame-shift insertion, likely arose among wild emmer. This allele was the target of a selective sweep, extending over several 100 kb. The NAM-B1 gene fulfils some criteria for being a domestication gene by encoding a trait of domestication relevance (seed size) and is here shown to have been under positive selection. The presence of both wild-type and null alleles in domesticated emmer does, however, suggest the gene to be a diversification gene in this species. Further studies of genotype-environment interactions are needed to find out under what conditions selection on different NAM-B1 alleles have been beneficial.


Gamma-ray spectrometry data collection and reduction by simple computing systems.
The review summarizes the present state of the involvement of relatively small computing devices in the collection and processing of gamma-ray spectrum data. An economic and utilitarian point of view has been chosen with regard to data collection in order to arrive at practically valuable conclusions in terms of feasibility of possible configurations with respect to their eventual application. A unified point of view has been adopted with regard to data processing by developing an information theoretical approach on a more or less intuitive level in an attempt to remove the largest part of the virtual disparity between the several processing methods described in the literature. A synoptical introduction to the most important mathematical methods has been incorporated, together with a detailed theoretical description of the concept gamma-ray spectrum. In accordance with modern requirements, the discussions are mainly oriented towards high-resolution semiconductor detector-type spectra. The critical evaluation of the processing methods reviewed is done with respect to a set of predefined criteria. Smoothing, peak detection, peak intensity determination, overlapping peak resolving and detection and upper limits are discussed in great detail. A preferred spectrum analysis method combining powerful data reduction properties with extreme simplicity and speed of operation is suggested. The general discussion is heavily oriented towards activation analysis application, but other disciplines making use of gamma-ray spectrometry will find the material presented equally useful. Final conclusions are given pointing to future developments and shifting their centre of gravity towards improving the quality of the measurements rather than expanding the use of tedious and sophisticated mathematical techniques requiring the limits of available computational power.


Diagnostic performance of IgG anti-deamidated gliadin peptide antibody assays is comparable to IgA anti-tTG in celiac disease.
Detection of IgG antibodies against deamidated gliadin peptides (DGP) is more sensitive and more specific for celiac disease than detection of IgG antibodies against native gliadin. Our aim was to evaluate the technical performance and diagnostic accuracy of four commercial IgG anti-DGP assays. Commercial IgG anti-DGP assays from Euroimmun, Inova, Phadia and The Binding Site were evaluated and their diagnostic accuracy (sensitivity and specificity) compared to other serologic assays for celiac disease (3IgA and 2IgG anti-tTG assays, 1IgA and 1IgG anti-gliadin assay, 1IgA anti-DGP assay). The study population consisted of 86 consecutive CD patients and 741 disease controls. The technical performance (linearity, interference and imprecision) of the IgG anti-DGP assays was acceptable. The sensitivity of the IgG anti-DGP assays varied between 76.7% and 86.0% at the cut-off recommended by the manufacturer and between 74.4% and 86.0% at the cut-off that corresponded to a specificity of 98%. The specificity varied between 97.3% and 99.3%. The diagnostic accuracy of the IgG anti-DGP assays was comparable to the diagnostic accuracy of the IgA anti-tTG assays. The sensitivity of the IgG anti-DGP assays was significantly better than sensitivity of the IgG anti-tTG assays (p<0.05) and the specificity was significantly better than the IgA and IgG anti-gliadin assays (p<0.05). The overall performance of the four IgG anti-DGP assays was acceptable and the diagnostic accuracy comparable to the three IgA anti-tTG assays.


Recombinant production of active microbial transglutaminase in E. coli by using self-cleavable zymogen with mutated propeptide.
Microbial transglutaminase from Streptomyces mobaraensis (MTG) has been widely used in food industry and also in research and medical applications, since it can site-specifically modify proteins by the cross-linking reaction of glutamine residue and the primary amino group. The recombinant expression system of MTG in E. coli provides better accessibility for the researchers and thus can promote further utilization of MTG. Herein, we report production of active and soluble MTG in E. coli by using a chimeric protein of tobacco etch virus (TEV) protease and MTG zymogen. A chimera of TEV protease and MTG zymogen with native propeptide resulted in active MTG contaminated with cleaved propeptide due to the strong interaction between the propeptide and catalytic domain of MTG. Introduction of mutations of K9R and Y11A to the propeptide facilitated dissociation of the cleaved propeptide from the catalytic domain of MTG and active MTG without any contamination of the propeptide was obtained. The specific activity of the active MTG was 22.7 ± 2.6 U/mg. The successful expression and purification of active MTG by using the chimera protein of TEV protease and MTG zymogen with mutations in the propeptide can advance the use of MTG and the researches using MTG mediated cross-linking reactions.


Intercellular Ca(2+) waves induce temporally and spatially distinct intracellular Ca(2+) oscillations in glia.
Mechanically induced intercellular Ca(2+) waves propagated for approximately 300 microm in primary glial cultures. Following the wave propagation, 34% of the cells displayed Ca(2+) oscillations in a zone 60-120 microm from the stimulated cell. The initiation, frequency, and duration of these Ca(2+) oscillations were dependent on the cells' distance from the wave origin but were not dependent on the cell type nor on the magnitude of the Ca(2+) wave. When an individual cell propagated two sequential intercellular Ca(2+) waves originating from different sites, the characteristics of the Ca(2+) oscillations initiated by each wave were determined by the distance of the cell from the origin of each wave. Each Ca(2+) oscillation commonly occurred as an intracellular Ca(2+) wave that was initiated from a specific site within the cell. The position of the initiation site and the direction of the intracellular Ca(2+) wave were independent of the orientation of the initial intercellular Ca(2+) wave. Because initiation and frequency of Ca(2+) oscillations are dependent on the intracellular inositol trisphosphate concentration ([IP(3)](i)), we propose that the zone of cells displaying Ca(2+) oscillations is determined by an intercellular gradient of [IP(3)](i), established by the diffusion of IP(3) through gap junctions during the propagation of the intercellular Ca(2+) wave. Exposure to acetylcholine, a muscarinic agonist that initiates IP(3) production, shifted the zone of oscillating cells about 45 microm farther away from the origin of the mechanically induced wave. These findings indicate that a glial syncytium can resolve information provided by a local Ca(2+) wave into a distinct spatial and temporal pattern of Ca(2+) oscillations.


[Neuronal Calcium Sensor-1: A Zinc/Redox-Dependent Protein of Nervous System Signaling Pathways].
Intracellular calcium signaling is involved in regulating the key functional mechanisms of the nervous system. The control of neuronal excitability and plasticity by calcium ions underlies the mechanisms of higher nervous activity, and the mechanisms of this control are of particular interest to researchers. A family of highly specialized neuronal proteins described in recent decades can translate the information contained in calcium signals into the regulation of channels, enzymes, receptors, and transcription factors. Neuronal calcium sensor-1 (NCS-1) is the most common member of the family, which is intensely expressed in central nervous system (CNS) cells; and controls several vital processes, such as neuronal growth and survival, reception, neurotransmission, and synaptic plasticity. In addition to calcium ions, NCS-1 can bind the so-called mobile, or signaling intracellular zinc, an increased concentration of which is a characteristic feature of cells in oxidative stress. Zinc coordination under these conditions stimulates NCS-1 oxidation to form a disulfide dimer (dNCS-1) with altered functional properties. A combined effect of mobile zinc and an increased redox potential of the medium can thus induce aberrant NCS-1 activity, including signals that promote survival of neuronal cells or induce their apoptosis and, consequently, the development of neurodegenerative processes. The review details the localization, expression regulation, structure, and molecular properties of NCS-1 and considers the current data on its signaling activity in health and disease, including zinc-dependent redox regulation cascades.


A Critical Review of the Removal of Radionuclides from Wastewater Employing Activated Carbon as an Adsorbent.
Radionuclide-contaminated water is carcinogenic and poses numerous severe health risks and environmental dangers. The activated carbon (AC)-based adsorption technique has great potential for treating radionuclide-contaminated water due to its simple design, high efficiency, wide pH range, quickness, low cost and environmental friendliness. This critical review first provides a brief overview of the concerned radionuclides with their associated health hazards as well as different removal techniques and their efficacy of removing them. Following this overview, this study summarizes the surface characteristics and adsorption capabilities of AC derived from different biomass precursors. It compares the adsorption performance of AC to other adsorbents, such as zeolite, graphene, carbon nano-tubes and metal-organic frameworks. Furthermore, this study highlights the different factors that influence the physical characteristics of AC and adsorption capacity, including contact time, solution pH, initial concentration of radionuclides, the initial dosage of the adsorbent, and adsorption temperature. The theoretical models of adsorption isotherm and kinetics, along with their fitting parameter values for AC/radionuclide pairs, are also reviewed. Finally, the modification procedures of pristine AC, factors determining AC characteristics and the impact of modifying agents on the adsorption ability of AC are elucidated in this study; therefore, further research and development can be promoted for designing a highly efficient and practical adsorption-based radionuclide removal system.


Neck Remnants and the Risk of Aneurysm Rupture After Endovascular Treatment With Coiling or Stent-Assisted Coiling: Much Ado About Nothing?
Neck remnants are not uncommon after endovascular treatment of cerebral aneurysms. Critics of endovascular treatments for cerebral aneurysms cite neck remnants as evidence in favor of microsurgical clipping. However, studies have failed to evaluate the true clinical significance of aneurysm neck remnants following endovascular therapies. To assess the clinical significance of residual aneurysm necks and to determine the rate of subsequent rupture following coiling or stent-assisted coiling of cerebral aneurysms. We retrospectively reviewed the records of 1292 aneurysm cases that underwent endovascular treatment at 4 institutions. Aneurysms treated by primary coiling or stent-assisted coiling were included in the study; those treated by flow diversion were excluded Aneurysms with residual filling (i.e., Raymond-Roy Occlusion Classification II, neck remnant; or III, residual aneurysm filling) were assessed for their risk of subsequent rupture. A total of 626 aneurysms were identified as having residual filling immediately posttreatment. Of these, 13 aneurysms (2.1%) ruptured during the follow-up period (mean 7.3 mo; range 1-84 mo). Eleven of the 13 (84.6%) were ruptured at presentation. Rupture at presentation, the size of the aneurysm, and the increasing age of the patient were predictive of posttreatment rupture. We found that unruptured aneurysms with residual necks following endovascular treatment posed a very low risk of rupture (0.6%). However, patients presenting with ruptured aneurysms had a higher risk of rerupture from a neck remnant (3.4%). These results highlight the importance of achieving complete angiographic occlusion of ruptured aneurysms.


A case law survey of the Personality Assessment Inventory: examining its role in civil and criminal trials.
Although professional surveys suggest that the Personality Assessment Inventory (PAI; Morey, 1991) is a popular instrument among forensic and correctional psychologists, relatively little is known about the specific types of legal cases in which it is applied, the particular types of questions it is used to address, or the extent to which its admissibility has been at issue in court cases. Using a comprehensive legal database, we surveyed all published U.S., Canadian, European, and Australian criminal and civil cases in which the PAI was administered. The PAI appears to be introduced by examiners in a wide variety of civil (e.g., child custody, personal injury) and criminal (e.g., insanity, competence) cases to aid in the assessment of a broad range of psychopathology. Additionally, the PAI seems to be used frequently to assess questions concerning potential dissimulation and response styles. Surprisingly, the admissibility of the PAI into evidence was never at issue in any of the cases reviewed.


Interhospital Variation in the Costs of Pediatric/Congenital Cardiac Catheterization Laboratory Procedures: Analysis of Data From the Pediatric Health Information Systems Database.
Background Cardiac catheterization is an important but costly component of health care for young patients with cardiac disease. Measurement of variation in their cost between hospitals and identification of the reasons for this variation may help reduce cost without compromising quality. Methods and Results Using data from Pediatric Health Information Systems Database from January 2007 to December 2015, the costs of 9 procedures were measured. Mixed-effects multivariable models were used to generate case-mix-adjusted estimates of each hospital's cost for each procedure and measure interhospital variation. Procedures (n=35 637) from 43 hospitals were studied. Median costs varied from $8249 (diagnostic catheterization after orthotopic heart transplantation) to $38 909 (transcatheter pulmonary valve replacement). There was marked variation in the cost of procedures between hospitals with 3.5- to 8.9-fold differences in the case-mix-adjusted cost between the most and least expensive hospitals. No significant correlation was found between hospitals' procedure-specific mortality rates and costs. Higher procedure volume was not associated with lower cost except for diagnostic procedures in heart transplant patients and pulmonary artery angioplasty. At the hospital level, the proportion of cases that were outliers (>95th percentile) was significantly associated with rank in terms of cost (Spearman's ρ ranging from 0.37 to 0.89, P<0.01). Conclusions Large-magnitude hospital variation in cost was not explained by case-mix or volume. Further research is necessary to determine the degree to which variation in cost is the result of differences in the efficiency of the delivery of healthcare services and the rate of catastrophic adverse outcomes and resultant protracted and expensive hospitalizations.


[Detection of cancer of the prostate. A study of 600 cases].
A free screening consultation for carcinoma of the prostate was proposed to men over the age of 50 years working in different companies in the areas of Paris. This consultation included a digital rectal examination, a blood test for determination of serum acid phosphatase and prostatic specific antigen, and two dimensional trans-rectal ultrasonography of the prostate. 600 patients were seen. 575 were evaluable. Prostate biopsy was recommended in 152 men. Ninety-three prostate biopsies were performed. Eighteen prostatic cancers and 1 urothelial cancer invading the prostate were detected with an overall incidence of prostate cancer of 3.1%. Radical prostatectomies were performed in 10 of the 18 patients with a prostate cancer. Sensitivity of digital rectal examination ultrasonography and PSA were respectively 42.8%, 47.3% and 68.4% with an abnormal serum PSA level defined as being greater than 5 ng/ml. The predictive value of a positive ultrasonography (18.7%) contrasts with the predictive value of a positive digital rectal examination (30.7%) and serum PSA (30%). Digital rectal examination and determination of serum prostatic specific antigen seem to be the most useful tests for mass screening of prostate cancer. Transrectal ultrasonography is very useful for guided prostatic biopsy and for a better topographic evaluation of the tumor.


The search for oculomotor inhibition: interactions with working memory.
When a saccadic target is presented simultaneously with a distractor, the distractor has to be inhibited in order to successfully perform an eye movement to the target. Insufficient inhibition results in an erroneous eye movement to the distractor. This study investigated whether the influence of a distractor on eye movements is mediated by working memory. A working memory task was added to a saccadic paradigm in which an irrelevant element had to be inhibited. Results show that participants made more erroneous saccades to the distractor when working memory was occupied. This suggests that working memory is involved in the oculomotor inhibition of saccadic distractors.


Angelica injection promotes peripheral nerve structure and function recovery with increased expressions of nerve growth factor and brain derived neurotrophic factor in diabetic rats.
Several nervous system injury models, such as sciatic crush and chronic cerebral hypoperfusion have been well studied in terms of neuroprotective effect of angelica injection. However, definitive experimental studies are lacking on diabetic peripheral neuropathy (DPN). This study sought to investigate the effects of angelica injection on DPN in type 1 diabetic rats. Diabetes was induced by single intraperitoneal injection of streptozotocin (STZ). To examine whether DPN model succeeded, tail-flick latency (TFL) and motor nerve conduction velocity (MNCV) were measured at 6 weeks after diabetes induction. Then, diabetic rats were treated with high- and low-dose angelica injection for 4 weeks. TFL, MNCV, morphology of sciatic nerve, myelinated nerve fiber density and the expressions of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) in soleus and sciatic nerve were measured at 10 weeks after diabetes induction. The results showed the TFL was significantly shortened (p<0.001) and the MNCV was reduced (p<0.01) in diabetic rats compared with normal control rats at 6 weeks after diabetes induction. The TFL was obviously prolonged and the MNCV was further reduced in diabetic control group at 10 weeks after diabetes induction. TFL, MNCV and morphology of sciatic nerve were remarkably ameliorated and myelinated nerve fiber density and the expressions of NGF and BDNF in soleus and sciatic nerve were increased in the angelica treatment groups. This study suggests angelica injection has potential therapeutic effects on DPN, and the mechanism might be related to direct increase in NGF expression and direct or indirect increase in BDNF expression.


Identification of polypeptide precursors to HSV-1 glycoproteins by cell-free translation.
Using antisera of limited specificity we have detected among the in vitro translation products of HSV-1 RNA, polypeptides antigenically related to infected cell glycoproteins. The results obtained suggest that non-glycosylated polypeptide precursors of mol. wt. 85,000 and 52,000 correspond to infected cell glycoproteins of mol. wt. 120,000 to 126,000 and 56,000 to 68,000 respectively.


Consensus statement on the role of acute dopaminergic challenge in Parkinson's disease.
Available evidence on the practice of acute pharmacological challenge tests in parkinsonian patients was reviewed by a committee of experts, which achieved a general consensus. The published data deal mainly with the acute administration of levodopa and apomorphine in Parkinson's disease. Such challenge may serve different purposes, e.g., research, diagnosis, or tailoring of treatment. Unique protocols describing the clinical setting and practice parameters are not available. The present paper describes the scientific background and supplies practical guidelines, whenever possible, to perform and evaluate acute challenge tests in parkinsonian syndromes. With the appropriate indication and setting, acute challenge tests are useful in diagnosis and therapy of Parkinson's disease and related disorders.


A reference profile-free deconvolution method to infer cancer cell-intrinsic subtypes and tumor-type-specific stromal profiles.
Patient stratification based on molecular subtypes is an important strategy for cancer precision medicine. Deriving clinically informative cancer molecular subtypes from transcriptomic data generated on whole tumor tissue samples is a non-trivial task, especially given the various non-cancer cellular elements intertwined with cancer cells in the tumor microenvironment. We developed a computational deconvolution method, DeClust, that stratifies patients into subtypes based on cancer cell-intrinsic signals identified by distinguishing cancer-type-specific signals from non-cancer signals in bulk tumor transcriptomic data. DeClust differs from most existing methods by directly incorporating molecular subtyping of solid tumors into the deconvolution process and outputting molecular subtype-specific tumor reference profiles for the cohort rather than individual tumor profiles. In addition, DeClust does not require reference expression profiles or signature matrices as inputs and estimates cancer-type-specific microenvironment signals from bulk tumor transcriptomic data. DeClust was evaluated on both simulated data and 13 solid tumor datasets from The Cancer Genome Atlas (TCGA). DeClust performed among the best, relative to existing methods, for estimation of cellular composition. Compared to molecular subtypes reported by TCGA or other similar approaches, the subtypes generated by DeClust had higher correlations with cancer-intrinsic genomic alterations (e.g., somatic mutations and copy number variations) and lower correlations with tumor purity. While DeClust-identified subtypes were not more significantly associated with survival in general, DeClust identified a poor prognosis subtype of clear cell renal cancer, papillary renal cancer, and lung adenocarcinoma, all of which were characterized by CDKN2A deletions. As a reference profile-free deconvolution method, the tumor-type-specific stromal profiles and cancer cell-intrinsic subtypes generated by DeClust were supported by single-cell RNA sequencing data. DeClust is a useful tool for cancer cell-intrinsic molecular subtyping of solid tumors. DeClust subtypes, together with the tumor-type-specific stromal profiles generated by this pan-cancer study, may lead to mechanistic and clinical insights across multiple tumor types.


Large-scale conservation planning in a multinational marine environment: cost matters.
Explicitly including cost in marine conservation planning is essential for achieving feasible and efficient conservation outcomes. Yet, spatial priorities for marine conservation are still often based solely on biodiversity hotspots, species richness, and/or cumulative threat maps. This study aims to provide an approach for including cost when planning large-scale Marine Protected Area (MPA) networks that span multiple countries. Here, we explore the incorporation of cost in the complex setting of the Mediterranean Sea. In order to include cost in conservation prioritization, we developed surrogates that account for revenue from multiple marine sectors: commercial fishing, noncommercial fishing, and aquaculture. Such revenue can translate into an opportunity cost for the implementation of an MPA network. Using the software Marxan, we set conservation targets to protect 10% of the distribution of 77 threatened marine species in the Mediterranean Sea. We compared nine scenarios of opportunity cost by calculating the area and cost required to meet our targets. We further compared our spatial priorities with those that are considered consensus areas by several proposed prioritization schemes in the Mediterranean Sea, none of which explicitly considers cost. We found that for less than 10% of the Sea's area, our conservation targets can be achieved while incurring opportunity costs of less than 1%. In marine systems, we reveal that area is a poor cost surrogate and that the most effective surrogates are those that account for multiple sectors or stakeholders. Furthermore, our results indicate that including cost can greatly influence the selection of spatial priorities for marine conservation of threatened species. Although there are known limitations in multinational large-scale planning, attempting to devise more systematic and rigorous planning methods is especially critical given that collaborative conservation action is on the rise and global financial crisis restricts conservation investments.


Gastric autoimmunity in children and adolescents with type 1 diabetes: a prospective study.
Type 1 diabetes (T1DM) is associated with gastric autoimmunity, which is characterized by the presence of parietal cell antibodies (APCA). We investigated gastric autoimmunity prevalence in T1DM children, its manifestations, determinants and association with thyroid gland (anti-Tg, anti-TPO) and pancreatic β-cell autoimmunity (anti-GAD) at baseline and 4 years later. The initial cohort (D1) included 97 children with T1DM. At follow-up after 4 years (D2), 84.5% of participants were evaluated. We assessed APCA, anti-Tg, anti-TPO, and anti-GAD presence, as well as symptoms of gastritis. APCA-positive patients were evaluated with gastrin, B₁₂, ferritin levels and were submitted to gastroscopy. Thyroid antibody positivity was increased among the APCA-positive patients. Four years later, among initially APCA-positive patients, 2/6 became APCA negative, while 4/6 developed high titers of APCA. On gastroscopy, 2 patients had chronic hypertrophic gastritis and one Helicobacter pylori gastritis. Gastric autoimmunity was associated with thyroid autoimmunity and anti-GAD persistence. After 4 years, the majority of APCA-positive patients developed high titers of APCA and mild symptoms of gastritis. Thus, patients with T1DM, and in particular those with thyroid and/or pancreatic autoimmunity, should have periodic autoantibody screening for the early diagnosis and follow-up of gastric autoimmunity.


Characterization of a 7Fe ferredoxin isolated from the marine denitrifier Pseudomonas nautica strain 617: spectroscopic and electrochemical studies.
A 7Fe ferredoxin, isolated from the marine denitrifier Pseudomonas nautica strain 617, was characterized. The NH2-terminal sequence analysis, performed until residue number 56, shows a high similarity with the 7Fe ferredoxins isolated from Azotobacter vinelandii, Pseudomonas putida, and Pseudomonas stutzeri. EPR and NMR spectroscopies identify the presence of both [3Fe-4S] and [4Fe-4S] clusters, with cysteinyl coordination. The electrochemical studies on [Fe-S] clusters show that a fast diffusion-dominated electron transfer, promoted by Mg(II), takes place between the ferredoxin and the glassy carbon electrode. Square wave voltammetry studies gave access to the electrosynthesis of a 4Fe center formed within the [3Fe-4S] core. The [3Fe-4S] cluster exhibited two reduction potentials at -175 and -680 +/- 10 mV and the [4Fe-4S] cluster was characterized by an unusually low reduction potential of -715 +/- 10 mV, at pH 7.6


Hospital "de-ministration" experiences in six teaching hospitals.
An experimental management programme at Sydney Hospital, first reported in this Journal in 1971, has now been repeated in five other teaching hospitals. These programmes confirm that when professional staff members are encouraged to participate in managing their hospital, they do so very effectively. Results include: better patient care, more patients treated, lower cost per patient, improved morale and flexibility in outlook. The benefits potentially available from the widespread introduction of this approach to managing hospitals are tremendous but to realize them requires radical changes in the way public hospitals are controlled by health authorities.


Pitfalls and progress in adrenocortical carcinoma diagnosis: the utility of a multidisciplinary approach, immunohistochemistry and genomics.
Adrenocortical carcinoma is a rare disease with poor prognosis whose clinical heterogeneity can at times present a challenge to accurate and timely diagnosis. We present the case of a patient who presented with extensive pulmonary lesions, mediastinal and hilar lymphadenopathy and an adrenal mass in whom the oncological diagnosis was initially uncertain. Through the use of immunohistochemistry, biochemistry and genomic testing, an accurate diagnosis of adrenocortical carcinoma was ultimately made which resulted in more directed treatment being administered. The use of multidisciplinary input and genomics to aid in diagnosis and prognosis of adrenocortical carcinoma is discussed. Adrenocortical carcinomas can present a diagnostic challenge to clinicians given it is a rare malignancy with significant clinical heterogeneity. Specialist multidisciplinary team input is vital in the diagnosis and management of adrenocortical carcinomas. Hormonal testing is recommended in the diagnostic workup of adrenal masses, even in the absence of overt clinical signs/symptoms of hormone excess. Immunostaining for the highly sensitive and specific steroidogenic factor-1 is vital for accurate diagnosis. Genomics can provide prognostic utility in management of adrenocortical carcinoma.


Development of relationship satisfaction across the life span: A systematic review and meta-analysis.
Previous research has not led to any agreement as to the normative trajectory of relationship satisfaction. In this systematic review and meta-analysis, we summarize the available evidence on development of relationship satisfaction, as a function of age and relationship duration. Data came from 165 independent samples including 165,039 participants. In the analyses, we examined cross-sectional information on mean level, that is, the percent-of-maximum-possible (POMP) score at the first assessment, and longitudinal information on mean change (i.e., change in POMP scores per year). The mean age associated with effect sizes ranged from 20 to 76 years and the mean relationship duration from 3 months to 46 years. Results on mean levels indicated that relationship satisfaction decreased from age 20 to 40, reached a low point at age 40, then increased until age 65, and plateaued in late adulthood. As regards the metric of relationship duration, relationship satisfaction decreased during the first 10 years of the relationship, reached a low point at 10 years, increased until 20 years, and then decreased again. Results on mean change indicated that relationship satisfaction decreased within a given relationship, with the largest declines in young adulthood and in the first years of a relationship. Moderator analyses suggested that presence of children and measure of relationship satisfaction explained variance in the mean level. Except for these two moderators, the pattern of findings held across characteristics such as birth cohort, sample type, country, ethnicity, gender, household shared with partner, marital status, relationship transitions, and dyadic data. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Real-world clinical outcomes and treatment patterns in patients with MDD treated with vortioxetine: a retrospective study.
This study included evaluation of the effectiveness of vortioxetine, a treatment for adults with major depressive disorder (MDD), using patient-reported outcome measures (PROMs) in a real-world setting. This retrospective chart review analyzed the care experiences of adult patients with a diagnosis of MDD from Parkview Physicians Group - Mind-Body Medicine, Midwestern United States. Patients with a prescription for vortioxetine, an initial baseline visit, and ≥ 2 follow-up visits within 16 weeks from September 2014 to December 2018 were included. The primary outcome measure was effectiveness of vortioxetine on depression severity as assessed by change in Patient Health Questionnaire-9 (PHQ-9) scores ~ 12 weeks after initiation of vortioxetine. Secondary outcomes included changes in depression-related symptoms (i.e., sexual dysfunction, sleep disturbance, cognitive function, work/social function), clinical characteristics, response, remission, and medication persistence. Clinical narrative notes were also analyzed to examine sleep disturbance, sexual dysfunction, appetite, absenteeism, and presenteeism. All outcomes were examined at index (start of vortioxetine) and at ~ 12 weeks, and mean differences were analyzed using pairwise t tests. A total of 1242 patients with MDD met inclusion criteria, and 63.9% of these patients had ≥ 3 psychiatric diagnoses and 65.9% were taking ≥ 3 medications. PHQ-9 mean scores decreased significantly from baseline to week 12 (14.15 ± 5.8 to 9.62 ± 6.03, respectively; p < 0.001). At week 12, the response and remission rates in all patients were 31.0% and 23.1%, respectively, and 67% continued vortioxetine treatment. Overall, results also showed significant improvements by week 12 in anxiety (p < 0.001), sexual dysfunction (p < 0.01), sleep disturbance (p < 0.01), cognitive function (p < 0.001), work/social functioning (p = 0.021), and appetite (p < 0.001). A significant decrease in presenteeism was observed at week 12 (p < 0.001); however, no significant change was observed in absenteeism (p = 0.466). Using PROMs, our study results suggest that adults with MDD prescribed vortioxetine showed improvement in depressive symptoms in the context of a real-world clinical practice setting. These patients had multiple comorbid psychiatric and physical diagnoses and multiple previous antidepressant treatments had failed.


Molecular cytogenetic characterisation of partial trisomy 9q in a case with pyloric stenosis and a review.
Partial trisomy 9q represents a rare and heterogeneous group of chromosomal aberrations characterised by various clinical features including pyloric stenosis. Here, we describe the case of a 1 year old female patient with different dysmorphic features including pyloric stenosis and prenatally detected partial trisomy 9q. This partial trisomy 9q has been analysed in detail to determine the size of the duplication and to characterise the chromosomal breakpoints. According to the data gained by different molecular cytogenetic techniques, such as fluorescence in situ hybridisation (FISH) with whole and partial chromosome painting probes, yeast artificial chromosome (YAC) probes, and comparative genomic hybridisation (CGH), the derivative chromosome 9 can be described as dup(9)(pter-->q22. 1::q31.1-->q22.1::q31.1--> q22.1::q31.1-->qter). Four breakpoint spanning YACs have been identified (y806f02, y906g6, y945f5, and y747b3) for the proximal breakpoint. According to this new case and previously published data, the recently postulated putative critical region for pyloric stenosis can be narrowed down to the subbands 9q22.1-q31.1 and is the result of either partial trisomy of gene(s) located in this region or a gene disrupted in 9q31.


Transcanalicular Diode Laser-Assisted Revision Surgery for Failed Dacryocystorhinostomy With or Without Distal or Common Canalicular Obstruction.
To report the outcomes of transcanalicular diode laser-assisted revision surgery for failed dacryocystorhinostomy with/without distal or common canalicular obstruction. The medical records and recorded videos of consecutive transcanalicular diode laser-assisted revision surgeries performed for failed dacryocystorhinostomy between May 2011 and May 2015 were reviewed. Cases of unavailability of video and cases lost to follow up after surgery were excluded from the study. With respect to the level of obstruction, lacrimal drainage systems were divided into Group 1 (obstruction at the level of the ostium) and Group 2 (obstruction at the level of the distal or common canaliculus). Data associated with anatomical and functional success were analyzed. Revision dacryocystorhinostomy surgeries were performed on 68 patients during the study period. Transcanalicular diode laser-assisted revision surgeries were performed on 48 eyes of 39 patients. Mean follow-up period after revision surgery was 13.3 ± 12.6 months. Overall, anatomical success rate was 83.3% (40/48) and functional success rate was 68.8% (33/48). Anatomical success rates and functional success rates in the 2 groups showed no significant difference (80.0% [24/30] vs. 86.7% [13/15], p = 0.699; 70.0% [21/30] vs. 66.7% [10/15], p = 1.000, respectively). Transcanalicular diode laser-assisted revision surgery may be an alternative technique for failed dacryocystorhinostomy. Distal or common canalicular obstruction did not affect the outcomes of revision surgeries.


A new progression scale for common lower-limb rehabilitation tasks.
The treatment of most injuries tends to have similar goals: to minimize initial pain and swelling, restore full range of motion, and return to full strength. One of the key problems is the gap between the traditional rehabilitation modalities and progression to normal locomotive and athletic activities. Closed kinetic chain exercises are a common feature of rehabilitation programs, yet progression of these exercises in a rehabilitation setting has traditionally been based on anecdotal advice, and there is a shortage of empirical evidence. The aim of this study is to use ground reaction force measures to guide progression of closed kinetic chain rehabilitation exercises for active individuals recovering from lower extremity injury. Twenty-four injury-free participants carried out 10 different movements including jumps, squats, and locomotive tasks. Force data collected via a Kistler force platform were used to quantify peak vertical force (Fz), peak vertical force relative to body weight (Fz/BW), and rate of force development (RFD). A Vicon motion analysis system provided kinematic data. There were significant interactions of task and peak Fz, task and peak Fz/BW, and task and RFD. For all force measures, the majority of tasks were significantly different from one another. The effect of kinematic variability was evaluated using the Pearson Correlation coefficient. A clear progression of exercises was seen in both peak Fz and peak Fz/BW, whereas RFD measures showed 3 distinct groups. Combining the data from the measures leads to the grouping the exercises into early, mid, late, and final stages of rehabilitation. We suggest that practitioners use this ranking to prescribe appropriate exercises for particular stages of rehabilitation.


Direct to consumer advertising in healthcare: history, benefits, and concerns.
Physicians, health plans, hospitals, pharmaceutical companies, and medical device manufacturers have all recognized the benefits of marketing their products and services directly to the end user. As a result, there has been tremendous growth of direct-to-consumer advertising (DTCA), illustrated by the increase in spending on DTCA related to prescription drugs from an estimated $55 million in 1991 to $3.2 billion in 2003. This increase in DTCA has sparked vigorous debate among the major stakeholders in healthcare over the benefits and drawbacks of advertising directly to the healthcare consumer. Issues with DTCA include its impact on the doctor-patient relationship, patient education, inappropriate resource utilization, healthcare costs, healthcare quality, and overall patient wellbeing. Orthopaedic surgery is no longer insulated from this expanding trend in DTCA, as orthopaedic surgeons and hospitals are responsible for a substantial portion of DTCA related to orthopaedic devices and procedures. The Food and Drug Administration has a limited regulatory role and limited power related to DTCA due to considerable inefficiencies in its review and disciplinary processes. Therefore, physicians, including orthopaedic surgeons, must take a leadership role on this issue to ensure the integrity of information provided to patients and to protect the sanctity of the doctor-patient relationship.


Three-dimensional crystals of an integral membrane protein: an initial x-ray analysis.
Matrix protein, a pore-forming transmembrane protein spanning the outer membrane of Escherichia coli, has been obtained in a variety of three-dimensional crystal forms amenable to both electron microscope and x-ray analyses. Successful association into large crystals depended on the use of alpha-octyl glucoside, a detergent with relatively low affinity for the protein. Electron micrographs of thin-sectioned crystals show a high degree of order. Preliminary crystallographic data suggest that the crystals, which exhibit diffraction to 3.8 A, have a cubic space group.


Avocado Creole Peel Ameliorates Metabolic Alterations Caused by a High Sucrose Fat Diet in a Wistar Rats Model.
High-sucrose high-fat diets are one of the causes of malnutrition, and may induce metabolic alterations such as dyslipidemia, insulin resistance, and adipogenesis. The objective of this work was to investigate the possible protective effect of traditionally edible avocado creole peel (Persea americana Mill var. drymifolia) when consuming a high-sucrose and fat diet (HSFD). The experimental animal model included 21 male Wistar rats divided in three groups: the control group received a standard diet of purina®, the HSFD group received a high fat diet plus 30% sucrose in drinking water, and finally the HSFD + AP group received the HSFD diet supplemented with 200 mg/kg of avocado peel for 14 weeks. It was observed that alterations included higher cholesterol, glucose, insulin, fatty acids and TNF-α levels as well as lower HDL, and adiponectin. The addition of avocado peel reverted some of these effects, resulting in normal values of triglicerides, insulin and adiponectin, while attenuated the levels of total cholesterol. Liver weight of the group added with avocado peel was similar to the control group. The neuronal density in the hippocampal areas CA1 and dentate gyrus DC were lower in the high glucose fat group, while the ingestion of the avocado peel showed a neuroprotective effect. The avocado creole ingestion reverted or attenuated most of the metabolic effects caused by a high-sucrose fat diet which was attributed to the compounds detected by HPLC-MS and GC-MS that included bioactive polyphenols such as flavanol quercetin, flavanone naringenin, flavan 3-ol catechin, cyanidin 3-glucoside, pelargonidin 3-glucoside, pelargonidin 3-rhamnoside, hydroxydelphinidin, eugenol and estragole.


The roles of mechanical compression and chemical irritation in regulating spinal neuronal signaling in painful cervical nerve root injury.
Both traumatic and slow-onset disc herniation can directly compress and/or chemically irritate cervical nerve roots, and both types of root injury elicit pain in animal models of radiculopathy. This study investigated the relative contributions of mechanical compression and chemical irritation of the nerve root to spinal regulation of neuronal activity using several outcomes. Modifications of two proteins known to regulate neurotransmission in the spinal cord, the neuropeptide calcitonin gene-related peptide (CGRP) and glutamate transporter 1 (GLT-1), were assessed in a rat model after painful cervical nerve root injuries using a mechanical compression, chemical irritation or their combination of injury. Only injuries with compression induced sustained behavioral hypersensitivity (p≤0.05) for two weeks and significant decreases (p<0.037) in CGRP and GLT-1 immunoreactivity to nearly half that of sham levels in the superficial dorsal horn. Because modification of spinal CGRP and GLT-1 is associated with enhanced excitatory signaling in the spinal cord, a second study evaluated the electrophysiological properties of neurons in the superficial and deeper dorsal horn at day 7 after a painful root compression. The evoked firing rate was significantly increased (p=0.045) after compression and only in the deeper lamina. The painful compression also induced a significant (p=0.002) shift in the percentage of neurons in the superficial lamina classified as low- threshold mechanoreceptive (sham 38%; compression 10%) to those classified as wide dynamic range neurons (sham 43%; compression 74%). Together, these studies highlight mechanical compression as a key modulator of spinal neuronal signaling in the context of radicular injury and pain.


High-density liquidlike component facilitates plastic flow in a model amorphous silicon system.
Molecular dynamics simulations show that plastic deformation of amorphous Si modeled by the Stillinger-Weber potential is very sensitive to the density of the initial unstressed state. Low-density systems exhibit a pronounced yield phenomenon, strain softening, and a dramatic drop in pressure during deformation at a constant volume. This behavior is explained by the presence in every system of a certain concentration of solidlike and liquidlike components, the latter being denser and more amenable to plastic flow.


Evaluation of molecules based on the electron donor-acceptor architecture as near-infrared β-amyloidal-targeting probes.
A novel class of near-infrared molecules based on the donor-acceptor architecture were synthesized and evaluated as Aβ imaging probes. In vivo imaging studies suggested that MCAAD-3 could penetrate the blood-brain barrier and label Aβ plaques in the brains of transgenic mice. Computational studies could reproduce the experimental trends well.


Recombinant human IL-11 attenuates the inflammatory response through down-regulation of proinflammatory cytokine release and nitric oxide production.
To elucidate the molecular mechanisms regulating the anti-inflammatory activities of recombinant human (rh)IL-11, the ability of rhIL-11 to reduce serum levels of inflammatory mediators such as TNF-alpha, IL-1beta, IL-12, and IFN-gamma in LPS-treated mice and to down-regulate macrophage function in culture was investigated. In a mouse model of endotoxemia, pretreatment with rhIL-11 blocked LPS-induced elevation of TNF-alpha, IL-1beta, and IFN-gamma serum levels, but had no effect on IL-12 p40, IL-6, or IL-10 serum levels. The effects of rhIL-11 on the production of inflammatory mediators in vivo may occur in part through direct interactions with macrophages. rhIL-11 pretreatment of thioglycollate-elicited peritoneal macrophages resulted in greater than 60% inhibition of LPS-induced production of TNF-alpha, IL-1beta, IL-12 p40, and nitric oxide. The activity of rhIL-11 was not mediated through induction of IL-10, IL-6, or TGF-beta1. These results indicate that the ability of rhIL-11 to modulate the inflammatory response is not dependent on known anti-inflammatory cytokines and substantiate a role for this cytokine in the attenuation of inflammatory conditions.


Further evidence for the bidimensionality of the components model of addiction: a reply to Amendola (2023).
In our original research article entitled "Deconstructing the components model of addiction: an illustration through "addictive" use of social media" (Fournier et al., 2023), we showed that the Bergen Social Media Addiction Scale, a six-item psychometric instrument derived from the components model of addiction to assess social media "addiction", did not form a unitary, but a bidimensional construct in which some components (i.e., salience, tolerance) were not associated with psychopathological symptoms, thus conflating central and peripheral features of addiction. Subsequently, in a recent commentary, Amendola (2023) sought to determine whether our findings were driven by the use of data aggregated from multiple independent datasets, i.e., a decision we transparently acknowledged as a limitation in our original research article. Following their re-analysis, Amendola (2023) claimed to have demonstrated that a unidimensional model best fitted the data. However, they only reported results for a partial set of models relevant to this investigation. In the present reply, through a transparent assessment and reporting of all unidimensional and bidimensional models relevant to this investigation, we show that the bidimensionality of the Bergen Social Media Addiction Scale is, in fact, tenable, robust, and consistent across multiple independent datasets. In line with the growing evidence demonstrating that many sets of criteria involved in operationalizing behavioral addictions pathologize involvement in appetitive behaviors, these results highlight the necessity to renew the conceptualization and assessment of behavioral addictions.


Infantile spasms (West syndrome): update and resources for pediatricians and providers to share with parents.
Infantile spasms (IS; West syndrome) is a severe form of encephalopathy that typically affects infants younger than 2 years old. Pediatricians, pediatric neurologists, and other pediatric health care providers are all potentially key early contacts for families who have an infant with IS. The objective of this article is to assist pediatric health care providers in the detection of the disease and in the counseling and guidance of families who have an infant with IS. Treatment guidelines, consensus reports, and original research studies are reviewed to provide an update regarding the diagnosis and treatment of infants with IS. Web sites were searched for educational and supportive resource content relevant to providers and families of patients with IS. Early detection of IS and pediatrician referral to a pediatric neurologist for further evaluation and initiation of treatment may improve prognosis. Family education and the establishment of a multidisciplinary continuum of care are important components of care for the majority of patients with IS. The focus of the continuum of care varies across diagnosis, initiation of treatment, and short- and long-term needs. Several on-line educational and supportive resources for families and caregivers of patients with IS were identified. Given the possibility of poor developmental outcomes in IS, including the emergence of other seizure disorders and cognitive and developmental problems, early recognition, referral, and treatment of IS are important for optimal patient outcomes. Dissemination of and access to educational and supportive resources for families and caregivers across the lifespan of the child with IS is an urgent need. Pediatric health care providers are well positioned to address these needs.


Epstein-Barr virus induces Fas (CD95) in T cells and Fas ligand in B cells leading to T-cell apoptosis.
Epstein-Barr virus (EBV) acute infectious mononucleosis (AIM) is characterized by transient immunosuppression in vivo and increased T-cell apoptosis after ex vivo culture of AIM peripheral blood mononuclear cells. We undertook experiments to test whether EBV or purified virion envelope glycoprotein gp350 could contribute to Fas-mediated T-cell apoptosis. Our in vitro results indicate that EBV increased Fas expression in CD4(+) T cells and Fas ligand (FasL) expression in B cells and macrophages. Purified gp350 was also shown to significantly increase CD95 expression in CD4(+) T cells. When T-cell CD95 was cross-linked, EBV-stimulated T cells underwent apoptosis. The induction of T-cell CD95 by EBV followed by CD95 cross-linking with anti-CD95 monoclonal antibody resulted in a loss in the number of T cells responding to the T-cell mitogens, anti-CD3 antibody, and interleukin-2. These results indicate that, in addition to serving as a principal ligand for the attachment of virus to target cells, gp350 may also act as an immunomodulatory molecule that promotes T-cell apoptosis.


NHE1 promotes invadopodial ECM proteolysis through acidification of the peri-invadopodial space.
Extracellular matrix (ECM) degradation is a critical process in tumor cell invasion and requires membrane and released proteases focalized at membrane structures called invadopodia. While extracellular acidification is important in driving tumor invasion, the structure/function mechanisms underlying this regulation are still unknown. Invadopodia are similar in structure and function to osteoclast podosomes responsible for bone degradation, and extracellular acidification is central to podosome action, suggesting that it could also be for invadopodial function. Here, utilizing a novel system for in situ zymography in native matrices, we show that the Na(+)/H(+) exchanger (NHE1) and NHE1-generated extracellular acidification are localized at and necessary for invadopodial-dependent ECM degradation, thereby promoting tumor invasion. Stimulation with EGF increased both NHE1-dependent proton secretion and ECM degradation. Manipulation of the NHE1 expression by RNA interference or activity via either transport-deficient mutation or the specific inhibitor cariporide confirmed that NHE1 expression and activity are required for invadopodia-mediated ECM degradation. Taken together, our data show a concordance among NHE1 localization, the generation of a well-defined acidic extracellular pH in the nanospace surrounding invadopodia, and matrix-degrading activity at invadopodia of human malignant breast carcinoma cells, providing a structural basis for the role of NHE1 in invasion and identifying NHE1 as a strategic target for therapeutic intervention.