Antitumor immunity induced by laser immunotherapy and its adoptive transfer.
The ideal cancer treatment modality should not only cause tumor regression and eradication but also induce a systemic antitumor immunity, which is essential for control of metastatic tumors and for long-term tumor resistance. Laser immunotherapy using a laser, a laser-absorbing dye, and an immunoadjuvant has induced such long-term immunity in treatment of a mammary metastatic tumor. The successfully treated rats established total resistance to multiple subsequent tumor challenges. To further study the mechanisms of the antitumor immunity induced by this novel treatment modality, passive adoptive transfer was performed using splenocytes as immune cells. The spleen cells that were harvested from successfully treated tumor-bearing rats provided 100% immunity in the naive recipients. The passively protected first cohort rats were immune to tumor challenge with an increased tumor dose; their splenocytes also prevented the establishment of tumor in the second cohort of naive recipient rats. This immunity transfer was accomplished without the usually required T-cell suppression in recipients.


Evaluation of cotton rats as a model for severe acute respiratory syndrome.
Experimental studies were conducted to evaluate two species of cotton rats, Sigmodon hispidus and Sigmodon fulviventer, as a model for severe acute respiratory syndrome (SARS). Blood and turbinate wash samples, and lung tissue were collected from each animal at different time points after SARS coronavirus (CoV) infection for determining the growth curve of virus, if any, by the standard infectivity assay in Vero E6 cells. In addition, sections of the lung, liver, spleen, and kidney were taken and used for histology analysis. All animals were observed daily for signs of illness, and in some experiments, animals were weighed on the day when they were sacrificed. The results indicated that the cotton rat species, S. hispidus and S. fulviventer, were not a useful model for either SARS-CoV infection or disease. This observation was supported by the absence of any signs of illness, the failure to consistently demonstrate virus in the blood and tissues, and the absent of any notable histopathology. However, infected animals were capable of producing neutralizing antibodies against SARS-CoV, suggesting the seroconversion did occur. Further studies are warranted to consider other animal species in efforts to find better animal models for the evaluation of SARS-CoV vaccines and antiviral drugs.


Gentamicin accumulation by sensitive strains of Escherichia coli and Pseudomonas aeruginosa.
Gentamicin accumulation with time shows multiphasic kinetics in strains of Escherichia coli and Pseudomonas aeruginosa. All but first phase accumulation may be prevented or reduced by inhibitors of electron transport, by a sulfhydryl poison, by agents which uncouple electron transport and oxidative phosphorylation and by an inhibitor of protein synthesis. The phases of accumulation which are sensitive to these inhibitors are required for loss of cell viability. Gentamicin can be extracted from cells in an unchanged form as judged by paper chromatography and is concentrated 4 to 250 times over extracellular concentrations within the bacterial cell. Gentamicin accumulation has been shown to occur before there is any evidence or release of acid-soluble 3H-adenine from cells. These data demonstrate that productive gentamicin accumulation capable of causing cell death is by active transport.


Cyclometalated iridium(III) complexes for phosphorescence sensing of biological metal ions.
Phosphorescence signaling provides a valuable alternative to conventional bioimaging based on fluorescence. The benefits of using phosphorescent molecules include improved sensitivity and capabilities for effective elimination of background signals by time-gated acquisition. Cyclometalated Ir(III) complexes are promising candidates for facilitating phosphorescent bioimaging because they provide synthetic versatility and excellent phosphorescence properties. In this Forum Article, we present our recent studies on the development of phosphorescence sensors for the detection of metal ions based on cyclometalated iridium(III) complexes. The constructs contained cyclometalating (C^N) ligands with the electron densities and band-gap energies of the C^N ligand structures systematically varied. Receptors that chelated zinc, cupric, and chromium ions were tethered to the ligands to create phosphorescence sensors. The alterations in the C^N ligand structures had a profound influence on the phosphorescence responses to metal ions. Mechanistic studies suggested that the phosphorescence responses could be explained on the basis of the modulation of photoinduced electron transfer (PeT) from the receptor to the photoexcited iridium species. The PeT behaviors strictly adhered to the Rehm-Weller principle, and the occurrence of PeT was located in the Marcus-normal region. It is thus anticipated that improved responses will be obtainable by increasing the excited-state reduction potential of the iridium(III) complexes. Femtosecond transient absorption experiments provided evidence for the presence of an additional photophysical mechanism that involved metal-ion-induced alteration of the intraligand charge-transfer (ILCT) transition state. Utility of the mechanism by PeT and ILCT has been demonstrated for the phosphorescence sensing of biologically important transition-metal ions. In particular, the phosphorescence zinc sensor could report the presence of intracellular zinc pools by using confocal laser scanning microscopy and photoluminescence lifetime imaging microscopy techniques. We hope that the significant knowledge gained from our studies will be of great help in the design of new molecules as phosphorescence sensors.


Adenosine alters glomerular filtration control by angiotensin II.
This study was designed to test the hypothesis that high renal levels of adenosine (ADO) may alter glomerular filtration rate (GFR) control by angiotensin II (ANG II). In normal kidneys, ANG II infusion (20 ng X kg-1 X min-1 iv) decreased renal blood flow (RBF) to 61 +/- 3% of control, increased filtration fraction (FF) to 173 +/- 21% of control, and did not change GFR significantly. During intrarenal ADO infusion at a rate of 1.0 mumol/min, ANG II (20 ng X kg-1 X min-1 iv) decreased RBF and GFR to 61 +/- 5 and 64 +/- 6% of control, respectively. After blocking changes in tubuloglomerular feedback by occluding the ureter during mannitol diuresis, ANG II increased stop-flow pressure and postglomerular resistance (RPG) markedly but did not alter preglomerular resistance (RA), suggesting that the direct actions of circulating ANG II are confined primarily to efferent arterioles in the absence of changes in tubuloglomerular feedback. However, during intrarenal ADO infusion and inhibition of tubuloglomerular feedback, ANG II decreased stop-flow ureteral pressure and raised RA and RPG to 213 +/- 27 and 155 +/- 7% of control, respectively, while decreasing RBF to 59 +/- 5% of control. These observations suggest that ADO markedly alters the control of GFR by ANG II, possibly by causing ANG II to constrict preglomerular vessels, an effect that is not apparent in most physiological conditions but which could play a role in lowering GFR when renal ADO and ANG II levels are both elevated, as in severe renal ischemia.


Cyanoacrylate sealant compared to fibrin glue in staple line reinforcement during laparoscopic sleeve gastrectomy. Pilot prospective observational study.
Laparoscopic Sleeve Gastrectomy (LSG) is associated with serious complications, such as staple line leaks and bleeding. This paper presents a novel approach aimed at the successful consolidation of the suture by the use of the cyanoacrylate, here compared to the use of fibrin glue. Fifty consecutive patients, recruited from October 2015 to March 2016, were submitted to laparoscopic sleeve gastrectomy by standardized surgical technique. The staple line was reinforced with cyanoacrylate or fibrin glue. There were no post-operative complications and no operative time prolongation. An early removal of the draining and a reduction of the average hospitalization were observed. The results suggest that staple line reinforcement with cyanoacrylate during laparoscopic sleeve gastrectomy is as easy, safe and cost-saving as with fibrin glue. Furthermore, cyanocrilate allows a chemical omentoplasty with the result of restoring the anatomy. Therefore, this approach is viable and useful for future trials on the efficacy in preventing surgical post-operative complications.


Integrative Analysis of Histopathological Images and Genomic Data Predicts Clear Cell Renal Cell Carcinoma Prognosis.
In cancer, both histopathologic images and genomic signatures are used for diagnosis, prognosis, and subtyping. However, combining histopathologic images with genomic data for predicting prognosis, as well as the relationships between them, has rarely been explored. In this study, we present an integrative genomics framework for constructing a prognostic model for clear cell renal cell carcinoma. We used patient data from The Cancer Genome Atlas (n = 410), extracting hundreds of cellular morphologic features from digitized whole-slide images and eigengenes from functional genomics data to predict patient outcome. The risk index generated by our model correlated strongly with survival, outperforming predictions based on considering morphologic features or eigengenes separately. The predicted risk index also effectively stratified patients in early-stage (stage I and stage II) tumors, whereas no significant survival difference was observed using staging alone. The prognostic value of our model was independent of other known clinical and molecular prognostic factors for patients with clear cell renal cell carcinoma. Overall, this workflow and the shared software code provide building blocks for applying similar approaches in other cancers. Cancer Res; 77(21); e91-100. ©2017 AACR.


Evaluation of two fast and easy methods for pesticide residue analysis in fatty food matrixes.
Two rapid methods of sample preparation and analysis of fatty foods (e.g., milk, eggs, and avocado) were evaluated and compared for 32 pesticide residues representing a wide range of physicochemical properties. One method, dubbed the quick, easy, cheap, effective, rugged, and safe (QuEChERS) method for pesticide residue analysis, entailed extraction of 15 g sample with 15 mL acetonitrile (MeCN) containing 1% acetic acid followed by addition of 6 g anhydrous magnesium sulfate and 1.5 g sodium acetate. After centrifugation, 1 mL of the buffered MeCN extract underwent a cleanup step (in a technique known as dispersive solid-phase extraction) using 50 mg each of C18 and primary secondary amine sorbents plus 150 mg MgSO4. The second method incorporated a form of matrix solid-phase dispersion (MSPD), in which 0.5 g sample plus 2 g C18 and 2 g anhydrous sodium sulfate was mixed in a mortar and pestle and added above a 2 g Florisil column on a vacuum manifold. Then, 5 x 2 mL MeCN was used to elute the pesticide analytes from the sample into a collection tube, and the extract was concentrated to 0.5 mL by evaporation. Extracts in both methods were analyzed concurrently by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry. The recoveries of semi-polar and polar pesticides were typically 100% in both methods (except that basic pesticides, such as thiabendazole and imazalil, were not recovered in the MSPD method), but recovery of nonpolar pesticides decreased as fat content of the sample increased. This trend was more pronounced in the QuEChERS method, in which case the most lipophilic analyte tested, hexachlorobenzene, gave 27 +/- 1% recovery (n=6) in avocado (15% fat) with a<10 ng/g limit of quantitation.


[The interaction of changes in the genitalia in the pathogenesis of sterility in men].
Alterations in testicular structures on the side of the pathologic process, contralateral testicle, epididymis, deferent duct, prostate, spermogramme, were found out to be related to the level of gonadotrophic and sex hormones in pathogenesis of infertility developing in varicocele, cryptorchidism, epididymitis, prostatitis, obstruction of the deferent duct, and action of low frequency electromagnetic field. The findings obtained will, we believe, help in diagnosing and prescribing the pathogenetically substantiated treatment.


Coexistence and relative abundance in annual plant assemblages: the roles of competition and colonization.
Although an interspecific trade-off between competitive and colonizing ability can permit multispecies coexistence, whether this mechanism controls the structure of natural systems remains unresolved. We used models to evaluate the hypothesized importance of this trade-off for explaining coexistence and relative abundance patterns in annual plant assemblages. In a nonspatial model, empirically derived competition-colonization trade-offs related to seed mass were insufficient to generate coexistence. This was unchanged by spatial structure or interspecific variation in the fraction of seeds dispersing globally. These results differ from those of the more generalized competition-colonization models because the latter assume completely asymmetric competition, an assumption that appears unrealistic considering existing data for annual systems. When, for heuristic purposes, completely asymmetric competition was incorporated into our models, unlimited coexistence was possible. However, in the resulting abundance patterns, the best competitors/poorest colonizers were the most abundant, the opposite of that observed in natural systems. By contrast, these natural patterns were produced by competition-colonization models where environmental heterogeneity permitted species coexistence. Thus, despite the failure of the simple competition-colonization trade-off to explain coexistence in annual plant systems, this trade-off may be essential to explaining relative abundance patterns when other processes permit coexistence.


Reactivity ratios, and mechanistic insight for anionic ring-opening copolymerization of epoxides.
Reactivity ratios were evaluated for anionic ring-opening copolymerizations of ethylene oxide (EO) with either allyl glycidyl ether (AGE) or ethylene glycol vinyl glycidyl ether (EGVGE) using a benzyl alkoxide initiator. The chemical shift for the benzylic protons of the initiator, as measured by (1)H NMR spectroscopy, were observed to be sensitive to the sequence of the first two monomers added to the initiator during polymer growth. Using a simple kinetic model for initiation and the first propagation step, reactivity ratios for the copolymerization of AGE and EGVGE with EO could be determined by analysis of the (1)H NMR spectroscopy for the resulting copolymer. For the copolymerization between EO and AGE, the reactivity ratios were determined to be r(AGE) = 1.31 ± 0.26 and r(EO) = 0.54 ± 0.03, while for EO and EGVGE, the reactivity ratios were r(EGVGE) = 3.50 ± 0.90 and r(EO) = 0.32 ± 0.10. These ratios were consistent with the compositional drift observed in the copolymerization between EO and EGVGE, with EGVGE being consumed early in the copolymerization. These experimental results, combined with density functional calculations, allowed a mechanism for oxyanionic ring-opening polymerization that begins with coordination of the Lewis-basic epoxide to the cation to be proposed. The calculated transition-state energies agree qualitatively with the observed relative rates for polymerization.


An Internet study of cybersex participants.
Cybersex is a subcategory of online sexual activities (OSA) and is defined as when two or more people are engaging in sexual talk while online for the purposes of sexual pleasure and may or may not include masturbation. Cybersex is a growing phenomenon with a significant impact on participants but very little research has been done on this subject to date. This study is the first to attempt to delineate characteristics of those who engage in cybersex. Data were collected through an online questionnaire in Swedish, administered through the Swedish web portal Passagen.se. Out of the total sample (N = 1828), almost a third, both men and women, reported to have engaged in cybersex. A logistic regression analysis showed that age, sex, and sexual orientation were important demographic variables to consider when investigating cybersex. A comparison of interval data showed those engaging in cybersex to have a higher likelihood of spending more time online for OSA and having more offline sex partners than those not engaging in cybersex.


Are Future Psychologists Willing to Accept and Use a Humanoid Robot in Their Practice? Italian and English Students' Perspective.
Despite general scepticism from care professionals, social robotics research is providing evidence of successful application in education and rehabilitation in clinical psychology practice. In this article, we investigate the cultural influences of English and Italian psychology students in the perception of usefulness and intention to use a robot as an instrument for future clinical practice and, secondly, the modality of presentation of the robot by comparing oral vs. video presentation. To this end, we surveyed 158 Italian and British-English psychology students after an interactive demonstration using a humanoid robot to evaluate the social robot's acceptance and use. The Italians were positive, while the English were negative toward the perceived usefulness and intention to use the robot in psychological practice in the near future. However, most English and Italian respondents felt they did not have the necessary abilities to make good use of the robot. We concluded that it is necessary to provide psychology students with further knowledge and practical skills regarding social robotics, which could facilitate the adoption and use of this technology in clinical settings.


The left atrial appendage in humans: structure, physiology, and pathogenesis.
For many years, the left atrial appendage (LAA) was considered a dormant embryological remnant; however, it is a structurally complex and functional organ that contributes to cardiac haemodynamic changes and volume homeostasis through both its contractile properties and neurohormonal peptide secretion. When dysfunctional, the LAA contributes to thrombogenesis and subsequent increased predisposition to cardioembolic events. Consequently, the LAA has gained much attention as a therapeutic target to lower this risk. In addition, attention has focused on the LAA in its role as an electrical trigger for atrial tachycardia and atrial fibrillation with ablation of the LAA to achieve electrical isolation showing promising results in the maintenance of sinus rhythm. This in-depth review explores the structure, physiology and pathophysiology of the LAA, as well as LAA intervention and their sequelae.


Characteristics of sludge developed under different loading conditions during UASB reactor start-up and granulation.
Sludge characteristics available inside the reactor are of vital importance to maximize advantages of UASB reactor. The organic loading rate and sludge loading rate applied during start-up are among the important parameters to govern the sludge characteristics. Effects of these loading rates on the characteristics of the sludge developed are evaluated in six laboratory scale UASB reactors. The sludge characteristics considered are VSS/SS ratio of the sludge, sludge volume index, specific gravity, settling velocity and metal contents of the sludge developed under different loading rates. The experimental results indicate that, for developing good characteristics sludge, during primary start-up from flocculent inoculum sludge, organic loading rate and sludge loading rate should be in the range of 2.0-4.5 kg COD/m3 d and 0.1-0.25 kg COD/kg VSS d, respectively (chemical oxygen demand, COD). Proper sludge granulation and higher COD removal efficiency will be achieved by these loading rates.


Transforming physician practices to patient-centered medical homes: lessons from the national demonstration project.
Many commentators view the conversion of small, independent primary care practices into patient-centered medical homes as a vital step in creating a better-performing health care system. The country's first national medical home demonstration, which ran from June 1, 2006, to May 31, 2008, and involved thirty-six practices, showed that this transformation can be lengthy and complex. Among other features, the transformation process requires an internal capability for organizational learning and development; changes in the way primary care clinicians think about themselves and their relationships with patients as well as other clinicians on the care team; and awareness on the part of primary care clinicians that they will need to make long-term commitments to change that may require three to five years of external assistance. Additionally, transforming primary care requires synchronizing practice redesign with development of the health care "neighborhood," which is made up of a broad range of health and health care resources available to patients. It also requires payment reform that supports practice development and a policy environment that sets reasonable expectations and time frames for the adoption of appropriate innovations.


Horizon scanning of potential threats to high-Arctic biodiversity, human health and the economy from marine invasive alien species: A Svalbard case study.
The high Arctic is considered a pristine environment compared with many other regions in the northern hemisphere. It is becoming increasingly vulnerable to invasion by invasive alien species (IAS), however, as climate change leads to rapid loss of sea ice, changes in ocean temperature and salinity, and enhanced human activities. These changes are likely to increase the incidence of arrival and the potential for establishment of IAS in the region. To predict the impact of IAS, a group of experts in taxonomy, invasion biology and Arctic ecology carried out a horizon scanning exercise using the Svalbard archipelago as a case study, to identify the species that present the highest risk to biodiversity, human health and the economy within the next 10 years. A total of 114 species, currently absent from Svalbard, recorded once and/or identified only from environmental DNA samples, were initially identified as relevant for review. Seven species were found to present a high invasion risk and to potentially cause a significant negative impact on biodiversity and five species had the potential to have an economic impact on Svalbard. Decapod crabs, ascidians and barnacles dominated the list of highest risk marine IAS. Potential pathways of invasion were also researched, the most common were found associated with vessel traffic. We recommend (i) use of this approach as a key tool within the application of biosecurity measures in the wider high Arctic, (ii) the addition of this tool to early warning systems for strengthening existing surveillance measures; and (iii) that this approach is used to identify high-risk terrestrial and freshwater IAS to understand the overall threat facing the high Arctic. Without the application of biosecurity measures, including horizon scanning, there is a greater risk that marine IAS invasions will increase, leading to unforeseen changes in the environment and economy of the high Arctic.


The Effect of N-Terminal Cyclization on the Function of the HIV Entry Inhibitor 5P12-RANTES.
Despite effective treatment for those living with Human Immunodeficiency Virus (HIV), there are still two million new infections each year. Protein-based HIV entry inhibitors, being highly effective and specific, could be used to protect people from initial infection. One of the most promising of these for clinical use is 5P12-RANTES, a variant of the chemokine RANTES/CCL5. The N-terminal amino acid of 5P12-RANTES is glutamine (Gln; called Q0), a residue that is prone to spontaneous cyclization when at the N-terminus of a protein. It is not known how this cyclization affects the potency of the inhibitor or whether cyclization is necessary for the function of the protein, although the N-terminal region of RANTES has been shown to be critical for receptor interactions, with even small changes having a large effect. We have studied the kinetics of cyclization of 5P12-RANTES as well as N-terminal variations of the protein that either produce an identical cyclized terminus (Glu0) or that cannot similarly cyclize (Asn0, Phe0, Ile0, and Leu0). We find that the half life for N-terminal cyclization of Gln is roughly 20 h at pH 7.3 at 37 °C. However, our results show that cyclization is not necessary for the potency of this protein and that several replacement terminal amino acids produce nearly-equally potent HIV inhibitors while remaining CC chemokine receptor 5 (CCR5) antagonists. This work has ramifications for the production of active 5P12-RANTES for use in the clinic, while also opening the possibility of developing other inhibitors by varying the N-terminus of the protein.


The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma.
Obesity has been associated to increased hepatocellular carcinoma (HCC) risk, but studies on the topic do not fully account for hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Likewise, an increased risk has been reported for diabetes mellitus (DM) but whether DM is an independent risk factor has not been established yet. To evaluate the association of obesity and DM with HCC risk, we conducted a hospital-based, case-control study in two Italian areas. From 1999 to 2003, 185 HCC cases and 404 hospital controls were enrolled. Blood samples were obtained for HBV and HCV screening. After allowance for known risk factors, body mass index >/=30 kg/m(2) [odds ratio (OR) = 1.9, 95% confidence interval (CI) 0.9-3.9] and DM (OR = 3.7, 95% CI 1.7-8.4) were associated to HCC risk. These associations persisted (OR = 3.5, 95% CI 1.6-7.7 for obesity; OR = 3.5, 95% CI 1.3-9.2 for DM) among subjects without HBV and/or HCV infection. Overall, 23% of HCC cases seemed attributable to these conditions, and this figure rose to 37% among subjects without HBV and/or HCV infections. The present study provides further evidence that obesity and DM increase HCC risk and that these factors may explain a relevant proportion of cases among subjects without markers of HBV/HCV infection.


Effects of a One Year Intensive Multidisciplinary Rehabilitation Program for Patients with Huntington's Disease: a Prospective Intervention Study.
To assess the effects of an intensive, multidisciplinary rehabilitation program for patients with early to mid-stage Huntington's disease. A prospective intervention study. Two Norwegian inpatient rehabilitation centers. 37 patients, with early- to midstage Huntington's disease Interventions: A one year rehabilitation program, consisting of three admissions of three weeks each, and a five-day evaluation stay approximately 3 months after the last rehabilitation admission. Focus was on physical exercise, social activities, and group/teaching sessions. There was also emphasis to implement of coordinated health care and social services for the patients. standard measures for motor function, including gait and balance, cognitive function, including MMSE and UHDRS cognitive assessment, anxiety and depression, activities of daily living (ADL), health related quality of life and Body Mass Index (BMI). Significant improvements were observed in gait function, balance, in physical quality of life, anxiety and depression, as well as in BMI. ADL-function remained stable with no significant decline. Only one cognitive measure (SDMT) showed significant decline, while no decline was observed for the remaining cognitive measures. A multidisciplinary intensive rehabilitation program in patients with early and mid stage HD is associated with improved balance, gait function, physical quality of life and with reduced depressive and anxiety symptoms. Longer follow-up is needed to assess if these positive effects are sustained. There should be emphasis to establishment of long term and coordinated health care services for the HD patient.


Protocol for a randomised controlled trial of chronic disease self-management support for older Australians with multiple chronic diseases.
The prevalence of older Australians with multiple chronic diseases is increasing and now accounts for a large proportion of total health care utilisation. Chronic disease self-management support (CDSMS) has become a core service component of many community based health programs because it is considered a useful tool in improving population health outcomes and reducing the financial burden of chronic disease care. However, the evidence base to justify these support programs is limited, particularly for older people with multiple chronic diseases. We describe an ongoing trial examining the effectiveness of a particular CDSMS approach called the Flinders Program. The Flinders Program is a clinician-led generic self-management intervention that provides a set of tools and a structured process that enables health workers and patients to collaboratively assess self-management behaviours, identify problems, set goals, and develop individual care plans covering key self-care, medical, psychosocial and carer issues. A sample of 252 older Australians that have two or more chronic conditions will be randomly assigned to receive either CDSMS or an attention control intervention (health information only) for 6 months. Outcomes will be assessed using self-reported health measures taken at baseline and post-intervention. This project will be the first comprehensive evaluation of CDSMS in this population. Findings are expected to guide consumers, clinicians and policymakers in the use of CDSMS, as well as facilitate prioritisation of public monies towards evidence-based services.


Surfactant secretion: evidence that cholinergic stimulation of secretion is indirect.
There is strong evidence that cholinergic agents stimulate the secretion of surfactant in vivo and in the isolated perfused lung and that they do not stimulate surfactant secretion in isolated type 2 alveolar cells. These observations suggest that in multicellular systems the cholinergic effect is indirect. In the present work we have accrued the following support for this hypothesis. 1) Propranolol blocked the in vivo stimulation of disaturated phosphatidylcholine (DSPC) secretion by pilocarpine. 2) Bilateral adrenalectomy decreased by 50% the in vivo stimulation of DSPC secretion by pilocarpine. 3) Bilateral vagotomy did not block the increased secretion of DSPC produced in vivo by periodic deep inflations. 4) Pilocarpine (10(-7) M) stimulated DSPC secretion in the isolated perfused lung, and this effect was blocked by indomethacin as well as by atropine. We conclude that cholinergic stimulation of the secretion of surfactant in rats is indirect, i.e., cholinergic agonists do not stimulate the secretion of surfactant by acting directly on type 2 alveolar cells.


Thyroid hormone is highly permissive in angioproliferative pulmonary hypertension in rats.
Epidemiological evidence links pulmonary arterial hypertension (PAH) with thyroid disease, but a mechanistic explanation for this association is lacking. Because a central hallmark of vascular remodelling in pulmonary hypertension is lumen obliteration by endothelial cell growth and because thyroid hormones are known to be angiogenic, we hypothesised that thyroid hormones play a role in the control of endothelial cell proliferation in experimental PAH in rats. Hypothyroidism was induced by subtotal thyroidectomy and treatment with propylthiouracil (PTU) in rats with experimental PAH after combined exposure to vascular endothelial growth factor receptor inhibition and hypoxia (the Sugen-chronic hypoxia (SuHx) model). Subtotal thyroidectomy prevented and PTU treatment reversed the development of severe experimental PAH. Thyroxin repletion restored the PAH phenotype in thyroidectomised SuHx rats. The prevention of PAH by thyroidectomy was associated with a reduced rate of cell turnover, reduced extracellular signal-regulated protein kinases 1 and 2 phosphorylation, and reduced expression of α(v)β(3) integrin, fibroblast growth factor (FGF)-2 and FGF receptor. Thyroidectomy mitigated hypoxia-induced pulmonary hypertension, but this effect was not associated with a decreased pulmonary vascular resistance. These data suggest that thyroid hormone permits endothelial cell proliferation in PAH. A causal link between thyroid diseases and the onset or progression of vascular remodelling in PAH patients remains to be determined.


Imaging of adrenal metastases.
This paper discusses the application of CT, MR imaging, and 131I-6 beta-iodomethyl-19-norcholesterol scintigraphy in establishing the nature of incidentally discovered adrenal masses. It is concluded that CT and MR imaging can permit confident differentiation between nonhyperfunctioning adenomas and metastases in cases of incidentalomas that meet all the criteria of a nonhyperfunctioning adenoma. In cancer patients, fine-needle aspiration biopsy of lesions is, in general, essential because a definitive diagnosis of metastatic disease is crucial to disease management. MR imaging and norcholesterol scintigraphy are useful if a relative contraindication for fine-needle biopsy exists or when biopsy results are inconclusive in patients with a presumably benign lesion.


Temporal relationship between diet-induced steatosis and onset of insulin/leptin resistance in male Wistar rats.
Rats fed with high-fat-high-sucrose (HFHS) diet are known to manifest metabolic syndrome including hyperinsulinemia, hyperleptinemia, hyperglycemia, diabetic dyslipidemia, and hepatic steatosis. The aim of the current study is to determine the temporal relationships between the development of hepatic steatosis and the onset of insulin and leptin resistance in hypothalamus and liver in male Wistar rats (six weeks of age) fed chow or HFHS diet for up to 8 weeks. Fasting plasma glucose, lipids/lipoproteins, insulin and leptin levels were quantified, histopathologic score of hepatic steatosis and inflammation were assessed, and the responses of common checkpoints of insulin and leptin signalling responsible for lipogenesis and gluconeogenesis were analyzed. In addition, acute insulin or leptin administration was performed at different stages of HFHS dieting to determine the responsiveness of the respective signalling pathways. Hyperinsulinemia, hyperglycemia, dyslipidemia, and increased homeostasis model assessment of basal insulin resistance occurred 1-week after HFHS dieting, coinciding with upregulation of suppressor of cytokine signalling 3 in both hypothalamus and liver. However, hepatosteatosis, accompanied with increased expression of sterol regulatory element binding protein 1c and phosphoenolpyruvate carboxykinase, did not manifest until 4- to 8-week after HFHS dieting. Lowered insulin sensitivity (shown by decreased insulin receptor substrate 1 and protein kinase B phosphorylation) occurred approximately 2 weeks prior to leptin resistance (shown by impaired signal transducer and activator of transcription 3 activation) in both the liver and hypothalamus. Acute insulin/leptin administration also demonstrated the impaired insulin or leptin signalling transduction. These data suggest that lowered insulin sensitivity and leptin resistance occurred at least 2-3 weeks earlier than the manifestation of hepatosteatosis in rats fed HFHS diet.


Pseudocooperative effects in reactivation of membrane-bound enzymes with phospholipids.
The kinetic mechanism for reactivation of membrane-bound enzymes by lipids is analyzed on the basis of multiple equilibriums between the enzyme (which is assumed to contain n identical, non-interacting binding sites) and the lipid. The rate equations derived when only the fully occupied enzyme species ELn (or ELn and the next most highly occupied species ELn-1, ELn-2,..., ELn-i) is catalytically active can fully account for the apparent positive cooperativity observed in the plots of enzyme activity as a function of phospholipid concentration. A general equation for the cases in which more than one lipid species are simultaneously present in the reaction medium is presented which allows to test whether the binding sites are indeed non-interacting, as well as whether the active species have the same catalytic constant (kcat), regardless the nature of the lipid bound to the binding sites. This analysis demonstrates that, in addition to apparent positive cooperativity, more complex curves resembling mixed cooperativity may be obtained with simple systems when interaction between protein subunits (i.e., association-dissociation equilibriums) are present. Finally, some theoretical problems and pitfalls in the interpretation of the experimental results will be discussed.


Development and evaluation of educational materials for pre-hospital and emergency department personnel on the care of patients with autism spectrum disorder.
With the rising prevalence of patients with autism spectrum disorder (ASD), there has been an increase in the acute presentation of these individuals to the general health care system. Emergency medical services and emergency department personnel commonly address the health care needs of patients with ASD at times of crisis. Unfortunately, there is little education provided to front-line emergency medical technicians, paramedics and emergency nurses on the characteristics of ASD and how these characteristics can create challenges for individuals with ASD and their health care providers in the pre-hospital and emergency department settings. This paper describes the development of educational materials on ASD and the results of training of emergency medical services and emergency department personnel.


Long-term intravenous tocolytic therapy.
Eighteen women required continuous intravenous tocolytic therapy with either ritodrine hydrochloride or magnesium sulfate for greater than 48 hours because of repetitively recurrent preterm labor; these were compared with a similar group of women successfully treated in less than 48 hours in a retrospective, case-controlled study. The mean gestational age at the time of diagnosis was 31 weeks for both groups. Tocolytic selection was similar in both groups, although the dosage per hour was significantly greater with long-term therapy. The mean interval from initiation of therapy until delivery was 41 days in the study group, compared with 39 days among controls (not statistically significant). The mean gestational age at delivery was 36 weeks in both groups. There were no significant difference in various measures of fetal outcome between groups. These data demonstrate that long-term intravenous tocolytic therapy can be a safe and effective means of prolonging gestation in those women who fail to respond to conventional treatment.


Radioimmunotherapy of B-cell lymphoma with radiolabelled anti-CD20 monoclonal antibodies.
CD20 has proven to be an excellent target for the treatment of B-cell lymphoma, first for the chimeric monoclonal antibody rituximab (Rituxan), and more recently for the radiolabelled antibodies Y-90 ibritumomab tiuxetan (Zevalin) and I-131 tositumomab (Bexxar). Radiation therapy effects are due to beta emissions with path lengths of 1-5 mm; gamma radiation emitted by I-131 is the only radiation safety issue for either product. Dose-limiting toxicity for both radiolabelled antibodies is reversible bone marrow suppression. They produce response rates of 70%-90% in low-grade and follicular lymphoma and 40%-50% in transformed low-grade or intermediate-grade lymphomas. Both products produce higher response rates than related unlabelled antibodies, and both are highly active in patients who are relatively resistant to rituximab-based therapy. Median duration of response to a single course of treatment is about 1 year with complete remission rates that last 2 years or longer in about 25% of patients. Clinical trials suggest that anti- CD20 radioimmunotherapy is superior to total body irradiation in patients undergoing stem cell supported therapy for B-cell lymphoma, and that it is a safe and efficacious modality when used as consolidation therapy following chemotherapy. Among cytotoxic treatment options, current evidence suggests that one course of anti-CD20 radioimmunotherapy is as efficacious as six to eight cycles of combination chemotherapy. A major question that persists is how effective these agents are in the setting of rituximab- refractory lymphoma. These products have been underutilised because of the complexity of treatment coordination and concerns regarding reimbursement.


Are your capsules vegetarian or nonvegetarian: An ethical and scientific justification.
Capsules are important component of day to day health management. But recently an issue came up whether the capsule you are using is of vegetarian or non-vegetarian origin. Capsule shell can be divided into vegetarian and non-vegetarian origin on the basis of their origin. Gelatin capsule shell are typically of animal origin and HPMC or starch based shells are of vegetarian origin. CDSCO received one proposal to replace all non veg capsule with capsule of vegetarian origin. CDSCO has invited comments from different stakeholders regarding this. So, in this editorial, we are addressing different issues lying behind veg and non-veg capsules and scientific justification of the same.


Polwarth and Texel ewe parturition duration and its association with lamb birth asphyxia.
The objective of the present study was to test the hypothesis that parturition duration is related to birth asphyxia in lambs and that asphyxia affects newborn lamb viability and vigor. Two sire and dam genotypes (Texel: TX; Polwarth: PW) and their crosses were represented in the study. Eighty lambs (25 PW sire × PW dam, 13 TX × TX, 25 TX × PW, and 17 PW × TX) born to 69 grazing ewes were used. At birth, the log₁₀ length of the second stage of parturition, birth weight, placental weight, and several body measurements were recorded on all lambs, and jugular blood samples were analyzed with the i-Stat Portable Clinical Analyzer (Abbott, Montevideo, Uruguay). A modified Apgar viability score at birth and lamb behavior during their first hour of life were recorded. Brain weight, muscle:bone ratio, and bone density were recorded in 20 male lambs (5 from each breed group) that were euthanized and dissected 24 h after birth. Data were analyzed by linear regression, least squares ANOVA, and ordinal and binary logistic regressions. Mean blood gas and acid-base variables were 7.21 ± 0.09 for pH, 18.4 ± 9.8 mmHg for partial pressure of oxygen, 53 ± 12.5 mmHg for partial pressure of carbon dioxide, and -4 ± 5.1 mmol/L for extracellular fluid base excess. Parturition duration increased with birth weight (P < 0.001) and was shorter in TX ewes (P < 0.001), female lambs (P < 0.05), twins (P < 0.09), and twin females (sex × litter size interaction, P < 0.02). Twenty-six (32.9%) lambs were born asphyxiated (pO₂ < 10 mmHg or pH <7.1). Parturition duration increased the risk of asphyxia (P < 0.001), decreased the viability score (P < 0.001), and increased the latency to suckle the udder (P < 0.05). Twin-born lambs presented at birth a 16-fold greater risk of asphyxia (P < 0.01) and reduced placental efficiency (P < 0.05). Texel-sired lambs appeared immature at birth, with less bone density (P < 0.05), smaller brain (P < 0.05), shorter forelimbs (P < 0.05), greater anterior (P < 0.001) and posterior (P < 0.05) neck circumference, and greater muscle:bone ratio (P < 0.05). Immaturity may explain greater TX biotype survival. Together these results demonstrate that a relationship exists between parturition duration, neonatal viability and behavior, and acid-base balance values in single- and twin-born lambs, suggesting that birth asphyxia is an important risk factor in perinatal lamb mortality.


COVID-19 Pandemic Lockdowns' Impact on Visual Acuity of Diabetic Macular Edema: A Large Cohort.
The objective of this study was to evaluate the impact of unplanned treatment gap, secondary to COVID-19 pandemic lockdowns, on visual acuity in previously treated diabetic macular edema (DME) patients. A multicenter, retrospective study of DME patients, previously treated with anti-VEGF injections, who were followed up during COVID-19 pandemic (2020) compared to pre-CO-VID-19 period (2019). A total of 634 DME patients with a mean age of 68.4 years met the inclusion criteria, 385 were assessed in 2019 (pre-COVID-19) and 239 patients assessed in 2020 (COVID-19). Baseline best corrected visual acuity (BCVA) among patients in 2019 and 2020 was 0.52 ± 0.44, 0.45 ± 0.43 (logarithm of the minimal angle of resolution, respectively). There was no significant difference between the years 2020 and 2019 in baseline BCVA (p = 0.07). Mean number of anti-VEGF injections was significantly lower (5 vs. 6, p < 0.01), with a major lower ratio of injections per patient in the COVID-19 first lockdown period (March-June 2020) in the COVID-19 group. Baseline BCVA (p < 0.01) was the only significant predictor of final BCVA. Number of injections, age, gender, and the year were not found as predictors of final BCVA. In a large cohort of DME patients, an unplanned delay in treatment with anti-VEGF injections for 2-3 months, due to COVID-19 pandemic lockdown, had no significance impact on visual acuity. For most patients, returning to routine treatment regimen was sufficient for maintaining BCVA.


Vaccine therapy for metastatic melanoma: systematic review and meta-analysis of clinical trials.
Clinical trials of melanoma vaccines have yielded inconclusive data on whether a positive melanoma-specific immune response predicts treatment benefit. The objective of this study was to evaluate the effect of different melanoma vaccine strategies and the association between immunologic response and survival. The authors conducted a systematic review and meta-analysis of phase II and III clinical trials of melanoma vaccine. Outcomes assessed included overall disease control, overall survival, and impact on immune response. For binary variables, proportions were reported for one-arm studies and risk ratios for controlled studies. For survival data, medians were reported for one-arm studies and hazard ratios for controlled studies. The existence and extent of heterogeneity between trials was evaluated using Cochran's Q statistic. A two-sided P value of less than 0.05 for meta-analysis results was considered statistically significant. Of 56 studies reporting data on 4375 patients, overall disease control was seen in 25.3% [95% confidence interval (CI): 20.7-30.5%] of patients. Subgroup analysis revealed that overall disease control for peptide vaccines plus interleukin-2 (IL-2) was improved compared with interleukin-2 alone (pooled risk ratio: 2.79, 95% CI: 1.62-4.80). Overall survival varied among six studies comparing vaccine with other treatments. Subgroup analysis revealed that tumor-specific immune response was associated with prolonged overall survival compared with the lack of response (pooled hazard ratio: 2.15, 95% CI: 1.88-2.44). Severe toxicity associated with vaccine treatment was uncommon. Overall, a melanoma-specific immune response predicted longer overall survival, although no evidence was found that vaccine therapy provides better overall disease control or overall survival compared with other treatments.


Health among Black children by maternal and child nativity.
We examined 5 health outcomes among Black children born to US-born and foreign-born mothers and whether differences by mother's region of birth could be explained by maternal duration of US residence, child's place of birth, and familial sociodemographic characteristics. Data were from the 2000-2011 National Health Interview Surveys. We examined 3 groups of children, based on mother's region of birth: US origin, African origin, and Latin American or Caribbean origin. We estimated multivariate regression models. Children of foreign-born mothers were healthier across all 5 outcomes than were children of US-born mothers. Among children of foreign-born mothers, US-born children performed worse on all health outcomes than children born abroad. African-origin children had the most favorable health profile. Longer duration of US residence among foreign-born mothers was associated with poorer child health. Maternal educational attainment and other sociodemographic characteristics did little to explain these differences. Further studies are needed to understand the role of selective migration and the behavioral, cultural, socioeconomic, and contextual origins of the health advantage of Black children of foreign-born mothers.


Designing rare disease care pathways in the Republic of Ireland: a co-operative model.
Rare diseases (RDs) are often complex, serious, chronic and multi-systemic conditions, associated with physical, sensory and intellectual disability. Patients require follow-up management from multiple medical specialists and health and social care professionals involving a high level of integrated care, service coordination and specified care pathways. This pilot study aimed to explore the best approach for developing national RD care pathways in the Irish healthcare system in the context of a lack of agreed methodology. Irish clinical specialists and patient/lived experience experts were asked to map existing practice against evidence-based clinical practice guidelines (CPGs) and best practice recommendations from the European Reference Networks (ERNs) to develop optimal care pathways. The study focused on the more prevalent, multisystemic rare conditions that require multidisciplinary care, services, supports and therapeutic interventions. 29 rare conditions were selected across 18 ERNs, for care pathway development. Multidisciplinary input from multiple specialisms was relevant for all pathways. A high level of engagement was experienced from clinical leads and patient organisations. CPGs were identified for 26 of the conditions. Nurse specialist, Psychology, Medical Social Work and Database Manager roles were deemed essential for all care pathways. Access to the therapeutic Health Service Professionals: Physiotherapy, Occupational Therapy, and Speech and Language Therapy were seen as key requirements for holistic care. Genetic counselling was highlighted as a core discipline in 27 pathways demonstrating the importance of access to Clinical Genetics services for many people with RDs. This study proposes a methodology for Irish RD care pathway development, in collaboration with patient/service user advocates. Common RD patient needs and health care professional interventions across all pathways were identified. Key RD stakeholders have endorsed this national care pathway initiative. Future research focused on the implementation of such care pathways is a priority.


Porcine collagenase from synovial fibroblasts: cDNA sequence and modulation of expression of RNA in vitro by various cytokines.
Collagenase is a metalloproteinase that is important in extracellular matrix turnover and is produced by synovial fibroblasts in response to various cytokines and growth factors. Porcine collagenase cDNA was cloned and the sequence shows a 469-amino acid (AA) peptide with high homology to the human and rabbit enzyme (84% and 83.4% respectively). Predicted amino acid sequence from position #99-114 agree well with previously obtained NH2-terminal AA sequence data of purified mature, active pig collagenase. Using the cloned porcine cDNA as a probe in Northern analysis, it was found that IL-1, TNF and EGF enhanced 24-hour steady state mRNA levels while TGF-beta inhibited basal expression of collagenase. When added 10 hours previously, TGF-beta partially inhibited the induction of collagenase by TNF and EGF, but did not affect induction by IL-1.


Functional and Neural Correlates Associated with Conditioned Pain Modulation in Patients with Chronic Knee Osteoarthritis Pain: A Cross-Sectional Study.
Background: In this study, we aimed to assess the factors that predict a dysfunctional conditioned pain modulation (CPM) in chronic knee OA. Methods: This is a cross-sectional analysis of patients with chronic knee OA from a prospective cohort study in Brazil (n = 85). We performed linear and logistic multivariate regression models using the purposeful selection approach to test the relationship between the CPM in both knees (average) as a dependent variable and demographics, clinical, and neurophysiological as independent variables. Results: A significant negative association between WOMAC pain scores and CPM (β: -0.13) was found. This association was modified by the subjects' race, being stronger in the non-white subjects. In our logistic regression models, pain intensity indexed with the WOMAC pain scale remained a significant association with dichotomized CPM. Furthermore, a significant CPM association with balance, indexed with the Berg Balance score, was evidenced (β: 0.04). Neurophysiological variables showed a significant negative relationship with CPM, such as the relative power of delta oscillations in the frontal area (β: -3.11) and central area (β: -3.23). There was no significant relationship between CPM and the following domains: cognitive, emotion, sleep, opioid receptor polymorphisms, and intrinsic variables of OA disease. There was no association of CPM with TMS-indexed inhibitory markers. Conclusions: These results may indicate that less function of the pain descending inhibitory system in patients with OA is correlated with higher activity-related pain (WOMAC), less balance, and cortical plasticity especially with increased low-frequency (delta) brain oscillations. These associations seem modified by race.


Trends in working conditions and health across three cohorts of older workers in 1993, 2003 and 2013: a cross-sequential study.
Over the past decades, the number of older workers has increased tremendously. This study examines trends from 1993 to 2013 in physical, cognitive and psychological functioning among three successive cohorts of Dutch older workers. The contribution of the changes in physical and psychosocial work demands and psychosocial work resources to change in functioning is examined. Insight in health of the older working population, and in potential explanatory variables, is relevant in order to reach sustainable employability. Data from three cohorts (observations in 1993, 2003 and 2013) of the Longitudinal Aging Study Amsterdam (LASA) were used. Individuals aged 55-65 with a paid job were included (N = 1307). Physical functioning was measured using the Timed Chair Stand Test, cognitive functioning by a Coding Task and psychological functioning by the positive affect scale from the CES-D. Working conditions were deduced from a general population job exposure matrix. Linear and logistic regression analyses were performed. From 1993 to 2013, time needed to perform the Timed Chair Stand Test increased with 1.3 s (95%CI = 0.89-1.71), to a mean of 11.5 s. Coding Task scores increased with 1.7 points (95%CI = 0.81-2.59), to a mean of 31 points. The proportion of workers with low positive affect increased non-significantly from 15 to 20% (p = 0.088). Only the improvement in cognitive functioning was associated with the change in working conditions. The observed decrease of physically demanding jobs and increase of jobs with higher psychosocial resources explained 8% of the improvement. Changes in working conditions may not contribute to improved physical and psychological functioning, but do contribute to improved cognitive functioning to some extent. Further adjustment of physical work demands and psychosocial work resources may help to reach sustainable employability of older workers.


Methylene Blue Reduces Mortality in Critically Ill and Perioperative Patients: A Meta-Analysis of Randomized Trials.
Vasodilatory hypotension is common in critically ill and perioperative patients, and is associated with adverse outcomes. As a nitric oxide production inhibitor, methylene blue (MB) exerts its vasoconstrictor property and is an adjuvant for catecholamine-refractory vasodilatory shock. However, the effects of MB on clinically relevant outcomes remain unclear. Therefore, the authors performed a meta-analysis of randomized trials on MB in critically ill and perioperative patients. The authors searched through databases for randomized trials on MB in critically ill and perioperative patients, which yielded 11 studies consisting of 556 patients. The primary outcome was mortality at the longest follow-up. Secondary outcomes included hemodynamic parameters and organ dysfunction (PROSPERO: CRD42023409243). Nine out of the 11 included randomized trials reported mortality, which was significantly lower in the MB group (risk ratio, 0.60 [95% CI 0.43-0.84] p = 0.003), with findings confirmed in septic shock and cardiac surgery subgroups. The authors found reduced lengths of stay in the intensive care unit (mean difference [MD], -0.9 days [95% CI -1.06 to -0.77] p < 0.001) and in the hospital (MD, -2.2 days [95% CI, -2.68 to -1.70] p < 0.001) in the MB group. MB was associated with increased mean arterial pressure (MD, 8.4 mmHg [95% CI 5.01-11.75] p < 0.001) and systemic vascular resistance (MD, 94.5 dyn/s/cm5 [95% CI 17.73-171.15] p = 0.02), with no difference in cardiac output (standardized MD, 0.16 [95% CI, -0.25 to 0.57] p = 0.45). This meta-analysis showed that MB reverses vasodilation in critically ill and perioperative patients and might improve survival. Further adequately powered randomized trials are needed to confirm these findings.


Cost-effectiveness analysis of boceprevir for the treatment of chronic hepatitis C virus genotype 1 infection in Portugal.
The recent approval of two protease inhibitors, boceprevir and telaprevir, is likely to change the management of chronic hepatitis C virus (HCV) genotype 1 infection. We evaluated the long-term clinical outcomes and the cost effectiveness of therapeutic strategies using boceprevir with peginterferon plus ribavirin (PR) in comparison with PR alone for treating HCV genotype 1 infection in Portugal. A Markov model was developed to project the expected lifetime costs and quality-adjusted life-years (QALYs) associated with PR alone and the treatment strategies outlined by the European Medicines Agency in the boceprevir summary of product characteristics. The boceprevir-based therapeutic strategies differ according to whether or not the patient was previously treated and whether or not the patient had compensated cirrhosis. The model simulated the experience of a series of cohorts of chronically HCV-infected patients (each defined by age, sex, race and fibrosis score). All treatment-related inputs were obtained from boceprevir clinical trials - SPRINT-2, RESPOND-2 and PROVIDE. Estimates of the natural history parameters and health state utilities were based on published studies. Portugal-specific annual direct costs of HCV health states were estimated by convening a panel of experts to derive health state resource use and multiplying the results by national unit costs. The model was developed from a healthcare system perspective with a timeframe corresponding to the remaining duration of the patients' lifetimes. Both future costs and QALYs were discounted at 5 %. To test the robustness of the conclusions, we conducted deterministic and probabilistic sensitivity analyses. In comparison with the treatment with PR alone, boceprevir-based regimens were projected to reduce the lifetime incidence of advanced liver disease, liver transplantation, and liver-related death by 45-51 % and increase life expectancy by 2.3-4.3 years. Although the addition of BOC increased treatment costs by €13,300-€19,700, the reduction of disease burden resulted in a decrease of €5,400-€9,000 in discounted health state costs and an increase of 0.68-1.23 in discounted QALYs per patient. The incremental cost-effectiveness ratios of the boceprevir-based regimens compared with PR among previously untreated and previously treated patients were €11,600/QALY and €8,700/QALY, respectively. The results were most sensitive to variations in sustained virologic response rates, discount rates and age at treatment. Adding boceprevir to PR was projected to reduce the number of liver complications and liver-related deaths, and to be cost effective in treating both previously untreated and treated patients.


Experimental autoimmune encephalomyelitis in the rat: lessons in T-cell immunology and autoreactivity.
Experimental autoimmune encephalomyelitis (EAE) in the rat is an acute paralytic disease from which most animals spontaneously recover. The disease can be induced in susceptible inbred Lewis and DA rats with myelin basic protein (MBP), or encephalitogenic MBP peptides administered in complete Freund's adjuvant (CFA). The disease can be adoptively transferred to syngeneic recipients with primed T cells that have been reactivated in vitro with antigen. EAE is mediated by CD4+ Th1 cells that secrete proinflammatory cytokines, and spontaneous remission is associated with CD4+ T cells that secrete transforming growth factor-beta (TGF-beta). Studies of EAE in susceptible rats have provided many important insights into the interactions of T cells and accessory cells that culminate in the induction of the autoimmune response.


[The structure and patterns of support in the encounters of the brown macaque (Macaca arctoides)].
Aid and cooperation in agonistic encounters have been studied in two groups of stumptail macaques keeping in the open-air cages of nature type. The basic agonistic ranks are found and the cases of aid in encounters are classified. A quantitative analysis using the coefficient reflecting the individual rank, kin and frequency of different aids is carried out. The existence of mechanisms of aggression removal within group is revealed, the role of individual ranks and kin in keeping stability in group is shown.


Physician-related barriers to hypertension management.
To investigate the levels of understanding and implementation of current hypertension guidelines among specialist physicians. A survey of the understanding and practice in the management of hypertension was conducted among 56 physicians who individually had managed more than 150 new hypertensive patients annually. All respondents were familiar with the current hypertension guidelines and 51.8% always or usually followed these guidelines in treating their patients. Most believed that the lowest blood pressure where pharmacological therapy should be initiated was 155/95 mm Hg. Forty-five (80.4%) physicians considered a blood pressure of less than 140/ 90 mm Hg should be achieved in hypertensive patients. Only 12 (21.4%) respondents provided routine advice on lifestyle modification to their patients. Fifty-four (96.4%) respondents ranked poor adherence to antihypertensive drugs as the major patient barrier to blood pressure control. Most physicians are familiar with the current hypertension guidelines but the implementation of these guidelines in clinical practice is inadequate. Systematic educational programs are needed to enhance physicians' awareness of the optimal goals of blood pressure control.


Investigating models of affect: relationships among EEG alpha asymmetry, depression, and anxiety.
The approach-withdrawal and valence-arousal models both predict that depressive and anxious profiles will be associated with relatively reduced left frontal and increased right frontal activity respectively, while the valence-arousal model also proposes a dissociation by lower and higher right parietotemporal activity, respectively. Recent work further suggests that subtypes of anxiety disorders may be characterized by distinctive patterns of activity depending on their type of arousal (anxious arousal/apprehension). The aim of this study was to investigate the relationships among nonclinical depression/anxiety and lateralized frontal/parietotemporal activity by categorizing participants (N=428) on the basis of both negative mood and alpha EEG. Key findings include: (i) greater right frontal lateralization in anxious participants, symmetrical frontal activity in depressed/comorbid, and left frontal lateralization in healthy controls; (ii) right frontal lateralization in anxious arousal participants, left frontal and right parietotemporal lateralization in anxious apprehension; (iii) bilateral increase in frontal and increased right parietotemporal activity in depressed/comorbid participants. Findings support predictions for frontal but not posterior regions. Grouping on the basis of EEG may not be reciprocally predictive of negative mood groupings, suggesting involvement of additional factors.


The effects of brain stem transections on the neuronal networks responsible for rhythmical jaw muscle activity in the guinea pig.
The purpose of this study was to determine the critical areas of brain stem necessary for the production of cortically induced rhythmical jaw muscle activity (RJMs) in the anesthetized guinea pig. It was found that longitudinal midline transections of the lower brain stem starting at the obex and extending to the rostral third of the inferior olivary nucleus (IO) were able to abolish rhythmical EMG activity in the jaw-opener muscle (digastric) on the same side (ipsilateral) as the cortical stimulus. Under these conditions, rhythmical activity in the contralateral digastric (DIG) EMG was not affected. Midline transections extending from the rostral superior colliculus to 500 microns rostral to the trigeminal motor nucleus had no effect on cortically evoked bilateral DIG rhythmical EMG activity. Serial transverse hemisections of the left side of the medulla, starting at the obex and extending to the rostral third of the IO, reduced the amplitude of the left DIG EMG without producing significant effects in the cycle characteristics [cycle duration (CD) or burst duration (BD)] of that muscle during stimulation of the contralateral (right) cortex. Hemisections more rostral to the IO completely abolished bilateral rhythmical DIG activity induced by stimulation of the cortex on the side opposite to the transection (right cortex). Under these conditions, stimulation of the cortex on the side ipsilateral to the left hemisection (left cortex) initiated rhythmical EMG activity with normal cycle characteristics in only the contralateral (right) DIG muscle. Transverse hemisections as little as 500 microns rostral to the trigeminal motor nucleus (Mot V), which spared the pyramidal tract, had no effect on RJMs induced by stimulation of either cortex. These data suggest that each ipsilateral cortex initiates activity in neuronal oscillatory networks located exclusively in the contralateral brain stem; bilateral rhythmical DIG activity is produced by neurons in the contralateral brain stem; each side of the lower brain stem is capable of producing rhythmical DIG activity independent of the integrity of the other side; and the location of the neuronal oscillators responsible for RJMs is between the rostral IO and the trigeminal motor nucleus.


Morphology-controlled copper nanowire synthesis and magnetic field assisted self-assembly.
Morphology, dimensions, crystalline structure and compositions of nanomaterials are very critical in determining their unique characteristics. Here we report how the reducing agent concentration affects the surface morphology of copper nanowires and establish the optimized reaction conditions to synthesize high aspect ratio nanowires with a smooth surface. Also, reported is the magnetic field assisted technique to control the orientational and positional ordering of cupronickel nanowires (Cu/Ni NWs) on a large-scale area. A combination of magnetic field, surface derivatization and photolithographic techniques allowed self-assembly of Cu/Ni NWs into channels. The channel resistance as a function of the applied magnetic field during fabrication shows an anomalous decrease owing to the positional end-to-end alignment of NWs. Magnetic field and areal NW density dependence of NW sheet resistance in channels is presented and analyzed using scaling theoretical models.


Clinical heterogeneity in sodium channelopathies. What is the meaning of carrying a genetic mutation?
Mutations in the SCN5A gene have been linked to a variety of diseases causing sudden cardiac death, with important variability in expressivity and phenotypic overlap. With the availability of genetic testing family members may now be diagnosed as carriers based solely on the presence of the genetic defect. Clinical decision making in this situation is complex and generates important ethical and medicolegal issues. We describe two families, 24-328 and 24-588, originally diagnosed with Brugada syndrome after the probands experienced cardiac arrest and we performed clinical and genetic analysis in their members. Both families had members with various electrocardiographic abnormalities including some with Brugada syndrome, long QT syndrome and conduction system disease. Both families had an important family history of sudden cardiac death. Direct sequencing of exons and exon-intron boundaries of the sodium channel gene SCN5A identified mutations in both families. These two families illustrate an increasingly common scenario when encountering families with ion channelopathies. Because a defibrillator is the only available therapeutic option at present in Brugada syndrome, physicians will be faced with extremely difficult therapeutic decisions that also have important legal, social and ethical implications, especially in children. These data indicate the need to develop guidelines on how to approach the results of genetic testing, especially in asymptomatic individuals.


Sex Differences in Early Embryogenesis: Inter-Chromosomal Regulation Sets the Stage for Sex-Biased Gene Networks: The dialogue between the sex chromosomes and autosomes imposes sexual identity soon after fertilization.
Sex-specific transcriptional and epigenomic profiles are detectable in the embryo very soon after fertilization. I propose that in male (XY) and female (XX) pre-implantation embryos sex chromosomes establish sexually dimorphic interactions with the autosomes, before overt differences become apparent and long before gonadogenesis. Lineage determination restricts expression biases between the sexes, but the epigenetic differences are less constrained and can be perpetuated, accounting for dimorphisms that arise later in life. In this way, sexual identity is registered in the epigenome very early in development. As development progresses, sex-specific regulatory modules are harbored within shared transcriptional networks that delineate common traits. In reviewing this field, I propose that analyzing the mechanisms for sexual dimorphisms at the molecular and biochemical level and incorporating developmental and environmental factors will lead to a greater understanding of sex differences in health and disease. Also see the video abstract here: https://youtu.be/9BPlbrHtkHQ.


Role of mitogen-activated protein kinases in the mechanism of oxidant-induced cell swelling in cultured astrocytes.
Cytotoxic brain edema, usually a consequence of astrocyte swelling, is an important complication of stroke, traumatic brain injury, hepatic encephalopathy, and other neurological disorders. Although mechanisms underlying astrocyte swelling are not fully understood, oxidative stress (OS) has generally been considered an important factor in its pathogenesis. To better understand the mechanism(s) by which OS causes cell swelling, we examined the potential involvement of mitogen-activated protein kinases (MAPKs) in this process. Cultures exposed to theoxidant H(2)O(2) (10, 25, 50 microM) for different time periods (1-24 hr) significantly increased cell swelling in a triphasic manner. Swelling was initially observed at 10 min (peaking at 30 min), which was followed by cell shrinkage at 1 hr. A subsequent increase in cell volume occurred at approximately 6 hr, and the rise lasted for at least 24 hr. Cultures exposed to H(2)O(2) caused the activation of MAPKs (ERK1/2, JNK and p38-MAPK), whereas inhibition of MAPKs diminished cell swelling induced by 10 and 25 microM H(2)O(2). These findings suggest that activation of MAPKs is an important factor in the mediation of astrocyte swelling following oxidative stress.


Resistance diagnosis and the changing epidemiology of antibiotic resistance.
Widespread adoption of point-of-care resistance diagnostics (POCRD) reduces ineffective antibiotic use but could increase overall antibiotic use. Indeed, in the context of a standard susceptible-infected epidemiological model with a single antibiotic, POCRD accelerates the rise of resistance in the disease-causing bacterial population. When multiple antibiotics are available, however, POCRD may slow the rise of resistance even as more patients receive antibiotic treatment, belying the conventional wisdom that antibiotics are "exhaustible resources" whose increased use necessarily promotes the rise of resistance.


Predictive value of the fragmented QRS complex in 6-month mortality and morbidity following acute coronary syndrome.
Fragmented QRS encompasses different RSR' patterns showing various morphologies of the QRS complexes with or without the Q wave on a resting 12-lead electrocardiogram. It has been shown possibly to cause adverse cardiac outcomes in patients with some heart diseases, including coronary artery disease. In view of the need for risk stratification of patients presenting with acute coronary syndrome in the most efficacious and cost-effective way, we conducted this study to clarify the value of developing fragmented QRS in a cohort of patients presenting with their first acute coronary syndrome in predicting 6-month mortality and morbidity. One hundred consecutive patients admitted to the coronary care unit at Shahid Madani Heart Center in Tabriz from December 2008 to March 2009 with their first acute coronary syndrome were enrolled in this prospective study. Demographic and electrocardiographic data on admission, inhospital mortality, and need for revascularization were recorded. Electrocardiography performed 2 months after the index event was examined for development of fragmented QRS. Mortality and morbidity was evaluated at 6-month follow-up in all patients. The patients were of mean age 57.7 ± 12.8 years, and 84% were men. The primary diagnosis was unstable angina in 17 (17%) patients, non-ST elevation myocardial infarction (MI) in 11 (11%), anterior or inferior ST elevation MI in 66 (66%), and postero-inferior MI in six (6%). Fragmented QRS was present in 30 (30%) patients during the first admission, which increased to 44% at the 2-month follow-up and to 53% at the 6-month follow-up. The presence of various coronary risk factors and drug therapy given, including fibrinolytic agents, had no effect on development of fragmented QRS. Mortality was significantly higher (P = 0.032) and left ventricular ejection fraction was significantly lower (P = 0.001) in the fragmented QRS group at the 6-month follow-up. This study strongly suggests that fragmented QRS on initial presentation with acute coronary syndrome is not predictive of subsequent events but, if present 6 months later, could be predictive of an adverse outcome.


Comparative analysis of SARS-CoV-2 variants Alpha (B.1.1.7), Gamma (P.1), Zeta (P.2) and Delta (B.1.617.2) in Vero-E6 cells: ultrastructural characterization of cytopathology and replication kinetics.
This study compares the effects of virus-cell interactions among SARS-CoV-2 variants of concern (VOCs) isolated in Brazil in 2021, hypothesizing a correlation between cellular alterations and mortality and between viral load and transmissibility. For this purpose, reference isolates of Alpha, Gamma, Zeta, and Delta variants were inoculated into monolayers of Vero-E6 cells. Viral RNA was quantified in cell supernatants by RT‒PCR, and infected cells were analyzed by Transmission Electron Microscopy (TEM) for qualitative and quantitative evaluation of cellular changes 24, 48, and 72 h Postinfection (hpi). Ultrastructural analyses showed that all variants of SARS-CoV-2 altered the structure and function of mitochondria, nucleus, and rough endoplasmic reticulum of cells. Monolayers infected with the Delta variant showed the highest number of modified cells and the greatest statistically significant differences compared to those of other variants. Viral particles were observed in the cytosol and the cell membrane in 100 % of the cells at 48 hpi. Alpha showed the highest mean particle diameter (79 nm), and Gamma and Delta were the smallest (75 nm). Alpha and Gamma had the highest particle frequency per field at 48 hpi, while the same was observed for Zeta and Delta at 72 hpi and 24 hpi, respectively. The cycle threshold of viral RNA varied among the target protein, VOC, and time of infection. The findings presented here demonstrate that all four VOCs evaluated caused ultrastructural changes in Vero-E6 cells, which were more prominent when infection occured with the Delta variant.


Nanoparticle size analysis with relaxation of induced grating by dielectrophoresis.
We propose an alternative approach to the use of dynamic light scattering (DLS) for the analysis of particle sizes ranging from 5 nm to 100 nm. This approach employs a combination of 1) diffusion, 2) density grating, and 3) dielectrophoresis (DEP), and measures the diffusion coefficient from the decay rate of the diffracted light intensity in the relaxation process of particle density modulation generated by DEP. Both the experiments and the theoretical analysis confirm the reliable determination of particle size independently of the refractive index. The new method records a decay signal directly without an autocorrelator and is expected to have a less extreme sensitivity dependence on particle size than DLS.


Intravitreal bevacizumab (avastin) for subfoveal neovascular age-related macular degeneration.
To report the visual and anatomic outcome of intravitreal bevacizumab (Avastin) injections in the treatment of subfoveal neovascular age-related macular degeneration (AMD). Interventional, consecutive, retrospective case series. Sixty-five eyes of 65 patients with subfoveal neovascular age-related macular degeneration (AMD) received three intravitreal bevacizumab (1.25 mg) injections. Outcome measures included visual acuity (VA), central retinal thickness (CRT), and size of lesion at 24 or more weeks follow-up. Thirty-five eyes had prior treatment with photodynamic therapy (PDT). At presentation, VA was 1.12 +/- 0.62 logMAR, CRT was 305 +/- 115 microm, and greatest linear diameter (GLD) of the lesion was 4,902 +/- 1,861 microm. There was no statistically significant difference between previous PDT and naïve eyes in VA, CRT, and GLD at presentation. After three bevacizumab injections, VA, CRT, and GLD significantly improved (P < 0.0001 in all groups). There was no statistically significant difference between CRT and GLD outcomes and subfoveal neovascular membrane type or age. Eyes with better VA at baseline and without previous PDT treatment achieved better final VA (P < 0.0001 and P = 0.045, respectively). A classic membrane type and lower age were somewhat associated with better post-treatment VA. Short-term results suggest that intravitreal bevacizumab is well tolerated and associated with improvement in VA, decreased CRT, and decreased lesion size in most patients. The most important predictors of final VA outcomes were baseline VA and no previous PDT treatment. Further evaluation of intravitreal bevacizumab for the treatment of subfoveal neovascular AMD is warranted.


Abnormal enamel and pulp dimensions in familial dysautonomia.
In familial dysautonomia (FD), a hereditary autonomic and sensory neuropathy, somatic growth is impaired. This study was conducted to explore the possibility that tooth dimensions are altered as a consequence of neural crest dysfunction known to be present in FD. Enamel, dentin, pulp, and tooth size measurements of mandibular primary and permanent molars from FD patients were compared with those of healthy controls. It was found that although tooth size in the FD patients was smaller than normal, the enamel was thicker on the occlusal table, while the pulp chamber was smaller and disproportional to tooth size. Our results suggest distorted tooth dimensions rather than a generalized growth arrest as observed in other hereditary syndromes, such as Down's or Crouzon.


Mechanical adaptations of cleavers (Galium aparine).
Cleavers (Galium aparine) is a fast-growing herbaceous annual with a semi-self-supporting, scrambling-ascending growth habit. Mature plants often use upright species for support. It is common in hedgerows and on waste ground. This study aims to characterize the mechanical behaviour of the stem and roots of cleavers and relate this to the arrangement of structural tissue, the net microfibrillar orientations in the cell walls, and plant growth habit. The morphology and mechanics of mature cleavers was investigated using plants grown in pots and ones collected from the grounds at the University of Lincoln, Lincoln, UK. Tensile tests were carried out on the stem and the basal section of the first-order lateral roots. The net orientation of cellulose microfibrils in the cell walls was investigated using polarized light microscopy. Results show that the basal regions of the stem and first-order lateral roots were highly extensible. Breaking strains of 24 +/- 7% were recorded for the stem base and 28 +/- 6% for the roots. Anatomical observations showed that the lower stem (base + 100 mm) was circular in cross-section with a solid central core of vascular tissue, whereas further up the stem the transverse section showed a typical four-angled shape with a ring-like arrangement of vascular tissue and sclerenchyma bundles in the corners. The net orientation of wall microfibrils in the secondary xylem diverges from the longitudinal by between 8 and 9 degrees . The basal region of the stem of cleavers is highly extensible, but the mechanism by which the stem is able to withstand such high breaking strains is unclear; reorientation of the cellulose fibrils in the stem along the axis of loading is not thought to be responsible.


Street Tree Planning to Improve Public Health and Ecosystem Resilience in Urban Areas: A Scenario Analysis Using a System Dynamics Model.
Increases in particulate matter in cities threaten both public health and ecosystems. Street trees, which are a corridor-type green infrastructure capable of absorbing particulate matter, have been promoted as one possible solution to this problem. However, planting selected trees solely with the goal of reducing particulate matter may adversely affect street tree ecosystem resilience by inhibiting species diversity. This study aims to investigate urban street tree planting strategies that reduce particulate matter while maintaining ecosystem resilience. To this end, a study site in Suwon, South Korea was selected, and street tree planting scenarios were developed based on the selected site information. A scenario analysis was conducted using a system dynamics model. The model simulated the long-term trends under each scenario regarding the amount of particulate matter absorbed by the trees and the changes in species diversity. The analysis results clearly show that strategic planting of street trees while focusing on only a specific purpose-reducing particulate matter-can adversely affect ecosystem resilience. The scenario analysis also revealed that increasing the number of street trees while maintaining a balance among various species is the best option for reducing particulate matter without degrading species diversity. Additionally, the results support the need to plant evergreen species to consider the winter season.


[Tanfelam: synthesis, study of ovicidal activity, and acute toxicity].
The papers describes the synthesis of N-(2-piperidinoethyl)-N-tosyl-n-anisidine (Tanfelam) which showed a 100% ovicidal activity when tested by the Harada and Mori methods (in vitro inhibited N.brasiliensis hatching and development test). Tanfelam has been transferred for in-depth tests.


Detecting deterrence from patrol data.
The threat posed to protected areas by the illegal killing of wildlife is countered principally by ranger patrols that aim to detect and deter potential offenders. Deterring poaching is a fundamental conservation objective, but its achievement is difficult to identify, especially when the prime source of information comes in the form of the patrols' own records, which inevitably contain biases. The most common metric of deterrence is a plot of illegal activities detected per unit of patrol effort (CPUE) against patrol effort (CPUE-E). We devised a simple, mechanistic model of law breaking and law enforcement in which we simulated deterrence alongside exogenous changes in the frequency of offences under different temporal patterns of enforcement effort. The CPUE-E plots were not reliable indicators of deterrence. However, plots of change in CPUE over change in effort (ΔCPUE-ΔE) reliably identified deterrence, regardless of the temporal distribution of effort or any exogenous change in illegal activity levels as long as the time lag between patrol effort and subsequent behavioral change among offenders was approximately known. The ΔCPUE-ΔE plots offered a robust, simple metric for monitoring patrol effectiveness; were no more conceptually complicated than the basic CPUE-E plots; and required no specialist knowledge or software to produce. Our findings demonstrate the need to account for temporal autocorrelation in patrol data and to consider appropriate (and poaching-activity-specific) intervals for aggregation. They also reveal important gaps in understanding of deterrence in this context, especially the mechanisms by which it occurs. In practical applications, we recommend the use of ΔCPUE-ΔE plots in preference to other basic metrics and advise that deterrence should be suspected only if there is a clear negative slope. Distinct types of illegal activity should not be grouped together for analysis, especially if the signs of their occurrence have different persistence times in the environment.


The major 85-kD surface antigen of the mammalian form of Trypanosoma cruzi is encoded by a large heterogeneous family of simultaneously expressed genes.
Trypanosoma cruzi is an obligate intracellular protozoan parasite. The parasite mammalian stage surface antigens exhibit extensive antigenic diversity. We have characterized a family of T. cruzi genes that code for a polymorphic set of 85-kD surface antigens, the SA85-1 antigens. The family contains greater than 100 genes and pseudogenes, of which a minimum of nine are transcribed. The gene family is expressed in the mammalian stage only. A subset of the gene family is present in two telomere-linked copies in the genome. Telomere linkage of other expressed SA85-1 genes has not been demonstrated. We have shown that at least three members of the SA85-1 gene family encode antigens at the surface of the mammalian stage of the parasite. Interestingly, these three antigens are expressed on all the trypanosomes examined. This suggests that T. cruzi simultaneously expresses a large repertoire of similar, but diverse antigens at its surface. Thus, T. cruzi exhibits extensive antigenic diversity in a system unique from that of African trypanosomes, perhaps reflecting its intracellular niche.


Scale development: factors affecting diet, exercise, and stress management (FADESM).
The objective of this study was to develop scales measuring personal and environmental factors that affect dietary fat intake behavior, physical activity, and stress management in low-income mothers. FADESM (factors affecting diet, exercise, and stress management) scales were developed using the Social Cognitive Theory to measure personal (outcome expectancies, self-efficacy, emotional coping response) and environmental (physical environment, social environment, situation) factors affecting dietary fat intake behavior, physical activity, and stress management. Low-income African American and white mothers were recruited from the Special Supplemental Nutrition Program for Women, Infants, and Children in three counties in Michigan. In Phase one, 45 mothers completed individual cognitive interviews. Content analyses were performed. In Phase two, items modified from the cognitive interviews were administered to 216 mothers. Factor analysis and multiple indicators/multiple causes were performed. Results of cognitive interviews were used to revise items for the instrument that was tested in Phase two. The factor solution revealed 19 dimensions to measure personal and environmental factors affecting dietary fat intake behavior (three dimensions), physical activity (eight dimensions), and stress management (eight dimensions). Results of multiple indicators/multiple causes model showed scale invariance. Of 19 dimensions, 15 had Cronbach alpha between 0.76 and 0.94 and four were between 0.66 and 0.69. All dimensions had composite construct reliability scores between 0.74 to 0.97 and satisfactory construct and discriminant validities. The theory-based FADESM scales have documented good validity and reliability for measuring factors affecting dietary fat intake behavior, physical activity, and stress management in low-income women. Results of this study support the use of these scales with low-income African American and white mothers in community settings.


Cost of New Technologies in Prostate Cancer Treatment: Systematic Review of Costs and Cost Effectiveness of Robotic-assisted Laparoscopic Prostatectomy, Intensity-modulated Radiotherapy, and Proton Beam Therapy.
Some of the high costs of robot-assisted radical prostatectomy (RARP), intensity-modulated radiotherapy (IMRT), and proton beam therapy may be offset by better outcomes or less resource use during the treatment episode. To systematically review the literature to identify the key economic trade-offs implicit in a particular treatment choice for prostate cancer. We systematically reviewed the literature according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement and protocol. We searched Medline, Embase, and Web of Science for articles published between January 2001 and July 2016, which compared the treatment costs of RARP, IMRT, or proton beam therapy to the standard treatment. We identified 37, nine, and three studies, respectively. RARP is costlier than radical retropubic prostatectomy for hospitals and payers. However, RARP has the potential for a moderate cost advantage for payers and society over a longer time horizon when optimal cancer and quality-of-life outcomes are achieved. IMRT is more expensive from a payer's perspective compared with three-dimensional conformal radiotherapy, but also more cost effective when defined by an incremental cost effectiveness ratio <$50 000 per quality-adjusted life year. Proton beam therapy is costlier than IMRT and its cost effectiveness remains unclear given the limited comparative data on outcomes. Using the Grades of Recommendation, Assessment, Development and Evaluation approach, the quality of evidence was low for RARP and IMRT, and very low for proton beam therapy. Treatment with new versus traditional technologies is costlier. However, given the low quality of evidence and the inconsistencies across studies, the precise difference in costs remains unclear. Attempts to estimate whether this increased cost is worth the expense are hampered by the uncertainty surrounding improvements in outcomes, such as cancer control and side effects of treatment. If the new technologies can consistently achieve better outcomes, then they may be cost effective. We review the cost and cost effectiveness of robot-assisted radical prostatectomy, intensity-modulated radiotherapy, and proton beam therapy in prostate cancer treatment. These technologies are costlier than their traditional counterparts. It remains unclear whether their use is associated with improved cure and reduced morbidity, and whether the increased cost is worth the expense.


Clonal rearrangement of the T-cell receptor gamma gene associated with a bizarre lymphoproliferative syndrome.
Investigations in an unusual patient with prolonged fever, fat necrosis and haemorrhagic tendency showed widespread histiocytic phagocytosis in fat and liver biopsy specimens. Lymph nodes were also infiltrated by morphologically normal T lymphocytes predominantly expressing the OKT4 antigen. Analysis of lymph node DNA using immunoglobulin and T-cell receptor (TCR) probes showed rearrangement restricted to the gamma TCR gene combined with polyclonal beta TCR gene rearrangements, thus providing evidence of a unique lymphoproliferative disorder of T cells. The patient displayed a striking response to cytotoxic chemotherapy.


Transcriptomic profile of epileptic children treated with ketogenic therapies.
Background: Ketogenic dietary therapies (KDT) are used as a treatment in childhood epilepsy. However, their mechanism has not yet been established. The main objective of this study was to determine the changes in the transcriptomic profile induced by KDT in children with epilepsy in order to shed light on its possible mechanisms. Methods: Eight children with refractory epilepsy were enrolled in the study. Peripheral blood mononuclear cells were obtained before and after the children were treated with KDT for a minimum of 6 months. RNA was extracted and mRNA and miRNA profiling were performed and analyzed. Results: Our intervention with KDT significantly reduced the seizure number in seven of the eight paediatric patients treated and caused important changes in their gene expression profile. Our study reveals modifications in the transcription of 4630 genes and 230 miRNAs. We found that the genes involved in the protection against epileptic crises were among those mainly changed. These genes collectively encode for ion channels, neurotransmitter receptors, and synapse structural proteins. Conclusions: Together our results explain the possible mechanisms of KDT and reinforce its clinical importance in the treatment of epilepsy.


Dll4 Suppresses Transcytosis for Arterial Blood-Retinal Barrier Homeostasis.
Central nervous system has low vascular permeability by organizing tight junction (TJ) and limiting endothelial transcytosis. While TJ has long been considered to be responsible for vascular barrier in central nervous system, suppressed transcytosis in endothelial cells is now emerging as a complementary mechanism. Whether transcytosis regulation is independent of TJ and its dysregulation dominantly causes diseases associated with edema remain elusive. Dll4 signaling is important for various vascular contexts, but its role in the maintenance of vascular barrier in central nervous system remains unknown. To find a TJ-independent regulatory mechanism selective for transcytosis and identify its dysregulation as a cause of pathological leakage. We studied transcytosis in the adult mouse retina with low vascular permeability and employed a hypertension-induced retinal edema model for its pathological implication. Both antibody-based and genetic inactivation of Dll4 or Notch1 induce hyperpermeability by increasing transcytosis without junctional destabilization in arterial endothelial cells, leading to nonhemorrhagic leakage predominantly in the superficial retinal layer. Endothelial Sox17 deletion represses Dll4 in retinal arteries, phenocopying Dll4 blocking-driven vascular leakage. Ang II (angiotensin II)-induced hypertension represses arterial Sox17 and Dll4, followed by transcytosis-driven retinal edema, which is rescued by a gain of Notch activity. Transcriptomic profiling of retinal endothelial cells suggests that Dll4 blocking activates SREBP1 (sterol regulatory element-binding protein 1)-mediated lipogenic transcription and enriches gene sets favorable for caveolae formation. Profiling also predicts the activation of VEGF (vascular endothelial growth factor) signaling by Dll4 blockade. Inhibition of SREBP1 or VEGF-VEGFR2 (VEGF receptor 2) signaling attenuates both Dll4 blockade-driven and hypertension-induced retinal leakage. In the retina, Sox17-Dll4-SREBP1 signaling axis controls transcytosis independently of TJ in superficial arteries among heterogeneous regulations for the whole vessels. Uncontrolled transcytosis via dysregulated Dll4 underlies pathological leakage in hypertensive retina and could be a therapeutic target for treating hypertension-associated retinal edema.


Child Maltreatment and Risk for Psychopathology in Childhood and Adulthood.
Although rates of child maltreatment are declining, more than 600,000 children in the United States are substantiated victims of abuse or neglect. The focus of this review is on the relationship between maltreatment and mental health problems in childhood and adulthood. Children and adults who are exposed to abuse or neglect in childhood are at risk for a range of poor mental health outcomes, including internalizing and externalizing psychopathology, posttraumatic stress disorder, psychotic symptoms, and personality disorders. I review three potential mechanisms by which maltreatment may increase risk for various forms of psychopathology, (a) hypervigilance to threat, (b) deficits in emotion recognition and understanding, and (c) low responsivity to reward. I also review genetic and psychosocial factors that moderate the relationship between maltreatment and risk for psychopathology. Finally, I discuss methodological limitations of the literature on maltreatment, with an emphasis on the challenges associated with establishing a causal role for maltreatment (and moderators or mediators of maltreatment) in the development of mental health problems and the reliance of many studies on retrospective self-reports.