Reconstitution of eukaryotic translation elongation in vitro following initiation by internal ribosomal entry.
The ability to reconstitute different stages of eukaryotic translation process in vitro is a prerequisite for detailed biochemical analysis of their mechanisms. Reconstitution of elongation and subsequent processes such as termination and recycling on natural mRNAs translated by the cap-dependent mechanism is very complicated, and has not so far been done because of the necessity to first reconstitute the process of translation initiation, which is the most complex stage of eukaryotic translation, which requires at least nine initiation factors. The recent discovery of internal ribosomal entry sites (IRESs) in the intergenic region (IGR) of the genomes of dicistroviruses such as cricket paralysis virus (CrPV) and Plautia stali intestine virus (PSIV) that mediate initiation of translation by a mechanism that does not involve aminoacylated initiator tRNA (Met-tRNA(i)Met) or any initiation factors has provided a simple means to assemble active ribosomes on an mRNA that can be used to investigate these downstream stages in the translation process. Here we describe the methods for the assembly of active mammalian ribosomes on the CrPV IGR IRES and for reconstitution and analysis of subsequent steps in the elongation process. The composition of the reconstituted in vitro translation system can be fully controlled, and we therefore suggest that the methods described here could in future be adapted to permit template-dependent synthesis of peptidomimetics by eukaryotic ribosomes, by reassigning individual codons in an mRNA to non-natural amino acids using tRNAs that have been appropriately mischarged either chemically or enzymatically.


Safety profile of sedative endoscopy including cognitive performance in liver cirrhosis: A double-blind randomized controlled trial.
The indiscriminate use of sedative drugs during endoscopy can pose multiple risks including cognitive impairment in advanced liver cirrhosis. However, the data are scarce regarding which sedative drugs are safest in these populations. The aim of this study was to evaluate the safety profiles including cognitive performance among midazolam, propofol, and combination therapy in advanced cirrhotic patients. This double-blind randomized controlled study included 60 consecutive advanced cirrhotic patients who underwent upper gastrointestinal endoscopy. The Stroop application was used to screen for cognitive impairment. Patients were randomly assigned to one of 3 groups, midazolam, propofol, or the combination group, and underwent Stroop test before and two hours after the completion of endoscopy. Hemodynamic safety and the subjective satisfaction score were also evaluated. Patients did not show significant changes in on-time or off-time on the Stroop test before and two hours after sedatives, and there was no significant difference among the 3 treatment groups. Also, there were no significant vital sign changes after sedatives. Time-to-recovery was longest in midazolam group, and patient awakening and patient memory were highest in propofol group. However, all 3 groups showed no difference in patient satisfaction, but the combination group was more preferred in terms of subjective satisfaction by physicians. Factors affecting worsened Stroop speed after sedatives were older age, low education level and high MELD score. All sedative methods using midazolam, propofol, or combination therapy showed similar safety profile in advanced cirrhosis, and were not associated with increased risk of cognitive impairment.


Pharmaceutical applications of solid dispersion systems: X-ray diffraction and aqueous solubility studies on griseofulvin-polyethylene glycol 6000 systems.
The X-ray diffraction method was used to characterize physiochemical properties of griseofulvin dispersed in polyethylene glycol 4000 and 6000. Results indicate a negligible or very limited solid solubility of griseofulvin in the pulverized solid dispersions. Pulverization and aging had pronounced effects on the X-ray diffraction spectrum. Results from aqueous solubility studies of griseofulvin in various concentrations of polyethylene glycol 6000 further indicate weak or insignificant interactions between the drug and the carrier. Mechanisms are postulated to account for the reported marked enhancement of dissolution rates and oral adsorption of griseofulvin dispersed in these carriers.


Interventional MRI-guided frameless stereotaxy in pediatric patients.
We prospectively reviewed our experience with intraoperative MRI (iMRI)-guided stereotactic procedures in pediatric patients. All procedures were performed within the magnet bore of the General Electric Signa SP MRI system, which allows for either continuous real-time or periodic imaging. The internal optical tracking system was used to plan and monitor target localization and instrument trajectory. Fifteen patients underwent 16 frameless stereotactic procedures, consisting of 4 tumor biopsies and 12 cyst aspirations and stereotactic catheter placements (average age 6 years, range 6 weeks to 18 years). There were no hemorrhagic, neurologic or infectious complications. iMRI is an important component in expanding the horizon of minimally invasive neurosurgery for pediatric patients. Thus far, we have found this technology to be safe, reliable and extremely useful for frameless stereotactic procedures.


Sequestered carbon on clay mineral probed by electron paramagnetic resonance and X-ray photoelectron spectroscopy.
This paper describes the interaction among soil organic matter components with kaolinite, an important clay mineral present in tropical soils, especially in Brazil. XPS data show that the soil organic matter adsorbed on kaolinite has aromatic and aliphatic structures, with phenolic and/or alcoholic functions and carbonyl carbons (CO) of amide and/or carboxylic groups. The N1s spectrum of the kaolinite shows an asymmetric peak that is assigned to amide and protonated ammines probably from humin. The interaction between them is strong enough to resist chemical oxidative or reductive attack besides loose amide functionalities. EPR data show that reductive treatment reduces some Fe3+ of the kaolinite structure, loosing organic components. A schematic representation of the reduction of structural Fe3+ in the concentrated domains and consequently increased concentration of Fe3+ ions in diluted domains of the spectrum is presented. This reinforces the hypothesis that humin is a stable carbon sink in soils when adsorbed to clays.


Evaluation of RU28318 and RU40555 as selective mineralocorticoid receptor and glucocorticoid receptor antagonists, respectively: receptor measures and functional studies.
Corticosterone regulates a wide range of physiological parameters. Two receptors for corticosterone have been identified, the mineralocorticoid (type I) receptor (MR) and the glucocorticoid (type II) receptor (GR). To determine the relative role of these two receptors in mediating the effects of endogenous corticosterone, many studies have relied on the use of putative selective corticosteroid receptor antagonists. This study further examined the in vivo receptor selectivity of two compounds, RU28318 and RU40555 that are believed to be selective antagonists for MR and GR, respectively. Acute treatment of adrenalectomized rats with RU28318 (10-50 mg/kg) selectively decreased ex-vivo available MR binding in the hippocampus, whereas acute treatment with RU40555 (10-30 mg/kg) selectively decreased available GR binding in the hippocampus and pituitary. These receptor binding measures suggest that RU28318 in vivo selectively occupied MR, and that RU40555 in vivo selectively occupied GR. In functional studies, RU28318 (50 mg/kg) blocked the normalizing effect of aldosterone (120 microg/kg) on saline intake of adrenalectomized rats. RU40555 (30 mg/kg) blocked the suppressive effect of dexamethasone (50 microg/kg) on acute stress-induced corticosterone secretion. These studies further support the in vivo corticosteroid receptor selectivity of these two compounds and confirms their effective corticosteroid antagonistic properties.


Electron microscopy of Merkel cell carcinoma from formalin-fixed tissue.
Merkel cell carcinomas have characteristic, but not pathognomonic, histomorphologic features. The diagnosis can be confirmed by immunohistochemistry studies and electron microscopy. However, differential diagnostic problems often occur only after all tumor material has been fixed in formalin and embedded in paraffin, which gives poor tissue preservation for electron microscopy. Therefore, in addition to histologic and immunohistochemical studies, parallel ultrastructural investigations were performed on tumor specimens fixed in glutaraldehyde and routinely processed, for electron microscopy, on formalin-fixed tissue and on formalin-fixed paraffin blocks. Formalin fixation led to an almost complete loss of neurosecretory granules and cell membranes; however, the characteristic paranuclear whorls of intermediate filaments were retained in all tumors. Merkel cell carcinomas are immunoreactive for neuron-specific enolase (NSE), but NSE-antisera have only recently become commercially available. Cytokeratin is demonstrable as a paranuclear clump, and this feature was found in four out of six tumors. Thus histologic, immunohistochemical, and electron microscopy studies of formalin-fixed tissue are able to confirm the diagnosis of neuroendocrine Merkel cell carcinoma.


Alpha-gal syndrome-Food or drug allergy: A case report.
Alpha-gal syndrome is an immunoglobulin E-mediated hypersensitivity characterized by delayed allergic reactions to ingested products containing alpha-gal carbohydrate. We present a patient with recurrent urticaria and suspected repaglinide hypersensitivity, who was eventually diagnosed with alpha-gal syndrome, wanting to emphasize possible drug allergy misdiagnosis and required caution with the medication choice.


Observations on herpes zoster: 1. Residual scarring and post-herpetic neuralgia; 2. Handedness and the risk of infection.
The risk of developing post-herpetic neuralgia is related to the degree of residual scarring. Subjects over the age of 60 with more than 10 cm2 of residual scarring have a very high risk of developing intractable post-herpetic neuralgia. Left-handed subjects are less likely to develop herpes zoster, and this could be due to a more efficient immune system.


Cavernous sinus lesions.
The cavernous sinus is a complex structure susceptible to a wide variety of vascular, neoplastic and inflammatory pathologies. Vascular pathologies include ICA aneurysms, carotid-cavernous fistulas, cavernous sinus thrombosis, and cavernous hemangioma. Neoplasms that involve the cavernous sinus include pituitary adenoma, meningioma, schwannoma, lymphoma, perineural tumor spread, metastases, and direct tumor invasion. Infectious and inflammatory diseases include Tolosa-Hunt syndrome, sarcoidosis, granulomatosis with polyangiitis, IgG-4 related disease and invasive fungal infections. In this article, we review the clinical and imaging findings of a number of pathologies involving the cavernous sinus, focusing on key features that can narrow the differential diagnosis and, in some cases, support a particular diagnosis.


A retrospective evaluation of causes of exempting living liver donors in an Egyptian centre.
Living-related liver transplantation has helped to solve the problem of shortage of deceased organ donors. However, studies showed significant donor complications occurring with adult living liver donation. This study aims at assessing different causes of exclusion of potent living donor transplantation in Egypt. The data of 158 living donors (corresponding to 50 consecutive transplanted cases) were retrospectively studied. Only 50 donors were found to meet all the preoperative assessment criteria while 108 potential donors were excluded at various assessment steps. Majority of the excluded potential donors were due to anatomical variations (52/108) followed by hepatic steatosis (19/108) and positive hepatitis B or C virus serology (11/108). Regarding the anatomic variations, biliary anomalies were ranked as the first cause to exclude donors with the majority of them having the type C biliary variant. Portal vein variations were the second most common cause of exclusion due to portal vein trifurcation. Hepatic artery variations were detected in a lesser number of excluded donors. No donors were excluded for hepatic vein anomalies. Anatomical variations are the most common causes to exempt living liver donors. Preoperative evaluation of anatomical variations, viral serology and hepatic steatosis plays the major role to accept or exclude the potential donors.


Key challenges and developments in wildlife ecological risk assessment: Problem formulation.
Problem formulation (PF) is a critical initial step in planning risk assessments for chemical exposures to wildlife, used either explicitly or implicitly in various jurisdictions to include registration of new pesticides, evaluation of new and existing chemicals released to the environment, and characterization of impact when chemical releases have occurred. Despite improvements in our understanding of the environment, ecology, and biological sciences, few risk assessments have used this information to enhance their value and predictive capabilities. In addition to advances in organism-level mechanisms and methods, there have been substantive developments that focus on population- and systems-level processes. Although most of the advances have been recognized as being state-of-the-science for two decades or more, there is scant evidence that they have been incorporated into wildlife risk assessment or risk assessment in general. In this article, we identify opportunities to consider elevating the relevance of wildlife risk assessments by focusing on elements of the PF stage of risk assessment, especially in the construction of conceptual models and selection of assessment endpoints that target population- and system-level endpoints. Doing so will remain consistent with four established steps of existing guidance: (1) establish clear protection goals early in the process; (2) consider how data collection using new methods will affect decisions, given all possibilities, and develop a decision plan a priori; (3) engage all relevant stakeholders in creating a robust, holistic conceptual model that incorporates plausible stressors that could affect the targets defined in the protection goals; and (4) embrace the need for iteration throughout the PF steps (recognizing that multiple passes may be required before agreeing on a feasible plan for the rest of the risk assessment). Integr Environ Assess Manag 2022;00:1-16. © 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC). This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.


Effective quorum quenching with a conformation-stable recombinant lactonase possessing a hydrophilic polymeric shell fabricated via electrospinning.
Quorum sensing (QS) in Gram-negative bacteria is frequently regulated by the diffusible signal N-acylhomoserine lactone (AHL) along with the production of virulence factors in pathogens. To inhibit QS, we fabricated heat-resistant, long-term-stable AHL-lactonase AiiM by electrospinning (ES) aqueous polyvinyl alcohol (PVA) solution containing genetically engineered AiiM with a maltose-binding protein (MBP) tag. MBP-AiiM was immobilized via its inclusion within a dense PVA shell formed during the drying process of ES, followed by cross-linking between hydroxyl groups on PVA. Secondary structure analysis via circular dichroism suggested no conformational change in the MBP-AiiM during ES. Even after pre-heating of MBP-AiiM/PVA fiber mats at 70 °C for 24 h, QS-dependent prodigiosin production in the model pathogen Serratia marcescens AS-1 was effectively inhibited to 0.13% that of the control. Additionally, relative prodigiosin production was reduced to ~20% that of the control after 5-month storage in buffer solution. These results suggest that a shear-thinning process using an entangled PVA aggregate during elongational changes to fibrous domains and a drying process during ES contributes not to enzymatic inactivation caused by conformational changes, but rather to the fabrication of a dense PVA shell around the MBP-AiiM molecules to protect them from disruptors including heating. The developed quorum-quenching enzyme has high potential to inhibit AHL-mediated QS frequently appearing in various Gram-negative bacteria.


Robotics in pediatric surgery: perspectives for imaging.
Robotic surgery will give surgeons the ability to perform essentially tremorless microsurgery in tiny spaces with delicate precision and may enable procedures never before possible on children, neonates, and fetuses. Collaboration with radiologists, engineers, and other scientists will permit refinement of image-guided technologies and allow the realization of truly remarkable concepts in minimally invasive surgery. While robotic surgery is now in clinical use in several surgical specialties (heart bypass, prostate removal, and various gastrointestinal procedures), the greatest promise of robotics lies in pediatric surgery. We will briefly review the history and background of robotic technology in surgery, discuss its present benefits and uses and those being explored, and speculate on the future, with attention to the current and potential involvement of imaging modalities and the role of image guidance.


Effect of short-term standard therapeutic regimens on neuropeptide Y and adipose tissue hormones in overweight insulin-resistant women with polycystic ovary syndrome.
The study was aimed at elucidating the influence of a 3-month treatment with routine therapeutic regimens--oral hormonal contraceptives (OHC) with antiandrogenic activity (a standard combination of ethynil estradiol 35 microg plus cyproterone acetate 2 mg) in combination with insulin sensitizing agents--metformin (Group I) and rosiglitazone (Group II) on adipose tissue hormones and hypothalamic neuropeptide Y (NPY) in women with polycystic ovary syndrome. The study included 66 overweight insulin resistant women with PCOS according to the recent ESHRE-ASRM criteria randomized into 2 age-matched therapeutic groups. Significant decrease of leptin (P < 0.01; P = 0.001, resp.), resistin (P < 0.01; P < 0.01, resp.), tumour necrosis factor alpha (TNF alpha) (P = 0.001; P < 0.001, resp.), and NPY (P < 0.05; P < 0.001, resp.) was observed in both groups after treatment. These findings were in parallel with a significant decrease in the anthropometric parameters of body weight in the metformin group only. No significant changes in hormonal characteristics of the groups were found except for a significant decrease in androstenedione and DHEA-S (P < 0.05) in the metformin group and in 17-OH-progesterone (P < 0.05) in the rosiglitazone group. HDL-cholesterol rose and diastolic blood pressure fell significantly (P < 0.05) in the metformin group. Our data suggest beneficial effects of the treatment on potential cardiovascular risk in insulin resistant PCOS women.


Acenocoumarol Pharmacogenetic Dosing Algorithms and Their Application in Two Bulgarian Patients with Low Anticoagulant Requirements.
The anticoagulant therapy with acenocoumarol is generally associated with a high risk of bleeding and thromboembolic events. We applied eight already existing acenocoumarol dosing algorithms to Bulgarian patients with low acenocoumarol dose requirements and investigated which of these algorithms would predict most precisely the dose anticoagulant. Two patients with Bulgarian origin were referred to the outpatient clinical laboratory of "St. Ekaterina" University Hospital for Cardiovascular Surgery and Cardiology, Sofia, Bulgaria. After obtaining written informed consent, both patients were genotyped for polymorphisms in genes for Cytochrome P450 2C9 (CYP2C9), Vitamin K epoxide reductase (VKORC1), Apolipoprotein E (APOE), and Cytochrome P450 4F2 (CYP4F2). All applied acenocoumarol dosing algorithms predicted relatively similar doses of coumarin anticoagulant in both patients. However, van Schie et al.'s algorithm allowed more accurate calculation of the optimal dose in our patients with extremely low acenocoumarol requirements. Genotyping of selected polymorphic variants in CYP2C9 and VKORC1 showed that both patients were compound heterozygotes for CYP2C9 (CYP2C9*2/*3) and homozygotes for both variants in VKORC1 (VKORC1 1173 T/T, and VKORC1-1639 A/A). This combination of genotypes suggested high sensitivity to acenocoumarol leading to the low anticoagulant dose requirements (0.25 and 1 mg/day, respectively) needed to reach the target International Normalized Ratio of 2.5-3.5. The genotyping of polymorphic variants in VKORC1 and CYP2C9, together with clinical and demographic parameters, can serve for more precise definition of the individual starting and maintenance doses of coumarin derivatives in each patient.


'We are the forgotten victims': Perspectives of adult siblings of persons with traumatic brain injury.
This study determined how the lives of a cross-national sample of adult siblings had changed since their brothers and sisters incurred a traumatic brain injury. A total of 272 participants provided responses to the question, 'How is your life different since your sibling had a TBI?' Responses were analysed through the constant comparative method of textual analysis. Responses were collected through a mailed-survey. The analysed question appeared at the end of a 243-item quantitatively-based survey containing five open-ended questions. Three themes emerged: (1) 'Family impacts' such as growing up with a sibling with TBI and impact on family closeness; (2) 'Caring' including caring for and about the family member; and (3) 'Making sense of the experience' through adjustment and personal development. The study demonstrates that having a sibling with a TBI can result in profound and enduring negative and positive life changes for non-injured siblings. Professionals need to attend to the needs of siblings for support and guidance and should be considered as key informants about their injured family members during intake and service planning.


[Normal anatomical variants of the superior labrum biceps tendon anchor complex. Anatomical and magnetic resonance findings].
There are difficulties in diagnosing pathologies of the labrum-biceps tendon complex (LBTC) because of the great individual variability of this structure. Anatomical variations, such as the sublabral recess, are frequently found and can also be misinterpreted as Andrews or SLAP II lesions. The etiology and mechanisms of creating such a sublabral recess are not exactly known. The examination of 31 cadaveric shoulder specimens from an age group between 49.3 and 83.6 years showed a sublabral recess in 63.6-85%. This high frequency of sublabral detachment of the labrum in older patients indicates that according to the high range of motion of the humeral head and therefore the changing angle of the long biceps tendon (LBS) a certain mobility of the superior LBTC is physiological and should not necessarily be seen as a sign of instability. Besides mobility-increasing factors such as overhead professions and sports with high repetitive maximal abduction and external rotation and the individual age, the type of insertion of the LBT at the glenoid influences the development of sublabral recess. Accordingly, posterior oriented insertion types of the LBT determine deeper and more posterior oriented sublabral recesses whereas in cases of anterior directed types of insertions no or less deep recesses can be found. Anamnestic aspects, such as the mechanism of injury and overhead activities, these macroscopic and functional associations in MR arthrography and arthroscopic inspection have to be considered in order to differentiate between physiological and traumatic changes of the labrum-biceps tendon complex.


Tear IgA-ELISA: a novel and sensitive method for diagnosis of ophthalmic cysticercosis.
For the first time, presence of locally secreted specific IgA antibodies in tear specimen from human with ophthalmic cysticercosis is documented in the present study. The ELISA using Taenia solium metacestode excretory secretory (ES) antigen demonstrated a diagnostic level of IgA antibodies in tears with 100% sensitivity (6 out of 6 confirmed cases of ophthalmic cysticercosis) whereas, 25 of 34 (73.52%) clinically suspected cases were diagnosed positive. The ELISA using T. solium metacestode somatic antigen detected a diagnostic titre of IgA antibody in tears with a sensitivity of 50% (3 out of 6 confirmed cases). The specificity of the tear IgAELISA using T. solium metacestode somatic and ES antigens is observed to be 94.87% and 92.3%, respectively. Overall in tears, the ELISA using T. solium metacestode ES antigens for detection of IgA antibodies shows a higher diagnostic efficiency (93.33%) compared to that using T. solium metacestode somatic antigen (88.88%). The sensitivities of the ELISA for detection of IgA antibodies in tears is observed to be higher than that for detection of IgG antibodies in serum using either somatic or ES antigens of the parasite.


Rapid assessment of insect fauna based on local knowledge: comparing ecological and ethnobiological methods.
The rapid assessment of biodiversity making use of surveys of local knowledge has been successful for different biological taxa. However, there are no reports on the testing of such tools for sampling insect fauna. The present study aimed to evaluate the efficiency of different ethnobiological techniques for rapid sampling of insect fauna. Field research for the conventional survey of insect fauna was conducted on a private farm (9 ° 43'38.95 "S, 37 ° 45'11.97" W) , where there was intensive cultivation of okra (Abelmoschus esculentus L. (Moench)). The survey of local entomological knowledge was conducted among all the producers of okra living in the rural villages Pereira, Santa Luzia, and Nassau de Souza, within the Jacaré Curituba irrigated settlement scheme. The combined use of the techniques "free list" and projective interviews was analyzed, using two types of visual stimuli: stock photos and an entomological box. During the conventional survey of insect fauna, the species Bemisia tabaci biotype B, Aphis gossypii, Phenacoccus sp., Icerya purchasi and Lagria villosa were the primary pests found in the okra crop. Regarding the survey of insect pests, the results were convergent in both techniques (conventional sampling and free list). Comparing the interview with visual stimuli (pictures) and specimen witnesses (entomological box) revealed that the latter was more effective. Techniques based on the recording and analysis of local knowledge about insects are effective for quick sampling of pest insects, but ineffective in sampling predator insects. The utilization of collected insects, infested branches, or photos of the symptoms of damage caused by pests in projective interviews is recommended.


Visual rehabilitation with keratoprosthesis after tenonplasty as the primary globe-saving procedure for severe ocular chemical injuries.
To analyze the outcome (functional and anatomic) of eyes that underwent tenonplasty as the primary globe-saving procedure in severe ocular chemical injuries (grade V-VI Dua's classification). The records of patients who underwent tenonplasty for associated scleral ischemia in severe chemical burns in our institute between October 2005 and June 2011 were analyzed retrospectively. Out of 31 eyes that underwent tenonplasty, 21 belonged to grade V and VI of Dua's classification with diffuse scleral ischemia for which a four-quadrant tenonplasty was performed and only these 21 eyes were included for further analysis. The time to presentation following chemical injury, the need for revision surgeries, the time to complete epithelization, the procedures performed for ocular surface reconstruction and for visual rehabilitation and their outcome, both functional and anatomic, were analyzed. Of the 21 eyes of 13 patients, four were unilateral and nine were bilateral cases of chemical injury. The mean time to presentation following chemical injury was 14.61 days. Tenonplasty with amniotic membrane transplantation (AMT) was performed as the primary surgery. Revision tenonplasty was required in six eyes (seven procedures), the mean time to complete epithelization of the ocular surface was 5.4 ± 4.03 months. Of the 21 eyes, three lost perception of light following phthisis, evisceration for corneal infection, and uncontrolled glaucoma. Eighteen of 21 eyes were salvaged anatomically, of which ten eyes of 13 patients underwent surgery for visual rehabilitation. Among the unilateral cases, two eyes underwent ex vivo limbal stem cell transplant (LSCT) with or without keratoplasty for further visual rehabilitation. Among the patients with bilateral burns, visual rehabilitative procedure was performed in only one eye. Modified osteo-odonto-keratoprosthesis (MOOKP) was performed in five eyes, Boston type 1 keratoprosthesis in two eyes, and penetrating keratoplasty with keratolimbal allograft with systemic immunosuppression in one eye. One patient with bilateral injury is awaiting Boston keratoprosthesis type 1 for one eye. Of these eight eyes (bilateral injuries), all achieved a BCVA of 20/200 or better over a mean follow-up period of 27.37 ± 14.5 months following visual rehabilitative procedure. Tenonplasty has a globe-saving role in eyes with severe chemical injuries with associated scleral ischemia, by accelerating the healing process. Further on, these eyes can undergo visual rehabilitative procedures and our results highlight the feasibility of achieving a good functional outcome following anatomical stability. The role of tenonplasty to salvage the eye in the initial management of chemical injury, the need for multiple surgeries, close follow-up, and monitoring of intraocular pressure prior to and after procedures for visual rehabilitation cannot be underemphasized.


Duration of symptoms does not correlate with results of T-cell gene rearrangement studies in patients evaluated for cutaneous T-cell lymphoma.
We aimed to determine if clonality on T-cell gene rearrangement studies correlated with duration of cutaneous symptoms in patients with skin disease who are being evaluated for cutaneous T-cell lymphoma (CTCL). Specifically, our goal was to determine if symptom duration could help better optimize sample selection for T-cell gene rearrangement studies. Biopsies were reviewed from patients within both general dermatology clinic and CTCL specialty clinic for clonality results in relation to disease duration. We did not find an association between duration and clonality in any group. The yield of T-cell gene rearrangement studies is similar between shorter and longer duration of disease implying that there is not an optimal duration range in which T-cell gene rearrangement studies are more likely to give a positive result.


Parietal white matter abnormalities in obsessive-compulsive disorder: a magnetic resonance spectroscopy study at 3-Tesla.
To identify a neurochemical basis for the hypothesis that an aberrant cortico-subcortical circuit underlies obsessive-compulsive disorder (OCD). The white matter was also investigated because of recent research which suggests the altered connectivity of axons. Using 3-Tesla magnetic resonance spectroscopy, the relative concentrations of N-acetylaspartate (NAA) and choline-containing compounds (Cho) to creatine/phosphocreatine (Cr) were measured in the anterior cingulate, basal ganglia, thalamus, frontal and parietal white matter of 12 OCD patients, and 32 control subjects. The mean concentration of Cho/Cr was significantly higher in the patients than in the controls, but only in the parietal white matter, while no significant group differences in NAA/Cr were observed in any of the brain regions. Parietal Cho/Cr correlated positively with the severity of OCD symptoms. This finding provides indirect evidence for the parietal white matter involvement in OCD, thus suggesting a change in the phospholipids of myelinated axons and/or glia cells.


Expression profile of porcine scavenger receptor A and its role in bacterial phagocytosis by macrophages.
Expression of scavenger receptor A (SRA) in macrophages plays key role in macrophage mediated uptake of microbes. However, little is known about the role of porcine scavenger receptor A (pSRA) in phagocytic function of macrophages in swine species. In this study, polyclonal antibody against pSRA was generated by using recombinant proteins to study expression and function of pSRA. We report broad expression of pSRA in different tissues. In the lungs, pSRA is mainly expressed by alveolar macrophages. Blockade of class A scavenger receptor by fucoidan treatment demonstrates that pSRA has role in bacterial phagocytosis by macrophages. Furthermore, importance of SRA-mediated bacterial phagocytosis has been shown using CHO cell line expressing pSRA. In summary, these findings reveal that pSRA, which is predominantly expressed in alveolar macrophages is likely to be an important receptor mediating recognition and uptake of bacteria in pig lungs.


Enhancement of antitumor activity of docetaxel by celecoxib in lung tumors.
Our study investigates the effect of a highly selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, on the cytotoxicity of docetaxel in nude mice bearing A549 tumor xenografts and elucidates the molecular mechanisms of the antitumor effect of this combination. Female nu/nu mice, xenografted with s.c. A549 tumors were treated with either celecoxib (150 mg/kg/day), docetaxel (10 mg/kg) or a combination of both. The tumor tissues were quantified for the induction of apoptosis, intratumor levels/expressions of prostaglandin E2 (PGE2), 15 deoxy prostaglandin J2 (15-d PGJ2), microsomal prostaglandin E synthase (mPGES) and cytoplasmic phospholipase A2 (cPLA2). The combination of celecoxib with docetaxel significantly inhibited the tumor growth (p < 0.03) as compared to celecoxib or docetaxel alone, decreased the levels of PGE2 by 10-fold and increased the 15-d PGJ2 levels by 4-fold as compared to control. The combination also enhanced the peroxisome proliferator-activated receptor (PPAR)-gamma expression, decreased the expression of cPLA2, mPGES and vascular endothelial growth factor (VEGF), but had no effect on the expression of COX-1 or COX-2 in tumor tissues. TUNEL staining of the tumor tissues showed a marked increase in the apoptosis in the combination group as compared to the celecoxib- or docetaxel-treated groups and this was associated with an increase in the intratumor p53 expression. In conclusion, the combination of celecoxib with docetaxel produces a greater antitumor effect in s.c. A549 tumors as compared to celecoxib or docetaxel alone and this effect is associated with concomitant alterations in the intratumor levels of PGE2 and 15-d PGJ2.


Transitioning Clinical Practice Guidelines into the Electronic Health Record through Clinical Pathways.
Clinical practice guidelines in oncology provide an evidence-based roadmap for most cancer care delivery but often lack directions for specific patient factors and disease conditions. Clinical pathways serve as a real-time clinical decision support system to translate guidelines to clinical practice. Pathways allow for the creation of a standardized, multidimensional roadmap for the continuum of care that can support clinical decision-making, maintain optimal outcomes, and limit unnecessary variation in cancer care. Here we describe the process to develop and implement clinical pathways in the electronic health record. This process includes building the appropriate foundation for a clinical pathways team with supports in the institutional ecosystem, creating visual representations of care paths, formalizing the pathway approval process, and translating clinical pathways into an electronic health record-integrated clinical decision support tool.


Development and commercial use of afla-Guard(®), an aflatoxin biocontrol agent.
A biopesticide, afla-guard(®), has been developed for controlling aflatoxin contamination in peanuts. This product provides the means of introducing a competitive, non-aflatoxigenic strain ofAspergillus flavus into soils where peanuts are being grown. The introduced strain competitively excludes toxigenic strains naturally present from invading developing peanuts. The biocontrol technology was made commercially available in 2004 by Circle One Global, Inc., upon receiving U.S. Environmental Protection Agency section 3 registration of afla-guard(®) as a biopesticide. The product was applied to approximately 2000 ha of peanuts in Georgia and Alabama during the 2004 crop year. Application of afla-guard(®) changed the composition ofA. flavus soil populations from an average 71.1% toxigenic strains in untreated fields to only 4.0% in treated soils. Analyses of farmer's stock peanuts being delivered at seven different locations showed a consistent reduction in aflatoxin contamination in peanuts from fields treated with afla-guard(®). Over all locations, aflatoxin averaged 78.9 ng/g in untreated peanuts compared with 11.7 ng/g in treated peanuts, an 85.2% reduction. Peanuts from treated and untreated fields were stored together in separate warehouse bins at two different locations. Aflatoxin analyses at the Unadilla, GA location showed that 48.4% of shelled edible lots from untreated fields contained unacceptable levels of aflatoxin (>15 ng/g). At the Dawson, GA location, 15.8% of shelled lots from untreated fields contained >15 ng/g. At both locations, no shelled edible lots from treated fields contained >15 ng/g. Mean aflatoxin concentrations in edible peanuts from untreated and treated fields at Unadilla were 36.2 and 0.9 ng/g, respectively. At Dawson the respective means were 7.2 and 2.2 ng/g.


Surgical Adjuncts for Glioblastoma.
Although surgical resection of the solid tumor component of glioblastoma has been shown to provide a survival advantage, it will never be a curative procedure. Yet, systemically applied adjuvants (radiation therapy and chemotherapy) also are not curative and their options are limited by the inability of most agents to cross the blood-brain barrier. Direct delivery of adjuvant therapies during a surgical procedure potentially provides an approach to bypass the blood-brain barrier and effectively treat residual tumor cells. This article summarizes the approaches and therapeutics that have been evaluated to date, and challenges that remain to be overcome.


Glucagon-like peptide-1 receptor agonist exendin-4 mitigates lipopolysaccharide-induced inflammatory responses in RAW264.7 macrophages.
Macrophages play a critical role in the immune response against pathogen invasion and injury. However, under pathological stress, macrophages could have aberrant roles and contribute to the pathogenesis of inflammatory associated diseases. Exenatide is a glucagon-like peptide 1(GLP-1) agonist, which belongs to the family of synthetic exendin-based incretin mimetic. Exendin related compounds reduce glucose levels in type 2 diabetes patients. The purpose of this study was to examine the anti-inflammatory effects of exendin-4 in LPS-induced activation of macrophages. We show that exendin-4 inhibits LPS-induced expression of inflammatory mediators (iNOS, COX-2, PGE2 and NO) and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in RAW264.7 macrophages. Exendin-4 pretreatment mitigates LPS induced cellular ROS production. Mechanistically, Exendin-4 suppresses the LPS-induced activation of the JNK and AP-1 pathway. Furthermore, exendin-4 suppresses both nuclear p65 accumulation and transfected NF-κB promoter activity, indicating it inhibits the activation of the NF-κB pathway. Our study demonstrates that the GLP-1 agonist exendin-4 has a potent anti-inflammatory effect independent on its glucose reducing ability, and exendin-4 has the potential implication to treat inflammatory associated diseases.


A mathematical model for reconstitution of granulopoiesis after high dose chemotherapy with autologous stem cell transplantation.
High dose chemotherapy supported with hematopoietic progenitor cells gives a characteristic neutropenic period (blood neutrophils < 0.5 x 10(9) c/l) ranging from 10 to 16 days. The question of a correlation between the CFU-GM content of the transplanted CD34+ cells and time to neutrophil recovery by patients having been given high-dose chemotherapy (HD-CT) with stem cell support was addressed by means of a mathematical model of granulopoiesis. The model utilizes a convection-reaction partial differential equation (PDE) with feedback from a cytokine compartment on proliferation, maturation, and mobilization of granulocytes from bone marrow to blood. The observed number of CFU-GM cells in the transplanted CD34+ cell autograft was used as input to the model. Using this approach, the observed gross relationship between CFU-GM content in the reinfused blood product and engraftment time could be reproduced. At the same time, the effects of assumed physiological mechanisms, especially some of the effects of G-CSF on proliferation rate, maturation rate, mobilization, and cell death, could be investigated and discussed relative to observed engraftment. The model makes it possible to explain how cytokines interfere with progenitor cell mobilization from bone marrow to blood, and it points out the implications of a regulating mechanism for the granulocyte maturation rate.


Standardisation of 89Sr using three different methods.
Three independent methods were used to standardise a 89Sr solution within the frame of an international comparison organised by BIPM/CCRI(II): 4pi liquid scintillation (LS) spectrometry, based on the CIEMAT/NIST efficiency tracing method, and direct activity measurements with a windowless 4pi CsI(Tl)-sandwich spectrometer and a 4pi pressurised gas proportional counter. Quantitative solid point-like sources were prepared paying special attention during the source drying phase. The impurities in the original solution were measured and corrected for in the results of all three methods. The activity concentration of 89Sr was found to be 26.21 +/- 0.08 kBq g(-1). A new half-life value for 89Sr of 50.61 +/- 0.05 days was determined from the LS measurements. The measurement methods, including the impurity measurements, are described and the results compared. considering the advantages and disadvantages of each method.


Erythrocyte deformability and oxidative stress in inflammatory bowel disease.
Oxidative stress and reduced microvascular flow are important factors in the pathogenesis of inflammatory bowel disease (IBD). The increased oxidative stress reduces the erythrocyte deformability. However, in IBD, there are no studies in the literature which evaluate erythrocyte deformability. In our study, we investigated the effect of oxidative stress and erythrocyte deformability in IBD. Forty-three patients with active IBD, 48 patients with inactive IBD and 45 healthy controls were included. The erytrocyte deformability, malonyldialdehyde levels, glutation peroxidase and sulfhydryl levels were measured in peripheral venous blood samples. Erytrocyte malonyldialdehyde levels in both active and inactive IBD were significantly increased compared with control groups. Plasma glutation peroxidase levels did not show statistically significant difference between all groups. The decreased plasma sulfhydryl levels in active IBD were statistically significant compared with both the inactive IBD and the control group, but plasma sulfhydryl levels in inactive IBD group did not show statistically significant differences when compared with the control group. Elongation index values in both active and inactive IBD increased significantly compared with the control group. Statistically significant correlations were not found between the elongation index and glutation peroxidase, malonyldialdehyde, sulfhydryl levels in all groups. Our study is the first to evaluate the erythrocyte deformability in IBD. In our study, increased erytrocyte malonyldialdehyde levels and decreased plasma sulfhydryl levels manifested the role of oxidative stress in the pathogenesis of the disease. It is thought that the increased erythrocyte malonyldialdehyde values cause the reduction in erythrocyte deformability.


Efficacy of capnometry in ventilatory management of cardiac patients.
The ability of capnometry to prevent hypercarbia and to safely help in weaning post-cardiac surgery patients was investigated. The first group, 60 patients, had arterial blood gases (ABG) determined after each new ventilator setting. The corresponding end-tidal CO2 (PETCO2) was recorded and PaCO2-PETCO2 gradients were established at each ABG determination. The initial gradient was maintained during ventilation in the patient. A later gradient, determined when the patient was waking, was used to wean. The next 50 patients, the second group, had responses to ventilator changes determined solely by capnometry. ABG were routinely drawn only to establish the maintenance and weaning PaCO2-PETCO2 gradients. The initial gradients of 8.43 +/- 3.45 (mean +/- SD) and 7.65 +/- 2.24 mmHg, in the first and second groups, narrowed to 1.27 +/- 3.79 and 2.21 +/- 3.96 mmHg, respectively, when the patients were ready to wean. All patients in both groups were safely weaned. Patients in the second group had fewer ABG determinations, 3.78 +/- 1.30 v 5.40 +/- 1.97, a decrease of 1.62 (95% confidence interval 1.54 to 1.70). No patient was hypercarbic. The study shows that capnometry can be used to safely wean patients, decrease the number of ABG, and prevent hypercarbia.


Current challenges in treatment options for visceral leishmaniasis in India: a public health perspective.
Visceral leishmaniasis (VL) is a serious parasitic disease causing considerable mortality and major disability in the Indian subcontinent. It is most neglected tropical disease, particularly in terms of new drug development for the lack of financial returns. An elimination campaign has been running in India since 2005 that aim to reduce the incidence of VL to below 1 per 10,000 people at sub-district level. One of the major components in this endeavor is reducing transmission through early case detection followed by complete treatment. Substantial progress has been made during the recent years in the area of VL treatment, and the VL elimination initiatives have already saved many lives by deploying them effectively in the endemic areas. However, many challenges remain to be overcome including availability of drugs, cost of treatment (drugs and hospitalization), efficacy, adverse effects, and growing parasite resistance. Therefore, better emphasis on implementation research is urgently needed to determine how best to deliver existing interventions with available anti-leishmanial drugs. It is essential that the new treatment options become truly accessible, not simply available in endemic areas so that they may promote healing and save lives. In this review, we highlight the recent advancement and challenges in current treatment options for VL in disease endemic area, and discuss the possible strategies to improve the therapeutic outcome.


Characterization and applicability of novel alkali-tolerant carbonatogenic bacteria as environment-friendly bioconsolidants for management of concrete structures and soil erosion.
Cracking and erosion are critical factors that reduce the mechanical properties and stability of concrete structures and soil, respectively. They are recognized worldwide as severe disasters causing the collapse of many structures including stone heritage and dams, and landslides. Therefore, it is essential to propose effective and environment-friendly management methods to prevent them. Carbonatogenesis has recently received considerable attention as a reliable biological process for remediating cracks in calcareous structures, stabilizing loose soils, and sequestering CO2 in the environment. Isolating and characterizing carbonatogenic bacteria with excellent performance is crucial for applying this process to the field of environmental and civil engineering. The aim of this study was to isolate new CaCO3-precipitating bacteria and investigate various properties for their use as bioconsolidants. Furthermore, the possibility of restoring damaged structures and stabilizing loose sandy soil using isolated strain was investigated. Strain LC13 with urease and CaCO3-precipitating activity was isolated from limestone cave soil in Korea and identified as Arthrobacter sulfureus by phenotypic characterization and 16S rRNA gene analysis. Although cell growth was observed after an adaptation period at pH 11, strain LC13 grew well at pH 7-11, indicating alkali tolerance. The optimal conditions for CaCO3 precipitation were 1.0% yeast extract, 2.5% urea, 0.35% NaHCO3, and 400 mM CaCl2, with an initial pH of 6.5 at 30 °C. Under optimized conditions, maximal CaCO3 (22.92 ± 0.14 g/l) precipitated after 3 days, which was 10.8-fold higher than the value in a urea-CaCl2 medium. CaCO3 precipitation by strain LC13 was associated with an increased pH due to ureolysis and protein deamination. Using an optimized medium as a cementation solution, strain LC13 completely remediated 340-760 μm wide cracks over 3 days, and also restored the spalling of concrete surfaces. Furthermore, the sand treated with LC13 solidified with a surface strength of 14.9 kPa. Instrumental analysis confirmed that the crystals precipitated were a mixture of CaCO3 polymorphs composed of rhombohedral calcite and spherical vaterite. These results suggest that A. sulfureus LC13 may be useful for implementing sustainable biorestoration and environmental management technologies such as the in situ remediation of structural cracks and in situ prevention of soil erosion.


Health-related quality of life and treatment effects on children with functional incontinence, and their parents.
To analyze treatment outcomes and the association between treatment effects and health-related quality of life (HRQoL) for incontinent children, and their parents. Health-related quality of life in 70 consecutively treated children, and their parents, was assessed with the Pediatric Incontinence Questionnaire and the WHO-Quality-Of-Life-BREF questionnaire. This was assessed before and after three months of standardized treatment. In 44.3% of children, symptoms decreased by 50-89%. After three months of treatment, the HRQoL of children improved significantly. Children with bladder and bowel dysfunction had a significantly lower HRQoL than children with isolated nocturnal enuresis, daytime urinary incontinence or fecal incontinence. Parental HRQoL did not change significantly within three months of treatment. Parents showed a significantly lower mean in the 'psychological' domain of the WHO-QoL-BREF questionnaire compared to norms. Children with different subtypes of incontinence can be treated effectively within three months of therapy. After three months, significant improvements of HRQoL were shown. Parents showed no general reduction in their quality of life (QoL). Specific aspects of parental QoL were impaired, but did not improve during the treatment of their children.


Patient-related benefits of amyloid PET imaging in dementia: Rationale and design of the German randomized coverage with evidence development study ENABLE.
The utility of amyloid positron emission tomography (PET) for the etiological diagnosis of dementia and its impact on functional status of patients in routine care are currently unclear. Here, we describe the design of ENABLE, a randomized controlled two-armed coverage with evidence development (CED) study in Germany. Approximately 1126 patients with mild to moderate dementia of unclear etiology will be randomly assigned to either an amyloid PET or a no amyloid PET group. Patients will be followed-up for 24 months. The study has been registered at the German Clinical Trials Register (https://drks.de/search/de/trial/DRKS00030839) with the registration code DRKS00030839. The primary endpoint of ENABLE is the ability to perform functional activities of daily living at 18 months. Secondary endpoints include change in diagnosis, diagnostic confidence, and cognitive and clinical outcomes of patients. We expect that the CED study ENABLE will inform about patient relevant effects of amyloid PET in routine care. Furthermore, we anticipate that ENABLE will support physicians' and payers' decisions on provision of health care for patients with dementia. Study design focuses on the usefulness of amyloid positron emission tomography (PET) in routine care.Study design addresses the patient-relevant effect of amyloid PET.Patient representatives were involved in the creation of the study design.The study will help improve routine care for people with dementia.


Impact of web application support versus standard management on adherence with adjuvant hormone therapy in patients treated for breast cancer: the WEBAPPAC study.
Non-metastatic breast cancer treatment is mainly based on surgery, with or without chemotherapy, radiotherapy and/or hormone therapy. To reduce the risk of hormone receptor positive (HR+) disease recurrence, hormone therapy is prescribed for at least 5 years. It may induce adverse drug reactions (ADRs) as joint pain, sexual dysfunction, weight increase, fatigue, mood disorders and vasomotor symptoms. Around 30-40% of patients withhold hormone therapy within 5 years after initiation. Based on encouraging results of mobile health in patient follow-up, we developed a web-application addressed for breast cancer patients initiating adjuvant hormonal therapy and aimed to assess its impact on hormone therapy adherence, ADRs management, and health-related quality of life. The WEBAPPAC trial is a randomized, open-label, prospective, single-center phase 3 study aiming to assess the interest of a web-application support as compared to standard management among breast cancer patients initiating hormone therapy. The main endpoint is the proportion of patients with hormone therapy adherence failure within 18 months after treatment start, in each arm. Eligible patients will be 1:1 randomized between the WEBAPPAC web-application support (experimental arm,) or standard support (control arm), with stratification on type of hormone therapy (Aromatase inhibitor or Tamoxifen). We plan to enroll 438 patients overall. Failure to hormone therapy will be assessed using the Morisky 8-item self-questionnaire (MMSA8), patient adherence logbook, and medical consultations. Secondary outcomes include hormone therapy adherence at 6 months, pain (Visual Analogue Scale and Brief Pain Inventory), quality of life (EORTC QLQ-C30 and BR23 self-questionnaires), anxiety and depression (Hospital and Depression Scale), and return to work and/or daily activities. The user experience with the WEBAPPAC web-application will be assessed using the System Usability Scale (SUS) questionnaire. Hormone therapy discontinuation or adherence failure in breast cancer patients may be indirectly related to an increased risk of recurrence. A better control of medication adherence, through the detection of side effects and some proposed actions trying to reduce them, appears therefore essential to limit the risk of disease recurrence. The WEBAPPAC web-application thus aims better monitoring and allowing higher level of responsiveness in case of ADRs, thus improving treatment adherence. NCT04554927, registered September 18, 2020. Version 2.1 dated from December 21, 2021.


Can we reduce disease burden from osteoarthritis?
The comparison of disparate interventions for the prevention and management of osteoarthritis (OA) is limited by the quality and quantity of published efficacy studies and the use of disparate measures for reporting clinical trial outcomes. The "transfer to utility" technique was used to translate published trial outcomes into a health-related quality-of-life (utility) scale, creating a common metric which supported comparisons between disparate interventions. Total hip replacement (THR) and total knee replacement (TKR) surgery were the most effective treatments and also highly cost-effective, at estimated cost per quality-adjusted life-year (QALY) of 7500 dollars for THR and 10000 dollars for TKR (best estimate). Other apparently highly cost-effective interventions were exercise and strength training for knee OA (< 5000 dollars/QALY), knee bracing, and use of capsaicin or glucosamine sulfate (< 10000 dollars/QALY). The cost per QALY estimates of non-specific and COX-2 inhibitor non-steroidal anti-inflammatory drugs were affected by treatment-related deaths and highly sensitive to the discounting of life-years lost. OA interventions that have been shown to be ineffective (eg, arthroscopy) are targets for redistribution of healthcare resources. OA interventions which lack efficacy studies (eg, prevention programs) require further research to assist priority setting. The application of the Health-sector Wide model to OA demonstrates its role as an evidence-based model that can be successfully applied to identify marginal interventions - those to be expanded and contracted to reduce the expected burden of disease, within current healthcare resources.


The role of miR-100 in regulating apoptosis of breast cancer cells.
Breast cancer is a serious health problem worldwide. Inhibition of apoptosis plays a major role in breast cancer tumorigenesis. MicroRNAs (miRNAs) play crucial roles in the regulation of apoptosis. However, the regulation of breast cancer apoptosis by miRNAs has not been intensively investigated. To address this issue, the effect of miR-100 on the cell proliferation of different breast cancer cells was characterized in the present study. The results showed that miR-100 was significantly upregulated in SK-BR-3 cells compared with other human breast cancer cells (MCF7, MDA-MB-453, T47D, HCC1954 and SUM149). Silencing miR-100 expression with anti-miRNA-100 oligonucleotide (AMO-miR-100) initiated apoptosis of SK-BR-3 cells in vitro and in vivo. However, the overexpression of miR-100 led to the proliferation inhibition of the miR-100-downregulated breast cancer cells. Antagonism of miR-100 in SK-BR-3 cells increased the expression of MTMR3, a target gene of miR-100, which resulted in the activation of p27 and eventually led to G2/M cell-cycle arrest and apoptosis. The downregulation of miR-100 sensitized SK-BR-3 cells to chemotherapy. Therefore, our finding highlights a novel aspect of the miR-100-MTMR3-p27 pathway in the molecular etiology of breast cancer.


Skin blood flow affects in vivo near-infrared spectroscopy measurements in human skeletal muscle.
Skin blood flow affects NIRS. Leg skin blood flow (SkBF) was increased and decreased following local heating and intradermal epinephrine injection. Epinephrine decreased muscle saturation (StO(2)), and heating the leg increased StO(2). The results suggest that changes in SkBF can significantly affect resting StO(2) as measured by near-infrared tissue spectroscopy.


The Impact of the Third Wave of the COVID-19 Pandemic on the Elderly and Very Elderly Population in a Tertiary Care Hospital in Portugal.
COVID-19 poses a significantly more serious threat to adults aged 65 and above, with a higher mortality rate. This study aims to describe the outcome of COVID-19 patients in the elderly and very elderly population admitted to a tertiary care Portuguese hospital. The authors defined the elderly population (65 to 79 years) and the very elderly population (≥ 80 years). We conducted a retrospective observational single center study in the internal medicine ward of a tertiary hospital from November 1, 2020 to January 31, 2021. All COVID-19 patients aged over 65 years were enrolled. Of the 824 patients with SARS-CoV-2 infection, 586 (71%) were aged above 65 years. Of them, 61.7% were very elderly and 32.9% were elderly. The hospital recorded 53 (27.5%) deaths in the elderly group and 182 (46.3%) in the over-80 group. In the elderly population, only 32 patients had critical illness compared to the 79 in the very elderly group. In addition to respiratory complications, acute kidney failure and liver dysfunction were noted. In both groups, mortality was higher when there was acute kidney injury (AKI). With respect to treatment, dexamethasone and azithromycin did not show a statistically significant difference between the groups. The need for oxygen therapy over 4L/min, high-flow therapy, and mechanical invasive ventilation was related to higher mortality in both groups. The very elderly group had a higher number of deaths compared to the elderly group due to multiple comorbidities. Respiratory failure was the most frequently occurring complication. Surprisingly, dexamethasone and azithromycin therapy did not show a statistically significant effect in both age groups despite their current widespread usage in COVID-19 treatment worldwide.


Water extract isolated from Chelidonium majus enhances nitric oxide and tumour necrosis factor-alpha production via nuclear factor-kappaB activation in mouse peritoneal macrophages.
Chelidonium majus is used to treat several inflammatory diseases and tumours. We have examined the effect of C. majus on nitric oxide (NO) production using mouse peritoneal macrophages. When C. majus was used in combination with recombinant interferon-gamma (rIFN-gamma, 10 U mL(-1)), there was a marked cooperative induction of NO production. Treatment of rIFN-gamma plus C. majus (1 mgmL(-1)) in macrophages caused a significant increase in tumour necrosis factor-alpha (TNF-alpha) production. The increased production of NO and TNF-alpha from rIFN-gamma plus C. majus-stimulated cells was almost completely inhibited by nuclear factor-kappaB (NF-kappaB) inhibitor, pyrrolidine dithiocarbamate (100 microM). These findings demonstrated that C. majus increased the production of NO and TNF-alpha by rIFN-gamma-primed macrophages and suggested that NF-kappaB played a critical role in mediating the effects of C. majus.


In silico identification of novel lead compounds with AT1 receptor antagonist activity: successful application of chemical database screening protocol.
AT1 receptor antagonists are clinically effective drugs for the treatment of hypertension, cardiovascular, and related disorders. In an attempt to identify new AT1 receptor antagonists, a pharmacophore-based virtual screening protocol was applied. The pharmacophore models were generated from 30 training set compounds. The best model was chosen on the basis of squared correlation coefficient of training set and internal test set. The validity of the developed model was also ensured using catScramble validation method and external test set prediction. The final model highlighted the importance of hydrogen bond acceptor, hydrophobic aliphatic, hydrophobic, and ring aromatic features. The model satisfied all the statistical criteria such as cost function analysis and correlation coefficient. The result of estimated activity for internal and external test set compounds reveals that the generated model has high prediction capability. The validated pharmacophore model was further used for mining of 56000 compound database (MiniMaybridge). Total 141 hits were obtained and all the hits were checked for druggability, this led to the identification of two active druggable AT1 receptor antagonists with diverse structure. A highly validated pharmacophore model generated in this study identified two novel druggable AT1 receptor antagonists. The developed model can also be further used for mining of other virtual database.


Long non-coding RNA PCAT19 safeguards DNA in quiescent endothelial cells by preventing uncontrolled phosphorylation of RPA2.
In healthy vessels, endothelial cells maintain a stable, differentiated, and growth-arrested phenotype for years. Upon injury, a rapid phenotypic switch facilitates proliferation to restore tissue perfusion. Here we report the identification of the endothelial cell-enriched long non-coding RNA (lncRNA) PCAT19, which contributes to the proliferative switch and acts as a safeguard for the endothelial genome. PCAT19 is enriched in confluent, quiescent endothelial cells and binds to the full replication protein A (RPA) complex in a DNA damage- and cell-cycle-related manner. Our results suggest that PCAT19 limits the phosphorylation of RPA2, primarily on the serine 33 (S33) residue, and thereby facilitates an appropriate DNA damage response while slowing cell cycle progression. Reduction in PCAT19 levels in response to either loss of cell contacts or knockdown promotes endothelial proliferation and angiogenesis. Collectively, PCAT19 acts as a dynamic guardian of the endothelial genome and facilitates rapid switching from quiescence to proliferation.


Bristow-Latarjet Technique: Still a Very Successful Surgery for Anterior Glenohumeral Instability - A Forty Year One Clinic Experience.
To evaluate the functional outcomes of the Bristow-Latarjet procedure in patients with recurrent anterior glenohumeral instability. Personal clinical records of 42 patients with 45 operated shoulders were reviewed retrospectively. Patient age at time of first dislocation, injury mechanism, and number of recurring dislocations before surgery were recorded. The overall function and stability of the shoulder was evaluated. Thirty five (78%) of the scapulohumeral humeral instabilities were caused by trauma. The mean number of recurring dislocations was 9 (95% confidence interval [CI], 0-18); one patient had had 17 recurrences. Mean follow-up 46 months (95% CI, 16-88). No dislocation happened postoperatively. Four patients have fibrous union (9%). Only two had clinical sign of pain and discomfort. One of them was reoperated for screw removal with very good post-operative result. The overall functional outcome was good, with a mean Rowe score of 88 points (95% CI, 78-100). Scores of 27 (64%) of the patients were excellent, 9 (22%) were good, 4 (9.5%) were fair, and 2 (4.5%) were poor. The Bristow-Latarjet procedure is a very good surgical treatment for recurrent anterior-inferior instability of the glenohumeral joint. It must not be used for multidirectional instability or psychogenic habitual dislocations.


Suppression of T-cell function in gastric cancer patients after total gastrectomy with splenectomy: implications of splenic autotransplantation.
Background. In Japan since the 1960s, patients with gastric cancer have routinely had splenectomy combined with gastrectomy to ensure that lymph node dissection is complete. However, the influence of splenectomy on long-term immunity is unclear.METHODS: Forty-nine gastric cancer patients who underwent total gastrectomy for cure with ( n = 25) and without ( n = 24) splenectomy were assessed for immunologic function, including the proportion of lymphocyte subsets, purified protein derivative from tuberculin (PPD) response, natural killer (NK) activity, and phytohemagglutinin (PHA) response.RESULTS: Peripheral T-cell mediated functions, e.g., PPD and PHA response, were significantly suppressed in patients who underwent gastrectomy with splenectomy compared with those who had gastrectomy alone. Decreased T-cell subsets (CD 3+, 4+, 8+) and increased NK cell subsets (CD 16+, 57+) were observed in patients who underwent splenectomy. Patients who did not undergo splenectomy had immunologic responses within the normal range.CONCLUSIONS: Splenectomy decreased T-cell mediated responses over the long term. As a potential means to co-rrect this T-cell dysfunction in patients with splenectomy, splenic autotransplantation should be considered in future research.


Invertebrate epithelial Na+ channels: amiloride-induced current-noise in crab gill.
Epithelial sheets (including cuticle) from posterior gills of the freshwater-adapted euryhaline crab Eriocheir sinensis were obtained according to the method of Schwarz and Graszynski ((1989) Comp. Biochem. Physiol. 92A, 601-604; (1989) Verh. Dtsch. Zool. Ges. 82, 211 and (1989) Arch. Int. Physiol. Biochim. 97, C45). With external NaCl-saline, the outward-directed short-circuit current (Isc) could hardly be influenced by external amiloride up to 100 mumol/l but was, on the contrary, strictly dependent on apical Cl- (Onken, Graszynski and Zeiske (1991) J. Comp. Physiol. B 161, 293-301). In absence of external chloride an inward-directed, amiloride-inhibitable Isc was observed which depended on external Na+ (thus, Isc approximately INa) in a two-step, saturating mode. The Isc-block by amiloride obeyed saturation kinetics (half-maximal at less than or equal to 1 mumol/l, suggesting apical Na(+)-channels). Only for Na+ concentrations below 100 mmol/l we found an indication for a competitive interaction between Na+ and amiloride at the channel. Current fluctuation analysis revealed the presence of an amiloride-induced relaxation (Lorentzian) component in the Isc-noise (so-called 'blocker-noise'). The Lorentzian parameter-shifts with increasing amiloride concentration indicate first-order kinetics of the blocker with its apical receptor. Using a 'two-state' blocking model we calculated, for amiloride concentrations between 2 and 5 mumol/l, a mean single-channel current of 0.46 pA and a mean channel density of 250.10(6) cm-2.


Prophylactic antibiotics for suction curettage abortion: results of a clinical controlled trial.
The prophylactic use of 300 mg doxycycline at the time of an abortion was evaluated in a randomized controlled trial. In the group with negative chlamydia screening results, only two (0.4%) of 502 patients who received prophylactic treatment developed pelvic infection, compared with 15 (3.0%) of 497 patients who received placebos (p = 0.001). The same effectiveness was found in women with positive chlamydia screening results. Vomiting was the major side effect of the medication and could limit its use. A simulation of selective prophylaxis in women with negative chlamydia screening results showed that its selective use in patients with a history of gonorrhea or in nulliparous women with multiple sex partners could be nearly two thirds as effective as general prophylaxis.


Two decades of occupational (meth)acrylate patch test results and focus on isobornyl acrylate.
Acrylates constitute an important cause of occupational contact dermatitis. Isobornyl acrylate sensitization has been reported in only 2 cases. We encountered an industrial process operator with occupational contact dermatitis caused by isobornyl acrylate. (i) To investigate whether it is relevant to add isobornyl acrylate to the (meth)acrylate test series. (ii) To report patients with (meth)acrylate contact allergy at an occupational dermatology clinic. Our patch test database was screened for positive reactions to (meth)acrylates between 1993 and 2012. A selected group of 14 patients was tested with an isobornyl acrylate dilution series: 0.3%, 0.1%, 0.033%, and 0.01%. Readings were performed on D2, D3, and D7. One hundred and fifty-one patients were tested with our (meth)acrylate series; 24 had positive reactions. Most positive reactions were to 2-hydroxypropyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxypropyl methacrylate, and diethyleneglycol diacrylate. Hypothetical screening with 2-hydroxypropyl acrylate, ethyleneglycol dimethacrylate, ethoxylated bisphenol A glycol dimethacrylate and trimethylolpropane triacrylate identified 91.7% of the 24 patients. No positive reactions were observed in 14 acrylate-positive patients tested with the isobornyl acrylate dilution series. The 0.3% isobornyl acrylate concentration induced irritant reactions in 3 patients. We report a rare case of allergic contact dermatitis caused by isobornyl acrylate. However, this study provides insufficient support for isobornyl acrylate to be added to a (meth)acrylate series.


Residual force enhancement following eccentric induced muscle damage.
During lengthening of an activated skeletal muscle, the force maintained following the stretch is greater than the isometric force at the same muscle length. This is termed residual force enhancement (RFE), but it is unknown how muscle damage following repeated eccentric contractions affects RFE. Using the dorsiflexors, we hypothesised muscle damage will impair the force generating sarcomeric structures leading to a reduction in RFE. Following reference maximal voluntary isometric contractions (MVC) in 8 young men (26.5±2.8y) a stretch was performed at 30°/s over a 30° ankle excursion ending at the same muscle length as the reference MVCs (30° plantar flexion). Surface electromyography (EMG) of the tibialis anterior and soleus muscles was recorded during all tasks. The damage protocol involved 4 sets of 25 isokinetic (30°/s) lengthening contractions. The same measures were collected at baseline and immediately post lengthening contractions, and for up to 10min recovery. Following the lengthening contraction task, there was a 30.3±6.4% decrease in eccentric torque (P<0.05) and 36.2±9.7% decrease in MVC (P<0.05) compared to baseline. Voluntary activation using twitch interpolation and RMS EMG amplitude of the tibialis anterior remained near maximal without increased coactivation for MVC. Contrary to our hypothesis, RFE increased (∼100-250%) following muscle damage (P<0.05). It appears stretch provided a mechanical strategy for enhanced muscle function compared to isometric actions succeeding damage. Thus, active force of cross-bridges is decreased because of impaired excitation-contraction coupling but force generated during stretch remains intact because force contribution from stretched sarcomeric structures is less impaired.


Distribution of disease at autopsy in 100 women with ovarian cancer.
Clinical and morphologic factors that affected the distribution of disease are described in 100 cases of ovarian cancer at autopsy. In addition to the expected pattern of pelvic and abdominal peritoneal spread, extensive visceral parenchymal metastases were seen: liver parenchyma (45%), lung parenchyma (39%), small and large intestinal wall (52% and 55%), lymph nodes (70%), pancreas (21%), ureter (24%), bone (11%), and brain (6%). Liver parenchymal metastases replaced more than one third of the liver in 25% of cases, whereas lung metastases always involved less than one third of the lungs. When intestinal wall invasion was seen, bowel obstruction was present more often (71%) than when only intestinal serosa was involved (30%). Lymphatic invasion was predictive of lymph node, small intestinal wall, pancreatic, and liver as well as lung parenchymal metastases. Blood vessel invasion was predictive of pancreatic and ureteral metastases. Clinical stage I at diagnosis was associated with high incidences of liver parenchymal (56%), lymph node (56%), lung parenchymal (44%), large intestinal wall (33%), and bone (33%) metastases. Thus, ovarian cancer has parenchymal metastases similar to other carcinomas in addition to its peritoneal spread. Lymphatic and blood vessel invasion is predictive of such involvement. Intestinal wall invasion predicts bowel obstruction.


New insights into chronic inflammation-induced immunosuppression.
Chronic inflammation is a common factor linking various pathologies that differ in their etiology and physiology such as cancer, autoimmune diseases, and infections. At a certain stage of each of these diseases, while the chronic inflammation proceeds, some key players of the immune system become immunosuppressed as natural killer (NK) cells and T cells. The suppressive environment induced during chronic inflammation is governed by a complex processes characterized by the accumulation and activation of immune suppressor cells, pro-inflammatory cytokines, chemokines, growth and angiogenic factors, and by the activation of several inflammatory signaling pathways mediated predominantly by NFκB and STAT3 transcription factors. A substantial body of evidence supports the notion that the development of a suppressive environment during chronic inflammation limits the success of immune-based and conventional therapies, skewing the balance in favor of a developing pathology. Thus, appropriate, well-designed and fine tuned immune interventions that could resolve inflammatory responses and associated immunosuppression could enhance disease regression and reinforce successful responses to a given therapy. This review describes the interrelationship between chronic inflammation and induced immunosuppression, and explains the current evidence linking inflammation and pathological processes, as found in cancer. We further highlight potential strategies, harnessing the immunosuppressive environment in treating autoimmune diseases and facilitating transplantation. In parallel, we emphasize the use of modalities to combat chronic inflammation-induced immunosuppression in cancer, to enhance the success of immune-based therapies leading to tumor regression. In both cases, the urgent necessity of identifying biomarkers for the evaluation of host immune status is discussed, with the goal of developing optimal personalized treatments.


[Vitamin A status and the carcinogenic action of N-nitrosobenzyl methylamine on the esophagus in the rat].
A state of pure vitamin A deficiency, without any clinical manifestations, rapidly induces a stimulation of ornithine decarboxylase (ODC) activity and some oesophageal mucosal abnormalities (hyperkeratosis, dyskeratosis, cytonuclear abnormalities) in rats treated with N-nitrosobenzylmethylamine (NBMA). Retinol deficient rats fed with retinoïc acid (all-trans) show a mucosal ODC induction, but no morphological lesion. The association of retinoïc acid + retinol, as does retinol alone, prevents simultaneously histological lesions and enzymatic induction. In the liver of vitamin A deficient rats treated with NBMA, a stimulation of the ODC system, without any macroscopical lesions, has been observed.


Identification of rapid progression of right ventricular functional measures using three-dimensional cardiac computed tomography after total surgical correction of tetralogy of Fallot.
To identify subsets of patients with tetralogy of Fallot (TOF) after total surgical correction demonstrating the rapid progression of right ventricle (RV) functional measures using cardiac computed tomography (CT) ventricular volumetry. Rapid or slow progression of RV functional measures was determined in 109 patients with TOF who underwent cardiac CT ventricular volumetry more than twice after total surgical correction. Patient age, body surface area, postoperative days, the time interval between the first and last cardiac CT examinations, and CT-based functional measures were evaluated using binary logistic regression to determine the predictors of the rapid progression. Receiver operating characteristic curve analysis was performed to evaluate diagnostic performance of the potential predictors. The rapid progression of indexed RV end-systolic volume (ESV) (≥2.7 mL/m2/year) and indexed RV end-diastolic volume (≥0.9 mL/m2/year) could be predicted by RV ejection fraction (EF) at the last cardiac CT with an odds ratio of 1.340 (95 % confidence interval [CI], 1.122-1.600; p = 0.001) and age at the last cardiac CT with an odds ratio of 8.255 (95 % CI, 1.531-44.513; p = 0.014), respectively. RV EF at the last cardiac CT showed the highest diagnostic performance (area under the curve = 0.799; p < 0.002) for the rapid progression of indexed RV ESV. Cardiac CT ventricular volumetry can be used to identify patients demonstrating the rapid progression of RV functional measures after total surgical correction of TOF and follow-up imaging protocols can be individually optimized based on initial progression rate.


Pain Recognition in Reptiles.
Advances in reptile cognitive research would help to (1) better qualify behavioral responses to pain experiences, (2) monitor welfare impacts, and (3) model analgesic studies with ecologically relevant insight to better qualify interventional responses. The focus of future analgesic studies in reptiles require the continued elucidation of the opiate systems and the given variations across taxa in efficacy in nociceptive tests.


Coronary artery stent for securing pancreatico-jejunal anastomosis after PD: The "Huscher technique".
The "Medici effect" is known as the effect that arises when the intersection of interrelated disciplines manifests an enriching link for the involved disciplines in their own identity. To a certain extent, we think that the "Medici Effect" can be applied in any field; more specifically we applied this concept in pancreatic surgery. So, may we borrow coronary stents from cardiology to settle pancreatic-jejunostomy (PJ) issues after pancreaticoduodenectomy (PD)?


Electron microscopic study of the effects of thallium poisoning on the rat cerebellum.
Rats were given thallium acetate (5 mg elemental thallium/kg body weight) intra-peritoneally daily for 7 days. The brain was fixed by perfusion-fixation and small pieces of the cerebellum were processed for electron microscopy. Variegated mitochondrial profiles, increased incidence of electron--dense bodies and proliferation of Golgi zones were observed in the thallium--poisoned rat cerebellum. Multilamellar cytoplasmic bodies were discernible in the cerebellar cortex of the thallium-treated rats.


Vaterite crystals contain two interspersed crystal structures.
Calcite, aragonite, and vaterite are the three anhydrous polymorphs of calcium carbonate, in order of decreasing thermodynamic stability. Although vaterite is not commonly found in geological settings, it is an important precursor in several carbonate-forming systems and can be found in biological settings. Because of difficulties in obtaining large, pure, single crystals, the crystal structure of vaterite has been elusive for almost a century. Using aberration-corrected high-resolution transmission electron microscopy, we found that vaterite is actually composed of at least two different crystallographic structures that coexist within a pseudo-single crystal. The major structure exhibits hexagonal symmetry; the minor structure, existing as nanodomains within the major matrix, is still unknown.


Inpatient rehabilitation approach for a young woman with conversion hemiparesis and sensory deficits.
In the treatment of conversion disorder, the inpatient rehabilitation setting supports interdisciplinary functional goals and a structured approach consistent with encouraging psychological well-being. This case presentation illustrates 1 approach to the rehabilitation of hemiparesis secondary to conversion disorder that includes a behavioral management plan, as well as protocols for "learning to walk" and "learning to use your arm." We provide a practical starting point for advancing function in patients with conversion disorder when functional loss is present in both upper and lower extremities.


[Donnan equilibrium and kinetics of uric acid transport across human erythrocyte membrane].
The study of the effects of varying pH and ionic composition of external solution on the uric acid ratio (see article) for human erythrocytes at equilibrium and on its permeability constant shows that the distribution of uric acid agrees with the laws of the Gibbs-Donnan equilibrium and its passage across the human erythrocyte membrane with the law of ionic diffusion.


ABCC2 expression in papillary renal cell carcinoma provides better prognostic stratification than WHO/ISUP nucleolar grade.
Papillary renal cell carcinoma (PRCC) classification has traditionally been divided into two histologic types, type 1 and type 2. A new biological stratification system has recently been proposed based on comprehensive morphologic and genomic analysis. The predominant molecular marker in this 4-tiered stratification is the renal drug transporter ABCC2. In this study, we assessed and validated the value of the biological grouping in a PRCC cohort of 176 patients and provided a comprehensive assessment of clinicopathological variables. Tissue microarrays (TMAs) were constructed from nephrectomy specimens. The TMAs were stained with ABCC2 and GATA3 antibodies, and the PRCC cohort was stratified into four groups PRCC1-PRCC4: PRCC1 25%, PRCC2 37%, PRCC3 36%, and PRCC4 2%. PRCC1 demonstrated lower disease stage (p = 0.041) than PRCC2 and PRCC3. The biological stratification was significant on univariate analysis when analyzing both overall survival (p = 0.039) and disease-free survival (p = 0.011). The biological groups maintained the significance of predicting overall survival after adjusting for WHO/ISUP grade, age, pathological stage, and necrosis (p = 0.049, hazard ratio: 5.008, 95% confidence interval: 1.007 to 24.909). In contrast, WHO/ISUP grade did not maintain its significance on multivariate survival analysis. ABCC2 expression profile also separated cases ≤ 4 cm, based on disease-free survival (p = 0.038). None of the patients in the PRCC1 group died of disease during the follow-up period. The proposed biologic stratification adds molecular markers to the traditional morphologic assessment to better stratify patients' prognosis. ABCC2 expression can also potentially serve as a predictive biomarker owing to its known implication in cancer biology and drug resistance.


A whole cell immunization-derived monoclonal antibody that protects cells from coxsackievirus A9 infection binds to both cell surface and virions.
Coxsackievirus A9 (CAV-9) infects human rhabdomyosarcoma (RD) cells using an unidentified RGD-independent receptor. Monoclonal antibodies were prepared by immunizing mice with intact RD cells and by selecting cells from the cytopathic effect of CAV-9 for protection. Here we describe a monoclonal antibody that binds to host cell plasma membrane and protects cells from virus infection. In addition, binding of the virus to cell monolayers was more efficient in the presence of the antibody, suggesting that the antibody is also capable of recognizing virus particles. Immunoprecipitation and electron microscopy studies with highly purified virus preparations verified binding of the monoclonal antibody to the virus particles. The antibody also recognized coxsackievirus A21 and all three serotypes of poliovirus, but without affecting their infectivity. The amino acid sequence of CAV-9 recognized by the monoclonal antibody was identified by peptide mapping and by producing escape mutants in the presence of the antibody.


The anteroposterior pericardial sac diameter measured by echocardiography correlates with the volume of pericardial effusion and with effort dyspnea.
To examine the value of the anteroposterior pericardial sac diameter (APD) for prediction of the volume of pericardial effusion. We measured the APD by echocardiography before 52 pericardiocentesis procedures and correlated it with the aspirate volume, etiology, symptoms, and clinical outcome. The volume of the aspirate ranged from 60 to 2300 ml (median 650 ml). The APD (range 8.0 cm-15.9 cm, median 12 cm) correlated well with the cubic root of the volume of the effusion [volume=(0.8APD-0.6)3, r2=0.533, p<0.01]. An APD>or=12 cm had a positive predictive value of 88% and a negative predictive value of 83% for effusion volume above the sample median (>or=650 ml) and a positive predictive value of 100% for effusion in the middle or upper aspirate volume tertiles. Effort dyspnea was more common among patients with APD>or=12.0 cm (n=13) than in those with APD<12.0 cm (n=11) (p=0.007). One-year survival after pericardiocentesis was closely related to the severity of the underlying etiology and was not influenced by the volume of the effusion before aspiration. The APD is a simple, valuable method for non-invasive prediction of pericardial fluid volume. A greater APD is associated with, and may explain, effort dyspnea.


Allelic frequency of the MCP-1 promoter -2518 polymorphism in the Turkish population and in Turkish patients with juvenile rheumatoid arthritis.
Although genetic and environmental factors contribute to the pathogenesis of juvenile rheumathoid arthritis (JRA), the etiology and pathogenesis remain controversial. The objective of this study was to investigate genotypic and allelic frequencies of monocyte chemoattractant protein-1 (MCP-1) gene -2518 (G/A) polymorphism in the healthy Turkish population and patients with JRA. Genomic DNA was collected from 66 JRA patients and 150 healthy individuals. To evaluate the association of the -2518 (G/A) MCP-1 gene polymorphism with the outcome of JRA, we analyzed the types of JRA and the score on the childhood health assessment questionnaire (C-HAQ score). In the healthy Turkish population, the frequencies of A and G alleles were 71 and 29%, respectively. No significant difference was observed between the JRA patients and healthy subjects in the distribution allelic and genotypic frequencies of the -2518 (G/A) MCP-1 gene polymorphism (p>0.05). However, the AG genotype was found to be higher and the AA genotype was found to be lower in the patients with systemic type JRA compared to those with the other types of JRA (p=0.019). When the JRA patients were evaluated according to the C-HAQ score, we found that the -2518 (G/A) MCP-1 gene polymorphism did not relate the prognosis (p>0.05). AG genotype was found to be higher in the systemic type of JRA. The results indicate that MCP-1 gene polymorphism might slightly associate with patients with systemic JRA. Further studies are needed to elucidate the role of this polymorphism in the pathogenesis of JRA in various populations because this polymorphism has a functional significance and an ethnic difference.


A food-web model as a tool for the ecosystem-level management of bivalves in an Atlantic coastal lagoon.
The Ria de Aveiro is an important coastal lagoon for wildlife in Portugal, where the production of bivalves reaches approximately 2700 tons annually. However, the illegal overfishing of bivalves is frequent in this lagoon, which causes critical changes in the ecosystem. In this study, using a developed food-web model (Ecopath model), the ecological carrying capacity (ECC) and maximum sustained yield (MSY) of the Manila clam, Ruditapes philippinarum were estimated, and the effects of further increases in clam biomass on other species were investigated. The results showed that 1) the current biomass and legal catch of R. philippinarum do not yet exceed the ECC (172.40 tons km-2) or the MSY (86.20 tons km-2 year-1) in Ria de Aveiro; 2) the harvested Manila clams of the MSY represent removing from the ecosystem ∼ 581 tons carbon (C) and ∼83 tons nitrogen (N) annually, with substantial ecological and economic implications; and 3) a further increase in the biomass levels of this species may cause the ecotrophic efficiency of other groups to become unrealistic, potentially leading to decreases in ecosystem transfer efficiency, biodiversity and health. The results here are expected to guide the sustainable development and management of bivalve aquaculture in Ria de Aveiro and the protection of the local environment.


Origin and Functional Evolution of the Cdc48/p97/VCP AAA+ Protein Unfolding and Remodeling Machine.
The AAA+ Cdc48 ATPase (alias p97 or VCP) is a key player in multiple ubiquitin-dependent cell signaling, degradation, and quality control pathways. Central to these broad biological functions is the ability of Cdc48 to interact with a large number of adaptor proteins and to remodel macromolecular proteins and their complexes. Different models have been proposed to explain how Cdc48 might couple ATP hydrolysis to forcible unfolding, dissociation, or remodeling of cellular clients. In this review, we provide an overview of possible mechanisms for substrate unfolding/remodeling by this conserved and essential AAA+ protein machine and their adaption and possible biological function throughout evolution.


Autofluorescence spectroscopy in liver transplantation: preliminary results from a pilot clinical study.
The evaluation of graft function at various stages after transplantation is relevant, particularly at the moment of organ harvest, when a decision must be made whether to use the organ. Autofluorescence spectroscopy is noninvasive technique to monitor the metabolic condition of a liver graft throughout its course, from an initial evaluation in the donor, through cold ischemia transportation, to reperfusion and reoxygenation in the recipient. Preliminary results are presented in six liver transplantations spanning the periods from liver harvest to implant. The laser-induced fluorescence spectrum at 532-nm excitation was investigated before cold perfusion (autofluorescence), during cold ischemia, at the back table procedure, as well as 5 and 60 minutes after reperfusion. The results showed that the fluorescence analysis was sensitive to changes during the transplantation procedure. Fluorescence spectroscopy potentially provides a real-time, noninvasive technique to monitor liver graft function. The information could potentially be valuable for surgical decisions and transplant success.


Towards health equity: core components of an extended home visiting intervention in disadvantaged areas of Sweden.
Understanding the mechanisms of implementation of public health interventions in community settings is a key aspect of programme assessments. To determine core components and establish a programme theory are important tools to improve functioning and support dissemination of programme models to new locations. An extended early childhood home visiting intervention has been developed on-site in a socioeconomically disadvantaged area of Sweden since 2013 with the aim of reducing persisting health inequities in the population. This study aimed at investigating the core programme components and how the intervention was perceived to contribute towards health equity from early childhood. Qualitative framework method was applied in a document analysis and subsequent semi-structured interviews with 15 key actors involved in the programme. The intervention was found to be constituted of five core components centred around the situation-based, parental strengthening work method delivered by a qualified team of child health care nurse and social worker. The programme theory foresaw positive effects on child and parental health, responsive parenting practices, families' use of welfare services according to need and increased integration and participation in society. The principles of Proportionate Universalism were recognised in the programme theory and the intervention was perceived as an important contribution to creating conditions for improved health equity for the families. Still, barriers to health equity were identified on the structural level which limit the potential impact of the programme. The core components of the Extended home visiting programme in Rinkeby correspond well to those of similar evidence-based home visiting interventions. Combining focus on early childhood development and responsive parenting with promoting access to the universal welfare services and integration into society are considered important steppingstones towards health equity. However, a favourable macro-political environment is required in the endeavour to balance the structural determinants' influence on health inequities. Improved availability and accessibility to welfare services that respond to the needs of the families regarding housing, education and employment are priorities. The study was retrospectively registered on 11/08/2016 in the ISRCTN registry ( ISRCTN11832097 ).


Engineering the thermostability of d-lyxose isomerase from Caldanaerobius polysaccharolyticus via multiple computer-aided rational design for efficient synthesis of d-mannose.
d-Mannose is an attractive functional sugar that exhibits many physiological benefits on human health. The demand for low-calorie sugars and sweeteners in foods are increasingly available on the market. Some sugar isomerases, such as d-lyxose isomerase (d-LIase), can achieve an isomerization reaction between d-mannose and d-fructose. However, the weak thermostability of d-LIase limits its efficient conversion from d-fructose to d-mannose. Nonetheless, few studies are available that have investigated the molecular modification of d-LIase to improve its thermal stability. In this study, computer-aided tools including FireProt, PROSS, and Consensus Finder were employed to jointly design d-LIase mutants with improved thermostability for the first time. Finally, the obtained five-point mutant M5 (N21G/E78P/V58Y/C119Y/K170P) showed high thermal stability and catalytic activity. The half-life of M5 at 65 °C was 10.22 fold, and the catalytic efficiency towards 600 g/L of d-fructose was 2.6 times to that of the wild type enzyme, respectively. Molecular dynamics simulation and intramolecular forces analysis revealed a thermostability mechanism of highly rigidity conformation, newly formed hydrogen bonds and π-cation interaction between and within protein domains, and redistributed surface electrostatic charges for the mutant M5. This research provided a promising d-LIase mutant for the industrial production of d-mannose from d-fructose.


Synthesis and Antimicrobial Activity of Methoxy- Substituted γ-Oxa-ε-lactones Derived from Flavanones.
Six γ-oxa-ε-lactones, 4-phenyl-3,4-dihydro-2H-1,5-benzodioxepin-2-one (5a) and its five derivatives with methoxy groups in different positions of A and B rings (5b-f), were synthesized from corresponding flavanones. Three of the obtained lactones (5b,c,f) have not been previously described in the literature. Structures of all synthesized compounds were confirmed by complete spectroscopic analysis with the assignments of signals on 1H and 13C-NMR spectra to the corresponding atoms. In most cases, lactones 5a-f exerted an inhibitory effect on the growth of selected pathogenic bacteria (Escherichia coli, Bacillus subtilis, and Staphylococcus aureus), filamentous fungi (Fusarium graminearum, Aspergillus niger, and Alternaria sp.), and yeast (Candida albicans). The broadest spectrum of activity was observed for unsubstituted lactone 5a, which was particularly active against filamentous fungi and yeast. Lactones with methoxy groups in the 3' (5c) and 4' (5d) position of B ring were more active towards bacteria whereas lactone substituted in the 7 position of the A ring (5e) exhibited higher antifungal activity. In most cases, the introduction of lactone function increased the activity of the compound compared to its flavonoid precursors, chalcones 3a-e, and flavanones 4a-f.