Anterior gradient 2 is correlated with EGFR mutation in lung adenocarcinoma tissues.
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) has demonstrated a promising therapeutic response in lung adenocarcinoma patients with EGFR gene mutations. However, the predictive factors for this therapy have not been established, except for the EGFR gene mutation status of carcinoma cells. We first performed microarray analysis in EGFR-TKI-sensitive lung adenocarcinoma cell lines. The results indicated anterior gradient 2 (AGR2) as a potential surrogate marker of EGFR-TKI. Therefore, we then evaluated the correlation between the status of AGR2 immunoreactivity and clinicopathological factors including overall survival (OS), progression-free survival (PFS) and clinical response to EGFR-TKI, in 147 cases of surgically resected lung adenocarcinoma. The biological significance of AGR2 was further evaluated by transfecting small interfering RNA (siRNA) against AGR2 in these cells. The status of AGR2 immunoreactivity was significantly higher in lung adenocarcinoma cases with EGFR gene mutations than in those with the wild type (p<0.0001), but there were no significant differences in OS, PFS and response of EGFR-TKI between the AGR2 high and low carcinoma cases. Knockdown of AGR2 gene expression following siRNA transfection resulted in a significantly lower response to EGFR-TKI in EGFR-mutated PC-3. AGR2 could serve as an adjunctive surrogate protein marker possibly reflecting EGFR gene mutations in lung adenocarcinoma patients. Results from in vitro analysis indicated that AGR2 could be a potential clinical biomarker of EGFR-TKI therapeutic sensitivity in lung adenocarcinoma cells.


Hormonal mechanism of sodium oleate-stimulated pancreatic secretion in rats.
We have investigated the role of two intestinal hormones, secretin and cholecystokinin (CCK), on the pancreatic exocrine secretion stimulated by sodium oleate in anesthetized rats. Each rat was prepared with a polyethylene tube in the proximal duodenum and ligation of the pylorus. To collect pancreatic juice, the common bile-pancreatic duct was cannulated near the duodenal wall while bile was diverted to the exterior. Intraduodenal infusion of sodium oleate at doses of 0.03, 0.06, 0.12, and 0.24 mmol/h resulted in significant increases in pancreatic secretion including fluid, bicarbonate, and protein output. The increases of the three parameters were dose dependent and were correlated well with the increases in plasma secretin and CCK concentrations. To further clarify their hormonal roles, we have repeated identical experiments under intravenous administration of a rabbit anti-secretin serum (0.1 ml) or CR 1409 (4 mg.kg-1.h-1), a CCK-receptor antagonist, or a combination of both the antiserum and CR 1409. The antiserum significantly suppressed volume flow and bicarbonate secretion with a minor inhibitory effect on protein secretion, whereas a normal rabbit serum did not. CR 1409 significantly suppressed all three parameters. The combined treatment with both the antiserum and CR 1409 almost completely abolished the pancreatic secretion. Atropine given intravenously significantly inhibited the protein output but did not influence volume flow or bicarbonate output in response to sodium oleate. We thus conclude that, in rats, fat-stimulated pancreatic secretion of volume flow and bicarbonate depends entirely on the circulating endogenous secretin and CCK but that the protein output appears to be under control of both hormonal and cholinergic controls.


Progress in teaching physician-patient communication in medical school; personal observations and experience of a medical educator.
In spite of the enormous progress of Western medicine during the past century there has not be a concomitant rise in the public's satisfaction with the medical profession. Much of the discontent relates to problems in physician-patient communication. The multiple advantages of good communication have been clearly demonstrated by numerous careful studies. While the past few decades have witnessed much more attention given to teaching communication skills in medical schools, there are a number of factors that create new problems in physician-patient communication and counteract the positive teaching efforts. The "hidden curriculum", the increased emphasis on technology, the greater time pressures, and the introduction of the computer in the interface between physician and patient present new challenges for the teaching of physician-patient communication.


Adhesion molecules during somitogenesis in the avian embryo.
In avian embryos, somites constitute the morphological unit of the metameric pattern. Somites are epithelia formed from a mesenchyme, the segmental plate, and are subsequently reorganized into dermatome, myotome, and sclerotome. In this study, we used somitogenesis as a basis to examine tissue remodeling during early vertebrate morphogenesis. Particular emphasis was put on the distribution and possible complementary roles of adhesion-promoting molecules, neural cell adhesion molecule (N-CAM), N-cadherin, fibronectin, and laminin. Both segmental plate and somitic cells exhibited in vitro calcium-dependent and calcium-independent systems of cell aggregation that could be inhibited respectively by anti-N-cadherin and anti-N-CAM antibodies. In vivo, the spatio-temporal expression of N-cadherin was closely associated with both the formation and local disruption of the somites. In contrast, changes in the prevalence of N-CAM did not strictly accompany the remodeling of the somitic epithelium into dermamyotome and sclerotome. It was also observed that fibronectin and laminin were reorganized secondarily in the extracellular spaces after CAM-mediated contacts were modulated. In an in vitro culture system of somites, N-cadherin was lost on individual cells released from somite explants and was reexpressed when these cells reached confluence and established intercellular contacts. In an assay of tissue dissociation in vitro, antibodies to N-cadherin or medium devoid of calcium strongly and reversibly dissociated explants of segmental plates and somites. Antibodies to N-CAM exhibited a smaller disrupting effect only on segmental plate explants. In contrast, antibodies to fibronectin and laminin did not perturb the cohesion of cells within the explants. These results emphasize the possible role of cell surface modulation of CAMs during the formation and remodeling of some transient embryonic epithelia. It is suggested that N-cadherin plays a major role in the control of tissue remodeling, a process in which N-CAM is also involved but to a lesser extent. The substratum adhesion molecules, fibronectin and laminin, do not appear to play a primary role in the regulation of these processes but may participate in cell positioning and in the stabilization of the epithelial structures.


Short-Term Anterior Segment Changes After Nd-YAG Laser Posterior Capsulotomy in Pseudophakic Eyes with Fuchs' Endothelial Dystrophy.
To describe the changes in the central corneal thickness (CCT), endothelial cell count (ECC), intraocular lens (IOL) position, and refractive error 1 and 3 months after Nd-YAG laser posterior capsulotomy (YAG-PC) for posterior capsular opacification (PCO) in pseudophakic eyes with Fuchs' endothelial cell dystrophy (FECD). Prospective case-control. Fifty pseudophakic eyes of 50 patients with visually significant PCO (25 with healthy corneas, and 25 with FECD grade 1 and 2). FECD was clinically graded, and only patients without clinically evident corneal edema were included in the study (grade 1 and 2). All patients received YAG-PC and were followed up after 1 and 3 months. Best-corrected visual acuity, refractive errors, ACD, CCT, and ECC were assessed and compared between the pre-laser values and that of the 2 follow-up visits. In both groups, BCVA showed significant improvement (P<0.05). Compared to healthy controls, a significant hyperopic shift was observed in the FECD eyes at the 2 follow-up visits (P=0.027, and 0.019). A significant backward movement of the IOL was observed in the FECD eyes in the 2 follow-up visits (P=0.043, and 0.02). There was a significant correlation between the hyperopic shift in the FECD eyes and the ACD deepening during the 1st month (R= -0.6, P=0.001) and 3rd month (R= -0.4, P=0.04). Significant drop in the ECC was noted in both groups but without significant increase in the CCT. Compared to controls, a hyperopic shift and backward movement of the IOL were observed in the FECD eyes after YAG-PC. No significant corneal thickening was found in both groups despite the significant drop in the ECC. Future studies are required to confirm our results and monitor the long-term changes after YAG-PC in FECD.


[Chromosome 18 long-arm deletion. Report of 1 case].
Authors report a ten month old girl with multiple malformations: midfacial hypoplasia, hypertelorism, carp mouth, very marked antihelix, poor muscular tone, spindle-shaped fingers with a high frequency of whirles and low levels of serum immunoglobulin A. In leukocyte culture, patient shows a deletion of the long arm of a 18 chromosome.


Directed evolution of a cellobiose utilization pathway in Saccharomyces cerevisiae by simultaneously engineering multiple proteins.
The optimization of metabolic pathways is critical for efficient and economical production of biofuels and specialty chemicals. One such significant pathway is the cellobiose utilization pathway, identified as a promising route in biomass utilization. Here we describe the optimization of cellobiose consumption and ethanol productivity by simultaneously engineering both proteins of the pathway, the β-glucosidase (gh1-1) and the cellodextrin transporter (cdt-1), in an example of pathway engineering through directed evolution. The improved pathway was assessed based on the strain specific growth rate on cellobiose, with the final mutant exhibiting a 47% increase over the wild-type pathway. Metabolite analysis of the engineered pathway identified a 49% increase in cellobiose consumption (1.78 to 2.65 g cellobiose/(L · h)) and a 64% increase in ethanol productivity (0.611 to 1.00 g ethanol/(L · h)). By simultaneously engineering multiple proteins in the pathway, cellobiose utilization in S. cerevisiae was improved. This optimization can be generally applied to other metabolic pathways, provided a selection/screening method is available for the desired phenotype. The improved in vivo cellobiose utilization demonstrated here could help to decrease the in vitro enzyme load in biomass pretreatment, ultimately contributing to a reduction in the high cost of biofuel production.


Adolescents and young adults with brain tumors in the context of molecular advances in neuro-oncology.
Adolescents and young adults (AYA) comprise a specific group of oncology patients with a distinct biological and epidemiological spectrum of central nervous system neoplasms. It has been well documented that they differ clinically, especially in relation to prognosis and chemotherapy tolerance; however, the underlying reasons for this are unclear. Recent advances in the genomics of both childhood and adult brain tumors have provided new explanations and insights into the previously described age-dependent heterogeneity. Herein, we summarize the current state of the AYA population in neuro-oncology, specifically how biological advances can help personalize therapy for this unique group of patients.


Prenatal MR imaging of the normal pituitary stalk.
Prenatal imaging data of the normal pituitary gland and in vivo information on the development of the pituitary region are lacking; however, we noticed that the pituitary stalk (PS) is visible occasionally in utero on MR images. Our main purpose was to establish the detection rate of the PS in healthy fetuses at various gestational ages (GAs) by using single-shot fast spin-echo T2-weighted images. We selected 73 fetal cases with normal findings on prenatal MR imaging and clinical postnatal follow-up. The GA ranged between 19 and 37 weeks. The 3 planes of MR imaging sections were 4 mm thick with 1.25 x 1.25 mm in-plane resolution. Two pediatric neuroradiologists evaluated in consensus whether the PS was present as a linear isointense structure connecting the hypothalamic region with the floor of sella turcica. In those cases in which the PS was visible on the sagittal section, the angle formed by the intersection of the PS and the sellar plane (SP) was measured (PS-SP angle). The PS was detectable on at least 1 coronal or sagittal section from 19 to 25 weeks' GA in 30/42 fetuses (71.4% sensitivity); from 26 to 37 weeks' GA, the PS was detected in all 31 fetuses (100% sensitivity). The PS-SP angle decreased significantly with GA, being <90 degrees in all fetuses after gestational week 25. At the current spatial resolution of clinical prenatal MR imaging, PS can be reliably detected after 25 weeks' GA, so in case of a missing visualization, a strong suspicion of pituitary region anomaly could be raised.


PDGF/PDGFR: A Possible Molecular Target in Scleroderma Fibrosis.
Systemic sclerosis (SSc) is a clinically heterogeneous disorder of the connective tissue characterized by vascular alterations, immune/inflammatory manifestations, and organ fibrosis. SSc pathogenesis is complex and still poorly understood. Therefore, effective therapies are lacking and remain nonspecific and limited to disease symptoms. In the last few years, many molecular and cellular mediators of SSc fibrosis have been described, providing new potential options for targeted therapies. In this review: (i) we focused on the PDGF/PDGFR pathway as key signaling molecules in the development of tissue fibrosis; (ii) we highlighted the possible role of stimulatory anti-PDGFRα autoantibodies in the pathogenesis of SSc; (iii) we reported the most promising PDGF/PDGFR targeting therapies.


Combat experience and the acquired capability for suicide.
Rising suicide rates are an increasing concern among military personnel. The interpersonal-psychological theory of suicide proposes that three necessary factors are needed to die by suicide: feelings that one does not belong with other people, feelings that one is a burden on others or society, and an acquired capability to overcome the fear and pain associated with suicide. The current study tests the theory's proposal that acquired capability may be particularly influenced by military experience, because combat exposure may cause habituation to fear of painful experiences such as suicide. Utilizing clinical and nonclinical samples of military personnel deployed to Iraq, results of the current study indicate that a greater range of combat experiences predicts acquired capability above and beyond depression and post-traumatic stress disorder symptoms, previous suicidality, and other common risk factors for suicide. Combat experiences did not, however, predict perceived burdensomeness or thwarted belongingness. The authors discuss how combat experiences might serve as a mechanism for elevating suicide risk and implications for clinical interventions and suicide prevention efforts.


Symbiotic bacteria confer insecticide resistance by metabolizing buprofezin in the brown planthopper, Nilaparvata lugens (Stål).
Buprofezin, a chitin synthesis inhibitor, is widely used to control several economically important insect crop pests. However, the overuse of buprofezin has led to the evolution of resistance and exposed off-target organisms present in agri-environments to this compound. As many as six different strains of bacteria isolated from these environments have been shown to degrade buprofezin. However, whether insects can acquire these buprofezin-degrading bacteria from soil and enhance their own resistance to buprofezin remains unknown. Here we show that field strains of the brown planthopper, Nilaparvata lugens, have acquired a symbiotic bacteria, occurring naturally in soil and water, that provides them with resistance to buprofezin. We isolated a symbiotic bacterium, Serratia marcescens (Bup_Serratia), from buprofezin-resistant N. lugens and showed it has the capacity to degrade buprofezin. Buprofezin-susceptible N. lugens inoculated with Bup_Serratia became resistant to buprofezin, while antibiotic-treated N. lugens became susceptible to this insecticide, confirming the important role of Bup_Serratia in resistance. Sequencing of the Bup_Serratia genome identified a suite of candidate genes involved in the degradation of buprofezin, that were upregulated upon exposure to buprofezin. Our findings demonstrate that S. marcescens, an opportunistic pathogen of humans, can metabolize the insecticide buprofezin and form a mutualistic relationship with N. lugens to enhance host resistance to buprofezin. These results provide new insight into the mechanisms underlying insecticide resistance and the interactions between bacteria, insects and insecticides in the environment. From an applied perspective they also have implications for the control of highly damaging crop pests.


Azide-Alkyne Click Conjugation on Quantum Dots by Selective Copper Coordination.
Functionalization of nanocrystals is essential for their practical application, but synthesis on nanocrystal surfaces is limited by incompatibilities with certain key reagents. The copper-catalyzed azide-alkyne cycloaddition is among the most useful methods for ligating molecules to surfaces, but has been largely useless for semiconductor quantum dots (QDs) because Cu+ ions quickly and irreversibly quench QD fluorescence. To discover nonquenching synthetic conditions for Cu-catalyzed click reactions on QD surfaces, we developed a combinatorial fluorescence assay to screen >2000 reaction conditions to maximize cycloaddition efficiency while minimizing QD quenching. We identify conditions for complete coupling without significant quenching, which are compatible with common QD polymer surfaces and various azide/alkyne pairs. Based on insight from the combinatorial screen and mechanistic studies of Cu coordination and quenching, we find that superstoichiometric concentrations of Cu can promote full coupling if accompanied by ligands that selectively compete with the Cu from the QD surface but allow it to remain catalytically active. Applied to the conjugation of a K+ channel-specific peptidyl toxin to CdSe/ZnS QDs, we synthesize unquenched QD conjugates and image their specific and voltage-dependent affinity for K+ channels in live cells.


NF2/Merlin suppresses proliferation and induces apoptosis in colorectal cancer cells.
Merlin ((Moesin-ezrin-radixin-like protein, also known as schwannomin) is a tumor suppressor protein which is encoded by the neurofibromatosis type 2 gene, NF2. Loss of function mutations or deletions in NF2 which normally restrains tumor growth, leads to the formation of multiple tumors including schwannoma, meningioma and ependymoma. We tested whether NF2/Merlin is expressed and exerts similar control on proliferation of colorectal cancer cells and modulates the rate of their apoptosis. Expression of NF2/Merlin was reduced in colorectal cancer cells as compared with adjacent non-cancerous cells. Overexpression of NF2 inhibited colony formation by tumor cells and inhibited proliferation of cancer cells both in vitro and in vivo. The rate of apoptosis was also increased in colorectal cancer cells by overexpression of NF2. These findings show that NF2/Merlin is also reduced in tumors that do not arise in the context of neurofibromatosis and that induction of its expression might be used to control tumor growth.


Plantar Reconstruction Using a Dermal Substitute: Description of 2 Cases.
Acral lentiginous melanoma is the most common subtype among melanomas on the foot. Reconstruction of a wide surgical defect once it is excised may result in a challenge that requires replacing the lost tissue with another tissue having similarly unique physical characteristics. Although reconstructive options such as skin grafts and either local or distant flaps offer adequate coverage, they often are subject of contraction, muscle atrophy, and contour abnormalities. Dermal substitutes provide support and structure and recreates the dermal layer to ensure a durable reconstruction. We report 2 cases of plantar melanoma in which adequate reconstruction was achieved using a dermal substitute.


Clear Cell Renal Cell Carcinoma With Syncytial-Type Multinucleated Giant Tumor Cells: A Clinicopathologic Study of 14 Cases.
The presence of syncytial-type multinucleated giant tumor cells with emperipolesis in clear cell renal cell carcinoma (RCC) is uncommon, with only 31 cumulative published cases to date. After a rereview of 125 clear cell RCC of World Health Organization/International Society of Urological Pathology grade 3 or 4, 14 clear cell RCCs with admixed syncytial-type giant cells (to our knowledge, the largest series to date) were found with a mean patient age of 67 years and with no sex difference (M = 7, F = 7). Mean tumor size was 7.3 cm. The syncytial-type giant cells comprised between 2% and 20% of the tumor and were present mainly around areas of necrosis. Five tumors were staged as pT1 or pT2, 8 as pT3, and 1 as pT4. Other findings included sarcomatoid differentiation (3/14), rhabdoid differentiation (4/14), and emperipolesis (12/14). Positive immunostains included keratin AE1/AE3 (13/13), carbonic anhydrase 9 and CD10 (12/14 each), vimentin (8/14), EMA (5/12), and alpha-methyacyl-CoA racemase (3/12). Keratin 7, keratin 20, human melanoma black 45, KIT, TFE3, cathepsin K, CD68, CD61, and beta human chorionic gonadotropin were negative. Six of 13 patients had recurrence or metastases during a mean follow-up time of 56 months. Four of 13 patients died of disease, 2 of 13 patients were alive with the disease, and 7 of 13 patients had no evidence of disease. Although the incidence of finding syncytial-type multinucleated giant tumor cells in clear cell RCC is low (approximately 1.2%), given that a subset of the patients showed poor outcomes while lacking other poor histologic parameters (eg, sarcomatoid or rhabdoid differentiation), it may be prudent to recognize and report this feature when encountered.


An improved biologically transparent illumination system that increases the accuracy of detecting the correct position of a nasogastric tube in the stomach.
The aim of this study was to determine whether an improved biologically transparent illumination system results in more reliable detection of the correct position of the nasogastric tube in surgical patients. In total, 102 patients undergoing general surgery were included in this prospective observational study. After general anesthesia, all patients were inserted a nasogastric tube equipped with an improved biologically transparent illumination catheter. Identification of biologically transparent light in the epigastric area indicated successful insertion of the nasogastric tube into the stomach. The position of the tube was confirmed by X-ray examination, and its findings were compared with those of the biologically transparent illumination system. We observed biologically transparent light in epigastric area in 87 of the 102 patients. X-ray examination revealed that the nasogastric tube was placed in the stomach in all of these 87 patients. Light was not observed in the remaining 15 patients; the tube position was confirmed in the stomach in 11 of these patients but not in the other 4 by X-ray examination. Illumination had a sensitivity of 88.8% and a specificity of 100%. Our results suggest that this improved biologically transparent illumination system increased the accuracy of detecting the correct position of a nasogastric tube in the stomach. X-ray examination is required to check the position of the nasogastric tube in patients when biologically transparent illumination light is negative.


Outcomes following proton therapy for pediatric esthesioneuroblastoma.
Pediatric esthesioneuroblastoma (EN) can infiltrate skull base anatomy, presenting challenges due to high radiation doses and pediatric tissue sensitivity. This study reports outcomes of pediatric EN treated with proton radiotherapy (PT). Using an IRB-approved prospective outcomes registry, we evaluated patient, tumor, and treatment-related variables impacting disease control and toxicity in pediatric nonmetastatic EN treated with modern multimodality therapy, including PT. Fifteen consecutive patients (median age 16) comprising Kadish stage B (n = 2), C (n = 9), and D (n = 4) tumors were assessed, including six with intracranial involvement, four with cranial nerve deficits, and four with cervical lymphadenopathy. Before radiation, two had subtotal and 13 had gross total resections (endoscopic or craniofacial). Two underwent neck dissection. Eleven received chemotherapy before radiation (n = 5), concurrent with radiation (n = 4), or both (n = 2). Median total radiation dose (primary site) was 66 Gy/CGE for gross disease and 54 Gy/CGE (cobalt Gray equivalent) for microscopic disease. Median follow-up was 4.8 years. No patients were lost to follow-up. Five-year disease-free and overall survival rates were 86% (no local or regional recurrences). Two patients developed vertebral metastases and died. Two required a temporary feeding tube for oral mucositis/dysphagia. Late toxicities included symptomatic retinopathy, major reconstructive surgery, cataracts, chronic otitis media, chronic keratoconjunctivitis, hypothyroidism, and in-field basal cell skin cancer. A multimodality approach for pediatric EN results in excellent local control. Despite the moderate-dose PT, serious radiation toxicity was observed; further dose and target volume reductions may benefit select patients. Longer follow-up and comparative data from modern photon series are necessary to fully characterize any relative PT advantage.


Adjuvant therapy for gallbladder and bile duct cancers: retrospective comparative study.
To study the efficacy of adjuvant therapy (chemotherapy and radiotherapy) in early stages (I-III) of gallbladder and bile duct cancers. The clinical and pathological characteristics, treatment details and survival data of patients operated with early stages (I-III) of gallbladder and bile duct cancers and followed up in our clinic between August 2002 - November 2009 were retrospectively evaluated. 52 patients (median age 64 years) with early stages of gallbladder (n=36) and bile duct (n=16) cancers were analysed. Twenty-three (44.2%) patients had stage I, 23 (44.2%) stage II, and 6 (11.5%) stage III cancers. Approximately half of the patients (n=25; 48.1%) received postoperative adjuvant chemotherapy and/or radiotherapy. Patients with adjuvant treatment were younger than those without (62 vs. 71 years, p=0.06). Eighteen patients received chemotherapy alone, 2 chemotherapy followed by radiotherapy, 1 chemotherapy concurrently with radiotherapy, and 4 radiotherapy alone as adjuvant therapy. The regimen most frequently used (57.1%) was CFF (cisplatin 50 mg/m(2), day 1; folinic acid 200 mg/m(2), day 1; 5-fluorouracil [5-FU] 400 mg/m(2) bolus day 1 and 1600 mg/m(2) 48h continuous infusion). Some poor prognostic factors like high tumor grade and vascular invasion were more frequent in patients who received adjuvant therapy. The median disease free survival (DFS) was 11.4 months for the patients that received adjuvant therapy vs. 8.2 months for those without adjuvant therapy (p=0.67). During follow up 11 patients (44.0%) with adjuvant therapy and 12 (44.4%) without have died (p=0.97). The estimated median survival was 29 months. Although previous studies had shown that 5-FU-based adjuvant chemotherapy may provide a small survival advantage, this was not confirmed in the present study. Prospective adjuvant trials with a standard chemotherapy regimen and larger numbers of patients are required.


A voice-controlled robotic assistant for neuroendoscopy.
This paper describes experiments with a voice-controlled robot system to be used in endoscopic neurosurgery. The robot was a modified version of the robot described in previous publications of the group at Fraunhofer IPA and HSK. To control the robot a voice-controlled user interface was developed. The experiments were conducted on cadavers for three standard approaches in neuroendoscopy. The goal was to gain experience with a voice-controlled user interface and also with the set-up and use of the robotic system under clinical conditions. The results indicate that modifications to the robot and user interface are necessary. However the overall feasibility of the application was demonstrated.


Nuclear resonance vibrational spectroscopy reveals the FeS cluster composition and active site vibrational properties of an O2-tolerant NAD+-reducing [NiFe] hydrogenase.
Hydrogenases are complex metalloenzymes that catalyze the reversible splitting of molecular hydrogen into protons and electrons essentially without overpotential. The NAD+-reducing soluble hydrogenase (SH) from Ralstonia eutropha is capable of H2 conversion even in the presence of usually toxic dioxygen. The molecular details of the underlying reactions are largely unknown, mainly because of limited knowledge of the structure and function the various metal cofactors present in the enzyme. Here all iron-containing cofactors of the SH were investigated by 57Fe specific nuclear resonance vibrational spectroscopy (NRVS). Our data provide experimental evidence for one [2Fe2S] center and four [4Fe4S] clusters, which is consistent with amino acid sequence composition. Only the [2Fe2S] cluster and one of the four [4Fe4S] clusters were reduced upon incubation of the SH with NADH. This finding explains the discrepancy between the large number of FeS clusters and the small amount of FeS cluster-related signals as detected by electron paramagnetic resonance spectroscopic analysis of several NAD+-reducing hydrogenases. For the first time, Fe-CO and Fe-CN modes derived from the [NiFe] active site could be distinguished by NRVS through selective 13C labeling of the CO ligand. This strategy also revealed the molecular coordinates that dominate the individual Fe-CO modes. The present approach explores the complex vibrational signature of the Fe-S clusters and the hydrogenase active site, thereby showing that NRVS represents a powerful tool for the elucidation of complex biocatalysts containing multiple cofactors.


Functional data analysis for identifying nonlinear models of gene regulatory networks.
A key problem in systems biology is estimating dynamical models of gene regulatory networks. Traditionally, this has been done using regression or other ad-hoc methods when the model is linear. More detailed, realistic modeling studies usually employ nonlinear dynamical models, which lead to computationally difficult parameter estimation problems. Functional data analysis methods, however, offer a means to simplify fitting by transforming the problem from one of matching modeled and observed dynamics to one of matching modeled and observed time derivatives-a regression problem, albeit a nonlinear one. We formulate a functional data analysis approach for estimating the parameters of nonlinear dynamical models and evaluate this approach on data from two real systems, the gap gene system of Drosophila melanogaster and the synthetic IRMA network, which was created expressly as a test case for genetic network inference. We also evaluate the approach on simulated data sets generated by the GeneNetWeaver program, the basis for the annual DREAM reverse engineering challenge. We assess the accuracy with which the correct regulatory relationships within the networks are extracted, and consider alternative methods of regularization for the purpose of overfitting avoidance. We also show that the computational efficiency of the functional data analysis approach, and the decomposability of the resulting regression problem, allow us to explicitly enumerate and evaluate all possible regulator combinations for every gene. This gives deeper insight into the the relevance of different regulators or regulator combinations, and lets one check for alternative regulatory explanations. Functional data analysis is a powerful approach for estimating detailed nonlinear models of gene expression dynamics, allowing efficient and accurate estimation of regulatory architecture.


Bovine parainfluenza-3 virus proteins recognized by antibodies of aerosol-exposed calves.
Bovine parainfluenza-3 (BPI-3) virus proteins were radiolabeled with [35S]methionine. Control serum containing antibodies to BPI-3 virus obtained from calves that had been immunized by aerosol exposure and by IM inoculation and sera of cattle that were exposed to BPI-3 virus by aerosol only were used to immunoprecipitate BPI-3 virus proteins. The immunoprecipitates were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Viral proteins with estimated molecular weights of 72,000, 70,000, and 58,000 were recognized by the control serum and the sera from calves exposed to BPI-3 virus only by aerosol. These proteins were the hemagglutinin/neuraminidase, nucleoprotein, and fusion protein. The results indicated that a single aerosol exposure to BPI-3 virus induces antibodies to the same BPI-3 virus proteins as do combined aerosol and parenteral inoculations with the virus.


Effect of GH/IGF-I deficiency on long-term renal changes and urinary albumin excretion in diabetic dwarf rats.
Growth hormone (GH) and insulin-like growth factor I (IGF-I) may play a role in early diabetic renal and glomerular growth and in the later development of experimental diabetic kidney disease. Rats from a genetic GH/IGF-I-deficient dwarf rat strain were made streptozotocin diabetic and were compared with nondiabetic dwarf rats. GH/IGF-I-intact rats with and without diabetes served as controls. After 6 mo of diabetes, kidney weight and total glomerular volume increased significantly in GH/IGF-I-intact diabetic rats compared with the nondiabetic GH/IGF-I-intact rats (P < 0.05), whereas the diabetic dwarf rats had insignificant changes compared with dwarf control rats. By the end of the study, urinary albumin excretion (UAE) increased from similar base levels of approximately 15-20 micrograms/24 h to 473 +/- 52 (SE) micrograms/24 h in GH/IGF-I-intact diabetic rats compared with 151 +/- 32 micrograms/24 h in diabetic dwarf rats (P < 0.01). In conclusion, isolated GH/IGF-I deficiency reduces the degree of renal and glomerular hypertrophy and the increase in UAE after 6 mo of experimental diabetes in GH/IGF-I-deficient rats.


Reading and spelling abilities in children with severe speech impairments and cerebral palsy at 6, 9, and 12 years of age in relation to cognitive development: a longitudinal study.
Development of literacy skills was studied in six children (one male, five females) with severe speech impairments and cerebral palsy (CP). These skills were related to intellectual development, phonological abilities, and short-term memory. Three of the children were diagnosed with dystonia, and three with diplegia. They had no, or severely restricted, independent mobility (Gross Motor Function Classification System Level IV for four children and Level V for two), and severe fine motor problems, including difficulty with pointing. As they had no intelligible speech, the Bliss system was the primary communication mode. Assessments were made at approximately 6, 9, and 12 years of age. The results revealed that the children had difficulties acquiring literacy skills, although intellectual level and phonological ability predicted otherwise. Positive development during the first 3 years was followed by an arrest. A conspicuous decrease in IQ points was also found. Thus, phonological ability does not seem to have the same predictive power for literacy development in children with severe speech impairments and CP as in typically developing children. Further studies are needed to clarify the role of phonological abilities, working memory, and strategies used in literacy acquisition in these children. Such studies might also clarify the importance of articulatory abilities in early literacy acquisition.


Herpes simplex virus infection downmodulates NKG2D ligand expression.
Herpes simplex virus (HSV) type 1 infection may cause orofacial infections in humans. The virus resides in a latent form in neural ganglia and occasionally reactivates and infects epithelial cells. Natural killer (NK) cells have been implicated in immune control of herpes virus infections, possibly by downmodulating major histocompatibility complex (MHC) class I and by other, as yet unidentified, mechanisms. Upon HSV-1 infection of cell lines, surface levels of NKG2D ligands MHC class I related proteins (MIC) A and UL16 binding protein 2 were downmodulated due to late viral gene product(s). As also MHC class I levels were reduced by HSV-1, NK cell recognition of HeLa cells was not affected by infection. Total cellular MICA contents remained unchanged, suggesting masking, internalization or intracellular retention of MICA as possible mechanisms of viral downregualtion of MICA surface levels. Furthermore, NK cells from patients with active HSV-1 infection had a tendency towards increased expression level of the activating receptor NKG2D. These data support a role for NKG2D-MICA interactions in immune responses to HSV-1 reactivation.


Effect of duloxetine in patients with fibromyalgia: tiredness subgroups.
This study tested the hypothesis that baseline ratings of fatigue/tiredness would be negatively associated with the efficacy of duloxetine on measures of pain and functional ability in patients with fibromyalgia. A post hoc analysis of pooled data from 4 double-blind, placebo-controlled studies of duloxetine in fibromyalgia was performed. The fibromyalgia impact questionnaire (FIQ) tiredness item score (0 to 10 scale) was used to define tiredness subgroups. Patients were stratified into 3 subgroups: mild (0 to 3), moderate (4 to 6), and severe (7 to 10) tiredness. Analysis of covariance models and logistic regressions were used to test treatment-by-tiredness subgroup interactions. Data from the first 3 months are included in this post hoc analysis (duloxetine N = 797, placebo N = 535). At baseline, the distribution of tiredness severity in the duloxetine and placebo groups respectively was 3.64% and 3.75% mild, 16.71% and 15.57% moderate, and 79.65% and 80.68% severe. Rates of clinically significant (≥30% and ≥50%) improvement in brief pain inventory (BPI) average pain were similar across the tiredness subgroups. Tiredness severity at baseline was not negatively associated with the effects of duloxetine on patients' reports of functional ability using the FIQ total score, FIQ measures of physical impairment, interference with work, pain, stiffness, and depression and the medical outcomes study short form-36 (SF-36). Studies of duloxetine in fibromyalgia have demonstrated clinically significant improvements in pain and functional ability (FIQ, SF-36). This post hoc analysis of data shows that the efficacy of duloxetine among patients with fibromyalgia does not vary as a function of baseline ratings of fatigue/tiredness.


Is mesocardia with left-sided caval vein draining to coronary sinus a contraindication for a percutaneous pulmonary valve implantation? A case description.
Introduction Although the right jugular vein approach for percutaneous pulmonary valve implantation is well described, there are no reports that describe a percutaneous pulmonary valve implantation through a left superior caval vein to coronary sinus pathway. Case A 14-year-old female with tetralogy of Fallot, mesocardia, left superior caval vein draining into the coronary sinus, and hemiazygos continuation of the inferior caval vein underwent ventricular septal defect closure, with homograft insertion from the right ventricle to the pulmonary artery, patch augmentation of the left pulmonary artery, and creation of an atrial communication. Thereafter followed numerous catheterisations and interventions with stent implantation for stenosis of the left pulmonary artery and the homograft, as did device closure of the atrial communication. When she was a 12-year-old, the indications for a percutaneous pulmonary valve implantation were fulfilled and she underwent implantation of a 22 mm Melody® valve through the left superior caval vein. The extra-stiff exchange wire was pre-formed into a "U-spiral"-type configuration, according to the underlying anatomy, in order to provide a smooth route for the delivery of stents, to create the landing zone, and for the implantation of the Melody "ensemble". The procedure was performed under deep sedation according to our standard protocol. The duration of the procedure was 172 min and the radiation time was 24.9 min. On the basis of this unique experience, percutaneous pulmonary valve implantation is safe and feasible even in patients with unusual anatomy. Crucial is the "U-spiral" shaped configuration of the guide wire.


The 29-kilodalton thiol-dependent peroxidase of Entamoeba histolytica is a factor involved in pathogenesis and survival of the parasite during oxidative stress.
The 29-kDa surface antigen (thiol-dependent peroxidase; Eh29) of Entamoeba histolytica exhibits peroxidative and protective antioxidant activities. During tissue invasion, the trophozoites are exposed to oxidative stress and need to deal with highly toxic reactive oxygen species (ROS). In this investigation, attempts have been made to understand the role of the 29-kDa peroxidase gene in parasite survival and pathogenesis. Inhibition of eh29 gene expression by antisense RNA technology has shown approximately 55% inhibition in eh29 expression, maximum ROS accumulation, and significantly lower viability in 29-kDa downregulated trophozoites during oxidative stress. The cytopathic and cytotoxic activities were also found to decrease effectively in the 29-kDa downregulated trophozoites. Size of liver abscesses was substantially lower in hamsters inoculated with 29-kDa downregulated trophozoites compared to the normal HM1:IMSS. These findings clearly suggest that the 29-kDa protein of E. histolytica has a role in both survival of trophozoites in the presence of ROS and pathogenesis of amoebiasis.


Hypertrophic pachymeningitis: significance of myeloperoxidase anti-neutrophil cytoplasmic antibody.
The aim of this study was to elucidate the characteristics, pathogenesis and treatment strategy of hypertrophic pachymeningitis that is associated with myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA). We retrospectively investigated clinical, radiological, immunological and pathological profiles of 36 patients with immune-mediated or idiopathic hypertrophic pachymeningitis, including 17 patients with myeloperoxidase-ANCA, four patients with proteinase 3-ANCA, six patients with other immune-mediated disorders, and nine patients with 'idiopathic' variety. Myeloperoxidase-ANCA-positive hypertrophic pachymeningitis was characterized by: (i) an elderly female predominance; (ii) 82% of patients diagnosed with granulomatosis with polyangiitis (previously known as Wegener's granulomatosis) according to Watts' algorithm; (iii) a high frequency of patients with lesions limited to the dura mater and upper airways, developing headaches, chronic sinusitis, otitis media or mastoiditis; (iv) a low frequency of patients with the 'classical or generalized form' of granulomatosis with polyangiitis involving the entire upper and lower airways and kidney, or progressing to generalized disease, in contrast to proteinase 3-ANCA-positive hypertrophic pachymeningitis; (v) less severe neurological damage according to the modified Rankin Scale and low disease activity according to the Birmingham Vasculitis Activity Score compared with proteinase 3-ANCA-positive hypertrophic pachymeningitis; (vi) increased levels of CXCL10, CXCL8 and interleukin 6 in cerebrospinal fluids, and increased numbers of T cells, neutrophils, eosinophils, plasma cells and monocytes/macrophages in autopsied or biopsied dura mater with pachymeningitis, suggesting TH1-predominant granulomatous lesions in hypertrophic pachymeningitis, as previously reported in pulmonary or renal lesions of granulomatosis with polyangiitis; and (vii) greater efficacy of combination therapy with prednisolone and cyclophosphamide compared with monotherapy with prednisolone. Proteinase 3-ANCA may be considered a marker for more severe neurological damage, higher disease activity and a higher frequency of the generalized form compared with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. However, categorization into 'granulomatosis with polyangiitis' according to Watts' algorithm and immunological or pathological features were common in both proteinase 3- and myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. These data indicate that most patients with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis should be categorized as having the central nervous system-limited form of ANCA-associated vasculitis, consistent with the concept of ophthalmic-, pulmonary- or renal-limited vasculitis.


Effects of nonpersistence with medication on outcomes in high-risk patients with cardiovascular disease.
The impact of nonpersistence on events and of events on persistence is unclear. We studied the effects of nonpersistence on outcomes and events on nonadherence in a randomized placebo controlled trial in 40 countries on 25,620 patients. In the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), persistent patients (n = 20,991) were compared with individuals who had permanently stopped study medications (n = 4,629). Older age, female gender, less physical activity, less education, and history of stroke/transient ischemic attack, depression, and diabetes were associated with nonpersistence. After adjustment, nonpersistence was associated with the composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure (hazard ratio 1.24, 99% CI 1.09-1.40, P < .0001), cardiovascular death alone (1.87, 1.60-2.19, P < .0001), and heart failure hospitalization alone (1.32, 1.04-1.67, P = .0023). Cardiovascular events increased when medications were stopped, whereas noncardiovascular outcomes did not. Nonpersistence rapidly increased within the first year after nonfatal events such as myocardial infarction (hazard ratio 3.37, 99% CI 2.72-4.16, P < .0001), stroke (3.25, 2.59-4.07, P < .0001), and hospitalization for heart failure (3.67, 2.95-4.57, P < .0001). Persistence was poorer with more frequent and earlier events. Patients stopping medication after an event were at greater risk for subsequent events. Improving medications persistence could interrupt this vicious circle and may improve outcomes.


Understanding the cross-talk between human microbiota and gastrointestinal cancer for developing potential diagnostic and prognostic biomarkers.
The interaction between gut microbes and gastrointestinal (GI) tract carcinogenesis has always attracted researchers' attention to identify therapeutic targets or potential prognostic biomarkers. Various studies have suggested that the microbiota do show inflammation and immune dysregulation, which led to carcinogenesis in GI tract. In this review, we have focused on the role of microbes present in the gut, intestine, or faeces in GI tract cancers, including esophageal cancer, gastric cancer, and colorectal cancer. Herein, we have discussed the importance of the microbes and their metabolites, which could serve as diagnostic biomarkers for cancer detection, especially in the early stage, and prognostic markers. To maximize the effect of the treatment strategies, an accurate evaluation of the prognosis is imperative for clinicians. There is a vast difference in the microbiota profiles within a population and across the populations depending upon age, diet, lifestyle, genetic makeup, use of antibiotics, and environmental factors. Therefore, the diagnostic efficiency of the microbial markers needs to be further validated. A deeper understanding of the GI cancer and the host microbiota is needed to acquire pivotal information about disease status.


Advice to Stay Active or Structured Exercise in the Management of Sciatica: A Systematic Review and Meta-analysis.
A systematic review and meta-analysis. To evaluate the evidence on comparative effectiveness of advice to stay active versus supervised structured exercise in the management of sciatica. Conservative management of sciatica usually includes interventions to promote physical activity in the form of advice to stay active or exercise, but there has been no systematic review directly comparing the effectiveness of these 2 approaches. Data Sources included MEDLINE, CINAHL, EMBASE, and PEDro databases. Studies were randomized controlled trials comparing advice with exercise. Two independent reviewers extracted data and assessed methodological quality using the PEDro scale. Pain and disability data were extracted for all time points and converted to a common 0 to 100 scale. Data were pooled with a random effects model for short, intermediate, and long-term follow-ups. The GRADE approach was used to summarize the strength of evidence. Five trials were included in the meta-analysis, which showed a significant, although small effect favoring exercise over advice for reducing leg pain intensity in the short term (weighted mean difference: 11.43 [95% confidence interval, 0.71-22.16]) but no difference for disability (weighted mean difference: 1.45 [95% confidence interval, -2.86 to 5.76]). Furthermore, there was no difference at intermediate and long-term follow-ups between advice and exercise for patient-relevant outcomes. There is low-quality evidence (GRADE) that exercise provides small, superior effects compared with advice to stay active on leg pain in the short term for patients experiencing sciatica. However, there is moderate-quality evidence showing no difference between advice to stay active and exercise on leg pain and disability status in people with sciatica in the long term. 1.


Peripheral administration of antisense oligonucleotides targeting the amyloid-β protein precursor reverses AβPP and LRP-1 overexpression in the aged SAMP8 mouse brain.
The senescence accelerated mouse-prone 8 (SAMP8) mouse model of Alzheimer's disease has a natural mutation leading to age-related increases in the amyloid-β protein precursor (AβPP) and amyloid-β (Aβ) in the brain, memory impairment, and deficits in Aβ removal from the brain. Previous studies show that centrally administered antisense oligonucleotide directed against AβPP can decrease AβPP expression and Aβ production in the brains of aged SAMP8 mice, and improve memory. The same antisense crosses the blood-brain barrier and reverses memory deficits when injected intravenously. Here, we give 6 μg of AβPP or control antisense 3 times over 2 week intervals to 12 month old SAMP8 mice. Object recognition test was done 48 hours later, followed by removal of whole brains for immunoblot analysis of AβPP, low-density lipoprotein-related protein-1 (LRP-1), p-glycoprotein (Pgp), receptor for advanced glycation endproducts (RAGE), or ELISA of soluble Aβ(40). Our results show that AβPP antisense completely reverses a 30% age-associated increase in AβPP signal (p < 0.05 versus untreated 4 month old SAMP8). Soluble Aβ(40) increased with age, but was not reversed by antisense. LRP-1 large and small subunits increased significantly with age (147.7%, p < 0.01 and 123.7%, p < 0.05 respectively), and AβPP antisense completely reversed these increases (p < 0.05). Pgp and RAGE were not significantly altered with age or antisense. Antisense also caused improvements in memory (p < 0.001). Together, these data support the therapeutic potential of AβPP antisense and show a unique association between AβPP and LRP-1 expression in the SAMP8 mouse.


Surgical templates for function and esthetics in dental implants.
The functional and esthetic importance of surgical templates associated with dental implants has been discussed. The design of the stent and proposed location of the fixtures basically determine the dentist's "wish list." Although ideal placement of an implant fixture often is achieved, it can be aided through use of a surgical template. Particularly useful in larger partially edentulous cases as described above, the ideal template is made of hard acrylic with holes slightly larger than the 3.0 mm drill often used during surgery. Construction of a template requires the dentist and surgeon to think about the case, create a wax-up, and decide on location before constructing the appliance. This process will benefit all, particularly the patient, and provide a foundation for a long-lasting prosthetic result.


A historical account of breast cancer surgery: beware of local recurrence but be not radical.
In the late 19th century, William Halsted proposed the radical mastectomy, which became the standard surgical treatment of breast cancer for nearly 100 years. Later in this period, theories suggesting that breast cancer was a systemic disease at inception were championed by Bernard Fisher. This alternative hypothesis of biological predeterminism was based upon results of randomized clinical trials comparing breast conserving therapy with mastectomy, which showed similar overall survival outcomes. Nonetheless, data from meta-analyses suggest that inadequate local therapy can increase risk of local recurrence, which can subsequently increase mortality. In this review, the authors provide an historical account of how local therapy of breast cancer has evolved in the face of improved adjuvant therapies and better understanding of disease biology.


Acidosis-induced downregulation of hepatocyte mitochondrial aquaporin-8 and ureagenesis from ammonia.
It has been proposed that, during metabolic acidosis, the liver downregulates mitochondrial ammonia detoxification via ureagenesis, a bicarbonate-consuming process. Since we previously demonstrated that hepatocyte mitochondrial aquaporin-8 channels (mtAQP8) facilitate the uptake of ammonia and its metabolism into urea, we studied whether mtAQP8 is involved in the liver adaptive response to acidosis. Primary cultured rat hepatocytes were adapted to acidosis by exposing them to culture medium at pH 7.0 for 40 h. Control cells were exposed to pH 7.4. Hepatocytes exposed to acid medium showed a decrease in mtAQP8 protein expression (-30%, p < 0.05). Ureagenesis from ammonia was assessed by incubating the cells with (15)N-labeled ammonia and measuring (15)N-labeled urea synthesis by nuclear magnetic resonance. Reduced ureagenesis was found in acidified hepatocytes (-31%, p < 0.05). In vivo studies in rats subjected to 7 days acidosis also showed decreased protein expression of hepatic mtAQP8 (-50%, p < 0.05) and reduced liver urea content (-35%; p < 0.05). In conclusion, our in vitro and in vivo data suggest that hepatic mtAQP8 expression is downregulated in acidosis, a mechanism that may contribute to decreased ureagenesis from ammonia in response to acidosis.


Nonlinear bending deformation of soft electrets and prospects for engineering flexoelectricity and transverse (d31) piezoelectricity.
Soft materials that exhibit electromechanical coupling are an important element in the development of soft robotics, flexible and stretchable electronics, energy harvesters, sensor and actuators. Truly soft natural piezoelectrics essentially do not exist and typical dielectric elastomers, predicated on electrostriction and the Maxwell stress effect, exhibit only a one-way electromechanical coupling. Extensive research however has shown that soft electrets i.e. materials with embedded immobile charges and dipoles, can be artificially engineered to exhibit a rather large piezoelectric-like effect. Unfortunately, this piezoelectric effect-large as it may be-is primarily restricted to an electromechanical coupling in the longitudinal direction or what is referred colloquially as the d33 piezoelectric coefficient. In sharp contrast, the transverse piezoelectric property (the so-called d31 coefficient) is rather small. This distinction has profound implications since these soft electrets exhibit negligible electromechanical coupling under bending deformation. As a result, the typically engineered soft electrets are rendered substantively ill-suited for energy harvesting as well as actuation/sensing of flexure motion that plays a critical role in applications like soft robotics. In this work, we analyze nonlinear bending deformation of a soft electret structure and examine the precise conditions that may lead to a strong emergent piezoelectric response under bending. Furthermore, we show that non-uniformly distributed dipoles and charges in the soft electrets lead to an apparent electromechanical response that may be ambiguously and interchangeably interpreted as either transverse piezoelectricity or flexoelectricity. We suggest pragmatic routes to engineer a large transverse piezoelectric (d31) and flexoelectric coefficient in soft electrets. Finally, we show that in an appropriately designed soft electret, even a uniform external electric field can induce curvature in the structure thus enabling its application as a bending actuator.


Utility of the microculture method for Leishmania detection in non-invasive samples obtained from a blood bank.
In recent years, the role of donor blood has taken an important place in epidemiology of Leishmaniasis. According to the WHO, the numbers of patients considered as symptomatic are only 5-20% of individuals with asymptomatic leishmaniasis. In this study for detection of Leishmania infection in donor blood samples, 343 samples from the Capa Red Crescent Blood Center were obtained and primarily analyzed by microscopic and serological methods. Subsequently, the traditional culture (NNN), Immuno-chromatographic test (ICT) and Polymerase Chain Reaction (PCR) methods were applied to 21 samples which of them were found positive with at least one method. Buffy coat (BC) samples from 343 blood donors were analyzed: 15 (4.3%) were positive by a microculture method (MCM); and 4 (1.1%) by smear. The sera of these 343 samples included 9 (2.6%) determined positive by ELISA and 7 (2%) positive by IFAT. Thus, 21 of (6.1%) the 343 subjects studied by smear, MCM, IFAT and ELISA techniques were identified as positive for leishmaniasis at least one of the techniques and the sensitivity assessed. According to our data, the sensitivity of the methods are identified as MCM (71%), smear (19%), IFAT (33%), ELISA (42%), NNN (4%), PCR (14%) and ICT (4%). Thus, with this study for the first time, the sensitivity of a MCM was examined in blood donors by comparing MCM with the methods used in the diagnosis of leishmaniasis. As a result, MCM was found the most sensitive method for detection of Leishmania parasites in samples obtained from a blood bank. In addition, the presence of Leishmania parasites was detected in donor bloods in Istanbul, a non-endemic region of Turkey, and these results is a vital importance for the health of blood recipients.


Cervical spinal cord injury without evidence of fracture or dislocation. An assessment of the radiological features.
An analysis of plain X-ray films, tomography and myelography in 30 patients with proven cervical spinal cord injury, whose X-ray films were negative, has been performed. Features considered were the sagittal diameter of the spinal canal, associated cervical spondylosis, soft tissue changes, mobility studies and the value in cases of cervical injury of two recently described radiological signs. The only consistent feature in the majority of patients was a large posterior osteophytic spur in the lower cervical spine. No other radiological feature was found to be of particular value in diagnosis.


Alzheimer's-Like Pathology at the Crossroads of HIV-Associated Neurological Disorders.
Despite the widespread success of combined antiretroviral therapy (cART) in suppressing viremia, the prevalence of human immunodeficiency virus (HIV)-associated neurological disorders (HAND) and associated comorbidities such as Alzheimer's disease (AD)-like symptomatology is higher among people living with HIV. The pathophysiology of observed deficits in HAND is well understood. However, it has been suggested that it is exacerbated by aging. Epidemiological studies have suggested comparable concentrations of the toxic amyloid protein, amyloid-β42 (Aβ42), in the cerebrospinal fluid (CSF) of HAND patients and in the brains of patients with dementia of the Alzheimer's type. Apart from abnormal amyloid-β (Aβ) metabolism in AD, a better understanding of the role of similar pathophysiologic processes in HAND could be of substantial value. The pathogenesis of HAND involves either the direct effects of the virus or the effect of viral proteins, such as Tat, Gp120, or Nef, as well as the effects of antiretrovirals on amyloid metabolism and tauopathy, leading, in turn, to synaptodendritic alterations and neuroinflammatory milieu in the brain. Additionally, there is a lack of knowledge regarding the causative or bystander role of Alzheimer's-like pathology in HAND, which is a barrier to the development of therapeutics for HAND. This review attempts to highlight the cause-effect relationship of Alzheimer's-like pathology with HAND, attempting to dissect the role of HIV-1, HIV viral proteins, and antiretrovirals in patient samples, animal models, and cell culture model systems. Biomarkers associated with Alzheimer's-like pathology can serve as a tool to assess the neuronal injury in the brain and the associated cognitive deficits. Understanding the factors contributing to the AD-like pathology associated with HAND could set the stage for the future development of therapeutics aimed at abrogating the disease process.


Hif-1α-Induced Expression of Il-1β Protects against Mycobacterial Infection in Zebrafish.
Drug-resistant mycobacteria are a rising problem worldwide. There is an urgent need to understand the immune response to tuberculosis to identify host targets that, if targeted therapeutically, could be used to tackle these currently untreatable infections. In this study we use an Il-1β fluorescent transgenic line to show that there is an early innate immune proinflammatory response to well-established zebrafish models of inflammation and Mycobacterium marinum infection. We demonstrate that host-derived hypoxia signaling, mediated by the Hif-1α transcription factor, can prime macrophages with increased levels of Il-1β in the absence of infection, upregulating neutrophil antimicrobial NO production, leading to greater protection against infection. Our data link Hif-1α to proinflammatory macrophage Il-1β transcription in vivo during early mycobacterial infection and importantly highlight a host protective mechanism, via antimicrobial NO, that decreases disease outcomes and that could be targeted therapeutically to stimulate the innate immune response to better deal with infections.


What is evolutionary novelty? Process versus character based definitions.
With the rise of EvoDevo, the topic of evolutionary novelty has received renewed attention. Indeed, it has been argued that one of the major contributions of EvoDevo to evolutionary theory is the explanation of phenotypic novelty. Despite such assertions, dispute continues over what exactly a novelty is and whether the term applies to a unique type of evolutionary phenomenon or whether it merely has informal meaning. In a recent special issue of J. Exp. Zool. (Mol. Dev. Evol.) dedicated to novelty, a new definition was introduced, linking novelty exclusively with adaptation and developmental constraint. In our commentary, we discuss how defining novelty in this process oriented manner leads to heightened difficulties with the application of the term and the identification of novelties. At the same time it conceals important implications for evolutionary studies. In contrast, we argue for a character based definition that is independent from adaptive necessities and promotes the integration of evolutionary factors not included in the standard theory. The implications of approaching novelty in this manner take the issue beyond definitional debates.


The dependence on Ca2+ of the guanine-nucleotide-activated polyphosphoinositide phosphodiesterase in neutrophil plasma membranes.
The requirement for Ca2+ for the activation of polyphosphoinositide phosphodiesterase was studied with the guanine nucleotide analogue guanosine 5'-[gamma-thio]triphosphate (GTP gamma S). Levels of Ca2+ that pertain in unstimulated neutrophils (100 nM) are obligatory for the full expression of enzyme activity stimulated with GTP gamma S. Reduction of Ca2+ to 1 nM leads to inhibition. Increasing the level of Ca2+ from 100 nM to 1000 nM does not alter enzyme activity. Guanosine 5'-[beta-thio]diphosphate (GDP beta S) does not stimulate the phosphodiesterase but is an effective inhibitor of activation by GTP gamma S. Ca2+ in the millimolar range can also activate the phosphodiesterase alone and this is not inhibited by GDP beta S. It is also shown that Sr2+ in the millimolar range can stimulate enzyme activity similarly to Ca2+.


A comparison of amplification methods to detect Avian Influenza viruses in California wetlands targeted via remote sensing of waterfowl.
Migratory waterfowl, including geese and ducks, are indicated as the primary reservoir of avian influenza viruses (AIv) which can be subsequently spread to commercial poultry. The US Department of Agriculture's (USDA) surveillance efforts of waterfowl for AIv have been largely discontinued in the contiguous United States. Consequently, the use of technologies to identify areas of high waterfowl density and detect the presence of AIv in habitat such as wetlands has become imperative. Here we identified two high waterfowl density areas in California using processed NEXt generation RADar (NEXRAD) and collected water samples to test the efficacy of two tangential flow ultrafiltration methods and two nucleic acid based AIv detection assays. Whole-segment amplification and long-read sequencing yielded more positive samples than standard M-segment qPCR methods (57.6% versus 3.0%, p < .0001). We determined that this difference in positivity was due to mismatches in published primers to our samples and that these mismatches would result in failing to detect in the vast majority of currently sequenced AIv genomes in public databases. The whole segment sequences were subsequently used to provide subtype and potential host information of the AIv environmental reservoir. There was no statistically significant difference in sequencing reads recovered from the RexeedTM filtration compared to the unfiltered surface water. This overall approach combining remote sensing, filtration and sequencing provides a novel and potentially more effective, surveillance approach for AIv.


Contribution of immune cells in synergistic anti-tumor effect of ablation and immunotherapy.
Thermal ablation results in the damage of tumor tissue, which leads to localized necrosis and incites a significant inflammatory response, accompanied by the infiltration of numerous immune cells. Nevertheless, depending solely on the singular approach of thermal ablation frequently is difficult in eliciting a robust anti-tumor response. Research suggests that integrating immune modulators into conventional ablation techniques has the potential to enhance the elicited immune response, finally initiating synergistic effect without significantly elevated risk profiles. This article comprehensively analyses the immunological effects resulting from post-ablation alone and its synergy with immunotherapies, and accentuates the heterogeneous alterations noted in immune cells across distinct malignancies. Collectively, the article delves into the theoretical framework and advancements in clinical trials concerning the combined thermal ablation and immunotherapy for treating malignant tumors.


The process of integration of schools of nursing into higher education.
Before 1989, with the exception of a small number of nursing degree courses, most of nursing education within England was located within the NHS. Yet by 1995, all schools of nursing had been integrated into higher education institutions. Despite the significance of this change, there has been little discussion or empirical research within the nursing press about the way it happened or the experiences of the individuals involved. The aims of this paper are: The design was qualitative and the methods used were policy analysis and interviews. Interviews were conducted with a national, purposive sample of 30 senior individuals involved in healthcare education in the late 1990s selected from higher education institutions, national and regional offices of the Department of Health and professional bodies. A number of key lessons can be learned for contemporary nurse education. Notably: the need for clarity of policy aims; the value of sensitivity to the culture in which change is taking place; the importance of ensuring that the key individuals involved have the skills to make effective change and the need to share good practice in change management.


Influence of diets to Wistar rats supplemented with soya, flaxseed and lupine products treated by lactofermentation to improve their gut health.
The present study proposes the contribution of lactic acid bacteria and plants rich in bioactive substances and high-quality proteins as alternative products for human diets in improving the gut environment as potential against pathogenic bacteria. The effect of diets supplemented with soya, flaxseed and lupine flours fermented with a Pediococcus acidilactici KTU05-7 probiotic strain in the gastrointestinal tract (GIT) of Wistar rats were analyzed. In vivo experiments showed a positive effect of long time lactofermentation of plant material on the body weight of rats. Diets with fermented yellow lupine resulted in enhanced activities of α-glucosidase, β-galactosidases, as well as high levels of lactic acid bacteria, bifidobacteria and enterococci in the GIT were determined. Lactofermentation of analyzed plant products had a significantly lowering effect on Escherichia coli compared with the control group. The dominant flora of large intestines like Bifidobacterium and anaerobic cocci were found in high levels after diets with fermented lupine.


Induction of apoptosis and reduction of MMP gene expression in the U373 cell line by polyphenolics in Aronia melanocarpa and by curcumin.
Malignant brain tumours are rare but are the most challenging types of cancers to treat. Despite conventional multimodality approaches available for their management, the outlook for most patients remains dismal due to the ability of the tumour cells to invade the normal brain. Attention has now focused on novel therapeutic interventions such as as the use of micronutrients. Both chokeberry extract (Aronia melanocarpa), which is rich in natural pigments such as anthocyanins and curcumin (diferuloylmethane) found in turmeric (Curcuma longa) have been reported to possess anticancer properties in other cancers. The aim of this study was to extend our previous research to evaluate the therapeutic potential of these two agents by testing their ability to induce apoptosis in an established glioblastoma cell line (U373). This was accomplished by treating the cells for 48 h with either chokeberry extract or curcumin, and using the Annexin-V assay. Gene profiles of 8 MMPs (2, 9, 14, 15, 16, 17, 24 and 25) and 4 TIMPs (1, 2, 3 and 4) were analysed for effects of mediators of invasion by quantitative real-time polymerase chain reaction (RT-PCR). The IC50 values determined for curcumin and chokeberry extract were 15 and 200 µg/ml, respectively. Our results also suggest that curcumin induces apoptosis but chokeberry extract is necrotic to this cell line. It is possible that chokeberry extract kills the cells by other non-apoptotic pathways. In addition, the RT-PCR results show downregulation of the gene expression of MMP-2, -14, -16 and -17 for both micronutrients. Taken together, the comparative data suggest that both curcumin and chokeberry extract may exhibit their anticancer potential by inducing apoptosis and inhibiting invasion by reducing MMP gene expression.


Multiplexed discrimination of SARS-CoV-2 variants via plasmonic-enhanced fluorescence in a portable and automated device.
Portable assays for the rapid identification of lineages of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed to aid large-scale efforts in monitoring the evolution of the virus. Here we report a multiplexed assay in a microarray format for the detection, via isothermal amplification and plasmonic-gold-enhanced near-infrared fluorescence, of variants of SARS-CoV-2. The assay, which has single-nucleotide specificity for variant discrimination, single-RNA-copy sensitivity and does not require RNA extraction, discriminated 12 lineages of SARS-CoV-2 (in three mutational hotspots of the Spike protein) and detected the virus in nasopharyngeal swabs from 1,034 individuals at 98.8% sensitivity and 100% specificity, with 97.6% concordance with genome sequencing in variant discrimination. We also report a compact, portable and fully automated device integrating the entire swab-to-result workflow and amenable to the point-of-care detection of SARS-CoV-2 variants. Portable, rapid, accurate and multiplexed assays for the detection of SARS-CoV-2 variants and lineages may facilitate variant-surveillance efforts.


Phenotype and severity of asthma determines bronchial epithelial immune responses to a viral mimic.
Asthma is characterised by an aggravated immune response to respiratory viral infections. This phenomenon is a clinically well-recognised driver of acute exacerbations, but how different phenotypes of asthma respond immunologically to viruses is unclear. To describe the association between different phenotypes and severity of asthma and bronchial epithelial immune responses to viral stimulation. In the Immunoreact study, healthy subjects (n=10) and 50 patients with asthma were included; 30 (60%) were atopic, and 34 (68%) were eosinophilic; 14 (28%) had severe asthma. All participants underwent bronchoscopy with collection of bronchial brushings. Bronchial epithelial cells (BECs) were expanded and stimulated with the viral replication mimic poly (I:C) (Toll-like receptor (TLR)3 agonist) in vitro. The expression of TLR3-induced pro-inflammatory and antiviral responses of BECs were analysed using reverse transcriptase quantitative PCR and multiplex ELISA and compared across asthma phenotypes and severity of disease. Patients with atopic asthma had increased induction of interleukin (IL)-4, interferon (IFN)-β, IL-6, tumour necrosis factor-α, and IL-1β after poly (I:C) stimulation compared to non-atopic patients, whereas in patients with eosinophilic asthma only IL-6 and IL-8 induction was higher than in non-eosinophilic asthma. Patients with severe asthma displayed a decreased antiviral IFN-β, and increased expression of IL-8, most pronounced in atopic and eosinophilic asthmatics. Furthermore, induction of IL-33 in response to poly (I:C) was increased in severe atopic and in severe eosinophilic asthma, but thymic stromal lymphopoietin only in severe eosinophilic asthma. The bronchial epithelial immune response to a viral mimic stimulation differs between asthma phenotypes and severities, which may be important to consider when targeting novel asthma treatments.


Contractile and mechanical properties of epithelia with perturbed actomyosin dynamics.
Mechanics has an important role during morphogenesis, both in the generation of forces driving cell shape changes and in determining the effective material properties of cells and tissues. Drosophila dorsal closure has emerged as a reference model system for investigating the interplay between tissue mechanics and cellular activity. During dorsal closure, the amnioserosa generates one of the major forces that drive closure through the apical contraction of its constituent cells. We combined quantitation of live data, genetic and mechanical perturbation and cell biology, to investigate how mechanical properties and contraction rate emerge from cytoskeletal activity. We found that a decrease in Myosin phosphorylation induces a fluidization of amnioserosa cells which become more compliant. Conversely, an increase in Myosin phosphorylation and an increase in actin linear polymerization induce a solidification of cells. Contrary to expectation, these two perturbations have an opposite effect on the strain rate of cells during DC. While an increase in actin polymerization increases the contraction rate of amnioserosa cells, an increase in Myosin phosphorylation gives rise to cells that contract very slowly. The quantification of how the perturbation induced by laser ablation decays throughout the tissue revealed that the tissue in these two mutant backgrounds reacts very differently. We suggest that the differences in the strain rate of cells in situations where Myosin activity or actin polymerization is increased arise from changes in how the contractile forces are transmitted and coordinated across the tissue through ECadherin-mediated adhesion. Altogether, our results show that there is an optimal level of Myosin activity to generate efficient contraction and suggest that the architecture of the actin cytoskeleton and the dynamics of adhesion complexes are important parameters for the emergence of coordinated activity throughout the tissue.


How does burnout affect physician productivity? A systematic literature review.
Interest in the well-being of physicians has increased because of their contributions to the healthcare system quality. There is growing recognition that physicians are exposed to workplace factors that increase the risk of work stress. Long-term exposure to high work stress can result in burnout. Reports from around the world suggest that about one-third to one-half of physicians experience burnout. Understanding the outcomes associated with burnout is critical to understanding its affects on the healthcare system. Productivity outcomes are among those that could have the most immediate effects on the healthcare system. This systematic literature review is one of the first to explore the evidence for the types of physician productivity outcomes associated with physician burnout. It answers the question, "How does burnout affect physician productivity?" A systematic search was performed of: Medline Current, Medline in process, PsycInfo, Embase and Web of Science. The search period covered 2002 to 2012. The searches identified articles about practicing physicians working in civilian settings. Articles that primarily looked only at residents or medical students were excluded. Productivity was captured by hours worked, patients seen, sick leave, leaving the profession, retirement, workload and presenteeism. Studies also were excluded if: (1) the study sample was not comprised of at least 50% physicians, (2) the study did not examine the relationship between burnout and productivity or (3) a validated measure of burnout was not used. The search identified 870 unique citations; 5 met the inclusion/exclusion criteria. This review indicates that globally there is recognition of the potential impact of physician burnout on productivity. Productivity was examined using: number of sick leave days, work ability, intent to either continue practicing or change jobs. The majority of the studies indicate there is a negative relationship between burnout and productivity. However, there is variation depending on the type of productivity outcome examined. There is evidence that burnout is associated with decreased productivity. However, this line of inquiry is still developing. A number of gaps are yet to be filled including understanding how to quantify the changes in productivity related to burnout.


Paramagnetic unit in spinach subchloroplast particles: estimation of size.
A pulsed ruby laser (wavelength, 694.3 nanometers) was used to measure the dependence on light intensity of light-induced electron paramagnetic resonance (ERR) signal 1 for short flashes of uniform duration (400 microseconds). Approximately 10(18) photons per square centimeter per flash from the unattenuated beam were available to the sample of subchloroplast "system 1" particles from spinach. The experimental dependence of the EPR signal height plotted as a function of the total number of incident photons per flash was exponential. From measurement of the slope at a very low relative photon flux and the saturated EPR signal amplitude, the value for the cross section or "effective size" of the light-induced paramagnetic unit, sigma(EPR), was found to be 300 x 10(-17) square centimeter. This result is compared with a measured optical absorption cross section, sigma(694nm), of 2.5 x 10(-17) square centimeter, for the identical sample at the laser wavelength. The hundredfold difference in size supports the thesis that the paramagnetic state is a property of an aggregate of chlorophyll molecules of the same general size as the photosynthetic unit.


Transcranial Direct Current Stimulation of the Dorsolateral Prefrontal Cortex Alters Emotional Modulation of Spinal Nociception.
Emotion has a strong modulatory effect on pain perception and spinal nociception. Pleasure inhibits pain and nociception, whereas displeasure facilitates pain and nociception. Dysregulation of this system has been implicated in development and maintenance of chronic pain. The current study sought to examine whether emotional modulation of pain could be altered through the use of transcranial direct current stimulation (tDCS) to enhance (via anodal stimulation) or depress (via cathodal stimulation) cortical excitability in the dorsolateral prefrontal cortex. Thirty-two participants (15 female, 17 male) received anodal, cathodal, and sham tDCS on three separate occasions, followed immediately by testing to examine the impact of pleasant and unpleasant images on pain and nociceptive flexion reflex (NFR) responses to electrocutaneous stimulation. Results indicated that tDCS modulated the effect of image content on NFR, F(2, 2175.06) = 3.20, P= .04, with the expected linear slope following anodal stimulation (ie, pleasant < neutral < unpleasant) but not cathodal stimulation. These findings provide novel evidence that the dorsolateral prefrontal cortex is critical to emotional modulation of spinal nociception. Moreover, the results suggest a physiological basis for a previously identified phenotype associated with risk for chronic pain and thus a potentially new target for chronic pain prevention efforts. PERSPECTIVE: This study demonstrated that reduction of dorsolateral prefrontal cortical excitability by transcranial direct current stimulation attenuates the impact of emotional image viewing on nociceptive reflex activity during painful electrocutaneous stimulation. This result confirms there is cortical involvement in emotional modulation of spinal nociception and opens avenues for future clinical research.


Single molecule mechanics resolves the earliest events in force generation by cardiac myosin.
Key steps of cardiac mechanochemistry, including the force-generating working stroke and the release of phosphate (Pi), occur rapidly after myosin-actin attachment. An ultra-high-speed optical trap enabled direct observation of the timing and amplitude of the working stroke, which can occur within <200 μs of actin binding by β-cardiac myosin. The initial actomyosin state can sustain loads of at least 4.5 pN and proceeds directly to the stroke or detaches before releasing ATP hydrolysis products. The rates of these processes depend on the force. The time between binding and stroke is unaffected by 10 mM Pi which, along with other findings, indicates the stroke precedes phosphate release. After Pi release, Pi can rebind enabling reversal of the working stroke. Detecting these rapid events under physiological loads provides definitive indication of the dynamics by which actomyosin converts biochemical energy into mechanical work.


Ultra-Orthodox Nursing Students' Cultural Challenges Inside and Outside Their Community during the COVID-19 Pandemic.
In line with findings that nurses from minority groups have an important role in making health services accessible to their community, our study aimed to identify the challenges ultra-Orthodox Jewish nurses faced during COVID-19 in their encounters with patients and health staff from other communities, as well as their own community. The ultra-Orthodox community is a highly religious group that maintains isolation from general society, a phenomenon that affected its member experiences during COVID-19. Our research followed sequential explanatory mixed methods. The quantitative phase included a questionnaire completed by 235 female students (111 ultra-Orthodox and 124 non-ultra-Orthodox), followed by a qualitative phase, which included six focus-groups (n = 15). The quantitative analysis showed that the ultra-Orthodox students felt a higher sense of responsibility toward their community. They used their authority and knowledge to guide their community during the pandemic. The qualitative analysis identified two themes expressed as challenges ultra-Orthodox nursing students encountered within their community and with other sections of Israeli society. Our research shows the important role that transcultural nurses play in mediating updated health information otherwise inaccessible to their community, especially in times of crises. It is important to address dilemmas this group faces inside and outside their respective communities.


Design of galardine analogs as putative psudolysin inhibitors based on ab initio fragment molecular orbital calculations.
Pseudolysin (PLN) is a metalloproteinase secreted from bacteria that degrades extracellular proteins to produce bacterial nutrition. It is thus expected that inhibitors against PLN can suppress the growth of bacteria and their pandemic spread. In addition, since these inhibitors do not attack to bacteria directly, there is a reduced risk for producing drug-resistant bacteria. On the other hand, as PLN has large structural similarity in the active sites with human matrix-metalloproteinases (MMPs), there is a possibility that the inhibitors for PLN also inhibit MMP activity, resulting in a loss of necessary nutrients to be produced by MMPs. Therefore, it is required the agents inhibiting the activity of only PLN not MMPs. In the present study, we employed a hydroxamate compound galardin, which has a significant inhibition effect against PLN and MMP, and investigated its specific interactions with PLN/MMP at atomic and electronic levels, by use of ab initio molecular simulations. Based on the results, we proposed several derivatives of galardin and elucidated which derivatives that can bind more strongly to PLN and be putative antimicrobial agents capable of inhibiting the PLN activity.Communicated by Ramaswamy H. Sarma.


Expression of fibroblast growth factor 23 by canine soft tissue sarcomas.
Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome of humans. Some mesenchymal tumours (often resembling haemangiopericytomas) express molecules that normally regulate phosphorus metabolism; most frequently, fibroblast growth factor 23. Patients develop renal phosphate wasting and inappropriately low serum concentrations of 1, 25 (OH)2 vitamin D3 , leading to osteomalacia. Surgical removal of the tumour is curative. The authors examined expression of canine fibroblast growth factor 23 in 49 soft tissue sarcomas, and control tissues from normal adult dogs. RNA extracted from bone or formalin-fixed, paraffin-embedded tissues was analysed by end point and quantitative reverse transcriptase-polymerase chain reaction. Fibroblast growth factor 23 expression was detected in bone, lung, kidney, lymph node and thymus. Fifteen of 49 sarcomas (31%) expressed fibroblast growth factor 23, three of these had high relative expression and some features resembling phosphatonin-expressing mesenchymal tumours of humans. Further work is required to determine whether TIO may occur in dogs.


Three-dimensional Change of Elastomeric Impression Materials During the First 24 Hours: A Pilot Study.
To evaluate the three-dimensional (3D) changes of three elastomeric impression materials using a novel measurement method for the first 24 hours after preparation. Three impression materials consisting of a low-viscosity polyvinyl siloxane (PVS) (Aquasil LV, Dentsply Sirona, Charlotte, NC, USA) and two vinyl polyether silicone (VPES) materials consisting of a light body (EXA'lence LB, GC America, Alsip, IL, USA) and monophase (EXA'lence Monophase, GC America) materials were used in this study. All materials were prepared following manufacturer's recommendations with approximately 1-2 millimeters of material placed on the measurement pedestal of a calibrated noncontact, video imaging based, volumetric change measuring device (AcuVol ver 2.5.9, Bisco, Schaumburg, IL, USA). Data collection was initiated immediately, with measurements made every 30 seconds for 24 hours. Each material was evaluated 10 times (n=10). Evaluated parameters included were 24-hour mean shrinkage, mean shrinkage at time of recommended first pour, mean shrinkage between recommended first pour and 24 hours, mean maximum shrinkage, and the time of maximum shrinkage. Mean data, both within and between each group, was evaluated using Kruskal-Wallis/Dunn's tests at a 95% level of confidence (α=0.05). All three materials were found to have significant differences (p<0.001) in volumetric shrinkage over 24 hours. Aquasil LV and EXA'lence LB polymerization shrinkage rates were statistically similar all through the 24-hour evaluation (p=0.92). All three materials demonstrated similar (p=0.19) shrinkage between 10 and 15 minutes after preparation, while between 5 and 16 hours both EXA'lence Monophase and low-viscosity materials demonstrated similar polymerization shrinkage values (p=0.22). EXA'lence Monophase demonstrated significantly greater 24-hour mean shrinkage (p<0.008) as well as shrinkage between recommended first pour time and 24 hours (p=0.003) than Aquasil LV and EXA'lence LB. EXA'lence Monophase demonstrated significantly greater (p=0.002) shrinkage at the recommended time of first pour as compared to Aquasil LV and EXA'lence LB that displayed similar shrinkage (p=0.89). Furthermore, all materials demonstrated increasing polymerization shrinkage values that reached a maximum between 16 for Aquasil LV and 20 hours for EXA'lence LB, after which some relaxation behavior was observed. However, EXA'lence Monophase did not display any relaxation behavior over the 24-hour evaluation. Under the conditions of this study, volumetric polymerization shrinkage was observed for one polyvinyl siloxane (PVS) and two vinyl polyether silicone (VPES) materials for up to 24 hours. All impression materials exhibited fast early volumetric shrinkage that continued past the manufacturer's recommended removal time. Dimensional change behavior was not uniform within or between groups; resultant volume change between the manufacturer recommended pouring time and 24 hours might represent up to from 20% to 30% of the total material shrinkage. It may be prudent to pour elastomeric impressions at the earliest time possible following the manufacturer's recommendations.


[Inequity and health in the workplace: exploring an emergent area].
Work, under fair employment and decent work, reduces inequities in health. Nowadays it seems, however, that obtaining and carrying out a job and worker performance take precedence over the aforementioned attributes. Workers are not only exposed to accidents, diseases caused by various agents, ergonomic and psychosocial risks but also affected by work modes imposed by the "wildmarket", such as the lack of social security benefits. Member countries of the International Labour Organization (ILO) should institute occupational health and safety policies in order to reduce the above mentioned inequities. Nonetheless, governments, which would guarantee such policies, seem to have become intermediaries in favor of large corporations. It is essential to define and strengthen actions that create jobs in decent and appropriate conditions with a view to generating equity, equality, and social well-being.


Trajectories of academic achievement for students with attention-deficit/hyperactivity disorder.
Attention-deficit/hyperactivity disorder (ADHD) is associated with negative social and occupational outcomes across the life course. However, there has been limited population-based research that quantifies the impact of ADHD on academic achievement and academic trajectories. To compare academic performance and academic trajectories of students with ADHD with students without a mental disorder. Data were drawn from Young Minds Matter, a national population-based sample of 6,310 Australian children and adolescents aged 4-17 years. Using linked achievement test data, the academic performance and trajectories of 327 students with ADHD were compared with those of 3,916 students without a mental disorder. Survey data were combined with scores on national standardized tests for literacy and numeracy over an 8-year period. In Year 3, students with ADHD were on average 1 year behind students with no mental disorder in reading and numeracy, and 9 months behind in writing. In Year 9, the gaps were much larger with students with ADHD on average 2.5 years behind in reading, 3 years behind in numeracy, and 4.5 years behind in writing. Students with ADHD have substantially lower achievement in reading, writing, and numeracy. Writing was the most adversely affected domain. For example, in Year 9 students with ADHD were on average writing at a Year 5 level. Children and adolescents with ADHD need substantial support to manage inattention, impulsivity, and hyperactivity. Skilled remediation in literacy and numeracy is required throughout all school years.


Avascular necrosis of the hallux metatarsal head.
Avascular necrosis of the first metatarsal head is rare. Although idiopathic cases have been reported, AVN of the first metatarsal head is usually iatrogenic following surgical correction of hallux valgus using a distal metatarsal osteotomy with or without lateral soft tissue release. A thorough understanding of the delicate vascular anatomy of the first metatarsal head is essential when surgery is considered. Careful operative technique permits a safe combination of distal osteotomy and lateral soft tissue release. Because the intraosseous blood supply is completely disrupted with distal metatarsal osteotomy, excessive capsular release and saw blade penetration into the lateral capsular vessels must be avoided. Among the thousands of reported distal metatarsal osteotomies performed using a variety of technique modifications of the original procedure described by Austin, the prevalence of AVN is low. Undoubtedly, the first metatarsal head has an excellent capacity to accommodate to changes in its blood supply. Although radiographic changes are frequently observed in the metatarsal head following a distal metatarsal osteotomy with or without lateral release, rarely do these changes progress to symptomatic AVN. These transient radiographic findings probably represent an adjustment period as the metatarsal head recovers from vascular compromise. Not only is AVN of the first metatarsal rare, but it is rare for it to be symptomatic. Many more cases that are never identified may exist. Management of symptomatic AVN of the first metatarsal head has not been standardized because of the infrequency of this condition. Anecdotal experience suggests that simple activity and shoe modifications may suffice; however, joint debridement and metatarsal head decompression may prove beneficial as they have in the management of other joints more commonly afflicted with AVN. Finally, severe head collapse may be salvaged with MTP joint arthrodesis. In the event that a substantial amount of avascular bone must be removed, consideration can be given to bone block distraction arthrodesis to avoid transfer metatarsalgia.


Role of PARP-1 and PARP-2 in the expression of apoptosis-regulating genes in HeLa cells.
Poly (ADP-ribose) polymerase-1 (PARP-1) is a DNA-binding enzyme involved in DNA damage processing, apoptosis, and genetic stability. Many lines of evidence suggest that PARP-1 is implicated in transcriptional regulation of various genes through the modulation of chromatin structure or through direct interaction with transcription factors and/or transcription factor-binding sites. In the present study, we applied TaqMan Low-Density Array analyses to investigate the expression of genes involved in apoptotic cell death induced by an alkylating agent. Using RNA interference, we determined the roles of PARP-1 and PARP-2 in transcriptional regulation during apoptosis in HeLa cells. Of the 93 genes monitored, 33 differentially expressed genes were identified after induction of apoptosis. Whereas the down-regulation of PARP-1 and PARP-2 had no impact on gene expression per se, we observed that Bcl10, c-Rel, and tumor necrosis factor-related apoptosis-inducing ligand receptor-1 and -2 are differentially expressed after induction of apoptosis in a PARP-1-dependent manner. These findings suggest that PARP-1-but not PARP-2-is required for proper expression of major genes involved in regulation of apoptosis.