International Conference on Harmonisation; Guidance on Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the International Conference on Harmonisation Regions; availability. Notice.
The Food and Drug Administration (FDA) is announcing the availability of a guidance entitled "Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions." The guidance was prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The guidance describes a process for the evaluation and recommendation by the ICH Q4B Expert Working Group (EWG) of selected pharmacopeial texts to facilitate their recognition by regulatory authorities for use as interchangeable in the ICH regions. Following favorable evaluations, ICH will issue topic-specific annexes with information about these texts and their implementation (the Q4B Outcomes). Implementation of the Q4B annexes is intended to avoid redundant testing by industry in favor of a common testing strategy in each ICH regulatory region.


Pure Laparoscopic Versus Open Approach for Living Donor Right Hepatectomy: A Systematic Review and Meta-Analysis.
Background: Pure laparoscopic liver donor right hepatectomy (LLDRH) remains challenging, and its value is still unclear compared with open liver donor right hepatectomy (OLDRH). Objective: To provide comprehensive evidence about the safety and efficacy of LLDRH. Methods: The MEDLINE, Embase, Web of Science, and Cochrane Library electronic databases were searched from the date of inception to July 2021. A fixed-effects or random-effects model was used to analyze the pooled data by using Review Manager Version 5.3. Results: A total of 1940 patients from 6 studies were enrolled in this meta-analysis. For perioperative outcomes of donors, LLDRH had a longer operative time than OLDRH (weighted mean difference [WMD] = 29.75 [4.23-55.26] minutes, P = .02), but it had lower overall morbidity (odds ratio [OR] = 0.67 [0.45-0.99], P = .04), fewer pulmonary complications (OR = 0.47 [0.29-0.76], P = .002), and shorter hospital stays (WMD = -1, P < .001) than OLDRH. However, major complications, biliary complications, portal vein problems, and intra-abdominal bleeding were comparable between the 2 groups. With regard to the postoperative data of recipients, the risks of biliary problems, hepatic artery problems, portal vein problems, hepatic vein problems, and postoperative liver failure were similar between the 2 groups. Conclusions: LLDRH for living donors is safe and effective, and it offers superior perioperative outcomes to OLDRH.


Pharmacokinetic profiles of current therapies for Alzheimer's disease: implications for switching to galantamine.
Although no pharmacologic treatments have been proved to alter the pathology of Alzheimer's disease, acetylcholinesterase inhibitor (AChEI) therapy offers symptomatic improvements in or delays in the progression of cognitive, behavioral, and functional deficits. Tacrine, donepezil, rivastigmine, and galantamine are the best studied agents in this class. These drugs have varying pharmacokinetic, safety, and tolerability profiles that can affect patient outcomes. Specifically, certain metabolic parameters (ie, half-life and route of metabolism/elimination) can affect a drug's tolerability and become important when a switch from one agent to another is contemplated. The mechanism of action of galantamine, the most recently approved AChEI. varies from that of the other AChEIs in that it has allosteric modulating activity at nicotinic receptors in addition to its ability to inhibit acetylcholinesterase. Benefits of this dual mode of action on the effects of the disease have been suggested.


[Medical registries].
The target-oriented distribution of increasingly limited health care resources requires knowledge about the benefit of established measures and the health care situation. This is the purpose of health care research. In this overview, the role of registries in regard to health care research is described. Registries, a collection of standardized medical and socioeconomic data, investigate systematically and comprehensively for a certain purpose and are therefore appropriate to describe the actual treatment in regard to undersupply, excess supply, and missupply. One example would Allbe the use of statins in risk profile-oriented primary and secondary prevention of cardiovascular events. Furthermore, positive experience from registries is available, as in the case of quality assurance management. In registries for myocardial infarction like MIR, MITRA and ACOS, feedback about therapy compared with guidelines along with the request to explain deviation from guidelines resulted in a significant reduction of hospital mortality. The methodological necessities and limitations of the informational value are pointed out. Registries are able to contribute substantially to health care research.


Case Report: Neoadjuvant PD-1 Blockade Plus Concurrent Chemoradiotherapy in Unresectable Locally Advanced Gastric Cancer Patients.
Programmed death 1(PD-1) blockade has shown promising efficacy in advanced gastric cancer. Here, we performed a retrospective analysis of three patients with locally advanced gastric cancer who received adjuvant PD-1 plus chemoradiotherapy as neoadjuvant treatment. Neoadjuvant sintilimab plus concurrent chemoradiotherapy had an acceptable side-effect profile. All three patients underwent surgical gastrectomy after a median of 3.9 months. A major pathological response occurred in two resected tumors and a pathologic complete response was observed in one patient. Our results suggest that PD-1 blockade combined with chemoradiotherapy is a promising strategy as a neoadjuvant therapy in patients with unresectable locally advanced gastric cancer.


Approval of a new rapid test for HIV antibody.
On November 7, 2002, the Food and Drug Administration announced approval of the OraQuick Rapid HIV-1 Antibody Test (OraSure Technologies, Inc., Bethlehem, Pennsylvania) for use by trained personnel as a point-of-care test to aid in the diagnosis of infection with human immunodeficiency virus type 1 (HIV-1). OraQuick is a simple, rapid test that can detect antibodies to HIV in fingerstick whole blood specimens and provide results in as little as 20 minutes [corrected]. The test has been categorized as moderate complexity under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). A second FDA-approved moderate-complexity rapid HIV test, Single Use Diagnostic System for HIV-1 (Abbott-Murex Inc., Norcross, Georgia), remains available in the United States for use with serum or plasma specimens.


Sexual bother following radical prostatectomyjsm.
The literature on sexual bother in men with prostate cancer is conflicting. While some data indicate high bother from erectile dysfunction (ED) following prostate cancer treatments, other results suggest the life-saving nature of the treatment may mitigate ED concern. (i) To determine if sexual bother increases post radical prostatectomy (RP); (ii) To determine if men psychologically adjust to diminished erections; (iii) To identify baseline predictors of post-RP sexual bother. We identified 183 men treated with RP who completed inventories including Erectile Function Domain (EFD) and Sexual Bother (SB) preoperatively and at 12 and 24 months postoperatively. Statistical analyses included repeated-measures analysis of variance and linear multiple regression. The EFD of the International Index of Erectile Function and the SB subscale from the Prostate-Health Related Quality-of-Life Questionnaire. The mean age of the sample was 58 +/- 7 years. The mean EFD scores decreased from baseline to the 24-month time point (24.8 vs. 16.7, P < 0.01). The mean SB scores increased from baseline to the 12 month time point (4.3 vs. 6.7, P < 0.01), and remained stable from the 12 month to 24 month time points (6.7 vs. 6.3, P = not significant [ns]). This was true for men with ED (EFD < 24) and without ED. Only 7% of men with ED moved from being "bothered" at 12 months to "no bother" at 24 months. There were no significant baseline predictors of sexual bother; baseline variables tested were: age, race, marital status, prostate-specific antigen (PSA) value, EFD, sexual desire, and intercourse satisfaction. The change in EFD scores was the only significant predictor of SB scores. Sexual bother increases post-RP, even in men with "good" erections postoperatively, and includes shame, embarrassment, and a reduction in general life happiness. Because men do not seem to "adjust" to ED, referral or evaluation should occur early in this population.


Palladium(II)-catalyzed oxidative C-H/C-H cross-coupling of heteroarenes.
An efficient methodology for the synthesis of unsymmetrical biheteroaryl molecules has been developed via Pd(II)-catalyzed oxidative C-H/C-H cross-coupling of heteroarenes. An inversion in reactivity and selectivity has been achieved successfully to perform the desired heterocoupling. This process allows the heterocoupling of not only electron-rich N-containing heteroarenes (e.g., xanthines, azoles, and indolizines) but also electron-poor pyridine N-oxides with various thiophenes or furans.


Interaction of opiate receptor binding sites and guanine nucleotide regulatory sites: selective protection from N-ethylmaleimide.
Guanine nucleotides decrease the binding of opiate agonists to opiate receptors by increasing dissociation rates. To explore the relationship between receptor binding and GTP regulation, rat brain membranes were incubated with N-ethylmaleimide (NEM) and assayed for GTP-induced decrease of 3H-agonist binding. NEM decreased both binding of [3H]dihydromorphine and the effect of GTP on binding. The GTP effect on D-[3H]Ala2-Met5-enkephalinamide (D-Ala-enk) binding was less sensitive to NEM than the binding itself. Incubation of membranes with 0.2 microM D-Ala-enk before addition of NEM significantly protected D-[3H]Ala-enk binding, but did not protect the GTP effect, actually increasing the effect of NEM and eliminating the GTP effect. These "unregulated" receptors were still inhibited by NaCl, but were not stimulated by divalent cations. Although opiate protection alone could not protect the GTP regulation, preincubation of membranes with GTP or guanyl-yl-5'-imidodiphosphate fully protected the GTP effect from NEM and also partially protected the binding site. Preincubation of membranes either with NaCl alone or with NaCl plus D-Ala-enk protected both the GTP effect and the binding site. These results suggest that although the sites for GTP regulation and opiate receptor binding are physically distinct, interactions between sites occur upon the binding of either opiate or guanine nucleotide ligands to their respective sites, and that sodium may play a crucial role in the coupling of these interactions.


Association between C-reactive protein, carotid intima-media thickness and P-wave dispersion in obese premenopausal women: an observational study.
The aim of the present study was to evaluate P-wave dispersion (PWD) in obese women, and to investigate the relationship between P-wave measurements, high sensitive C-reactive protein (hsCRP), carotid intima-media thickness (CIMT) and echocardiographic findings. Forty-four patients with obese premenopausal women and 30 females with normal weight were enrolled this cross sectional, observational study. Results of anthropometric measurements, laboratory assays, electrocardiographic and echocardiographic findings were recorded for each participant. Student t, Mann-Whitney U and Pearson Chi-square tests, and Spearman correlation analysis were used for statistical analysis. Multiple regression analysis was used to identify independent factors associated with PWD development. The obese group had significantly higher values for PWD (41.8 ± 11.8 ms vs. 28.5 ± 9.3ms; p<0.001) as well as for P max (105.2 ± 14.3 ms vs. 89.0 ± 13.3 ms; p<0.001). Correlation analyses revealed the presence of a positive correlation between PWD and each of insulin, systolic blood pressure, diastolic blood pressure, hsCRP, CIMT, left atrial diameter (LAD), waist circumference, waist to hip ratio and body mass index in obese participants. The only significant association that was observed on multiple linear regression analysis, after adjustments for confounding risk factors, was between LAD and PWD (β=4.290, 95% CI:1.870-9.720, p=0.032). We found that increased PWD values in obese patients are correlated positively with hsCRP, CIMT and abdominal obesity. However, independent and significant association was found only between LAD and PWD.


Increased preeclampsia in mothers delivering very low-birth-weight infants between 1994 and 2006.
We sought to determine if there has been any change in the proportion of mothers with preeclampsia in a sample of very low-birth-weight (VLBW) infants over time. We performed a retrospective cohort study. Study sample included infants with birth weights 1500 g or less cared for from July 1994 to July 2006 ( n = 2045) from a single level 3 neonatal intensive care unit in Delaware. The main outcome examined was the occurrence of maternal preeclampsia over the study time. The proportion of mothers with preeclampsia delivering VLBW infants increased over time. After controlling for potential confounding variables, the odds of maternal preeclampsia were increased (1.3, 95% confidence interval 1.2 to 1.5) in infants born between 2003 and 2006 compared with those born between 1994 and 1997. In our population of VLBW infants, the proportion of mothers with the diagnosis of preeclampsia increased over time. From our investigation, we cannot determine if the increase in the proportion of mothers with preeclampsia is related to a true increase in the disease, changes in diagnostic surveillance, or other factors.


Molecular Links Between Alzheimer's Disease and Gastrointestinal Microbiota: Emphasis on Helicobacter pylori Infection Involvement.
Alzheimer's disease (AD) is a neurodegenerative disease and the main form of dementia, characterized by progressive cognitive decline and detrimental consequences in both personal-family and global level. Within this narrative review, we provide recent molecular aspects of Tau, a microtubule AD-associated protein, as well as amyloid beta, involved in AD pathophysiology. Moreover, we provide additional emerging data from basic research as well as clinical studies indicating an implicating role of gastrointestinal microbiota (GI-M), including Helicobacter pylori infection (Hp-I), in AD pathophysiology. Likewise, we identified through a molecular prism the current evidence of AD pathogenesis as well as its linkage with GI-M and emphasizing the role of Hp-I. All in all, additional large-scale studies are required for the further clarification of AD pathophysiology and its connection with GI-M and Hp-I, so as novel therapies on molecular basis become available.


Preparing the ocular surface for glaucoma filtration surgery: an unmet clinical need.
The mutual relationship among medical therapy, ocular surface (OS) and filtration surgery (FS) represents one of the most crucial issues in glaucoma management. As the long-term use of intraocular pressure-lowering medications significantly affect the OS health, patients with an uncontrolled disease frequently undergo glaucoma surgery in less-than-ideal conditions. As we known, OS changes strongly affect the post-operative bleb filtration capability. Therefore, improving the OS conditions before proceeding with FS is needed. Currently, given the rapid diffusion of new surgical procedures, this need is even more perceived. Nevertheless, despite surgeons retain the OS preparation of primary importance, and recognize the OS disease (OSD) as the only modifiable risk factor for filtration failure, there is no agreement on which strategies should be preferred to prepare patients. This is largely due to the lack of validated guidelines, which forces clinicians to adopt personal approaches based on evidence derived from low-quality studies. In this review, we provided an overview of risk factors involved in the FS failure, with particular attention to those depending on OS changes, and how OSD negatively affects the aqueous humor resorption after surgery. Moreover, we reported the most exploited measures to mitigate the OSD before surgery, the possible reasons underlying the absence of shared approaches, and the upcoming area of intervention to preserve the OS health during glaucoma management. Finally, based on the current evidence, we proposed a pre-operative outline reporting the main risk factors that should be considered before surgery, and the therapeutical options available to improve the OS.


Analysis of he-ne laser surface reflections from an off-axis parabolic mirror.
Surface reflections from an off-axis parabolic mirror are analyzed in three dimensions applying the techniques of vector analysis and ray tracing. A He-Ne laser is directed onto the mirror surface and held fixed while the parabolic mirror is rotated through an angle of 360 degrees on an axis that is parallel to that of the original paraboloid. The reflection from the mirror traces a closed figure in a plane perpendicular to the paraboloidal axis when the mirror undergoes one complete revolution about its center axis. The shape of this figure depends on the value of the off-axis distance and the focal length; consequently, this figure yields information about the parameters specified in the construction of off-axis parabolic mirrors.


Posttraumatic Stress Disorder and Aggression Among Post-9/11 Veterans: The Role of Shame.
Posttraumatic stress disorder (PTSD) is often accompanied by elevated aggression. PTSD and combat exposure alone do not fully explain the reliable finding of heightened aggression among trauma-exposed veterans. Shame may be an important affective feature in this relationship. The present study examined the role of shame from a social hierarchy theoretical perspective in a sample of 52 combat veterans from the post-9/11 era. Correlational analyses indicated moderately strong positive relationships among PTSD, shame, and aggression. Trait shame was found to significantly mediate the relationship between total PTSD severity and physical aggression, but not other forms of aggression. For veterans within the context of a hierarchical military culture, separation from the military and PTSD diagnosis may be very salient markers of social loss and social exclusion. Aggression may operate to reduce the negative affective experience associated with shame and to regain social standing. Findings implicate shame as an important emotional component in the relationship between PTSD and aggression.


Superparamagnetic iron oxide nanoparticles for MRI: contrast media pharmaceutical company R&D perspective.
Superparamagnetic iron oxide (SPIO) nanoparticles are a relatively large class of contrast agents for magnetic resonance imaging. According to their biodistribution, distinct classes of SPIO nanoparticles have been investigated for clinical applications either as macrophage imaging agents or blood pool agents. Contrast agents which are pharmaceutics followed the same development rules as therapeutic drugs. Several drawbacks such as clinical development difficulties, organization of market access and imaging technological developments have limited the widespread use of these products. SPIO nanoparticles that are composed of thousands iron atoms providing large T2* effects are particularly suitable for theranostic. Stem cell migration and immune cell trafficking, as well as targeted SPIO nanoparticles for molecular imaging studies are mainly at the stage of proof of concept. A major economic challenge in the development of molecular imaging associated with a therapeutic treatment/procedure is to define innovative business models compatible with the needs of all players taking into account that theranostic solutions are promising to optimize resource allocation and ensure that expensive treatments are prescribed to responding patients.


Dipeptide analogues containing 4-ethoxy-3-pyrrolin-2-ones.
[reaction: see text] Pyrrolidine-2,4-diones (1) are naturally occurring analogues of amino acids. We herein present a facile synthesis of N-acylated, O-alkylated pyrrolin-2-ones (2) in high yield and excellent enantiopurity. Molecular mechanics calculations suggest that the resulting dipeptide analogues adopt a linear, extended conformation.


Overview of Pharmacological Treatment Options for Pediatric Patients with Refractory Kawasaki Disease.
Kawasaki disease is an autoimmune disease found predominantly in children under the age of 5 years. Its incidence is higher in those who live in Asian countries or are of Asian descent. Kawasaki disease is characterized as an acute inflammation of the vasculature bed affecting mainly the skin, eyes, lymph nodes, and mucosal layers. Although the disease is usually self-limiting, patients may develop cardiac abnormalities that can lead to death. The exact cause of the disease is unknown; however, researchers hypothesize that an infectious agent is responsible for causing Kawasaki disease. Initial treatment options with intravenous immune globulin and aspirin are sufficient to cure most patients who acquire this disease. Unfortunately, in up to one-quarter of patients, the disease will be refractory to initial therapy and will require further management with corticosteroid, immunomodulatory, or cytotoxic agents. The lack of randomized, controlled trials makes treatment of refractory disease difficult to manage. Until larger randomized, controlled trials are published to give more guidance on therapy for this stage of disease, clinicians should use the data available from observational studies and case reports in conjunction with their clinical expertise to make treatment decisions.


Rho kinase-1 mediates cardiac fibrosis by regulating fibroblast precursor cell differentiation.
Highly proliferative, CD34+/CD45+ fibroblasts derived from monocytic, blood-borne precursor cells play a critical role in the development of fibrosis in a murine ischaemic/reperfusion cardiomyopathy (I/RC) model. The differentiation of human monocytes into fibroblasts in vitro occurs after transendothelial migration (TEM) induced by monocyte chemoattractant protein 1 (MCP-1). Because Rho-associated kinase-1 (ROCK-1) has been implicated in fibrosis and leukocyte TEM, we investigated its involvement in I/RC. We subjected mice with genetic deletion of ROCK-1 to I/RC. We found that ROCK-1(-/-) mice did not develop the fibrosis and cardiac dysfunction characteristic for I/RC: compared with wild-type, ROCK-1(-/-) hearts showed markedly lower numbers of I/RC-induced alpha-smooth muscle actin+ fibroblasts and CD34+/CD45+ fibroblast precursors. Isolated cardiac fibroblasts from ROCK-1(-/-) mice undergoing I/RC were large and slowly proliferating, similar to fibroblasts isolated from sham-treated hearts. We also performed in vitro assays in which human peripheral blood mononuclear cells (PBMC) migrated through endothelial cells in response to MCP-1. Prior to migration, PBMC were incubated with ROCK-1-targeting small interfering RNA to silence ROCK-1 expression. We found that an 80% reduction of ROCK-1 protein did not inhibit TEM, but significantly reduced the amount of mononuclear cells that differentiated into fibroblasts by >20-fold. Our data implicate an important role for ROCK-1 in the differentiation, but not in the TEM of monocytes that mature into cardiac fibroblasts. These cells mediate non-adaptive fibrosis.


Health service utilisation and access for people who inject drugs during COVID-19.
The wide-spread implementation of interventions to limit transmission and public health consequences of COVID-19 in the Australian state of Victoria had flow-on consequences for people who use and inject drugs. Consequences included the interruption of illicit drug supply and drug procurement, and the disruption to the delivery of health services. To inform strategies that can minimise the adverse outcomes of similar future disruptive events, this study explored how COVID-19 restrictions impacted access to harm reduction and drug treatment services for people who inject drugs in Melbourne, Victoria. Qualitative semi-structured interviews were conducted via an online calling app, with 11 participants of a broader cohort study (the SuperMIX study) in April 2020. Interviews were focused on participants experiences of accessing and using harm reduction and drug treatment services. Data were thematically analysed using a process of blended coding. Findings revealed how disruptions in the delivery of harm reduction and drug treatment services-in response to COVID-19 restrictions-created barriers accessing sterile injecting equipment, increased risk of arrest by police and exacerbated social isolation. Participants reported difficulties adapting to changes in services access, with some increases in injecting risk behaviours. However, improvements in opioid agonist therapy prescriptions were noted as a beneficial outcome. By examining the impacts of COVID-19 and the resultant restrictions on people who inject drugs' access to health services in Melbourne, Victoria, findings provide guidance for future responses to the unanticipated large-scale effects of the COVID-19 pandemic, and similar disruptive events.


Metabolic Profile and Mycoherbicidal Activity of Three Alternaria alternata Isolates for the Control of Convolvulus arvensis, Sonchus oleraceus, and Xanthium strumarium.
Alternaria alternata isolates C1, S1, and X3 were isolated respectively from the weeds Convolvulus arvensis, Sonchus oleraceus, and Xanthium strumarium in Algiers during 2016 and identified by morphological and molecular analyses. The aim of this investigation was to chemically characterize the exometabolome of these fungi and to evaluate the myco-herbicidal potential of their culture filtrates, crude extracts, or fractions towards target weeds. Results revealed a great heterogeneity in the biochemical profiles of the exometabolome with the remarkable presence of two compounds: tenuazonic acid (TeA) and triprenyl phenol-7 (SMTP-7). To the best of our knowledge, SMTP-7-found in all the isolates-as well as 12-methoxycitromycin detected in the culture filtrate of isolate C1, have never been reported to be produced by A. alternata. Some fractions of isolates C1 and S1 showed symptoms (necrosis and chlorosis) on the detached leaves of C. arvensis and S. oleraceus, respectively with up to 100% phytotoxic effect at low concentration. In conclusion, biochemical characterization revealed great difference of C1, S1, and X3 exometabolome that is likely to explain the difference in their phytotoxic activity. Some fractions (d1, e1, h1, i1, a2, and f2) of isolates C1 and S1 of A. alternata caused severe necrosis and chlorosis on the injured detached leaves of C. arvensis and S. oleraceus, respectively.


Genomic loss of 18p predicts an adverse clinical outcome in patients with high-risk breast cancer.
The impact of the genomic imbalances on the clinical outcome of 34 patients with lymph-node positive high-risk breast cancer (HRBC) was investigated using comparative genomic hybridization. All of the patients were uniformly treated with high-dose chemotherapy and autologous stem cell transplantation. The average number of chromosomal imbalances per tumor was 11 (range, 2-24), including DNA overrepresentation on chromosomes 1q (59%), 17q (38%), 8q and 16p (35% each), 20q (32%), and 19p (26%), and genomic losses involving 9p and 18q (41%), 8p, 11q, and 18p (38%), 17p (32%), 4p and Xq (29%), and 16q (26%). The most significant association among genomic changes and clinical-pathological features was the correlation of the loss of 8p with progesterone receptor positivity (P < 0.005). With a median follow-up time of 74 months, 15 patients (44%) have relapsed. In the univariate analysis, patients with gain/amplification of 17q including the HER-2/neu gene locus had a longer disease-free survival (P = 0.02), whereas those with genomic loss of 18p had a higher probability of relapse (P = 0.003). In multivariate analysis, the loss of 18p was the only parameter correlated with shorter disease-free survival (relative risk, 4.8; 95% confidence interval, 1.57-14.8; P = 0.006). In summary, our data indicate that the tumoral genomic profile may represent a valuable marker for predicting the clinical outcome in HRBC. Furthermore, the genomic loss of 18p may identify a poor prognostic subgroup of patients with HRBC.


Cationic Net Charge and Counter Ion Type as Antimicrobial Activity Determinant Factors of Short Lipopeptides.
To get a better insight into the antimicrobial potency of short cationic lipopeptides, 35 new entities were synthesized using solid phase peptide strategy. All newly obtained lipopeptides were designed to be positively charged from +1 to +4. This was achieved by introducing basic amino acid - lysine - into the lipopeptide structure and had a hydrophobic fatty acid chain attached. Lipopeptides were subjected to microbiological tests using reference strains of Gram-negative bacteria: Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, Pseudomonas aeruginosa, Gram-positive bacteria: Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Enterococcus faecalis, and fungi: Candida albicans, Candida tropicalis, Aspergillus brasiliensis. The minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and minimal fungicidal concentration (MFC) were established for each strain. The toxicity toward human cells was determined by hemolysis tests via minimum hemolytic concentration (MHC) determination. The effect of the trifluoroacetic acid (TFA) counter ion on the antimicrobial activity of lipopeptides was also examined by its removing and performing the antimicrobial tests using counter ion-free compounds. The study shows that lipopeptides are more potent against Gram-positive than Gram-negative strains. It was revealed that positive charge equals at least +2 is a necessary condition to observe significant antimicrobial activity, but only when it is balanced with a proper length of hydrophobic fatty acid chain. The hemolytic activity of lipopeptides strongly depends on amino acid composition of the hydrophilic portion of the molecule as well as fatty acid chain length. Compounds endowed with a greater positive charge were more toxic to human erythrocytes. This should be considered during new lipopeptide molecules design. Our studies also revealed the TFA counter ion has no significant effect on the antimicrobial behavior of cationic lipopeptides.


Low-energy electron stimulated desorption of neutrals from multilayers of SiCl4 on Si(111).
The interaction of low-energy electrons with multilayers of SiCl(4) adsorbed on Si(111) leads to production and desorption of Cl((2)P(32)), Cl((2)P(12)), Si, and SiCl. Resonant structure in the yield versus incident electron energy (E(i)) between 6 and 12 eV was seen in all neutral channels and assigned to dissociative electron attachment (DEA), unimolecular decay of excited products produced via autodetachment and direct dissociation. These processes yield Cl((2)P(32)) and Cl((2)P(12)) with nonthermal kinetic energies of 425 and 608 meV, respectively. The Cl((2)P(12)) is produced solely at the vacuum surface interface, whereas the formation of Cl((2)P(32)) likely involves subsurface dissociation, off-normal trajectories, and collisions with neighbors. Structure in the Cl((2)P(32)) yield near 14 and 25 eV can originate from excitation of electrons in the 2e, 7t(2) and 6t(2), 6a(1) levels, respectively. Although the 14 eV feature was not present in the Cl((2)P(12)) yield, the broad 25 eV feature, which involves complex Auger filling of holes in the 6t(2) and 6a(1) levels of SiCl(4), is observed. Direct ionization, exciton decay, and DEA from secondary electron scattering all occur at E(i)>14 eV. Si and SiCl were detected via nonresonant ionization of SiCl(x) precursors that are produced via the same states and mechanisms that yield Cl. The Si retains the kinetic energy profile of the desorbed precursors.


A medicinal-chemistry-guided approach to selective and druglike sigma 1 ligands.
Based on a medicinal-chemistry-guided approach, three novel series of druglike cycloalkyl-annelated pyrazoles were synthesized and display high affinity (pKi>8) for the sigma1 receptor. Structure-affinity relationships were established, and the different scaffolds were optimized with respect to sigma1 binding and selectivity versus the sigma2 receptor and the hERG channel, resulting in selective compounds that have Ki values (for sigma1) in the subnanomolar range. Selected compounds were screened for cytochrome P450 inhibition (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4), metabolic stability (rat and human liver microsomes), and cell-membrane permeability (Caco-2). They showed favorable in vitro ADME properties as well as favorable calculated druglike and experimental physicochemical properties. Furthermore, compounds 7 f and 17 a, for example, displayed high selectivity (affinity) for the sigma1 receptor against a wide range of other receptors (>60). With these valuable tool compounds in hand, we are further exploring the role of the sigma1 receptor in relevant animal models corresponding to such medicinal indications as drug abuse, pain, depression, anxiety, and psychosis.


Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q.
Autism is a neurodevelopmental disorder that usually arises on the basis of a complex genetic predisposition. The most significant susceptibility region in the first whole genome screen of multiplex families was on chromosome 7q, although this linkage was evident only in UK IMGSAC families. Subsequently all other genome screens of non-UK families have found some evidence of increased allele sharing in an overlapping 40 cM region of 7q. To further characterize this susceptibility locus, linkage analysis has now been completed on 170 multiplex IMGSAC families. Using a 5 cM marker grid, analysis of 125 sib pairs meeting stringent inclusion criteria resulted in a multipoint maximum LOD score (MLS) of 2.15 at D7S477, whereas analysis of all 153 sib pairs generated an MLS of 3.37. The 71 non-UK sib pairs now contribute to this linkage. Linkage disequilibrium mapping identified two regions of association-one lying under the peak of linkage, the other some 27 cM distal. These results are supported in part by findings in independent German and American singleton families.


Developing an usability-engineered Excel-based nursing administrative e-form generator.
Head nurses in hospitals always need to do lots of administrative work and are burdened with heavy information load. The purpose of this study is to develop a usability-engineered nursing administrative e-form generator to assist them to easily design a simple management information system to collect and analyze data. System was designed using Excel VBA. This system contains form generator, data collection and analysis is easy for healthcare professionals without computer literacy to operate.


Predictive factors for endothelial cell loss after penetrating keratoplasty.
To assess the influence of donor age, donor endothelial cell density, recipient age, and diagnosis on loss of endothelial cell density after penetrating keratoplasty, we evaluated endothelial cell density data from specular endothelial images collected during the follow-up penetrating keratoplasty surgeries performed from 1980 through 1985 at one center. Univariate and multivariate analyses of information from 265 grafts showed consistent and statistically significant associations between 1-year postoperative loss of endothelial cell density and donor age, donor endothelial cell density, and recipient age. Corneas obtained from older donors, corneas with higher donor endothelial cell density, and corneas transplanted to older recipients demonstrated greater percentage of loss of endothelial cell density 1 year after surgery. These three factors accounted for 17% of the total variance in percentage of loss of endothelial cell density 1 year after surgery.


The health of our nation - the future of our health system: the national expert commission on the move.
The looming end of 2011 finds CNA's National Expert Commission wrapping up a jam-packed fall during which we had the privilege of speaking with nurses, members of the public and government leaders in all six of Canada's time zones, literally from Victoria to St. John's, and from the Far North to downtown Toronto.


Transcriptome in paraffin samples for the diagnosis and prognosis of adrenocortical carcinoma.
Molecular classification is important for the diagnosis and prognosis of adrenocortical tumors (ACT). Transcriptome profiles separate adrenocortical adenomas 'C2' from carcinomas, and identify two groups of carcinomas 'C1A' and 'C1B', of poor and better prognosis respectively. However, many ACT cannot be profiled because of improper or absent freezing procedures, a mandatory requirement so far. The main aim was to determine transcriptome profiles on formalin-fixed paraffin-embedded (FFPE) samples, using the new 3'-end RNA-sequencing technology. A secondary aim was to demonstrate the ability of this technique to explore large FFPE archives, by focusing on the rare oncocytic ACT variants. We included 131 ACT: a training cohort from Cochin hospital and an independent validation cohort from Wuerzburg hospital. The 3' transcriptome was generated from FFPE samples using QuantSeq (Lexogen, Vienna, Austria) and NextSeq500 (Illumina, San Diego, CA, USA). In the training cohort, unsupervised clustering identified three groups: 'C1A' aggressive carcinomas (n = 28, 29%), 'C1B' more indolent carcinomas (n = 28, 29%), and 'C2' adenomas (n = 39, 41%). The prognostic value of FFPE transcriptome was confirmed in the validation cohort (5-year OS: 26% in 'C1A' (n = 26) and 100% in 'C1B' (n = 10), P = 0.003). FFPE transcriptome was an independent prognostic factor in a multivariable model including tumor stage and Ki-67 (OS HR: 7.5, P = 0.01). Oncocytic ACT (n = 19) did not form any specific cluster. Oncocytic carcinomas (n = 6) and oncocytic ACT of uncertain malignant potential (n = 4) were all in 'C1B'. The 3' RNA-sequencing represents a convenient solution for determining ACT molecular class from FFPE samples. This technique should facilitate routine use and large retrospective studies.


Understanding disordered and unfolded proteins using single-molecule FRET and polymer theory.
Understanding protein folding and the functional properties of intrinsically disordered proteins (IDPs) requires detailed knowledge of the forces that act in polypeptide chains. These forces determine the dimensions and dynamics of unfolded and disordered proteins and have been suggested to impact processes such as the coupled binding and folding of IDPs, or the rate of protein folding reactions. Much of the progress in understanding the physical and chemical properties of unfolded and intrinsically disordered polypeptide chains has been made possible by the recent developments in single-molecule fluorescence techniques. However, the interpretation of the experimental results requires concepts from polymer physics in order to be understood. Here, I review some of the theories used to describe the dimensions of unfolded polypeptide chains under varying solvent conditions together with their more recent application to experimental data.


On the Acceptance of "Fake" Histopathology: A Study on Frozen Sections Optimized with Deep Learning.
The fast acquisition process of frozen sections allows surgeons to wait for histological findings during the interventions to base intrasurgical decisions on the outcome of the histology. Compared with paraffin sections, however, the quality of frozen sections is often strongly reduced, leading to a lower diagnostic accuracy. Deep neural networks are capable of modifying specific characteristics of digital histological images. Particularly, generative adversarial networks proved to be effective tools to learn about translation between two modalities, based on two unconnected data sets only. The positive effects of such deep learning-based image optimization on computer-aided diagnosis have already been shown. However, since fully automated diagnosis is controversial, the application of enhanced images for visual clinical assessment is currently probably of even higher relevance. Three different deep learning-based generative adversarial networks were investigated. The methods were used to translate frozen sections into virtual paraffin sections. Overall, 40 frozen sections were processed. For training, 40 further paraffin sections were available. We investigated how pathologists assess the quality of the different image translation approaches and whether experts are able to distinguish between virtual and real digital pathology. Pathologists' detection accuracy of virtual paraffin sections (from pairs consisting of a frozen and a paraffin section) was between 0.62 and 0.97. Overall, in 59% of images, the virtual section was assessed as more appropriate for a diagnosis. In 53% of images, the deep learning approach was preferred to conventional stain normalization (SN). Overall, expert assessment indicated slightly improved visual properties of converted images and a high similarity to real paraffin sections. The observed high variability showed clear differences in personal preferences.


Differential genetic etiology of reading disability as a function of IQ.
To test the hypothesis that the genetic etiology of reading disability differs as a function of IQ, composite reading performance data from 223 pairs of identical twins and 169 pairs of same-gender fraternal twins in which at least one member of each pair was classified with reading disability were subjected to multiple regression analysis (DeFries & Fulker, 1985, 1988). In the total sample, heritability of the group deficit in reading performance (h(g)2) was .58 (+/- .08). However, when the basic regression model was fitted separately to data from twin pairs with average Wechsler (1974, 1981) full scale IQ scores below 100 or 100 and above, resulting estimates of h(g)2 were .43 and .72, respectively, a significant difference (p < or = .03, one-tailed). The results of fitting extended regression models to reading performance and continuous IQ data provide evidence that the genetic etiology of reading disability differs as a linear function of IQ (p < or = .007, one-tailed). These results suggest that IQ is relevant for the diagnosis of reading disability and that environmental influences may be more salient as a cause of reading difficulties in children with lower IQ scores.


Parental Knowledge, Attitudes, and Behaviours towards Human Papillomavirus Vaccination for Their Children: A Systematic Review from 2001 to 2011.
Objectives. A systematic review of parental surveys about HPV and/or child HPV vaccination to understand parental knowledge, attitudes, and behaviour before and after FDA approval of the quadrivalent HPV vaccine and the bivalent HPV vaccine. Search Strategy. Searches were conducted using electronic databases limited to published studies between 2001 and 2011. Findings. The percentage of parents who heard about HPV rose over time (from 60% in 2005 to 93% in 2009), as did their appreciation for the HPV infection and cervical cancer link (from 70% in 2003 to 91% in 2011). During the FDA approval, there was a stronger vaccine awareness but it has waned. The same pattern is seen with parents whose children received the HPV vaccine (peak at 84% in 2010 and now 36% in 2011) or the intention to vaccinate (peak at 80% in 2008 and now 41% in 2011). Conclusions. Parents had safety concerns and wanted more information their physician from to recommend and to confidently HPV vaccinate their children.


Maintenance energy requirements in miniature colony dogs.
There are numerous reports of maintenance energy requirements (MER) in dogs, but little information is available about energy requirements of miniature dog breeds. In this prospective, observational, cohort study, we aimed to determine MER in dogs from a number of miniature breeds and to determine which factors were associated with it. Forty-two dogs participated in the study. MER was calculated by determining daily energy intake (EI) during a period of 196 days (28-359 days) when body weight did not change significantly (e.g. ±2% in 12 weeks). Estimated median MER was 473 kJ/kg(0.75) /day (285-766 kJ/kg(0.75) /day), that is, median 113 kcal/kg(0.75) /day (68-183 kcal/kg(0.75) /day). In the obese dogs that lost weight, median MER after weight loss was completed was 360 kJ/kg(0.75) /day (285-515 kJ/kg(0.75) /day), that is, 86 kcal/kg(0.75) /day, (68-123 kcal/kg(0.75) /day). Simple linear regression analysis suggested that three breeds (e.g. Chihuahua, p = 0.002; Yorkshire terrier, p = 0.039; dachshund, p = 0.035) had an effect on MER. In addition to breed, simple linear regression revealed that neuter status (p = 0.079) and having previously been overweight (p = 0.002) were also of significance. However, with multiple linear regression analysis, only previous overweight status (MER less in dogs previously overweight p = 0.008) and breed (MER greater in Yorkshire terriers [p = 0.029] and less in Chihuahuas [p = 0.089]) remained in the final model. This study is the first to estimate MER in dogs of miniature breeds. Although further information from pet dogs is now needed, the current work will be useful for setting energy and nutrient requirement in such dogs for the future.


Integrating Health and Care in China: Lessons Learned and Future Outlook.
An aging population is one of the key drivers reshaping health care systems. In China, the complex needs of its huge aging population require integration across the health and care sectors. Over the past decade, the central government of China promulgated a series of policies to promote the establishment of aftercare facilities, specify approaches to integrate health and care service delivery at institutional and community levels, pilot long-term care insurance (LTCI) as a funding mechanism, and reform administrative structures in favor of integration. Progress has been made towards organizational and clinical integration of service delivery both at institutional and community levels. LTCI has been introduced as the financing mechanism covering long term care services. The experiences of China in the integration of health and care could be summarized as a top-down approach in policy formulation and implementation, the significant employment of pilots and demonstrations, and the activation of market forces. However, China is still in the initial stage of integrating health and care and is faced with system-level challenges in its financing, management, and workforce, and faces technical challenges, such as a lack of tools, and standards. In the future, these issues need to be addressed.


Avoiding predatory publishing for early-career ophthalmologists.
This article aims at analyzing the impact of predatory publishing in ophthalmology, criteria to identify a legitimate journal, red flags of a predatory journal, sources, and checkpoints available before publishing scientific work in a standard ophthalmology journal. A retrospective review was performed and a list of suspected Ophthalmology predatory journals was extracted through four major so-called blacklists: Beall's, Cabell's, Manca's, and Strinzel's list. This list of journals was then cross-referenced with the UGC CARE and vetted whitelist of vision science journals to remove the legitimate journals. Moreover, as all the predatory journals are supposed to be open access, all possible types of open-access journals on the Scimago webpage were also searched. A gross estimate in terms of publication cost was searched for, and a list of authentic links to find out a legitimate journal was prepared. Additionally, the methodology by which these predatory journals penetrate legitimate indexes such as PubMed was also evaluated. A total of 51 ophthalmology predatory journals were enlisted. Thirty-eight out of 124 Ophthalmology journals listed on Scimago were open access, and the cost of publishing in predatory journals ranged from USD50-500, which is substantially lower than that in legitimate journals (USD 50-3000). A total of 13 open-access platforms exist, with 10 characteristic red flags to identify a predatory journal. These journals have penetrated legitimate indexes such as PubMed by similar-sounding names to the legitimate journals and have published articles with external funding, which needs indexing. Predatory publishing impacts the quality of research in every field, including Ophthalmology, and must be discouraged.


Photobiomodulation as adjunctive therapy for guided bone regeneration. A microCT study in osteoporotic rat model.
Regeneration of diseased bone is challenging. Guided bone regeneration (GBR) has been applied to favor the bone repair. Photobiomodulation (PBM) is also a recognized therapy able to improve bone repair in healthy and diseased individuals. Thus, with the hypothesis that PBM therapy could improve the GBR of diseased bone, this study evaluated the effect of PBM as adjunctive therapy to GBR in osteoporotic rats. Osteoporosis was induced in rats using the oophorectomy model. Then, 5-mm calvaria bone defects were created and treated according to the experimental groups, as follows: with no further treatment (Control); conventional GBR (Membrane), GBR and PBM applied with 3 s, 4 J/cm2 and 0.12 J per point (PBM-1) and GBR and PBM applied with 10s, 14 J/cm2, 0.4 J per point (PBM-2). PBM therapy (808 nm, 40 mW, 1.42 W/cm2) was applied immediately, 48 and 96 h postoperatively. Four and eight weeks later, the samples were harvested and processed for micro-computerized tomography (Micro CT). Data were statistically compared (p < 0.05). From 4 to 8 weeks mostly significant changes were observed in the PBM groups. The bone volume fraction and number of trabeculae of the PBM groups, especially the PBM-1, were significantly higher than those of Control (p < 0.0001). The values of thickness and separation of the trabeculae and structural model index of the PBM groups were significantly smaller than Control (p < 0.0001). The connectivity density was significantly higher on Membrane and PBM groups than Control (p < 0.0004). The application of PBM as adjunctive therapy to GBR results in enhanced bone formation and maturation in comparison to the conventional GBR in the regeneration of lesions of osteoporotic bone in rats. Overviewing the challenges that face bone regeneration in patients with osteoporosis, our findings open new perspectives on the treatment of bone defects under osteoporotic conditions.


RNA-dependent RNA switches in bacteria.
The versatility of RNA as a regulatory molecule has become increasingly apparent in recent years. RNA elements within a transcript can sense a large variety of physiological signals, resulting in modulation of expression of the gene(s) encoded on that transcript by effects on transcript synthesis, mRNA stability, and translation. The response of the transcript to the signal can result in direct sequestration of elements involved in various steps of gene expression, or promotion of a structural rearrangement of the target mRNA that affects the activity of elements important for expression. The regulatory signal can be as simple as a change in temperature, or as complex as a translating ribosome, the processivity of which is affected by the appropriate cellular parameter. Among these many regulatory mechanisms are those in which the regulatory signal is a specific RNA that binds to the target mRNA. Systems of this type are widespread in bacteria, and they fall into several classes based on the type of RNA that acts as the regulator, and the mode of interaction of the regulatory RNA with its target. These include systems in which the regulatory RNA is encoded on the opposite strand of its target, systems in which the regulatory RNA is encoded elsewhere in the genome, and systems in which RNAs (such as tRNAs) that are normally used for a different cellular process are borrowed for use as regulatory molecules. This review will summarize these classes of regulatory mechanisms and their use in bacterial systems.


Correction: The novel anti-inflammatory activity of mcIRBP from Momordica charantia is associated with the improvement of diabetic nephropathy.
Correction for 'The novel anti-inflammatory activity of mcIRBP from Momordica charantia is associated with the improvement of diabetic nephropathy' by Pei-Yung Liao et al., Food Funct., 2022, DOI: 10.1039/d1fo03620c.


Analysis of major histocompatibility complex gene products in tissues isolated from the developing human nervous system.
We have examined the expression of the major histocompatibility complex (MHC) class I and II gene products in the developing human fetal peripheral nervous system. As determined by RNA blot hybridization analysis, MHC class I RNA was readily detectable in extracts prepared from dorsal root ganglia (DRG) obtained from aborted human fetal material. However, utilizing similar methodology, it was not possible to detect MHC class II RNA. In conjunction with these studies, expression of MHC class I and II proteins in primary human fetal DRG tissue was examined by fluorescence-activated flow cytometry and protein immunoblotting. Consistent with the detection of MHC-specific RNA, the accumulation of MHC class I-specific protein was readily detectable in human fetal DRG neural cell populations with little, if any, accumulation of MHC class II-specific protein evident. These studies suggest that MHC gene products may be expressed early in the development of the human nervous system resulting in the generation of specific immunocompetent neural cell populations.


Influence of incorporation of ZrO2 nanoparticles on the repair strength of polymethyl methacrylate denture bases.
Repeated fracture of the denture base is a common problem in prosthodontics, and it represents a nuisance and a time sink for the clinician. Therefore, the possibility of increasing repair strength using new reinforcement materials is of great interest to prosthodontists. This study aimed to evaluate the effects of incorporation of zirconia nanoparticles (nano-ZrO2) on the flexural strength and impact strength of repaired polymethyl methacrylate (PMMA) denture bases. One hundred eighty specimens of heat-polymerized acrylic resin were fabricated (90 for each test) and divided into three main groups: one control group (intact specimens) and two groups divided according to surface design (45° bevels and butt joints), in which specimens were prepared in pairs to create 2.5 mm gaps. Nano-ZrO2 was added to repair resin in 2.5 wt%, 5 wt%, and 7.5 wt% concentrations of acrylic powder. A three-point bending test was used to measure flexural strength, and a Charpy-type test was used to measure impact strength. Scanning electron microscopy was used to analyze the fracture surfaces and nano-ZrO2 distribution. The results were analyzed with a paired sample t-test and an unpaired t-test, with a P-value of ≤0.05 being significant. Incorporation of nano-ZrO2 into the repair resin significantly increased flexural strength (P<0.05). The highest value was found in the bevel group reinforced with 7.5% nano-ZrO2, whereas the lowest value was found in the butt group reinforced with 2.5% nano-ZrO2. The impact strength values of all repaired groups were significantly lower than those of the control group (P<0.05). Among repaired groups, the higher impact strength value was seen in the butt group reinforced with 2.5% nano-ZrO2. The bevel joint demonstrated mainly cohesive failure, whereas the butt joint demonstrated mainly adhesive failure. Incorporation of nano-ZrO2 into the repair resin improved the flexural strength of repaired denture bases, whereas it decreased impact strength, especially with high nano-ZrO2 concentrations.


Event-related potentials and visual avoidance in blood phobics: is there any attentional bias?
The possible presence of processing biases for threat-relevant information in blood-injection-injury phobia has been largely neglected in the literature. This issue was addressed by recording the late components (P300 and slow waves) of event-related potentials (ERPs) in the context of affective picture perception, as indicators of processing resources allocation. Blood phobics and healthy controls were shown threat-relevant, emotional threat-irrelevant, and neutral pictures. Free viewing time (VT) was measured as an index of voluntary visual avoidance, along with self-reports of pleasantness and arousal. No group differences as a function of picture content emerged for ERPs. Blood phobics spent less time viewing mutilations than did controls, but they did not show a clear-cut visual avoidance. As expected, individuals with phobias rated blood-related pictures as more unpleasant and arousing relative to controls. ERP results are in line with the limited behavioral data in the literature in demonstrating that blood phobics do not show an attentional bias toward threat-relevant stimuli.


Behaviour of Yersinia enterocolitica and Aeromonas hydrophila in skim milk during fermentation by various lactobacilli.
In this study, behaviour of Yersinia enterocolitica and Aeromonas hydrophila in skim milk during fermentation by various Lactobacillus sp. were determined. pH values of the skim milk samples were also examined during fermentation. The amount of produced lactic acid and diacetyl/acetoin productions of the Lactobacillus sp. were estimated. Antimicrobial effects of the lactobacilli on Y. enterocolitica and A. hydrophila were also determined by an agar diffusion method. While Y. enterocolitica was not inhibited and grew during fermentation, A. hydrophila was inhibited, in part, and the growth was retarded. Results were supported by the agar diffusion method for Y. enterocolitica, whereas inhibition activity was not found for A. hydrophila. The highest lactic acid productions were estimated in L. bulgaricus (7.50 mg/ml) and L. acidophilus (5.63 mg/ml) and four out of six Lactobacillus sp. were found to be diacetyl/acetoin producers.


Metal Nanoparticle-Decorated Silicon Nanowire Arrays on Silicon Substrate and their Applications.
Herein, we report an efficient method to produce silver (Ag) nanoparticle-decorated silicon (Si) nanowire (NW) arrays on a pyramidal Si (P-Si) substrate by using a pure chemical method and rapid thermal annealing in different atmospheres. A metal-assisted chemical etching technique was used to produce vertical Si NW arrays on pyramidal Si. The etching was observed to be heavily dependent on the substrate type. On planar Si (100), the etching was observed to occur in a uniform manner. However, the etching rate was observed to increase from the top to the base of the Si pyramid. The Si NWs produced from P-Si have zig-zag sidewalls as observed from high-resolution transmission electron microscopy images. However, for the same oxidant concentration, Si NWs produced from planar Si (100) consist of straight and amorphous sidewalls. Local variation of oxidant concentration is responsible for the formation of different sidewalls. The substrates are both surface-enhanced Raman scattering (SERS) active and hydrophobic. The hydrophobicity is due to the dual scale of roughness contributed to by both pyramidal and NW structures. Finite-difference time-domain simulation shows that the gap between two Ag spheres and also the gap between Si NWs and Ag spheres contributed to SERS enhancement.


Laser-Assisted in Situ Keratomileusis with Optimized, Fast-Repetition, and Cyclotorsion Control Excimer Laser to Treat Hyperopic Astigmatism with High Cylinder.
To evaluate the visual outcomes after femtosecond laser-assisted laser in situ keratomileusis (LASIK) surgery to correct primary compound hyperopic astigmatism with high cylinder using a fast repetition rate excimer laser platform with optimized aspheric profiles and cyclotorsion control. Eyes with primary simple or compound hyperopic astigmatism and a cylinder power ≥3.00 D had uneventful femtosecond laser-assisted LASIK with a fast repetition rate excimer laser ablation, aspheric profiles, and cyclotorsion control. Visual, refractive, and aberrometric results were evaluated at the 3- and 6-month follow-up. The astigmatic outcome was evaluated using the Alpins method and ASSORT software. This study enrolled 80 eyes at 3 months and 50 eyes at 6 months. The significant reduction in refractive sphere and cylinder 3 and 6 months postoperatively (p<0.01) was associated with an improved uncorrected distance visual acuity (p<0.01). A total of 23.75% required retreatment 3 months after surgery. Efficacy and safety indices at 6 months were 0.90 and 1.00, respectively. At 6 months, 80% of eyes had an SE within ±0.50 D and 96% within ±1.00 D. No significant differences were detected between the third and the sixth postoperative months in refractive parameters. A significant increase in the spherical aberration was detected, but not in coma. The correction index was 0.94 at 3 months. Laser in situ keratomileusis for primary compound hyperopic astigmatism with high cylinder (>3.00 D) using the latest excimer platforms with cyclotorsion control, fast repetition rate, and optimized aspheric profiles is safe, moderately effective, and predictable.


The structure of RalF, an ADP-ribosylation factor guanine nucleotide exchange factor from Legionella pneumophila, reveals the presence of a cap over the active site.
The Legionella pneumophila protein RalF is secreted into host cytosol via the Dot/Icm type IV transporter where it acts to recruit ADP-ribosylation factor (Arf) to pathogen-containing phagosomes in the establishment of a replicative organelle. The presence in RalF of the Sec7 domain, present in all Arf guanine nucleotide exchange factors, has suggested that recruitment of Arf is an early step in pathogenesis. We have determined the crystal structure of RalF and of the isolated Sec7 domain and found that RalF is made up of two domains. The Sec7 domain is homologous to mammalian Sec7 domains. The C-terminal domain forms a cap over the active site in the Sec7 domain and contains a conserved folding motif, previously observed in adaptor subunits of vesicle coat complexes. The importance of the capping domain and of the glutamate in the "glutamic finger," conserved in all Sec7 domains, to RalF functions was examined using three different assays. These data highlight the functional importance of domains other than Sec7 in Arf guanine nucleotide exchange factors to biological activities and suggest novel mechanisms of regulation of those activities.


Microsatellite loci in urine supernatant and stored samples from racehorses.
To evaluate whether urine supernatant contains amplifiable DNA and to determine factors that influence genotyping of samples from racehorses after storage and transportation. 580 urine, 279 whole blood, and 40 plasma samples obtained from 261 Thoroughbreds and Standardbreds. Genomic DNA was isolated from stored blood and urine samples collected from racehorses after competition. Quantified DNA was evaluated to determine whether 5 equine microsatellite loci (VHL20, HTG4, AHT4, HMS6, and HMS7) could be amplified by use of PCR techniques. Fragment size of each amplified locus was determined by use of capillary electrophoresis. High-molecular-weight and amplifiable DNA were recovered from refrigerated blood samples, but recovery from urine varied. Deoxyribonucleic acid was recovered from both urine supernatant and sediment. Freeze-thaw cycles of urine caused accumulation of amplifiable DNA in the supernatant and clearance of naked DNA. Repeated freeze-thaw cycles significantly decreased DNA yield and induced DNA degradation, which resulted in failure to detect microsatellite loci. Select drugs detected in test samples did not affect PCR amplification. Contaminants in DNA isolates inhibited PCR amplification and resulted in partial microsatellite profiles. Properly stored urine and blood samples were successfully genotyped, but subjecting urine to freeze-thaw cycles was most detrimental to the integrity of DNA. Increasing the volume of urine used improved recovery of DNA.


Arthroscopic stapling for detached superior glenoid labrum.
Superior labral tears of the shoulder involve the biceps tendon and labrum complex which may be detached, displaced inferiorly, and interposed between the glenoid and the humeral head. We have treated ten young athletes with painful shoulders due to this lesion by arthroscopic stapling. Arthroscopy at the time of staple removal, after three to six months, showed that all the lesions had been stabilised. Clinical review at over 24 months showed an excellent or good result in 80%. The two relative failures were due in one to residual subacromial bursitis, and the other to multidirectional shoulder instability. Arthroscopic stapling can restore the shoulder anatomy, and it is recommended for active adolescent athletes with this lesion.


Human immune response and Chlamydia trachomatis infection.
Chlamydia trachomatis is a prevalent pathogen in human populations in both developing and developed areas of the globe. Disease burden is heavy, since both acute and chronic complications can arise from infection. Emerging knowledge of the immune response to infection suggests that many of the complications of chlamydial infection are accompanied by important alterations in immunoregulation; new information suggests that both antibody-mediated and cell-mediated immune effectors may be significant in eliminating or limiting chlamydial infection. Further studies of the pathophysiologic mechanisms of host defense and the ways in which C. trachomatis escapes these defenses are needed. Elucidation of the immune response may provide the information necessary to redevelop a vaccine approach to disease control.


mTOR-Mediated Regulation of Immune Responses in Cancer and Tumor Microenvironment.
The mechanistic/mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways, which plays a pivotal role in regulating numerous cellular functions including cell growth, proliferation, survival, and metabolism by integrating a variety of extracellular and intracellular signals in the tumor microenvironment (TME). Dysregulation of the mTOR pathway is frequently reported in many types of human tumors, and targeting the PI3K/Akt/mTOR signaling pathway has been considered an attractive potential therapeutic target in cancer. The PI3K/Akt/mTOR signaling transduction pathway is important not only in the development and progression of cancers but also for its critical regulatory role in the tumor microenvironment. Immunologically, mTOR is emerging as a key regulator of immune responses. The mTOR signaling pathway plays an essential regulatory role in the differentiation and function of both innate and adaptive immune cells. Considering the central role of mTOR in metabolic and translational reprogramming, it can affect tumor-associated immune cells to undergo phenotypic and functional reprogramming in TME. The mTOR-mediated inflammatory response can also promote the recruitment of immune cells to TME, resulting in exerting the anti-tumor functions or promoting cancer cell growth, progression, and metastasis. Thus, deregulated mTOR signaling in cancer can modulate the TME, thereby affecting the tumor immune microenvironment. Here, we review the current knowledge regarding the crucial role of the PI3K/Akt/mTOR pathway in controlling and shaping the immune responses in TME.


Prevalence of Primary Glaucoma as Diagnosed by Study Optometrists of L. V. Prasad eye Institute - Glaucoma Epidemiology and Molecular Genetics Study.
To report the prevalence of primary glaucoma as identified by study optometrists of the L. V. Prasad Eye Institute - Glaucoma Epidemiology and Molecular Genetics Study (LVPEI-GLEAMS). Two study optometrists and a total number of 3833 individuals participated in the LVPEI-GLEAMS. All subjects underwent a complete medical history and comprehensive eye examination including slit lamp photography, imaging of anterior and posterior segment, frequency doubling technology and standard automated perimetry including gonioscopy with a Sussman 4 mirror goniolens, post dilated evaluation of the optic disc and fundus was done with a 90 D lens by the study optometrist. A diagnosis of primary open angle glaucoma (POAG), primary angle closure suspect (PACS), primary angle closure (PAC), primary angle closure glaucoma (PACG), normal tension glaucoma (NTG), glaucoma/disc suspect or no glaucoma was made based on the clinical examination. Estimated prevalence of OAG (POAG and NTG) was 1.07% (0.74-1.39), PACS 2.03% (1.58-2.48), PAC 1.77% (1.35-2.19), PACG 0.21% (0.06-0.35) as identified by the study optometrists on site. Prevalence of all the categories of primary glaucoma, as reported by the study optometrists of LVPEI-GLEAMS was comparable to previous findings of other regions in South India.


MRNA Transcription, Translation, and Defects in Developmental Cognitive and Behavioral Disorders.
The growth of expertise in molecular techniques, their application to clinical evaluations, and the establishment of databases with molecular genetic information has led to greater insights into the roles of molecular processes related to gene expression in neurodevelopment and functioning. The goal of this review is to examine new insights into messenger RNA transcription, translation, and cellular protein synthesis and the relevance of genetically determined alterations in these processes in neurodevelopmental, cognitive, and behavioral disorders.


Hydrogen solubility in cristobalite at high pressure.
Powder samples of cristobalite-I are loaded with hydrogen at pressures up to 90 kbar and T = 250 °C and quenched under pressure to the liquid N2 temperature. The quenched samples are examined at ambient pressure by X-ray diffraction, Raman spectroscopy, and thermal desorption analysis. The hydrogen content of the samples is found to increase with pressure and reach a molecular ratio of H2/SiO2 ∼ 0.10 at P = 90 kbar. At ambient pressure, the samples consist of a mixture of approximately 80% cristobalite-I phase and 20% cristobalite-II-like phase, the crystal lattices of both phases being slightly expanded due to the hydrogen uptake. According to Raman spectroscopy, the hydrogen is dissolved in these phases in the form of H2 molecules.


Suppression of experimental autoimmune uveoretinitis by inducing differentiation of regulatory T cells via activation of aryl hydrocarbon receptor.
Purpose. Aryl hydrocarbon receptor (AHR) has been identified as a regulator of CD25(+)CD4(+) regulatory T-cell (T(reg)) and Th17 cell differentiation in mice, and activation of AHR by its ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces functional T(reg) cells. In this study, the authors examined whether the AHR-mediated effect of TCDD suppresses mouse experimental autoimmune uveitis (EAU) by inducing T(reg) cell differentiation. Methods. C57BL/6 mice were injected with TCDD 1 day before immunization with human interphotoreceptor retinoid-binding protein peptide 1-20 (hIRBP-p), and the severity of EAU was assessed clinically and histopathologically. Immunologic responses of draining lymph node cells and splenocytes to hIRBP-p and anti-CD3 monoclonal antibody (mAb) were assessed by T-cell proliferation and cytokine production. In addition, differentiation of Foxp3(+) T cells and their immunosuppressive roles in TCDD-injected mice were evaluated. Results. TCDD injection increased Foxp3(+) T cells in the lymph nodes and in the spleen. Development of EAU was completely suppressed by TCDD injection, and suppression was abolished by treatment with anti-CD25 mAb before TCDD injection. Both lymphocytes and splenocytes obtained from TCDD-injected mice immunized with hIRBP-p failed to produce IFN-gamma and IL-17 on stimulation with hIRBP-p, and the failure of IL-17 production was observed even when stimulated with anti-CD3 mAb. However, this protocol did not interfere with IL-10 production and T-cell proliferation response when assessed on stimulation with anti-CD3 mAb. Conclusions. Activation of AHR by TCDD markedly suppressed autoimmune uveoretinitis through mechanisms that expand CD25(+)Foxp3(+) T(reg) cells and interfere with the activation of Th1 and Th17 cells.


Molecular and genetic aspects of the pathogenesis of viral infections of the central nervous system.
Viral pathogenesis can be defined in terms of a series of successive interactions between a virus and its target host. In order for a virus to injure a target organ such as the central nervous system (CNS), it must first enter the host animal, replicate in some primary site near its place of entry, spread from this site to the CNS and infect and injure specific populations of cells within the CNS. At each of these steps, the virus must avoid or overcome a variety of immunological and nonimmunological host defenses. It has recently become possible to begin to identify the role of specific viral genes and the proteins they encode at specific steps in the pathogenesis cycle. This review focuses on current knowledge concerning the molecular and genetic basis for the pathogenesis of viral infections of the CNS. Emphasis is placed on recent research with a wide variety of neurotropic viruses including reoviruses, bunyaviruses, lymphocytic choriomeningitis virus, rabies virus, polio virus, herpes viruses, lentiviruses, and the unconventional agents responsible for disease such as scrapie.


Laparoscopic Mitrofanoff continent catheterisable stoma in children with spina bifida.
In 1980, Mitrofanoff described the creation of an appendicovesicostomy for continent urinary diversion. This procedure greatly facilitates clean intermittent catheterisation in patients with neurogenic bladder. The purpose of our study was to determine the clinical efficacy of the laparoscopic Mitrofanoff catheterisable stoma for children and adolescents with spina bifida. Review of hospital records revealed that 11 children with spina bifida underwent a laparoscopic Mitrofanoff procedure with at least 1-year of follow-up. A four-port transperitoneal laparoscopic approach was used to create a Mitrofanoff appendicovesicostomy. The child was followed-up in the urology clinic at 6 weeks, 3 months, 6 months, 1-year, and then semiannually after that. Questionnaires were administered to determine, from the children's perspective, the level of satisfaction with catheterisation and the psychosocial implications of catheterisation before and after the creation of the Mitrofanoff continent catheterisable stoma. Of the 11 children, six were female, and five were male. The mean age at presentation to Paediatric urological services was 11 × 3.22 years. Overall the mean operative time was 144.09 × 17.00 min. Mean estimated blood loss was 37.36 × 11.44 cc. None of the cases needed conversion to open. Patient satisfaction with their catheterisation was measured at 2.18 × 0.98 preoperatively, Post-operatively, this improved to 4.27 × 0.46. Statistical analysis using paired t-test showed significance with P < 001. Laparoscopic Mitrofanoff catheterisable stoma is feasible in children with spina bifida and is associated with reasonable outcome with early recovery, resumption of normal activities and excellent cosmesis.


Exercise Intervention for Anti-Sarcopenia in Community-Dwelling Older People.
Sarcopenia is an age-related health problem in general communities. Effective exercise programs against sarcopenia remain necessary for community-dwelling older people. In order to summarize the available knowledge on this subject, we collected English articles from a MEDLINE/Pubmed database examining the effects of exercise interventions on sarcopenia-related outcome measures in community-dwelling older people. When nine articles, including eight randomized controlled trials, were reviewed, most studies demonstrated significant improvements in some outcome measures. Indeed, a significant improvement in the muscle mass in one study, muscle strength in two studies and physical performance in two studies was reported among five studies using exercise (E) alone. A significant improvement in the muscle mass in two studies, muscle strength in one study and physical performance in two studies was also reported among four studies using exercise plus nutritional supplementation (EN). Notably, the EN studies appeared to have less extensive exercise interventions than the E studies. One EN study further exhibited significant improvements in all outcome measures. Collectively, exercise could be used as anti-sarcopenic strategies and nutritional interventions when combined with exercise might play a compensated or perhaps a comprehensive role among community-dwelling older people. Limited studies exist and more studies are required for the optimum programs in the community settings.


Targeting B7-H3 via chimeric antigen receptor T cells and bispecific killer cell engagers augments antitumor response of cytotoxic lymphocytes.
B7-H3, an immune-checkpoint molecule and a transmembrane protein, is overexpressed in non-small cell lung cancer (NSCLC), making it an attractive therapeutic target. Here, we aimed to systematically evaluate the value of B7-H3 as a target in NSCLC via T cells expressing B7-H3-specific chimeric antigen receptors (CARs) and bispecific killer cell engager (BiKE)-redirected natural killer (NK) cells. We generated B7-H3 CAR and B7-H3/CD16 BiKE derived from an anti-B7-H3 antibody omburtamab that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. Antitumor efficacy and induced-immune response of CAR and BiKE were evaluated in vitro and in vivo. The effects of B7-H3 on aerobic glycolysis in NSCLC cells were further investigated. B7-H3 CAR-T cells effectively inhibited NSCLC tumorigenesis in vitro and in vivo. B7-H3 redirection promoted highly specific T-cell infiltration into tumors. Additionally, NK cell activity could be specially triggered by B7-H3/CD16 BiKE through direct CD16 signaling, resulting in significant increase in NK cell activation and target cell death. BiKE improved antitumor efficacy mediated by NK cells in vitro and in vivo, regardless of the cell surface target antigen density on tumor tissues. Furthermore, we found that anti-B7-H3 blockade might alter tumor glucose metabolism via the reactive oxygen species-mediated pathway. Together, our results suggest that B7-H3 may serve as a target for NSCLC therapy and support the further development of two therapeutic agents in the preclinical and clinical studies.


Neurochemical effects of ingested hydroxylamine.
Hydroxylamine chloride (0.3 g/l) in drinking water was given to 3-mo-old male Wistar rats for 1 to 63 days. The treatment caused splenomegalia while no effect was noted on the weight gain. Cerebral RNA content was also unaffected whereas slight decrease in the cerebral homogenate and isolated glial cell succinate dehydrogenase activities was found. Creatine kinase activity in the glial cell fractions increased after 63 days. An initial increase in the muscle acetylcholinesterase activity resolved in muscle after 2 wks while increased muscle creatine kinase activity was found throughout the experiment. The splenomegalia might have been caused by methemoglobinemic red cell fragility, an established NH2OH effect, while the neurochemical effects and effects on muscle might have resulted from direct toxicity rather than from the relative hypoxia because of impaired oxygen transport capacity.


Choice of vehicle affects pyraclostrobin toxicity in mice.
Pyraclostrobin is a strobilurin fungicide that inhibits mitochondrial complex III of fungal and mammalian cells. In toxicity studies that were used to estimate the safety factor, pyraclostrobin was added to animal feed or to aqueous vehicles. However, foods containing residues of pyraclostrobin and other strobilurin fungicides (azoxystrobin, trifloxystrobin, fluoxastrobin) are frequently prepared in vegetable oil prior to human consumption. The primary objective of this study was to determine if pyraclostrobin dissolved in an oil-based vehicle had adverse health outcomes in mice when compared to aqueous-based vehicles. We found that pyraclostrobin does not fully dissolve in aqueous methyl cellulose (MC) or carboxymethyl cellulose (CMC), two vehicles used in industry-sponsored toxicity studies, but does fully dissolve in corn oil. Moreover, C57BL/6 mice receiving pyraclostrobin in corn oil displayed adverse health outcomes, including loss of body weight, hypothermia and diarrhea at lower doses than when added to feed or to aqueous vehicles. Our data suggest that previous studies underestimated the true toxicity of pyraclostrobin in mammals. Additional toxicity tests using oil-based vehicles are recommended to verify current safety recommendations for strobilurin fungicides.


Toll-like receptor 4 confers inflammatory response to Suilysin.
Streptococcus suis serotype 2 (SS2) is an emerging human pathogen worldwide. A large outbreak occurred in the summer of 2005 in China. Serum samples from this outbreak revealed that levels of the main proinflammatory cytokines were significantly higher in patients with streptococcal toxic-shock-like syndrome (STSLS) than in patients with meningitis only. However, the mechanism underlying the cytokine storm in STSLS caused by SS2 remained unclear. In this study, we found that suilysin (SLY) is the main protein inflammatory stimulus of SS2 and that native SLY (nSLY) stimulated cytokines independently of its haemolytic ability. Interestingly, a small amount of SLY (Å Mol/L) induced strong, long-term TNF-α release from human PBMCs. We also found that nSLY stimulated TNF-α in wild-type macrophages but not in macrophages from mice that carried a spontaneous mutation in TLR4 (P712H). We demonstrated for the first time that SLY stimulates immune cells through TLR4. In addition, the Myd88 adaptor-p38-MAPK pathway was involved in this process. The present study suggested that the TLR4-dependent inflammatory responses induced by SLY in host might contribute to the STSLS caused by SS2 and that p38-MAPK could be used as a target to control the release of excess TNF-α induced by SS2.


Comparison of three-dimensional orthodontic load systems of different commercial archwires for space closure.
To experimentally quantify the effects of the loop design on three-dimensional orthodontic load systems of two types of commercial closing loop archwires: Teardrop and Keyhole. An orthodontic force tester and custom-made dentoform were used to measure the load systems produced on two teeth during simulated space closure. The system included three force components along and three moment components about three clinically defined axes on two target teeth: the left maxillary canine and the lateral incisor. The archwires were attached to the dentoform and were activated following a standard clinical procedure. The resulting six load components produced by the two archwires were reported and compared. The results were also compared with those of the T-loop archwire published previously. The three designs deliver similar loading patterns; however, the component magnitudes are dependent on the design. All of the designs result in lingual tipping of the teeth, canine lingual-mesial displacement, canine crown-mesial-in rotation, and incisor crown-distal-in rotation.


Cross axis VOR induced by pursuit training in monkeys: further properties of adaptive responses.
We have shown recently in alert monkeys that repeated interaction between the pursuit and vestibular systems in the orthogonal plane induces adaptive changes in the VOR. To examine further properties of adaptive cross axis VOR induced by pursuit training, sinusoidal whole body rotation was applied either in the pitch or yaw plane while presenting a target spot that moved orthogonally to the rotation plane with either 90 degrees phase-lead or 90 degrees phase-lag to the chair signal. After one hour of training at 0.5 Hz (+/- 10 degrees), considerable phase-shift was observed in orthogonal eye movement responses consistent with the training paradigms by identical chair rotation in complete darkness, with further lead at lower frequencies and lag at higher frequencies. However, gains (eye/chair) induced by phase- shift pursuit training was different during pitch and yaw rotation. Although frequency tuning was maintained during pitch in the phase-shift paradigms, it was not maintained during yaw, resulting in higher gains at lower stimulus frequencies compared to the gains during yaw. This difference may reflect otolith contribution during pitch rotation. To understand further the nature of signals that induce adaptive cross axis VOR, we examined interaction of pursuit, whole field-visual pattern and vestibular stimuli. Magnitudes of the cross axis VOR with a spot alone on one hand and with a spot and pattern moving together in the same plane on the other during chair rotation were similar, and when one of the two visual stimuli was stationary during chair rotation, our well trained monkeys did not induce the cross axis VOR. These results suggest that the cross axis VOR induced by pursuit training shares common mechanisms with the cross axis VOR induced by whole field-slip stimuli and that if conflicting information is given between the two visual stimuli, adaptive changes are inhibited. Horizontal GVPs were recorded in the cerebellar floccular lobe during pitch rotation coupled with horizontal pursuit stimuli. These GVPs did not respond to pitch in the dark before training, but responded after 60 min of pursuit training with eye velocity sensitivities similar to those before training. Adaptive change in the VOR was specific to smooth eye movements but not to saccades in our paradigms.


Tularemia as a biological weapon: medical and public health management.
The Working Group on Civilian Biodefense has developed consensus-based recommendations for measures to be taken by medical and public health professionals if tularemia is used as a biological weapon against a civilian population. The working group included 25 representatives from academic medical centers, civilian and military governmental agencies, and other public health and emergency management institutions and agencies. MEDLINE databases were searched from January 1966 to October 2000, using the Medical Subject Headings Francisella tularensis, Pasteurella tularensis, biological weapon, biological terrorism, bioterrorism, biological warfare, and biowarfare. Review of these references led to identification of relevant materials published prior to 1966. In addition, participants identified other references and sources. Three formal drafts of the statement that synthesized information obtained in the formal evidence-gathering process were reviewed by members of the working group. Consensus was achieved on the final draft. A weapon using airborne tularemia would likely result 3 to 5 days later in an outbreak of acute, undifferentiated febrile illness with incipient pneumonia, pleuritis, and hilar lymphadenopathy. Specific epidemiological, clinical, and microbiological findings should lead to early suspicion of intentional tularemia in an alert health system; laboratory confirmation of agent could be delayed. Without treatment, the clinical course could progress to respiratory failure, shock, and death. Prompt treatment with streptomycin, gentamicin, doxycycline, or ciprofloxacin is recommended. Prophylactic use of doxycycline or ciprofloxacin may be useful in the early postexposure period.


In vivo primed mouse T cells selectively express T cell-specific serine proteinase-1 and the proteinase-like molecules granzyme B and C.
Previous studies have shown that mouse CD8+ T lymphocyte clones (TLC) produce T cell-specific serine proteinase-1 (MTSP-1) as well as a family of six homologous molecules, termed granzymes B - G, which are structurally related to serine proteinases. Of these proteins, only MTSP-1 has been studied in detail. It has been shown to occur in the majority of CD8+ and a fraction of CD4+ T effector cells in vivo and in vitro and has demonstrable enzyme activity in these cells. The presence of the other serine proteinase-like molecules in T cells is less well defined. We have now analyzed the expression of mRNA species specific for granzymes B - G in activated T cell populations using the sensitive polymerase chain reaction which allows the detection of mRNA species from as little as 2 pg of total cytoplasmic RNA. We demonstrate that MTSP-1 and all six serine proteinase-like transcripts are expressed in a panel of four CD8+ and six CD4+ long-term-cultured TLC, though at greatly differing concentrations. In contrast, in vivo primed T cells of both phenotypes, CD4+ and CD8+, and in vitro activated T cells derived from short-term cultures only express mRNA species specific for MTSP-1 and CCP1 and little of those for CCP2, but no transcripts for granzymes D - G. These findings argue against the participation of granzymes D - G in T cell-mediated functions in vivo.


[A case-control study on tea consumption and the risk of lung cancer].
To investigate the association between tea consumption and lung cancer. A case-control study was conducted, including 1225 newly diagnosed cases with lung cancer and 1234 healthy control subjects frequently matched by gender and age (+/- 3 year). Epidemiological data were collected by in-person interviews using a standard questionnaire. The adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated by fitting multivariate unconditional logistic regression models that included potential confounding factors. A protective effect of tea drinking on risk of lung cancer was observed for non-smokers with adjusted OR was 0.465 (95% 0.345 - 0.625), and the risks decreased with increased years of tea drinking. The adjusted ORs for drinking green tea, black tea, oolong tea and others was 0.333 (95% CI 0.154 -0.720), 0.522 (95% CI 0.356 - 0.767), 0.735 (95% CI 0.424 - 1.274) and 0.267 (95% CI 0.143 - 0.497), respectively. The inverse associations were also observed between frequency, concentration, consumption and risk of lung cancer among non-smokers. Tea drinking was associated with decreased risk of lung cancer for those smokers with drinking tea < 3 times/week and low concentration, with the adjusted ORs of 0.453 (95% CI 0.286 - 0.717) and 0.518 (95% CI 0.346 - 0.778), respectively. The protective effect of tea drinking was observed on the risk of lung cancer, especially for non-smokers.


Nutritional Risk Index Predicts Survival in Patients With Breast Cancer Treated With Neoadjuvant Chemotherapy.
Nutritional risk index (NRI) is an index based on ideal body weight that aims to present body weight and serum albumin levels. It has been utilized to discriminate patients at risk of postoperative complications and predict the postoperative outcome of major surgeries. However, this index remains limited for breast cancer patients treated with neoadjuvant chemotherapy (NACT). The research explores the clinical and prognostic significance of NRI in breast cancer patients. This study included 785 breast cancer patients (477 cases received NACT and 308 cases did not) were enrolled in this retrospective study. The optimal NRI cutoff value was evaluated by receiver operating characteristic (ROC) curve, then reclassified as low NRI group (<112) and high NRI group (≥112). The results demonstrated that NRI independently predicted survival on disease-free survival (DFS) and overall survival (OS) by univariate and multivariate Cox regression survival analyses [P = 0.019, hazard ratio (HR): 1.521, 95% CI: 1.071-2.161 and P = 0.004, HR: 1.415, 95% CI: 1.119-1.789; and P = 0.026, HR:1.500, 95% CI: 1.051-2.143 and P < 0.001, HR: 1.547, 95% CI: 1.221-1.959]. According to the optimal cutoff value of NRI, the high NRI value patients had longer mean DFS and OS time in contrast to those with low NRI value patients (63.47 vs. 40.50 months; 71.50 vs. 56.39 months). Furthermore, the results demonstrated that the high NRI score patients had significantly longer mean DFS and OS time than those with low NRI score patients in early-stage breast cancer (χ2 = 9.0510, P = 0.0026 and χ2 = 9.2140, P = 0.0024) and advanced breast cancer (χ2 = 6.2500, P = 0.0124 and χ2 = 5.8880, P = 0.0152). The mean DFS and OS values in patients with high NRI scores were significantly longer in contrast to those with low NRI scores in different molecular subtypes. The common toxicities after NACT were hematologic and gastrointestinal reactions, and the NRI had no statistically significant effects on toxicities, except in nausea (χ2 = 9.2413, P = 0.0024), mouth ulcers (χ2 = 4.8133, P = 0.0282), anemia (χ2 = 8.5441, P = 0.0140), and leukopenia (χ2 = 11.0951, P = 0.0039). NRI serves as a minimally invasive, easily accessible and convenient prognostic tool for evaluating breast cancer prognoses and treatment efficacy, and may help doctors in terms of selecting measures of greater efficiency or appropriateness to better treat breast cancer.


How Do Children of Parents With Mental Illness Experience Stigma? A Systematic Mixed Studies Review.
Stigma can have devastating health and wellbeing impacts, not just on people with mental health problems, but on people associated with the stigmatized person. This is called stigma-by-association. Children whose parents have mental health problems are a particularly vulnerable group, and stigma acts as a mechanism, contributing to the transgenerational transmission of mental disorders. The current study is a systematic mixed studies review, synthesizing knowledge about how this group of children experience stigma-by-association. Overall, 32 studies were included, after a systematic search including quantitative, qualitatative, and mixed methods studies. The methodological quality was assessed and qualitative content analysis undertaken. We grouped children's stigma experiences into four dimensions, i.e., experienced stigma, anticipated stigma, internalized stigma, and structural discrimination. Results show that stigma is an important factor in those children's lives, and needs further investigation in qualitative and quantitative research. The current study emphasizes the importance of anti-stigma interventions and campaigns.


Experience in different modes of delivery in twin pregnancy.
Vaginal delivery, compared with Cesarean delivery, remains a less chosen mode of delivery for twin pregnancy. We studied the maternal and perinatal outcomes of twin pregnancy with different modes of delivery. A retrospective study with data collected from a regional hospital, including vital twin pregnancies delivered at gestational age of 32 weeks and above. Medical charts were reviewed for prenatal conditions and postpartum outcomes. Ninety-eight pairs of twins were included and 44.9% were delivered via vaginal delivery. Women in the vaginal delivery group were significantly younger (32.5 ±4.3 years versus 34.8 ±4.6 years, p < 0.01), multiparous (34.1% versus 18.5%) and with more twins in vertex-vertex presentation (70.5% versus 33.3%) compared with women in the Cesarean delivery group. There were no differences between maternal postpartum complications and neonatal outcomes in both groups. The outcomes showed longer inter-twin delivery time interval (5.7 ± 5.6 versus 1.5 ± 0.9 min, p < 0.01), less estimated blood loss (198.7 ± 144.1 versus 763.2 ± 332.3 mL, p < 0.01), and shorter maternal hospital stay (3.0 ± 0.5 versus 5.7 ± 0.5 days, p< 0.01) in the vaginal delivery group. Twenty newborns had Apgar score below seven at birth. Logistic regression analysis revealed that low Apgar score was independently related to younger maternal age, maternal obstetric diseases and fetal non-vertex presentation. Gestational weeks and mode of delivery were not related to low Apgar score. With careful case selection, vaginal delivery could be safely performed in twin pregnancies with less estimated blood loss and better recovery than Cesarean delivery.


Towards more powerful learning environments through combining the perspectives of designers, teachers, and students.
In order to reach the main aims of modern education, powerful learning environments are designed. The characteristics of the design of PLEs are expected to have positive effects on student learning. Additionally, teachers' conceptions of learning and teaching do influence the implementation of a PLE. Moreover, students' perceptions of a learning environment affect their subsequent learning behaviour and the quality of the learning outcomes. The different perspectives of educational designers, teachers, and students are summarized in the Combination-of-perspectives (COOP) model. Combining these perspectives by mutual exchange of conceptions and perceptions is expected to have positive effects on the power of PLEs.


Using ecological null models to assess the potential for marine protected area networks to protect biodiversity.
Marine protected area (MPA) networks have been proposed as a principal method for conserving biological diversity, yet patterns of diversity may ultimately complicate or compromise the development of such networks. We show how a series of ecological null models can be applied to assemblage data across sites in order to identify non-random biological patterns likely to influence the effectiveness of MPA network design. We use fish census data from Caribbean fore-reefs as a test system and demonstrate that: 1) site assemblages were nested, such that species found on sites with relatively few species were subsets of those found on sites with relatively many species, 2) species co-occurred across sites more than expected by chance once species-habitat associations were accounted for, and 3) guilds were most evenly represented at the richest sites and richness among all guilds was correlated (i.e., species and trophic diversity were closely linked). These results suggest that the emerging Caribbean marine protected area network will likely be successful at protecting regional diversity even if planning is largely constrained by insular, inventory-based design efforts. By recasting ecological null models as tests of assemblage patterns likely to influence management action, we demonstrate how these classic tools of ecological theory can be brought to bear in applied conservation problems.