Lack of evidence for frequent heterosexual transmission of human herpesvirus 8 in Zimbabwe.
There is conflicting evidence about the contribution of heterosexual transmission to the spread of human herpesvirus 8 (HHV-8) in southern Africa. This study evaluated the hypothesis that HHV-8 infection is associated with risk factors for human immunodeficiency virus type 1 (HIV-1) and other sexually transmitted infections among Zimbabwean men. HHV-8 seroprevalence was determined for 2750 participants in the Zimbabwe AIDS Prevention Project cohort of male factory workers in Harare, Zimbabwe. Potential associations of HHV-8 antibody detection with risk factors for HIV-1 infection were examined by univariate analysis. Variables with P < .1 in the univariate analysis were included in a multivariate logistic regression model. HHV-8 seroprevalence was also determined among 297 heterosexual couples. Prevalence of HHV-8, HIV-1, and HHV-8 and HIV-1 coinfection was 28.5% (95% confidence interval [CI], 26.8%-30.2%), 19.5% (95% CI, 18.0%-20.9%), and 6.5% (95% CI, 5.6%-7.5%), respectively. Detection of HHV-8 antibodies was independently associated with older age and HIV-1 infection but not with number of recent sex partners, marital status, education, condom use, prior sexually transmitted infections, payment for sex, chronic hepatitis B infection, or incident HIV-1 infection. HHV-8 seroprevalence was 31.7% (95% CI, 26.3-37.0) among wives in the couples tested, but HHV-8 infection of wives was not associated with HHV-8 infection of husbands (odds ratio, 1.08; 95% CI, 0.62-1.88; P = .8). HHV-8 and HIV-1 infection did not have common sexual risk factors among urban Zimbabwean men. Sexual transmission does not explain the high prevalence of HHV-8 in this population.


Purification and Characterization of Glutamine Synthetase and NADP-Glutamate Dehydrogenase from the Ectomycorrhizal Fungus Laccaria laccata.
Glutamine synthetase (GS) and NADP-dependent glutamate dehydrogenase (NADP-GDH) play a key role in nitrogen assimilation in the ectomycorrhizal fungus Laccaria laccata (Scop. ex Fr. Cke) strain S 238. The two enzymes were purified to apparent electrophoretic homogeneity by a three-step procedure involving diethylaminoethyl (DEAE)-Trisacryl and affinity chromatography, and DEAE-5PW fast protein liquid chromatography. This purification scheme resulted in a 23 and 62% recovery of the initial activity for GS and NADP-GDH, respectively. Purified GS had a specific activity of 713 nanomoles per second per milligram protein and a pH optimum of 7.2. Michaelis constants (millimolar) for the substrates were NH(4) (+) (0.024), glutamate (3.2), glutamine (30), ATP (0.18), and ADP (0.002). The molecular weight (M(r)) of native GS was approximately 380,000; it was composed of eight identical subunits of M(r) 42,000. Purified NADP-GDH had a specific activity of 4130 nanomoles per second per milligram protein and a pH optimum of 7.2 (amination reaction). Michaelis constants (millimolar) for the substrates were NH(4) (+) (5), 2-oxoglutarate (1), glutamate (26), NADPH (0.01), and NADP (0.03). Native NADP-GDH was a hexamer with a M(r) of about 298,000 composed of identical subunits with M(r) 47,000. Polyclonal antibodies were produced against purified GS and NADP-GDH. Immunoprecipitation tests and immunoblot analysis showed the high reactivity and specificity of the immune sera against the purified enzymes.


Enzyme-linked immunosorbent assay for the in-vitro detection of sensitivity of Chlamydia trachomatis to antimicrobial drugs.
A new method of testing antimicrobial activity in vitro against Chlamydia trachomatis by enzyme-linked immunosorbent assay (ELISA) was developed by using a monoclonal antibody reacting with the major outer membrane protein of C. trachomatis LGV2 serotype. ELISA was compared with standard iodine stain, with immunofluorescence assay (IFA) and immunoperoxidase assay (IPA) performed with the same monoclonal antibody as in the ELISA. The MICs and MBCs of rifampicin, oxytetracycline, erythromycin, chloramphenicol and cefazolin detected by ELISA were higher than those determined by iodine stain and slightly lower than those determined by IFA and IPA. Since ELISA was at least as informative as the previously described techniques, but more rapid and standardizable and easier to perform, the assay may be useful in measuring the antimicrobial drug susceptibility of C. trachomatis.


Hyperventilation: A Possible Explanation for Long-Lasting Exercise Intolerance in Mild COVID-19 Survivors?
Since the outbreak of the coronavirus (COVID-19) pandemic, most attention has focused on containing transmission and addressing the surge of critically ill patients in acute care settings. As we enter the second phase of the pandemic, emphasis must evolve to post-acute care of COVID-19 survivors. Persisting cardiorespiratory symptoms have been reported at several months after the onset of the infection. Information is lacking on the pathophysiology of exercise intolerance after COVID-19. Previous outbreaks of coronaviruses have been associated with persistent dyspnea, muscle weakness, fatigue and reduced quality of life. The extent of Covid-19 sequelae remains to be evaluated, but persisting cardiorespiratory symptoms in COVID-19 survivors can be described as two distinct entities. The first type of post-Covid symptoms are directly related to organ injury in the acute phase, or the complications of treatment. The second type of persisting symptoms can affect patients even with mild initial disease presentation without evidence of organ damage. The mechanisms are still poorly qualified to date. There is a lack of correlation between initial symptom severity and residual symptoms at exertion. We report exercise hyperventilation as a major limiting factor in COVID-19 survivors. The origin of this hyperventilation may be related to an abnormality of ventilatory control, by either hyperactivity of activator systems (automatic and cortical ventilatory control, peripheral afferents, and sensory cortex) or failure of inhibitory systems (endorphins) in the aftermath of pulmonary infection. Hyperventilation-induced hypocapnia can cause a multitude of extremely disabling symptoms such as dyspnea, tachycardia, chest pain, fatigue, dizziness and syncope at exertion.


Characteristics and Treatment Outcomes of Retreatment Tuberculosis Patients in Benin.
Objective. To determine among retreatment tuberculosis patients in Benin baseline characteristics, culture, and drug sensitivity testing (DST) results and treatment outcomes. Materials and Methods. A retrospective national cohort study of all retreatment tuberculosis patients in Benin in 2013 using registers and treatment cards. Results. Of 3957 patients with tuberculosis, 241 (6%) were retreatment cases. Compared to new pulmonary bacteriologically confirmed tuberculosis (NPBCT) patients, there were significantly higher numbers of males (P = 0.04), patients from "Atlantique-Littoral" (P = 0.006), patients aged 45-64 years (P = 0.007), and HIV-positive patients (P = 0.04) among those retreated. Overall, 171 (71%) patients submitted sputum for DST, of whom (163) 95% were positive for Mycobacterium tuberculosis on Xpert MTB/RIF and/or culture and 17 (10%) were rifampicin resistant (9 with MDR-TB and 8 monoresistant to rifampicin). For those without MDR-TB (n = 224), treatment success was 93%. Worse outcomes occurred in those with unknown HIV status (RR: 0.27; 0.05-1.45; P < 0.01) while better outcomes occurred in those who relapsed (RR: 1.06, 95 CI: 1.02-1.10, P = 0.04). Conclusion. In 2013, a high proportion of retreatment patients received DST. Treatment success was good although more needs to be done to systematically increase the final follow-up smear examination. Reasons of high losses to follow-up from "Oueme-Plateau" should be investigated.


Aberrant methylation of hMLH1 and p16INK4a in Tunisian patients with sporadic colorectal adenocarcinoma.
The methylation of CpG islands in the promoters is associated with loss of protein via repression of gene transcription. Several studies have demonstrated that tumour suppressor and DNA repair genes are often aberrantly hypermethylated in colorectal cancer. The present study was conducted to examine whether the methylation profile of p16INK4a and hMLH1 (human mutL homologue 1) promoters was associated with clinical features and patients' survival in CRC (colorectal carcinoma). Aberrant methylation of p16INK4a and hMLH1 promoters was found in 47.2 and 53.4% of tumours respectively. For adjacent non-tumoral mucosa, p16INK4a was fully unmethylated in 30% of the cases, whereas hMLH1 was predominantly unmethylated (76%). Methylation of p16INK4a correlated with gender and tumour size (P=0.005 and 0.035 respectively), whereas those of hMLH1 significantly correlated with overall survival (P log rank=0.007). Concomitant methylation of p16INK4a and hMLH1 was associated with TNM (tumour, lymph node and metastases) stage and tumour size (P=0.024 and 0.021 respectively). Our data show that loss of hMLH1 expression through aberrant methylation could be used as a marker of poor prognosis in CRC.


Effects of dietary L-isoleucine on laying performance and immunomodulation of laying hens.
Isoleucine may be a limiting amino acid for laying hens fed diets with a lowered protein level. An experiment was conducted to examine laying performance and the immune function of laying hens provided diets varying in digestible isoleucine levels during the peak production period. A total number of 400 Lohmann Brown laying hens, 28 wk of age, were allocated to 5 dietary treatment groups, each of which included 5 replicates of 16 hens per replicate (4 cages / replicate; 80 hens / treatment). L-isoleucine was added to the experimental diet (14% CP) containing synthetic amino (methionine, lysine, threonine, tryptophan, and valine) by zero, 1.0, 2.0, 3.0, and 4.0 g/kg, corresponding to 0.54%, 0.64%, 0.74%, 0.84, and 0.94% digestible isoleucine, respectively. At the end of the experiment (wk 40), dietary isoleucine did not affect laying performance or egg quality. Serum albumin concentration increased quadratically (P < 0.05) in response to digestible dietary isoleucine at 0.74%. Serum free isoleucine and lysine increased (P < 0.05) in response to digestible dietary isoleucine at 0.74%. Digestible dietary isoleucine levels did not affect the serum concentrations of total antioxidative capability (T-AOC), total superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and CuZn-superoxide dismutase (CuZn-SOD). There was no significant (P > 0.05) response of excess digestible isoleucine level on the serum level of IgG, IgA, or IgM. In addition, dietary isoleucine levels did not affect the concentrations of secretory immunoglobulin A (sIgA), tumor necrosis factor alpha (TNFα), or interleukin (IL-2 and IL-6) in the ileum. Also, expressions of ileal MUC2 mRNA, sIgA mRNA, and IL-1β mRNA were not changed (P > 0.05) by excess digestible isoleucine level. Furthermore, excess digestible isoleucine level did not change mRNA expression of ileal tight junction protein (claudin-1 and occludin). No effect occurred when isoleucine was supplemented, suggesting that it is not a limiting amino acid in the low crude protein diet on laying performance and intestinal mucosal immune.


The Global Prader-Willi Syndrome Registry: Development, Launch, and Early Demographics.
Advances in technologies offer new opportunities to collect and integrate data from a broad range of sources to advance the understanding of rare diseases and support the development of new treatments. Prader-Willi syndrome (PWS) is a rare, complex neurodevelopmental disorder, which has a variable and incompletely understood natural history. PWS is characterized by early failure to thrive, followed by the onset of excessive appetite (hyperphagia). Additional characteristics include multiple endocrine abnormalities, hypotonia, hypogonadism, sleep disturbances, a challenging neurobehavioral phenotype, and cognitive disability. The Foundation for Prader-Willi Research's Global PWS Registry is one of more than twenty-five registries developed to date through the National Organization of Rare Disorders (NORD) IAMRARE Registry Program. The Registry consists of surveys covering general medical history, system-specific clinical complications, diet, medication and supplement use, as well as behavior, mental health, and social information. Information is primarily parent/caregiver entered. The platform is flexible and allows addition of new surveys, including updatable and longitudinal surveys. Launched in 2015, the PWS Registry has enrolled 1696 participants from 37 countries, with 23,550 surveys completed. This resource can improve the understanding of PWS natural history and support medical product development for PWS.


Association of recently identified type 2 diabetes gene variants with Gestational Diabetes in Asian Indian population.
Earlier studies have provided evidence that the gestational diabetes mellitus (GDM) and Type 2 diabetes mellitus (T2DM) share common genetic background. A recent genome wide association study (GWAS) showed a strong association of six novel gene variants with T2DM among south Asians but not with Europeans. The aim of this study was to investigate whether these variants that confer susceptibility to T2DM in Asian Indian population also correlate with GDM in Asian Indian population. In addition to these novel variants, three T2DM associated SNPs that were previously identified by GWAS in Caucasian populations, which also showed association with T2DM in south Indian population in our previous study were also evaluated for their susceptibility to GDM in our population. The study groups comprised unrelated pregnant women with GDM (n = 518) and pregnant women with normal glucose tolerance (NGT) (n = 1220). A total of nine SNPs in or near nine loci, namely AP3S2 (rs2028299), BAZ1B (rs12056034), CDKN2A/B (rs7020996), GRB14 (rs3923113), HHEX (rs7923837), HMG20A (rs7178572), HNF4A (rs4812829), ST6GAL1 (rs16861329) and VPS26A (rs1802295) were genotyped using the MassARRAY system. Among these nine SNPs that previously showed an association with T2DM in Asian Indians, HMG20A (rs7178572) and HNF4A (rs4812829) gene variants showed a significant association with GDM. The risk alleles of rs7178572 in HMG20A and rs4812829 in HNF4A gene conferred 1.24 and 1.28 times higher risk independently and about 1.44 and 1.97 times increased susceptibility to GDM for one and two risk genotypes, respectively. We report that the HMG20A (rs7178572) and HNF4A (rs4812829) variants that have previously shown a strong association with T2DM in Asian Indians also contributes significant risk to GDM in this population. This is the first report of the association of HMG20A (rs7178572) and HNF4A (rs4812829) variants with GDM.


Bioluminescent bacterial biosensors for the assessment of metal toxicity and bioavailability in soils.
A major factor governing the toxicity of heavy metals in soils is their bioavailability. Traditionally, sequential extraction procedures using different extractants followed by chemical analysis have been used for determining the biologically available fraction of metals in soils. Yet, the transfer of results obtained on non-biological systems to biological ones is certainly questionable. Therefore, bioluminescence-based bacterial biosensors have been developed using genetically engineered microorganisms, constructed by fusing transcriptionally active components of metal resistance mechanisms to lux genes from naturally bioluminescent bacteria like Vibrio fischeri for the assessment of metal toxicity and bioavailability in polluted soils. As compared to chemical methods, bacterial biosensors present certain advantages, such as selectivity, sensitivity, simplicity, and low cost. Despite certain inherent limitations, bacterial bioluminescent systems have proven their usefulness in soils under laboratory and field conditions. Finally, green fluorescent protein-based bacterial biosensors are also applicable for determining with high sensitivity the bioavailability of heavy metals in soil samples.


Glucose tolerance: hypothesis testing on Malaysian diabetic community.
Our study objective was to evaluate glucose tolerance and effecting factors among diabetes patients' with home care program (PHCP) in Malaysian community. A 24-week longitudinal quasi-experimental -single blind - pre/post-test study design was used to assess the effectiveness of a diabetes education program to enhance self-care practices. An attrition rate of 25% implied longitudinal design of the study in the calculation of sample size. Hence the sample size of the study was 106 subjects (53 cases and 53 focus group). The level of significance was set at 0.05. Ethical clearance had been made prior to conducting this study. Of the 109 subjects who met the study-entry criteria, 3 subjects declined to participate due to lack of time and interest. No significant parameters were revealed in the demographic and clinical characteristics of participants who completed the study. Focus group showed significant reduction in HbA1c value with mean 1.1% as compared to cases with a mean 0.06%. Similarly, hypothesis on self-care management suggest significantly improved practices among focus group [M=2.94, SD=2.25] for case group M=0.47, SD=1.36; t[127.64]=-8.23, p≤0.001] with moderate effect size [eta squared=0.06]. Total physical activity was defined as the combination of non-leisure and leisure activities. There was a statistically significant difference for increase in total physical levels between the focus [M=14.01, SD=6.41] and case groups [13.21, SD=5.22; t[148.04]=-3.15, p=0.002] with no difference in the non-leisure activity [p=0.43]. As for the case group, there was no significant difference in SMBG practices from baseline [M=0.70, SD=1.35] to follow-up [M=0.47, SD=1.36, t[72]=0.97, P=0.34] and no relationship was found between the number of blood glucose tests done with demographic or clinical variables. This study offered improved self-care practices and physical activity after PHCP but with problematic dietary care. This might be due to social and cultural habits among Malaysian population.


Autologous cytokine-induced killer cell immunotherapy may improve overall survival in advanced malignant melanoma patients.
Our study was conducted to explore the efficacy of autologous cytokine-induced killer (CIK) cells in patients with advanced malignant melanoma. Materials & Methods: Here we reviewed 113 stage IV malignant melanoma patients among which 68 patients received CIK cell immunotherapy alone, while 45 patients accepted CIK cell therapy combined with chemotherapy. Results: We found that the median survival time in CIK cell group was longer than the combined therapy group (21 vs 15 months, p = 0.07). In addition, serum hemoglobin level as well as monocyte proportion and lymphocyte count were associated with patients' survival time. These indicated that CIK cell immunotherapy might extend survival time in advanced malignant melanoma patients. Furthermore, serum hemoglobin level, monocyte proportion and lymphocyte count could be prognostic indicators for melanoma.


Longitudinal study of occurrence of diarrheal disease in day care centers.
Sixty day care centers (DCC) randomly selected from 736 licensed child care facilities in Harris County (Houston), Texas were surveyed for the incidence of diarrhea by periodic visits and weekly telephone calls over two years. A total of 2,708 episodes of diarrhea were reported in 3,800 children under 6 years of age, and 84 cases occurred in center staff. Overall incidence was 0.44 episodes/person/year among children and 0.14 among staff. Attack rates among the 60 DCC ranged from none to 3.64 cases/year in each child. The incidence for children under 36 months of age was 17 times higher than for the older group. Characteristics of DCC associated with higher rates of disease among children were the presence of young, non-bowel trained children, staff who both diapered infants and prepared food on a regular basis, DCC for profit management, and DCC whose only guidelines were provided by the State. The socioeconomic burden associated with DCC disease, its transmission, and control is considerable and needs to be further addressed.


FSees: Customized Enumeration of Chemical Subspaces with Limited Main Memory Consumption.
In the search for new marketable drugs, new ideas are required constantly. Particularly with regard to challenging targets and previously patented chemical space, designing novel molecules is crucial. This demands efficient and innovative computational tools to generate libraries of promising molecules. Here we present an efficient method to generate such libraries by systematically enumerating all molecules in a specific chemical space. This space is defined by a fragment space and a set of user-defined physicochemical properties (e.g., molecular weight, tPSA, number of H-bond donors and acceptors, or predicted logP). In order to enumerate a very large number of molecules, our algorithm uses file-based data structures instead of memory-based ones, thus overcoming the limitations of computer main memory. The resulting chemical library can be used as a starting point for computational lead-finding technologies, like similarity searching, pharmacophore mapping, docking, or virtual screening. We applied the algorithm in different scenarios, thus creating numerous target-specific libraries. Furthermore, we generated a fragment space from all approved drugs in DrugBank and enumerated it with lead-like constraints, thus generating 0.5 billion molecules in the molecular weight range 250-350.


[The effect of steroids on organ-cultured porcine trabecular meshwork--an ultrastructural, biochemical, and lectin histochemical study].
The effect of corticosteroid administration on porcine trabecular meshwork (PTM) was studied by ultrastructural and biochemical analysis. Electron microscopic observations showed an increase of elastic fibers in PTM treated with steroids. Two-dimensional polyacrylamide gel electrophoresis with silver staining showed an increase of proteins with molecular weights of 52 kDa, 66 kDa and 70 kDa. The 66 kDa protein was assumed to be a glycoprotein containing N-acetyl-D-glucosamine, as it was stained positively in the lectin blot analysis with Triticum vulgaris (WGA) and Datura stramonium (DSA). The elastic fibers reacted positively to WGA and DSA, and the degree of this reaction was strengthened by steroid treatment. These results demonstrated that steroid treatment induces ultrastructural and biochemical changes in PTM, and an increase of elastic fibers containing glycoprotein with N-acetyl-D-glucosamine.


Structural characterization and immunomodulatory effect of a polysaccharide HCP-2 from Houttuynia cordata.
Immunomodulation of natural polysaccharides has been the hot topic of research in recent years. In order to explore the immunomodulatory effect of Houttuynia cordata Thunb., the water extract was studied and a polysaccharide HCP-2 with molecular weight of 60,000 Da was isolated by chromatography using DEAE Sepharose CL-6B and Sephacryl S-500 [corrected] HR columns. The structure characterization of HCP-2 was performed by Fourier transform infrared spectroscopy (FTIR), acidic hydrolysis, PMP derivation, HPLC analysis and nuclear magnetic resonance spectra (NMR). HCP-2 was elucidated as a pectic polysaccharide with a linear chain of 1,4-linked α-D-galacturonic acid residues in which part of the 6-carboxyl groups were methyl esterified and part of 2-hydroxyl groups were acetylated. The bioactivity assays showed that HCP-2 could increase the secretions of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), macrophage inhibitory protein-1α (MIP-1α), macrophage inhibitory protein-1β (MIP-1β), and RANTES (regulated on activation, normal T cell expressed and secreted) in human peripheral blood mononuclear cells (PBMCs), which play critical roles in the innate immune system and shape the adaptive immunity. Our results implied that HCP-2 could be an immune enhancer.


International health links: an evaluation of partnerships between health-care organizations in the UK and developing countries.
Increasingly, international health links are evolving between UK health-care institutions and those in developing countries, the core aims of which are to seek the transfer of ideas, knowledge, skills and training. This study aimed to evaluate established health links, what constitutes them and how they are supported. Benefits and challenges associated with the links, as perceived both by link coordinators in the UK and their overseas partners, were explored. Fourteen links between health-care organizations in the UK and those in developing countries were identified and interviews were successfully conducted with 22 link coordinators: 13 in the UK and nine in developing countries. The interviews indicated that health links offer mutual benefits to both partners in terms of shared skills and the promotion of global awareness. Links can act as important catalysts; stimulating increases in institutional capacity for research and training. They provide opportunities for personal and professional development of staff and promote the development of friendships and supportive networks between diverse communities. Many of the health links showed signs of evolving from uniprofessional links between individual institutions into broader, multidisciplinary community partnerships. The main challenges facing health links arise from cultural differences, funding problems, communication difficulties and bureaucracy. There was broad agreement that greater recognition of the value and importance of health links by the NHS and closer collaboration between government departments to provide support and resources could promote wider and more effective link partnerships.


Incidence, risk factors, and outcomes of unplanned extubation in adult patients in a resource-limited teaching hospital in the Philippines: a cohort study.
We aimed to determine the incidence, risk factors, and outcomes of unplanned extubation among adult patients. We conducted a prospective cohort study of adult intubated patients admitted to the charity wards of a government tertiary teaching hospital in the Philippines. Patients managed in both intensive care and nonintensive care settings were included. Patients were followed-up until discharge or until seven days postextubation. The outcomes of the 191 included patients were planned extubation (35%), unplanned extubation (19%), death (39%), and discharge against advice (7%). Competing risk regression showed that male sex (Crude OR: 2.25, 95%CI: 1.10 - 4.63) and age (Crude OR 0.976, 95%CI: 0.957 - 0.996) were significant baseline factors. The night shift (Crude OR: 24.6, 95%CI: 2.87 - 211) was also consistently associated with more unplanned extubations. Among postextubation outcomes, reintubation (unplanned extubation: 61.1% versus planned extubation: 25.4%), acute respiratory failure (unplanned extubation: 38.9% versus planned extubation: 17.5%), and cardiovascular events (unplanned extubation: 8.33% versus planned extubation: 1.49%) occurred significantly more often among the unplanned extubation patients. Admission in an intensive care unit was not associated with a lower risk of unplanned extubation (Crude OR 1.15, 95%CI: 0.594 - 2.21). Many intubated patients had unplanned extubation. Patients admitted in nonintensive care unit settings did not have significantly higher odds of unplanned extubation.


The effect of performing a dual-task on postural control and selective attention of older adults when stepping backward.
[Purpose] The purpose of the study was to investigate the postural control and cognitive performance of older adults when stepping backward with and without a concurrent cognitive task. [Subjects and Methods] Thirty young adults and twenty-eight older adults (mean age=21.3 ± 1.2 and 72.2 ± 5.7 years, respectively) were recruited. Participants were asked to step backward and then maintain a single-leg stance for 10 seconds with and without a concurrent auditory response task. The reaction time and error rate while performing the cognitive task were recorded. Postural stability after stepping back was measured in terms of total sway path and total sway area. [Results] The older subjects had significantly longer reaction times and higher error rates in both single- and dual-tasking. When dual-tasking, both groups had significantly longer reaction times than when single-tasking. Only the older adults showed significantly higher error rates. The older adults also had significantly longer total sway paths and larger total sway areas of single-leg stance after stepping back. Neither group showed a significant difference in total sway path and sway area between single- and dual-tasking. [Conclusion] Older adults have poorer cognitive performance and postural stability during both single- and dual-tasking. They tend to prioritize postural control over cognition in dual-tasking.


Pancreatic ablation: minimally invasive treatment options.
Despite the significant improvement of knowledge and technologies in tumor treatments, pancreatic tumor remains a complex disease still characterized by a poor prognosis. The increasing role of minimally invasive techniques started to drive the effort of scientific medicine to evaluate the possibilities of application of these techniques to pancreatic cancer. The purpose of this paper is to present a brief summary of the different ablative techniques available and proposed for pancreatic tumor treatment considering invasive, noninvasive, thermal and non-thermal techniques.


Assessment of physiological redox state with novel FRET protein probes.
Development of redox-sensing fluorescent proteins (redox probe proteins) have enabled live imaging of the physiological redox state within a cell, generating new strategies for detecting changes in the redox state during developmental, pathogenic, and aging processes. Several of the probe proteins utilize their characteristic redox-sensing segments as linkers in between two fluorophores, where structural alternations of the segments lead to changes in FRET efficiencies across the fluorophores. In this review we summarize two types of novel FRET-based redox probe proteins, namely redox linker (RL)-derived probes and Redoxfluor. After these FRET-based redox probe proteins were generated, their responsiveness toward redox-related compounds as well as toward reactive oxygen species or reducing stimuli was investigated in vitro. Notably, both the RL-derived probe and Redoxfluor were found to directly respond to the redox state of glutathione, a main redox-formulating compound, showing a promising property for their use in subsequent in vivo analyses. Redoxfluor was not only used for redox sensing in the cytoplasm, but also utilized for assessing the redox state within peroxisomes. In contrast to "one-fluorophore" redox probes such as roGFP and rxYFP proteins, whose usage has been established and widely expanded to various experimental systems, FRET-based redox probes were invented very recently and their applications to in vivo studies are still in their infancy. FRET-based redox probes provide novel approaches for redox sensing that are complementary to other methodologies.


Interventions for replacing missing teeth: antibiotics at dental implant placement to prevent complications.
Some dental implant failures may be due to bacterial contamination at implant insertion. Infections around biomaterials are difficult to treat, and almost all infected implants have to be removed. In general, antibiotic prophylaxis in surgery is only indicated for patients at risk of infectious endocarditis; with reduced host-response; when surgery is performed in infected sites; in cases of extensive and prolonged surgical interventions; and when large foreign materials are implanted. A variety of prophylactic systemic antibiotic regimens have been suggested to minimise infections after dental implant placement. More recent protocols recommended short-term prophylaxis, if antibiotics have to be used. Adverse events may occur with the administration of antibiotics, and can range from diarrhoea to life-threatening allergic reactions. Another major concern associated with the widespread use of antibiotics is the selection of antibiotic-resistant bacteria. The use of prophylactic antibiotics in implant dentistry is controversial. To assess the beneficial or harmful effects of systemic prophylactic antibiotics at dental implant placement versus no antibiotic or placebo administration and, if antibiotics are beneficial, to determine which type, dosage and duration is the most effective. We searched the Cochrane Oral Health Group's Trials Register (to 17 June 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 5), MEDLINE via OVID (1946 to 17 June 2013) and EMBASE via OVID (1980 to 17 June 2013). There were no language or date restrictions placed on the searches of the electronic databases. Randomised controlled clinical trials (RCTs) with a follow-up of at least three months, that compared the administration of various prophylactic antibiotic regimens versus no antibiotics to people undergoing dental implant placement. Outcome measures included prosthesis failures, implant failures, postoperative infections and adverse events (gastrointestinal, hypersensitivity, etc). Screening of eligible studies, assessment of the risk of bias of the trials and data extraction were conducted in duplicate and independently by two review authors. Results were expressed as risk ratios (RRs) using a random-effects model for dichotomous outcomes with 95% confidence intervals (CIs). Heterogeneity, including both clinical and methodological factors, was to be investigated. Six RCTs with 1162 participants were included: three trials compared 2 g of preoperative amoxicillin versus placebo (927 participants), one compared 3 g of preoperative amoxicillin versus placebo (55 participants), one compared 1 g of preoperative amoxicillin plus 500 mg four times a day for two days versus no antibiotics (80 participants), and one compared four groups: (1) 2 g of preoperative amoxicillin; (2) 2 g of preoperative amoxicillin plus 1 g twice a day for seven days; (3) 1 g of postoperative amoxicillin twice a day for seven days, and (4) no antibiotics (100 participants). The overall body of evidence was considered to be of moderate quality. The meta-analyses of the six trials showed a statistically significant higher number of participants experiencing implant failures in the group not receiving antibiotics (RR 0.33; 95% CI 0.16 to 0.67, P value 0.002, heterogeneity: Tau(2) 0.00; Chi(2) 2.87, df = 5 (P value 0.57); I(2) 0%). The number needed to treat for one additional beneficial outcome (NNTB) to prevent one person having an implant failure is 25 (95% CI 14 to 100), based on an implant failure rate of 6% in participants not receiving antibiotics. There was borderline statistical significance for prosthesis failures (RR 0.44; 95% CI 0.19 to 1.00), with no statistically significant differences for infections (RR 0.69; 95% CI 0.36 to 1.35), or adverse events (RR 1; 95% CI 0.06 to 15.85) (only two minor adverse events were recorded, one in the placebo group). No conclusive information can be derived from the only trial that compared three different durations of antibiotic prophylaxis since no event (implant/prosthesis failures, infections or adverse events) occurred in any of the 25 participants included in each study group. There were no trials that evaluated different antibiotics or different antibiotic dosages. Scientific evidence suggests that, in general, antibiotics are beneficial for reducing failure of dental implants placed in ordinary conditions. Specifically 2 g or 3 g of amoxicillin given orally, as a single administration, one hour preoperatively significantly reduces failure of dental implants. No significant adverse events were reported. It might be sensible to suggest the use of a single dose of 2 g prophylactic amoxicillin prior to dental implant placement. It is still unknown whether postoperative antibiotics are beneficial, and which antibiotic is the most effective.


Intracranial pressure and cerebral perfusion pressure in severe head injury.
Monitoring and management of intracranial pressure (ICP) are fundamental to modern neurotraumatology. Although never formally proven to independently improve outcome in prospective, randomized, placebo-controlled trials, there is such a predominance of indirect support for this modality that most neurotrauma protocols are impossible with-out its inclusion and ethical considerations virtually preclude placebo-controlled trials of its efficacy. In addition to the question of improving outcome, ICP monitoring is also useful in guiding the use of potentially harmful treatment modalities such as hyperventilation, mannitol, and barbiturates, and also provides important prognostic data. ICP monitoring provides information on the likelihood of cerebral herniation and allows calculation of the cerebral perfusion pressure (CPP). Although there is no constant threshold for herniation, the most commonly used treatment threshold is 20 to 25 mm Hg. In addition, ICP trends are indispensable in providing the earliest possible indication of critical intracranial mass effects when combined with other clinical indicators. CPP is the difference between mean arterial pressure and ICP. CPP is an important clinical indicator of cerebral blood flow (CBF). Cerebral autoregulation generally remains at least partially preserved after severe head injury, although the CPP value at which it is activated appears to be shifted upward. Therefore, maintaining adequate CBF appears to require using an elevated minimal CPP threshold when treating the injured brain. A generally accepted value of 70 mm Hg is suggested.


Molecular markers of serine protease evolution.
The evolutionary history of serine proteases can be accounted for by highly conserved amino acids that form crucial structural and chemical elements of the catalytic apparatus. These residues display non- random dichotomies in either amino acid choice or serine codon usage and serve as discrete markers for tracking changes in the active site environment and supporting structures. These markers categorize serine proteases of the chymotrypsin-like, subtilisin-like and alpha/beta-hydrolase fold clans according to phylogenetic lineages, and indicate the relative ages and order of appearance of those lineages. A common theme among these three unrelated clans of serine proteases is the development or maintenance of a catalytic tetrad, the fourth member of which is a Ser or Cys whose side chain helps stabilize other residues of the standard catalytic triad. A genetic mechanism for mutation of conserved markers, domain duplication followed by gene splitting, is suggested by analysis of evolutionary markers from newly sequenced genes with multiple protease domains.


Light at the end of the tunnel: the learning curve associated with endoscopic transsphenoidal skull base surgery.
Endoscopic transsphenoidal resection of skull base lesions has been introduced widely as an alternative to microscopic transmucosal approaches. We report the introduction of this technique to our unit, including the learning curve recognized for this procedure, comparing techniques in a concurrent case-control fashion. All patients operated on for sellar, suprasellar, or clival lesions were considered for endoscopic surgery, with 51 patients undergoing endoscopic surgery and 46 having microscopic surgery with the operating method determined by the availability of the ear, nose, and throat surgeon involved with the procedures. Endoscopic surgery compared favorably with microscopic surgery with respect to endocrine control, length of stay, diabetes insipidus, and cerebrospinal fluid leakage. A learning curve was found with a significant fall in complication rates between the first third and most recent third of the cohort. Endoscopic skull base surgery has superior results to microscopic approaches once the initial learning curve is overcome, but this can be done quickly and safely.


Metonymic objects, cultural practices and narrative repair: Sri Lankan responses to the Indian Ocean tsunami.
The 2004 Indian Ocean tsunami resulted in a tragic loss of life and immense suffering. This article explores the ways in which a group of people from Sri Lanka worked to address the disruption to their life narratives caused by the loss of loved ones. We go beyond a focus on 'talk' in narrative research in health psychology to explore the importance of material objects in sustaining continued bonds with the deceased. This article provides an alternative to the tendency in mainstream psychology to pathologise grief and highlights the importance of culturally patterned responses to disaster.


Nimotuzumab, a novel monoclonal antibody to the epidermal growth factor receptor, in the treatment of non-small cell lung cancer.
The epidermal growth factor receptor (EGFR) is a promising therapeutic target in non-small cell lung cancer, and several therapeutic agents that target this receptor, including EGFR tyrosine kinase inhibitors and monoclonal antibodies to EGFR, have been developed. Such monoclonal antibodies have shown efficacy in combination with chemotherapy and radiotherapy. Nimotuzumab (h-R3) is a humanized monoclonal antibody to EGFR, and its effects in combination with radiation have been sufficiently promising to warrant further investigation in several types of cancer. Furthermore, the typical severe dermatologic toxicities associated with other monoclonal antibodies to EGFR have not been observed with nimotuzumab. We here summarize the results of preclinical studies as well as of previous and ongoing clinical trials of nimotuzumab for the treatment of non-small cell lung cancer.


A requirement for sucrose in xylem sap flow from dormant maple trees.
The response of excised stem segments of several tree species to freezing and thawing cycles was studied. All species studied (Thuja occidentalis, Fagus grandifolia, and Betula papyrifera) except maple (Acer spp.) exuded sap while freezing and absorbed on thawing. Maple stems absorbed sap while freezing and exuded sap during the thaw only when sucrose was present in the vessel solution. Increased concentration of sucrose in the vessel sap led to increased exudation. In the absence of sucrose, maple stems absorbed sap on thawing. The presence of sucrose enhanced sap absorption during freezing cycles in maples. In general, large sugars, disaccharides and larger, could substitute for sucrose in the maple exudation response while sugar hexoses could not. The results are discussed in relation to the O'Malley-Milburn model (1983 Can J Bot 61: 3100-3106) of sap flow in maples.


Nonlinear component of the electroretinogram recorded from the posterior pole of normal and highly myopic human eyes.
To extract the nonlinear component of the electroretinogram (ERG) from the posterior pole (pp) of the human ocular fundus and to evaluate the possibility of its clinical application, three types of stimulus modes - double-flash, single-flash, and delayed single-flash stimuli - were produced using a conventional electrophysiological system. A large hexagonal element was presented on a CRT monitor, and ppERGs were recorded from 14 normal eyes and 16 eyes of eight highly myopic patients. The nonlinear component of the ppERG was obtained by subtracting the single-flash ERG and delayed single-flash ERG responses from the double flash ERG response. Three peaks were commonly observed in the nonlinear component of ppERG, all of which were significantly depressed in patients with high myopia. ppERGs that can be obtained using a simple algorithm might be useful in clinical applications.


Triple PLGA/PCL Scaffold Modification Including Silver Impregnation, Collagen Coating, and Electrospinning Significantly Improve Biocompatibility, Antimicrobial, and Osteogenic Properties for Orofacial Tissue Regeneration.
Biodegradable synthetic scaffolds hold great promise for oral and craniofacial guided tissue regeneration and bone regeneration. To overcome the limitations of current scaffold materials in terms of osteogenic and antimicrobial properties, we have developed a novel silver-modified/collagen-coated electrospun poly-lactic-co-glycolic acid/polycaprolactone (PLGA/PCL) scaffold (PP-pDA-Ag-COL) with improved antimicrobial and osteogenic properties. Our novel scaffold was generated by electrospinning a basic PLGA/PCL matrix, followed by silver nanoparticles (AgNPs) impregnation via in situ reduction, polydopamine coating, and then coating by collagen I. The three intermediate materials involved in the fabrication of our scaffolds, namely, PLGA/PCL (PP), PLGA/PCL-polydopamine (PP-pDA), and PLGA/PCL-polydopamine-Ag (PP-pDA-Ag), were used as control scaffolds. Scanning electron micrographs and mechanical testing indicated that the unique three-dimensional structures with randomly oriented nanofibrous electrospun scaffold architectures, the elasticity modulus, and the tensile strength were maintained after modifications. CCK-8 cell proliferation analysis demonstrated that the PP-pDA-Ag-COL scaffold was associated with higher MC3T3 proliferation rates than the three control scaffolds employed. Scanning electron and fluorescence light microscopy illustrated that PP-pDA-Ag-COL scaffolds significantly enhanced MC3T3 cell adhesion compared to the control scaffolds after 12 and 24 h culture, in tandem with the highest β1 integrin expression levels, both at the mRNA level and the protein level. Alkaline phosphatase activity, BMP2, and RUNX2 expression levels of MC3T3 cells cultured on PP-pDA-Ag-COL scaffolds for 7 and 14 days were also significantly higher when compared to controls (P < 0.001). There was a wider antibacterial zone associated in PP-pDA-Ag-COL and PP-pDA-Ag scaffolds versus control scaffolds (P < 0.05), and bacterial fluorescence was reduced on the Ag-modified scaffolds after 24 h inoculation against Staphylococcus aureus and Streptococcus mutans. In a mouse periodontal disease model, the PP-pDA-Ag-COL scaffold enhanced alveolar bone regeneration (31.8%) and was effective for periodontitis treatment. These results demonstrate that our novel PP-pDA-Ag-COL scaffold enhanced biocompatibility and osteogenic and antibacterial properties and has therapeutic potential for alveolar/craniofacial bone regeneration.


Relation between cerebral oxygen delivery and neuronal cell damage in fetal sheep near term.
Asphyxia is one of the major causes for fetal brain damage. Although the quality of life of the so affected children is mostly very limited, the pathogenesis of hypoxic fetal brain damage is poorly understood. Particularly, there is a lack of studies, in which cerebral oxygen delivery is directly correlated to the extent of neuronal cell damage in the same brain specimens. Therefore, we measured cerebral oxygen delivery before (- 1 h), during (+3 min & +27 min) and after (+10 min, +4 h, +72 h) 30 min of ischaemia in 5 chronically catheterized normoxemic fetal sheep at 129 +/- 1 days gestation (term is at 147 days) using the microsphere method. In contrast to previous studies (Williams et al. 1990), we arrested carotid arterial blood flow above the lingual artery for 30 min during surgery. Seventy-two hours later the fetal brains were fixed in vivo under barbiturate anaesthesia of both the fetus and the ewe. After cerebral blood flow analysis neuronal cell damage was assessed with light microscopy in 43 specimens of the fetal brain after cresyl violet/fuchsin staining using a scoring system. After arrest of carotid arterial blood flow cerebral blood flow was reduced by 80%. Neuronal cell damage was focussed on the cerebral cortex. Almost no damage could be detected in deeper parts of the brain. In the cerebrum there was threshold oxygen delivery of 3 ml O2/100 g tissue/min, below which neuronal damage occurred. However, there was no correlation between cerebral oxygen delivery and neuronal cell damage in specimens of the cerebrum, in which oxygen delivery was less than 3 ml O2/100 g tissue/min, suggesting selective vulnerability. Therefore, in addition to the reduction in cerebral oxygen delivery, other variables, e.g. neurotransmitter release, receptor pattern or oxygen radicals, may be involved in the development of brain damage.


Osseous Metaplasia (Cataracta Ossea) of Lens Remnants in Chronic Uveitis-A Clinicopathologic Report.
To describe clinically and pathologically the rare occurrence of calcification and osseous metaplasia in lens remnants in both eyes of a patient with pseudophakic chronic uveitis. We performed 25-gauge pars plana vitrectomy, removal of dislocated intraocular lens (IOL), and secondary IOL fixation in the left eye. A similar procedure was performed in the right eye with 27-gauge pars plana vitrectomy. The postoperative visual acuities were 20/30 OD and 20/125 OS. Hematoxylin and eosin staining demonstrated an abundance of calcified tissue and rare osteoclasts in lacunae, compatible with osseous metaplasia (cataracta ossea). To our knowledge this is the first clinicopathologic report demonstrating cellular metaplasia that resulted in osseous transformation of the cortical lens remnants into bone in both eyes of a psuedophakic patient with chronic granulomatous pan uveitis of unknown etiology. The surgical technique described in the supplemental videos demonstrates an effective way of managing this complication.


Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer's disease.
The discovery of TREM2 as a myeloid-specific Alzheimer's disease (AD) risk gene has accelerated research into the role of microglia in AD. While TREM2 mouse models have provided critical insight, the normal and disease-associated functions of TREM2 in human microglia remain unclear. To examine this question, we profile microglia differentiated from isogenic, CRISPR-modified TREM2-knockout induced pluripotent stem cell (iPSC) lines. By combining transcriptomic and functional analyses with a chimeric AD mouse model, we find that TREM2 deletion reduces microglial survival, impairs phagocytosis of key substrates including APOE, and inhibits SDF-1α/CXCR4-mediated chemotaxis, culminating in an impaired response to beta-amyloid plaques in vivo. Single-cell sequencing of xenotransplanted human microglia further highlights a loss of disease-associated microglial (DAM) responses in human TREM2 knockout microglia that we validate by flow cytometry and immunohistochemistry. Taken together, these studies reveal both conserved and novel aspects of human TREM2 biology that likely play critical roles in the development and progression of AD.


Recent Advances in Non-Fullerene Acceptors of the IDIC/ITIC Families for Bulk-Heterojunction Organic Solar Cells.
The introduction of the IDIC/ITIC families of non-fullerene acceptors has boosted the photovoltaic performances of bulk-heterojunction organic solar cells. The fine tuning of the photophysical, morphological and processability properties with the aim of reaching higher and higher photocurrent efficiencies has prompted uninterrupted worldwide research on these peculiar families of organic compounds. The main strategies for the modification of IDIC/ITIC compounds, described in several contributions published in the past few years, can be summarized and classified into core modification strategies and end-capping group modification strategies. In this review, we analyze the more recent advances in this field (last two years), and we focus our attention on the molecular design proposed to increase photovoltaic performance with the aim of rationalizing the general properties of these families of non-fullerene acceptors.


Dynamic contrast-enhanced MRI in oncology drug development.
Angiogenesis, long recognized as a key factor in tumor growth and metastasis, has been the target of new anticancer treatment paradigms. Development of antiangiogenesis drugs is challenging, mainly due to the difficulty of determining the correct dosage and the time required to observe a clinical effect. In the past decade, imaging has shown potential to answer these questions and accelerate the drug development process by providing functional, morphological, and even molecular characterization. In this review, we describe existing challenges to modern drug development and the potential of imaging biomarkers to monitor drug bioactivity and establish early response of drug efficacy. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), particularly attractive for its non-invasiveness and high spatial resolution, has been useful for measuring properties of tumor microvasculature. The general methodology of DCE-MRI is described, in addition to measurable hemodynamic parameters compared to other imaging modalities. Experience with DCE-MRI in antiangiogenesis cancer therapy and results from correlative studies are examined. Current challenges for DCE-MRI, especially in relation to the required sensitivity and reproducibility, are highlighted. We conclude with an outlook on the future of DCE-MRI, including its role in the emerging field of imaging molecular markers of angiogenesis for target-specific therapy.


Skin dendritic cells in burn patients.
The body's immunological response to burn injury has been a subject of great inquiry in recent years. Burn injury disturbs the immune system, resulting in a progressive suppression of the immune response that is thought to contribute to the development of sepsis. Dendritic cells (DCs) are potent antigen-presenting cells that possess the ability to stimulate naïve T cells.DCs are derived from bone marrow progenitors and circulate in the blood as immature precursors prior to migration into peripheral tissues. Within different tissues, DCs differentiate and become active in the taking up and processing of antigens, and their subsequent presentation on the cell surface is linked to major histocompatibility molecules. Upon appropriate stimulation, DCs undergo further maturation and migrate to secondary lymphoid tissues, where they present antigen to T cells and induce an immune response. The purpose of this study was to determine the effects of burn injury on skin DCs in terms of percentage, HLA-DR, and Toll-like receptor-4 (TLR-4) expression. The skin DCs were isolated from burned skin and non-burned skin in the same patient at 7 days post-injury, and skin DCs were isolated from unburned healthy individuals as control. DCs from burned skin notably express low levels of HLA-DR and TLR-4 soon after cell isolation. In the post-burn period the ability of skin DCs to respond to bacterial stimuli is impaired. These changes in DC behaviour might contribute to the impaired host defences against bacteria during burn sepsis.


Electrocardiographic predictors of response to cardiac resynchronization therapy in patients with intraventricular conduction delay.
Little is known about predictors of response to cardiac resynchronization therapy (CRT) in patients with intraventricular conduction delay (IVCD). The purpose of this study was to investigate the benefits of CRT and significant variables on surface electrocardiogram (ECG) to predict response to CRT in those patients. Among the cohort of 152 CRT patients, 40 patients with IVCD were evaluated. Sixteen patients (40%) were responders. At baseline, responders had a wider QRS duration (158±18 vs. 144±18ms, P=0.02) and a higher frequency of left axis deviation (LADEV; 75% vs. 29%, P=0.004) compared with non-responders. After CRT, greater shortening of QRS duration (ΔQRS; 26±24 vs. 7±24ms, P=0.02), axis shift from LADEV to right axis deviation (RADEV; 69% vs. 13%, P<0.001), and both rightward forces in lead I and anterior forces in V1 (56% vs. 13%, P=0.003) were found more frequently in responders. Multivariable logistic regression analysis showed that LADEV at baseline, or ΔQRS and axis shift from LADEV to RADEV after CRT were independent predictors of response to CRT. Patients with IVCD may not respond to CRT, but LADEV at baseline and reversal of ventricular activation after CRT on surface ECG could be important to predict response to CRT.


Analysis of the pivotal residues of the immunodominant and highly uveitogenic determinant of interphotoreceptor retinoid-binding protein.
Interphotoreceptor retinoid-binding protein (IRBP), a retinal-specific Ag, induces experimental autoimmune uveitis in a variety of animals. We have previously shown that sequence 1169-1191 of bovine IRBP is the immunodominant epitope of this protein in Lewis rats and is highly immunogenic and uveitogenic in these rats. The active site of peptide 1169-1191 was determined by testing its truncated forms. The shortest peptide to be immunologically active was found to be 1182-1190 (WEGVGVVPD). To determine the role of individual residues of this sequence, we have tested the immunologic activities of nine analogs of peptide 1181-1191, in which each of residues 1182-1190 was substituted with alanine (A). The tested activities included the capacity to induce experimental autoimmune uveitis and cellular responses in immunized rats, as well as the capability to stimulate lymphocytes sensitized against IRBP or the parent peptide 1181-1191. Analogs that did not stimulate these lymphocytes were also tested for their capacity to competitively inhibit the proliferative response to 1181-1191. Analogs A(1184), A(1186), and A(1187) resembled 1181-1191 in their activities, whereas the other analogs exhibited remarkably reduced activities, with several patterns being noticed. Analog A(1182) was inactive in all tests. Analog A(1190) was very weakly uveitogenic and non-immunogenic, but it stimulated lymphocytes sensitized against IRBP or 1181-1191 when added at exceedingly high concentrations. Analogs A(1183) and A(1185) resembled A(1190) in being weakly uveitogenic and A(1185) was also found to be poorly immunogenic. In addition, relatively high concentrations of A(1183) and A(1185) were needed to stimulate lymphocytes sensitized against IRBP or 1181-1191. However, a different pattern of activities was exhibited by analogs A(1188) and A(1189). These peptides were uveitogenic and immunogenic, but failed to stimulate lymphocytes sensitized to IRBP or 1181-1191. Furthermore, A(1188) and A(1189), but not A(1182), also inhibited the response to 1181-1191 of a cell line specific toward this parent peptide. The data are interpreted to show that residues 1188 and 1189 are involved in the interaction of the peptide with the TCR, whereas residues 1182 and 1190 and, perhaps, 1183 and 1185, are pivotal for the binding of peptide 1181-1190 to the MHC molecules on APC.


[Mutational activation of H-ras and K-ras (Codon 12,61) genes in 7,12 dimethylbenz(a)anthracene induced rat ovarian tumors].
We had studied the histogenesis and p21 expression in ovarian tumor induced by 7,12-dimethylbenz(a)anthracene (DMBA). The present study was done to elucidate point mutation of the ras gene in tumors. Cases with immunohistological p21 expression; 3 adenomas, 5 adenocarcinomas and 2 sarcomas were examined by polymerase chain reaction (PCR). 1) The products of PCR were confirmed the presence of amplified sequences by electrophoresis. 2) No point mutation of H-ras (Codon 12,61) or K-ras (Codon 12,61) genes was found in the ovarian tumors induced by DMBA. 3) These results suggested that the mutational activation of ras genes in tumorigenesis was dependent on another mechanism.


An evidence-based review of dental matrix systems.
The restoration of proximal surface cavities, originating from Class II carious lesions, to "normal" anatomical specifications is a fundamental objective for the dental practitioner. Cognitive interpretation of tooth morphology attained from evidence-based resources, together with the necessary psychomotor skills for correct design and completion, are considered essential strategies for restoration success. Also, the visualization of the original tooth structure, if present, should substantially benefit the dentist in the creation of a clinically satisfactory restoration. The purpose of this evidence-based review is to define the cause and effect of decisions based on optimum treatment standards of care for the patient. The concepts of form and function, as related to the oral environment, and the consequences of unsatisfactory dental restorative care will be scrutinized. This article will identify and explain the different challenges and solutions for restoration of dental proximal lesions and provide an overview of past, present, and future procedures.


Tamoxifen and anastrozole as a sequencing strategy: a randomized controlled trial in postmenopausal patients with endocrine-responsive early breast cancer from the Austrian Breast and Colorectal Cancer Study Group.
Anastrozole (ANA) alone delivers significant disease-free survival benefits over tamoxifen (TAM) monotherapy in postmenopausal women with early estrogen receptor-positive breast cancer. The ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) study is a large phase III clinical trial addressing the sequence strategy containing ANA in comparison with 5 years of TAM in a low- to intermediate-risk group of postmenopausal patients. Endocrine receptor-positive patients with G1 or G2 tumors were eligible. After surgery, patients were randomly assigned to 5 years of TAM or 2 years of TAM followed by 3 years of ANA. Adjuvant chemotherapy and G3 and T4 tumors were exclusion criteria. Intention-to-treat and censored analyses of on-treatment recurrence-free survival (RFS) were performed, and exploratory survival end points and toxicity were investigated. Information from 3,714 patients, including 17,563 woman-years, with a median of 60 months of follow-up was available for this analysis. Median age was 63.8 years, 75% were node negative, and 75% had T1 tumors. Sequencing of ANA after identical 2-year treatment with TAM in both arms did not result in a statistically significant improvement of RFS (hazard ratio [HR], 0.80; 95% CI, 0.63 to 1.01; P = .06). Exploratory analyses of distant relapse-free survival indicated a 22% improvement (HR, 0.78; 95% CI, 0.60 to 1.00). On-treatment adverse events and serious adverse events were consistent with known toxicity profiles of ANA and TAM treatment. Despite a low overall rate of recurrence in a population with breast cancer at limited risk of relapse, the a priori sequence strategy of 2 years of TAM followed by 3 years of ANA led to small outcome and toxicity benefits.


IL17A critically shapes the transcriptional program of fibroblasts in pancreatic cancer and switches on their protumorigenic functions.
A hallmark of cancer, including pancreatic ductal adenocarcinoma (PDA), is a massive stromal and inflammatory reaction. Many efforts have been made to identify the anti- or protumoral role of cytokines and immune subpopulations within the stroma. Here, we investigated the role of interleukin-17A (IL17A) and its effect on tumor fibroblasts and the tumor microenvironment. We used a spontaneous PDA mouse model (KPC) crossed to IL17A knockout mice to show an extensive desmoplastic reaction, without impaired immune infiltration. Macrophages, especially CD80+ and T cells, were more abundant at the earlier time point. In T cells, a decrease in FoxP3+ cells and an increase in CD8+ T cells were observed in KPC/IL17A-/- mice. Fibroblasts isolated from IL17A+/+ and IL17A-/- KPC mice revealed very different messenger RNA (mRNA) and protein profiles. IL17A-/- fibroblasts displayed the ability to restrain tumor cell invasion by producing factors involved in extracellular matrix remodeling, increasing T cell recruitment, and producing higher levels of cytokines and chemokines favoring T helper 1 cell recruitment and activation and lower levels of those recruiting myeloid/granulocytic immune cells. Single-cell quantitative PCR on isolated fibroblasts confirmed a very divergent profile of IL17A-proficient and -deficient cells. All these features can be ascribed to increased levels of IL17F observed in the sera of IL17A-/- mice, and to the higher expression of its cognate receptor (IL17RC) specifically in IL17A-/- cancer-associated fibroblasts (CAFs). In addition to the known effects on neoplastic cell transformation, the IL17 cytokine family uniquely affects fibroblasts, representing a suitable candidate target for combinatorial immune-based therapies in PDA.


Epidemiology of brain lymphoma among people with or without acquired immunodeficiency syndrome. AIDS/Cancer Study Group.
In recent years, brain lymphoma incidence has dramatically increased, presumably because of elevated risk of brain lymphoma among persons with acquired immunodeficiency syndrome (AIDS). The objective of this study was to estimate independent incidence and survival rates of brain lymphoma among persons with or without AIDS and to understand the epidemiologic features of this cancer. We linked AIDS and cancer registry reports at nine state and local health departments and compared the demographics, histology, and survival of brain lymphoma cases among persons with or without AIDS. The data were limited to people under 70 years of age. We calculated the incidence of brain lymphoma among persons with AIDS and compared observed cases with those expected. The differences were statistically analyzed using the Poisson test. Epidemiologic features of brain lymphoma in persons with or without AIDS were compared using the chi-squared test, the Student's t test, and the chi-squared test for linear trend. The logrank test was used to compare survival rates estimated by the Kaplan-Meier technique. All P values were two-sided. We matched 50,989 AIDS registry reports to 859,398 cancer registry reports (data from 1981 to 1990) and found 431 people with both AIDS and brain lymphoma. Among people with AIDS, those developing brain lymphoma versus those without brain lymphoma were more likely to be white (70% versus 59%; P < .001) and had homosexuality as their only human immunodeficiency virus risk factor (75% versus 64%; P < .001). Of the 431 patients, 223 developed brain lymphomas during 47,465 person-years of observation after diagnosis of AIDS. The absolute incidence rate of brain lymphoma among persons with AIDS was 4.7/1000 person-years (95% confidence interval = 4.1-5.3/1000 person-years), 3600-fold higher than the base-line rate in the general population. From 1980 through 1989, overall counts of brain lymphoma increased ninefold. Most of this increase was derived from persons with AIDS, but a substantial increase also occurred among persons without AIDS (0.04/100,000 in 1982 to 0.28/100,000 in 1989) (chi-squared test for trend; P < .05). The median survival was shortest for persons with AIDS and brain lymphoma (2 months), was intermediate for persons with brain lymphoma without AIDS (5-7 months), and was longest for persons with AIDS without brain lymphoma (14 months) (P < .05 for all comparisons). This analysis distinguishes the separate epidemiologies of brain lymphoma incidence among persons with or without AIDS and shows brain lymphoma incidence among persons with AIDS to be several thousand-fold higher than that in the general population. The study documents the overwhelming effect of AIDS-associated brain lymphoma on the overall rate in the general population and demonstrates a significantly rising trend, although of a lesser magnitude, among persons without AIDS. This study emphasizes a greater need to bring health care resources to this burgeoning epidemic.


Clinical manifestation and perceived symptoms of walking-related performance fatigability in persons with multiple sclerosis.
Fatigue and walking difficulties are common impairments and activity limitations in persons with multiple sclerosis (PwMS). Walking fatigability (WF) can be measured by a Distance Walked Index and is defined as a decline in walking distance of 10% or more during the six-minute walking test (6MWT). However, the clinical manifestation and perceived symptoms related to fatigability are still not well documented. Forty-nine PwMS [Expanded Disability Status Scale (EDSS) ≤6] and 28 healthy controls (HC) performed a 6MWT. The perceived severity of 11 common symptoms was rated on a visual analogue scale of 0-10 before, immediately after, and 10, 20 and 30 minutes after the 6MWT by means of the symptom inventory. Short motor impairment screening tests at baseline together with other descriptive measures were performed. Twenty pwMS were categorized in the WF group and were more disabled (EDSS: 4.16 ± 1.41) than the non-walking fatigability group (n = 29, EDSS: 2.62 ± 1.94). PwMS showed exacerbations of several perceived symptoms in MS, where most symptoms returned to baseline within 10 minutes after the walking test. The WF group showed significantly more muscle weakness and gait impairment, together with balance problems, and experienced an increase in spasticity, pain and dizziness after 6MWT. Our findings showed that perceived severity of symptoms are higher in pwMS presenting WF, and increase temporally after the 6MWT. Future research with quantitative measurement during and after walking is recommended.


Functional characterization of nutraceuticals using spectral clustering: Centrality of caveolae-mediated endocytosis for management of nitric oxide and vitamin D deficiencies and atherosclerosis.
It is well recognized that redox imbalance, nitric oxide (NO), and vitamin D deficiencies increase risk of cardiovascular, metabolic, and infectious diseases. However, clinical studies assessing efficacy of NO and vitamin D supplementation have failed to produce unambiguous efficacy outcomes suggesting that the understanding of the pharmacologies involved is incomplete. This raises the need for using systems pharmacology tools to better understand cause-effect relationships at biological systems levels. We describe the use of spectral clustering methodology to analyze protein network interactions affected by a complex nutraceutical, Cardio Miracle (CM), that contains arginine, citrulline, vitamin D, and antioxidants. This examination revealed that interactions between protein networks affected by these substances modulate functions of a network of protein complexes regulating caveolae-mediated endocytosis (CME), TGF beta activity, vitamin D efficacy and host defense systems. Identification of this regulatory scheme and the working of embedded reciprocal feedback loops has significant implications for treatment of vitamin D deficiencies, atherosclerosis, metabolic and infectious diseases such as COVID-19.


Probabilistic stability analysis: the way forward for stability analysis of sustainable power systems.
Future power systems will be significantly different compared with their present states. They will be characterized by an unprecedented mix of a wide range of electricity generation and transmission technologies, as well as responsive and highly flexible demand and storage devices with significant temporal and spatial uncertainty. The importance of probabilistic approaches towards power system stability analysis, as a subsection of power system studies routinely carried out by power system operators, has been highlighted in previous research. However, it may not be feasible (or even possible) to accurately model all of the uncertainties that exist within a power system. This paper describes for the first time an integral approach to probabilistic stability analysis of power systems, including small and large angular stability and frequency stability. It provides guidance for handling uncertainties in power system stability studies and some illustrative examples of the most recent results of probabilistic stability analysis of uncertain power systems.This article is part of the themed issue 'Energy management: flexibility, risk and optimization'.


The inactive form of recA protein: the 'compact' structure.
When recA protein is enzymatically inactive in vitro, it adopts a more compact helical polymer form than that of the active protein polymerized onto DNA in the presence of ATP. Here we describe some aspects of this structure. By cryo-electron microscopy, a pitch of 76 A is found for both the self-polymer and the inactive complex with ssDNA. A smaller pitch of 64 A is observed in conventional electron micrographs. The contour length of complexes with ssDNA was used to estimate the binding stoichiometry in the compact complex, 6 +/- 1 nt/recA. In addition, the compact structure was observed in vivo in Escherichia coli: inclusion bodies produced upon induction of recA expression in an overproducing strain have a fibrous morphology with the structural parameters of the compact polymer.


Long-term follow-up of behavioural treatment for primary encopresis in people with intellectual disability in the community.
Encopresis is a major problem in high-dependency fields such as intellectual disability. Little information is available with respect to either the prevalence or aetiology of encopresis, probably because it is widely regarded as part and parcel of the handicapping condition. Consequently, treatment reports are rare and confined to a small number of case studies. There is a dearth of long-term follow-up on the behavioural treatment of encopresis in the general population, and no long-term follow-up studies are available for the treatment of encopresis in intellectual disability. The present report provides follow-up data for nine out of 10 people with mainly severe intellectual disability who had received behavioural treatment for primary retentive or non-retentive encopresis between 5 and 17 years previously. Six out of the nine subjects for whom data were available were accident-free and a further two clients were very substantially improved. Interestingly, those whose former encopresis was retentive in nature maintained more successfully, despite the severity of their original impaction. The limitations of the present study are discussed.


Severe pneumococcal meningitis heralding a deep hypogammaglobulinaemia related to common variable immunodeficiency, at the age of 27 years.
Common variable immunodeficiency with an associated broad immunoglobulin (0.7%) deficit affecting all subclasses, was revealed in a 27-y-old previously healthy female, upon development of a severe pneumococcal meningitis. We report the third case of purulent meningitis complicating this primary immunodeficiency, and the second due to Streptococcus pneumoniae. Clinicians should maintain an elevated suspicion for congenital immunodeficiency, especially when observing adult patients with a negligible prior history.


Myocardial infarction and coronary artery involvement in giant cell arteritis.
To describe the pathologic findings in an unusual case of giant cell arteritis that presented initially with visual loss and rapidly culminated in myocardial infarction. After the death of the patient, a complete autopsy was performed, including bilateral enucleation. All specimens, including a temporal artery biopsy completed before the patients death, were processed for routine paraffin histology and initially stained with hematoxylin and eosin. Elastic stains were subsequently used on specimens of temporal and coronary artery. The patient presented with loss of vision in the right eye. The clinical diagnosis was anterior ischemic optic neuropathy, secondary to temporal arteritis. The temporal artery biopsy was positive. Despite high-dose corticosteroid administration, the patient progressed to neurologic impairment, and subsequently to a fatal myocardial infarction. Previous reports of temporal arteritis with coronary involvement are summarized. Myocardial infarction may be a more common early complication of temporal arteritis than appreciated previously. This important complication can occur despite administration of high-dose corticosteroid therapy.


High frequency of virus-specific B lymphocytes in germinal centers of simian-human immunodeficiency virus-infected rhesus monkeys.
The etiology of the lymphadenopathy and follicular hyperplasia associated with human immunodeficiency virus type 1 (HIV-1) infection has remained unclear. To determine whether the B-lymphocyte expansions characteristic of this syndrome represent polyclonal and virus-specific processes, the antigen specificity of B cells in lymphoid tissues of monkeys infected with simian-human immunodeficiency virus (SHIV) chimeras was assessed using an inverse immunohistochemical assay with biotinylated HIV-1 envelope gp120 (Env) as an antigen probe. Env-binding B cells were found aggregated in lymph node and splenic germinal centers (GCs). Most Env-binding GCs also contained an unstained population of B cells, suggesting the GCs were formed by a polyclonal (oligoclonal) process. By day 42 following infection, Env-binding B cells were present in 19% of all lymph node GCs. Env-binding cells were present in 25% of GCs even during chronic infection. This extraordinarily high frequency of Env-specific B lymphocytes suggests that the expansion of virus-specific B cells may largely account for the follicular hyperplasia in AIDS virus-infected individuals.


Factors associated with rapid labour in nulliparae.
The objective of this study was to assess the factors which may influence rapid labour in nulliparae. This is a cohort study of 991 consecutive nulliparae who were admitted in spontaneous labour with a singleton pregnancy and cephalic presentation. The setting was the National Maternity Hospital, Dublin where active management of labour is applied to all nulliparae fitting the above criteria. Rapid labour of 2 hours or less occurred in 82 patients (8.3%). Dilatation of 2 cm of the cervix on admission in labour, gestation of less than 37 weeks, and diminishing birthweight, were more common in rapid labours compared with other labours. Women in rapid labour were not surprisingly less likely to require oxytocin augmentation, or to need operative vaginal delivery or Caesarean section, receive epidural anaesthesia, or attend antenatal classes, compared with other women in labour. Rapid labour was not influenced by the finding that the membranes were already ruptured before admission, the time spent at home with contractions, or social background. Women with rapid labour were more likely to arrive in hospital within 4 hours compared with other women in labour. Rapid labour depends on the efficiency of uterine action which is reflected by the dilatation of the cervix on admission.


A Model of Generating Visual Place Cells Based on Environment Perception and Similar Measure.
It is an important content to generate visual place cells (VPCs) in the field of bioinspired navigation. By analyzing the firing characteristic of biological place cells and the existing methods for generating VPCs, a model of generating visual place cells based on environment perception and similar measure is abstracted in this paper. VPCs' generation process is divided into three phases, including environment perception, similar measure, and recruiting of a new place cell. According to this process, a specific method for generating VPCs is presented. External reference landmarks are obtained based on local invariant characteristics of image and a similar measure function is designed based on Euclidean distance and Gaussian function. Simulation validates the proposed method is available. The firing characteristic of the generated VPCs is similar to that of biological place cells, and VPCs' firing fields can be adjusted flexibly by changing the adjustment factor of firing field (AFFF) and firing rate's threshold (FRT).


Ox-LDL-Induced MicroRNA-155 Promotes Autophagy in Human Endothelial Cells via Repressing the Rheb/ mTOR Pathway.
Autophagy, an evolutionary conserved biological process, is activated in cells to cope with various types of stress. MicroRNAs control several activities related to autophagy. However, the role of autophagy-related microRNAs during atherosclerosis is far from known. MicroRNA-155 was identified to be a crucial regulator of atherosclerosis. The objectives of the study were to analyze the effect of microRNA-155 on autophagic signaling and explore its mechanism in human endothelial cells under ox-LDL stress. The study included human endothelial cells surrogate EA.hy926 lines (EA.hy926 cells). The expression of microRNA-155 was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effect of microRNA-155 on endothelial autophagy was observed along with the expression levels of Rheb, LC3B, Beclin1, and P62/SQSTM1 by western blotting (WB) and immunofluorescence through microRNA-155 overexpression or inhibition. Bioinformatics analysis and Luciferase reporter assay were used to explore the target gene of microRNA-155. Cell viability and apoptosis were examined by 3-[4,5-dimethylthiazol-2-yl]-5- [3-carboxy-methoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium inner salt (MTS) assay and TdT-mediated dUTP Nick-End Labeling (TUNEL) apoptosis assay. MicroRNA-155 expression was significantly increased under ox-LDL stress. MicroRNA-155 increased autophagic activity, while inhibition of it alleviated ox-LDL-induced autophagy in EA.hy926 endothelial cells. In addition, dual-luciferase reporter assays showed that microRNA-155 suppressed Rheb transcription. MicroRNA-155 increased autophagic activity in EA.hy926 cells via inhibition of Rheb-mediated mTOR/P70S6kinase/4EBP signaling pathway. Furthermore, we demonstrated that microRNA-155 could regulate not only autophagy but also apoptosis in EA.hy926 cells. MicroRNA-155 works as a regulator of endothelial function under ox-LDL stress, making it a potential candidate for the novel therapeutic strategies against atherosclerotic diseases.


Latinos and the Pandemic: Results from the National Social Life, Health, and Aging Project-COVID-19 Study.
Pre-pandemic disparities placed Latinos at risk for COVID-19. This report describes the associations between increased viral exposure through social contact and material hardship and the uneven distribution of COVID-19 morbidity among Latino older adults using data from the recently released supplement to the National Social Life, Heath, and Aging Project (NSHAP) (N = 2672), a population-based panel study of adults born 1920-1965. Logistic regression revealed that material hardship and reliance on outside help were significantly correlated with COVID-19 infection, which may partially explain the disproportionate burden Latinos experience during the pandemic.


Modulation Phase Distribution of Ruddlesden-Popper Quasi-2D Perovskites with a Similarly Spaced Dion-Jacobson Phase.
Quasi-two-dimensional (quasi-2D) perovskites exhibit excellent performance when applied to light-emitting diodes (LEDs). However, quasi-2D perovskite films generally have nonuniform n phases and irregular internal crystal structures, which degrade the device's performance. Here, we propose using a Dion-Jacobson (DJ)-type organic spacer to modulate the phase distribution of the Ruddlesden-Popper (RP) quasi-2D perovskite. A DJ-type organic spacer cation, 1.6-hexamethylenediamine (HDABr2), was introduced into the perovskite as the second spacer cation with propylamine hydrobromide (PABr). As DJ-type and RP-type perovskites have similar spacings, RP-DJ style does not cause a chaotic crystalline structure; instead, it modulates the perovskite crystallization and narrows the phase distribution. In parallel, there is a substantial improvement in the maximum luminance, current efficiency, external quantum efficiency, and device stability of the quasi-2D perovskite LEDs. This work provides a novel concept for combining the organic spacer cations for quasi-2D perovskites.


Adverse Reactions Associated With Cannabis Consumption as Evident From Search Engine Queries.
Cannabis is one of the most widely used psychoactive substances worldwide, but adverse drug reactions (ADRs) associated with its use are difficult to study because of its prohibited status in many countries. Internet search engine queries have been used to investigate ADRs in pharmaceutical drugs. In this proof-of-concept study, we tested whether these queries can be used to detect the adverse reactions of cannabis use. We analyzed anonymized queries from US-based users of Bing, a widely used search engine, made over a period of 6 months and compared the results with the prevalence of cannabis use as reported in the US National Survey on Drug Use in the Household (NSDUH) and with ADRs reported in the Food and Drug Administration's Adverse Drug Reporting System. Predicted prevalence of cannabis use was estimated from the fraction of people making queries about cannabis, marijuana, and 121 additional synonyms. Predicted ADRs were estimated from queries containing layperson descriptions to 195 ICD-10 symptoms list. Our results indicated that the predicted prevalence of cannabis use at the US census regional level reaches an R2 of .71 NSDUH data. Queries for ADRs made by people who also searched for cannabis reveal many of the known adverse effects of cannabis (eg, cough and psychotic symptoms), as well as plausible unknown reactions (eg, pyrexia). These results indicate that search engine queries can serve as an important tool for the study of adverse reactions of illicit drugs, which are difficult to study in other settings.


The neural basis of drug craving: an incentive-sensitization theory of addiction.
This paper presents a biopsychological theory of drug addiction, the 'Incentive-Sensitization Theory'. The theory addresses three fundamental questions. The first is: why do addicts crave drugs? That is, what is the psychological and neurobiological basis of drug craving? The second is: why does drug craving persist even after long periods of abstinence? The third is whether 'wanting' drugs (drug craving) is attributable to 'liking' drugs (to the subjective pleasurable effects of drugs)? The theory posits the following. (1) Addictive drugs share the ability to enhance mesotelencephalic dopamine neurotransmission. (2) One psychological function of this neural system is to attribute 'incentive salience' to the perception and mental representation of events associated with activation of the system. Incentive salience is a psychological process that transforms the perception of stimuli, imbuing them with salience, making them attractive, 'wanted', incentive stimuli. (3) In some individuals the repeated use of addictive drugs produces incremental neuroadaptations in this neural system, rendering it increasingly and perhaps permanently, hypersensitive ('sensitized') to drugs and drug-associated stimuli. The sensitization of dopamine systems is gated by associative learning, which causes excessive incentive salience to be attributed to the act of drug taking and to stimuli associated with drug taking. It is specifically the sensitization of incentive salience, therefore, that transforms ordinary 'wanting' into excessive drug craving. (4) It is further proposed that sensitization of the neural systems responsible for incentive salience ('for wanting') can occur independently of changes in neural systems that mediate the subjective pleasurable effects of drugs (drug 'liking') and of neural systems that mediate withdrawal. Thus, sensitization of incentive salience can produce addictive behavior (compulsive drug seeking and drug taking) even if the expectation of drug pleasure or the aversive properties of withdrawal are diminished and even in the face of strong disincentives, including the loss of reputation, job, home and family. We review evidence for this view of addiction and discuss its implications for understanding the psychology and neurobiology of addiction.


Towards a mechanistic understanding of particle shrinkage during biomass pyrolysis via synchrotron X-ray microtomography and in-situ radiography.
Accurate modelling of particle shrinkage during biomass pyrolysis is key to the production of biochars with specific morphologies. Such biochars represent sustainable solutions to a variety of adsorption-dependent environmental remediation challenges. Modelling of particle shrinkage during biomass pyrolysis has heretofore been based solely on theory and ex-situ experimental data. Here we present the first in-situ phase-contrast X-ray imaging study of biomass pyrolysis. A novel reactor was developed to enable operando synchrotron radiography of fixed beds of pyrolysing biomass. Almond shell particles experienced more bulk shrinkage and less change in porosity than did walnut shell particles during pyrolysis, despite their similar composition. Alkaline pretreatment was found to reduce this difference in feedstock behaviour. Ex-situ synchrotron X-ray microtomography was performed to study the effects of pyrolysis on pore morphology. Pyrolysis led to a redistribution of pores away from particle surfaces, meaning newly formed surface area may be less accessible to adsorbates.


[Cardiopulmonary resuscitation].
Presented is a basic care plan that nurses should put into practice before and after cardiopulmonary resuscitation. Besides the typical resuscitation maneuvers, all health care professionals should know and be able to evaluate the possible complications that could arise so that they can detect them beforehand and plan their prevention. Also explained are details regarding ways to help the patient and his/her family cope with this physical and emotional crisis.


Evolutionary synthetic biology.
Signaling networks process vast amounts of environmental information to generate specific cellular responses. As cellular environments change, signaling networks adapt accordingly. Here, I will discuss how the integration of synthetic biology and directed evolution approaches is shedding light on the molecular mechanisms that guide the evolution of signaling networks. In particular, I will review studies that demonstrate how different types of mutations, from the replacement of individual amino acids to the shuffling of modular domains, lead to markedly different evolutionary trajectories and consequently to diverse network rewiring. Moreover, I will argue that intrinsic evolutionary properties of signaling proteins, such as the robustness of wild type functions, the promiscuous nature of evolutionary intermediates, and the modular decoupling between binding and catalysis, play important roles in the evolution of signaling networks. Finally, I will argue that rapid advances in our ability to synthesize DNA will radically alter how we study signaling network evolution at the genome-wide level.


Alcohol, caffeine, and nicotine consumption in adolescents: hair analysis versus self-report.
Clinical reliability of self-reported data for alcohol, caffeine, and nicotine consumptions is lacking, particularly in adolescents. To compare a self-report questionnaire and hair analysis to assess the reliability and effectiveness of the self-report. A cross-sectional study on 14-15-year-old Italian students (n = 874, 38% males, 62% females) was performed comparing self-reported data to hair analysis. The latter quantified hair concentrations of caffeine, nicotine, cotinine, ethyl glucuronide (EtG), and fatty acid ethyl esters (FAEEs) using mass spectrometry. Concordance between self-report and hair testing ranged from good to poor across substances and levels of use: poor for heavy alcohol intake (EtG: k = 0.36, 20 positive cases by hair analysis, false negative by self-report, 2.3% of total sample; FAEE k = 0.31, 25 positive cases, 2.9% of total sample); fair to poor for active smokers (k = 0.40, 125 positive cases, 14.3% of total sample); and moderate for caffeine (k = 0.57, 56 positive cases, 6.4% of total sample). Epidemiological studies on alcohol, caffeine, and nicotine consumption in adolescents may benefit from the inclusion of toxicological analysis on hair samples to overcome the under-reporting phenomenon of questionnaires and detect more cases of problematic substance use.


The crystal structure of the DNA-binding domain of yeast RAP1 in complex with telomeric DNA.
Telomeres, the nucleoprotein complexes at the ends of eukaryotic chromosomes, are essential for chromosome stability. In the yeast S. cerevisiae, telomeric DNA is bound in a sequence-specific manner by RAP1, a multifunctional protein also involved in transcriptional regulation. Here we report the crystal structure of the DNA-binding domain of RAP1 in complex with telomeric DNA site at 2.25 A resolution. The protein contains two similar domains that bind DNA in a tandem orientation, recognizing a tandemly repeated DNA sequence. The domains are structurally related to the homeodomain and the proto-oncogene Myb, but show novel features in their DNA-binding mode. A structured linker between the domains and a long C-terminal tail contribute to the binding specificity. This structure provides insight into the recognition of the conserved telomeric DNA sequences by a protein.


Synergistic Effects of Photo-Irradiation and Curcumin-Chitosan/Alginate Nanoparticles on Tumor Necrosis Factor-Alpha-Induced Psoriasis-Like Proliferation of Keratinocytes.
Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation of the epidermal cells and is clinically presented as thick, bright red to pink plaques with a silvery scale. Photodynamic therapy (PDT) using visible light has become of increasing interest in the treatment of inflammatory skin diseases. In this study, we demonstrate that a combination of curcumin-loaded chitosan/alginate nanoparticles (Cur-CS/Alg NPs) and blue light emitting diodes (LED) light irradiation effectively suppressed the hyperproliferation of tumor necrosis factor-alpha (TNF-α)-induced cultured human kerlatinocyte (HaCaT) cells. The Cur-CS/Alg NPs were fabricated by emulsification of curcumin in aqueous sodium alginate solution and ionotropic gelation with calcium chloride and chitosan using an optimized formulation derived from a Box-Behnken design. The fabricated Cur-CS/Alg NPs were characterized for their particle size, zeta potential, encapsulation efficiency, and loading capacity. The surrogate 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, to measure the relative number of viable cells, showed that the CS/Alg NPs were nontoxic to normal HaCaT cells, while 0.05 µg/mL and 0.1 µg/mL of free curcumin and Cur-CS/Alg NPs inhibited the hyperproliferation of HaCaT cells induced by TNF-α. However, the Cur-CS/Alg NPs demonstrated a stronger effect than the free curcumin, especially when combined with blue light irradiation (10 J/cm²) from an LED-based illumination device. Therefore, the Cur-CS/Alg NPs with blue LED light could be potentially developed into an effective PDT system for the treatment of psoriasis.


Obesity and cardiovascular outcomes: a review.
The prevalence of obesity is increasing at an epidemic rate globally with more than 1 billion adults overweight and at least 300 million of them clinically obese. This is expected to rise further in the next 20 to 30 years. Obesity is known to be an independent risk factor for serious health conditions, including hypertension, type 2 diabetes, and cardiovascular diseases. Given the association of obesity with cardiovascular disease, it could be speculated that obese individuals would have adverse outcomes after a cardiovascular event compared to those with normal body mass index (BMI). However, various studies have reported a paradoxical U-shaped relationship between obesity and mortality from various diseases, including myocardial infarction and heart failure, suggesting that patients with higher BMI have similar or lower short- and long-term mortality rates. This phenomenon has been termed the 'obesity paradox' or 'reverse epidemiology'. The goal of this review is to evaluate the potential mechanisms behind the obesity paradox and its implications.


Plasma heme oxygenase-1 concentration is elevated in individuals with type 2 diabetes mellitus.
Circulating concentrations of heme oxygenase-1 (HO-1) have been recently reported to be elevated in several chronic disorders. However, no study has ever examined the association between circulating HO-1 concentrations and type 2 diabetes mellitus (T2DM). 581 cases with newly-diagnosed T2DM (New-T2DM) and 611 comparison controls were recruited in this two-phase case-control study, comprising 420 cases and 429 controls collected in the first phase study and 161 cases and 182 controls in the second phase replication study. Analyses, using both separated data and combined data from the two-phase studies, show that plasma HO-1 concentrations were significantly increased in New-T2DM cases compared to controls (P<0.001). Plasma HO-1 concentrations were significantly correlated with plasma glucose concentrations, HOMA-beta and HOMA-IR (P<0.001). After adjustment for age, sex, BMI and family history of diabetes, the ORs for New-T2DM in the highest quartile of plasma HO-1 concentrations, compared with the lowest, was 8.23 (95% CI 5.55-12.21; P for trend <0.001). The trend remained significant after additional adjustment for fasting plasma glucose/insulin, HOMA-beta/HOMA-IR, TC/TG, smoking, drinking and history of hypertension, and even in further stratification analysis by age, sex, BMI, smoking, drinking and history of hypertension. Elevated plasma HO-1 concentrations are associated with higher ORs for New-T2DM, which add more knowledge regarding the important role of oxidative stress in T2DM. More consequent studies were warranted to confirm the clinical utility of plasma HO-1, especially in diagnosis and prognosis of T2DM and its complications.


Ig H and L chain contributions to autoimmune specificities.
An Ig H chain expression vector has been constructed by using the V region of 3H9, an antibody that binds ssDNA, dsDNA, and cardiolipin. The H chain construct was transfected into six hybridoma cell lines expressing Ig L chains. All resulting H and L chain combinations had at least some affinity for ssDNA, whereas five also bound dsDNA to a similar degree as 3H9. The loss of dsDNA binding was correlated with a single amino acid difference between two V kappa 8 L chains. A further characteristic of 3H9, its immunofluorescent staining pattern, was shared by four of the recombinant antibodies, whereas its specificity for cardiolipin was shared with five. The transfections reported here show that a V kappa 3 L chain confers specificity for an RNA-associated epitope and that a V kappa 21E L chain prevents cardiolipin binding. These experiments suggest that the 3H9 H chain contributes essential determinants required for binding to DNA as well as cardiolipin but that L chains can modulate or prevent this binding. L chains may also expand the specificity of a recombinant antibody.