The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever.
The clinical profile in familial Mediterranean fever (FMF), including its major manifestation, amyloidosis, is influenced by MEFV allelic heterogeneity and other genetic and/or environmental factors. In this study, we analyzed the contribution of genotypes at the MEFV and SAA1 loci to disease severity and to the development of amyloidosis, and further defined the factors affecting the clinical profile of FMF. We investigated a sample of 277 FMF patients (154 men and 123 women), including 62 patients with nephropathic amyloidosis, in whom both FMF alleles had been identified. A detailed chart review, interview, and physical examination were undertaken to determine the patients' demographic characteristics, medical history, clinical manifestations, and treatment. The disease severity score was calculated from the Tel-Hashomer key. Genotypes at the SAA1 locus (isoforms alpha, beta, and gamma) were determined in all patients. The SAA1 13C/T polymorphism of the SAA1 promotor was analyzed in a subset of cases. The male:female ratio (154:123, or 1.3) was higher among patients with amyloidosis (40:22, or 1.8) compared with patients without amyloidosis (114:101, or 1.1). Logistic regression analysis showed that homozygosity for the M694V allele (odds ratio [OR] 4.27, 95% confidence interval [95% CI] 2.01-9.07), the presence of the SAAalpha/alpha genotype (OR 2.99, 95% CI 1.47-6.09), the occurrence of arthritis attacks (OR 2.43, 95% CI 1.17-5.06), and male sex (OR 1.73, 95% CI 0.90-3.33) were significantly and independently associated with renal amyloidosis. Disease severity was mainly influenced by MEFV mutations and was not associated with genotypes at the SAA1 locus. The SAA1 13T allele was rare, being associated mainly with the SAA gamma isoform, and not related to renal amyloidosis. Overall, disease severity and the development of amyloidosis in FMF are differentially affected by genetic variations within and outside the MEFV gene.


Eosinophil cationic protein aggregation: identification of an N-terminus amyloid prone region.
Eosinophil cationic protein (ECP) is an antimicrobial protein belonging to the superfamily of RNase A. ECP exhibits a broad spectrum of action against bacteria and, at higher concentrations, displays cytotoxic activity to eukaryotic cells. Recently, a powerful aggregation activity for lipid vesicles and for the gram-negative E. coli specie has also been related to the protein toxicity. Here we present the amyloid-like aggregation capacity of ECP. This is the first report of amyloid aggregation in a native nonengineered ribonuclease. The ECP aggregates are able to bind the amyloid-diagnostic dyes Thioflavin T and Congo Red and display a protofibril morphology when observed under electronic microscopy. We have also identified an N-terminus hydrophobic patch (residues 8-16) that is required for the amyloid aggregation process. A single substitution, I13A, breaks the aggregation prone sequence and abolishes the amyloid aggregation ability. Moreover, the corresponding R1N19 peptide is able to reproduce the protein amyloid-like aggregation behavior. The results may provide new clues on the protein antimicrobial mechanism and its toxicity to the host tissues in inflammation processes.


Dissemination of enteroviruses in the production chain of organic lettuce in Rio de Janeiro, Brazil.
This study aimed to survey the environmental dissemination of enterovirus (EV) in a site of organic lettuce situated in the mountainous region of the state of Rio de Janeiro, Brazil. For this purpose, a total of 96 environmental samples, including water and lettuce samples obtained in different stages of the production chain (e.g., irrigation water, seedlings, lettuces grown, and washed lettuces ready-to-eat), were analyzed. EV genomes were detected in 12.5% (12/96) of the tested samples (eight from irrigation water and 4 from lettuce samples). Levels of viral concentration ranged from 3.37 × 103 to 4.72 × 106 genomic copies per liter (gc L-1 ) and from 2.14 × 104 to 5.56 × 104 genome copies per 25 grams (gc 25 g-1 ) for the water and lettuce samples, respectively. Such findings suggest that the use of viruses as human fecal contamination markers must be considered in order to improve food safety in organic supply chains.


Methotrexate-Induced Accelerated Nodulosis in a Patient with Systemic Lupus Erythematosus.
Methotrexate (MTX)-induced accelerated nodulosis (MIAN) reportedly occurs in patients with rheumatic arthritis receiving MTX therapy. However, it has also been reported in patients with other autoinflammatory conditions, such as systemic lupus erythematosus (SLE). A 38-year-old woman diagnosed with SLE presented with multiple movable, firm, flesh-colored nodules on both hands that had developed 3 years ago. She was taking oral medications, specifically hydroxychloroquine, azathioprine, and MTX. Histopathological examination revealed palisaded granulomatous inflammation, surrounded by histiocytes and lymphocytes, along the dermis to the subcutaneous fat layer. Fibrinoid degeneration was observed at the center of the granulomatous inflammation, and dermal mucin deposition was not observed. The patient was diagnosed with MIAN, and therefore discontinuation of MTX was recommended. Subsequently, the lesions almost completely disappeared with no signs of recurrence. MIAN exhibits clinicopathological features similar to those of rheumatoid nodules; therefore, it can be easily misdiagnosed. Herein, we report a case of MIAN in a patient with SLE to contribute to the accurate diagnosis and appropriate management.


Autonomic regulation of T-lymphocytes: Implications in cardiovascular disease.
The nervous and immune systems both serve as essential assessors and regulators of physiological function. Recently, there has been a great interest in how the nervous and immune systems interact to modulate both physiological and pathological states. In particular, the autonomic nervous system has a direct line of communication with immune cells anatomically, and moreover, immune cells possess receptors for autonomic neurotransmitters. This circumstantial evidence is suggestive of a functional interplay between the two systems, and extensive research over the past few decades has demonstrated neurotransmitters such as the catecholamines (i.e. dopamine, norepinephrine, and epinephrine) and acetylcholine have potent immunomodulating properties. Furthermore, immune cells, particularly T-lymphocytes, have now been found to express the cellular machinery for both the synthesis and degradation of neurotransmitters, which suggests the ability for both autocrine and paracrine signaling from these cells independent of the nervous system. The details underlying the functional interplay of this complex network of neuroimmune communication are still unclear, but this crosstalk is suggestive of significant implications on the pathogenesis of a number of autonomic-dysregulated and inflammation-mediated diseases. In particular, it is widely accepted that numerous forms of cardiovascular diseases possess imbalanced autonomic tone as well as altered T-lymphocyte function, but a paucity of literature exists discussing the direct role of neurotransmitters in shaping the inflammatory microenvironment during the progression or therapeutic management of these diseases. This review seeks to provide a fundamental framework for this autonomic neuroimmune interaction within T-lymphocytes, as well as the implications this may have in cardiovascular diseases.


Economic implications of COVID-19 for the HIV epidemic and the response in Zimbabwe.
Understanding the economic implications of COVID-19 for the HIV epidemic and response is critical for designing policies and strategies to effectively sustain past gains and accelerate progress to end these colliding pandemics. While considerable cross-national empirical evidence exists at the global level, there is a paucity of such deep-dive evidence at national level. This article addresses this gap. While Zimbabwe experienced fewer COVID-19 cases and deaths than most countries, the pandemic has had profound economic effects, reducing gross domestic product by nearly 7% in 2020. This exacerbates the long-term economic crisis that began in 1998. This has left many households vulnerable to the economic fallout from COVID-19, with the number of the extreme poor having increased to 49% of the population in 2020 (up from 38% in 2019). The national HIV response, largely financed externally, has been one of the few bright spots. Overall, macro-economic and social conditions heavily affected the capacity of Zimbabwe to respond to COVID-19. Few options were available for borrowing the needed sums of money. National outlays for COVID-19 mitigation and vaccination amounted to 2% of GDP, with one-third funded by external donors. Service delivery innovations helped sustain access to HIV treatment during national lockdowns. As a result of reduced access to HIV testing, the number of people initiating HIV treatment declined. In the short term, there are likely to be few immediate health care consequences of the slowdown in treatment initiation due to the country's already high level of HIV treatment coverage. However, a longer-lasting slowdown could impede national progress towards ending HIV and AIDS. The findings suggest a need to finance the global commons, specifically recognising that investing in health care is investing in economic recovery.


Neurotrophin and Trk expression by cells of the human lamina cribrosa following oxygen-glucose deprivation.
Ischemia within the optic nerve head (ONH) may contribute to retinal ganglion cell (RGC) loss in primary open angle glaucoma (POAG). Ischemia has been reported to increase neurotrophin and high affinity Trk receptor expression by CNS neurons and glial cells. We have previously demonstrated neurotrophin and Trk expression within the lamina cribrosa (LC) region of the ONH. To determine if ischemia alters neurotrophin and Trk protein expression in cells from the human LC, cultured LC cells and ONH astrocytes were exposed to 48 hours of oxygen-glucose deprivation (OGD). Also cells were exposed to 48 hours of OGD followed by 24 hours of recovery in normal growth conditions. Cell number, neurotrophin and Trk receptor protein expression, neurotrophin secretion, and Trk receptor activation were examined. Cell number was estimated using an assay for cell metabolism following 24, 48 and 72 hours of OGD. A statistically significant decrease in LC and ONH astrocyte cell number did not occur until 72 hours of OGD, therefore cellular protein and conditioned media were collected at 48 hours OGD. Protein expression of NGF, BDNF and NT-3 by LC cells and ONH astrocytes increased following OGD, as did NGF secretion. Recovery from OGD increased BDNF protein expression in LC cells. In ONH astrocytes, recovery from OGD increased NGF protein expression, and decreased BDNF secretion. Trk A expression and activation in LC cells was increased following OGD while expression and activation of all other Trk receptors was decreased. A similar increase in Trk A expression and activation was observed in ONH astrocytes following recovery from OGD. In vitro conditions that mimic ischemia increase the expression and secretion of neurotrophins by cells from the ONH. Increased Trk A expression and activation in LC cells following OGD and in ONH astrocytes following recovery from OGD suggest autocrine/paracrine neurotrophin signaling could be a response to ONH ischemia in POAG. Also, the increase in NGF, BDNF and NT-3 protein expression and NGF secretion following OGD also suggest LC cells and ONH astrocytes may be a paracrine source of neurotrophins for RGCs.


Utilizing a user-centered approach to develop and assess pharmacogenomic clinical decision support for thiopurine methyltransferase.
A pharmacogenomic clinical decision support tool (PGx-CDS) for thiopurine medications can help physicians incorporate pharmacogenomic results into prescribing decisions by providing up-to-date, real-time decision support. However, the PGx-CDS user interface may introduce errors and promote alert fatigue. The objective of this study was to develop and evaluate a prototype of a PGx-CDS user interface for thiopurine medications with user-centered design methods. This study had two phases: In phase I, we conducted qualitative interviews to assess providers' information needs. Interview transcripts were analyzed through a combination of inductive and deductive qualitative analysis to develop design requirements for a PGx-CDS user interface. Using these requirements, we developed a user interface prototype and evaluated its usability (phase II). In total, 14 providers participated: 10 were interviewed in phase I, and seven providers completed usability testing in phase II (3 providers participated in both phases). Most (90%) participants were interested in PGx-CDS systems to help improve medication efficacy and patient safety. Interviews yielded 11 themes sorted into two main categories: 1) health care providers' views on PGx-CDS and 2) important design features for PGx-CDS. We organized these findings into guidance for PGx-CDS content and display. Usability testing of the PGx-CDS prototype showed high provider satisfaction. This is one of the first studies to utilize a user-centered design approach to develop and assess a PGx-CDS interface prototype for Thiopurine Methyltransferase (TPMT). This study provides guidance for the development of a PGx-CDS, and particularly for biomarkers such as TPMT.


Absence of zero-bias anomaly in spin-polarized vacuum tunneling in Co(0001).
In a joint experimental and theoretical study, we investigate the bias-voltage dependence of the tunnel magnetoresistance (TMR) through a vacuum barrier. The TMR observed by spin-polarized scanning tunneling microscopy between an amorphous magnetic tip and a Co(0001) sample is almost independent of the bias voltage at large tip-sample separations. Whereas qualitative understanding is achieved by means of the electronic surface structure of Co, the experimental findings are compared quantitatively with bias-voltage dependent first-principles calculations for ballistic tunneling. At small tip-sample separations, a pronounced minimum in the experimental TMR was found at +200 mV bias.


The plant secretory pathway for the trafficking of cell wall polysaccharides and glycoproteins.
Plant endomembranes are required for the biosynthesis and secretion of complex cell wall matrix polysaccharides, glycoproteins and proteoglycans. To define the biochemical roadmap that guides the synthesis and deposition of these cell wall components it is first necessary to outline the localization of the biosynthetic and modifying enzymes involved, as well as the distribution of the intermediate and final constituents of the cell wall. Thus far, a comprehensive understanding of cell wall matrix components has been hampered by the multiplicity of trafficking routes in the secretory pathway, and the diverse biosynthetic roles of the endomembrane organelles, which may exhibit tissue and development specific features. However, the recent identification of protein complexes producing matrix polysaccharides, and those supporting the synthesis and distribution of a grass-specific hemicellulose are advancing our understanding of the functional contribution of the plant secretory pathway in cell wall biosynthesis. In this review, we provide an overview of the plant membrane trafficking routes and report on recent exciting accomplishments in the understanding of the mechanisms underlying secretion with focus on cell wall synthesis in plants.


An Open-Source, Automated Home-Cage Sipper Device for Monitoring Liquid Ingestive Behavior in Rodents.
Measuring ingestive behavior of liquids in rodents is commonly used in studies of reward, metabolism, and circadian biology. Common approaches for measuring liquid intake in real time include computer-tethered lickometers or video-based systems. Additionally, liquids can be measured or weighed to determine the amount consumed without real-time sensing. Here, we built a photobeam-based sipper device that has the following advantages over traditional methods: (1) it is battery powered and fits in vivarium caging to allow home-cage measurements; (2) it quantifies the intake of two different liquids simultaneously for preference studies; (3) it is low cost and easily constructed, enabling high-throughput experiments; and (4) it is open source so that others can modify it to fit their experimental needs. We validated the performance of this device in three experiments. First, we calibrated our device using time-lapse video-based measurements of liquid intake and correlated sipper interactions with liquid intake. Second, we used the sipper device to measure preference for water versus chocolate milk, demonstrating its utility for two-bottle choice tasks. Third, we integrated the device with fiber photometry, establishing its utility for measuring neural activity in studies of ingestive behavior. This device requires no special equipment or caging, and is small, battery powered, and wireless, allowing it to be placed directly in rodent home cages. The total cost of fabrication is less than $100, and all design files and code are open source. Together, these factors greatly increase scalability and utility for a variety of behavioral neuroscience applications.


Clostridium difficile cytotoxin in a pediatric population.
Assays for cytotoxin of Clostridium difficile were performed on stool samples submitted to the laboratory for routine microbiologic study. Cytotoxin was recovered from 8.6% of 208 pediatric patients studied. Cytotoxin was identified significantly more often in younger patients (median age, 11 months) and in those with hospital-associated illness (17%) and antibiotic-associated illness (18%). Hospitalization and antibiotic use were significant independent risk factors. Clinical diagnoses in patients with C difficile cytotoxin included classic pseudomembranous colitis, acute self-resolving diarrheal syndrome, chronic diarrhea with failure to thrive, infant botulism, and asymptomatic carriage.


Nosocomial poisoning associated with emergency department treatment of organophosphate toxicity--Georgia, 2000.
Emergency department (ED) staff caring for patients contaminated with toxic chemicals are at risk for developing toxicity from secondary contamination. This report describes three cases of occupational illnesses associated with organophosphate toxicity caused by exposure to a contaminated patient and underscores the importance of using personal protection equipment (PPE) and establishing and following decontamination procedures in EDs and other areas of acute care hospitals.


Method for the Development of Accessible Mobile Serious Games for Children with Autism Spectrum Disorder.
Autism spectrum disorder (ASD) covers a range of neurodevelopmental disorders that begin in early childhood and affects developmental activities. This condition can negatively influence the gaining of knowledge, skills, and abilities, such as communication. Over time, different techniques and methods have been put into practice to teach and communicate with children with ASD. With the rapid advancement in the field of technology, specifically in smartphones, researchers have generated creative applications, such as mobile serious games, to help children with ASD. However, usability and accessibility have not been often taken into account in the development of this type of applications. For that reason, in this work we considered that both, usability and especially accessibility are a very important differentiators for the quality and efficiency of mobile serious games. Our approach has two important contributions, the incorporation of accessibility as a fundamental requirement in the development of a mobile serious game and the proposal of a method for the development of this type of applications for children with ASD, a method that can be used by other developers.


Contribution of aldehyde oxidase, xanthine oxidase, and aldehyde dehydrogenase on the oxidation of aromatic aldehydes.
Aliphatic aldehydes have a high affinity toward aldehyde dehydrogenase activity but are relatively poor substrates of aldehyde oxidase and xanthine oxidase. In addition, the oxidation of xenobiotic-derived aromatic aldehydes by the latter enzymes has not been studied to any great extent. The present investigation compares the relative contribution of aldehyde dehydrogenase, aldehyde oxidase, and xanthine oxidase activities in the oxidation of substituted benzaldehydes in separate preparations. The incubation of vanillin, isovanillin, and protocatechuic aldehyde with either guinea pig liver aldehyde oxidase, bovine milk xanthine oxidase, or guinea pig liver aldehyde dehydrogenase demonstrated that the three aldehyde oxidizing enzymes had a complementary substrate specificity. Incubations were also performed with specific inhibitors of each enzyme (isovanillin for aldehyde oxidase, allopurinol for xanthine oxidase, and disulfiram for aldehyde dehydrogenase) to determine the relative contribution of each enzyme in the oxidation of these aldehydes. Under these conditions, vanillin was rapidly oxidized by aldehyde oxidase, isovanillin was predominantly metabolized by aldehyde dehydrogenase activity, and protocatechuic aldehyde was slowly oxidized, possibly by all three enzymes. Thus, aldehyde oxidase activity may be a significant factor in the oxidation of aromatic aldehydes generated from amines and alkyl benzenes during drug metabolism. In addition, this enzyme may also have a role in the catabolism of biogenic amines such as dopamine and noradrenaline where 3-methoxyphenylacetic acids are major metabolites.


Human melanomas and ovarian cancers overexpressing mechanical barrier molecule genes lack immune signatures and have increased patient mortality risk.
We have identified eight genes whose expression in human melanoma metastases and ovarian cancers is associated with a lack of Th1 immune signatures. They encode molecules with mechanical barrier function in the skin and other normal tissues and include filaggrin (FLG), tumor-associated calcium signal transducer 2 (TACSTD2), and six desmosomal proteins (DST, DSC3, DSP, PPL, PKP3, and JUP). This association has been validated in an independent series of 114 melanoma metastases. In these, DST expression alone is sufficient to identify melanomas without immune signatures, while FLG and the other six putative barrier molecules are overexpressed in a different subset of melanomas lacking immune signatures. Similar associations have been identified in a set of 186 ovarian cancers. RNA-seq data from 471 melanomas and 307 ovarian cancers in the TCGA database further support these findings and also reveal that overexpression of barrier molecules is strongly associated with early patient mortality for melanoma (p = 0.0002) and for ovarian cancer (p < 0.01). Interestingly, this association persists for FLG for melanoma (p = 0.012) and ovarian cancer (p = 0.006), whereas DST overexpression is negatively associated with CD8+ gene expression, but not with patient survival. Thus, overexpression of FLG or DST identifies two distinct patient populations with low immune cell infiltration in these cancers, but with different prognostic implications for each. These data raise the possibility that molecules with mechanical barrier function in skin and other tissues may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction.


Colorectal cancer with liver metastases: neoadjuvant chemotherapy, surgical resection first or palliation alone?
Colorectal cancer (CRC) is one of the commonest cancers with 1.2 million new cases diagnosed each year in the world. It remains the fourth most common cause of cancer-related mortality in the world and accounts for > 600000 cancer-related deaths each year. There have been significant advances in treatment of metastatic CRC in last decade or so, due to availability of new active targeted agents and more aggressive approach towards the management of CRC, particularly with liver-only-metastases; however, these drugs work best when combined with conventional chemotherapy agents. Despite these advances, there is a lack of biomarkers to inform us about the accurate management of the patients with metastatic CRC. It is therefore imperative to carefully select the patients with comprehensive multi-disciplinary team input in order to optimise the management of these patients. In this review we will discuss various treatment options available in management of colorectal liver metastases with potential guidance on how and when to choose these options along with consideration on future directions in management of this disease.


CORONA, a member of the class III homeodomain leucine zipper gene family in Arabidopsis, regulates stem cell specification and organogenesis.
Organogenesis at the shoot meristem requires a delicate balance between stem cell specification and differentiation. In Arabidopsis thaliana, WUSCHEL (WUS) is a key factor promoting stem cell identity, whereas the CLAVATA (CLV1, CLV2, and CLV3) loci appear to promote differentiation by repressing WUS expression. In a screen for mutations modifying clv1 mutants, we have identified a novel regulator of meristem development we term CORONA (CNA). Whereas cna single mutant plants exhibit subtle defects in meristem development, clv cna double mutants develop massively enlarged apices that display early loss of organogenesis, misexpression of WUS and CLV3, and eventual differentiation of the entire apex. The CNA gene was isolated by positional cloning and found to encode a class III homeodomain Leu zipper protein. A missense mutation resulting in the dominant-negative cna-1 allele was identified in a conserved domain of unknown function, and a likely null allele was shown to display a similar but weaker phenotype. CNA is expressed in developing vascular tissue, diffusely through shoot and flower meristems, and within developing stamens and carpels. Our analysis of WUS expression in wild-type, clv, and clv cna plants revealed that, contrary to current models, WUS is neither necessary nor sufficient for stem cell specification and that neither WUS nor CLV3 is a marker for stem cell identity. We propose that CNA functions in parallel to the CLV loci to promote organ formation.


Quantum Yield for Production of CH3NC in the Photolysis of CH3NCS.
The ultraviolet spectrum of methyl isothiocyanate (CH(3)NCS) and the quantum yield for its dissociation into methyl isocyanide (CH(3)NC) and atomic sulfur at 308 nanometers, Phi = 0.98 +/- 0.24, were measured. Methyl isothiocyanate is widely used as an agricultural fumigant and readily enters the atmosphere during and after application. The results indicate that photodissociation by sunlight is an effective pathway for its removal from the atmosphere.


Progress in translational reproductive science: testicular tissue transplantation and in vitro spermatogenesis.
Since the birth of the first child conceived via in vitro fertilization 40 years ago, fertility treatments and assisted reproductive technology have allowed many couples to reach their reproductive goals. As of yet, no fertility options are available for men who cannot produce functional sperm, but many experimental therapies have demonstrated promising results in animal models. Both autologous (stem cell transplantation, de novo morphogenesis, and testicular tissue grafting) and outside-the-body (xenografting and in vitro spermatogenesis) approaches exist for restoring sperm production in infertile animals with varying degrees of success. Once safety profiles are established and an ideal patient population is chosen, some of these techniques may be ready for human experimentation in the near future, with likely clinical implementation within the next decade.


Spontaneous production of an interleukin 1-like factor by cloned rheumatoid synovial cells in long-term culture.
We have cloned adherent synovial cells from rheumatoid synovitis. These can be generally divided into three types, including cells that have the characteristic features of dendritic cells (DCs), macrophagelike cells (MCs) and fibroblastlike cells (FCs), as classified by morphology and immunofluorescent staining. The cloned cells were able to divide and were cultured for up to 11 mo without any significant morphological changes. All the cloned cells were HLA-DR+ after gamma-interferon treatment. Spontaneous production of a factor with interleukin 1 activity by the cloned cells was detected even after long-term culture (the ability, on a per cell basis, being in the following order: DC greater than MC greater than FC). These synovial cells may be important for bony destruction in rheumatoid joints.


Communication in critical care: family rounds in the intensive care unit.
Communication with family members of patients in intensive care units is challenging and fraught with dissatisfaction. We hypothesized that family attendance at structured interdisciplinary family rounds would enhance communication and facilitate end-of-life planning (when appropriate). The study was conducted in the 26-bed medical intensive care unit of a tertiary care, academic medical center from April through October 2006. Starting in July 2006, families were invited to attend daily interdisciplinary rounds where the medical team discussed the plan for care. Family members were surveyed at least 1 month after the patient's stay in the unit, completing the validated "Family Satisfaction in the ICU" tool before and after implementation of family rounds. Of 227 patients enrolled, 187 patients survived and 40 died. Among families of survivors, participation in family rounds was associated with higher family satisfaction regarding frequency of communication with physicians (P = .004) and support during decision making (P = .005). Participation decreased satisfaction regarding time for decision making (P = .02). Overall satisfaction scores did not differ between families who attended rounds and families who did not. For families of patients who died, participation in family rounds did not significantly change satisfaction. In the context of this pilot study of family rounds, certain elements of satisfaction were improved, but not overall satisfaction. The findings indicate that structured interdisciplinary family rounds can improve some families' satisfaction, whereas some families feel rushed to make decisions. More work is needed to optimize communication between staff in the intensive care unit and patients' families, families' comprehension, and the effects on staff workload.


Dynamics of Microbial Community Structure, Function and Assembly Mechanism with Increasing Stand Age of Slash Pine (Pinus elliottii) Plantations in Houtian Sandy Area, South China.
Establishing slash pine plantations is the primary method for restoring sandification land in the Houtian area of South China. However, the microbial variation pattern with increasing stand age remains unclear. In this study, we investigated microbial community structure and function in bare sandy land and four stand age gradients, exploring ecological processes that determine their assembly. We did not observe a significant increase in the absolute abundance of bacteria or fungi with stand age. Bacterial communities were dominated by Chloroflexi, Actinobacteria, Proteobacteria, and Acidobacteria; the relative abundance of Chloroflexi significantly declined while Proteobacteria and Acidobacteria significantly increased with stand age. Fungal communities showed succession at the genus level, with Pisolithus most abundant in soils of younger stands (1- and 6-year-old). Turnover of fungal communities was primarily driven by stochastic processes; both deterministic and stochastic processes influenced the assembly of bacterial communities, with the relative importance of stochastic processes gradually increasing with stand age. Bacterial and fungal communities showed the strongest correlation with the diameter at breast height, followed by soil available phosphorus and water content. Notably, there was a significant increase in the relative abundance of functional groups involved in nitrogen fixation and uptake as stand age increased. Overall, this study highlights the important effects of slash pine stand age on microbial communities in sandy lands and suggests attention to the nitrogen and phosphorus requirements of slash pine plantations in the later stages of sandy management.


Antimicrobial Nonsusceptibility of Gram-Negative Bloodstream Isolates, Veterans Health Administration System, United States, 2003-20131.
Bacteremia caused by gram-negative bacteria is associated with serious illness and death, and emergence of antimicrobial drug resistance in these bacteria is a major concern. Using national microbiology and patient data for 2003-2013 from the US Veterans Health Administration, we characterized nonsusceptibility trends of community-acquired, community-onset; healthcare-associated, community-onset; and hospital-onset bacteremia for selected gram-negative bacteria (Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, and Acinetobacter spp.). For 47,746 episodes of bacteremia, the incidence rate was 6.37 episodes/10,000 person-years for community-onset bacteremia and 4.53 episodes/10,000 patient-days for hospital-onset bacteremia. For Klebsiella spp., P. aeruginosa, and Acinetobacter spp., we observed a decreasing proportion of nonsusceptibility across nearly all antimicrobial drug classes for patients with healthcare exposure; trends for community-acquired, community-onset isolates were stable or increasing. The role of infection control and antimicrobial stewardship efforts in inpatient settings in the decrease in drug resistance rates for hospital-onset isolates needs to be determined.


Effect of surface treatment, ferrule height, and luting agent type on pull-out bond strength of monolithic zirconia endocrowns.
To evaluate the effect of different surface treatments, ferrule heights, and luting agents on the pull-out bond strength (PBS) of computer-aided design/computer-aided manufacturing (CAD-CAM) monolithic endocrowns. After endodontic treatment and preparation for two endocrown designs (ferrule height 0 mm or 2 mm), CAD-CAM monolithic zirconia endocrowns were fabricated for 80 mandibular molars. Each endocrown design group was then divided on the basis of surface treatment into two groups: half were air-abraded and half were air-abraded/laser-irradiated. Then, all treated groups were further divided into two subgroups (n = 10) and cemented to teeth with either a 10-methacryloyloxydecyl dihydrogen phosphate (MDP)-containing resin luting agent (Panavia SA) or a combination of MDP-containing primer and MDP-free resin luting agent (Monobond Plus/Multilink Automix). PBS was measured with a universal test machine after simulated chewing and thermocycling. Three-way ANOVA and the post-hoc Bonferroni test were used for statistical analysis. PBS was significantly associated with type of surface treatment, type of luting agent, and ferrule height. Air-abraded/laser-irradiated endocrowns with a 2-mm ferrule that were cemented with Monobond Plus/Multilink Automix had the highest PBS (P < 0.05). Surface treatment with air abrasion/laser irradiation, presence of a ferrule, and priming with an MDP-containing primer increased the PBS of monolithic zirconia endocrowns.


Relationship between neighbourhood cohesion and disability: findings from SWADES population-based survey, Kerala, India.
Background: The burden of disability on individuals and society is enormous in India, and informal care systems try to reduce this burden. This study investigated the association between neighbourhood cohesion and disability in a community-based population in Kerala, India. To the best of our knowledge, no previous studies have examined this association in India. Methods: A cross-sectional household survey was conducted with 997 participants aged 30 years and above, in Kerala. Neighbourhood cohesion was assessed by three scales: trust, community participation, and perceived safety. Functional ability was measured by WHODAS 2.0. Explanatory covariates included chronic disease conditions, age, gender, education, income, and mental health conditions. Results: Of 997 participants (37% male; mean age, 53.9 [range, 30-90] years), the majority were married or cohabiting. Univariate analysis showed functional ability to be positively associated with most demographic and health characteristics. However, after adjustment, only social cohesion, age, income, education, chronic diseases and mental health conditions remained significant. Mediation analysis showed the effect of personal and health characteristics on functional ability as mediated by social cohesion. Conclusion: Social cohesion is an important moderator of functional ability. Interventions targeting the creation of stronger ties among neighbours and a sense of belonging should be scaled-up and evaluated in future research.


Anatomical radical retropubic prostatectomy in patients with a preexisting three-piece inflatable prosthesis: a series of case reports.
Only few reports addressed the outcome of patients submitted to anatomical radical retropubic prostatectomy (RRP) with an indwelling inflatable penile prosthesis (IPP). To assess the feasibility and safety of RRP in patients with clinically localized prostate cancer and a previously implanted with an IPP. We evaluated the surgical parameters and the follow-up functional results in this particular patient population. Four patients previously submitted to IPP implant for severe erectile dysfunction underwent RRP for organ-confined prostate cancer. Patients' charts were carefully reviewed to investigate pre- and perioperative details. Patients were evaluated by the International Index of Erectile Function (IIEF) preoperatively and at 6 months postoperatively. Patients were then contacted to assess long-term functional and oncological outcome. The outcome of the procedures was comparable to a normal population in terms of operating time, estimated blood loss, hospitalization time, and pathological outcome. No injury to the preexisting penile implant was reported. Continence was obtained in 3 (75%) patients at catheter removal, and in 1 (25%) patient at the 1-month follow-up. No major intra- and postoperative complications were reported. All patients were able to use their prosthesis after RRP. No statistical difference in pre- and post-RRP EF domain scores was found. The presence of an IPP in patients with prostate cancer is not a contraindication to perform an anatomical RRP. Surgery can be performed safely without injuring the implant and the clinical outcome in these patients is satisfactory. Postoperative implant use is not affected by RRP.


An early effect of diphtheria toxin on the metabolism of mammalian cells growing in culture.
At concentrations of 0.1 Lf (0.25 microg.)/ml., or greater, diphtheria toxin produces an immediate decrease (40 +/- 5 per cent) in the steady-state level of incorporation of inorganic phosphate into ATP by cultures of normal human kidney cells growing at 37 degrees C. in the presence of glucose. The effect is readily reversible by specific antitoxin for a period of 30 minutes or more after adding toxin. Protein synthesis in these cells continues at a normal rate for 60 minutes after adding toxin and the toxin-treated cells are able to take up and concentrate potassium ions normally for at least 1 hour. Even high concentrations of toxin (5 Lf/ml. or more) fail to effect either protein synthesis or ATP formation by cultures of spleen cells from the mouse, an animal that is relatively resistant to the lethal action of the toxin. Of various inhibitors studied, antimycin A most closely resembles toxin in its action, both on protein synthesis and on ATP formation. Mouse cells are considerably more resistant to antimycin A than are human kidney cells. Human kidney cells treated with saturating doses of toxin continue to form RNA at a normal rate for about 1 hour, after which the rates of both P(i) (32) incorporation and of 6-C(14)-orotic acid incorporation into RNA sharply decline and continue at about 40 to 50 per cent their initial rate. At 37 degrees C., S(35)-methionine incorporation into cell protein ceases altogether 60 to 75 minutes after addition of a saturating dose of toxin. The effect of saturating doses of toxin on S(35)-methionine incorporation into human kidney cell protein at different temperatures, has been studied. It is concluded from the present studies that diphtheria toxin exerts a primary, reversible effect at the surface of susceptible cells where it inhibits cytochrome-linked phosphorylation concerned with transport of inorganic phosphate across the cell membrane.


The biochemical basis of relapse and drug response in schizophrenia: review and hypothesis.
This review of the literature suggests that antipsychotic drug response is determined by dopamine (DA) turnover and norepinephrine (NE) activity prior to treatment. The data suggest that NE modulates the DA system. Drug-free psychotic patients with relatively increased DA and NE activity, including release, are more likely to be treatment responsive, while patients who show evidence of enhanced DA and NE activity during treatment with antipsychotic drugs are likely to relapse soon after neuroleptic withdrawal. Basal release of DA and NE is decreased and associated with residual positive and negative symptoms. Improvement during neuroleptic treatment is associated with decreases in DA and NE phasic or stimulus induced release. The variable response to antipsychotic drugs is most likely to be a result of dysregulated DA and NE release, i.e. under state-dependent control, rather than evidence of a heterogeneous aetiology. Because catecholamines regulate gain, signal-to-noise ratio and gating in the brain, this model allows for environmental factors to interact with biochemical state and drug treatment. The author proposes that impaired homeostasis of NE and DA in schizophrenia causes instability in NE and DA neuronal firing and release, presumably related to mechanisms down-stream from the receptors, such as G proteins. This instability of catecholamine release may explain the observed variability in clinical states and drug response in schizophrenia.


Meditative Movement Affects Working Memory Related to Neural Activity in Adolescents: A Randomized Controlled Trial.
Numerous studies have revealed that meditative movement changes brain activity and improves the cognitive function of adults. However, there is still insufficient data on whether meditative movement contributes to the cognitive function of adolescents whose brain is still under development. Therefore, this study aimed to uncover the effects of meditative movement on the cognitive performance and its relation with brain activity in adolescents. Forty healthy adolescent participants (mean age of 17∼18) were randomly allocated into two groups: meditative movement and control group. The meditative movement group was instructed to perform the meditative movement, twice a day for 9 min each, for a duration of 3 weeks. During the same time of the day, the control group was instructed to rest under the same condition. To measure changes in cognitive abilities, a dual n-back task was performed before and after the intervention and analyzed by repeated two-way analysis of variance (ANOVA). During the task, electroencephalogram signals were collected to find the relation of brain activity with working memory performance and was analyzed by regression analysis. A repeated two-way ANOVA with Bonferroni correction showed that working memory performance was significantly increased by meditative movement compared with the retest effect. Based on regression analysis, the amplitude of high-beta rhythm in the F3 channel showed a significant correlation with dual n-back score in the experimental group after the intervention, while there was no correlation in the control group. Our results suggest that meditative movement improves the performance of working memory, which is related to brain activity in adolescents. Clinical Trial Registration: cris.nih.go.kr/cris, identifier KCT0004706.


Trends in physical activity behaviours and attitudes among South Australian youth between 1985 and 2004.
Rising youth obesity is a serious public health concern. There is a widespread view that declining physical activity is contributing to this trend. A total of 929 young South Australians (age=9-15 years) were surveyed in 1985 and 2004 on usual physical activity in several contexts, including attitudes to physical activity. Eight of 10 South Australian schools participating in the 1985 Schools Health and Fitness Survey were revisited in 2004. Comparisons were made on: organised sport, active transport, physical education (PE), playground activity, vigorous physical activity (VPA), total leisure-time physical activity (LTPA), and attitudes to PE and school sport. The questionnaire and method of administration were identical in both surveys. There were no differences between surveys in club and school sport participation, walking to school, and reported enjoyment of PE and school sport. In 2004 fewer children rode to school, but PE classes were more frequent. The percentage of children who 'sit and talk' during school breaks had increased, with a decreased percentage of older girls who 'run around' during school breaks. There was a significantly higher LTPA in MET.min in 2004 for boys, which was particularly evident at higher percentiles. There were no changes in mean or distribution of LTPA for the whole sample or girls. The percentage of respondents reporting >/=3 bouts of VPA in the previous week rose from 51% (1985) to 76% (2004). There is no consistent evidence of declining physical activity among South Australian youth. It is apparent that physical activity in some contexts has declined, while in other contexts levels are the same or higher than in 1985. This underscores the complex nature of physical activity and the influences on this behaviour.


Growth-phase dependence of susceptibility to antimicrobial peptides in Staphylococcus aureus.
Bacterial cell surface charge is responsible for susceptibility to cationic antimicrobial peptides. Previously, Staphylococcus aureus dlt and mprF were identified as factors conferring a positive charge upon cell surfaces. In this study, we investigated the regulation of cell surface charge during growth. Using a group of S. aureus MW2 mutants, which are gene-inactivated in 15 types of two-component systems (TCSs), we tested dltC and mprF expression and found that two TCSs, aps and agr, were associated with dltC and mprF expression in a growth phase-dependent manner. The first of these, aps, which had already been identified as a sensor of antimicrobial peptides and a positive regulator of dlt and mprF expression, was expressed strongly in the exponential phase, while its expression was significantly suppressed by agr in the stationary phase, resulting in higher expression of dltC and mprF in the exponential phase and lower expression in the stationary phase. Since both types of expression affected the cell surface charge, the susceptibility to antimicrobial peptides and cationic antibiotics was changed during growth. Furthermore, we found that the ability to sense antimicrobial peptides only functioned in the exponential phase. These results suggest that cell surface charge is tightly regulated during growth in S. aureus.


Mesenchymal stromal cells from donors varying widely in age are of equal cellular fitness after in vitro expansion under hypoxic conditions.
Mesenchymal stromal cells (MSC) are gaining in popularity as an experimental therapy for a number of conditions that often require expansion ex vivo prior to use. Data comparing clinical-grade MSC from various ages of donors are scant. We hypothesized that MSC from older donors may display differences in cellular fitness when expanded for clinical use. We evaluated the expression of several markers of aging, oxidative stress and growth kinetics, and telomere length, in MSC obtained from a wide age range (8 months to 58 years). To evaluate cellular fitness we compared MSC expanded from younger (8 months-6 years) versus older (38-58 years) donors in terms of selected cell-surface markers, lipofuscin, migration ability, telomere length and expression of iNOS, PGE₂, p16INK and SOD. Results did not differ between these groups. Neither SOD activity (0.025 versus 0.028 U/mL) nor death after oxidative challenge was significantly different (1% versus 1.5%, P = 0.14). We did find that, although MSC from older individuals produced slightly fewer cells over a 28-day culture period and had a slightly longer doubling time (54 h versus 42 hr, a satisfactory clinical product could still be obtained regardless of age cohort. Collectively, these data show that MSC can be expanded without significant alterations in expansile properties or obvious changes in parameters associated with senescence. Because cellular fitness was equivalent in these cohorts, MSC from donors up to age 58 years can be used as a source of cells for cellular therapy.


The Effect of Lifestyle Intervention on Pregnancy and Birth Outcomes on Obese Infertile Women: A Systematic Review and Meta-Analysis.
Obesity has been associated with negative effects on natural fertility and poor prognosis when assisted reproductive technologies (ART) are performed. Patients attending for fertility treatments are often advised to optimize their weights to improve the outcomes. There is lack of enough information on how weight-loss would be effective for improving fertility in women who are overweight or obese. We conducted a systematic review to evaluate whether weight-loss achieved by lifestyle program improves natural or assisted reproduction in obese infertile women. We searched CENTRAL, MEDLINE, and EMBASE up to March 2018. Two reviews were selected as randomised trials assessing a lifestyle intervention in women with obesity before receiving treatments for infertility and appraised their risk of bias. We extracted data on pregnancy, birth, and miscarriage rates as the primary outcomes and pooled effect estimates using a random effects model. The primary outcome was the live birth rate. We reported summary measures as the relative risk (RR), 95% confidence interval (CI), and percentage of heterogeneity (I2). We included eight randomised trials with 1175 women. Lifestyle programmes, improved pregnancy rates (RR: 1.43, CI: 95% 1.02 to 2.01; I2=60%; 8 RCTs; N=1098) but had no impact on live births (RR: 1.39, CI: 95% 0.90 to 2.14; I2=64%; 7RCTs; N=1034). Our findings suggest that women participating in lifestyle interventions had an increased risk of miscarriage (RR: 1.50, CI: 95% 1.04 to 2.16; I2=0; 6RCTs; N=543). We rated the quality of evidence for these outcomes as the moderate-to-low. Lifestyle interventions slightly increased the pregnancy rate, while it would be uncertain whether it can improve the live birth. Lifestyle interventions can increase the risk of miscarriage. More research is needed to further explore lifestyle interventions on reproductive outcomes in obese infertile women.


Preferential hybridization: amplification of hybridization signals with nested probes.
This paper describes a protocol for the amplification of hybridization signals using single-stranded, digoxigenin-labeled probes of increasing length. Probes of different lengths were produced by a unidirectional polymerase chain reaction. Labeled probes were purified and collectively applied for the detection of immobilized nucleic acids. The method provides for a higher signal intensity than that observed with probes that cover the entire length of the target sequence. An increase of up to 4-fold in the intensity of the detection signal was observed.


Early description of synchronous double spinal vascular malformations by Łucja Frey in 1928.
The Polish neurologist Łucja Frey (1889-1942) is principally remembered for her description of the auriculotemporal nerve (or Frey's) syndrome. She also reported a complex case of spinal cord vascular malformation in 1928, which included one of the earliest accurate anatomopathological depictions of a spinal arteriovenous malformation as well as the first known observation of double synchronous spinal cord vascular malformation. An abbreviated translation of Frey's report is followed by a discussion of the place occupied by her contribution in the development of our current understanding of spinovascular disorders.


A single-cell genome reveals diplonemid-like ancestry of kinetoplastid mitochondrial gene structure.
Euglenozoa comprises euglenids, kinetoplastids, and diplonemids, with each group exhibiting different and highly unusual mitochondrial genome organizations. Although they are sister groups, kinetoplastids and diplonemids have very distinct mitochondrial genome architectures, requiring widespread insertion/deletion RNA editing and extensive trans-splicing, respectively, in order to generate functional transcripts. The evolutionary history by which these differing processes arose remains unclear. Using single-cell genomics, followed by small sub unit ribosomal DNA and multigene phylogenies, we identified an isolated marine cell that branches on phylogenetic trees as a sister to known kinetoplastids. Analysis of single-cell amplified genomic material identified multiple mitochondrial genome contigs. These revealed a gene architecture resembling that of diplonemid mitochondria, with small fragments of genes encoded out of order and or on different contigs, indicating that these genes require extensive trans-splicing. Conversely, no requirement for kinetoplastid-like insertion/deletion RNA-editing was detected. Additionally, while we identified some proteins so far only found in kinetoplastids, we could not unequivocally identify mitochondrial RNA editing proteins. These data invite the hypothesis that extensive genome fragmentation and trans-splicing were the ancestral states for the kinetoplastid-diplonemid clade but were lost during the kinetoplastid radiation. This study demonstrates that single-cell approaches can successfully retrieve lineages that represent important new branches on the tree of life, and thus can illuminate major evolutionary and functional transitions in eukaryotes. This article is part of a discussion meeting issue 'Single cell ecology'.


Conjunction search is relational: Behavioral and electrophysiological evidence.
Attention selects behaviorally relevant stimuli for further capacity-limited processing and gates their access to awareness. Given the importance of attention for conscious perception, it is important to determine the factors and mechanisms that drive attention. A widespread view is that attention is biased to the specific feature values of a conjunction target (e.g., vertical, red, medium). By contrast, the results of the present study show that attention is tuned to the 2 relative features that distinguish a conjunction target from the irrelevant nontargets (e.g., larger and bluer). Moreover, an irrelevant conjunction cue that is briefly presented prior to the target can automatically attract attention, even in the absence of any feature contrasts. Importantly, automatic orienting to the conjunction cue was completely independent of the physical similarity between cue and target, and depended only on whether the conjunction cue matched the relative features of the target. These results demonstrate that attentional orienting is determined by a mechanism that can rapidly extract information about feature relationships and guide attention to the stimulus that best matches the relative attributes of the target. These results are difficult to reconcile with extant feature-specific accounts or object-based accounts of attention and argue for a relational account of conjunction search. (PsycINFO Database Record


Multidimensional generalized-ensemble algorithms for complex systems.
We give general formulations of the multidimensional multicanonical algorithm, simulated tempering, and replica-exchange method. We generalize the original potential energy function E(0) by adding any physical quantity V of interest as a new energy term. These multidimensional generalized-ensemble algorithms then perform a random walk not only in E(0) space but also in V space. Among the three algorithms, the replica-exchange method is the easiest to perform because the weight factor is just a product of regular Boltzmann-like factors, while the weight factors for the multicanonical algorithm and simulated tempering are not a priori known. We give a simple procedure for obtaining the weight factors for these two latter algorithms, which uses a short replica-exchange simulation and the multiple-histogram reweighting techniques. As an example of applications of these algorithms, we have performed a two-dimensional replica-exchange simulation and a two-dimensional simulated-tempering simulation using an alpha-helical peptide system. From these simulations, we study the helix-coil transitions of the peptide in gas phase and in aqueous solution.


What are the experiences of people with dementia in employment?
Statistics show that an increase in the statutory retirement age in the UK will mean that many more people will develop a dementia while still in employment. A review of the literature confirmed that there are no existing studies in the UK which examine this issue in any detail. The aim of this study was to investigate the experiences of people who develop a dementia while still in employment and to understand how they make sense of these experiences; therefore a qualitative explorative inquiry based on an Interpretive Phenomenological Analysis methodology was used. Interviews with five people who had developed a dementia while still in employment were carried out, with ages ranging from 58 to 74 years. Interview transcripts were analysed and four super-ordinate themes were identified: the realization that something is wrong; managing the situation in the workplace; trying to make sense of change; and coming to terms with retirement or unemployment. The results showed that people who develop a dementia while still in employment do not always receive the 'reasonable adjustments' in the workplace to which they are entitled under the Equality Act (2010). Some of the participants felt that they were poorly treated by their workplace and described some distressing experiences. The study highlights the need for more effective specialized advice and support regarding employment issues and more research into the numbers of people in the UK that are affected by this issue.


Autopsy findings in EPG5-related Vici syndrome with antenatal onset.
Vici syndrome is one of the most extensive inherited human multisystem disorders and due to recessive mutations in EPG5 encoding a key autophagy regulator with a crucial role in autophagosome-lysosome fusion. The condition presents usually early in life, with features of severe global developmental delay, profound failure to thrive, (acquired) microcephaly, callosal agenesis, cataracts, cardiomyopathy, hypopigmentation, and combined immunodeficiency. Clinical course is variable but usually progressive and associated with high mortality. Here, we present a fetus, offspring of consanguineous parents, in whom callosal agenesis and other developmental brain abnormalities were detected on fetal ultrasound scan (US) and subsequent MRI scan in the second trimester. Postmortem examination performed after medically indicated termination of pregnancy confirmed CNS abnormalities and provided additional evidence for skin hypopigmentation, nascent cataracts, and hypertrophic cardiomyopathy. Genetic testing prompted by a suggestive combination of features revealed a homozygous EPG5 mutation (c.5870-1G>A) predicted to cause aberrant splicing of the EPG5 transcript. Our findings expand the phenotypical spectrum of EPG5-related Vici syndrome and suggest that this severe condition may already present in utero. While callosal agenesis is not an uncommon finding in fetal medicine, additional presence of hypopigmentation, cataracts and cardiomyopathy is rare and should prompt EPG5 testing.


Programmed cell death-1 (PD-1) at the heart of heterologous prime-boost vaccines and regulation of CD8+ T cell immunity.
Developing new vaccination strategies and optimizing current vaccines through heterologous prime-boost carries the promise of integrating the benefits of different yet synergistic vectors. It has been widely thought that the increased immunity afforded by heterologous prime-boost vaccination is mainly due to the minimization of immune responses to the carrier vectors, which allows a progressive build up of immunity against defined epitopes and the subsequent induction of broader immune responses against pathogens. Focusing on CD8+ T cells, we put forward a different yet complementary hypothesis based primarily on the systematic analysis of DNA vaccines as priming agents. This hypothesis relies on the finding that during the initiation of immune response, acquisition of co-inhibitory receptors such as programmed cell death-1 (PD-1) is determined by the pattern of antigen exposure in conjunction with Toll-like receptor (TLR)-dependent stimulation, critically affecting the magnitude and profile of secondary immunity. This hypothesis, based upon the acquisition and co-regulation of pivotal inhibitory receptors by CD8+ T cells, offers a rationale for gene-based immunization as an effective priming strategy and, in addition, outlines a new dimension to immune homeostasis during immune reaction to pathogens. Finally, this model implies that new and optimized immunization approaches for cancer and certain viral infections must induce highly efficacious T cells, refractory to a broad range of immune-inhibiting mechanisms, rather than solely or primarily focusing on the generation of large pools of vaccine-specific lymphocytes.


Immunogenicity and safety of a virosomal hepatitis A vaccine (Epaxal) in the elderly.
Protection against hepatitis A virus (HAV) in the elderly is becoming more important as more senior travelers visit areas of high HAV endemicity, and less have protective antibodies acquired after natural infection during childhood. This study assessed the immunogenicity and safety of hepatitis A vaccine in elderly compared to young adults. In this open, uncontrolled study, subjects of 18 to 45 years or < or = 50 years of age received two doses of aluminum-free, virosomal HAV vaccine, Epaxal (Berna Biotech Ltd, formerly Swiss Serum and Vaccine Institute, Bern, Switzerland) 12 months apart. After both the basic and the booster doses, geometric mean titers (GMT) for anti-HAV antibodies were 1.7-fold higher in subjects younger than 45 years compared with those < or = 50 years of age. The proportional increase in GMT after the booster dose, however, was similar in younger and older subjects. Seroprotection (< or = 20 mIU/mL) rates in the younger and older subjects were 100 and 65%, respectively, after the first vaccination and 100 and 97%, respectively, after the booster dose. Systemic and local adverse events were mainly mild and short-lived. These data show that HAV virosomal vaccine (Epaxal) is well tolerated and immunogenic in elderly subjects. The clinical relevance of lower seroconversion rates after the primary dose is unknown in this population of travelers.


A new algorithm for image noise reduction using mathematical morphology.
Morphological openings and closings are useful for the smoothing of gray-scale images. However, their use for image noise reduction is limited by their tendency to remove important, thin features from an image along with the noise. The paper presents a description and analysis of a new morphological image cleaning algorithm (MIC) that preserves thin features while removing noise. MIC is useful for gray-scale images corrupted by dense, low-amplitude, random, or patterned noise. Such noise is typical of scanned or still-video images. MIC differs from previous morphological noise filters in that it manipulates residual images-the differences between the original image and morphologically smoothed versions. It calculates residuals on a number of different scales via a morphological size distribution. It discards regions in the various residuals that it judges to contain noise. MIC creates a cleaned image by recombining the processed residual images with a smoothed version. The paper describes the MIC algorithm in detail, discusses the effects of parametric variations, presents the results of a noise analysis and shows a number of examples of its use, including the removal of scanner noise. It also demonstrates that MIC significantly improves the JPEG compression of a gray-scale image.


Neuroprotective effects of alkaloids from Piper longum in a MPTP-induced mouse model of Parkinson's disease.
Alkaloids of Piper longum L. (Piperaceae) (PLA) include piperine and piperlonguminine. Piper longum and piperine have multiple biological properties including antioxidant activity. The present study investigated the neuroprotective effects of PLA in a MPTP-induced mouse model of Parkinson's disease. PLA was prepared by extracting the dry seed of P. longum using 85% ethanol. Adult male C57BL/6 mice were divided into eight groups of 12 rats each. Experimental and control groups received an equivalent volume of saline, 0.5% CMC-Na, and 0.1% Tween 80, treated groups received oral PLA (30, 60, and 120 mg/kg), other groups treated with piperine (60 mg/kg) or Madopar (50 mg/kg). The PLA prevention group (PLA-Pr) administrated PLA (120 mg/kg) for 1 week before MPTP challenged. Except for the PLA-Pr group, others were treated for seven consecutive weeks. Parkinson's disease was induced by injecting MPTP intraperitoneally (25 mg/kg) twice weekly for five consecutive weeks. Dopaminerigic (DA) neurons and their metabolism were detected by UFLC-MS/MS. Tyrosine hydroxylase (TH)-immunohistochemistry assay and Western blotting were performed. The antioxidant enzymatic levels were determined by kit-based assays. The LD50 value of PLA was determined at 1509 mg/kg of body weight. PLA (60 mg/kg) can significantly increase total movement time and distance (p < 0.05), increase levels of DA (p < 0.05) and DOPAC (p < .05), increase glutathione (GSH) level and superoxide dismutase (SOD) activity (p < 0.05), and decrease the lipid peroxidation of malondiadehycle (MDA) (p < 0.05) in PLA-treated groups as compared with the control group. Our results indicate that PLA possesses neuroprotective effects and has ameliorative properties in dopaminergic neurons.


NDRG1 functions in LDL receptor trafficking by regulating endosomal recycling and degradation.
N-myc downstream-regulated gene 1 (NDRG1) mutations cause Charcot-Marie-Tooth disease type 4D (CMT4D). However, the cellular function of NDRG1 and how it causes CMT4D are poorly understood. We report that NDRG1 silencing in epithelial cells results in decreased uptake of low-density lipoprotein (LDL) due to reduced LDL receptor (LDLR) abundance at the plasma membrane. This is accompanied by the accumulation of LDLR in enlarged EEA1-positive endosomes that contain numerous intraluminal vesicles and sequester ceramide. Concomitantly, LDLR ubiquitylation is increased but its degradation is reduced and ESCRT (endosomal sorting complex required for transport) proteins are downregulated. Co-depletion of IDOL (inducible degrader of the LDLR), which ubiquitylates the LDLR and promotes its degradation, rescues plasma membrane LDLR levels and LDL uptake. In murine oligodendrocytes, Ndrg1 silencing not only results in reduced LDL uptake but also in downregulation of the oligodendrocyte differentiation factor Olig2. Both phenotypes are rescued by co-silencing of Idol, suggesting that ligand uptake through LDLR family members controls oligodendrocyte differentiation. These findings identify NDRG1 as a novel regulator of multivesicular body formation and endosomal LDLR trafficking. The deficiency of functional NDRG1 in CMT4D might impair lipid processing and differentiation of myelinating cells.


Biomechanical and histological evaluation of glycerol-preserved human sclerae.
To determine the histological and biomechanical characteristics of glycerol-preserved human sclera. A total of 114 paired human sclerae were cleaned and preserved with 98% glycerol under refrigeration at 4 to 8 degrees C. The samples were divided into a control group with no preservation and 5 groups of 19 sclerae in 7, 15, 30, 90 and 180 days of preservation. Each specimen was submitted to histological examination and tested for traction distensibility functions. Preservation in glycerol did not cause alterations in the histological architecture of the scleral tissue. The mean load required to break the scleral tissue increased according to preservation time as a sigmoid function. A significant increase in mechanical resistance and decrease in distension of scleral tissue occurred after 90 days of preservation. Scleral preservation in glycerol keeps tissue integrity. The preserved material is less distensible after 90 days. Surgeons who use sclera in ophthalmic procedures should be aware of the mechanical characteristics of glycerol-preserved sclera and take into account tissue preservation time.


Efficacy of a formulation containing Serenoa repens, Crocus sativus and Pinus massoniana extracts in men with concomitant LUTS and erectile dysfunction.
The relationship between lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) has received increased attention recently. This study aims to evaluate the efficacy of IDIProst® Gold, a product containing Serenoa repens, Crocus sativus and Pinus massoniana bark extract (PMBE), in improving sexual function, urinary symptoms and quality of life in patients with concomitant LUTS and ED. A total 140 men (mean age 48 years) were enrolled and treated in this study. All patients were administered IDIProst® Gold (Crocus sativus, PMBE, Serenoa repens) once daily for three months. At visit (T0) and after ninety days of treatment (T90), the patients were evaluated and asked to complete two self-administered questionnaires: International Prostate Symptoms Score (IPSS), International Index of Erectile Function (IIEF-5). The main outcomes were the improved IIEF-5 and IPSS scores in the 40-60 age group. The secondary outcome was the improved quality of life score among treated patients. The baseline mean scores at T0 were 17.29 and 15.12 for the IPSS and IIEF-5 respectively. After three months of treatment (T90), the questionnaire results were as follows: 10.21 and 20.53 for IPSS and IIEF-5 respectively. Statistically significant differences (P<0.001) were reported between the two visits in terms of IPSS and IIEF-5 for all the groups treated, but particularly the 40-60 age group. There was also a statistically significant improvement (P<0.001) in quality of life between T0 and T90 (3.82 vs. 1.45). Compliance with the study protocol was 100%. 140 patients were enrolled out of a population of 164. No adverse events were reported. Treatment once daily with IDIProst® Gold (Serenoa repens, Crocus sativus and PMBE) for three months significantly improved sexual function, urinary symptoms and quality of life in patients with concomitant LUTS and ED, especially in the 40-60 age group.


Drug discovery approaches to irritable bowel syndrome.
Irritable bowel syndrome (IBS) is defined by symptoms of abdominal pain and altered bowel habits without detectable organic disease. Antidepressants and serotonin receptor modulators are used to treat IBS, but rare serious adverse events highlight the safety hurdle. Newer drugs with secretory and motility effects via local gut mechanisms have been successfully approved for IBS, often by registering first in a related, non-IBS condition to optimize dosing, formulation and therapeutic window. This review looks at approaches for novel IBS drug discovery. The underlying pathologies can be tackled locally from the 'outside-in' (intestinal lumen, mucosa and neuromuscular) to identify therapeutic targets. The article discusses the mechanisms associated with bile acid malabsorption, microbial dysbiosis, decreased intestinal barrier function, immune dysregulation, motility and visceral hypersensitivity. Challenges for new drug discovery are the unknown mechanisms underlying IBS, making it difficult to predict clinically efficacious molecular targets, limited options for translational research and disease progression biomarkers. Drugs acting locally via multiple targets (e.g., eluxadoline [The U.S. Food and Drug Administration approved Viberzi (eluxadoline) for IBS-D on May 27th 2015], crofelemer) to validated mechanisms are proving successful with tolerable safety margins. Novel mechanisms, identified and optimized based on the emerging role of nutrient signaling, probiotics or microbial products, are promising. Therapeutic treatment earlier in disease progression may improve response and have longer term benefits.


The localization of retinol-binding protein in rat liver by immunofluorescence microscopy.
The localization of immunoreactive retinol-binding protein (RBP) in rat liver was studied by immunofluorescence microscopy. The study employed specific antisera to rat RBP prepared in a rabbit and in a sheep. The indirect, two-stage method of localizing tissue antigens was employed, and livers of both normal and vitamin A-deficient rats were examined. Fab' fragments of immunoglobulins were used, to minimize non-specific labelling of the frozen sections of liver. With these techniques, the specific immune staining of RBP was observed within liver parenchymal cells. This staining appeared as both particulate and diffuse within the cytoplasm of the parenchymal cells, and was not concentrated within one region of the liver cell or lobule. Staining for RBP was not observed in nuclei or in cells other than parenchymal cells. Similar particulate and diffuse immune staining for RBP was observed in liver sections from both vitamin A-deficient and normal rats. More intense immune staining appeared to be present in the sections of vitamin A-deficient animals, in good correlation with the expected higher levels of RBP in deficient as compared to normal liver. When liver sections were exposed to an antiserum to rat albumin, instead of one to rat RBP, immune cytoplasmic staining was observed which was entirely of a diffuse nature, and did not appear particulate or granular. The findings suggest that RBP, unlike albumin, is localized in part within cytoplasmic vesicles or granules which are large enough to be detected with immunofluorescence, and which are present in livers of both normal and vitamin A-deficient animals. The nature of these putative RBP-containing particles remains to be explored.


Comprehensive insight into the pharmacology, pharmacokinetics, toxicity, detoxification and extraction of hypaconitine from Aconitum plants.
Hypaconitine (HA), a diterpenoid alkaloid, mainly derived from Aconitum plants such as Acoitum carmichaeli Debx. And Aconitum nagarum Stapf., has recently piqued significant interest among the scientific community given its multifaceted attributes including anti-inflammatory, anticancer, analgesic, and cardio-protective properties. This review presents a comprehensive exploration of the research advancements regarding the traditional uses, pharmacology, pharmacokinetics, toxicity, and toxicity reduction of HA. It aims to provide a thorough understanding of HA's multifaceted properties and its potential applications in various fields. A systematic literature search was conducted using several prominent databases including PubMed, Web of Science, NCBI, and CNKI. The search was performed using specific keywords such as "hypaconitine," "heart failure," "anti-inflammatory," "aconite decoction," "pharmacological," "pharmacokinetics," "toxicity," "detoxification or toxicity reduction," and "extraction and isolation." The inclusion of these keywords ensured a comprehensive exploration of relevant studies and enabled the retrieval of valuable information pertaining to the various aspects of HA. Existing research has firmly established that HA possesses a range of pharmacological effects, encompassing anti-cardiac failure, anti-inflammatory, analgesic, and anti-tumor properties. The therapeutic potential of HA is promising, with potential applications in heart failure, ulcerative colitis, cancer, and other diseases. Pharmacokinetic studies suggest that HA exhibits high absorption rates, broad distribution, and rapid metabolism. However, toxic effects of HA on the nerves, heart, and embryos have also been observed. To mitigate these risks, HA needs attenuation before use, with the most common detoxification methods being processing and combined use with other drugs. Extraction methods for HA most commonly include cold maceration, soxhlet reflux extraction, and ultrasonic-assisted extraction. Despite the potential therapeutic benefits of HA, further research is warranted to elucidate its anti-heart failure effects, particularly in vivo, exploring aspects such as in vivo metabolism, distribution, and metabolites. Additionally, the therapeutic effects of HA monomers on inflammation-induced diseases and tumors should be validated in a more diverse range of experimental models, while the mechanisms underlying the therapeutic effects of HA should be investigated in greater detail. This review serves to emphasize the therapeutic potential of HA and highlights the crucial need to address its toxicity concerns before considering clinical application. Further research is required to comprehensively investigate the pharmacological properties of HA, with particular emphasis on its anti-cardiac failure and anti-inflammatory activities. Such research endeavors have the potential to unveil novel treatment avenues for a broad spectrum of diseases.


Hyperattenuated intracerebral lesions after mechanical recanalization in acute stroke.
Following mechanical recanalization of an acute intracranial vessel occlusion, hyperattenuated lesions are frequently found on postinterventional cranial CT. They represent either blood or-more frequently-enhancement of contrast agent. Here, we aimed to evaluate the prognostic value of these hyperattenuated intracerebral lesions. One hundred one consecutive patients with acute stroke in the anterior circulation who underwent mechanical recanalization were included. Risk factors for hyperattenuated intracerebral lesions were assessed, and lesion volume was compared with the volume of final infarction. Clinical outcome and relative risk of secondary hemorrhage were determined in patients with and without any hyperattenuated lesions and compared. The frequency of hyperattenuated lesions was 84.2%. Risk factors for hyperattenuated lesions were female sex, higher NIHSS score on admission, and higher amount of contrast agent applied. On follow-up, 3 patients showed no infarction; 53 patients, an ischemic infarction; and 45 patients, a hemorrhagic infarction. In all except 1 case, final volume of infarction (median = 92.4 mL) exceeded the volume of hyperattenuated intracerebral lesions (median = 5.6 mL). Patients with hyperattenuated lesions were at a 4 times higher relative risk for hemorrhagic transformation but had no significantly worse clinical outcome. Our data show that the extent of postinterventional hyperattenuated intracerebral lesions underestimates the volume of final infarction. Although hyperattenuated lesions indicate a higher risk of secondary hemorrhagic transformation, their presence seems not to be of any prognostic value regarding clinical outcome.


Removal of ofloxacin using a porous carbon microfiltration membrane based on in-situ generated •OH.
This study investigated the removal performance of ofloxacin (OFL) by a novel electro-Fenton enhanced microfiltration membrane. The membranes used in this study consisted of metal-organic framework derived porous carbon, carbon nanotubes and Fe2+, which were able to produce hydroxyl radicals (•OH) in-situ via reducing O2 to hydrogen peroxide. Herein, membrane filtration with bias not only concentrated the pollutants to the level that could be efficiently treated by electro-Fenton but also confined/retained the toxic intermediates within the membrane to ensure a prolonged contact time with the oxidants. After validated by experiments, the applied bias of -1.0 V, pH of 3 and electrolyte concentration of 0.1 M were the relatively optimum conditions for OFL degradation. Under these conditions, the average OFL removal rate could be reach 75% with merely 5% membrane flux loss after 4 cycles operation by filtrating 1 mg/L OFL. Via decarboxylation reaction, piperazinyl ring opening, dealkylation and ipso substitution reaction, etc., ofloxacin could be gradually and efficiently degraded to intermediate products and even to CO2 by •OH. Moreover, the oxidation reaction was preferred to following first-order reaction kinetics. This research verified a possibility for antibiotic removal by electro-enhanced microfiltration membrane.


Cyclophilin A Impairs Efferocytosis and Accelerates Atherosclerosis by Overexpressing CD 47 and Down-Regulating Calreticulin.
Impairment of efferocytosis in apoptotic macrophages is a known determinant of the severity of atherosclerosis and the vulnerability of plaques to rupture. The precise mechanisms involved in impaired efferocytosis are unclear. Given the well-recognized role of the inflammatory cytokine cyclophilin A (Cyp A) in modulating several atherogenic mechanisms in high-glucose primed monocytes, we investigated the role of Cyp A in macrophage efferocytosis. The efficiency of efferocytosis in RAW 264.7 macrophages grown in vitro and primed with cyclophilin A was assessed using flow cytometry and confocal assays. Cholesterol content in cells was measured using cell-based cholesterol efflux assay. Proteomic analysis and bioinformatics tools were employed to decipher the link between cyclophilin A and the known ligand receptors involved in efferocytosis. Cyclophilin A was found to impair efferocytosis in apoptotic macrophages by reducing ABCA1-mediated cholesterol efflux in foam cells derived from macrophages. Cyclophilin A-primed macrophages showed an increase in expression of the don't-eat-me signal CD 47 and a decrease in the expression of the eat-me signal, calreticulin. Phagocytosis was restored upon silencing of cyclophilin A. New Zealand white rabbits were fed a high-fat diet, and lesions in their aortae were analyzed histologically for evidence of atherosclerosis and the expression of Cyp A, CD 47 and calreticulin, the ligand receptor involved in efferocytosis. Gene and protein expressions in aortae and macrophages were analyzed by real-time PCR and Western blotting. Cyclophilin A, via its effects on the expression of CD 47 and calreticulin, impairs efferocytosis in apoptotic macrophages. Together with its impact on cholesterol efflux from macrophages, these effects can amplify other mechanisms of Cyp A in accelerating the progression of atherosclerosis.


Metabolism of albumin and immunoglobulins in the nephrotic syndrome.
The nephrotic syndrome is characterized by the increased urinary excretion of albumin and of other serum proteins of intermediate molecular weight accompanied by a decrease in their serum concentration. Albumin synthesis is increased at the level of mRNA synthesis in response to decreased serum oncotic pressure. However, the magnitude of these responses is dependent upon dietary protein and is insufficient to normalize serum albumin. The absolute rate of albumin catabolism is decreased, serving to normalize serum albumin stores, but in contrast to what occurs in other hypoalbuminemic states, the fractional rate of albumin catabolism is increased. This observation is consistent with a hypothesis that increased renal catabolism contributes to total albumin catabolism in nephrosis. Like albumin, IgG is lost in the urine, its serum concentration is decreased, and the fractional rate of its catabolism is increased, suggesting that the kidney contributes to IgG catabolism in the presence of proteinuria. IgG synthesis responds in a variable fashion in the nephrotic syndrome, and may be decreased, thus contributing to its reduced serum concentration. In contrast, the serum concentration of the high-molecular-weight immunoglobulin IgM is increased, as is the serum concentration of a variety of high-molecular-weight liver-derived proteins. It is unknown by what mechanism serum IgM concentration is increased, but this response serves to defend serum protein concentration and oncotic pressure.


Fibroblasts stimulated via HLA-II molecules produce prostaglandin E₂ and regulate cytokine production from helper T cells.
Fibroblasts act as important immune regulatory cells via their ability to cross-talk with T cells accumulating in lesions. Our previous study showed that fibroblasts produce several cytokines and chemokines by crosslinking HLA class II (HLA-II) molecules with monoclonal antibodies or by making T-cell receptor-peptide-HLA complexes. It is thus conceivable that the interaction of T cells and fibroblasts via HLA-II affects fibroblast responses to stimuli. This study used human gingival fibroblasts (HGF) to investigate possible effects of these fibroblast-derived soluble factors on the differentiation of naïve T cells and on the subsequent fibroblast responses. After mixed lymphocyte reaction culture between naïve T cells and allogeneic dendritic cells in the presence of culture supernatant from HGF stimulated via HLA-DQ molecules (DQ-sup), but not via DR, T cells exhibited a Th2-shifted phenotype, thereby producing quantitatively more IL-13 and IL-5 compared with interferon-γ. Astonishingly, analyses to identify possible factors affecting the Th2 polarization secreted from HLA-II-stimulated HGF, prostaglandin E₂, was detected only in DQ-sup. The Th2 polarization of naïve T cells was blocked in the presence of supernatants from indomethacin-treated HGF with HLA-DQ stimulation. In addition, we found that the culture supernatants of Th cells activated following mixed lymphocyte reaction culture in the presence of DQ-sup had the potential to induce gene expression of type I and III collagens in HGF. These results suggested that fibroblasts stimulated via HLA-DQ molecules promote Th2 polarization in Th-cell responses and showed the counter activation of collagen synthesis, implicating orchestrated responses among these cells in the fibrosis of chronic inflammatory lesions.


The N-terminal subdomain of insulin-like growth factor (IGF) binding protein 6. Structure and interaction with IGFs.
Insulin-like growth factor binding proteins (IGFBPs) modulate the activity and distribution of insulin-like growth factors (IGFs). IGFBP-6 differs from other IGFBPs in being a relatively specific inhibitor of IGF-II actions. Another distinctive feature of IGFBP-6 is its unique N-terminal disulfide linkages; the N-domains of IGFBPs 1-5 contain six disulfides and share a conserved GCGCC motif, but IGFBP-6 lacks the two adjacent cysteines in this motif, so its first three N-terminal disulfide linkages differ from those of the other IGFBPs. The contributions of the N- and C-domains of IGFBP-6 to its IGF binding properties and their structure-function relationships have been characterized in part, but the structure and function of the distinctive N-terminal subdomain of IGFBP-6 are unknown. Here we report the solution structure of a polypeptide corresponding to residues 1-45 of the N-terminal subdomain of IGFBP-6 (NN-BP-6). The extended structure of the N-terminal subdomain of IGFBP-6 is very different from that of the short two-stranded beta-sheet of the N-terminal subdomain of IGFBP-4 and, by implication, the other IGFBPs. NN-BP-6 contains a potential cation-binding motif; lanthanide ion binding was observed, but no significant interaction was found with physiologically relevant metal ions like calcium or magnesium. However, this subdomain of IGFBP-6 has a higher affinity for IGF-II than IGF-I, suggesting that it may contribute to the marked IGF-II binding preference of IGFBP-6. The extended structure and flexibility of this subdomain of IGFBP-6 could play a role in enhancing the rate of ligand association and thereby be significant in IGF recognition.


Radiographic findings after cricopharyngeal myotomy.
Single film examinations (iodine and/or barium) were reviewed in 28 patients who had undergone surgery on the cricopharyngeal muscle due to Zenker diverticula (24 patients), cricopharyngeal muscle incoordination (3 patients) and pharyngoesophageal web (one patient). All patients had had a myotomy which included the cricopharyngeal muscle and up to 3 cm of the cervical esophagus. Lateral and anterior deviation of the pharynx and cervical esophagus occurred regularly. A pharyngocutaneous fistula developed in 2 patients which healed within 3 weeks. In 5 patients there was a posterior leak of contrast medium during the first postoperative week which healed within 2 weeks. Six of these seven patients with a fistula or a leak had had either a diverticulum removed or sustained an accidental mucosal perforation. No patient had recurrence of diverticula, although, 9 patients developed a cricopharyngeal muscle impression. Iodine and barium examinations are important for monitoring early and late postoperative changes after cricopharyngeus myotomy.


The problem with defining foreign birth as a risk factor in tuberculosis epidemiology studies.
To examine how stratifying persons born outside Canada according to tuberculosis (TB) incidence in their birth country and other demographic factors refines our understanding of TB epidemiology and local TB transmission. Population-level TB surveillance programs and research studies in low incidence settings often report all persons born outside the country in which the study is conducted as "foreign-born"-a single label for a highly diverse population with variable TB risks. This may mask important TB epidemiologic trends and not accurately reflect local transmission patterns. We used population-level data from two large cohorts in British Columbia (BC), Canada: an immigration cohort (n = 337,492 permanent residents to BC) and a genotyping cohort (n = 2290 culture-confirmed active TB cases). We stratified active TB case counts, incidence rates, and genotypic clustering (an indicator of TB transmission) in BC by birth country TB incidence, age at immigration, and years since arrival. Persons from high-incidence countries had a 12-fold higher TB incidence than those emigrating from low-incidence settings. Estimates of local transmission, as captured by genotyping, versus reactivation of latent TB infection acquired outside Canada varied when data were stratified by birthplace TB incidence, as did patient-level characteristics of individuals in each group, such as age and years between immigration and diagnosis. Categorizing persons beyond simply "foreign-born", particularly in the context of TB epidemiologic and molecular data, is needed for a more accurate understanding of TB rates and patterns of transmission.


Altmetrics - A Collated Adjunct Beyond Citations for Scholarly Impact: A Systematic Review.
In emerging Figures, scholars are unifying social media tools like blogs, Twitter, and Mendeley into their professional communications. The online, open nature of these tools reveals the scholarly action to be clear and unambiguous. Metrics which is set on these activities could enlighten broader, faster measures of impact, supplementing traditional citation metrics. The present review aims to analyse the correlation of altmetrics with the traditional citations in medical research. The search strategy used a combination of controlled vocabulary and free text terms. The main database searched were PubMed, PubMed Central, Cochrane Review, Embase and Google Scholar from 2010 to 2016. Out of the total 78 titles appeared seven articles fulfilled the criteria and were selected for the review. The positive correlation between altmetrics and traditional citations indicates that the two are not entirely different from each other and are familiar with each other. Altmetrics are usually accessible earlier and enable us to evaluate the social impact of scholarly research, almost at the actual time. Much work is needed to develop this research which will focus on the clarity of the impact signal. Thus newer dimensions, such as altmetrics and article-level metrics are an effort to explore the influence of research across the worldwide population.


Aspirin Inhibits Fibronectin Expression and Reverses Fibronectin-Mediated Cell Invasiveness by Activating Akt Signaling in Preeclampsia.
Preeclampsia is a severe gestational hypertensive disorder that may lead to maternal multiple organ dysfunction and adverse fetal outcomes. Aspirin provides a protective effect by reducing the risk of preeclampsia; however, its mechanism of action is unclear. Fibronectin (FN) is a key factor in cell motility and is associated with preeclampsia. Here, we demonstrated that cellular FN expression was elevated in the placenta of preeclamptic patients. The functional roles of plasma and cellular FN in trophoblasts were investigated by treating HTR-8/SVneo cells with exogenous recombinant human FN protein (rhFN) and siRNA, respectively. Trophoblast migration and invasion were inhibited by rhFN and facilitated by FN knockdown. Moreover, rhFN activated ERK and Akt signaling in trophoblasts, and FN-suppressed cell motility was rescued by ERK and/or Akt inhibitors. In this study, aspirin suppressed trophoblast cellular FN expression and reversed FN-mediated cell functions, including cell migration, invasion, and ERK/Akt signal changes. Taken together, the results of this study revealed the effects of FN on trophoblast motility and signaling; aspirin inhibits FN expression and reverses FN-mediated trophoblast biology. These results provide a drug mechanism for disease prevention and a target for preeclampsia intervention.


Cholesterol lowering treatment restores blood global DNA methylation in chronic kidney disease (CKD) patients.
Chronic kidney disease (CKD) is characterized by increased oxidative stress (OS). In consideration of the well-known link between OS and DNA methylation we assessed DNA methylcytosine (mCyt) concentrations in CKD patients at baseline and during cholesterol lowering treatment. DNA methylation and OS indices (malonyldialdehyde, MDA; allantoin/uric acid ratio, All/UA) were measured in 30 CKD patients randomized to three cholesterol lowering regimens for 12 months (simvastatin 40 mg/day, ezetimibe/simvastatin 10/20 mg/day, or ezetimibe/simvastatin 10/40 mg/day) and 30 age- and sex-matched healthy controls. DNA methylation was significantly lower in CKD patients vs. controls (4.06 ± 0.20% vs. 4.27 ± 0.17% mCyt, p = 0.0001). Treatment significantly increased mCyt DNA concentrations in all patients (4.06 ± 0.04% at baseline; 4.12 ± 0.03% at 4 months; 4.17 ± 0.03% at 8 months; and 4.20 ± 0.02% at 12 months, p = 0.0001 for trend). A trend for a greater effect on DNA methylation was observed with combined treatment ezetimibe/simvastatin 10/40 mg/day (+5.2% after one year treatment). The treatment-associated mCyt increase was significantly correlated with the concomitant reduction in MDA concentrations and All/AU ratios. Our results demonstrate that CKD patients have a lower degree of DNA methylation and that cholesterol lowering treatment restores mCyt DNA concentrations to levels similar to healthy controls. The treatment-associated increase in DNA methylation is correlated with a concomitant reduction in OS markers. The study was registered at clinicaltrials.gov (NCT00861731).


[Pharyngo-laryngeal consequences of gastroesophageal reflux. Value of esophageal pH measurements in 74 patients].
Ambulatory 24 hour oesophageal pH monitoring was performed in order to detect gastro-oesophageal reflux disease (GERD) in 74 patients presenting with poorly explained ear-nose-throat complaints. A significant number of these patients also benefited from other currently used methods for diagnosing GERD. Oesophageal pH-monitoring demonstrated GERD in half of the patients. For atypical GERD, 24 hour oesophageal pH-monitoring seems to be the most sensitive procedure.


[The role of macrophages in asbestos-induced carcinogenesis].
Data available on the pathways of asbestos (fibrous) carcinogenesis still leaves much to be desired. Asbestos is regarded as a non-genotoxic substance by most researchers. There is insufficient evidence on the interaction of fibres, target-cells and macrophages. Macrophages secreted proteins (ca. 450 kD) to inhibit proliferation of intact mesothelium and cytoxine (3-5 kD) which stimulated the cellular sensitivity of intact mesothelium and mesotheliomas to the toxic influence of asbestos. It was suggested that the effect was due to the triggering of intrinsic causation of cell death. Like any other fibres, carcinogenic effect of asbestos could be accounted for by such significant factor as active oxygen radicals. When exposed to asbestos, both intact mesothelial and mesothelioma cells and macrophages synthesized those substances. Free radical-like substances in conjunction with macrophage-conditioned media produced toxic effect on mesothelial cells. The role of active oxygen radicals in fibre-induced carcinogenesis is discussed.


Antimicrobial resistance. Its importance and efforts to control it.
The World Health Organization estimates that bacterial resistance will cause 10 million deaths by 2050. As part of the Global Action Plan on Antimicrobial Resistance, it proposed networks of specialized laboratories in order to preserve strains and optimize the use of antimicrobials. That is the case of the Latin American Surveillance Network of Antimicrobials Resistance. In a 2019 study, the main bacteria of the ESKAPE group (which are highly resistant to the most widely used antibiotics) that cause infections in Mexican Hospitals were identified to be multidrug-resistant (MDR) and extended-spectrum beta-lactamase (ESBL)-producing Klebsiella spp., ESBL-producing Enterobacter spp., Acinetobacter baumannii, MDR Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. With information on drug resistance, regimens are recommended to treat infection caused by Helicobacter pylori, a pathogen related to the development of cancer and whose prevalence in the adult population of Latin America is estimated to range between 60 and 70 %.