An AP1-binding site in the c-fos gene can mediate induction by epidermal growth factor and 12-O-tetradecanoyl phorbol-13-acetate.
We have demonstrated that two sequence elements in the c-fos promoter can mediate the response of the gene to epidermal growth factor and the tumor promoter 12-O-tetradecanoyl phorbol-13-acetate (TPA). The first is the previously described serum response element. The second is a sequence element highly homologous to the consensus binding site for the HeLa cell transcription factor AP1. Although recent reports have shown that fos protein binds to AP1-binding sites through an interaction with AP1 protein and have raised the speculation that fos protein may negatively regulate expression of the c-fos gene via this interaction, we found no role for the AP1 consensus homology in the downregulation of c-fos expression following induction by epidermal growth factor and TPA.


Factors influencing treatment outcomes of tuberculosis patients attending health facilities in Galkayo Puntland, Somalia.
This study evaluated the underlying factors associated with poor tuberculosis (TB) treatment outcomes among patients attending health care facilities in Galkayo, Puntland, Somalia. An institution-based cross-sectional study was conducted between 2016 and 2017 in three selected TB clinics. Data were collected from 400 TB patients, through medical record review and structured questionnaire. Multivariate logistic regression analyses were performed. Of the 400 TB respondents, 57.3% were new cases, 12.3% had smear-negative TB and 12.5% had extrapulmonary TB. The median age was (35.66 ± 13.16) with majority being male (65.5%). Overall, 85% of patients were successfully treated, 9.7% failed and 5.3% defaulted. Multivariate analysis revealed that patient's body weight (odds ratio [OR]: 1.078); diabetes (OR: 8.022); family size (OR: 3.851); patients' delay in diagnosis (OR: 11.946); frequency of receiving anti-TB medication (OR: 9.068); smoker (OR: 5.723); category of patients (retreatment versus new, OR: 5.504; retreatment versus transfer in, OR: 4.957); health facilities (OR: 6.716) and treatment duration (OR: 132.091) were independent factors associated with poor TB outcomes. Our findings highlight the need to improve TB services for vulnerable groups. They also emphasize the need for health system strengthening, public awareness and risk of treatment interruption. This may reduce both patients' delay in seeking care and TB treatment failure in Galkayo district.


Screening for bipolar disorder in patients treated for depression in a family medicine clinic.
The prevalence of bipolar disorder in patients being treated for depression with antidepressants in a family medicine clinic was investigated in this study. Adult patients with depression who were treated with an antidepressant in a general outpatient family medicine clinic at the University of Texas were screened for bipolar disorder using the Mood Disorder Questionnaire (MDQ), a brief self-report inventory. A subsample of subjects received the Structured Clinical Interview based on the DSM-IV (SCID) to test the operating characteristics of the MDQ in this population. of the patients taking an antidepressant for depression, 21.3% screened positive for bipolar disorder on the MDQ. These patients were somewhat younger, more likely to be white, more likely to be living alone, much less likely to be married, and less likely to be employed than those who screen negative. Nearly two thirds of those screened positive had never received diagnosis of bipolar disorder. The sensitivity and specificity of the MDQ in this population, after adjusting for the sampling protocol, were 0.580 (0.454 to 0.706, 95% CI) and 0.930 (0.878 to 0.981, 95% CI) respectively. Bipolar disorder frequently occurs in patients being treated with antidepressants in primary care settings. Most are unrecognized and undiagnosed. Screening for bipolar disorder in such patients may improve recognition, identification, and appropriate treatment.


Conformational selection and induced fit mechanism underlie specificity in noncovalent interactions with ubiquitin.
Noncovalent binding interactions between proteins are the central physicochemical phenomenon underlying biological signaling and functional control on the molecular level. Here, we perform an extensive structural analysis of a large set of bound and unbound ubiquitin conformers and study the level of residual induced fit after conformational selection in the binding process. We show that the region surrounding the binding site in ubiquitin undergoes conformational changes that are significantly more pronounced compared with the whole molecule on average. We demonstrate that these induced-fit structural adjustments are comparable in magnitude to conformational selection. Our final model of ubiquitin binding blends conformational selection with the subsequent induced fit and provides a quantitative measure of their respective contributions.


A recurring motif for antibody recognition of the receptor-binding site of influenza hemagglutinin.
Influenza virus hemagglutinin (HA) mediates receptor binding and viral entry during influenza infection. The development of receptor analogs as viral-entry blockers has not been successful, which suggests that sialic acid may not be an ideal scaffold to obtain broad, potent HA inhibitors. Here, we report crystal structures of Fab fragments from three human antibodies that neutralize the 1957 pandemic H2N2 influenza virus in complex with H2 HA. All three antibodies use an aromatic residue to plug a conserved cavity in the HA receptor-binding site. Each antibody interacts with the absolutely conserved HA1 Trp153 at the cavity base through π-π stacking with the signature Phe54 of two VH1-69-encoded antibodies or a tyrosine from HCDR3 in the other antibody. This highly conserved interaction can be used as a starting point to design inhibitors targeting this conserved hydrophobic pocket in influenza viruses.


Retinal neurogenesis and ontogenetic changes in the visual system of the brown banded bamboo shark, Chiloscyllium punctatum (Hemiscyllidae, Elasmobranchii).
The development of the eye of the oviparous brown banded bamboo shark, Chiloscyllium punctatum, was monitored from egg deposition through adulthood. The order and timing of retinal cell differentiation were assessed by light and transmission electron microscopy. As in other vertebrates, the ganglion cells are the first to differentiate, in this case by 81 days post-egg deposition (dpd). The order then deviates from what is typically quoted for vertebrates, with the Müller and amacrine cells differentiating morphologically around the same time, followed by the bipolar cells (101 dpd) and finally the horizontal cells and photoreceptors (124 dpd). The neural retina is fully differentiated and synaptic connections are formed approximately 1 month prior to hatching, which occurs at about 158 dpd. The mature retina is duplex, with a peak rod to cone ratio of approximately 12:1. The eye and lens of C. punctatum continue to grow throughout life and become less aspherical with growth; the equatorial (nasotemporal) lens diameter is 12% larger than the axial (anterior-posterior) lens diameter in embryos and 8% larger in adults. Access to developmental stages and the protracted gestational period of C. punctatum make it a highly valuable model for developmental studies of the visual system. This study also provides an evolutionary perspective on retinal neurogenesis in an elasmobranch.


The Hidden Culprit: A Case of Repeated Anaphylaxis to Cremophor.
Drug-induced anaphylaxis is a big pitfall in patients receiving antineoplastic chemotherapy. We report a case of lung cancer patient who experienced two near-fatal anaphylactic reactions that resulted from paclitaxel and multivitamin, seperately. Recurrent severe reactions to different agents led to further investigation to which material the patient was hypersensitive. The skin prick test revealed sensitization to cremophor, which is a commonly used emulsifying agent. This case emphasizes the importance of correctly identifying the culprit drug of anaphylaxis to avoid potentially fatal reaction.


Biodegradability and denitrification potential of settleable chemical oxygen demand in domestic wastewater.
The effect of settling on mass balance and biodegradation characteristics of domestic wastewater and on denitrification potential was studied primarily using model calibration and evaluation of oxygen uptake rate profiles. Raw domestic wastewater was settled for a period of 30 minutes and a period of 2 hours to assess the effect of primary settling on wastewater characterization and composition. Mass balances in the system were made to evaluate the effect of primary settling on major parameters. Primary settling of the selected raw wastewater for 2 hours resulted in the removal of 32% chemical oxygen demand (COD), 9% total Kjeldahl nitrogen, 9% total phosphorus, and 47% total suspended solids. Respirometric analysis identified COD removed by settling as a new COD fraction, namely settleable slowly biodegradable COD (X(ss)), characterized by a hydrolysis rate of 1.0 day(-1) and a hydrolysis half-saturation coefficient of 0.08. A model simulation to test the fate and availability of suspended (X(s)) and settleable (X(ss)) COD fractions as carbon sources for denitrification showed that both particulate COD components were effectively removed aerobically at sludge ages higher than 1.5 to 2.0 days. Under anoxic conditions, the biodegradation of both COD fractions was reduced, especially below an anoxic sludge retention time of 3.0 days. Consequently, modeling results revealed that the settleable COD removed by primary settling could represent up to approximately 40% of the total denitrification potential of the system, depending on the specific configuration selected for the nitrogen removal process. This way, the results showed the significant effect of primary settling on denitrification, indicating that the settleable COD fraction could contribute an additional carbon source in systems where the denitrification potential associated with the influent becomes rate-limiting for the denitrification efficiency.


Assignment of five polymorphic ovine microsatellites to bovine syntenic groups.
A panel of bovine somatic cell hybrids was used to map ovine microsatellites. Five of seven microsatellites were assigned to five bovine syntenic groups. These microsatellites were designated D5S10 (MAF23), D1S4 (MAF46), D13S1 (MAF18), D4S3 (MAF50), and DXS2 (MAF45), mapped to syntenic groups U3 (chromosome 5), U10 (chromosome 1), U11, U13, and the X chromosome, respectively. Two remaining sheep microsatellites amplified rodent DNA in the hybrid somatic cell panel, and were not assigned to bovine syntenic groups. Assignment of ovine-derived microsatellites to bovine syntenic groups provides additional evidence of the usefulness of microsatellites for mapping closely related species. The use of ovine and bovine microsatellites will aid in development of comparative genomic maps for these two species.


Inhibitory functioning across ADHD subtypes: recent findings, clinical implications, and future directions.
Although growing consensus supports the role of deficient behavioral inhibition as a central feature of the combined subtype of ADHD (ADHD/C; Barkley 1997 Psychol Bull 121:65-94; Nigg 2001 Psychol Bull 127:571-598), little research has focused on how this finding generalizes to the primarily inattentive subtype (ADHD/I). This question holds particular relevance in light of recent work suggesting that ADHD/I might be better characterized as a disorder separate from ADHD/C (Diamond 2005 Dev Psychopathol 17:807-825; Milich et al. 2001 Clin Psychol Sci Pract 8:463-488). This article describes major findings in the area of inhibitory performance in ADHD and highlights recent research suggesting important areas of divergence between the subtypes. In particular, preliminary findings point to potential differences between the subtypes with respect to how children process important contextual information from the environment, such as preparatory cues that precede responses and rewarding or punishing feedback following behavior. These suggestive findings are discussed in the context of treatment implications, which could involve differential intervention approaches for each subtype targeted to the specific deficit profiles that characterize each group of children. Future research avenues aimed toward building a sound theoretical model of ADHD/I and a better understanding of its relation to ADHD/C are also presented. Specifically, investigators are encouraged to continue studying the complex interplay between inhibitory and attentional processes, as this area seems particularly promising in its ability to improve our understanding of the potentially distinct pathologies underlying the ADHD subtypes.


Interleukin-4 receptor signaling modulates neuronal network activity.
Evidence is emerging that immune responses not only play a part in the central nervous system (CNS) in diseases but may also be relevant for healthy conditions. We discovered a major role for the interleukin-4 (IL-4)/IL-4 receptor alpha (IL-4Rα) signaling pathway in synaptic processes, as indicated by transcriptome analysis in IL-4Rα-deficient mice and human neurons with/without IL-4 treatment. Moreover, IL-4Rα is expressed presynaptically, and locally available IL-4 regulates synaptic transmission. We found reduced synaptic vesicle pools, altered postsynaptic currents, and a higher excitatory drive in cortical networks of IL-4Rα-deficient neurons. Acute effects of IL-4 treatment on postsynaptic currents in wild-type neurons were mediated via PKCγ signaling release and led to increased inhibitory activity supporting the findings in IL-4Rα-deficient neurons. In fact, the deficiency of IL-4Rα resulted in increased network activity in vivo, accompanied by altered exploration and anxiety-related learning behavior; general learning and memory was unchanged. In conclusion, neuronal IL-4Rα and its presynaptic prevalence appear relevant for maintaining homeostasis of CNS synaptic function.


Efficacy of pre-emptive kidney transplantation for adults with end-stage kidney disease: a systematic review and meta-analysis.
Pre-emptive kidney transplantation (PEKT), i.e., transplantation performed before initiation of maintenance dialysis, is considered an ideal renal replacement therapy because there is no exposure to long-term dialysis therapy. Therefore, we summarized advantages/disadvantages of PEKT to assist in deciding whether kidney transplantation should be performed pre-emptively. This study was registered with PROSPERO, CRD42021269163. Observational studies comparing clinical outcomes between PEKT and non-PEKT were included; those involving only pediatric recipients or simultaneous multi-organ transplantations were excluded. The PubMed/MEDLINE, Cochrane Library, and Ichushi-Web databases were searched on 1 August 2021. Studies were pooled using the generic inverse-variance method with random effects model, and risk of bias was assessed using ROBINS-I. Seventy-six studies were included in the systematic review (sample size, 23-121,853; enrollment year, 1968-2019). PEKT patients had lower all-cause mortality (adjusted HR: 0.78 [95% CI 0.66-0.92]), and lower death-censored graft failure (0.81 [0.67-0.98]). Unadjusted RRs for the following outcomes were comparable between the two patient groups: cardiovascular disease, 0.90 (0.58-1.40); biopsy-proven acute rejection, 0.75 (0.55-1.03); cytomegalovirus infection, 1.04 (0.85-1.29); and urinary tract infection, 0.89 (0.61-1.29). Mean differences in post-transplant QOL score were comparable in both groups. The certainty of evidence for mortality and graft failure was moderate and that for other outcomes was very low following the GRADE classification. The present meta-analysis shows the potential benefits of PEKT, especially regarding patient and graft survival, and therefore PEKT is recommended for adults with end-stage kidney disease.


Structural studies on the major component of Gladiolus style mucilage, an arabinogalactan-protein.
The major component of the Gladiolus style mucilage was shown to be an arabinogalactan-protein. The arabinogalactan-protein was isolated from the style extract by affinity chromatography with tridacnin (the galactose-binding lectin from the clam Tridacna maxima) coupled to Sepharose 4B. The isolated arabinogalactan-protein represents 40% of the soluble style extract; it contains 90% (w/w) carbohydrate and 3% protein. The major monosaccharides of the carbohydrate component are galactose and arabinose, in the proportions 6:1. A component with a similar composition was also isolated from the crude extract by precipitation with the beta-glucosyl artifical carbohydrate antigen. The protein moiety of the arabinogalactan-protein remained associated with the carbohydrate after chromatography in urea, and has high contents of serine, glutamic acid, aspartic acid, glycine and alanine. The arabinogalactan-protein is apparently chemically homogeneous; it eluted as a single symmetrical peak from Sepharose 4B, and three fractions collected across the peak were structurally similar. Ultracentrifugal studies showed it to be polydisperse in the mol.wt. range 150 000--400 000. The information obtained from methylation analyses, oxalic acid and enzymic hydrolyses is consistent with a model having a beta 1 leads to 3 galactan backbone, branched through C(O)6 to beta 1 leads to 6 galactan side chains. The arabinose is exclusively present as terminal alpha-L-arabinofuranosyl residues. Enzymic removal of the arabinose residues resulted in a marked decrease in solubility of the molecule. The localization of the arabinogalactan-protein in the mucilage of the style canal was demonstrated cytochemically. The possible roles of the arabinogalactan-protein in relation to recognition of compatible pollen and pollen-tube growth are discussed.


Barrier and mechanical properties of milk protein-based edible films containing nutraceuticals.
Calcium caseinate (CC) and whey protein isolate (WPI) films were prepared to contain 5 or 10% Gluconal Cal (GC), a mixture of calcium lactate and gluconate, or 0.1 or 0.2% alpha-tocopheryl acetate (VE), respectively. The pH and viscosity of film-forming solutions and the water vapor permeability and tensile property of the films were determined using standard procedures. CC and WPI films have the capabilities to carry high concentration of GC or VE, but some of the film functionality might be compromised. Adding VE to CC and WPI films increased film elongation at break, whereas incorporating 0.2% VE decreased WVP of CC films and tensile strength of both CC and WPI films. Incorporation of GC reduced the tensile strength of CC films (P < 0.05), with 10% GC decreasing both elongation at break and WVP (P < 0.05). These types of films may be used for wrapping or coating to enhance the nutritional value of foods. The concentration of GC and VE added to the films must be carefully selected to meet required water barrier and mechanical properties of the films depending on their specific applications.


How Human Papillomavirus Replication and Immune Evasion Strategies Take Advantage of the Host DNA Damage Repair Machinery.
The DNA damage response (DDR) is a complex signalling network activated when DNA is altered by intrinsic or extrinsic agents. DDR plays important roles in genome stability and cell cycle regulation, as well as in tumour transformation. Viruses have evolved successful life cycle strategies in order to ensure a chronic persistence in the host, virtually avoiding systemic sequelae and death. This process promotes the periodic shedding of large amounts of infectious particles to maintain a virus reservoir in individual hosts, while allowing virus spreading within the community. To achieve such a successful lifestyle, the human papilloma virus (HPV) needs to escape the host defence systems. The key to understanding how this is achieved is in the virus replication process that provides by itself an evasion mechanism by inhibiting and delaying the host immune response against the viral infection. Numerous studies have demonstrated that HPV exploits both the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and rad3-related (ATR) DDR pathways to replicate its genome and maintain a persistent infection by downregulating the innate and cell-mediated immunity. This review outlines how HPV interacts with the ATM- and ATR-dependent DDR machinery during the viral life cycle to create an environment favourable to viral replication, and how the interaction with the signal transducers and activators of transcription (STAT) protein family and the deregulation of the Janus kinase (JAK)-STAT pathways may impact the expression of interferon-inducible genes and the innate immune responses.


The protein quality control system manages plant defence compound synthesis.
Jasmonates are ubiquitous oxylipin-derived phytohormones that are essential in the regulation of many development, growth and defence processes. Across the plant kingdom, jasmonates act as elicitors of the production of bioactive secondary metabolites that serve in defence against attackers. Knowledge of the conserved jasmonate perception and early signalling machineries is increasing, but the downstream mechanisms that regulate defence metabolism remain largely unknown. Here we show that, in the legume Medicago truncatula, jasmonate recruits the endoplasmic-reticulum-associated degradation (ERAD) quality control system to manage the production of triterpene saponins, widespread bioactive compounds that share a biogenic origin with sterols. An ERAD-type RING membrane-anchor E3 ubiquitin ligase is co-expressed with saponin synthesis enzymes to control the activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), the rate-limiting enzyme in the supply of the ubiquitous terpene precursor isopentenyl diphosphate. Thus, unrestrained bioactive saponin accumulation is prevented and plant development and integrity secured. This control apparatus is equivalent to the ERAD system that regulates sterol synthesis in yeasts and mammals but that uses distinct E3 ubiquitin ligases, of the HMGR degradation 1 (HRD1) type, to direct destruction of HMGR. Hence, the general principles for the management of sterol and triterpene saponin biosynthesis are conserved across eukaryotes but can be controlled by divergent regulatory cues.


Correlates of directiveness in the interactions of fathers and mothers of children with developmental delays.
Twenty preschool-age children with developmental delays and language impairment participated in this study, which compared fathers' and mothers' directiveness and parental stress. Similarities between fathers and mothers were found for turntaking control, response referents, and responses to the child's participation. However, fathers differed from mothers in two of the dimensions of directiveness examined: fathers used more response control and topic control than mothers. Both parents reported similarly low levels of child-related and parenting stress, but mothers perceived more stress than fathers related to the responsibilities associated with parenting a child with a handicap. Correlations between directiveness, child characteristics, and stress revealed that fathers used greater turntaking control and topic control with children who were developmentally less mature, whereas mothers used greater topic control with children who were less involved in interaction. Both fathers' and mothers' use of response control was positively related to stress. Implications for involving fathers in parent-focused intervention include screening father-child interactions before intervention, interpreting parent-child interaction styles in terms of their role in enhancing the child's social participation, and acknowledging the role of familial factors (such as stress) on interaction styles.


Further characterization of the interaction between the cytoskeletal proteins talin and vinculin.
The cytoskeletal protein talin, which is thought to couple integrins to F-actin, contains three binding sites (VBS1-VBS3) for vinculin, a protein implicated in the negative regulation of cell motility and whose activity is modulated by an intramolecular interaction between the vinculin head (Vh) and vinculin tail (Vt) domains. In the present study we show that recombinant talin polypeptides containing the three VBSs (VBS1, residues 498-636; VBS2, residues 727-965; and VBS3, residues 1943-2157) each bind tightly to the same or overlapping sites within vinculin(1-258). A short synthetic talin VBS3 peptide (residues 1944-1969) was sufficient to inhibit binding of a (125)I-labelled talin VBS3 polypeptide to vinculin(1-258), and NMR spectroscopy confirmed that this peptide forms a 1:1 complex in slow exchange with vinculin(1-258). Binding of the (125)I-labelled VBS3 polypeptide was markedly temperature dependent, but was not inhibited by 1 M salt or 10% (v/v) 2-methyl-2-propanol. Attempts to further define the talin-binding site within vinculin(1-258) using a gel-blot assay were unsuccessful, but near maximal talin-binding activity was retained by a construct spanning vinculin residues 1-131 in a yeast two-hybrid assay. Interestingly, the talin VBS3 polypeptide was a potent inhibitor of the Vh-Vt interaction, and the VBS3 synthetic peptide was able to expose the actin-binding site in intact vinculin, which is otherwise masked by the Vh-Vt interaction. The results suggest that under certain conditions, talin may be an effective activator of vinculin.


Natural history of benign multiple sclerosis: Clinical and HLA correlates in a Western Australian cohort.
Benign multiple sclerosis (BMS) is a controversial term that has been used for MS patients with minimal disability decades after disease onset. Herein, we evaluated disease status after 20 years in a Western Australian cohort defined as BMS based on an Expanded Disability Status Scale (EDSS) score ≤ 3.0 at 10 years from onset. MS patients with an EDSS score ≤ 3.0 at 10 years from onset and minimum of 20 years follow up were included in the study. The 20-year EDSS score was considered the primary outcome. Associations with demographic and clinical characteristics and HLA-DRB1 genotype were investigated. Among 120 patients with a benign course at 10 years, 78 (65%) remained benign at the 20-year follow up, but patients with an EDSS ≥ 2.5 were more likely to go on to develop more severe disability in the next decade. When considering factors associated with an increase in EDSS score ≤ 1 from 10 to 20 years, indicating limited progression, apart from the EDSS score at 10 years, poly-symptomatic presentation (p = 0.004) and cerebellar/brainstem mono-symptomatic presentation (p = 0.016) were independently associated with more rapid progression compared with other mono-symptomatic presentations. Carriage of the high risk HLA-DRB1*1501 allele was marginally associated with slower progression. In this geographically isolated MS cohort of predominantly Anglo-Celtic origin clinical progression in the benign MS group was similar to that in other published series from Western countries. These results are in keeping with the view that patients labeled as benign MS are part of a heterogeneous continuum of disease progression and do not possess unique clinical characteristics. Possible genetic determinants of a benign course warrant further investigation.


Disseminated Hormographiella aspergillata Infection with Lung and Brain Involvement after Allogenic Hematopoietic Stem-Cell Transplantation in a 54-Year-Old Man.
Hormographiella is a rare fungal pathogen in humans; however, case reports have described disseminated infection in immunocompromised hosts. This pathogen has been described to yield poor prognosis in patients who harbor it. Herein, we present a case report of autopsy-proven disseminated Hormographiella aspergillata infection, confirmed by DNA sequencing, in a patient experiencing a relapse of leukemia. This 54-year-old Caucasian man with chronic myelogenous leukemia (CML) that had been diagnosed in 1989, after having received a hematopoietic cell allotransplant from a compatible sibling donor, had B-cell lymphoid-blast phase of CML in April of 2013, with multiple relapses. His most recent relapse was in September of 2016, when bone marrow biopsy showed 90% blasts. The results of bronchoalveolar lavage (BAL) cultures were positive for filamentous fungus infection. The patient developed encephalopathy and worsening respiratory statusand tachycardia with flutter and hypotension, which resulted in his death. At autopsy, bilateral pleural effusions, multiple right pleural nodules, and subarachnoid hemorrhage were noted. Angioinvasive hyphal fungi were found in the right frontal lobe of the brain and the right upper lobe of the lung. Morphologically, the fungi had multiseptate, branching hyphae. The bronchoalveolar lavage specimen grew a fungus for which the colony morphologic characteristics and microscopic features were compatible with a Hormographiella species. H. aspergillata from the bronchoalveolar lavage was further identified by sequencing the D2 hypervariable region of the large-subunit (LSU) ribosomal DNA gene and the full internal transcribed spacer (ITS) regions.


Microglial tissue surveillance: The never-resting gardener in the developing and adult CNS.
Immunosurveillance by microglia is a dynamic process in the central nervous system (CNS) with versatile functions to maintain tissue homeostasis and provide immune defense. A tightly controlled microglia network throughout the CNS parenchyma facilitates efficient immunosurveillance, where each cell guards a certain tissue territory. Each cell is constantly surveilling its environment and the surrounding cells, screening for pathogens but also removing cell debris and metabolites, grooming neighboring cells and facilitating cellular crosstalk. In the absence of inflammation, this "tissue surveillance" by microglia presents an essential process for CNS homeostasis and development. In this review, we provide a summary on different tissue surveillance functions mediated by microglia, the underlying molecular machineries, and how defects, such as genetic mutations, can alter these surveillance mechanisms and cause disease onset.


Does the measure of economic disadvantage matter? Exploring the effect of individual and relative deprivation on intrauterine growth restriction.
This paper examines the relation between health, individual income, and relative deprivation. Three alternative measures of relative deprivation are described, Yitzhaik relative deprivation, Deaton relative deprivation, and log income difference relative deprivation, with attention to problems in measuring permanent disadvantage when the underlying income distribution is changing over time. We used data from the National Longitudinal Surveys of Youth, a US-based longitudinal survey, to examine the associations between disadvantage, measured cross-sectionally and aggregated over the life course, and intrauterine growth restriction (IUGR). We reject the hypotheses that any of the economic measures, whether permanent/contemporaneous or individual/relative, have different associations with IUGR in terms of sign and significance. There was some evidence that permanent economic disadvantage was associated with greater risk of IUGR than those on the corresponding contemporaneous measures. The fitted values from logistic regressions on each measure of disadvantage were compared with the two-way plots of the observed IUGR-income pattern. Deaton relative deprivation and log income difference tracked the observed probability of IUGR as a function of income more closely than the other two measures of relative deprivation. Finally, we examined the determinants of each measure of disadvantage. Observed characteristics in childhood and adulthood explained more of the variance in log income difference and Deaton relative deprivation than in the other two measures of disadvantage. They also explained more of the variance in permanent disadvantage than in the contemporaneous counterpart.


New species of Auritella (Inocybaceae) from Cameroon, with a worldwide key to the known species.
Two new species in the genus Auritella (Inocybaceae) are described as new from tropical rainforest in Cameroon. Descriptions, photographs, line drawings, and a worldwide taxonomic key to the described species of Auritella are presented. Phylogenetic analysis of 28S rDNA and rpb2 nucleotide sequence data suggests at least five phylogenetic species that can be ascribed to Auritella occur in the region comprising Cameroon and Gabon and constitute a strongly supported monophyletic subgroup within the genus. Phylogenetic analysis of ITS data supports the conspecificity of numerous collections attributed to the two new species as well as the monophyly of Australian species of Auritella. This work raises the known number of described species of Auritella to thirteen worldwide, four of which occur in tropical Africa, one in tropical India, and eight in temperate and tropical regions of Australia. This is the first study to confirm an ectomycorrhizal status of Auritella using molecular data.


Attention bias modification treatment augmenting effects on cognitive behavioral therapy in children with anxiety: randomized controlled trial.
Attention bias modification treatment (ABMT) is a promising novel treatment for anxiety disorders, but clinical trials have focused largely on stand-alone formats among adults. This randomized controlled trial examined the augmenting effects of threat-based ABMT on cognitive behavioral therapy (CBT) in clinically anxious youth. Sixty-three treatment-seeking children with anxiety disorder were randomly assigned to 1 of the following 3 treatment groups: ABMT + CBT; ABMT placebo + CBT; and CBT-alone. Participants in the 2 ABMT conditions received repeated training on dot-probe tasks either designed to shift attention away from threats (active) or designed to induce no changes in attention patterns (placebo). Primary outcome measures were frequency and severity of anxiety symptoms as determined by a clinician using a semi-structured interview. Self- and parent-rated anxiety measures and threat-related attention bias scores were also measured before and after treatment. Both the active and placebo ABMT groups showed greater reductions in clinician-rated anxiety symptoms than the CBT-alone group. Furthermore, only the active ABMT group showed significant reduction in self- or parent-rated anxiety symptoms. Finally, all groups showed a shift in attention patterns across the study, starting with a bias toward threat at baseline and shifting attention away from threat after treatment. Active and placebo ABMT might augment the clinical response to CBT for anxiety. This effect could arise from benefits associated with performing computer-based paradigms such as the dot-probe task. Given the absence of group differences in attention-bias changes during treatment, possible mechanisms and methodological issues underlying the observed findings are discussed. Clinical trial registration information-Augmenting Effects of ABMT on CBT in Anxious Children: A Randomized Clinical Trial; http://clinicaltrials.gov/; NCT01730625.


Living-donor liver transplant in 3 patients with Budd-Chiari syndrome: case report.
Budd-Chiari syndrome is a rare but life-threatening disorder characterized by obstruction of the hepatic venous outflow. Treatment depends on the underlying cause, the location, and extent of the obstruction, and the functional capacity of the liver. A stepwise therapeutic approach is commonly accepted. When all other therapy options are unsuccessful, or in case of end-stage liver disease, transplant should be considered. We present case reports of 3 patients with Budd-Chiari syndrome who underwent living-donor liver transplant. Characteristic features of Budd-Chiari syndrome, diagnostic and therapeutic interventions, complications, and overall outcomes are discussed. We believe that when a deceased donor graft is unavailable, a living-donor liver transplant can be a safe option for patients with end-stage liver disease associated with Budd-Chiari syndrome.


Exploring in vitro roles of siRNA in cardiovascular disease.
RNA interference (RNAi) is an adaptive defense mechanism through which double stranded RNAs silence cognate genes in a sequence-specific manner. It has been employed widely as a powerful tool in functional genomics studies, target validation and therapeutic product development. Similarly, the application of small interfering RNA (siRNA) to the silencing of the disease-causing genes involved in cardiovascular diseases has made great progress. In this overview, we attempt to provide a brief outline of the current understanding of the mechanism of RNAi and its potential application to the cardiovascular system, with particular emphasis on its ability to identify the pathophysiological function of genes related to several important cardiovascular disorders. The prospects of RNAi-based therapeutics, as well as the advantages and potential problems, are also discussed.


Multivariate dispersion as a measure of beta diversity.
Beta diversity can be defined as the variability in species composition among sampling units for a given area. We propose that it can be measured as the average dissimilarity from individual observation units to their group centroid in multivariate space, using an appropriate dissimilarity measure. Differences in beta diversity among different areas or groups of samples can be tested using this approach. The choice of transformation and dissimilarity measure has important consequences for interpreting results. For kelp holdfast assemblages from New Zealand, variation in species composition was greater in smaller holdfasts, while variation in relative abundances was greater in larger holdasts. Variation in community structure of Norwegian continental shelf macrobenthic fauna increased with increases in environmental heterogeneity, regardless of the measure used. We propose a new dissimilarity measure which allows the relative weight placed on changes in composition vs. abundance to be specified explicitly.


Punctuated equilibrium in a neontological context.
The theory of punctuated equilibrium, which proposes that biological species evolve rapidly when they originate rather than gradually over time, has sparked intense debate between palaeontologists and evolutionary biologists about the mode of character evolution and the importance of natural selection. Difficulty in interpreting the fossil record prevented consensus, and it remains disputed as to what extent gradual change in established species is responsible for phenotypic differences between species. Against the historical background of the concept of evolution concentrated in speciation events, we review attempts to investigate tempo and mode of evolution using present-day species since the introduction of the theory of punctuated equilibrium in 1972. We discuss advantages, disadvantages, and prospects of using neontological data, methodological advances, and the findings of some recent studies.


Effect of C/N ratios on nitrogen removal and microbial communities in the anaerobic baffled reactor (ABR) with an anammox-coupling-denitrification process.
Effects of different C/N (NO2 -N) ratios on nitrogen removal and microbial community structure were investigated using an anaerobic baffled reactor (ABR). Results indicated that the C/N ratio exerted an important effect on nitrogen removal in the anammox-coupling-denitrification process associated with the ABR. When the C/N ratio was 1.29, the ABR could achieve the highest total nitrogen (TN) removal efficiency of 99.9%. Most of TN was removed in the 1st and 2nd compartment, accounting for about 81.0-97.6% of total TN removal. The nitrogen removal resulted from the interaction among anammox, heterotrophic denitrificans, and other microbes within the ABR. The contribution of anammox to nitrogen removal varied from 6.8% to 32.4%. High-throughput MiSeq sequencing analyses revealed that the C/N ratio was one of the most important factors regulating the microbial community structure, and the predominant phylum changed from Proteobacteria to Chloroflexi with the elevated C/N ratio. In addition, the Candidatus Brocadia was the major anammox bacterium, and its percentage varied from 1.0-2.9% at day 9 to 2.8-9.1% at day 46.


Connecting the retina to the brain.
The visual system is beautifully crafted to transmit information of the external world to visual processing and cognitive centers in the brain. For visual information to be relayed to the brain, a series of axon pathfinding events must take place to ensure that the axons of retinal ganglion cells, the only neuronal cell type in the retina that sends axons out of the retina, find their way out of the eye to connect with targets in the brain. In the past few decades, the power of molecular and genetic tools, including the generation of genetically manipulated mouse lines, have multiplied our knowledge about the molecular mechanisms involved in the sculpting of the visual system. Here, we review major advances in our understanding of the mechanisms controlling the differentiation of RGCs, guidance of their axons from the retina to the primary visual centers, and the refinement processes essential for the establishment of topographic maps and eye-specific axon segregation. Human disorders, such as albinism and achiasmia, that impair RGC axon growth and guidance and, thus, the establishment of a fully functioning visual system will also be discussed.


Laparoscopic pyeloplasty: role of preoperative retrograde pyelography.
Laparoscopic dismembered pyeloplasty is a minimally invasive, safe and effective therapy for pelvi-ureteric junction obstruction with low morbidity, shorter convalescence and excellent outcomes. To maximize an efficacious outcome, minimally invasive treatment of this condition requires preoperative planning with adequate imaging, but the role of retrograde pyelography remains controversial. We present a report in which retrograde pyelography accurately contributed to the perioperative diagnosis of ureteral fibroepithelial polyps, subsequently altering surgical management.


Cholinergic component in the human pancreatic secretory response to intraintestinal oleate.
To determine the role of cholinergic reflexes on pancreatic secretory response to food, we studied the effect of atropine on amylase secretion in response to the octapeptide of cholecystokinin (CCK8) and to intraintestinal oleate. Four studies were done in six healthy volunteers. The duodenal content was aspirated by a double lumen tube while synthetic secretin (41 pmol/kg/h) was infused as a background in all the studies. Graded doses of CCK8 IV or 0.42 M oleate pH 9.4 at 25 ml/h into the intestine with and without atropine 1.8 mg were given on different days. CCK-like immunoreactivity (LI) in the plasma was measured by RIA during the intraintestinal oleate studies. CCK8 stimulated pancreatic enzyme secretion in a dose related fashion, an effect that was not modified by atropine. Intraintestinal oleate also stimulated pancreatic secretion and increased the CCK-LI in the plasma. Atropine significantly (p less than 0.05) decreased the pancreatic enzyme secretion before and during intraintestinal oleate, without effect on the CCK-LI levels. We conclude: (1) that the effect of exogenous CCK on pancreatic secretion of enzymes is not affected by atropine; (2) intraintestinal oleate stimulates pancreatic enzyme secretion significantly by an atropine-sensitive mechanism; (3) probably the atropine effect is a blockade of a cholinergic enteropancreatic reflex.


Pathogenesis of Autographa californica multiple nucleopolyhedrovirus in fifth-instar Anticarsia gemmatalis larvae.
We have investigated infection and pathogenesis of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) in Anticarsia gemmatalis (velvetbean caterpillar) larvae using a lacZ recombinant virus (AcMNPV-hsp70/lacZ) to track the temporal progression of infection in the midgut intestine and haemocoel. A. gemmatalis was highly resistant to fatal infection by occlusion bodies (OBs; LD(50)>5.5 x 10(5) OB) and budded virus (BV; LD(50)>3 x 10(5) BV) administered via oral and systemic routes, respectively. Orally administered occlusion-derived virus (ODV) efficiently attached and fused to midgut cells; however, high levels of infection-induced apoptosis limited infection in the midgut. Transcriptional analysis of AcMNPV genes expressed in the midgut of OB-inoculated A. gemmatalis larvae showed high levels of mRNA encoding the major capsid protein VP39 in the absence of immediate-early transactivator 1 (ie-1) expression. In the midgut, virus was efficiently transferred from infected midgut epithelial cells to nearby tracheolar cells and circulating haemocytes to initiate systemic infection in the haemocoel. However, haemocoelic BV did not efficiently disseminate infection and only cuticular epidermal cells displayed high levels of viral infection. Flow cytometry analysis of haemocytes isolated from BV-inoculated A. gemmatalis larvae showed low-level expression of the BV envelope protein GP64 on the cell surface, suggesting that A. gemmatalis haemocytes have a limited capacity for amplifying virus. These results show that AcMNPV is not an effective biological control agent for limiting crop damage caused by A. gemmatalis larvae.


[Role of the infection and inflammation in atherosclerosis development (literature review)].
ecent researches have shown that the atherosclerosis is a chronic inflammatory disease. In particular, chronic inflammation plays a key role in coronary artery plaque instability and subsequent occlusive thrombosis. Inflammatory and immune mechanisms, employing monocytes, innate receptors, cytokines are suggested to be involved in atherogenesis. Among the initiation pathways of atherogenesis are innate mechanisms, such as toll-like-receptors (TLRs). TLRs are expressed in the cardiovascular system and could thus be a key link between cardiovascular diseases and the immune system. Stimulation ofthese receptors results in the activation of a diversity of intracellular signal transduction pathways and the production of pro-inflammatory cytokines, which ultimately can contribute to atherosclerotic lesion development. Thus, bacterial endotoxin is a potential source of vascular inflammation and may be an important risk factor for atherosclerosis. Many prospective studies have shown independent associations between myocardial infarction and C-reactive protein, interleukin-6, fibrinogen, von Willebrandfactor, fibrin D-dimerand tissue plasminogen activator antigen. Numerous researches antiinflammatory therapies at an atherosclerosis, are inconsistent enough, however they allow to hope for success, in preventive maintenance and treatment cardiovascular events.


FAD/NADH Dependent Oxidoreductases: From Different Amino Acid Sequences to Similar Protein Shapes for Playing an Ancient Function.
Flavoprotein oxidoreductases are members of a large protein family of specialized dehydrogenases, which include type II NADH dehydrogenase, pyridine nucleotide-disulphide oxidoreductases, ferredoxin-NAD+ reductases, NADH oxidases, and NADH peroxidases, playing a crucial role in the metabolism of several prokaryotes and eukaryotes. Although several studies have been performed on single members or protein subgroups of flavoprotein oxidoreductases, a comprehensive analysis on structure-function relationships among the different members and subgroups of this great dehydrogenase family is still missing. Here, we present a structural comparative analysis showing that the investigated flavoprotein oxidoreductases have a highly similar overall structure, although the investigated dehydrogenases are quite different in functional annotations and global amino acid composition. The different functional annotation is ascribed to their participation in species-specific metabolic pathways based on the same biochemical reaction, i.e., the oxidation of specific cofactors, like NADH and FADH2. Notably, the performed comparative analysis sheds light on conserved sequence features that reflect very similar oxidation mechanisms, conserved among flavoprotein oxidoreductases belonging to phylogenetically distant species, as the bacterial type II NADH dehydrogenases and the mammalian apoptosis-inducing factor protein, until now retained as unique protein entities in Bacteria/Fungi or Animals, respectively. Furthermore, the presented computational analyses will allow consideration of FAD/NADH oxidoreductases as a possible target of new small molecules to be used as modulators of mitochondrial respiration for patients affected by rare diseases or cancer showing mitochondrial dysfunction, or antibiotics for treating bacterial/fungal/protista infections.


Molecularly specific detection of bacterial lipoteichoic acid for diagnosis of prosthetic joint infection of the bone.
Discriminating sterile inflammation from infection, especially in cases of aseptic loosening versus an actual prosthetic joint infection, is challenging and has significant treatment implications. Our goal was to evaluate a novel human monoclonal antibody (mAb) probe directed against the Gram-positive bacterial surface molecule lipoteichoic acid (LTA). Specificity and affinity were assessed in vitro. We then radiolabeled the anti-LTA mAb and evaluated its effectiveness as a diagnostic imaging tool for detecting infection via immunoPET imaging in an in vivo mouse model of prosthetic joint infection (PJI). In vitro and ex vivo binding of the anti-LTA mAb to pathogenic bacteria was measured with Octet, ELISA, and flow cytometry. The in vivo PJI mouse model was assessed using traditional imaging modalities, including positron emission tomography (PET) with [18F]FDG and [18F]NaF as well as X-ray computed tomography (CT), before being evaluated with the zirconium-89-labeled antibody specific for LTA ([89Zr]SAC55). The anti-LTA mAb exhibited specific binding in vitro to LTA-expressing bacteria. Results from imaging showed that our model could reliably simulate infection at the surgical site by bioluminescent imaging, conventional PET tracer imaging, and bone morphological changes by CT. One day following injection of both the radiolabeled anti-LTA and isotype control antibodies, the anti-LTA antibody demonstrated significantly greater (P < 0.05) uptake at S. aureus-infected prosthesis sites over either the same antibody at sterile prosthesis sites or of control non-specific antibody at infected prosthesis sites. Taken together, the radiolabeled anti-LTA mAb, [89Zr]SAC55, may serve as a valuable diagnostic molecular imaging probe to help distinguish between sterile inflammation and infection in the setting of PJI. Future studies are needed to determine whether these findings will translate to human PJI.


Meta-analysis of aberrant lymphatic drainage in recurrent breast cancer.
Sentinel node biopsy (SNB) in recurrent breast cancer offers targeted axillary staging compared with axillary lymph node dissection (ALND) or no treatment. The evidence for lymphatic mapping in recurrent breast cancer is reviewed, focusing on aberrant drainage and its implications for patient management. A meta-analysis of studies evaluating lymphatic mapping in recurrent breast cancer was performed. Outcomes included sentinel node identification, aberrant lymphatic pathways and metastatic node rates in aberrant drainage and ipsilateral axilla. Pooled odds ratios (ORs) and 95 per cent confidence intervals (c.i.) were estimated using fixed-effect analyses, or random-effects analyses in the event of statistically significant heterogeneity. Seven studies reported data on lymphatic mapping in 1053 patients with recurrent breast cancer. The intraoperative sentinel node identification rate was 59·6 (95 per cent c.i. 56·7 to 62·6) per cent, and significantly greater when the original axillary surgery was SNB compared with ALND (OR 2·97, 95 per cent c.i. 1·66 to 5·32). The rate of aberrant lymphatic drainage identification was 25·7 (23·0 to 28·3) per cent, and significantly greater when the original axillary surgery was ALND (OR 0·27, 0·19 to 0·38). The metastatic sentinel node rate was 10·4 (8·6 to 12·3) per cent, and a significantly greater metastatic nodal burden was identified in the ipsilateral axilla (OR 6·31, 1·03 to 38·79). Lymphatic mapping is feasible in recurrent breast cancer. It avoids ALND in over 50 per cent of patients who have undergone SNB, and allows the 4 per cent of patients with metastatically involved aberrant nodes to receive targeted surgical and adjuvant therapies.


Refining the content and design of an alcohol reduction app, Drink Less, to improve its usability and effectiveness: a mixed methods approach.
Background: Digital interventions have the potential to reduce alcohol consumption, although evidence on the effectiveness of apps is lacking. Drink Less is a popular, evidence-informed app with good usability, putting it in a strong position to be improved upon prior to conducting a confirmatory evaluation. This paper describes the process of refining Drink Less to improve its usability and likely effectiveness. Methods: The refinement consisted of three phases and involved qualitative and quantitative (mixed) methods: i) identifying changes to app content, based on findings from an initial evaluation of Drink Less, an updated review of digital alcohol interventions and a content analysis of user feedback; ii) designing new app modules with public input and a consultation with app developers and researchers; and iii) improving the app's usability through user testing. Results: As a result of the updated review of digital alcohol interventions and user feedback analysis in Phase 1, three new modules: 'Behaviour Substitution', 'Information about Antecedents' and 'Insights', were added to the app. One existing module - 'Identity Change' - was removed based on the initial evaluation of Drink Less. Phases 2 and 3 resulted in changes to existing features, such as improving the navigational structure and onboarding process, and clarifying how to edit drinks and goals. Conclusions: A mixed methods approach was used to refine the content and design of Drink Less, providing insights into how to improve its usability and likely effectiveness. Drink Less is now ready for a confirmatory evaluation.


Increased Qa-m7 antigen expression is characteristic of primitive hemopoietic progenitors in regenerating marrow.
Developmentally early murine hemopoietic progenitor cells of high proliferative potential (HPP-CFC), which are detectable in clonal agar culture in the presence of the lineage-specific hemopoietic growth factor, colony-stimulating factor-1 (CSF-1) plus hemopoietin-1 (H-1), or interleukin 3 (IL 3), express relatively high levels of the Qa-m7 antigenic determinant. This determinant is progressively lost during differentiation, and the more committed progenitors which grow in the presence of CSF-1 alone are essentially devoid of Qa-m7. Significant increases in both the proportion of Qa-m7-positive myeloid cells and the level of Qa-m7 antigen expression have been observed in bone marrow cells regenerating after the administration of the cytotoxic agent 5-fluorouracil (5-FU). By exploiting this increase in Qa-m7 antigen expression during regeneration and the HPP-CFC-sparing properties of 5-FU, we have been able to enrich HPP-CFC from marrows 8 days post-5-FU treatment (FU8d) to purities of greater than 20%. Furthermore, discontinuous gradient centrifugation and fluorescence-activated cell sorting of FU8d bone marrow cells on the basis of their light-scattering properties and Qa-m7 expression has unmasked a further subset of HPP-CFC which strictly requires the combined stimulus of three hemopoietic growth factors (H-1, IL 3, and CSF-1) for clonal growth. These highly enriched subsets of HPP-CFC are either identical to or co-fractionate with transplantable multipotential hemopoietic progenitors capable of reconstituting the hemopoietic system of lethally irradiated mice. Up to one in three cells in these highly enriched fractions is an HPP-CFC, and up to one in two cells may be CFU-S assayed 13 days post-transplantation. In addition, these fractions contain progenitors capable of reconstituting the platelet, erythroid, and myeloid compartments of the marrow.


Haemozoin as a marker of placental parasitization.
Both Plasmodium vivax and P. falciparum malaria can cause the delivery of low birthweight babies. In this report, we have quantitated haemozoin levels in placentas from women living on the Thai-Burmese border in a region of low transmission for both P. falciparum and P. vivax malaria from June 1995 to January 2000. P. falciparum malaria infections during pregnancy lead to the accumulation of haemozoin (malaria pigment) in the placenta, especially in infections near term and in primigravid pregnancies. Haemozoin concentration was not associated with adverse birth outcomes. Women with P. vivax infections during pregnancy do not have measurable levels of placental haemozoin suggesting that P. vivax-infected erythrocytes do not accumulate in the placenta as much as P. falciparum-infected ones.


Immune suppression and the cost of reproduction in the ground cricket, Allonemobius socius.
One of the most common life history trade-offs in animals is the reduction in survivorship with increasing reproductive effort. Despite the prevalence of this pattern, its underlying physiological mechanisms are not well understood. Here we test the hypothesis that immune suppression mediates this phenotypic trade-off by manipulating reproductive effort and measuring immune function and mortality rates in the striped ground cricket, Allonemobius socius. Because A. socius males provide females with a hemolymph-based nuptial gift during copulation, and many structural components of immunity reside in the hemolymph, we also predicted that sexual selection may differentially affect how disease resistance evolves in males and females. We found that an increased mating effort resulted in a reduced immune ability, coupled with an increased rate in age-specific mortality for both sexes. Thus, immune suppression appears to be a link between reproductive effort and cost in this system. In addition, males and females appeared to differentially invest in several aspects of immunity prior to mating, with males exhibiting a higher concentration of circulating hemocytes and a superior bacterial defense capability. This pattern may be the result of previously established positive selection on gift size due to its affect on female fecundity. In short, female choice for larger gifts may lead to a sexually dimorphic immune ability.


Feature selection based on mutual information and redundancy-synergy coefficient.
Mutual information is an important information measure for feature subset. In this paper, a hashing mechanism is proposed to calculate the mutual information on the feature subset. Redundancy-synergy coefficient, a novel redundancy and synergy measure of features to express the class feature, is defined by mutual information. The information maximization rule was applied to derive the heuristic feature subset selection method based on mutual information and redundancy-synergy coefficient. Our experiment results showed the good performance of the new feature selection method.


The kidney triggers graft-versus-host disease in experimental combined transplantation of kidney and stem cell-enriched peripheral leukocytes.
As a preclinical step to human studies with combined stem cell-enriched peripheral leukocytes and organ transplantation from the same donor, a series of studies in rats was undertaken. These studies indicated that Lewis rats infused intravenously with major histocompatibility complex-incompatible (from Brown-Norway rats), stem cell-enriched peripheral leukocyte preparation alone never developed graft-versus-host disease (GHVD). However, GVHD invariably manifested in all animals a few days after the kidney was transplanted in rats that had been previously primed with stem cell-enriched peripheral leukocytes from the same kidney donor strain. GVHD was prevented by substituting the crude preparation of stem cell-enriched peripheral leukocytes with a purified preparation that was almost completely free of T lymphocytes. However, in these latter experiments all rats rejected their kidney graft within 10 days from the surgery. In rats previously given the crude stem cell-enriched peripheral leukocyte preparation, perioperative administration of the fusion protein CTLA4lg also prevented GVHD and prolonged kidney graft survival up to 106 to 175 days. By contrast, animals with kidney transplants, which were given CTLA4lg without stem cells, rejected their grafts within 35 days. All together, these findings may possibly contribute to the creation of rationally designed strategies of combining organ and bone marrow from the same donor to enhance mixed chimerism and prolong survival after organ transplantation.


Quarter of a century of change: caries experience in Australian children, 1977-2002.
The establishment of the evaluation programme of the Australian School Dental Scheme has led to continuous surveillance of child oral health extending from 1977 to the present day. The aims of this study were to examine the state of child oral health in Australia in 2002 and to explore longer term trends across the quarter of a century of recorded surveillance activity. Caries data were obtained for children who were enrolled in the School Dental Services of each state and territory for the years 1977-2002. Data collection derived from routine examinations within the School Dental Service with oral examinations carried out by dentists and dental therapists. There were considerable declines in caries experience between 1977 and the mid to late 1990s, with mean decayed, missing and filled deciduous teeth (dmft) for 6-year-old children decreasing from over 3 in 1977 to approximately 1.6 in 1996, and permanent 12-year-old decayed, missing and filled teeth (DMFT) decreasing from 4.8 in 1977 to 0.89 in 1998. However, since the mid to late 1990s, deciduous 6-year-old dmft has increased by 24 per cent and 12-year-old DMFT has increased by almost 15 per cent. Reductions in caries experience of those children with the most disease have also ceased, and between 1999 and 2002 an increase in the Significant Caries Index occurred. Improvements in the oral health of Australian children halted during the mid 1990s, after which caries experience has increased. It is important that we understand the changes taking place and their causes, so that action can be taken to halt any further possible declines in child oral health.


Suicidal behaviour: a continuing cause for concern.
There is an increase in suicidal behaviour in the western world providing a major challenge to health care providers. There is an increase in the number of suicides among elderly people in Europe. The problem of suicides among elderly people is in itself a social problem, not solely a medical one. The general practitioner may be the only source of social contact for the elderly. Elderly individuals often present their problems to doctors as somatic complaints; these complaints must not be taken at face value but understood as expressions of psychosocial and social distress. The rise in suicide rates among young people is also alarming. The warning signs of escalating distress in adolescents are known and a treatment programme coordinating medical initiatives, such that recidivism of suicidal behaviour in adolescents is reduced, is necessary. The general practitioner is urged to sense when the problem presented by the individual stems from a source which is predominantly social, and to suggest an appropriate solution which may entail a family intervention. The general practitioner is in the front line of treatment and he or she may be better advised to treat both the social situation and the individual person in cases of attempted suicide. Medical initiatives must incorporate aspects of social medicine whereby community solutions are found for the management of individual distress. Social disruption, isolation, conflict and neglect are the doors to the house of despair. While medicine must respond to those who enter that house, it is the social level at which we must be the architects of change. People will die.(ABSTRACT TRUNCATED AT 250 WORDS)


Syncope and electrocardiogram.
Suspected transient loss of consciousness and syncope are common causes of hospitalization in older patients. Arrhythmias are the most common cardiac causes of syncope. Although a number of instrumental diagnostic procedures are usually routinely performed in patients with suspected syncope, a 12-lead electrocardiogram (ECG) is the only instrumental test recommended for the initial evaluation of these patients. In this paper current literature on this topic will be reviewed, including ECG diagnostic criteria and findings suggestive of cardiac syncope. The ECG may disclose an arrhythmia associated with a high likelihood of syncope, avoiding further evaluations and permitting institution of specific treatment in 7% of patients referred to emergency department. When the cause of syncope remains uncertain after initial evaluation the next step is to assess the risk of major cardiovascular events or sudden cardiac death. An abnormal ECG selected patients with high probability of cardiac syncope. ECG diagnostic criteria and ECG findings suggesting arrhythmic syncope are presented. Indications and potential clinical implications of ECG monitoring will be discussed too. A careful, well-conducted medical history focused on the suspected syncopal event is crucial for the diagnosis. In this setting, the ECG is a mandatory diagnostic tool which, although normal in the majority of patients of syncope, has the potential to identify patients with high likelihood of cardiac syncope due to arrhythmic or cardiopulmonary disorder.


Targeting of an abundant cytosolic form of the protein import receptor at Toc159 to the outer chloroplast membrane.
Chloroplast biogenesis requires the large-scale import of cytosolically synthesized precursor proteins. A trimeric translocon (Toc complex) containing two homologous GTP-binding proteins (atToc33 and atToc159) and a channel protein (atToc75) facilitates protein translocation across the outer envelope membrane. The mechanisms governing function and assembly of the Toc complex are not yet understood. This study demonstrates that atToc159 and its pea orthologue exist in an abundant, previously unrecognized soluble form, and partition between cytosol-containing soluble fractions and the chloroplast outer membrane. We show that soluble atToc159 binds directly to the cytosolic domain of atToc33 in a homotypic interaction, contributing to the integration of atToc159 into the chloroplast outer membrane. The data suggest that the function of the Toc complex involves switching of atToc159 between a soluble and an integral membrane form.


Crystal structures of HLA-A*0201 complexed with antigenic peptides with either the amino- or carboxyl-terminal group substituted by a methyl group.
The crystal structures of class I major histocompatibility complex (MHC) molecules complexed with antigenic peptides revealed a network of hydrogen bonds between the charged amino- and carboxyl-termini of the peptides and conserved MHC residues at both ends of the peptide binding site. These interactions were shown to contribute substantially to the stability of class I MHC/peptide complexes by thermal denaturation studies using synthetic peptides in which either the amino- or carboxyl-terminal group is substituted by a methyl group. Here we report crystal structures of HLA-A*0201 complexed with these terminally modified synthetic peptides showing that they adopt the same bound conformation as antigenic peptides. A number of variations in peptide conformation were observed for the terminally modified peptides, including in one case, a large conformational difference in four central peptide residues that is apparently caused by the lattice contact. This is reminiscent of the way binding a T-cell receptor changed the conformation of central residues of an MHC-bound peptide. The structures determined identify which conserved hydrogen bonds are eliminated in terminally substituted peptides and suggest an increased energetic importance of the interactions at the peptide termini for MHC-peptide stability.


The effects of magnesium sulfate on blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats.
The study was performed to evaluate whether magnesium sulfate could alter the degree of disruption of the blood-brain barrier (BBB) caused by hyperosmotic mannitol. Wistar adult female rats were infused with 25% mannitol into the left internal carotid artery. Each animal received intraperitoneally a 300 mg/kg loading dose of magnesium sulfate, dissolved in 0.9% saline, followed by a further 100 mg/kg dose. In the other group, intracarotid infusion of magnesium sulfate was performed at a dose of 150 mg/kg 10 min before mannitol administration. Evans blue (EB) dye was used as a marker of BBB disruption. The measured serum glucose and magnesium levels increased after mannitol and/or magnesium administration when compared with their initial values before treatment (P < 0.01). Water content of the left hemisphere was significantly increased by hyperosmotic mannitol (P < 0.01). The increased water content in the mannitol-perfused hemisphere was significantly decreased by magnesium treatment (P < 0.05). The content of EB dye in the mannitol-perfused hemisphere markedly increased when compared with the right hemisphere of the same brain (P < 0.01). The EB dye content in the mannitol-perfused hemisphere following both intraperitoneal and intraarterial administration of magnesium decreased when compared with mannitol alone (P < 0.01). We conclude that although magnesium sulfate administration by both intracarotid arterial and intraperitoneal routes attenuates BBB disruption caused by hyperosmolar mannitol, particularly intraperitoneal route of magnesium sulfate administration may provide a useful strategy to limit the transient osmotic opening of the BBB.


Longitudinal associations between case management and supportive services use among black and Latina HIV-positive women in New York City.
The literature analyzing the relationship between case management and supportive service use longitudinally among African American and Latina HIV-positive women is limited. This retrospective analysis of participant case management, supportive service, and medical charts sought to examine both descriptive and relational data on use of case management and supportive services over a 2-year period from 2002 to 2005 and to analyze moderating person- level or institution-level factors. The analyzed case management, supportive service, and medical charts revealed that participants interacted with their case manager four times and received 3.6 supportive services per month. Transportation, primary healthcare/medical specialists, and support groups were the services most used, with rates ranging from 70% to 80%. Using hierarchical linear modeling (HLM), the unconditional growth models showed that case management and supportive service use patterns remained constant over the 24-month period. Additionally, the multivariate unconditional model suggests a significant positive relationship between case management and supportive services. No moderation was indicated in the association between case management and supportive service use by person-level (e.g., mental illness, substance use) and institution-level (i.e., service delivery model) factors. Participants use supportive and case management services in a similar manner based on individual need. This synergistic relationship suggests that increases in either may result in retaining women in care. Implications for service delivery point to the need for skills building training for case managers, outreach workers, or system navigators to assist with short-term goals of establishing rapport and maintaining the client relationship, as this may lead to HIV-positive women accessing services. Additionally, outreach and engagement strategies need to be developed for those who typically underuse these services.


Tetracycline resistance in Moraxella (Branhamella) catarrhalis: demonstration of two clonal outbreaks by using pulsed-field gel electrophoresis.
Two tetracycline-resistant (Tcr) Moraxella (Branhamella) catarrhalis strains from England were compared with two previously characterized Tcr Texas strains. Both pairs carried the Tet B determinant, which was nontransferable. Pulsed-field gel electrophoresis of their genomic DNA restriction fragments demonstrated that the strains from the same area were identical (clonal); however, the Texas and English strains differed from each other.


[Genesis and extension of intraductal papillomas of the breast--a three-dimensional morphological study].
Graphic reconstruction of semi-serially sectioned breast specimens allowed a three-dimensional observation of intraductal proliferative lesions and their growth characteristics. Ten surgical specimens with intraductal papillomas obtained by microdochectomy were subjected to this study, and the primary site and extending behavior of papillomas were analysed. The results indicated: (1) In seven out of the ten cases papillomas appeared to arise from terminal duct lobular unit (TDLU) as multiple foci three-dimensionally independent of each other. (2) Secondary ductal involvement by multiple papillomas attained to as far as subsegmental or segmental level. (3) On the other hand solitary papilloma arose from segmental duct without involving TDLU. (4) Both solitary and multiple papillomas transformed and distorted the duct system while sustaining its basically arborescent pattern. (5) Duct papillomatosis, situated within TDLU, was often proved to be connected with multiple papillomas in more proximal ducts, and therefore was regarded as a prepapillomatous lesion. (6) Retention cysts associated with multiple papillomas were accounted for by intraductal proliferations obstructing outflow tracts.


[Operations in injuries and strictures of bile ducts].
Analysis of surgical treatment of 336 patients with cicatricial strictures and iatrogenic external fistulas of extrahepatic bile ducts is presented. The causes of these complications were intrasurgical injuries during cholecystectomy (n=302), resection of the stomach (n=21) and echinococcectomy (n=13). In all the cases correction of water-electrolytic balance, treatment and prophylaxis of hepatic and renal insufficiency, control of anaerobic infection were carried out before and after surgery. Restorative operations were performed in 31 (9.2%) patients, reconstructive surgeries -- in 305 (90.7%). Recurrence of the stricture required surgical intervention in 38 (11,3%) patients. Various postoperative complications were diagnosed in 119 (35.4%) patients, 26 (7.7%) patients died. The main causes of death were insufficiency of anastomotic sutures, intoxication, hepatic and renal insufficiency due to purulent cholangitis and cholangiolytic abscesses of the liver.


Perioperative Management and In-Hospital Outcomes After Minimally Invasive Repair of Pectus Excavatum: A Multicenter Registry Report From the Society for Pediatric Anesthesia Improvement Network.
There are few comparative data on the analgesic options used to manage patients undergoing minimally invasive repair of pectus excavatum (MIRPE). The Society for Pediatric Anesthesia Improvement Network was established to investigate outcomes for procedures where there is significant management variability. For our first study, we established a multicenter observational database to characterize the analgesic strategies used to manage pediatric patients undergoing MIRPE. Outcome data from the participating centers were used to assess the association between analgesic strategy and pain outcomes. Fourteen institutions enrolled patients from June 2014 through August 2015. Network members agreed to an observational methodology where each institution managed patients based on their institutional standards and protocols. There was no requirement to standardize care. Patients were categorized based on analgesic strategy: epidural catheter (EC), paravertebral catheter (PVC), wound catheter (WC), no regional (NR) analgesia, and intrathecal morphine techniques. Primary outcomes, pain score and opioid consumption by postoperative day (POD), for each technique were compared while adjusting for confounders using multivariable modeling that included 5 covariates: age, sex, number of bars, Haller index, and use of preoperative pain medication. Pain scores were analyzed using repeated-measures analysis of variance with Bonferroni correction. Opioid consumption was analyzed using a multivariable quantile regression. Data were collected on 348 patients and categorized based on primary analgesic strategy: EC (122), PVC (57), WC (41), NR (120), and intrathecal morphine (8). Compared to EC, daily median pain scores were higher in patients managed with PVC (POD 0), WC (POD 0, 1, 2, 3), and NR (POD 0, 1, 2), respectively (P < .001-.024 depending on group). Daily opioid requirements were higher in patients managed with PVC (POD 0, 1), WC (POD 0, 1, 2), and NR (POD 0, 1, 2) when compared to patients managed with EC (P < .001). Our data indicate variation in pain management strategies for patients undergoing MIRPE within our network. The results indicate that most patients have mild-to-moderate pain postoperatively regardless of analgesic management. Patients managed with EC had lower pain scores and opioid consumption in the early recovery period compared to other treatment strategies.


Enriched Marine Oil Supplement Increases Specific Plasma Specialized Pro-Resolving Mediators in Adults with Obesity.
Specialized pro-resolving mediators (SPMs), synthesized from PUFAs, resolve inflammation and return damaged tissue to homeostasis. Thus, increasing metabolites of the SPM biosynthetic pathway may have potential health benefits for select clinical populations, such as subjects with obesity who display dysregulation of SPM metabolism. However, the concentrations of SPMs and their metabolic intermediates in humans with obesity remains unclear. The primary objective of this study was to determine if a marine oil supplement increased specific metabolites of the SPM biosynthetic pathway in adults with obesity. The second objective was to determine if the supplement changed the relative abundance of key immune cell populations. Finally, given the critical role of antibodies in inflammation, we determined if ex vivo CD19 + B-cell antibody production was modified by marine oil intervention. Twenty-three subjects [median age: 56 y; BMI (in kg/m2): 33.1] consumed 2 g/d of a marine oil supplement for 28-30 d. The supplement was particularly enriched with 18-hydroxyeicosapentaenoic (HEPE), 14-hydroxydocosahexaenoic acid (14-HDHA), and 17-HDHA. Blood was collected pre- and postsupplementation for plasma mass spectrometry oxylipin and fatty acid analyses, flow cytometry, and B-cell isolation. Paired t-tests and Wilcoxon tests were used for statistical analyses. Relative to preintervention, the supplement increased 6 different HEPEs and HDHAs accompanied by changes in plasma PUFAs. Resolvin E1 and docosapentaenoic acid-derived maresin 1 concentrations were increased 3.5- and 4.7-fold upon intervention, respectively. The supplement did not increase the concentration of D-series resolvins and had no effect on the abundance of immune cells. Ex vivo B-cell IgG but not IgM concentrations were lowered postsupplementation. A marine oil supplement increased select SPMs and their metabolic intermediates in adults with obesity. Additional studies are needed to determine if increased concentrations of specific SPMs control the resolution of inflammation in humans with obesity. This trial was registered at clinicaltrials.gov as NCT04701138.


Steatosis as a risk factor in liver surgery.
To review present knowledge of the influence of hepatic steatosis in liver surgery as derived from experimental and clinical studies. Hepatic steatosis is the most common chronic liver disease in the Western world, and it is associated with obesity, diabetes, and metabolic syndrome. Fatty accumulation affects hepatocyte homeostasis and potentially impairs recovery of steatotic livers after resection. This is reflected clinically in increased mortality and morbidity after liver resection in patients with any grade of steatosis. Because of the epidemic increase of obesity, hepatic steatosis will play an even more significant role in liver surgery. A literature review was performed using MEDLINE and key words related to experimental and clinical studies concerning steatosis. Experimental studies show the increased vulnerability of steatotic livers to various insults, attributed to underlying metabolic and pathologic derangements induced by fatty accumulation. In clinical studies, the severity of steatosis has an important impact on patient outcome and mortality. Even the mildest form of steatosis increases the risk of postoperative complications. Hepatic steatosis is a major factor determining patient outcome after surgery. Further research is needed to clarify the clinical relevance of all forms and severity grades of steatosis for patient outcome. Standardized grading and diagnostic methods need to be used in future clinical trials to be able to compare outcomes of different studies.


Differentiating population stratification from genotyping error using family data.
Identifying population stratification and genotyping error are important for candidate gene association studies using the Transmission Disequilibrium Test (TDT). Although the TDT retains the prespecified Type I error in the presence of population stratification, the test may have decreased power in the presence of population stratification. Genotyping error can also cause the TDT to have an elevated Type I error. Differentiating population stratification from genotyping error remains a challenge for geneticists. Both genotyping error and population stratification can result in an increase in the observed homozygosity of a sample relative to that expected assuming Hardy-Weinberg Equilibrium (HWE). We show that when family data are available, even if a limited number of markers are genotyped, evaluating the markers that show statistically significant deviation from HWE with the Mating Type Distortion Test (MTDT)--a test based on the mating type distribution--can reliably differentiate genotyping error from population stratification. We simulate data based on several models of genotyping error in previously published literature, and show how this method could be used in practice to assist in differentiating population stratification from systematic genotyping error.


Non-opsonic phagocytosis of Trichophyton mentagrophytes arthroconidia by human neutrophils in vitro.
A non-opsonic mechanism of binding and phagocytosis by human neutrophils of Trichophyton mentagrophytes arthroconidia is described. This was in direct contrast to the complement dependency of Candida albicans phagocytosis. Both serum complement and specific antibody to T. mentagrophytes promoted maximal phagocytosis (61% and 40% of neutrophils, respectively, contained arthroconidia). Increasing the ratio of arthroconidia to neutrophils did not increase non-opsonic phagocytosis (18-26%). Phagocytosis of arthroconidia exposed to trypsin in the absence of opsonin was not affected (18%). However, proteinase and chitinase reduced the level of non-opsonic and opsonic phagocytosis to negligible levels (6.3% and 4.5%, respectively). When mannose was added to neutrophils, mannose receptors on the phagocyte membrane were partially blocked when arthroconidia were opsonised, but this did not reduce the level of non-opsonic phagocytosis. The non-opsonic mechanism proposed here may have direct relevance in skin sites poor in opsonins.


Derivatives of N,N-bis(alpha, alpha, alpha-trifluoro-m-tolyl)amine.
Amongst a series of novel derivatives of N,N-bis-(alpha, alpha, alpha-trifluoro-m-tolyl)amine, several were found to possess antiinflammatory, hypotensive, antibacterial and antifungal activity. The synthesis of these compounds is described and their biological properties are discussed.


Thymoquinone anticancer activity is enhanced when combined with royal jelly in human breast cancer.
Breast cancer is the most common cause of the majority of cancer-related deaths in women, among which triple-negative breast cancer is the most aggressive type of breast cancer diagnosed with limited treatment options. Thymoquinone (TQ), the main bioactive constituent of Nigella sativa, has been extensively studied as a potent anticancer molecule against various types of cancers. Honeybee products such as the royal jelly (RJ), the nutritive secretion fed to honeybee queens, exhibit a variety of biological activities besides its anticancer effect. However, the anticancer activity of the combination of TQ and RJ against breast cancer is still unknown. To investigate cytotoxicity of RJ in FHs 74 Int cells and the anticancer effects of TQ, RJ, and their combinations in the MDA-MB-231 cell line. Cells were treated with TQ, RJ, and their combinations for 24 h. Using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, we determined the half-maximal inhibitory concentration of TQ. Trypan blue and 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays were then performed to assess the cell viability in response to different treatment conditions. Cell death and cycle regulation were investigated using propidium iodide deoxyribonucleic acid staining followed by flow cytometry in response to a single dose of TQ, RJ, and their combination. Immunostaining for cleaved caspase 3 and Ki67 expression was used to determine apoptosis induction and changes in cell proliferation. TQ alone inhibited cell viability in a dose-dependent manner at concentrations below and above the half-maximal inhibitory concentration. RJ exhibited relatively nontoxic effects against MDA-MB-231 cells and FHs 74 Int small intestinal cells at concentrations below 5 µg/mL. High doses of RJ (200 µg/mL) had greater toxicity against MDA-MB-231 cells. Interestingly, the inhibition of cell viability was most pronounced in response to 15 µmol/L TQ and 5 µg/mL RJ. A dose of 15 µmol/L TQ caused a significant increase in the PreG1 population, while a more pronounced effect on cell viability inhibition and PreG1 increase was observed in response to TQ and RJ combinations. TQ was the main inducer of caspase 3-dependent apoptosis when applied alone and in combination with RJ. In contrast, no significant regulation of Ki67 expression was observed, indicating that the decrease in cell viability was due to apoptosis induction rather than to inhibition of cell proliferation. This study is the first to report enhanced anticancer effects of TQ and RJ combination against MDA-MB-231 breast cancer cells, which could confer an advantage for cancer therapy.


The impact of anti-mould prophylaxis on Aspergillus PCR blood testing for the diagnosis of invasive aspergillosis.
The performance of the galactomannan enzyme immunoassay (GM-EIA) is impaired in patients receiving mould-active antifungal therapy. The impact of mould-active antifungal therapy on Aspergillus PCR testing needs to be determined. To determine the influence of anti-mould prophylaxis (AMP) on the performance of PCR blood testing to aid the diagnosis of proven/probable invasive aspergillosis (IA). As part of the systematic review and meta-analysis of 22 cohort studies investigating Aspergillus PCR blood testing in 2912 patients at risk of IA, subgroup analysis was performed to determine the impact of AMP on the accuracy of Aspergillus PCR. The incidence of IA was calculated in patients receiving and not receiving AMP. The impact of two different positivity thresholds (requiring either a single PCR positive test result or ≥2 consecutive PCR positive test results) on accuracy was evaluated. Meta-analytical pooling of sensitivity and specificity was performed by logistic mixed-model regression. In total, 1661 (57%) patients received prophylaxis. The incidence of IA was 14.2%, significantly lower in the prophylaxis group (11%-12%) compared with the non-prophylaxis group (18%-19%) (P < 0.001). The use of AMP did not affect sensitivity, but significantly decreased specificity [single PCR positive result threshold: 26% reduction (P = 0.005); ≥2 consecutive PCR positive results threshold: 12% reduction (P = 0.019)]. Contrary to its influence on GM-EIA, AMP significantly decreases Aspergillus PCR specificity, without affecting sensitivity, possibly as a consequence of AMP limiting the clinical progression of IA and/or leading to false-negative GM-EIA results, preventing the classification of probable IA using the EORTC/MSGERC definitions.


Frailty in Chile: Development of a Frailty Index Score Using the Chilean National Health Survey 2016-2017.
The Frailty Index (FI) is used to quantify and summarize vulnerability status in people. In Chile, no development and assessment of a FI have been explored. To develop and evaluate a FI using representative data from Chilean adults aged 40 years and older stratified by sex. Cross-sectional study. National representative data from the Chilean National Health Survey 2016-2017 (CNHS 2016-2017). 3,036 participants older than 40 years with complete data for all variables. A 49-item FI was developed and evaluated. This FI included deficits from comorbidities, functional limitations, mental health status, physical activity, anthropometry, medications, and falls. A score between 0 and 1 was calculated for each person. Descriptive statistics and linear regression models were employed to evaluate the FI's performance in the population. Comparative analyses were carried out to evaluate the FI score by age (1<60 and ≥ 60 years). The mean FI score was 0.15 (SD:0.09), with a 99% upper limit of 0.46. Scores were greater in women than men (0.17 [SD:0.09]) vs. 0.12 [0.08]); in people older than 80 years (0.22 [0.11]), and in people with ≤8 years of education (0.18 [0.10]) compared with those with >12 years (0.12 [0.08]). The average age-related increase in the FI was 2.3%. When a cut-off point ≥ 0.25 was applied, the prevalence of frail individuals was 11.8% (95% CI: 10.0 to 13.8) in the general population. The prevalence was higher in women 15.9% [95% CI: 13.3 to 18.9] than men 7.4% [95% CI: 5.3 to 10.1]. In a comparative analysis by age, higher FI mean scores and prevalence of frail were observed in people ≥ 60 than younger than 60. The mean FI score and frailty prevalence were higher in women than men, in people with fewer years of formal education, and incremented markedly with age. This FI can be used for early detection of frailty status focusing on women and middle-aged people as a strategy to delay or prevent frailty-related consequences.


Identification of spatiotemporal nutrient patterns in a coastal bay via an integrated k-means clustering and gravity model.
This study presents an integrated k-means clustering and gravity model (IKCGM) for investigating the spatiotemporal patterns of nutrient and associated dissolved oxygen levels in Tampa Bay, Florida. By using a k-means clustering analysis to first partition the nutrient data into a user-specified number of subsets, it is possible to discover the spatiotemporal patterns of nutrient distribution in the bay and capture the inherent linkages of hydrodynamic and biogeochemical features. Such patterns may then be combined with a gravity model to link the nutrient source contribution from each coastal watershed to the generated clusters in the bay to aid in the source proportion analysis for environmental management. The clustering analysis was carried out based on 1 year (2008) water quality data composed of 55 sample stations throughout Tampa Bay collected by the Environmental Protection Commission of Hillsborough County. In addition, hydrological and river water quality data of the same year were acquired from the United States Geological Survey's National Water Information System to support the gravity modeling analysis. The results show that the k-means model with 8 clusters is the optimal choice, in which cluster 2 at Lower Tampa Bay had the minimum values of total nitrogen (TN) concentrations, chlorophyll a (Chl-a) concentrations, and ocean color values in every season as well as the minimum concentration of total phosphorus (TP) in three consecutive seasons in 2008. The datasets indicate that Lower Tampa Bay is an area with limited nutrient input throughout the year. Cluster 5, located in Middle Tampa Bay, displayed elevated TN concentrations, ocean color values, and Chl-a concentrations, suggesting that high values of colored dissolved organic matter are linked with some nutrient sources. The data presented by the gravity modeling analysis indicate that the Alafia River Basin is the major contributor of nutrients in terms of both TP and TN values in all seasons. With this new integration, improvements for environmental monitoring and assessment were achieved to advance our understanding of sea-land interactions and nutrient cycling in a critical coastal bay, the Gulf of Mexico.


Risky behaviors in late adolescence: co-occurrence, predictors, and consequences.
Advances in research have broadened our understanding of the risky behaviors that significantly threaten adolescent health and well-being. Advances include: using person-centered, rather than behavior-centered approaches to examine how behaviors co-occur; greater focus on how environmental factors, such as family, or peer-level characteristics, influence behavior; and examination of how behaviors affect well-being in young adulthood. Use of nationally representative, longitudinal data would expand research on these critical relationships. Using data from the National Longitudinal Survey of Youth, 1997 cohort, a nationally representative sample of adolescents who are being followed over time, the present study: (1) identifies profiles of risky behaviors, (2) investigates how environmental characteristics predict these profiles of risky behaviors (e.g., delinquency, smoking, drug use, drinking, sexual behavior, and exercise), and (3) examines how these profiles of risky behaviors relate to positive and negative youth outcomes. Four "risk profiles" were identified: a high-risk group (those who report high levels of participation in numerous behaviors), a low-risk group (those who engage in very few risky behaviors), and two moderate risk-taking groups. We found that profiles with any negative behaviors were predictive of negative outcomes. It is important for practitioners to examine health behaviors in multiple domains concurrently rather than individually in isolation. Interventions and research should not simply target adolescents engaging in high levels of risky behavior but also adolescents who are engaging in lower levels of risky behavior.


Biomarkers in melanoma and non-melanoma skin cancer prevention and risk stratification.
The rates of melanoma and non-melanoma skin cancer (NMSC) have been increasing over the last twenty years in the United States, and this has been attributed to increased ultraviolet radiation exposure (UVR). Given these rising rates, preventative measures have become increasingly important to reduce the incidence and promote early detection of these cancers. Skin cancer prevention remains a challenging task to accomplish mainly due to the lack of reliable and sensitive methods to provide objective risk information that can educate and motivate individuals to avoid sunburn. Currently, minimal erythema dose (MED) is used as a marker of UVR. However, it is not an ideal marker because significant cancer-related molecular damage can occur after UVR exposure that cannot be detected by MED. Thus, over the recent years there has been significant interest in development of biomarkers indicative of exposure to UVR to improve early detection of cutaneous malignancies. Here, we will discuss emerging biomarkers for melanoma and NMSC that can help with risk stratification and targeted prevention and treatment.


Investigating the efficacy of bisphosphonates treatment against multiple myeloma induced bone disease using a computational model.
Multiple myeloma (MM)-induced bone disease is mortal for most MM patients. Bisphosphonates are first-line treatment for MM-induced bone disease, since it can inhibit osteoclast activity and the resultant bone resorption by suppressing the differentiation of osteoclast precursors into mature osteoclasts, promoting osteoclast apoptosis and disrupting osteoclast function. However, it is still unclear whether bisphosphonates have an anti-tumour effect. In our previous work, a computational model was built to simulate the pathology of MM-induced bone disease. This paper extends this proposed computational model to investigate the efficacy of bisphosphonates treatment and then clear the controversy of this therapy. The extended model is validated through the good agreement between simulation results and experimental data. The simulation results suggest that bisphosphonates indeed have an anti-tumour effect.