The east-west-north colonization history of the Mediterranean and Europe by the coastal plant Carex extensa (Cyperaceae).
Coastal plants are ideal models for studying the colonization routes of species because of the simple linear distributions of these species. Carex extensa occurs mainly in salt marshes along the Mediterranean and European coasts. Variation in cpDNA sequences, amplified fragment length polymorphisms (AFLPs) and simple sequence repeats (SSRs) of 24 populations were analysed to reconstruct its colonization history. Phylogenetic relationships indicate that C. extensa together with the South American Carex vixdentata and the southern African Carex ecklonii form a monophyletic group of halophilic species. Analyses of divergence times suggest that early lineage diversification may have occurred between the late Miocene and the late Pliocene (Messinian crisis). Phylogenetic and network analyses of cpDNA variation revealed the monophyly of the species and an ancestral haplotype contained in populations of the eastern Mediterranean. The AFLP and SSR analyses support a pattern of variation compatible with these two lineages. These analyses also show higher levels of genetic diversity and differentiation in the eastern population group, which underwent an east-to-west Mediterranean colonization. Quaternary climatic oscillations appear to have been responsible for the split between these two lineages. Secondary contacts may have taken place in areas near the Ligurian Sea in agreement with the gene flow detected in Corsican populations. The AFLP and SSR data accord with the 'tabula rasa' hypothesis in which a recent and rapid colonization of northern Europe took place from the western Mediterranean after the Last Glacial Maximum. The unbalanced west-east vs. west-north colonization may be as a result of 'high density blocking' effect.


Nicotine promotes initiation and progression of KRAS-induced pancreatic cancer via Gata6-dependent dedifferentiation of acinar cells in mice.
Although smoking is a leading risk factor for pancreatic ductal adenocarcinoma (PDAC), little is known about the mechanisms by which smoking promotes initiation or progression of PDAC. We studied the effects of nicotine administration on pancreatic cancer development in Kras(+/LSLG12Vgeo);Elas-tTA/tetO-Cre (Ela-KRAS) mice, Kras(+/LSLG12D);Trp53+/LSLR172H;Pdx-1-Cre (KPC) mice (which express constitutively active forms of KRAS), and C57/B6 mice. Mice were given nicotine for up to 86 weeks to produce blood levels comparable with those of intermediate smokers. Pancreatic tissues were collected and analyzed by immunohistochemistry and reverse transcriptase polymerase chain reaction; cells were isolated and assayed for colony and sphere formation and gene expression. The effects of nicotine were also evaluated in primary pancreatic acinar cells isolated from wild-type, nAChR7a(-/-), Trp53(-/-), and Gata6(-/-);Trp53(-/-) mice. We also analyzed primary PDAC cells that overexpressed GATA6 from lentiviral expression vectors. Administration of nicotine accelerated transformation of pancreatic cells and tumor formation in Ela-KRAS and KPC mice. Nicotine induced dedifferentiation of acinar cells by activating AKT-ERK-MYC signaling; this led to inhibition of Gata6 promoter activity, loss of GATA6 protein, and subsequent loss of acinar differentiation and hyperactivation of oncogenic KRAS. Nicotine also promoted aggressiveness of established tumors as well as the epithelial-mesenchymal transition, increasing numbers of circulating cancer cells and their dissemination to the liver, compared with mice not exposed to nicotine. Nicotine induced pancreatic cells to acquire gene expression patterns and functional characteristics of cancer stem cells. These effects were markedly attenuated in K-Ras(+/LSL-G12D);Trp53(+/LSLR172H);Pdx-1-Cre mice given metformin. Metformin prevented nicotine-induced pancreatic carcinogenesis and tumor growth by up-regulating GATA6 and promoting differentiation toward an acinar cell program. In mice, nicotine promotes pancreatic carcinogenesis and tumor development via down-regulation of Gata6 to induce acinar cell dedifferentiation.


Tikhonov gamma variate adaptive regularization applied to technetium Tc 99m diethylenetriamine pentaacetic acid plasma clearance, compared with three other methods, for measuring glomerular filtration rate in cats.
To evaluate agreement of 4 methods (Tikhonov gamma variate adaptive regularization of plasma concentration-time curve fitting applied to technetium Tc 99m diethylenetriamine pentaacetic acid [99mTc-DTPA] plasma clearance [Tk-GV], plasma clearance of exogenous creatinine [CrCL], Gates gamma camera-based measurement method with 99mTc-DTPA renal clearance and dynamic scintigraphy [GTS], and iohexol renal clearance assessed with dynamic CT with Patlak plotting [CT-Pp]) for measuring glomerular filtration rates (GFR) in healthy cats. 7 healthy, laboratory-raised cats. Each method for measuring GFR was performed twice in 7 cats at 24-day intervals. The Wilcoxon signed-rank sum test was used to compare the results obtained from the 14 studies for each method. Results from the 4 methods were assessed for agreement and correlation. The median GFR values were 2.75, 2.83, 3.14, and 4.26 mL/min/kg, for Tk-GV, CT-Pp, plasma CrCL, and GTS, respectively. Analysis with Wilcoxon signed-rank sum tests identified significant pairwise differences between results obtained with the Tk-GV versus the plasma CrCL method, the Tk-GV versus the GTS method, and the plasma CrCL versus the GTS method. The least variable method was Tk-GV, with an SD of 1.27 (mL/min/kg). Findings indicated that Tk-GV yielded GFR measurements comparable with those obtained with CT-Pp, plasma CrCL, and GTS; however, the Tk-GV method yielded the tightest range of results among the methods evaluated.


Temporal dynamics of active Archaea in oxygen-depleted zones of two deep lakes.
Deep lakes are of specific interest in the study of archaeal assemblages as chemical stratification in the water column allows niche differentiation and distinct community structure. Active archaeal community and potential nitrifiers were investigated monthly over 1 year by pyrosequencing 16S rRNA transcripts and genes, and by quantification of archaeal amoA genes in two deep lakes. Our results showed that the active archaeal community patterns of spatial and temporal distribution were different between these lakes. The meromictic lake characterized by a stable redox gradient but variability in nutrient concentrations exhibited large temporal rearrangements of the dominant euryarchaeal phylotypes, suggesting a variety of ecological niches and dynamic archaeal communities in the hypolimnion of this lake. Conversely, Thaumarchaeota Marine Group I (MGI) largely dominated in the second lake where deeper water layers exhibited only short periods of complete anoxia and constant low ammonia concentrations. Investigations conducted on archaeal amoA transcripts abundance suggested that not all lacustrine Thaumarchaeota conduct the process of nitrification. A high number of 16S rRNA transcripts associated to crenarchaeal group C3 or the Miscellaneous Euryarchaeotic Group indicates the potential for these uncharacterized groups to contribute to nutrient cycling in lakes.


Ocimum sanctum Linn. (Holy Basil) ethanolic leaf extract protects against 7,12-dimethylbenz(a)anthracene-induced genotoxicity, oxidative stress, and imbalance in xenobiotic-metabolizing enzymes.
The present study was designed to evaluate the protective effects of ethanolic Ocimum sanctum leaf extract against 7,12-dimethylbenz[a]anthracene (DMBA)-induced genotoxicity, oxidative stress, and imbalance in xenobiotic-metabolizing enzymes. Four different concentrations of ethanolic O. sanctum leaf extract (100, 200, 300, and 400 mg/kg of body weight) were administered to Wistar rats by intragastric intubation for five consecutive days followed by intraperitoneal injection of DMBA (35 mg/kg of body weight) 90 minutes after the final dose of the extract. Administration of DMBA increased bone marrow micronuclei, phase I enzymes, lipid peroxidation, and protein carbonyl formation. This was accompanied by a significant decrease in the activities of phase II detoxification enzymes and antioxidants in the liver, erythrocytes, and bone marrow. Pretreatment with ethanolic O. sanctum leaf extract at a concentration of 300 mg/kg of body weight significantly reduced micronuclei formation and phase I enzymes as well as lipid and protein oxidation with enhanced antioxidant and phase II enzyme activities. The results of the present study suggest that ethanolic O. sanctum leaf extract inhibits DMBA-induced genotoxicity and oxidative stress by modulating xenobiotic-metabolizing enzymes, reducing the extent of lipid and protein oxidation and up-regulating antioxidant defenses.


Efficacy and tolerability of 16% subcutaneous immunoglobulin compared with 20% subcutaneous immunoglobulin in primary antibody deficiency.
Multiple subcutaneous immunoglobulin (SCIG) products are available to treat primary antibody deficiency (PAD). The efficacy and tolerability of 16% SCIG (Vivaglobin(®) ) was compared with 20% SCIG (Hizentra(®) ) in PAD subjects. The study was a prospective, single-centre, open-label study of PAD subjects transitioning Vivaglobin to equivalent Hizentra doses, rounded to the nearest vial size. Comparisons included immunoglobulin (Ig)G levels; tetanus, varicella and Streptococcus pneumoniae titres; adverse events (AEs), annual infection rate and quality of life during 8 weeks of Vivaglobin and 24 weeks of Hizentra. Thirty-two subjects (aged 2-75 years) participated. Rounding to the nearest Hizentra vial size resulted in a 12·8% (± 2·9%) increase in SCIG dose. Median immunoglobulin (Ig)G level following 8 weeks of Vivaglobin was similar to 24 weeks of Hizentra (1050 versus 1035 mg/dl, respectively; P = 0·77). Both products had similar protective titres to tetanus, varicella and serotypes of S. pneumoniae, which were variable but well above protective levels. After 12 weeks of Hizentra, subjects reported fewer local site reactions compared with Vivaglobin. Switching products resulted in increased systemic AEs in some subjects but, overall, not significantly higher than during Vivaglobin treatment. Average infusion time decreased from 104·7 min (3·3 sites) with Vivaglobin to 70·7 min (2·2 sites) with Hizentra (P = 0·0005). Acute serious bacterial infections were similar. Treatment satisfaction was superior with Hizentra. Hizentra and Vivaglobin have similar pharmacokinetics and efficacy. Although transition to a different SCIG product initially increased AEs, Hizentra is well tolerated and can be infused more rapidly and with fewer sites compared to Vivaglobin.


Experiences of parents of children with special needs at school entry: a mixed method approach.
The transition from pre-school to kindergarten can be complex for children who need special assistance due to mental or physical disabilities (children with 'special needs'). We used a convergent mixed method approach to explore parents' experiences with service provision as their children transitioned to school. Parents (including one grandparent) of 37 children aged 4 to 6 years completed measures assessing their perceptions of and satisfaction with services. Semi-structured interviews were also conducted with 10 parents to understand their experience with services. Post transition, parents reported lower perceptions of services and decreased satisfaction than pre-transition. The following themes emerged from the qualitative data: qualities of services and service providers, communication and information transfer, parent advocacy, uncertainty about services, and contrasts and contradictions in satisfaction. The qualitative findings indicate that parents were both satisfied and concerned with aspects of the post-transition service provision. While the quantitative results suggested that parents' experience with services became less positive after their children entered school, the qualitative findings illustrated the variability in parents' experiences and components of service provision that require improvements to facilitate a successful school entry.


Isotretinoin use and subsequent depression and suicide: presenting the evidence.
The growing number of reported cases of depression and suicide associated with isotretinoin (a retinoid receptor agonist) use in patients with acne has prompted concern among dermatologists, patients, and their relatives and has triggered new warnings from regulators including depression-related, patient-informed consent forms. In establishing a cause-effect relationship, it is useful to judiciously consider whether there is an association, what is the nature of that association, if there is a plausible biological mechanism of action, the validity and reliability of measures used and the strength of study designs. Hoffmann-La Roche estimates that by April 2001 approximately 12 million patients worldwide have used isotretinoin, with 5 million patients in the US.A MEDLINE search between January 1966 and May 14 2003 of the published medical literature found 24 documented cases of isotretinoin-associated depression, with 3 suicides. One additional patient committed suicide during the fourth month of isotretinoin treatment and 3 further patients attempted suicide by taking an overdose of isotretinoin. The US FDA's Adverse Event Reporting System (AERS) contains almost 23,000 reports for isotretinoin from its approval in 1982 to December 2002. As of November 30, 2002, AERS contained 3,104 reports (US and foreign) with at least one reported psychiatric event. The FDA is aware of 173 reports of suicide (both US and foreign) in association with isotretinoin. Reports of positive dechallenge and rechallenge present a strong signal pointing to an association between isotretinoin and depression. A Hoffmann-La Roche sponsored epidemiological study failed to find any evidence of an association between isotretinoin and depression or suicide. However, the design of the study was flawed and the evidence was deemed inconclusive. Further studies using strong study designs, reliable and valid measures, and adequate sample sizes may bring us closer to the answer. The evidence suggesting a relationship between isotretinoin and depression needs to be weighed against the increasing prevalence of depression among adolescents and young adults and the psychological impact of acne. The literature contains credible evidence that isotretinoin treatment may reduce the psychosocial impact of acne in some patients. At the present time, there is no known pharmacological mechanism that would account for psychiatric symptomatology as a result of isotretinoin treatment; however, retinoid receptors are widely distributed in the brain and more research is needed to ascertain whether they have a role in depression. In the meantime, for the practitioner, the obvious benefit of isotretinoin in treating acne should encourage continued use. However, patients and their relatives must be informed and depressive symptoms should be actively assessed at each visit and, if necessary, referral to a psychiatrist, antidepressant therapy or discontinuation of isotretinoin should be considered.


Management of high-level waste repository siting.
The selection of sites to store high-level radioactive waste will require more than technical decisions; an acceptable site must gain widespread public support. Ad hoc approaches have recently served as a stimulus to overcome institutional inertia in radioactive waste management, as exemplified by the Interagency Review Group and the State Planning Council for Radioactive Waste Management, but ad hoc approaches have not characteristically succeeded in resolving intense conflicts. Acceptable sites can best be established through traditional processes of legal and scientific advocacy, and their ultimate legitimacy will depend on the proper use of established democratic processes.


In vivo growth characteristics of leucine and methionine auxotrophic mutants of Mycobacterium bovis BCG generated by transposon mutagenesis.
Insertional mutagenesis in Mycobacterium bovis BCG, a member of the slow-growing M. tuberculosis complex, was accomplished with transposons engineered from the Mycobacterium smegmatis insertion element IS1096. Transposons were created by placing a kanamycin resistance gene in several different positions in IS1096, and the resulting transposons were electroporated into BCG on nonreplicating plasmids. These analyses demonstrated that only one of the two open reading frames was necessary for transposition. A library of insertions was generated. Southern analysis of 23 kanamycin-resistant clones revealed that the transposons had inserted directly, with no evidence of cointegrate formation, into different restriction fragments in each clone. Sequence analysis of nine of the clones revealed junctional direct 8-bp repeats with only a slight similarity in target sites. These results suggest that IS1096-derived transposons transposed into the BCG genome in a relatively random fashion. Three auxotrophs, two for leucine and one for methionine, were isolated from the library of transposon insertions in BCG. They were characterized by sequencing and found to be homologous to the leuD gene of Escherichia coli and a sulfate-binding protein of cyanobacteria, respectively. When inoculated intravenously into C57BL/6 mice, the leucine auxotrophs, in contrast to the parent BCG strain or the methionine auxotroph, showed an inability to grow in vivo and were cleared within 7 weeks from the lungs and spleen.


Release of neuropeptides during intracellular stimulation of single identified Aplysia neurons in culture.
An important criterion for classifying a substance as a neurotransmitter is that it is released in an activity-dependent fashion. We have utilized cell culture of individual neurons of Aplysia to demonstrate the release of the neuropeptides SCPA and SCPB (small cardioactive peptides A and B). Neurons B1 and B2 were isolated from the buccal ganglion of Aplysia and maintained in cell culture. The cells grew new processes, which were immunoreactive to antibodies for the neuropeptide SCPB. These processes contained SCPA and SCPB that were detectable by bioassay on snail heart. The cells synthesized the SCPs from radiolabeled precursors and transported the peptides to their neurites. Single cells released SCPs in a calcium-dependent fashion upon intracellular electrical stimulation. Taken together, these results provide critical evidence that SCPs are neurotransmitters. The results also indicate that the cell culture of individual identified neurons can be used to investigate the release of peptides.


Regional genetic structuring and evolutionary history of the impala Aepyceros melampus.
Samples of 162 impala antelope (Aepyceros melampus) from throughout its distribution range in sub-Saharan Africa were surveyed using eight polymorphic microsatellite loci. Furthermore, 155 previously published mitochondrial DNA (mtDNA) sequences from the same localities were reanalyzed. Two subspecies of impala are presently recognized--the isolated black-faced impala (Aepyceros melampus petersi) in southwest Africa and the common impala (Aepyceros melampus melampus) abundant in southern and east Africa. All tests performed indicated significant genetic differentiation at the subspecific level. Furthermore, individual-based analyses split the common impala subspecies into two distinct genetic groups, conforming with regional geographic affiliation to southern or east Africa. This was supported by assignment tests, genetic distance measures, pairwise theta values, and analysis of molecular variance. We suggest that the presence of such previously unknown regional structuring within the subspecies reflects a pattern of colonization from a formerly large panmictic population in southern Africa toward east Africa. This scenario was supported by a progressive decline in population diversity indices toward east Africa and a significant increase in the quantity theta/(1 - theta). Both microsatellite and mtDNA data indicated a genetic distinctiveness of the Samburu population in Kenya.


Leucocyte count predicts cardiovascular risk in heart failure with preserved ejection fraction: insights from TOPCAT Americas.
Prior evidence has implicated leucocyte expansion in several cardiovascular disorders, including heart failure (HF) with reduced ejection fraction (rEF). However, the prognostic importance of leucocyte count in HF with preserved EF (HFpEF) remains largely unexplored. The Americas cohort of the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT-Americas) was used to evaluate the association between total leucocyte count and clinical outcomes in HFpEF. The primary outcome was a composite of aborted cardiac arrest, cardiovascular mortality, or hospitalization for HF. Secondary outcomes were hospitalization for HF, aborted cardiac arrest, stroke, non-fatal myocardial infarction (MI), cardiovascular mortality, non-cardiovascular mortality, and all-cause mortality. Survival models were used to identify the risk of the primary and secondary outcomes in those with leucocyte count above the median (7100 cells/μL), as compared to those with leucocyte count below the median, during the follow-up period. A total of 1746 (out of 1767; 99%) patients from TOPCAT-Americas were available for the analyses with a median follow up of 2.4 (25th to 75th percentile 1.4-3.9) years. Patients with leucocyte count >7100 cells/μL were 36% more likely to experience the primary endpoint compared to those with ≤7100 cells/μL (hazard ratio: 1.36, 95% confidence interval: 1.14-1.61). This association remained significant after extensive adjustment for potential confounders (hazard ratio: 1.27, 95% confidence interval: 1.06-1.52). We also observed a greater incidence of HF hospitalization and non-fatal MI in patients with higher leucocyte count. These associations remained robust on sensitivity analyses, suggesting a low probability of confounding. Exploratory analyses suggested that both higher leucocyte count (integrating the combined influence of both myeloid and lymphoid immune cells) and augmented platelet count (as a surrogate for myeloid immune cell expansion) in the same model were associated with the primary outcome (both P < 0.05). Leucocyte count >7100 cells/μL was independently associated with adverse clinical outcomes in HFpEF patients from TOPCAT-Americas. These results were primarily driven by the HF hospitalization outcome but were also accompanied by an excess of non-fatal MI. Further research is needed to define the mechanisms underlying our findings and their prognostic implications.


Korean frailty and aging cohort study (KFACS): cohort profile.
The purpose of the Korean Frailty and Aging Cohort Study (KFACS) is to initiate a nationwide, population-based prospective cohort study of older adults living in the community to assess their frailty status and explore transitions between frailty states over time in Korea. The KFACS is a multicentre longitudinal study with the baseline survey conducted from May 2016 to November 2017. Each centre recruited participants using quota sampling stratified by age and sex. The number of participants recruited through 2 years of baseline study from 10 centres was 3014, with each site accounting for approximately 300 participants. The inclusion criteria were: having an age of 70-84 years, currently living in the community, having no plans to move out in the next 2 years, having no problems with communication and no prior dementia diagnosis. To define physical frailty, the KFACS used a modified version of the Fried Frailty Phenotype (FFP) consisting of five components of frailty: unintended weight loss, weakness, self-reported exhaustion, slowness and low physical activity. In the baseline study of 2016-2017, 2907 of 3014 individuals fulfilled all five components of FFP. The results indicated that 7.8% of the participants (n=228) were frail, 47.0% (n=1366) were prefrail and 45.2% (n=1313) were robust. The prevalence of frailty increased with age in both sexes; in the group aged 70-74 years, 1.8% of men and 3.7% of women were frail, whereas in the 80-84 years age group, 14.9% of men and 16.7% of women were frail. Women tended to exhibit a higher prevalence of frailty than men in all age groups. The KFACS plans to identify outcomes and risk factors associated with frailty by conducting a 10-year cohort study, with a follow-up every 2 years, using 3014 baseline participants.


The delay between symptom onset and seeking professional treatment for anxiety and depressive disorders in a rural Australian sample.
Epidemiological research has revealed that the utilisation of professional mental health services is low among rural Australians, despite a similar prevalence of mental illness to urban communities. However, the extent of this unmet need and the length of delay to first seek treatment in rural communities remain unclear. The aim of this study was to investigate the delay among rural Australians in seeking treatment for anxiety and depressive disorders. A total of 124 participants with an anxiety or depressive disorder according to the Composite International Diagnostic Interview (CIDI) who were participants of the Australian Rural Mental Health Study (ARMHS) were included in this study. Multivariate methods examined the contribution of clinical (onset age, disorder type and comorbidity), attitudinal/demographic (perceived stigma and current age) and structural (rurality) variables to the delay to first seek help. The average length of the delay was 18.7 years across disorders (range 0-67). The shortest delays were in depressive disorders (10.41 years) and the longest for social phobia (28.02 years). Multivariate analysis indicated that younger onset age, older current age, diagnosis of panic disorder or depressive disorder, and living in a remote (R) or very remote area (VR) were associated with delays of more than one year. Delays to first seek treatment for anxiety and depressive disorders appear to be far more prolonged in rural compared to urban Australia. This is particularly the case for Australian residents living in R and VR areas. This is of particular concern due to the significant mental health needs of rural Australians.


Effects of cerebrolysin on functional recovery in patients with severe disability after traumatic brain injury: A historical cohort study.
To determine the effects of cerebrolysin on functional recovery in patients with severe disability after traumatic brain injury (TBI). This was a retrospective cohort study being performed during a 2-year period in a level I trauma center in Southern Iran including all the adult patients (>16years) with severe disability (GOS of 2 and 3) 1-month after trauma. We excluded those with posttraumatic seizures and those with meningitis or current infections. Some patients received cerebrolysin (n=65) and some did not (n=64). Cerebrolysin was administered intravenously in 10mL dosage daily for 30days. Patients in two study groups were matched regarding the baseline characteristics including age, gender, GCS on admission, pupil reactivity and Rotterdam score. The administered cerebrolysin dosage was 10mL intravenously daily for 30days. The 3- and 6-month Glasgow Outcome Scale Extended (GOSE) was recorded. The outcome scales were compared between two study groups. Overall we included 129 patients with severe disability 1-month after TBI. The baseline characteristics were comparable between groups. We found that GOSE at 3-month (p=0.017) and 6-month (p=0.009) was significantly higher in those receiving cerebrolysin. Cerebrolysin administration was associated with lower mortality rate, and higher good recovery after 6 month of therapy (p=0.024). Cerebrolysin administration was also associated with higher favorable and lower unfavorable outcome (p=0.043). Cerebrolysin was associated with higher seizure rate (p=0.042). Cerebrolysin administration in patients with severe disability after TBI is associated with improved functional recovery, decreased mortality rate and increased favorable outcome. Seizure is important side effect of cerebrolysin administration in TBI patients.


Monoterpenoid extract of sage (Salvia lavandulaefolia) with cholinesterase inhibiting properties improves cognitive performance and mood in healthy adults.
Extracts of sage (Salvia officinalis/lavandulaefolia) with terpenoid constituents have previously been shown to inhibit cholinesterase and improve cognitive function. The current study combined an in vitro investigation of the cholinesterase inhibitory properties and phytochemical constituents of a S. lavandulaefolia essential oil, with a double-blind, placebo-controlled, balanced crossover study assessing the effects of a single dose on cognitive performance and mood. In this latter investigation 36 healthy participants received capsules containing either 50 µL of the essential oil or placebo on separate occasions, 7 days apart. Cognitive function was assessed using a selection of computerized memory and attention tasks and the Cognitive Demand Battery before the treatment and 1-h and 4-h post-dose. The essential oil was a potent inhibitor of human acetylcholinesterase (AChE) and consisted almost exclusively of monoterpenoids. Oral consumption lead to improved performance of secondary memory and attention tasks, most notably at the 1-h post-dose testing session, and reduced mental fatigue and increased alertness which were more pronounced 4-h post-dose. These results extend previous observations of improved cognitive performance and mood following AChE inhibitory sage extracts and suggest that the ability of well-tolerated terpenoid-containing extracts to beneficially modulate cholinergic function and cognitive performance deserves further attention.


[Update on Current Care Guideline: Depression].
Treatment of depression is based on comprehensive diagnostic, clinical and psychosocial evaluation. Brief psychotherapies (cognitive, interpersonal, psychodynamic or problem-solving) are effective in mild to moderate depression; antidepressants in mild to severe, and electroconvulsive therapy in severe or psychotic. Combining antidepressants and psychotherapy is more effective than either alone. After the acute phase, antidepressants should be continued for six months to prevent relapses, and maintenance treatment considered after three lifetime episodes. Primary care is responsible for treatment of mild to moderate depressions; developing psychiatric consultation services and use of nurse case managers are recommended.


Depletion of DNA methyltransferase 1 and/or DNA methyltransferase 3b mediates growth arrest and apoptosis in lung and esophageal cancer and malignant pleural mesothelioma cells.
DNA methyltransferase (DNMT)1, DNMT3b, or both, facilitate malignant transformation through chromatin remodeling mechanisms. The present study was undertaken to examine the effects of antisense-mediated inhibition of DNMT expression in cultured thoracic malignancies. CALU-6 and A549 lung cancer, SKGT5 and BIC esophageal adenocarcinoma, and H2373 and H2052 malignant pleural mesothelioma (MPM) cells, as well as normal human bronchial epithelial (NHBE) cells, were transfected with phosphorothioate-modified antisense oligos targeting DNMT1, DNMT3b, or both, or mismatch oligos. Quantitative reverse transcription-polymerase chain reaction, Western blotting, trypan blue exclusion, and ApoBrdU techniques were used to evaluate DNMT expression, proliferation, and apoptosis after antisense oligo transfections. Gene expression profiles were assessed by using long-oligo array techniques. Antisense oligos mediated specific and dose-dependent depletion of DNMT1 and DNMT3b, resulting in pronounced inhibition of proliferation of all thoracic cancer lines, but not NHBE cells. Depletion of DNMT1 or DNMT3b coincided with dramatic, caspase-dependent, p53-independent apoptosis in 4 of the 6 thoracic cancer lines. The antiproliferative effects of the antisense oligos were not attributable to induction of RASSF1A, p16, or p21 tumor suppressor genes, and did not coincide with demethylation of genes encoding cancer-testis antigens. DNA methyltransferase knockdown mediated induction of numerous genes regulating response to genotoxic stress. Gene expression profiles after DNMT1, DNMT3b, or combined DNMT1/3b depletion were remarkably similar, yet distinctly different from expression profiles mediated by 5 aza 2' deoxycytidine. Antisense oligos targeting DNMT1 and DNMT3b induce genomic stress, and mediate potent growth inhibition in lung and esophageal cancer and MPM cells. These findings support further evaluation of DNMT knockdown strategies for cancer therapy.


Evaluating and mitigating the potential indirect effect of COVID-19 on control programmes for seven neglected tropical diseases: a modelling study.
In line with movement restrictions and physical distancing essential for the control of the COVID-19 pandemic, WHO recommended postponement of all neglected tropical disease (NTD) control activities that involve community-based surveys, active case finding, and mass drug administration in April, 2020. Following revised guidance later in 2020, and after interruptions to NTD programmes of varying lengths, NTD programmes gradually restarted in the context of an ongoing pandemic. However, ongoing challenges and service gaps have been reported. This study aimed to evaluate the potential effect of the programmatic interruptions and strategies to mitigate this effect. For seven NTDs, namely soil-transmitted helminths, schistosomiasis, lymphatic filariasis, onchocerciasis, trachoma, visceral leishmaniasis, and human African trypanosomiasis, we used mathematical transmission models to simulate the effect of programme interruptions on the dynamics of each of these diseases in different endemic settings. We also explored the potential benefit of implementing mitigation strategies, primarily in terms of minimising the delays to control targets. We show that the effect of the COVID-19-induced interruption in terms of delay to achieving elimination goals might in some cases be much longer than the duration of the interruption. For schistosomiasis, onchocerciasis, trachoma, and visceral leishmaniasis, a mean delay of 2-3 years for a 1-year interruption is predicted in areas of highest prevalence. We also show that these delays can largely be mitigated by measures such as additional mass drug administration or enhanced case-finding. The COVID-19 pandemic has brought infectious disease control to the forefront of global consciousness. It is essential that the NTDs, so long neglected in terms of research and financial support, are not overlooked, and remain a priority in health service planning and funding. Bill & Melinda Gates Foundation, Medical Research Council, and the UK Foreign, Commonwealth & Development Office.


Bone allograft and implant fixation tested under influence of bio-burden reduction, periosteal augmentation and topical antibiotics. Animal experimental studies.
Loosening of an artificial joint prosthesis is a painful and debilitating condition that can be treated only by re-operation. Re-operations accounted for approximately 15% of all hip replacement operations performed in Denmark between the year 1995 and 2010. The process of loosening is often accompanied by destructive inflammation and osteolysis, which leads to insufficient bone stock that often requires extensive bone grafting. Impacted morselized bone graft is a well-established method for improving the amount and quality of bone stock that ensures sufficient stability and anchorage of the revision implants. Among bone graft options, the autologous bone graft is considered the gold standard. It is naturally biocompatible, but its use in revision surgery is curtailed by its limited volume and by considerable donor site morbidity. Allograft bone is readily available and is the most commonly used graft material. However, it has been shown that the incorporation of allograft bone into the host bone is not always complete, and substantial fibrous tissue formation has been described. A reason for this may be that allograft bone is a foreign tissue, which, contrary to autogenic bone, may induce an immunogenic response that leads to increased fibrous tissue formation. Furthermore, the fresh-frozen allograft has minimal osteoinductive and no osteogenic capacity. The studies in this thesis have investigated ways of improving the incorporation of allograft bone by adding osteoinductive cells from the periosteum and reducing the immunogenic load of the allograft bone by rinsing. Furthermore, the impact of antibiotic protection of the bone graft has been evaluated. The same experimental implant model was used in all three studies. This model enables evaluation of early implant fixation and osseointegration of an uncemented implant surrounded by impacted morselized bone graft. Unloaded gap implants were inserted into the metaphysis of the proximal tibia (Study I) and distal femur (Study II and III) in dogs. The observation period was four weeks and the bone-implant specimens were evaluated by mechanical tests and histomorphometry. Study I compared the fixation of grafted implants where the morselized allograft bone was either rinsed in saline or not. Since the majority of immunogenic factors in allograft bone are present in the blood, the marrow and fat, the objective of this study was to investigate whether rinsing of the allograft bone would lower the immunogenic load and thereby improve osseointegration and bone graft incorporation. We found no statistically significant difference in the histomorphometric or the mechanical evaluations between the two groups. Study II investigated the addition of minced periosteal tissue to the allograft bone. The objective of this study was to investigate whether adding autologous tissue containing bone-forming cells could augment the bioactivity of allograft bone and thereby improve bone graft incorporation. Contrary to our hypothesis, we found no benefit of adding autologous periosteum to the allograft bone. No differences in mechanical fixation were observed, and the periosteum-treated implants had reduced new-bone ongrowth and increased amounts of fibrous tissue. Study III evaluated the impact of antibiotic impregnation of the allograft bone prior to impaction. Antibiotic-impregnated bone graft has been used in one-stage septic revisions and in cases where potential infection is suspected, but its potentially harmful effect on bone graft incorporation has not been studied. The aim of this study was to evaluate the impact of Tobramycin impregnation of bone-grafted implants by mechanical testing and histomorphometric assessment. We hypothesized that Tobramycin impregnation would impair implant fixation. Under the conditions of the present study, Tobramycin impregnation of allograft bone did not appear to impair implant fixation or tissue in-growth. In conclusion, under the premises of the present studies, no benefits of periosteal augmentation or rinsing of the bone graft prior to impaction were found. Antibiotic impregnation seems safe in terms of osseointegration, but surgeons should weigh the potentially cytotoxic effect of Tobramycin against its beneficial anti-microbial effect in joint arthroplasty revisions until further basic data on toxicity are available.


Travel history and malaria infection risk in a low-transmission setting in Ethiopia: a case control study.
Malaria remains the leading communicable disease in Ethiopia, with around one million clinical cases of malaria reported annually. The country currently has plans for elimination for specific geographic areas of the country. Human movement may lead to the maintenance of reservoirs of infection, complicating attempts to eliminate malaria. An unmatched case-control study was conducted with 560 adult patients at a Health Centre in central Ethiopia. Patients who received a malaria test were interviewed regarding their recent travel histories. Bivariate and multivariate analyses were conducted to determine if reported travel outside of the home village within the last month was related to malaria infection status. After adjusting for several known confounding factors, travel away from the home village in the last 30 days was a statistically significant risk factor for infection with Plasmodium falciparum (AOR 1.76; p=0.03) but not for infection with Plasmodium vivax (AOR 1.17; p=0.62). Male sex was strongly associated with any malaria infection (AOR 2.00; p=0.001). Given the importance of identifying reservoir infections, consideration of human movement patterns should factor into decisions regarding elimination and disease prevention, especially when targeted areas are limited to regions within a country.


Ectopic cardiovascular fat in middle-aged men: effects of race/ethnicity, overall and central adiposity. The ERA JUMP study.
Higher volumes of ectopic cardiovascular fat (ECF) are associated with greater risk of coronary heart disease (CHD). Identifying factors that are associated with ECF volumes may lead to new preventive efforts to reduce risk of CHD. Significant racial/ethnic differences exist for overall and central adiposity measures, which are known to be associated with ECF volumes. Whether racial/ethnic differences also exist for ECF volumes and their associations with these adiposity measures remain unclear. Body mass index (BMI), computerized tomography-measured ECF volumes (epicardial, pericardial and their summation) and visceral adipose tissue (VAT) were examined in a community-based sample of 1199 middle-aged men (24.2% Caucasians, 7.0% African-Americans, 23.6% Japanese-Americans, 22.0% Japanese, 23.2% Koreans). Significant racial/ethnic differences existed in ECF volumes and their relationships with BMI and VAT. ECF volumes were the highest among Japanese-Americans and the lowest among African-Americans. The associations of BMI and VAT with ECF differed by racial/ethnic groups. Compared with Caucasians, for each 1-unit increase in BMI, African-Americans had lower, whereas Koreans had higher increases in ECF volumes (P-values<0.05 for both). Meanwhile, compared with Caucasians, for each 1-unit increase in log-transformed VAT, African-Americans, Japanese-Americans and Japanese had similar increases, whereas Koreans had a lower increase in ECF volumes (P-value<0.05). Racial/ethnic groups differed in their propensity to accumulate ECF at increasing level of overall and central adiposity. Future studies should evaluate whether reducing central adiposity or overall weight will decrease ECF volumes more in certain racial/ethnic groups. Evaluating these questions might help in designing race-specific prevention strategy of CHD risk associated with higher ECF.


Purification, crystallization and preliminary X-ray analysis of a fusion of the LIM domains of LMO2 and the LID domain of Ldb1.
LMO2 (LIM domain only 2), also known as rhombotin-2, is a transcriptional regulator that is essential for normal haematopoietic development. In malignant haematopoiesis, its ectopic expression in T cells is involved in the pathogenesis of leukaemia. LMO2 contains four zinc-finger domains and binds to the ubiquitous nuclear adaptor protein Ldb1 via the LIM-interaction domain (LID). Together, they act as scaffolding proteins and bridge important haematopoietic transcription factors such as SCL/Tal1, E2A and GATA-1. Solving the structure of the LMO2:Ldb1-LID complex would therefore be a first step towards understanding how haematopoietic specific protein complexes form and would also provide an attractive target for drug development in anticancer therapy, especially for T-cell leukaemia. Here, the expression, purification, crystallization and data collection of a fusion protein consisting of the two LIM domains of LMO2 linked to the LID domain of Ldb1 via a flexible linker is reported. The crystals belonged to space group C2, with unit-cell parameters a = 179.9, b = 51.5, c = 114.7 Å, β = 90.1°, and contained five molecules in the asymmetric unit. Multiple-wavelength anomalous dispersion (MAD) data have been collected at the zinc X-ray absorption edge to a resolution of 2.8 Å and the data were used to solve the structure of the LMO2:Ldb1-LID complex. Refinement and analysis of the electron-density map is in progress.


Molecular screening for Neisseria gonorrhoeae antimicrobial resistance markers in Nigerian men who have sex with men and transgender women.
Antimicrobial-resistant Neisseria gonorrhoeae (NG) is a global public health issue that threatens effectiveness of current treatments of NG. Increased use of nucleic acid amplification tests (NAATs) in lieu of cultures makes obtaining clinical isolates for susceptibility testing difficult and samples collected in commercial transport buffer for NAATs do not preserve viable organism, while molecular methods of assessing antibiotic susceptibility do not require viable organism. We evaluated 243 NG-positive samples in Aptima transport media including urine, oral, and rectal swabs from Nigerian men who have sex with men for markers to penicillinase-producing NG, ciprofloxacin ( GyrA and ParC mutations), and extended spectrum cephalosporins (ESCs, PenA mosaic [allele X], PonA, mtrR, PorB mutations) by real-time PCR. NG DNA was recovered in 75% (183/243) of samples. Of these, 93% (171/183) were positive for at least one resistance marker. We observed a prevalence of dual resistance markers to penicillin and ciprofloxacin at 46.2% (79/171). Six percent of samples (10/171) tested positive for the PenA mosaic (allele X) ESC marker. These data indicate that antibiotic-resistant NG is common in Nigeria. Laboratory and clinical capacity building in Nigeria should include development of methods to culture NG and determine antimicrobial susceptibility.


Negative edges and soft thresholding in complex network analysis of resting state functional connectivity data.
Complex network analyses of functional connectivity have consistently revealed non-random (modular, small-world, scale-free-like) behavior of hard-thresholded networks constructed from the right-tail of the similarity histogram. In the present study we determined network properties resulting from edges constrained to specific ranges across the full correlation histogram, in particular the left (negative-most) tail, and their dependence on the confound signal removal strategy employed. In the absence of global signal correction, left-tail networks comprised predominantly long range connections associated with weak correlations and were characterized by substantially reduced modularity and clustering, negative assortativity and γ<1 Deconvolution of specific confound signals (white matter, CSF and motion) resulted in the most robust within-subject reproducibility of global network parameters (ICCs~0.5). Global signal removal altered the network topology in the left tail, with the clustering coefficient and assortativity converging to zero. Networks constructed from the absolute value of the correlation coefficient were thus compromised following global signal removal since the different right-tail and left-tail topologies were mixed. These findings informed the construction of soft-thresholded networks, replacing the hard thresholding or binarization operation with a continuous mapping of all correlation values to edge weights, suppressing rather than removing weaker connections and avoiding issues related to network fragmentation. A power law adjacency function with β=12 yielded modular networks whose parameters agreed well with corresponding hard-thresholded values, that were reproducible in repeated sessions across many months and evidenced small-world-like and scale-free-like properties.


Phase I study of intermittent oral dosing of the insulin-like growth factor-1 and insulin receptors inhibitor OSI-906 in patients with advanced solid tumors.
We determined the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906, a potent, oral, dual inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR), in patients with advanced solid tumors. This was a multicenter, open-label, dose escalation phase I study evaluating three intermittent dosing schedules of once-daily OSI-906 [schedule (S) 1, days 1-3 every 14 days; S2, days 1-5 every 14 days; S3, days 1-7 every 14 days]. A fed-fasting expansion cohort was included in the study. Seventy-nine patients were enrolled: 62 in S1, 4 in S2, and 13 in S3. S2 was discontinued. Dose-limiting toxicity comprised grade 3-4 hyperglycemia, vomiting, fatigue, and prolonged QTc interval. The MTD and recommended phase II dose of OSI-906 was 600 mg for both S1 and S3 schedules. Other common adverse events were grade 1-2 nausea, vomiting, fatigue, and diarrhea. The pharmacokinetics of OSI-906 was dose linear, and the terminal half-life ranged between 2 and 6 hours. High-fat meals had a moderate effect on the pharmacokinetics of OSI-906. At the MTD, inhibition of IGF1R and IR was observed in peripheral blood mononuclear cells. An increase in plasma IGF1 concentrations, an indirect measure of IGF1R signaling inhibition, was seen at doses ≥ 450 mg. Two patients with adrenocortical carcinoma achieved partial responses. The MTD of 600 mg was well tolerated and associated with preliminary antitumor activity. These data support further evaluation of OSI-906 in solid tumors.


Regulation of steatohepatitis and PPARγ signaling by distinct AP-1 dimers.
Nonalcoholic fatty liver disease (NAFLD) affects up to 30% of the adult population in Western societies, yet the underlying molecular pathways remain poorly understood. Here, we identify the dimeric Activator Protein 1 as a regulator of NAFLD. Fos-related antigen 1 (Fra-1) and Fos-related antigen 2 (Fra-2) prevent dietary NAFLD by inhibiting prosteatotic PPARγ signaling. Moreover, established NAFLD and the associated liver damage can be efficiently reversed by hepatocyte-specific Fra-1 expression. In contrast, c-Fos promotes PPARγ expression, while c-Jun exerts opposing, dimer-dependent functions. Interestingly, JunD was found to be essential for PPARγ signaling and NAFLD development. This unique antagonistic regulation of PPARγ by distinct AP-1 dimers occurs at the transcriptional level and establishes AP-1 as a link between obesity, hepatic lipid metabolism, and NAFLD.


A case-control study of the association between ulcerative colitis and hyperthyroidism in an Asian population.
Ulcerative colitis (UC) is a chronic relapsing inflammatory disease with significant clinical diversity. However, the aetiology, pathogenesis and optimal treatment of UC remain unclear. The purpose of this case-control study was to investigate the association between previously diagnosed hyperthyroidism and UC using a large population-based data set in Taiwan. The data for this population-based case-control study were retrieved from the Taiwan Longitudinal Health Insurance Database 2005. We included 2709 patients with UC as cases and 8127 sex- and age-matched patients without UC as controls. A conditional logistic regression analysis was conducted to compute the odds ratio (OR) and corresponding 95% confidence interval (CI) for the association between UC and prior hyperthyroidism. We found that, in total, 327 of the 10 836 sampled patients (3.02%) had previously been diagnosed with hyperthyroidism. There was a higher proportion of prior hyperthyroidism among cases than controls (4.10% vs 2.66%, P<.001). A conditional logistic regression showed that the OR of prior hyperthyroidism was 1.57 (95% CI=1.24-1.98) compared to controls. Similarly, after adjusting for monthly income, geographic location and urbanization level, cases were still more likely to have previously been diagnosed with hyperthyroidism than controls (OR=1.61, 95% CI=1.27-2.05). Furthermore, we analysed the ORs of prior hyperthyroidism between cases and controls according to age group. We found that of the youngest group of sampled patients (18-39 years), cases had the greatest adjusted OR for having previously been diagnosed with hyperthyroidism than controls (OR=1.98, 95% CI=1.04-3.79). This study demonstrated an association between UC and hyperthyroidism.


Supporting family caregiver engagement in the care of old persons living in hard to reach communities: A scoping review.
Today, 8.5% of the world's population is 65 and over, and this statistic will reach 17% by 2050 (He et al., U.S. Census Bureau, international population reports, P95/16-1, An ageing world: 2015, U.S., 2016). They are the people who, with increasing age, will find themselves more closely interfacing with the national health system, which in many countries shows strong imbalances between rural and urban areas. In this context, a fundamental role is played by the relatives who find themselves becoming informal caregivers to compensate for lack of services. To date, however, little has been done to help these people. In this article, we want to identify the nature and extent of research evidence that had its objective to help informal caregivers in rural, hard to reach areas (Grant & Booth, Health Information & Libraries Journal, 2009, 26, 91). Following the approach set out by Arksey and O'Malley (International Journal of Social Research Methodology, 2005, 8, 19), we conducted a scoping review in May 2018 and closed the review with an update in September 2018. We identified 14 studies published from 2012, the European Year of Active Ageing, promoted by the European Commission, which had three domains of implementation: emotional support to decrease the emotional burden of caregivers, educational support to increase their skills, and organisational support to improve the mobility of caregivers and carereceivers. Although informal caregivers play a fundamental role in many countries, the studies that have been involved in alleviating their caring burden are few; nevertheless, they provide interesting indications. This lack of attention confirms how this portion of the population is still neglected by scientific research and risks having unequal access to health and social care. Future research is needed, not only to create and improve services to caregivers in rural, hard to reach areas, but also to evaluate and focus on the participation and the engagement of caregivers in the co-design of these services.


Malignancies in Primary Sclerosing Cholangitis--A Continuing Threat.
Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease of unknown etiology, primarily targeting cholangiocytes at any portion of the biliary tree. No effective medical treatments are currently available. A unique feature of PSC is its close association (about 80%) with inflammatory bowel disease (IBD), mainly ulcerative colitis (UC). As in many chronic inflammatory conditions, cancer development can complicate PSC, accounting for >40% of deaths. Cholangiocarcinoma (CCA), gallbladder carcinoma (GBC) and colorectal carcinoma (CRC) have been variably associated to PSC, with a prevalence up to 13-14%. The risk of cancer is one of the most challenging issues in the management of PSC; it raises several questions about cancer surveillance, early diagnosis, prevention and treatment. Among the different cancers complicating PSC, CCA is the most relevant, because it is more frequent (incidence of 0.5-1.5%) and because the prognosis is poor (5-year survival <10%). Early diagnosis of CCA in PSC can be difficult because lesions may not be evident in radiological studies. Surgical resection provides disappointing results; liver transplantation combined with neoadjuvant chemoradiotherapy is being proposed, but this approach is limited to a highly selected group of patients and is available only in a few specialized centers. Similar to CCA, GBC carries a dismal prognosis. Since it is difficult to discriminate GBC from other gallbladder abnormalities, cholecystectomy has been proposed in all gallbladder lesions detected in PSC, regardless of their size. CRC is a frequent complication of PSC associated to UC; its incidence steadily increases with time of colitis, reaching up to 20-30% of the patients after 20 years. Colonoscopy with extensive histologic sampling at an annual/biannual interval is an effective surveillance strategy. However, when dysplastic lesions are detected, preemptive proctocolectomy should be considered. PSC may be regarded as paradigmatic of the sequence leading from chronic inflammatory epithelial damage to neoplastic transformation. Understanding the molecular mechanisms regulating this pathogenetic sequence, may improve strategies of disease surveillance and cancer prevention and treatment. PSC is a chronic inflammatory cholangiopathy of unknown etiology but likely immune-mediated, characterized by peribiliary inflammation and fibrosis leading to strictures in any portion (intra- and/or extrahepatic) of the bile duct system. No effective medical treatments are currently available. A unique feature of PSC is the close association (about 80%) with IBD, mainly UC, often diagnosed before PSC (PSC/UC). As in other chronic inflammatory diseases, development of malignancies is a feared complication of PSC.


Phenylmethylene hydantoins as prostate cancer invasion and migration inhibitors. CoMFA approach and QSAR analysis.
Prostrate cancer constitutes the second leading cause of cancer deaths in men in United States. In the process of discovery of new antiproliferative and anti-metastatic agents against prostate cancer, marine-derived phenylmethylene hydantoin (PMH) derivatives were identified with activity level range between 50 and 200 μM. 3D-QSAR CoMFA model was used in virtual screening of commercially available derivatives of PMH. PMH derivatives with manifold increase in anti-migratory and anti-invasive activities were discovered using wound-healing and Cultrex invasion assays. Benzene ring replacement with other heterocyclic rings did not significantly improve the methylene hydantoins activities. Multivariate analysis performed on the whole series of methylene hydantoins, which further supported the findings of CoMFA model. Predictive QSAR model with conventional r(2) and cross-validated coefficient (q(2)) values up to 0.982 and 0.803 were established. The molecular volume (MV) and the logP were identified as critical parameters for methylene hydatoins migration inhibitory activity. PMH is a novel anti-metastatic lead class with potential therapeutic activity against prostate cancer.


The validity and value of inclusive fitness theory.
Social evolution is a central topic in evolutionary biology, with the evolution of eusociality (societies with altruistic, non-reproductive helpers) representing a long-standing evolutionary conundrum. Recent critiques have questioned the validity of the leading theory for explaining social evolution and eusociality, namely inclusive fitness (kin selection) theory. I review recent and past literature to argue that these critiques do not succeed. Inclusive fitness theory has added fundamental insights to natural selection theory. These are the realization that selection on a gene for social behaviour depends on its effects on co-bearers, the explanation of social behaviours as unalike as altruism and selfishness using the same underlying parameters, and the explanation of within-group conflict in terms of non-coinciding inclusive fitness optima. A proposed alternative theory for eusocial evolution assumes mistakenly that workers' interests are subordinate to the queen's, contains no new elements and fails to make novel predictions. The haplodiploidy hypothesis has yet to be rigorously tested and positive relatedness within diploid eusocial societies supports inclusive fitness theory. The theory has made unique, falsifiable predictions that have been confirmed, and its evidence base is extensive and robust. Hence, inclusive fitness theory deserves to keep its position as the leading theory for social evolution.


Wirelessly Powered Light and Temperature Sensors Facilitated by Electrically Small Omnidirectional and Huygens Dipole Antennas.
Wirelessly powered, very compact sensors are highly attractive for many emerging Internet-of-things (IoT) applications; they eliminate the need for on-board short-life and bulky batteries. In this study, two electrically small rectenna-based wirelessly powered light and temperature sensors were developed that operate at 915 MHz in the 902-928-MHz industrial, scientific, and medical (ISM) bands. First, a metamaterial-inspired near-field resonant parasitic (NFRP) Egyptian axe dipole (EAD) antenna was seamlessly integrated with a highly efficient sensor-augmented rectifier without any matching network. It was electrically small and very thin, and its omnidirectional property was ideal for capturing incident AC wireless power from any azimuthal direction and converting it into DC power. Both a photocell as the light sensor and a thermistor as the temperature sensor were demonstrated. The resistive properties of the photocell and thermistor changed the rectifier's output voltage level; an acoustic alarm was activated once a threshold value was attained. Second, an electrically small, low-profile NFRP Huygens antenna was similarly integrated with the same light- and temperature-sensor-augmented rectifiers. Their unidirectional nature was very suitable for surface-mounted wireless power transfer (WPT) applications (i.e., on-body and on-wall sensors). Measurements of the prototypes of both the light- and temperature-sensor-augmented omni- and unidirectional rectenna systems confirmed their predicted performance characteristics.


The outcome of depressive disorders in neurology patients: a prospective cohort study.
In a previous prospective study of 300 consecutive new attenders at neurology outpatient clinics, depressive disorders were diagnosed in 119 patients (40%) and major depressive disorder in 77 (26%). To describe the eight month outcome of depression in this cohort. Patients were reinterviewed eight months after their baseline assessment. Mental state was examined using the primary care evaluation of mental disorders (PRIME-MD) interview and the hospital anxiety and depression (HAD) self rating scale. Health status was measured using the medical outcome study 36 item short form scale (SF-36). Of the original cohort of 300, 226 (75%) participated in the follow up. Among them, 88 had a depressive disorder at baseline and 69 (78%) of those were still depressed at follow up; 54 had major depression at baseline and 46 (85%) of those still had a major depressive disorder at follow up. Among the 138 patients who had no depression at baseline, 20 new major depressive disorders had developed by the time of follow up. Resolution of major depressive disorders was associated with an improvement in health status. Most depressive disorders detected in neurology outpatients persist at an eight month follow up, and a substantial number of new cases arise. Resolution of depressive disorders, particularly major depressive disorder, is associated with an improvement in health status.


THE INFLUENCE OF BILE ON METABOLISM.
1. Bile increases the digestion of fat when given by the mouth in pill form. The percentage of fat lost in the stools of our patient with a complete biliary fistula was 63 per cent in the first period and 57 per cent in the third. This closely corresponds to the results that Müller obtained in human beings and dogs with complete obstruction of the common duct. Under bile medication the stools contained 23 per cent less fat than in the first period, and 17 per cent less than in the third. This represents an actual diminution of the amount of fat lost in the stools. Looking at the result in another way, it may be said that the average digestion of fat in the periods without bile was 40 per cent; in the periods with bile, 60 per cent, i. e., bile increased the digestion of fat relatively by 50 per cent. 2. The digestion of nitrogenous food is improved by the use of bile pills when the amount of fat in the stools is large. Instead of an average of 15 per cent being lost in the faeces, but 7 per cent escaped digestion during the four days the patient took bile. The reason for this, perhaps, lies in the better digestion of fat at this time, in consequence of which the proteid elements of the food were more thoroughly exposed to the digestive juices. 3. Ox bile is a cholagogue. The amount of bile-solids secreted in the bile period was 47 per cent greater than in the periods before and after. This confirms the work of Pfaff and Balch, here in Boston, on a human being, and that of Stadelmann and his pupils, in Germany, on dogs. 4. The effect of the bile on the bowels in this case was not remarkable, although they moved more satisfactorily during the bile period. In my experiments with dogs I usually obtained diarrhoea when giving bile. I do not feel sure, however, that this should be attributed wholly to the medication, for the diarrhoeas as a rule appeared six or more days after the beginning of the experiment and the animals were then in poor condition. Dr. Pfaff, who has had more experience with the administration of bile than I, tells me that he has found its action variable in patients. In some cases it is a laxative; in others, in which there is diarrhoea, due apparently to large amounts of fat in the food, it has the opposite effect. 5. As to the general effect of bile on body metabolism, it was observed that the urea and nitrogen were excreted in greater amount in the bile period than in either of the others. No definite conclusions can be drawn from this fact, because more nitrogen was ingested during these four days; moreover, it must be borne in mind that in these results the salol may have been a factor. 6. The amount of urine was increased by more than 50 per cent in the bile period. It is interesting to note that the amount was about the same during this bile period as in the second experiment when the bile was again taking its natural course. Von Noorden has recorded a similar increase in the amount of urine following the removal of the obstruction in acute catarrhal jaundice. The salol coating of the bile pills, which amounted to one and a quarter grammes a day, is not sufficient to account for this effect. This is evident from the work of Kumagawa, who gave two grammes of sodium salicylate daily to a dog of 25 kilos without essentially changing the amount of urine secreted. On the other hand, in taking the 30 pills daily the patient drank several extra glasses of water, and in the second experiment her general condition was naturally better than at any other time.


Characteristic and functional analysis of toll-like receptors (TLRs) in the lophotrocozoan, Crassostrea gigas, reveals ancient origin of TLR-mediated innate immunity.
The evolution of TLR-mediated innate immunity is a fundamental question in immunology. Here, we report the characterization and functional analysis of four TLR members in the lophotrochozoans Crassostreagigas (CgTLRs). All CgTLRs bear a conserved domain organization and have a close relationship with TLRs in ancient non-vertebrate chordates. In HEK293 cells, every CgTLR could constitutively activate NF-κB responsive reporter, but none of the PAMPs tested could stimulate CgTLR-activated NF-κB induction. Subcellular localization showed that CgTLR members have similar and dual distribution on late endosomes and plasma membranes. Moreover, CgTLRs and CgMyD88 mRNA show a consistent response to multiple PAMP challenges in oyster hemocytes. As CgTLR-mediated NF-κB activation is dependent on CgMyD88, we designed a blocking peptide for CgTLR signaling that would inhibit CgTLR-CgMyD88 dependent NF-κB activation. This was used to demonstrate that a Vibrio parahaemolyticus infection-induced enhancement of degranulation and increase of cytokines TNF mRNA in hemocytes, could be inhibited by blocking CgTLR signaling. In summary, our study characterized the primitive TLRs in the lophotrocozoan C. gigas and demonstrated a fundamental role of TLR signaling in infection-induced hemocyte activation. This provides further evidence for an ancient origin of TLR-mediated innate immunity.


Minimal effect of conditional ferroportin KO in the neural retina implicates ferrous iron in retinal iron overload and degeneration.
Iron-induced oxidative stress can cause or exacerbate retinal degenerative diseases. Retinal iron overload has been reported in several mouse disease models with systemic or neural retina-specific knockout (KO) of homologous ferroxidases ceruloplasmin (Cp) and hephaestin (Heph). Cp and Heph can potentiate ferroportin (Fpn) mediated cellular iron export. Here, we used retina-specific Fpn KO mice to test the hypothesis that retinal iron overload in Cp/Heph DKO mice is caused by impaired iron export from neurons and glia. Surprisingly, there was no indication of retinal iron overload in retina-specific Fpn KO mice: the mRNA levels of transferrin receptor in the retina were not altered at 7-10-months age. Consistent with this, levels and localization of ferritin light chain were unchanged. To "stress the system", we injected iron intraperitoneally into Fpn KO mice with or without Cp KO. Only mice with both retina-specific Fpn KO and Cp KO had modestly elevated retinal iron levels. These results suggest that impaired iron export through Fpn is not sufficient to explain the retinal iron overload in Cp/Heph DKO mice. An increase in the levels of retinal ferrous iron caused by the absence of these ferroxidases, followed by uptake into cells by ferrous iron importers, is most likely necessary.


An in-situ study of the impacts of urban wastewater on the immune and reproductive systems of the freshwater mussel Elliptio complanata.
The goal of this study was to examine the disruptive effects of municipal effluents on the immune and reproductive systems of freshwater mussels. For 30 days, caged mussels were immersed in the Rivière des Mille Iles (Quebec, Canada), 150 m both upstream and downstream from two urban wastewater treatment plants: station F (Fabreville) and station A (Auteuil), which serve the city of Laval. Station F is 12 km upstream from station A. The immune and reproductive statuses of the mussels were thereafter determined. Though the weight/shell length ratio was not affected, the effluent induced mortality up to 60% at downstream sites. Total hemocyte counts increased, and phagocytosis and lysozyme activities were induced at station F, whereas these responses were suppressed at station A. Heterotrophic bacteria levels in mussels were negatively correlated with phagocytosis, showing the importance of this process in defending against infection. Inflammation biomarkers such as nitric oxide and cyclooxygenase activity were the same for all sites but were positively correlated with phagocytosis activity. The production of vitellogenin (Vtg)-like proteins was significantly induced at the site downstream from station A and was strongly associated with phagocytosis. This was further supported through analysis of covariance, of Vtg responses against phagocytosis, revealing that Vtg was no longer induced at the sites upstream and downstream from station A. The data support the contention that Vtg was involved, in part at least, in the immune system in mussels. Both Vtg and immune status are impacted by urban effluents and should be considered when using the Vtg biomarker to search for the presence of (xeno)estrogens in contaminated environments.


Transmembrane molecular transport during versus after extremely large, nanosecond electric pulses.
Recently there has been intense and growing interest in the non-thermal biological effects of nanosecond electric pulses, particularly apoptosis induction. These effects have been hypothesized to result from the widespread creation of small, lipidic pores in the plasma and organelle membranes of cells (supra-electroporation) and, more specifically, ionic and molecular transport through these pores. Here we show that transport occurs overwhelmingly after pulsing. First, we show that the electrical drift distance for typical charged solutes during nanosecond pulses (up to 100 ns), even those with very large magnitudes (up to 10 MV/m), ranges from only a fraction of the membrane thickness (5 nm) to several membrane thicknesses. This is much smaller than the diameter of a typical cell (∼16 μm), which implies that molecular drift transport during nanosecond pulses is necessarily minimal. This implication is not dependent on assumptions about pore density or the molecular flux through pores. Second, we show that molecular transport resulting from post-pulse diffusion through minimum-size pores is orders of magnitude larger than electrical drift-driven transport during nanosecond pulses. While field-assisted charge entry and the magnitude of flux favor transport during nanosecond pulses, these effects are too small to overcome the orders of magnitude more time available for post-pulse transport. Therefore, the basic conclusion that essentially all transmembrane molecular transport occurs post-pulse holds across the plausible range of relevant parameters. Our analysis shows that a primary direct consequence of nanosecond electric pulses is the creation (or maintenance) of large populations of small pores in cell membranes that govern post-pulse transmembrane transport of small ions and molecules.


Comparative systems biology analysis to study the mode of action of the isothiocyanate compound Iberin on Pseudomonas aeruginosa.
Food is now recognized as a natural resource of novel antimicrobial agents, including those that target the virulence mechanisms of bacterial pathogens. Iberin, an isothiocyanate compound from horseradish, was recently identified as a quorum-sensing inhibitor (QSI) of the bacterial pathogen Pseudomonas aeruginosa. In this study, we used a comparative systems biology approach to unravel the molecular mechanisms of the effects of iberin on QS and virulence factor expression of P. aeruginosa. Our study shows that the two systems biology methods used (i.e., RNA sequencing and proteomics) complement each other and provide a thorough overview of the impact of iberin on P. aeruginosa. RNA sequencing-based transcriptomics showed that iberin inhibits the expression of the GacA-dependent small regulatory RNAs RsmY and RsmZ; this was verified by using gfp-based transcriptional reporter fusions with the rsmY or rsmZ promoter regions. Isobaric tags for relative and absolute quantitation (iTRAQ) proteomics showed that iberin reduces the abundance of the LadS protein, an activator of GacS. Taken together, the findings suggest that the mode of QS inhibition in iberin is through downregulation of the Gac/Rsm QS network, which in turn leads to the repression of QS-regulated virulence factors, such as pyoverdine, chitinase, and protease IV. Lastly, as expected from the observed repression of small regulatory RNA synthesis, we also show that iberin effectively reduces biofilm formation. This suggests that small regulatory RNAs might serve as potential targets in the future development of therapies against pathogens that use QS for controlling virulence factor expression and assume the biofilm mode of growth in the process of causing disease.


Host cell remodelling in malaria parasites: a new pool of potential drug targets.
When in their human hosts, malaria parasites spend most of their time housed within vacuoles inside erythrocytes and hepatocytes. The parasites extensively modify their host cells to obtain nutrients, prevent host cell breakdown and avoid the immune system. To perform these modifications, malaria parasites export hundreds of effector proteins into their host cells and this process is best understood in the most lethal species to infect humans, Plasmodium falciparum. The effector proteins are synthesized within the parasite and following a proteolytic cleavage event in the endoplasmic reticulum and sorting of mature proteins into the correct vesicular trafficking pathway, they are transported to the parasite surface and released into the vacuole. The effector proteins are then unfolded before extrusion across the vacuole membrane by a unique translocon complex called Plasmodium translocon of exported proteins. After gaining access to the erythrocyte cytoplasm many effector proteins continue their journey to the erythrocyte surface by utilising various membranous structures established by the parasite. This complex trafficking pathway and a large number of the effector proteins are unique to Plasmodium parasites. This pathway could, therefore, be developed as new drug targets given that protein export and the functional role of these proteins are essential for parasite survival. This review explores known and potential drug targetable steps in the protein export pathway and strategies for discovering novel drug targets.


A paradigm shift in the monitoring of patients with acromegaly: last available growth hormone may overestimate risk.
Acromegaly is associated with reduced life expectancy, which has been reported to be normalized if treatment is successful in controlling GH/IGF-I levels. Most previous studies have invariably used the last available GH/IGF-I, which may be biased as it only assesses exposure at a single point in time. We compared the last available GH/IGF-I analysis to a "time-dependent" and cumulative method, during follow-up to assess risk of mortality in the West Midlands Acromegaly study (n = 501). Using the last available GH, there was a statistically significant increase in mortality comparing groups as low as GH ≤ 1 μg/L vs >1 μg/L (relative risks [RR] 1.8, P = .03). This was not the case when using the "time-dependent method," where only comparisons of GH values of GH ≤5 μg/L vs >5 μg/L were suggestive of being associated with an increased risk of mortality (RR = 1.5, P = .08). When the time-dependent GH method of analysis was used, the RR of mortality at each level was lower and the associated P value was less significant. Irrespective of using the last available or time-dependent method, when IGF-I was divided into levels according to quartile or arbitrary cutoffs, there was no significant increase in mortality with higher levels. This study emphasizes the potential bias of using the latest available GH/IGF-I levels to predict mortality. Our study again highlights the limitations of IGF-I in predicting mortality.


CT and MR imaging of the upper extremity vasculature: pearls, pitfalls, and challenges.
Imaging is needed for diagnosis, treatment planning, and follow-up of patients with pathologies affecting upper extremity vasculature. With growth and evolution of imaging modalities [especially CT angiography (CTA) and MR angiography (MRA)], there is need to recognize the advantages and disadvantages of various modalities and obtain the best possible imaging diagnostic test. Understanding various limitations and pitfalls as well as the best practices to minimize and manage these pitfalls is very important for the diagnosis. This article reviews the upper extremity arterial vascular anatomy, discusses the CTA and MRA imaging, various pitfalls, and challenges and discuss imaging manifestations of upper extremity arterial pathologies.


Tell me more: Can a memory test reduce analogue traumatic intrusions?
Information processing theories of post-traumatic stress disorder (PTSD) state that intrusive images emerge due to a lack of integration of perceptual trauma representations in autobiographical memory. To test this hypothesis experimentally, participants were shown an aversive film to elicit intrusive images. After viewing, they received a recognition test for just one part of the film. The test contained neutrally formulated items to rehearse information from the film. Participants reported intrusive images for the film in an intrusion diary during one week after viewing. In line with expectations, the number of intrusive images decreased only for the part of the film for which the recognition test was given. Furthermore, deliberate cued-recall memory after one week was selectively enhanced for the film part that was in the recognition test a week before. The findings provide new evidence supporting information processing models of PTSD and have potential implications for early interventions after trauma.


Applications of the Amplatzer Vascular Plug 4.
The purpose of this study was to present our initial experience with the Amplatzer® Vascular Plug (AVP) 4 in various arterial environments. This material was designed for the embolization of peripheral small vessels using a diagnostic catheter. Herein, the following three procedures using the AVP 4 were described: hemodialysis fistula occlusion as a treatment for the steal phenomenon, gastroduodenal artery embolization prior to liver radioembolization, and vertebral artery embolization for the treatment of subclavian artery pseudoaneurysm and arteriovenous fistula. All of the treated vessels were successfully occluded, and the devices remained in the original locations and configurations during the follow-up period. When compared with the previous generation of vascular plugs, the AVP 4 allows faster and safer procedures with less radiation exposure to the patients and angiography team.


How spatial variation in areal extent and configuration of labile vegetation states affect the riparian bird community in Arctic tundra.
The Arctic tundra is currently experiencing an unprecedented combination of climate change, change in grazing pressure by large herbivores and growing human activity. Thickets of tall shrubs represent a conspicuous vegetation state in northern and temperate ecosystems, where it serves important ecological functions, including habitat for wildlife. Thickets are however labile, as tall shrubs respond rapidly to both abiotic and biotic environmental drivers. Our aim was to assess how large-scale spatial variation in willow thicket areal extent, configuration and habitat structure affected bird abundance, occupancy rates and species richness so as to provide an empirical basis for predicting the outcome of environmental change for riparian tundra bird communities. Based on a 4-year count data series, obtained through a large-scale study design in low arctic tundra in northern Norway, statistical hierarchical community models were deployed to assess relations between habitat configuration and bird species occupancy and community richness. We found that species abundance, occupancy and richness were greatly affected by willow areal extent and configuration, habitat features likely to be affected by intense ungulate browsing as well as climate warming. In sum, total species richness was maximized in large and tall willow patches of small to intermediate degree of fragmentation. These community effects were mainly driven by responses in the occupancy rates of species depending on tall willows for foraging and breeding, while species favouring other vegetation states were not affected. In light of the predicted climate driven willow shrub encroachment in riparian tundra habitats, our study predicts that many bird species would increase in abundance, and that the bird community as a whole could become enriched. Conversely, in tundra regions where overabundance of large herbivores leads to decreased areal extent, reduced height and increased fragmentation of willow thickets, bird community richness and species-specific abundance are likely to be significantly reduced.


[Prevalence of adenovirus antigens in children presenting with acute diarrhoea].
Viral diarrhoea remains a major cause of childhood morbidity and mortality worldwide. Four major categories of viruses are now recognized as clinically important, including rotavirus, astrovirus, adenovirus, and calicivirus. This retrospective epidemiological study was conducted in the East centre part of Tunisia. A total of 638 stool samples were collected from children under 5 years of age presenting with acute diarrhoea at hospitals the East centre part of Tunisia between October 2003 and September 2005. All samples were analyzed using commercially available immunoenzymatic assay (EIA) kits to detect specific adenovirus antigens. Samples positive for adenovirus antigen were further screened using an ELISA technique allowing specific detection of species F enteric adenovirus types 40 and 41. Adenovirus was detected in 6% of the stools tested using ELISA. Among stool samples testing positive for adenovirus, 57% (20/35) were found to contain species F adenovirus types 40/41. In addition to diarrhoea that was present in all children studied, vomiting and fever were observed in 89% and 53% respectively and were associated with respiratory troubles in 32%. Enteric adenoviruses appear to play an important role in paediatric diarrhoea in Tunisia. Use of simple effective viral diagnostic techniques in paediatric hospitals could improve patient care by reducing unnecessary use of antibiotics.


SOD1 aggregation in ALS mice shows simplistic test tube behavior.
A longstanding challenge in studies of neurodegenerative disease has been that the pathologic protein aggregates in live tissue are not amenable to structural and kinetic analysis by conventional methods. The situation is put in focus by the current progress in demarcating protein aggregation in vitro, exposing new mechanistic details that are now calling for quantitative in vivo comparison. In this study, we bridge this gap by presenting a direct comparison of the aggregation kinetics of the ALS-associated protein superoxide dismutase 1 (SOD1) in vitro and in transgenic mice. The results based on tissue sampling by quantitative antibody assays show that the SOD1 fibrillation kinetics in vitro mirror with remarkable accuracy the spinal cord aggregate buildup and disease progression in transgenic mice. This similarity between in vitro and in vivo data suggests that, despite the complexity of live tissue, SOD1 aggregation follows robust and simplistic rules, providing new mechanistic insights into the ALS pathology and organism-level manifestation of protein aggregation phenomena in general.


Imaging in psoriasis and psoriatic arthritis: GRAPPA 2008.
At the 2008 meeting of GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis), the primary focus of the imaging session was the enthesis. Presentations from Dennis McGonagle (Leeds, UK), Richard Hodgson (Leeds, UK), and Paolo Gisondi (Verona, Italy) elaborated on this theme and prepared the meeting attendees for group discussions of further work in this area. Imaging, notably magnetic resonance imaging (MRI) and ultrasonography, provides evidence of pathological change at the enthesis in psoriatic arthritis (PsA). Further, imaging abnormalities are found at sites that are asymptomatic in both PsA and psoriasis. The role of newer imaging modalities, such as ultra-short echo time (UTE) MRI, is promising but remains to be fully elucidated. The implication of these findings in relation to subclinical and predisease status is intriguing and requires further study in longitudinal studies. Further work is also required to examine the proposed common biomechanical basis between joint and skin, the mechanism of the resulting inflammation, and how these mechanisms differ from those seen in rheumatoid arthritis.


The residual-based predictiveness curve: A visual tool to assess the performance of prediction models.
It is agreed among biostatisticians that prediction models for binary outcomes should satisfy two essential criteria: first, a prediction model should have a high discriminatory power, implying that it is able to clearly separate cases from controls. Second, the model should be well calibrated, meaning that the predicted risks should closely agree with the relative frequencies observed in the data. The focus of this work is on the predictiveness curve, which has been proposed by Huang et al. (Biometrics 63, 2007) as a graphical tool to assess the aforementioned criteria. By conducting a detailed analysis of its properties, we review the role of the predictiveness curve in the performance assessment of biomedical prediction models. In particular, we demonstrate that marker comparisons should not be based solely on the predictiveness curve, as it is not possible to consistently visualize the added predictive value of a new marker by comparing the predictiveness curves obtained from competing models. Based on our analysis, we propose the "residual-based predictiveness curve" (RBP curve), which addresses the aforementioned issue and which extends the original method to settings where the evaluation of a prediction model on independent test data is of particular interest. Similar to the predictiveness curve, the RBP curve reflects both the calibration and the discriminatory power of a prediction model. In addition, the curve can be conveniently used to conduct valid performance checks and marker comparisons.


The G67E mutation in hMLH1 is associated with an unusual presentation of Lynch syndrome.
Germline mutations in the mismatch repair (MMR) genes are associated with Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Here, we characterise a variant of hMLH1 that confers a loss-of-function MMR phenotype. The mutation changes the highly conserved Gly67 residue to a glutamate (G67E) and is reminiscent of the hMLH1-p.Gly67Arg mutation, which is present in several Lynch syndrome cohorts. hMLH1-Gly67Arg has previously been shown to confer loss-of-function (Shimodaira et al, 1998), and two functional assays suggest that the hMLH1-Gly67Glu protein fails to sustain normal MMR functions. In the first assay, hMLH1-Gly67Glu abolishes the protein's ability to interfere with MMR in yeast. In the second assay, mutation of the analogous residue in yMLH1 (yMLH1-Gly64Glu) causes a loss-of-function mutator phenotype similar to yMLH1-Gly64Arg. Despite these molecular similarities, an unusual spectrum of tumours is associated with hMLH1-Gly67Glu, which is not typical of those associated with Lynch syndrome and differs from those found in families carrying the hMLH1-Gly67Arg allele. This suggests that hMLH1 may have different functions in certain tissues and/or that additional factors may modify the influence of hMLH1 mutations in causing Lynch syndrome.


Genetic fingerprinting of salmon louse (Lepeophtheirus salmonis) populations in the North-East Atlantic using a random forest classification approach.
Caligid sea lice represent a significant threat to salmonid aquaculture worldwide. Population genetic analyses have consistently shown minimal population genetic structure in North Atlantic Lepeophtheirus salmonis, frustrating efforts to track louse populations and improve targeted control measures. The aim of this study was to test the power of reduced representation library sequencing (IIb-RAD sequencing) coupled with random forest machine learning algorithms to define markers for fine-scale discrimination of louse populations. We identified 1286 robustly supported SNPs among four L. salmonis populations from Ireland, Scotland and Northern Norway. Only weak global structure was observed based on the full SNP dataset. The application of a random forest machine-learning algorithm identified 98 discriminatory SNPs that dramatically improved population assignment, increased global genetic structure and resulted in significant genetic population differentiation. A large proportion of SNPs found to be under directional selection were also identified to be highly discriminatory. Our data suggest that it is possible to discriminate between nearby L. salmonis populations given suitable marker selection approaches, and that such differences might have an adaptive basis. We discuss these data in light of sea lice adaption to anthropogenic and environmental pressures as well as novel approaches to track and predict sea louse dispersal.


The relative importance of whole body vibration and occupational lifting as risk factors for low-back pain.
To explore the impact of occupational exposure to whole body vibration (WBV) on low back pain (LBP) in the general population and to estimate the burden of LBP attributable to occupational WBV in comparison with that due to occupational lifting. A questionnaire including sections on WBV at work, LBP, and potential risk factors was mailed to a community sample of 22 194 men and women of working age. Sources and durations of exposure to occupational WBV were ascertained for the past week and personal vibration doses (eVDV) were estimated. Analysis was confined to subjects reporting exposures in the past week as typical of their work. Associations of LBP with eVDV, driving industrial vehicles, and occupational lifting were explored by logistic regression and attributable numbers were calculated. Significant associations were found between daily lifting of weights greater than 10 kg at work and LBP, troublesome LBP (which made it difficult to put on hosiery), and sciatica (prevalence ratios 1.3 to 1.7); but the risk of these outcomes in both sexes varied little by eVDV and only weak associations were found with riding on industrial vehicles. Assuming causal associations, the numbers of cases of LBP in Britain attributable to occupational WBV were estimated to be 444 000 in men and 95 000 in women. This compared with an estimated 940 000 male cases and 370 000 female cases of LBP from occupational lifting. The burden of LBP in Britain from occupational exposure to WBV is smaller than that attributable to lifting at work.


Report on the 2nd International Consortium on Hallucination Research: evolving directions and top-10 "hot spots" in hallucination research.
This article presents a report on the 2nd meeting of the International Consortium on Hallucination Research, held on September 12th and 13th 2013 at Durham University, UK. Twelve working groups involving specialists in each area presented their findings and sought to summarize the available knowledge, inconsistencies in the field, and ways to progress. The 12 working groups reported on the following domains of investigation: cortical organisation of hallucinations, nonclinical hallucinations, interdisciplinary approaches to phenomenology, culture and hallucinations, subtypes of auditory verbal hallucinations, a Psychotic Symptoms Rating Scale multisite study, visual hallucinations in the psychosis spectrum, hallucinations in children and adolescents, Research Domain Criteria behavioral constructs and hallucinations, new methods of assessment, psychological therapies, and the Hearing Voices Movement approach to understanding and working with voices. This report presents a summary of this meeting and outlines 10 hot spots for hallucination research, which include the in-depth examination of (1) the social determinants of hallucinations, (2) translation of basic neuroscience into targeted therapies, (3) different modalities of hallucination, (4) domain convergence in cross-diagnostic studies, (5) improved methods for assessing hallucinations in nonclinical samples, (6) using humanities and social science methodologies to recontextualize hallucinatory experiences, (7) developmental approaches to better understand hallucinations, (8) changing the memory or meaning of past trauma to help recovery, (9) hallucinations in the context of sleep and sleep disorders, and (10) subtypes of hallucinations in a therapeutic context.


Automated detection of cribriform growth patterns in prostate histology images.
Cribriform growth patterns in prostate carcinoma are associated with poor prognosis. We aimed to introduce a deep learning method to detect such patterns automatically. To do so, convolutional neural network was trained to detect cribriform growth patterns on 128 prostate needle biopsies. Ensemble learning taking into account other tumor growth patterns during training was used to cope with heterogeneous and limited tumor tissue occurrences. ROC and FROC analyses were applied to assess network performance regarding detection of biopsies harboring cribriform growth pattern. The ROC analysis yielded a mean area under the curve up to 0.81. FROC analysis demonstrated a sensitivity of 0.9 for regions larger than [Formula: see text] with on average 7.5 false positives. To benchmark method performance for intra-observer annotation variability, false positive and negative detections were re-evaluated by the pathologists. Pathologists considered 9% of the false positive regions as cribriform, and 11% as possibly cribriform; 44% of the false negative regions were not annotated as cribriform. As a final experiment, the network was also applied on a dataset of 60 biopsy regions annotated by 23 pathologists. With the cut-off reaching highest sensitivity, all images annotated as cribriform by at least 7/23 of the pathologists, were all detected as cribriform by the network and 9/60 of the images were detected as cribriform whereas no pathologist labelled them as such. In conclusion, the proposed deep learning method has high sensitivity for detecting cribriform growth patterns at the expense of a limited number of false positives. It can detect cribriform regions that are labelled as such by at least a minority of pathologists. Therefore, it could assist clinical decision making by suggesting suspicious regions.


Loss of SOCS3 gene expression converts STAT3 function from anti-apoptotic to pro-apoptotic.
The transcription factor STAT3 is activated by interleukin-6-related cytokines and has been implicated as an oncogene; it promotes cell proliferation and is anti-apoptotic. However, in some cases, STAT3 has been shown to be pro-apoptotic, especially in mammary epithelial cells. In this report, we generated SOCS3-deficient murine embryonic fibroblasts (MEFs), in which STAT3 activation is extremely enhanced and prolonged. We found that LIF induces caspase-3 activation and apoptosis of SOCS3(-/-) MEFs. Exogenous expression of the dominant negative form of STAT3 but not STAT1 suppressed LIF-induced apoptosis of SOCS3(-/-) MEFs, indicating that STAT3 plays a critical role in apoptosis induction. As shown in mammary gland epithelial cells, expression of the phosphatidylinositol 3-kinase regulatory subunits p50alpha and p55alpha was induced in response to LIF in SOCS3(-/-) MEFs but not in wild-type MEFs, and Akt/protein kinase B activity was substantially reduced in SOCS3(-/-) MEFs. Furthermore, we found that some of the STAT3 target genes related to apoptosis and proliferation, such as Bcl-2 and cyclin D1, were repressed upon LIF treatment in SOCS3(-/-) cells. Not only the up-regulation of p50alpha and p55alpha but also the repression of cyclin D1 and Bcl-2 in SOCS3(-/-) MEFs was inhibited by dominant negative STAT3. These data suggest that prolonged activation of STAT3 could induce apoptosis/growth arrest rather than anti-apoptosis and proliferation in certain cases, and SOCS3 is a critical regulator of this balance.