Impact of Noise Exposure on Risk of Developing Stress-Related Metabolic Effects: A Systematic Review and Meta-Analysis.
Exposure to noise can increase biological stress reactions, which may increase adverse health effects, including metabolic disorders; however, the certainty in the association between exposure to noise and metabolic outcomes has not been widely explored. The objective of this review is to evaluate the evidence between noise exposures and metabolic effects. A systematic review of English and comparative studies available in PubMed, Cochrane Central, EMBASE, and CINAHL databases between January 1, 1980 and December 29, 2021 was performed. Risk of Bias of Nonrandomized Studies of Exposures was used to assess risk of bias of individual studies and certainty of the body of evidence for each outcome was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Fifty-six primary studies reporting on cortisol, cholesterol levels, waist circumference, glucose levels, and adrenaline and/or noradrenaline were identified. Although meta-analyses suggested that there may be an increase in waist circumference and adrenaline with increased noise exposure, the certainty in the evidence is very low. Overall, the certainty in the evidence of an effect of increased noise on all the outcomes were low to very low due to concerns with risk of bias, inconsistency across exposure sources, populations, and studies, and imprecision in the estimates of effects. The certainty of the evidence of increased noise on metabolic effects was low to very low, which likely reflects the inability to compare across the totality of the evidence for each outcome. The findings from this review may be used to inform policies involving noise reduction and mitigation strategies, and to direct further research in areas that currently have limited evidence available.


Should intervening benign tissue be included in the measurement of discontinuous foci of cancer on prostate needle biopsy? Correlation with radical prostatectomy findings.
Currently, there is no consensus as to the optimal method for measuring tumor length or percentage of cancer on a core when there are 2 or more foci of prostate cancer in a single core separated by benign intervening stroma. One option is to measure discontinuous foci of cancer as if they were 1 single continuous focus. The other option is to add the measurements of the individual separate foci of cancer, ignoring the extent of the intervening benign prostate tissue. The surgical pathology database at The Johns Hopkins Hospital was searched for outside consult cases of prostate needle biopsies reviewed between 2005 and 2010 when the patient came to our institution for radical prostatectomy (RP). Cases were restricted to those with biopsy Gleason score 6 in which there was at least 15% discordance between the outside and our institution in terms of the reported highest percentage of cancer per core per case. One hundred and nine patients were identified fulfiling our inclusion criteria. Seventy-nine showed the same Gleason score in the RP, and 30 had an upgrade to Gleason ≥7. Including all cases (scores 6, 7, and 8 at RP), there was no significant association between the maximum percentage of cancer per core with organ-confined disease or risk of positive surgical margins, regardless if the cores were measured at Hopkins or at the outside institutions. For cases with no upgrade at RP, the differences between the maximum percentage of cancer per core per case recorded at Hopkins and the outside institutions ranged from 15% to 80%, in which the mean and median differences were 35% and 30%, respectively. The maximum percentages of tumor involvement on a core per case given at our institution more strongly correlated with the presence of organ-confined disease (P=0.004) compared with the percentages given at the outside institutions (P=0.027). Surgical margin positivity was also associated with the maximum percentages of tumor involvement per core given at our institution (P=0.004), whereas the outside percentages were not significant predictors of margin status (P=0.2). In a multivariable analysis, maximum percentage of cancer per core per case measured at Hopkins which includes intervening benign prostate tissue in the measurement was also more predictive of stage and margins than ignoring intervening benign tissue. In summary, our study demonstrated that for prostate cancer in which the needle biopsy grade is representative of the entire tumor, quantifying cancer extent on biopsy by measuring discontinuous cancer on biopsy from one end to the other as opposed to "collapsing" the cancer by subtracting out the intervening benign prostate tissue correlates better with organ-confined disease and risk of positive margins.


Subsets of a large cognitive battery better power clinical trials on early stage Alzheimer's disease.
Cognitive batteries routinely used by the Alzheimer's disease (AD) research community may contain items that are uninformative for tracking disease progression to power clinical trials on early stage AD. We aim to identify the subsets of the most informative items from an existing cognitive battery to better power clinical trials on early AD. Longitudinal change in item scores from the battery was associated with the onset of mild cognitive impairment (MCI) in 1,513 elderly individuals. Items whose longitudinal changes were correlated with the onset of MCI were selected as informative for tracking the early cognitive progression. 226 items in the battery were annually assessed over a follow-up of up to 13 years. Changes of item scores over time from 187 items were significantly correlated with the onset of MCI. For clinical trials on preclinical AD and on MCI, informative items permit smaller or similar sample sizes as compared to the entire battery, whereas uninformative items require much larger sample sizes. Longitudinal changes in item scores from about 17% of items in the cognitive battery are uninformative for tracking early disease progression. Clinical trials on early AD can be better powered using informative items rather than the entire battery.


Epithelial cell cycling predicts p53 responsiveness to gamma-irradiation during post-natal mammary gland development.
The tumor suppressor gene, TP53, plays a major role in surveillance and repair of radiation-induced DNA damage. In multiple cell types, including mammary epithelial cells, abrogation of p53 (encoded by Trp53) function is associated with increased tumorigenesis. We examined gamma-irradiated BALB/c-Trp53(+/+) and -Trp53(-/-) female mice at five stages of post-natal mammary gland development to determine whether radiation-induced p53 activity is developmentally regulated. Our results show that p53-mediated responses are attenuated in glands from irradiated virgin and lactating mice, as measured by induction of p21/WAF1 (encoded by Cdkn1a) and apoptosis, while irradiated early- and mid-pregnancy glands exhibit robust p53 activity. There is a strong correlation between p53-mediated apoptosis and the degree of cellular proliferation, independent of the level of differentiation. In vivo, proliferation is intimately influenced by steroid hormones. To determine whether steroid hormones directly modulate p53 activity, whole organ cultures of mammary glands were induced to proliferate using estrogen plus progesterone or epidermal growth factor plus transforming growth factor-alpha and p53 responses to gamma-irradiation were measured. Regardless of mitogens used, proliferating mammary epithelial cells show comparable p53 responses to gamma-irradiation, including expression of nuclear p53 and p21/WAF1 and increased levels of apoptosis, compared to non-proliferating irradiated control cultures. Our study suggests that differences in radiation-induced p53 activity during post-natal mammary gland development are influenced by the proliferative state of the gland, and may be mediated indirectly by the mitogenic actions of steroid hormones in vivo.


Trade-off between mating opportunities and parental care: brood desertion by female Kentish plovers.
Why do some parents care for their young whereas others divorce from their mate and abandon their offspring? This decision is governed by the trade-off between the value of the current breeding event and future breeding prospects. In the precocial Kentish plover Charadrius alexandrinus females frequently, but not always, abandon their broods to be cared for by their mate, and seek new breeding partners within the same season. We have shown previously that females' remating opportunities decline with date in the season, so brood desertion should be particularly favourable for early breeding females. However, the benefits are tempered by the fact that single-parent families have lower survival expectancies than those where the female remains to help the male care for the young. We therefore tested the prediction that increasing the value of the current brood (by brood-size manipulation) should increase the duration of female care early in the season, but that in late breeders, with reduced remating opportunities, desertion and thus the duration of female care should be independent of current brood size. These predictions were fulfilled, indicating that seasonally modulated trade-offs between current brood value and remating opportunities can be important in the desertion decisions of species with flexible patterns of parental care.


MILANO--custom annotation of microarray results using automatic literature searches.
High-throughput genomic research tools are becoming standard in the biologist's toolbox. After processing the genomic data with one of the many available statistical algorithms to identify statistically significant genes, these genes need to be further analyzed for biological significance in light of all the existing knowledge. Literature mining--the process of representing literature data in a fashion that is easy to relate to genomic data--is one solution to this problem. We present a web-based tool, MILANO (Microarray Literature-based Annotation), that allows annotation of lists of genes derived from microarray results by user defined terms. Our annotation strategy is based on counting the number of literature co-occurrences of each gene on the list with a user defined term. This strategy allows the customization of the annotation procedure and thus overcomes one of the major limitations of the functional annotations usually provided with microarray results. MILANO expands the gene names to include all their informative synonyms while filtering out gene symbols that are likely to be less informative as literature searching terms. MILANO supports searching two literature databases: GeneRIF and Medline (through PubMed), allowing retrieval of both quick and comprehensive results. We demonstrate MILANO's ability to improve microarray analysis by analyzing a list of 150 genes that were affected by p53 overproduction. This analysis reveals that MILANO enables immediate identification of known p53 target genes on this list and assists in sorting the list into genes known to be involved in p53 related pathways, apoptosis and cell cycle arrest. MILANO provides a useful tool for the automatic custom annotation of microarray results which is based on all the available literature. MILANO has two major advances over similar tools: the ability to expand gene names to include all their informative synonyms while removing synonyms that are not informative and access to the GeneRIF database which provides short summaries of curated articles relevant to known genes. MILANO is available at http://milano.md.huji.ac.il.


Identification of a myosin heavy chain gene from Entamoeba histolytica.
The myosin heavy chain gene A, mhcA, from E. histolytica was identified by polymerase chain reaction. There is only one copy of this gene on the ameba genome. The mhcA gene encodes a 6 kb messenger RNA. The predicted protein sequence is homologous to myosin II from both, Dictyostelium discoideum and Acanthamoeba castellanii. Specific areas of the N-terminal region of myosin II are highly conserved reflecting a similarity in functional domains, like the ATP or the actin binding sites.


Male pubertal development: are endocrine-disrupting compounds shifting the norms?
Endocrine-disrupting compounds (EDCs) are synthetic or natural compounds that interfere with endogenous endocrine action. The frequent use of chemicals with endocrine active properties in household products and contamination of soil, water, and food sources by persistent chemical pollutants result in ubiquitous exposures. Wildlife observations and animal toxicological studies reveal adverse effects of EDCs on reproductive health. In humans, a growing number of epidemiological studies report an association with altered pubertal timing and progression. While these data are primarily reported in females, this review will focus on the small number of studies performed in males that report an association of polychlorinated biphenyls with earlier sexual maturity rating and confirm subtle effects of lead, dioxins, and endosulfan on delaying pubertal onset and progression in boys. Recent studies have also demonstrated that EDC exposure may affect pubertal testosterone production without having a noticeable effect on sexual maturity rating. A limitation to understand the effects of EDCs in humans is the potential for confounding due to the long temporal lag from early-life exposures to adult outcomes. The complex interplay of multiple environmental exposures over time also complicates the interpretation of human studies. These studies have identified critical windows of vulnerability during development when exposures to EDCs alter critical pathways and affect postnatal reproductive health. Contemporaneous exposures can also disrupt the hypothalamic-pituitary-gonadal axis. This paper will review the normal process of puberty in males and summarize human data that suggest potential perturbations in pubertal onset and tempo with early-life exposures to EDCs.


Urocortin suppresses endometrial cancer cell migration via CRFR2 and its system components are differentially modulated by estrogen.
Urocortin (UCN1) peptide shares structural and functional homology with corticotropin-releasing factor (CRF). UCN1 is significantly reduced in endometrial adenocarcinoma compared to healthy controls. However, there are no data which evaluate the effects of UCN1 in the endometrium, or how it is modulated. We used proliferation and transwell assays to determine the effect of UCN1 on the proliferation and migration of Ishikawa and HEC1A cells. We also determined the expression levels of UCN1 and its receptors produced by estrogen receptor agonists, and the effect of UCN1 on estrogen receptor expression, using quantitative polymerase chain reaction. UCN1 suppressed migration of endometrial cancer cells in vitro. This effect appears to be specific to CRF receptor 2 (CRFR2), as selective antagonism of CRFR2 but not CRFR1 completely eliminated suppression of migration. Activation of ERA reduced UCN1 expression, but only had a small effect on the expression of CRFR1. However, expression of CRFR2 was more notably reduced at both the mRNA and protein levels by activation of ERB. UCN1 in turn reduced both ERA and ERB expression, as assessed by real-time quantitative PCR. We demonstrate that UCN1 significantly suppresses the migration of endometrial cancer cells but has no effect on their proliferation. Thus, loss of UCN1 in endometrial cancer may promote invasion and metastatic spread. There is a complex relationship between the UCN1 system and estrogen receptors, which may provide insights into endometrial carcinogenesis, a disease known to be driven by estrogen excess.


Thrombelastographic method to quantify the contribution of factor XIII to coagulation kinetics.
Factor XIII (FXIII) plays a critical role in clot strength, and FXIII deficiency or excess is associated with hemorrhage or thrombosis, respectively. Our goal was to design a thrombelastography-based method to characterize the effects of FXIII on plasma clot strength. Normal human plasma was exposed to 0 or 200 mug/ml anti-FXIII antibodies for 20 min prior to celite activation and calcium addition. Other plasma had addition of fibrinogen (625 mg/dl)/FXIII (2 U/ml) or 30% dilution with hydroxyethyl starch before exposure to 0 or 200 mug/ml anti-FXIII antibodies. Thromboelastography was performed and data were collected until stable clot strength was observed. The exposure of normal plasma to anti-FXIII antibodies resulted in a significant (P < 0.05) decrease in clot strength (63%) compared with plasma without antibodies. Further samples exposed to anti-FXIII antibodies had clot strength no different from FXIII-deficient plasma. The FXIII-mediated clot strength varied between 44 and 50% in hypercoagulable and hypocoagulable plasma, respectively. In conclusion, the present investigation successfully demonstrated a novel method to detect the impact of FXIII activity in plasma samples. Further actuarial investigation will be required to determine the utility of this approach in the diagnosis and treatment of patients with either acquired FXIII deficiency or excess and concordant coagulopathy.


Neurofibromin plays a critical role in modulating osteoblast differentiation of mesenchymal stem/progenitor cells.
Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1, a pandemic autosomal dominant genetic disorder with an incidence of 1:3000. Individuals with NF1 have a variety of malignant and non-malignant manifestations, including skeletal manifestations, such as osteoporosis, scoliosis and short statures. However, the mechanism(s) underlying the osseous manifestations in NF1 are poorly understood. In the present study, utilizing Nf1 haploinsufficient (+/-) mice, we demonstrate that Nf1+/- mesenchymal stem/progenitor cells (MSPC) have increased proliferation and colony forming unit-fibroblast (CFU-F) capacity compared with wild-type (WT) MSPC. Nf1+/- MSPC also have fewer senescent cells and have a significantly higher telomerase activity compared with WT MSPC. Nf1+/- MSPC have impaired osteoblast differentiation as determined by alkaline phosphatase staining, and confirmed by single CFU-F replating assays. The impaired osteoblast differentiation in Nf1+/- MSPC is consistent with the reduced expression of osteoblast markers at the mRNA level, including osteocalcin and osteonectin. Importantly, re-expression of the full-length NF1 GTPase activating related domain (NF1 GAP-related domain) is sufficient to restore the impaired osteoblast differentiation in Nf1+/- MSPC. Taken together, our results suggest that neurofibromin plays a crucial role in modulating MSPC differentiation into osteoblasts, and the defect in osteoblast differentiation may contribute at least in part to the osseous abnormalities seen in individuals with NF1.


Diesel exposure suppresses natural killer cell function and resolution of eosinophil inflammation: a randomized controlled trial of exposure in allergic rhinitics.
Exposure to diesel exhaust (DE) is known to exacerbate allergic inflammation, including virus-induced eosinophil activation in laboratory animals. We have previously shown that in human volunteers with allergic rhinitis a short-term exposure to DE prior to infection with the live attenuated influenza virus (LAIV) increases markers of allergic inflammation in the nasal mucosa. Specifically, levels of eosinophilic cationic protein (ECP) were significantly enhanced in individuals exposed to DE prior to inoculation with LAIV and this effect was maintained for at least seven days. However, this previous study was limited in its scope of nasal immune endpoints and did not explore potential mechanisms mediating the prolonged exacerbation of allergic inflammation caused by exposure to DE prior to inoculation with LAIV. In this follow-up study, the methods were modified to expand experimental endpoints and explore the potential role of NK cells. The data presented here suggest DE prolongs viral-induced eosinophil activation, which was accompanied by decreased markers of NK cell recruitment and activation. Separate in vitro studies showed that exposure to DE particles decreases the ability of NK cells to kill eosinophils. Taken together, these follow-up studies suggest that DE-induced exacerbation of allergic inflammation in the context of viral infections may be mediated by decreased activity of NK cells and their ability to clear eosinophils.


Dissociation of cGMP accumulation and relaxation in myometrial smooth muscle: effects of S-nitroso-N-acetylpenicillamine and 3-morpholinosyndonimine.
In guinea pig, primate and man, nitric oxide (NO)-induced regulation of myometrial smooth muscle contraction is distinct from other smooth muscles because cyclic guanosine 3',5'-cyclic monophosphate (cGMP) accumulation is neither necessary nor sufficient to relax the tissue. To further our understanding of the mechanism of action of NO in myometrium, we employed the NO donors, S-nitroso-N-acetylpenicillamine (SNAP), and 3-morpholinosyndonimine (SIN-1) proposed to relax airway smooth muscle by disparate mechanisms involving elevation in intracellular calcium ([Ca(2+)](i)) or cGMP accumulation, respectively. Treatment of guinea pig myometrial smooth muscle with either NO donor at concentrations thought to produce maximal relaxation of smooth muscles resulted in significant elevations in cGMP that were accompanied by phosphorylation of the cGMP-dependent protein kinase substrate vasodilator-stimulated phosphoprotein (VASP), shown here for the first time to be present and phosphorylated in myometrium. Stimulation of myometrial strips with oxytocin (OT, 1 microM) produced an immediate increase in contractile force that persisted in the continued presence of the agonist. Addition of SNAP (100 microM) in the presence of OT relaxed the tissue completely as might be expected of an NO donor. SIN-1 failed to relax the myometrium at any concentration tested up to 300 microM. In Fura-2 loaded myometrial cells prepared from guinea pig, addition of SNAP (100 microM) in the absence of other agonists caused a significant, reproducible elevation of intracellular calcium while SIN-1 employed under the same conditions did not. Our data further support the notion that NO action in myometrium is distinct from that in other smooth muscles and underscores the possibility that discrete regional changes in [Ca(2+)](i), rather than cGMP, signal NO-induced relaxation of the muscle.


Regulation of peroxiredoxin expression versus expression of Halliwell-Asada-Cycle enzymes during early seedling development of Arabidopsis thaliana.
During early seedling development of oil seed plants, the transition from lipid based heterotrophic to photoautotrophic carbohydrate metabolism is accompanied with a biphasic control of the chloroplast antioxidant system. In continuous light, organellar peroxiredoxins (Prx) and thylakoid-bound ascorbate peroxidase (tAPx) are activated early in seedling development, while stromal ascorbate peroxidase (sAPx), Cu/Zn-superoxide dismutase-2 (Csd2) and monodehydroascorbate reductase (MDHAR) and the cytosolic peroxiredoxins PrxIIB, PrxIIC and PrxIID are fully activated between 2.5 and 3 days after radicle emergence (DARE). Discontinuous light synchronized the expression of chloroplast antioxidant enzymes, but defined diurnally specific typeII-Prx-patterns in the cytosol and initiated chloroplast senescence around 2.5 DARE. Carbohydrate feeding uncoupled sAPx expression from the light pattern. In contrast, sucrose-feeding did not significantly impact on Prx transcript amounts. It is concluded that upon post-germination growth Prxs are activated endogenously to provide early antioxidant protection, which is supported by the Halliwell-Asada-Cycle, whose expressional activation depends on metabolic signals provided only later in development or in day-night-cycles.


Genomewide Association Study of Leisure-Time Exercise Behavior in Japanese Adults.
Although several genetic factors may play a role in leisure-time exercise behavior, there is currently no evidence of a significant genomewide association, and candidate gene replication studies have produced inconsistent results. We conducted a two-stage genomewide association study and candidate single-nucleotide polymorphisms (SNP) association study on leisure-time exercise behavior using 13,980 discovery samples from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study, and 2036 replication samples from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center-2 study. Leisure-time physical activity was measured using a self-administered questionnaire that inquired about the type, frequency and duration of exercise. Participants with ≥4 MET·h·wk of leisure-time physical activity were defined as exhibiting leisure-time exercise behavior. Association testing using mixed linear regression models was performed on the discovery and replication samples, after which the results were combined in a meta-analysis. In addition, we tested six candidate genetic variants derived from previous genomewide association study. We found that one novel SNP (rs10252228) located in the intergenic region between NPSR1 and DPY19L1 was significantly associated with leisure-time exercise behavior in discovery samples. This association was also significant in replication samples (combined P value by meta-analysis = 2.2 × 10). Several SNP linked with rs10252228 were significantly associated with gene expression of DPY19L1 and DP19L2P1 in skeletal muscle, heart, whole blood, and the nervous system. Among the candidate SNP, rs12612420 in DNAPTP6 demonstrated nominal significance in discovery samples but not in replication samples. We identified a novel genetic variant associated with regular leisure-time exercise behavior. Further functional studies are required to validate the role of these variants in exercise behavior.


Meningeal Infiltration of the Spinal Cord by Non-Classically Activated B Cells is Associated with Chronic Disease Course in a Spontaneous B Cell-Dependent Model of CNS Autoimmune Disease.
We characterized B cell infiltration of the spinal cord in a B cell-dependent spontaneous model of central nervous system (CNS) autoimmunity that develops in a proportion of mice with mutant T and B cell receptors specific for myelin oligodendrocyte glycoprotein. We found that, while males are more likely to develop disease, females are more likely to have a chronic rather than monophasic disease course. B cell infiltration of the spinal cord was investigated by histology and FACs. CD4(+) T cell infiltration was pervasive throughout the white and in some cases gray matter. B cells were almost exclusively restricted to the meninges, often in clusters reminiscent of those described in human multiple sclerosis. These clusters were typically found adjacent to white matter lesions and their presence was associated with a chronic disease course. Extensive investigation of these clusters by histology did not identify features of lymphoid follicles, including organization of T and B cells into separate zones, CD35(+) follicular dendritic cells, or germinal centers. The majority of cluster B cells were IgD(+) with little evidence of class switch. Consistent with this, B cells isolated from the spinal cord were of the naïve/memory CD38(hi) CD95(lo) phenotype. Nevertheless, they were CD62L(lo) and CD80(hi) compared to lymph node B cells suggesting that they were at least partly activated and primed to present antigen. Therefore, if meningeal B cells contribute to CNS pathology in autoimmunity, follicular differentiation is not necessary for the pathogenic mechanism.


Histopathological findings after retinal endovascular lysis in central retinal vein occlusion.
This case study explores the histopathological findings 9 months after retinal endovascular lysis (REVL) in a 62-year-old woman having a 7-week-old, highly ischaemic central retinal vein occlusion (CRVO) with hand movement vision. Angiographic examination 3 days postoperatively did not show improved arteriovenous passage time. In addition, the patient's postoperative vision did not change, and despite intensive photocoagulation and cryotherapy in the early postoperative period, the globe had to be removed 9 months later because of painful phthisis. Histological findings at the site of puncture were epiretinal membrane, interrupted internal limiting membrane and thickened venous wall. This is the first case to show the histological changes after surgical REVL in a human eye. In this case, REVL did not prevent neovascular glaucoma despite successful recombinant tissue plasminogen activator (rt-PA) injection in a venous branch close to the papilla. It was concluded that rt-PA injection after 7 weeks of CRVO is too late.


Oxygen taxis and proton motive force in Azospirillum brasilense.
The microaerophilic nitrogen-fixing bacterium Azospirillum brasilense formed a sharply defined band in a spatial gradient of oxygen. As a result of aerotaxis, the bacteria were attracted to a specific low concentration of oxygen (3 to 5 microM). Bacteria swimming away from the aerotactic band were repelled by the higher or lower concentration of oxygen that they encountered and returned to the band. This behavior was confirmed by using temporal gradients of oxygen. The cellular energy level in A. brasilense, monitored by measuring the proton motive force, was maximal at 3 to 5 microM oxygen. The proton motive force was lower at oxygen concentrations that were higher or lower than the preferred oxygen concentration. Bacteria swimming toward the aerotactic band would experience an increase in the proton motive force, and bacteria swimming away from the band would experience a decrease in the proton motive force. It is proposed that the change in the proton motive force is the signal that regulates positive and negative aerotaxis. The preferred oxygen concentration for aerotaxis was similar to the preferred oxygen concentration for nitrogen fixation. Aerotaxis is an important adaptive behavioral response that can guide these free-living diazotrophs to the optimal niche for nitrogen fixation in the rhizosphere.


Liquid-liquid separation of aqueous solutions: A molecular dynamics study.
In the liquid-liquid phase transition scenario, supercooled water separates into the high density liquid (HDL) and low density liquid (LDL) phases at temperatures lower than the second critical point. We investigate the effects of hydrophilic and hydrophobic solutes on the liquid-liquid phase transition using molecular dynamics simulations. It is found that a supercooled aqueous NaCl solution separates into solute-rich HDL and solute-poor LDL parts at low pressures. By contrast, a supercooled aqueous Ne solution separates into solute-rich LDL and solute-poor HDL parts at high pressures. Both the solutes increase the high temperature limit of the liquid-liquid separation. The degree of separation is quantified using the local density of solute particles to determine the liquid-liquid coexistence region in the pressure-temperature phase diagram. The effects of NaCl and Ne on the phase diagram of supercooled water are explained in terms of preferential solvation of ions in HDL and that of small hydrophobic particles in LDL, respectively.


Conformational control in the cyclization of hydrogen-bonded supramolecular polymers.
Bifunctional 2-ureido-4[1H]-pyrimidinone (UPy) derivatives can form small cyclic oligomers as well as long supramolecular polymers in chloroform solutions using the quadruple hydrogen-bonding motif. Ring-chain equilibria of a set of supramolecular monomers containing methyl-substituted alkyl linkers between the hydrogen-bonding UPy moieties were investigated by (1)H NMR spectroscopy and viscometry. The data were characterized in terms of critical concentration (CC, denoting the onset of polymerization) and equilibrium cyclic dimer concentration (EDC, representing preorganization of the monomer toward selective formation of cyclic dimer). Methyl substituents in the monomer were found to promote conformations favorable for cyclic dimerization, leading to an increase in both the EDC and the CC with respect to unsubstituted monomer. Furthermore, we observed an odd-even effect in the CC and EDC with increasing length of the linker between the hydrogen-bonding units. The combined results allow tuning of the critical concentration over a broad range and offer detailed information on the correlation between monomer structure, conformation, and polymerizability which may provide new insights for the study and design of other ring-chain equilibria or helix-random coil transitions.


p16INK4a reporter mice reveal age-promoting effects of environmental toxicants.
While murine-based systems to identify cancer-promoting agents (carcinogens) are established, models to identify compounds that promote aging (gerontogens) have not been described. For this purpose, we exploited the transcription of p16INK4a, which rises dynamically with aging and correlates with age-associated disease. Activation of p16INK4a was visualized in vivo using a murine strain that harbors a knockin of the luciferase gene into the Cdkn2a locus (p16LUC mice). We exposed p16LUC mice to candidate gerontogens, including arsenic, high-fat diet, UV light, and cigarette smoke and serially imaged animals to monitor senescence induction. We show that exposure to a high-fat diet did not accelerate p16INK4a expression, whereas arsenic modestly augmented, and cigarette smoke and UV light potently augmented, activation of p16INK4a-mediated senescence. This work provides a toxicological platform to study mammalian aging and suggests agents that directly damage DNA promote molecular aging.


Blood cigarettes: cigarette smuggling and war economies in central and eastern Africa.
To analyse cigarette smuggling practices in central and eastern Africa. Primary data were gathered during long-term qualitative field research in which about 400 interviews were conducted. Analysis of secondary sources included academic literature and reports from non-government organisations, multilateral organisations and the press. Our research suggests that the following factors play an important role in cigarette smuggling in eastern and central Africa: (1) government officials encounter difficulties monitoring the long and porous borders; (2) there is a general problem of corrupt government officials and particularly those who allow large-scale smugglers to operate; (3) criminal elements also play an important role in smuggling--cigarette smuggling has helped rebel groups to finance their activities, something illustrated through examples from the war economy in the eastern part of the Democratic Republic of Congo. Our research suggests that cigarette smuggling in this region is not primarily the result of different taxation levels in neighbouring states, but rather the outcome of weak state capacity, high levels of corruption and the activities of rebel groups. Under these conditions smuggling cigarettes becomes an attractive option as taxation is so easily avoided. This explains why in the low-income countries in this study there are high levels of smuggling in spite of low cigarette prices. Comprehensive supply control and enforcement legislation, and cooperation at national, regional and global level are needed to tackle fraudulent practices facilitated by corruption at state level, and to effectively punish interaction between cigarette traders and rebel groups.


Applicability of intermittent global ischemia for repeat coronary artery operations.
Despite the increasing popularity of cardioplegic techniques there is no consensus as to the optimal myocardial protective technique for first-time or repeat coronary artery bypass grafting. Intermittent global ischemia was used in 159 consecutive patients (142 male; 17 female) undergoing repeat coronary artery bypass grafting during a 6-year period (1987 to 1992). The median age of the patients was 60 years (90% confidence interval: 47 to 70 years) and the median interval from the first operation was 9 years (90% confidence interval: 2 to 14 years). One third of the patients required emergency (within 24 hours) or urgent (within 7 days) operations because of failure of symptoms to resolve with medical therapy. Compared with events at the initial operation there was an increased prevalence of impaired ventricular function (ejection fraction < 50%) and increased use of the internal thoracic artery (48% versus 9%). Two of 12 patients who required emergency operations died in the hospital, which resulted in an overall mortality rate at 30 days of 1%. Intraaortic balloon pump support was required in five patients (3%) and cardiac dose inotropic support in 21% of patients for up to 24 hours after operation. There was definite electrocardiographic evidence of infarction in 11 patients (7%). The mean postoperative blood loss, without aprotinin, was 627 ml (standard deviation 327 ml) and two patients required reexploration because of bleeding. Five patients had a hemiparesis (3%) and a further four patients (3%) had a mild or transient postoperative focal neurologic deficit. The median postoperative hospital stay was 9 days (90% confidence interval: 7 to 20 days) although 10% of patients required a hospital stay in excess of 21 days. No patient was lost to follow-up. The median (and interquartile range) period of follow-up was 1.6 (1 to 3) years. Eight patients died in the follow-up period, which resulted in an estimated survival of 80% at 5 years. At a mean follow-up period of 2 years (and with or without antianginal medication) 83% of patients had no or minimal angina, 12% had angina on moderate exertion, and 5% had angina on minimal exertion. In comparison with other current series of repeat coronary revascularization our results suggest that repeat coronary artery bypass grafting can be done with intermittent global ischemia with early and intermediate results at least equivalent to those obtained with cardioplegic methods.


Sensitive quantification of somatic mutations using molecular inversion probes.
Somatic mutations in DNA can serve as cancer specific biomarkers and are increasingly being used to direct treatment. However, they can be difficult to detect in tissue biopsies because there is often only a minimal amount of sample and the mutations are often masked by the presence of wild type alleles from nontumor material in the sample. To facilitate the sensitive and specific analysis of DNA mutations in tissues, a multiplex assay capable of detecting nucleotide changes in less than 150 cells was developed. The assay extends the application of molecular inversion probes to enable sensitive discrimination and quantification of nucleotide mutations that are present in less than 0.1% of a cell population. The assay was characterized by detecting selected mutations in the KRAS gene, which has been implicated in up to 25% of all cancers. These mutations were detected in a single multiplex assay by incorporating the rapid flow cytometric readout of multiplexable DNA biosensors.


Patients' online access to their electronic health records and linked online services: a systematic review in primary care.
Online access to medical records by patients can potentially enhance provision of patient-centred care and improve satisfaction. However, online access and services may also prove to be an additional burden for the healthcare provider. To assess the impact of providing patients with access to their general practice electronic health records (EHR) and other EHR-linked online services on the provision, quality, and safety of health care. A systematic review was conducted that focused on all studies about online record access and transactional services in primary care. Data sources included MEDLINE, Embase, CINAHL, Cochrane Library, EPOC, DARE, King's Fund, Nuffield Health, PsycINFO, OpenGrey (1999-2012). The literature was independently screened against detailed inclusion and exclusion criteria; independent dual data extraction was conducted, the risk of bias (RoB) assessed, and a narrative synthesis of the evidence conducted. A total of 176 studies were identified, 17 of which were randomised controlled trials, cohort, or cluster studies. Patients reported improved satisfaction with online access and services compared with standard provision, improved self-care, and better communication and engagement with clinicians. Safety improvements were patient-led through identifying medication errors and facilitating more use of preventive services. Provision of online record access and services resulted in a moderate increase of e-mail, no change on telephone contact, but there were variable effects on face-to-face contact. However, other tasks were necessary to sustain these services, which impacted on clinician time. There were no reports of harm or breaches in privacy. While the RoB scores suggest many of the studies were of low quality, patients using online services reported increased convenience and satisfaction. These services positively impacted on patient safety, although there were variations of record access and use by specific ethnic and socioeconomic groups. Professional concerns about privacy were unrealised and those about workload were only partly so.


Determinants of efficacy and safety in epicutaneous allergen immunotherapy: summary of three clinical trials.
The results of our third trial on epicutaneous allergen-specific immunotherapy (EPIT) will be presented and discussed in the context of our previous trials. This monocentric, placebo-controlled, double-blind phase I/IIa trial included 98 patients with grass pollen rhinoconjunctivitis. Prior to the pollen season 2009, patients received six patches (allergen extract: n = 48; placebo: n = 50) with weekly intervals, administered onto tape-stripped skin. Allergen EPIT produced a median symptom improvement of 48% in 2009 and 40% in the treatment-free follow-up year 2010 as compared to 10% and 15% improvement after placebo EPIT (P = 0.003). After allergen EPIT but not placebo EPIT, conjunctival allergen reactivity was significantly decreased and allergen-specific IgG4 responses were significantly elevated (P < 0.001). In conclusion, our three EPIT trials found that allergen EPIT can ameliorate hay fever symptoms. Overall, treatment efficacy appears to be determined by the allergen dose. Local side-effects are determined by the duration of patch administration, while risk of systemic allergic side-effects is related to the degree of stratum corneum disruption.


A case of late-onset central hypoventilation syndrome with hypothalamic dysfunction: through a new phenotype.
Congenital central hypoventilation syndrome (CCHS) is a rare disorder with uncertain nosology that usually presents early in life. The syndrome is characterized by ventilatory response impairment to carbon dioxide and may result in respiratory failure at birth. Recent reports have identified a similar clinical presentation beyond infancy called late-onset central hypoventilation syndrome (LO-CHS) as a disease continuum of CCHS with similar and overlapping pathophysiology. However, some have proposed that the syndrome accompanied by hypothalamic dysfunction (HD) be classified as a distinct clinical entity, LO-CHS/HD. To the best of our knowledge, the case reported herein is the oldest case of LO-CHS/HD in childhood, at 13 years old. He suffered from recurrent pulmonary edema, acute convulsive seizures, hypersomnia, hyperphagia, obesity, impaired glucose tolerance test, and hypercapnia, diagnosed as LO-CHS/HD, and was successfully treated with nasal bi-level positive airway pressure.


Fluorescent conjugated polyelectrolyte as an indicator for convenient detection of DNA methylation.
A convenient, sensitive, and label-free method to determine the DNA methylation status of CpG sites of plasmid and human colon cancer cell has been developed. The system relies on highly selective single base extension reaction and significant optical amplification of cationic conjugated polyelectrolytes (CCP-1). The higher fluorescence resonance energy transfer efficiency between CCP-1 and fluorescein-labeled dGTP (dGTP-Fl) is correlated to the incorporation of dGTP-Fl into the probe DNA by single base extension reaction when the target/probe pair is complementary at the methylation site. As low as 1% methylation status can be determined by this new assay method. Because of the optical amplification property of CCP-1, the method exhibited high sensitivity with a concentration of analyte DNA at the picomolar level. The CCP-1 can form a complex with negatively charged DNA through electrostatic interactions, avoiding labeling the DNA target and probe by covalent linking. The isolation steps employed in other typical assays were avoided to simplify operations and increase repeatability. These features make the system promising for future use for early cancer diagnosis.


Angioimmunoblastic lymphadenopathy with dysproteinemia--lack of a prognostic value of clear cell morphology.
It has been suggested that angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is closely related to peripheral T cell lymphoma (PTCL). However, the clinical course of AILD-like PTCL is notoriously unpredictable. A minor portion of patients enjoyed prolonged remission with steroid-only treatments (indolent AILD) while most others died rapidly despite the use of intensive chemotherapy (aggressive AILD). Recently, it has been suggested that histological features such as the presence or absence of clear cells and convoluted cells are of high prognostic value. The validity of this observation was addressed in this study. Eighteen patients who presented between 1977 and 1994 at the National Taiwan University Hospital were retrospectively studied. There were 11 men and 7 women, with a median age of 47 years. Twelve patients had received various regimens of systemic chemotherapy, and the other 3 patients had been treated with steroids alone. Eight patients had indolent AILD and 6 aggressive AILD. The follow-up period in 4 patients was too short to be analyzed. The histopathology of these cases was divided, according to the criteria of Aozasa et al., into group I (neither cells), 4 patients; group II (only convoluted cells), 1 patient, and group III (clear cells with or without convoluted cells), 13 patients. Contrary to others, our data revealed that group III patients were doing better than group I patients. Univariate analysis of other pertinent clinical features, including sex, age, lymphadenopathy, B symptoms, hepatosplenomegaly, hypergammaglobulinemia, elevated serum lactate dehydrogenase, and treatment regimens, revealed none of them to be prognostically relevant. However, patients who had achieved complete remission by steroids or other systemic chemotherapy had a significantly better prognosis than those who had not. Together, these preliminary data suggested that (1) the presence or absence of clear cells and convoluted cells failed to predict the clinical behavior, and (2) induction of complete remission by steroids or other chemotherapeutic agents is an important prognostic index.


Epidemiology of melanoma.
Melanoma incidence and morality rates are increasing in most countries throughout the world where they are being recorded. The annual incidence rates have increased in the order of 3-7% in fair-skinned populations in recent decades. The mortality rates have increased at a rate lower than for incidence. This has been attributed to educational programs designed to improve the early detection of melanoma, as the treatment of melanoma has not changed substantially in recent decades. There has been a decrease in the thickness of melanoma with an increasing proportion of thin melanomas at diagnosis. Causation of melanoma is a combination of constitutional risk factors of which skin colour is the major factor. The presence and number of common acquired and dysplastic melanocytic naevi is also a major constitutional risk factor in fair-skinned people. The only environmental risk factor that has been shown consistently is exposure to sunlight, particularly large doses of sunlight sufficient to cause sunburn in childhood that will be remembered many years later. However, recreational activity leading to sunburn in adulthood is also associated with risk. To date, no other environmental factors have been shown epidemiologically to be clearly associated with risk of melanoma. Recent epidemiological data from some studies suggesting that there is an increased risk of melanoma in sunscreen users requires further explanation.


Tensile strain-induced Ets-2 phosphorylation by CaMKII and the homeostasis of cranial sutures.
Mechanotransduction underpins the homeostasis of musculoskeletal tissues, including cranial sutures. Intracellular calcium, [Ca 2+]ic, and protein phosphorylation are two intermediate variables in signal relay during mechanotransduction. This project establishes a chain of cause and effect, linking cellular strain to substrate phosphorylation, and identifies the agent and target sites of phosphorylation. Cyclic tensile force (0.5 N at 1 Hz) was applied to 1-day-old rat sagittal sutures. [Ca 2+]ic was measured by FURA-2. Ets-2 phosphorylation by CaMKII was tested using Western blot autoradiography. Peptide array was constructed to determine the precise sites of phosphorylation. The results were confirmed with mass spectroscopy and Western blots using phospho-specific antibodies. [Ca 2+]ic increased rapidly in response to tensile stress. In the presence of Ca2+, CaMKII caused Ets-2 phosphorylation. Of the three possible sites for phosphorylation of Ets-2 by CaMKII, RVPS, FESF, RLSS, Serine 246, 310, and 313 were the targets. Furthermore, the contiguous sequence modified this effect. Mass spectroscopy showed 80 Da (molecular weight of phosphate group, -PO3) right shifts consistent with phosphorylation. There was cytosolic translocation of Ets-2 on tensile deformation of suture cells. CaMKII binding of Ets-2 occurred within 30 minutes after the onset of tensile strain. Cranial suture cells can respond to tensile forces by increasing [Ca 2+]ic, which causes CaMKII to phosphorylate Ets-2, thus altering Ets-2 binding to its downstream promoters. Of note, Ets-2 is at the intersection of three key pathways important in craniosynostosis: fibroblast growth factor-2, transforming growth factor-beta, and mechanotransduction.


New horizons from novel therapies in malignant pleural mesothelioma.
Malignant pleural mesothelioma (MPM) is a relatively rare, but highly lethal cancer of the pleural mesothelial cells. Its pathoge-nesis is integrally linked to asbestos exposure. In spite of recent developments providing a more detailed understanding of the pathogenesis, the outcomes continue to be poor. To date, trimodality therapy involving surgery coupled with chemotherapy and/or radiotherapy remains the standard of therapy. The development of resistance of the tumor cells to radiation and several che-motherapeutic agents poses even greater challenges in the management of this cancer. Ionizing radiation damages cancer cell DNA and aids in therapeutic response, but it also activates cell survival signaling pathways that helps the tumor cells to overcome radiation-induced cytotoxicity. A careful evaluation of the biology involved in mesothelioma with an emphasis on the workings of pro-survival signaling pathways might offer some guidance for treatment options. This review focuses on the existing treatment options for MPM, novel treatment approaches based on recent studies combining the use of inhibitors which target different pro-survival pathways, and radiotherapy to optimize treatment.


A remotely powered implantable biomedical system with location detector.
An universal remote powering and communication system is presented for the implantable medical devices. The system be interfaced with different sensors or actuators. A mobile external unit controls the operation of the implantable chip and reads the sensor's data. A locator system is proposed to align the mobile unit with the implant unit for the efficient magnetic power transfer. The location of the implant is detected with 6 mm resolution from the rectified voltage level at the implanted side. The rectified voltage level is fedback to the mobile unit to adjust the magnetic field strength and maximize the efficiency of the remote powering system. The sensor's data are transmitted by using a free running oscillator modulated with on-off key scheme. To tolerate large data carrier drifts, a custom designed receiver is implemented for the mobile unit. The circuits have been fabricated in 0.18 um CMOS technology. The remote powering link is optimized to deliver power at 13.56 MHz. On chip voltage regulator creates 1.8 V from a 0.9 V reference voltage to supply the sensor/actuator blocks. The implantable chip dissipates 595 μW and requires 1.48 V for start up.


In VitroStreptococcus pneumoniae Biofilm Formation and In Vivo Middle Ear Mucosal Biofilm in a Rat Model of Acute Otitis Induced by S. pneumoniae.
Streptococcus pneumoniae is one of the most common pathogens of otitis media (OM) that exists in biofilm, which enhances the resistance of bacteria against antibiotic killing and diagnosis, compared to the free-floating (planktonic) form. This study evaluated biofilm formation by S. pneumoniae on an abiotic surface and in the middle ear cavity in a rat model of OM. In vitro biofilm formation was evaluated by inoculation of a 1:100 diluted S. pneumoniae cell suspension in a 96-well microplate. Adherent cells were quantified spectrophotometrically following staining with crystal violet by measurement of optical density at 570 nm. The ultrastructure of pneumococcal biofilm was assessed by scanning electron microscopy (SEM). For in vitro biofilm study, S. pneumoniae cell suspensions containing 1×10(7) colony forming units were injected through transtympanic membrane into the middle ear cavity of Sprague Dawley rats. The ultrastructure of middle ear mucus was observed by SEM 1 and 2 weeks post-inoculation. The in vitro study revealed robust biofilm formation by S. pneumoniae after 12-18 hours of incubation in high glucose medium, independent of exogenously supplied competence stimulating peptide and medium replacement. Adherent cells formed three-dimensional structures approximately 20-30 µm thick. The in vivo study revealed that ciliated epithelium was relatively resistant to biofilm formation and that biofilm formation occurred mainly on non-ciliated epithelium of the middle ear cavity. One week after inoculation, biofilm formation was high in 50% of the treated rats and low in 25% of the rats. After 2 weeks, biofilm formation was high and low in 25% and 37.5% of rats, respectively. The results imply that glucose level is important for the S. pneumoniae biofilm formation and S. pneumoniae biofilm formation may play important role in the pathophysiology of OM.


Subxiphoid uniportal bilateral lung wedge resection.
Subxiphoid uniportal bilateral lung wedge resection, in which all manipulations are performed via a 3-cm wound positioned below the xiphoid process, can be performed in the supine position without the patient having to change positions. It also enables one-stage bilateral lung resection. We report the surgical procedure and initial results of subxiphoid uniportal bilateral lung wedge resection. A 3-cm transverse incision was made 1 cm caudally below the xiphoid process. A port for uniportal surgery was inserted. After CO2 insufflation at 8 mmHg, the lung was grasped and lifted with bent grasping forceps, and by bending the tip of a stapler, the surgeon resected the affected portion of the bilateral lungs. In this approach, there is one incision, no intercostal nerve damage and bilateral surgery can be performed in the same procedure; therefore, the technique may have the benefit of lesser invasiveness for the patient. Furthermore, a detailed comparison of subxiphoid uniportal bilateral lung wedge resection with the one-stage lateral intercostal approach with a larger subject sample is needed.


Vibrational energy transport through a capping layer of appropriately designed peptide helices over gold nanoparticles.
We design and characterize spherical gold nanoparticles, which are covalently linked to and completely covered by 3(10)-helical peptides. These helices provide a scaffold to place (13)C=O isotope labels at defined distances from the gold surface, which we employ as local thermometers. Probing these reporter groups with transient infrared spectroscopy, we monitor the vibrational energy flow across the peptide capping layer following excitation of the nanoparticle plasmon resonance.


Hydrogen peroxide release and hydroxyl radical formation in mixtures containing mineral fibres and human neutrophils.
The ability of different mineral fibres (rock wool, glass wool, ceramic fibres, chrysotile A, chrysotile B, amosite, crocidolite, antophyllite, erionite, and wollastonite) to stimulate hydrogen peroxide (H2O2) and hydroxyl radical (OH.) formation in mixtures containing human polymorphonuclear leucocytes (PMNLs) was investigated. In the presence of azide, all the fibres caused considerable H2O2 formation, and about twice as much H2O2 was found in mixtures with the natural fibres (asbestos, erionite, and wollastonite) than in mixtures with the manmade fibres (rock wool, glass wool, and ceramic fibres). In the presence of externally added iron, all the fibres were found to generate OH. and the natural fibres caused about three times more OH. formation than the manmade fibres. In the absence of external iron, there was less OH. formation; however, amosite, crocidolite, antophyllite, erionite, and wollastonite still generated considerable amounts of OH., also under circumstances in which only small amounts of OH. were produced in mixtures with the manmade fibres. These findings indicate that natural fibres generate more H2O2 and OH. than manmade fibres when incubated with PMNLs in the presence of external iron. They also suggest that the natural fibres, amosite, crocidolite, antophyllite, erionite, and wollastonite may act catalytically in the dissociation of H2O2 to OH. in the absence of external iron, whereas manmade fibres such as rock wool, glass wool, and ceramic fibres, do not seem to be able to generate OH. in the absence of external iron.


The dual face of parathyroid hormone and prostaglandins in the osteoimmune system.
The microenvironment of bone marrow, an extraordinarily heterogeneous and dynamic system, is populated by bone and immune cells, and its functional dimension has been at the forefront of recent studies in the field of osteoimmunology. The interaction of both marrow niches supports self-renewal, differentiation, and homing of the hematopoietic stem cells and provides the essential regulatory molecules for osteoblast and osteoclast homeostasis. Impaired signaling within the niches results in a pathological tableau and enhances disease, including osteoporosis and arthritis, or the rejection of hematopoietic stem cell transplants. Discovering the anabolic players that control these mechanisms has become warranted. In this review, we focus on parathyroid hormone (PTH) and prostaglandins (PGs), potent molecular mediators, both of which carry out a multitude of functions, particularly in bone lining cells and T cells. These two regulators proved to be promising therapeutic agents when strictly clinical protocols on dose treatments were applied.


42.7 Gbit/s electro-optic modulator in silicon technology.
CMOS-compatible optical modulators are key components for future silicon-based photonic transceivers. However, achieving low modulation voltage and high speed operation still remains a challenge. As a possible solution, the silicon-organic hybrid (SOH) platform has been proposed. In the SOH approach the optical signal is guided by a silicon waveguide while the electro-optic effect is provided by an organic cladding with a high χ(2)-nonlinearity. In these modulators the optical nonlinear region needs to be connected to the modulating electrical source. This requires electrodes, which are both optically transparent and electrically highly conductive. To this end we introduce a highly conductive electron accumulation layer which is induced by an external DC "gate" voltage. As opposed to doping, the electron mobility is not impaired by impurity scattering. This way we demonstrate for the first time data encoding with an SOH electro-optic modulator. Using a first-generation device at a data-rate of 42.7 Gbit/s, widely open eye diagrams were recorded. The measured frequency response suggests that significantly larger data rates are feasible.


Tryptophan Metabolism and Related Pathways in Psychoneuroimmunology: The Impact of Nutrition and Lifestyle.
In the past, accelerated tryptophan breakdown was considered to be a feature of clinical conditions, such as infection, inflammation, and malignant disease. More recently, however, the focus has changed to include the additional modulation of tryptophan metabolism by changes in nutrition and microbiota composition. The regulation of tryptophan concentration is critical for the maintenance of systemic homeostasis because it integrates essential pathways involved in nutrient sensing, metabolic stress response, and immunity. In addition to tryptophan being important as a precursor for the synthesis of the neurotransmitter serotonin, several catabolites along the kynurenine axis are neuroactive. This emphasizes the importance of the immunometabolic fate of this amino acid for processes relevant to neuropsychiatric symptoms. In humans, besides hepatic catabolism, there is usually a strong relationship between immune activation-associated tryptophan breakdown and increased levels of biomarkers, such as neopterin, which has particular relevance for both acute and chronic diseases. A shift towards neopterin synthesis during oxidative stress may indicate a corresponding decrease in tetrahydrobiopterin, a cofactor of several mono-oxygenases, providing a further link between tryptophan metabolism and serotonergic and catecholaminergic neurotransmission. The psychoneuroimmunological consequences of tryptophan metabolism and the susceptibility of this pathway to modulation by a variety of nutritional and lifestyle-related factors have important implications for the development of both diagnostic and treatment options.


HIV-1 co-receptor expression on trophoblastic cells from early placentas and permissivity to infection by several HIV-1 primary isolates.
We examined CD4 and major HIV-1 co-receptor expression by trophoblast cells (TC) from early placentas, and the permissiveness of TC for infection by several natural HIV-1 isolates in vitro. Ten early placentas (4-6 weeks of gestation) from HIV- women were obtained after elective abortion. CD4 and HIV-1 co-receptor expression by TC was examined in terms of both mRNA and protein. The same TC were then challenged with three clinical HIV isolates of known phenotype, two originating from mothers who transmitted the virus to their child and one from a vertically infected newborn. TC infection was detected by polymerase chain reaction. CD4 expression was detected in five of the 10 placentas, while membrane protein expression of CCR3, CXCR4 and CCR5 was detected in every case, despite quantitative differences among individuals. Bonzo, GPR1 and ChemR23 mRNAs were detected in all TC preparations. TC from seven out of eight placentas were permissive to HIV entry, but no productive viral replication was detected (reverse transcriptase activity in culture supernatants). Interestingly, the addition of chemokine(s) or a CD4-blocking antibody to the cultures failed to inhibit TC virus entry. These data point to marked interindividual variability in HIV co-receptor expression by trophoblast cells and show that TC from early placentas can be infected in vitro by clinical HIV-1 isolates. They also suggest that viral entry in vitro might occur through a mechanism independent of both CD4 and chemokine receptors.


A computational investigation of the phase behavior and capillary sublimation of water confined between nanoscale hydrophobic plates.
Thin films of water under nanoscopic confinement are prevalent in natural and manufactured materials. To investigate the equilibrium and dynamic behavior of water in such environments, we perform molecular dynamics simulations of water confined between atomistically detailed hydrophobic plates at T = 298 K for pressures (-0.1) ≤ P ≤ 1.0 GPa and plate separations of 0.40 ≤ d ≤ 0.80 nm. From these simulations, we construct an expanded P-d phase diagram for confined water, and identify and characterize a previously unreported confined monolayer ice morphology. We also study the decompression-induced sublimation of bilayer ice in a d = 0.6 nm slit, employing principal component analysis to synthesize low-dimensional embeddings of the drying trajectories and develop insight into the sublimation mechanism. Drying is observed to proceed by the nucleation of a bridging vapor cavity at one corner of the crystalline slab, followed by expansion of the cavity along two edges of the plates, and the subsequent recession of the remaining promontory of bilayer crystal into the bulk fluid. Our findings have implications for the understanding of diverse phenomena in materials science, nanofluidics, and protein folding and aggregation.


Leucocyte common antigen is present on osteoclasts.
Using a large panel of monoclonal antibodies which recognize the leucocyte common antigen (LCA), the presence of LCA on osteoclasts in both fetal and adult human bone specimens has been determined by immunohistochemistry. LCA is evident on the surface of fetal human osteoclasts in bone imprints and cryostat sections. LCA was also found on osteoclasts in specimens of fixed, decalcified osteoarthritic bone. The intensity and pattern of osteoclast reactivity were similar to those of foreign-body type macrophage polykaryons in inflammatory lesions. These results favour derivation of osteoclasts and their precursors from the multipotential haemopoietic stem cell which produces peripheral blood leucocytes and argues against their origin from a separate stem cell.


HIV Tat induces expression of ICAM-1 in HUVECs: implications for miR-221/-222 in HIV-associated cardiomyopathy.
Cardiac involvement is a well-documented complication of human immunodeficiency virus-1 (HIV-1) infection. Previous studies have demonstrated increased adhesion of monocytes to human vascular endothelial cells in HIV-infected individuals. HIV Tat protein, which is the transactivator of transcription (Tat), plays a key role in activating endothelial cells. In the present study, we demonstrated that exposure of HUVECs to HIV Tat protein resulted in induced expression of cell adhesion molecules specifically ICAM-1, leading to increased adhesion of monocytes to the endothelium. This effect of Tat was mediated through activation of mitogen-activated protein kinases and downstream transcription factor NF-κB. Increased expression of ICAM-1 was regulated by microRNA (miRNA) miR-221 and to some extent by miR-222, both of which are known to target ICAM-1. Functional inhibition of the respective miRNAs with anti-miR oligonucleotides resulted in induction of ICAM-1 protein in HUVECs. Furthermore, Tat-stimulated regulation of ICAM-1 via miR-221/-222 involved the NF-kB-dependent pathway. Functional implication and specificity of up-regulated ICAM-1 was confirmed using the ICAM-1 neutralizing antibody in the in vitro cell adhesion assays. These findings were further confirmed in vivo using the HIV transgenic (Tg) rats. These animals not only demonstrated increased expression of ICAM-1 mRNA, with a concomitant reduction in the expression of miR-221 in the aorta and heart, but also had increased expression of the ICAM-1 protein that was predominantly in the endothelial cell layer. Taken together, these findings implicate that Tat-mediated induction of ICAM-1 expression plays a critical role in monocyte adhesion observed in HIV-1-associated cardiomyopathies.


Prevalence of impaired renal function among rural and urban populations: findings of a cross-sectional study in Malawi.
Background: Sub-Saharan Africa faces region-specific risk factors for chronic kidney disease (CKD), such as nephrotoxic herbal medicines, antiretroviral therapy and infections, in addition to hypertension and diabetes. However, large epidemiological studies from this area are scarce. Methods: In a cross-sectional survey of non-communicable diseases, we conducted a prevalence sub-study of CKD in two Malawian populations. Study participants (N=5264) of 18 years of age and above were recruited and data on demographics and CKD risk factors were collected. Glomerular filtration rate was estimated (eGFR) using the CKD-EPI equation. Results: The prevalence of eGFR<60ml/min/1.73m 2 was 1.4% (95% CI 1.1 - 1.7%) and eGFR<90ml/min/1.73m 2 was 20.6% (95% CI 19.5 - 21.7%). The rural area had higher age-standardized prevalence of both eGFR<60ml/min/1.73m 2, at 1.8% (95% CI 1.4 - 2.3) and eGFR <90 ml/min/1.73m², at 21.1% (95% CI 19.9 - 22.3), than urban location, which had a prevalence of 1.5%, (95% CI 1.0 - 2.2) and 19.4% (95% CI 18.0 - 20.8), respectively, with overlapping confidence intervals. The prevalence of CKD was lower in females than in males in both rural and urban areas. Older age (p < 0.001), a higher level of education (p = 0.03) and hypertension (p < 0.001) were associated with a higher adjusted odds ratio (aOR) of low eGFR. Diabetes was associated with a reduced aOR of eGFR<90ml/min/1.73m 2 of 0.69 (95% CI 0.49-0.96; p=0.03). Of participants with eGFR<60ml/min/1.73m 2, 14 (19.4%) had no history of hypertension, diabetes or HIV, while 36 (50%) had a single risk factor of being hypertensive. Conclusion s: Impaired renal function is prevalent, but lower than expected, in rural and urban Malawi. Further research is needed to increase understanding of CKD incidence, survival and validation of eGFR calculations in this population.


Intestinal tissues induce an SNP mutation in Pseudomonas aeruginosa that enhances its virulence: possible role in anastomotic leak.
The most feared complication following intestinal resection is anastomotic leakage. In high risk areas (esophagus/rectum) where neoadjuvant chemoradiation is used, the incidence of anastomotic leaks remains unacceptably high (≈ 10%) even when performed by specialist surgeons in high volume centers. The aims of this study were to test the hypothesis that anastomotic leakage develops when pathogens colonizing anastomotic sites become in vivo transformed to express a tissue destroying phenotype. We developed a novel model of anastomotic leak in which rats were exposed to pre-operative radiation as in cancer surgery, underwent distal colon resection and then were intestinally inoculated with Pseudomonas aeruginosa, a common colonizer of the radiated intestine. Results demonstrated that intestinal tissues exposed to preoperative radiation developed a significant incidence of anastomotic leak (>60%; p<0.01) when colonized by P. aeruginosa compared to radiated tissues alone (0%). Phenotype analysis comparing the original inoculating strain (MPAO1- termed P1) and the strain retrieved from leaking anastomotic tissues (termed P2) demonstrated that P2 was altered in pyocyanin production and displayed enhanced collagenase activity, high swarming motility, and a destructive phenotype against cultured intestinal epithelial cells (i.e. apoptosis, barrier function, cytolysis). Comparative genotype analysis between P1 and P2 revealed a single nucleotide polymorphism (SNP) mutation in the mexT gene that led to a stop codon resulting in a non-functional truncated protein. Replacement of the mutated mexT gene in P2 with mexT from the original parental strain P1 led to reversion of P2 to the P1 phenotype. No spontaneous transformation was detected during 20 passages in TSB media. Use of a novel virulence suppressing compound PEG/Pi prevented P. aeruginosa transformation to the tissue destructive phenotype and prevented anastomotic leak in rats. This work demonstrates that in vivo transformation of microbial pathogens to a tissue destroying phenotype may have important implications in the pathogenesis of anastomotic leak.


Integrating DNA Methylation and Gene Expression Data in the Development of the Soybean-Bradyrhizobium N2-Fixing Symbiosis.
Very little is known about the role of epigenetics in the differentiation of a bacterium from the free-living to the symbiotic state. Here genome-wide analysis of DNA methylation changes between these states is described using the model of symbiosis between soybean and its root nodule-forming, nitrogen-fixing symbiont, Bradyrhizobium diazoefficiens. PacBio resequencing of the B. diazoefficiens genome from both states revealed 43,061 sites recognized by five motifs with the potential to be methylated genome-wide. Of those sites, 3276 changed methylation states in 2921 genes or 35.5% of all genes in the genome. Over 10% of the methylation changes occurred within the symbiosis island that comprises 7.4% of the genome. The CCTTGAG motif was methylated only during symbiosis with 1361 adenosines methylated among the 1700 possible sites. Another 89 genes within the symbiotic island and 768 genes throughout the genome were found to have methylation and significant expression changes during symbiotic development. Of those, nine known symbiosis genes involved in all phases of symbiotic development including early infection events, nodule development, and nitrogenase production. These associations between methylation and expression changes in many B. diazoefficiens genes suggest an important role of the epigenome in bacterial differentiation to the symbiotic state.


Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis.
Breast cancer almost invariably metastasizes to bone in patients with advanced disease and causes local osteolysis. Much of the morbidity of advanced breast cancer is a consequence of this process. Despite the importance of the problem, little is known of the pathophysiology of local osteolysis in the skeleton or its prevention and treatment. Observations in patients with bone metastases suggest that breast cancer cells in bone express parathyroid hormone-related protein (PTHrP) more frequently than in soft tissue sites of metastasis or in the primary tumor. Thus, the role of PTHrP in the causation of breast cancer metastases in bone was examined using human breast cancer cell lines. Four of eight established human breast cancer cell lines expressed PTHrP and one of these cell lines, MDA-MB-231, was studied in detail using an in vivo model of osteolytic metastases. Mice inoculated with MDA-MB-231 cells developed osteolytic bone metastasis without hypercalcemia or increased plasma PTHrP concentrations. PTHrP concentrations in bone marrow plasma from femurs affected with osteolytic lesions were increased 2.5-fold over corresponding plasma PTHrP concentrations. In a separate experiment, mice were treated with either a monoclonal antibody directed against PTHrP(1-34), control IgG, or nothing before tumor inoculation with MDA-MB-231 and twice per week for 26 d. Total area of osteolytic lesions was significantly lower in mice treated with PTHrP antibodies compared with mice receiving control IgG or no treatment. Histomorphometric analysis of bone revealed decreased osteoclast number per millimeter of tumor/bone interface and increased bone area, as well as decreased tumor area, in tumor-bearing animals treated with PTHrP antibodies compared with respective controls. These results indicate that tumor-produced PTHrP can cause local bone destruction in breast cancer metastatic to bone, even in the absence of hypercalcemia or increased circulating plasma concentrations of PTHrP. Thus, PTHrP may have an important pathogenetic role in the establishment of osteolytic bone lesions in breast cancer. Neutralizing antibodies to PTHrP may reduce the development of destructive bone lesions as well as the growth of tumor cells in bone.


US pharmacists' effect as team members on patient care: systematic review and meta-analyses.
One approach postulated to improve the provision of health care is effective utilization of team-based care including pharmacists. The objective of this study was to conduct a comprehensive systematic review with focused meta-analyses to examine the effects of pharmacist-provided direct patient care on therapeutic, safety, and humanistic outcomes. The following databases were searched from inception to January 2009: NLM PubMed; Ovid/MEDLINE; ABI/INFORM; Health Business Fulltext Elite; Academic Search Complete; International Pharmaceutical Abstracts; PsycINFO; Cochrane Database of Systematic Reviews; National Guideline Clearinghouse; Database of Abstracts of Reviews of Effects; ClinicalTrials.gov; LexisNexis Academic Universe; and Google Scholar. Studies selected included those reporting pharmacist-provided care, comparison groups, and patient-related outcomes. Of these, 56,573 citations were considered. Data were extracted by multidisciplinary study review teams. Variables examined included study characteristics, pharmacists' interventions/services, patient characteristics, and study outcomes. Data for meta-analyses were extracted from randomized controlled trials meeting meta-analysis criteria. A total of 298 studies were included. Favorable results were found in therapeutic and safety outcomes, and meta-analyses conducted for hemoglobin A1c, LDL cholesterol, blood pressure, and adverse drug events were significant (P < 0.05), favoring pharmacists' direct patient care over comparative services. Results for humanistic outcomes were favorable with variability. Medication adherence, patient knowledge, and quality of life-general health meta-analyses were significant (P < 0.05), favoring pharmacists' direct patient care. Pharmacist-provided direct patient care has favorable effects across various patient outcomes, health care settings, and disease states. Incorporating pharmacists as health care team members in direct patient care is a viable solution to help improve US health care.


Risk markers associated with challenging behaviours in people with intellectual disabilities: a meta-analytic study.
A meta-analysis of prevalence and cohort studies conducted over the last 30 years was carried out to identify risk markers for challenging behaviour shown by individuals with intellectual disabilities (IDs). A total of 86 potential studies was identified from the review, with 22 (25.6%) containing sufficient data to enable a statistical analysis to be conducted. Results indicated that males were significantly more likely to show aggression than females, and that individuals with a severe/profound degree of ID were significantly more likely to show self-injury and stereotypy than individuals with a mild/moderate degree of ID. Individuals with a diagnosis of autism were significantly more likely to show self-injury, aggression and disruption to the environment whilst individuals with deficits in receptive and expressive communication were significantly more likely to show self-injury. In most cases, tests for heterogeneity were statistically significant, as expected. The meta-analysis highlighted the paucity of methodologically robust studies of risk markers for challenging behaviours and the lack of data on incidence, prevalence and chronicity of challenging behaviour in this population.


Association of Resting Heart Rate with the Risk of Stroke in Men.
A resting heart rate may be correlated with an increased risk of stroke. Therefore, we explored the independent and joint influences of heart rate and body mass index on the incidence of stroke and its sub-types in a Chinese rural population. Cox proportional hazard models were adopted for measuring the influence exerted by heart rate on stroke in the Tongxiang China Kadoorie Biobank prospective cohort analyses, in which 23,132 men and 32,872 women were included. Incident stroke refers to '24-hour acute focal disorder, considered to result from ischemia or intracranial hemorrhage'. Over a 6.9 year mean follow up period, 986 men and 925 women developed stroke, representing an incidence of 6.35 and 4.00 per 1,000 person-years. In contrast to men with heart rate < 69 beats/minute, men at heart rate ≥ 90 beats/minute could more probably develop stroke and ischemic stroke with representing hazard ratio [95% confidence interval (CI)] 1.29 (1.05 - 1.58), and 1.35 (1.06 - 1.71). An adjusted hazard ratio of 1.37 (95% CI = 1.06 - 1.74) and 1.46 (95% CI = 1.08 - 1.96) were respectively identified for stroke and ischemic stroke in non-overweight/obese male patients with heart rate ≥ 90 beats/minute. Joint analyses also favored the results. Unfortunately, non-significant results were found in women. Higher resting heart rate acts as an independent predictor of any stroke and ischemic stroke risk in adult Chinese male but not in female. This relationship was particularly evident among nonoverweight/obese male participants.


Continuing care following residential alcohol and other drug treatment: Continuing care worker perceptions.
Little is known about the experiences of continuing care workers (CCW) in the implementation of continuing care programs. The current study sought to understand CCWs and supervisor perceptions of the successes and challenges of implementing a telephone-based continuing care intervention following residential alcohol and other drug treatment services. It also aimed to provide recommendations for treatment providers wishing to integrate continuing care into their treatment model, including the resources, training and supervision needs of CCWs. The participants were eight CCWs and two independent supervisors who completed semi-structured interviews. Interview coding and analysis was guided by Iterative Categorisation procedures and an implementation framework. The Consolidated Framework for Implementation Research was used. Telephone delivery was advantageous, but even more enhanced, when there was a face-to-face session first to build rapport. Other key successes included CCWs who were confident and competent, as well as a match between the organisation's values and the philosophy of the continuing care program. Key challenges faced by CCWs related to a perceived lack of support from managers, difficulties accessing quiet office spaces and participant disengagement. Interviews revealed several factors that may influence successful delivery of continuing care as part of alcohol and other drug treatment. These included features of the intervention (e.g. telephone delivery, evidence-based content), characteristics of the individual CCWs (e.g. flexibility in delivery of the intervention while maintaining fidelity), organisational culture (e.g. alignment of organisational values with continuing care) and resources (e.g. office space, flexible work schedules).


An outbreak of Trichinella spiralis infection in southern Lebanon.
An outbreak of trichinosis occurred during January 1995 in a south Lebanese village with a population of 800-1000 persons. The estimated number of persons treated for a Trichinella-like illness was 200. Sixty-three persons sought medical attention at a local infirmary: 44 of them were diagnosed as having trichinosis or suspected trichinosis according to their clinical symptoms, signs and laboratory tests. An environmental investigation indicated that the source of infection was pork obtained from a single butcher in the village and consumed uncooked, as an ingredient of 'kubeniye' (a local dish), during Christmas and New Year's meals. Sera of patients, suspected patients, and asymptomatic controls were tested for the presence of anti-Trichinella antibodies. Eight (89%) of the 9 tested patients were positive, 1 (11%) was negative. Among the 7 suspected patients, 2 (28.5%) were positive, 3 (42.9%) had equivocal results, and 2 (28.5%) were negative. Among the 20 asymptomatic persons, 3 (15%) were positive, 12 (60%) negative and 5 (25%) had equivocal results. Specimens from the implicated pork meat were examined by microscopy and were found to contain encysted larvae of Trichinella spiralis. This outbreak of trichinosis is one of the largest reported. Previous outbreaks in Lebanon occurred under very similar circumstances, indicating a need to control and prevent the trading of pork meat that is not under veterinary control, and to increase the awareness of the population for this problem.


Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.
Fingolimod (FTY720), a sphingosine-1-phosphate-receptor modulator that prevents lymphocyte egress from lymph nodes, showed clinical efficacy and improvement on imaging in a phase 2 study involving patients with multiple sclerosis. In this 12-month, double-blind, double-dummy study, we randomly assigned 1292 patients with relapsing-remitting multiple sclerosis who had a recent history of at least one relapse to receive either oral fingolimod at a daily dose of either 1.25 or 0.5 mg or intramuscular interferon beta-1a (an established therapy for multiple sclerosis) at a weekly dose of 30 microg. The primary end point was the annualized relapse rate. Key secondary end points were the number of new or enlarged lesions on T(2)-weighted magnetic resonance imaging (MRI) scans at 12 months and progression of disability that was sustained for at least 3 months. A total of 1153 patients (89%) completed the study. The annualized relapse rate was significantly lower in both groups receiving fingolimod--0.20 (95% confidence interval [CI], 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% CI, 0.12 to 0.21) in the 0.5-mg group--than in the interferon group (0.33; 95% CI, 0.26 to 0.42; P<0.001 for both comparisons). MRI findings supported the primary results. No significant differences were seen among the study groups with respect to progression of disability. Two fatal infections occurred in the group that received the 1.25-mg dose of fingolimod: disseminated primary varicella zoster and herpes simplex encephalitis. Other adverse events among patients receiving fingolimod were nonfatal herpesvirus infections, bradycardia and atrioventricular block, hypertension, macular edema, skin cancer, and elevated liver-enzyme levels. This trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a. Longer studies are needed to assess the safety and efficacy of treatment beyond 1 year. (ClinicalTrials.gov number, NCT00340834.)


Misuse of booster seats.
To describe several aspects of booster seat use and misuse in a sample of children attending child safety seat clinics. Booster seat practices were assessed at 76 child safety seat clinics held between April 1997 and January 1999 in Pennsylvania and southern New Jersey. At each assessment, a child passenger safety team evaluated the booster seat and identified modes of misuse. Altogether 227 booster seats were observed. Sixty eight per cent (68%) of shield boosters and 20% of belt positioning boosters were misused. Thirty two per cent of the children using a shield booster weighed more than 40 lb (18.1 kg); 68% of children in shield boosters and 63% in belt positioning boosters weighed less than 40 lb. This study identified a relatively high rate of booster seat misuse. Shield boosters were more likely to be misused than belt positioning booster seats. Significant numbers of children weighing more than 40 lb were using possibly dangerous shield boosters. The majority of children in this study were less than 40 lb. In this weight range, a convertible child restraint system provides better protection than a booster seat. Booster seat use should only be initiated once the child has completely outgrown their convertible child restraint system.


Visualization of transepithelial passage of the immunogenic 33-residue peptide from alpha-2 gliadin in gluten-sensitive macaques.
Based on clinical, histopathological and serological similarities to human celiac disease (CD), we recently established the rhesus macaque model of gluten sensitivity. In this study, we further characterized this condition based on presence of anti-tissue transglutaminase 2 (TG2) antibodies, increased intestinal permeability and transepithelial transport of a proteolytically resistant, immunotoxic, 33-residue peptide from alpha(2)-gliadin in the distal duodenum of gluten-sensitive macaques. Six rhesus macaques were selected for study from a pool of 500, including two healthy controls and four gluten-sensitive animals with elevated anti-gliadin or anti-TG2 antibodies as well as history of non-infectious chronic diarrhea. Pediatric endoscope-guided pinch biopsies were collected from each animal's distal duodenum following administration of a gluten-containing diet (GD) and again after remission by gluten-free diet (GFD). Control biopsies always showed normal villous architecture, whereas gluten-sensitive animals on GD exhibited histopathology ranging from mild lymphocytic infiltration to villous atrophy, typical of human CD. Immunofluorescent microscopic analysis of biopsies revealed IgG+ and IgA+ plasma-like cells producing antibodies that colocalized with TG2 in gluten-sensitive macaques only. Following instillation in vivo, the Cy-3-labeled 33-residue gluten peptide colocalized with the brush border protein villin in all animals. In a substantially enteropathic macaque with "leaky" duodenum, the peptide penetrated beneath the epithelium into the lamina propria. The rhesus macaque model of gluten sensitivity not only resembles the histopathology of CD but it also may provide a model for studying intestinal permeability in states of epithelial integrity and disrepair.


Sustained oscillations, irregular firing, and chaotic dynamics in hierarchical modular networks with mixtures of electrophysiological cell types.
The cerebral cortex exhibits neural activity even in the absence of external stimuli. This self-sustained activity is characterized by irregular firing of individual neurons and population oscillations with a broad frequency range. Questions that arise in this context, are: What are the mechanisms responsible for the existence of neuronal spiking activity in the cortex without external input? Do these mechanisms depend on the structural organization of the cortical connections? Do they depend on intrinsic characteristics of the cortical neurons? To approach the answers to these questions, we have used computer simulations of cortical network models. Our networks have hierarchical modular architecture and are composed of combinations of neuron models that reproduce the firing behavior of the five main cortical electrophysiological cell classes: regular spiking (RS), chattering (CH), intrinsically bursting (IB), low threshold spiking (LTS), and fast spiking (FS). The population of excitatory neurons is built of RS cells (always present) and either CH or IB cells. Inhibitory neurons belong to the same class, either LTS or FS. Long-lived self-sustained activity states in our network simulations display irregular single neuron firing and oscillatory activity similar to experimentally measured ones. The duration of self-sustained activity strongly depends on the initial conditions, suggesting a transient chaotic regime. Extensive analysis of the self-sustained activity states showed that their lifetime expectancy increases with the number of network modules and is favored when the network is composed of excitatory neurons of the RS and CH classes combined with inhibitory neurons of the LTS class. These results indicate that the existence and properties of the self-sustained cortical activity states depend on both the topology of the network and the neuronal mixture that comprises the network.


Anogenital distance is determined during early gestation in humans.
Does cord blood androgen level obtained at birth affect the AGD in human newborns? In human newborns, though males have a significantly longer AGD compared to females (as early as 22 weeks of gestation) the AGD is not affected by androgen levels at birth in both the sexes. Animal studies have reported a critical time period in early fetal life, termed the masculinization programming window (MPW) during which AGD is fixed by in utero androgen action and is unaffected by testosterone levels later during gestation. Thus, AGD may serve as a lifelong biomarker of androgen exposure during this window. This MPW is hypothesized to occur in humans at 8-14 weeks of gestation during which AGD is fixed. The effect of androgens (testosterone) on AGD after the MPW in humans is not known. Furthermore, altered AGD has been associated with various human reproductive health disorders in both males and females. A prospective descriptive cohort study was performed using data from randomly selected neonates (n = 205) born at a single center over a period of 1 year (August 2015 to August 2016). AGDs in male (n = 117) and female infants (n = 88) together with penile width, glans girth and stretched penile length were measured by trained caregivers. Gestation ranged from 22 to 41 weeks and infants were examined within 24 h of birth (within 48-72 h in very sick preterm infants after clinical stabilization). AGD-1 was measured from the center of the anus to the posterior base of scrotum in males or to the posterior fourchette in females. AGD-2 was measured from the center of the anus to the anterior base of the penis in males or to the clitoris in females. Sex steroid hormones (testosterone, 17-OH progesterone (17-OHP) and androstenedione) were measured in serum prepared from umbilical cord blood samples taken at birth, using liquid chromatography-tandem mass spectrometry. Males had a significantly lower gestational age (mean ± SD; 34.6 ± 4.9 versus 36.1 ± 4.1 weeks, P = 0.04), and a significantly longer AGD-1 (mean ± SD; 21.6 ± 6.0 versus 12.7 ± 3.8 mm, P < 0.001) and AGD-2 (41.9 ± 8.7 versus 33.9 ± 7.1 mm, P = 0.004) compared to female infants, respectively. The cord serum testosterone levels were significantly higher for male than female infants [median, interquartile range; 13.0 (7.3, 20.5) versus 4.1 (2.5, 5.9), ng/dl, P < 0.001]. There was no difference in levels of 17-OHP (P = 0.697) or androstenedione (P = 0.601) between the two sexes. On multiple regression analysis after adjusting for potential confounders, none of the AGD's in both males and females correlated with any sex steroid hormonal levels. We also provide normative charts for penile length, penile width and glans girth in preterm and term infants. No data were collected on family history of genital malformation, infertility or hormonal disorders, parental endocrine-disrupting chemical exposure or diet pattern, any of which might have influenced the AGD and/or sex steroid hormone levels in the offspring. Our results suggest that AGD in humans, like animals, is fixed in early gestation (likely during the hypothesized MPW) and is unaffected by androgen levels thereafter. Thus, AGD can serve as a biomarker of in utero androgen action during early gestation (likely 8-14 weeks) in humans. As such, causes of human newborn and adult reproductive health disorders, such as endocrine disruptors, should be explored during early gestation. However, further larger studies are needed to help corroborate these findings. No specific funding was obtained for this study, and all authors have no conflict of interest to declare.


Significance of incidentally detected subcentimeter enhancing lesions on preoperative breast MRI: role of second-look ultrasound in lesion detection and management.
OBJECTIVE. The purpose of this article is to evaluate the clinical significance of subcentimeter enhancing lesions incidentally detected on preoperative breast MRI in patients with breast cancer and the role of second-look ultrasound in lesion detection and characterization. MATERIALS AND METHODS. From January 2010 through December 2010, 180 lesions measuring less than 10 mm incidentally detected on MRI in 108 women with second-look ultrasound examinations were included (mean patient age, 47.9 years; mean [± SD] lesion size, 5.56 ± 1.64 mm). Seventy-two (40.0%) lesions were smaller than 5 mm, and 108 (60.0%) were 5 mm or larger. Of the 180 lesions, 103 (57.2%) had been biopsied or excised by localization, and 77 (42.8%) with benign ultrasound features had been followed with ultrasound for at least 2 years. Clinical and imaging features were recorded for analysis. RESULTS. Of the 180 enhancing lesions detected on MRI, 14 (7.8%) were malignant and 166 (92.2%) were benign. The malignancy rate of lesions 5 mm or larger was higher than that for lesions smaller than 5 mm (10.2% vs 4.2%), without statistical significance (p = 0.344). The washout enhancement pattern was statistically significantly associated with malignancy (p = 0.032). Although malignant ultrasound features such as nonparallel orientation were more common in malignant lesions, most malignancies had benign features, including oval shape, parallel orientation, and circumscribed margins, with BI-RADS category 4a (n = 12; 85.8%) as the final assessment. CONCLUSION. Second-look ultrasound is a feasible method for evaluating MRI-detected subcentimeter sized lesions in preoperative assessment of patients with breast cancer. A lower threshold should be applied with consideration of MRI features in deciding whether to biopsy or excise these lesions.