Hyperbaric oxygen as an adjunctive therapy in treatment of malignancies, including brain tumours.
Hyperbaric oxygen (HBO) therapy is widely used as an adjunctive treatment for various pathological states, predominantly related to hypoxic and/or ischaemic conditions. It also holds promise as an approach to overcoming the problem of oxygen deficiency in the poorly oxygenated regions of the neoplastic tissue. Occurrence of local hypoxia within the central areas of solid tumours is one of the major issues contributing to ineffective medical treatment. However, in anti-cancer therapy, HBO alone gives a limited curative effect and is typically not applied by itself. More often, HBO is used as an adjuvant treatment along with other therapeutic modalities, such as radio- and chemotherapy. This review outlines the existing data regarding the medical use of HBO in cancer treatment, with a particular focus on the use of HBO in the treatment of brain tumours. We conclude that the administration of HBO can provide many clinical benefits in the treatment of tumours, including management of highly malignant gliomas. Applied immediately before irradiation, it is safe and well tolerated by patients, causing rare and limited side effects. The results obtained with a combination of HBO/radiotherapy protocol proved to be especially favourable compared to radiation treatment alone. HBO can also increase the cytostatic effect of certain drugs, which may render standard chemotherapy more effective. The currently available data support the legitimacy of conducting further research on the use of HBO in the treatment of malignancies.


Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part I. A cooperative study in Europe, Australia, New Zealand, and South Africa.
Findings from previous multicenter clinical trials have suggested that tirilazad mesylate, a synthetic nonhormonal 21-aminosteroid, might be effective in preventing delayed cerebral ischemia following subarachnoid hemorrhage (SAH). This beneficial effect, however, was greater in males than females, possibly because of gender-related pharmacokinetic differences. The authors sought to assess the effects of administering a larger dose of tirilazad in women with SAH. To test the efficacy of a higher tirilazad mesylate dose in female patients, a prospective randomized, double-blind, vehicle-controlled trial was conducted at 56 neurosurgical centers in Europe, Australia, New Zealand, and South Africa. Eight hundred nineteen patients were randomly assigned to receive either 15 mg/kg/day of tirilazad mesylate or a placebo containing the citrate vehicle. The two groups were similar in prognostic factors for delayed cerebral ischemia and overall outcome. High-dose tirilazad appeared to be well tolerated because no differences in the incidence of untoward medical events were noted between the two groups. Medical and surgical interventions were no different in the two treatment groups except for hyperdynamic therapy (intentional hypervolemia, induced hypertension, and/or hemodilution), which was more often used in the placebo-treated group to counteract symptomatic vasospasm (24% of patients given placebo compared with 18% of patients given tirilazad, p = 0.02). Mortality rates and overall outcome, assessed using the Glasgow Outcome Scale at 3 months post-SAH, were not different between the two groups, despite a significantly lower incidence of delayed cerebral ischemia in patients given tirilazad. Post hoc subgroup analysis by neurological grade also did not reveal significant differences in outcome, although a trend toward a lower mortality rate favoring the study drug was present in patients with neurological Grade IV and V at admission (32% compared with 37%). Symptomatic vasospasm occurred in 33.7% of the placebo-treated patients as opposed to 24.8% of the patients who were given tirilazad (p = 0.005). The severity of symptomatic vasospasm was also attenuated by administration of the study drug (severe symptomatic vasospasm was reported in 11% of the placebo-treated patients compared with 6% of patients in the tirilazad-treated group (p = 0.008). Clinical cerebral infarction from vasospasm was also reduced from 13% in the vehicle-treated group to 8% in the tirilazad-treated group (p < 0.04). The authors conclude that high-dose tirilazad mesylate is well tolerated in women with aneurysmal SAH. Although a significant reduction in the incidence of symptomatic vasospasm was observed in the treatment group, the primary end point (mortality rate at 3 months post-SAH) was not affected by the study drug. The use of other potentially effective rescue therapies (that is, hypervolemia, hemodilution, and induced hypertension) to counteract vasospasm may have been responsible for these contrasting observations between the two groups.


The complex nature of constitutional de novo apparently balanced translocations in patients presenting with abnormal phenotypes.
To describe the systematic analysis of constitutional de novo apparently balanced translocations in patients presenting with abnormal phenotypes, characterise the structural chromosome rearrangements, map the translocation breakpoints, and report detectable genomic imbalances. DNA microarrays were used with a resolution of 1 Mb for the detailed genome-wide analysis of the patients. Array CGH was used to screen for genomic imbalance and array painting to map chromosome breakpoints rapidly. These two methods facilitate rapid analysis of translocation breakpoints and screening for cryptic chromosome imbalance. Breakpoints of rearrangements were further refined (to the level of spanning clones) using fluorescence in situ hybridisation where appropriate. Unexpected additional complexity or genome imbalance was found in six of 10 patients studied. The patients could be grouped according to the general nature of the karyotype rearrangement as follows: (A) three cases with complex multiple rearrangements including deletions, inversions, and insertions at or near one or both breakpoints; (B) three cases in which, while the translocations appeared to be balanced, microarray analysis identified previously unrecognised imbalance on chromosomes unrelated to the translocation; (C) four cases in which the translocation breakpoints appeared simple and balanced at the resolution used. This high level of unexpected rearrangement complexity, if generally confirmed in the study of further patients, will have an impact on current diagnostic investigations of this type and provides an argument for the more widespread adoption of microarray analysis or other high resolution genome-wide screens for chromosome imbalance and rearrangement.


The biology and therapeutic potential of the DDAH/ADMA pathway.
Asymmetric dimethylarginine (ADMA) is an endogenously produced molecule that inhibits nitric oxide synthase and consequently may have adverse effects on physiology, in particular in the cardiovascular system. This review highlights the mechanisms involved in the synthesis and metabolism of ADMA and their role in the control of nitric oxide (NO) synthesis. We describe how the effects of both cellular and circulating ADMA can alter physiological function involving both NO dependent and independent pathways and go on to describe how the metabolism of ADMA by dimethylarginine dimethylaminohydrolase (DDAH) is the major endogenous mechanism by which ADMA levels are regulated. Furthermore, we discuss the association of ADMA concentrations with cardiovascular disease and how ADMA levels can be modulated therapeutically by altering its production and/or metabolism. Finally we discuss the effects of some of the current pharmaceutical therapies used to treat cardiovascular disease and their involvement in the modulation of the ADMA/DDAH pathway.


Reconstruction of caribou evolutionary history in Western North America and its implications for conservation.
The role of Beringia as a refugium and route for trans-continental exchange of fauna during glacial cycles of the past 2million years are well documented; less apparent is its contribution as a significant reservoir of genetic diversity. Using mitochondrial DNA sequences and 14 microsatellite loci, we investigate the phylogeographic history of caribou (Rangifer tarandus) in western North America. Patterns of genetic diversity reveal two distinct groups of caribou. Caribou classified as a Northern group, of Beringian origin, exhibited greater number and variability in mtDNA haplotypes compared to a Southern group originating from refugia south of glacial ice. Results indicate that subspecies R. t. granti of Alaska and R. t. groenlandicus of northern Canada do not constitute distinguishable units at mtDNA or microsatellites, belying their current status as separate subspecies. Additionally, the Northern Mountain ecotype of woodland caribou (presently R. t. caribou) has closer kinship to caribou classified as granti or groenlandicus. Comparisons of mtDNA and microsatellite data suggest that behavioural and ecological specialization is a more recently derived life history characteristic. Notably, microsatellite differentiation among Southern herds is significantly greater, most likely as a result of human-induced landscape fragmentation and genetic drift due to smaller population sizes. These results not only provide important insight into the evolutionary history of northern species such as caribou, but also are important indicators for managers evaluating conservation measures for this threatened species.


DIGGER: exploring the functional role of alternative splicing in protein interactions.
Alternative splicing plays a major role in regulating the functional repertoire of the proteome. However, isoform-specific effects to protein-protein interactions (PPIs) are usually overlooked, making it impossible to judge the functional role of individual exons on a systems biology level. We overcome this barrier by integrating protein-protein interactions, domain-domain interactions and residue-level interactions information to lift exon expression analysis to a network level. Our user-friendly database DIGGER is available at https://exbio.wzw.tum.de/digger and allows users to seamlessly switch between isoform and exon-centric views of the interactome and to extract sub-networks of relevant isoforms, making it an essential resource for studying mechanistic consequences of alternative splicing.


Transpedicle body augmenter for vertebral augmentation in symptomatic multiple osteoporotic compression fractures.
Multiple osteoporotic vertebral compression fractures (VCFs) have been treated with polymethylmethacrylate augmentation; however, there are cement complications and long-term fracture healing that are unknown. Transpedicle body augmenter (a porous titanium spacer) has been reported as an internal support to reconstruct the vertebral body combining short-segment fixation in burst fracture and Kümmell's disease with cord compression. Transpedicle body augmenter for vertebral augmentation (TpBA) also has been reported successfully in treating single painful VCF and vertebral metastasis lesions including pending fractures and pathologic compression fractures. To test the hypothesis that TpBA can effectively and safely treat the symptomatic multiple VCFs, this retrospective study was done by analyzing the radiographic and clinical results. We retrospectively reviewed clinical and radiographic results of TpBA for symptomatic multiple (more than two levels) VCFs in 62 patients with a total of 236 levels, i.e. 3.8 VCFs per patient. Manual reduction and TpBA via paramedian incisions with blunt dissection were done. One incision was made for two continuous levels and alternative side was selected for next incision. Mean age was 74.3 years (range, 62-87 years), and female-male ratio was 5.2:1. Anterior vertebral height and wedge angle by radiographic findings were measured at preoperative, initial follow-up and final follow-up. Clinical results were assessed by questionnaires and clinical observations. By July 2008, 58 patients returned to answer the questionnaire including quantification of pain on the visual analog scale, the response to operations (better, same, or worse after operation), returned to their pre-fracture function (yes/no) and satisfaction (a scale of 0 = completely dissatisfied to 10 = completely satisfied). The mean symptom duration was 7 months, and follow-up, 48 months. The average operation time was 21 min per level, blood loss was 74 cc per level and hospitalization was 4.4 days. No patient had neurological deterioration. There was no dislodgement of implant in the final visit. Forty-eight patients (77.4%) could walk within 6-8 h after operation and the others, within 24 h. The anterior vertebral restoration was 7.3 mm initially and 6.2 mm at final follow-up. Wedge angle correction was 10.4 degrees initially and was 9.3 degrees at final follow-up. Pain, by the visual analog scale, was 8.5 preoperatively, 2.7 at day 7 follow-up and 2.9 at final follow-up. By the questionnaire, 52 of 58 respondents reported a decrease in discomfort after TpBA and 48 of 58 patients reported a return to normal activity after operation. The final satisfaction rate was 89.7%. The symptoms of multiple osteoporotic compression fracture may be due to unstable fracture, radiculopathy, and global traumatic kyphosis with posture changes, which can be corrected by multiple TpBA. The transpedicle body augmenter was initially stabilized by the sinking and locking mechanism and finally by bone ingrowth. TpBA via a minimally invasive method led to early and medium-term clinical improvements and anatomic restoration of multiple symptomatic VCFs.


Clinical Utility of 18F-FDG PET/CT in Staging Localized Breast Cancer Before Initiating Preoperative Systemic Therapy.
18F-fluorodeoxyglucose PET/CT is recommended as an optional study in the current NCCN Clinical Practice Guidelines in Oncology for Breast Cancer after CT of the chest, abdomen, and pelvis with contrast and bone scan (CTBS) in stage IIA-IIIC breast cancer. We evaluated our experience with the use of PET/CT in this setting before beginning primary systemic therapy (PST) prior to planned surgery. We performed medical record abstractions of all adult female patients with clinical stage IIA-IIIC breast cancer diagnosed at Montefiore Medical Center from January 1, 2014, through January 1, 2019, who underwent PET/CT before PST. We calculated the proportion of patients upstaged after PET/CT and examined the cost and radiation exposure associated with PET/CT compared with CTBS. A total of 195 patients with 196 breast cancers (bilateral disease in 1 patient) met the study inclusion criteria and had PET/CT as the first imaging study before PST. The overall upstaging rate for regional nodal metastasis and/or distant metastasis was 37% (73/196), including 24% for stage IIA (9/38), 39% for stage IIB (31/79), 54% for stage IIIA (22/41), 27% for stage IIIB (8/30), and 37% for stage IIIC (3/8). The overall upstaging rate for distant metastasis was 14% (27/196), including 0% for stage IIA, 13% for stage IIB (10/79), 22% for stage IIIA (9/41), 17% for stage IIIB (5/30), and 37% for stage IIIC (3/8). Medicare reimbursement rates were $1,604.37 for PET/CT and $1,679.94 for CTBS. The radiation dose for PET/CT was 14 mSv versus 21 mSv for CTBS. Approximately 37% of patients with clinical stage IIA-IIIC breast cancer who underwent PET/CT before PST showed more extensive disease, including 23% with more extensive nodal metastasis and 14% with distant metastasis. Given its high detection rate, comparable cost, lower radiation dose, and greater convenience, PET/CT should be considered as an alternative to CTBS rather than "optional" after CTBS, especially in patients who require an efficient and expeditious workup before initiating PST.


Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson's disease model.
Parkinson's disease (PD) is characterized by the presence of α-synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between α-synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) expressing human, aggregation-prone truncated 1-120 α-synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of α-synuclein in dopaminergic neurons of the substantia nigra pars compacta and their striatal terminals. This is associated with a progressive reduction of striatal dopamine release, reduced striatal innervation and significant nigral dopaminergic nerve cell death starting from 6 and 12 months of age, respectively. In the MI2 mice, alterations in gait impairment can be detected by the DigiGait test from 9 months of age, while gross motor deficit was detected by rotarod test at 20 months of age when 50% of dopaminergic neurons in the substantia nigra pars compacta are lost. These changes were associated with an increase in the number and density of 20-500 nm α-synuclein species as shown by dSTORM. Treatment with the oligomer modulator anle138b, from 9 to 12 months of age, restored striatal dopamine release, prevented dopaminergic cell death and gait impairment. These effects were associated with a reduction of the inner density of large α-synuclein aggregates and an increase in dispersed small α-synuclein species as revealed by dSTORM. The MI2 mouse model recapitulates the progressive dopaminergic deficit observed in PD, showing that early synaptic dysfunction is associated to fine behavioral motor alterations, precedes dopaminergic axonal loss and neuronal death that become associated with a more consistent motor deficit upon reaching a certain threshold. Our data also provide new mechanistic insight for the effect of anle138b's function in vivo supporting that targeting α-synuclein aggregation is a promising therapeutic approach for PD.


Long-Term Alcohol Consumption and Breast, Upper Aero-Digestive Tract and Colorectal Cancer Risk: A Systematic Review and Meta-Analysis.
Cancers of female breast, upper aero-digestive tract (UADT) (oral cavity, pharynx, larynx, oesophagus) and colorectum are causally related to alcohol consumption. Although alcohol consumption is likely to vary during life, the few studies that have explicitly measured lifetime consumption or intake over time have not been summarised. We therefore conducted a systematic review and meta-analysis. Studies were identified by searching the Medline, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and Scopus databases through January 2015 using broad search criteria. Studies reporting relative risks (RR) for quantitatively defined categories of alcohol consumption over time for breast, UADT or colorectal cancer were eligible. A two-stage random-effects meta-analysis was used to estimate a dose-response relationship between alcohol intake and each cancer site. RRs were also calculated for the highest relative to the lowest intake category. Sixteen articles for breast, 16 for UADT and 7 for colorectal cancer met the eligibility criteria. We observed a weak non-linear dose-response relationship for breast cancer and positive linear dose-response relationships for UADT and colorectal cancer. The pooled RRs were 1.28 (95% confidence interval, CI: 1.07, 1.52) for breast, 2.83 (95% CI: 1.73, 4.62) for UADT, 4.84 (95% CI: 2.51, 9.32) for oral cavity and pharynx, 2.25 (95% CI: 1.49, 3.42) for larynx, 6.71 (95% CI: 4.21, 10.70) for oesophageal and 1.49 (95% CI: 1.27, 1.74) for colorectal cancer. Our findings confirm dose-dependent associations between long-term alcohol intake and breast, UADT and colorectal cancer.


The impact of cell heterogeneity and immunophenotypic changes on monitoring minimal residual disease in acute myeloid leukemia.
Monitoring of minimal residual disease (MRD) becomes increasingly important for the more accurate stratification of the therapy in acute leukemia. The purpose of this study was to characterize in detail the phenotypes of heterogeneous population in various AML subtypes and to identify the leukemia associated aberrant phenotype (LAP) in individual patients with AML for precise investigation of MRD. The impact of heterogeneity of pathological populations, the effectiveness of location AML blasts on CD45/SSC dot plots in AML patients during follow-up and phenotype changes on MRD monitoring were evaluated in the second step. Bone marrow samples from 63 patients with AML were analyzed at diagnosis, 33 were selected for monitoring of MRD during follow-up and 13 analyzed at relapse using a wide antibody panel in quadruple combinations by multiparameter flow cytometry. In 88% of AML patients at least one LAP was defined at diagnosis, two or more aberrancies coexisted in 60% of them. The total number of LAPs identified by application of various combinations of antibodies was 112 (mean = 2.04 LAP/patient) and the median percentage of blasts carrying the LAP was 53.57%. In half of the patients, we were able to detect the presence of at least two subpopulations, which not always shared the same aberrancy. Although AML cells often have light scattering properties similar to those of normal (myeloid and B-lymphoid precursors, basophiles etc.) in a fraction of cases we found also very useful the location on CD45/SSC dot plots for MRD discrimination. In 13 patients relapse occurred and although we found in 69% changes of phenotype when comparing diagnosis and the first relapse, at least one LAP was constant in 92%. According to our observations, in majority of patients with AML monitoring of MRD by multiparameter flow cytometry is feasible although in some cases could present some specific difficulties owing to their immunophenotypic heterogeneity, similarity with other cell subpopulations or shifts at relapse. In conclusion, investigation of MRD should be based on the phenotypic characteristics of each subpopulation even if it is present in low frequencies.


Analysis of Genetic and Molecular Identity Among Field Isolates of the Rice Blast Fungus with an International Differential System, Rep-PCR, and DNA Sequencing.
The Pi-ta gene deployed in southern U.S. rice germplasm is effective in preventing the infection by strains of Magnaporthe oryzae isolates that carry the avirulence (AVR) gene AVR-Pita1. In the present study, 169 isolates from rice (Oryza sativa) cultivars, with and without Pi-ta, were analyzed for their genetic identity using an international differential system, repetitive element-based polymerase chain reaction (Rep-PCR), and sequence analysis of PCR products of AVR-Pita1. These isolates belong to the races IA1, IB1, IB17, IC1, and IC17 of M. oryzae. These isolates were further classified into 15 distinct groups by Rep-PCR. There was a predominant group within each race. Pathogenicity assays on 'Katy' (Pi-ta) and 'M202' (pi-ta) rice determined that IC1 was virulent to Katy and M202; IB17, IC17, and most of IA1 and IB1 were avirulent to Katy and virulent to M202, suggesting that the Pi-ta gene in Katy is responsible for preventing infection by these isolates. Consistently, AVR-Pita1 was not amplified from 28 virulent isolates. One AVR-Pita1 allele was amplified by AVR-Pita1-specific primers in 78 avirulent isolates. Interestingly, different AVR-Pita1 alleles were found in each of the 12 avirulent isolates, as determined by DNA sequencing. Sequence analysis of 90 PCR products revealed 10 AVR-Pita1 haplotypes, 4 of which were new. In total, 12 amino acid changes were identified in the new variants when compared with the first described AVR-Pita sequence (AF207841). The finding of isolates with altered AVR-Pita1 from rice cultivars with and without Pi-ta suggests that these virulent isolates were adapted to the field environments in the southern United States. Further research will be needed to verify this prediction.


CD4-specific transgenic expression of human cyclin T1 markedly increases human immunodeficiency virus type 1 (HIV-1) production by CD4+ T lymphocytes and myeloid cells in mice transgenic for a provirus encoding a monocyte-tropic HIV-1 isolate.
Human immunodeficiency virus type 1 (HIV-1)-encoded Tat provides transcriptional activation critical for efficient HIV-1 replication by interacting with cyclin T1 and recruiting P-TEFb to efficiently elongate the nascent HIV transcript. Tat-mediated transcriptional activation in mice is precluded by species-specific structural differences that prevent Tat interaction with mouse cyclin T1 and severely compromise HIV-1 replication in mouse cells. We investigated whether transgenic mice expressing human cyclin T1 under the control of a murine CD4 promoter/enhancer cassette that directs gene expression to CD4(+) T lymphocytes and monocytes/macrophages (hu-cycT1 mice) would display Tat responsiveness in their CD4-expressing mouse cells and selectively increase HIV-1 production in this cellular population, which is infected primarily in HIV-1-positive individuals. To this end, we crossed hu-cycT1 mice with JR-CSF transgenic mice carrying the full-length HIV-1(JR-CSF) provirus under the control of the endogenous HIV-1 long terminal repeat and demonstrated that human cyclin T1 expression is sufficient to support Tat-mediated transactivation in primary mouse CD4 T lymphocytes and monocytes/macrophages and increases in vitro and in vivo HIV-1 production by these stimulated cells. Increased HIV-1 production by CD4(+) T lymphocytes was paralleled with their specific depletion in the peripheral blood of the JR-CSF/hu-cycT1 mice, which increased over time. In addition, increased HIV-1 transgene expression due to human cyclin T1 expression was associated with increased lipopolysaccharide-stimulated monocyte chemoattractant protein 1 production by JR-CSF mouse monocytes/macrophages in vitro. Therefore, the JR-CSF/hu-cycT1 mice should provide an improved mouse system for investigating the pathogenesis of various aspects of HIV-1-mediated disease and the efficacies of therapeutic interventions.


Alternative splicing of AMPA subunits in prefrontal cortical fields of cynomolgus monkeys following chronic ethanol self-administration.
Functional impairment of the orbital and medial prefrontal cortex underlies deficits in executive control that characterize addictive disorders, including alcohol addiction. Previous studies indicate that alcohol alters glutamate neurotransmission and one substrate of these effects may be through the reconfiguration of the subunits constituting ionotropic glutamate receptor (iGluR) complexes. Glutamatergic transmission is integral to cortico-cortical and cortico-subcortical communication and alcohol-induced changes in the abundance of the receptor subunits and/or their splice variants may result in critical functional impairments of prefrontal cortex in alcohol dependence. To this end, the effects of chronic ethanol self-administration on glutamate receptor ionotropic AMPA (GRIA) subunit variant and kainate (GRIK) subunit mRNA expression were studied in the orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC) of male cynomolgus monkeys. In DLPFC, total AMPA splice variant expression and total kainate receptor subunit expression were significantly decreased in alcohol drinking monkeys. Expression levels of GRIA3 flip and flop and GRIA4 flop mRNAs in this region were positively correlated with daily ethanol intake and blood ethanol concentrations (BEC) averaged over the 6 months prior to necropsy. In OFC, AMPA subunit splice variant expression was reduced in the alcohol treated group. GRIA2 flop mRNA levels in this region were positively correlated with daily ethanol intake and BEC averaged over the 6 months prior to necropsy. Results from these studies provide further evidence of transcriptional regulation of iGluR subunits in the primate brain following chronic alcohol self-administration. Additional studies examining the cellular localization of such effects in the framework of primate prefrontal cortical circuitry are warranted.


Tuning linkage isomerism and magnetic properties of bi- and tri-metallic cage silsesquioxanes by cation and solvent effects.
Herein, the effect of replacement of the surrounding solvent and/or the partial substitution of sodium ions in the cage-like copper, sodium phenylsilsesquioxane [(PhSiO1.5)12(CuO)4(NaO0.5)4(n-BuOH)6] 1 with a globular structure was investigated; the synthesis of ten new derivatives of complex 1 was performed, and their crystal structures were determined. Solvate replacement of n-butanol in 1 with dimethyl sulfoxide, acetonitrile, 1,4-dioxane/EtOH, and 1,4-dioxane/PhCN afforded the complexes [(PhSiO1.5)12(CuO)4(NaO0.5)4(DMSO)8] (2), [(PhSiO1.5)12(CuO)4(NaO0.5)4(MeCN)6(H2O)2]·2MeCN (3), [(PhSiO1.5)12(CuO)4(NaO0.5)4(C4H8O2)(EtOH)4]·0.5EtOH (4), and [(PhSiO1.5)12(CuO)4(NaO0.5)4(C4H8O2)4(H2O)3]·2PhCN·2C4H8O2·H2O (5). In an aqueous solution of EtOH, a rearrangement reaction occurred instead of substitution, which resulted in a new complex, [(PhSiO1.5)10(CuO)2(NaO0.5)2(H2O)6] (6), with a cooling tower molecular structure. Transmetalation reactions of 1 with KCl or CsF resulted in the formation of the trimetallic complexes [(PhSiO1.5)12(CuO)4(NaO0.5)2(KO0.5)2(DMF)6] (7), [(PhSiO1.5)12(CuO)4(NaO0.5)(CsO0.5)3(DMF)4(DMSO)(H2O)]·1.5DMF (8), [(PhSiO1.5)12(CuO)4(NaO0.5)2(CsO0.5)2(DMF)8]·0.5H2O (9), and [(PhSiO1.5)12(CuO)4(NaO0.5)3(CsO0.5)(DMF)4] (10). The replacement of sodium ions of 1 by the bulky non-metallic cation PhMe3N+ upon the interaction of 1 with PhMe3NCl in a MeCN medium afforded the complex (PhNMe3)2[(PhSiO1.5)12(CuO)4(NaO0.5)2(O)(MeCN)4]·4MeCN (11). X-ray analysis confirmed the successful replacement of terminal butanol molecules in all complexes and the stability of the globular cage of the parent complex under the reaction conditions, with the exceptions of complexes 6 and 9 that underwent an unprecedented reorganization of cage metallasilsesquioxane (CLMS) units into the cooling tower and sandwich-like cages, respectively. The stability of the cage during substitution reactions provides the first experimental evidence that polynuclear cage metallasilsesquioxanes can act as building blocks for the construction of coordination polymers, opening new ways for the synthesis of hybrid CLMS-based frameworks. In particular, the compounds 4, 6, 7, 9, and 10 are one-dimensional coordination polymers, and 5 and 8 are two-dimensional coordination polymers with a square lattice topology. A magnetism study of the coordination polymer compounds 5, 6, 8, and 9 showed antiferromagnetic behavior between copper centers.


Sex chromosome-linked species recognition and evolution of reproductive isolation in flycatchers.
Interbreeding between species (hybridization) typically produces unfit offspring. Reduced hybridization should therefore be favored by natural selection. However, this is difficult to accomplish because hybridization also sets the stage for genetic recombination to dissociate species-specific traits from the preferences for them. Here we show that this association is maintained by physical linkage (on the same chromosome) in two hybridizing Ficedula flycatchers. By analyzing the mating patterns of female hybrids and cross-fostered offspring, we demonstrate that species recognition is inherited on the Z chromosome, which is also the known location of species-specific male plumage traits and genes causing low hybrid fitness. Limited recombination on the Z chromosome maintains associations of Z-linked genes despite hybridization, suggesting that the sex chromosomes may be a hotspot for adaptive speciation.


Expression of Vascular Endothelial Growth Factor in Odontogenic Cysts: Is There Any Impression on Clinical Outcome?
The recent scientific reports have shown that angiogenesis can affect biological behavior of pathologic lesions. Regarding unique clinical outcome of Odontogenic keratocyst (OKC), the present study was aimed to compare angiogenesis in Odontogenic keratocyst and Dentigerous cyst (DC). In this experimental study, tissue sections of 46 samples of OKC and DC were stained through immunohistochemical method using Vascular Endothelial Growth Factor (VEGF) antibody. VEGF expression was evaluated in epithelial cells, fibroblasts and endothelial cells. The average percentage of stained cells in any samples was categorized to 3 groups as follows: SCORE 0: 10% of cells or less are positive. SCORE 1: 10 to 50% of cells are positive. SCORE 2: more than 50% of cells are positive. Mann-U-Whitney, T-test and chi-square was used for statistical analysis. The average of VEGF expression in 24 samples of DC was 20.2% and in 22 samples of OKC was 52.6%, respectively. The average of VEGF expression in these two cysts had statistical significant differences. (PV= 0.045). There was significant statistical differences between two cysts in the terms of VEGF SCORE (PV= 0.000). OKC samples had significantly higher SCORE for the purpose of VEGF incidence than DC. Also, there were no differences between VEGF expression in epithelial cells of two cysts (PV= 0.268) there were significant statistical differences between two cysts in terms of endothelial cell staining. The endothelial cell staining was significantly higher in OKC than DC (PV= 0.037%). Regarding higher expression of Vascular Endothelial Growth factor in OKC than DC, it seems that angiogenesis may have great impression on clinical outcome of OKC.


Effects of Fluorescent Lighting Versus Sunlight Exposure on Calcium, Magnesium, Vitamin D, and Feather Destructive Behavior in Hispaniolan Amazon Parrots (Amazona ventralis).
Low exposure to ultraviolet light, and resulting vitamin D deficiency, has recently been linked to autism spectrum disorder in people. Captive psittacine birds that exhibit feather destructive behavior share similarities with people affected by autism spectrum disorder, such as repetitive (stereotypies) and self-harming behaviors. The metabolic and psychological effects of housing pet parrots indoors without ultraviolet B lighting are not typically considered in animal husbandry or veterinary care. Calcifediol (serum vitamin D), ionized calcium, and ionized magnesium levels were compared between 10 Hispaniolan Amazon parrots (Amazona ventralis) housed indoors and 10 Hispaniolan Amazon parrots historically housed outdoors. Although ionized calcium and magnesium levels were not significantly different, calcifediol levels were significantly greater in the colony of birds housed outdoors. Further, these 2 research colonies of individually housed birds were feather scored. Subjectively, the birds that were housed indoors had greater self-inflicted feather damage than did those housed outdoors; however, the difference was not statistically significant.


Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety.
Fischer 344 rats (60/sex/group) were given daily subcutaneous injections of recombinant human parathyroid hormone (PTH)(1-34) for 2 years at doses of 0, 5, 30, or 75 microg/kg. Treatment caused substantial increases in bone mass consistent with the known pharmacologic effects of once-daily administration. As determined by quantitative computed tomography (QCT) and histomorphometry, bone mass was markedly increased. Substantial new bone formation resulted in a large decrease in marrow space accompanied by altered bone architecture. Bone proliferative lesions were observed in all PTH( 1-34)-treated groups. Osteosarcoma occurred in 3, 21, and 31 male rats and in 4, 12, and 23 female rats in the 5-, 30-, and 75-microg/kg treatment groups, respectively. Focal osteoblast hyperplasia, osteoma, and osteoblastoma were much less frequent. Although the specific cellular or molecular mechanisms responsible for the rat bone tumors have not been fully elucidated, the data suggest that these lesions resulted from the long duration of treatment and the exaggerated pharmacologic response of the rat skeleton to daily treatment with PTH(1-34). Important differences between the rat study and clinical use in adult humans suggest that the increased incidence of bone neoplasia in rats treated for 2 years is likely not predictive of an increased risk of bone cancer in skeletally mature adult humans being given PTH(1-34) for a limited period of time in the treatment of osteoporosis.


Postacute care model of stroke in one hospital.
The National Health Insurance Bureau of Taiwan has established a postacute care model of stroke (PAC-stroke). Patients with acute stroke occurring within the preceding 30 days and with modified Rankin scale (mRS) scores of 2-4 can be transferred to PAC hospitals for 6-12 weeks of rehabilitation. We conducted a retrospective review to explore the results of PAC-stroke. From April 2015 to December 2017, patients who transferred from our hospital to four PAC hospitals were reviewed. We evaluated their functional status using the mRS, Barthel index (BI), functional oral intake scale, EuroQoL-5D, Lawton-Brody instrumental activities of daily living scale, Berg balance test, usual gait speed, 6-min walk test, Fugl-Meyer sensory and motor assessments, mini-mental state examination, motor activity log quantity and quality tests, and concise Chinese aphasia test, before and after the PAC program. A total of 53 patients with initial mRS score of 3 (6 patients) or 4 (47 patients) were enrolled, including 39 with cerebral infarction and 14 with cerebral hemorrhage, with a median age of 67 (mean: 68.3 ± 13.3) years. Seven patients had serious complications, including six cases of pneumonia and one fracture. The readmission rates within 14 days after transfer to the PAC hospital and in the overall PAC program were 3.8% and 13.2%, respectively. After exclusion of eight patients who dropped out early, 45 patients completed the PAC program. The median lengths of stay at the upstream hospital and PAC hospitals were 26 and 63 days, respectively. Improved mRS and BI scores were observed in 42% and 78% of the patients, respectively. The results of all 14 functional assessments improved significantly after the PAC program. Significant improvements in mRS and BI scores and all functional assessments within an average of 63 days of PAC hospital stay helped 73% of the patients to return home.


Effect of an aerobic exercise intervention on cardiac autonomic regulation: A worksite RCT among cleaners.
The aim of this randomized controlled trial (RCT) was to determine whether aerobic exercise during work hours affects cardiac autonomic regulation in cleaners characterized by high levels of occupational physical activity and poor cardiorespiratory fitness. Eligible cleaners (n=116) were randomized to an aerobic exercise group (n=59) or a reference group (n=57) with lectures. The intervention group received two 30-min sessions per week of supervised aerobic exercise over 4months. Diurnal measurements of heart rate variability (HRV) and physical activity (accelerometry) were obtained at baseline and at 4-month follow-up. Time and frequency domain indices of HRV were derived during work, leisure time and sleep to evaluate cardiac autonomic regulation. Linear mixed models were used to determine the effect of the intervention on HRV indices, with adjustment for age, gender and daily use of antihypertensive and/or heart medication. Compared with the reference group, the exercise group increased all HRV indices apart from a reduction in LF/HF ratio from baseline to follow-up both during work (p<0.05) and leisure (p<0.05). In contrast, during sleep, the HRV indices tended to decrease in the exercise group compared with the reference group from baseline to follow-up, being significant for the HF spectral component (p=0.03). Among cleaners, a worksite aerobic exercise intervention improved cardiac autonomic regulation during work and leisure, but not during sleep. The health effect of this contrasting change in autonomic regulation needs further investigation.


Prospective Prediction of Depression and Anxiety by Integrating Negative Emotionality and Cognitive Vulnerabilities in Children and Adolescents.
Negative emotionality (NE) and multiple cognitive vulnerabilities (CVs) (negative inferential style, brooding, self-criticism, dependency, dysfunctional attitudes) independently predict internalizing outcomes. The present study examined whether NE and CVs could be structurally integrated into a common factor reflecting shared variance across risks, and specific factors reflecting unique variance in risks. We evaluated the validity and utility of this integrated model via prospective prediction of future depression and anxiety compared to alternative models (NE and CVs individually, a correlated factor model). Youth from a large community sample (N = 571; M = 13.58 years old; 55% girls, 44% boys) reported on NE and CVs. Depression and anxiety symptoms based on youth report, and disorder onset based on youth and caregiver diagnostic interviews were assessed over a 1½ years follow-up. Results supported a structural model including a general NE-CV dimension and specific dimensions for NE, common cognitive risk, negative inferential style, and brooding; model invariance was obtained from late childhood through late adolescence and for girls and boys. The integrated general NE-CV factor more consistently and strongly predicted future depressive (β = 0.58) and anxiety (β = 0.56) symptoms, and onsets of depression (OR = 1.81) and anxiety (OR = 2.23) relative to NE and CV risk dimensions across alternative models (ps < .01). The general NE-CV dimension represents an important means to efficiently represent transdiagnostic risk for internalizing outcomes among youth.


Tales of transforming cities: Transformative climate governance capacities in New York City, U.S. and Rotterdam, Netherlands.
Climate change actions in cities worldwide are driving deep changes in urban governance. We ask whether new capacities for transformative climate governance are emerging in two cities that have experimented with urban climate governance: Rotterdam, the Netherlands, and New York City (NYC), United States. Transformative climate governance creates the conditions for developing integrated and innovative climate mitigation and adaptation policies and interventions that respond to and shape urban transformation dynamics and contribute to sustainability and resilience. The comparison of capacities for transformative climate governance in Rotterdam and NYC offers insights into the emerging features of urban climate governance vis-à-vis existing urban governance regimes: how urban climate governance is driven and delivered, what new governance conditions emerge, and whether these conditions enable transformative climate governance. In both cities, an integrated, experimental and inclusive approach to climate governance is emerging, which crosses multiple policy sectors and domains (e.g. transport, energy, health, justice), involves a variety of actors and facilitates innovative solutions. Envisioning, long-term goal and knowledge integration, experimentation and tapping into coalitions for change help to provide the basis (including guiding principles, urgency, actor networks, innovative solutions) for transformative climate governance. However, these transformative approaches tend to be still subordinate to business-as-usual interests and policy and planning approaches, which favour isolated, incremental and short-term responses. The challenge for strengthening transformative climate governance will be to develop rigorous institutional and organisational conditions that decisively stipulate a prioritisation of climate change across scales and sectors, provide action mandates and enable wider coordination, collaboration and learning.


Immune mechanisms in fibrotic pulmonary sarcoidosis.
Sarcoidosis is an immune-mediated disorder. Its immunopathology has been steadily mapped out over the past few decades. Despite this, the underpinning mechanisms for progressive fibrotic sarcoidosis is an almost uncharted area. Consequently, there has been little change in the clinical management of fibrotic sarcoidosis over the decades and an unfocused search for new therapeutics. In this review, we provide a comprehensive examination of the relevant immune findings in fibrotic and/or progressive pulmonary sarcoidosis and propose a unifying mechanism for the pathobiology of fibrosis in sarcoidosis.


Characteristics and clinical outcomes of head-injured cyclists with and without helmets in urban and rural areas of Taiwan: A 15-year study.
Bicycle riding is increasingly popular in Taiwan, but the number of cyclists injured and cyclists' death rates are both increasing. The aim of this study was to investigate the different characteristics and clinical outcomes of traffic accident-related head injuries among cyclists in urban and rural areas. Records of 812 patients (533 urban and 279 rural) admitted to 27 hospitals in Taipei City and Hualien County as the result of a traumatic head injury while bicycling between 1998 and 2013 were retrieved for study. Demographics, details about the accident, protective helmet use, and clinical outcomes were then subjected to analysis. Urban victims were more likely to be injured during morning and early evening rush hours and rural victims during the day; most urban victims were between 19 and 34 years of age and injured in the slow lane; rural victims tended to be younger or older and were injured in the fast lane (all P ≤.001). Riders who wore a helmet were less likely to suffer loss of consciousness (odds ratio [OR] = 0.31), amnesia (OR = 0.069), neurological disorders (OR = 0.205), or facial fractures (OR = 0.369). Older age, more severe head injuries, and bicycle-motor vehicle collisions influenced the severity of symptoms on admission and the residual effects at discharge. Differences in the characteristics of injuries in urban and rural areas and the utilization of protective helmets may help government authorities adopt appropriate policies to promote safer and more enjoyable cycling.


Prevalence of headache among handheld cellular telephone users in Singapore: a community study.
We carried out a cross-sectional community study in Singapore to determine the prevalence of specific central nervous system (CNS) symptoms among hand-held cellular telephone (HP) users compared to nonusers and to study the association of risk factors and CNS symptoms among HP users. A total of 808 men and women between 12 and 70 years of age, who lived in one community, were selected using one-stage cluster random sampling and responses to a structured questionnaire. The prevalence of HP users was 44.8%. Headache was the most prevalent symptom among HP users compared to non-HP users, with an adjusted prevalence rate ratio of 1.31 [95% confidence interval, 1.00-1.70]. There is a significant increase in the prevalence of headache with increasing duration of usage (in minutes per day). Prevalence of headache was reduced by more than 20% among those who used hand-free equipment for their cellular telephones as compared to those who never use the equipment. The use of HPs is not associated with a significant increase of CNS symptoms other than headache.


Age- and temperature-dependent somatic mutation accumulation in Drosophila melanogaster.
Using a transgenic mouse model harboring a mutation reporter gene that can be efficiently recovered from genomic DNA, we previously demonstrated that mutations accumulate in aging mice in a tissue-specific manner. Applying a recently developed, similar reporter-based assay in Drosophila melanogaster, we now show that the mutation frequency at the lacZ locus in somatic tissue of flies is about three times as high as in mouse tissues, with a much higher fraction of large genome rearrangements. Similar to mice, somatic mutations in the fly also accumulate as a function of age, but they do so much more quickly at higher temperature, a condition which in invertebrates is associated with decreased life span. Most mutations were found to accumulate in the thorax and less in abdomen, suggesting the highly oxidative flight muscles as a possible source of genotoxic stress. These results show that somatic mutation loads in short-lived flies are much more severe than in the much longer-lived mice, with the mutation rate in flies proportional to biological rather than chronological aging.


Multimodal characterization of compositional, structural and functional features of human atherosclerotic plaques.
Detection of atherosclerotic plaque vulnerability has critical clinical implications for avoiding sudden death in patients with high risk of plaque rupture. We report on multimodality imaging of ex-vivo human carotid plaque samples using a system that integrates fluorescence lifetime imaging (FLIM), ultrasonic backscatter microscopy (UBM), and photoacoustic imaging (PAI). Biochemical composition is differentiated with a high temporal resolution and sensitivity at the surface of the plaque by the FLIM subsystem. 3D microanatomy of the whole plaque is reconstructed by the UBM. Functional imaging associated with optical absorption contrast is evaluated from the PAI component. Simultaneous recordings of the optical, ultrasonic, and photoacoustic data present a wealth of complementary information concerning the plaque composition, structure, and function that are related to plaque vulnerability. This approach is expected to improve our ability to study atherosclerotic plaques. The multimodal system presented here can be translated into a catheter based intraluminal system for future clinical studies.


Cancer is a functional repair tissue.
When a wound occurs, growth and repair genes (GR genes, such as oncogenes, proto-oncogenes, etc.) in surrounding cells are activated and secretion of growth and repair factors (GR factors, such as growth, stem cell, and stimulating factors, etc.) is induced to heal the wound. However, if the wound is persistent due to chronic physical (radiation, electromagnetic field, trauma, particles, etc.), chemical (carcinogens, toxic chemicals, heavy metals etc.) or biological (aging, free radicals, inflammation, nutrient deficiency, bacteria and virus infections, stress, etc.) damage, amplification of GR gene activation in surrounding cells may lead to a clinical cancer. Based on the commonalities between cancer and wound healing, a new hypothesis of cancer is presented: malignancies are not passive mutated useless masses; rather, they are functional tissues produced by GR gene activation to secrete GR factors in an effort to heal persistent wounds in the body. Based on the hypothesis, current cancer treatments aimed at killing cancer cells only may be misguided. The logical extension of the hypothesis is that cancer treatment focused on wound healing by limiting causes of persistent wounds, providing repair cells, GR factors, and substrates required by repair cells may yield more fruitful results than treatments focused on killing cancer cells alone. Spontaneous regressions of cancer, although rare, may be successful examples of serendipitous spontaneous wound healing. Standard therapies aimed at killing cancer cells, should be limited to adjuvant status for limiting symptoms or buying time for completion of the wound healing process. Attempts to destroy cancer cells without healing underlying persistent wounds will allow for eventual recurrence.


Organically versus conventionally grown produce: common production inputs, nutritional quality, and nitrogen delivery between the two systems.
One distinguishing conclusion found in most reviews of research studies comparing organically and conventionally grown produce is that variables shared alike by organic and conventional produce during production, harvest, and postharvest handling and storage were not applied. As a result, accurate and meaningful conclusions comparing the nutritional quality of organic and conventional produce are difficult to ascertain. Pairing common production variables such as the physical, biological, and chemical/nutritional attributes of soils, the irrigation sources and amounts, crop varieties, crop maturities and harvest dates, pre- and postharvest processing, handling, and/or storage methods, individually and collectively, provide greater clarity as to how inputs unique to organic and conventional systems affect produce quality. Variables to be paired during production, harvest, and postharvest handling and storage studies comparing organic and conventional produce are discussed along with findings indicating that organic crops often have higher dry matter, ascorbic acid, phenolic, and sugar and lower moisture, nitrate, and protein contents and yields than conventionally grown crops. Recent studies of nutritional quality in organic versus conventional produce also indicate that soil nitrogen delivery rates strongly affect nutritional quality. Nitrogen profiling is a promising new approach to improving the nutritional quality of both organic and conventional produce.


Individual difference in configural associative learning.
Individuals differ in their ability to acquire associations between stimuli and paired outcomes, an ability that has been proposed to be independent of general metrics of intelligence or memory (e.g., Kaufman, DeYoung, Gray, Brown, & Mackintosh, 2009). The nature of these differences may reflect the type of associative structures acquired during learning, for instance, configuring stimuli to facilitate flexible learning and memory. We test the hypothesis that individuals differ in configural associative learning as distinct from simpler (elemental) stimulus-outcome learning. In Experiment 1 participants were screened for attentional scope and we found that attentional scope predicted configural associative learning that could not be explained simply in terms of differences in strength of associative learning. In Experiment 2, attentional scope was trained resulting in a shift in participants' ability to learn about subsequent configurations unrelated to the training material. We discuss how the differences between individual learners reflect differences in configuring rather than simply differences in strength or speed of learning. (PsycINFO Database Record


Longitudinal Serum Neurofilament Levels of Multiple Sclerosis Patients Before and After Treatment with First-Line Immunomodulatory Therapies.
Serum neurofilament light chain (NfL) has been shown to correlate with neuroaxonal damage in multiple sclerosis (MS) and various other neurological diseases. While serum NfL is now regularly reported in clinical approval studies, there is a lack of longitudinal data from patients treated with established basic immunotherapies outside of study conditions. In total, 34 patients with early relapsing-remitting MS (RRMS) were included. The follow-up period was 24 months with regular follow-up visits after 3, 6, 9, 12 and 18 months. Therapy with glatiramer acetate was initiated in 20 patients and with interferon-beta in 12 patients. The disease course was monitored by the events of relapses, Expanded Disability Status Scale (EDSS) score and MRI parameters. Overall, serum NfL levels were higher at time points with a current relapse event than at time points without relapse (12.8 pg/mL vs. 9.7 pg/mL, p = 0.011). At follow-up, relapse-free patients showed significantly reduced serum NfL levels starting from 9 months compared to baseline (p < 0.05) and reduced levels after 12 months compared to baseline (p = 0.013) in patients without EDSS progression for 12 months. In this explorative observational study, our data suggest that the longitudinal measurement of serum NfL may be useful in addition to MRI to monitor disease activity and therapy response.


Visual impairment in the 40- to 64-year-old population of Shahroud, Iran.
To determine the prevalence of visual impairment by age and gender in Shahroud. Using random cluster sampling, 6311 Shahroud inhabitants who were between 40 and 64 years old were invited for ophthalmological examinations. Visual acuity worse than 0.5 LogMAR (20/60) and 1.3 LogMAR (20/400) in the better eye was regarded as low vision and blindness, respectively. The cause of blindness was determined by an ophthalmologist and in a person with more than one cause, the most correctable cause was regarded as the main cause. This study was conducted on 5190 participants (response rate: 82.2%). On the basis of presenting visual acuity, the prevalence of low vision and blindness was found to be 1.8% (95% confidence interval (CI): 1.4-2.10) and 0.5% (95% CI: 0.3-0.7), respectively. Based on corrected vision, these values were 0.5% (95% CI: 0.3-0.7) and 0.3% (95% CI: 0.1-0.4), respectively. Visual impairment increased with age in women (P<0.001). Uncorrected refractive errors (63.9%), cataract (20.2%), and amblyopia (5.9%) were the most common causes of visual impairment based on presenting vision. Based on corrected vision, however, cataract (42.5%), amblyopia (12.5%), and retinitis pigmentosa (7.5%) were the most common causes of visual impairment. Although the prevalence of visual impairment in the city of Shahroud was determined to be lower than two previous studies in the country, correction of refractive errors and cataract could minimize the rate of visual impairment in this population as they were shown to comprise 85% of the causes of visual impairment. The elderly women need to receive more attention.


Object crowding.
Crowding occurs when stimuli in the peripheral fields become harder to identify when flanked by other items. This phenomenon has been demonstrated extensively with simple patterns (e.g., Gabors and letters). Here, we characterize crowding for everyday objects. We presented three-item arrays of objects and letters, arranged radially and tangentially in the lower visual field. Observers identified the central target, and we measured contrast energy thresholds as a function of target-to-flanker spacing. Object crowding was similar to letter crowding in spatial extent but was much weaker. The average elevation in threshold contrast energy was in the order of 1 log unit for objects as compared to 2 log units for letters and silhouette objects. Furthermore, we examined whether the exterior and interior features of an object are differentially affected by crowding. We used a circular aperture to present or exclude the object interior. Critical spacings for these aperture and "donut" objects were similar to those of intact objects. Taken together, these findings suggest that crowding between letters and objects are essentially due to the same mechanism, which affects equally the interior and exterior features of an object. However, for objects defined with varying shades of gray, it is much easier to overcome crowding by increasing contrast.


Functional dyspepsia, upper gastrointestinal symptoms, and transit in children.
To assess the prevalence of abnormal gastric emptying and small bowel transit in children with functional dyspepsia at a tertiary care center, and the relationship between abnormal gastric and small bowel transit and symptoms in pediatric patients with functional gastrointestinal disorders. Patients were selected by a cross-sectional chart review based on the following inclusion criteria: (1) completion of scintigraphic study of the gastric emptying of solids at 2 hours (GE2), 4 hours (GE4), and small bowel transit at 6 hours (SBT) using a standardized egg meal labeled with 99mTechnetium sulfur colloid, and (2) gastrointestinal (GI) complaints without mucosal or organic disease. Logistic regression analysis was used to assess the association between the presence of upper GI symptoms, and each parameter of gastric and small bowel transit. Children with upper GI symptoms (n=96) were identified. Among 57 children with functional dyspepsia, 40% had slow SBT. Fast GE at 4 hours, and slow SBT were independently associated with bloating. Children with fast SBT were less likely to report abdominal pain. Incorporating assessments of gastric and small bowel transit may be useful in the evaluation of pediatric patients with upper GI symptoms and functional dyspepsia.


A novel β-glucosidase from Saccharophagus degradans 2-40T for the efficient hydrolysis of laminarin from brown macroalgae.
Laminarin is a potential biomass feedstock for the production of glucose, which is the most preferable fermentable sugar in many microorganisms by which it can be converted to biofuels and bio-based chemicals. Also, laminarin is a good resource as functional materials because it consists of β-1,3-glucosidic linkages in its backbone and β-1,6-glucosidic linkages in its branches so that its oligosaccharides driven from laminarin have a variety of biological activities. It is industrially important to be able to produce laminarioligosaccharides as well as glucose from laminarin by a single enzyme because the enzyme cost accounts for a large part of bio-based products. In this study, we investigated the industrial applicability of Bgl1B, a unique β-glucosidase from Saccharophagus degradans 2-40T, belonging to the glycoside hydrolase family 1 (GH1) by characterizing its activity of hydrolyzing laminarin under various conditions. Bgl1B was cloned and overexpressed in Escherichia coli from S. degradans 2-40T, and its enzymatic activity was characterized. Similar to most of β-glucosidases in GH1, Bgl1B was able to hydrolyze a variety of disaccharides having different β-linkages, such as laminaribiose, cellobiose, gentiobiose, lactose, and agarobiose, by cleaving β-1,3-, β-1,4-, and β-1,6-glycosidic linkages. However, Bgl1B showed the highest specific activity toward laminaribiose with a β-1,3-glycosidic linkage. In addition, it was able to hydrolyze laminarin, one of the major polysaccharides in brown macroalgae, into glucose with a conversion yield of 75% of theoretical maximum. Bgl1B also showed transglycosylation activity by producing oligosaccharides from laminarin and laminaribiose under a high mass ratio of substrate to enzyme. Furthermore, Bgl1B was found to be psychrophilic, exhibiting relative activity of 59-85% in the low-temperature range of 2-20 °C. Bgl1B can directly hydrolyze laminarin into glucose with a high conversion yield without leaving any oligosaccharides. Bgl1B can exhibit high enzymatic activity in a broad range of low temperatures (2-20 °C), which is advantageous for establishing energy-efficient bioprocesses. In addition, under high substrate to enzyme ratios, Bgl1B can produce high-value laminarioligosaccharides via its transglycosylation activity. These results show that Bgl1B can be an industrially important enzyme for the production of biofuels and bio-based chemicals from brown macroalgae.


Ultrasound imaging for the rheumatologist XLIII. Ultrasonographic evaluation of shoulders and hips in patients with polymyalgia rheumatica: a systematic literature review.
Musculoskeletal ultrasonography (US) has lately been applied to patients with polymyalgia rheumatica for the examination of shoulders and hip, and included in the 2012 PMR classification criteria. We aimed to perform a comprehensive overview of the literature on this topic with a systematic review. We searched PubMed, Embase, the Cochrane library and the proceedings from EULAR and ACR congresses (2011-2012). We included studies evaluating patients with confirmed or suspected PMR, undergoing US of shoulders and/or hips. The diagnosis of PMR could be based on expert opinion or diagnostic criteria. Cohort, case-control, diagnostic accuracy studies and case-series were eligible for inclusion. The features of the included studies were presented. When available, sensitivities and specificities were calculated for primary studies. Out of 1736 papers identified by our search, 13 articles and 1 abstract were finally included in the review. Eight studies focused on shoulder US, 1 on hip US, 4 on both. Studies were extremely variable in terms of population, US examination, reference standard and control population. In general, at the shoulder, pathological bilateral US findings in most studies were more prevalent in patients with PMR compared to controls. When sensitivity and specificity could be calculated, bilateral findings were more sensitive. Notably, less information was available on hip US. US (especially in shoulder examination) is confirmed to be a potentially useful instrument to integrate clinical information in the management of patients with PMR. Its additional value in conjunction with the new classification criteria should be further tested.


Characterization of Biostimulant Mode of Action Using Novel Multi-Trait High-Throughput Screening of Arabidopsis Germination and Rosette Growth.
Environmental stresses have a significant effect on agricultural crop productivity worldwide. Exposure of seeds to abiotic stresses, such as salinity among others, results in lower seed viability, reduced germination, and poor seedling establishment. Alternative agronomic practices, e.g., the use of plant biostimulants, have attracted considerable interest from the scientific community and commercial enterprises. Biostimulants, i.e., products of biological origin (including bacteria, fungi, seaweeds, higher plants, or animals) have significant potential for (i) improving physiological processes in plants and (ii) stimulating germination, growth and stress tolerance. However, biostimulants are diverse, and can range from single compounds to complex matrices with different groups of bioactive components that have only been partly characterized. Due to the complex mixtures of biologically active compounds present in biostimulants, efficient methods for characterizing their potential mode of action are needed. In this study, we report the development of a novel complex approach to biological activity testing, based on multi-trait high-throughput screening (MTHTS) of Arabidopsis characteristics. These include the in vitro germination rate, early seedling establishment capacity, growth capacity under stress and stress response. The method is suitable for identifying new biostimulants and characterizing their mode of action. Representatives of compatible solutes such as amino acids and polyamines known to be present in many of the biostimulant irrespective of their origin, i.e., well-established biostimulants that enhance stress tolerance and crop productivity, were used for the assay optimization and validation. The selected compounds were applied through seed priming over a broad concentration range and the effect was investigated simultaneously under control, moderate stress and severe salt stress conditions. The new MTHTS approach represents a powerful tool in the field of biostimulant research and development and offers direct classification of the biostimulants mode of action into three categories: (1) plant growth promotors/inhibitors, (2) stress alleviators, and (3) combined action.


Return to the ED and hospitalisation following minor injuries among older persons treated in the emergency department: predictors among independent seniors within 6 months.
minor traumatic injuries among independent older people have received little attention to date, but increasingly the impact of such injuries is being recognised. we assessed the frequency and predictors of acute health care use, defined as return to the emergency department (ED) or hospitalisation. national multicentre prospective observational study. eight Canadian teaching EDs between April 2009 and April 2013. a total of 1,568 patients aged 65-100 years, independent in basic activities of daily living, discharged from ED following a minor traumatic injury. trained assessors measured baseline data including demographics, functional status, cognition, comorbidities, frailty and injury severity. We then conducted follow-up telephone interviews at 6 months to assess subsequent acute health care use. We used log-binomial regression analyses to identify predictors of acute health care use, and reported relative risks and 95% CIs. participants' mean age was 77.0, 66.4% female, and their injuries included contusions (43.5%), lacerations (25.1%) and fractures (25.4%). The cumulative rate of acute health care use by 6 months post-injury was 21.5% (95% CI: 19.0-24.3%). The strongest predictors of acute health care use within 6 months were cognitive impairment, RR = 1.6 (95% IC: 1.2-2.1) and the mechanism of injury including pedestrian struck or recreational injuries, RR = 1.6 (95% CI 1.2-2.2). among independent community living older persons with a minor injury, cognitive impairment and mechanism of injury were independent risk factors for acute healthcare use. Future studies should look at whether tailored discharge planning can reduce the need for acute health care use.


Human leukocyte antigens A*3001 and A*3002 show distinct peptide-binding patterns of the Mycobacterium tuberculosis protein TB10.4: consequences for immune recognition.
High-tuberculosis (TB)-burden countries are located in sub-Saharan Africa. We examined the frequency of human leukocyte antigen (HLA) alleles, followed by recombinant expression of the most frequent HLA-A alleles, i.e., HLA-A*3001 and HLA-A*3002, to study differences in mycobacterial peptide presentation and CD8(+) T-cell recognition. We screened a peptide library (9-mer peptides with an 8-amino-acid overlap) for binding, affinity, and off-rate of the Mycobacterium tuberculosis-associated antigen TB10.4 and identified only three TB10.4 peptides with considerable binding to HLA-A*3001. In contrast, 22 peptides bound to HLA-A*3002. This reflects a marked difference in the binding preference between the two alleles, with A*3002 tolerating a more promiscuous peptide-binding pattern and A*3001 accommodating only a very selective peptide repertoire. Subsequent analysis of the affinity and off-rate of the binding peptides revealed a strong affinity (8 nM to 7 μM) and moderate off-rate (20 min to 3 h) for both alleles. Construction of HLA-A*3001 and HLA-A*3002 tetramers containing selected binding peptides from TB10.4, including a peptide which was shared among both alleles, QIMYNYPAM (TB10.4(3-11)), allowed us to enumerate epitope-specific T cells in HLA-A*3001- and HLA-A*3002-typed patients with active TB. HLA-A*3001 and HLA-A*3002 major histocompatibility complex-peptide complexes were recognized in individuals with active TB, irrespective of their homozygous HLA-A*3001 or HLA-A*3002 genetic background. The antigen-specific T cells exhibited the CD45RA(+) CCR7(+) precursor phenotype and the interleukin-7 receptor (CD127), which were different from the phenotype and receptor exhibited by the parental CD8(+) T-cell population.


Legionella pneumophila major acid phosphatase and its role in intracellular infection.
Legionella pneumophila is an intracellular pathogen of protozoa and alveolar macrophages. This bacterium contains a gene (pilD) that is involved in both type IV pilus biogenesis and type II protein secretion. We previously demonstrated that the PilD prepilin peptidase is crucial for intracellular infection by L. pneumophila and that the secreted pilD-dependent proteins include a metalloprotease, an acid phosphatase, an esterase/lipase, a phospholipase A, and a p-nitrophenyl phosphorylcholine hydrolase. Since mutants lacking type IV pili, the protease, or the phosphorylcholine hydrolase are not defective for intracellular infection, we sought to determine the significance of the secreted acid phosphatase activity. Three mutants defective in acid phosphatase activity were isolated from a population of mini-Tn10-mutagenized L. pneumophila. Supernatants as well as cell lysates from these mutants contained minimal acid phosphatase activity while possessing normal levels of other pilD-dependent exoproteins. Genetic studies indicated that the gene affected by the transposon insertions encoded a novel bacterial histidine acid phosphatase, which we designated Map for major acid phosphatase. Subsequent inhibitor studies indicated that Map, like its eukaryotic homologs, is a tartrate-sensitive acid phosphatase. The map mutants grew within macrophage-like U937 cells and Hartmannella amoebae to the same degree as did wild-type legionellae, indicating that this acid phosphatase is not essential for L. pneumophila intracellular infection. However, in the course of characterizing our new mutants, we gained evidence for a second pilD-dependent acid phosphatase activity that, unlike Map, is tartrate resistant.


Atrial fibrillation for internists: current practice.
Atrial fibrillation (AF) has become a global epidemic and puts affected patients at high risk of adverse events. In this review we summarise the current evidence on risk factors and complications of AF, describe current treatment strategies, and outline new fields of research. Current evidence shows that hypertension and obesity are the two most important modifiable risk factors for the development of AF. Patients with AF face an increased stroke risk. Oral anticoagulation reduces this risk substantially. Mainly for reasons of safety and ease of use, non-vitamin K antagonist oral anticoagulants are preferred for stroke prevention. Rate and rhythm control interventions remain important and are mainly used for symptom control in AF patients. Rate control is recommended as an initial treatment and in patients with a low or absent symptom burden. Following the advent of AF ablation 20 years ago, the chances of successful sustained rhythm control have increased. Nevertheless, the procedural risks, although low, must be discussed with the patient in the context of the potential benefits. Heart failure and AF often coexist, which creates a further challenge for optimal AF management. Recent studies have shown that AF patients have a high burden of silent brain lesions, and that these lesions are associated with cognitive dysfunction. A better understanding of these interrelationships may eventually help the development of new prevention and treatment strategies to decrease the burden and complications associated with AF.


Assessment of the effects of increasing levels of physiological realism in the computational fluid dynamics analyses of implanted coronary stents.
Coronary stent implantation can improve blood flow in an artery that has been narrowed by the build up of arterial plaque. However, the implantation of the stent will change the geometry of the vessel wall. The haemodynamic effects of the stents presence and alteration of the vessel wall are unclear. The redistribution of flow induced vessel wall shear stress (WSS) and wall shear stress gradient (WSSG) may directly contribute to restenosis (re-blockage). Computational fluid dynamics (CFD) is used extensively to identify these parameters in stented vessels. However, simplifications to the model of the stented artery are common. In this paper, computational domains of stented arteries with increasing levels of physiological realism are created. CFD is used to predict the WSS and WSSG for each set of computational domains. Finally, the results show that certain simplifications are not valid for CFD analyses of implanted coronary stents.


Safety Evaluation of Fluoride Content in Tea Infusions Consumed in the Azores-a Volcanic Region with Water Springs naturally Enriched in Fluoride.
Tea is the second most commonly consumed beverage in the world. It is well recognized that the consumption of tea in high quantities can promote the development of fluorosis. The main objective of this study is to estimate the exposure to fluoride in the Azores through drinking tea prepared with water from different volcanic locations, by i) investigating the fluoride (F) content of various commercial brands of tea (Camellia sinensis) marketed in Azores and ii) comparing tea releasing rates of F according to brewing time, considering the fluoride concentration in the different types of water used for the infusion. Fluoride contents were determined by ion-selective electrode in 30 samples of drinking water from three different locations and in 450 samples of tea (black and green tea) from three different brands. Fluoride concentration in water ranged from 0.29 to 1.56 ppm (Porto Formoso and Sete Cidades village, respectively). Fluoride concentrations increased with brewing time, reaching the highest values in the Azorean black and green tea infusions. For all the studied brands, a negative correlation was found between tea fluoride contents and the pH of the water used to prepare the infusion. Fluoride concentration in infusions was significantly associated with the background fluoride concentration in drinking water. Since the fluoride concentration in groundwater varies accordingly to the geological conditions and tea consumption can contribute to fluoride intake, it is important to define the limits for tea consumption, particularly in fluoride-rich areas. Graphical Abstract Fluoride concentrations in black and green tea for 3 minutes of brewing time and, association between fluoride concentration and pH with brewing time.


Profiles of orofacial dysfunction in different diagnostic groups using the Nordic Orofacial Test (NOT-S)--a review.
The Nordic Orofacial Test-Screening (NOT-S) was developed as a comprehensive method to assess orofacial function. Results from the screening protocol have been presented in 11 international publications to date. This study reviewed these publications in order to compile NOT-S screening data and create profiles of orofacial dysfunction that characterize various age groups and disorders. NOT-S results of nine reports meeting the inclusion criteria were reviewed. Seven of these studies not only provided data on the mean and range of total NOT-S scores, but also on the most common domains of orofacial dysfunction (highest rate of individuals with dysfunction scores), allowing the construction of orofacial dysfunction profiles based on the prevalence of dysfunction in each domain of NOT-S. The compiled data comprised 669 individuals, which included healthy control subjects (n = 333) and various patient groups (n = 336). All studies reported differences between individuals with diagnosed disorders and healthy control subjects. The NOT-S data could measure treatment effects and provided dysfunction profiles characterizing the patterns of orofacial dysfunction in various diagnoses. This review corroborates previous results that the NOT-S differentiates well between patients and healthy controls and can also show changes in individuals after treatment. NOT-S could be used as a standard instrument to assess orofacial dysfunction, evaluate the outcomes of oral habilitation and rehabilitation and improve comparability in clinical practice and research.


Specific ablation of thyroid follicle cells in adult transgenic mice.
The coding region of the herpes simplex type 1 virus thymidine kinase gene was coupled to the promoter of the bovine thyroglobulin gene and introduced into the genome of mice. The viral thymidine kinase (HSV1-TK) was expressed mainly in the thyroid glands and testis. Upon treatment of transgenic females with the antiherpetic agent Ganciclovir the thyroid regressed, while the parathyroid gland was unaffected. The number of thyroid follicle cells was greatly reduced after 3 days, and they were completely absent after 7 days of treatment. After 14 days, the levels of circulating T4 and T3 were below the limits of detection, total soluble protein recovered from the thyroid and parathyroid glands together was 10% of the control value, and the level of thyroid HSV1-TK was more than 100-fold lower than that in transgenic controls. Levels of circulating PTH and calcitonin remained normal. At the time of treatment the mice were adults. Thus, the thyroid follicle cells were selectively ablated after normal development with a functional thyroid gland. When treatment with Ganciclovir was terminated after 14 days, no circulating T4 or T3 or other indications of thyroid regeneration were detected for a subsequent period of 90 days. During this time the mice gained weight more slowly than controls, at a rate consistent with the suppression of GH synthesis by thyroid deficiency. The production of mouse major urinary protein (MUP) ceased in the treated mice and was completely restored by the administration of T4. MUP production was not restored by GH, demonstrating that the expression of the Mup genes requires T4 in addition to GH.


Properties and therapeutic potential of transient receptor potential channels with putative roles in adversity: focus on TRPC5, TRPM2 and TRPA1.
Mammals contain 28 genes encoding Transient Receptor Potential (TRP) proteins. The proteins assemble into cationic channels, often with calcium permeability. Important roles in physiology and disease have emerged and so there is interest in whether the channels might be suitable therapeutic drug targets. Here we review selected members of three subfamilies of mammalian TRP channel (TRPC5, TRPM2 and TRPA1) that show relevance to sensing of adversity by cells and biological systems. Summarized are the cellular and tissue distributions, general properties, endogenous modulators, protein partners, cellular and tissue functions, therapeutic potential, and pharmacology. TRPC5 is stimulated by receptor agonists and other factors that include lipids and metal ions; it heteromultimerises with other TRPC proteins and is involved in cell movement and anxiety control. TRPM2 is activated by hydrogen peroxide; it is implicated in stress-related inflammatory, vascular and neurodegenerative conditions. TRPA1 is stimulated by a wide range of irritants including mustard oil and nicotine but also, controversially, noxious cold and mechanical pressure; it is implicated in pain and inflammatory responses, including in the airways. The channels have in common that they show polymodal stimulation, have activities that are enhanced by redox factors, are permeable to calcium, and are facilitated by elevations of intracellular calcium. Developing inhibitors of the channels could lead to new agents for a variety of conditions: for example, suppressing unwanted tissue remodeling, inflammation, pain and anxiety, and addressing problems relating to asthma and stroke.


Sarcoma European and Latin American Network (SELNET) Recommendations on Prioritization in Sarcoma Care During the COVID-19 Pandemic.
The COVID-19 outbreak has resulted in collision between patients infected with SARS-CoV-2 and those with cancer on different fronts. Patients with cancer have been impacted by deferral, modification, and even cessation of therapy. Adaptive measures to minimize hospital exposure, following the precautionary principle, have been proposed for cancer care during COVID-19 era. We present here a consensus on prioritizing recommendations across the continuum of sarcoma patient care. A total of 125 recommendations were proposed in soft-tissue, bone, and visceral sarcoma care. Recommendations were assigned as higher or lower priority if they cannot or can be postponed at least 2-3 months, respectively. The consensus level for each recommendation was classified as "strongly recommended" (SR) if more than 90% of experts agreed, "recommended" (R) if 75%-90% of experts agreed and "no consensus" (NC) if fewer than 75% agreed. Sarcoma experts from 11 countries within the Sarcoma European-Latin American Network (SELNET) consortium participated, including countries in the Americas and Europe. The European Society for Medical Oncology-Magnitude of clinical benefit scale was applied to systemic-treatment recommendations to support prioritization. There were 80 SRs, 35 Rs, and 10 NCs among the 125 recommendations issued and completed by 31 multidisciplinary sarcoma experts. The consensus was higher among the 75 higher-priority recommendations (85%, 12%, and 3% for SR, R, and NC, respectively) than in the 50 lower-priority recommendations (32%, 52%, and 16% for SR, R, and NC, respectively). The consensus on 115 of 125 recommendations indicates a high-level of convergence among experts. The SELNET consensus provides a tool for sarcoma multidisciplinary treatment committees during the COVID-19 outbreak. The Sarcoma European-Latin American Network (SELNET) consensus on sarcoma prioritization care during the COVID-19 era issued 125 pragmatical recommendations distributed as higher or lower priority to protect critical decisions on sarcoma care during the COVID-19 pandemic. A multidisciplinary team from 11 countries reached consensus on 115 recommendations. The consensus was lower among lower-priority recommendations, which shows reticence to postpone actions even in indolent tumors. The European Society for Medical Oncology-Magnitude of Clinical Benefit scale was applied as support for prioritizing systemic treatment. Consensus on 115 of 125 recommendations indicates a high level of convergence among experts. The SELNET consensus provides a practice tool for guidance in the decisions of sarcoma multidisciplinary treatment committees during the COVID-19 outbreak.


Biosynthetic human proinsulin. Review of chemistry, in vitro and in vivo receptor binding, animal and human pharmacology studies, and clinical trial experience.
To describe the rationale for the preclinical and clinical developmental course of human proinsulin (HPI), the second product after human insulin for the treatment of diabetes mellitus to be manufactured by DNA technology. The relevant and available published and unpublished preclinical and clinical information generated on pork proinsulin and human proinsulin has been integrated to demonstrate how certain clinically attractive features of pork proinsulin (a soluble intermediate-acting and possibly hepatospecific insulin agonist) led to the development of HPI. Clinical pharmacology studies demonstrated that HPI was definitely, although marginally, hepatospecific. More striking was the finding that the intrasubject/patient coefficient of variation of response to HPI was significantly less than that observed with NPH insulin. However, the fact that unique efficacy in controlled multicenter studies was not demonstrated suggested that these pharmacological features were not translated into clinical benefit. In one multicenter new patient study there were six myocardial infarctions, including two deaths, in patients treated for greater than or equal to 1 yr with HPI and none in the control group. To obtain an independent review of the risks and benefits of HPI, in February 1988, Lilly convened a consultant group that examined all relevant information on HPI available. These experts shared our concerns about the safety of HPI in light of the failure to demonstrate unique efficacy. Accordingly, clinical trials with HPI were suspended in February 1988. Experience with HPI demonstrates the challenge associated with the development of new drugs in general and insulin agonists in particular.


Risk Taking with Left- and Right-Skewed Lotteries.
While much literature has focused on preferences regarding risk, preferences over skewness also have significant economic implications. An important and understudied aspect of skewness preferences is how they affect risk taking. In this paper, we design a novel laboratory experiment that elicits certainty equivalents over lotteries where the variance and skewness of the outcomes are orthogonal to each other. This design enables us to cleanly measure both skewness seeking/avoiding and risk taking behavior, and their interaction, without needing to make parametric assumptions. Our experiment includes both left- and right-skewed lotteries. The results reveal that the majority of subjects are skewness avoiding risk takers who correspondingly also take more risk when facing less skewed lotteries. Our second contribution is to link these choices to individual rank-dependent utility preference parameters estimated using a separate lottery choice protocol. Using a latent-class model, we are able to identify two classes of subjects: skewness avoiders with the classic inverse s-shaped probability weighting function and skewness neutral subjects that do not have an inverse s-shaped probability weighting function. Our results thus demonstrate the link between probability distortion and skewness seeking/avoidance choices. They also highlight the importance of accounting for individual heterogeneity. The online version contains supplementary material available at 10.1007/s11166-021-09345-w.


p53-dependent transcriptional repression of p21(waf1) by hepatitis C virus NS3.
Hepatitis C virus (HCV) NS3 protein is known to affect normal cellular functions, such as cell proliferation and cell death, and to be involved, either directly or indirectly, in HCV hepatocarcinogenesis. In this study, we demonstrated that NS3 protein could specifically repress the promoter activity of p21 in a dose-dependent manner. The effect was not cell type-specific and was synergistic when combined with HCV core protein. Repression of the p21 promoter by NS3 was almost completely lost when p53 binding sites present on the p21 promoter were removed. Furthermore, p53 binding sites were sufficient to confer a strong NS3 responsiveness to an heterologous promoter, suggesting that NS3 represses the transcription of p21 by modulating the activity of p53. Although the NS3 protein domain required for the majority of p21 repression was located on the protease domain, the proteinase activity itself does not seem to be necessary for repression. Both transcription and protein stability of p53 were unaffected by NS3, suggesting that NS3 might repress transcription of p21 by inhibiting the regulatory activity of p53 via protein-protein interaction(s). Finally, the growth rate of NS3-expressing cell lines was at least twice as fast as that of the parent NIH 3T3 cells, indicating that the repression of p21 is actually reflected by the stimulation of cell growth.


Audiometric thresholds and prevalence of tinnitus among male veterans in the United States: data from the National Health and Nutrition Examination Survey, 1999-2006.
Hearing loss and tinnitus are the two most prevalent service-connected disabilities among U.S. veterans. The number of veterans receiving compensation and services from the Department of Veterans Affairs (VA) for these conditions continues to increase annually. However, the majority of veterans in the United States do not use VA medical centers or clinics for healthcare and do not receive VA compensation payments. Therefore, the prevalence of hearing loss and tinnitus among U.S. veterans is unknown. This study used National Health and Nutrition Examination Survey data to estimate the prevalence of these auditory conditions among male veterans. Between 1999 and 2006, pure tone audiometric data collected from 845 male veterans were compared with pure tone thresholds collected from 2,086 male nonveterans. We used questionnaire data collected between 1999 and 2004 to calculate and compare the prevalence of tinnitus for 2,174 veterans and 4,995 nonveterans. In general, pure tone thresholds did not differ significantly between veterans and nonveterans for most frequencies tested (500-8,000 Hz). The overall prevalence of tinnitus was greater for veterans than that for nonveterans (p < 0.001), with statistically significant differences in the 50 to 59 and 60 to 69 age groups.


Breast cancer statistics, 2011.
In this article, the American Cancer Society provides an overview of female breast cancer statistics in the United States, including trends in incidence, mortality, survival, and screening. Approximately 230,480 new cases of invasive breast cancer and 39,520 breast cancer deaths are expected to occur among US women in 2011. Breast cancer incidence rates were stable among all racial/ethnic groups from 2004 to 2008. Breast cancer death rates have been declining since the early 1990s for all women except American Indians/Alaska Natives, among whom rates have remained stable. Disparities in breast cancer death rates are evident by state, socioeconomic status, and race/ethnicity. While significant declines in mortality rates were observed for 36 states and the District of Columbia over the past 10 years, rates for 14 states remained level. Analyses by county-level poverty rates showed that the decrease in mortality rates began later and was slower among women residing in poor areas. As a result, the highest breast cancer death rates shifted from the affluent areas to the poor areas in the early 1990s. Screening rates continue to be lower in poor women compared with non-poor women, despite much progress in increasing mammography utilization. In 2008, 51.4% of poor women had undergone a screening mammogram in the past 2 years compared with 72.8% of non-poor women. Encouraging patients aged 40 years and older to have annual mammography and a clinical breast examination is the single most important step that clinicians can take to reduce suffering and death from breast cancer. Clinicians should also ensure that patients at high risk of breast cancer are identified and offered appropriate screening and follow-up. Continued progress in the control of breast cancer will require sustained and increased efforts to provide high-quality screening, diagnosis, and treatment to all segments of the population.


Idiotype connectance in the immune system. I. Expression of a cross-reactive idiotype on induced anti-p-azophenylarsonate antibodies and on endogenous antibodies not specific for arsonate.
A new cross-reactive idiotope family (CRIAD8) is described that contains subpopulations of antibodies binding to different epitopes. One subpopulation occurs naturally in normal sera from strain A mice, is found mainly on IgG2 and IgG3 subclasses, does not bind p-azobenzenearsonate (ABA)+, does not express CRI5Ci, and can be selectively stimulated by low doses of antiidiotype antibody (AD8). The second subpopulation is not found in normal serum, binds ABA, is found on all IgG subclasses, expresses CRI5Ci, and is selectively stimulated by ABA-conjugated proteins. Since CRIAD8 was found on both subpopulations of antibody, and since each subpopulation could be selectively expanded, it was possible to study the effect that expansion of the ABA- CRIAD8+ set had on subsequent responses elicited by ABA-keyhole limpet hemocyanin (KLH) in the ABA+ CRIAD8+ set. In these experiments, prior immunization with AD8 restricted the subsequent response of the ABA+ CRIAD8+ set to ABA-KLH. Furthermore, only those doses of AD8 that stimulated the ABA-CRIAD8+ set reduced the responsiveness of the ABA+ CRIAD8+ set to ABA-KLH, suggesting that the two phenomena are causally related. These findings argue that CRIAD8 correlates well with a regulatory idiotope and that immune responses by lymphocyte clones that have different antigen-binding specificities can affect one another as a result of their sharing such an idiotope. These results strongly favor a network organization of the immune system.


Functional characterization of Synechocystis sp. PCC 6803 delta psbU and delta psbV mutants reveals important roles of cytochrome c-550 in cyanobacterial oxygen evolution.
The functions of cytochrome c-550 and a 12 kDa protein in cyanobacterial oxygen evolution were studied with directed deletion mutants delta psbV and delta psbU of Synechocystis sp. PCC 6803, and the following results were obtained. (1) In contrast to the delta psbU mutant which is capable of autotrophic growth in the absence of Ca2+ or Cl- at a reduced rate, the delta psbV mutant lacking cytochrome c-550 could not grow at all without Ca2+ or Cl-. (2) The delta psbV mutant had a significantly reduced thermoluminescence emission intensity and flash oxygen yield, whereas the delta psbU mutant showed slight decreases in thermoluminescence intensity and flash oxygen yield, indicating corresponding decreases in the concentrations of O2-evolving centers in these mutants. (3) The delta psbV and delta psbU mutants exhibited elevated peak temperature for the thermoluminescence B- and Q-bands indicative of more stable S2 states. (4) The rise time of the O2 signal during the S3-[S4]-S0 transition was increased slightly in the delta psbV mutant but not in the delta psbU mutant. (5) The oxygen evolution was inactivated in the dark rapidly in the delta psbV mutant with a half-time of 28 min, but this did not happen in the delta psbU mutant. (6) Photoactivation of the oxygen-evolving complex after removal of the manganese cluster by hydroxylamine showed a higher quantum yield in the delta psbV mutant than in the delta psbU mutant or wild type. Taken together, these results indicated that cytochrome c-550 plays a substantial role in maintaining the stability and function of the manganese cluster in algal photosystem II, whereas the 12 kDa protein plays primarily a regulatory role in maintaining normal S-state transitions. These functional features of cytochrome c-550 and the 12 kDa protein were compared with those of the 23 and 17 kDa proteins in higher plant photosystem II and of the 33 kDa protein in both algal and plant photosystem II.


Tissue-specific significance of BAP1 gene mutation in prognostic prediction and molecular taxonomy among different types of cancer.
BAP1 is an emerging tumor suppressor whose inactivating mutations have been found to play critical roles in tumor development. This study was conducted to elucidate the potential value of BAP1 mutation in guiding prognostic prediction and clinical stratification. We conducted a comprehensive analysis of relevant studies from multiple databases, to determine the impact of BAP1 mutation on the overall survival and disease-free survival of patients in various cancers. A total of 2457 patients from 21 studies were included in the final analysis. Although the pooled results demonstrated that BAP1 mutation was a negative indicator of overall survival (hazard ratio = 1.73; 95% confidence interval = 1.23-2.42) and disease-free survival (hazard ratio = 2.25; 95% confidence interval = 1.47-3.45), this prognostic value was only applicable to uveal melanoma and clear cell renal cell carcinoma, but not to malignant pleural mesothelioma or cholangiocarcinoma. Consistently, BAP1 mutation was correlated with critical clinicopathological features only in uveal melanoma and clear cell renal cell carcinoma. In uveal melanoma, BAP1 mutation and SF3B1/EIF1AX mutations were negatively correlated, and BAP1-mutant tumors indicated significant worse prognosis than SF3B1/EIF1AX-mutant tumors ( p = 0.028). While in clear cell renal cell carcinoma, BAP1 mutation was mutually exclusive with PBRM1 mutations, and BAP1-mutant clear cell renal cell carcinomas also showed significantly worse prognosis than PBRM1-mutant clear cell renal cell carcinomas ( p = 0.001). Our study revealed a unique tissue-specific significance of BAP1 mutation in prognostic prediction among different types of cancer. Clinically, combining detection of BAP1 mutation and other driver mutations may further allow for a more precise molecular taxonomy to stratify patients into distinct subgroups in uveal melanoma and clear cell renal cell carcinoma.