[Gene transfer into renal cancer cell by electroporation].
For the purpose of elucidating the role of oncogenes like c-myc in renal cell carcinoma, the methods of introducing exogenous genes into human cells might be powerful tools. In the present study, the electroporation gene transfer method was investigated for its application to renal cancer cells. A mixture of ACHN cells (human renal cancer cell line, which cannot grow in the presence of neomycin) and DNA of neomycin-resistant genes with SV 40 promoters was exposed to electric pulses from an electroporated (Bio-Pulser 101, UNISOKU). And the cells were cultured in a medium containing Geneticin (neomycin analog) for 3 weeks. Then, the number of formed neomycin-resistant neoR colonies was counted. In the cells of neoR colonies, the existence of neoR genes and their expression were confirmed by Southern and Northern blot gene analyses. The transformation efficiency (number of neoR colonies/inoculated cells) was positively correlated with cell densities, DNA concentrations, and discharged voltages under our experimental conditions. The transformation efficiency was 1.3 - 3.3 x 10(-4)/cell in the condition of 1 x 10(7) cells/ml, 1 microgram DNA/10(6) cells, and 2 kV/cm. These results suggest that the electroporation gene transfer method is applicable for the study of phenotypic alterations after introducing oncogenes into human renal cancer cells.


Flexible feature-based inhibition in visual search mediates magnified impairments of selection: evidence from carry-over effects under dynamic preview-search conditions.
Evidence for inhibitory processes in visual search comes from studies using preview conditions, where responses to new targets are delayed if they carry a featural attribute belonging to the old distractor items that are currently being ignored-the negative carry-over effect (Braithwaite, Humphreys, & Hodsoll, 2003). We examined whether inhibition was applied in the same manner across different types of displays or whether the inhibitory weighting applied to different features varied with their utility for the search task. To test this, we present the first empirical investigation of negative carry-over effects under the ecologically valid conditions of dynamic visual search. Experiment 1 investigated preview search using dynamic moving and static displays. Detection was very poor when new targets carried the color of the old distractors, and this negative carry-over effect was significantly exaggerated with moving, compared with static, displays. Experiments 2a and 2b demonstrated that this effect could not be attributed to an increased role of preattentive grouping between new and old items for dynamic displays. Collectively, the findings suggest that feature-based inhibition contributes strongly to preview search through dynamic displays, and this leads to an amplified attentional blindness to new targets. The data specifically indicate that inhibitory processes in search differentially weight color and location in moving and static displays, and that feature-based inhibition may underlie many instances of sustained inattentional blindness in everyday life.


Intracavity ionization and pulse formation in femtosecond enhancement cavities.
We experimentally and numerically investigate the intracavity ionization of a dilute gas target by an ultrashort pulse inside a femtosecond enhancement cavity. Numerical simulations detail how the dynamic ionization of the gas target limits the achievable peak intensity of the evolving intracavity pulse beyond that of linear cavity losses, setting a constraint on the strength of the nonlinear interaction that can be sustained in such optical cavities. Experimental measurements combined with numerical simulations predict ionization levels in a femtosecond enhancement cavity for the first time. We demonstrate how the resonant response of the femtosecond enhancement cavity can itself be used as a sensitive probe of optical nonlinearities at high intensities.


Psychosocial risk and protective factors for postpartum depression in the United Arab Emirates.
Limited research has been conducted in the United Arab Emirates in relation to postpartum depression. The purpose of this study was to investigate the risk and protective factors of postpartum depression in women in Sharjah, United Arab Emirates. We carried out a prospective study in which we followed women from the second trimester of pregnancy until 4 months postpartum. Data were collected during the second and third trimesters and then at 2- and 4- months postpartum. The risk/protective factors that were investigated included: depression and anxiety during pregnancy, stressful life events, breastfeeding, employment status following delivery, religiosity, and socio-demographic variables. The Edinburgh Postnatal Depression Scale (screening) and the Mini International Neuropsychiatric Inventory (diagnostic) were used as outcome variables. Using the Mini International Neuropsychiatric Inventory (diagnostic), 10% of the 137 participants in the study were diagnosed with postpartum depression. The following variables were found to be predictive of postpartum depression: depression during pregnancy in both the second and third trimesters: number of children, religion, and use of formula for feeding. Several factors were of borderline significance including educational level of mother, lack of breastfeeding, personal stressful life events, and employment status following delivery. These risk factors are important as they indicate potential areas for early identification. Screening of pregnant women during pregnancy and in the postpartum phase would be important. This study forms the foundation for further research and development related to prevention and intervention for postpartum depression in this Arab context.


Self-reported health assessments in the 2002 World Health Survey: how do they correlate with education?
To assess the value of self-rated health assessments by examining the association between education and self-rated poor health. We used the globally representative population-based sample from the 2002 World Health Survey, composed of 219,713 men and women aged 25 and over in 69 countries, to examine the association between education and self-rated poor health. In a binary regression model with a logit link function, we used self-rated poor health as the binary dependent variable, and age, sex and education as the independent variables. Globally, there was an inverse association between years of schooling and self-rated poor health (odds ratio, OR: 0.929; 95% confidence interval, CI: 0.926-0.933). Compared with the individuals in the highest quintile of years of schooling, those in the lowest quintile were twice as likely to report poor health (OR: 2.292; 95% CI: 2.165-2.426). We found a dose-response relationship between quintiles of years of schooling and the ORs for reporting poor health. This association was consistent among men and women; low-, middle- and high-income countries; and regions. Our findings suggest that self-reports of health may be useful for epidemiological investigations within countries, even in low-income settings.


Human herpesvirus 8 (KSHV) contamination of peripheral blood and autograft products from multiple myeloma patients.
Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), has recently been identified within the bone marrow dendritic cells of multiple myeloma (MM) patients. This virus contains homologues to human cytokines such as IL-6 that could potentially stimulate myeloma cell growth and contribute to disease pathogenesis. Since mobilization chemotherapy may increase circulating dendritic cell numbers, we searched for HHV-8 in peripheral blood mononuclear cells (PBMCs) before and after mobilization chemotherapy given to MM patients. Furthermore, we determined if autograft purging using the CEPRATE SC device would reduce the percentage of HHV-8 infected stem cell products. Only two of the 39 PBMC samples collected prior to mobilization chemotherapy contained PCR detectable virus, yet nine of 37 PBMCs collected on the first day of leukapheresis had detectable HHV-8 (P = 0.016). HHV-8 was more frequently identified in autograft products before vs after Ceprate SC selection (40% vs 15%, P = 0.016). Although the role HHV-8 plays in myeloma pathogenesis remains unclear, these results imply that mobilization chemotherapy increases the numbers of circulating HHV-8-infected dendritic cells within the peripheral blood. In addition, CD34 selection of autograft products in MM patients may reduce the reintroduction of virally infected cells following high-dose chemotherapy. Bone Marrow Transplantation (2000) 25, 153-160.


Central region morphometry in a child brain; age and gender differences.
Data on central region morphometry of a child brain is important not only in terms of providing us with information about central region anatomy of the brain but also in terms of the help of this information for the plans to be applied in neurosurgery. In the present study, central region morphometry of a child brain in mid-sagittal MR images was analyzed in age and gender groups. Different points determined previously, commissura posterior0 (PC) and the distances between cerebral cortex point (VCS) vertical to commissura anterior- commissura posterior line, sulcus centralis (CS), sulcus marginalis (MS), and the angle (α) between CS-PC-MS were determined and measured together with difference of gender in three different age groups (aged 6-9, 10-13, and 14-17). Central region measures of the brains of boys aged 6-17 are higher than girls except for MS-PC distance. While VCS-PC, CS-PC, and MS-PC measures display a significant difference in the girls aged 14-17 when compared to the other age groups of 6-9 and 10-13 (P < 0.05), angle α is not significantly different in age and gender groups (P > 0.05). However, while VCS-PC, CS-PC and MS-PC distances show a significant increase in girls beginning from the age of 14, this increase is limited in boys. Morphometric differences observed in different age groups in boys and girls shall contribute our evaluation of the alterations in brain development in both of genders and shall be useful in preparation of surgical operation plans to be applied to the central region.


Multisensory representation of frequency across audition and touch: high density electrical mapping reveals early sensory-perceptual coupling.
The frequency of environmental vibrations is sampled by two of the major sensory systems, audition and touch, notwithstanding that these signals are transduced through very different physical media and entirely separate sensory epithelia. Psychophysical studies have shown that manipulating frequency in audition or touch can have a significant cross-sensory impact on perceived frequency in the other sensory system, pointing to intimate links between these senses during computation of frequency. In this regard, the frequency of a vibratory event can be thought of as a multisensory perceptual construct. In turn, electrophysiological studies point to temporally early multisensory interactions that occur in hierarchically early sensory regions where convergent inputs from the auditory and somatosensory systems are to be found. A key question pertains to the level of processing at which the multisensory integration of featural information, such as frequency, occurs. Do the sensory systems calculate frequency independently before this information is combined, or is this feature calculated in an integrated fashion during preattentive sensory processing? The well characterized mismatch negativity, an electrophysiological response that indexes preattentive detection of a change within the context of a regular pattern of stimulation, served as our dependent measure. High-density electrophysiological recordings were made in humans while they were presented with separate blocks of somatosensory, auditory, and audio-somatosensory "standards" and "deviants," where the deviant differed in frequency. Multisensory effects were identified beginning at ∼200 ms, with the multisensory mismatch negativity (MMN) significantly different from the sum of the unisensory MMNs. This provides compelling evidence for preattentive coupling between the somatosensory and auditory channels in the cortical representation of frequency.


Structure analysis by diffraction of amorphous zones created by Ni ion implantation into pure Al
The implantation of Ni ions into pure Al leads to the formation of approximately 10 nm amorphous zones (AZ) which induce diffuse rings in the diffraction pattern in addition to the diffraction spots of the crystal. Measurements by energy dispersive spectrometry and electron energy loss spectrometry attributed to the amorphous zones an average Ni concentration of 25 at%. The exact structure of these AZ is still unknown. The structure is characterized here by both the total and partial radial distribution functions (RDF). Structure factor deduced from experiments is compared to calculated one. For this purpose, molecular dynamic (MD) simulations are used to model the AZ structure. The RDF are determined using this structure and analytical calculation of the diffraction pattern is achieved. Simulations of the diffraction pattern of the simulated MD sample using both a kinematic and a dynamic approach are achieved to refine the analytical procedure used on the experimental diffraction patterns. It appears that the amorphous structure is well reproduced by the MD simulations. Analytical calculation reveals the presence of a well-established chemical order in the amorphous material.


Normalized Compression Distance of Multisets with Applications.
Pairwise normalized compression distance (NCD) is a parameter-free, feature-free, alignment-free, similarity metric based on compression. We propose an NCD of multisets that is also metric. Previously, attempts to obtain such an NCD failed. For classification purposes it is superior to the pairwise NCD in accuracy and implementation complexity. We cover the entire trajectory from theoretical underpinning to feasible practice. It is applied to biological (stem cell, organelle transport) and OCR classification questions that were earlier treated with the pairwise NCD. With the new method we achieved significantly better results. The theoretic foundation is Kolmogorov complexity.


Segment formation in Annelids: patterns, processes and evolution.
The debate on the origin of segmentation is a central question in the study of body plan evolution in metazoans. Annelids are the most conspicuously metameric animals as most of the trunk is formed of identical anatomical units. In this paper, I summarize the various patterns of evolution of the metameric body plan in annelids, showing the remarkable evolvability of this trait, similar to what is also found in arthropods. I then review the different modes of segment formation in the annelid tree, taking into account the various processes taking place in the life histories of these animals, including embryogenesis, post-embryonic development, regeneration and asexual reproduction. As an example of the variations that occur at the cellular and genetic level in annelid segment formation, I discuss the processes of teloblastic growth or posterior addition in key groups in the annelid tree. I propose a comprehensive definition for the teloblasts, stem cells that are responsible for sequential segment addition. There are a diversity of different mechanisms used in annelids to produce segments depending on the species, the developmental time and also the life history processes of the worm. A major goal for the future will be to reconstitute an ancestral process (or several ancestral processes) in the ancestor of the whole clade. This in turn will provide key insights in the current debate on ancestral bilaterian segmentation.


Real-time data-reusing adaptive learning of a radial basis function network for tracking evoked potentials.
Tracking variations in both the latency and amplitude of evoked potential (EP) is important in quantifying properties of the nervous system. Adaptive filtering is a powerful tool for tracking such variations. In this paper, a data-reusing non-linear adaptive filtering method, based on a radial basis function network (RBFN), is implemented to estimate EP. The RBFN consists of an input layer of source nodes, a single hidden layer of non-linear processing units and an output layer of linear weights. It has built-in nonlinear activation functions that allow learning of function mappings. Moreover, it produces satisfactory estimates of signals against a background noise without a priori knowledge of the signal, provided that the signal and noise are independent. In clinical situations where EP responses change rapidly, the convergence rate of the algorithm becomes a critical factor. A carefully designed data-reusing RBFN can accelerate the convergence rate markedly and, thus, enhance its performance. Both theoretical analysis and simulation results support the improved performance of our new algorithm.


Standardization of evaluation method and prognostic significance of histological response to preoperative chemotherapy in high-grade non-round cell soft tissue sarcomas.
Preoperative chemotherapy is widely applied to high-grade localized soft tissue sarcomas (STSs); however, the prognostic significance of histological response to chemotherapy remains controversial. This study aimed to standardize evaluation method of histological response to chemotherapy with high agreement score among pathologists, and to establish a cut-off value closely related to prognosis. Using data and specimens from the patients who had registered in the Japan Clinical Oncology Group study, JCOG0304, a phase II trial evaluating the efficacy of perioperative chemotherapy with doxorubicin (DOX) and ifosfamide (IFO), we evaluated histological response to preoperative chemotherapy at the central review board. A total of 64 patients were eligible for this study. The percentage of viable tumor area ranged from 0.1% to 97.0%, with median value of 35.7%. Regarding concordance proportion between pathologists, the weighted kappa coefficient (κ) score in all patients was 0.71, indicating that the established evaluation method achieved substantial agreement score. When the cut-off value of the percentage of the residual tumor area was set as 25%, the p-value for the difference in overall survival showed the minimum value. Hazard ratio of the non-responder with percentage of the residual tumor < 25%, to the responder was 4.029 (95% confidence interval 0.893-18.188, p = 0.070). The standardized evaluation method of pathological response to preoperative chemotherapy showed a substantial agreement in the weighted κ score. The evaluation method established here was useful for estimating of the prognosis in STS patients who were administered perioperative chemotherapy with DOX and IFO. UMIN Clinical Trials Registry C000000096. Registered 30 August, 2005 (retrospectively registered).


Clinically Significant Drug Interaction Between Clotrimazole and Tacrolimus in Pancreas Transplant Recipients and Associated Risk of Allograft Rejection.
To examine the clinical significance of clotrimazole troche discontinuation on tacrolimus trough levels and risk of allograft rejection after pancreas transplantation. Retrospective cohort study. Academic medical center. Sixty-five pancreas transplant recipients (simultaneous pancreas-kidney transplants [39 patients], pancreas after kidney transplants [4 patients], and pancreas transplant alone [22 patients]) who were discharged after transplantation receiving a maintenance immunosuppressive regimen of tacrolimus, mycophenolate, and prednisone, and a clotrimazole troche to prevent oral mucosal candidiasis; per protocol, the clotrimazole troche was discontinued at 3 months after transplantation. Patients were followed for 1 year after transplantation. The primary outcome measure was the difference in tacrolimus trough level before and after discontinuation of the clotrimazole troche. The secondary outcome measure was the difference in tacrolimus trough level when patients were stratified by the cohort that had a documented rejection episode 3-12 months after transplantation (rejection group) and the cohort that did not experience a rejection episode (no-rejection group). The incidence of rejection was evaluated in relation to mean tacrolimus trough concentrations above or below a protocol-defined level of significance (6 ng/ml). For the primary outcome, the mean tacrolimus trough level before discontinuation of the clotrimazole troche was significantly higher than the mean trough level after discontinuation (mean ± SD 9.6 ± 3.0 ng/ml vs 7.1 ± 2.6 ng/ml, p = 0.000003). For the secondary outcome, the mean tacrolimus trough level difference before and after clotrimazole troche discontinuation remained significant in both the no-rejection group (9.5 ± 3.0 ng/ml vs 7.4 ± 2.4 ng/ml, p = 0.00007) and rejection group (10.9 ± 3.3 ng/ml vs 4.1 ± 2.5 ng/ml, p = 0.0008). Between groups, the mean tacrolimus serum trough level after clotrimazole troche discontinuation was lower in the rejection group (4.1 ± 2.5 ng/ml) than that in the no-rejection group (7.4 ± 2.4 ng/ml; p = 0.005). The mean tacrolimus trough level difference between before and after discontinuation was greater in the rejection group (6.8 ± 1.5 ng/ml) versus the no-rejection group (2.1 ± 3.8 ng/ml, p = 0.009). Tacrolimus trough levels below 6 ng/ml (19 patients) after clotrimazole troche discontinuation were associated with an increased incidence of rejection episodes within 3-12 months after transplantation (odds ratio 12, 95% confidence interval 1.24-115.91, p = 0.032) versus trough levels of 6 ng/ml or higher (46 patients). Clotrimazole troche discontinuation at 3 months after transplantation may cause significant tacrolimus trough level reductions. In addition, when trough levels are below 6 ng/ml, these fluctuations may contribute to the occurrence of allograft rejection.


Natural history of Type A Niemann-Pick disease: possible endpoints for therapeutic trials.
To describe the disease course and natural history of Type A Niemann-Pick disease (NPD). Ten patients with NPD-A (six male, four female; age range at entry: 3 to 6 months) were serially evaluated including clinical neurologic, ophthalmologic, and physical examinations, and assessment of development. Laboratory analyses, abdominal and brain ultrasounds, and chest radiographs also were obtained and information on intercurrent illnesses and cause of mortality was collected. All affected infants had a normal neonatal course and early development. The first symptom detected in all patients was hepatosplenomegaly. Developmental age did not progress beyond 10 months for adaptive behavior, 12 months for expressive language, 9 months for gross motor skills, and 10 months for fine motor skills. Non-neurologic symptoms included frequent vomiting, failure to thrive, respiratory infections, irritability, and sleep disturbance. Neurologic examination at the time of presentation was normal in most patients. Later neurologic examinations revealed progressive hypotonia with loss of the deep tendon reflexes. All patients had cherry red spots by 12 months. The median time from diagnosis to death was 21 months. The cause of death was respiratory failure in nine patients and complications from bleeding in the tenth. The clinical course in Type A Niemann-Pick disease is similar among affected patients and is characterized by a relentless neurodegenerative course that leads to death, usually within 3 years.


[Brainstem anesthesia after extraconal retrobulbar block: can it be avoided? Case report].
The CEROF-HC is a public hospital specialized in ophthalmology. Anesthetic blocks for ophthalmic surgeries are common and effective. But the technique is not devoid of risks, and there is the possibility of meningeal perforation and injection of the local anesthetic (LA) in the central nervous system (CNS). The objective of this study was to report a case of brainstem anesthesia as a complication of the ophthalmologic regional anesthesia, stress the importance of preventing this accident, and discuss the treatment. A female patient, 60 years old, ASA II, with a diagnosis of grade II cataract, was scheduled for a facectomy and implantation of intraocular lens in the right eye. The patient had a past medical history of hypertension and vitrectomy. Physical exam, laboratory and cardiologic exams were normal. An extraconal retrobulbar block was performed with local anesthetic (lidocaine and bupivacaine) and hyaluronidase (total volume of 5 mL). Immediately after, the patient developed apnea and loss of consciousness. She was treated with tracheal intubation and mechanical ventilation, remaining stable. The surgery was performed as planned. Thirty minutes after the intubation, the patient began to move, recovering completely, without deficits. Although safe, ophthalmic block is not devoid of risks. The main risk factor is improper anesthetic technique. In the ophthalmic block, the local anesthetic (LA) can reach the CNS by inadvertently puncturing the ophthalmic artery or the meninges that surround the optic nerve, with dispersion to the subarachnoid space. Although rare, it can lead to a severe complication with respiratory arrest that can be fatal if it is not diagnosed promptly. Here we present the possibilities of such a complication, and discuss the nomenclature of anesthetic blocks used in ophthalmology. The importance of the knowledge of this and other complications by the surgical team is paramount, as well as the preparation and adequate monitoring to diagnose and treat immediately this complication to minimize the risks to the patient.


The association of health insurance with use of prescription contraceptives.
Given that substantial proportions of women of reproductive age lack health insurance coverage, it is important to assess whether lack of insurance is associated with the use of prescription contraceptives, which are the most expensive but also the most effective methods for preventing pregnancy. Data from 26,674 females aged 18-44 who participated in the 2002 Behavioral Risk Factor Surveillance System survey (representing more than 25 million women in the U.S. population) were used to assess risk of unintended pregnancy, prescription contraceptive use and health insurance status. Logistic regression models tested the likelihood of prescription contraceptive use among insured versus uninsured respondents after controlling for socioeconomic characteristics and self-reported overall health. A significantly higher proportion of insured women than of uninsured women reported use of prescription contraceptives (54% vs. 45%). In multiple regression analysis, women lacking health insurance were 30% less likely to report using prescription contraceptive methods than were women with private or public health insurance. Results were similar across racial, age and income subgroups. Lack of health insurance is associated with reduced use of prescription contraceptives. Universal insurance coverage is needed to ensure access to the most effective contraceptive methods for all women in need.


DNA vaccines to target the cancer testis antigen PASD1 in human multiple myeloma.
We previously described PASD1 as a new cancer testis antigen in multiple myeloma (MM) that is retained post-therapy, suggesting the use of vaccination strategies to induce anti-PASD1 immunity in a setting of minimal residual disease. We have focused on DNA fusion gene vaccines, coupling fragment C domain (DOM) of tetanus toxin with PASD1 sequence, and examined efficacy in Human Leukocyte Antigen (HLA)-A2 (HHD) transgenic mice using a human MM cell line expressing PASD1 protein and chimeric HLA-A2 class I molecules as target. DNA vaccines encoded two HLA-A2-restricted epitopes (p.DOM-PASD1(1), p.DOM-PASD1(2)) and full-length PASD1 (p.DOM-PASD1FL). p.DOM-PASD1(1) proved superior to p.DOM-PASD1(2) in generating T-cell responses in HHD mice, able to lyse the chimeric murine RMA-HHD cells. Boosting by electroporation significantly enhanced p.DOM-PASD1(1). Only p.DOM-PASD1(1) induced cytotoxic T-lymphocytes (CTLs) were able to lyse human MM target cells expressing endogenous antigen. The p.DOM-PASD1FL vaccine predominantly induced strong PASD1(1) over PASD1(2) T-cell immune responses, indicative of immunodominance. Importantly, p.DOM-PASD1FL generated immune-mediating killing of native chimeric MM cells, in the absence of exogenous added peptide, implicating PASD1(1) specific CTLs. These data demonstrate that PASD1-derived epitopes are both efficiently and selectively processed and presented by native human MM cells. Notably, they permit the use of PASD1-encoding DNA vaccine therapy in a clinical setting.


The pyrazolyl-urea GeGe3 inhibits tumor angiogenesis and reveals dystrophia myotonica protein kinase (DMPK)1 as a novel angiogenesis target.
The limitation of targeting VEGF/VEGFR2 signalling to stop angiogenesis in cancer therapy has been blamed on re-activation of alternative receptor tyrosine kinases by compensatory angiogenic factors. Targeting MAPK and PI3K signaling pathways in endothelial cells may be an alternative or complementary approach. Herein we aimed to evaluate the antitumor and antiangiogenic potential of a novel pyrazolyl-urea kinase inhibitor, GeGe3, and to identify its kinase targets. We found GeGe3 to inhibit the proliferation of HUVEC and endothelial tube formation. GeGe3 impaired inter-segmental angiogenesis during development of zebrafish embryos. In mice, GeGe3 blocked angiogenesis and tumor growth in transplanted subcutaneous Lewis Lung Carcinomas. Screening for GeGe3-targeted kinases revealed Aurora B, Aurora C, NEK10, polo-like kinase (PLK)2, PLK3, DMPK1 and CAMK1 as candidate targets. Biochemical analysis of these kinases showed DMPK1 regulation upon VEGF challenge. Investigation of the role of DMPK1 in endothelial cells revealed DMPK1 as a novel mediator of angiogenesis that controls the activation of MAPK signaling, proliferation and migration. GeGe3 alters angiogenesis by targeting DMPK in tumor endothelial cells and pericytes. The pyrazolyl-urea GeGe3, a novel blocker of MAPK and PI3K pathways, strongly inhibits physiological and tumor angiogenesis. We also report GeGe3-targeted kinase DMPK as a novel mediator of angiogenesis.


Interspecific interactions and learning variability jointly drive geographic differences in mate preferences.
Co-occurrence of closely related species can cause behavioral interference in mating and increase hybridization risk. Theoretically, this could lead to the evolution of more species-specific mate preferences and sexual signaling traits. Alternatively, females can learn to reject heterospecific males, to avoid male sexual interference from closely related species. Such learned mate discrimination could also affect conspecific mate preferences if females generalize from between species differences to prefer more species-specific mating signals. Female damselflies of the banded demoiselle (Calopteryx splendens) learn to reject heterospecific males of the beautiful demoiselle (C. virgo) through direct premating interactions. These two species co-occur in a geographic mosaic of sympatric and microallopatric populations. Whereas C. virgo males have fully melanized wings, male C. splendens wings are partly melanized. We show that C. splendens females in sympatry with C. virgo prefer smaller male wing patches in conspecific males after learning to reject heterospecific males. In contrast, allopatric C. splendens females with experimentally induced experience with C. virgo males did not discriminate against larger male wing patches. Wing patch size might indicate conspecific male quality in allopatry. Co-occurrence with C. virgo therefore causes females to prefer conspecific male traits that are more species specific, contributing to population divergence and geographic variation in female mate preferences.


Engineered triple inhibitory receptor resistance improves anti-tumor CAR-T cell performance via CD56.
The inhibitory receptors PD-1, Tim-3, and Lag-3 are highly expressed on tumor-infiltrating lymphocytes and compromise their antitumor activity. For efficient cancer immunotherapy, it is important to prevent chimeric antigen receptor T (CAR-T)-cell exhaustion. Here we downregulate these three checkpoint receptors simultaneously on CAR-T cells and that show the resulting PTL-CAR-T cells undergo epigenetic modifications and better control tumor growth. Furthermore, we unexpectedly find increased tumor infiltration by PTL-CAR-T cells and their clustering between the living and necrotic tumor tissue. Mechanistically, PTL-CAR-T cells upregulate CD56 (NCAM), which is essential for their effector function. The homophilic interaction between intercellular CD56 molecules correlates with enhanced infiltration of CAR-T cells, increased secretion of interferon-γ, and the prolonged survival of CAR-T cells. Ectopically expressed CD56 promotes CAR-T cell survival and antitumor response. Our findings demonstrate that genetic blockade of three checkpoint inhibitory receptors and the resulting high expression of CD56 on CAR-T cells enhances the inhibition of tumor growth.


The relationship between long-range chromatin occupancy and polymerization of the Drosophila ETS family transcriptional repressor Yan.
ETS family transcription factors are evolutionarily conserved downstream effectors of Ras/MAPK signaling with critical roles in development and cancer. In Drosophila, the ETS repressor Yan regulates cell proliferation and differentiation in a variety of tissues; however, the mechanisms of Yan-mediated repression are not well understood and only a few direct target genes have been identified. Yan, like its human ortholog TEL1, self-associates through an N-terminal sterile α-motif (SAM), leading to speculation that Yan/TEL1 polymers may spread along chromatin to form large repressive domains. To test this hypothesis, we created a monomeric form of Yan by recombineering a point mutation that blocks SAM-mediated self-association into the yan genomic locus and compared its genome-wide chromatin occupancy profile to that of endogenous wild-type Yan. Consistent with the spreading model predictions, wild-type Yan-bound regions span multiple kilobases. Extended occupancy patterns appear most prominent at genes encoding crucial developmental regulators and signaling molecules and are highly conserved between Drosophila melanogaster and D. virilis, suggesting functional relevance. Surprisingly, although occupancy is reduced, the Yan monomer still makes extensive multikilobase contacts with chromatin, with an overall pattern similar to that of wild-type Yan. Despite its near-normal chromatin recruitment, the repressive function of the Yan monomer is significantly impaired, as evidenced by elevated target gene expression and failure to rescue a yan null mutation. Together our data argue that SAM-mediated polymerization contributes to the functional output of the active Yan repressive complexes that assemble across extended stretches of chromatin, but does not directly mediate recruitment to DNA or chromatin spreading.


A phase II study of induction chemotherapy followed by thoracic radiotherapy and erlotinib in poor-risk stage III non-small-cell lung cancer: results of CALGB 30605 (Alliance)/RTOG 0972 (NRG).
Patients with stage III non-small-cell lung cancer and poor performance status and/or weight loss do not seem to benefit from standard therapy. Based on the preclinical interaction between epidermal growth factor receptor inhibitors and radiation, we designed a trial of induction chemotherapy followed by thoracic radiotherapy and concurrent erlotinib. Patients with poor-risk unresectable stage III non-small-cell lung cancer received two cycles of carboplatin at an AUC of 5 and nab-paclitaxel at 100 mg/m on days 1 and 8 every 21 days, followed by erlotinib administered concurrently with thoracic radiotherapy. Maintenance was not permitted. Molecular analysis was performed in available specimens. Seventy-two eligible patients were required to test whether the 1-year survival rate was less than 50% or greater than or equal to 65% with approximately 90% power at a significance level of 0.10. From March 2008 to October 2011, 78 patients were enrolled, three of whom were ineligible. The median age was 68 (range, 39-88) and 32% were aged greater than or equal to 75 years. Patients were evenly distributed between stages IIIA and IIIB and the majority had performance status 2. The overall response rate was 67% and the disease control rate was 93%. Treatment was well tolerated. The median PFS and OS were 11 and 17 months, respectively. The overall 12-month OS was 57%, which narrowly missed the prespecified target for significance. Patients with poor-risk stage III non-small-cell lung cancer had better than expected outcomes with a regimen of induction carboplatin/nab-paclitaxel followed by thoracic radiotherapy and erlotinib. However, as per the statistical design, the 12-month OS was not sufficiently high to warrant further studies.


Effects of ageing on the biomechanical properties of rat articular cartilage.
Previous studies have demonstrated that male Sprague Dawley (SD) rats experience age-related bone loss with the same characteristics as that in ageing men. As articular cartilage, like bone, is a critical component of the health and function of the musculoskeletal system, the authors hypothesized that articular cartilage in the untreated male SD rats could be a suitable model for studying the age-related deterioration of articular cartilage in men. To test this hypothesis, male SD rats were killed at between 6 and 27 months. The right femur of each rat was removed. The effects of ageing on the structural integrity of the distal femoral articular cartilage were studied by biomechanical testing with a creep indentation apparatus. The aggregate modulus, Poisson's ratio, permeability, thickness, and percentage recovery of articular cartilage were determined using finite element/non-linear optimization modelling. No significant differences were observed in these biomechanical properties of the distal femoral articular cartilage as a function of age. Therefore, untreated male SD rats appear to be unsuitable for studying the age-related changes of articular cartilage as they occur in men. However, and more intriguingly, it is also possible that ageing does not affect the biomechanical properties of articular cartilage in the absence of cartilage pathology.


Emotional processing in male adolescents with childhood-onset conduct disorder.
Boys with early onset of conduct disorder (CD), most of whom also meet diagnostic criteria of a comorbid attention deficit hyperactivity disorder (ADHD), tend to exhibit high levels of aggression throughout development. While a number of functional neuroimaging studies on emotional processing have been performed in antisocial adults, little is known about how CD children process emotional information. Functional magnetic resonance imaging data were analyzed in 22 male adolescents aged 12 to 17 years with childhood-onset CD (16 of them with comorbid ADHD) compared to 22 age-matched male healthy controls. In order to consider the likely confounding of results through ADHD comorbidity, we performed a supplementary study including 13 adolescent subjects with pure ADHD who were compared with healthy controls. To challenge emotional processing of stimuli, a passive viewing task was applied, presenting pictures of negative, positive or neutral valence. When comparing CD/combined disorder patients with healthy controls, we found enhanced left-sided amygdala activation in response to negative pictures as compared to neutral pictures in the patient group. In addition, these boys exhibited no reduced activation in the orbitofrontal, anterior cingulate and insular cortices. By contrast, children with pure ADHD did not show any abnormalities in amygdala activation but showed decreased neural activity in the insula only in response to negative pictures. Increased rather than reduced amygdala activation found in our study may indicate an enhanced response to environmental cues in adolescents with early-onset CD (most of whom also met the condition of ADHD), and is not consistent with the assumption of a reduced capacity to take note of affective information in the social environment. Further studies with an emphasis on developmental aspects of affect regulation are needed to clarify the relationship between CD and adult personality pathology associated with different modes of persistent antisocial behavior.


Differences in the production of spliced antigenic peptides by the standard proteasome and the immunoproteasome.
Peptide splicing allows the production of antigenic peptides composed of two fragments initially non-contiguous in the parental protein. The proposed mechanism of splicing is a transpeptidation occurring within the proteasome. Three spliced peptides, derived from FGF-5, melanoma protein gp100 and nuclear protein SP110, have been described. Here, we compared the production of these spliced peptides by the standard proteasome and the immunoproteasome. Differential isotope labelling was used to quantify (by mass spectrometry) the fragments contained in digests obtained with precursor peptides and purified proteasomes. The results show that both the standard and the immunoproteasomes can produce spliced peptides although they differ in their efficiency of production of each peptide. The FGF-5 and gp100 peptides are more efficiently produced by the standard proteasome, whereas the SP110 peptide is more efficiently produced by the immunoproteasome. This seems to result from differences in the production of the two splicing partners, which depends on a balance between cleavages liberating or destroying those fragments. By showing that splicing depends on the efficiency of production of the splicing partners, these results also support the transpeptidation model of peptide splicing. Furthermore, given the presence of immunoproteasomes in dendritic cells and cells exposed to IFN-γ, the findings may be relevant for vaccine design.


Effects of Diesel, Heavy Metals and Plastics Pollution on Penguins in Antarctica: A Review.
Antarctica is a relatively pristine continent that attracts scientists and tourists alike. However, the risk of environmental pollution in Antarctica is increasing with the increase in the number of visitors. Recently, there has been a surge in interest regarding diesel, heavy metals and microplastics pollution. Contamination from these pollutants poses risks to the environment and the health of organisms inhabiting the continent. Penguins are one of the most prominent and widely distributed animals in Antarctica and are at major risk due to pollution. Even on a small scale, the impacts of pollution toward penguin populations are extensive. This review discusses the background of penguins in Antarctica, the anthropogenic pollution and cases, as well as the impacts of diesel, heavy metals and microplastics toxicities on penguins. The trends of the literature for the emerging risks of these pollutants are also reviewed through a bibliometric approach and network mapping analysis. A sum of 27 articles are analyzed on the effects of varying pollutants on penguins in Antarctica from 2000 to 2020 using the VOSviewer bibliometric software, Microsoft Excel and Tableau Public. Research articles collected from the Scopus database are evaluated for the most applicable research themes according to the bibliometric indicators (articles, geography distribution, annual production, integrated subject areas, key source journals and keyword or term interactions). Although bibliometric studies on the present research theme are not frequent, our results are sub-optimal due to the small number of search query matches from the Scopus database. As a result, our findings offer only a fragmentary comprehension of the topics in question. Nevertheless, this review provides valuable inputs regarding prospective research avenues for researchers to pursue in the future.


An objective comparison of cell-tracking algorithms.
We present a combined report on the results of three editions of the Cell Tracking Challenge, an ongoing initiative aimed at promoting the development and objective evaluation of cell segmentation and tracking algorithms. With 21 participating algorithms and a data repository consisting of 13 data sets from various microscopy modalities, the challenge displays today's state-of-the-art methodology in the field. We analyzed the challenge results using performance measures for segmentation and tracking that rank all participating methods. We also analyzed the performance of all of the algorithms in terms of biological measures and practical usability. Although some methods scored high in all technical aspects, none obtained fully correct solutions. We found that methods that either take prior information into account using learning strategies or analyze cells in a global spatiotemporal video context performed better than other methods under the segmentation and tracking scenarios included in the challenge.


Identification and characterization of non-tuberculous mycobacteria isolated from tuberculosis suspects in Southern-central China.
The incidence of non-tuberculous mycobacteria (NTM)-related death has increased globally recently. To obtain information of the species and characterization of pathogens involved in NTM pulmonary infection in Southern-central China, we identified 160 non-tuberculous infection cases from 3995 acid-fast bacilli (AFB)-positive tuberculous suspects. We then randomly selected 101 non-tuberculous patients, isolated bacteria from their sputa and genotyped the pathogens using the 16S rRNA gene and 16S-23S rRNA internal transcribed spacer sequences. M. intracellulare (32.67%, 33/101), M. abscessus (32.67%, 33/101) and M. fortuitum (7.92%, 8/101) are identified in these isolates. Surprisingly, non-mycobacteria including Gordonia (8.91%, 9/101), Nocardia (5.94%, 6/101) and Tsukamurella (0.99%, 1/101) are also discovered, and the case of Tsukamurella pulmonis infection is first discovered in Southern-central China. Moreover, species of M. mucogenicum group, M. chubuense, M. kansasii, M. gastri, M. avium, M. porcinum and M. smegmatis are identified. In addition, nine immune compromised cases (8.91%, 9/101), including type two diabetes mellitus and HIV/AIDS are found to be infected with non-tuberculous bacteria. This study revealed the distribution and characteristics of non-tuberculous AFB pathogen infection occurred in Southern-central China, and suggested that physicians should be alert of the emerging of NTM and non-mycobacteria infection in AFB positive cases and take caution when choosing chemotherapy for tuberculosis-like pulmonary infections. Generally, this study may help with the development of new strategy for the diagnosis and treatment of mycobacterial infection.


A case of extragastrointestinal anisakiasis involving a mesocolic lymph node.
In a 43-year-old Korean man who underwent radical gastrectomy due to a malignant stromal tumor, was found to have an enlarged lymph node at transverse mesocolon. The lymph node exhibited histologically necrotizing eosinophilic granuloma formed around a track containing sections of a nematode larva. The well preserved nematode sections revealed polymyarian muscle cells, Y-shaped lateral cord, a large excretory gland cell, intestine and eosinophilic cuticle. The nematode sections were identified as a larva of Anisakis species. In Korea, this is the first case of extragastrointestinal anisakiasis.


Bundle sheath cells and cell-specific plastid development in Arabidopsis leaves.
Bundle sheath cells form a sheath around the entire vascular tissue in Arabidopsis leaves and constitute a distinct leaf cell type, as defined by their elongate morphology, their position adjacent to the vein and by differences in their chloroplast development compared to mesophyll cells. They constitute about 15% of chloroplast-containing cells in the leaf. In order to identify genes which play a role in the differential development of bundle sheath and mesophyll cell chloroplasts, a screen of reticulate leaf mutants of Arabidopsis was used to identify a new class of mutants termed dov (differential development of vascular-associated cells). The dov1 mutant clearly demonstrates a cell-specific difference in chloroplast development. Mutant leaves are highly reticulate with a green vascular pattern. The underlying bundle sheath cells always contain normal chloroplasts, whereas chloroplasts in mesophyll cells are abnormal, reduced in number per cell and seriously perturbed in morphology at the ultrastructural level. This demonstrates that differential chloroplast development occurs between the bundle sheath and mesophyll cells in the Arabidopsis leaf.


Unrelated donor reduced-intensity allogeneic hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma.
Myeloablative allogeneic hematopoietic cell transplantation (HCT) may cure patients with relapsed or refractory Hodgkin lymphoma (HL), but is associated with a high treatment-related mortality (TRM). Reduced-intensity and nonmyeloablative (RIC/NST) conditioning regimens aim to lower TRM. We analyzed the outcomes of 143 patients undergoing unrelated donor RIC/NST HCT for relapsed and refractory HL between 1999 and 2004 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Patients were heavily pretreated, including autologous HCT in 89%. With a median follow-up of 25 months, the probability of TRM at day 100 and 2 years was 15% (95% confidence interval [CI] 10%-21%) and 33% (95% CI 25%-41%), respectively. The probabilities of progression free survival (PFS) and overall survival (OS) were 30% and 56% at 1 year and 20% and 37% at 2 years. The presence of extranodal disease and the Karnofsky Performance Scale (KPS) <90 were significant risk factors for TRM, PFS, and OS, whereas chemosensitivity at transplantation was not. Dose intensity of the conditioning regimen (RIC versus NST) did not impact outcomes. Unrelated donor HCT with RIC/NST can salvage some patients with relapsed/refractory HL, but relapse remains a common reason for treatment failure. Clinical studies should be aimed at reducing the incidence of acute graft-versus-host disease (GVHD) and relapse.


Supervised exercise plus acupuncture for moderate to severe knee osteoarthritis: a small randomised controlled trial.
Although total knee replacement (TKR) is cost effective and successful in most cases, patient-reported outcome measures demonstrate 20% of people remain unsatisfied at 1 year after a technically successful procedure. Our group has previously shown that patients with severe knee osteoarthritis (OA) awaiting surgery can achieve a short-term reduction in symptom severity when treated with acupuncture, and that a trend towards improved walking distance, as a measure of function, is achieved with preoperative supervised exercise. The aim of this study was to evaluate the effect of combined acupuncture and physiotherapy on preoperative and postoperative pain and function. A total of 56 patients awaiting TKR surgery were randomised to receive either combined physiotherapy and acupuncture or a standardised exercise and advice leaflet. Pain and function were measured primarily using the Oxford Knee Score (OKS), with assessments at baseline prior to intervention, 6 and 12 weeks after intervention and at 3 months postoperatively. Due to the introduction of the 18-week waiting times target during this study, the required sample size was not achieved. There were no significant differences demonstrated between the control and treatment groups for OKS. Seven patients withdrew from surgery because of symptomatic improvement in their knees: six from the treatment group and one from the control group (OR 7.64, 95% CI 0.86 to 68.20). This study demonstrated that the use of combined acupuncture and physiotherapy in the treatment of patients with moderate to severe knee OA preoperatively did not improve patient outcome postoperatively. As the study was underpowered, a larger trial is required to examine this result further.


Nasal and temporal retinal ganglion cells projecting to the midbrain: implications for "blindsight".
We placed pellets of horseradish peroxidase in the superior colliculus of four macaque monkeys and retrogradely labelled the retinal ganglion cells of both eyes. The ratio of labelled cells in the contralateral nasal retina and the ipsilateral temporal retina was no different from the ratio found after implants in the optic nerve, which label the entire afferent pathway. Our finding therefore invalidates the proposal that prominent differences in the properties of "blindsight" in monocular nasal and temporal visual fields arise from differences in the projection from the nasal and temporal retina to the midbrain. We also measured the size of the soma and dendritic field of the labelled ganglion cells (mostly gamma cells) and compared them with those of alpha and beta cells that project to the dorsal lateral geniculate nucleus. Soma size was very close to that of beta cells at all eccentricities but was much smaller than that of alpha cells. Dendritic field size was significantly larger than that of beta cells but was smaller than that of alpha cells. The number of primary dendrites was counted for cells labelled from the midbrain and in samples of alpha and beta cells labelled from the optic nerve. At eccentricities of 3-7 mm there was a consistent and prominent difference between beta and gamma cells. The results show that at intermediate eccentricities even ganglion cells whose distal dendrites are too poorly labelled to reveal their morphological class can never the less be categorized as alpha, beta or gamma by using a combination of soma size and number of primary dendrites. This is particularly useful when attempting to classify retinal ganglion cells following microinjections into selected target nuclei of optic axons.


A genetic approach to the development of new therapeutic phages to fight pseudomonas aeruginosa in wound infections.
Pseudomonas aeruginosa is a frequent participant in wound infections. Emergence of multiple antibiotic resistant strains has created significant problems in the treatment of infected wounds. Phage therapy (PT) has been proposed as a possible alternative approach. Infected wounds are the perfect place for PT applications, since the basic condition for PT is ensured; namely, the direct contact of bacteria and their viruses. Plenty of virulent ("lytic") and temperate ("lysogenic") bacteriophages are known in P. aeruginosa. However, the number of virulent phage species acceptable for PT and their mutability are limited. Besides, there are different deviations in the behavior of virulent (and temperate) phages from their expected canonical models of development. We consider some examples of non-canonical phage-bacterium interactions and the possibility of their use in PT. In addition, some optimal approaches to the development of phage therapy will be discussed from the point of view of a biologist, considering the danger of phage-assisted horizontal gene transfer (HGT), and from the point of view of a surgeon who has accepted the Hippocrates Oath to cure patients by all possible means. It is also time now to discuss the possible approaches in international cooperation for the development of PT. We think it would be advantageous to make phage therapy a kind of personalized medicine.


Generation and Processing of Simulated Underwater Images for Infrastructure Visual Inspection with UUVs.
The development of computer vision algorithms for navigation or object detection is one of the key issues of underwater robotics. However, extracting features from underwater images is challenging due to the presence of lighting defects, which need to be counteracted. This requires good environmental knowledge, either as a dataset or as a physic model. The lack of available data, and the high variability of the conditions, makes difficult the development of robust enhancement algorithms. A framework for the development of underwater computer vision algorithms is presented, consisting of a method for underwater imaging simulation, and an image enhancement algorithm, both integrated in the open-source robotics simulator UUV Simulator. The imaging simulation is based on a novel combination of the scattering model and style transfer techniques. The use of style transfer allows a realistic simulation of different environments without any prior knowledge of them. Moreover, an enhancement algorithm that successfully performs a correction of the imaging defects in any given scenario for either the real or synthetic images has been developed. The proposed approach showcases then a novel framework for the development of underwater computer vision algorithms for SLAM, navigation, or object detection in UUVs.


Nonrandom Distribution of Cabbage Aphids (Hemiptera: Aphididae) in Dryland Canola (Brassicales: Brassicaceae).
Characterization of spatial distribution patterns of pests in large-scale agricultural fields is important because these patterns affect the sampling effort needed to accurately detect and estimate their population density. In this study, we conducted experimental releases of alate cabbage aphids (Brevicoryne brassicae L.) into centers of small plots of canola (Brassica napus L.), and their gradual spread over a 7-wk period was characterized. The small-plot experiment demonstrated gradient effects from plot centers and a nonrandom vertical distribution, with initial colonization occurring on the abaxial side of lower canopy leaves and, later, highest numbers of cabbage aphids occurring on racemes. We also conducted large-scale distribution analyses of cabbage aphid infestations in two commercial canola fields, using visual inspection and sweep net sampling. We used canola plant phenological and landscape features as explanatory variables of the spatial distribution of cabbage aphid counts. These large-scale experiments showed strong edge effects with negative associations between cabbage aphid counts and distance to crop edges, including tree lines and contour banks. Cabbage aphid distribution was more effectively displayed using logistic regression than ordinary regression, Spatial Analysis by Distance IndicEs, or both. Based on the study findings, a nonrandom or optimized inspection approach is proposed to focus monitoring efforts on canola plants within 20 m from field edges with particular attention to the abaxial side of lower-canopy leaves. Detection of advanced cabbage aphid infestations should target the racemes within 20 m from field edges.


Inheritance law in an aging society.
An exploratory analysis of states' inheritance law changes between 1961 and 1990 was conducted in order to discern major trends and their implications for older families. Results suggested that states were modifying their laws in ways similar to suggestions of the law community's Uniform Probate Code, with about one third of the states adopting the Code itself. Consequently, inheritance law has become less traditional and paternalistic and more like "facilitative law," that is, flexible, accommodating, and supportive of family autonomy and decisionmaking authority. These changes and new laws that simplify procedures, protect the dependent and vulnerable, treat marital property more like community property, recognize variant family forms, and enable extrafamilial bequests, may serve to minimize family disruption, conserve resources, and allow families to tailor property divisions and procedures to particular needs and wishes. An impact study is proposed for disclosing the actual effects on inheritance law reforms. Also, while trends observed in this study were fairly evident, states' adoption of new laws was uneven and selective, inviting continuing trend analyses and further research into the reasons for interstate variation.


Agents of their health? How the Swedish welfare state introduces expectations of individual responsibility.
In recent years, the notion of individual responsibility for one's health has been introduced into Swedish medico-political debate. Formerly expressed as a recommendation, it has now taken on the form of expectations. In a Swedish context, this shift from collective to individual responsibility is novel because it implies a break with well-established welfare state practice of comprehensive care for their citizens. Using a systems-theoretical approach, we interpret this shift of expectations as a political solution to the problem of legitimate allocation of scarce resources. A more inclusive medical conception of illness has facilitated the introduction of many new diagnoses that, in turn, have lead to a strong increase in claims for medical treatment and for compensation. This semantic change in medicine aggravates the budgetary situation of the welfare state. The political solution lies in a reorientation of the expectations the medical system can have on citizens as well as a shift of the expectations regarding the rights and obligations citizens can have on the medical system. Individuals are increasingly expected to live healthy lifestyles and to avoid hazardous habits. If they do not live up to these expectations, they have to face low prioritisation or denial of treatment.


Childhood maltreatment and migraine (part III). Association with comorbid pain conditions.
To evaluate in a headache clinic population the relationship of childhood maltreatment on the prevalence of pain conditions comorbid with migraine. Childhood maltreatment is highly prevalent and has been frequently associated with recurrent headache. The relationship of maltreatment and pain has, however, been a subject of some debate. Cross-sectional data on self-reported physician-diagnosed pain conditions were electronically collected from persons with migraine (diagnosed according to International Classification of Headache Disorders-2), seeking treatment in headache clinics at 11 centers across the US and Canada. These included irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), fibromyalgia (FM), interstitial cystitis (IC), arthritis, endometriosis, and uterine fibroids. Other information included demographics, migraine characteristics (frequency, headache-related disability), remote and current depression (The Patient Health Questionnaire-9), and remote and current anxiety (The Beck Anxiety Inventory). Patients also completed the Childhood Trauma Questionnaire regarding sexual, emotional, and physical abuse, and emotional and physical neglect under the age of 18 years old. Statistical analyses accounted for the survey design and appropriate procedures in SAS such as surveymeans, surveyfreq, and surveylogistic were applied to the weighted data. A total of 1348 migraineurs (88% women) were included in this study (mean age 41 years). Based on physician diagnosis or validated criteria, 31% had IBS, 16% had CFS, and 10% had FM. Diagnosis of IC was reported by 6.5%, arthritis by 25%, and in women, endometriosis was reported by 15% and uterine fibroids by 14%. At least 1 comorbid pain condition was reported by 61%, 2 conditions by 18%, and 3 or more by 13%. Childhood maltreatment was reported by 58% of the patients. Emotional abuse was associated with increased prevalence of IBS, CFS, arthritis, and physical neglect with arthritis. In women, physical abuse was associated with endometriosis and physical neglect with uterine fibroids. Emotional abuse, and physical abuse and neglect (P < .0001 for all) were also associated with increased total number of comorbid conditions. In ordinal logistic regression models, adjusted for sociodemographics and current depression (prevalence 28%) and anxiety (prevalence 56%), emotional abuse (odds ratios [OR] = 1.69, 95% confidence intervals [CI]: 1.224-2.33) and physical neglect (OR = 1.73, 95% CI: 1.22-2.46) were independently associated with an increased number of pain conditions. The cohort of women, similarly, had associations of emotional abuse (OR = 1.94, 95% CI: 1.40-2.72) and physical neglect (OR = 1.90, 95% CI: 1.34-2.68) with an increased number of pain comorbidities. The association of childhood maltreatment and pain was stronger in those reporting multiple pain conditions and multiple maltreatment types. This finding suggests that in migraineurs childhood maltreatment may be a risk factor for development of comorbid pain disorders.


Mesenchymal Chondrosarcoma of the Lacrimal Gland.
A 23-year-old woman presented with right-sided painless proptosis that developed in 12 months. MRI studies demonstrated a well-delineated tumorous enlargement of the right lacrimal gland with homogenous signal intensity and compressing the globe. The tumor was removed totally and in 1 piece with the tentative diagnosis of a pleomorphic adenoma. Pathologic examination revealed biphasic neoplastic elements, which were composed of the cartilaginous matrix and small round cell component. Immunohistopathological examination showed positive CD99 staining and negative reaction to S100, panCK, and CD15. The patient then received a total of 64 Gy orbital radiotherapy in 32 fractionations. There has been no recurrence or metastasis during 14 months of follow up. This case showed that mesenchymal chondrosarcoma may arise from the lacrimal gland and must be considered in the differential diagnosis of lacrimal gland tumors in young adults.


Concordance between substance use self-report and hair analysis in community-based adolescents.
Background: Accurate drug use identification through subjective self-report and toxicological biosample (hair) analysis are necessary to determine substance use sequelae in youth. Yet consistency between self-reported substance use and robust, toxicological analysis in a large sample of youth is understudied.Objectives: We aim to assess concordance between self-reported substance use and hair toxicological analysis in community-based adolescents.Methods: Hair results by LC-MS/MS and GC-MS/MS and self-reported past-year substance use from an Adolescent Brain Cognitive Development (ABCD) Study subsample (N = 1,390; ages 9-13; 48% female) were compared. The participants were selected for hair selection through two methods: high scores on a substance risk algorithm selected 93%; 7% were low-risk, randomly selected participants. Kappa coefficients the examined concordance between self-report and hair results.Results: 10% of youth self-reported any past-year substance use (e.g. alcohol, cannabis, nicotine, and opiates), while a mostly non-overlapping 10% had hair results indicating recent substance use (cannabis, alcohol, non-prescription amphetamines, cocaine, nicotine, opiates, and fentanyl). In randomly selected low-risk cases, 7% were confirmed positive in hair. Combining methods, 19% of the sample self-reported substance use and/or had a positive hair sample. Kappa coefficient of concordance between self-report and hair results was low (kappa = 0.07; p = .007).Conclusions: Hair toxicology identified substance use in high-risk and low-risk ABCD cohort subsamples. Given low concordance between hair results and self-report, reliance on either method alone would incorrectly categorize 9% as non-users. Multiple methods for characterizing substance use history in youth improves accuracy. Larger representative samples are needed to assess the prevalence of substance use in youth.


Permanent central synaptic disconnection of proprioceptors after nerve injury and regeneration. I. Loss of VGLUT1/IA synapses on motoneurons.
Motor and sensory proprioceptive axons reinnervate muscles after peripheral nerve transections followed by microsurgical reattachment; nevertheless, motor coordination remains abnormal and stretch reflexes absent. We analyzed the possibility that permanent losses of central IA afferent synapses, as a consequence of peripheral nerve injury, are responsible for this deficit. VGLUT1 was used as a marker of proprioceptive synapses on rat motoneurons. After nerve injuries synapses are stripped from motoneurons, but while other excitatory and inhibitory inputs eventually recover, VGLUT1 synapses are permanently lost on the cell body (75-95% synaptic losses) and on the proximal 100 μm of dendrite (50% loss). Lost VGLUT1 synapses did not recover, even many months after muscle reinnervation. Interestingly, VGLUT1 density in more distal dendrites did not change. To investigate whether losses are due to VGLUT1 downregulation in injured IA afferents or to complete synaptic disassembly and regression of IA ventral projections, we studied the central trajectories and synaptic varicosities of axon collaterals from control and regenerated afferents with IA-like responses to stretch that were intracellularly filled with neurobiotin. VGLUT1 was present in all synaptic varicosities, identified with the synaptic marker SV2, of control and regenerated afferents. However, regenerated afferents lacked axon collaterals and synapses in lamina IX. In conjunction with the companion electrophysiological study [Bullinger KL, Nardelli P, Pinter MJ, Alvarez FJ, Cope TC. J Neurophysiol (August 10, 2011). doi:10.1152/jn.01097.2010], we conclude that peripheral nerve injuries cause a permanent retraction of IA afferent synaptic varicosities from lamina IX and disconnection with motoneurons that is not recovered after peripheral regeneration and reinnervation of muscle by sensory and motor axons.


The influence of time from injury to surgery on motor recovery and length of hospital stay in acute traumatic spinal cord injury: an observational Canadian cohort study.
To determine the influence of time from injury to surgery on neurological recovery and length of stay (LOS) in an observational cohort of individuals with traumatic spinal cord injury (tSCI), we analyzed the baseline and follow-up motor scores of participants in the Rick Hansen Spinal Cord Injury Registry to specifically assess the effect of an early (less than 24 h from injury) surgical procedure on motor recovery and on LOS. One thousand four hundred and ten patients who sustained acute tSCIs with baseline American Spinal Injury Association Impairment Scale (AIS) grades A, B, C, or D and were treated surgically were analyzed to determine the effect of the timing of surgery (24, 48, or 72 h from injury) on motor recovery and LOS. Depending on the distribution of data, we used different types of generalized linear models, including multiple linear regression, gamma regression, and negative binomial regression. Persons with incomplete AIS B, C, and D injuries from C2 to L2 demonstrated motor recovery improvement of an additional 6.3 motor points (SE=2.8 p<0.03) when they underwent surgical treatment within 24 h from the time of injury, compared with those who had surgery later than 24 h post-injury. This beneficial effect of early surgery on motor recovery was not seen in the patients with AIS A complete SCI. AIS A and B patients who received early surgery experienced shorter hospital LOS. While the issues of when to perform surgery and what specific operation to perform remain controversial, this work provides evidence that for an incomplete acute tSCI in the cervical, thoracic, or thoracolumbar spine, surgery performed within 24 h from injury improves motor neurological recovery. Early surgery also reduces LOS.


A Meta-analysis of Studies Comparing Outcomes of Diverse Acellular Dermal Matrices for Implant-Based Breast Reconstruction.
The current diversity of the available acellular dermal matrix (ADM) materials for implant-based breast reconstruction raises the issue of whether there are any differences in postoperative outcomes according to the kind of ADM used. The present meta-analysis aimed to investigate whether choice of ADM products can affect outcomes. Studies that used multiple kinds of ADM products for implant-based breast reconstruction and compared outcomes between them were searched. Outcomes of interest were rates of postoperative complications: infection, seroma, mastectomy flap necrosis, reconstruction failure, and overall complications. A total of 17 studies met the selection criteria. There was only 1 randomized controlled trial, and the other 16 studies had retrospective designs. Comparison of FlexHD, DermaMatrix, and ready-to-use AlloDerm with freeze-dried AlloDerm was conducted in multiple studies and could be meta-analyzed, in which 12 studies participated. In the meta-analysis comparing FlexHD and freeze-dried AlloDerm, using the results of 6 studies, both products showed similar pooled risks for all kinds of complications. When comparing DermaMatrix and freeze-dried AlloDerm with the results from 4 studies, there were also no differences between the pooled risks of complications of the two. Similarly, the meta-analysis of 4 studies comparing ready-to-use and freeze-dried AlloDerm demonstrated that the pooled risks for the complications did not differ. This meta-analysis demonstrates that the 3 recently invented, human cadaveric skin-based products of FlexHD, DermaMatrix, and ready-to-use AlloDerm have similar risks of complications compared with those of freeze-dried AlloDerm, which has been used for longer. However, as most studies had low levels of evidence, further investigations are needed.


Primary care management of the coronavirus (COVID-19).
South Africa is in the grip of a novel coronavirus pandemic (COVID-19). Primary care providers are in the frontline. COVID-19 is spread primarily by respiratory droplets contaminating surfaces and hands that then transmit the virus to another person's respiratory system. The incubation period is 2-9 days and the majority of cases are mild. The most common symptoms are fever, cough and shortness of breath. Older people and those with cardiopulmonary co-morbidities or immunological deficiency will be more at risk of severe disease. If people meet the case definition, the primary care provider should immediately adopt infection prevention and control measures. Diagnosis is made by a RT-PCR test using respiratory secretions, usually nasopharyngeal and oropharyngeal swabs. Mild cases can be managed at home with self-isolation, symptomatic treatment and follow-up if the disease worsens. Contact tracing is very important. Observed case fatality is between 0.5% and 4%, but may be overestimated as mild cases are not always counted. Primary care providers must give clear, accurate and consistent messages on infection prevention and control in communities and homes.


A comparison of latanoprost and dorzolamide in patients with glaucoma and ocular hypertension: a 3 month, randomised study. Ireland Latanoprost Study Group.
To compare the effects on intraocular pressure (IOP) and side effects of monotherapy with either latanoprost or dorzolamide in patients with glaucoma or ocular hypertension. 224 patients with open angle glaucoma or ocular hypertension were recruited to a 3 month open labelled study. Previous glaucoma medications were washed out and the patients were randomised to receive either latanoprost 0.005% once daily or dorzolamide 2% three times daily. Of 224 patients 213 were included in the analysis of efficacy. After 3 months, latanoprost reduced mean baseline diurnal IOP from 27.2 (SD 3.0) mm Hg by 8.5 (3.3) mm Hg. The corresponding figures for dorzolamide were 27.2 (3.4) and 5.6 (2.6) mm Hg. The difference of 2.9 mm Hg (95% CI: 2.3-3.6) was highly significant (p<0.001, ANCOVA). Latanoprost reduced IOP at peak by 8.6 mm Hg (32%) compared with 6.2 mm Hg (23%) for dorzolamide, and the difference of 2.4 mm Hg was significant (p<0.001, ANCOVA). The corresponding figures at trough were 8.1 mm Hg (31%) for latanoprost and 4.7 mm Hg (17%) for dorzolamide, a significant difference of 3.4 mm Hg (p<0.001, ANCOVA). Both drugs were well tolerated systemically and locally. Latanoprost was superior to dorzolamide in reducing the IOP, judged both from the effect on IOP at peak and trough and by the effect on diurnal IOP.


Fearing shades of grey: individual differences in fear responding towards generalisation stimuli.
Individual differences in fear generalisation have been proposed to play a role in the aetiology and/or maintenance of anxiety disorders, but few data are available to directly support that claim. The research that is available has focused mostly on generalisation of peripheral and central physiological fear responses. Far less is known about the generalisation of avoidance, the behavioural component of fear. In two experiments, we evaluated how neuroticism, a known vulnerability factor for anxiety, modulates an array of fear responses, including avoidance tendencies, towards generalisation stimuli (GS). Participants underwent differential fear conditioning, in which one conditioned stimulus (CS+) was repeatedly paired with an aversive outcome (shock; unconditioned stimulus, US), whereas another was not (CS-). Fear generalisation was observed across measures in Experiment 1 (US expectancy and evaluative ratings) and Experiment 2 (US expectancy, evaluative ratings, skin conductance, startle responses, safety behaviours), with overall highest responding to the CS+, lowest to the CS- and intermediate responding to the GSs. Neuroticism had very little impact on fear generalisation (but did affect GS recognition rates in Experiment 1), in line with the idea that fear generalisation is largely an adaptive process.


Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: The PDGene database.
More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of -27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P < 5 × 10(-8)) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P = 1.3 × 10(-8)). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.


A prediction-correction scheme for forcing alveolar gases along certain time courses.
A computerized prediction-correction scheme has been devised for the control of alveolar gases. First, a model is run off-line to predict the inspiratory gas tensions at each second that should yield the desired alveolar patterns. Second, during the experiment, there is feedback correction based on the deviation of the actual alveolar values from the desired alveolar values. The actual alveolar values are found by a second computer and passed to the controlling computer using interrupts. The controlling computer has four digital-toi-analog outputs for controlling CO2, O2, N2, and air flows so as to achieve the commanded inspiratory PCO2 and PO2 (CO2 and O2 partial pressures, respectively). The scheme is illustrated for the generation of sinusoidal alveolar PCO2 with alveolar PO2 held constant and for steps of alveolar PCO2 at constant alveolar PO2.


T4 DNA polymerase. Rates and processivity on single-stranded DNA templates.
Three different methods have been used to determine the rate at which an individual bacteriophage T4 DNA polymerase molecule moves when synthesizing DNA on a single-stranded DNA template chain. These methods agree in suggesting an in vitro rate for this enzyme of about 250 nucleotides per second at 37 degrees C. This rate is close to the rate at which bacteriophage T4 replication forks move in vivo (about 500 nucleotides per second). Comparison with the overall amount of DNA synthesis seen in in vitro reactions reveals that only a small fraction of the T4 DNA polymerase molecules present are synthesizing DNA at any one time. This is explicable in terms of the limited processivity of the enzyme in these reactions, along with its capacity for non-productive DNA binding to the DNA template molecules.


Post-operative imaging of pulmonary vessels.
Complications following cardiothoracic surgery are responsible for prolonged hospital stay, increase cost in patient care and increased morbidity and mortality. Vascular complications in particular are significant contributors to poor patient outcome due to either hemorrhage or thrombosis and ischemia. Evaluation of vascular complications in the postoperative patient requires a rapid and reliable imaging approach. Vascular complications after cardiothoracic surgery include pulmonary artery thrombosis, pseudoaneurysm, pulmonary vein thrombosis, vascular fistulas, stenosis and infarction. Multidetector CT (MDCT), often the imaging modality of choice, offers a one-stop-shop capability to visualize the entire cardiothoracic vasculature, airways, lung parenchyma, mediastinum and chest wall with excellent temporal and spatial resolution.


Usefulness of Noninvasive Positive-pressure Ventilation During Surgery of Flaccid Neuromuscular Scoliosis.
This is a retrospective study. To assess the effects of noninvasive positive-pressure ventilation (NIPPV) through evaluations of outcomes and incidences of postoperative pulmonary complications among patients with flaccid neuromuscular scoliosis for pulmonary support in the perioperative periods. There is no report on the effects of NIPPV on neuromuscular scoliosis patient during the perioperative periods. We retrospectively reviewed 73 patients diagnosed with neuromuscular scoliosis who underwent staged anterior and posterior spinal surgery and instrumentations for deformity correction from 2003 to 2010. A total of 73 patients were divided depending on whether they had received NIPPV treatment or not during the perioperative period. Twenty-eight patients who received NIPPV for respiratory support and 45 patients with no mechanical ventilation were compared according to age, sex, body mass index, number of fusion levels, and end-tidal pressure of CO(2) and forced vital capacity values. The incidence of pulmonary complications associated with either group (pneumonia, atelectasis, pneumothorax, prolonged ventilator support, and postoperative tracheostomy) was then evaluated. In between the 2 groups, the forced vital capacity (41% vs. 64%, P<0.0001) were observed to be significantly decreased with the use of NIPPV. End-tidal pressure of CO(2) was not statistically different between the 2 groups. Although statistically not significant, patients in the non-NIPPV group had a higher incidence of pulmonary complications (38% vs. 21%, P=0.1584). None of the aforementioned patients required tracheostomy. In addition, no other mortality or neurological complications were noted postoperatively. There is a definite advantage of using NIPPV, because the incidence of postoperative pulmonary complications and the need for tracheostomy in patients with severely decreased pulmonary function are not increased from the use of NIPPV.


Germline mutation in RNASEL predicts increased risk of head and neck, uterine cervix and breast cancer.
THE BACKGROUND: Ribonuclease L (RNASEL), encoding the 2'-5'-oligoadenylate (2-5A)-dependent RNase L, is a key enzyme in the interferon induced antiviral and anti-proliferate pathway. Mutations in RNASEL segregate with the disease in prostate cancer families and specific genotypes are associated with an increased risk of prostate cancer. Infection by human papillomavirus (HPV) is the major risk factor for uterine cervix cancer and for a subset of head and neck squamous cell carcinomas (HNSCC). HPV, Epstein Barr virus (EBV) and sequences from mouse mammary tumor virus (MMTV) have been detected in breast tumors, and the presence of integrated SV40 T/t antigen in breast carcinomas correlates with an aggressive phenotype and poor prognosis. A genetic predisposition could explain why some viral infections persist and induce cancer, while others disappear spontaneously. This points at RNASEL as a strong susceptibility gene. To evaluate the implication of an abnormal activity of RNase L in the onset and development of viral induced cancers, the study was initiated by searching for germline mutations in patients diagnosed with uterine cervix cancer. The rationale behind is that close to 100% of the cervix cancer patients have a persistent HPV infection, and if a defective RNase L were responsible for the lack of ability to clear the HPV infection, we would expect to find a wide spectrum of mutations in these patients, leading to a decreased RNase L activity. The HPV genotype was established in tumor DNA from 42 patients diagnosed with carcinoma of the uterine cervix and somatic tissue from these patients was analyzed for mutations by direct sequencing of all coding and regulatory regions of RNASEL. Fifteen mutations, including still uncharacterized, were identified. The genotype frequencies of selected single nucleotide polymorphisms (SNPs) established in the cervix cancer patients were compared between 382 patients with head and neck squamous cell carcinomas (HNSCC), 199 patients with primary unilateral breast cancer and 502 healthy Danish control individuals. We found that the genotype frequencies of only one of the 15 mutations, the yet uncharacterized 5'UTR mutation rs3738579 differed significantly between cancer patients and control individuals (P-value: 4.43x10(-5)). In conclusion, we have discovered an increased risk, a heterozygous advantage and thereby a protective effect linked to the RNASEL SNP rs3738579. This effect is found for patients diagnosed with carcinoma of the uterine cervix, HNSCC, and breast cancer thus pointing at RNASEL as a general marker for cancer risk and not restricted to familial prostate cancer.


Identification of interleukin-1beta regulated genes in uterine smooth muscle cells.
We analyzed the response of uterine smooth muscle cells to interleukin-1beta (IL-1beta). We first showed that PHM1-31 myometrial cells, our cellular model, are contractile. To determine the molecular mechanisms of uterine smooth muscle cell activation by proinflammatory cytokines, we performed genechip expression array profiling studies of PHM1-31 cells in the absence and the presence of IL-1beta. In total, we identified 198 known genes whose mRNA levels are significantly modulated (> 2.0-fold change) following IL-1beta exposure. We confirmed the expression changes for selected genes by independent mRNA and protein analysis. The group of genes induced by IL-1beta includes transcription factors and inflammatory response genes such as nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFkappaB), pentraxin-related gene (PTX3), and tumor necrosis factor alpha-induced protein 3/A20 (TNFAIP3/A20). We also found up-regulation of chemokines like C-X-C motif ligand 3 (CXCL3) and extracellular matrix remodeling signaling molecules like tenascin C (TNC). Our data suggest that IL-1beta elicits the rapid activation of a cellular network of genes particularly implicated in inflammatory response that may create a cellular environment favorable for myometrial cell contraction. Our results provide novel insights into the mechanisms of uterine smooth muscle cell regulation and possibly infection-induced preterm labor.


Hospitals and plastics. Dioxin prevention and medical waste incinerators.
CHLORINATED DIOXINS and related compounds are extremely potent toxic substances, producing effects in humans and animals at extremely low doses. Because these compounds are persistent in the environment and accumulate in the food chain, they are now distributed globally, and every member of the human population is exposed to them, primarily through the food supply and mothers' milk. An emerging body of information suggests that dioxin contamination has reached a level that may pose a large-scale, long-term public health risk. Of particular concern are dioxin's effects on reproduction, development, immune system function, and carcinogenesis. Medical waste incineration is a major source of dioxins. Polyvinyl chloride (PVC) plastic, as the dominant source of organically bound chlorine in the medical waste stream, is the primary cause of "iatrogenic" dioxin produced by the incineration of medical wastes. Health professionals have a responsibility to work to reduce dioxin exposure from medical sources. Health care institutions should implement policies to reduce the use of PVC plastics, thus achieving major reductions in medically related dioxin formation.


H4K12ac is regulated by estrogen receptor-alpha and is associated with BRD4 function and inducible transcription.
Hormone-dependent gene expression requires dynamic and coordinated epigenetic changes. Estrogen receptor-positive (ER+) breast cancer is particularly dependent upon extensive chromatin remodeling and changes in histone modifications for the induction of hormone-responsive gene expression. Our previous studies established an important role of bromodomain-containing protein-4 (BRD4) in promoting estrogen-regulated transcription and proliferation of ER+ breast cancer cells. Here, we investigated the association between genome-wide occupancy of histone H4 acetylation at lysine 12 (H4K12ac) and BRD4 in the context of estrogen-induced transcription. Similar to BRD4, we observed that H4K12ac occupancy increases near the transcription start sites (TSS) of estrogen-induced genes as well as at distal ERα binding sites in an estrogen-dependent manner. Interestingly, H4K12ac occupancy highly correlates with BRD4 binding and enhancer RNA production on ERα-positive enhancers. Consistent with an importance in estrogen-induced gene transcription, H4K12ac occupancy globally increased in ER-positive cells relative to ER-negative cells and these levels were further increased by estrogen treatment in an ERα-dependent manner. Together, these findings reveal a strong correlation between H4K12ac and BRD4 occupancy with estrogen-dependent gene transcription and further suggest that modulators of H4K12ac and BRD4 may serve as new therapeutic targets for hormone-dependent cancers.


Variable pathways for developmental changes of mitosis and cytokinesis in Physarum polycephalum.
The development of a uninucleate ameba into a multinucleate, syncytial plasmodium in myxomycetes involves a change from the open, astral mitosis of the ameba to the intranuclear, anastral mitosis of the plasmodium, and the omission of cytokinesis from the cell cycle. We describe immunofluorescence microscopic studies of the amebal-plasmodial transition (APT) in Physarum polycephalum. We demonstrate that the reorganization of mitotic spindles commences in uninucleate cells after commitment to plasmodium formation, is completed by the binucleate stage, and occurs via different routes in individual developing cells. Most uninucleate developing cells formed mitotic spindles characteristic either of amebae or of plasmodia. However, chimeric mitotic figures exhibiting features of both amebal and plasmodial mitoses, and a novel star microtubular array were also observed. The loss of the ameba-specific alpha 3-tubulin and the accumulation of the plasmodium-specific beta 2-tubulin isotypes during development were not sufficient to explain the changes in the organization of mitotic spindles. The majority of uninucleate developing cells undergoing astral mitoses (amebal and chimeric) exhibited cytokinetic furrows, whereas cells with the anastral plasmodial mitosis exhibited no furrows. Thus, the transition from astral to anastral mitosis during the APT could be sufficient for the omission of cytokinesis from the cell cycle. However, astral mitosis may not ensure cytokinesis: some cells undergoing amebal or chimeric mitosis contained unilateral cytokinetic furrows or no furrow at all. These cells would, most probably, fail to divide. We suggest that a uninucleate committed cell undergoing amebal or chimeric mitosis can either divide or else form a binucleate cell. In contrast, a uninucleate cell with a mitotic spindle of the plasmodial type gives rise only to a binucleate cells. Further, the decision to enter mitosis after commitment to the APT is independent of the developmental changes in the organization of the mitotic spindle and cytokinesis.


Brugia Rapid™ antibody responses in communities of Indonesia in relation to the results of 'transmission assessment surveys' (TAS) for the lymphatic filariasis elimination program.
The Global Programme to Eliminate Lymphatic Filariasis recommends the transmission assessment survey (TAS) as the preferred methodology for determining whether mass drug administration can be stopped in an endemic area. Because of the limited experience available globally with the use of Brugia Rapid™ tests in conducting TAS in Brugia spp. areas, we explored the relationship between the antibody test results and Brugia spp. infection as detected by microfilaremia in different epidemiological settings. The study analyzes the Brugia Rapid™ antibody responses and microfilaremia in all ages at three study sites in: i) a district which was classified as non-endemic, ii) a district which passed TAS, and iii) a district which failed TAS. Convenience sampling was done in each site, in one to three purposefully selected villages with a goal of 500 samples in each district. A total of 1543 samples were collected from residents in all three study sites. In the site which was classified as non-endemic and where MDA had not been conducted, 5 % of study participants were antibody positive, none was positive for microfilaremia, and age-specific antibody prevalence peaked at almost 8 % in the 25-34 year-old age range, with no antibody-positive results found in children under eight years of age. In the site that had passed TAS, 1 % of participants were antibody positive and none was positive for microfilaremia. In the site which failed TAS, 15 % of participants were antibody positive, 0.2 % were microfilaremic, and age-specific antibody prevalence was highest in 6-7 year olds (30 %), but above 8 % in all age levels above 8 years old. These results from districts which followed the current WHO guidance for mapping, MDA, and implementing TAS, while providing antibody profiles of treated and untreated populations under programmatic settings, support the choice of antibody prevalence in the 6- and 7-year-old age group in TAS for making stopping MDA decisions. Since only one study participant was microfilaremic, no conclusions could be drawn about the relationship between antibodies and microfilaremia and further longitudinal studies are required to understand this relationship.


Lability of arterial pressure after baroreceptor denervation is not pressure dependent.
The mechanisms of increased arterial pressure lability after sinoaortic deafferentation remain unknown. We have shown previously in rats with chronic sinoaortic deafferentation (7-14 days after sinoaortic deafferentation) that ganglionic blockade significantly reduced mean arterial pressure and arterial pressure lability. The present study investigated the possibility that lability is related to the level of arterial pressure. Rats were instrumented chronically and heart rate and mean arterial pressure were sampled every 5 seconds in the conscious, freely moving state. Graded sustained increases in pressure (+10 to +82 mm Hg) produced by constant infusion of angiotensin II, phenylephrine, or vasopressin did not affect lability (standard deviation of 30-minute sampling period); whereas, graded hypotension (-10 to -70 mm Hg) produced by infusions of adenosine, nitroprusside, or nisoldipine appeared to reduce lability. Analysis of covariance and orthogonal polynomial curve fitting demonstrated a significant correlation between the decrease in mean arterial pressure and the decrease in lability produced by nisoldipine but not by adenosine or nitroprusside. Lability does not appear to be solely dependent on the level of arterial pressure because lability was reduced by adenosine when pressure was maintained at control levels by simultaneous infusion of phenylephrine. We conclude that 1) arterial pressure lability is not influenced by elevation of arterial pressure but can be reduced when pressure is lowered by certain vasodilators and 2) pressure alone does not appear to be the major determinant of lability because it can be attenuated by vascular smooth muscle relaxants even when pressure is maintained.


Indoor use of plastic sheeting impregnated with carbamate combined with long-lasting insecticidal mosquito nets for the control of pyrethroid-resistant malaria vectors.
The combined efficacy of a long-lasting insecticidal net (LLIN) and a carbamate-treated plastic sheeting (CTPS) or indoor residual spraying (IRS) for control of insecticide-resistant mosquitoes was evaluated in experimental huts in Burkina Faso. Anopheles gambiae from the area is resistant to pyrethroids and to a lesser extent, carbamates. Relatively low mortality rates were observed with the LLIN (44%), IRS (42%), and CTPS (52%), whereas both combinations killed significantly more mosquitoes (~70% for LLIN + CTPS and LLIN + IRS). Blood feeding by An. gambiae was uninhibited by IRS and CTPS compared with LLIN (43%), LLIN + CTPS (58%), and LLIN + IRS (56%). No evidence for selection of the kdr and ace-1(R) alleles was observed with the combinations, whereas a survival advantage of mosquitoes bearing the ace-1(R) mutation was observed with IRS and CTPS. The results suggest that the combination of the two interventions constitutes a potential tool for vector-resistance management.