339 research outputs found
Androgen receptor expression in metastatic adenocarcinoma in females favors a breast primary
BACKGROUND: The differential diagnosis of metastatic mammary adenocarcinoma and adenocarcinomas from other primary sites can be challenging, particularly in tumors that are poorly differentiated and negative for Estrogen/Progesterone receptors (ER/PR). With progression of disease, Androgen receptors (AR) are preserved with higher frequency than ER/PR in metastatic mammary carcinoma. This study was undertaken to evaluate the diagnostic significance of AR expression in adenocarcinoma of breast and other morphologically similar adenocarcinomas. DESIGN: Formalin-fixed paraffin-embedded tissue sections of 113 primary adenocarcinoma of various sites [breast (34, all females), lung (23, M- 6, F-17), colon (9, M-2, F-7), stomach (6, M-4, F-2), liver and bile duct (11, M-5, F-6), pancreas (7, M-2, F-5), ovary (10), endometrium (7), and cervix (6)] were immunostained with monoclonal antibody for AR. Except for well differentiated lobular carcinoma of breast (5) and bronchoalveolar carcinoma of lung (10), majority of the tumors were moderately to poorly differentiated. Tumors immunoreactive for β₯ 10% of nuclei were considered AR positive. However, AR immunoreactivity in the cytoplasm only was also recorded. RESULTS: 56% (19/34) mammary carcinoma and 20% (2/10) adenocarcinoma of ovary were positive for AR. Remaining 69 adenocarcinomas did not show nuclear immunoreactivity for AR in β₯ 10% nuclei; however, 52% (36/69) showed variable cytoplasmic immunoreactivity. CONCLUSION: Significant proportion of mammary carcinomas and some ovarian carcinomas express AR in the nuclei of more than 10% tumor cells. If metastatic tumor with unknown primary in a female is AR positive, breast and ovary are the most likely primary sites. Cytoplasmic immunoreactivity alone without nuclear immunoreactivity for AR was non-specific for this differential diagnosis
Developing a utility index for the Aberrant Behavior Checklist (ABC-C) for fragile X syndrome
Purpose This study aimed to develop a utility index (the
ABC-UI) from the Aberrant Behavior Checklist-Community
(ABC-C), for use in quantifying the benefit of
emerging treatments for fragile X syndrome (FXS).
Methods The ABC-C is a proxy-completed assessment of
behaviour and is a widely used measure in FXS. A subset
of ABC-C items across seven dimensions was identified to
include in health state descriptions. This item reduction
process was based on item performance, factor analysis and
Rasch analysis performed on an observational study dataset,
and consultation with five clinical experts and a
methodological expert. Dimensions were combined into
health states using an orthogonal design and valued using
time trade-off (TTO), with lead-time TTO methods used
where TTO indicated a state valued as worse than dead.
Preference weights were estimated using mean, individual
level, ordinary least squares and random-effects maximum
likelihood estimation [RE (MLE)] regression models.
Results A representative sample of the UK general public
(n = 349; mean age 35.8 years, 58.2 % female) each valued
12 health states. Mean observed values ranged from
0.92 to 0.16 for best to worst health states. The RE (MLE)
model performed best based on number of significant
coefficients and mean absolute error of 0.018. Mean utilities
predicted by the model covered a similar range to that
observed.
Conclusions The ABC-UI estimates a wide range of
utilities from patient-level FXS ABC-C data, allowing
estimation of FXS health-related quality of life impact for
economic evaluation from an established FXS clinical trial
instrument
Mid-infrared passively switched pulsed dual wavelength Ho3+ -doped fluoride fiber laser at 3 ΞΌm and 2 ΞΌm
Cascade transitions of rare earth ions involved in infrared host fiber provide the potential to generate dual or multiple wavelength lasing at mid-infrared region. In addition, the fast development of saturable absorber (SA) towards the long wavelengths motivates the realization of passively switched mid-infrared pulsed lasers. In this work, by combing the above two techniques, a new phenomenon of passively Q-switched ~3βΞΌm and gain-switched ~2βΞΌm pulses in a shared cavity was demonstrated with a Ho3+-doped fluoride fiber and a specifically designed semiconductor saturable absorber (SESAM) as the SA. The repetition rate of ~2βΞΌm pulses can be tuned between half and same as that of ~3βΞΌm pulses by changing the pump power. The proposed method here will add new capabilities and more flexibility for generating mid-infrared multiple wavelength pulses simultaneously that has important potential applications for laser surgery, material processing, laser radar, and free-space communications, and other areas
Modulation of dendritic spine development and plasticity by BDNF and vesicular trafficking: fundamental roles in neurodevelopmental disorders associated with mental retardation and autism
The process of axonal and dendritic development establishes the synaptic circuitry of the central nervous system (CNS) and is the result of interactions between intrinsic molecular factors and the external environment. One growth factor that has a compelling function in neuronal development is the neurotrophin brain-derived neurotrophic factor (BDNF). BDNF participates in axonal and dendritic differentiation during embryonic stages of neuronal development, as well as in the formation and maturation of dendritic spines during postnatal development. Recent studies have also implicated vesicular trafficking of BDNF via secretory vesicles, and both secretory and endosomal trafficking of vesicles containing synaptic proteins, such as neurotransmitter and neurotrophin receptors, in the regulation of axonal and dendritic differentiation, and in dendritic spine morphogenesis. Several genes that are either mutated or deregulated in neurodevelopmental disorders associated with mental retardation have now been identified, and several mouse models of these disorders have been generated and characterized. Interestingly, abnormalities in dendritic and synaptic structure are consistently observed in human neurodevelopmental disorders associated with mental retardation, and in mouse models of these disorders as well. Abnormalities in dendritic and synaptic differentiation are thought to underlie altered synaptic function and network connectivity, thus contributing to the clinical outcome. Here, we review the roles of BDNF and vesicular trafficking in axonal and dendritic differentiation in the context of dendritic and axonal morphological impairments commonly observed in neurodevelopmental disorders associated with mental retardation
Solonamide B Inhibits Quorum Sensing and Reduces Staphylococcus aureus Mediated Killing of Human Neutrophils
Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a serious human pathogen, and particularly the spread of community associated (CA)-MRSA strains such as USA300 is a concern, as these strains can cause severe infections in otherwise healthy adults. Recently, we reported that a cyclodepsipeptide termed Solonamide B isolated from the marine bacterium, Photobacterium halotolerans strongly reduces expression of RNAIII, the effector molecule of the agr quorum sensing system. Here we show that Solonamide B interferes with the binding of S. aureus autoinducing peptides (AIPs) to sensor histidine kinase, AgrC, of the agr two-component system. The hypervirulence of USA300 has been linked to increased expression of central virulence factors like Ξ±-hemolysin and the phenol soluble modulins (PSMs). Importantly, in strain USA300 Solonamide B dramatically reduced the activity of Ξ±-hemolysin and the transcription of psma encoding PSMs with an 80% reduction in toxicity of supernatants towards human neutrophils and rabbit erythrocytes. To our knowledge this is the first report of a compound produced naturally by a Gram-negative marine bacterium that interferes with agr and affects both RNAIII and AgrA controlled virulence gene expression in S. aureus
Verbal instructions override the meaning of facial expressions
Psychological research has long acknowledged that facial expressions can implicitly trigger affective
psychophysiological responses. However, whether verbal information can alter the meaning of facial
emotions and corresponding response patterns has not been tested. This study examined emotional
facial expressions as cues for instructed threat-of-shock or safety, with a focus on defensive responding.
In addition, reversal instructions were introduced to test the impact of explicit safety instructions on
fear extinction. Forty participants were instructed that they would receive unpleasant electric shocks,
for instance, when viewing happy but not angry faces. In a second block, instructions were reversed
(e.g., now angry faces cued shock). Happy, neutral, and angry faces were repeatedly presented, and
auditory startle probes were delivered in half of the trials. The defensive startle reflex was potentiated
for threat compared to safety cues. Importantly, this effect occurred regardless of whether threat
was cued by happy or angry expressions. Although the typical pattern of response habituation was
observed, defense activation to newly instructed threat cues remained significantly enhanced in the
second part of the experiment, and it was more pronounced in more socially anxious participants.
Thus, anxious individuals did not exhibit more pronounced defense activation compared to less anxious
participants, but their defense activation was more persistent
Patterns of Loss and Regeneration of Tropical Dry Forest in Madagascar: The Social Institutional Context
Loss of tropical forests and changes in land-use/land-cover are of growing concern worldwide. Although knowledge exists about the institutional context in which tropical forest loss is embedded, little is known about the role of social institutions in influencing regeneration of tropical forests. In the present study we used Landsat images from southern Madagascar from three different years (1984, 1993 and 2000) and covering 5500 km(2), and made a time-series analysis of three distinct large-scale patterns: 1) loss of forest cover, 2) increased forest cover, and 3) stable forest cover. Institutional characteristics underlying these three patterns were analyzed, testing the hypothesis that forest cover change is a function of strength and enforcement of local social institutions. The results showed a minor decrease of 7% total forest cover in the study area during the whole period 1984β2000, but an overall net increase of 4% during the period 1993β2000. The highest loss of forest cover occurred in a low human population density area with long distances to markets, while a stable forest cover occurred in the area with highest population density and good market access. Analyses of institutions revealed that loss of forest cover occurred mainly in areas characterized by insecure property rights, while areas with well-defined property rights showed either regenerating or stable forest cover. The results thus corroborate our hypothesis. The large-scale spontaneous regeneration dominated by native endemic species appears to be a result of a combination of changes in precipitation, migration and decreased human population and livestock grazing pressure, but under conditions of maintained and well-defined property rights. Our study emphasizes the large capacity of a semi-arid system to spontaneously regenerate, triggered by decreased pressures, but where existing social institutions mitigate other drivers of deforestation and alternative land-use
Clinically Unapparent Infantile Thiamin Deficiency in Vientiane, Laos
Infantile beriberi, or clinical thiamin (vitamin B1) deficiency in infants, is a forgotten disease in Asia, where 100 years ago it was a major public health problem. Infants with this deficiency, commonly aged βΌ 2β3 months, present in cardiac failure but usually rapidly improve if given thiamin injections. It remains relatively common in Vientiane, Lao PDR (Laos), probably because of prolonged intra- and post-partum food avoidance behaviours. Clinical disease may be the tip of an iceberg with subclinical thiamin deficiency contributing to sickness in infants without overt clinical beriberi. We therefore recruited 778 sick infants admitted during one year at Mahosot Hospital, Vientiane, without clinical evidence of beriberi, and performed erythrocyte transketolase (ETK) assays. 13.4 % of infants had basal ETK<0.59 micromoles/min/gHb suggesting biochemical thiamin deficiency. Mortality was 5.5% but, among infants β₯2 months old, mortality was higher in those with basal ETK<0.59 micromoles/min/gHb (3/47, 6.4%) than in those with basal ETKβ₯0.59 micromoles/min/gHb (1/146, 0.7%) (Pβ=β0.045, relative riskβ=β9.32 (95%CI 0.99 to 87.5)). We conclude that clinically unapparent thiamin deficiency is common among sick infants (β₯2 months old) admitted to hospital in Vientiane. This may contribute to mortality and a low clinical threshold for providing thiamin to sick infants may be needed
GM-CSF drives dysregulated hematopoietic stem cell activity and pathogenic extramedullary myelopoiesis in experimental spondyloarthritis
Dysregulated hematopoiesis occurs in several chronic inflammatory diseases, but it remains unclear how hematopoietic stem cells (HSCs) in the bone marrow (BM) sense peripheral inflammation and contribute to tissue damage in arthritis. Here, we show the HSC gene expression program is biased toward myelopoiesis and differentiation skewed toward granulocyte-monocyte progenitors (GMP) during joint and intestinal inflammation in experimental spondyloarthritis (SpA). GM-CSF-receptor is increased on HSCs and multipotent progenitors, favoring a striking increase in myelopoiesis at the earliest hematopoietic stages. GMP accumulate in the BM in SpA and, unexpectedly, at extramedullary sites: in the inflamed joints and spleen. Furthermore, we show that GM-CSF promotes extramedullary myelopoiesis, tissue-toxic neutrophil accumulation in target organs, and GM-CSF prophylactic or therapeutic blockade substantially decreases SpA severity. Surprisingly, besides CD4+ T cells and innate lymphoid cells, mast cells are a source of GM-CSF in this model, and its pathogenic production is promoted by the alarmin IL-33
Interleukin 12B (IL12B) Genetic Variation and Pulmonary Tuberculosis: A Study of Cohorts from The Gambia, Guinea-Bissau, United States and Argentina
We examined whether polymorphisms in interleukin-12B (IL12B) associate with susceptibility to pulmonary tuberculosis (PTB) in two West African populations (from The Gambia and Guinea-Bissau) and in two independent populations from North and South America. Nine polymorphisms (seven SNPs, one insertion/deletion, one microsatellite) were analyzed in 321 PTB cases and 346 controls from Guinea-Bissau and 280 PTB cases and 286 controls from The Gambia. For replication we studied 281 case and 179 control African-American samples and 221 cases and 144 controls of European ancestry from the US and Argentina. First-stage single locus analyses revealed signals of association at IL12B 3β² UTR SNP rs3212227 (unadjusted allelic pβ=β0.04; additive genotypic pβ=β0.05, ORβ=β0.78, 95% CI [0.61β0.99]) in Guinea-Bissau and rs11574790 (unadjusted allelic pβ=β0.05; additive genotypic pβ=β0.05, ORβ=β0.76, 95% CI [0.58β1.00]) in The Gambia. Association of rs3212227 was then replicated in African-Americans (rs3212227 allelic pβ=β0.002; additive genotypic pβ=β0.05, ORβ=β0.78, 95% CI [0.61β1.00]); most importantly, in the African-American cohort, multiple significant signals of association (seven of the nine polymorphisms tested) were detected throughout the gene. These data suggest that genetic variation in IL12B, a highly relevant candidate gene, is a risk factor for PTB in populations of African ancestry, although further studies will be required to confirm this association and identify the precise mechanism underlying it
- β¦