Human 3D multicellular microtissues: An upgraded model for the in vitro mechanistic investigation of inflammation-associated drug toxicity.

Inflammation is one of the factors that may increase the sensitivity of hepatic cells to acetaminophen (APAP) induced toxicity. To investigate the mechanisms, we exposed 3-dimensional (3D) Human Liver Microtissues, a co-culture of primary human hepatocytes (PHH) and Kupffer cells (KCs), to 0, 0.5 (low), 5 (median) and 10 mM (high dose) APAP for 24 h, with/without lipopolysaccharide (LPS). Microarray-technology was used to evaluate the transcriptome changes. In the presence of LPS, the median-dose of APAP is sufficient to inhibit the expression of respiratory chain- and antioxidant-related genes, suggesting the involvement of reactive oxygen species (ROS) and oxidative stress. Furthermore, the median- and high-dose of APAP inhibited the expression of Fc fragment receptor (FcγR)-coding genes, regardless of the presence of LPS. The toll-like receptor 4 (TLR4) expression, however, was continuously elevated after the LPS/APAP co-exposures, which may result in reduced KC-phagocytosis and unbalanced cytokine patterns. Compared to the treatment with LPS only, LPS/APAP co-exposures induced the production of interleukin (IL)-8, a pro-inflammatory cytokine, but suppressed the secretion of IL-6, a cytokine regulating hepatic regeneration, along with the increase in APAP dosages. In addition to the disrupted mitochondrial functions, the presence of LPS exacerbated APAP toxicity. These findings suggest that 3D Microtissues are a suitable model for the mechanistic exploration of inflammation-associated drug toxicity.

Multi-cell type human liver microtissues for hepatotoxicity testing.

Current 2-dimensional hepatic model systems often fail to predict chemically induced hepatotoxicity due to the loss of a hepatocyte-specific phenotype in culture. For more predictive in vitro models, hepatocytes have to be maintained in a 3-dimensional environment that allows for polarization and cell-cell contacts. Preferably, the model will reflect an in vivo-like multi-cell type environment necessary for liver-like responses. Here, we report the characterization of a multi-cell type microtissue model, generated from primary human hepatocytes and liver-derived non-parenchymal cells. Liver microtissues were stable and functional for 5 weeks in culture enabling, for example, long-term toxicity testing of acetaminophen and diclofenac. In addition, Kupffer cells were responsive to inflammatory stimuli such as LPS demonstrating the possibility to detect inflammation-mediated toxicity as exemplified by the drug trovafloxacin. Herewith, we present a novel 3D liver model for routine testing in 96-well format capable of reducing the risk of unwanted toxic effects in the clinic.

Long-term results of screening with magnetic resonance imaging in women with BRCA mutations.

BACKGROUND: The addition of breast magnetic resonance imaging (MRI) to screening mammography for women with BRCA mutations significantly increases sensitivity, but there is little data on clinical outcomes. We report screening performance, cancer stage, distant recurrence rate, and breast cancer-specific mortality in our screening study. METHODS: From 1997 to 2009, 496 women aged 25 to 65 years with a known BRCA1/2 mutation, of whom 380 had no previous cancer history, were enrolled in a prospective screening trial that included annual MRI and mammography. RESULTS: In 1847 screening rounds, 57 cancers were identified (53 screen-detected, 1 interval, and 3 incidental at prophylactic mastectomy), of which 37 (65%) were invasive. Sensitivity of MRI vs mammography was 86% vs 19% over the entire study period (P<0.0001), but was 74% vs 35% from 1997 to 2002 (P=0.02) and 94% vs 9% from 2003 to 2009 (P<0.0001), respectively. The relative sensitivities of MRI and mammography did not differ by mutation, age, or invasive vs non-invasive disease. Of the incident cancers, 97% were Stage 0 or 1. Of 28 previously unaffected women diagnosed with invasive cancer, 1 BRCA1 mutation carrier died following relapse of a 3 cm, node-positive breast cancer diagnosed on her first screen at age 48 (annual breast cancer mortality rate=0.5%). Three patients died of other causes. None of the 24 survivors has had a distant recurrence at a median follow-up of 8.4 years since diagnosis. CONCLUSION: Magnetic resonance imaging surveillance of women with BRCA1/2 mutations will detect the majority of breast cancers at a very early stage. The absence of distant recurrences of incident cancers to date is encouraging. However, longer follow-up is needed to confirm the safety of breast surveillance.

Not 'Islands, Entire of Themselves': Exploring the Spatial Context of City-level Robbery Rates.

The current study examines spatial dependence in robbery rates for a sample of 1,056 cities with 25,000 or more residents over the 2000-2003 period. Although commonly considered in some macro-level research, spatial processes have not been examined in relation to city-level variation in robbery. The results of our regression analyses suggest that city robbery rates are not spatially independent. We find that spatial dependence is better accounted for by spatial error models than by spatial lag models. Further exploration of various spatial weights matrices indicates that robbery rates of cities within the same state are related to robbery rates of other cities within the same state, regardless of their proximity. Our analyses illustrate how systematic inquiry into spatial processes can alert researchers to important omitted variable biases and identify intriguing problems for future research.

Microfluidics: an opportunity for trend-setting drug delivery.

The past has demonstrated that when working with microfluidics only the following scenario is likely to lead to successful system development: a high level of component integration at an early development stage with an application-specific, simple (reliable) design, and a high interdisciplinary level of know-how over a broad range of technologies, pharmacology and medicine. The mere application of existing nonspecifically designed or outsourced microfluidic components is likely to fail because the system behaviour in the microworld is far different from that in the macroworld.

Why do some women bypass their family physician in seeking preventive care?: a qualitative study [abstract]

The Health Watch clinic at Women's College Hospital, Toronto, provides screening and preventive services primarily to women in Ontario. These services can be seen as a duplication of those that can be provided by family physicians. Nevertheless, some Ontario women continue to bypass their family physicians and attend this clinic. This study was done to understand the decision-making processes women go through in deciding to bypass their family physician when seeking preventive health services and to understand which features of this model of preventive care are so attractive. Seventeen women attending the Health Watch Clinic agreed to participate. In-depth interviews were carried out until saturation was achieved. The interviews were taped and later transcribed. The data were analyzed using qualitative methods, specifically, grounded in theory. Emergent themes were extracted while listening to tapes and reading transcripts. Themes were discussed between researchers and an agreement was arrived at. These themes were relayed back to participants to confirm interpretation. The emerging themes suggest that women bypass the family physician for several reasons, including: "Women negative" experiences, the inherent qualities of the woman, such as her locus of control, normative influences, and perceived positive aspects of the Health Watch Clinic and the Women's College Hospital. The findings suggest that women who bypass their family doctor have generally had a negative experience with the traditional healthcare system. The women in this study were highly educated with high internal motivation and tended to have extensive family and friend support and advice regarding health matters. (AU)

Evolution of reduced dispersal mortality and 'fat-tailed' dispersal kernels in autocorrelated landscapes.

Models describing the evolution of dispersal strategies have mostly focused on the evolution of dispersal rates. Taking trees as a model for organisms with undirected, passive dispersal, we have developed an individual-based, spatially explicit simulation tool to investigate the evolution of the dispersal kernel, P(r), and its resulting cumulative seed-density distribution, D(r). Simulations were run on a variety of fractal landscapes differing in the fraction of suitable habitat and the spatial autocorrelation. Starting from a uniform D(r), evolution led to an increase in the fraction of seeds staying in the home cell, a reduction of the dispersal mortality (arrival in unsuitable habitat), and the evolution of 'fat-tailed' D(r) in autocorrelated landscapes and approximately uniform D(r) in random landscapes. The evolutionary process was characterized by long periods of stasis with a few bouts of rapid change in the dispersal rate.

Alcohol and crime in China.

This study examines the pattern of alcohol involvement across violent and property crimes in China. We describe and discuss the cultural and biological differences between Chinese and Westerners concerning alcohol and the features of Chinese culture concerning violence. Drawing upon the disinhibition perspective in alcohol and crime, a specific hypothesis derived from the sociocultural context of Chinese society is that alcohol is more likely to be involved with violent crime than with property crime. Using data from a survey of inmates in China, we assess this hypothesis and the possible variables that may moderate this hypothesis. The data support the hypothesis that disinhibition is applicable to the alcohol-violence relationship in Chinese culture. However, the predicted pattern of alcohol use in violent and property crimes does not vary across different offender groups, which is inconsistent with some United States research. A tentative explanation is provided for this inconsistency.

Immunomodulatory action of G-CSF in a rat model of endotoxin-induced liver injury: an intravital microscopic analysis of Kupffer cell and leukocyte response.

In contrast to the anticipation that in sepsis granulocyte colony-stimulating factor (G-CSF) would overactivate the nonspecific immune system by recruiting and priming leukocytes with consequent aggravation of inflammatory tissue lesions, recombinant (r) G-CSF pretreatment was protective in various experimental non-neutropenic models of inflammation. The mechanisms of protection, however, are not fully understood. Using intravital fluorescence microscopy, we show that rG-CSF enhances leukocyte endothelial cell interaction within the microvasculature of normal rat livers, whereas rG-CSF pretreatment of animals exposed to lipopolysaccharide (LPS) attenuates the LPS-induced leukocytic response, including stasis in sinusoids as well as rolling and adherence in postsinusoidal venules with subsequent tissue infiltration. Moreover, rG-CSF, which did not affect Kupffer cell activity in normal rat livers, reduced the immediate activation of Kupffer cells on LPS exposure, as indicated in vivo by the delayed adherence/phagocytosis of intra-arterially administered latex particles associated with attenuation of proinflammatory cytokine release (tumor necrosis factor alpha and interleukin-6). Finally, rG-CSF reduced LPS-induced nutritive perfusion failure and hepatocellular excretory dysfunction. This study provides evidence for a distinct, possibly tumor necrosis factor alpha-dependent modulation of LPS-induced cellular response within the liver by rG-CSF, thereby achieving protection against microcirculatory perfusion failure and hepatic dysfunction.

The influences of cognitive resources on adaptation and old age.

In the Georgia Centenarian Study, cognitive resources were estimated by fluid and crystallized intelligence, acquisition and retrieval of new information, retrieval of familiar information, and problem-solving ability in community-dwelling and nondemented adults ranging from sixty to one hundred plus years of age. Five clusters of results were found: 1) cognitive performances were lower for the older cohorts; 2) when cognitive activities were dependent on everyday experiences, no age-related problem-solving decline was found; 3) physical health and mental health can significantly influence cognitive performances; 4) cognitive and personality factors can combine to account for a larger amount of adaptation variance than can be accounted for by either of the factors alone; and 5) individuals with a high level of intelligence and affect sustain their instrumental activities of daily living. Cognitive resources were an important contributor to successful adaptation for the oldest-old.

Research on cultural and socioeconomic factors in criminal violence.

This article has discussed two particularly influential approaches to the explanation of the role of social factors in criminal violence. One of these approaches emphasizes cultural orientations and the other, socioeconomic deprivation. The cultural perspective depicts criminal violence as the outcome of normal processes of social learning. Certain groups allegedly endorse values that are supportive of violent behavior. Consequently, well-socialized members of these groups are predisposed to employ violence as a means for dealing with common, interpersonal disputes. One variant of the cultural approach, the "thesis of a subculture of violence," has been used to explain the high rates of criminal violence that have been widely observed for certain sociodemographic groups in society. A similar type of argument has been formulated to account for high levels of homicide in the southern part of the United States. In this latter argument, a "regional culture of violence" has been hypothesized. Both of these arguments describe values supportive of violence as being deviant from the dominant values of society. A third cultural approach attributes violent behavior to values favorable to violence that are part of the dominant culture. The research pertaining to these cultural arguments is best described as inconclusive. In general, stronger support for the cultural perspective can be found in the qualitative evidence in comparison with the quantitative data. This may reflect the difficulties in devising truly satisfactory, quantitative measures of cultural orientations. The cultural approach nevertheless continues to be regarded by many as a useful way of explaining the social distribution of violent crime largely because of the supportive qualitative evidence and the rather compelling logic of the substantive arguments. The socioeconomic approach offers a slightly different explanation for violent crime. The key causal factors here are not so much positive cultural evaluations of violence but hardships and deprivations. In an important sense, individuals are viewed as being driven to violence because of their unfortunate location in the social structure. These socioeconomic approaches have directed attention to poverty, general economic inequality, and inequality based on ascribed characteristics such as race. The research in the socioeconomic perspectives is also mixed, but some general patterns appear. Measures of socioeconomic deprivation are typically related to indicators of criminal violence in the theoretically expected manner, even though statistical significance is often problematic.(ABSTRACT TRUNCATED AT 400 WORDS)

Determination of spectinomycin dihydrochloride by liquid chromatography with electrochemical detection.

Spectinomycin dihydrochloride is determined by liquid chromatography with electrochemical detection. The drug is chromatographed on a reverse-phase Nucleosil C18 column using an eluent containing 0.02 M sodium citrate and 0.0015 M octyl sodium sulfate (pH 6.10 with perchloric acid) and acetonitrile (100:4). Detection is performed using a coulometric detector (porous carbon working electrode) at +0.85 V. The drug and primary degradation product are detectable. Detector response is linear to at least 20 micrograms/ml, which is four times the assay level. The procedure has relative standard deviations of +/- 1.21 to +/- 2.72% for three lots of bulk drug. Sensitivity is greater than 0.1 microgram/ml of spectinomycin (5 ng on column). Repeatability at this level is +/- 4.94%.

Idiopathic preretinal fibrosis with concurrent cystoid macular edema.

Idiopathic preretinal fibrosis is a common disorder which typically affects elderly individuals. The epiretinal membranes are of glial origin in the retina where they migrate through breaks in the internal limiting membrane to form fibroglial sheets on the surface of the retina. Although visual symptomatology is rare, the epiretinal membranes may, in some instances, grow rapidly and contract causing tractional changes to occur involving the underlying retina and retinal vessels. This paper presents a case of preretinal fibrosis with accompanying cystoid macular edema and consequent dramatically reduced vision. The diagnosis, pathophysiology and management of preretinal fibrosis are discussed.

A study of homicides in Manhattan, 1981.

There were 573 persons murdered in Manhattan (New York) during 1981 for an overall rate of 40.5 per 100,000 population. The male, young, and Black or Latino populations were at higher risk of being homicide victims. For male victims, the homicides were the result of disputes in 37.6 per cent of the cases, drug-related activities in 37.6 per cent, and robbery and other criminal activities in 24.8 per cent of cases. For female victims, homicides resulted from disputes in 62.2 per cent of cases, drug-related activities in 13.8 per cent, and robberies in 20.0 per cent of cases. The observed proportion of homicides related to drug and other criminal activities was higher than has been reported previously in the United States. The role of alcohol continued to be important in homicides related to disputes. The authors stress the importance of differentiating drug-related homicides from those associated with other criminal activities.

Differentiating opioids by their pupillary effects in the rat.

Pupillary effects of several opioids were examined as part of a broader in vivo study of multiple opioid receptors in the rat. Agonist activity, stereospecificity, and naloxone sensitivity were determined by methadone (Me), ethylketocyclazocine (EK), and N-allylnormetazocine (SKF 10,047), selected for their purportedly predominant actions at mu, kappa, and sigma receptors, respectively. After an acute, subcutaneous injection of each drug, pupil area and fluctuations in pupil size were measured by means of an infrared video pupillometer on line with a microcomputer data processing and storage system. Despite differences in the magnitude of the response, each opioid tested produced an increase in pupil size which was stereospecific, independent of behavioral responses to the drugs and, for 1-Me and 1-SKF 10,047, dose-related. Other differences among the opioids were found in their ability to induce fluctuations (1-Me and 1-EK) and a pendular nystagmus (1-SKF 10,047 only), and in their sensitivity to naloxone. Although 1.0 mg/kg naloxone completely reversed 1-Me-induced mydriasis, 10 mg/kg was needed to reverse 1-EK, and this dose only partially antagonized 1-SKF 10,047. These characteristic patterns of pupillary responses to opioids in terms of agonist activities and naloxone sensitivities indicate that the different opioid receptor types subserve different functions with respect to pupillary control.