Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes

The integrase inhibitor (INI) dolutegravir (DTG; S/GSK1349572) has significant activity against HIV-1 isolates with raltegravir (RAL)- and elvitegravir (ELV)-associated resistance mutations. As an initial step in characterizing the different resistance profiles of DTG, RAL, and ELV, we determined the dissociation rates of these INIs with integrase (IN)-DNA complexes containing a broad panel of IN proteins, including IN substitutions corresponding to signature RAL and ELV resistance mutations. DTG dissociates slowly from a wild-type IN-DNA complex at 37°C with an off-rate of 2.7 × 10(-6) s(-1) and a dissociative half-life (t(1/2)) of 71 h, significantly longer than the half-lives for RAL (8.8 h) and ELV (2.7 h). Prolonged binding (t(1/2), at least 5 h) was observed for DTG with IN-DNA complexes containing E92, Y143, Q148, and N155 substitutions. The addition of a second substitution to either Q148 or N155 typically resulted in an increase in the off-rate compared to that with the single substitution. For all of the IN substitutions tested, the off-rate of DTG from IN-DNA complexes was significantly slower (from 5 to 40 times slower) than the off-rate of RAL or ELV. These data are consistent with the potential for DTG to have a higher genetic barrier to resistance, provide evidence that the INI off-rate may be an important component of the mechanism of INI resistance, and suggest that the slow dissociation of DTG may contribute to its distinctive resistance profile.     

Risk factors for adult-onset asthma: A 14-year longitudinal study

Background and objectives:   Few longitudinal studies have examined the risk factors and natural history of adult-onset asthma. This study assessed the subject characteristics and lifestyle factors that predicted the new diagnosis of asthma in adulthood and how these factors changed over time in those who developed asthma compared with those who do not.
Methods:   The study enrolled 1554 adults from the Busselton Health Study seen in 1981 and again in 1994–1995 who initially reported never having had doctor-diagnosed asthma. Questionnaire measures were used to assess doctor-diagnosed asthma, respiratory history and tobacco smoking. Height, weight and spirometric measures of lung function were measured. Atopy was assessed by skin prick tests. Logistic regression analysis was used to identify risk factors for adult-onset asthma and changes over time.
Results:   Reported wheeze, rhinitis, chronic cough, smoking and lower levels of lung function in 1981 each predicted asthma diagnosis by 1994–1995. Neither initial skin-prick reactivity nor newly positive skin-prick tests at follow up were associated with adult-onset asthma. Those diagnosed with asthma were more likely to have new wheeze, new rhinitis, new habitual snoring, weight gain and excess decline in lung function.
Conclusions:   Adult-onset asthma has risk factors that are distinct from those observed in childhood asthma. The presence of upper airway symptoms including rhinitis, as well as lifestyle factors, such as smoking, predicts those at greatest risk. However, neither pre-existing atopy nor new atopy as measured by skin prick tests was associated with adult-onset asthma.     

Mercury Concentrations in Fish Jerky Snack Food: Marlin, Ahi, and Salmon

Background

Dried meat and fish have served as an important durable nutrition source for humans for centuries. Because omega 3 fatty acids in fish are recognized as having antioxidant and anti inflammatory properties found to be beneficial for good health, many consumers are looking to fish as their main source of protein. Unfortunately, contaminants such as methylmercury can accumulate in some species of fish. The purpose of this research is to test commercially available fish jerky snack foods for mercury contamination.

Methods

Fifteen bags of marlin jerky, three bags of ahi jerky, and three bags of salmon jerky were purchased from large retail stores in Hawaii and California, and directly from the proprietors' Internet websites. Five individual strips of jerky per bag were analyzed for a total of one hundred and five tests.

Results

From the seventy-five marlin jerky samples, mercury concentration ranged from 0.052-28.17 μg/g, with an average of 5.53 μg/g, median 4.1 μg/g. Fifty-six (75%) marlin samples had mercury concentrations that exceeded the FDA's current mercury action level of 1.0 μg/g, while six samples had greater than 10 μg/g. Fifteen samples of ahi had mercury concentrations ranging from 0.09-0.55 μg/g, while mercury concentrations in fifteen salmon samples ranged from 0.030-0.17 μg/g.

Conclusions

This study found that mercury concentrations in some fish jerky can often exceed the FDA's allowable mercury limit and could be a significant source of mercury exposure.     

Psychosocial characteristics of subtle and blatant racists as compared to tolerant individuals

Studies in psychology have demonstrated that tolerant individuals demonstrate good psychological health and prejudiced individuals demonstrate poor psychosocial functioning. Past investigations have shown disturbances in interpersonal relationships for prejudiced individuals in childhood. Blatant racists aggressively assert that members of minority groups are inferior. Subtle racists blame social inequities on minority group cultures and customs. A questionnaire to distinguish tolerant individuals from blatant and subtle racists was employed. Tolerant individuals were shown to be psychologically healthier than both blatant and subtle racists. Both blatant and subtle racists show maladaptive patterns in psychosocial functioning. Both blatant and subtle racists report predicted disturbances in parental relationships, as well as insecure and hostile ties with peers. © 1997 John Wiley & Sons, Inc. J Clin Psychol 53 : 369–374, 1997.     

CD34+ human marrow cells that express low levels of Kit protein are enriched for long-term marrow-engrafting cells

Using in utero transplantation into fetal sheep, we examined the capability of human bone marrow CD34+ cells fractionated based on Kit protein expression to provide long-term in vivo engraftment. Twelve hundred to 5,000 CD34+ Kit-, CD34+ Kit(low), and CD34+ Kit(high) cells were injected into a total of 14 preimmune fetal sheep recipients using the amniotic bubble technique. Six fetuses were killed in utero 1.5 months after bone marrow cell transplantation. Two fetuses receiving CD34+ Kit(low) cells showed signs of engraftment according to analysis of CD45+ cells in their bone marrow cells and karyotype studies of the colonies grown in methylcellulose culture. In contrast, two fetuses receiving CD34+ Kit(high) cells and two fetuses receiving CD34+ Kit- cells failed to show evidence of significant engraftment. Two fetuses were absorbed. A total of six fetuses receiving different cell populations were allowed to proceed to term, and the newborn sheep were serially examined for the presence of chimerism. Again, only the two sheep receiving CD34+ Kit(low) cells exhibited signs of engraftment upon serial examination. Earlier in studies of murine hematopoiesis, we have shown stage-specific changes in Kit expression by the progenitors. The studies of human cells reported here are in agreement with observations in mice, and indicate that human hematopoietic stem cells are enriched in the Kit(low) population.     

Digital imaging of the chest

During the past several years, image acquisition in nuclear medicine, computed tomography, ultrasonography, subtraction angiography, and magnetic resonance has been by digitization. Despite these advances, research in the development of digital imaging in conventional radiography has lagged behind. Although studies with a variety of digital techniques have been carried out on several fronts, we still do not possess a method that has captured the imagination of the majority of radiologists and other physicians to a point where it could replace conventional screen-film imaging. This article reviews the current status and general principles of the technology, focusing on the four digital radiographic techniques that have shown the greatest promise - film digitization, an image intensifier - based system, photostimulable phosphor plates, and a scanned projection system. The physical aspects of each of the four systems and the clinical results that have been reported to date, as well as the advantages and disadvantages of each system, are presented.     

Computer graphics for digitally formatted images

The increasing use of digitally formatted imaging systems requires high-quality interactive gray-scale computer raster graphics systems for the management, display, and analog film recording of digital image and alphanumeric information. These systems are a combination of computer hardware and software and implement a set of graphics protocols. This paper describes a set of interactive graphics protocols that has been developed for clinical use.