126 research outputs found
The Impact of HAART on the Respiratory Complications of HIV Infection: Longitudinal Trends in the MACS and WIHS Cohorts
Objective: To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART). Design: Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women's Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively. Methods: Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era. Results: Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2-2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3-1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8-2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02-8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3-1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5-2.4; p<0.001). Conclusion: HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality. © 2013 Gingo et al
HIV Tropism and Decreased Risk of Breast Cancer
During the first two decades of the U.S. AIDS epidemic, and unlike some malignancies, breast cancer risk was significantly lower for women with human immunodeficiency virus (HIV) infection compared to the general population. This deficit in HIV-associated breast cancer could not be attributed to differences in survival, immune deficiency, childbearing or other breast cancer risk factors. HIV infects mononuclear immune cells by binding to the CD4 molecule and to CCR5 or CXCR4 chemokine coreceptors. Neoplastic breast cells commonly express CXCR4 but not CCR5. In vitro, binding HIV envelope protein to CXCR4 has been shown to induce apoptosis of neoplastic breast cells. Based on these observations, we hypothesized that breast cancer risk would be lower among women with CXCR4-tropic HIV infection.We conducted a breast cancer nested case-control study among women who participated in the WIHS and HERS HIV cohort studies with longitudinally collected risk factor data and plasma. Cases were HIV-infected women (mean age 46 years) who had stored plasma collected within 24 months of breast cancer diagnosis and an HIV viral load≥500 copies/mL. Three HIV-infected control women, without breast cancer, were matched to each case based on age and plasma collection date. CXCR4-tropism was determined by a phenotypic tropism assay. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer were estimated by exact conditional logistic regression. Two (9%) of 23 breast cancer cases had CXCR4-tropic HIV, compared to 19 (28%) of 69 matched controls. Breast cancer risk was significantly and independently reduced with CXCR4 tropism (adjusted odds ratio, 0.10, 95% CI 0.002-0.84) and with menopause (adjusted odds ratio, 0.08, 95% CI 0.001-0.83). Adjustment for CD4+ cell count, HIV viral load, and use of antiretroviral therapy did not attenuate the association between infection with CXCR4-tropic HIV and breast cancer.Low breast cancer risk with HIV is specifically linked to CXCR4-using variants of HIV. These variants are thought to exclusively bind to and signal through a receptor that is commonly expressed on hyperplastic and neoplastic breast duct cells. Additional studies are needed to confirm these observations and to understand how CXCR4 might reduce breast cancer risk
Development of an in-vivo active reversible butyrylcholinesterase inhibitor
Alzheimer’s disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the molecular basis of its low nanomolar potency. Additionally, this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD
Detection and Molecular Characterization of 9000-Year-Old Mycobacterium tuberculosis from a Neolithic Settlement in the Eastern Mediterranean
Background: Mycobacterium tuberculosis is the principal etiologic agent of human tuberculosis. It has no environmental reservoir and is believed to have co-evolved with its host over millennia. This is supported by skeletal evidence of the disease in early humans, and inferred from M. tuberculosis genomic analysis. Direct examination of ancient human remains for M. tuberculosis biomarkers should aid our understanding of the nature of prehistoric tuberculosis and the host/pathogen relationship.Methodology/Principal Findings: We used conventional PCR to examine bone samples with typical tuberculosis lesions from a woman and infant, who were buried together in the now submerged site of Atlit-Yam in the Eastern Mediterranean, dating from 9250-8160 years ago. Rigorous precautions were taken to prevent contamination, and independent centers were used to confirm authenticity of findings. DNA from five M. tuberculosis genetic loci was detected and had characteristics consistent with extant genetic lineages. High performance liquid chromatography was used as an independent method of verification and it directly detected mycolic acid lipid biomarkers, specific for the M. tuberculosis complex.Conclusions/Significance: Human tuberculosis was confirmed by morphological and molecular methods in a population living in one of the first villages with evidence of agriculture and animal domestication. The widespread use of animals was not a source of infection but may have supported a denser human population that facilitated transmission of the tubercle bacillus. The similarity of the M. tuberculosis genetic signature with those of today gives support to the theory of a long-term co-existence of host and pathogen
Thyroid and pituitary gland development from hatching through metamorphosis of a teleost flatfish, the Atlantic halibut
Fish larval development, not least the spectacular
process of flatfish metamorphosis, appears to be
under complex endocrine control, many aspects of
which are still not fully elucidated. In order to obtain
data on the functional development of two major
endocrine glands, the pituitary and the thyroid, during
flatfish metamorphosis, histology, immunohistochemistry
and in situ hybridization techniques were applied on
larvae of the Atlantic halibut (Hippoglossus hippoglossus),
a large, marine flatfish species, from hatching
through metamorphosis. The material was obtained
from a commercial hatchery. Larval age is defined as
day-degrees (D =accumulated daily temperature from
hatching). Sporadic thyroid follicles are first detected in
larvae at 142 D (27 days post-hatch), prior to the
completion of yolk sack absorption. Both the number
and activity of the follicles increase markedly after yolk
sack absorption and continue to do so during subsequent
development. The larval triiodothyronine (T3)
and thyroxine (T4) content increases, subsequent to yolk
absorption, and coincides with the proliferation of thyroid
follicles. A second increase of both T3 and T4 occurs
around the start of metamorphosis and the T3 content
further increases at the metamorphic climax. Overall,
the T3 content is lower than T4. The pituitary gland can
first be distinguished as a separate organ at the yolk sack
stage. During subsequent development, the gland becomes
more elongated and differentiates into neurohypophysis (NH), pars distalis (PD) and pars intermedia
(PI). The first sporadic endocrine pituitary cells are observed
at the yolk sack stage, somatotrophs (growth
hormone producing cells) and somatolactotrophs (somatolactin
producing cells) are first observed at 121 D
(23 days post-hatch), and lactotrophs (prolactin producing
cells) at 134 D (25 days post-hatch). Scarce
thyrotrophs are evident after detection of the first thyroid
follicles (142 D ), but coincident with a phase in
which follicle number and activity increase (260 D ).
The somatotrophs are clustered in the medium ventral
region of the PD, lactotrophs in the anterior part of the
PD and somatolactotrophs are scattered in the mid and
posterior region of the pituitary. At around 600 D ,
coinciding with the start of metamorphosis, somatolactotrophs
are restricted to the interdigitating tissue of the
NH. During larval development, the pituitary endocrine
cells become more numerous. The present data on thyroid
development support the notion that thyroid hormones
may play a significant role in Atlantic halibut
metamorphosis. The time of appearance and the subsequent
proliferation of pituitary somatotrophs, lactotrophs,
somatolactotrophs and thyrotrophs indicate at
which stages of larval development and metamorphosis
these endocrine cells may start to play active regulatory
roles.This work has been carried out within the
projects ‘‘Endocrine Control as a Determinant of Larval Quality in
Fish Aquaculture’’ (CT-96-1422) and ‘‘Arrested development: The
Molecular and Endocrine Basis of Flatfish Metamorphosis’’
(Q5RS-2002-01192), with financial support from the Commission
of the European Communities. However, it does not necessarily
reflect the Commission’s views and in no way anticipates its future
policy in this area. This project was further supported by the
Swedish Council for Agricultural and Forestry Research and Pluriannual
funding to CCMAR by the Portuguese Science and
Technology Council
Management education and the theatre of the absurd
In this paper we adopt a humanities perspective to reflect on the nature of business schools and management education (Vargish, 1991; March & Weil, 2005; Adler, 2006; McAuley & Sims, 2009). Business schools have been criticised for becoming the “hired hands” of business (Khurana, 2007) to the detriment of a higher purpose, institutions that champion a utilitarian morality, the shallowness and indeed the dangers of which are revealed in various business scandals and especially the financial crisis of 2007-8, the effects of which cast a long shadow over today’s economic and social landscape. This has led to the criticism that business schools have lost part of their essential “philosophic connection” to issues of humanity and human identities (Augier & March, 2011: 233-4). We argue that one way to encourage philosophical reconnection is to expand management education’s engagement with the humanities (Czarniawska & Gagliardi, 2006)
Genetic Background and Sex: Impact on Generalizability of Research Findings in Pharmacology Studies
Animal models consisting of inbred laboratory rodent strains have been a powerful tool for decades, helping to unravel the underpinnings of biological problems and employed to evaluate potential therapeutic treatments in drug discovery. While inbred strains demonstrate relatively reliable and predictable responses, using a single inbred strain alone or as a background to a mutation is analogous to running a clinical trial in a single individual and their identical twins. Indeed, complex etiologies drive the most common human diseases, and a single inbred strain that is a surrogate of a single genome, or data generated from a single sex, is not representative of the genetically diverse patient populations. Further, pharmacological and toxicology data generated in otherwise healthy animals may not translate to disease states where physiology, metabolism, and general health are compromised. The purpose of this chapter is to provide guidance for improving generalizability of preclinical studies by providing insight into necessary considerations for introducing systematic variation within the study design, such as genetic diversity, the use of both sexes, and selection of appropriate age and disease model. The outcome of implementing these considerations should be that reproducibility and generalizability of significant results are significantly enhanced leading to improved clinical translation
Effects of host switching on gypsy moth ( Lymantria dispar (L.)) under field conditions
Effects of various single and two species diets on the performance of gypsy moth ( Lymantria dispar (L.)) were studied when this insect was reared from hatch to population on intact host trees in the field. The tree species used for this study were red oak ( Quercus rubra L.), white oak (Q. alba L.), bigtooth aspen ( Populus grandidentata Michaux), and trembling aspen ( P. tremuloides Michaux). These are commonly available host trees in the Lake States region. The study spanned two years and was performed at two different field sites in central Michigan. Conclusions drawn from this study include: (1) Large differences in gypsy moth growth and survival can occur even among diet sequences composed of favorable host species. (2) Larvae that spent their first two weeks feeding on red oak performed better during this time period than larvae on all other host species in terms of mean weight, mean relative growth rate (RGR), and mean level of larval development, while larvae on a first host of bigtooth aspen were ranked lowest in terms of mean weight, RGR, and level of larval development. (3) Combination diets do not seem to be inherently better or worse than diets composed of only a single species; rather, insect performance was affected by the types of host species eaten and the time during larval development that these host species were consumed instead of whether larvae ate single species diets or mixed species diets. (4) In diets composed of two host species, measures of gypsy moth performance are affected to different extents in the latter part of the season by the two different hosts; larval weights and development rates show continued effects of the first host fed upon while RGRs, mortality, and pupal weights are affected strongly by the second host type eaten. (5) Of the diets investigated in this study, early feeding on red oak followed by later feeding on an aspen, particularly trembling aspen, is most beneficial to insects in terms of attaining high levels of performance throughout their lives.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47802/1/442_2004_Article_BF00323144.pd
Pinpointing beta adrenergic receptor in ageing pathophysiology: victim or executioner? Evidence from crime scenes
In Vitro Starch Binding Experiments: Study of the Proteins Related to Grain Hardness of Wheat
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