bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduced Maximal Inhibition in Phenotypic Susceptibility Assays Indicates that Viral Strains Resistant to the CCR5 Antagonist Maraviroc Utilize Inhibitor-Bound Receptor for Entry
Authors: Westby Mike , Smith-Burchnell Caroline , Mori Julie , Lewis Marilyn , Mosley Michael , Stockdale Mark , Dorr Patrick , Ciaramella Giuseppe , Perros Manos 
Published: December 2006

ABSTRACT
Maraviroc is a CCR5 antagonist in clinical development as one of a new class of antiretrovirals targeting human immunodeficiency virus type 1 (HIV-1) coreceptor binding. We investigated the mechanism of HIV resistance to maraviroc by using in vitro sequential passage and site-directed mutagenesis. Serial passage through increasing maraviroc concentrations failed to select maraviroc-resistant variants from some laboratory-adapted and clinical isolates of HIV-1. However, high-level resistance to maraviroc was selected from three of six primary isolates passaged in peripheral blood lymphocytes (PBL). The SF162 strain acquired resistance to maraviroc in both treated and control cultures; all resistant variants were able to use CXCR4 as a coreceptor. In contrast, maraviroc-resistant virus derived from isolates CC1/85 and RU570 remained CCR5 tropic, as evidenced by susceptibility to the CCR5 antagonist SCH-C, resistance to the CXCR4 antagonist AMD3100, and an inability to replicate in CCR5 Δ32/Δ32 PBL. Strain-specific mutations were identified in the V3 loop of maraviroc-resistant CC1/85 and RU570. The envelope-encoding region of maraviroc-resistant CC1/85 was inserted into an NL4-3 background. This recombinant virus was completely resistant to maraviroc but retained susceptibility to aplaviroc. Reverse mutation of gp120 residues 316 and 323 in the V3 loop (numbering from HXB2) to their original sequence restored wild-type susceptibility to maraviroc, while reversion of either mutation resulted in a partially sensitive virus with reduced maximal inhibition (plateau). The plateaus are consistent with the virus having acquired the ability to utilize maraviroc-bound receptor for entry. This hypothesis was further corroborated by the observation that a high concentration of maraviroc blocks the activity of aplaviroc against maraviroc-resistant virus.
Enhancement of Hepatitis B Virus Replication by the Regulatory X Protein In Vitro and In Vivo
Authors: Keasler Victor V. , Hodgson Amanda J. , Madden Charles R. , Slagle Betty L. 
Published: December 2006

ABSTRACT
The 3.2-kb hepatitis B virus (HBV) genome encodes a single regulatory protein termed HBx. While multiple functions have been identified for HBx in cell culture, its role in virus replication remains undefined. In the present study, we combined an HBV plasmid-based replication assay with the hydrodynamic tail vein injection model to investigate the function(s) of HBx in vivo. Using a greater-than-unit-length HBV plasmid DNA construct (payw1.2) and a similar construct with a stop codon at position 7 of the HBx open reading frame (payw1.2*7), we showed that HBV replication in transfected HepG2 cells was reduced 65% in the absence of HBx. These plasmids were next introduced into the livers of outbred ICR mice via hydrodynamic tail vein injection. At the peak of virus replication, at 4 days postinjection, intrahepatic markers of HBV replication were reduced 72% to 83% in mice injected with HBx-deficient payw1.2*7 compared to those measured in mice receiving wild-type payw1.2. A second plasmid encoding HBx was able to restore virus replication from payw1.2*7 to wild-type levels. Finally, viremia was monitored over the course of acute virus replication, and at 4 days postinjection, it was reduced by nearly 2 logs in the absence of HBx. These studies establish that the role for HBx in virus replication previously shown in transfected HepG2 cells is also apparent in the mouse liver within the context of acute hepatitis. Importantly, the function of HBx can now be studied in an in vivo setting that more closely approximates the cellular environment for HBV replication.
Cytosolic Prion Protein Toxicity Is Independent of Cellular Prion Protein Expression and Prion Propagation
Authors: Norstrom Eric M. , Ciaccio Mark F. , Rassbach Benjamin , Wollmann Robert , Mastrianni James A. 
Published: December 2006

ABSTRACT

Prion diseases are transmissible neurodegenerative diseases caused by a conformational isoform of the prion protein (PrP), a host-encoded cell surface sialoglycoprotein. Recent evidence suggests a cytosolic fraction of PrP (cyPrP) functions either as an initiating factor or toxic element of prion disease. When expressed in cultured cells, cyPrP acquires properties of the infectious conformation of PrP (PrP
Sc
), including insolubility, protease resistance, aggregation, and toxicity. Transgenic mice (2D1 and 1D4 lines) that coexpress cyPrP and PrP
C
exhibit focal cerebellar atrophy, scratching behavior, and gait abnormalities suggestive of prion disease, although they lack protease-resistant PrP. To determine if the coexpression of PrP
C
is necessary or inhibitory to the phenotype of these mice, we crossed Tg1D4(
Prnp

+/+

) mice with PrP-ablated mice (Tg
Prnp
o/o
) to generate Tg1D4(
Prnp
o/o
) mice and followed the development of disease and pathological phenotype. We found no difference in the onset of symptoms or the clinical or pathological phenotype of disease between Tg1D4(
Prnp

+/+

) and Tg1D4(
Prnp
o/o
) mice, suggesting that cyPrP and PrP
C
function independently in the disease state. Additionally, Tg1D4(
Prnp
o/o
) mice were resistant to challenge with mouse-adapted scrapie (RML), suggesting cyPrP is inaccessible to PrP
Sc
. We conclude that disease phenotype and cellular toxicity associated with the expression of cyPrP are independent of PrP
C
and the generation of typical prion disease.
Role of Host Cytokine Responses in the Pathogenesis of Avian H5N1 Influenza Viruses in Mice
Authors: Szretter Kristy J. , Gangappa Shivaprakash , Lu Xuihua , Smith Chalanda , Shieh Wun-Ju , Zaki Sherif R. , Sambhara Suryaprakash , Tumpey Terrence M. , Katz Jacqueline M. 
Published: December 2006

ABSTRACTHighly pathogenic avian H5N1 influenza viruses are now widespread in poultry in Asia and have recently spread to some African and European countries. Interspecies transmission of these viruses to humans poses a major threat to public health. To better understand the basis of pathogenesis of H5N1 viruses, we have investigated the role of proinflammatory cytokines in transgenic mice deficient in interleukin-6 (IL-6), macrophage inflammatory protein 1 alpha (MIP-1α), IL-1 receptor (IL-1R), or tumor necrosis factor receptor 1 (TNFR1) by the use of two avian influenza A viruses isolated from humans, A/Hong Kong/483/97 (HK/483) and A/Hong Kong/486/97 (HK/486), which exhibit high and low lethality in mice, respectively. The course of disease and the extent of virus replication and spread in IL-6- and MIP-1α-deficient mice were not different from those observed in wild-type mice during acute infection with 1,000 50% mouse infective doses of either H5N1 virus. However, with HK/486 virus, IL-1R-deficient mice exhibited heightened morbidity and mortality due to infection, whereas no such differences were observed with the more virulent HK/483 virus. Furthermore, TNFR1-deficient mice exhibited significantly reduced morbidity following challenge with either H5N1 virus but no difference in viral replication and spread or ultimate disease outcome compared with wild-type mice. These results suggest that TNF-α may contribute to morbidity during H5N1 influenza virus infection, while IL-1 may be important for effective virus clearance in nonlethal H5N1 disease.
Uterine tumour resembling ovarian sex cord tumour is an immunohistochemically polyphenotypic neoplasm which exhibits coexpression of epithelial, myoid and sex cord markers
Authors: Hurrell D P , McCluggage W G 
Published: December 2006

Aims:To describe the clinicopathological and immunohistochemical findings in four cases of uterine tumour resembling ovarian sex cord tumour (UTROSCT).Methods:Four UTROSCTs were stained with a wide range of antibodies, including epithelial (AE1/3, epithelial membrane antigen), myoid (desmin, α smooth muscle actin, h-caldesmon), sex cord (α inhibin, calretinin, melan A, CD99) and neuroendocrine (chromogranin, CD56) markers as well as hormone receptors (oestrogen receptor, progesterone receptor, androgen receptor), vimentin, CD10, WT1 and HMB45.Results:The tumours ranged from 0.8 to 19.5 cm. Three were relatively well circumscribed intramural myometrial lesions; the other was a pedunculated mass attached to the uterine serosa. The tumours were variably composed of solid, corded, trabecular, nested, glandular and retiform arrangements of tumour cells. In three cases, cells with eccentric nuclei and abundant eosinophilic cytoplasm, resulting in a rhabdoid appearance, were a prominent feature. Three cases were diffusely positive with AE1/3 and all with epithelial membrane antigen. Positivity with myoid markers was common with 3, 4 and 1 case respectively staining with desmin, α smooth muscle actin and h-caldesmon; 2, 4, 1 and 2 cases respectively were positive with α inhibin, calretinin, melan A and CD99. All were chromogranin negative and exhibited diffuse strong staining with CD56. All were diffusely positive with oestrogen receptor, progesterone receptor, vimentin and WT1. Three cases were androgen receptor positive and all were CD10 and HMB45 negative.Conclusions:UTROSCT exhibits a polyphenotypic immunophenotype with coexpression of markers of epithelial, myoid and sex cord lineage as well as hormone receptors.
Percutaneous absorption of aromatic amines in rubber industry workers: impact of impaired skin and skin barrier creams
Authors: Korinth G , Weiss T , Penkert S , Schaller K H , Angerer J , Drexler H 
Published: December 2006

Background:Several aromatic amines (AA) could cause bladder cancer and are an occupational hygiene problem in the workplace. However, little is known about the percutaneous absorption of chemicals via impaired skin and about the efficacy of skin protection measures to reduce internal exposure.Aims:To determine the impact of skin status and of skin protection measures on the internal exposure to AA in workers manufacturing rubber products.Methods:51 workers occupationally exposed to aniline and o-toluidine were examined. The workplace conditions, risk factors for skin and the use of personal protective equipment were assessed by means of a self-administered questionnaire. The skin of hands and forearms was clinically examined. Exposure to aniline and o-toluidine was assessed by ambient air and biological monitoring (analyses of urine samples and of haemoglobin adducts).Results:Haemoglobin-AA-adduct levels in workers with erythema (73%) were significantly higher (p<0.04) than in workers with healthy skin (mean values: aniline 1150.4 ng/l vs 951.7 ng/l, o-toluidine 417.9 ng/l vs 118.3 ng/l). The multiple linear regression analysis showed that wearing gloves significantly reduced the internal exposure. A frequent use of skin barrier creams leads to a higher internal exposure of AA (p<0.03). However, the use of skincare creams at the workplace was associated with a reduced internal exposure (p<0.03). From these findings we assume that internal exposure of the workers resulted primarily from the percutaneous uptake.Conclusions:The study demonstrates a significantly higher internal exposure to AA in workers with impaired skin compared with workers with healthy skin. Daily wearing of gloves efficiently reduced internal exposure. However, an increased use of skin barrier creams enhances the percutaneous uptake of AA. Skincare creams seem to support skin regeneration and lead to reduced percutaneous uptake.
Pain tolerance in patients presenting to primary care and physiotherapy services with upper limb disorders: Table 1
Authors: Ryall Claire , Coggon David , Peveler Robert , Reading Isabel , Palmer Keith T 
Published: December 2006

Background:Arm pain is a common cause of incapacity for work and is often attributed to occupational activities, but in many cases the pathogenesis is unclear.Objective:To investigate whether arm pain in the absence of identifiable underlying pathology is associated with reduced tolerance of painful sensory stimuli.Methods:133 incident cases of arm pain, recruited from primary care and physiotherapy services, were classified according to a validated diagnostic algorithm. Pain tolerance was measured at three sites in each arm in response to electrocutaneous stimulation. Associations with pain tolerance (the geometric mean of the six measurements at 5 Hz) were assessed by linear regression, and findings were summarised as proportional changes in pain tolerance.Results:Pain tolerance was generally lower than in an earlier community survey. Women had a lower tolerance than men. After allowance for sex, age, use of analgesics and anatomical extent of pain, there was no indication of reduced tolerance in patients with non-specific pain relative to those with specific local pathology.Conclusions:Pain tolerance may be generally reduced in patients presenting to medical services with arm pain, but those with non-specific pain do not seem to have lower tolerance than those with identifiable local pathology.
Pesticides and other agricultural factors associated with self-reported farmer’s lung among farm residents in the Agricultural Health Study
Authors: Hoppin Jane A , Umbach David M , Kullman Greg J , Henneberger Paul K , London Stephanie J , Alavanja Michael C R , Sandler Dale P 
Published: December 2006

Background:Farmer’s lung, or hypersensitivity pneumonitis, is an important contributor to respiratory morbidity among farmers.Methods:Using the 1993–7 enrolment data from the Agricultural Health Study, we conducted a cross-sectional study of occupational risk factors for farmer’s lung among ∼50 000 farmers and farm spouses in Iowa and North Carolina using hierarchical logistic regression controlling for age, state, and smoking status. Participants provided information on agricultural exposures, demographic characteristics, and medical history via self-administered questionnaires. Approximately 2% of farmers (n = 481) and 0.2% of spouses (n = 51) reported doctor-diagnosed farmer’s lung during their lifetime. We assessed farmers and spouses separately due to different information on occupational exposure history. Only pesticide exposures represented lifetime exposure history, all other farm exposures represented current activities at enrolment.Results:Among farmers, handling silage (OR = 1.41, 95% CI 1.10 to 1.82), high pesticide exposure events (OR = 1.75, 95% CI 1.39 to 2.21), and ever use of organochlorine (OR = 1.34, 95% CI 1.04 to 1.74) and carbamate pesticides (OR = 1.32, 95% CI 1.03 to 1.68) were associated with farmer’s lung in mutually-adjusted models. The insecticides DDT, lindane, and aldicarb were positively associated with farmer’s lung among farmers. Current animal exposures, while not statistically significant, were positively associated with farmer’s lung, particularly for poultry houses (OR = 1.55, 95% CI 0.93 to 2.58) and dairy cattle (OR = 1.28, 95% CI 0.86 to 1.89). The occupational data were more limited for spouses; however, we saw similar associations for dairy cattle (OR = 1.50, 95% CI 0.72 to 3.14) and organochlorine pesticides (OR = 1.29, 95% CI 0.64 to 2.59).Conclusion:While historic farm exposures may contribute to the observed associations with pesticides, these results suggest that organochlorine and carbamate pesticides should be further evaluated as potential risk factors for farmer’s lung.
Association of allergic rhinitis with pesticide use among grape farmers in Crete, Greece
Authors: Chatzi Leda , Alegakis Athanasios , Tzanakis Nikolaos , Siafakas Nikolaos , Kogevinas Manolis , Lionis Christos 
Published: December 2006

Objective:To explore the association of allergic rhinitis with the use of pesticides among grape farmers in Crete.Methods:A cross-sectional study of 120 grape farmers and 100 controls at the Malevisi region in Northern Crete was conducted. The protocol consisted of a questionnaire, skin prick tests for 16 common allergens, measurement of specific IgE antibodies against 8 allergens, and spirometry before and after bronchodilatation.Results:Grape farmers who used pesticides had higher prevalence rates of allergic rhinitis symptoms (OR, 3.0; 95% CI, 1.4 to 6.2) compared with grape farmers who reported no current use of pesticides, and control subjects. Logistic regression models controlling for age, sex and smoking status showed that 6 of the 12 predefined groups of major pesticides were significantly related to allergic rhinitis symptoms. The highest risks were observed for paraquat and other bipyridyl herbicides (OR, 2.2; 95% CI, 1.0 to 4.8), dithiocarbamate fungicides (OR, 2.5; 95% CI, 1.1 to 5.3) and carbamate insecticides (OR, 3.0; 95% CI, 1.4 to 6.5). A factor analysis of pesticides used identified 3 distinct factors. The most common factor was that of multiple pesticide use that included 9 pesticides and was significantly associated with allergic rhinitis (OR, 1.5; 95% CI, 1.0 to 2.3). ORs were higher when allergic rhinitis was defined using both questionnaire data on symptoms and atopy.Conclusions:Occupational exposure to multiple agricultural chemicals could be related to allergic rhinitis in grape farmers.
Dynamical Origin of Low-Frequency Variability in a Highly Nonlinear Midlatitude Coupled Model
Authors: Kravtsov S. , Berloff P. , Dewar W. K. , Ghil M. , McWilliams J. C. 
Published: December 2006

AbstractA novel mechanism of decadal midlatitude coupled variability, which crucially depends on the nonlinear dynamics of both the atmosphere and the ocean, is presented. The coupled model studied involves quasigeostrophic atmospheric and oceanic components, which communicate with each other via a constant-depth oceanic mixed layer. A series of coupled and uncoupled experiments show that the decadal coupled mode is active across parameter ranges that allow the bimodality of the atmospheric zonal flow to coexist with oceanic turbulence. The latter is most intense in the regions of inertial recirculation (IR). Bimodality is associated with the existence of two distinct anomalously persistent zonal-flow modes, which are characterized by different latitudes of the atmospheric jet stream. The IR reorganizations caused by transitions of the atmosphere from its high- to low-latitude state and vice versa create sea surface temperature anomalies that tend to induce transition to the opposite atmospheric state. The decadal–interdecadal time scale of the resulting oscillation is set by the IR adjustment; the latter depends most sensitively on the oceanic bottom drag. The period T of the nonlinear oscillation is 7–25 yr for the range of parameters explored, with the most realistic parameter values yielding T ≈ 20 yr.Aside from this nonlinear oscillation, an interannual Rossby wave mode is present in all coupled experiments. This coupled mode depends neither on atmospheric bimodality, nor on ocean eddy dynamics; it is analogous to the mode found previously in a channel configuration. Its time scale in the model with a closed ocean basin is set by cross-basin wave propagation and equals 3–5 yr for a basin width comparable with the North Atlantic.
A Distribution Law for Free-Tropospheric Relative Humidity
Authors: Sherwood Steven C. , Kursinski E. Robert , Read William G. 
Published: December 2006

Abstract
The probability distribution of local relative humidity ℛ in the free troposphere is explored by comparing a simple theoretical calculation with observations from the global positioning system (GPS) and the Microwave Limb Sounder (MLS). The calculation is based on a parcel of air that conserves its composition during diabatic subsidence, until it is resaturated by randomly entering a convective system. This simple “advection–condensation” model of relative humidity predicts a probability density for ℛ proportional to ℛr−1, where r is the ratio of time scales associated with subsidence drying and random moistening. The observations obey this distribution remarkably well from 600 to 200 hPa in the Tropics and midlatitudes; possible reasons for this are discussed. The lowest values of ℛ are predicted, and observed, to be the most probable. The observed vertical variation of ℛ is well explained by that of the subsidence time scale, which is set by large-scale dynamics and radiation. These results imply that cloud microphysics exerts little control on water vapor’s greenhouse effect, but that relatively subtle dynamical changes have the potential to alter the strength of its feedback on climate change.
The General Circulation and Robust Relative Humidity
Authors: Sherwood S. C. , Meyer C. L. 
Published: December 2006

Abstract
The sensitivity of free-tropospheric relative humidity to cloud microphysics and dynamics is explored using a simple 2D humidity model and various configurations of the National Center for Atmospheric Research (NCAR) Community Atmosphere Model version 3 (CAM3) atmospheric general circulation model (AGCM). In one configuration the imposed surface temperatures and radiative perturbations effectively eliminated the Hadley and Walker circulations and the main westerly jet, creating instead a homogeneous “boiling kettle” world in low and midlatitudes. A similarly homogeneous state was created in the 2D model by rapid horizontal mixing.
Relative humidity ℛ simulated by the AGCM was insensitive to surface warming. Doubling a parameter governing cloud water reevaporation increased tropical mean ℛ near the midtroposphere by about 4% with a realistic circulation, but by more than 10% in the horizontally homogeneous states. This was consistent in both models. AGCM microphysical sensitivity decreased in the upper troposphere, and vanished outside the Tropics. Convective organization by the general circulation evidently makes relative humidity much more robust to microphysical details by concentrating the rainfall in moist environments. Models that fail to capture this will overestimate the microphysical sensitivity of humidity.
Based on these results, the uncertainty in the strength of the water vapor feedback associated with cloud microphysical processes seems unlikely to exceed a few percent. This does not include uncertainties associated with large-scale dynamics or cloud radiative effects, which cannot be quantified, although radical CAM3 circulation changes reported here had surprisingly little impact on simulated relative humidity.
PDO–ENSO Effects in the Climate of Mexico
Authors: Pavia Edgar G. , Graef Federico , Reyes Jorge 
Published: December 2006

Abstract
The role of the Pacific decadal oscillation (PDO) in El Niño–Southern Oscillation (ENSO)-related Mexican climate anomalies during winter and summer is investigated. The precipitation and mean temperature data of approximately 1000 stations throughout Mexico are considered. After sorting ENSO events by warm phase (El Niño) and cold phase (La Niña) and prevailing PDO phase: warm or high (HiPDO) and cold or low (LoPDO), the authors found the following: 1) For precipitation, El Niño favors wet conditions during summers of LoPDO and during winters of HiPDO. 2) For mean temperature, cooler conditions are favored during La Niña summers and during El Niño winters, regardless of the PDO phase; however, warmer conditions are favored by the HiPDO during El Niño summers.