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1.  Randomized controlled trial of atorvastatin in clinically isolated syndrome 
Neurology  2012;78(15):1171-1178.
Objective:
To test efficacy and safety of atorvastatin in subjects with clinically isolated syndrome (CIS).
Methods:
Subjects with CIS were enrolled in a phase II, double-blind, placebo-controlled, 14-center randomized trial testing 80 mg atorvastatin on clinical and brain MRI activity. Brain MRIs were performed quarterly. The primary endpoint (PEP) was development of ≥3 new T2 lesions, or one clinical relapse within 12 months. Subjects meeting the PEP were offered additional weekly interferon β-1a (IFNβ-1a).
Results:
Due to slow recruitment, enrollment was discontinued after 81 of 152 planned subjects with CIS were randomized and initiated study drug. Median (interquartile range) numbers of T2 and gadolinium-enhancing (Gd) lesions were 15.0 (22.0) and 0.0 (0.0) at baseline. A total of 53.1% of atorvastatin recipients (n = 26/49) met PEP compared to 56.3% of placebo recipients (n = 18/32) (p = 0.82). Eleven atorvastatin subjects (22.4%) and 7 placebo subjects (21.9%) met the PEP by clinical criteria. Proportion of subjects who did not develop new T2 lesions up to month 12 or to starting IFNβ-1a was 55.3% in the atorvastatin and 27.6% in the placebo group (p = 0.03). Likelihood of remaining free of new T2 lesions was significantly greater in the atorvastatin group compared with placebo (odds ratio [OR] = 4.34, p = 0.01). Likelihood of remaining free of Gd lesions tended to be higher in the atorvastatin group (OR = 2.72, p = 0.11). Overall, atorvastatin was well tolerated. No clear antagonistic effect of atorvastatin plus IFNβ-1a was observed on MRI measures.
Conclusion:
Atorvastatin treatment significantly decreased development of new brain MRI T2 lesion activity, although it did not achieve the composite clinical and imaging PEP.
Classification of Evidence:
This study provided Class II evidence that atorvastatin did not reduce the proportion of patients with CIS meeting imaging and clinical criteria for starting immunomodulating therapy after 12 months, compared to placebo. In an analysis of a secondary endpoint (Class III), atorvastatin was associated with a reduced risk for developing new T2 lesions.
doi:10.1212/WNL.0b013e31824f7fdd
PMCID: PMC3320055  PMID: 22459680
2.  Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse 
Annals of Oncology  2013;24(6):1491-1498.
Background
Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. This study explores the effect of tetrathiomolybdate (TM), an anti-angiogenic copper chelator, on EPCs in patients at high risk for breast cancer recurrence.
Patients and methods
This phase 2 study enrolled breast cancer patients with stage 3 and stage 4 without evidence of disease (NED), and stage 2 if triple-negative. TM 100 mg orally was administered to maintain ceruloplasmin <17 mg/dl for 2 years or until relapse. The primary end point was change in EPCs.
Results
Forty patients (28 stage 2/3, 12 stage 4 NED) were enrolled. Seventy-five percent patients achieved the copper depletion target by 1 month. Ninety-one percent of triple-negative patients copper-depleted compared with 41% luminal subtypes. In copper-depleted patients only, there was a significant reduction in EPCs/ml by 27 (P = 0.04). Six patients relapsed while on study, of which only one patient had EPCs maintained below baseline. The 10-month relapse-free survival was 85.0% (95% CI 74.6%–96.8%). Only grade 3/4 toxicity was hematologic: neutropenia (3.1% of cycles), febrile neutropenia (0.2%), and anemia (0.2%).
Conclusions
TM is safe and appears to maintain EPCs below baseline in copper-depleted patients. TM may promote tumor dormancy and ultimately prevent relapse.
doi:10.1093/annonc/mds654
PMCID: PMC3707432  PMID: 23406736
breast cancer; endothelial progenitor cells; tetrathiomolybdate
3.  A framework to evaluate the development and implementation of a comprehensive public health strategy 
Public health  2013;127(8):791-793.
doi:10.1016/j.puhe.2013.02.010
PMCID: PMC3959767  PMID: 23871395
4.  A multi-center, cross-sectional study on quality of life in cutaneous lupus erythematosus patients 
The British journal of dermatology  2012;168(1):145-153.
Background
A study at the University of Pennsylvania (UPenn) Medical Center demonstrated that quality of life in cutaneous lupus erythematosus (CLE) patients is negatively impacted. Whether CLE patients in other geographic locations have similar quality of life is unknown.
Objective
We sought to compare quality of life indicators between CLE patients at the University of Texas Southwestern (UTSW) Medical Center at Dallas and UPenn.
Methods
248 CLE patients at UTSW (N=91) and UPenn (N=157) completed the Skindex-29+3 and Short Form-36 (SF-36) surveys related to quality of life. Additional information including demographics, presence of SLE, and disease severity were collected from UTSW CLE patients.
Results
Most Skindex-29+3 and SF-36 sub-domain scores between UTSW and UPenn CLE patients were similar. However, UTSW CLE patients were significantly more affected in the functioning and lupus-specific Skindex-29+3 domains, and physical functioning, role-physical, and general health SF-36 subscales than UPenn CLE patients (p<0.05). Factors related to poor quality of life in UTSW CLE patients include gender, income, education, presence of SLE, and skin disease activity.
Conclusions
Most quality of life indicators were similar between the two CLE populations. Differences in psychosocial behavior, and a larger proportion of SLE patients and females in the UTSW group likely attributed to differences in a minority of Skindex-29+3 and SF-36 sub-domains. Capturing data from CLE populations in different locations provides a more thorough picture of the quality of life that CLE patients experience on a daily basis with special attention to quality of life issues in select CLE patients.
doi:10.1111/j.1365-2133.2012.11106.x
PMCID: PMC3467361  PMID: 22708924
cutaneous lupus erythematosus; quality of life; Short Form-36; Skindex-29; Cutaneous Lupus Erythematosus Disease Area and Severity Index; multi-center
5.  Offering fragile X syndrome carrier screening: a prospective mixed-methods observational study comparing carrier screening of pregnant and non-pregnant women in the general population 
BMJ Open  2013;3(9):e003660.
Introduction
Fragile X syndrome (FXS) is the leading cause of inherited intellectual and developmental disability. Policy development relating to carrier screening programmes for FXS requires input from large studies examining not only test uptake but also psychosocial aspects. This study will compare carrier screening in pregnant and non-pregnant populations, examining informed decision-making, psychosocial issues and health economics.
Methods and Analysis
Pregnant and non-pregnant women are being recruited from general practices and obstetric services. Women receive study information either in person or through clinic mail outs. Women are provided pretest counselling by a genetic counsellor and make a decision about testing in their own time. Data are being collected from two questionnaires: one completed at the time of making the decision about testing and the second 1 month later. Additional data are gathered through qualitative interviews conducted at several time points with a subset of participating women, including all women with a positive test result, and with staff from recruiting clinics. A minimum sample size of 500 women/group has been calculated to give us 88% power to detect a 10% difference in test uptake and 87% power to detect a 10% difference in informed choice between the pregnant and non-pregnant groups. Questionnaire data will be analysed using descriptive statistics and multivariate logistic regression models. Interview data will be thematically analysed. Willingness-to-pay and cost effectiveness analyses will also be performed. Recruitment started in July 2009 and data collection will be completed by December 2013.
Ethics and Dissemination
Ethics approval has been granted by the Universities of Melbourne and Western Australia and by recruiting clinics, where required. Results will be reported in peer-reviewed publications, conference presentations and through a website http://www.fragilexscreening.net.au. The results of this study will make a significant contribution to discussions about the wider introduction of population carrier screening for FXS.
doi:10.1136/bmjopen-2013-003660
PMCID: PMC3773647  PMID: 24022395
Genetics; Public Health
6.  The embryonic transcription factor Brachyury blocks cell cycle progression and mediates tumor resistance to conventional antitumor therapies 
Cell Death & Disease  2013;4(6):e682-.
The T-box transcription factor Brachyury, a molecule frequently detected in human cancers but seldom found in normal adult tissue, has recently been characterized as a driver of the epithelial-to-mesenchymal switch of human carcinomas. In the current investigation, we present data demonstrating that in two different human lung carcinoma models expression of Brachyury strongly correlates with increased in vitro resistance to cytotoxic therapies, such as chemotherapy and radiation. We also demonstrate that chemotherapy treatment in vitro selects for tumor cells with high levels of Brachyury and that the degree of resistance to therapy correlates with the level of Brachyury expression. In vitro and in vivo, human lung carcinoma cells with higher levels of Brachyury divide at slower rates than those with lower levels of Brachyury, a phenomenon associated with marked downregulation of cyclin D1, phosphorylated Rb and CDKN1A (p21). Chromatin immunoprecipitation and luciferase reporter assays revealed that Brachyury binds to a half T-box consensus site located within the promoter region of the p21 gene, indicating a potential mechanism for the observed therapeutic resistance associated with Brachyury expression. Finally, we demonstrate that in vivo treatment of tumor xenografts with chemotherapy results in the selective growth of resistant tumors characterized by high levels of Brachyury expression. Altogether, these results suggest that Brachyury expression may attenuate cell cycle progression, enabling tumor cells to become less susceptible to chemotherapy and radiation in human carcinomas.
doi:10.1038/cddis.2013.208
PMCID: PMC3702290  PMID: 23788039
EMT; Brachyury; therapeutic resistance; CDKN1A
7.  In non-severe hemophilia A the risk of inhibitor after intensive factor treatment is greater in older patients: a case–control study 
Summary
Background
Twenty-five percent of new anti-factor VIII (FVIII) antibodies (inhibitors) that complicate hemophilia A occur in those with mild and moderate disease. Although intensive FVIII treatment has long been considered a risk factor for inhibitor development in those with non-severe disease, its strength of association and the influence of other factors have remained undefined.
Objective
To evaluate risk factors for inhibitor development in patients with non-severe hemophilia A.
Methods
Information on clinical and demographic variables and FVIII genotype was collected on 36 subjects with mild or moderate hemophilia A and an inhibitor and 62 controls also with mild or moderate hemophilia A but without an inhibitor.
Results
Treatment with FVIII for six or more consecutive days during the prior year was more strongly associated with inhibitor development in those ≥ 30 years of age compared with those < 30 years of age [adjusted odds ratio (OR) 12.62; 95% confidence interval (CI), 2.76–57.81 vs. OR 2.54; 95% CI, 0.61–10.68]. Having previously received < 50 days of FVIII was also not statistically associated with inhibitor development on univariate or multivariate analysis.
Conclusions
These findings suggest that inhibitor development in mild and moderate hemophilia A varies with age, but does not vary significantly with lifetime FVIII exposure days: two features distinct from severe hemophilia A.
doi:10.1111/j.1538-7836.2010.04013.x
PMCID: PMC3612936  PMID: 20704648
hemophilia A; inhibitor
8.  Relationship of increased aurora kinase A gene copy number, prognosis and response to chemotherapy in patients with metastatic colorectal cancer 
British Journal of Cancer  2012;106(4):748-755.
Background:
Increased Aurora kinase A gene copy number (AURKA-CN) has been reported in metastatic colorectal cancer (mCRC), with unknown relationship to clinical outcome. We correlated increased AURKA-CN in mCRC tumours with KRAS mutation status, overall and progression-free survival (OS, PFS).
Methods:
Sixty-one mCRC tumours were analysed for AURKA-CN using q-PCR, and KRAS mutation status by direct sequencing. Expression of AURKA protein was analysed by immunohistochemistry. Cox-proportional hazard method, Kaplan–Meier curves and log-rank statistics were used to estimate and compare the hazard ratios and median survival between the groups.
Results:
In all, 68% of tumour exhibited high AURKA-CN, and 29% had a KRAS mutation, without correlation between the two. Patients with high AURKA-CN tumours had longer median OS (48.6 vs 18.8 months, P=0.01), with stronger trend among KRAS wild-type tumours (median OS not reached vs 18.8 months, P=0.003). Progression-free survival was longer on first-line or second-line chemotherapy among patients with KRAS wild-type and high vs low AURKA-CN (first: 17.6 vs 5.13 months, P=0.04; second: 10.4 vs 5.1 months, P=0.01). AURKA-CN level did not affect outcomes among patients with KRAS mutant tumours.
Conclusion:
Increased AURKA-CN is common in mCRC tumours and is associated with longer OS and longer PFS during chemotherapy, particularly in KRAS wild-type tumours.
doi:10.1038/bjc.2011.587
PMCID: PMC3322945  PMID: 22240781
colon cancer; aurora kinase A; copy number; KRAS mutation
12.  Evidence-based guideline: Treatment of painful diabetic neuropathy 
Neurology  2011;76(20):1758-1765.
Objective:
To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN).
Methods:
We performed a systematic review of the literature from 1960 to August 2008 and classified the studies according to the American Academy of Neurology classification of evidence scheme for a therapeutic article, and recommendations were linked to the strength of the evidence. The basic question asked was: “What is the efficacy of a given treatment (pharmacologic: anticonvulsants, antidepressants, opioids, others; and nonpharmacologic: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?”
Results and Recommendations:
Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL.
doi:10.1212/WNL.0b013e3182166ebe
PMCID: PMC3100130  PMID: 21482920
13.  Post-traumatic anxiety associates with failure of the innate immune receptor TLR9 to evade the pro-inflammatory NFκB pathway 
Translational Psychiatry  2012;2(2):e78-.
Post-traumatic anxiety notably involves inflammation, but its causes and functional significance are yet unclear. Here, we report that failure of the innate immune system Toll-like receptor 9 (TLR9) to limit inflammation is causally involved with anxiety-associated inflammation and that peripheral administration of specific oligonucleotide activators of TLR9 may prevent post-traumatic consequences in stressed mice. Suggesting involvement of NFκB-mediated enhancement of inflammatory reactions in the post-traumatic phenotype, we found association of serum interleukin-1β increases with symptoms severity and volumetric brain changes in post-traumatic stress disorder patients. In predator scent-stressed mice, the moderate NFκB-activating oligonucleotides mEN101 and its human ortholog BL-7040, but not the canonic NFκB activator oligonucleotide ODN1826, induced anxiolytic effects. In stressed mice, peripherally administered mEN101 prevented delayed stress-inducible serum interleukin-1β increases while limiting stress-characteristic hippocampal transcript modifications and the anxiety-induced EGR1-mediated neuronal activation. Attesting to the TLR9 specificity of this response, BL-7040 suppressed NFκB-mediated luciferase in transfected cells co-expressing TLR9, but not other TLRs. Furthermore, TLR9−/− mice were mEN101 and BL-7040 resistant and presented unprovoked anxiety-like behavior and anxiety-characteristic hippocampal transcripts. Our findings demonstrate functional relevance of TLR9 in protecting stressed mammals from overreacting to traumatic experiences and suggest using oligonucleotide-mediated peripheral TLR9 activation to potentiate the innate immune system and prevent post-traumatic inflammation and anxiety.
doi:10.1038/tp.2012.4
PMCID: PMC3309554  PMID: 22832815
inflammation; innate immune system; NFκB; oligonucleotide; post-traumatic stress; TLR9
14.  EEG Oscillations Reveal Neural Correlates of Evidence Accumulation 
Recent studies have begun to elucidate the neural correlates of evidence accumulation in perceptual decision making, but few of them have used a combined modeling-electrophysiological approach to studying evidence accumulation. We introduce a multivariate approach to EEG analysis with which we can perform a comprehensive search for the neural correlate of dynamics predicted by accumulator models. We show that the dynamics of evidence accumulation are most strongly correlated with ramping of oscillatory power in the 4–9 Hz theta band over the course of a trial, although it also correlates with oscillatory power in other frequency bands. The rate of power decrease in the theta band correlates with individual differences in the parameters of drift diffusion models fitted to individuals’ behavioral data.
doi:10.3389/fnins.2012.00106
PMCID: PMC3398314  PMID: 22822389
EEG; drift diffusion model; decision making; oscillations
16.  Higher Volume at Time of Breast Conserving Surgery Reduces Re-Excision in DCIS 
Purpose. The purpose of this study was to compare the surgical and pathological variables which impact rate of re-excision following breast conserving therapy (BCS) with or without concurrent additional margin excision (AM). Methods. The pathology database was queried for all patients with DCIS from January 2004 to September 2008. Pathologic assessment included volume of excision, subtype, size, distance from margin, grade, necrosis, multifocality, calcifications, and ER/PR status. Results. 405 cases were identified and 201 underwent BCS, 151-BCS-AM, and 53-mastectomy. Among the 201 BCS patients, 190 underwent re-excision for close or involved margins. 129 of these were treated with BCS and 61 with BCS-AM (P < .0001). The incidence of residual DCIS in the re-excision specimens was 32% (n = 65) for BCS and 22% (n = 33) for BCS-AM (P < .05). For both the BCS and the BCS-AM cohorts, volume of tissue excised is inversely correlated to the rate of re-excision (P = .0284). Multifocality (P = .0002) and ER status (P = .0382) were also significant predictors for rate of re-excision and variation in surgical technique was insignificant. Conclusions. The rate of positive margins, re-excision, and residual disease was significantly higher in patients with lower volume of excision. The performance of concurrent additional margin excision increases the efficacy of BCS for DCIS.
doi:10.1155/2011/785803
PMCID: PMC3263677  PMID: 22312524
17.  Altered Lung Morphogenesis, Epithelial Cell Differentiation and Mechanics in Mice Deficient in the Wnt/β-Catenin Antagonist Chibby 
PLoS ONE  2010;5(10):e13600.
The canonical Wnt/β-catenin pathway plays crucial roles in various aspects of lung morphogenesis and regeneration/repair. Here, we examined the lung phenotype and function in mice lacking the Wnt/β-catenin antagonist Chibby (Cby). In support of its inhibitory role in canonical Wnt signaling, expression of β-catenin target genes is elevated in the Cby−/− lung. Notably, Cby protein is prominently associated with the centrosome/basal body microtubule structures in embryonic lung epithelial progenitor cells, and later enriches as discrete foci at the base of motile cilia in airway ciliated cells. At birth, Cby−/− lungs are grossly normal but spontaneously develop alveolar airspace enlargement with reduced proliferation and abnormal differentiation of lung epithelial cells, resulting in altered pulmonary function. Consistent with the Cby expression pattern, airway ciliated cells exhibit a marked paucity of motile cilia with apparent failure of basal body docking. Moreover, we demonstrate that Cby is a direct downstream target for the master ciliogenesis transcription factor Foxj1. Collectively, our results demonstrate that Cby facilitates proper postnatal lung development and function.
doi:10.1371/journal.pone.0013600
PMCID: PMC2963606  PMID: 21049041
18.  Bug22p, a Conserved Centrosomal/Ciliary Protein Also Present in Higher Plants, Is Required for an Effective Ciliary Stroke in Paramecium ▿ † 
Eukaryotic Cell  2010;9(4):645-655.
Centrioles, cilia, and flagella are ancestral conserved organelles of eukaryotic cells. Among the proteins identified in the proteomics of ciliary proteins in Paramecium, we focus here on a protein, Bug22p, previously detected by cilia and basal-body high-throughput studies but never analyzed per se. Remarkably, this protein is also present in plants, which lack centrioles and cilia. Bug22p sequence alignments revealed consensus positions that distinguish species with centrioles/cilia from plants. In Paramecium, antibody and green fluorescent protein (GFP) fusion labeling localized Bug22p in basal bodies and cilia, and electron microscopy immunolabeling refined the localization to the terminal plate of the basal bodies, the transition zone, and spots along the axoneme, preferentially between the membrane and the microtubules. RNA interference (RNAi) depletion of Bug22p provoked a strong decrease in swimming speed, followed by cell death after a few days. High-speed video microscopy and morphological analysis of Bug22p-depleted cells showed that the protein plays an important role in the efficiency of ciliary movement by participating in the stroke shape and rigidity of cilia. The defects in cell swimming and growth provoked by RNAi can be complemented by expression of human Bug22p. This is the first reported case of complementation by a human gene in a ciliate.
doi:10.1128/EC.00368-09
PMCID: PMC2863418  PMID: 20118210
19.  Epstein–Barr virus-associated lymphoproliferative disease in non-immunocompromised hosts: a status report and summary of an international meeting, 8–9 September 2008 
Annals of Oncology  2009;20(9):1472-1482.
Background: Recently novel Epstein–Barr virus (EBV) lymphoproliferative diseases (LPDs) have been identified in non-immunocompromised hosts, both in Asia and Western countries. These include aggressive T-cell and NK-cell LPDs often subsumed under the heading of chronic active Epstein–Barr virus (CAEBV) infection and EBV-driven B-cell LPDs mainly affecting the elderly.
Design: To better define the pathogenesis, classification, and treatment of these disorders, participants from Asia, The Americas, Europe, and Australia presented clinical and experimental data at an international meeting.
Results: The term systemic EBV-positive T-cell LPD, as adopted by the WHO classification, is preferred as a pathological classification over CAEBV (the favored clinical term) for those cases that are clonal. The disease has an aggressive clinical course, but may arise in the background of CAEBV. Hydroa vacciniforme (HV) and HV-like lymphoma represent a spectrum of clonal EBV-positive T-cell LPDs, which have a more protracted clinical course; spontaneous regression may occur in adult life. Severe mosquito bite allergy is a related syndrome usually of NK cell origin. Immune senescence in the elderly is associated with both reactive and neoplastic EBV-driven LPDs, including EBV-positive diffuse large B-cell lymphomas.
Conclusion: The participants proposed an international consortium to facilitate further clinical and biological studies of novel EBV-driven LPDs.
doi:10.1093/annonc/mdp064
PMCID: PMC2731018  PMID: 19515747
chronic active EBV infection; diffuse large B-cell lymphoma; hemophagocytic syndrome; hydroa vacciniforme; immune senescence; senile EBV-positive lymphoproliferative disease; systemic EBV-positive lymphoproliferative disease
20.  Small Interfering Peptide (siP) for In Vivo Examination of the Developing Lung Interactonome 
To understand the role of reactive oxygen species in mechanicosensory control of lung development a new approach to interfere with protein-protein interactions via a short interacting peptide was developed. This technology was used in the developing rodent lung to examine the role of NADPH oxidase (NOX), CK2 (casein kinase 2), and the cystic fibrosis transmembrane conductance regulator (CFTR) in stretch induced differentiation. Interactions between these molecules was targeted in an in utero system with rAAV containing inserted DNA sequences that express a control peptide or small interfering peptides (siPs) specific for subunit interaction or phosphorylation predicted to be necessary for multimeric enzyme formation. In all cases only siPs with sequences necessary for a predicted normal function were found to interfere with assembly of the multimeric enzyme. A non-interfering control siP to non-essential regions or reporter genes alone had no effect. Physiologically, it was shown that siPs that interfered with the NOX-CFTR-CK2 complex that we call an “interactonome” affected markers of stretch induced lung organogenesis including Wnt/β-catenin signaling.
doi:10.1002/dvdy.21834
PMCID: PMC2808203  PMID: 19161244
21.  Adult onset lung disease following transient disruption of fetal stretch-induced differentiation 
Respiratory Research  2009;10(1):34.
One of the mechanisms by which adult disease can arise from a fetal origin is by in utero disruption of organogenesis. These studies were designed to examine respiratory function changes in aging rats following transient disruption of lung growth at 16 days gestation. Fetuses were treated in utero with a replication deficient adenovirus containing the cystic fibrosis conductance transmembrane regulator (CFTR) gene fragment cloned in the anti-sense direction. The in utero-treated rats demonstrated abnormal lung function beginning as early as 30 days of age and the pathology progressed as the animals aged. The pulmonary function abnormalities included decreased static compliance as well as increased conducting airway resistance, tissue damping, and elastance. Pressure volume (PV) curves demonstrated a slower early rise to volume and air trapping at end-expiration. The alterations of pulmonary function correlated with lung structural changes determined by morphometric analysis. These studies demonstrate how transient disruption of lung organogensis by single gene interference can result in progressive change in lung function and structure. They illustrate how an adult onset disease can arise from subtle changes in gene expression during fetal development.
doi:10.1186/1465-9921-10-34
PMCID: PMC2685416  PMID: 19419569
22.  Domestic dogs and cats as sources of Trypanosoma cruzi infection in rural northwestern Argentina 
Parasitology  2006;134(Pt 1):69-82.
SUMMARY
The reservoir capacity of domestic cats and dogs for Trypanosoma cruzi infection and the host-feeding patterns of domestic Triatoma infestans were assessed longitudinally in 2 infested rural villages in north-western Argentina. A total of 86 dogs and 38 cats was repeatedly examined for T. cruzi infection by serology and/or xenodiagnosis. The composite prevalence of infection in dogs (60%), but not in cats, increased significantly with age and with the domiciliary density of infected T. infestans. Dogs and cats had similarly high forces of infection, prevalence of infectious hosts (41–42%), and infectiousness to bugs at a wide range of infected bug densities. The infectiousness to bugs of seropositive dogs declined significantly with increasing dog age and was highly aggregated. Individual dog infectiousness to bugs was significantly autocorrelated over time. Domestic T. infestans fed on dogs showed higher infection prevalence (49%) than those fed on cats (39%), humans (38%) or chickens (29%) among 1085 bugs examined. The basic reproduction number of T. cruzi in dogs was at least 8·2. Both cats and dogs are epidemiologically important sources of infection for bugs and householders, dogs nearly 3 times more than cats.
doi:10.1017/S0031182006001259
PMCID: PMC2669415  PMID: 17032467
surveillance; host-feeding; incidence; triatomine bugs; Chagas disease; Trypanosoma cruzi; Triatoma infestans; dogs; cats; infectiousness
23.  Transient in utero disruption of Cystic Fibrosis Transmembrane Conductance Regulator causes phenotypic changes in Alveolar Type II cells in adult rats 
BMC Cell Biology  2009;10:24.
Background
Mechanicosensory mechanisms regulate cell differentiation during lung organogenesis. We have previously demonstrated that cystic fibrosis transmembrane conductance regulator (CFTR) was integral to stretch-induced growth and development and that transient expression of antisense-CFTR (ASCFTR) had negative effects on lung structure and function. In this study, we examined adult alveolar type II (ATII) cell phenotype after transient knock down of CFTR by adenovirus-directed in utero expression of ASCFTR in the fetal lung.
Results
In comparison to (reporter gene-treated) Controls, ASCFTR-treated adult rat lungs showed elevated phosphatidylcholine (PC) levels in the large but not in the small aggregates of alveolar surfactant. The lung mRNA levels for SP-A and SP-B were lower in the ASCFTR rats. The basal PC secretion in ATII cells was similar in the two groups. However, compared to Control ATII cells, the cells in ASCFTR group showed higher PC secretion with ATP or phorbol myristate acetate. The cell PC pool was also larger in the ASCFTR group. Thus, the increased surfactant secretion in ATII cells could cause higher PC levels in large aggregates of surfactant. In freshly isolated ATII cells, the expression of surfactant proteins was unchanged, suggesting that the lungs of ASCFTR rats contained fewer ATII cells. Gene array analysis of RNA of freshly isolated ATII cells from these lungs showed altered expression of several genes including elevated expression of two calcium-related genes, Ca2+-ATPase and calcium-calmodulin kinase kinase1 (CaMkk1), which was confirmed by real-time PCR. Western blot analysis showed increased expression of calmodulin kinase I, which is activated following phosphorylation by CaMkk1. Although increased expression of calcium regulating genes would argue in favor of Ca2+-dependent mechanisms increasing surfactant secretion, we cannot exclude contribution of alternate mechanisms because of other phenotypic changes in ATII cells of the ASCFTR group.
Conclusion
Developmental changes due to transient disruption of CFTR in fetal lung reflect in altered ATII cell phenotype in the adult life.
doi:10.1186/1471-2121-10-24
PMCID: PMC2675516  PMID: 19335897
24.  Health and Human Rights Concerns of Drug Users in Detention in Guangxi Province, China 
PLoS Medicine  2008;5(12):e234.
Background
Although confinement in drug detoxification (“detox”) and re-education through labor (RTL) centers is the most common form of treatment for drug dependence in China, little has been published about the experience of drug users in such settings. We conducted an assessment of the impact of detention on drug users' access to HIV prevention and treatment services and consequent threats to fundamental human rights protections.
Methods and Findings
Chinese government HIV and anti-narcotics legislation and policy documents were reviewed, and in-depth and key informant interviews were conducted with 19 injection drug users (IDUs) and 20 government and nongovernmental organization officials in Nanning and Baise, Guangxi Province. Significant contradictions were found in HIV and antinarcotics policies, exemplified by the simultaneous expansion of community-based methadone maintenance therapy and the increasing number of drug users detained in detox and RTL center facilities. IDU study participants reported, on average, having used drugs for 14 y (range 8–23 y) and had been confined to detox four times (range one to eight times) and to RTL centers once (range zero to three times). IDUs expressed an intense fear of being recognized by the police and being detained, regardless of current drug use. Key informants and IDUs reported that routine HIV testing, without consent and without disclosure of the result, was the standard policy of detox and RTL center facilities, and that HIV-infected detainees were not routinely provided medical or drug dependency treatment, including antiretroviral therapy. IDUs received little or no information or means of HIV prevention, but reported numerous risk behaviors for HIV transmission while detained.
Conclusions
Legal and policy review, and interviews with recently detained IDUs and key informants in Guangxi Province, China, found evidence of anti-narcotics policies and practices that appear to violate human rights and imperil drug users' health.
Based on their review of Chinese government legislation and policy documents, and using interviews with recently detained injection drug users and officials in Guangxi Province, Elizabeth Cohen and Joseph Amon find evidence of antinarcotics policies and practices that may compromise the health and human rights of drug users.
Editors' Summary
Background.
Ever since the AIDS (acquired immunodeficiency syndrome) epidemic began, needle sharing by injection drug users (IDUs) has been a major transmission route for the human immunodeficiency virus (HIV), the blood-borne virus that causes AIDS. In China, for example, the AIDS epidemic began in earnest in 1989 when 146 HIV-positive IDUs were identified in Southwest Yunnan. By 1998, HIV infections had been reported throughout China, 60%–70% of which were in IDUs. These days, nearly half of new HIV infections in China are associated with injection drug use and 266,000 of the 700,000 HIV-positive people in China are drug users. Faced with these figures, the Chinese government has recently introduced measures to reduce HIV transmission among the estimated 3–4 million IDUs in China. These measures include increased provision of methadone maintenance treatment clinics and needle exchanges and the establishment of HIV prevention programs that target IDUs.
Why Was This Study Done?
Alongside these progressive public-health practices, China has extremely punitive anti-narcotics policies. IDUs are routinely confined without legal review in drug detoxification centers or sent to re-education through labor (RTL) centers, sometimes for many years. In 2005, these centers housed more than 350,000 drug users yet little is known about the conditions in these centers or how the Chinese anti-narcotic policy affects human rights or access to HIV prevention and treatment services. In this study, the researchers investigated these issues by interviewing IDUs and “key informants” (government officials and members of nongovernmental organizations [NGOs] who provide services to IDUs) about their experiences of detoxification centers and RTL centers in two cities in Guangxi Province, China.
What Did the Researchers Do and Find?
The researchers recruited 19 IDUs who had been recently confined in a detoxification center or RTL center and 20 key informants (including a doctor at a detoxification center and a former RTL center guard). In the interviews the researchers used a semi-structured questionnaire to ask the participants about their experiences of detoxification centers and RTL centers. All the IDUs reported that they were repeatedly tested for HIV while in detention but never given their test results even when they asked for them. Key informants confirmed that repeated HIV testing without result disclosure is the current policy in detoxification centers and RTL centers. All the IDUs expressed concerns about inadequate access to health care in detention. In particular, most of the IDUs who were taking antiretroviral drugs before detention were unable to continue their treatment during detention, although two received antiretroviral drugs by negotiating with their guards. The IDUs and key informants also both noted that very little information or means of HIV prevention was provided in the detoxification centers and RTL centers and that HIV-related risk behaviors, including injection drug use and unsafe sex, occurred in both types of center. Finally, the IDUs reported that their fear of being recognized by the police and detained even if not taking drugs prevented them from seeking HIV tests, HIV treatment, and help for their drug addiction.
What Do These Findings Mean?
This study has several limitations in addition to its small size. For example, because the IDUs were self selected—they responded to posters asking if they would be interviewed—their views may not be representative of all IDUs. Similarly, the key informants who were interviewed might have had different opinions from those who chose not to participate. Furthermore, the results reported here cannot be generalized to other areas of China. Nevertheless, the consistent experiences reported by the IDUs and confirmed by the key informants suggest that China's anti-narcotic policies and practices violate the human rights of IDUs and put their health in danger by making it hard for them to access HIV prevention and treatment or adequate treatment for their drug addiction. This situation, if not remedied, is likely to jeopardize China's attempts to control its HIV epidemic.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050234.
This study is further discussed in a PLoS Medicine Perspective by Steve Koester
Avert, an international AIDS charity, provides information on all aspects of HIV/AIDS, including HIV and AIDS in China and HIV prevention, harm reduction, and injecting drug use
The UNAIDS 2008 Country Progress Report provides up-to-date details about the AIDS situation in China
HIVInSite provides links to more information about HIV/AIDS in China.
Human Rights Watch works on health and human rights and human rights developments in China
The US National Institute on Drug Abuse provides a booklet entitled Principles of Drug Addiction Treatment: A Research Based Guide (in English and Spanish)
UN Office on Drugs and Crime has information on HIV/AIDS in prisons
doi:10.1371/journal.pmed.0050234
PMCID: PMC2596857  PMID: 19071954
25.  Hos2p/Set3p Deacetylase Complex Signals Secretory Stress through the Mpk1p Cell Integrity Pathway▿  
Eukaryotic Cell  2008;7(7):1191-1199.
Perturbations in secretory function activate stress response pathways critical for yeast survival. Here we report the identification of the Hos2p/Set3p deacetylase complex (SET3C) as an essential component of the secretory stress response. Strains lacking core components of the Hos2p/Set3p complex exhibit hypersensitivity to secretory stress. Although not required for the unfolded protein response (UPR) and ribosomal gene repression, the Hos2p complex is required for proper activation of the Mpk1p/Slt2p cell integrity kinase cascade. Disruption of the Hos2p complex results in abrogated Mpk1p phosphorylation, whereas constitutive activation of the Mpk1p pathway rescues the hos2Δ mutant growth defect in response to secretory stress. Furthermore, Hos2p activity is required for the Mpk1p-mediated activation of stress-responsive transcription factor Rlm1p, but not for the stress-induced degradation of the C-type cyclin Ssn8p. Our results identify the Hos2p complex as a critical component of the secretory stress response and support the existence a coordinated stress response consisting of the UPR, ribosomal gene repression, and mitogen-activated protein kinase signaling in response to defects in secretory function.
doi:10.1128/EC.00059-08
PMCID: PMC2446675  PMID: 18487345

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