Background:
Mammographic microcalcifications represent one of the most reliable features of nonpalpable breast cancer yet remain largely unexplored and poorly understood.
Methods:
We report a novel model to investigate the in vitro mineralisation potential of a panel of mammary cell lines. Primary mammary tumours were produced by implanting tumourigenic cells into the mammary fat pads of female BALB/c mice.
Results:
Hydroxyapatite (HA) was deposited only by the tumourigenic cell lines, indicating mineralisation potential may be associated with cell phenotype in this in vitro model. We propose a mechanism for mammary mineralisation, which suggests that the balance between enhancers and inhibitors of physiological mineralisation are disrupted. Inhibition of alkaline phosphatase and phosphate transport prevented mineralisation, demonstrating that mineralisation is an active cell-mediated process. Hydroxyapatite was found to enhance in vitro tumour cell migration, while calcium oxalate had no effect, highlighting potential consequences of calcium deposition. In addition, HA was also deposited in primary mammary tumours produced by implanting the tumourigenic cells into the mammary fat pads of female BALB/c mice.
Conclusion:
This work indicates that formation of mammary HA is a cell-specific regulated process, which creates an osteomimetic niche potentially enhancing breast tumour progression. Our findings point to the cells mineralisation potential and the microenvironment regulating it, as a significant feature of breast tumour development.
doi:10.1038/bjc.2011.583
PMCID: PMC3273345
PMID: 22233923
microcalcifications; breast cancer; mineralisation; calcifications; hydroxyapatite; mammography
Dean, C J | Sykes, J R | Cooper, R A | Hatfield, P | Carey, B | Swift, S | Bacon, S E | Thwaites, D | Sebag-Montefiore, D | Morgan, A M
Objectives
MRI is the preferred staging modality for rectal carcinoma patients. This work assesses the CT–MRI co-registration accuracy of four commercial rigid-body techniques for external beam radiotherapy treatment planning for patients treated in the prone position without fiducial markers.
Methods
17 patients with biopsy-proven rectal carcinoma were scanned with CT and MRI in the prone position without the use of fiducial markers. A reference co-registration was performed by consensus of a radiologist and two physicists. This was compared with two automated and two manual techniques on two separate treatment planning systems. Accuracy and reproducibility were analysed using a measure of target registration error (TRE) that was based on the average distance of the mis-registration between vertices of the clinically relevant gross tumour volume as delineated on the CT image.
Results
An automated technique achieved the greatest accuracy, with a TRE of 2.3 mm. Both automated techniques demonstrated perfect reproducibility and were significantly faster than their manual counterparts. There was a significant difference in TRE between registrations performed on the two planning systems, but there were no significant differences between the manual and automated techniques.
Conclusion
For patients with rectal cancer, MRI acquired in the prone treatment position without fiducial markers can be accurately registered with planning CT. An automated registration technique offered a fast and accurate solution with associated uncertainties within acceptable treatment planning limits.
doi:10.1259/bjr/11855927
PMCID: PMC3473927
PMID: 22190750
doi:10.1186/bcr3289
PMCID: PMC3542670
The amyloid β-peptide (Aβ), strongly implicated in the pathogenesis of Alzheimer’s disease (AD), is produced from the amyloid β-protein precursor (APP) through consecutive proteolysis by β- and γ-secretases. The latter protease contains presenilin as the catalytic component of a membrane-embedded aspartyl protease complex. Missense mutations in presenilin are associated with early-onset familial AD, and these mutations generally both decrease Aβ production and increase the proportion of the aggregation-prone 42-residue form (Aβ42) over the 40-residue form (Aβ40). The connection between these two effects is not understood. Besides Aβ40 and Aβ42, γ-secretase produces a range of Aβ peptides, the result of initial cutting at the ε site to form Aβ48 or Aβ49 and subsequent trimming every 3–4 residues. Thus, γ-secretase displays both overall proteolytic activity (ε cutting) and processivity (trimming) toward its substrate APP. Here we tested whether a decrease in total activity correlates with decreased processivity using wild type and AD-mutant presenilin-containing protease complexes. Changes in pH, temperature and salt concentration that reduced overall activity of the wild type enzyme did not consistently result in increased proportions of longer Aβ peptides. Low salt concentrations and acidic pH were notable exceptions that subtly alter the proportion of individual Aβ peptides, suggesting that the charged state of certain residues may influence processivity. Five different AD-mutant complexes, representing a broad range of effects on overall activity, Aβ42-to-Aβ40 ratios, and ages of disease onset were also tested, revealing again that changes in total activity and processivity can be dissociated. Factors that control initial proteolysis of APP at the ε site apparently differ significantly from factors affecting subsequent trimming and the distribution of Aβ peptides.
doi:10.1021/bi2007146
PMCID: PMC3205908
PMID: 21919498
Due to the lipophilicity of the metal-ion receptor, previously reported Cu(I)-selective fluorescent probes form colloidal aggregates as revealed by dynamic light scattering. To address this problem, we have developed a hydrophilic triarylpyrazoline-based fluorescent probe, CTAP-2, that dissolves directly in water and shows a rapid, reversible, and highly selective 65-fold fluorescence turn-on response to Cu(I) in aqueous solution. CTAP-2 proved to be sufficiently sensitive for direct in-gel detection of Cu(I) bound to the metallochaperone Atox1, thus demonstrating the potential for cation selective fluorescent probes to serve as tools in metalloproteomics for identifying proteins with readily accessible metal-binding sites.
doi:10.1021/ja207004v
PMCID: PMC3388948
PMID: 21916472
Toxic cyanobacterial blooms have persisted in freshwater systems around the world for centuries and appear to be globally increasing in frequency and severity. Toxins produced by bloom-associated cyanobacteria can have drastic impacts on the ecosystem and surrounding communities, and bloom biomass can disrupt aquatic food webs and act as a driver for hypoxia. Little is currently known regarding the genomic content of the Microcystis strains that form blooms or the companion heterotrophic community associated with bloom events. To address these issues, we examined the bloom-associated microbial communities in single samples from Lake Erie (North America), Lake Tai (Taihu, China), and Grand Lakes St. Marys (OH, USA) using comparative metagenomics. Together the Cyanobacteria and Proteobacteria comprised >90% of each bloom bacterial community sample, although the dominant phylum varied between systems. Relative to the existing Microcystis aeruginosa NIES 843 genome, sequences from Lake Erie and Taihu revealed a number of metagenomic islands that were absent in the environmental samples. Moreover, despite variation in the phylogenetic assignments of bloom-associated organisms, the functional potential of bloom members remained relatively constant between systems. This pattern was particularly noticeable in the genomic contribution of nitrogen assimilation genes. In Taihu, the genetic elements associated with the assimilation and metabolism of nitrogen were predominantly associated with Proteobacteria, while these functions in the North American lakes were primarily contributed to by the Cyanobacteria. Our observations build on an emerging body of metagenomic surveys describing the functional potential of microbial communities as more highly conserved than that of their phylogenetic makeup within natural systems.
doi:10.1371/journal.pone.0044002
PMCID: PMC3430607
PMID: 22952848
Kari, Laszlo | Whitmire, William M. | Olivares-Zavaleta, Norma | Goheen, Morgan M. | Taylor, Lacey D. | Carlson, John H. | Sturdevant, Gail L. | Lu, Chunxue | Bakios, Lauren E. | Randall, Linnell B. | Parnell, Michael J. | Zhong, Guangming | Caldwell, Harlan D.
In cynomolgus macaques, ocular infection with a live trachoma strain lacking the conserved 7.5-kb plasmid induced no ocular pathology but facilitated solid or partial protection from subsequent infection with a virulent strain of trachoma.
Blinding trachoma is an ancient neglected tropical disease caused by Chlamydia trachomatis for which a vaccine is needed. We describe a live-attenuated vaccine that is safe and efficacious in preventing trachoma in nonhuman primates, a model with excellent predictive value for humans. Cynomolgus macaques infected ocularly with a trachoma strain deficient for the 7.5-kb conserved plasmid presented with short-lived infections that resolved spontaneously without ocular pathology. Multiple infections with the attenuated plasmid-deficient strain produced no inflammatory ocular pathology but induced an anti-chlamydial immune response. Macaques vaccinated with the attenuated strain were either solidly or partially protected after challenge with virulent plasmid-bearing organisms. Partially protected macaques shed markedly less infectious organisms than controls. Immune correlates of protective immunity were not identified, but we did detect a correlation between MHC class II alleles and solid versus partial protection. Epidemiological models of trachoma control indicate that a vaccine with this degree of efficacy would significantly reduce the prevalence of infection and rates of reinfection, known risk factors which drive blinding disease.
doi:10.1084/jem.20111266
PMCID: PMC3201208
PMID: 21987657
The formation, maturation and dissolution of focal adhesions are basic prerequisites of cell migration and rely upon the recruitment, signalling and endocytosis of integrins. In many instances, extracellular matrix molecules are recognised by a number of integrins, and it is the sequential involvement of different integrins that allows establishment of cell polarity and migration toward a matrix stimulus. In this review we consider both the similarities and differences between two key fibronectin receptors: αvβ3 and α5β1 integrin. By considering the GTPase and kinase signalling and trafficking of two such closely-related receptors we begin to understand how cell migration is coordinated.
doi:10.1002/iub.200
PMCID: PMC3328205
PMID: 19514020
Integrin; signalling; trafficking; endocytosis; focal adhesion; migration
Copper(I)-responsive fluorescent probes based on photoinduced electron transfer (PET) switching consistently display incomplete recovery of emission upon Cu(I) binding compared to the corresponding isolated fluorophores, raising the question of whether Cu(I) might engage in adverse quenching pathways. To address this question, we performed detailed photophysical studies on a series of Cu(I)-responsive fluorescent probes that are based on a 16-membered thiazacrown receptor ([16]aneNS3) tethered to 1,3,5-triarylpyrazoline-fluorophores. The fluorescence enhancement upon Cu(I) binding, which is mainly governed by changes in the photoinduced electron transfer (PET) driving force between the ligand and fluorophore, was systematically optimized by increasing the electron withdrawing character of the 1-aryl-ring, yielding a maximum 29-fold fluorescence enhancement upon saturation with Cu(I) in methanol and a greater than 500-fold enhancement upon protonation with trifluoroacetic acid. Time-resolved fluorescence decay data for the Cu(I)-saturated probe indicated the presence of three distinct emissive species in methanol. Contrary to the notion that Cu(I) might engage in reductive electron transfer quenching, femtosecond time-resolved pump-probe experiments provided no evidence for formation of a transient Cu(II) species upon photoexcitation. Variable temperature 1H NMR experiments revealed a dynamic equilibrium between the tetradentate NS3-coordinated Cu(I) complex and a ternary complex involving coordination of a solvent molecule, an observation that was further supported by quantum chemical calculations. The combined photophysical, electrochemical, and solution chemistry experiments demonstrate that electron transfer from Cu(I) does not compete with radiative deactivation of the excited fluorophore, and hence, that the Cu(I)-induced fluorescence switching is kinetically controlled.
doi:10.1021/ja908326z
PMCID: PMC3199569
PMID: 20020716
copper; fluorescent probes; photoinduced intramolecular electron transfer; PET; Marcus theory; pyrazoline fluorophores
Campylobacter is a leading cause of bacterial gastroenteritis in humans and is often linked to contaminated poultry products. Live Salmonella vectors expressing three linear peptide epitopes from Campylobacter proteins Cj0113 (Omp18/CjaD), Cj0982c (CjaA), and Cj0420 (ACE393) were administered to chicks by oral gavage on the day of hatch, and the chicks were challenged with Campylobacter jejuni on day 21. All three candidate vaccines produced consistent humoral immune responses with high levels of serum IgG and mucosal secretory IgA (sIgA), with the best response from the Cj0113 peptide-expressing vector. Campylobacter challenge following vaccination of three candidate vaccine groups decreased Campylobacter recovery from the ileum compared to that for controls on day 32. The Cj0113 peptide-expressing vector reduced Campylobacter to below detectable levels. The Salmonella-vectored Cj0113 subunit vaccine appears to be an excellent candidate for further evaluation as a tool for the reduction of Campylobacter in poultry for improved food safety.
doi:10.1128/CVI.00379-10
PMCID: PMC3067390
PMID: 21177910
We have prepared and characterized a Cu(I)-responsive fluorescent probe, constructed using a large tetradentate, 16-membered thiazacrown ligand ([16]aneNS3) and 1,3,5-triaryl-substituted pyrazoline fluorophores. The fluorescence contrast ratio upon analyte binding, which is mainly governed by changes of the photoinduced electron transfer (PET) driving force between the ligand and fluorophore, was systematically optimized by increasing the electron withdrawing character of the 1-aryl-ring, yielding a maximum 50-fold fluorescence enhancement upon saturation with Cu(I) in methanol and a greater than 300-fold enhancement upon protonation with trifluoroacetic acid. The observed fluorescence increase was selective towards Cu(I) over a broad range of mono- and divalent transition metal cations. Previously established Hammett LFERs proved to be a valuable tool to predict two of the PET key parameters, the acceptor potential E(A/A−) and the excited state energy ΔE00, and thus to identify a set of pyrazolines that would best match the thermodynamic requirements imposed by the donor potential E(D+/D) of the thiazacrown receptor. The described approach should be applicable for rationally designing high-contrast pyrazoline-based PET probes selective towards other metal cations.
doi:10.1039/b918311f
PMCID: PMC3164304
PMID: 20066271
Rein, Chantelle M. | Anderson, Brian L | Ballard, Morgan M. | Domes, Christopher M. | Johnston, Joshua M. | Madsen, R. Jared | Wolper, Kathryn K. M. | Terker, Andrew S. | Strother, John M. | Deloughery, Thomas G. | Farrell, David H.
The dysfibrinogen γR275C can be a clinically silent mutation, with only two out of seventeen cases in the literature reporting a hemorrhagic presentation, and four cases reporting a thrombotic presentation. We describe here a particularly severe presentation in 54-year-old female patient who required a hysterectomy at 47 years of age due to heavy menstrual bleeding. Coagulation studies revealed a prolonged prothrombin time and thrombin time, a normal fibrinogen antigen level, and a low fibrinogen activity level. Molecular analysis of the patient’s DNA revealed a γ chain gene mutation resulting in an amino acid substitution at residue 275 (γR275C). Protein sequencing of the fibrinogen γ chain confirmed this mutation, which was named Fibrinogen Portland I. This case demonstrates that the γR275C mutation can lead to a severe hemorrhagic phenotype.
doi:10.1097/MBC.0b013e3283393c7c
PMCID: PMC2896445
PMID: 20386430
fibrinogen; hemorrhage; mutation
Przyklenk, K. | Frelinger, A. L. | Linden, M. D. | Whittaker, P. | Li, Y. | Barnard, M. R. | Adams, J. | Morgan, M. | Al-Shamma, H. | Michelson, A. D.
Summary
Background
Release of serotonin and activation of serotonin 5HT2A receptors on platelet surfaces is a potent augmentative stimulus for platelet aggregation. However, earlier-generation serotonin receptor antagonists were not successfully exploited as antiplatelet agents, possibly owing to their lack of specificity for the 5HT2A receptor subtype.
Objective
To assess whether targeted inhibition of the serotonin 5HT2A receptor attenuates recurrent thrombosis and improves coronary patency in an in vivo canine model mimicking unstable angina.
Methods
In protocol 1, anesthetized dogs were pretreated with a novel, selective inverse agonist of the 5HT2A receptor (APD791) or saline. Recurrent coronary thrombosis was then initiated by coronary artery injury + stenosis, and coronary patency was monitored for 3 h. Protocol 2 was similar, except that: (i) treatment with APD791 or saline was begun 1 h after the onset of recurrent thrombosis; (ii) template bleeding time was measured; and (iii) blood samples were obtained for in vitro flow cytometric assessment of platelet responsiveness to serotonin.
Results
APD791 attenuated recurrent thrombosis, irrespective of the time of treatment: in both protocols, flow–time area (index of coronary patency; normalized to baseline coronary flow) averaged 58–59% (P < 0.01) following administration of APD791 vs. 21–28% in saline controls. Moreover, the in vivo antithrombotic effect of APD791 was not accompanied by increased bleeding, but was associated with significant and selective inhibition of serotonin-mediated platelet activation.
Conclusion
5HT2A receptor inhibition with APD791, even when initiated after the onset of recurrent thrombosis, improves coronary patency in the in vivo canine model.
doi:10.1111/j.1538-7836.2009.03693.x
PMCID: PMC2916638
PMID: 19922435
angina; platelets; serotonin; thrombosis
Kari, Laszlo | Whitmire, William M. | Crane, Deborah D. | Reveneau, Nathalie | Carlson, John H. | Goheen, Morgan M. | Peterson, Ellena M. | Pal, Sukumar | de la Maza, Luis M. | Caldwell, Harlan D.
A vaccine is likely the most effective strategy for controlling human chlamydial infections. Recent studies have shown immunization with Chlamydia muridarum major outer membrane protein (MOMP) can induce significant protection against infection and disease in mice if its native trimeric structure is preserved (nMOMP). The objective of this study was to investigate the immunogenicity and vaccine efficacy of Chlamydia trachomatis nMOMP in a non-human primate trachoma model. Cynomolgus monkeys (Macaca fascicularis) were immunized systemically with nMOMP and monkeys were challenged ocularly. Immunization induced high serum IgG and IgA ELISA antibody titers, with antibodies displaying high strain-specific neutralizing activity. The PBMC of immunized monkeys produced a broadly cross-reactive, antigen-specific IFN-γ response equivalent to that induced by experimental infection. Immunized monkeys exhibited a highly significant decrease in infectious burden during the early peak shedding periods (days 3-14). However, at later time points they exhibited no difference from control animals in either burden or duration of infection. Immunization had no effect on the progression of ocular disease. These results show that systemically administered nMOMP is highly immunogenic in non-human primates and elicits partially protective immunity against ocular chlamydial challenge. This is the first time a subunit vaccine has shown a marked, significant reduction in ocular shedding in non-human primates. A partially protective vaccine, particularly one that significantly reduces infectious burden following primary infection of children, could interrupt the natural trachoma re-infection cycle. This could have a beneficial effect on the transmission between children and sensitized adults which drives blinding inflammatory disease.
doi:10.4049/jimmunol.0804375
PMCID: PMC2692073
PMID: 19494332
Vaccination; Mucosa; Bacterial; Antigens/Peptides/Epitopes; Other Animals
Sturdevant, Gail L. | Kari, Laszlo | Gardner, Donald J. | Olivares-Zavaleta, Norma | Randall, Linnell B. | Whitmire, William M. | Carlson, John H. | Goheen, Morgan M. | Selleck, Elizabeth M. | Martens, Craig | Caldwell, Harlan D.
Chlamydia trachomatis is a human pathogen of global importance. An obstacle to studying the pathophysiology of human chlamydial disease is the lack of a suitable murine model of C. trachomatis infection. Mice are less susceptible to infection with human isolates due in part to innate mouse-specific host defense mechanisms to which human strains are sensitive. Another possible factor that influences the susceptibility of mice to infection is that human isolates are commonly cultivated in vitro prior to infection of mice; therefore, virulence genes could be lost as a consequence of negative selective pressure. We tested this hypothesis by infecting innate immunity-deficient C3H/HeJ female mice intravaginally with a human serovar D urogenital isolate that had undergone multiple in vitro passages. We observed early and late infection clearance phenotypes. Strains of each phenotype were isolated and then used to reinfect naïve mice. Following infection, the late-clearance strain was significantly more virulent. It caused unvarying infections of much longer durations with greater infectious burdens that naturally ascended to the upper genital tract, causing salpingitis. Despite contrasting in vivo virulence characteristics, the strains exhibited no differences in the results of in vitro infectivity assays or sensitivities to gamma interferon. Genome sequencing of the strains revealed mutations that localized to a single gene (CT135), implicating it as a critical virulence factor. Mutations in CT135 were not unique to serovar D but were also found in multiple oculogenital reference strains. Our findings provide new information about the pathogenomics of chlamydial infection and insights for improving murine models of infection using human strains.
doi:10.1128/IAI.00386-10
PMCID: PMC2937465
PMID: 20547745
Patterson, Thomas L. | Semple, Shirley J. | Staines, Hugo | Lozada, Remedios | Orozovich, Prisci | Bucardo, Jesus | Philbin, Morgan M. | Pu, Minya | Fraga, Miguel | Amaro, Hortensia | de la Torre, Adela | Martinez, Gustavo | Magis-Rodríguez, Carlos | Strathdee, Steffanie A.
Background
We examined HIV prevalence and correlates among female sex workers (FSWs) in Tijuana and Ciudad Juarez, two large Mexico-U.S. border cities.
Methods
FSWs aged ≥18 years underwent interviews and testing for HIV, syphilis, gonorrhea and Chlamydia. Logistic regression identified factors associated with HIV infection.
Results
Of 924 FSWs, prevalence of HIV, gonorrhea, Chlamydia and syphilis titers >1:8 was 6%, 6.4%, 13% and 14.2%. Factors independently associated with HIV were injecting cocaine (OR= 2.96), smoking/snorting/inhaling methamphetamine (OR=3.32) and having syphilis titers >1:8 (OR= 4.16).
Conclusions
Culturally appropriate interventions are needed to identify and treat ulcerative STIs and reduce HIV risks associated with stimulants among FSWs in the Mexico-U.S. border region.
doi:10.1086/527379
PMCID: PMC2872174
PMID: 18260766
Mexico; female sex workers; sexually transmitted infections; HIV; methamphetamine; cocaine; drug use; non-injection; injection drug use; unprotected sex
Persistent fetal vasculature (PFV) is most often a condition of unknown cause. It represents persisting elements of fetal ocular vessels including the hyaloid arterial network. Protein C is a vitamin K-dependent serine protease, which regulates coagulation. Deficiency of protein C leads to a prothrombotic state. We report the case of a male infant born at 34 weeks gestation to non-consanguineous parents. Ophthalmic examination found bilateral PFV, microphthalmia and vitreoretinal dysplasia. He also suffered bilateral renal vein thrombosis and purpura fulminans and was diagnosed with severe protein C deficiency. Genetic analysis of the PROC gene revealed two separate pathogenic mutations, confirming compound heterozygote status. Both parents were found to be heterozygous. While ocular manifestations (commonly haemorrhages) are often seen in protein C-deficient patients, a search of the literature reveals very few recorded cases of PFV in severe protein C deficiency. We hypothesise that protein C deficiency was the cause of PFV in this patient. Intraocular thrombotic events in utero could affect the normal development of ocular vessels and lead to persistent elements of fetal vasculature in the eye. Consideration should be given to the possibility of protein C deficiency in patients presenting with PFV, particularly if bilateral.
doi:10.1159/000302372
PMCID: PMC2941843
PMID: 21045961
Bilateral renal vein thrombosis; Leukocoria; Microphthalmia; Persistent fetal vasculature; Persistent hyperplastic primary vitreous; PROC; Protein C deficiency; Purpura fulminans; Vitreoretinal dysplasia
A comparison of exercise tests
doi:10.1136/thx.2006.069195
PMCID: PMC2092460
PMID: 17387209
doi:10.1136/emj.2006.036061
PMCID: PMC2579615
PMID: 16988321
pneumothorax
Objective
To assess the opinions and practice patterns of obstetrician‐gynaecologists on acceptance and use of free drug samples and other incentive items from pharmaceutical representatives.
Methods
A questionnaire was mailed in March 2003 to 397 members of the American College of Obstetricians and Gynecologists who participate in the Collaborative Ambulatory Research Network.
Results
The response rate was 55%. Most respondents thought it proper to accept drug samples (92%), an informational lunch (77%), an anatomical model (75%) or a well‐paid consultantship (53%) from pharmaceutical representatives. A third (33%) of the respondents thought that their own decision to prescribe a drug would probably be influenced by accepting drug samples. Respondents were more likely to think the average doctor's prescribing would be influenced by acceptance of the items than theirs would be (p<0.002). Respondents who distributed drug samples to patients indicated doing so because of patients' financial need (94%) and for their convenience (76%) and less so as a result of knowledge of the efficacy of the sample product (63%). A third (34%) of respondents agreed that interactions with industry should be more strictly regulated.
Conclusion
Obstetrician‐gynaecologists largely indicated that they would act in accordance with what they think is proper regarding accepting incentive items from pharmaceutical representatives. Although accepting free drug samples was considered to be appropriate more often than any other item, samples were most commonly judged to be influential on prescribing practices. The widely accepted practice of receiving and distributing free drug samples needs to be examined more carefully.
doi:10.1136/jme.2005.014480
PMCID: PMC2563313
PMID: 17012493
Background
The evidence of benefit for pulmonary rehabilitation (PR) programmes is established. However, the optimal duration of a PR programme is not known. A randomised controlled trial was undertaken in patients with chronic obstructive pulmonary disease (COPD) to assess whether a 4 week PR programme was equivalent to our conventional 7 week PR programme at equivalent time points of 7 weeks and 6 months.
Methods
One hundred patients (56 men) with stable COPD of mean (SD) age 70 (8) years and forced expiratory volume in 1 second (FEV1) 1.13 (0.50) litres were randomised to either a 7 week (n = 50) or 4 week (n = 50) supervised PR programme. Patients were assessed at baseline, at completion of the supervised PR programme, and 6 months later. Patients randomised to the 4 week group were also assessed at the 7 week time point. Outcome measures were the Incremental Shuttle Walk Test, Endurance Shuttle Walk Test (ESWT), Chronic Respiratory Questionnaire‐Self Reported, and the Breathing Problems Questionnaire.
Results
Forty one patients in each group completed the PR programme. Patients made significant within group improvements after supervised rehabilitation. There were no statistically significant differences between the groups for any other measure at the 7 week or 6 month time points, except that patients in the 4 week group attained higher ESWT times (mean difference 124 seconds (95% CI 17.00 to 232.16), p = 0.024) at the 7 week time point.
Conclusions
A shortened 4 week supervised PR programme is equivalent to a 7 week supervised PR programme at the comparable time points of 7 weeks and 6 months.
doi:10.1136/thx.2005.048173
PMCID: PMC2117104
PMID: 16449270
pulmonary rehabilitation; chronic obstructive pulmonary disease; exercise
doi:10.1136/bjo.2006.090779
PMCID: PMC1857384
PMID: 16929067
streptococcal cellulites; necrotising fasciitis; linezolid; eyelid necrosis
Background
Injection drug use is a growing public health crisis along the U.S.–Mexican border and rising rates of blood-borne infections highlight the pressing need for harm reduction interventions. We explored the acceptability and feasibility of such interventions in Tijuana, a city adjacent to San Diego, California.
Methods
Using in-depth qualitative interviews conducted from August 2006–March 2007 with 40 key stakeholders – pharmacists, legal professionals, health officials, religious officials, drug treatment providers, and law enforcement personnel – we explored the acceptability and feasibility of interventions to reduce drug-related harm in Tijuana, Mexico. Interviews were taped with consent, transcribed verbatim, and translated. Content analysis was conducted to identify themes which included barriers, structural limitations, and suggestions for implementation.
Results
Topics included acceptance and feasibility of needle exchange programmes (NEPs), syringe vending machines, and safer injection facilities (SIFs), structural barriers and suggestions for implementation. Of these interventions, NEPs were deemed the most acceptable (75%); however, only half believed these could be feasibly implemented, citing barriers involving religion, police, and lack of political will, public awareness, and funding.
Conclusions
Increasing HIV infection rates among injection drug users in Tijuana have prompted interest in public health responses. Our results may assist policy strategists in implementing social-structural interventions that will help create enabling environments that facilitate the scale-up and implementation of harm reduction in Tijuana.
doi:10.1016/j.drugpo.2008.09.002
PMCID: PMC2727467
PMID: 18963906
Mexico; HIV/AIDS; Harm reduction; Injection drug use
Background
Since 1998 the Joint United Nations Programme on HIV/AIDS and the World Health Organization has provided estimates on the magnitude of the HIV epidemic for individual countries. Starting with the 2003 estimates, plausibility bounds about the estimates were also reported. The bounds are intended to serve as a guide as to what reasonable or plausible ranges are for the uncertainty in HIV incidence, prevalence, and mortality.
Methods
Plausibility bounds were developed for three situations: for countries with generalised epidemics, for countries with low level or concentrated epidemics (LLC), and for regions. The techniques used build on those developed for the previous reporting round. However the current bounds are based on the available surveillance and survey data from each individual country rather than on data from a few prototypical countries.
Results
The uncertainty around the HIV estimates depends on the quality of the surveillance system in the country. Countries with population based HIV seroprevalence surveys have the tightest plausibility bounds (average relative range about the adult HIV prevalence (ARR) of −18% to +19%.) Generalised epidemic countries without a survey have the next tightest ranges (average ARR of −46% to +59%). Those LLC countries which have conducted multiple surveys over time for HIV among the populations most at risk have the bounds similar to those in generalised epidemic countries (ARR −40% to +67%). As the number and quality of the studies in LLC countries goes down, the plausibility bounds increase (ARR of −38% to +102% for countries with medium quality data and ARR of −53% to +183% for countries with poor quality data). The plausibility bounds for regions directly reflect the bounds for the countries in those regions.
Conclusions
Although scientific, the plausibility bounds do not represent and should not be interpreted as formal statistical confidence intervals. However in order to make the bounds as meaningful as possible the authors have tried to apply reasonable statistical approaches and assumptions to their derivation. An understanding of the uncertainty in the HIV estimates may help policy makers take better informed decisions to address the epidemic in their respective countries.
doi:10.1136/sti.2006.021097
PMCID: PMC2576724
PMID: 16735297
HIV; estimates; plausibility; uncertainty
Strathdee, Steffanie A. | Philbin, Morgan M. | Semple, Shirley J. | Pu, Minya | Orozovich, Prisci | Martinez, Gustavo | Lozada, Remedios | Fraga, Miguel | de la Torre, Adela | Staines, Hugo | Magis-Rodríguez, Carlos | Patterson, Thomas L.
Objective:
To characterize the overlap between injection drug use and sex work by women in Tijuana and Cd. Juarez, situated on the Mexico-U.S. border.
Methods:
FSWs aged ≥18 years who were not knowingly HIV-positive and reported having unprotected sex with ≥1 client in the prior two months underwent interviews and testing for HIV, syphilis gonorrhea and Chlamydia. Logistic regression identified factors associated with injecting drugs within the last month.
Results:
Of 924 FSWs, 18.0% had ever injected drugs. Among FSW-IDUs (N=114), prevalence of HIV, syphilis titers >1:8, gonorrhea and Chlamydia was significantly higher at 12.3%, 22.7%, 15.2% and 21.2% compared to 4.8%, 13.1%, 5.2% and 11.9% among other FSWs (N=810). FSW-IDUs also had more clients in the past six months (median: 300 vs. 240, p=0.02). Factors independently associated with injecting drugs in the past month included living in Tijuana, being younger, being married/common-law, longer duration in the sex trade, speaking English, earning less for sex without condoms, often using drugs before sex, and knowing other FSWs who injected drugs.
Conclusions:
FSW-IDUs had higher STI levels, engaged in riskier behaviors and were more vulnerable to having unsafe sex with clients compared to other FSWs, indicating that this subgroup is an important bridge population requiring focused prevention.
doi:10.1016/j.drugalcdep.2007.07.001
PMCID: PMC2213538
PMID: 17714888
female sex worker; prostitution; injection drug use; needle sharing; Mexico; women