Promotional tone in reviews of menopausal hormone therapy after the Women's Health Initiative: an analysis of published articles

Background

Even after the Women''s Health Initiative (WHI) found that the risks of menopausal hormone therapy (hormone therapy) outweighed benefit for asymptomatic women, about half of gynecologists in the United States continued to believe that hormones benefited women''s health. The pharmaceutical industry has supported publication of articles in medical journals for marketing purposes. It is unknown whether author relationships with industry affect promotional tone in articles on hormone therapy. The goal of this study was to determine whether promotional tone could be identified in narrative review articles regarding menopausal hormone therapy and whether articles identified as promotional were more likely to have been authored by those with conflicts of interest with manufacturers of menopausal hormone therapy.

Methods and Findings

We analyzed tone in opinion pieces on hormone therapy published in the four years after the estrogen-progestin arm of the WHI was stopped. First, we identified the ten authors with four or more MEDLINE-indexed reviews, editorials, comments, or letters on hormone replacement therapy or menopausal hormone therapy published between July 2002 and June 2006. Next, we conducted an additional search using the names of these authors to identify other relevant articles. Finally, after author names and affiliations were removed, 50 articles were evaluated by three readers for scientific accuracy and for tone. Scientific accuracy was assessed based on whether or not the findings of the WHI were accurately reported using two criteria: (1) Acknowledgment or lack of denial of the risk of breast cancer diagnosis associated with hormone therapy, and (2) acknowledgment that hormone therapy did not benefit cardiovascular disease endpoints. Determination of promotional tone was based on the assessment by each reader of whether the article appeared to promote hormone therapy. Analysis of inter-rater consistency found moderate agreement for scientific accuracy (κ = 0.57) and substantial agreement for promotional tone (κ = 0.65). After discussion, readers found 86% of the articles to be scientifically accurate and 64% to be promotional in tone. Themes that were common in articles considered promotional included attacks on the methodology of the WHI, arguments that clinical trial results should not guide treatment for individuals, and arguments that observational studies are as good as or better than randomized clinical trials for guiding clinical decisions. The promotional articles we identified also implied that the risks associated with hormone therapy have been exaggerated and that the benefits of hormone therapy have been or will be proven. Of the ten authors studied, eight were found to have declared payment for speaking or consulting on behalf of menopausal hormone manufacturers or for research support (seven of these eight were speakers or consultants). Thirty of 32 articles (90%) evaluated as promoting hormone therapy were authored by those with potential financial conflicts of interest, compared to 11 of 18 articles (61%) by those without such conflicts (p = 0.0025). Articles promoting the use of menopausal hormone therapy were 2.41 times (95% confidence interval 1.49–4.93) as likely to have been authored by authors with conflicts of interest as by authors without conflicts of interest. In articles from three authors with conflicts of interest some of the same text was repeated word-for-word in different articles.

Conclusion

There may be a connection between receiving industry funding for speaking, consulting, or research and the publication of promotional opinion pieces on menopausal hormone therapy. Please see later in the article for the Editors'' Summary     

Exfoliative cytology of the oral mucosa in burning mouth syndrome: a cytomorphological and cytomorphometric analysis

doi:10.1111/j.1741‐2358.2009.00319.x
Exfoliative cytology of the oral mucosa in burning mouth syndrome: a cytomorphological and cytomorphometric analysis Objective: The aim of this study was to evaluate oral epithelial cells by exfoliative cytology in burning mouth syndrome (BMS). Material and methods: Oral smears were collected from clinically normal‐appearing mucosa by liquid‐based exfoliative cytology in 40 individuals (20 BMS patients and 20 healthy controls matched for age and gender) and analysed for cytological and cytomorphometric techniques. Results: Mean values of nuclear area (NA) for experimental and control groups were, respectively, 67.52 and 55.64 μm² (p < 0.05). Cytoplasmic area (CA) showed the following mean values: 1258.0 (experimental) and 2069.0 μm² (control). Nucleus‐to‐cytoplasm area ratio for the experimental group was 0.07, besides the control group was 0.03 (p < 0.05). Morphologically, oral smears exhibited normal epithelial cells in both experimental and control groups. There was a significant predominance of nucleated cells of the superficial layer in the smears of BMS patients (p = 0.00001). Conclusion: This study revealed that oral mucosa of BMS patients exhibited significant cytomorphometric changes in the oral epithelial cells. These changes probably are associated with epithelial atrophy and a deregulated maturation process that may contribute to the oral symptoms of pain and discomfort in BMS.     

Phospholipase gene expression during Paracoccidioides brasiliensis morphological transition and infection

Phospholipase is an important virulence factor for pathogenic fungi. In this study, we demonstrate the following: (i) the Paracoccidioides brasiliensis pld gene is preferentially expressed in mycelium cells, (ii) the plb1 gene is mostly up-regulated by infection after 6 h of co-infection of MH-S cells or during BALB/c mice lung infection, (iii) during lung infection, plb1, plc and pld gene expression are significantly increased 6-48 h post-infection compared to 56 days after infection, strongly suggesting that phospholipases play a role in the early events of infection, but not during the chronic stages of pulmonary infection by P. brasiliensis.     

At the core of survival: autophagy delays the onset of both apoptotic and necrotic cell death in a model of ischemic cell injury

Ischemic cell injury leads to cell death. Three main morphologies have been described: apoptosis, cell death with autophagy and necrosis. Their inherent dynamic nature, a point of no return (PONR) and molecular overlap have been stressed. The relationship between a defined cell death type and the severity of injury remains unclear. The functional role of autophagy and its effects on cell death onset is largely unknown. In this study we report a differential induction of cell death, which is dependent on the severity and duration of an ischemic insult. We show that mild ischemia leads to the induction of autophagy and apoptosis, while moderate or severe ischemia induces both apoptotic and necrotic cell death without increased autophagy. The autophagic response during mild injury was associated with an ATP surge. Real-time imaging and Fluorescence Resonance Energy Transfer (FRET) revealed that increased autophagy delays the PONR of both apoptosis and necrosis significantly. Blocking autophagy shifted PONR to an earlier point in time. Our results suggest that autophagic activity directly alters intracellular metabolic parameters, responsible for maintaining mitochondrial membrane potential and cellular membrane integrity. A similar treatment also improved functional recovery in the perfused rat heart. Taken together, we demonstrate a novel finding: autophagy is implicated only in mild injury and positions the PONR in cell death.     

Overlooked post-translational modifications of proteins in Plasmodium falciparum: N- and O-glycosylation -- a review

Human malignant malaria is caused by Plasmodium falciparum and accounts for almost 900,000 deaths per year, the majority of which are children and pregnant women in developing countries. There has been significant effort to understand the biology of P. falciparum and its interactions with the host. However, these studies are hindered because several aspects of parasite biology remain controversial, such as N- and O-glycosylation. This review describes work that has been done to elucidate protein glycosylation in P. falciparum and it focuses on describing biochemical evidence for N- and O-glycosylation. Although there has been significant work in this field, these aspects of parasite biochemistry need to be explored further.     

Estimating Protistan Diversity Using High‐Throughput Sequencing

Sequencing hypervariable regions from the 18S rRNA gene is commonly employed to characterize protistan biodiversity, yet there are concerns that short reads do not provide the same taxonomic resolution as full‐length sequences. A total of 7,432 full‐length sequences were used to perform an in silico analysis of how sequences of various lengths and target regions impact downstream ecological interpretations. Sequences that were longer than 400 nucleotides and included the V4 hypervariable region generated results similar to those derived from full‐length 18S rRNA gene sequences. Present high‐throughput sequencing capabilities are approaching protistan diversity estimation comparable to whole gene sequences.     

Integrative transformation of the ascomycete Podospora anserina: identification of the mating-type locus on chromosome VII of electrophoretically separated chromosomes

Summary Protoplasts of wild-type strain s and a long-lived extrachromosomal mutant (AL2) of the ascomycete Podospora anserina were transformed using a plasmid (pAN7-1) which contains the hygromycin B phosphotransferase gene (hph) of Escherichia coli under the control of Aspergillus nidulans regulatory sequences. After optimizing the transformation procedure, transformation efficiencies of 15–21 transformants/ plasmid DNA were obtained. Using a second selectable vector (pBT3), which contains the -tubuline gene of a benomyl-resistant Neurospora crassa mutant, the cotransformation rate was determined. Southern blot hybridization experiments revealed that the transforming plasmid became integrated into the genome of the recipient either as a single copy or as multiple copies. In addition, the data from molecular as well as from classical genetic analyses indicated that in independent transformants vector integration occurred at different positions. The mitotic and meiotic stability of transformants proved to be dependent on the number of integrated plasmid copies. Genetic analyses revealed a transformant in which the integrated vector is closely linked to the mating-type locus. Fractination of whole chromosomes by pulsed field gel electrophoresis and subsequent hybridization of the immobilized DNAs against radiolabelled vector sequences indicated the largest of seven chromosomes as the chromosome containing the integrated vector and thus the mating-type locus. Offprint requests to: K. Esser     

Unique long terminal repeat and surface glycoprotein gene sequences of feline leukemia virus as determinants of disease outcome

The outcome of feline leukemia virus (FeLV) infection in nature is variable, including malignant, proliferative, and degenerative disorders. The determinants of disease outcome are not well understood but are thought to include viral, host, and environmental factors. In particular, genetic variations in the FeLV long terminal repeat (LTR) and SU gene have been linked to disease outcome. FeLV-945 was previously identified as a natural isolate predominant in non-T-cell neoplastic and nonneoplastic diseases in a geographic cohort. The FeLV-945 LTR was shown to contain unique repeat elements, including a 21-bp triplication downstream of the enhancer. The FeLV-945 SU gene was shown to encode mutational changes in functional domains of the protein. The present study details the outcomes of infection with recombinant FeLVs in which the LTR and envelope (env) gene of FeLV-945, or the LTR only, was substituted for homologous sequences in a horizontally transmissible prototype isolate, FeLV-A/61E. The results showed that the FeLV-945 LTR determined the kinetics of disease. Substitution of the FeLV-945 LTR into FeLV-A/61E resulted in a significantly more rapid disease onset but did not alter the tumorigenic spectrum. In contrast, substitution of both the FeLV-945 LTR and env gene changed the disease outcome entirely. Further, the impact of FeLV-945 env on the disease outcome was dependent on the route of inoculation. Since the TM genes of FeLV-945 and FeLV-A/61E are nearly identical but the SU genes differ significantly, FeLV-945 SU is implicated in the outcome. These findings identify the FeLV-945 LTR and SU gene as determinants of disease.     

Signal transduction in myocardial ischaemia and reperfusion

Recent studies in the non-ischaemic myocardium indicated that drugs stimulating cAMP formation inhibit ₁-mediated inositol phosphate generation, while ₁-adrenergic stimulation lowered tissue CAMP levels, implicating cross-talk between ₁,- and -adrenergic signalling pathways in normal physiological conditions. Massive amounts of endogenous catecholamines, predominantly noradrenaline, are released during myocardial ischaemia and reperfusion, causing stimulation of both ₁- and -adrenergic receptors which, in turn, may contribute to intracellular Ca²⁺ overload and subsequent cell damage. Since no information is available regarding cross-talk in pathophysiological conditions, the aim of this study was to evaluate the interactions between ₁- and -adrenergic signalling pathways during different periods of ischaemia and reperfusion.Isolated rat hearts were perfused retrogradely for 30 min before being subjected to (i) 5–25 min global ischaemia and (ii) 1–5 min of reperfusion after 20 min global ischaemia. Drugs (prazosin, 10^–7 M; propranolol, 10^–6 M; phenylephrine 3 × 10^–5 M; isoproterenol 10^–9 M) were added 10 min before the onset of ischaemia and were present during reperfusion.Increasing periods of ischaemia caused an immediate rise and progressive lowering in tissue cAMP and Ins(1,4,5)P₃ levels respectively. In contrast, reperfusion caused an elevation in Ins(1,4,5)P₃ levels and reduced cAMP. Prazosin elevated cAMP levels during both ischaemia and reperfusion, while propranolol had no effects on tissue Ins(1,4,5)P_3–. The activity of the ₁-adrenergic signal transduction pathway appears to have an inhibitory effect on the activity of the -adrenergic system during ischaemia and reperfusion.     

Decreased PGC1-α levels and increased apoptotic protein signaling are associated with the maladaptive cardiac hypertrophy in hyperthyroidism

Hyperthyroidism can lead to the activation of proteins which are associated with inflammation, apoptosis, hypertrophy, and heart failure. This study aimed to explore the inflammatory and apoptotic proteins involved in the hyperthyroidism-induced cardiac hypertrophy establishment. Male Wistar rats were divided into control and hyperthyroid (12 mg/L L-thyroxine, in drinking water for 28 days) groups. The expression of inflammatory and apoptotic signaling proteins was quantified in the left ventricle by Western blot. Hyperthyroidism was confirmed by evaluation of T3 and T4 levels, as well as cardiac hypertrophy development. There was no change in the expression of HSP70, HIF1-α, TNF-α, MyD88, p-NFκB, NFκB, p-p38, and p38. Reduced expression of p53 and PGC1-α was associated with increased TLR4 and decreased IL-10 expression. Decreased Bcl-2 expression and increased Bax/Bcl-2 ratio were also observed. The results suggest that reduced PGC1-α and IL-10, and elevated TLR4 proteins expression could be involved with the diminished mitochondrial biogenesis and anti-inflammatory response, as well as cell death signaling, in the establishment of hyperthyroidism-induced maladaptive cardiac hypertrophy.