Publications

Hormone-sensitive tumours are among the most common cancers in women. Specific inhibition of the estrogen receptor by selective estrogen receptor downregulators or selective estrogen receptor modulators (SERMs) is effective for the treatment of breast and endometrial cancers and may be used for the prevention of breast cancer. Due to differential recruitment of co-activators and corepressors, SERMs are tissue specific and may have antiestrogenic effects in some tissues, with estrogen agonist activity in others. The ideal SERM would have antiestrogenic effects on the breast and endometrium, but pro-estrogenic effects on bone and lipids. The SERM, arzoxifene (LY-353381.HCl) meets all of these criteria. This review summarises the development, preclinical studies and the clinical outcome of arzoxifene and places it in context with other modalities in the treatment of hormone receptor-positive tumours.

The minimally invasive nature of endoscopically placed gastrostomy tubes makes them a viable consideration in palliative care. Complications related to the procedure appear to correlate with age and underlying comorbidities.However, in many instances, the scientific basis for establishing benefit or harm from tube placement is methodologically inadequate. Decisions must be preceded by a discussion of the value and potential risk of artificial nutrition in a particular setting, respecting the wishes and beliefs of each patient and his or her family. The decision to use PEG placement for any reason should be consistent with legal and ethical principles, reflect patient autonomy over any other consideration (including beneficence), and arise from a clear determination of the goals of care (and whether the PEG placement will truly help meet those goals). Whenever possible, further studies with better design are needed to evaluate whether the use of PEG truly affects quality of life and patient outcome in palliative care. PEG tubes for decompression are placed successfully most of the time. Symptom relief occurs usually within 7 days of the procedure. Overall, the morbidity related to the PEG procedure for decompression is only slightly higher than when the same technique is used for nutritional purposes. The appropriate timing for PEG tube placement for nutritional support and for decompression throughout the course of disease progression may be difficult to determine and yet may be a factor in its overall efficiency. Only minor modifications of the basic technique used for PEG placement for nutritional purposes are required to adapt the technique to a variety of other applications in palliative care.

Guidelines for asthma management have proposed that initial treatment should be based on assessment of asthma severity. The treatments proposed for different degrees of asthma severity are essentially estimates of the intensity of treatment needed to achieve asthma control. Responsiveness to treatment is heterogeneous, however, even among asthmatic patients with asthma of similar severity. This heterogeneity calls attention to the importance of assessing asthma control and adjusting treatment accordingly. Application of a guidelines-based approach to asthma management thus requires general agreement on what is meant by severity, control, and responsiveness and requires further an awareness of asthma as causing symptoms and functional impairment in the present and also as causing risk of adverse events in the future.

CONTEXT

Heterozygous mutations in the melanocortin-4 receptor (MC4R) gene are the most common monogenic form of severe obesity in children. There are conflicting reports regarding the prevalence, nature, and pathogenic effects of MC4R mutations in adults with severe late-onset obesity.

OBJECTIVE

Our objective was to determine the prevalence of MC4R mutations in a cohort of severely obese adults and to determine the clinical phenotype and the phenotype-genotype relationship within adult MC4R mutation carriers.

DESIGN AND SETTING

We conducted an observational study at a referral center.

PATIENTS OR OTHER PARTICIPANTS

Participants included 769 adult patients with body mass index of at least 35 kg/m(2) and 444 nonobese control individuals.

INTERVENTIONS

There were no interventions.

MAIN OUTCOME MEASURES

We assessed the prevalence of pathogenic MC4R mutations, functional characteristics of the detected mutations, phenotype, and phenotype-genotype relationship within mutation carriers.

RESULTS

The global prevalence of obesity-specific MC4R mutations was 2.6%, and the 95% confidence interval (CI(95)) was 1.5-3.7. The prevalence of MC4R mutations was similar in patients developing obesity in childhood (2.83%; CI(95), 0.9-4.8) and in patients with a later onset of the disease (2.35%; CI(95), 0.9-3.8). Adult obese MC4R mutation carriers did not present with binge eating or with any specific clinical phenotype. The severity of the functional alterations of the mutated MC4Rs and in particular the intracellular retention of the receptor correlates both with the severity and the onset of the obesity in the mutation carriers.

CONCLUSIONS

Obese adult carriers of functionally relevant MC4R mutations do not specifically present with binge-eating disorder or a history of early-onset obesity. The onset and severity of the obesity in the carriers is related to the functional severity of the MC4R mutations.

The aim of the study was to investigate the impact of ischemia/reperfusion injury on the proteome of Kupffer cells. Lean Zucker rats (n = 6 each group) were randomized to 75 min of warm ischemia or sham operation. After reperfusion for 8 h, Kupffer cells were isolated by enzymatic perfusion and density gradient centrifugation. Proteins were tryptically digested into peptides and differentially labeled with iTRAQ (isobaric tags for relative and absolute quantitation) reagent. After fractionation by cation exchange chromatography, peptides were identified by mass spectrometry (ESI-LC-MS/MS). Spectra were interrogated against the Swiss-Prot database and quantified using ProteinProspector. The results for heat shock protein 70 and myeloperoxidase were validated by ELISA. Quantitative information for more than 1559 proteins was obtained. In the ischemia group proteins involved in inflammation were significantly up-regulated. The ratio for calgranulin B in the ischemia/sham group was 1.81 +/- 0.97 (p < 0.0001), for complement C3 the ratio was 1.81 +/- 0.49 (p < 0.0001), and for myeloperoxidase the ratio was 1.30 +/- 0.32. Myeloperoxidase was only recently documented in Kupffer cells. The antioxidative proteins Cu,Zn-superoxide dismutase (1.34 +/- 0.19; p < 0.001) and catalase (1.23 +/- 0.43; p < 0.001) were also elevated. In conclusion, ischemia/reperfusion injury induces alterations in the Kupffer cell proteome. Isotope ratio mass spectrometry is a powerful tool to investigate these reactions. The ability to simultaneously monitor several pathways involved in reperfusion stress may result in important mechanistic insight and possibly new treatment options.