The Institute for the History of Rheumatology, an offspring of the Italian Society of Rheumatology, is born in Venice.

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An interconnected hierarchical model of cell death regulation by the BCL-2 family.

Multidomain pro-apoptotic BAX and BAK, once activated, permeabilize mitochondria to trigger apoptosis, whereas anti-apoptotic BCL-2 members preserve mitochondrial integrity. The BH3-only molecules (BH3s) promote apoptosis by either activating BAX-BAK or inactivating anti-apoptotic members. Here, we present biochemical and genetic evidence that NOXA is a bona fide activator BH3. Using combinatorial gain-of-function and loss-of-function approaches in Bid(-/-)Bim(-/-)Puma(-/-)Noxa(-/-) and Bax(-/-)Bak(-/-) cells, we have constructed an interconnected hierarchical model that accommodates and explains how the intricate interplays between the BCL-2 members dictate cellular survival versus death. BID, BIM, PUMA and NOXA directly induce stepwise, bimodal activation of BAX-BAK. BCL-2, BCL-XL and MCL-1 inhibit both modes of BAX-BAK activation by sequestering activator BH3s and 'BH3-exposed' monomers of BAX-BAK, respectively. Furthermore, autoactivation of BAX and BAK can occur independently of activator BH3s through downregulation of BCL-2, BCL-XL and MCL-1. Our studies lay a foundation for targeting the BCL-2 family for treating diseases with dysregulated apoptosis.

PUMA and BIM are required for oncogene inactivation-induced apoptosis.

The clinical efficacy of tyrosine kinase inhibitors supports the dependence of distinct subsets of cancers on specific driver mutations for survival, a phenomenon called "oncogene addiction." We demonstrate that PUMA and BIM are the key apoptotic effectors of tyrosine kinase inhibitors in breast cancers with amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) and lung cancers with epidermal growth factor receptor (EGFR) mutants. The BH3 domain containing proteins BIM and PUMA can directly activate the proapoptotic proteins BAX and BAK to permeabilize mitochondria, leading to caspase activation and apoptosis. We delineated the signal transduction pathways leading to the induction of BIM and PUMA by tyrosine kinase inhibitors. Inhibition of the mitogen-activated or extracellular signal-regulated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway caused increased abundance of BIM, whereas antagonizing the phosphoinositide 3-kinase (PI3K)-AKT pathway triggered nuclear translocation of the FOXO transcription factors, which directly activated the PUMA promoter. In a mouse breast tumor model, the abundance of PUMA and BIM was increased after inactivation of HER2. Moreover, deficiency of Bim or Puma impaired caspase activation and reduced tumor regression caused by inactivation of HER2. Similarly, deficiency of Puma impeded the regression of EGFR(L858R)-driven mouse lung tumors upon inactivation of the EGFR-activating mutant. Overall, our study identified PUMA and BIM as the sentinels that interconnect kinase signaling networks and the mitochondrion-dependent apoptotic program, which offers therapeutic insights for designing novel cell death mechanism-based anticancer strategies.

Conflicting perceptions between health care professionals and patients on the psychological morbidity following miscarriage.

BACKGROUND: Miscarriage is common and may result in significant psychological morbidity for women. Recent research has revealed that health care professionals often tend to neglect this factor. This negligence may lead to delayed diagnosis and appropriate care. AIMS: To assess health care professionals' and patients' attitudes towards the psychological impact of miscarriage. METHODS: A prospective, cross-sectional survey of nearly 3000 subjects was conducted. Of these, 1269 were health care professionals and 1519 were pregnant women or their spouses. Their perceptions of the psychological impact of miscarriage, in comparison with postnatal depression were studied. RESULTS Health care professionals were less aware of the psychological impact of miscarriage compared with postnatal depression (91.9 vs 98.4%, P = 0.02). Furthermore, they believed that the psychological impact of miscarriage was less than that of postnatal depression (79.9 vs 88.9%, P < 0.001). However, more patients believed that psychological impact after miscarriage can seriously affect women (59.0 vs for health care professionals 38.3%, P < 0.001). A higher proportion of patients compared with health care professionals (85.2 vs 74.3%, P < 0.001) believed that routine psychological support should be provided after miscarriage, but few agreed that primary health professionals were the most suitable people to provide this care although most health care professionals thought this to be appropriate (9.1 vs 59.7%, P < 0.001). CONCLUSION: Health care professionals should be more aware of the psychological morbidity associated with miscarriage and also be sensitive to a currently unmet need for psychological care.

What drives communities' decisions and behaviours in the reuse of wastewater.

This paper outlines a five year investigation which aimed to develop a measurement to predict community intended behaviour in relation to the reuse of wastewater. It has been apparent that communities support the concept of water reuse as a means of responsible water resources management. However, reactions from people when it comes to actually using the recycled water are frequently quite different, particularly when it involves close personal contact or ingestion of the water. Little has been known of how people make their decisions to accept or reject schemes. Therefore, a research program was designed to systematically identify, measure and test the major factors that govern people's decision-making. A social experiment was designed whereby a large group of random community members participated in tasting and swallowing what they believed to be recycled water from different sources and products grown with recycled waters. This provided an immediate experience for the development of measures of psychological and other factors in decisions to taste and/or swallow. This then formed the basis for whole of city surveys which tested and refined an hypothesised model of intended behaviour, and three case studies over time which sought to replicate the model.

Three-dimensional ultrasound features of the polycystic ovary and the effect of different phenotypic expressions on these parameters.

BACKGROUND: The aim of this study was to quantify the three-dimensional (3D) ultrasound characteristics of ovaries in Caucasian women with polycystic ovarian syndrome (PCOS) and to examine if these values differed between different phenotypic forms. METHODS: 3D pelvic ultrasound was performed in 40 women with PCOS and in 40 controls. Total ovarian volume, stromal volume and echogenicity and antral follicle count (AFC) were measured and ovarian blood flow was quantified using both 3D power Doppler and two-dimensional pulsed-wave Doppler. RESULTS: Women with PCOS had a higher AFC (median 16.3 versus 5.5 per ovary, P < 0.001) and ovarian volume (12.56 versus 5.66 ml, P < 0.001). Stromal volume (10.79 versus 4.69 ml, P < 0.001) and stromal vascularization (VI: 3.85 versus 2.79%, P < 0.001; VFI: 1.27 versus 0.85, P < 0.001) were also increased in women with PCOS. There were no significant differences in stromal echogenicity or pulsed-wave Doppler indices between women with PCOS and the controls. Among the women with PCOS, ovarian vascularity was significantly higher in 30 women who were hirsute compared with normoandrogenic women (FI: 33.94 versus 29.30, P < 0.05) and in 14 women with PCOS who were of normal weight compared with obese women (VI: 4.51 versus 3.25%, P < 0.05; VFI: 1.56 versus 1.22, P < 0.05). CONCLUSIONS: Based on 3D ultrasound, women with PCOS have an increased stromal volume and vascularity. Stromal vascularity is significantly higher in women with PCOS who are hirsute and of normal weight.

Where are we with postmenopausal hormone therapy in 2005?

Recently, two large randomized placebo-controlled studies on long-term postmenopausal hormone replacement therapy, the Heart and Estrogen/progestin Replacement Study (HERS) and the Women's Health Initiative (WHI), have raise a lot of controversies, especially on the cardiovascular aspects. We briefly review these two trials and discuss what we know and do not know about postmenopausal hormone therapy, including the evidence on novel choices such as raloxifene and tibolone.

Intensity-modulated radiotherapy for early-stage nasopharyngeal carcinoma: a prospective study on disease control and preservation of salivary function.

BACKGROUND: Xerostomia is a uniform complication after radiotherapy (RT) for nasopharyngeal carcinoma (NPC). Dosimetric studies suggested that intensity-modulated RT (IMRT) can spare part of the parotid glands from high-dose radiation. Disease control and salivary function after IMRT for early-stage NPC was studied prospectively. METHODS: Thirty-three patients with T1,N0-N1,M0 NPC were treated with IMRT from 2000 to 2002. The prescribed dose was 68-70 grays (Gy) in 34 fractions to gross tumor volume, 64-68 Gy to the planning target volume, and 70 Gy to enlarged cervical lymph nodes. Nineteen patients had stimulated whole salivary (SWS) flow assessment and stimulated parotid salivary (SPS) flow assessment at baseline and at 2 months, 6 months, 12 months, 18 months, and 24 months after the completion of IMRT. RESULTS: At a median follow-up of 2 years, only 1 neck failure was observed. The 2-year and 3-year local control, distant metastases-free, and overall survival rates all were 100%. The lymph node control and progression-free survival rates were 100% at 2 years and 92.3% at 3 years, respectively. The average mean dose to the parotid gland was 38.8 Gy. The SWS and SPS flow showed continuous recovery: 60% and 47.1% of patients recovered at least 25% of their baseline SPS flow and SWS flow, respectively, at 1 year after completion of IMRT, and the proportions rose to 85.7% and 71.4%, respectively, by 2 years. The pH and buffering capacity of saliva also improved with time. CONCLUSIONS: Parotid-sparing IMRT achieved good locoregional control, and there was continuous recovery of salivary flow, pH, and buffering capacity in the first 2 years after IMRT in patients with NPC.

A randomized, placebo-controlled, crossover study of tibolone (Livial) on menopause symptoms, psychological well-being, and dyadic relationship of postmenopausal Chinese women and their spouses.

OBJECTIVE: To investigate the effects of 6-month treatment of tibolone on menopause symptoms, psychological well-being, and the dyadic relationship of postmenopausal Chinese women and their spouses. DESIGN: A randomized, double-blind, crossover study was conducted in 100 postmenopausal Hong Kong Chinese women who received tibolone (2.5mg/day) and placebo. At baseline, 6-month and 13-month visits, the women filled in the Greene Climacteric Scale (GCS), 12-item General Health Questionnaire (GHQ) and Dyadic Adjustment Scale (DAS), and their spouses completed GHQ and DAS. RESULTS: Both tibolone and placebo treatment were associated with a significant reduction in the GCS total scores after the first 6-month interventional period (95% CI: -8.0 to -2.5 for tibolone, and -5.7 to -0.7 for placebo). After the correction for placebo response, tibolone treatment was associated with a significant reduction in the GCS somatic subscore (-1.1 +/- 0.4 for tibolone group versus 0.6 +/- 0.5 for placebo group, P < 0.05). There were no significant changes in the GHQ and DAS total scores of the women and their spouses after tibolone treatment, both with and without the correction for placebo response. CONCLUSIONS: Tibolone treatment had a significant beneficial effect on the somatic menopause symptoms but had no effect on the psychological well-being or marital relationship of the postmenopausal Chinese women and their spouses.

Repeated courses of antenatal corticosteroids: is it justified?

The benefits of a single course of antenatal corticosteroids on neonatal outcomes are well established. There is, however, much controversy about how long this treatment should continue, and whether repeated courses should be administered if the women remain at risk for preterm delivery 7 days after the initial therapy. This review aims to discuss current evidence on the effectiveness and safety of repeated courses of antenatal corticosteroids.

Nadir prostate-specific antigen as a predictor of progression to androgen-independent prostate cancer.

OBJECTIVES: To determine the value of the before and after treatment level of prostate-specific antigen (PSA) to predict the time to androgen-independent progression (AIP) in patients with advanced prostate cancer who received androgen-deprivation therapy (ADT) at the time of recurrence or progression. METHODS: The records of 153 patients with advanced or metastatic prostate cancer who were treated with ADT were retrospectively reviewed. Fifty-six percent of the patients were initially treated with ADT. In the remainder, ADT was started at progression and/or failure. AIP was defined as two consecutive elevations of serum PSA above the nadir value by any threshold. Kaplan-Meier and multiple logistic regression analyses were used to determine the potential predictors of AIP. RESULTS: The median duration of the PSA response was 24 months. The most important predictors of the time to AIP were the initial Gleason grade and the nadir PSA level after the initiation of ADT. The odds ratio of having a response greater than 24 months was 15-times higher in patients achieving an undetectable serum PSA level versus those who did not. For each point increase in the Gleason sum, patients had a five times higher chance of progressing to AIP in 24 months or less. CONCLUSIONS: The ability to achieve an undetectable nadir PSA level and the initial Gleason grade are significant predictors of the time to AIP in men treated with ADT for metastatic and advanced prostate cancer.

Psychosocial consequences of childhood and adolescent cancer survival.

A Connecticut Addendum to a multi-center National Cancer Institute study was developed to investigate psychosocial effects of long-term childhood and adolescent cancer survival. Cases (450), drawn from the files of the Connecticut Tumor Registry and 587 of their siblings were located and interviewed. Overall response rate was 84%. The frequency of lifetime major depression in survivors (males, 15%; females, 22%) did not appear to differ from that of their siblings (males, 12%; females, 24%) and was similar to those reported in the literature for the general population. The usual correlates of depression (sex, marital status, perception of health) were observed, independent of a history of a childhood malignancy. There were no differences in the reported frequencies of suicide attempts, running away or psychiatric hospitalizations for either sex. Eighty percent of the male survivors were rejected from the armed forces, 13% from college and 32% from employment. These values were significantly higher than those of the male siblings. Female survivors were significantly more likely than their sisters to be denied entrance into the military (p less than 0.05), but no differences were observed between females with respect to college or employment. Both sexes had more difficulty obtaining health and life insurance than their siblings (p less than 0.0001). Although survivors of childhood and adolescent cancer do not seem to be at excess risk for major depression, they do appear to have difficulty attaining certain major socioeconomic goals.