Nodal promotes invasive phenotypes via a mitogen-activated protein kinase-dependent pathway.

The progression of cancer from localized to invasive disease is requisite for metastasis, and is often characterized by epithelial-to-mesenchymal transition (EMT) and alterations in cellular adhesion and migration. Studies have shown that this transition is associated with an upregulation of embryonic stem cell-associated genes, resulting in a dedifferentiated phenotype and poor patient prognosis. Nodal is an embryonic factor that plays a critical role in promoting early invasive events during development. Nodal is silenced as stem cells differentiate; however, it re-emerges in adult life during placentation and mammary gland development, and is aberrantly expressed in many cancers. Here, we show that Nodal overexpression, in poorly invasive breast cancer and choriocarcinoma cells, causes increased invasion and migration in vitro. Furthermore, we show that Nodal overexpression in these epithelial cancer types induces an EMT-like event concomitant with the internalization of E-Cadherin. This ability of Nodal to promote cellular invasion and EMT-like phenomena is dependent upon the phosphorylation of ERK1/2. As Nodal normally signals through SMADs, these findings lend insight into an alternative pathway that is hijacked by this protein in cancer. To evaluate the clinical implications of our results, we show that Nodal inhibition reduces liver tumor burden in a model of spontaneous breast cancer metastasis in vivo, and that Nodal loss-of-function in aggressive breast cancer lines results in a decrease in invasive phenotypes. Our results demonstrate that Nodal is involved in promoting invasion in multiple cellular contexts, and that Nodal inhibition may be useful as a therapeutic target for patients with progressive disease.

Fast versus slow onset of depressive episodes: a clinical criterion for subtyping patients with major depression.

PURPOSE: The speed of onset of depressive episodes is a clinical aspect of affective disorders that has not been sufficiently investigated. Thus, we aimed to explore whether patients with fast onset of the full-blown depressive symptomatology (≤7 days) differ from those with slow onset (>7 days) with regard to demographic and clinical aspects. SUBJECTS AND METHODS: Data were obtained within an observational study conducted in outpatients with major depression who were treated with duloxetine (30-120 mg/day). Onset of depression (without any preceding critical life event) was fast in 416 (less than one week) and slower in 2220 patients. RESULTS: Compared to patients with slow onset, those with fast onset of depression had more suicide attempts in the previous 12 months (2.7% versus 1.3%, P=0.046) and less somatic comorbidity (61.7% versus 74.1%, P<0.0001). In addition, they were slightly younger at onset of depression (mean±SD 40.2±14.6 versus 42.8±14.2 years, P<0.001) and used analgesics at baseline significantly less frequently (22.8% versus 33.4%, P<0.0001). DISCUSSION AND CONCLUSION: The speed of onset of depression has to be regarded as a relevant clinical characteristic in patients with unipolar depression.

[Results of the French cohort of the European observational study FINDER: quality of life of patients treated with antidepressants]. / Résultats de la cohorte française de l'étude observationnelle européenne FINDER : qualité de vie de patients traités par antidépresseurs.

OBJECTIVES: To describe health-related quality of life (HRQoL), pain, clinical outcomes and treatment patterns in French patients with depression treated by general practitioners and psychiatrists. METHODS: Factors Influencing Depression Endpoints Research (FINDER) is a European longitudinal observational, naturalistic, multicentre study to determine the HRQoL (SF-36 and EQ-5D) and to assess outcomes of depression and anxiety (Hospital Anxiety and Depression Scale [HADS]), and pain (VAS) in a population of depressed patients initiating antidepressant treatment. Clinical diagnosis of depression was based on physician's clinical judgment. Physicians decided at their own discretion and clinical practice to initiate pharmacological treatment for depression. Adult patients with a first or new episode of depression were enrolled between May 2004 and September 2005, and followed up for 6 months. Across Europe, 437 physicians observed 3468 patients. RESULTS: In France, 606 patients (approximately 17% of the whole sample) were enrolled by 57 psychiatrists and 46 general practitioners. These patients were (mean ± SD) 45.6 ± 13.0 years old, 69% female and 39% having had a previous depressive episode in the last 2 years. According to the patient-rated HADS score greater or equal to 11, most patients (75%) were classified as cases of depression as well as cases of anxiety (84%); 51% of patients rated their overall pain severity (based on VAS cut-off of 30 mm) as moderate/severe, with 65% of these patients reporting no medical explanation for their pain. The majority (81%) of the patients were prescribed selective serotonin reuptake inhibitors (SSRI). During the 6-month follow-up, the majority of the patients (73%) remained on the same antidepressant at the same dose during the course of treatment. Between baseline and 6-month endpoint, French patients improved their mean scores (SD) on the SF-36 physical score by+3.5 (9.0) (P<0.001) and mental score by+20.6 (14.2) (P<0.001); on the EQ-5D Health State Index by+0.37 (0.32) (P<0.001) and the EQ-5D VAS by+32.3 (25.0) (P<0.001); on the HADS depression score by-8.1 (6.0) (P<0.001) and HADS anxiety score by-6.9 (5.0) (P<0.001). Patients with moderate/severe pain at baseline improved their overall pain on a mean VAS score by-34.1 (28.7) (P<0.001). CONCLUSIONS: More than half of the French patients enrolled in the study experienced pain associated with depression. During follow-up, patients improved all of their outcome measurements (physical and mental SF-36 scores, depression and anxiety HADS scores, pain VAS, EQ-5D Health State Index and VAS) and most patients remained on the same antidepressant at the same dose.

Does pain improve earlier than mood in depressed patients with painful physical symptoms treated with duloxetine?

INTRODUCTION: In depressed patients tricyclic antidepressants and selective serotonin and noradrenaline reuptake inhibitors can reduce not only depressive, but also painful physical symptoms. We investigated whether under treatment with duloxetine pain improves earlier than mood. METHODS: Data were obtained within a prospective 6-month multi-centre naturalistic study in adult out-patients with depressive episodes treated with duloxetine (fl exible doses: 30-120 mg/day). Pain and mood were assessed daily by visual analogue scales. For responders (n = 622) "time to 50 % pain response" and "time to 50 % mood response" were determined by counting the earliest day between day 0 and 27, at which the patient achieved 50 % improvement. RESULTS: Mean time to 50 % pain response (mean 6.3 days, SD 5.3) was significantly shorter than time to 50 % mood response (mean 7.6 days, SD 6.0, mean difference 1.3 days, SD 6.4; p < 0.0001). DISCUSSION: In duloxetine-responders to both pain and mood, self-rated pain improved slightly earlier than self-rated mood. The short temporal dissociation between pain and mood improvement might be explained by an earlier conscious perception of pain than mood changes.

Presence and predictors of pain in depression: results from the FINDER study.

BACKGROUND: Patients with depression often experience pain. There is limited understanding of the relation between pain and other symptoms (depressive, anxious and non-painful somatic symptoms). This exploratory study assesses pain severity and interference of pain with functioning in a clinically depressed population and investigates the relation between the different groups of symptoms. METHODS: FINDER was a 6-month prospective, observational study investigating health-related quality of life of outpatients with depression initiating antidepressant treatment. Patients completed ratings on the Hospital Anxiety and Depression Scale (HADS), Somatic Symptom Inventory (SSI-28), and overall pain severity and interference of pain with functioning using Visual Analogue Scales (VAS) at baseline and at 3 and 6 months. Regression analyses identified factors associated with overall pain severity and interference of pain with functioning, at baseline and over the observation period. RESULTS: Of 3468 eligible patients at baseline, 56.3% experienced moderate to severe pain and 53.6% had moderate to severe pain-related interference with functioning. At 6 months of follow-up, these proportions decreased to 32.5% and 28.1%, respectively. Higher baseline SSI-somatic scores (non-painful) were strongly associated with greater pain severity and greater pain-related interference with functioning at baseline and over 6 months. Certain socio-demographic (increasing age, being unemployed) and depression-related factors (more previous episodes, longer duration of current episode) were also significantly associated with greater pain severity and interference over 6 months, while higher baseline severity of depression (HADS-D) and further education were associated with less severe pain or pain-related interference with functioning over 6 months. CONCLUSIONS: Over half of depressed patients in this study experienced moderate to severe pain. Painful somatic symptoms appear to be closely related to non-painful somatic symptoms, more than to depressive or anxious symptoms suggesting that painful and non-painful somatic symptoms can be considered as one group of 'somatic symptoms,' all of them associated with depressive and anxious symptoms.

How are women with SUI-symptoms treated with duloxetine in real life practice? - preliminary results from a large observational study in Germany.

BACKGROUND: Duloxetine was found safe and effective in the treatment of moderate to severe female stress urinary incontinence (SUI) in controlled clinical trials; complementary data from routine clinical practice are still wanted. OBJECTIVES: To explore the use of various initial duloxetine doses by physicians in the treatment of female SUI in routine clinical practice and its implications on drug safety and patients' subjective impression of effectiveness. METHODS: Adult women treated with duloxetine for SUI symptoms were documented as part of an ongoing large-scale observational study in Germany. Data collected at baseline, after 4 and 12 weeks, were evaluated by initial doses. Statistics were descriptive, 95% confidence intervals were calculated for adverse event (AE) rates. RESULTS: A total of 7888 adult women were treated with duloxetine; their mean age was 61.4 years, body mass index 27 kg/m(2), incontinence episode frequency (IEF) 14.0 per week. Previous SUI treatments were observed in 52.2%, comorbidities in 60.4% of the patients. A total of 90.7% reported reduced frequency of SUI-episodes, 12.1% any AE; nausea (5.7%) and vertigo (1.6%) were reported most frequently. In all, 52.2% of patients were initiated on a duloxetine dose of 40 mg/day. Only minor differences in patient characteristics, effectiveness and tolerability were associated with varying initial duloxetine doses. CONCLUSIONS: Many women received lower duloxetine doses than expected based on evidence-based dosing recommendations. Although SUI patients in this study had a higher health risk because of old age and multiple comorbidities than in previous controlled clinical trials, AE rates were lower, possibly because of the observational character of the study and/or the use of rather low doses. Similar AE rates for varying initial doses possibly reflect sensible dose-adjustment to individual needs.

Efficacy of pergolide in treatment of restless legs syndrome: the PEARLS Study.

OBJECTIVE: To evaluate the short- and long-term safety and efficacy of pergolide therapy for restless legs syndrome (RLS) in a double-blind, placebo-controlled, randomized trial (Pergolide European Australian RLS [PEARLS] study). METHODS: We randomized 100 patients with idiopathic RLS were randomized to pergolide, 0.25 to 0.75 mg, in the evening or placebo for 6 weeks (phase 1); thereafter, patients with response on the Patient Global Impression (PGI) scale continued on double-blind pergolide or placebo, and nonresponders received open-label pergolide up to 1.5 mg/d for 12 months of treatment (phase 2). Sleep efficiency (SE) and periodic limb movements during sleep (PLMS) arousal index were monitored by centrally evaluated polysomnography (PSG). The severity of RLS was assessed using the validated International RLS Scale (IRLS). RESULTS: In phase 1 (change from baseline to week 6), pergolide reduced PLMS arousal index vs placebo (mean +/- SD, -12.6 +/- 10.0 vs -3.6 +/- 15.9; p = 0.004), and SE did not improve (mean +/- SD, +11.3 +/- 11.9% vs +6.1 +/- 18.6%; p = 0.196). Pergolide improved RLS severity score (-12.2 +/- 9.9 vs -1.8 +/- 7.5 placebo; p < 0.001) and was associated with a higher PGI response (68.1% vs 15.1%; p < 0.001) and improvements in periodic limb movements (PLM) index, PGI improvement scale, Clinical Global Impression improvement, and IRLS (all p < 0.001), patient-reported SE (p = 0.019), and quality of sleep (p < 0.001). After 12 months (phase 2), double-blind pergolide maintained improvements in PLMS arousal index and PLM index. Placebo patients switched to open-label pergolide in phase 2 exhibited marked improvements in these measures that were maintained at 12 months. Pooled results from the blinded and open-label pergolide groups demonstrated improvements at 12 months in the PLMS arousal index (p = 0.028) and PLM index (p < 0.0001) compared with placebo. Nausea and headache were more frequent with pergolide than with placebo treatment. CONCLUSIONS: Pergolide substantially improves periodic limb movement measures and subjective sleep disturbance associated with restless legs syndrome. Low-dose pergolide was well tolerated and maintained its efficacy in the long term.

Discontinuation symptoms: comparison of brief interruption in fluoxetine and paroxetine treatment.

Abrupt interruption or cessation of selective serotonin reuptake inhibitor (SSRI) treatment may result in discontinuation or treatment interruption symptoms. Recent reports suggested these symptoms occur more frequently with shorter half-life SSRIs. Previous studies indicated a 5-8-day treatment interruption resulted in fewer discontinuation-emergent adverse events in fluoxetine-treated patients than in paroxetine-treated patients. This study examines the effects of shorter treatment interruption (3-5 days), as would occur if patients miss just a few doses of medication. Patients successfully treated for depression with fluoxetine or paroxetine underwent treatment interruption in a double-blind fashion. Treatment interruption-emergent symptoms were assessed using the Discontinuation-Emergent Signs and Symptoms checklist. Other assessments included the Montgomery-Asberg Depression Rating Scale, Clinical Global Impressions-Severity scale and a social functioning questionnaire. Of 150 patients enrolled, 141 completed the study. Following treatment interruption, fluoxetine-treated patients experienced fewer treatment interruption-emergent events than did paroxetine-treated patients. The paroxetine treatment group also experienced significant increases in depressive symptoms, clinical global severity scores and difficulty in social functioning; the fluoxetine treatment group did not. These results are consistent with reports suggesting abrupt interruption of treatment with paroxetine is more often associated with somatic and psychological symptoms than is abrupt interruption of fluoxetine. Patients treated with fluoxetine appeared to be protected by its longer half-life.

Differential effects of raloxifene and continuous combined hormone replacement therapy on biochemical markers of cardiovascular risk: results from the Euralox 1 study.

OBJECTIVE: To compare the effects of the selective estrogen receptor modulator (SERM) raloxifene (Evista) and a continuous combined hormone replacement therapy (ccHRT) formulation containing estradiol and norethisterone acetate (Kliogest) on lipid and fibrinogen levels of postmenopausal women. METHODS: Euralox 1 was a prospective, randomized, double-blind trial. After a placebo wash-out, healthy postmenopausal women (n = 1008, average age 56.1 +/- 4.9 years) with a health risk profile that suggested a potential benefit from either treatment were randomly assigned to either 60 mg raloxifene or ccHRT consisting of 2 mg estradiol and 1 mg norethisterone acetate (NETA) per day for 6 months. MEASUREMENTS: Total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol with its fractions HDL2 and HDL3, the LDL/HDL ratio, triglycerides and fibrinogen were assessed at baseline and after 6 months or on early drop-out. RESULTS: Baseline values were comparable between the two groups. Blood samples of 841 women (83.4%) were available at baseline and endpoint. Total and LDL cholesterol decreased statistically significantly from baseline to endpoint in both treatment arms (by 7.2% and 3.8% with raloxifene and by 13.0% and 8.9% with ccHRT, respectively). Raloxifene produced a statistically significant increase in HDL cholesterol by 4.2%, while ccHRT induced a decline by 9.5%. Triglycerides were moderately suppressed with raloxifene and ccHRT, by 3.6 and 5.4%, respectively. Fibrinogen fell by 7.0% with raloxifene and rose by 3.6% with ccHRT. CONCLUSIONS: Continuous combined HRT was associated with decreases in total cholesterol and LDL cholesterol about twice as large as with raloxifene, but also with a decrease in HDL cholesterol. The smaller decreases in total cholesterol and LDL cholesterol associated with raloxifene were accompanied by an increase in HDL cholesterol and a decrease in fibrinogen. In conclusion, raloxifene affects fibrinogen concentrations and the overall cholesterol profile more favorably than ccHRT; these differences may have important implications for the reduction of cardiovascular disease.

A multi-centre, placebo controlled comparative study between 200 mg and 400 mg celiprolol in patients with mild to moderate essential hypertension.

A two-centre, double-blind, placebo controlled, randomized 3-way crossover study was undertaken to assess the efficacy, tolerability and safety of celiprolol in mild to moderate essential hypertension. A 4-week single-blind placebo run-in/screening period, during which no antihypertensive medication was given, was followed by 3 consecutive 4-week treatment periods with placebo or celiprolol (200 mg or 400 mg daily). At the end of the 4-week placebo run-in/screening period, 26 hospital out-patients with a seated mean blood pressure (systolic/diastolic) of 161.4/101.7 mmHg and a mean pulse rate of 75 beats/min entered the double-blind crossover phase of the study. Results showed that there was no significant difference in seated mean systolic or diastolic blood pressure between 200 mg celiprolol daily (149.2/92.3 mmHg) and 400 mg celiprolol daily (149.1/92.5 mmHg). However, mean seated systolic and diastolic blood pressures were significantly (p less than 0.05) lower on celiprolol than on placebo (157.1/98.2 mmHg). Neither dose of celiprolol had a significant effect on seated pulse rate. No patient was withdrawn due to an adverse event and no laboratory assessment outside the normal range was reported to be of any clinical significance. It is concluded that oral celiprolol, 200 mg or 400 mg daily, is effective and well tolerated for controlling mild to moderate essential hypertension. Since both doses had very similar effects on blood pressure there is no advantage in this group of patients for the 400 mg daily dose of celiprolol.