ECNP consensus meeting. Bipolar depression. Nice, March 2007.

DIAGNOSIS AND EPIDEMIOLOGY: DSM-IV, specifically its text revision DSM-IV-TR, remains the preferred diagnostic system. When employed in general population samples, prevalence estimates of bipolar disorder are relatively consistent across studies in Europe and USA. In community studies, first onset of bipolar mood disorder is usually in the mid-teenage years and twenties, and the occurrence of a major depressive episode or hypomania is usually its first manifestation. Since reliable criteria for delineating unipolar (UP) and bipolar (BI) depression cross-sectionally are currently lacking, there is a longitudinal risk - probably over 10% - that initial UP patients ultimately turn out as BP in the longer run. Its early onset implies a severe potential burden of disease in terms of impaired social and neuropsychological development, most of which is attributable to depression. BIPOLAR DEPRESSION IN CHILDREN: Bipolar I disorder is rare in prepubertal children, when defined according to unmodified DSM-IV-TR criteria. A broad diagnosis of bipolar disorder risks confounding with other childhood psychopathology and has less predictive value for bipolar disorder in adulthood than the conservative definition. Nevertheless, empirical studies of drug and other treatments and longitudinal studies to assess validity of the broadly defined phenotype in children and adolescents are desirable, rather than extrapolation from adult bipolar practice. The need for an increased capacity to conduct reliable trials in children and adolescents is a challenge to Europe, whose healthcare system should allow greater participation and collaboration than other regions, via clinical networks. ECNP will aspire to facilitate such developments. BIPOLAR DEPRESSION IN ADULTS - UNIPOLAR/BIPOLAR CONTRAST: Despite some differences in symptom profiles and severity measures, a cross-sectional categorical distinction between bipolar (BP) and unipolar (UP) depression is currently impossible. For regulatory purposes, a major depressive episode, meeting DSM-IV-TR criteria, remains the same diagnosis, irrespective of the overall course of the disorder. However, in refining diagnosis in future studies and DSM-V, a probabilistical approach to the UP/BP distinction is more likely to be informative as recommended by the International Society for Bipolar Disorders (ISBD). Anxiety is a commonly present, often at syndromal levels, in bipolar populations. Thus, RCT inclusion criteria for trials not targeting anxiety, should accept co-morbid anxiety disorders as part of the history and even current anxiety symptoms, where these are not dominating the mental state at recruitment to a study. Rapid cycling patients defined as those suffering from 4 or more episodes per year, may also be recruited into trials of bipolar depression without impairing assay sensitivity. Illness severity critically affects assay sensitivity. The minimum scores for entry into a bipolar depression trials should be >20 on HAM-D (17 item scale). However, efficacy is best detected in patients with HAM-D >24 at baseline. THE USE OF RATING SCALES IN BIPOLAR DEPRESSION: There is some dissatisfaction with the HAM-D or MADRS as the preferred primary outcome for trials, although they probably capture global severity adequately. Secondary measures to capture so-called atypical symptoms (such as hypersomnia or hyperphagia), or specific psychopathology more common in bipolar participants (such as lability of mood), could be informative as secondary measures. TREATMENT STUDIES IN BIPOLAR DEPRESSION: Monotherapy trials against placebo remain the gold-standard design for determining efficacy in bipolar depression. The confounding effects of co-medication are emerging from the literature on antidepressant studies in bipolar depression, often conducted in combination with antimanic agents to avoid possible switch to mood elevation. Three arm trials, including the compound to be tested, placebo, and a standard comparator, are generally preferred in order to ensure assay sensitivity and a better picture of benefit-risk ratio. However, in the absence of any gold-standard, two-arm trials may be enough. If efficacy happens to be proven as monotherapy, new compounds may be tested in adjunctive-medication placebo-controlled designs. Younger adults, without an established need for long-term medication, may be particularly suitable for clinical trials requiring placebo controls. The conversion rate of initial UP depression, converting to become BP in the long run is estimated to be 10%. Switch to mania or hypomania may be the consequence of active treatment for bipolar depression. Some medicines such as the tricyclic antidepressants and venlafaxine may be more likely to provoke switch than others, but this increased rate of switch may not be seen until about 10 weeks of treatment. Twelve week trials against placebo are necessary to determine the risk of switch and to establish continuing effects. Careful assessment at 6-8 weeks is required to ensure that patients who are failing to respond do not continue in a study for unacceptable periods of time. To capture a switch event, studies should include scales to define the phenomenology of the event (e.g. hypomania or mania) and its severity. These may be best applied shortly after the clinical decision that switch is occurring. Long-term treatment is commonly required in bipolar disorder. Trials to detect maintenance of effect or continued response in bipolar depression should follow a 'relapse prevention' design: i.e. patients are treated in an index episode with the medicine of interest and then randomized to either continue the active treatment or placebo. However, acute withdrawal of active medication after treatment response might artificially enhance effect size due to active drug withdrawal effects. A short taper is usually desirable. Longer periods of stabilisation are also desirable for up to 3 months: protocol compliance may then be difficult to achieve in practice and so will certainly make studies more difficult and expensive to conduct. The addition of a medicine to other agents during or after the resolution of a depressive or manic episode, and its subsequent investigation as monotherapy against placebo to prevent further relapse (as in the lamotrigine maintenance trials) is clinically informative. Assay sensitivity and patient acceptability are enhanced if the outcome in long-term studies is 'time to intervention for a new episode' for discontinuation designs.     

Management of a complicated crown-root fracture using adhesive fragment reattachment and orthodontic extrusion

Abstract –  Dental trauma is more common in young patients and its sequelae may impair the establishment and accomplishment of an adequate treatment plan. This paper reports a case of complicated crown-root fracture in a young adult that was treated using adhesive tooth fragment reattachment and orthodontic root extrusion. Considering the time elapsed to follow up, the fracture extension, the amount of remaining root portion and the patient's low socioeconomic status, the treatment approach proposed for this case provided good functional and aesthetic outcomes. Clinical and radiographic results after 2 years were successful. This case report demonstrates the importance of establishing a multidisciplinary approach for a successful dental trauma management.     

Fluorodeoxyglucose–Positron Emission Tomography Imaging Versus Sentinel Node Biopsy in the Primary Staging of Melanoma Patients

BACKGROUND: Positron emission tomography (PET) imaging is superior to conventional techniques for the evaluation of patients with stage III and stage IV cutaneous melanoma. Several studies have highlighted the advantages of this noninvasive technique for the assessment of lymph node involvement. OBJECTIVE: To compare PET imaging with sentinel node biopsy for primary staging of cutaneous melanoma and to discuss the technical limitations of PET scanning. METHODS: Twenty-five consecutive patients with a histologic diagnosis of melanoma with a Breslow thickness equal or greater to 1 mm underwent a preoperative PET to assess lymph node involvement. RESULTS: Sentinel node biopsy and PET showed a sensitivity of 100% and 22%, respectively, in the identification of lymph node metastases. CONCLUSION: PET is not a sensitive technique for the primary staging of cutaneous melanoma.     

Family history of alcoholism is associated with lower 5-HT2A receptor binding in the prefrontal cortex

Background: 5‐Hydroxytryptophan (5‐HT_2A) receptor involvement in alcoholism is suggested by less 5‐HT_2A binding in alcohol preferring rats, association of a 5‐HT_2A receptor gene polymorphism with alcohol dependence and reduced alcohol intake with 5‐HT_2A antagonists. We sought to determine postmortem whether 5‐HT_2A receptors are altered in the prefrontal cortex (PFC) of alcoholics. Methods: Brain tissue from 25 alcoholics and 19 controls was collected at autopsy. Diagnosis of DSM‐IV alcoholism/abuse and other psychiatric disorders and the determination of family history of alcoholism were made by psychological autopsy. Specific binding to 5‐HT_2A (³H‐ketanserin) receptors in the PFC was measured by quantitative autoradiography. Results: 5‐HT_2A binding decreased with age [Brodmann areas (BA) 9, 46 gyrus; r = ?0.381, ?0.334, p < 0.05]. No differences in receptor binding between alcoholics and controls were detected in the gyrus or sulcus of any PFC area examined. Cases (controls or alcoholics) with a family history of alcoholism (n = 23) had less 5‐HT_2A binding throughout PFC than subjects without (n = 21) a family history of alcoholism (p < 0.05). 5‐HT_2A receptor binding in alcoholics without a family history of alcoholism (n = 7) did not differ from controls without a family history of alcoholism (n = 14). There was no association between alcoholism or alcohol rating and genotype. There was an association between genotype and the total amount of ³H‐ketanserin binding in BA46 with the TT genotype having more binding (TT>TC≈CC). Conclusions: Lower 5‐HT_2A receptor binding in the PFC of cases with a family history of alcoholism suggests a genetic predisposition to alcoholism. Alcohol abuse by itself did not have a significant effect on PFC 5‐HT_2A binding and as 5‐HT_2A binding in alcoholics is not different from controls and antagonists may be therapeutic, fewer receptors may result in downstream developmental effects on the brain resulting in a predisposition to alcoholism.     

Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents

Primary aldosteronism (PA) is a common form of endocrine hypertension previously believed to account for less than 1% of hypertensive patients. Hypokalemia was considered a prerequisite for pursuing diagnostic tests for PA. Recent studies applying the plasma aldosterone/plasma renin activity ratio (ARR) as a screening test have reported a higher prevalence. This study is a retrospective evaluation of the diagnosis of PA from clinical centers in five continents before and after the widespread use of the ARR as a screening test. The application of this strategy to a greater number of hypertensives led to a 5- to 15-fold increase in the identification of patients affected by PA. Only a small proportion of patients (between 9 and 37%) were hypokalemic. The annual detection rate of aldosterone-producing adenoma (APA) increased in all centers (by 1.3-6.3 times) after the wide application of ARR. Aldosterone-producing adenomas constituted a much higher proportion of patients with PA in the four centers that employed adrenal venous sampling (28-50%) than in the center that did not (9%). In conclusion, the wide use of the ARR as a screening test in hypertensive patients led to a marked increase in the detection rate of PA.     

Current and future perspectives on acute-on-chronic liver failure: Challenges of transplantation,machine perfusion,and beyond

Acute-on-chronic liver failure (ACLF) is a syndrome that occurs in patients with chronic liver disease and is characterized by acute decompensation, organ failure and high short-term mortality. Partially due to the lack of universal diagnostic criteria, the actual ACLF prevalence remains unclear; nevertheless, it is expected to be a highly prevalent condition worldwide. Earlier transplantation is an effective protective measure for selected ACLF patients. Besides liver trans-plantation, diagnosing and treating precipitant events and providing supportive treatment for organ failures are currently the cornerstone of ACLF therapy. Although new clinical specific therapies have been researched, more studies are necessary to assess safety and efficacy. Therefore, future ACLF management strategies must consider measures to improve access to liver transplantation because the time window for this life-saving therapy is frequently narrow. Thus, an urgent and global discussion about allocation and prioritization for transplantation in critically ill ACLF patients is needed because there is evidence suggesting that the current model may not portray their waitlist mortality. In addition, while donor organ quality is meant to be a prognostic factor in the ACLF setting, recent evidence suggests that machine perfusion of the liver may be a safe tool to improve the donor organ pool and expedite liver transplantation in this scenario.     

Lipid profile in congenital adrenal hyperplasia

Glucocorticoids have been reported to exert a marked effect on lipoprotein metabolism. Several studies have shown a potential risk of hyperlipidemia in patients under long-term glucocorticoid therapy. Current management of patients with congenital adrenal hyperplasia (CAH) includes the use of glucocorticoids to attenuate the increased production of undesirable adrenal hormones. A case-control study was designed to compare the serum lipid profiles of 14 patients with CAH under glucocorticoid therapy and 14 normal controls and to determine the characteristics of the profiles. A total of 9 patients (64.3%) had serum total cholesterol (TC) greater than 4.4 mmol/L (170 mg/dL), compared with 6 individuals in the control group (42.3%). Nine patients with CAH (64.3%) had serum triglycerides (TGs) more than 1.0 mmol/L (90 mg/dL), compared with only 2 in the control group (14.3%). Similarly, the mean serum TG was higher in the CAH group versus the controls, 1.33 mmol/L (118 mg/dL) versus 0.75 mmol/L (67 mg/dL), respectively. Serum low-density lipoprotein, (LDL-C) and high-density, lipoprotein (HDL-C) cholesterol were determined in 13 children with CAH and in the 14 controls. Nine CAH patients (69.2%) and 8 controls (57%) had LDL-C greater than 2.8 mmol/L (<110 mg/dL). For HDL-C, 2 children with CAH (15.4%) and 4 controls (28.6%) had levels less than 0.9 mmol/L (35 mg/dL). There were no significant differences for the cholesterol index, 0.24 for the controls and 0.22 for the CAH group. In the CAH group, the mean serum TG level and the percentage of individuals with TGs greater than 1.0 mmol/L were statistically significant compared with the controls. The mean serum TC and LDL-C, as well as the percentage of subjects with levels over the cutoff point, although slightly higher in the CAH group, were of no statistical significance. The results of this pilot study suggest that long-term glucocorticoid therapy in patients with CAH may induce abnormalities in the serum lipid profile characterized mainly by an increment in serum TGs.     

BB-10010, an Analog of Macrophage Inflammatory Protein-1α, Protects Murine Small Intestine Against Radiation

Irradiation of the small intestine can result in depletion of the epithelial stem cell compartment and is often the dose-limiting factor for radiotherapeutic treatment of tumors in the abdominal and pelvic region. Since mitotic cells are most sensitive to radiation, significant radioprotection can be achieved by reducing the number of cells in mitosis at the time of irradiation. We have previously shown that administration of macrophage inflammatory protein (MIP) -1 induces a transient 50% reduction in the number of mitotic cells in small intestinal crypts, including the stem cell region, and therefore, MIP-1 pretreatment before radiation exposure could result in a substantial reduction of the side effects associated with radiotherapy. Groups of adult mice were exposed to different doses of radiation (6, 8, 10, or 12 Gy), with or without prior administration of 200 g BB-10010/kg 3 hr before irradiation and radiation damage was assessed by means of the microcolony survival assay. MIP-1 pretreatment resulted in significantly increased numbers of surviving crypts (10%) when compared to untreated irradiated animals. The observed radioprotective effects of MIP-1 in the small intestine should translate into reduced side effects in a clinically relevant radiotherapy context and could allow larger doses of radiation to be delivered to patients with tumors in the abdominal or pelvic region.