Lithium levels and lifestyle in patients with bipolar disorder: a new tool for self-management.

BACKGROUND: Patients should get actively involved in the management of their illness. The aim of this study was to assess the influence of lifestyle factors, including sleep, diet, and physical activity, on lithium levels in patients with bipolar disorder. METHODS: A multicenter study was performed. In total, 157 lithium measurements were done biweekly in a sample of 65 patients (35 women) over 6 weeks. Lifestyle, based on total sleep hours and physical activity, was assessed by actigraphy. Diet was evaluated using the Mediterranean Lifestyle Index (Medlife). RESULTS: 35.4% of patients had a normal weight. The mean Medlife score was 14.5 (± 2.5) (moderate-good adherence to Mediterranean diet). BMI, daily dose of lithium and intensity of physical activity had a combined effect on lithium levels, after adjustment for other variables. Patients who practiced intense physical exercise, who took lower doses and had a higher BMI exhibited lower levels of lithium. CONCLUSIONS: Higher physical activity and BMI contribute to lower lithium levels. Patients should be made aware of these relationships to improve their perception of control and self-management. Lifestyle-based interventions contribute to establishing a more personalized medicine.

Pas Kinase Deficiency Triggers Antioxidant Mechanisms in the Liver.

Metabolic dysfunction in the liver is the cause of numerous pathologies, which are associated with an altered redox state. PASK (PAS Domain Kinase) is a nutrient and bioenergetic sensor. We contend that PASK could act as an oxidative stress sensor in liver and/or control the metabolic balance, playing a role in the mitochondrial homeostasis. Using PASK-deficient mice, we observed that PASK deficiency promotes antioxidant response mechanisms: a lower production of ROS/RNS under non-fasting conditions, overexpression of genes coding to ROS-detoxifying enzymes and mitochondrial fusion proteins (MnSod Gpx, Mfn1 and Opa1), coactivator Ppargc1a, transcription factors (Pparg and FoxO3a) and deacetylase Sirt1. Also, under fasting conditions, PASK deficiency induced the overexpression of Ppargc1a, Ppara, Pparg, FoxO3a and Nrf2 leading to the overexpression of genes coding to antioxidant enzymes such as MnSOD, Cu/ZnSOD, GPx, HO1 and GCLm. Additionally, inducing PINK1 involved in cell survival and mitophagy. These changes kept ROS steady levels and improved the regenerative state. We suggest a new role for PASK as a controller of oxidative stress and mitochondrial dynamics in the liver. In fact, antioxidant response is PASK dependent. PASK-targeting could therefore be a good way of reducing the oxidative stress in order to prevent or treat liver diseases.

Dynamics of dual-polarization VCSEL-based optical frequency combs under optical injection locking.

The present experimental work studies the dynamics of dual-polarization optical frequency combs (OFCs) based on gain switching (GS) vertical-cavity surface-emitting laser (VCSEL) diodes under optical injection locking (OIL). This study presents two main results. First, we have obtained an overall comb formed by two orthogonally polarized sub-combs with comparable span and power. The overall comb shows enhanced optical span and flatness and high coherence between its modes. The second result is that we have been able to control the polarization state of the overall comb by tuning the polarization state of the injected light by locking the same single teeth of the comb. This produces an overall comb with single polarization that is parallel or orthogonal. These are novel findings that provide for the development of efficient and compact OFCs based on GS VCSEL sources with versatile polarization dynamics.

Occupational disability in bipolar disorder: analysis of predictors of being on severe disablement benefit (PREBIS study data).

OBJECTIVE: Patients diagnosed with bipolar disorder (BD) are reported to have significant work impairment during interepisode intervals. This study was carried out to assess potential predictors of occupational disability in a longitudinal follow-up of euthymic patients. METHOD: We included 327 euthymic patients diagnosed with BD type I or type II, 226 of whom were employed and 101 were receiving a severe disablement benefit (SDB). Sociodemographic data were studied and episode recurrence was assessed along a 1-year follow-up. Logistic regression analysis was applied to determine predictors of receiving SDB. Cox regression was built to study recurrences. RESULTS: Predictors of receiving SDB were: axis II comorbidity [Odds Ratio (OR) = 2.94, CI: 1.26-6.86, P = 0.013], number of manic episodes (OR = 1.21, CI: 1.10-1.34, P < 0.001), being without stable partner (OR = 2.44, CI: 1.34-4.44, P = 0.004) and older age (OR = 1.08, CI: 1.05-1.12, P < 0.001). Bipolar patients receiving SDB presented more episodic recurrences regardless of polarity than employed bipolar patients (P = 0.002). The time until recurrence in 25% of the bipolar patients receiving SDB was 6.08 months (CI: 4.44-11.77) being 13.08 months (CI: 9.60 to -) in the employed group. CONCLUSION: Occupational disability in bipolar patients is associated with axis II comorbidity, more previous manic episodes, not having a stable relationship, older age, and more recurrences at 1-year follow-up.

Subthreshold symptoms and time to relapse/recurrence in a community cohort of bipolar disorder outpatients.

BACKGROUND: Researchers have previously found that persistent subthreshold symptoms increase the risk and shorten the time until an affective relapse in bipolar disorder (BD) patients. Research has mainly focused on patients from tertiary Care Centers in USA. We tested the hypothesis that even in a different setting, BD outpatients with subsyndromal affective symptoms would re.turn to a subsequent major affective episode significantly faster than completely asymptomatic at baseline. Secondarily, we analysed other variables related to time and risk to relapse. METHODS: A community cohort of BD outpatients from Madrid (Spain) followed-up in a systematic prospective follow-up protocol for up to five years were evaluated. Patients in clinical euthymia at baseline were included and evaluated quarterly. RESULTS: Initially, 225 patients were included in the survival analysis. Of them, according to predefined psychometric criteria, 163 were in euthymia (72.4%) and 62 (27.6%) suffered subsyndromal symptoms. Median follow-up was 157.6 weeks (95% CI, 78.14 to 111); 57.3% of patients experienced at least one affective episode during their follow-up. Median survival time to first affective episode was 109 weeks for patients in euthymia at baseline, versus 35 weeks for those with subsyndromal symptoms (p<0.0001). Psychosocial stress (p=0.003; HR 2.20; 95% CI 1.31-3.68) and the affective mood baseline state, subsyndromal vs. euthymic (p=0.046; HR 1.74; 95%CI 1.009-3.020), were related to time to first affective episode. LIMITATIONS: Naturalistic study, some of the data collected were necessarily retrospective. CONCLUSIONS: In Spanish non-tertiary psychiatric outpatients, subsyndromal BD symptoms and psychosocial stress at baseline predict earlier episode relapse/recurrence.

Syndromal and subsyndromal illness status and five-year morbidity using criteria of the International Society for Bipolar Disorders compared to alternative criteria.

BACKGROUND: Subsyndromal symptoms have been recognized as relevant in the course and outcome of bipolar disorder (BD) patients. Nevertheless, their definition and cutoff points on current depression and mania scales are uncertain. The recently defined International Society for Bipolar Disorders (ISBD) operational criteria for the assessment of the course and outcome of bipolar illness have never been tested until now. METHODS: A naturalistic longitudinal follow-up study of up to 5 years included a cohort of 317 DSM-IV-TR BD outpatients. For the first time, we assessed the proportion of visits in different affective states using the ISBD criteria. Secondarily, we compared the results with those obtained applying other cutoff points. RESULTS: Patients were symptomatic in 39.1% (95% CI 35.3-42.9) of the visits. Subsyndromal symptoms, primarily subsyndromal depression, were present in 15.9% of patients (95% CI 13.4-18.4). No significant differences were found between bipolar I patients and bipolar II patients. There were differences in the total percentage of visits in euthymia depending on the cutoff points (p < 0.05). CONCLUSIONS: Applying ISBD criteria, bipolar patients have significant clinical morbidity and are often symptomatic, both with threshold symptoms and with subthreshold symptoms, especially with depression. The chosen cutoff points modify the apparent results. LIMITATIONS: The cutoff points used have not been validated. Psychopharmacologic treatments were naturalistic.

Observation of phase noise reduction in photonically synthesized sub-THz signals using a passively mode-locked laser diode and highly selective optical filtering.

A Continuous Wave (CW) sub-THz photonic synthesis setup based on a single Passively Mode-Locked Laser Diode (PMLLD) acting as a monolithic Optical Frequency Comb Generator (OFCG) and highly selective optical filtering has been implemented to evaluate the phase noise performance of the generated sub-THz signals. The analysis of the synthesized sub-THz signals up to 120 GHz gives as a result an effective reduction of the electrical linewidth when compared to direct harmonic generation that begins at 50 GHz and becomes greater as the frequency increases. The phase noise reduction offered by the setup, along with its integration potential, cost and bandwidth, make it a promising candidate to the development of an integrated and high performance low phase noise local oscillator in the sub-THz range.

Reversible parkinsonism and cognitive decline due to a possible interaction of valproic acid and quetiapine.

WHAT IS KNOWN AND OBJECTIVE: Combination therapy with valproic acid plus quetiapine is recommended as one of the first-line approaches to treatment of manic or mixed episodes in patients with bipolar disorder. CASE SUMMARY: A 66-year-old patient with this psychiatric disease developed parkinsonism and cognitive decline during concomitant treatment with both drugs. The rapid onset of symptoms soon after use of the combination suggested an interaction/using the Karch-Lasagna criteria, the interaction was judged to be definite. WHAT IS NEW AND CONCLUSION: Their evidence on a pharmacokinetic drug interaction between the two drugs is conflicting but possible underlying mechanisms proposed include CYP3A4 inhibition. As concomitant use of valproate and quetiapine is now quite frequent in bipolar disorder, this potential interaction should be closely monitored, especially in the elderly.

[Profile of bipolar disorder outpatients: a cross-sectional study in the Madrid Community]. / Perfil de los pacientes ambulatorios con trastorno bipolar: un estudio transversal en la Comunidad de Madrid.

INTRODUCTION: The purpose of this cross-sectional study is to obtain a sociodemographic, clinical, psychosocial functioning and therapeutic profile of bipolar outpatients in the Madrid Community. METHODS: A total of 115 outpatients were consecutively recruited by 10 psychiatrists. RESULTS: Mean time between initial symptoms and an accurate bipolar diagnosis was of 7.6 years. A depressive episode was the onset of the illness in most patients independently of clinical subtype. Syndromal or subsyndromal symptoms were present in 47% of the patient population, dominating the depressive polarity (33.1%). A subjectively reduced perception of quality of life was associated to the presence of depressive symptoms and a worse clinical outcome last year. More than half of the patients (58.2%) were overweight or obese. Lithium was the most frequently used mood stabilizer (71.3%), whereas 41% of the patients were taking at least three psychotropic drugs. CONCLUSIONS: Results of this study widely confirm previous data on bipolar disorder. Reduction in quality of life of bipolar patients associated to depressive symptoms must be highlighted. It is necessary to optimize treatments in bipolar disorder in order to improve prognosis.

Mapping of IFN-beta epitopes important for receptor binding and biologic activation: comparison of results achieved using antibody-based methods and alanine substitution mutagenesis.

The epitopes important for receptor binding and activation of human interferon-beta1a (IFN-beta1a) were mapped with monoclonal antibodies (mAb), grouped on the basis of their specificity and ability to neutralize biologic activity, and alanine scanning mutagenesis (ASM). The binding properties of nine mAb were defined, using ASM-IFN-beta mutants having alanine substituted at targeted, surface-exposed residues. The results were correlated with the mAb neutralizing potency. Of six mAb that bound either at or adjacent to the IFNAR-2 receptor chain binding site defined by the ASM epitopes, only three had measurable neutralizing activity. Two of these inhibited IFN-beta/IFNAR-2 complex formation, suggesting that steric hindrance of receptor binding constitutes their mechanism of neutralization. However, two mAb that bound to sites remote from the IFNAR-2 binding site on IFN-beta also inhibited IFN-beta/IFNAR-2 complex formation and demonstrated potent neutralizing activity. Thus, neutralizing mAb may employ mechanisms other than steric blockade to inhibit directly the binding of receptor by cytokine, limiting their usefulness as tools to define precise receptor-ligand interaction sites.