Early clinical predictors and correlates of long-term morbidity in bipolar disorder

OBJECTIVES: Identifying factors predictive of long-term morbidity should improve clinical planning limiting disability and mortality associated with bipolar disorder (BD). METHODS: We analyzed factors associated with total, depressive and mania-related long-term morbidity and their ratio D/M, as %-time ill between a first-lifetime major affective episode and last follow-up of 207 BD subjects. Bivariate comparisons were followed by multivariable linear regression modeling. RESULTS: Total % of months ill during follow-up was greater in 96 BD-II (40.2%) than 111 BD-I subjects (28.4%; P=0.001). Time in depression averaged 26.1% in BD-II and 14.3% in BD-I, whereas mania-related morbidity was similar in both, averaging 13.9%. Their ratio D/M was 3.7-fold greater in BD-II than BD-I (5.74 vs. 1.96; P<0.0001). Predictive factors independently associated with total %-time ill were: [a] BD-II diagnosis, [b] longer prodrome from antecedents to first affective episode, and [c] any psychiatric comorbidity. Associated with %-time depressed were: [a] BD-II diagnosis, [b] any antecedent psychiatric syndrome, [c] psychiatric comorbidity, and [d] agitated/psychotic depressive first affective episode. Associated with %-time in mania-like illness were: [a] fewer years ill and [b] (hypo)manic first affective episode. The long-term D/M morbidity ratio was associated with: [a] anxious temperament, [b] depressive first episode, and [c] BD-II diagnosis. CONCLUSIONS: Long-term depressive greatly exceeded mania-like morbidity in BD patients. BD-II subjects spent 42% more time ill overall, with a 3.7-times greater D/M morbidity ratio, than BD-I. More time depressed was predicted by agitated/psychotic initial depressive episodes, psychiatric comorbidity, and BD-II diagnosis. Longer prodrome and any antecedent psychiatric syndrome were respectively associated with total and depressive morbidity

Mouse Panx1 Is Dispensable for Hearing Acquisition and Auditory Function

Panx1 forms plasma membrane channels in brain and several other organs, including the inner ear. Biophysical properties, activation mechanisms and modulators of Panx1 channels have been characterized in detail, however the impact of Panx1 on auditory function is unclear due to conflicts in published results. To address this issue, hearing performance and cochlear function of the Panx1−/− mouse strain, the first with a reported global ablation of Panx1, were scrutinized. Male and female homozygous (Panx1−/−), hemizygous (Panx1+/−) and their wild type (WT) siblings (Panx1+/+) were used for this study. Successful ablation of Panx1 was confirmed by RT-PCR and Western immunoblotting in the cochlea and brain of Panx1−/− mice. Furthermore, a previously validated Panx1-selective antibody revealed strong immunoreactivity in WT but not in Panx1−/− cochleae. Hearing sensitivity, outer hair cell-based “cochlear amplifier” and cochlear nerve function, analyzed by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) recordings, were normal in Panx1+/− and Panx1−/− mice. In addition, we determined that global deletion of Panx1 impacts neither on connexin expression, nor on gap-junction coupling in the developing organ of Corti. Finally, spontaneous intercellular Ca2+ signal (ICS) activity in organotypic cochlear cultures, which is key to postnatal development of the organ of Corti and essential for hearing acquisition, was not affected by Panx1 ablation. Therefore, our results provide strong evidence that, in mice, Panx1 is dispensable for hearing acquisition and auditory function

Heterogeneity of Signal Transducer and Activator of Transcription Binding Sites in the Long-Terminal Repeats of Distinct HIV-1 Subtypes

HIV-1 can be subdivided into distinct subtypes; the consequences of such a genomic variability remain largely speculative. The long terminal repeats (LTR) control HIV transcription and reflect the major differences of distinct viral subtypes. Three regions in the HIV-1 subtype B LTR are close matches to the Signal Transducer and Activator of Transcription (STAT) consensus sequence. Here, we show heterogeneity in these putative STAT binding sites among HIV-1 LTR subtypes A through G. Transfection of constitutively activated STAT5 lead to transcriptional activation of HIV-1 expression in 293T cells transfected with a reporter assay driven by HIV-1 LTR subtype B. Constitutively activated STAT5 transactivated the LTR of various subtypes in U937 cells with different potency. These findings support and expand the potential relevance of STAT5 activation in HIV infection and may bear relevance for a differential regulation of latency and expression of different subtypes of HIV-1

Multicomponent Synthesis of Polyphenols and Their In Vitro Evaluation as Potential \u3b2-Amyloid Aggregation Inhibitors

While plant polyphenols possess a variety of biological properties, exploration of chemical diversity around them is still problematic. Here, an example of application of the Ugi multicomponent reaction to the combinatorial assembly of artificial, yet \u201cnatural-like\u201d, polyphenols is presented. The synthesized compounds represent a second-generation library directed to the inhibition of \u3b2-amyloid protein aggregation. Chiral enantiopure compounds, and polyphenol-\u3b2-lactam hybrids have been prepared too. The biochemical assays have highlighted the importance of the key pharmacophores in these compounds. A lead for inhibition of aggregation of truncated protein A\u3b2pE3-42 was selected

Columnar Cell Lesion and Apocrine Hyperplasia of the Breast: Is There a Common Origin? The Role of Prolactin-induced Protein

Noninvasive breast lesions encompass a heterogeneous group of risk indicators and nonobligate precursors of breast cancer, such as apocrine hyperplasia (AH) and columnar cell lesions (CCLs). Given the different expression of ER and ER-regulated genes in AH and CCL, these two alterations are currently considered discrete conditions. However, whether they share early biologic changes is not clear to date. Here, we sought to define the clinicopathologic and immunohistochemical features of a prospective series of combined lesions made up by CCLs and AH forming a continuum within single terminal duct-lobular units. The study group included 19 cases, whereas 25 cases of synchronous contiguous CCLs and AH served as control group. The different components of each case were subjected to immunohistochemical analysis for ER, PR, AR, HER2, BCL2, CCND1, MUC1, and PIP. Although CCLs and AHs arising in continuity showed opposite patterns of ER expression, the PIP-positive apocrine signature was consistently present in both components. In conclusion, apocrine changes are highly recurrent in CCLs growing within foci of AH, regardless of the ER activation. Our results suggest that PIP-positive and PIP-negative CCLs are likely to represent biologically distinct conditions and that apocrine changes might occur earlier than ER activation in the natural history of breast precursor lesions

Inflammatory effects of atazanavir/ritonavir versus darunavir/ritonavir in treatment naïve, HIV-1-infected patients

Background: Limited studies have compared the impact of different antiretroviral regimens on soluble markers of inflammation with discordant results. Methods: In this prospective study, treatment naïve HIV-1-infected patients were included if they started their current regimen with atazanavir/ritonavir (ATV/r) (N = 73, Group 1) or darunavir/ritonavir (DRV/r) (N = 85, Group 2) plus tenofovir/emtricitabine. The analysis of IL-6, MCP-1, sCD163, VCAM-1, ox-LDL, and adiponectine was performed on two stored plasma samples, the first prior to antiretroviral therapy initiation and the second one year after initiation. Results: The results of our analysis show a difference in ox-LDL between the two groups with higher mean (SD) values in ATV/r based group 608.5 ± 137.4 versus 519.1 ± 119.6 in DRV/r group, after controlling for baseline levels of ox-LDL as well as other potential confounding factors controlled by means of matching design or linear regression modelling. Conclusions: Our analysis provides further data examining the association between the modulation of vascular inflammatory and of activation markers with specific protease inhibitors-based treatments over one year of exposure to these drugs. The data show little evidence for an association, supporting the notion that antiretroviral regimens has generally poor efficiency in downregulating these soluble markers

Conformational altered p53 as an early marker of oxidative stress in Alzheimer\u27s disease

In order to study oxidative stress in peripheral cells of Alzheimer\u27s disease (AD) patients, immortalized lymphocytes derived from two peculiar cohorts of patients, referring to early onset AD (EOSAD) and subjects harboured AD related mutation (ADmut), were used. Oxidative stress was evaluated measuring i) the typical oxidative markers, such as HNE Michel adducts, 3 Nitro-Tyrosine residues and protein carbonyl on protein extracts, ii) and the antioxidant capacity, following the enzymatic kinetic of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRD). We found that the signs of oxidative stress, measured as oxidative marker levels, were evident only in ADmut but not in EOSAD patients. However, oxidative imbalance in EOSAD as well as ADmut lymphocytes was underlined by a reduced SOD activity and GRD activity in both pathological groups in comparison with cells derived from healthy subjects. Furthermore, a redox modulated p53 protein was found conformational altered in both EOSAD and ADmut B lymphocytes in comparison with control cells. This conformational altered p53 isoform, named unfolded p53 , was recognized by the use of two specific conformational anti-p53 antibodies. Immunoprecipitation experiments, performed with the monoclonal antibodies PAb1620 (that recognizes p53wt) and PAb240 (that is direct towards unfolded p53), and followed by the immunoblotting with anti-4-hydroxynonenal (HNE) and anti- 3-nitrotyrosine (3NT) antibodies, showed a preferential increase of nitrated tyrosine residues in unfolded p53 isoform comparing to p53 wt protein, in both ADmut and EOSAD. In addition, a correlation between unfolded p53 and SOD activity was further found. Thus this study suggests that ROS/RNS contributed to change of p53 tertiary structure and that unfolded p53 can be considered as an early marker of oxidative imbalance in these patients