Strong phenotypic divergence in spite of low genetic structure in the endemic Mangrove Warbler subspecies (Setophaga petechia xanthotera) of Costa Rica

Despite the enormous advances in genetics, links between phenotypes and genotypes have been made for only a few nonmodel organisms. However, such links can be essential to understand mechanisms of ecological speciation. The Costa Rican endemic Mangrove Warbler subspecies provides an excellent subject to study differentiation with gene flow, as it is distributed along a strong precipitation gradient on the Pacific coast with no strong geographic barriers to isolate populations. Mangrove Warbler populations could be subject to divergent selection driven by precipitation, which influences soil salinity levels, which in turn influences forest structure and food resources. We used single nucleotide polymorphisms (SNPs) and morphological traits to examine the balance between neutral genetic and phenotypic divergence to determine whether selection has acted on traits and genes with functions related to specific environmental variables. We present evidence showing: (a) associations between environmental variables and SNPs, identifying candidate genes related to bill morphology (BMP) and osmoregulation, (b) absence of population genetic structure in neutrally evolving markers, (c) divergence in bill size across the precipitation gradient, and (d) strong phenotypic differentiation (P_ST) which largely exceeds neutral genetic differentiation (F_ST) in bill size. Our results indicate an important role for salinity, forest structure, and resource availability in maintaining phenotypic divergence of Mangrove Warblers through natural selection. Our findings add to the growing body of literature identifying the processes involved in phenotypic differentiation along environmental gradients in the face of gene flow.     

Resveratrol increases vascular oxidative stress resistance

Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. However, the mechanisms by which resveratrol exerts its vasculoprotective effects are not completely understood. Because oxidative stress and endothelial cell injury play a critical role in vascular aging and atherogenesis, we evaluated whether resveratrol inhibits oxidative stress-induced endothelial apoptosis. We found that oxidized LDL and TNF-alpha elicited significant increases in caspase-3/7 activity in endothelial cells and cultured rat aortas, which were prevented by resveratrol pretreatment (10(-6)-10(-4) mol/l). The protective effect of resveratrol was attenuated by inhibition of glutathione peroxidase and heme oxygenase-1, suggesting a role for antioxidant systems in the antiapoptotic action of resveratrol. Indeed, resveratrol treatment protected cultured aortic segments and/or endothelial cells against increases in intracellular H(2)O(2) levels and H(2)O(2)-mediated apoptotic cell death induced by oxidative stressors (exogenous H(2)O(2), paraquat, and UV light). Resveratrol treatment also attenuated UV-induced DNA damage (comet assay). Resveratrol treatment upregulated the expression of glutathione peroxidase, catalase, and heme oxygenase-1 in cultured arteries, whereas it had no significant effect on the expression of SOD isoforms. Resveratrol also effectively scavenged H(2)O(2) in vitro. Thus resveratrol seems to increase vascular oxidative stress resistance by scavenging H(2)O(2) and preventing oxidative stress-induced endothelial cell death. We propose that the antioxidant and antiapoptotic effects of resveratrol, together with its previously described anti-inflammatory actions, are responsible, at least in part, for its cardioprotective effects.     

Treatment with the mitochondrial‐targeted antioxidant peptide SS‐31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice

Moment‐to‐moment adjustment of cerebral blood flow (CBF) via neurovascular coupling has an essential role in maintenance of healthy cognitive function. In advanced age, increased oxidative stress and cerebromicrovascular endothelial dysfunction impair neurovascular coupling, likely contributing to age‐related decline of higher cortical functions. There is increasing evidence showing that mitochondrial oxidative stress plays a critical role in a range of age‐related cellular impairments, but its role in neurovascular uncoupling remains unexplored. This study was designed to test the hypothesis that attenuation of mitochondrial oxidative stress may exert beneficial effects on neurovascular coupling responses in aging. To test this hypothesis, 24‐month‐old C57BL/6 mice were treated with a cell‐permeable, mitochondria‐targeted antioxidant peptide (SS‐31; 10 mg kg^?1 day^?1, i.p.) or vehicle for 2 weeks. Neurovascular coupling was assessed by measuring CBF responses (laser speckle contrast imaging) evoked by contralateral whisker stimulation. We found that neurovascular coupling responses were significantly impaired in aged mice. Treatment with SS–31 significantly improved neurovascular coupling responses by increasing NO‐mediated cerebromicrovascular dilation, which was associated with significantly improved spatial working memory, motor skill learning, and gait coordination. These findings are paralleled by the protective effects of SS–31 on mitochondrial production of reactive oxygen species and mitochondrial respiration in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, mitochondrial oxidative stress contributes to age‐related cerebromicrovascular dysfunction, exacerbating cognitive decline. We propose that mitochondria‐targeted antioxidants may be considered for pharmacological microvascular protection for the prevention/treatment of age‐related vascular cognitive impairment (VCI).     

The Disability Rate of 5-Year Post-Stroke and Its Correlation Factors: A National Survey in China

Few studies on long-term functional outcome have been conducted in post-stroke patients in China. The objective of this study was to conduct a nationwide survey in China to investigate the 5-year prevalence of post-stroke disability and its correlation factors. A total of 893 patients with ischemic stroke were included. Demographic, clinical and neuro-imaging information were collected with standardized instruments that assessed stroke severity, depression, cognitive impairment, stroke recurrence and physical disability. Disability was assessed with the modified Ranking Score (mRS), of which a cutoff score ≥2 indicates disability. Statistical analysis included chi-square tests, two independent samples t-tests, Mann-Whitney U test and multiple logistic regression analysis. The frequency of disability in this study population was 45%. Multivariate analyses revealed that older age, lower education level, previous history of stroke, stroke severity at admission, depression, cognitive impairment at 3 months, and stroke recurrence within 5 years follow up were all significantly associated with post-stroke disability. The disability rate in 5-year post-stroke was high in Chinese patients. Treatment of depression, secondary prevention of stroke and rehabilitation may benefit disabled patients with stroke in China.     

Increases in endothelial Ca(2+) activate K(Ca) channels and elicit EDHF-type arteriolar dilation via gap junctions

In skeletal muscle arterioles, the pathway leading to non-nitric oxide (NO), non-prostaglandin-mediated endothelium-derived hyperpolarizing factor (EDHF)-type dilations is not well characterized. To elucidate some of the steps in this process, simultaneous changes in endothelial intracellular Ca(2+) concentration ([Ca(2+)](i)) and the diameter of rat gracilis muscle arterioles (approximately 60 microm) to acetylcholine (ACh) were measured by fura 2 microfluorimetry (in the absence of NO and prostaglandins). ACh elicited rapid increases in endothelial [Ca(2+)](i) (101 +/- 7%), followed by substantial dilations (73 +/- 2%, coupling time: 1.3 +/- 0.2 s) that were prevented by endothelial loading of an intracellular Ca(2+) chelator [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid]. Arteriolar dilations to ACh were also inhibited by intraluminal administration of the Ca(2+)-activated K(+) (K(Ca)) channel blockers charybdotoxin plus apamin or by palmitoleic acid, an uncoupler of myoendothelial gap junctions without affecting changes in endothelial [Ca(2+)](i). The presence of large conductance K(Ca) channels on arteriolar endothelial cells was demonstrated with immunohistochemisty. We propose that in skeletal muscle arterioles, EDHF-type mediation is evoked by an increase in endothelial [Ca(2+)](i), which by activating endothelial K(Ca) channels elicits hyperpolarization that is conducted via myoendothelial gap junctions to the smooth muscle resulting in decreases in [Ca(2+)](i) and consequently dilation.     

Selected contribution: NO released to flow reduces myogenic tone of skeletal muscle arterioles by decreasing smooth muscle Ca(2+) sensitivity.

To clarify the contribution of intracellular Ca(2+) concentration ([Ca(2+)](i))-dependent and -independent signaling mechanisms in arteriolar smooth muscle (aSM) to modulation of arteriolar myogenic tone by nitric oxide (NO), released in response to increases in intraluminal flow from the endothelium, changes in aSM [Ca(2+)](i) and diameter of isolated rat gracilis muscle arterioles (pretreated with indomethacin) were studied by fluorescent videomicroscopy. At an intraluminal pressure of 80 mmHg, [Ca(2+)](i) significantly increased and myogenic tone developed in response to elevations of extracellular Ca(2+) concentration. The Ca(2+) channel inhibitor nimodipine substantially decreased [Ca(2+)](i) and completely inhibited myogenic tone. Dilations to intraluminal flow (that were inhibited by N(omega)-nitro-L-arginine methyl ester) or dilations to the NO donor S-nitroso-N-acetyl-DL-penicillamine (that were inhibited by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) were not accompanied by substantial decreases in aSM [Ca(2+)](i). 8-Bromoguanosine cGMP and the cGMP-specific phosphodiesterase inhibitor zaprinast significantly dilated arterioles yet elicited only minimal decreases in [Ca(2+)](i). Thus flow-induced endothelial release of NO elicits relaxation of arteriolar smooth muscle by a cGMP-dependent decrease of the Ca(2+) sensitivity of the contractile apparatus without substantial changes in the pressure-induced level of [Ca(2+)](i).     

Serotonin reuptake inhibitors fluoxetine and citalopram relax intestinal smooth muscle

Selective serotonin reuptake inhibitor antidepressants (SSRIs) exert depressant effects on cardiac myocytes and vascular smooth muscle cells by inhibiting Ca2+ channels. We hypothesized that the SSRIs fluoxetine and citalopram affect the contractile activity of intestinal smooth muscle by interfering with Ca2+ entry and (or) signaling pathways. The effects of fluoxetine and citalopram on contractions of guinea-pig ileum longitudinal muscle-myenteric plexus preparations (LMMP) were compared with the effects of the voltage-operated Ca2+ channel inhibitors nifedipine and diltiazem. In a concentration-dependent manner, nifedipine, diltiazem, fluoxetine, and citalopram elicited relaxation of LMMPs contracted by electrical field stimulation (EC50 values of 4 x 10(-7) M, 1.4 x 10(-6) M, 1.4 x 10(-5), and 6.8 x 10(-6) M, respectively). Nifedipine, diltiazem, fluoxetine, and citalopram also relaxed LMMPs contracted with a depolarizing concentration of KCl (48 mM; EC50 values of 1.8 x 10(-8) M, 1.4 x 10(-7) M, 3.7 x 10(-6) M, and 6.3 x 10(-6), respectively), a response that could be reversed by increasing the extracellular Ca2+ concentration (2.5-30 mM). These data suggest that fluoxetine and citalopram elicit relaxation of intestinal smooth muscle, likely by inhibiting Ca2+ channel(s). This effect may be of clinical importance.     

The Bipolar II Depression Questionnaire: A Self-Report Tool for Detecting Bipolar II Depression

Bipolar II (BP-II) depression is often misdiagnosed as unipolar (UP) depression, resulting in suboptimal treatment. Tools for differentiating between these two types of depression are lacking. This study aimed to develop a simple, self-report screening instrument to help distinguish BP-II depression from UP depressive disorder. A prototype BP-II depression questionnaire (BPIIDQ-P) was constructed following a literature review, panel discussions and a field trial. Consecutively assessed patients with a diagnosis of depressive disorder or BP with depressive episodes completed the BPIIDQ-P at a psychiatric outpatient clinic in Hong Kong between October and December 2013. Data were analyzed using discriminant analysis and logistic regression. Of the 298 subjects recruited, 65 (21.8%) were males and 233 (78.2%) females. There were 112 (37.6%) subjects with BP depression [BP-I = 42 (14.1%), BP-II = 70 (23.5%)] and 182 (62.4%) with UP depression. Based on family history, age at onset, postpartum depression, episodic course, attacks of anxiety, hypersomnia, social phobia and agoraphobia, the 8-item BPIIDQ-8 was constructed. The BPIIDQ-8 differentiated subjects with BP-II from those with UP depression with a sensitivity/specificity of 0.75/0.63 for the whole sample and 0.77/0.72 for a female subgroup with a history of childbirth. The BPIIDQ-8 can differentiate BP-II from UP depression at the secondary care level with satisfactory to good reliability and validity. It has good potential as a screening tool for BP-II depression in primary care settings. Recall bias, the relatively small sample size, and the high proportion of females in the BP-II sample limit the generalization of the results.