Genetic determinants of serum testosterone concentrations in men

Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone''s high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2×10⁻⁴¹ and rs6258, p = 2.3×10⁻²²). Subjects with ≥3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6×10⁻¹⁶). The rs6258 polymorphism in exon 4 of SHBG affected SHBG''s affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.     

Molecular pathways involved in the cyclic activity of frog (Pelophylax esculentus) Harderian gland: Influence of temperature and testosterone

The Harderian gland of Pelophylax esculentus (previously: Rana esculenta) shows seasonal secretory activity changes. Specifically, the secretory activity reaches a maximum during the hottest months, i.e., July and August, drops in September and slowly increases from October onwards. Expressions of P-CaMKII, P-ERK1 and P-Akt1 correlate well with gland secretory activity; i.e., they peak immediately before the hottest part of the year (maximum secretory activity). When the gland activity declines, kinase expressions drop and remain low until February. Experiments of thermal manipulation indicate that high temperature induces the activation of CaMKII, ERK1 and Akt1, and at low temperatures, Akt1 expression decreases. Experiments of chemical castration indicate that the Harderian gland of Cyproterone acetate-treated frogs shows lower Akt1 activity as compared to controls, but the CaMKII and ERK1 activities remain unchanged. Furthermore, in a period of resumed gland activity (October–December) we observed the highest expression of PCNA, a mitotic marker. Immediately after the proliferative phase, we found the highest expression of caspase 3, an enzyme that plays a key role in apoptosis. In combination, the results suggest the following: 1) CaMKII, ERK1, and Akt1 modulate the annual secretory activity of the frog Harderian gland; 2) CaMKII and ERK1 activities are regulated by temperature, whereas both temperature and testosterone likely play a central role in Akt1 regulation; and 3) proliferation and apoptosis occur to restore and balance, respectively, an adequate cell number, which is essential to gland function.     

Evaluating the effects of climate change on tree species abundance and distribution in the Italian peninsula

Question: What is the effect of climate change on tree species abundance and distribution in the Italian peninsula? Location: Italian peninsula. Methods: Regression tree analysis, Random Forest, generalized additive model and geostatistical methods were compared to identify the best model for quantifying the effect of climate change on tree species distribution and abundance. Future potential species distribution, richness, local colonization, local extinction and species turnover were modelled according to two scenarios (A2 and B1) for 2050 and 2080. Results: Robust Random Forest proved to be the best statistical model to predict the potential distribution of tree species abundance. Climate change could lead to a shift in tree species distribution towards higher altitudes and a reduction of forest cover. Pinus sylvestris and Tilia cordata may be considered at risk of local extinction, while the other species could find potential suitable areas at the cost of a rearrangement of forest community composition and increasing competition. Conclusions: Geographical and topographical regional characteristics can have a noticeable influence on the impact of predicted climate change on forest ecosystems within the Mediterranean basin. It would be highly beneficial to create a standardized and harmonized European forest inventory in order to evaluate, at high resolution, the effect of climate change on forest ecosystems, identify regional differences and develop specific adaptive management strategies and plans.     

Nocturnal hypoxia and loss of kidney function

Background

Although obstructive sleep apnea (OSA) is more common in patients with kidney disease, whether nocturnal hypoxia affects kidney function is unknown.

Methods

We studied all adult subjects referred for diagnostic testing of sleep apnea between July 2005 and December 31 2007 who had serial measurement of their kidney function. Nocturnal hypoxia was defined as oxygen saturation (SaO2) below 90% for ≥12% of the nocturnal monitoring time. The primary outcome, accelerated loss of kidney function, was defined as a decline in estimated glomerular filtration rate (eGFR) ≥4 ml/min/1.73 m² per year.

Results

858 participants were included and followed for a mean study period of 2.1 years. Overall 374 (44%) had nocturnal hypoxia, and 49 (5.7%) had accelerated loss of kidney function. Compared to controls without hypoxia, patients with nocturnal hypoxia had a significant increase in the adjusted risk of accelerated kidney function loss (odds ratio (OR) 2.89, 95% confidence interval [CI] 1.25, 6.67).

Conclusion

Nocturnal hypoxia was independently associated with an increased risk of accelerated kidney function loss. Further studies are required to determine whether treatment and correction of nocturnal hypoxia reduces loss of kidney function.     

New insights into Alzheimer's disease progression: a combined TMS and structural MRI study

Background:

Combination of structural and functional data of the human brain can provide detailed information of neurodegenerative diseases and the influence of the disease on various local cortical areas.

Methodology and Principal Findings:

To examine the relationship between structure and function of the brain the cortical thickness based on structural magnetic resonance images and motor cortex excitability assessed with transcranial magnetic stimulation were correlated in Alzheimer''s disease (AD) and mild cognitive impairment (MCI) patients as well as in age-matched healthy controls. Motor cortex excitability correlated negatively with cortical thickness on the sensorimotor cortex, the precuneus and the cuneus but the strength of the correlation varied between the study groups. On the sensorimotor cortex the correlation was significant only in MCI subjects. On the precuneus and cuneus the correlation was significant both in AD and MCI subjects. In healthy controls the motor cortex excitability did not correlate with the cortical thickness.

Conclusions:

In healthy subjects the motor cortex excitability is not dependent on the cortical thickness, whereas in neurodegenerative diseases the cortical thinning is related to weaker cortical excitability, especially on the precuneus and cuneus. However, in AD subjects there seems to be a protective mechanism of hyperexcitability on the sensorimotor cortex counteracting the prominent loss of cortical volume since the motor cortex excitability did not correlate with the cortical thickness. Such protective mechanism was not found on the precuneus or cuneus nor in the MCI subjects. Therefore, our results indicate that the progression of the disease proceeds with different dynamics in the structure and function of neuronal circuits from normal conditions via MCI to AD.     

A fibre optic catheter for simultaneous measurement of longitudinal and circumferential muscular activity in the gastrointestinal tract

Diagnostic catheters based on fibre Bragg gratings (FBG's) are proving to be highly effective for measurement of the muscular activity associated with motility in the human gut. While the primary muscular contractions that generate peristalsis are circumferential in nature, it has long been known that there is also a component of longitudinal contractility present, acting in harmony with the circumferential component to improve the overall efficiency of material movement. We report the detection of longitudinal motion in mammalian intestine using an FBG technique that should be viable for similar detection in humans. The longitudinal sensors have been combined with our previously reported FBG pressure sensing elements to form a composite catheter that allows the relative phase between the two components to be detected. The catheter output has been validated using video mapping in an ex‐vivo rabbit ileum preparation. (© 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Purinergic signaling induces cyclooxygenase-1-dependent prostanoid synthesis in microglia: roles in the outcome of excitotoxic brain injury

Cyclooxygenases (COX) are prostanoid synthesizing enzymes constitutively expressed in the brain that contribute to excitotoxic neuronal cell death. While the neurotoxic role of COX-2 is well established and has been linked to prostaglandin E(2) synthesis, the role of COX-1 is not clearly understood. In a model of N-Methyl-D-aspartic acid (NMDA) induced excitotoxicity in the mouse cerebral cortex we found a distinctive temporal profile of COX-1 and COX-2 activation where COX-1, located in microglia, is responsible for the early phase of prostaglandin E(2) synthesis (10 minutes after NMDA), while both COX-1 and COX-2 contribute to the second phase (3-24 hours after NMDA). Microglial COX-1 is strongly activated by ATP but not excitatory neurotransmitters or the Toll-like receptor 4 ligand bacterial lipopolysaccharide. ATP induced microglial COX-1 dependent prostaglandin E(2) synthesis is dependent on P2X7 receptors, extracellular Ca(2+) and cytoplasmic phospholipase A2. NMDA receptor activation induces ATP release from cultured neurons leading to microglial P2X7 receptor activation and COX-1 dependent prostaglandin E(2) synthesis in mixed microglial-neuronal cultures. Pharmacological inhibition of COX-1 has no effect on the cortical lesion produced by NMDA, but counteracts the neuroprotection exerted by inhibition of COX-2 or observed in mice lacking the prostaglandin E(2) receptor type 1. Similarly, the neuroprotection exerted by the prostaglandin E(2) receptor type 2 agonist butaprost is not observed after COX-1 inhibition. P2X7 receptors contribute to NMDA induced prostaglandin E(2) production in vivo and blockage of P2X7 receptors reverses the neuroprotection offered by COX-2 inhibition. These findings suggest that purinergic signaling in microglia triggered by neuronal ATP modulates excitotoxic cortical lesion by regulating COX-1 dependent prostanoid production and unveil a previously unrecognized protective role of microglial COX-1 in excitotoxic brain injury.     

Irrelevant features of a stimulus can either facilitate or disrupt performance in a working memory task: the role of fluid intelligence

It has been shown that fluid intelligence (gf) is fundamental to overcome interference due to information of a previously encoded item along a task-relevant domain. However, the biasing effect of task-irrelevant dimensions is still unclear as well as its relation with gf. The present study aimed at clarifying these issues. Gf was assessed in 60 healthy subjects. In a different session, the same subjects performed two versions (letter-detection and spatial) of a three-back working memory task with a set of physically identical stimuli (letters) presented at different locations on the screen. In the letter-detection task, volunteers were asked to match stimuli on the basis of their identity whereas, in the spatial task, they were required to match items on their locations. Cross-domain bias was manipulated by pseudorandomly inserting a match between the current and the three back items on the irrelevant domain. Our findings showed that a task-irrelevant feature of a salient stimulus can actually bias the ongoing performance. We revealed that, at trials in which the current and the three-back items matched on the irrelevant domain, group accuracy was lower (interference). On the other hand, at trials in which the two items matched on both the relevant and irrelevant domains, the group showed an enhancement of the performance (facilitation). Furthermore, we demonstrated that individual differences in fluid intelligence covaries with the ability to override cross-domain interference in that higher gf subjects showed better performance at interference trials than low gf subjects. Altogether, our findings suggest that stimulus features irrelevant to the task can affect cognitive performance along the relevant domain and that gf plays an important role in protecting relevant memory contents from the hampering effect of such a bias.     

Fatty acid composition of the tropical lichen Teloschistes flavicans and its cultivated symbionts

Fatty acid components, in both the free and combined form of the intact tropical lichen Teloschistes flavicans, and its isolated photobiont and mycobiont, were analyzed by GC-MS of derived methyl esters. Its rDNA analysis confirmed that the isolated cultured symbionts belong to the genera Trebouxia and Teloschistes, respectively. The fatty acid composition of the lichen did not correspond to those found in the isolated symbionts, suggesting that the fatty acid metabolism is markedly influenced by the symbiosis. Differences in the fatty acid composition in the lichen were observed during the summer (27 degrees C), when the main fatty acids were saturated and in the winter (22 degrees C) when an increase of unsaturated fatty acids occurred. Similar differences of composition were also observed for the cultured mycobiont at different temperatures. The increase in the unsaturation level at low temperatures would maintain the membrane fluidity. Our results are the first on the fatty acids of a tropical lichen and suggest that it is sensitive to small temperature variations, which influences its saturated and unsaturated fatty acid composition.