Hypogonadotropic hypogonadism and pituitary hypoplasia as recurrent features in Ulnar-Mammary syndrome

Ulnar-mammary syndrome (UMS) is characterized by ulnar defects, and nipple or apocrine gland hypoplasia, caused by TBX3 haploinsufficiency. Signs of hypogonadism were repeatedly reported, but the mechanisms remain elusive. We aim to assess the origin of hypogonadism in two families with UMS. UMS was suspected in two unrelated probands referred to an academic center with delayed puberty because of the evident ulnar ray and breast defects in their parents. Clinical, biochemical and genetic investigations proved the existence of congenital normosmic IHH (nIHH) associated with pituitary hypoplasia in the two probands who were heterozygous for novel TBX3 pathogenic variants. The mutations co-segregated with delayed puberty, midline defects (nose, teeth and tongue anomalies) and other variable features of UMS in the two families (absent axillary hairs and nipple hypoplasia, asymmetrical features including unilateral ulnar or renal abnormalities). The combined analysis of these findings and of the previous UMS reports showed delayed puberty and other signs of hypogonadism in 79 and 37% of UMS males, respectively. Proband 1 was followed up to adulthood with persistence of nIHH. In conclusion, UMS should be suspected in patients with delayed puberty and midline defects, including pituitary hypoplasia, in the presence of mild cues for TBX3 mutation, even in the absence of limb malformations. In addition, TBX3 should be included among candidate genes for congenital nIHH

Predominant Functional Expression of Kv1.3 by Activated Microglia of the Hippocampus after Status epilepticus

BACKGROUND:Growing evidence indicates that the functional state of microglial cells differs according to the pathological conditions that trigger their activation. In particular, activated microglial cells can express sets of Kv subunits which sustain delayed rectifying potassium currents (Kdr) and modulate differently microglia proliferation and ability to release mediators. We recently reported that hippocampal microglia is in a particular activation state after a status epilepticus (SE) and the present study aimed at identifying which of the Kv channels are functionally expressed by microglia in this model. METHODOLOGY/PRINCIPAL FINDINGS:SE was induced by systemic injection of kainate in CX3CR1(eGFP/+) mice and whole cell recordings of fluorescent microglia were performed in acute hippocampal slices prepared 48 h after SE. Microglia expressed Kdr currents which were characterized by a potential of half-maximal activation near -25 mV, prominent steady-state and cumulative inactivations. Kdr currents were almost abolished by the broad spectrum antagonist 4-Aminopyridine (1 mM). In contrast, tetraethylammonium (TEA) at a concentration of 1 mM, known to block Kv3.1, Kv1.1 and 1.2 subunits, only weakly reduced Kdr currents. However, at a concentration of 5 mM which should also affect Kv1.3 and 1.6, TEA inhibited about 30% of the Kdr conductance. Alpha-dendrotoxin, which selectively inhibits Kv1.1, 1.2 and 1.6, reduced only weakly Kdr currents, indicating that channels formed by homomeric assemblies of these subunits are not important contributors of Kdr currents. Finally, agitoxin-2 and margatoxin strongly inhibited the current. CONCLUSIONS/SIGNIFICANCE:These results indicate that Kv1.3 containing channels predominantly determined Kdr currents in activated microglia after SE

The commissioning of the CUORE experiment: the mini-tower run

CUORE is a ton-scale experiment approaching the data taking phase in Gran Sasso National Laboratory. Its primary goal is to search for the neutrinoless double-beta decay in 130Te using 988 crystals of tellurim dioxide. The crystals are operated as bolometers at about 10 mK taking advantage of one of the largest dilution cryostat ever built. Concluded in March 2016, the cryostat commissioning consisted in a sequence of cool down runs each one integrating new parts of the apparatus. The last run was performed with the fully configured cryostat and the thermal load at 4 K reached the impressive mass of about 14 tons. During that run the base temperature of 6.3 mK was reached and maintained for more than 70 days. An array of 8 crystals, called mini-tower, was used to check bolometers operation, readout electronics and DAQ. Results will be presented in terms of cooling power, electronic noise, energy resolution and preliminary background measurements

Results from the Cuore Experiment

The Cryogenic Underground Observatory for Rare Events (CUORE) is the first bolometric experiment searching for neutrinoless double beta decay that has been able to reach the 1-ton scale. The detector consists of an array of 988 TeO2 crystals arranged in a cylindrical compact structure of 19 towers, each of them made of 52 crystals. The construction of the experiment was completed in August 2016 and the data taking started in spring 2017 after a period of commissioning and tests. In this work we present the neutrinoless double beta decay results of CUORE from examining a total TeO2 exposure of 86.3kg yr, characterized by an effective energy resolution of 7.7 keV FWHM and a background in the region of interest of 0.014 counts/ (keV kg yr). In this physics run, CUORE placed a lower limit on the decay half- life of neutrinoless double beta decay of 130Te > 1.3.1025 yr (90% C. L.). Moreover, an analysis of the background of the experiment is presented as well as the measurement of the 130Te 2vo3p decay with a resulting half- life of T2 2. [7.9 :- 0.1 (stat.) :- 0.2 (syst.)] x 10(20) yr which is the most precise measurement of the half- life and compatible with previous results

Status epilepticus induces a particular microglial activation state characterized by enhanced purinergic signaling.: Activated microglia in the epileptic hippocampus

International audienceMicroglia cells are the resident macrophages of the CNS, and their activation plays a critical role in inflammatory reactions associated with many brain disorders, including ischemia, Alzheimer's and Parkinson's diseases, and epilepsy. However, the changes of microglia functional properties in epilepsy have rarely been studied. Here, we used a model of status epilepticus (SE) induced by intraperitoneal kainate injections to characterize the properties of microglial cells in hippocampal slices from CX3CR1(eGFP/+) mice. SE induced within 3 h an increased expression of inflammatory mediators in the hippocampus, followed by a modification of microglia morphology, a microglia proliferation, and a significant neurodegeneration in CA1. Changes in electrophysiological intrinsic membrane properties of hippocampal microglia were detected at 24-48 h after SE with, in particular, the appearance of new voltage-activated potassium currents. Consistent with the observation of an upregulation of purinergic receptor mRNAs in the hippocampus, we also provide pharmacological evidence that microglia membrane currents mediated by the activation of P2 receptors, including P2X(7), P2Y(6), and P2Y(12), were increased 48 h after SE. As a functional consequence of this modification of purinergic signaling, motility of microglia processes toward a source of P2Y(12) receptor agonist was twice as fast in the epileptic hippocampus. This study is the first functional description of microglia activation in an in vivo model of inflammation and provides evidence for the existence of a particular microglial activation state after a status epilepticus

Adaptive phenotype of microglial cells during the normal postnatal development of the somatosensory “Barrel” cortex

International audienc

Calcium-activated potassium currents in resting and activated microglia.

<p>A, B Examples of currents induced by voltage steps from 0 to +80 mV before (black traces) and after (red traces) bath application of TEA (1 mM) with 1 µM (left panel) and 0 µM (right panel) estimated intracellular free calcium in microglial cells from control (A) and from epileptic (B) mice. C Summary of the effects of TEA (1 mM, red column) and intracellular calcium on the current densities induced by voltage steps from 0 to +80 mV in microglia of control and epileptic mice (paired <i>t test</i>, *p<0.05).</p

Biophysical properties of potassium channels expressed in microglial cells after <i>status epilepticus</i>.

<p>A1 Example of currents used to obtain activation and inactivation curves in microglia after <i>status epilepticus</i>. Microglia cells were held at a potential of −70 mV and stepped at different potentials for 1 s before a final step of 250 ms at +50 mV. The inset represents the voltage steps corresponding to the current traces showed in the figure. A2 Average of activation and inactivation curves (n = 13) normalized to maximal conductance. B1 Examples of currents induced in another microglial cell by 10 consecutive pulses from −70 to +30 mV with 30 s interval (left panel) or 0.4 s interval (right panel). B2 Evolution of the peak current amplitude obtained at every pulse expressed as percentage of the first response for 7 tested cells. Note that the smaller is the inter-pulse interval, the higher is the inactivation of the current.</p

Effects of broad spectrum blockers of potassium channels on the outward rectifying current expressed by microglia 48 h after the induction of <i>status epilepticus</i>.

<p>A Example of the current (left panel) induced by a voltage step from −70 to +30 mV in control (black trace) and after perfusion of 4-AP (1 mM, red trace), and the I/V relationships in the same cell (right panel). Note that 4-AP almost completely abolished the outward rectifying currents without affecting the inward currents. B–C Examples of leak subtracted currents induced by a voltage step from −70 to +40 mV in control (black trace) and after 4-AP 1 mM (B, red trace) or TEA 5 mM (C). The leak conductances of the cells in B and C were 585 and 256 pS, respecitively. The graphs on the right represent the conductance, normalized to its maximum value, as a function of membrane potential and its inhibition induced by 4-AP (B, n = 8), TEA (C) 1 mM (n = 9) and 5 mM (n = 7).</p

Summary of the effects induced by the different drugs tested on the outward rectifying potassium current evoked by a voltage step from −70 to +30 mV.

<p>The histogram represents the average of the leak subtracted current after drug application and normalized to its pre-drug value. The “time matched control” bar corresponds to experiments in which the current was measured during 10 to 15 minutes without any drug application to control for the absence of any significant run-down of the current. Statistical tests were done on raw data (paired <i>t test</i>, **p<0.01; the number of tested cells for each condition is that given in the legends of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0006770#pone-0006770-g003" target="_blank">figures 3</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0006770#pone-0006770-g004" target="_blank">4</a>).</p