The small GTPase Rheb is required for spermatogenesis but not oogenesis.

The process of germ cell development is under the tight control of various signaling pathways, among which the PI3K-Akt-mTOR pathway is of critical importance. Previous studies have demonstrated sex-specific roles for several components of this pathway. In the current study, we aimed to evaluate the role of Rheb, a member of the small GTPase superfamily and a critical component for mTORC1 activation, in male and female gametogenesis. The function of Rheb in development and the nervous system has been extensively studied, but little is known about its role in the germ line. We have exploited genetic approaches in the mouse to study the role of Rheb in the germ line and have identified an essential role in spermatogenesis. Conditional knockout (cKO) of Rheb in the male germ line resulted in severe oligoasthenoteratozoospermia and male sterility. More detailed phenotypic analyses uncovered an age-dependent meiotic progression defect combined with subsequent abnormalities in spermiogenesis as evidenced by abnormal sperm morphology. In the female, however, germ-cell specific inactivation of Rheb was not associated with any discernible abnormality; these cKO mice were fertile with morphologically unremarkable ovaries, normal primordial follicle formation, and subsequent follicle maturation. The absence of an abnormal ovarian phenotype is striking given previous studies demonstrating a critical role for the mTORC1 pathway in the maintenance of primordial follicle pool. In conclusion, our findings demonstrate an essential role of Rheb in diverse aspects of spermatogenesis but suggest the existence of functionally redundant factors that can compensate for Rheb deficiency within oocytes.

Sustained-release fampridine in Multiple Sclerosis.

Sustained-release fampridine, a slow release formulation of 4-aminopryridine, is a voltage-dependent potassium channel blocker licensed for the treatment of walking difficulties in multiple sclerosis (MS). Studies have demonstrated that approximately one-third of MS patients respond with a clear benefit to their walking speed. Sustained-release Fampridine is not currently available on the National Health Service (NHS), although it has been approved by the Food and Drug Administration (FDA) in the USA and European Medicine Agency (EMA). It appears to have an acceptable adverse event profile, with data from open-label extension studies now becoming available. Concerns have been raised that the use of fampridine may increase the risk of seizures, which were seen at higher rates in patients treated with high doses of sustained-release fampridine. The rate of seizures in those patients on lower doses has not been found to be significantly increased. There are significant barriers at present to the widespread use of fampridine in the UK, which have limited its use in clinical practice to date. Patients with MS are in need of interventions to improve walking and many clinicians feel that this drug may have a role in the symptomatic management of MS.

Percutaneous pediculoplasty for traumatic pedicle fracture. A technical case report.

The objective of this case is to illustrate a technique for performing fluoroscopically guided percutaneous pediculoplasty in the setting of traumatic or non-neoplastic pedicle fractures. Pediculoplasty has been described in the literature as a complimentary technique performed during vertebroplasty. In this case, isolated pediculoplasty is demonstrated using existing vertebroplasty equipment, which may be utilized as a primary intervention for pedicle fractures in patients who are poor surgical candidates.

Event-by-event fluctuations of azimuthal particle anisotropy in Au+Au collisions at square root(sNN) = 200 GeV.

This Letter presents the first measurement of event-by-event fluctuations of the elliptic flow parameter v(2) in Au+Au collisions at square root(s(NN))=200 GeV as a function of collision centrality. The relative nonstatistical fluctuations of the v(2) parameter are found to be approximately 40%. The results, including contributions from event-by-event elliptic flow fluctuations and from azimuthal correlations that are unrelated to the reaction plane (nonflow correlations), establish an upper limit on the magnitude of underlying elliptic flow fluctuations. This limit is consistent with predictions based on spatial fluctuations of the participating nucleons in the initial nuclear overlap region. These results provide important constraints on models of the initial state and hydrodynamic evolution of relativistic heavy ion collisions.

High transverse momentum triggered correlations over a large pseudorapidity acceptance in Au + Au collisions at square root(s(NN)) = 200 GeV.

A measurement of two-particle correlations with a high transverse momentum trigger particle (p(T)(trig) > 2.5 GeV/c) is presented for Au+Au collisions at square root(s(NN)) = 200 GeV over the uniquely broad longitudinal acceptance of the PHOBOS detector (-4 < Delta eta < 2). A broadening of the away-side azimuthal correlation compared to elementary collisions is observed at all Delta eta. As in p+p collisions, the near side is characterized by a peak of correlated partners at small angle relative to the trigger particle. However, in central Au+Au collisions an additional correlation extended in Delta eta and known as the "ridge" is found to reach at least |Delta eta| approximately = 4. The ridge yield is largely independent of Delta eta over the measured range, and it decreases towards more peripheral collisions. For the chosen (p(T)(trig) cut, the ridge yield is consistent with zero for events with less than roughly 100 participating nucleons.

Imaging and treatment of sacral insufficiency fractures.

SIFs are a common, though often unsuspected, cause of low back pain in the elderly. Although numerous radiographic modalities can be used to diagnose SIFs, bone scintigraphy and MR imaging are the most sensitive. Conservative management involves various combinations of bed rest, rehabilitation, and analgesics. More recently, sacroplasty has emerged as an alternative therapy for the treatment of SIFs, with prospective studies and case reports suggesting that it is a safe and effective therapy. This article reviews the imaging appearance of SIFs and discusses treatment options with a focus on sacroplasty.

Monophyly of terrestrial adephagan beetles as indicated by three nuclear genes (Coleoptera: Carabidae and Trachypachidae).

The beetle suborder Adephaga is traditionally divided into two sections on the basis of habitat, terrestrial Geadephaga and aquatic Hydradephaga. Monophyly of both groups is uncertain, and the relationship of the two groups has implications for inferring habitat transitions within Adephaga. Here we examine phylogenetic relationships of these groups using evidence provided by DNA sequences from all four suborders of beetles, including 60 species of Adephaga, four Archostemata, three Myxophaga, and ten Polyphaga. We studied 18S ribosomal DNA and 28S ribosomal DNA, aligned with consideration of secondary structure, as well as the nuclear protein-coding gene wingless. Independent and combined Bayesian, likelihood, and parsimony analyses of all three genes supported placement of Trachypachidae in a monophyletic Geadephaga, although for analyses of 28S rDNA and some parsimony analyses only if Coleoptera is constrained to be monophyletic. Most analyses showed limited support for the monophyly of Hydradephaga. Outside of Adephaga, there is support from the ribosomal genes for a sister group relationship between Adephaga and Polyphaga. Within the small number of sampled Polyphaga, analyses of 18S rDNA, wingless, and the combined matrix supports monophyly of Polyphaga exclusive of Scirtoidea. Unconstrained analyses of the evolution of habitat suggest that Adephaga was ancestrally aquatic with one transition to terrestrial. However, in analyses constrained to disallow changes from aquatic to terrestrial habitat, the phylogenies imply two origins of aquatic habit within Adephaga.

System size, energy, and centrality dependence of pseudorapidity distributions of charged particles in relativistic heavy-ion collisions.

We present the first measurements of the pseudorapidity distribution of primary charged particles in Cu+Cu collisions as a function of collision centrality and energy, sqrt[s_{NN}]=22.4, 62.4, and 200 GeV, over a wide range of pseudorapidity, using the PHOBOS detector. A comparison of Cu+Cu and Au+Au results shows that the total number of produced charged particles and the rough shape (height and width) of the pseudorapidity distributions are determined by the number of nucleon participants. More detailed studies reveal that a more precise matching of the shape of the Cu+Cu and Au+Au pseudorapidity distributions over the full range of pseudorapidity occurs for the same N{part}/2A rather than the same N_{part}. In other words, it is the collision geometry rather than just the number of nucleon participants that drives the detailed shape of the pseudorapidity distribution and its centrality dependence at RHIC energies.

System size, energy, pseudorapidity, and centrality dependence of elliptic flow.

This Letter presents measurements of the elliptic flow of charged particles as a function of pseudorapidity and centrality from Cu-Cu collisions at 62.4 and 200 GeV using the PHOBOS detector at the Relativistic Heavy Ion Collider. The elliptic flow in Cu-Cu collisions is found to be significant even for the most central events. For comparison with the Au-Au results, it is found that the detailed way in which the collision geometry (eccentricity) is estimated is of critical importance when scaling out system-size effects. A new form of eccentricity, called the participant eccentricity, is introduced which yields a scaled elliptic flow in the Cu-Cu system that has the same relative magnitude and qualitative features as that in the Au-Au system.

Sacroplasty versus vertebroplasty: comparable clinical outcomes for the treatment of fracture-related pain.

BACKGROUND AND PURPOSE: Little is known about the long-term clinical outcomes of sacroplasty, a relatively new minimally invasive percutaneous procedure for the treatment of sacral insufficiency fractures. The first purpose of the present study, therefore, was to investigate the effects of sacroplasty on pain, mobility, and activities of daily living (ADLs). A second purpose was to compare clinical outcomes of sacroplasty with those of vertebroplasty, a similar but more established procedure. MATERIALS AND METHODS: A retrospective case series of 12 patients who had a sacroplasty and a control group of 21 patients who had undergone a vertebroplasty was conducted. A 12-item questionnaire and subsequent telephone interview requested each patient to rate the intensity of pain, as well as the ability to ambulate and perform ADLs, before sacroplasty or vertebroplasty, and at the time of the interview. RESULTS: There was a statistically significant decrease in overall self-reported pain, as well as an increase in self-reported ability to ambulate and perform ADLs after sacroplasty or vertebroplasty. These improvements were equivalent, regardless of which procedure the patient received. CONCLUSION: The present study suggests that the treatment of sacral insufficiency fractures with sacroplasty produces relatively long-lasting improvements in pain, mobility, and the ability to perform ADLs. These data also suggest that the clinical outcomes of sacroplasty are comparable with those of vertebroplasty, an accepted and more routinely performed procedure.

muO-conotoxin MrVIB selectively blocks Nav1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits.

The tetrodotoxin-resistant voltage-gated sodium channel (VGSC) Na(v)1.8 is expressed predominantly by damage-sensing primary afferent nerves and is important for the development and maintenance of persistent pain states. Here we demonstrate that muO-conotoxin MrVIB from Conus marmoreus displays substantial selectivity for Na(v)1.8 and inhibits pain behavior in models of persistent pain. In rat sensory neurons, submicromolar concentrations of MrVIB blocked tetrodotoxin-resistant current characteristic of Na(v)1.8 but not Na(v)1.9 or tetrodotoxin-sensitive VGSC currents. MrVIB blocked human Na(v)1.8 expressed in Xenopus oocytes with selectivity at least 10-fold greater than other VGSCs. In neuropathic and chronic inflammatory pain models, allodynia and hyperalgesia were both reduced by intrathecal infusion of MrVIB (0.03-3 nmol), whereas motor side effects occurred only at 30-fold higher doses. In contrast, the nonselective VGSC blocker lignocaine displayed no selectivity for allodynia and hyperalgesia versus motor side effects. The actions of MrVIB reveal that VGSC antagonists displaying selectivity toward Na(v)1.8 can alleviate chronic pain behavior with a greater therapeutic index than nonselective antagonists.

Energy dependence of directed flow over a wide range of pseudorapidity in Au + Au collisions at the BNL Relativistic Heavy Ion Collider.

We report on measurements of directed flow as a function of pseudorapidity in Au + Au collisions at energies of square root of SNN = 19.6, 62.4, 130 and 200 GeV as measured by the PHOBOS detector at the BNL Relativistic Heavy Ion Collider. These results are particularly valuable because of the extensive, continuous pseudorapidity coverage of the PHOBOS detector. There is no significant indication of structure near midrapidity and the data surprisingly exhibit extended longitudinal scaling similar to that seen for elliptic flow and charged particle pseudorapidity density.

System size and centrality dependence of charged hadron transverse momentum spectra in Au + Au and Cu + Cu collisions at square root of SNN = 62.4 and 200 GeV.

We present transverse momentum distributions of charged hadrons produced in Cu + Cu collisions at square root of SNN = 62.4 and 200 GeV. The spectra are measured for transverse momenta of 0.25 < pT < 5.0 GeV/c at square root of SNN = 62.4 GeV and 0.25 < pT < 7.0 GeV/c at square root of SNN = 200 GeV, in a pseudorapidity range of 0.2 < eta < 1.4. The nuclear modification factor R(AA) is calculated relative to p + p data at both collision energies as a function of collision centrality. At a given collision energy and fractional cross section, R(AA) is observed to be systematically larger in Cu + Cu collisions compared to Au + Au. However, for the same number of participating nucleons, R(AA) is essentially the same in both systems over the measured range of pT, in spite of the significantly different geometries of the Cu + Cu and Au + Au systems.

Energy dependence of elliptic flow over a large pseudorapidity range in Au+Au collisions at the BNL relativistic heavy ion collider.

This Letter describes the measurement of the energy dependence of elliptic flow for charged particles in Au+Au collisions using the PHOBOS detector at the Relativistic Heavy Ion Collider. Data taken at collision energies of square root of s(NN)=19.6, 62.4, 130, and 200 GeV are shown over a wide range in pseudorapidity. These results, when plotted as a function of eta(')=|eta|-y(beam), scale with approximate linearity throughout eta('), implying no sharp changes in the dynamics of particle production as a function of pseudorapidity or increasing beam energy.

Centrality dependence of charged hadron transverse momentum spectra in Au+Au collisions from sqrt[s(NN)]=62.4 to 200 GeV.

We have measured transverse momentum distributions of charged hadrons produced in Au+Au collisions at sqrt[s(NN)]=62.4 GeV. The spectra are presented for transverse momenta 0.25

Pseudorapidity distribution of charged particles in d+Au collisions at sqrt[sNN]=200 GeV.

The measured pseudorapidity distribution of primary charged particles in minimum-bias d+Au collisions at sqrt[s(NN)]=200 GeV is presented for the first time. This distribution falls off less rapidly in the gold direction as compared to the deuteron direction. The average value of the charged particle pseudorapidity density at midrapidity is |eta|< or =0.6)=9.4+/-0.7(syst) and the integrated primary charged particle multiplicity in the measured region is 82+/-6(syst). Estimates of the total charged particle production, based on extrapolations outside the measured pseudorapidity region, are also presented. The pseudorapidity distribution, normalized to the number of participants in d+Au collisions, is compared to those of Au+Au and p+(-)p systems at the same energy. The d+Au distribution is also compared to the predictions of the parton saturation model, as well as microscopic models.

Centrality dependence of charged-hadron transverse-momentum spectra in d+Au collisions at sqrt[s(NN)]=200 GeV.

We have measured transverse momentum distributions of charged hadrons produced in d+Au collisions at sqrt[s(NN)]=200 GeV. The spectra were obtained for transverse momenta 0.25

Significance of the fragmentation region in ultrarelativistic heavy-ion collisions.

We present measurements of the pseudorapidity distribution of primary charged particles produced in Au+Au collisions at three energies, sqrt[s(NN)]=19.6, 130, and 200 GeV, for a range of collision centrali-ties. The distribution narrows for more central collisions and excess particles are produced at high pseudorapidity in peripheral collisions. For a given centrality, however, the distributions are found to scale with energy according to the "limiting fragmentation" hypothesis. The universal fragmentation region described by this scaling grows in pseudorapidity with increasing collision energy, extending well away from the beam rapidity and covering more than half of the pseudorapidity range over which particles are produced. This approach to a universal limiting curve appears to be a dominant feature of the pseudorapidity distribution and therefore of the total particle production in these collisions.

Characteristics of late Na(+) current in adult rat small sensory neurons.

Na(+) currents were recorded using patch-clamp techniques from small-diameter (<25 micrometers) dorsal root ganglion neurons, cultured from adult rats (>150 g). Late Na(+) currents maintained throughout long-duration voltage-clamp steps (>/=200 ms) were of two types: a low-threshold, tetrodotoxin-sensitive (TTX-s) current that was largely blocked by 200 nM TTX, and a high-threshold, TTX-resistant (TTX-r) current. TTX-s late current was found in approximately 28% (10/36) of small-diameter neurons and was recorded only in neurons exhibiting TTX-s transient current. TTX-s transient current activation/inactivation gating overlap existed over a narrow potential range, centered between -30 and -40 mV, whereas late current operated over a wider range. The kinetics associated with de-inactivation of TTX-s late current were slow (tau approximately 37 ms at -50 mV), strongly suggesting that different subpopulations of TTX-s channel generate transient and late current. High-threshold TTX-r late current was only present in neurons generating TTX-r transient current. TTX-r late current operated over the same potential range as that for TTX-r transient current activation/inactivation gating overlap, and activation/inactivation gating overlap could be measured even after 1.5-s-duration pre-pulses. We suggest that TTX-s late sodium current results from channel openings different from those generating transient current. As in large-diameter sensory neurons, TTX-s channels generating late openings may play a key role in controlling membrane excitability. In contrast, a single population of high-threshold TTX-r channels may account for both transient and late TTX-r currents.

Pseudorapidity and centrality dependence of the collective flow of charged particles in Au+Au collisions at sqrt[s(NN)]=130 GeV.

This paper describes the measurement of collective flow for charged particles in Au+Au collisions at sqrt[s(NN)]=130 GeV using the PHOBOS detector at the Relativistic Heavy Ion Collider (RHIC). The measured azimuthal hit anisotropy is presented over a wide range of pseudorapidity (-5.0