Individuals experiencing suicidal thoughts and behaviors (STBs) show less specificity and positivity during episodic future thinking (EFT). Here, we present findings from two studies aiming to (1) ...further our understanding of how STBs may relate to neural responsivity during EFT and (2) examine the feasibility of modulating EFT-related activation using real-time fMRI neurofeedback (rtfMRI-nf). Study 1 involved 30 individuals with major depressive disorder (MDD; half with STBs) who performed an EFT task during fMRI, for which they imagined personally-relevant future positive, negative, or neutral events. Positive EFT elicited greater ventromedial prefrontal cortex (vmPFC) activation compared to negative EFT. Importantly, the MDD + STB group exhibited reduced vmPFC activation across all EFT conditions compared to MDD-STB; although EFT fluency and subjective experience remained consistent across groups. Study 2 included rtfMRI-nf focused on vmPFC modulation during positive EFT for six participants with MDD + STBs. Results support the feasibility and acceptability of the rtfMRI-nf protocol and quantitative and qualitative observations are provided to help inform future, larger studies aiming to examine similar neurofeedback protocols. Results implicate vmPFC blunting as a promising treatment target for MDD + STBs and suggest rtfMRI-nf as one potential technique to explore for enhancing vmPFC engagement.
•Greater vmPFC activation is observed for positive versus negative future thinking.•Suicidal thoughts and behaviors relate to vmPFC blunting during future thinking.•Real-time fMRI neurofeedback of the vmPFC is feasible and acceptable.
Radial glial cells: Key organisers in CNS development Barry, Denis S.; Pakan, Janelle M.P.; McDermott, Kieran W.
The international journal of biochemistry & cell biology,
January 2014, 2014-Jan, 2014-01-00, 20140101, Letnik:
46
Journal Article
Recenzirano
Radial glia are elongated bipolar cells present in the CNS during development. Our understanding of the unique roles these cells play has significantly expanded in the last decade. Historically, ...radial glial cells were primarily thought to provide an architectural framework for neuronal migration. Recent research reveals that radial glia play a more dynamic and integrated role in the development of the brain and spinal cord. They represent a major progenitor pool during early development and can give rise to a small population of multipotent cells in neurogenic niches of the adult CNS. Radial glial cells are a heterogeneous population, with divergent and often poorly understood roles across different brain and spinal cord regions during development; this heterogeneity extends to specialised adult subtypes, such as tanycytes, Müller glial cells and Bergman glial cells which possess morphological similarities to radial glial but play distinct functional roles in the CNS.
Bortezomib therapy has proven successful for the treatment of relapsed/refractory, relapsed, and newly diagnosed multiple myeloma (MM); however, dose-limiting toxicities and the development of ...resistance limit its long-term utility. Here, we show that P5091 is an inhibitor of deubiquitylating enzyme USP7, which induces apoptosis in MM cells resistant to conventional and bortezomib therapies. Biochemical and genetic studies show that blockade of HDM2 and p21 abrogates P5091-induced cytotoxicity. In animal tumor model studies, P5091 is well tolerated, inhibits tumor growth, and prolongs survival. Combining P5091 with lenalidomide, HDAC inhibitor SAHA, or dexamethasone triggers synergistic anti-MM activity. Our preclinical study therefore supports clinical evaluation of USP7 inhibitor, alone or in combination, as a potential MM therapy.
► P5091 is a potent and selective inhibitor of deubiquitylating enzyme USP7 ► P5091 triggers in vitro and in vivo antimyeloma activity ► P5091 activates HDM2/p53/p21 signaling axis ► Synergistic anti-MM activity of P5091 with SAHA, lenalidomide, or dexamethasone
Surgery is an effective, high-cost procedure used increasingly to treat refractory epilepsy. For surgery to be cost-effective, long-term cost savings from reduced health care use should provide some ...offset to the initial costs of evaluation and surgery. There is little information about how health care costs are affected by evaluation and surgery.
To determine whether health care costs change when seizures become controlled after surgery.
Health care costs for the 2 years prior to surgical evaluation and for 2 years afterward were calculated from medical records of 68 subjects with temporal lobe epilepsy (TLE) participating in a multicenter observational study. Costs were compared among patients who did not have surgery, patients who had persisting seizures after surgery, and patients who were seizure free after surgery.
Antiepileptic drugs (AEDs) accounted for more than half of the costs of care in the pre-evaluation period. Total costs for seizure-free patients had declined 32% by 2 years following surgery due to less use of AEDs and inpatient care. Costs did not change in patients with persisting seizures, whether they had surgery or not. In the 18 to 24 months following evaluation, epilepsy-related costs were $2,068 to $2,094 in patients with persisting seizures vs $582 in seizure-free patients.
Costs remain stable over 2 years post-evaluation in patients with temporal lobe epilepsy whose seizures persist, but patients who become seizure free after surgery use substantially less health care than before surgery. Further cost reductions in seizure-free patients can be expected as antiepileptic drugs are successfully eliminated.
To determine the rate of disease progression in Charcot-Marie-Tooth disease type 1A (CMT1A).
CMT1A is the most common inherited peripheral neuropathy, affecting approximately 1:5,000 people ...irrespective of ethnic background or gender. There is no cure for CMT1A. Clinical trials are being initiated that use the CMT Neuropathy Score (CMTNS), a composite score based on patient symptoms, signs, and neurophysiologic abnormalities, as the primary outcome variable. The sensitivity of the CMTNS or any other score to change over time, as a measure of CMT1A progression, has yet to be determined.
We determined the CMTNS as well as the Neuropathy Impairment Score (NIS) on 72 patients followed for up to 8 years. The rate of disease progression was evaluated for the CMTNS and NIS using mixed effects linear regression models, adjusting for age and gender.
Both CMTNS and NIS showed changes over time. The CMTNS increased an average of 0.686 points per year (95% CI 0.461 to 0.911, p <or= 0.0001). The NIS increased 1.368 points per year on average (95% CI 0.616 to 2.121, p = 0.0005). There was a suggestion that the rate of progression increased with age.
Progression of CMT1A can be detected by both the CMT Neuropathy Score (CMTNS) and the Neuropathy Impairment Score (NIS). This supports the feasibility of clinical trials to detect a slowing of disease progression using either or both of these scales as outcome measures. Since the CMTNS combines symptoms, signs, and electrophysiology and the NIS is based solely on the neurologic examination, the two scales may be complementary.
A recombinant vaccine containing Aventis Pasteur's canarypox vector (ALVAC)-HIV and gp120 alum decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution of alum with the more ...immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC-simian immunodeficiency virus (SIV) and gp120 alum (ALVAC-SIV + gp120) equivalent vaccine, but not an ALVAC-SIV + gp120 MF59 vaccine, was efficacious in delaying the onset of SIVmac251 in rhesus macaques, despite the higher immunogenicity of the latter adjuvant. Vaccine efficacy was associated with alum-induced, but not with MF59-induced, envelope (Env)-dependent mucosal innate lymphoid cells (ILCs) that produce interleukin (IL)-17, as well as with mucosal IgG to the gp120 variable region 2 (V2) and the expression of 12 genes, ten of which are part of the RAS pathway. The association between RAS activation and vaccine efficacy was also observed in an independent efficacious SIV-vaccine approach. Whether RAS activation, mucosal ILCs and antibodies to V2 are also important hallmarks of HIV-vaccine efficacy in humans will require further studies.
Based on the knowledge that Tourette's syndrome (TS) is associated with several clinical features that can impair school function and growing evidence that the disorder is much more common than ...previously thought, the authors hypothesized that TS and related tic disorders would be associated with school problems in the childhood population at large.
Direct, blinded (to educational placement) interviews of 1,596 schoolchildren in Monroe County, Rochester, NY, were conducted.
Twenty-seven percent of 341 students classified as receiving special education (SpEd) had tics compared with 19.7% (p = 0.008) of 1,255 students in regular classroom programs (RegEd). The weighted prevalence estimates for tics were 23.4% in SpEd and 18.5% in RegEd. A higher percentage of students in SpEd (7.0%) met diagnostic criteria for TS than students in RegEd (3.8%; p = 0.01).
Although possibly influenced by selection bias, our results indicate that tic disorders are common in children and are highly associated with school dysfunction. Tics may represent an identifiable sign of an underlying brain developmental disorder that contributes to academic difficulties.
Demographic and epidemiological field data were used in a deterministic model to describe dog rabies transmission in Machakos District, Kenya and to predict the impact of potential vaccination ...strategies for its control. The basic reproduction number (R0) was estimated to be 2.44 (1.52–3.36, 95% confidence limits). There were three key model predictions. The first was that a threshold dog density (KT) of 4.5 dogs km−2 (3.8–5.2 dogs km−2, 95% confidence limits) was required to maintain transmission. The second was that the estimated annual vaccination rate of 24% failed to decrease incidence and actually increased the stability of transmission and may be counter-productive. Thirdly, to control rabies, it was predicted that 59% (34%–70%, 95% confidence limits) of dogs should be vaccinated at any one time. This requires approximately 70% coverage for annual but only 60% coverage for semi-annual vaccination campaigns. Community-level vaccination trials are needed to test these predictions.
ADAM-17 is a matrix metalloproteinase-like enzyme involved in the release of several ligands that have been shown to promote both cancer formation and progression. These ligands include transforming ...growth factor-α, amphiregulin, heparin-binding epidermal growth factor, epiregulin and tumor necrosis factor-α. In this investigation, we measured the expression of total ADAM-17 by enzyme-linked immunosorbent assay in 153 invasive breast cancers. We also measured the precursor and active forms by western blotting in 140 invasive breast cancers. Expression of ADAM-17 was significantly increased in high-grade compared with low-grade tumors and was independent of tumor size, lymph node metastasis and estrogen receptor status. Patients with high expression of ADAM-17 had a significantly shorter overall survival compared with those with low expression. Significantly, the prognostic impact of ADAM-17 was independent of conventional prognostic factors for breast cancer. Our results are further evidence that ADAM-17 is involved in breast cancer progression and thus provides further impetus for exploiting ADAM-17 as new target for cancer treatment.
Animal and human studies suggest that beta(2)-adrenergic agonists exert anabolic effects on muscles, inducing and preventing atrophy after a variety of insults. Based on data from an open-label trial ...of albuterol in 15 patients with facioscapulohumeral dystrophy (FSHD), the authors conducted a randomized, double-blind, placebo-controlled trial of sustained-release albuterol in this disease.
Ninety patients were randomized to three groups: placebo; 8.0 mg albuterol twice daily; or 16.0 mg albuterol twice daily. Patients were treated for 1 year with assessments at baseline and weeks 13, 26, and 52. The primary outcome was the 52-week change in global strength by maximum voluntary isometric contraction testing (MVICT). Secondary outcomes included changes at 52 weeks in strength by manual muscle testing (MMT), grip strength, functional testing, and muscle mass assessed by dual energy x-ray absorptiometry (DEXA).
Eighty-four patients completed the study. The mean changes in composite MVICT scores were not significantly different between the groups (mean +/- SD: placebo 0.20 +/- 0.91; low dose -0.04 +/- 0.84; high dose 0.08 +/- 0.98). Similarly, there were no differences in the mean MMT change (placebo 0.04 +/- 0.16; low dose -0.03 +/- 0.13; high dose 0.00 +/- 0.15). Grip improved in both treatment groups compared to placebo (placebo -0.53 +/- 4.13, low dose +1.90 +/- 3.34 p = 0.02, high dose +1.70 +/- 4.13 p = 0.03). The high-dose group had a significant increase in lean mass by DEXA (+1.57 +/- 1.71 kg) compared to placebo (0.25 +/- 2.24; p = 0.007). Albuterol was well tolerated; side effects included cramps, tremors, insomnia, and nervousness.
Although albuterol did not improve global strength or function in patients with FSHD, it did increase muscle mass and improve some measures of strength.
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