Human T-cell function is dependent on T-cell antigen receptor (TCR) and co-signalling as evidenced by immunodeficiencies affecting TCR-dependent signalling pathways. Here, we show four human patients ...with EBV
disseminated smooth muscle tumours that carry two homozygous loss-of-function mutations in the CARMIL2 (RLTPR) gene encoding the capping protein regulator and myosin 1 linker 2. These patients lack regulatory T cells without evidence of organ-specific autoimmunity, and have defective CD28 co-signalling associated with impaired T-cell activation, differentiation and function, as well as perturbed cytoskeletal organization associated with T-cell polarity and migration disorders. Human CARMIL2-deficiency is therefore an autosomal recessive primary immunodeficiency disorder associated with defective CD28-mediated TCR co-signalling and impaired cytoskeletal dynamics.
The double-gamma (γγ)-decay of a quantum system in an excited state is a fundamental second-order process of quantum electrodynamics. In contrast to the well-known single-gamma (γ)-decay, the ...γγ-decay is characterized by the simultaneous emission of two γ quanta, each with a continuous energy spectrum. In nuclear physics, this exotic decay mode has only been observed for transitions between states with spin-parity quantum numbers J(π) = 0(+) (refs 1-3). Single-gamma decays-the main experimental obstacle to observing the γγ-decay-are strictly forbidden for these 0(+) → 0(+) transitions. Here we report the observation of the γγ-decay of an excited nuclear state (J(π) = 11/2(-)) that is directly competing with an allowed γ-decay (to ground state J(π) = 3/2(+)). The branching ratio of the competitive γγ-decay of the 11/2(-) isomer of (137)Ba to the ground state relative to its single γ-decay was determined to be (2.05 ± 0.37) × 10(-6). From the measured angular correlation and the shape of the energy spectra of the individual γ-rays, the contributing combinations of multipolarities of the γ radiation were determined. Transition matrix elements calculated using the quasiparticle-phonon model reproduce our measurements well. The γγ-decay rate gives access to so far unexplored important nuclear structure information, such as the generalized (off-diagonal) nuclear electric polarizabilities and magnetic susceptibilities.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
To explore the molecular profile and its prognostic implication in systemic mastocytosis (SM), we analyzed the mutation status of granulocyte-macrophage colony-forming progenitor cells (CFU-GM) in ...patients with KIT D816V(+) indolent SM (ISM, n=4), smoldering SM (SSM, n=2), aggressive SM (ASM, n=1), SM with associated clonal hematologic non-mast cell lineage disorder (SM-AHNMD, n=5) and ASM-AHNMD (n=7). All patients with (A)SM-AHNMD (n=12) carried 1-4 (median 3) additional mutations in 11 genes tested, most frequently TET2, SRSF2, ASXL1, CBL and EZH2. In multi-mutated (A)SM-AHNMD, KIT D816V(+) single-cell-derived CFU-GM colonies were identified in 8/12 patients (median 60%, range 0-95). Additional mutations were identified in CFU-GM colonies in all patients, and logical hierarchy analysis indicated that mutations in TET2, SRSF2 and ASXL1 preceded KIT D816V. In ISM/SSM, no additional mutations were detected and CFU-GM colonies were exclusively KIT D816V(-). These data indicate that (a) (A)SM-AHNMD is a multi-mutated neoplasm, (b) mutations in TET2, SRSF2 or ASXL1 precede KIT D816V in ASM-AHNMD,
To compare long-term quality-of-life outcomes in vestibular schwannoma patients managed with observation, microsurgery, or stereotactic radiation.
ross-sectional survey with retrospective chart ...review.
Tertiary care center.
The Penn Acoustic Neuroma Quality of Life (PANQOL) survey was mailed to 600 patients treated for vestibular schwannoma. Patients were separated by treatment and subsequently subdivided by years of follow-up (0-5, 6-10, and >10 years). Composite quality-of-life (cQOL) scores and subscores for hearing, balance, facial nerve, pain, anxiety, energy, and general health were calculated. Scores were compared among treatment groups as a whole, among treatment groups at each time interval, and within treatment groups over time using a 2-tailed analysis of variance and paired t test.
The survey return rate was 49%, and the mean follow-up was 7.9 years. The only significant difference in cQOL occurred at 0 to 5 years, where stereotactic radiation scores were better than both microsurgery and observation (P = .009). No significant differences were detected in cQOL after 5 years. Within the radiation group, cQOL was significantly lower at 6 to 10 years than at 0 to 5 years (P = .013). At no point was cQOL for stereotactic radiation less than that for observation or microsurgery.
Long-term (>5 years) quality-of-life outcomes measured by the PANQOL in vestibular schwannoma patients show no significant differences between stereotactic radiation, observation, and microsurgical intervention. Studies are needed to fully evaluate very-long-term QOL for patients with vestibular schwannoma.
Anticancer agents often have a narrow therapeutic index (TI), requiring precise dosing to ensure sufficient exposure for clinical activity while minimizing toxicity. These agents frequently have ...complex pharmacology, and combination therapy may cause schedule‐specific effects and interactions. We review anticancer drug development, showing how integration of modeling and simulation throughout development can inform anticancer dose selection, potentially improving the late‐phase success rate. This article has a companion article in Clinical Pharmacology & Therapeutics with practical examples.
CPT Pharmacometrics Syst. Pharmacol. (2015) 4, 12–27; doi:10.1002/psp4.16; published online 21 January 2015
To examine the results of a randomized clinical trial (RCT) of Teen Online Problem Solving (TOPS), an online problem solving therapy model, in increasing problem-solving skills and decreasing ...depressive symptoms and global distress for caregivers of adolescents with traumatic brain injury (TBI).
Families of adolescents aged 11-18 who sustained a moderate to severe TBI between 3 and 19 months earlier were recruited from hospital trauma registries. Participants were assigned to receive a web-based, problem-solving intervention (TOPS, n = 20), or access to online resources pertaining to TBI (Internet Resource Comparison; IRC; n = 21). Parent report of problem solving skills, depressive symptoms, global distress, utilization, and satisfaction were assessed pre- and posttreatment. Groups were compared on follow-up scores after controlling for pretreatment levels. Family income was examined as a potential moderator of treatment efficacy. Improvement in problem solving was examined as a mediator of reductions in depression and distress.
Forty-one participants provided consent and completed baseline assessments, with follow-up assessments completed on 35 participants (16 TOPS and 19 IRC). Parents in both groups reported a high level of satisfaction with both interventions. Improvements in problem solving skills and depression were moderated by family income, with caregivers of lower income in TOPS reporting greater improvements. Increases in problem solving partially mediated reductions in global distress.
Findings suggest that TOPS may be effective in improving problem solving skills and reducing depressive symptoms for certain subsets of caregivers in families of adolescents with TBI.
Light-weight components are of crucial interest for all branches that produce moving masses. The aim to reduce weight has to be accompanied by high production efficiency and component performance. ...Laser beam joining offers the possibility to manufacture joints of all light metals and their combinations. This paper will give examples for structures built with aluminium, titanium, magnesium and their combinations and explain how the requirements of the industry could be fulfilled by applying laser beam joining. For aluminium the weldability of the so-called non-weldable alloys by use of powder filler will be explained for aerospace applications. Another example will deal with increased process stability during laser beam welding of aluminium. Especially for future car manufacturing applications, Al–steel and Al–Mg joints will be presented for optimised material use. Stiffened titanium structures for aerospace applications will demonstrate the potential of a combination of laser welding and straightening for precision manufacturing.
Abstract Bipolar disorder (BD) is characterized by frequent recurrence, incomplete recovery, cognitive dysfunction and poor functioning. Impairment lingers in the interepisodic period and mechanisms ...leading to this dysfunctional state are not fully comprehended. To our knowledge the association of biological rhythm dysfunction with functioning in BD has not been assessed directly. The objective of this study was to measure and quantify the impact of rhythm dysfunction on interepisodic functioning in BD. We also tested the association between executive functioning and sleep and rhythm problems. Eighty-one outpatients with BD and 79 matched control subjects were consecutively recruited. Functional impairment was assessed with the Functioning Assessment Short Test (FAST) and biological rhythms with the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN). A subsample had their executive functioning assessed with the Wisconsin Card Sorting Test (WCST). Patients and control subjects were well matched. Functioning and rhythm scores were correlated in patients and control subjects. The BRIAN score was the strongest predictor of functioning in the regression model. Biological rhythms partially mediated the impairment associated with bipolar disorder. The rhythm score was also associated with executive functioning. Biological rhythm dysfunction was a potent predictor of functioning in interepisodic patients with bipolar disorder; it may also mediate much of the disorder-induced disability. These results further the notion that biological rhythms may be interesting targets for diverse interventions aiming to improve functioning and prevent relapse in interepisodic bipolar disorder.
Objective
Surgery of the pediatric skull base has multiple unique challenges and has seen recent rapid advances. The objective of this review is to assess key issues in pediatric skull base surgery ...(SBS), including anatomic limitations, surgical approaches, reconstruction techniques, postoperative care, complications, and outcomes.
Data Sources
PubMed literature review.
Review Methods
A review of the literature was conducted to assess the challenges, recent advances, and reported outcomes in pediatric SBS.
Results
The pediatric skull base presents multiple anatomic challenges, including variable patterns of pneumatization, narrow piriform aperture width, and narrow intercarotid distance at the level of the cavernous sinus but not the superior clivus. These issues may be particularly challenging in patients less than 2 years of age. Endoscopic endonasal approaches in the sagittal and coronal plane have been applied to the pediatric skull base while open approaches may still be necessary in the setting of extensive intracranial or orbital disease, as well as disease lateral to critical neurovascular structures. While the nasoseptal flap was initially called into question for pediatric cases, it has been shown through multiple reports to be a feasible and robust reconstructive option. Complications and outcomes often depend upon the pathology. In children, response to noxious stimuli, ability to avoid Valsalva, and adherence to nasal precautions is variable. The use of lumbar drains is more common in pediatric than adult patients.
Conclusion
While the pediatric skull base presents unique challenges, outcomes data support that endoscopic endonasal approaches are a pertinent surgical technique in appropriately selected patients.
Level of Evidence
3a
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