To determine the protective effects of memantine on cognitive function in patients receiving whole-brain radiotherapy (WBRT).
Adult patients with brain metastases received WBRT and were randomized to ...receive placebo or memantine (20 mg/d), within 3 days of initiating radiotherapy for 24 weeks. Serial standardized tests of cognitive function were performed.
Of 554 patients who were accrued, 508 were eligible. Grade 3 or 4 toxicities and study compliance were similar in the 2 arms. There was less decline in delayed recall in the memantine arm at 24 weeks (P = .059), but the difference was not statistically significant, possibly because there were only 149 analyzable patients at 24 weeks, resulting in only 35% statistical power. The memantine arm had significantly longer time to cognitive decline (hazard ratio 0.78, 95% confidence interval 0.62-0.99, P = .01); the probability of cognitive function failure at 24 weeks was 53.8% in the memantine arm and 64.9% in the placebo arm. Superior results were seen in the memantine arm for executive function at 8 (P = .008) and 16 weeks (P = .0041) and for processing speed (P = .0137) and delayed recognition (P = .0149) at 24 weeks.
Memantine was well tolerated and had a toxicity profile very similar to placebo. Although there was less decline in the primary endpoint of delayed recall at 24 weeks, this lacked statistical significance possibly due to significant patient loss. Overall, patients treated with memantine had better cognitive function over time; specifically, memantine delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed in patients receiving WBRT. RTOG 0614, ClinicalTrials.gov number CT00566852.
The inclusion of neurocognitive end points in clinical trials of patients with CNS tumors is increasing. Neurocognitive end points are used to understand what cognitive problems exist before ...treatment to establish a baseline by which the effect of treatment is judged, and to determine whether different treatment regimens improve neurocognitive function due to better tumor control, slow expected neurocognitive deterioration due to the tumor, or have more or less short- and long-term neurotoxicity. However, the use of neurocognitive end points in clinical trials for patients with CNS tumors is in its infancy, so that long-term outcomes are difficult to predict and the ability to determine the effects of different agents and treatment approaches is scant. Including this aspect of patient evaluation in addition to survival and time to tumor progression will yield better risk-versus-benefit assessments as well as provide a basis for improving interventions.
Carboplatin (C) and paclitaxel (P) are standard treatments for carcinoma of unknown primary (CUP). Everolimus, an mTOR inhibitor, exhibits activity in diverse cancer types. We did a phase II trial ...combining everolimus with CP for CUP. We also evaluated whether a gene expression profiling (GEP) test that predicts tissue of origin (TOO) could identify responsive patients.
A tumor biopsy was required for central confirmation of CUP and GEP. Patients with metastatic, untreated CUP received everolimus (30 mg weekly) with P (200 mg/m2) and C (area under the curve 6) every 3 weeks. The primary end point was response rate (RR), with 22% needed for success. The GEP test categorized patients into two groups: those having a TOO where CP is versus is not considered standard therapy.
Of 45 assessable patients, the RR was 36% (95% confidence interval 22% to 51%), which met criteria for success. Grade ≥3 toxicities were predominantly hematologic (80%). Adequate tissue for GEP was available in 38 patients and predicted 10 different TOOs. Patients with a TOO where platinum/taxane is a standard (n = 19) tended to have higher RR (53% versus 26%) and significantly longer PFS (6.4 versus 3.5 months) and OS (17.8 versus 8.3 months, P = 0.005), compared with patients (n = 19) with a TOO where platinum/taxane is not standard.
Everolimus combined with CP demonstrated promising antitumor activity and an acceptable side-effect profile. A tumor biomarker identifying TOO may be useful to select CUP patients for specific antitumor regimens.
NCT00936702.
We describe a novel mechanism for vital fluorescent dye entry into sensory cells and neurons: permeation through ion channels. In addition to the slow conventional uptake of styryl dyes by ...endocytosis, small styryl dyes such as FM1-43 rapidly and specifically label hair cells in the inner ear by entering through open mechanotransduction channels. This labeling can be blocked by pharmacological or mechanical closing of the channels. This phenomenon is not limited to hair cell transduction channels, because human embryonic kidney 293T cells expressing the vanilloid receptor (TRPV1) or a purinergic receptor (P2X2) rapidly take up FM1-43 when those receptor channels are opened and not when they are pharmacologically blocked. This channel permeation mechanism can also be used to label many sensory cell types in vivo. A single subcutaneous injection of FM1-43 (3 mg/kg body weight) in mice brightly labels hair cells, Merkel cells, muscle spindles, taste buds, enteric neurons, and primary sensory neurons within the cranial and dorsal root ganglia, persisting for several weeks. The pattern of labeling is specific; nonsensory cells and neurons remain unlabeled. The labeling of the sensory neurons requires dye entry through the sensory terminal, consistent with permeation through the sensory channels. This suggests that organic cationic dyes are able to pass through a number of different sensory channels. The bright and specific labeling with styryl dyes provides a novel way to study sensory cells and neurons in vivo and in vitro, and it offers new opportunities for visually assaying sensory channel function.
Abstract
We describe a project that brings together researchers from atomic physics, nuclear physics and sub-atomic particle physics, to develop a high-precision laboratory-scale experiment able to ...search for very weakly coupled sterile neutrinos in the mass range extending from 5–10 keV/
c
2
to several 100 keV/
c
2
. Observed neutrino flavor eigenstates are known to be quantum mixtures of at least three sub-eV/
c
2
mass eigenstates. There is a strong theoretical belief that there may exist further neutrino mass eigenstates at higher mass levels, and which, if in the keV/
c
2
mass range, might form all or part of the galactic dark matter. This has led to many searches for anomalous events in both astrophysical and particle physics experiments, and searches for distortions in beta decay spectra. The present experiment will utilize
K
-capture events in a population of
131
Cs atoms suspended in vacuum by a magneto-optical trap (MOT). Using AMO and nuclear physics techniques, individual events will be fully reconstructed kinematically. Normally each event would be consistent with an emitted neutrino mass close to zero, but the existence of a sterile neutrino of keV/
c
2
mass that mixes with the electron type neutrino produced in the decay would result in a separated population of events with non-zero reconstructed missing mass (up to the
Q
= 352 keV available energy of the reaction). Detailed calculations and simulations of all significant background processes have been made, in particular for scattering in the source itself, radiative
K
-capture, local radioactivity, cosmic ray muons, and knock-out of electrons by x-rays. A phase 1 of the experiment, under construction with funding from the W M Keck Foundation, has the potential to reach sterile neutrino mixing angles down to sin
2
θ
∼ 10
−4
. With further upgrades this technique could be progressively improved to eventually reach much lower coupling levels ∼10
−10
, in particular reaching the level needed to be consistent with galactic dark matter below the astrophysical x-ray limits.
Impaired insight into delusions is associated with a lower probability of remission of psychotic depression, independent of illness severity. The relationship between participant characteristics and ...impaired insight into delusions in remitted psychotic depression, and whether impaired insight is associated with risk of relapse of psychotic depression during continuation pharmacotherapy were examined.
Data were analyzed from 126 participants in the STOP-PD II study who experienced sustained remission of psychotic depression during 8-week stabilization treatment with sertraline plus olanzapine and were then randomized to 36 weeks of continuation treatment with sertraline plus either olanzapine or placebo. Insight into delusions was assessed with the Resolution of Delusions Scale (RODS). Linear regression analyses examined the associations between participant characteristics and insight into delusions. Cox proportional-hazards models examined whether i) change in RODS during stabilization treatment; or ii) RODS at the end of stabilization treatment predicted risk of relapse during 36 weeks of continuation treatment.
Severity of psychosis before initiation of treatment was the only participant characteristic associated with the change in insight during stabilization treatment. Neither change in insight during stabilization treatment nor insight at the end of stabilization treatment was associated with risk of relapse.
Insufficient statistical power and the lack of variability in RODS scores at the time of randomization may have contributed to the absence of a relationship between RODS and risk of relapse.
Residual or reemergent insight impairment following acute treatment does not preclude patients from sustaining remission of psychotic depression in a randomized placebo-controlled trial.
•Impaired insight into delusions in remitted psychotic depression was not associated with risk of relapse of the disorder.•Inability to gain full insight into a remitted delusion may not preclude patients from sustained remission of psychotic depression.•This finding can be reassuring for clinicians, patients, and caregivers.
Status epilepticus is a life-threatening emergency that affects 65,000
1
to 150,000
2
people in the United States each year. Generalized convulsive status epilepticus is the most common and most ...dangerous type.
Phenobarbital,
3
–
5
phenytoin,
6
–
14
diazepam plus phenytoin,
15
,
16
and lorazepam
17
–
28
have been advocated for the initial treatment of generalized convulsive status epilepticus, and each is used by a substantial number of physicians.
3
There are few data from controlled trials, however, to document the efficacy of these treatments, and they have not been directly compared. We therefore undertook this study to compare the efficacy of standard doses of these four . . .
The bladder urothelium exhibits dynamic sensory properties that adapt to changes in the local environment. These studies investigated
the localization and function of bradykinin receptor subtypes B1 ...and B2 in the normal and inflamed (cyclophosphamide (CYP)-induced
cystitis) bladder urothelium and their contribution to lower urinary tract function in the rat. Our findings indicate that
the bradykinin 2 receptor (B2R) but not the bradykinin 1 receptor (B1R) is expressed in control bladder urothelium. B2R immunoreactivity
was localized throughout the bladder, including the urothelium and detrusor smooth muscle. Bradykinin-evoked activation of
this receptor elevated intracellular calcium (EC 50
= 8.4 n m ) in a concentration-related manner and evoked ATP release from control cultured rat urothelial cells. In contrast, B1R mRNA
was not detected in control rat urinary bladder; however, following acute (24 h) and chronic (8 day) CYP-induced cystitis
in the rat, B1R mRNA was detected throughout the bladder. Functional B1Rs were demonstrated by evoking ATP release and increases
in Ca 2+ i in CYP (24 h)-treated cultured rat urothelial cells with a selective B1 receptor agonist (des-Arg 9 -bradykinin). Cystometry performed on control anaesthetized rats revealed that intravesical instillation of bradykinin activated
the micturition pathway. Attenuation of this response by the P2 receptor antagonist PPADS suggests that bradykinin-induced
micturition facilitation may be due in part to increased purinergic responsiveness. CYP (24 h)-treated rats demonstrated bladder
hyperactivity that was significantly reduced by intravesical administration of either B1 (des-Arg 10 -Hoe-140) or B2 (Hoe-140) receptor antagonists. These studies demonstrate that urothelial expression of bradykinin receptors
is plastic and is altered by pathology.
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