Dopamine Transporter Regulation during Four Nights of REM Sleep Deprivation Followed by Recovery – An in vivo Molecular Imaging Study in Humans

Objectives:

To assess the influence of total or selective REM sleep deprivation on the dopamine transporter (DAT) densities and sleep patterns of healthy volunteers.

Design:

Prospective study.

Setting:

Evaluation of polysomnography recordings and DAT density after 4 nights of selective REM sleep deprivation followed by 3 nights of sleep recovery compared to a control group and a group that was subjected to 2 nights of total sleep deprivation. Single positron emission computed tomography and [^99mTc]TRODAT-1 were used to assess the cerebral DAT density in the striatum at baseline, after REM sleep deprivation and total sleep deprivation as well as after sleep recovery. Blood was collected daily to examine prolactin and estradiol levels, which were correlated with dopaminergic activity.

Patients or Participants:

Thirty healthy male volunteers ranging from 19 to 29 years of age were randomly assigned to one of three experimental groups after giving written informed consent (10 non-sleep deprived, 10 total sleep deprived, and 10 REM sleep deprived).

Measurements and Results:

Four nights of REM sleep deprivation and 2 nights of total sleep deprivation induced distinct and heterogeneous patterns of sleep recovery. No significant modulation of DAT availability was observed within groups. In the recovery nights, changes in cortisol, prolactin and estradiol concentrations were significantly correlated with specific sleep stages in the total and REM sleep deprived groups. In addition, DAT density was positively correlated with estradiol concentration and inversely associated with SWS latency only after total sleep deprivation.

Conclusion:

Our study demonstrates that although sleep deprivation did not promote significant alterations in DAT density within the striatum, there were significant correlations among transporter availability, hormonal concentrations and sleep parameters.

Citation:

Martins, RCS; Andersen ML; Garbuio SA; Bittencourt LR: Guindalini C; Shih MC; Hoexter MQ; Bressan RA; Castiglioni MLV; Tufik S. Dopamine transporter regulation during four nights of REM sleep deprivation followed by recovery – an in vivo molecular imaging study in humans. SLEEP 2010;33(2):243-251.     

Mesenchymal Stem Cells Arrest Intervertebral Disc Degeneration Through Chondrocytic Differentiation and Stimulation of Endogenous Cells

Degenerative disc disease (DDD) is a common disease which affects millions of people. Autograft of the bone marrow derived mesenchymal stem cells (BMSCs) have been shown to have the ability to arrest degeneration in rabbit and canine intervertebral discs. In this study, we have used the mouse model to investigate the mechanism of degeneration arrest. BMSC from Egfp transgenic mice were injected into the degenerated murine intervertebral discs induced by annular puncture. We found that BMSC could arrest the progressive degeneration of the discs with significant regeneration of the nucleus pulposus (NP). In the regeneration, expression of proteoglycan genes were upregulated and extracellular matrix (ECM) progressively accumulated in the NP after BMSC injection. Combined in situ hybridization and immunohistochemistry revealed that BMSC underwent chondrocytic differentiation in the regeneration process. Interestingly, BMSC-induced an increase of endogenous notochordal cells in NP and expression of chondrocytic markers. In this study, we have firstly shown that the BMSC could arrest the degeneration of the murine notochordal NP and contribute to the augmentation of the ECM in the NP by both autonomous differentiation and stimulatory action on endogenous cells.     

Carboplatin instead of cisplatin in combination with dexamethasone,high-dose cytarabine with or without rituximab (DHAC+/−R) is an effective treatment with low toxicity in Hodgkin’s and non-Hodgkin’s lymphomas

The DHAP regimen (high-dose cytarabine in combination with dexamethasone and cisplatin) with or without rituximab (DHAP+/?R) is one of the most common regimens in daily practice. It is considered the standard treatment for relapse or refractory Hodgkin’s and non-Hodgkin’s lymphoma (NHL). Cisplatin nephrotoxicity is a major concern, and other platinum compounds are being tried. We performed a monocentric retrospective analysis to evaluate the use of carboplatin, so-called DHAC+/?R regimen. The purpose was to assess the toxicity of the DHAC+/?R regimen in real-life. The Dexamethasone, Cytarabine, Carboplatin (DHAC) regimen consisted of carboplatin AUC = 5 mg/ml/min (targeted area under the curve with Calvert’s formula) on day 1, cytarabine 2 g/m² twice a day on day 2 and IV dexamethasone 40 mg from days 1 to 4. Rituximab was administrated at 375 mg/m² on day 1 for CD20+ NHL. The interval between courses was 21 days. During the period considered, 199 patients received DHAC+/?R. For the entire cohort, median follow-up is 24 months (range, 2–82), median OS is not reached (NR), estimated 2-year OS is 75% (95% CI, 69–83) and median progression-free survival (PFS) is 46 months (95% CI, 22-NA). Of 144 patients scheduled for autologous stem cell transplantation (ASCT), 102 (71%, NA = 2) were in response after DHAC+/?R and all except 4 underwent ASCT. Grade ≥ 3 haematological toxicities were mainly thrombocytopenia (n = 101) and anaemia (n = 95). Grade ≥ 3 neutropenia occurred in 10 patients. No grade ≥ 3 renal and one grade 3 neurological toxicity were reported. DHAC+/?R is feasible in daily practice, provides good response rates and jeopardises neither stem cell collection nor ASCT.