BackgroundTrials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to determine if daily fluoxetine for 6 months after stroke improves functional outcome in Australasian and Vietnamese patients. MethodsAFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial conducted in 43 hospital stroke units in Australia (n=29), New Zealand (4), and Vietnam (10). Eligible patients were adults with a clinical diagnosis of stroke in the previous 2-15 days and a persisting neurological deficit. Patients were randomised via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20mg or matching placebo for 6 months. Patients, investigators and outcome assessors were masked to the treatment allocation. The primary outcome was functional outcome, measured by the modified Rankin scale (mRS), at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Analyses were according to the patient's treatment allocation. The trial is registered with the ACTRN registry, number 12611000774921. FindingsPowered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation 1280 patients were recruited in Australia (n=532), New Zealand (n=42) and Vietnam (n=706) between 11 January 2013 and 30 June 2019; 642 were allocated fluoxetine and 638 placebo. Adherence to trial medication (mean 167 [SD 48] days) was similar between groups. At 6 months, mRS data were available in 624 (97.2%) patients allocated fluoxetine and 632 (99.1%) placebo. The distribution of mRS categories at 6 months was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0.936, 95% CI 0.762-1.150; p=0.53), and consistent among all pre-defined subgroups. Compared to placebo, patients allocated fluoxetine had more falls (20 [3.12%] vs 7 [1.10%]; p=0.02), bone fractures (19 [2•96%] vs 6 [0.94%]; p=0.01) and epileptic seizures (10 [1.56%] vs 2 [0.31%]; p=0.04) at 6 months. InterpretationFluoxetine 20mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and seizures. These results do not support the use of fluoxetine to improve outcome after stroke.
Background Animal studies describe changes in the spleen following a stroke, with an immediate reduction in volume associated with changes in the counts of specific blood WBCs. This brain–spleen cell cycling after stroke affects systemic inflammation and the brain inflammatory milieu and may be a target for emerging therapeutic studies. This study aimed to evaluate features of this brain-spleen model in human patients admitted for acute stroke. Methods Medical and imaging records were retrospectively reviewed for 82 consecutive patients admitted for acute stroke in whom an abdominal CT scan was performed. Results Mean ± SD splenic volume was 224.5 ± 135.5 cc. Splenic volume varied according to gender (p=0.014) but not stroke subtype (ischemic vs. hemorrhagic, p=0.76). The change in splenic volume over time was biphasic (p=0.04), with splenic volumes initially decreasing over time, reaching a nadir 48 hours after stroke onset, then increasing thereafter. Splenic volume was related inversely to percent blood lymphocytes (r= -0.36, p= 0.001) and positively to percent blood neutrophils (r= 0.30, p= 0.006). Conclusions Current results support that several features of brain–spleen cell cycling after stroke described in preclinical studies extend to human subjects, including the immediate contraction of splenic volume associated with proportionate changes in blood WBC counts. Splenic volume may be useful as a biomarker of systemic inflammatory events in clinical trials of interventions targeting the immune system after stroke.
We present the case of a 43-year-old man who presented with metastatic abdominal wall synovial sarcoma. CT of the abdomen showed a 6 cm anterior abdominal wall mass with a nodular, non-homogeneous pattern of enhancement. A chest radiograph showed metastases to the lungs.
CollaborationIMPORTANCE One in 3 adults experiences clinically significant symptoms of depression during the first year after a stroke, but evidence to support the use of antidepressants in this population remains scant.OBJECTIVE To investigate whether daily treatment with 20 mg of fluoxetine hydrochloride reduces the proportion of people affected by clinically significant symptoms of depression after stroke. DESIGN, SETTING, AND PARTICIPANTSIn this secondary analysis of the Assessment of Fluoxetine in Stroke Recovery parallel-group, randomized (1:1 assignment), double-blind, placebo-controlled clinical trial, 1221 participants in Australia, New Zealand, and Vietnam were recruited between January 11, 2013, and June 30, 2019, and were followed up for 6 months. Adults aged 18 years or older were recruited 2 to 15 days after experiencing a stroke associated with modified Rankin Scale score of 1 or higher.INTERVENTIONS Fluoxetine hydrochloride, 20 mg, or matched placebo daily for 26 weeks. MAIN OUTCOMES AND MEASURESA 9-item Patient Health Questionnaire (PHQ-9) score of 9 or lower was a prespecified secondary outcome of the trial. Assessments were completed at baseline and at 4, 12, and 26 weeks. Other outcomes of interest included participant-reported clinician diagnosis of depression, prescription of a nontrial antidepressant, or nonpharmacologic treatment of depression. Analysis was on an intention-to-treat basis.RESULTS A total of 607 participants (378 men [62.3%]; mean [SD] age, 64.3 [12.2] years) were randomly assigned treatment with placebo, and 614 participants (397 men [64.7%]; mean [SD] age, 63.4 [12.4] years) were randomly assigned treatment with 20 mg of fluoxetine hydrochloride daily. The groups were balanced for demographic and clinical measures. At baseline, 112 patients (18.5%) in the placebo group and 116 patients (18.9%) in the fluoxetine group had PHQ-9 scores of 9 or higher. During follow-up, 126 of 596 participants (21.1%) treated with placebo and 121 of 598 participants (20.2%) treated with fluoxetine had PHQ-9 scores of 9 or higher (P = .70). A similar proportion of participants with PHQ-9 scores less than 9 at baseline who were treated with fluoxetine hydrochloride and placebo developed PHQ-9 scores of 9 or higher during the trial (placebo, 72 of 488 [14.8%]; and fluoxetine, 63 of 485 [13.0%]; P = .43). A slightly higher number of participants in the placebo group than in the fluoxetine group had a participant-reported clinician diagnosis of depression (42 of 602 [7.0%] vs 26 of 601 [4.3%]; P = .05). By week 26, 14 participants (2.3%) in the placebo group and 12 participants (1.9%) in the fluoxetine group had died (P = .67). CONCLUSIONS AND RELEVANCERoutine daily treatment with 20 mg of fluoxetine did not decrease the proportion of people affected by clinically significant symptoms of depression after a stroke, nor did it affect the proportion of people prescribed an antidepressant or receiving nonpharmacologic treatments compared with placebo.
Previous studies have shown that estrogen and progesterone play an important role in facilitating sexual receptivity by regulating the activity of the μ-opioid receptor (MOR) in the medial preoptic nucleus (MPN) and the opioid receptor like receptor (ORL-1) in the ventral medial hypothalamus (VMH). Estrogen rapidly activates MOR in the MPN via the release of β-endorphin originating from neurons in the arcuate, which inhibit lordosis. Subsequent progesterone facilitates lordosis by activating ORL-1 through the release of OFQ/N into the VMH or ARH. Since the ARH projects into the MPN, we hypothesize that infusion of orphanin FQ/nociceptin (OFQ/N) exogenous ligand into the VMH-ARH region will facilitate lordosis by attenuating the activity of MOR inhibitory circuit. Secondly, we will test whether OFQ/N is the endogenous ligand acting in the VMN-ARH region to facilitate lordosis. To test whether OFQ/N activation in the VMH-ARH blocks MOR activity in the MPN and facilitates lordosis, two groups of estrogen primed, nonreceptive ovariectomized rats were either implanted with bilateral cannula aimed at the VMH or a unilateral cannulae aimed at the ARH, using standard stereotaxic procedures. The VMH group was infused with either anti-OFQ (Phoenix 1:10, Neuromics 1:2) to passively immunoneutralize endogenous OFQ/N or normal rabbit serum as control 48 hours post 5 μg estradiol benzoate injection and tested 10 and 90 minutes later to measure sexual receptivity, as measured by lordosis quotient. One week after the behavioral experiment, these animals and the unilateral ARH cannulated animals were treated with 2 μg estrogen and 30 hours later infused with either 25 nmol OFQ/N or artifical cerebrospinal fluid (aCSF). Thirty minutes later, both groups were perfused transcardially with paraformaldehyde and the MPN of each animal was processed for MOR immunohistochemistry. The level of MOR internalization, a marker for receptor activation, was measured by density of immunoreactivity. Immunoneutralization of OFQ/N in the VMH blocked the facilitation of lordosis, indicating that OFQ/N is a relevant ligand in the facilitation of lordosis in the VMH (ANOVA, p < .05). Furthermore, microinfusion of OFQ/N ligand into the VMH and ARH decreased MOR immunoreactivity density in the MPN compared to aCSF controls. These experiments together indicated that estrogen and progesterone facilitation of sexual receptivity involves OFQ/N acting via ORL-1 receptors in the VMH/ARH that subsequently attenuate the MOR inhibition in the MPN by preventing the release of β-endorphins from neurons in the ARH.
Background and Purpose: The AFFINITY trial (Assessment of Fluoxetine in Stroke Recovery) reported that oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and seizures. After trial medication was ceased at 6 months, survivors were followed to 12 months post-randomization. This preplanned secondary analysis aimed to determine any sustained or delayed effects of fluoxetine at 12 months post-randomization. Methods: AFFINITY was a randomized, parallel-group, double-blind, placebo-controlled trial in adults (n=1280) with a clinical diagnosis of stroke in the previous 2 to 15 days and persisting neurological deficit who were recruited at 43 hospital stroke units in Australia (n=29), New Zealand (4), and Vietnam (10) between 2013 and 2019. Participants were randomized to oral fluoxetine 20 mg once daily (n=642) or matching placebo (n=638) for 6 months and followed until 12 months after randomization. The primary outcome was function, measured by the modified Rankin Scale, at 6 months. Secondary outcomes for these analyses included measures of the modified Rankin Scale, mood, cognition, overall health status, fatigue, health-related quality of life, and safety at 12 months. Results: Adherence to trial medication was for a mean 167 (SD 48) days and similar between randomized groups. At 12 months, the distribution of modified Rankin Scale categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio, 0.93 [95% CI, 0.76–1.14]; P =0.46). Compared with placebo, patients allocated fluoxetine had fewer recurrent ischemic strokes (14 [2.18%] versus 29 [4.55%]; P =0.02), and no longer had significantly more falls (27 [4.21%] versus 15 [2.35%]; P =0.08), bone fractures (23 [3.58%] versus 11 [1.72%]; P =0.05), or seizures (11 [1.71%] versus 8 [1.25%]; P =0.64) at 12 months. Conclusions: Fluoxetine 20 mg daily for 6 months after acute stroke had no delayed or sustained effect on functional outcome, falls, bone fractures, or seizures at 12 months poststroke. The lower rate of recurrent ischemic stroke in the fluoxetine group is most likely a chance finding. REGISTRATION: URL: http://www.anzctr.org.au/ ; Unique identifier: ACTRN12611000774921.
Introduction: Inflammatory events have a major influence on acute injury and on neural repair after stroke, and may also be important mediators of treatment effects for some cellular therapies. Preclinical studies suggest that splenic events may be important to the evolution of post-stroke inflammation, and that reduced splenic volume may be a useful marker of these events. The current study extended these findings to humans by examining spleen volumes and their clinical correlates in patients admitted for stroke in order to test the hypothesis that splenic volume is related to 4 variables of interest (1) time post-stroke, (2) level of blood lymphocytes, (3) level of blood neutrophils, and (4) volume of cerebral infarct. METHODS: This retrospective study examined patients admitted for a new stroke between 2006-2011 at a single institution who also had an abdominal CT scan performed. Clinical data were extracted from medical records. Splenic volume was measured from abdominal CT scan by radiologists with expertise in abdominal imaging. Infarct volumes were calculated from brain CT or MRI. RESULTS: A total of 90 patients were identified, 4 of whom had abdominal CT prior to stroke, leaving 86 patients. These 86 had age 66 ± 14 yr (mean ± SD), gender 51M/35F, and infarct volume 51 ± 70 cc. Infarcts were ischemic in 58 (67%), 7 of whom (12%) received tPA, and intracerebral hemorrhage in 28 (33%). Spleen volumes were 225±137 cc, and correlated with gender (M>F, p<0.03), but not with age or stroke subtype. In terms of the variables of interest, splenic volume correlated with % lymphocytes (r=-0.27, p<0.02) and % neutrophils (r=0.23, p<0.04), but not with time post-stroke or infarct volume. CONCLUSIONS: Among patients admitted for stroke, a smaller spleen was found in relation to high lymphocyte and lower neutrophil levels in the blood, consistent with prior findings in rodents and in humans. Although the retrospective nature of the current study introduces potential for bias, these results further suggest that splenic events may be important to inflammatory events arising after stroke.
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