Efficacy and Safety of Cilostazol in Mild Cognitive Impairment: A Randomized Clinical Trial.

Importance: Recent evidence indicates the efficacy of ß-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote ß-amyloid removal from the brain. Cilostazol, a selective type 3 phosphodiesterase inhibitor, promotes such clearance by facilitating intramural periarterial drainage. Objective: To determine the safety and efficacy of cilostazol in mild cognitive impairment. Design, Setting, and Participants: The COMCID trial (A Trial of Cilostazol for Prevention of Conversion from Mild Cognitive Impairment to Dementia) was an investigator-initiated, double-blind, phase 2 randomized clinical trial. Adult participants were registered between May 25, 2015, and March 31, 2018, and received placebo or cilostazol for up to 96 weeks. Participants were treated in the National Cerebral and Cardiovascular Center and 14 other regional core hospitals in Japan. Patients with mild cognitive impairment with Mini-Mental State Examination (MMSE) scores of 22 to 28 points (on a scale of 0 to 30, with lower scores indicating greater cognitive impairment) and Clinical Dementia Rating scores of 0.5 points (on a scale of 0, 0.5, 1, 2, and 3, with higher scores indicating more severe dementia) were enrolled. The data were analyzed from May 1, 2020, to December 1, 2020. Interventions: The participants were treated with placebo, 1 tablet twice daily, or cilostazol, 50 mg twice daily, for up to 96 weeks. Main Outcomes and Measures: The primary end point was the change in the total MMSE score from baseline to the final observation. Safety analyses included all adverse events. Results: The full analysis set included 159 patients (66 [41.5%] male; mean [SD] age, 75.6 [5.2] years) who received placebo or cilostazol at least once. There was no statistically significant difference between the placebo and cilostazol groups for the primary outcome. The least-squares mean (SE) changes in the MMSE scores among patients receiving placebo were -0.1 (0.3) at the 24-week visit, -0.8 (0.3) at 48 weeks, -1.2 (0.4) at 72 weeks, and -1.3 (0.4) at 96 weeks. Among those receiving cilostazol, the least-squares mean (SE) changes in MMSE scores were -0.6 (0.3) at 24 weeks, -1.0 (0.3) at 48 weeks, -1.1 (0.4) at 72 weeks, and -1.8 (0.4) at 96 weeks. Two patients (2.5%) in the placebo group and 3 patients (3.8%) in the cilostazol group withdrew owing to adverse effects. There was 1 case of subdural hematoma in the cilostazol group, which may have been related to the cilostazol treatment; the patient was successfully treated surgically. Conclusions and Relevance: In this randomized clinical trial, cilostazol was well tolerated, although it did not prevent cognitive decline. The efficacy of cilostazol should be tested in future trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02491268.

The impact of electrosurgical devices on electromyography-based neuromuscular monitoring during abdominal laparotomy: a case series.

The present study aimed to evaluate the effect of electrosurgical devices on neuromuscular monitoring using an electromyography (EMG)-based neuromuscular monitor during abdominal laparotomy. Seventeen women (aged 32-64 years) undergoing gynecological laparotomy under total intravenous general anesthesia were enrolled in the study. A TetraGraph™ was placed to stimulate the ulnar nerve and to monitor the abductor digiti minimi muscle. After device calibration, train-of-four (TOF) measurements were repeated at intervals of 20 s. Rocuronium 0.6 to 0.9 mg/kg was administered for induction, and additional doses of 0.1 to 0.2 mg/kg were administered to maintain TOF counts ≤ 2 during the surgery. The primary outcome of the study was the ratio of measurement failure. The secondary outcomes of the study were the total number of measurements, the number of measurement failures, and the most extended consecutive number of measurement failures. The data are expressed as median (range). Of the 3091 (1480-8134) measurements, the number of measurement failures was 94 (60-200), resulting in a failure ratio of 3.5% (1.4-6.5%). The most extended consecutive number of measurement failures was 8 (4-13). All attending anesthesiologists were able to maintain and reverse neuromuscular blocks under EMG guidance. This prospective observational study demonstrated that the use of EMG-based neuromuscular monitoring does not seem to be heavily affected by electrical interference during lower abdominal laparotomic surgery. Trial registration This trial was registered in the University Hospital Medical Information Network under registration number UMIN000048138 (registration date; June 23, 2022).

Comparing Conscious Sedation With Regional Anesthesia Versus General Anesthesia in Minimally Invasive Mitral Valve Surgery With Right-Sided Minithoracotomy: A Retrospective Study.

OBJECTIVES: The aims of the present study were to evaluate and compare the safety and feasibility, including hospitalization, intensive care unit (ICU) stay, frequency of conversion to general anesthesia (GA), pH, PaCO2, and PaO2, of selected patients who underwent minimally invasive mitral valve surgery (MIMVS) via a right minithoracotomy under conscious sedation (CS) to avoid GA. The authors also aimed to evaluate the perioperative management of spontaneous breathing. DESIGN: A retrospective, observational study. SETTING: Single-center. PARTICIPANTS: This study enrolled 101 patients who underwent MIMVS under CS or GA. INTERVENTIONS: The patients who underwent MIMVS were managed under CS or GA according to indication criteria. MEASUREMENTS AND MAIN RESULTS: ICU stay (p = 0.010), postoperative time until first fluid intake (p < 0.0001), and duration of mechanical ventilation (p = 0.004) were shorter in the CS group than in the GA group. No patients converted to GA from CS. PaCO2 during cardiopulmonary bypass (CPB) in the CS group was significantly lower than that in the GA group. However, PaCO2 at the termination of CPB in the CS group was significantly higher than that in the GA group. CONCLUSIONS: In the CS group, advanced-age patients with comorbidities underwent mitral surgery without postoperative complications. The authors' findings suggested that MIMVS under CS could be a potentially less-invasive method, providing a quicker recovery than MIMVS under GA.

Visually-Rated Medial Temporal Lobe Atrophy with Lower Educational History as a Quick Indicator of Amnestic Cognitive Impairment after Stroke.

BACKGROUND: Time and resource limitations prevent cognitive assessment in acute-to-subacute settings, even in comprehensive stroke centers. OBJECTIVE: To assess cognitive function in acute stroke patients undergoing routine clinical, laboratory, and radiological investigations, with a view to improving post-stroke care and treatment. METHODS: Sixty-nine patients (72.6±11.1 years; 65% male) were prospectively enrolled within 14 days of acute ischemic stroke. Patients with altered consciousness, aphasia, or dysarthria were excluded. Clinical features including modified Rankin and NIH stroke scales, and vascular risk factors were assessed, as well as neuroimaging parameters by semi-quantitative evaluation of medial temporal lobe atrophy (MTLA) using MRA source images, FLAIR images for white matter changes (Fazekas scores), and T2∗ images for cerebral microbleeds. Neuropsychological screening was conducted using the Montreal Cognitive Assessment (MoCA) test. Univariate and multivariate analyses were used to evaluate the influence of variables on MoCA total and subscale scores. RESULTS: Lower MoCA scores of 22 or less were associated with MTLA [OR (95% CI), 5.3 (1.0-27.5); p = 0.045], education years [OR (95% CI), 0.71 (0.55-0.91); p = 0.007], and modified Rankin scale at discharge [OR (95% CI), 2.4 (1.3-4.5); p = 0.007]. The delayed recall MoCA score was correlated with MTLA (r = - 0.452, p < 0.001), periventricular (r = - 0.273, p = 0.024), and deep (r = - 0.242, p = 0.046), white matter changes. CONCLUSIONS: MTLA, together with lower educational history, are quick indicators of amnestic cognitive impairment after stroke. The association between cognitive impairment and physical disability at discharge may signify the importance of earlier cognitive assessment.

Lyoprotective Effect of Alkyl Sulfobetaines for Freeze-drying 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine Liposomes.

A liposome is a molecular assembly in the form of a vesicle comprised of a phospholipid bilayer. Liposomes can be used as molecular containers in various fields such as pharmaceutical, cosmetic, and food industries. It is difficult to maintain the original structure of liposomes in an aqueous medium. Phospholipids, which are components of liposomes, are susceptible to hydrolysis, which causes disruption of the liposomal structure and dysfunction of the molecular container. In this context, freeze-drying liposomes is a preferable method to improve the shelf life of liposomes. However, when freeze-drying liposomes, a lyoprotective agent is required to preserve their original structure. In this study, we investigate whether alkyl sulfobetaines (SBn, n: number of carbons in the alkyl chain, n = 1-18) can be used as lyoprotectants for 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes. The results indicated that the length of the alkyl chain of the SBn was an important factor to prevent liposome disruption during the freeze-drying and subsequent rehydration processes. The use of SBn with an alkyl chain of intermediate length (n = 6-10) could prevent liposome disruption and remarkably reduce the gel-to-liquid crystal phase transition temperature (Tm) of the freeze-dried liposomes. This indicates that these SBn could intercalate in the dried bilayer and reduce intermolecular interaction between DPPC in the bilayer. The Tm reduction of the freeze-dried liposomes should contribute to prevention of the gel-to-liquid phase transition of the liposomes during the rehydration process, which has been known to be a main cause of liposome disruption. We expect that the results from this study will provide an insight into the influence of zwitterionic additives on freeze-dried lipid bilayers and the lyoprotective effect, which should be useful in many biochemical and biomedical fields.

A novel mouse model of subcortical infarcts with dementia.

Subcortical white matter (WM) is a frequent target of ischemic injury and extensive WM lesions are important substrates of vascular cognitive impairment (VCI) in humans. However, ischemic stroke rodent models have been shown to mainly induce cerebral infarcts in the gray matter, while cerebral hypoperfusion models show only WM rarefaction without infarcts. The lack of animal models consistently replicating WM infarct damage may partially explain why many neuroprotective drugs for ischemic stroke or VCI have failed clinically, despite earlier success in preclinical experiments. Here, we report a novel animal model of WM infarct damage with cognitive impairment can be generated by surgical implantation of different devices to the right and left common carotid artery (CCA) in C57BL/6J mice. Implantation of an ameroid constrictor to the right CCA resulted in gradual occlusion of the vessel over 28 d, whereas placement of a microcoil to the left CCA induced ∼50% arterial stenosis. Arterial spin labeling showed a gradual reduction of cerebral blood flow over 28 d post operation. Such reductions were more marked in the right, compared with the left, hemisphere and in subcortical, rather than the cortical, areas. Histopathological analysis showed multiple infarct damage in right subcortical regions, including the corpus callosum, internal capsule, hippocampal fimbria, and caudoputamen, in 81% of mice. Mice displaying such damage performed significantly poorer in locomotor and cognitive tests. The current mouse model replicates the phenotypes of human subcortical VCI, including multiple WM infarcts with motor and cognitive impairment.

Necklace cytoplasmic bodies in hereditary myopathy with early respiratory failure.

BACKGROUND: In hereditary myopathy with early respiratory failure (HMERF), cytoplasmic bodies (CBs) are often localised in subsarcolemmal regions, with necklace-like alignment (necklace CBs), in muscle fibres although their sensitivity and specificity are unknown. OBJECTIVE: To elucidate the diagnostic value of the necklace CBs in the pathological diagnosis of HMERF among myofibrillar myopathies (MFMs). METHODS: We sequenced the exon 343 of TTN gene (based on ENST00000589042), which encodes the fibronectin-3 (FN3) 119 domain of the A-band and is a mutational hot spot for HMERF, in genomic DNA from 187 patients from 175 unrelated families who were pathologically diagnosed as MFM. We assessed the sensitivity and specificity of the necklace CBs for HMERF by re-evaluating the muscle pathology of our patients with MFM. RESULTS: TTN mutations were identified in 17 patients from 14 families, whose phenotypes were consistent with HMERF. Among them, 14 patients had necklace CBs. In contrast, none of other patients with MFM had necklace CBs except for one patient with reducing body myopathy. The sensitivity and specificity were 82% and 99%, respectively. Positive predictive value was 93% in the MFM cohort. CONCLUSIONS: The necklace CB is a useful diagnostic marker for HMERF. When muscle pathology shows necklace CBs, sequencing the FN3 119 domain of A-band in TTN should be considered.

Cilostazol add-on therapy in patients with mild dementia receiving donepezil: a retrospective study.

GOAL: Combinatorial therapy directed at both vascular and neurodegenerative aspects of dementia may offer a promising strategy for treatment of dementia, which often has a multifactorial basis in the elderly. We investigated whether the phosphodiesterase III inhibitor cilostazol, which is often used in the prevention of stroke and peripheral artery disease, may delay cognitive decline in the elderly receiving donepezil. METHODS: Medical records were retrospectively surveyed to identify patients who had received donepezil for more than one year and had undergone Mini-Mental State Examination (MMSE) at least at two time points. Those with an initial MMSE score of less than 27 points were subjected to analysis (n = 156), with a cut-point of 21/22 applied to assign them to mild (n = 70) and moderate/severe (n = 86) dementia. The change of total MMSE score per year was compared between patients who had received donepezil and those given both donepezil and cilostazol. FINDINGS: In patients with mild dementia who had received donepezil and cilostazol (n = 34; 77.2±6.8 years old), the annual change in MMSE score was -0.5±1.6 during an observational period of 28.6±11.7 months, with those receiving donepezil only (n = 36; 78.4±6.5 years old) scoring less (-2.2±4.1) during 30.4±12.8 months with a statistical intergroup difference (p = 0.022). Multivariate analysis showed that absence of cilostazol treatment was the only significant predictor of MMSE decline. A positive effect of cilostazol was found in three subscale scores of MMSE, orientation for time or place and delayed recall. By clear contrast, in patients with moderate/severe dementia, there were no intergroup differences in decrease of total or subscale MMSE scores between the two groups. CONCLUSIONS: These results suggest potential for cilostazol treatment in the suppression of cognitive decline in patients receiving donepezil with mild dementia but not in those with moderate/severe dementia.