Preventive effect of aripiprazole once-monthly on relapse into mood episodes in bipolar disorder: A multicenter, one-year, retrospective, mirror image study.

BACKGROUND: We conducted a one-year, retrospective, mirror-image study to investigate the clinical effectiveness and safety of aripiprazole once monthly (AOM) in patients with bipolar disorder (BD). We compared pre-treatment conditions with outcomes after 12 months of AOM treatment. METHODS: Seventy-five bipolar patients were recruited from 12 hospitals in Korea. We included 75 patients with BD who had received at least three AOM treatments from September 2019 to September 2022 and had accessible electronic medical record (EMRs) for the year before and after the baseline visit. RESULTS: The overall number of mood episodes significantly decreased from a mean of 1.5 ± 1.2 episodes pre-AOM to 0.5 ± 1.2 episodes post-AOM. Manic episodes significantly decreased from 0.8 ± 0.8 episodes pre-AOM to 0.2 ± 0.5 episodes post-AOM, and depressive episodes significantly decreased from 0.5 ± 0.8 episodes pre-AOM to 0.2 ± 0.6 episodes post-AOM (p = 0.017). Moreover, the number of psychiatric medications and pills and the proportion of patients treated with complex polypharmacy were significantly decreased post-AOM. LIMITATIONS: The small sample size was insufficient to fully represent the entire population of individuals with BD, and potential selection bias was introduced due to only including subjects who received AOM three or more times. CONCLUSION: The results of this study suggest that AOM can reduce mood episode relapse and may be clinically beneficial in the treatment of BD patients, potentially reducing issues associated with polypharmacy in some individuals.

Machine-learning-based diagnosis of drug-naive adult patients with attention-deficit hyperactivity disorder using mismatch negativity.

Relatively little is investigated regarding the neurophysiology of adult attention-deficit/hyperactivity disorder (ADHD). Mismatch negativity (MMN) is an event-related potential component representing pre-attentive auditory processing, which is closely associated with cognitive status. We investigated MMN features as biomarkers to classify drug-naive adult patients with ADHD and healthy controls (HCs). Sensor-level features (amplitude and latency) and source-level features (source activation) of MMN were investigated and compared between the electroencephalograms of 34 patients with ADHD and 45 HCs using a passive auditory oddball paradigm. Correlations between MMN features and ADHD symptoms were analyzed. Finally, we applied machine learning to differentiate the two groups using sensor- and source-level features of MMN. Adult patients with ADHD showed significantly lower MMN amplitudes at the frontocentral electrodes and reduced MMN source activation in the frontal, temporal, and limbic lobes, which were closely associated with MMN generators and ADHD pathophysiology. Source activities were significantly correlated with ADHD symptoms. The best classification performance for adult ADHD patients and HCs showed an 81.01% accuracy, 82.35% sensitivity, and 80.00% specificity based on MMN source activity features. Our results suggest that abnormal MMN reflects the adult ADHD patients' pathophysiological characteristics and might serve clinically as a neuromarker of adult ADHD.

Combinatorial glucose, nicotinic acid and N-acetylcysteine therapy has synergistic effect in preclinical C. elegans and zebrafish models of mitochondrial complex I disease.

Mitochondrial respiratory chain disorders are empirically managed with variable antioxidant, cofactor and vitamin 'cocktails'. However, clinical trial validated and approved compounds, or doses, do not exist for any single or combinatorial mitochondrial disease therapy. Here, we sought to pre-clinically evaluate whether rationally designed mitochondrial medicine combinatorial regimens might synergistically improve survival, health and physiology in translational animal models of respiratory chain complex I disease. Having previously demonstrated that gas-1(fc21) complex I subunit ndufs2-/-C. elegans have short lifespan that can be significantly rescued with 17 different metabolic modifiers, signaling modifiers or antioxidants, here we evaluated 11 random combinations of these three treatment classes on gas-1(fc21) lifespan. Synergistic rescue occurred only with glucose, nicotinic acid and N-acetylcysteine (Glu + NA + NAC), yielding improved mitochondrial membrane potential that reflects integrated respiratory chain function, without exacerbating oxidative stress, and while reducing mitochondrial stress (UPRmt) and improving intermediary metabolic disruptions at the levels of the transcriptome, steady-state metabolites and intermediary metabolic flux. Equimolar Glu + NA + NAC dosing in a zebrafish vertebrate model of rotenone-based complex I inhibition synergistically rescued larval activity, brain death, lactate, ATP and glutathione levels. Overall, these data provide objective preclinical evidence in two evolutionary-divergent animal models of mitochondrial complex I disease to demonstrate that combinatorial Glu + NA + NAC therapy significantly improved animal resiliency, even in the face of stressors that cause severe metabolic deficiency, thereby preventing acute neurologic and biochemical decompensation. Clinical trials are warranted to evaluate the efficacy of this lead combinatorial therapy regimen to improve resiliency and health outcomes in human subjects with mitochondrial disease.

Minithoracotomy and Beating Heart Strategy for Mitral Surgery in Secondary Mitral Regurgitation.

BACKGROUND: In patients with secondary mitral regurgitation (MR) associated with low ejection fraction or previous heart surgery, minimally invasive mitral valve surgery without aortic cross-clamp (MIMVS-WAC) has shown promising results. We report our experience for this strategy in our centers. METHODS: Between August 2011 and April 2017, 46 patients (mean age 69 ± 11 years, 76% males) received MIMVS-WAC. Indications for this technique were prior coronary bypass surgery (26%), severe or recent left ventricular (LV) dysfunction (30%), or both (39%). The mean EuroSCORE II was 12 ± 10. RESULTS: For each procedure, we conducted right minithoracotomy and hypothermic cardiopulmonary bypass (CPB) after peripheral cannulation. Mean CPB time was 159 ± 39 minutes. A mitral valve replacement (MVR) was performed in 23 cases (50%), an annuloplasty in 22 cases (48%), and a prosthesis pannus removal in 1 case (2%). Mean hospital length of stay was 12 ± 5.4 days. We report no sternotomy conversions, six reoperations for bleeding, and three deaths at 30 days. Transfusion was requested in 62% (mean infusion 2 ± 2.4 packed red blood cells). The postoperative echocardiography showed an LV function preservation in 69% of cases and a reduction of pulmonary arterial pressure in 73% of cases. Four additional deaths occurred in the long-term follow-up (mean 637 ± 381 days, median 593 days). No mitral reoperation was required, with a MR ≤ 2 in 90% of patients. CONCLUSION: In high-risk patients, the MIMVS-WAC is a safe technique. It avoids hard dissections while ensuring excellent preservation of cardiac function.

Pre-clinical evaluation of cysteamine bitartrate as a therapeutic agent for mitochondrial respiratory chain disease.

Cysteamine bitartrate is a US Food and Drug Administration-approved therapy for nephropathic cystinosis also postulated to enhance glutathione biosynthesis. We hypothesized this antioxidant effect may reduce oxidative stress in primary mitochondrial respiratory chain (RC) disease, improving cellular viability and organismal health. Here, we systematically evaluated the therapeutic potential of cysteamine bitartrate in RC disease models spanning three evolutionarily distinct species. These pre-clinical studies demonstrated the narrow therapeutic window of cysteamine bitartrate, with toxicity at millimolar levels directly correlating with marked induction of hydrogen peroxide production. Micromolar range cysteamine bitartrate treatment in Caenorhabditis elegans gas-1(fc21) RC complex I (NDUFS2-/-) disease invertebrate worms significantly improved mitochondrial membrane potential and oxidative stress, with corresponding modest improvement in fecundity but not lifespan. At 10 to 100 µm concentrations, cysteamine bitartrate improved multiple RC complex disease FBXL4 human fibroblast survival, and protected both complex I (rotenone) and complex IV (azide) Danio rerio vertebrate zebrafish disease models from brain death. Mechanistic profiling of cysteamine bitartrate effects showed it increases aspartate levels and flux, without increasing total glutathione levels. Transcriptional normalization of broadly dysregulated intermediary metabolic, glutathione, cell defense, DNA, and immune pathways was greater in RC disease human cells than in C. elegans, with similar rescue in both models of downregulated ribosomal and proteasomal pathway expression. Overall, these data suggest cysteamine bitartrate may hold therapeutic potential in RC disease, although not through obvious modulation of total glutathione levels. Careful consideration is required to determine safe and effective cysteamine bitartrate concentrations to further evaluate in clinical trials of human subjects with primary mitochondrial RC disease.

N-acetylcysteine and vitamin E rescue animal longevity and cellular oxidative stress in pre-clinical models of mitochondrial complex I disease.

Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials. Here, lifespan effects of N-acetylcysteine (NAC), vitamin E, vitamin C, coenzyme Q10 (CoQ10), mitochondrial-targeted CoQ10 (MS010), lipoate, and orotate were evaluated as the primary outcome in a well-established, short-lived C. elegans gas-1(fc21) animal model of RC complex I disease. Healthspan effects were interrogated to assess potential reversal of their globally disrupted in vivo mitochondrial physiology, transcriptome profiles, and intermediary metabolic flux. NAC or vitamin E fully rescued, and coenzyme Q, lipoic acid, orotic acid, and vitamin C partially rescued gas-1(fc21) lifespan toward that of wild-type N2 Bristol worms. MS010 and CoQ10 largely reversed biochemical pathway expression changes in gas-1(fc21) worms. While nearly all drugs normalized the upregulated expression of the "cellular antioxidant pathway", they failed to rescue the mutant worms' increased in vivo mitochondrial oxidant burden. NAC and vitamin E therapeutic efficacy were validated in human fibroblast and/or zebrafish complex I disease models. Remarkably, rotenone-induced zebrafish brain death was preventable partially with NAC and fully with vitamin E. Overall, these pre-clinical model animal data demonstrate that several classical antioxidant drugs do yield significant benefit on viability and survival in primary mitochondrial disease, where their major therapeutic benefit appears to result from targeting global cellular, rather than intramitochondria-specific, oxidative stress. Clinical trials are needed to evaluate whether the two antioxidants, NAC and vitamin E, that show greatest efficacy in translational model animals significantly improve the survival, function, and feeling of human subjects with primary mitochondrial RC disease.

Long-term Clinical and Radiological Outcomes after Central Decompressive Laminoplasty for Lumbar Spinal Stenosis.

OBJECTIVE: There are many technical modifications of decompressive lumbar laminectomy. The purpose of this study was to report long-term clinical and radiological outcomes of central decompressive laminoplasty (CDL), the corresponding author's own modification of lumbar laminectomy for lumbar spinal stenosis (LSS). METHODS: Among 100 patients who underwent CDL by a single surgeon between December 2010 and March 2014, 68 patients were included in this study. Mean follow-up time was 37.7 months. Clinical and radiological data were gathered prospectively and reviewed retrospectively. Clinical outcome was measured by using visual analog scale (VAS) for back/buttock and leg, and the Oswestry Disability Index (ODI). Radiological outcome was measured by neutral slippage percentage, dynamic slippage percentage, and dynamic intervertebral angel on sagittal X-ray. Outcomes after CDL were assessed by changes of clinical and radiological parameters from the baseline. Mixed effect model with random patients' effect as used to test for differences in the repeated measured clinical and radiological data. RESULTS: The patients had no serious complications with an uneventful recovery during the early postoperative period. In the early postoperative period, VAS scores for back/buttock and leg improved significantly and were kept with time (p<0.001). ODI also improved significantly during the postoperative follow-up period (p<0.001). The radiologic parameters were well maintained and showed no progression of instability. During the follow-up, a case of herniated disc at same level recurrence was noted after lifting trauma, and 2 adjacent foraminal stenosis needed additional surgery. CONCLUSION: CDL provides long-term pain relief and functional restoration without progression of radiological instability.

Effectiveness of Osteoporosis Drug in Postmenopausal Women with Spinal Compression Fracture: Combined Consecutive Therapy of Teriparatide and Raloxifene versus Bisphosphonate Single.

OBJECTIVE: Bisphosphonate, a typical bone resorption inhibitor, is an important first-line drug for treating osteoporosis. Recent studies show a novel paradigm in stimulating bone formation. Teriparatide, which is composed of recombinant human parathyroid hormone, stimulates osteoblasts and induces bone regeneration. Bone mineral density (BMD) that was used before and after the treatment with anti-osteoporosis drug was compared for the effectiveness in therapy between a combination of teriparatide and selective estrogen receptor modulator (SERM), and bisphosphonate. METHODS: We retrospectively reviewed the outcomes of 85 postmenopausal women who were concurrently diagnosed with osteoporosis and spinal compression fracture between November 2008 and January 2015. The targeted group were treated with teriparatide and SERM (TS group, n=26) and bisphosphonate (B group, n=59). RESULTS: In both groups, BMD of femur neck was not improved after the medication. In the TS group, on the other hand the BMD and T-score of lumbar spine has significantly improved. BMD ratio of lumbar spine was prominently higher than those of TS group. CONCLUSION: The combination therapy of teriparatide and SERM was very effective in treating the lumbar spine, compared to that of bisphosphonate. Although the period of teriparatide treatment has been relatively short, the preventive effects of compression fracture were considerable. Thus, combination therapy of teriparatide and SERM is highly recommended for patients who are concerned with spinal compression fracture from osteoporosis.

Presumed Pseudotumor Cerebri Syndrome After Withdrawal of Inhaled Glucocorticoids.

Pseudotumor cerebri syndrome (PTCS) is characterized by increased intracranial pressure with normal brain parenchyma and cerebrospinal fluid constituents. PTCS after withdrawal of systemic corticosteroids also has been described in children. In contrast, to our knowledge, PTCS after withdrawal of inhaled glucocorticoids has not previously been described. Here we report the case of an 8-year and 6-month-old girl who developed signs and symptoms consistent with PTCS after withdrawal of inhaled glucocorticoids. The patient had excellent adherence to inhaled glucocorticoid therapy for ∼1 year before presentation, after which the therapy was stopped for concern related to poor growth. The withdrawal of inhaled glucocorticoids was associated with the development of severe headaches and diplopia, and further clinical examination led to the patient's diagnosis of likely PTCS. Although its occurrence is likely rare, clinicians caring for the many children receiving inhaled glucocorticoid therapy should be aware of the potential for PTCS after abrupt withdrawal of such treatment, and consider ophthalmology evaluation if patients report suggestive symptoms, such as headaches or vision changes in this context.

An integrated mechanism of pediatric pseudotumor cerebri syndrome: evidence of bioenergetic and hormonal regulation of cerebrospinal fluid dynamics.

Pseudotumor cerebri syndrome (PTCS) is defined by the presence of elevated intracranial pressure (ICP) in the setting of normal brain parenchyma and cerebrospinal fluid (CSF). Headache, vision changes, and papilledema are common presenting features. Up to 10% of appropriately treated patients may experience permanent visual loss. The mechanism(s) underlying PTCS is unknown. PTCS occurs in association with a variety of conditions, including kidney disease, obesity, and adrenal insufficiency, suggesting endocrine and/or metabolic derangements may occur. Recent studies suggest that fluid and electrolyte balance in renal epithelia is regulated by a complex interaction of metabolic and hormonal factors; these cells share many of the same features as the choroid plexus cells in the central nervous system (CNS) responsible for regulation of CSF dynamics. Thus, we posit that similar factors may influence CSF dynamics in both types of fluid-sensitive tissues. Specifically, we hypothesize that, in patients with PTCS, mitochondrial metabolites (glutamate, succinate) and steroid hormones (cortisol, aldosterone) regulate CSF production and/or absorption. In this integrated mechanism review, we consider the clinical and molecular evidence for each metabolite and hormone in turn. We illustrate how related intracellular signaling cascades may converge in the choroid plexus, drawing on evidence from functionally similar tissues.

Central decompressive laminoplasty for treatment of lumbar spinal stenosis : technique and early surgical results.

OBJECTIVE: Lumbar spinal stenosis is a common degenerative spine disease that requires surgical intervention. Currently, there is interest in minimally invasive surgery and various technical modifications of decompressive lumbar laminectomy without fusion. The purpose of this study was to present the author's surgical technique and results for decompression of spinal stenosis. METHODS: The author performed surgery in 57 patients with lumbar spinal stenosis between 2006 and 2010. Data were gathered retrospectively via outpatient interviews and telephone questionnaires. The operation used in this study was named central decompressive laminoplasty (CDL), which allows thorough decompression of the lumbar spinal canal and proximal two foraminal nerve roots by undercutting the lamina and facet joint. Kyphotic prone positioning on elevated curvature of the frame or occasional use of an interlaminar spreader enables sufficient interlaminar working space. Pain was measured with a visual analogue scale (VAS). Surgical outcome was analyzed with the Oswestry Disability Index (ODI). Data were analyzed preoperatively and six months postoperatively. RESULTS: The interlaminar window provided by this technique allowed for unhindered access to the central canal, lateral recess, and upper/lower foraminal zone, with near-total sparing of the facet joint. The VAS scores and ODI were significantly improved at six-month follow-up compared to preoperative levels (p<0.001, respectively). Excellent pain relief (>75% of initial VAS score) of back/buttock and leg was observed in 75.0% and 76.2% of patients, respectively. CONCLUSION: CDL is easily applied, allows good field visualization and decompression, maintains stability by sparing ligament and bony structures, and shows excellent early surgical results.

Long-term clinical and radiologic outcomes of minimally invasive posterior cervical foraminotomy.

OBJECTIVE: To report long-term clinical and radiological outcomes of minimally invasive posterior cervical foraminotomy (MI-PCF) performed in patients with unilateral single-level cervical radiculopathy. METHODS: Of forty-six patients who underwent MI-PCF for unilateral single-level radiculopathy between 2005 and 2013, 33 patients were included in the study, with a mean follow-up of 32.7 months. Patients were regularly followed for clinical and radiological assessment. Clinical outcome was measured by visual analogue scale (VAS) for the neck/shoulder and arm, and the neck disability index (NDI). Radiological outcome was measured by focal/global angulation and disc height index (DHI). Outcomes after MI-PCF were evaluated as changes of clinical and radiological parameters from the baseline. Mixed effect model with random patients' effect was used to test for differences in the clinical and radiological parameters repeat measures. RESULTS: There were no complications and all patients had an uneventful recovery during the early postoperative period. VAS scores for neck/shoulder and arm improved significantly in the early postoperative period (3 months) and were maintained with time (p<0.001). NDI improved significantly post-operatively and tended to decrease gradually during the follow-up period (p<0.001). There were no statistically significant changes in focal and global angulation at follow-up. Percent DHIs of the upper adjacent or operated disc were maintained without significant changes with time. During the follow-up, same site recurrence was not noted and adjacent segment disease requiring additional surgery occurred in two patients (6%) on the contra-lateral side. CONCLUSION: MI-PCF provides long-term pain relief and functional restoration, accompanied by good long-term radiological outcome.

Comparison of Serum CRP and Procalcitonin in Patients after Spine Surgery.

OBJECTIVE: Classical markers of infection cannot differentiate reliably between inflammation and infection after neurosurgery. This study investigated the dynamics of serum procalcitonin (PCT) in patients who had elective spine surgeries without complications. METHODS: Participants were 103 patients (47 women, 56 men) who underwent elective spinal surgery. Clinical variables relevant to the study included age, sex, medical history, body mass index (BMI), site and type of surgery, and surgery duration. Clinical and laboratory data were body temperature, white blood cell count (WBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and PCT, all measured preoperatively and postoperatively on days 1, 3, and 5. RESULTS: PCT concentrations remained at <0.25 ng/mL during the postoperative course except in 2 patients. PCT concentrations did not correlate with age, sex, DM, hypertension, BMI, operation time, operation site, or use of instrumentation. In contrast, CRP concentrations were significantly higher with older age, male, DM, hypertension, longer operation time, cervical operation, and use of instrumentation. CONCLUSION: PCT may be useful in the diagnosing neurosurgical patients with postoperative fever of unknown origin.

Minimally Invasive Muscle Sparing Transmuscular Microdiscectomy : Technique and Comparison with Conventional Subperiosteal Microdiscectomy during the Early Postoperative Period.

OBJECTIVE: The authors introduce a minimally invasive muscle sparing transmuscular microdiscectomy (MSTM) to treat herniated lumbar disc disease. Its results are compared with conventional subperiosteal microdiscectomy (CSM) to validate the effectiveness. METHODS: Muscle sparing transmuscular microdiscectomy, which involves muscle dissection approach using the natural fat cleavage plane between the multifidus to expose the interlaminar space, was performed in 23 patients to treat a single level unilateral lumbar radiculopathy. The creatine phosphokinase (CPK)-MM serum levels were measured on admission and at 1, 3, and 5 days postoperatively. Postoperative pain was evaluated using a 10-point visual analogue scale (VAS) and recorded on admission and at 1, 3, and 5 days postoperatively. The results were compared to those from the conventional subperiosteal microdiscectomy (43 patients). RESULTS: The CPK-MM levels were significantly lower in the serum of the MSTM group compared to the CSM group on postoperative days three and five (p = 0.03 and p = 0.02, respectively). The clinical scales for back pain using VAS were significantly lower in the MSTM group than in the CSM group on postoperative days three (p = 0.04). The mean VAS scores for leg pain in both groups showed no significant differences during the early postoperative period. CONCLUSION: Muscle sparing transmuscular microdiscectomy is a minimally invasive surgical option to treat lumbar radiculopathy due to herniated disc. The approach affected minimal injury to posterior lumbar supporting structures with alleviated postoperative back pain.