Background: The potassium voltage-gated channel subfamily Q member 1 (KCNQ1) gene has recently received much attention as a candidate susceptibility gene for type 2 diabetes mellitus, especially in Asian populations. We previously reported that Kcnq1 mutant mice exhibit reduced insulin secretion and hyperglycemia due to a decrease in pancreatic β-cell mass. Through in vivo and in vitro analyses, we ascertained that this mechanism is the result of the downregulation of the non-coding RNA ‘Kcnq1ot1,’ which is expressed in the paternal allele of the Kcnq1 gene region, causing an increase in the expression of the cell cycle inhibitor cyclin dependent kinase inhibitor 1C (Cdkn1c). It was found that decreased Kcnq1ot1 expression resulted in pancreatic β-cell failure; however, the degree of pancreatic β-cell volume reduction was not severe. Methods: We induced obesity in Kcnq1ot1 truncation mice by feeding them a high-fat diet and evaluated pancreatic β-cell mass. Results: In the present study, we reveal that CCAAT/enhancer binding protein beta (C/EBPβ), which is expressed at higher levels in pancreatic β-cells in obese individuals, further increases the expression of Cdkn1c, which is upregulated by the Kcnq1 gene mutation. We found that simultaneous Cdkn1c hypomethylation and C/EBPβ overexpression in pancreatic β-cells causes a synergistic decrease in pancreatic β-cell mass. Conclusion This finding suggests that the synergistic effect of genetic factors such as Kcnq1 gene mutations and environmental factors such as obesity and overeating, which lead to increased expression of C/EBPβ, contribute to the regulation of pancreatic β-cell mass. This study is the first to show that the Kcnq1 gene is related to pancreatic β-cell mass through genetic-environment interactions.

Methods: Forty-nine adults who underwent single-level L4/5 interbody fusion for degenerative spondylolisthesis were divided into BE-ELIF (n=27) and OLIF (n=22) groups based on the surgical approach used. Clinical outcomes were assessed using the Visual Analog Scale and the Japanese Orthopedic Association Back Pain Evaluation Questionnaire (JOABPEQ). Radiographic parameters, including distance of spondylolisthesis, disc height, segmental lordosis, lumbar lordosis, pelvic tilt, and sagittal vertical axis, were evaluated preoperatively and at final follow-up. Results: OLIF provided significantly better relief of pain in lower limbs and buttocks at 1-year follow-up. No significant between-group differences were observed in JOABPEQ domains. BE-ELIF resulted in greater improvements in spondylolisthesis distance and disc height, while other parameters did not differ significantly between the two groups. Conclusions For L4/5 degenerative spondylolisthesis, BE-ELIF demonstrated superior spondylolisthesis reduction and disc height improvement than OLIF. Although BE-ELIF was associated with some inferior clinical outcomes, it provided satisfactory results, effective realignment, and a low complication risk.

Methods: Forty-nine adults who underwent single-level L4/5 interbody fusion for degenerative spondylolisthesis were divided into BE-ELIF (n=27) and OLIF (n=22) groups based on the surgical approach used. Clinical outcomes were assessed using the Visual Analog Scale and the Japanese Orthopedic Association Back Pain Evaluation Questionnaire (JOABPEQ). Radiographic parameters, including distance of spondylolisthesis, disc height, segmental lordosis, lumbar lordosis, pelvic tilt, and sagittal vertical axis, were evaluated preoperatively and at final follow-up. Results: OLIF provided significantly better relief of pain in lower limbs and buttocks at 1-year follow-up. No significant between-group differences were observed in JOABPEQ domains. BE-ELIF resulted in greater improvements in spondylolisthesis distance and disc height, while other parameters did not differ significantly between the two groups. Conclusions For L4/5 degenerative spondylolisthesis, BE-ELIF demonstrated superior spondylolisthesis reduction and disc height improvement than OLIF. Although BE-ELIF was associated with some inferior clinical outcomes, it provided satisfactory results, effective realignment, and a low complication risk.

Methods: Forty-nine adults who underwent single-level L4/5 interbody fusion for degenerative spondylolisthesis were divided into BE-ELIF (n=27) and OLIF (n=22) groups based on the surgical approach used. Clinical outcomes were assessed using the Visual Analog Scale and the Japanese Orthopedic Association Back Pain Evaluation Questionnaire (JOABPEQ). Radiographic parameters, including distance of spondylolisthesis, disc height, segmental lordosis, lumbar lordosis, pelvic tilt, and sagittal vertical axis, were evaluated preoperatively and at final follow-up. Results: OLIF provided significantly better relief of pain in lower limbs and buttocks at 1-year follow-up. No significant between-group differences were observed in JOABPEQ domains. BE-ELIF resulted in greater improvements in spondylolisthesis distance and disc height, while other parameters did not differ significantly between the two groups. Conclusions For L4/5 degenerative spondylolisthesis, BE-ELIF demonstrated superior spondylolisthesis reduction and disc height improvement than OLIF. Although BE-ELIF was associated with some inferior clinical outcomes, it provided satisfactory results, effective realignment, and a low complication risk.

This review summarizes improvements in understanding the pathophysiology and early clinical symptoms of multiple system atrophy (MSA) and advancements in diagnostic methods and disease-modifying therapies for the condition. In 2022, the Movement Disorder Society proposed new diagnostic criteria to develop disease-modifying therapies and promote clinical trials of MSA since the second consensus was proposed in 2008. Regarding pathogenesis, cutting-edge findings have accumulated on the interactions of α-synuclein, neuroinflammation, and oligodendroglia with neurons. In neuroimaging, introducing artificial intelligence, machine learning, and deep learning has notably improved diagnostic accuracy and individual analyses. Advancements in treatment have also been achieved, including immunotherapy therapy against α-synuclein and serotonin-targeted and mesenchymal stem cell therapies, which are thought to affect several aspects of the disease, including neuroinflammation. The accelerated progress in clarifying the pathogenesis of MSA over the past few years and the development of diagnostic techniques for detecting early-stage MSA are expected to facilitate the development of disease-modifying therapies for one of the most intractable neurodegenerative diseases.

Methods: A total of 14 patients with unilateral radicular symptoms and five healthy subjects were subjected to simultaneous apparent T2 mapping and neurography with nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement signaling (SHINKEI-Quant) using a 3-Tesla magnetic resonance imaging. The Visual Analog Scale (VAS) score for neck pain and upper arm pain was used to evaluate clinical symptoms. T2 relaxation times of the cervical dorsal root ganglia of the brachial plexus were measured bilaterally from C4 to C8 in patients with radicular symptoms and from C5 to C8 in healthy controls. The T2 ratio was calculated as the affected side to unaffected side. Results: When comparing nerve roots bilaterally at each spinal level, no significant differences in T2 relaxation times were found between patients and healthy subjects. However, T2 relaxation times of nerve roots in the patients with unilateral radicular symptoms were significantly prolonged on the involved side compared with the uninvolved side (p<0.05). The VAS score for upper arm pain was not significantly correlated with the T2 relaxation times, but was positively correlated with the T2 ratio. Conclusions In patients with cervical radiculopathy, the SHINKEI-Quant technique can be used to quantitatively evaluate the compressed cervical nerve roots. The VAS score for upper arm pain was positively correlated with the T2 ratio. This suggests that the SHINKEI-Quant is a potential tool for the diagnosis of cervical nerve entrapment.

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a newly emerging viral disease with fatal outcomes. However, no MERS-CoV-specific treatment is commercially available. Given the absence of previous structure-based drug discovery studies targeting MERS-CoV fusion proteins, this set of compounds is considered the first generation of MERS-CoV small molecule fusion inhibitors. After a virtual screening campaign of 1.56 million compounds followed by cell-cell fusion assay and MERS-CoV plaques inhibition assay, three new compounds were identified. Compound numbers 22, 73, and 74 showed IC50 values of 12.6, 21.8, and 11.12 μM, respectively, and were most effective at the onset of spike-receptor interactions. The compounds exhibited safe profiles against Human embryonic kidney cells 293 at a concentration of 20 μM with no observed toxicity in Vero cells at 10 μM. The experimental results are accompanied with predicted favorable pharmacokinetic descriptors and drug-likeness parameters. In conclusion, this study provides the first generation of MERS-CoV fusion inhibitors with potencies in the low micromolar range.

Multiple system atrophy (MSA) is an adult-onset, progressive neurodegenerative disorder. Patients with MSA show various phenotypes during the course of their illness, including parkinsonism, cerebellar ataxia, autonomic failure, and pyramidal signs. Patients with MSA sometimes present with isolated autonomic failure or motor symptoms/signs. The median duration from onset to the concomitant appearance of motor and autonomic symptoms is approximately 2 years but can range up to 14 years. As the presence of both motor and autonomic symptoms is essential for the current diagnostic criteria, early diagnosis is difficult when patients present with isolated autonomic failure or motor symptoms/signs. In contrast, patients with MSA may show severe autonomic failure and die before the presentation of motor symptoms/signs, which are currently required for the diagnosis of MSA. Recent studies have also revealed that patients with MSA may show nonsupporting features of MSA such as dementia, hallucinations, and vertical gaze palsy. To establish early diagnostic criteria and clinically definitive categorization for the successful development of disease-modifying therapy or symptomatic interventions for MSA, research should focus on the isolated phase and atypical symptoms to develop specific clinical, imaging, and fluid biomarkers that satisfy the requirements for objectivity, for semi- or quantitative measurements, and for uncomplicated, worldwide availability. Several novel techniques, such as automated compartmentalization of the brain into multiple parcels for the quantification of gray and white matter volumes on an individual basis and the visualization of α-synuclein and other candidate serum and cerebrospinal fluid biomarkers, may be promising for the early and clinically definitive diagnosis of MSA.
Biomarkers ; Brain ; Cerebellar Ataxia ; Cerebrospinal Fluid ; Dementia ; Diagnosis ; Early Diagnosis ; Hallucinations ; Humans ; Multiple System Atrophy ; Neurodegenerative Diseases ; Paralysis ; Parkinsonian Disorders ; Phenotype ; White Matter

BACKGROUND: We hypothesized that ketamine, when administered as the anesthetic induction agent, may prevent cardiovascular depression during high-dose remifentanil administration, unlike propofol. To test our hypothesis, we retrospectively compared the hemodynamic effects of ketamine, during high-dose remifentanil administration, with those of propofol. METHODS: Thirty-eight patients who underwent oral surgery at the Nagasaki University Hospital between April 2014 and June 2015 were included in this study. Anesthesia was induced by the following procedure: First, high-dose remifentanil (0.3-0.5 µg/kg/min) was administered 2-3 min before anesthesia induction; next, the anesthetic induction agent, either propofol (Group P) or ketamine (Group K), was administered. Mean arterial pressure (MAP) and the heart rate were recorded by the automated anesthesia recording system at four time points: immediately before the administration of high-dose remifentanil (T1); immediately before the administration of propofol or ketamine (T2); 2.5 min (T3), and 5 min (T4) after the administration of the anesthetic induction agent. RESULTS: In Group P, the MAP at T3 (75.7 ± 15.5 mmHg, P = 0.0015) and T4 (68.3 ± 12.5 mmHg, P < 0.001) were significantly lower than those at T1 (94.0 ± 12.4 mmHg). However, the MAP values in the K group were very similar (P = 0.133) at all time points. The heart rates in both Groups P (P = 0.254) and K (P = 0.859) remained unchanged over time. CONCLUSIONS: We showed that ketamine, when administered as the anesthetic induction agent during high-dose remifentanil administration, prevents cardiovascular depression.
Anesthesia ; Arterial Pressure ; Depression ; Heart Rate ; Hemodynamics* ; Humans ; Ketamine* ; Propofol* ; Retrospective Studies* ; Surgery, Oral