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Long-term potentiation (LTP) at glutamatergic synapses is considered to underlie learning and memory and is associated with the enlargement of dendritic spines. Because the consolidation of memory and LTP require protein synthesis, it is important to clarify how protein synthesis affects spine enlargement. In rat brain slices, the repetitive pairing of postsynaptic spikes and two-photon uncaging of glutamate at single spines (a spike-timing protocol) produced both immediate and gradual phases of spine enlargement in CA1 pyramidal neurons. The gradual enlargement was strongly dependent on protein synthesis and brain-derived neurotrophic factor (BDNF) action, often associated with spine twitching, and was induced specifically at the spines that were immediately enlarged by the synaptic stimulation. Thus, this spike-timing protocol is an efficient trigger for BDNF secretion and induces protein synthesis-dependent long-term enlargement at the level of single spines.

Pharmacological strategies that boost intracellular NAD + are highly coveted for their therapeutic potential. One approach is activation of nicotinamide phosphoribosyltransferase (NAMPT) to increase production of nicotinamide mononucleotide (NMN), the predominant NAD + precursor in mammalian cells. A high-throughput screen for NAMPT activators and hit-to-lead campaign yielded SBI-797812, a compound that is structurally similar to active-site directed NAMPT inhibitors and blocks binding of these inhibitors to NAMPT. SBI-797812 shifts the NAMPT reaction equilibrium towards NMN formation, increases NAMPT affinity for ATP, stabilizes phosphorylated NAMPT at His247, promotes consumption of the pyrophosphate by-product, and blunts feedback inhibition by NAD + . These effects of SBI-797812 turn NAMPT into a “super catalyst” that more efficiently generates NMN. Treatment of cultured cells with SBI-797812 increases intracellular NMN and NAD + . Dosing of mice with SBI-797812 elevates liver NAD + . Small molecule NAMPT activators such as SBI-797812 are a pioneering approach to raise intracellular NAD + and realize its associated salutary effects. Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate determining step for NAD + synthesis and is of interest as a drug target. Here the authors identify and characterize a small molecule NAMPT activator SBI-797812, elucidate its mode of action and show that it increases intracellular NMN and NAD + levels in cultured cells and elevates liver NAD + in mice.

The presence of nerves is an important factor in successful organ regeneration in amphibians. The Mexican salamander, Ambystoma mexicanum, is able to regenerate limbs, tail, and gills when nerves are present. However, the nerve-dependency of tooth regeneration has not been evaluated. Here, we reevaluated tooth regeneration processes in axolotls using a three-dimensional reconstitution method called CoMBI and found that tooth regeneration is nerve-dependent although the dentary bone is independent of nerve presence. The induction and invagination of the dental lamina were delayed by denervation. Exogenous Fgf2, Fgf8, and Bmp7 expression could induce tooth placodes even in the denervated mandible. Our results suggest that the role of nerves is conserved and that Fgf+Bmp signals play key roles in axolotl organ-level regeneration. The presence of nerves is an important factor in successful organ regeneration in amphibians. The Mexican salamander, Ambystoma mexicanum, is able to regenerate limbs, tail, and gills when nerves are present. However, the nervedependency of tooth regeneration has not been evaluated. Here, we reevaluated tooth regeneration processes in axolotls using a three-dimensional reconstitution method called CoMBI and found that tooth regeneration is nerve-dependent although the dentary bone is independent of nerve presence. The induction and invagination of the dental lamina were delayed by denervation. Exogenous Fgf2, Fgf8, and Bmp7 expression could induce tooth placodes even in the denervated mandible. Our results suggest that the role of nerves is conserved and that Fgf+Bmp signals play key roles in axolotl organ-level regeneration.

Despite standard treatment with systemic corticosteroids and/or antifungal triazoles, a substantial proportion of patients with allergic bronchopulmonary aspergillosis (ABPA) experience frequent relapses and require long-term treatment despite unfavorable adverse effects. We investigated the efficacy and safety of anti-interleukin (IL)-5/IL-5 receptor α chain (Rα) monoclonal antibodies (mAbs) in patients with ABPA complicated by asthma. ABPA cases treated with anti-IL-5/IL-5Rα mAbs were collected from 132 medical institutes in 2018 and published case reports in Japan. Clinical outcomes, laboratory and physiological data, and radiographic findings during 32 weeks before and after treatment were retrospectively evaluated. We analyzed 29 cases of ABPA: 20 treated with mepolizumab and nine with benralizumab. Treatment with anti-IL-5/IL-5Rα mAbs reduced the frequency of exacerbations ( p  = 0.03), decreased the dose of oral corticosteroids ( p  < 0.01), and improved pulmonary function ( p  = 0.01). Mucus plugs in the bronchi shrank or diminished in 18 patients (82%). Despite the clinical/radiographical improvement, serum levels of total IgE, the key biomarker for the pharmacological response in ABPA, were unchanged. Anti-IL-5/IL-5Rα mAbs that directly target eosinophils are promising candidates for the treatment of patients with ABPA, especially those with mucus plugs in the bronchi.

Background Although frailty and cognitive impairment are critical risk factors for disability and mortality in the general population of older inhabitants, the prevalence and incidence of these factors in individuals treated in the specialty outpatient clinics are unknown. Methods We recently established a frailty clinic for comprehensive assessments of conditions such as frailty, sarcopenia, and cognition, and planned 3-year prospective observational study to identify the risk factors for progression of these aging-related statuses. To date, we recruited 323 patients who revealed symptoms suggestive of frailty mainly from a specialty outpatient clinic of cardiology and diabetes. Frailty status was diagnosed by the modified Cardiovascular Health Study (mCHS) criteria and some other scales. Cognitive function was assessed by Mini-Mental State Examination (MMSE), Japanese version of the Montreal Cognitive Assessment (MoCA-J), and some other modalities. Sarcopenia was defined by the criteria of the Asian Working Group for Sarcopenia (AWGS). In this report, we outlined our frailty clinic and analyzed the background characteristics of the subjects. Results Most patients reported hypertension (78%), diabetes mellitus (57%), or dyslipidemia (63%), and cardiovascular disease and probable heart failure also had a higher prevalence. The prevalence of frailty diagnosed according to the mCHS criteria, cognitive impairment defined by MMSE (≤27) and MoCA-J (≤25), and of AWGS-defined sarcopenia were 24, 41, and 84, and 31%, respectively. The prevalence of frailty and cognitive impairment increased with aging, whereas the increase in sarcopenia prevalence plateaued after the age of 80 years. No significant differences were observed in the prevalence of frailty, cognitive impairment, and sarcopenia between the groups with and without diabetes mellitus, hypertension, or dyslipidemia with a few exceptions, presumably due to the high-risk subjects who had multiple cardiovascular comorbidities. A majority of the frail and sarcopenic patients revealed cognitive impairment, whereas the frequency of suspected dementia among these patients were both approximately 20%. Conclusions We found a high prevalence of frailty, cognitive impairment, and sarcopenia in patients with cardiometabolic disease in our frailty clinic. Comprehensive assessment of the high-risk patients could be useful to identify the risk factors for progression of frailty and cognitive decline.

Background Anastomotic leakage is one of the most serious complications following laparoscopic low anterior resection (LAR) for rectal cancers. The purpose of this study was to investigate whether transanal tube placement can reduce anastomotic leakage following laparoscopic LAR. Methods Retrospective assessment was performed on 205 patients with rectal cancers who underwent laparoscopic LAR. A transanal tube was placed after anastomosis in 96 patients (group A). Another 109 patients were operated on without a transanal tube (group B). Clinicopathological and operative variables, the frequencies of anastomotic leakage and re-operation after leakage were investigated. Results Patient age, gender, body mass index, tumor size, Dukes’ stage, intra-operative blood loss, and the rate of left colic artery preservation were comparable between the two groups. Tumor location was lower and operative time was significantly longer in group A than group B ( p  < 0.001). Overall rate of leakage was 9.3 % (19/205). The frequency of leakage was 4.2 % (4/96) in group A and was 13.8 % (15/109) in group B. The rate of leakage was significantly lower in group A ( p  < 0.05). Furthermore, the re-operation rate for symptomatic anastomotic leakage was 0 % (0/4) in group A, while in contrast it was 73.3 % (10/15) in group B. The rate of re-operation was lower in group A than group B ( p  < 0.05) and all cases with symptomatic leakage in group A were cured by conservative treatment. Conclusions Transanal tube placement was effective for prevention of anastomotic leakage following laparoscopic LAR and avoiding re-operation after symptomatic leakage.

To evaluate the improvement of drop foot following lumbar decompression surgery and determine the prognostic factors that might influence the recovery of drop foot. Drop foot is a common but serious problem that can lead to deteriorate patient’s daily activities. There are numerous studied regarding the prognostic factors for the recovery of drop foot. However a few reports have been described the pathophysiological etiology of not only drop foot but also Trendelenburg’s sign due to the L5 nerve root palsy. Therefore, there is a possibility drop foot caused by peroneal nerve palsy is included. In addition, none have evaluated the presence or absence of radicular leg pain with drop foot patients. The purpose of this study was to evaluate the improvement of paretic leg muscles and determine the prognostic factors that might influence the recovery of drop foot. Fifty-five drop foot patients were included in the study. Prognostic factors were retrospectively studied.Patients were assessed in terms of 10 items: 1) age, 2) sex, 3) diagnosis (LDH or LSS), 4) muscle strength of tibialis anterior, 5) muscle strength of extensor halluces longus, 6) muscle strength of gluteus medius, 7) presence or absence of radicular leg pain, 8) duration before surgery, 9) surgical treatment (spinal fusion or not), 10) anamnesis of diabetes mellitus. Thirty-two (58.2%) of 55 patients recovered from their drop foot (manual muscle test of tibialis anterior ≥ 4 at final follow-up), while 23 (41.8%) did not (manual muscle test of tibialis anterior ≤ 3 at final follow-up). The strength of all muscles that were innervated and controlled by the L5 nerve root had recovered at the final follow-up when evaluated as averages. Multivariate logistic regression analysis revealed significant differences in terms of 2 items: “duration before surgery” and “presence or absence of radicular leg pain”. “Duration before surgery” and “presence or absence of radicular leg pain” are important to predict the recovery of drop foot. Painless drop foot patients with lumbar degenerative disease are difficult to recover their paralysis. •We evaluated the prognostic factors that might influence the recovery of drop foot.•Longer duration before surgery affect the recovery of drop foot.•Painless drop foot with lumbar degenerative disease is difficult to recover.•Early decompression surgery is important to recover in painless drop foot patients.

The total cerebral small vessel disease (SVD) score is a proposed comprehensive index of SVD severity in the brain. However, data on lifestyle-related risk factors affecting SVD scores are limited. We conducted a cross-sectional study with 858 neurologically healthy adults who underwent brain magnetic resonance imaging (MRI). Information on clinical and lifestyle-related risk factors was obtained from health screenings. The SVD score (0-4) was calculated from the presence of lacunes, cerebral microbleeds, moderate to severe white matter lesions, and basal ganglia perivascular spaces on MRI. Subjects were divided into two groups by SVD score; potential risk factors and their joint effects in the two groups were assessed by logistic regression. Biologic interactions were estimated using the synergy index. After adjustment for possible confounders, the adjusted odds ratio for moderate to severe SVD scores (SVD score ≥ 2) was 1.12 (95% confidence interval (CI) 1.08-1.16) for age per year, 1.33 (95% CI 1.02-1.74) for body mass index per standard deviation, 3.39 (95% CI 1.90-6.03) for hypertension, 2.31 (95% CI 1.14-4.69) for diabetes, and 2.35 (95% CI 1.10-5.02) for smoking. Hypertension and current smoking had a synergistic effect on the risk of moderate to severe SVD (OR 10.59, 95% CI 3.97-28.3; synergy index 4.03, 95% CI 1.17-28.30), and the combination of hypertension and diabetes had an additive effect on the risk of moderate to severe SVD (OR 9.48, 95% CI 3.80-23.66; synergy index 2.12, 95% CI 0.68-6.67). Therefore, combined strategies for managing hypertension, smoking, and diabetes may be effective for preventing SVD.

Whether sodium–glucose cotransporter-2 inhibitors (SGLT2is) reduce ventricular arrhythmias and sudden cardiac death is controversial. Ventricular repolarization heterogeneity is associated with ventricular arrhythmias; however, the effect of SGLT2is on ventricular repolarization in patients with heart failure with reduced ejection fraction (HFrEF) has not been fully investigated. We prospectively evaluated 31 HFrEF patients in sinus rhythm who were newly started on dapagliflozin 10 mg/day. Changes in QT interval, corrected QT interval (QTc), QT dispersion (QTD), corrected QTD (QTcD), T peak to T end (TpTe), TpTe/QT ratio, and TpTe/QTc ratio were evaluated at 1-year follow-up. QT interval, QTc interval, QTD, QTcD, TpTe, and TpTe/QTc ratio decreased significantly at 1-year follow-up (427.6 ± 52.6 ms vs. 415.4 ± 35.1 ms; p  = 0.047, 437.1 ± 37.3 ms vs. 425.6 ± 22.7 ms; p  = 0.019, 54.1 ± 11.8 ms vs. 47.6 ± 14.7 ms; p  = 0.003, 56.0 ± 11.2 ms vs. 49.4 ± 12.3 ms; p  = 0.004, 98.0 ± 15.6 ms vs. 85.5 ± 20.9 ms; p  = 0.018, and 0.225 ± 0.035 vs. 0.202 ± 0.051; p  = 0.044, respectively). TpTe/QT ratio did not change significantly (0.231 ± 0.040 vs. 0.208 ± 0.054; p  = 0.052). QT interval, QTD, and TpTe were significantly reduced 1 year after dapagliflozin treatment in patients with HFrEF. The beneficial effect of dapagliflozin on the heterogeneity of ventricular repolarization may contribute to the suppression of ventricular arrhythmias. Registry information https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000049428 . Registry number: UMIN000044902.

In patients hospitalized for acute decompensation of heart failure (HF), the impact of angiotensin receptor-neprilysin inhibitor (ARNI) on diuresis and renal function has not been fully investigated. Patients with HF and reduced ejection fraction who were hospitalized for acute decompensation and newly initiated ARNI after hemodynamic stabilization were enrolled. Changes in urine volume (UV), body weight, estimated glomerular filtration rate (eGFR), and urine N-acetyl-beta-d-glucosaminidase (uNAG) levels before and after ARNI initiation were investigated. Changes in the diuretic response [DR, calculated as urine volume/(intravenous furosemide volume/40 mg)], N-terminal pro-brain natriuretic peptide (NT-proBNP), hematocrit, and plasma volume (PV) were also evaluated. A total of 60 patients were enrolled. ARNI was initiated at a median of 6 [5, 7] days after hospitalization. After initiation of ARNI, body weight, NT-proBNP, and PV decreased. UV and DR increased only on the day of ARNI initiation (delta UV 400 ± 957 ml and delta DR 1100 ± 3107 ml/40 mg furosemide) and then decreased to baseline levels. In the multivariable linear regression analysis, younger age, higher BMI, and higher NT-proBNP levels were significantly associated with greater UV after ARNI initiation. eGFR and uNAG did not significantly change after the initiation of ARNI [delta eGFR -1.7 ± 12.0 mL/min/1.73 m 2 and delta uNAG 2.0 (−5.6, 6.9) IU/L]. In patients hospitalized for HF, the initiation of ARNI was associated with a small and transient increase in UV and DR, and was not associated with worsening of renal function or tubular injury.