Outpatient Treatment of Mild Dysphagia in Ear-Nose-and-Throat Clinics.

OBJECTIVE: Many reports on inpatient dysphagia rehabilitation in acute and convalescent rehabilitation hospitals exist, but there are a few reports on outpatient treatments. Otolaryngologists still take a trial-and-error approach when treating dysphagia. Here, we explore the effectiveness and limitations of outpatient treatment in ear-nose-and-throat (ENT) clinics. METHODS: Sixty-four patients (41 males and 23 females) aged 27-101 years (mean 78 years) visited an outpatient clinic specialising in feeding and swallowing conditions (the Fukuyo ENT Clinic). All were able to perform the activities of daily living (ADL) to the extent that outpatient visits were possible; no home visits were made. The weekly outpatient day was staffed by an otolaryngologist and a speech-language-hearing therapist (SLHT). All patients were subjected to fibreoptic endoscopic evaluation of swallowing (FEES), followed by appropriate training as revealed by the examinations. RESULTS: Salivary retention in the glottis valley and piriform sinuses improved (both p < 0.05) in 30 patients who underwent repeat FEES; we compared the initial and final figures. In 14 cases in whom maximal tongue pressure (TP) was measured, this was higher at the final than at the first examination (p < 0.01). CONCLUSION: Outpatient treatment at ENT clinics for patients who are able to maintain their ADLs to the extent that they are able to walk to a hospital is an option for the treatment of age-related dysphagia. For severe cases, however, house calls and collaboration with the home and nursing care sector will be necessary and should be considered in the future.

Verification of the efficacy of topical sirolimus gel for systemic rare vascular malformations: a pilot study.

Numerous clinical trials of sirolimus, an inhibitor of mechanistic/mammalian target of rapamycin complex 1, for the treatment of vascular malformations have been conducted. However, aside from lymphatic malformations, the efficacy of sirolimus for venous and capillary malformations has not been established. Moreover, no generalized venous or capillary malformations have been treated with topical sirolimus. To evaluate the safety and efficacy of topical sirolimus for venous and capillary malformations and to compare the efficacy of topical and systemic sirolimus therapy, an open-label single-arm pilot study with 0.2% sirolimus gel was conducted from July 19, 2019, to January 30, 2020, in four patients diagnosed with different vascular malformations (blue rubber bleb nevus syndrome, common venous malformation, phakomatosis pigmentovascularis type IVb, and angiokeratoma in Fabry disease). The primary endpoint was the safety evaluation of sirolimus gel. The main secondary endpoint was the improvement rate evaluated by the Central Judgment Committee at 12 weeks using photographs. No adverse events were observed. Blood sirolimus was not detected in any patient. Two patients (50%) had mild improvement, and the remaining two patients (50%) showed no change after 12 weeks of treatment. Blue rubber bleb nevus syndrome, a generalized venous malformation, showed the greatest response. In conclusion, 0.2% sirolimus gel was found to be as clinically effective as systemic sirolimus treatment in patients with venous and capillary malformations and more effective for early active lesions, even systemic venous malformations.

123I-BMIPP Scintigraphy Shows That CNT-01 (Tricaprin) Improves Myocardial Lipolysis in Patients with Idiopathic Triglyceride Deposit Cardiomyovasculopathy: First Randomized Controlled, Exploratory Trial for TGCV.

Background: Triglyceride deposit cardiomyovasculopathy (TGCV) is a rare intractable cardiovascular disorder (Orphanet ORPHAcode: 565612) in which defective intracellular lipolysis results in heart failure and coronary artery disease. Myocardial scintigraphy with 123I-ß-methyl-p-iodophenylpentadecanoic acid (BMIPP) is useful to evaluate myocardial TG metabolism; its washout rate (WR) reflects myocardial lipolysis. This study reports the effects of CNT-01 (tricaprin), a developing orphan drug to facilitate lipolysis, on BMIPP-WR in patients with TGCV. Methods: An investigator-initiated, multicenter, randomized, double-blind exploratory, trial (Phase IIa) was conducted (UMIN000035403). Seventeen patients with idiopathic TGCV were orally administered 1.5 g/day of CNT-01 or placebo for 8 weeks. Endpoints included delta BMIPP-WR and clinical parameters such as 6-minwalk distance and TGCV severity score. Results: During the protocol, delta BMIPP-WRs were -0.26±3.28 and 7.08±3.28% (95% confidence intervals, -7.36 to 6.84 and -0.01 to 14.18) in the placebo and CNT-01 groups, respectively. The baseline-adjusted difference of delta BMIPP-WR between the two groups was significant (p=0.035) after one patient was excluded from the placebo group because of pseudonormalization of BMIPP-WR related to coronary bypass graft stenosis. Clinical parameters did not show significant changes. Conclusions: This study proved the mechanism of CNT-01 to improve myocardial lipolysis in TGCV, as demonstrated by BMIPP scintigraphy.

Long-Term Sequelae in Young Convalescent COVID-19 Patients.

As of March 2022, over 78 million cases of COVID-19 and 900,000 deaths have been reported in the United States. The consequences in the acute phase due to the SARS-COV-2 infection are well defined. Beyond the direct effects of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) involving the lung parenchyma, the post-viral complications within the central nervous system are still largely unknown, and a comprehensive evaluation regarding the long-term neuropsychological sequelae from this disease is not well characterized. An increasing number of patients previously diagnosed with COVID-19 have now presented with ongoing symptoms of inattention, executive function, and memory difficulties. These symptoms are collectively and commonly known by the public as 'brain fog', with many expressing concerns over their inability to engage in the workplace due to these symptoms. Here, we describe three patients who were seen in the Memory Disorders Clinic at Duke University to characterize the long-term neuropsychological symptoms, neuropsychological test results and brain MRI findings after infection with SARS-CoV-2 in a cohort of patients under the age of 60.

Analysis of factors contributing to medication errors during self-management of medication in the rehabilitation ward: a case control study.

BACKGROUND: In the rehabilitation ward, many elderly patients require continuous use of medication after a stroke or bone fracture, even after discharge. They are encouraged to self-manage their medications from the time of admission. Medication errors, such as a missed dose or incorrect administered medication can worsen conditions, resulting in recurrent strokes, fractures, or adverse effects. The study was aimed to identify risk factors, such as medication and prescription, contributing to errors in self-management of medication. METHODS: This study was conducted on patients who self-managed their medication in the rehabilitation ward of Higashinagoya National Hospital from April 2018 to March 2020. The patient background including age and sex were investigated. The medication factors examined include the number of medications and administrations per day, dosing frequency on indicated days, prescription and start date are the same, medications from multiple prescriptions, and one package or one tablet at each dosage. The group of medication error cases were defined as the medication error group and that of control cases as the no-medication error group. A logistic regression analysis was performed for factors related to medication errors. RESULTS: A total of 348 patients were included in the study, of which 154 patients made medication errors, with 374 total medication error cases. The median number of medications in the medication error group was six, and that in the no-medication error group was five. Statistically significant factors correlated with errors made during self-management of medication were the number of medications, number of administrations per day, dosing frequency on indicated days, and medication from multiple prescriptions. CONCLUSIONS: When a patient is self-managing their medications, errors are likely to occur due to a high number of medicines they are taking and the complexity of the dosage regimen. Therefore, to prevent medication errors, reviewing the prescribed medications and devise ways to simplify the dosage regimens is crucial.

The Effectiveness of Mobile Cloud 12-Lead Electrocardiogram Transmission System in Patients with ST-Segment Elevation Myocardial Infarction.

Backgroundand Objectives: Delay of reperfusion therapy is related to high mortality in cases of ST-segment elevation myocardial infarction (STEMI). Guidelines emphasize that the first-medical-contact-to-balloon (FMCTB) time should be within 90 min. A mobile cloud-based 12-lead electrocardiogram (MC-ECG) transmission system might be useful in such cases, especially in rural areas. Materials and Methods: From April 2019 to June 2021, both an MC-ECG transmission system and the conventional method in which a physician checks the ECG in a hospital (Conventional) were used for transport by emergency medical services in Shin-Yukuhashi Hospital, Fukuoka, Japan. During this period, 8684 consecutive patients were transported to this hospital. Among them, we investigated 48 STEMI patients. The MC-ECG group (n = 23) and the Conventional group (n = 25) were enrolled. Results: There was no significant difference in FMCTB time between the MC-ECG and Conventional groups (MC-ECG: 72.0 (60.5-107) min vs. Conventional: 80.0 (63.0-92.0) min, p = 0.77). The length of hospital stay in the MC-ECG group was significantly shorter than that in the Conventional group (12.0 (10.0-15.0) days vs. 16.0 (12.0-19.0) days, p = 0.039). The logistic regression model showed that patients' non-use of MC-ECG was associated with a risk of more than 15-day length of hospital stay with an adjusted odd ratio of 0.08 (95% CI: 0.013-0.55, p = 0.0098). Conclusions: Using the MC-ECG, the length of hospital stay in patients with STEMI was significantly reduced.

Effect of dose and dose rate of gamma irradiation on the formation of micronuclei in bone marrow cells isolated from whole-body-irradiated mice.

It is well-known that the cytotoxicity and mutagenic effects of high dose rate (HDR) ionizing radiation (IR) are increased by increasing the dose but less is known about the effects of chronic low dose rate (LDR). In vitro, we have shown that in addition to the immediate interaction of IR with DNA (the direct and indirect effects), low doses and chronic LDR exposure induce endogenous oxidative stress. During elevated oxidative stress, reactive oxygen species (ROS) react with DNA modifying its structure. Here, BL6 mice were exposed to IR at LDR and HDR and were then sacrificed 3 hours and 3 weeks after exposure to examine early and late effects of IR. The levels of micronuclei, MN, were determined in bone marrow cells. Our data indicate that the effects of 200 mGy on MN-induction are transient, but 500 and 1000 mGy (both HDR and LDR) lead to increased levels of MN up to 3 weeks after the exposure.

MicroRNA-29 is an essential regulator of brain maturation through regulation of CH methylation.

Although embryonic brain development and neurodegeneration have received considerable attention, the events that govern postnatal brain maturation are less understood. Here, we identify the miR-29 family to be strikingly induced during the late stages of brain maturation. Brain maturation is associated with a transient, postnatal period of de novo non-CG (CH) DNA methylation mediated by DNMT3A. We examine whether an important function of miR-29 during brain maturation is to restrict the period of CH methylation via its targeting of Dnmt3a. Deletion of miR-29 in the brain, or knockin mutations preventing miR-29 to specifically target Dnmt3a, result in increased DNMT3A expression, higher CH methylation, and repression of genes associated with neuronal activity and neuropsychiatric disorders. These mouse models also develop neurological deficits and premature lethality. Our results identify an essential role for miR-29 in restricting CH methylation in the brain and illustrate the importance of CH methylation regulation for normal brain maturation.

Simple Synthesis of a Heterocyclophane Exhibiting Anti-c-Met Activity by Acting as a Hatch Blocking Access to the Active Site*.

A simple approach to the synthesis of heterocyclophane consisting of two 4,4'-bithiazoles has been developed in mild conditions. The heterocyclophane with two short chains was conveniently prepared by Hantzsch thiazoles synthesis using the reaction of 3-tert-butoxycarbonyl-3-azapentanethiocarboxamide with 1,4-dibromobutane-2,3-dione in methanol under reflux for only 15 min. Amino groups at the linkers of this heterocyclophane can be functionalized to give acylated and carbamate derivatives. Their properties as protein kinase inhibitors were investigated, and one of the heterocyclophanes exhibited specific anti-activity for c-mesenchymal epithelial transition factor (IC50 =603 nm), among seven types of protein kinases investigated. The computational site identification by ligand competitive saturation method was used to determine why the one heterocyclophane exhibited strong anti-activity for c-mesenchymal epithelial transition factor.

Decreased Colonic Guanylin/Uroguanylin Expression and Dried Stool Property in Mice With Social Defeat Stress.

Psychological stress is deeply involved in the pathophysiology of not only mental illness but also functional gastrointestinal disorders. In the present study, we examined the relationship between psychological stress and abnormality of stool properties, focusing on the alteration of plasma glucocorticoid and guanylin (GN)/uroguanylin (UGN) expression in the colon. A murine model of chronic social defeat stress (CSDS) was established by exposing a C57BL/6N intruder mouse to a CD-1 aggressor mouse for 3-5 min. Thereafter the mice were kept in the same cage but separated by a divider for the remainder of the day. This procedure was repeated for 10 consecutive days, and then a social interaction test was performed to evaluate social avoidance. Fresh fecal and blood samples were collected for stool property analysis and measurement of the plasma glucocorticoid level by ELISA. The expression of GN, UGN, and guanylate cyclase 2C in the colonic tissues was examined by real-time RT-PCR and immunohistochemistry. Moreover, Lovo cells were stimulated with dexamethasone, and the expression of GN/UGN mRNA was examined. In the CSDS group, the time spent in the social interaction zone was significantly shorter when the CD-1 aggressor mouse was present than when it was absent. The social interaction ratio was also significantly lower in the CSDS group relative to the controls. The mean Bristol scale score was significantly lower in the CSDS group, but the fecal sodium concentration did not differ between CSDS mice and controls. The level of plasma corticosterone was significantly higher in the CSDS group than in the controls immediately after the 10th day of CSDS. The expression of both GN and UGN was significantly decreased in the CSDS mice. GN was expressed in all colonic epithelial cells, and UGN was expressed in ovoid or pyramidal epithelial cells in the colonic mucosa. The expression of both GN and UGN was significantly decreased in the CSDS mice relative to controls. The expression of both GN and UGN was significantly suppressed in Lovo cells upon stimulation with dexamethasone. Psychological stress-induced glucocorticoid may suppress colonic GN/UGN expression, resulting in a change in stool properties leading to constipation.

Involvement of cannabinoid type 1 receptor in fasting-induced analgesia.

The endocannabinoid system (ECS) is known to modulate not only food intake but also pain, especially via the cannabinoid type 1 receptor (CB1R) expressed throughout the central nervous system and the peripheral tissues. Our previous study demonstrated that fasting produces an analgesic effect in adult male mice, which is reversed by intraperitoneal (i.p.) administration of CB1R antagonist (SR 141716). In the present study, we further examined the effect of CB1R expressed in the peripheral tissues. In the formalin-induced inflammatory pain model, i.p. administration of peripherally restricted CB1R antagonist (AM 6545) reversed fasting-induced analgesia. However, intraplantar administration of SR 141716 did not affect fasting-induced analgesia. Furthermore, mRNA expression of CB1R did not change in the formalin model by fasting in the dorsal root ganglia. The formalin-induced c-Fos expression at the spinal cord level was not affected by fasting, and in vivo recording from the superficial dorsal horn of the lumbar spinal cord revealed that fasting did not affect formalin-induced neural activity, which indicates minimal involvement of the spinal cord in fasting-induced analgesia. Finally, when we performed subdiaphragmatic vagotomy to block the hunger signal from the gastrointestinal (GI) system, AM 6545 did not affect fasting-induced analgesia, but SR 141716 still reversed fasting-induced analgesia. Taken together, our results suggest that both peripheral and central CB1Rs contribute to fasting-induced analgesic effects and the CB1Rs in the GI system which transmit fasting signals to the brain, rather than those in the peripheral sensory neurons, may contribute to fasting-induced analgesic effects.

Characterization of a Cul9-Parkin double knockout mouse model for Parkinson's disease.

Mitochondrial quality control is essential for the long-term survival of postmitotic neurons. The E3 ubiquitin ligase Parkin promotes the degradation of damaged mitochondria via mitophagy and mutations in Parkin are a major cause of early-onset Parkinson's disease (PD). Surprisingly however, mice deleted for Parkin alone are rather asymptomatic for PD-related pathology, suggesting that other complementary or redundant mitochondrial quality control pathways may exist in neurons. Mitochondrial damage is often accompanied by the release of toxic proteins such as cytochrome c. We have reported that once in the cytosol, cytochrome c is targeted for degradation by the E3 ligase CUL9 in neurons. Here we examined whether CUL9 and Parkin cooperate to promote optimal neuronal survival in vivo. We generated mice deficient for both Cul9 and Parkin and examined them for PD-related phenotypes. Specifically, we conducted assays to examine behavioural deficits (locomotor, sensory, memory and learning) and loss of dopaminergic neurons in both males and females. Our results show that the loss of Cul9 and Parkin together did not enhance the effect of Parkin deficiency alone. These results indicate that while both Parkin and CUL9 participate in mitochondrial quality control, neurons likely have multiple redundant mechanisms to ensure their long-term survival.

Regression and Stabilization of Coronary Vulnerable Plaque by Evolocumab as Assessed by Multidetector Row Computed Tomography.

A 65-year-old man was followed for his coronary conditions using 320-multi detector row computed tomography (MDCT) for 30 months. He had soft plaque in the right coronary artery (RCA) [mean density of plaque was 22 hounsfield units (HU)]. His initial serum low-density lipoprotein cholesterol (LDL-C) was 72 mg/dL. After 30 months, his serum LDL-C was 26 mg/dL under 5.0 mg/day rosuvastatin and evolocumab 140 mg/2 weeks. MDCT showed a regression of the plaque in the RCA and the plaque density was 114 HU (intermediate plaque). In conclusion, intensive lipid-lowering therapy with evolocumab induced the regression and stabilization of coronary vulnerable plaque.

Associations between the psoas major muscle index and the presence and severity of coronary artery disease.

The associations between the presence and severity of coronary artery disease (CAD) and measurements of the psoas major muscle (PMM) as assessed by multidetector row coronary computed tomography angiography (MDCT) are not known.We enrolled 793 patients who were clinically suspected to have CAD or had at least one cardiac risk factor and had undergone MDCT. The number of significantly stenosed coronary vessels (VD) and measurements of the PMM index (PMMI) were determined using MDCT.PMMI in the CAD group was significantly lower than that in the non-CAD group in males, but not females. In addition, the levels of PMMI tended to increase as the number of VD decreased in males. When male patients were divided into 2 groups according to median value of age, that is, relatively younger (53.4 ±â€Š9.2 years) and older (72.6 ±â€Š5.7 years) groups, the presence of CAD was independently associated with PMMI in the younger group by a multiple logistic regression analysis. The cut-off level of PMMI that gave the greatest sensitivity and specificity for the diagnosis of CAD in younger males was 8.3 cm/m (sensitivity 0.441, specificity 0.752).In conclusion, PMMI may be an imaging marker for evaluating the presence and/or severity of CAD in males, and particularly in the non-elderly.

Responsiveness of lumbosacral superficial dorsal horn neurons during the voiding reflex and functional loss of spinal urethral-responsive neurons in streptozotocin-induced diabetic rats.

AIMS: Sensory information from the lower urinary tract (LUT) is conveyed to the spinal cord to trigger and co-ordinate micturition. However, it is not fully understood how spinal dorsal horn neurons are excited during the voiding reflex. In this study, we developed an in vivo technique allowing recording of superficial dorsal horn (SDH) neurons concurrent with intravesical pressure (IVP) during the micturition cycle in both normal and diabetic rats. METHODS: Lumbosacral dorsal horn neuronal activity and IVP were recorded from urethane-anesthetized naive and streptozotocin (STZ)-induced diabetic rats. Saline was continuously perfused into the urinary bladder through a cannula to induce micturition. RESULTS: We classified SDH neurons into bladder- and urethral-responsive neurons, based on their responsiveness during the voiding reflex. Bladder-responsive SDH neurons responded to the rapid increase in IVP at the start of voiding. In contrast, urethral-responsive SDH neuronal firing increased at the peak IVP and their firing lasted during the voiding phase (the high-frequency oscillations). Urethral-responsive SDH neurons were more sensitive to capsaicin, received C afferent fiber inputs, and were rarely detected in STZ-diabetes rats. Administration of a cyclohexenoic long-chain fatty alcohol (TAC-302), which is reported to promote neurite outgrowth of peripheral nerves in STZ-diabetic rats, prevented the functional loss of spinal urethral response. CONCLUSIONS: Sensory information from the bladder and urethra is conveyed separately to different groups of SDH neurons. Functional loss of spinal urethral sensory information through unmyelinated C afferent fibers may contribute to diabetic bladder dysfunction.

Investigator-initiated clinical study of a functional peptide, SR-0379, for limb ulcers of patients with Werner syndrome as a pilot study.

AIM: An investigator-initiated clinical study was carried out to evaluate the therapeutic potency of SR-0379 for the treatment of leg ulcers in patients with Werner syndrome. METHODS: A multicenter, open-label study was carried out from September 2017 to February 2018. The inclusion criteria for leg ulcers were: (i) leg ulcers in patients with Werner syndrome, diabetes or critical limb ischemia/venous stasis; and (ii) a wound size of >1 cm and <6 cm in diameter. Four individuals with Werner syndrome and diabetic ulcers, respectively, were enrolled. SR-0379 (0.1%) was sprayed on skin ulcers once per day for 4 weeks. Efficacy was evaluated by determining the rate of wound size reduction as a primary end-point at 4 weeks after the first treatment compared with the pretreatment wound size. As secondary end-points, the DESIGN-R score index, the 50% wound size reduction ratio, time to wound closure and quantification of wound bacteria were also evaluated. The safety of SR-0379 was evaluated during the study period. RESULTS: The reduction rate of ulcer size treated with 0.1% SR-0379 was 22.90% (mean) in the Werner syndrome ulcers group (n = 4) and 35.70% (mean) in the diabetic ulcers group (n = 4), respectively. The DESIGN-R score decreased by 4.0 points in the Werner syndrome ulcers group and 4.3 points in the diabetic ulcers group. Two mild adverse events were reported in two patients, and causal relationships were denied in any events. CONCLUSION: Treatment with SR-0379 was safe, well-tolerated, and effective for leg ulcers of both Werner syndrome and diabetes patients. Geriatr Gerontol Int 2019; 19: 1118-1123.

Preventative effects of the partial RANKL peptide MHP1-AcN in a mouse model of imiquimod-induced psoriasis.

We recently developed a partial peptide of receptor activator of nuclear factor-кB ligand (RANKL) known as microglial healing peptide 1 (MHP1-AcN), that inhibits Toll-like receptor (TLR)-related inflammation through RANKL/RANK signaling in microglia and macrophages without promoting osteoclast activation. The abnormal activation of TLRs contributes to the initiation and maintenance of psoriasis, which is a chronic inflammatory skin disease that involves the aberrant expression of proinflammatory cytokines and the subsequent dermal γδ T cell and T helper 17 (Th17) cell responses. The inhibition of TLR-mediated inflammation provides an important strategy to treat psoriasis. Here, we examined the preventative effects of MHP1-AcN in a mouse model of imiquimod (a TLR 7/8 agonist)-induced psoriasis. Topical imiquimod application induced psoriasis-like skin lesions on the ear and dorsal skin. Systemic administration of MHP1-AcN by daily subcutaneous injection significantly prevented the development of skin lesions, including erythema, scaling and thickening. Mice treated with MHP1-AcN showed reduced levels of skin Il6 mRNA at 32 h and reduced levels of Il23 and Il17a mRNA at d9. Serum levels of IL-6 and IL-23 were reduced at 32 h, and IL-17A was reduced at d9. These results indicated that MHP1-AcN could decrease imiquimod-induced IL-6, IL-23 and IL-17A production. MHP1-AcN is potentially an alternative treatment for psoriasis.