The Novel Tetra-Specific Drug C-192, Conjugated Using UniStac, Alleviates Non-Alcoholic Steatohepatitis in an MCD Diet-Induced Mouse Model.

Non-alcoholic steatohepatitis (NASH) is a complex disease resulting from chronic liver injury associated with obesity, type 2 diabetes, and inflammation. Recently, the importance of developing multi-target drugs as a strategy to address complex diseases such as NASH has been growing; however, their manufacturing processes remain time- and cost-intensive and inefficient. To overcome these limitations, we developed UniStac, a novel enzyme-mediated conjugation platform for multi-specific drug development. UniStac demonstrated high conjugation yields, optimal thermal stabilities, and robust biological activities. We designed a tetra-specific compound, C-192, targeting glucagon-like peptide 1 (GLP-1), glucagon (GCG), fibroblast growth factor 21 (FGF21), and interleukin-1 receptor antagonist (IL-1RA) simultaneously for the treatment of NASH using UniStac. The biological activity and treatment efficacy of C-192 were confirmed both in vitro and in vivo using a methionine-choline-deficient (MCD) diet-induced mouse model. C-192 exhibited profound therapeutic efficacies compared to conventional drugs, including liraglutide and dulaglutide. C-192 significantly improved alanine transaminase levels, triglyceride accumulation, and the non-alcoholic fatty liver disease activity score. In this study, we demonstrated the feasibility of UniStac in creating multi-specific drugs and confirmed the therapeutic potential of C-192, a drug that integrates multiple mechanisms into a single molecule for the treatment of NASH.

Predictive factors for favorable short-term response to interlaminar epidural block for cervical radiculopathy.

PURPOSE: We sought to identify clinical predictors of favorable short-term outcomes associated with cervical interlaminar epidural injection (CIEI). Previous studies investigating the predictive factors of CIEI efficacy have shown inconsistent results. Gaining information on the possible response determinants of CIEI is necessary for appropriate treatment selection and outcomes prediction in the treatment of cervical radiculopathy. METHODS: We analyzed the clinical data of 72 patients who received fluoroscopic-guided CIEI using the paramedian approach for cervical radiculopathy to identify the predictive factors for short-term outcomes of CIEI. Demographic characteristics, history of neck surgery, diagnosis, initial numeric rating score, duration of symptoms, Douleur Neuropathique 4 (DN4) questions, painDETECT questionnaire, neck disability index, and ventral epidural spread of contrast medium were assessed. Treatment success was defined as at least a 50% reduction in the numeric rating score after CIEI and was designated as a good response. RESULTS: The short-term success rate of CIEI for cervical radiculopathy was 55.56%. Multivariate logistic regression analysis established that spinal stenosis (odds ratio 0.183; P = 0.012), a longer duration of > 24 weeks of symptoms (odds ratio 0.206; P = 0.026), and combined positive results for the DN4 and painDETECT (odds ratio, 0.019; P = 0.008) decreased the odds ratio of a good response, 2-3 weeks after CIEI. CONCLUSIONS: CIEI provides a significant short-term outcome in patients with cervical radiculopathy. However, CIEI efficacy may be negatively affected in patients with spinal stenosis, the presence of a chronic state, and a possible neuropathic pain component.

Varicella-Zoster Virus Reactivation During the Incubation Period for Scrub Typhus: A Case Report.

BACKGROUND Herpes zoster caused by the reactivation of latent varicella-zoster virus is thought to result from the waning of specific cell-mediated immunity. Scrub typhus, an acute infectious disease caused by Orientia tsutsugamushi, affects multiple organs and is characterized by microangiopathies that result in significant vascular leakage and subsequent end-organ injury. Very few cases of reactivation of the varicella-zoster virus following scrub typhus occurrence have been reported. Furthermore, no previous studies have directly investigated whether Orientia tsutsugamushi infection is a potential risk factor for herpes zoster. CASE REPORT We present the case of a 64-year-old woman without a previous illness who simultaneously developed herpes zoster of the thoracic dermatome and scrub typhus. Clinical symptoms of scrub typhus appeared during the treatment course for herpes zoster symptoms. Based on positive virus antibody test results, the patient was diagnosed with scrub typhus. This is a unique case of reactivation of the varicella-zoster virus that occurred during a silent incubation period for scrub typhus. CONCLUSIONS This report indicates the possibility of reactivation of latent varicella-zoster virus following Orientia tsutsugamushi infection, although the relationship between the 2 remains undetermined. Physicians should be aware that scrub typhus might be a potential determinant of varicella-zoster virus reactivation.

Neuropathic Pain Component in Patients with Cervical Radicular Pain: A Single-Center Retrospective Study.

Background and Objectives: Evidence regarding the prevalence of neuropathic pain in patients with cervical radicular pain is limited. This study aimed to investigate the prevalence of neuropathic pain components in patients with cervical radicular pain using established screening tools and identify the relationship between neuropathic pain components and clinical factors. Materials and Methods: Data from 103 patients (aged ≥ 20 years) with cervical radicular pain who visited our pain clinic were analyzed retrospectively. Demographic characteristics, history of neck surgery, pain intensity using numeric rating score, dominant pain site, duration of symptoms, and neck disability index were assessed. The prevalence of neuropathic pain components was defined according to the Douleur Neuropathique 4 questions and painDETECT questionnaire tools. Patient characteristics were compared using the chi-square test or Fisher's exact test for categorical variables and the independent t-test or Mann−Whitney U test for continuous variables. The correlation between neck disability index and other variables was analyzed using Pearson's correlation coefficient. Results: Of the 103 patients, 29 (28.1%) had neuropathic pain components. The neck disability index was significantly higher (p < 0.001) for patients in the neuropathic pain group (23.79 ± 6.35) than that in the non- neuropathic pain group (18.43 ± 7.68). The Douleur Neuropathique 4 questions (r = 0.221, p < 0.025) and painDETECT questionnaire (r = 0.368, p < 0.001) scores positively correlated with the neck disability index score. Conclusions: The prevalence of neuropathic pain components in patients with cervical radicular pain was low. The patients in our study showed a strong correlation between functional deterioration and their neuropathic pain screening score. This study may be useful in understanding the characteristics of cervical radicular pain.

Effect of performing preoperative echocardiography in patients with cardiovascular risk on intraoperative anesthetic management and postoperative outcomes: A retrospective study.

Although echocardiography is widely used for preoperative cardiac risk evaluation, few studies have analyzed the effect of performing preoperative echocardiography on intraoperative anesthetic management and postoperative outcomes. We investigated the effect of performing echocardiography on intraoperative anesthetic management and postoperative outcomes in patients with cardiovascular risk. We retrospectively evaluated patients who had undergone major abdominal surgery and satisfied 2 or more of the following criteria: hypertension, diabetes mellitus, age ≥70 years, and previous cardiac disease. Patients were categorized into a group in which preoperative echocardiography was performed (echo) and a group in which it was not (non-echo). The primary outcomes were postoperative 30-day mortality and incidence of cardiovascular complications. Secondary outcomes were length of hospital stay, intraoperative incidence of hypotension, use of vasopressors, and findings on intraoperative invasive hemodynamic monitoring. There were no differences in 30-day mortality, incidence of postoperative cardiovascular complications, length of hospital stay, and intraoperative events between the groups. Only the incidence of cardiac output monitoring was lower in the echo group than in the non-echo group (59.6% vs 73.9%). Preoperative echocardiography does not affect postoperative outcomes, but it has the potential to affect intraoperative anesthetic management such as invasive hemodynamic monitoring during surgery.

Atypical Course of Vertebral Artery Identified by Ultrasound Prescan before Performing a Stellate Ganglion Block.

Ultrasound provides direct visualization of blood vessels and soft tissues around the sympathetic chain and potentially minimizes injury to these critical anatomic structures when performing stellate ganglion block (SGB). We report an atypical left vertebral artery course detected during an ultrasound prescan before performing a SGB. The left vertebral and inferior thyroid arteries were identified on the longus colli muscle's ventral surface at the C6 level. This report was the first to demonstrate ultrasound images of a vulnerable vertebral artery to intravascular injection. The study emphasized the importance of identifying the sonoanatomy before performing procedures involving the anterior cervical vertebrae.

Effect of Remifentanil on Postoperative Vomiting After Strabismus Surgery in Preschool Children: A Prospective Randomized Controlled Trial.

Background: Strabismus surgery and the use of opioid are risk factors of postoperative vomiting. We evaluated whether there is a dose-dependent effect of remifentanil on the incidence of postoperative vomiting. Methods: Sixty pediatric patients who were scheduled for strabismus surgery were enrolled. Patients were randomly divided into three groups; Group H (high-dose remifentanil group), Group L (low-dose remifentanil group), and Group C (control group). After endotracheal intubation, patients in the Group H and L received an intravenous bolus dose of remifentanil of 1.0 µg/kg and 0.5 µg/kg over 2 min, respectively. Group H and L patients received a continuous infusion of remifentanil (0.1 µg/kg/min) during the surgery. The patients in Group C did not have any dose of remifentanil. Intravenous fentanyl (1 µg/kg) was administered to the patients for postoperative pain control. Results: The primary outcome was a difference of the incidence of postoperative vomiting within 24 hours after surgery. There was no significant difference in incidence of postoperative vomiting between three groups. The degree of emergence agitation and postoperative pain did not show any significant difference between three groups. Conclusions: The intraoperative administration of remifentanil did not show dose-dependent effect on postoperative vomiting in pediatric strabismus surgery.

Spontaneous intracranial hypotension following spinal anesthesia initially misdiagnosed as postdural puncture headache.

Spontaneous intracranial hypotension (SIH) is not rare, but its diagnosis remains challenging. SIH tends to be misdiagnosed as postdural puncture headache when orthostatic headache develops subsequent to spinal anesthesia because both have similar symptoms. We report the case of a 35-year-old man with orthostatic headache following spinal anesthesia, who did not respond to conventional therapy for postdural puncture headache. SIH was confirmed after epidural fluid collection was identified at the thoracic spine level on magnetic resonance myelography. Physicians must consider SIH despite a history of neuraxial block. Diagnostic work-up is necessary to identify potential cerebrospinal fluid leakage in refractory cases.

Thenar Compartment Syndrome Related to Tightened Radial Arterial Line During Robotic Laparoscopic Surgery: A Case Report.

We present a 54-year-old man who developed an unexpected thenar space compartment syndrome after robotic laparoscopic surgery, which was caused when the radial arterial pressure tubing was pulled too tightly around the base of the thumb while changing the surgical position. A conventional method of securing the tubing by looping it around the thumb appeared to be the primary cause. This complication went unnoticed during the surgery because the arm was tucked out of sight; there were no remarkable findings on monitoring. This case highlights the risks of looping tubing around the thumb, especially if continual inspection is not possible.

Comment to: The utility of ultrasound examination in cubital tunnel syndrome caused by heterotopic ossification.

Ultrasound (US) could visualize the pathological anatomy of HO and the enlargement site and compression location of the nerve in the cubital tunnel [1]. We read with great interest the article of Jacisko et al[2]. In addition, we report rare US images of HO in direct contact with the swollen ulnar nerve in the cubital tunnel that was not detected by plain radiography. A 60-year-old female presented with a six-month history of elbow pain. Her pain was located at the medial side of the right elbow joint and accompanied by numbness of the fifth finger. She had a history of excessive manual labor due to her occupation as a gardener over the past few decades. The numbness began with the fifth finger initially and gradually extended toward the medial side of the elbow joint. US images showed hyperechoic masses causing acoustic shadowing, in direct contact with the ulnar nerve in the cubital tunnel. The HO seems to be related to compression of the ulnar nerve. The ulnar nerve was swollen (Figure 1-a, b). The maximal cross-sectional-area was 0.10 cm2. Plain elbow radiographs demonstrated osteophyte formation in the coronoid process of the ulna, the coronoid fossa of the humerus, and in the radial head (Figure 1-c). Radiographic imaging showed no heterotopic bone formation in the soft tissues surrounding the medial side of the right elbow. We performed US-guided perineural injection with a mixture of 1 cc of 10 mg triamcinolone and 3 cc of 0.2 % ropivacaine. Her pain and numbness gradually diminished with no adverse effects. Her pain reduced by 70% after two weeks, with pain improvement sustained for 6 months after the injection. Jacisko et al[2]have presented some diagnostic US imaging on neuropathy caused by HO located close to the ulnar nerve in the cubital tunnel. Especially, this case showed definite heterotopic bone formation in the soft tissue surrounding the medial side of the elbow on plain radiography. The classic sonographic patterns of HO were defined by the presence of central hypoechoic area surrounded by foci of calcification [3, 4]. The distortion of normal soft tissue and the formation of hypoechoic areas, with or without foci of calcification can also be shown as early signs[3, 4]. The use of US for HO is highly sensitive and provides an earlier diagnosis compared with other radiologic modalities [3-5]. It can be an effective treatment strategy and may improve the prognosis of neuropathy. We highlight that US evaluation can provide early diagnostic information about ulnar nerve morphology and various HO formations even if plane radiographs did not show heterotopic bone formation in the soft tissues surrounding the medial side of the elbow.

Leriche Syndrome Misdiagnosed as Complex Regional Pain Syndrome in a Patient with Neuropathic Pain Caused by a Chip Fracture: A Case Report.

INTRODUCTION: Leriche syndrome is an aortoiliac occlusive disease caused by atherosclerotic occlusion. We report a case of Leriche syndrome with a fracture that was suspected as complex regional pain syndrome (CRPS), as the post-traumatic pain gradually worsened in the form of excruciating neuropathic pain. CASE REPORT: A 52-year-old woman with a history of hypertension was referred to the Department of Pain Medicine from a local orthopedic clinic because of suspected CRPS for excruciating neuropathic pain for one month. She complained of gait dysfunction and severe pain in the right foot following an incident of trauma with the right first toe. The average pain intensity assessed using the visual analog scale (VAS) was 90 (0: no pain, 100: the worst pain imaginable), and the neuropathic pain was evident as a score of 6/10 on Douleur neuropathique 4. Allodynia, hyperalgesia, blue discoloration of the skin, asymmetric temperature change (1.38 °C), and edematous soft tissue changes were observed. Ultrasonography showed a chip fracture in the first distal phalanx of the right first toe. The diagnosis was most probably CRPS type I according to the Budapest research criteria for CRPS. However, multiple pain management techniques were insufficient in controlling the symptoms. A month and a half later, an ankle-brachial index score of less than 0.4 suggested severe peripheral artery disease. Computed tomography angiography showed total occlusion between the infrarenal abdominal aorta and the bilateral common iliac arteries. Therefore, she underwent aortic-bifemoral bypass surgery with a diagnosis of Leriche syndrome. Three months after the surgery, the average pain intensity was graded as 10 on the VAS (0-100), the color of the skin of the right first toe improved and no gait dysfunction was observed. CONCLUSION: A chip fracture in a region with insufficient blood flow could manifest as excruciating neuropathic pain in Leriche syndrome.

The Influence of Ultrasound-Guided Technique Using a Catheter-Over-Needle on the Incidence of Accidental Intravascular Injection during Caudal Block-A Retrospective Case Series Study.

Background and Objectives: This study was conducted to investigate the influence of an ultrasound-guided technique using a catheter-over-needle when an intravascular injection occurs in patients undergoing a caudal block. Material and Methods: We retrospectively investigated 41 cases of an ultrasound-guided technique using an angiocatheter for caudal block. These had been performed between November 2019 through August 2020 to manage pain of lumbosacral origin. Under ultrasound guidance, after advancing the introducer needle through the sacrococcygeal ligament and then slowly withdrawing it, the outer catheter was continuously advanced into the sacral hiatus. We confirmed proper needle placement under fluoroscopic imaging, using 5 mL of contrast media. We assessed the contrast spread pattern with fluoroscopic imaging and checked it for the presence of intravascular injection. Results: In all recruited cases, the catheter-over-needle was guided successfully to the sacral hiatus and into the caudal epidural space. There was 100% accuracy under ultrasound guidance, without intravascular uptake, as confirmed by contrast media fluoroscopy. The incidence of ventral spread was 84.2% above the S1 with 5 mL of contrast. Conclusions: The technique of using a catheter-over-needle under ultrasound induced successful block without intravascular injection. Thus, this technique is a reliable option for conventional caudal block.

The Relationship between the Timing of Sugammadex Administration and the Upper Airway Obstruction during Awakening from Anesthesia: A Retrospective Study.

Background and Objectives: The harmonization of recovery of consciousness and muscular function is important in emergence from anesthesia. Even if muscular function is recovered, tracheal extubation without adequate recovery of consciousness may increase the risk of respiratory complications. In particular, upper airway obstruction is one of the common respiratory complications and can sometimes be fatal. However, the association between the timing of sugammadex administration and the upper airway obstruction that can occur during awakening from anesthesia has rarely been studied. Materials and Methods: The medical records of 456 patients who had surgery under general endotracheal anesthesia (GETA) at the Haeundae Paik Hospital between October 2017 and July 2018 and who received intravenous sugammadex to reverse rocuronium-induced neuromuscular blockade were analyzed. The correlations between bispectral index (BIS) and minimum alveolar concentration (MAC) at the time of sugammadex administration, the incidence of complications, and the time to tracheal extubation were analyzed to investigate how different timings of sugammadex administration affected upper airway obstruction after tracheal extubation. Conclusions: The effect of BIS and the duration from anesthetic discontinuation to sugammadex administration on upper airway obstruction was not statistically significant. However, the odds ratio of complication rates with MAC < 0.3 compared with MAC ≥ 0.3 was 0.40 (95% confidence interval 0.20 to 0.81, p = 0.011), showing a statistically significant increase in risk with MAC ≥ 0.3 for upper airway obstruction.

Severe Atrophy of the Ipsilateral Psoas Muscle Associated with Hip Osteoarthritis and Spinal Stenosis-A Case Report.

Pathology of the lumbar spine and hip joint can commonly coexist in the elderly. Anterior and lateral leg pain as symptoms of hip osteoarthritis and spinal stenosis can closely resemble each other, with only subtle differences in both history and physical examinations. It is not easy to identify the origin of this kind of hip pain. The possibility of hip osteoarthritis should not be underestimated, as this could lead to an incorrect diagnosis and inappropriate spinal surgery. We report the case of a 54-year-old female with chronic right anterior and lateral leg pain who did not respond to repeated spinal blocks based on lumbar MRI, but in whom hip osteoarthritis was considered since severe atrophy of the ipsilateral psoas muscle was identified. We suggest that severe psoas muscle atrophy can be a clinical clue to identify hip osteoarthritis and is related to lower extremity pain, even if there is a coexisting lumbar spine pathology.

Evaluation of Contrast Flow Patterns with Cervical Interlaminar Epidural Injection: Comparison of Midline and Paramedian Approaches.

Background and objectives: The purpose of this study was to compare and to analyze contrast spread patterns between the paramedian and midline approaches to cervical interlaminar epidural injection (CIEI). Materials and Methods: We retrospectively enrolled 84 CIEI cases that had been performed for unilateral cervical spinal pain from April 2019 to April 2020. After 3 mL of contrast had been injected into the epidural space, fluoroscopic images were obtained. The CIEI was divided into a midline (Group M, n = 42) and a paramedian (Group P, n = 42) approach by anteroposterior imaging. The P Group was classified into a more medial (Group Pm, n = 26) and a more lateral (Group Pl, n = 16) group. Using ImageJ on an anteroposterior image, we assessed the grayscale brightness ratio of the ipsilateral or contralateral side of the vertebral body as well as the intervertebral disc space one level just above the needle location. We identified the dispersion of contrast into the ventral epidural space. Results: The grayscale brightness ratio was significantly higher in Group P than in Group M (p < 0.001). The incidence of ventral epidural spread in Group M was 57.1% versus 88.1% in Group P, which was significantly different (p = 0.001). Conclusions: The fluoroscopic CIEI finding in the paramedian approach predominantly showed an excellent delivery of the injectate to the ipsilateral side in comparison to the contralateral side. This showed a greater advantage in delivery toward ventral epidural space as compared to the midline approach.

Superior cervical sympathetic ganglion block under ultrasound guidance promotes recovery of abducens nerve palsy caused by microvascular ischemia.

The abducens nerve palsy is most likely caused by microvascular issue. Spontaneous recovery of vasculopathic abducens nerve palsies was common at 3-6 months. But recovery time was longer when many risk factors were present. Several patients had residual esotropia or abduction deficit. Cervical sympathetic block has an established use in treating patients with disorders related to cranial circulatory insufficiency. It causes a significant increase in cerebral blood flow. We report a case of a 67-year-old man with acute horizontal diplopia and right periocular pain. He had been diagnosed with right abducens nerve palsy caused by microvascular ischemia. We performed ultrasound-guided superior cervical sympathetic ganglion blocks. After 4 weeks, the symptoms had been completely resolved. We introduce ultrasound-guided superior cervical sympathetic ganglion blocks for management of abducens nerve palsy caused by microvascular ischemia, which could be an effective novel method to promote recovery from diplopia.

Solution structure of the transmembrane 2 domain of the human melanocortin-4 receptor in sodium dodecyl sulfate (SDS) micelles and the functional implication of the D90N mutant.

The melanocortin receptors (MCRs) are members of the G protein-coupled receptor (GPCR) 1 superfamily with seven transmembrane (TM) domains. Among them, the melanocortin-4 receptor (MC4R) subtype has been highlighted recently by genetic studies in obese humans. In particular, in a patient with severe early-onset obesity, a novel heterozygous mutation in the MC4R gene was found in an exchange of Asp to Asn in the 90th amino acid residue located in the TM 2 domain (MC4RD90N). Mutations in the MC4R gene are the most frequent monogenic causes of severe obesity and are described as heterozygous with loss of function. We determine solution structures of the TM 2 domain of MC4R (MC4RTM2) and compared secondary structure of Asp90 mutant (MC4RTM2-D90N) in a micelle environment by nuclear magnetic resonance (NMR) spectroscopy. NMR structure shows that MC4RTM2 forms a long α-helix with a kink at Gly98. Interestingly, the structure of MC4RTM2-D90N is similar to that of MC4RTM2 based on data from CD and NMR spectrum. However, the thermal stability and homogeneity of MC4RD90N is quite different from those of MC4R. The structure from molecular modeling suggests that Asp90(2.50) plays a key role in allosteric sodium ion binding. Our data suggest that the sodium ion interaction of Asp90(2.50) in the allosteric pocket of MC4R is essential to its function, explaining the loss of function of the MC4RD90N mutant.