Hydrophobicity Tuning of Cationic Polyaspartamide Derivatives for Enhanced Antisense Oligonucleotide Delivery.

Various cationic polymers are used to deliver polyplex-mediated antisense oligonucleotides (ASOs). However, few studies have investigated the structural determinants of polyplex functionalities in polymers. This study focused on the polymer hydrophobicity. A series of amphiphilic polyaspartamide derivatives possessing various hydrophobic (R) moieties together with cationic diethylenetriamine (DET) moieties in the side chain (PAsp(DET/R)s) were synthesized to optimize the R moieties (or hydrophobicity) for locked nucleic acid (LNA) gapmer ASO delivery. The gene knockdown efficiencies of PAsp(DET/R) polyplexes were plotted against a hydrophobicity parameter, logD7.3, of PAsp(DET/R), revealing that the gene knockdown efficiency was substantially improved by PAsp(DET/R) with logD7.3 higher than -2.4. This was explained by the increased polyplex stability and improved cellular uptake of ASO payloads. After intratracheal administration, the polyplex samples with a higher logD7.3 than -2.4 induced a significantly higher gene knockdown in the lung tissue compared with counterparts with lower hydrophobicity and naked ASO. These results demonstrate that the hydrophobicity of PAsp(DET/R) is crucial for efficient ASO delivery in vitro and in vivo.

Interleukin-6 blockade reduces salt-induced cardiac inflammation and fibrosis in subtotal nephrectomized mice.

Cardiovascular disease is the most common comorbidity in patients with chronic kidney disease (CKD), affecting both their prognosis and quality of life. Cardiac fibrosis is common in patients with CKD with left ventricular diastolic dysfunction, and it is associated with increased risk of heart failure and mortality. Recent evidence suggests that high salt intake activates immune responses associated with local accumulation of sodium. We reported that high salt intake promotes cardiac inflammation in subtotal nephrectomized (Nx) mice. We investigated the effects of administration of MR16-1, a rat anti-mouse monoclonal interleukin (IL)-6 receptor antibody, in Nx mice with salt loading (Nx-salt). Expression of monocyte chemoattractant protein-1, tumor necrosis factor-α, IL-1ß, and IL-6 mRNAs and macrophage infiltration was significantly reduced in the heart of Nx-salt mice treated with MR16-1 (Nx-salt-MR16-1) compared with Nx-salt mice treated with control rat rat IgG1 (Nx-salt-rat IgG1). Correspondingly, cardiac fibrosis was significantly attenuated in Nx-salt-MR16-1 mice compared with Nx-salt-rat IgG1 mice. Furthermore, in the heart of Nx-salt-MR16-1 mice, expression of mRNA for nicotinamide adenine dinucleotide phosphate oxidase-2, an oxidative stress marker, was significantly downregulated compared with Nx-salt-rat IgG1 mice. Increases in cardiac metabolites, including histidine and γ-butyrobetaine, were also reversed by IL-6 blockade treatment. In conclusion, IL-6 blockade exerts anti-inflammatory, antifibrotic, and partial antioxidative effects in the heart of Nx-salt mice.NEW & NOTEWORTHY In the present study, IL-6 blockade exerted anti-inflammatory, antifibrotic, and partial antioxidative effects on the hearts of mice with CKD on a high-salt diet. Therefore, IL-6 potentially mediates cardiac fibrosis induced by high salt intake in patients with CKD, a finding with therapeutic implications. Of note, the next therapeutic implication may simply be the reinforcement of low-salt diets or diuretics and further research on the anti-inflammatory effects of these measures rather than IL-6 blockade with high-salt diet.

An Anatomical Study of Posterior Trunk Recipient Vessels, and Comparisons of Outcome following Pedicled- and Free-Flap Transfers for Treatment of Sarcoma in the Posterior Trunk.

BACKGROUND: Reconstruction after wide resection of a large sarcoma arising in the posterior trunk may require free-flap transfer to reduce the postoperative complications. Here, we describe the recipient vessels on the whole posterior trunk. Moreover, to show the reliability of these vessels, we describe an institutional series of free-flap reconstruction. METHODS: In the cadaveric study, 20 posterior trunk regions from 10 fixed cadavers were dissected. The location and the diameter of the perforating artery and vein on the posterior were documented. In the clinical study, 54 patients undergoing immediate reconstruction surgery with only a pedicled flap (n = 45) and with a free flap (n = 9) after sarcoma resection on the posterior trunk between July 2005 and September 2021 were identified. One-to-one propensity score matching was performed to compare the postoperative complications. RESULTS: In the cadaveric study, a total of 178 perforators were identified. The average diameter of the superficial cervical artery (SCA) and vein, dorsal scapular artery (DSA) and vein, medial branch of dorsal intercostal artery perforator (m-DICAP) and vein, lateral branch of dorsal intercostal artery perforator (l-DICAP) and vein, and dorsolateral intercostal artery perforator (DLICAP) and vein were 1.03, 1.67, 1.38, 1.84, 1.28, 1.84, 1.01, 1.60, 1.11, and 1.70 mm. In the clinical study, the propensity score-matched analysis involving eight pairs showed a significantly higher occurrence of total complications in the pedicled-flap group than the free-flap group (62.5 vs. 0%, p = 0.03). CONCLUSION: The cadaveric study showed that the perforators from the SCA, DSA, and posterior intercostal artery are constantly present. The clinical study demonstrated the feasibility and reliability of a free-flap transfer.

Comparison Between Conventional Flash and Off-Response Intraoperative Visual Evoked Potential Monitoring for Endoscopic Endonasal Surgery.

BACKGROUND: Intraoperative flash stimulation visual evoked potential (VEP) monitoring has been used for endoscopic endonasal approach (EEA). Recently, off-response VEP, which is recorded when the light stimulus is turned off, was introduced to monitor visual function intraoperatively. OBJECTIVE: To evaluate off-response VEP monitoring in comparison with the conventional flash stimulation VEP monitoring for EEA. METHODS: From March 2015 to March 2020, 70 EEA surgeries with intraoperative VEP monitoring (140 eyes) were performed. Light stimuli were delivered by a pair of goggle electrodes. Recording electrodes were placed on the scalp over the occipital region. The warning signal was prompted by a reduction of the peak-to-peak amplitude of the VEP by more than 50% compared to the initial amplitude. Visual function was assessed pre- and postoperatively. Results of flash and off-response VEP monitoring were compared. RESULTS: VEP was recorded in 134 eyes. Warning signal occurred in 23 eyes (transient in 17 eyes and permanent in 6 eyes). Two eyes showed permanent VEP attenuation for flash VEP monitoring, in which one patient had postoperative visual function deterioration. Four eyes showed permanent VEP attenuation for off-response VEP monitoring, where 2 patients had postoperative visual function deterioration. Sensitivity, specificity, positive predictive value, and negative predictive value were 100%, 98.9%, 50%, and 100%, respectively, for flash stimulation VEP, and 100%, 97.8%, 50%, and 100%, respectively, for off-response VEP. CONCLUSION: VEP monitoring was useful to monitor visual function in EEA surgery. Off-response VEP monitoring was not inferior to conventional flash stimulation VEP monitoring.

Surgical strategy for symptomatic pineal cyst: is endoscopit third ventriculostomy necessary in addition to cyst fenestration?

Symptomatic large pineal cyst (PC) remains a rare entity. The stable natural course of asymptomatic PCs is well established. However, large cysts may cause pressure-related symptoms necessitating surgical intervention. The surgical strategy for symptomatic PCs is still controversial. Regardless of the approach, total resection of the cyst is not mandatory. The endoscopic approach allows cyst fenestration in patients with associated obstructive hydrocephalus. On the other hand, the necessity of simultaneous endoscopic third ventriculostomy (ETV) is still debatable. Here, we report a case of a woman who underwent endoscopic cyst fenestration, biopsy, and third ventriculostomy for a large symptomatic PC and discuss the surgical strategy. A 30-year-old woman presented with headache and diplopia, MRI showed a large PC and accompanying obstructive hydrocephalus. Simultaneous cyst fenestration, biopsy and ETV with endoscopy was successfully completed. She had an uneventful recovery period with immediate relief of symptoms. Although, the aqueduct was communicated due to cyst shrinkage, the patency of the third ventricular stoma was demonstrated in long-term follow-up scans. Based on clinical course of the present case, we concluded that ETV in addition to cyst fenestration should be considered necessary and beneficial in cases of large symptomatic PC with associated hydrocephalus whenever an endoscopic intraventricular approach is considered.

The effectiveness and safety of computed tomographic peritoneography and video-assisted thoracic surgery for hydrothorax in peritoneal dialysis patients: A retrospective cohort study in Japan.

INTRODUCTION: Albeit uncommon, hydrothorax is an important complication of peritoneal dialysis (PD). Due to paucity of evidence for optimal treatment, this study aimed to evaluate the effectiveness and safety of computed tomographic (CT) peritoneography and surgical intervention involving video-assisted thoracic surgery (VATS) for hydrothorax in a retrospective cohort of patients who underwent PD in Japan. METHODS: Of the 982 patients who underwent PD from six centers in Japan between 2007 and 2019, 25 (2.5%) with diagnosed hydrothorax were enrolled in this study. PD withdrawal rates were compared between patients who underwent VATS for diaphragm repair (surgical group) and those who did not (non-surgical group) using the Kaplan-Meier method and log-rank test. RESULTS: The surgical and non-surgical groups comprised a total of 11 (44%) and 14 (56%) patients, respectively. Following hydrothorax diagnosis by thoracentesis and detection of penetrated sites on the diaphragm using CT peritoneography, VATS was performed at a median time of 31 days (interquartile range [IQR], 20-96 days). During follow-up (median, 26 months; IQR, 10-51 months), 9 (64.3%) and 2 (18.2%) patients in the non-surgical and surgical groups, respectively, withdrew from PD (P = 0.021). There were no surgery-related complications or hydrothorax relapse in the surgical group. CONCLUSIONS: This study demonstrated the effectiveness and safety of CT peritoneography and VATS for hydrothorax. This approach may be useful in hydrothorax cases to avoid early drop out of PD and continue PD in the long term. Further studies are warranted to confirm these results.

Acromegaly in preadolescence: A case report of a 9-year-old boy with acromegaly.

BACKGROUND: Acromegaly has been reported in adolescents and young adults, but it is unusual in preadolescence. Diagnosis and management pose different challenges in this age group. Here, we present a rare case of acromegaly in preadolescence. CASE DESCRIPTION: A 9-year-old boy presented with acromegalic features and MRI revealed a pituitary tumor. He was diagnosed as having growth hormone secreting pituitary adenoma based on the multidisciplinary assessment, and underwent gross total tumor resection through an endoscopic endonasal approach (EEA) with subsequent normalization of the hormonal parameters. CONCLUSIONS: Advances in EEA have made safe removal and cure possible even in children. However, long- term follow-up is needed in such younger patients with multidisciplinary management by neurosurgeons, endocrinologists, pediatricians, and ENT surgeons.

Superficial Siderosis Associated with Craniopharyngioma.

BACKGROUND: Superficial siderosis (SS) associated with craniopharyngioma is an extremely rare occurrence. To our knowledge, only 3 cases have been reported in literature. Two of the cases occurred following resection of the tumor. Similar to the present case, 1 of the cases was discovered before surgical intervention, "pure tumor-related" SS. The clinical presentation, diagnosis, management, and outcome are discussed in this article. CASE DESCRIPTION: A 50-year-old man presented with an 11-month history of left-sided tinnitus, hearing impairment, and a 2-month history of visual disturbance. Cerebellar ataxia and gait disturbance were found on examination. Brain magnetic resonance imaging findings were consistent with SS. Cerebrospinal fluid (CSF) analysis before surgery revealed xanthochromia confirming an existing chronic sustainable subarachnoid hemorrhage. He underwent a tumor resection in endoscopic endonasal approach followed by stereotactic radiosurgery. On follow-up, the visual symptoms resulting from craniopharyngioma subsided, whereas hearing impairment, cerebellar ataxia, and gait disturbance associated with SS did not progress but were unchanged despite subsequent evidence of watery-clear CSF. CONCLUSIONS: In the present case, SS could be associated with craniopharyngioma on the basis of CSF findings and clinical symptoms. Detection and early treatment aimed at eliminating the bleeding source offer the best chance of halting the disease process.

Exit Site Infection due to Mycobacterium chelonae in an Elderly Patient on Peritoneal Dialysis.

Nontuberculous mycobacteria (NTM) are rarely isolated from peritoneal dialysis (PD)-associated catheter infections. However, NTM infection is usually difficult to treat and leads to catheter loss. Prompt diagnosis is essential for appropriate treatment. A 70-year-old Japanese man who had been on PD for 2 years and with a medical history of 2 episodes of exit site infections (ESIs) due to methicillin-resistant Staphylococcus aureus was admitted to the hospital due to suspected ESI recurrence. However, Gram staining of the pus revealed no gram-positive cocci. Instead, weakly stained gram-positive rods were observed after 7 days of incubation, which were also positive for acid-fast staining. Rapidly growing NTM Mycobacterium chelonae was isolated on day 14. Despite administering a combination antibiotic therapy, ESI could not be controlled, and catheter removal surgery was performed on day 21. Although PD was discontinued temporarily, the patient did not require hemodialysis, without any uremic symptoms. The catheter was reinserted on day 48, and PD was reinitiated on day 61. The patient was discharged on day 65. Antibiotic therapy was continued for 3 months after discharge, with no indications of recurrent infections observed. It is important to consider the risk of NTM infections in patients on PD. Acid-fast staining could be a key test for prompt diagnosis and provision of an appropriate treatment.

Severe refractory TAFRO syndrome requiring continuous renal replacement therapy complicated with Trichosporon asahii infection in the lungs and myocardial infarction: an autopsy case report and literature review.

BACKGROUND: TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis/renal failure, and organomegaly) syndrome is a systemic inflammatory disorder and unique clinicopathological variant of idiopathic multicentric Castleman disease that was proposed in Japan. Prompt diagnosis is critical because TAFRO syndrome is a progressive and life threating disease. Some cases are refractory to immunosuppressive treatments. Renal impairment is frequently observed in patients with TAFRO syndrome, and some severe cases require hemodialysis. Histological evaluation is important to understand the pathophysiology of TAFRO syndrome. However, systemic histopathological evaluation through autopsy in TAFRO syndrome has been rarely reported previously. CASE PRESENTATION: A 46-year-old Japanese man with chief complaints of fever and abdominal distension was diagnosed with TAFRO syndrome through imaging studies, laboratory findings, and pathological findings on cervical lymph node and bone marrow biopsies. Interleukin (IL)-6 and vascular endothelial growth factor (VEGF) levels were remarkably elevated in both blood and ascites. Methylprednisolone (mPSL) pulse therapy was initiated on day 10, followed by combination therapy with PSL and cyclosporine A. However, the amount of ascites did not respond to the treatment. The patient became anuric, and continuous renal replacement therapy was initiated from day 50. However, the patient suddenly experienced cardiac arrest associated with myocardial infarction (MI) on the same day. Although the emergent percutaneous coronary intervention was successfully performed, the patient died on day 52, despite intensive care. Autopsy was performed to ascertain the cause of MI and to identify the histopathological characteristics of TAFRO syndrome. CONCLUSIONS: Bacterial peritonitis, systemic cytomegalovirus infection, and Trichosporon asahii infection in the lungs were observed on autopsy. In addition, sepsis-related myocardial calcification was suspected. Management of infectious diseases is critical to reduce mortality in patients with TAFRO syndrome. Although the exact cause of MI could not be identified on autopsy, we considered embolization by fungal hyphae as a possible cause. Endothelial injury possibly caused by excessive secretion of IL-6 and VEGF contributed to renal impairment. Fibrotic changes in anterior mediastinal fat tissue could be a characteristic pathological finding in patients with TAFRO syndrome.

Successful Recovery from Spontaneous Spinal Epidural Hematoma in a Patient Undergoing Hemodialysis.

BACKGROUND Spontaneous spinal epidural hematoma (SSEH) occurs in the spinal epidural space in the absence of traumatic or iatrogenic causes, and is considered to be a neurological emergency, as spinal cord compression may lead to neurological deficit. Prompt diagnosis of SSEH can be difficult due to the variety of presenting symptoms, which may resemble those of stroke. Patients who undergo hemodialysis (HD) are at risk of bleeding due to anticoagulation during dialysis and uremia. However, SSEH in HD patients undergoing HD has rarely been reported. CASE REPORT A 70-year-old Japanese man, who has been undergoing maintenance HD for the previous three years, was admitted to Kariya Toyota General Hospital, Aichi, Japan, with acute chest and abdominal pain, and with complete paraplegia. The patient denied any recent trauma or medical procedures. Magnetic resonance imaging showed an extensive hematoma in the thoracic and lumbar epidural space, extending from T8 to L5. The patient's symptoms improved within three hours following hospital admission, and after three days without HD treatment, the SSEH decreased in size, and the patient successfully recovered without residual neurological deficits and without requiring surgery. CONCLUSIONS The management of SSEH in patients undergoing HD can be difficult, due to anticoagulation during dialysis and uremia. Prompt diagnosis and close neurological monitoring are important for appropriate management. In patients whose symptoms improve within a short period, conservative management may be considered.