Viral load and the duration of viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important determinants of the transmission of coronavirus disease 2019.In this study, we examined the effects of viral doses on the lung and spleen of K18-hACE2 transgenic mice by temporal histological and transcriptional analyses. Approximately, 1×105 plaque-forming units (PFU) of SARS-CoV-2 induced strong host responses in the lungs from 2 days post inoculation (dpi) which did not recover until the mice died, whereas responses to the virus were obvious at 5 days, recovering to the basal state by 14 dpi at 1×102 PFU. Further, flow cytometry showed that number of CD8+ T cells continuously increased in 1×102 PFU-virusinfected lungs from 2 dpi, but not in 1×105 PFU-virus-infected lungs. In spleens, responses to the virus were prominent from 2 dpi, and number of B cells was significantly decreased at 1×105PFU; however, 1×102 PFU of virus induced very weak responses from 2 dpi which recovered by 10 dpi. Although the defense responses returned to normal and the mice survived, lung histology showed evidence of fibrosis, suggesting sequelae of SARS-CoV-2 infection. Our findings indicate that specific effectors of the immune response in the lung and spleen were either increased or depleted in response to doses of SARS-CoV-2. This study demonstrated that the response of local and systemic immune effectors to a viral infection varies with viral dose, which either exacerbates the severity of the infection or accelerates its elimination.

Background: For acute ischemic stroke (AIS) patients with history of prior stroke (PS) and diabetes mellitus (DM), intravenous recombinant tissue plasminogen activator (IV-tPA) therapy in the 3- to 4.5-hour window is off-label in Korea. This study aimed to assess the safety and efficacy of IV-tPA in these patients. Methods: Using data from a prospective multicenter stroke registry between January 2009 and March 2021, we identified AIS patients who received IV-tPA in the 3- to 4.5-hour window, and compared the outcomes of symptomatic intracranial hemorrhage (SICH), 3-month mortality, 3-month modified Rankin Scale (mRS) score 0-1 and 3-month mRS distribution between patients with both PS and DM (PS/DM, n=56) versus those with neither PS nor DM, or with only one (non-PS/DM, n=927). Results: The PS/DM group versus the non-PS/DM group was more likely to have a prior disability, hypertension, hyperlipidemia, coronary heart disease and less likely to have atrial fibrillation. The PS/DM and the non-PS/DM groups had comparable rates of SICH (0% vs. 1.7%; p>0.999) and 3-month mortality (10.7% vs. 10.2%; p=0.9112). The rate of 3-month mRS 0-1 was non-significantly lower in the PS/DM group than in the non-PS/DM group (30.4% vs. 40.7%; adjusted odds ratio [95% confidence interval], 0.81 [0.41-1.59]). Conclusions In the 3- to 4.5-hour window, AIS patients with PS/DM, as compared to those with non-PS/DM, might benefit less from IV-tPA. However, given the similar risks of SICH and mortality, IV-tPA in the late time window could be considered in patients with both PS and DM.

PURPOSE: The purpose of this study is to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and recommended phase II dose of an oral drug composed of paclitaxel and HM30181A, which is an inhibitor of P-glycoprotein, in patients with advanced cancers. MATERIALS AND METHODS: Patients with advanced solid tumors received standard therapy were given the study drug at escalating doses, using a 3+3 design. The study drug was orally administered on days 1, 8, and 15, with a 28-day cycle of administration. The dose of paclitaxel was escalated from 60 to 420 mg/m2, and the dose of HM30181A was escalated from 30-210 mg/m2. RESULTS: A total of twenty-four patients were enrolled. Only one patient experienced a dose-limiting toxicity-a grade 3 neutropenia that persisted for more than 2 weeks, at 240 mg/m2 of paclitaxel. MTD was not reached. The maximum plasma concentration was obtained at a dose level of 300 mg/m2 and the area under the curve of plasma concentration-time from 0 to the most recent plasma concentration measurement of paclitaxel was reached at a dose level of 420 mg/m2. The absorption of paclitaxel tends to be limited at doses that exceed 300 mg/m2. The effective plasma concentration of paclitaxel was achieved at a dose of 120 mg/m2. Responses of 23 patients were evaluated; 8 (34.8%) had stable disease and 15 (65.2%) had progressive disease. CONCLUSION: The study drug appears to be well tolerated, and the effective plasma concentration of paclitaxel was achieved. The recommended phase II dose for oral paclitaxel is 300 mg/m2.
Absorption ; Humans ; Maximum Tolerated Dose ; Neutropenia ; P-Glycoprotein* ; Paclitaxel* ; Pharmacokinetics ; Plasma

KIOM-79, a mixture of ethanol extracts from four herbs (parched Puerariae radix, gingered Magnoliae cortex, Glycyrrhizae radix and Euphorbiae radix), has been developed for the potential therapeutic application to diabetic symptoms. Because screening of unexpected cardiac arrhythmia is compulsory for the new drug development, we investigated the effects of KIOM-79 on the action potential (AP) and various ion channel currents in cardiac myocytes. KIOM-79 decreased the upstroke velocity (Vmax) and plateau potential while slightly increased the duration of action potential (APD). Consistent with the decreased Vmax and plateau potential, the peak amplitude of Na+ current (INa) and Ca2+ current (ICa,L) were decreased by KIOM-79. KIOM-79 showed dual effects on hERG K+ current; increase of depolarization phase current (Idepol) and decreased tail current at repolarization phase (Itail). The increase of APD was suspected due to the decreased Itail. In computer simulation, the change of cardiac action potential could be well simulated based on the effects of KIOM-79 on various membrane currents. As a whole, the influence of KIOM-79 on cardiac ion channels are minor at concentrations effective for the diabetic models (0.1-10 microg/mL). The results suggest safety in terms of the risk of cardiac arrhythmia. Also, our study demonstrates the usefulness of the cardiac computer simulation in screening drug-induced long-QT syndrome.
Action Potentials/*drug effects ; Animals ; Cell Line ; Computer Simulation ; Female ; Ginger/chemistry ; Humans ; Ion Channels/*physiology ; Long QT Syndrome/diagnosis ; Male ; Membrane Potentials/drug effects/physiology ; Myocytes, Cardiac/*drug effects/physiology ; Patch-Clamp Techniques ; Plant Extracts/*pharmacology ; Pueraria/chemistry ; Purkinje Fibers/drug effects/physiology ; Rabbits ; Rats ; Rats, Sprague-Dawley

KIOM-79, a mixture of ethanol extracts from four herbs (parched Puerariae radix, gingered Magnoliae cortex, Glycyrrhizae radix and Euphorbiae radix), has been developed for the potential therapeutic application to diabetic symptoms. Because screening of unexpected cardiac arrhythmia is compulsory for the new drug development, we investigated the effects of KIOM-79 on the action potential (AP) and various ion channel currents in cardiac myocytes. KIOM-79 decreased the upstroke velocity (Vmax) and plateau potential while slightly increased the duration of action potential (APD). Consistent with the decreased Vmax and plateau potential, the peak amplitude of Na+ current (INa) and Ca2+ current (ICa,L) were decreased by KIOM-79. KIOM-79 showed dual effects on hERG K+ current; increase of depolarization phase current (Idepol) and decreased tail current at repolarization phase (Itail). The increase of APD was suspected due to the decreased Itail. In computer simulation, the change of cardiac action potential could be well simulated based on the effects of KIOM-79 on various membrane currents. As a whole, the influence of KIOM-79 on cardiac ion channels are minor at concentrations effective for the diabetic models (0.1-10 microg/mL). The results suggest safety in terms of the risk of cardiac arrhythmia. Also, our study demonstrates the usefulness of the cardiac computer simulation in screening drug-induced long-QT syndrome.
Action Potentials/*drug effects ; Animals ; Cell Line ; Computer Simulation ; Female ; Ginger/chemistry ; Humans ; Ion Channels/*physiology ; Long QT Syndrome/diagnosis ; Male ; Membrane Potentials/drug effects/physiology ; Myocytes, Cardiac/*drug effects/physiology ; Patch-Clamp Techniques ; Plant Extracts/*pharmacology ; Pueraria/chemistry ; Purkinje Fibers/drug effects/physiology ; Rabbits ; Rats ; Rats, Sprague-Dawley

Infections of the oral and maxillofacial region are one of the most common conditions for which a patient presents to a maxillofacial surgeons. Although these infections can arise from a variety of source, dental disease is the most common etiology. So, odontogenic infection are frequently encountered in the practice of oral and maxillofacial surgery. These infections often respond to antimicrobial chemotherapy or surgical intervention, such as extraction of teeth, incision and drainage through clinical features. But, odontogenic infections have the potential to spread via the fascial spaces in the head and neck region, and, they spread to cavernous sinus, deep musculofascial space and other vital structure. We have undertaken clinical studies on infections in the oral and maxillofacial regions by analyzing retrospectively hospitalized patients in the Department of Oral and Maxillofacial Surgery, Chonbuk National University Hospital past 5 years from 2000 to 2004. And, the patients'age, sex, medical history, causes of the infection, surgical intervention, and other clinical parameters were reviewed. The obtained results were as follows: 1. The most frequent cause of oral and maxillofacial infection was odontogenic. And in the odontogenic cause, dental caries was the most common cause (47.2%). 2. The most common fascial space involved was the submandibular space (15.7%), followed by the buccal space (14.8%). 3. 60.4% of all patients required surgical drainage of the abscess, endodontic treatment or tooth extraction or periodontal treatment with drainage. 4. The most causative organism isolated from the pus culture were streptococcus viridans (53.9%). 5. Underlying medical problems were found in 136 patients (41.9%), the most common being hypertension (27.9%) and diabetes (14.7%).
Abscess ; Cavernous Sinus ; Dental Caries ; Drainage ; Drug Therapy ; Head ; Humans ; Hypertension ; Jeollabuk-do ; Neck ; Retrospective Studies ; Stomatognathic Diseases ; Suppuration ; Surgery, Oral ; Tooth ; Tooth Extraction ; Viridans Streptococci

The kinesin proteins (KIFs) make up a large superfamily of molecular motors that transport cargo such as vesicles, protein complexes, and organelles. KIF1A is a monomeric motor that conveys synaptic vesicle precursors and plays an important role in neuronal function. Here, we used the yeast two-hybrid system to identify the neuronal protein (s) that interacts with the tail region of KIF1A and found a specific interaction with synaptotagmin XI. The amino acid residues between 830 and 1300 of KIF1A are required for the interaction with synaptotagmin XI. KIF1A also bound to the tail region of synaptotagmin IV but not to other synaptotagmin in the yeast two-hybrid assay. KIF1A interacted with GST-synaptotagim XI fusion proteins, but not with GST alone. An antibody to synaptotagmin XI specifically co-mmunoprecipitated KIF1A associated with synaptotagimin from mouse brain extracts. These results suggest that KIF1A motor protein transports of synaptotagmin XI-containing synaptic vesicle precursors along microtubule.
Animals ; Brain ; Kinesin* ; Mice ; Microtubules ; Neurons ; Organelles ; Protein Transport ; Synaptic Vesicles ; Synaptotagmins* ; Two-Hybrid System Techniques

Despite therapeutic advance, the prevalence of ischemic heart disease continues to increase. Recently, cell transplantation of stem cell has been proposed as a strategy for cardiac repair following myocardial damage. However, low differentiation efficiency into cardiomyocyte and poor cell viability associated with transplantation have limited the reparative capacity of these cell. In this study, we engineered P19 embryonal carcinoma cells using plasmid vector to overexpress the transcription factor MEF2c, Nkx2.5 involved in cardiomyogenesis. We investigated 1) formation of intercellular junction of P19 in mono-culture and co-culture with cardiomyocyte for functional and structural synchronous contraction after transplantation, 2) differentiation into cardiomyocyte, 3) resistance to hypoxic condition. An P19 embryonal carcinoma cell line expressing GFP, MEF2c, Nkx2.5 was generated by gene transfection and clonal selection. Nkx2.5 overexpression induced connexin43 expression level decrease. Electron microscopy revealed myofibril organization and immunostaining with cTnT showed positive staining in P19-Nkx2.5, consistent with early stage cardiomyocyte. Connexin43 and N-cadherin was expressed between P19-MEF2c and cardiomyocyte, P19- Nkx2.5 and cardiomyocyte in co-culture. And beating rate of cardiomyocyte co-cultured with P19-Nkx2.5 increased much more than other group, even if P19-Nkx2.5 did not have synchronous contraction with cardiomyocyte. Additionally, P19-Nkx2.5 had a resistance against hypoxia. These result suggest that overexpression of Nkx2.5 induced differentiation of P19 into cardiomyocyte and would be electro-mechanical coupling with cardiomyocyte after transplantation. Futhermore, Nkx2.5 overexpression had protection potential to hypoxic injury. Therefore, P19 cell overexpressed Nkx2.5 would be promising cell source for further study of new therapy of myocardial disease and building up in vitro model.
Anoxia ; Cadherins ; Cardiomyopathies ; Cardiomyoplasty* ; Cell Survival ; Cell Transplantation ; Coculture Techniques ; Connexin 43 ; Embryonal Carcinoma Stem Cells ; Intercellular Junctions ; Microscopy, Electron ; Myocardial Ischemia ; Myocytes, Cardiac ; Myofibrils ; Plasmids ; Prevalence ; Stem Cells ; Transcription Factors* ; Transfection ; Transplants

Recently, new treatments for human heart disease such as ischemia, infarction, cardiomyopathy, coronary heart disease have been developed. transplantation various kinds of cells from skeletal muscle, endothelium, mesenchyme, hemopoietic tissue to injured area after infarction were challenged. It's so called 'Cell Transplantation'. This therapeutic strategy already adopted and got a good result in clinical trial. But several limitations are still remained, including ethics, donor cell numbers, side effects, therapeutic efficiency. In this research, we investigated the formation of intercellular junction and synchronous contraction between cardiomyocyte and H9c2 cell line in co-culture to establish experimental model in vitro for cell transplantation. For this purpose, two kinds of cells, primary cultured cardiomyocyte and H9c2 (cardiomyoblast cell line) were used. Cultured cardiomyocytes had repetitive contraction-relaxation pattern along longitudinal axis both in single and coculture. But their contractions were slower, less regular, less strong in co-culture than in cardiomyocyte culture only. H9c2 cells did not contracted actively themselves, but moved toward cardiomyocyte passively coincided with contraction. In contact region between two kinds of cells, there was no signal after immunocytochemical staining labeled with connexin43 (gap junction), desmoplakin (desmosome), N-cadherin (adherent junction) even though they had membrane contact. Moreover, F-actin and striation were less developed. These results suggested that co-culture system interfere with remodelling of contractile apparatus, intercellular junction formation as well as contraction-relaxation. Furthermore cardiomyocyte could not induce H9c2 cells differentiation into cardiomyocyte. Therefore, much more research would be essential for clinical application of cell transplantation and this study would be the basic source for further study of new therapy of myocardial disease and building up in vitro model.
Actins ; Axis, Cervical Vertebra ; Cadherins ; Cardiomyopathies ; Cell Count ; Cell Line* ; Cell Transplantation ; Coculture Techniques* ; Connexin 43 ; Coronary Disease ; Desmoplakins ; Endothelium ; Ethics ; Heart Diseases ; Humans ; Infarction ; Intercellular Junctions* ; Ischemia ; Membranes ; Mesoderm ; Models, Theoretical ; Muscle, Skeletal ; Myocytes, Cardiac* ; Tissue Donors ; Transplants

A 25-yr-old woman presented with a right pleural effusion. Destruction of 9th through 12th ribs, adjacent vertebral bodies, and transverse processes was noted on plain radiograph and a large low-attenuated, irregular shaped mass lesion with peripheral rim enhancement, destroying vertebral body and transverse process, was revealed on the computed tomographic scan. Magnetic resonance imaging showed high signal on T1- weighted image and iso- and low signal on T2-weighted image for the mass lesion replacing the vertebral bony cortex and marrow space. An open rib biopsy revealed the histopathological changes of Gorham's disease (essential osteolysis), even though only bloody fluid filling the empty space and rib and vertebral transverse process destruction were grossly observed on operation. Even though there was no definite response to radiotherapy and pleurodesis, the patient showed stable condition up to 20 months after diagnosis.
Adult ; Chylothorax/complications/*pathology/radiotherapy ; Female ; Humans ; Magnetic Resonance Imaging/methods ; Osteolysis, Essential/complications/*pathology/*radiotherapy ; Pleurodesis ; Time Factors ; Tomography, X-Ray Computed ; Treatment Outcome