Cytotoxic effects of aporphine alkaloids from the stems and leaves of Stephania dielsiana Y.C.Wu.

Phytochemical studies of the stems and leaves of Stephania dielsiana Y.C.Wu yielded two new aporphine alkaloids (1 and 5), along with six known alkaloids (2-4 and 6-8). Their structures were characterised based on analyses of spectroscopic data, including one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy and high-resolution electrospray ionisation mass spectrometry (HR-ESI-MS). The cytotoxic activities of the isolated compounds against a small panel of tumour cell lines were assessed by MTS assay. Interestingly, compound 2 exhibited particularly strong cytotoxic activities against HepG2, MCF7 and OVCAR8 cancer cell lines, with IC50 values of 3.20 ± 0.18, 3.10 ± 0.06 and 3.40 ± 0.007 µM, respectively. Furthermore, molecular docking simulations were carried out to explore the interactions and binding mechanisms of the most active compound (compound 2) with proteins. Our results contribute to understanding the secondary metabolites produced by S. dielsiana and provide a scientific rationale for further investigations of cytotoxicity of this valuable medicinal plant.

Enzyme Kinetics and Molecular Docking Investigation of Acetylcholinesterase and Butyrylcholinesterase Inhibitors from the Marine Alga Ecklonia cava

Ecklonia cava Kjellman (Laminareaceae) grows along the coast of Jeju Island, Korea, and is wellknown in Korea for its use as a food ingredient, animal feed, and medicine. This seaweed contains phlorotannins, polymerized units of phloroglucinol, a term derived from phloroglucinol, the building block of these complex molecules, which is also the common name for these compounds. Phlorotannins are secondary metabolites that hold significance for human health due to their various beneficial properties, including antioxidant, anti-cancer, anti-allergy, and anti-HIV activities. In this study, 10 phlorotannins (1–10) were isolated from an 80% EtOH extract of E. cava. The structures of these compounds were determined through spectroscopic analysis and comparison with the literature. The inhibitory effects of compounds 1–10 on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were investigated. In an AChE inhibition assay, compounds 1, 2, 4, and 6–10 had IC50 values ranging from 0.9 ± 0.8 to 66.5 ± 0.4 µM; compounds 4, 6, and 9 had potent BuChE inhibitory effects, with IC50 values ranging from 1.4 ± 3.8 to 25.2 ± 0.1 µM. Furthermore, enzyme kinetics and molecular docking simulations were conducted to gain insights into the inhibition mode, binding mechanism, and crucial interactions between these active compounds and the target enzyme. This indicates that E. cava is a potentially valuable natural source of AChE and BuChE inhibitors.

Role of non‑pulmonary vein triggers in persistent atrial fibrillation

Pulmonary vein isolation is an well-established treatment strategy for atrial fibrillation (AF), and it is especially effective for patients with paroxysmal AF. However, the success rate is limited for patients with persistent AF, because non-pul‑ monary vein triggers which increase AF recurrence are frequently found in these patients. The major non-pulmonary vein triggers are from the left atrial posterior wall, left atrial appendage, ligament of Marshall, coronary sinus, superior vena cava, and crista terminalis, but other atrial sites can also generate AF triggers. All these sites have been known to contain atrial myocytes with potential arrhythmogenic electrical activity. The prevalence and clinical characteristics of these non-pulmonary vein triggers are well studied; however, the clinical outcome of catheter ablation for persistent AF is still unclear. Here, we reviewed the current ablation strategies for persistent AF and the clinical implications of major non-pulmonary vein triggers.

Endovenous radiofrequency ablation using a new bipolar electrode in a canine model: a new endovenous radiofrequency electrode

Purpose@#This study aimed to determine the effectiveness and safety of a newly developed endovenous radiofrequency (RF) catheter compared with that of the existing RF catheter in a canine model. @*Methods@#Seven dogs underwent ablation using 1 control catheter (ClosureFAST, CF; Covidien) and 1 experimental catheter (VENISTAR, VS; STARmed Co., Ltd.) in the femoral and cephalic veins. The ablated vein was evaluated macroscopically (2,3,5-triphenyltetrazolium chloride staining, TTC), microscopically (hematoxylin and eosin staining), and ultrasonographically. Vessel injury score was used to evaluate the ablating effect objectively. Veins from 1 dog were evaluated on the day of ablation, while in the remaining 6 dogs, the ablated veins were evaluated 2 weeks later. @*Results@#A total of 23 veins (CF, 11 veins; VS, 12 veins) were ablated in 7 dogs. Non–TTC-stained vein wall areas were identified in all ablated veins. No significant difference was observed in the mean vessel injury score (2.54 ± 1.16 vs. 2.42 ± 1.13, P = 0.656) and the mean vessel wall thickness (0.32 ± 0.03 mm vs. 0.31 ± 0.05 mm, P = 0.212) between CF and VS. There was no blood flow in all veins ablated with VS, whereas there was remaining blood flow in 1 vein ablated with CF. Perivenous complication was not observed. @*Conclusion@#Endovenous RF ablation using a newly developed VS RF catheter seems to provide comparable occlusion rate and degree of vein wall injury without perivenous adverse events compared to the most commonly used RF catheter (CF).

Anti-inflammatory activity and cytotoxicity against ovarian cancer cell lines by amide alkaloids and piperic esters isolated from Piper longum fruits: In vitro assessments and molecular docking simulation.

Three new amide alkaloids, piperlongumamides D-F (14, 19, and 32); a new piperic ester, piperlongumester A (45); and two new natural compounds, methyl (2E,4Z)-5-(1,3-benzodioxol-5-yl)penta-2,4-dienoate (46) and trans-piperolein B ester (47), along with 41 known compounds were isolated from the fruits of Piper longum L. Their structures were identified by analyzing spectroscopic data, including mass spectrometry, 1D, and 2D NMR data. The anti-inflammatory and cytotoxic activities of all isolated compounds (1-47) were evaluated. Compounds 3, 6, and 19 inhibited nitric oxide production with IC50 values of 16.1 ± 0.94, 14.5 ± 0.57, and 27.3 ± 1.11 µM, respectively, whereas compound 1 exhibited strong cytotoxic activity toward three ovarian cancer cell lines A2780, TOV-112D, and SK-OV3, with IC50 values of 6.7 ± 0.77, 5.8 ± 0.29, and 48.3 ± 0.40 µM, respectively. Molecular docking simulations were performed to identify the interaction and binding mechanisms of these active metabolites with proteins related to inflammation and cancer.

The Relationship between Systemic Anti-Psoriatic Treatment and Positive Interferon-Gamma Release Assay Rate in Moderate-Severe Korean Psoriasis Patients / 대한피부과학회지

Background@#The relationship between latent tuberculosis and the use of certain biologics is well known, but the relationship between the test for latent tuberculosis results and psoriasis itself or systemic anti-psoriatic treatment (cyclosporine and methotrexate) has not been elucidated to date. @*Objective@#To assess the influence of psoriasis and systemic anti-psoriatic treatment on results of the interferon-gamma release assay. @*Methods@#A retrospective study was conducted on 353 patients who were screened for latent tuberculosis before the use of medicines for moderate to severe psoriasis. The screening was based on results of the interferon-gamma release assay. The control group included 2,025 health care workers who were screened for latent tuberculosis during a general medical examination. @*Results@#Interferon-gamma release assay was positive in 35.4% of the patients and 11.6% of the subjects from the control group. There was a statistically significant correlation between psoriasis and assay positivity (p＜0.05). Among the patients, no statistically-relevant association regarding previous use of cyclosporine or methotrexate was found (cyclosporine: p=0.284, methotrexate: p=0.231). Furthermore, patients were divided into two groups according to treatment duration, i.e., shorter or longer than 6 months. There were no relevant differences in treatment duration cyclosporine: p=0.243, methotrexate: p=0.743). @*Conclusion@#This study revealed a higher prevalence of interferon-gamma release assay positivity in patients with psoriasis. However, conventional anti-psoriatic drugs, such as cyclosporine and methotrexate, showed no significant difference regarding the assay positivity.

A Novel Mutation in the MBTPS2 Gene Resulting in Ichthyosis Follicularis, Atrichia, and Photophobia Syndrome

Ichthyosis follicularis, atrichia, and photophobia (IFAP) syndrome is a rare genetic disorder caused by mutations in the MBTPS2 gene. It is characterized by ichthyosis and alopecia from birth. Photophobia may be present in infancy or early childhood. Its mode of inheritance is X-linked recessive; thus, it mostly affects male. The disease severity varies, ranging from mild cases limited to the skin to the severe variant involving multiple extracutaneous features. A 7-year-old boy presented with scanty hair on scalp and eyebrows at birth. On physical examination, scaly patches were observed on the whole body and spiky follicular hyperkeratotic papules were observed on the face and trunk. He also suffered from severe photophobia. Histopathological examination of the scalp showed miniaturized hair follicles without perifollicular fibrosis. Genetic analysis revealed a novel mutation in the MBTPS2 gene which was a homozygous missense mutation of c.245T>C leading to an amino-acid substitution from phenylalanine to serine (p.Phe82Ser). We diagnosed this patient with IFAP syndrome. To date, 25 pathogenic MBTPS2 gene mutations have been identified. To our knowledge, c.245T>C is a novel homozygous missense mutation in the MBTPS2 gene, which has not been reported in Human Gene Mutation Database, ClinVar Database, and Leiden Open Variation Database. Previous reports suggested genotype-phenotype correlations in the MBTPS2 gene mutations. Supported by a previous notion that genotype correlates with phenotype, this novel mutation can be a predictive factor for the mild form of IFAP syndrome, restricted to the classic symptom triad.

Sequential treatment from mandibulectomy to reconstruction on mandibular oral cancer – Case review II: mandibular anterior and the floor of the mouth lesion of basaloid squamous cell carcinoma and clear cell odontogenic carcinoma

Preoperative patient analysis for oral cancer involves multiple considerations that are based on multiple factors; these include TNM stages, histopathologic findings, and adjacent anatomical structures. Once the decision is made to excise the lesion, the margin of dissection and its extent should be considered along with the best form of reconstruction and airway management. Treatment methods include surgical resection, radiotherapy, and chemotherapy. Although the combined method of treatment is controversial, surgical resection is considered predominantly, and immediate reconstruction after surgical resection follows. The choice of treatment is dictated by the anticipated functional and esthetic results of treatment and also by the availability of a surgeon with the required expertise. Segmental mandibulectomy with primary reconstruction has been shown to have advantages in both functional and esthetic results. A 52-year-old male patient with basaloid squamous cell carcinoma of the floor of the mouth, and the anterior portion of the mandible was treated with surgical procedures that included segmental mandibulectomy with both supraomohyoid neck dissection (SOHND) at Levels I–III and mandible reconstruction with a left fibula free flap. A 55-year-old male patient with clear cell odontogenic carcinoma of the oral cavity underwent segmental mandibulectomy with both SOHND at Levels I–III and mandible reconstruction with a left fibula free flap. The purpose of this study was to review the anatomic and functional results of patients after immediate reconstruction with a fibula free flap following resection of carcinoma in the anterior portion of the mandible and floor of the mouth.

Increased Melanoma-Associated Antigen C2 Expression Affords Resistance to Apoptotic Deathin Suspension-Cultured Tumor Cells / 한국유방암학회지

Purpose@#Melanoma-associated antigen C2 (MAGEC2) is an oncogene associated with various types of cancers. However, the biological function of MAGEC2 in circulating tumor cells remains unclear. In this study, we investigated the role of MAGEC2 using adapted suspension cells (ASCs), which were previously developed to study circulating tumor cells (CTCs). @*Methods@#Differential gene expression in adherent cells (ADs) and ASCs was examined using RNA-seq analysis. MAGEC2 expression was assessed using reverse transcription quantitative polymerase chain reaction (RT-qPCR), immunoblotting, and ChIP-seq analysis. Depletion of MAGEC2 expression was performed using siRNA. MAGEC2-depleted ADs and ASCs were used to investigate changes in the proliferation rate and cell cycle. Then, the protein levels of signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3, and downstream of STAT3 were measured using control and MAGEC2-depleted ADs and ASCs. In ASCs, the direct effect of active STAT3 inhibition with Stattic, a STAT3 inhibitor, was assessed in terms of proliferation and apoptosis. Finally, an Annexin V/7-AAD assay was performed to determine the percentage of apoptotic cells in the Stattic-treated cells. @*Results@#MAGEC2 was highly expressed in ASCs when compared with ADs. Depletion of MAGEC2 reduced the proliferation rate and viability of ASCs. To elucidate the underlying mechanism, the level of STAT3 was examined owing to its oncogenic properties. Tyrosinephosphorylated active STAT3 was highly expressed in ASCs and decreased in MAGEC2-depleted ASCs. Furthermore, on treating ASCs with Stattic, an active STAT3 inhibitor, the cells were markedly sensitive to intrinsic pathway-mediated apoptosis. @*Conclusions@#High MAGEC2 expression may play an important role in the survival of ASCs by maintaining the expression of activated STAT3 to prevent apoptotic cell death.

A cell function study on calcium regulation of a novel calcium-sensing receptor mutation (p.Tyr825Phe)

Purpose@#Autosomal dominant hypocalcemia with hypercalciuria is a genetic disease characterized by hypoparathyroidism with hypercalciuria. We discovered a novel variant (p.Tyr825Phe[Y825F]) of the CASR gene in a neonate with congenital hypoparathyroidism and hypercalciuria and conducted a cell function study to determine whether the CASR-Y825F variant was pathogenic. @*Methods@#To perform a functional study on CaSR-Y825F, we constructed expression vectors expressing wild-type (WT) CASR and CASR-Y825F. After transfection of each expression vector into HEK293 cells, we examined alterations in intracellular signaling. Mitogen-activated protein kinase (MAPK) signaling activity of HEK293 cells expressing CASR-WT or CASR-Y825F was determined. Changes in intracellular calcium ions ([Ca2+]i) by extracellular calcium ion ([Ca2+]e) stimulation were quantitatively compared and analyzed. @*Results@#Cells expressing CASR-Y825F showed elevated of MAPK signaling (phospho-ERK [pERK], phospho-JNK [pJNK], phospho-p38 [pp38]) and increased [Ca2+]i levels at low [Ca2+]e stimulation compared with cells expressing CASR-WT. Additionally, [Ca2+]i levels in HEK293 cells expression CASR-WT and CASR-Y825F were determined at 340 nm/380 nm wavelength ratios using Fura-2 AM. At [Ca2+]e concentrations of 2.5 mM and 3 mM, the ratios of CASR-Y825F cells were higher (2.6 and 3.5, respectively) than those of CASR-WT cells (1.04 and 1.40, respectively). @*Conclusion@#This cell function study proved that the CASR-Y825F expressed in HEK293 cells elevated MAPK signaling (pERK, pJNK, pp38) and increased [Ca2+]i to induce hypocalcemia.

Effectiveness of Cytochrome c Oxidase Subunit 1 Gene Nested Polymerase Chain Reaction Compared to Dermoscopy or Microscopy Alone for the Detection and Diagnosis of Sarcoptes scabiei var. hominis Infection

Background@#While microscopy (MS) evaluation of skin scrapings has a 100% positive predictive value and specificity by definition for scabies diagnosis, it has low sensitivity. Dermoscopy (DS) has not yet been widely accepted for diagnosis, and long-term clinician training is required. @*Objective@#To evaluate the diagnostic validity of cytochrome c oxidase subunit 1 (cox1) gene nested polymerase chain reaction (PCR) as an adjunctive method for diagnosing scabies. @*Methods@#This was a prospective, single institution study, conducted on a total of 302 skin lesions from 50 patients suspected of scabies at Kangdong Sacred Heart Hospital in Seoul, Korea. DS, MS, and cox1 nested PCR were performed on all patients. @*Results@#Of the 302 lesions, 145 (48.0%) were obtained at first visit and 157 (52.0%) were identified in the course of follow-up visits after treatment. For all lesions, DS and MS sensitivity levels were 55.9% (73/136) and 55.2% (75/136), respectively, with cox1 gene nested PCR considered as 100%. The results of DS and MS identification showed no difference between each other and showed significant difference from that of cox1 gene nested PCR. @*Conclusion@#Nested PCR detecting cox1 may be prospectively used to comprehensively diagnose lesions of scabies in clinical practice.

The Effects of an Integrated Management Program on Physical Function, Cognitive Function, and Depression in Patients with Subacute stroke / 중환자간호학회지

Purpose@#: This study examined the effects of an integrated management program on physical function, cognitive function, and depression in patients with subacute stroke. @*Methods@#: A nonequivalent control group design was adopted. The participants were assigned to either the experimental group (n=20) or control group (n=23). The experimental group received an 8-week integrated management program and standard rehabilitation service (i.e., physical therapy and occupational therapy), while the control group received the standard rehabilitation service only. Physical function was measured as gait speed and balance ability using the Berg Balance Scale (BBS). Cognitive function was measured with neuro-behavioral cognitive status examination (NCSE), and depression was measured using the Beck Depression Inventory-II (BDI-II). Repeated measure ANOVA was used to determine changes in physical function, cognitive function, and depression over 8-weeks. @*Results@#: The interaction between group and time was significant, indicating that the experimental group showed improvement in gait speed, balance ability, cognitive function (linguistic ability, linguistic memory, reasoning), and a decrease in depression compared to the control group. @*Conclusion@#: These results indicate that the integrated management program developed herein was beneficial in restoring physical function, cognitive function, and depression in subacute stroke patients.

Cryosurgery as a Minimally Invasive Alternative Treatment for a Patient with Erosive Adenomatosis of the Nipple

Erosive adenomatosis of the nipple (EAN), also known as nipple adenoma, florid papillomatosis, or papillary adenoma of the nipple, is a benign neoplasm originating from a lactiferous duct of the breast. Although the potential for malignant change is invariably negligible, the nature of the disease is quite intractable despite several treatment methods. Surgical excision is known as the treatment of choice, but this invasive approach is generally not acceptable to the vast majority of patients due to the cosmetic outcomes. Cryosurgery could be an alternative choice to preserve the structure of the nipple-areola complex, though its application has not been studied due to the paucity of cases. A 22-year-old female presented with a unilateral, crater-like erosion of the left nipple with serosanguineous discharge. The skin biopsy revealed proliferation of tubular structures, which corresponded to EAN. She was treated with 4 sessions of cryosurgery (open cryospray with liquid nitrogen) over 6 months, and the skin lesion resolved completely without any recurrence for 12 months. Although further study is required to determine the optimal treatment regimen for EAN, cryosur-gery should be considered as an effective option to surgical excision.

Increased Melanoma-Associated Antigen C2 Expression Affords Resistance to Apoptotic Deathin Suspension-Cultured Tumor Cells / 한국유방암학회지

Purpose@#Melanoma-associated antigen C2 (MAGEC2) is an oncogene associated with various types of cancers. However, the biological function of MAGEC2 in circulating tumor cells remains unclear. In this study, we investigated the role of MAGEC2 using adapted suspension cells (ASCs), which were previously developed to study circulating tumor cells (CTCs). @*Methods@#Differential gene expression in adherent cells (ADs) and ASCs was examined using RNA-seq analysis. MAGEC2 expression was assessed using reverse transcription quantitative polymerase chain reaction (RT-qPCR), immunoblotting, and ChIP-seq analysis. Depletion of MAGEC2 expression was performed using siRNA. MAGEC2-depleted ADs and ASCs were used to investigate changes in the proliferation rate and cell cycle. Then, the protein levels of signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3, and downstream of STAT3 were measured using control and MAGEC2-depleted ADs and ASCs. In ASCs, the direct effect of active STAT3 inhibition with Stattic, a STAT3 inhibitor, was assessed in terms of proliferation and apoptosis. Finally, an Annexin V/7-AAD assay was performed to determine the percentage of apoptotic cells in the Stattic-treated cells. @*Results@#MAGEC2 was highly expressed in ASCs when compared with ADs. Depletion of MAGEC2 reduced the proliferation rate and viability of ASCs. To elucidate the underlying mechanism, the level of STAT3 was examined owing to its oncogenic properties. Tyrosinephosphorylated active STAT3 was highly expressed in ASCs and decreased in MAGEC2-depleted ASCs. Furthermore, on treating ASCs with Stattic, an active STAT3 inhibitor, the cells were markedly sensitive to intrinsic pathway-mediated apoptosis. @*Conclusions@#High MAGEC2 expression may play an important role in the survival of ASCs by maintaining the expression of activated STAT3 to prevent apoptotic cell death.

A cell function study on calcium regulation of a novel calcium-sensing receptor mutation (p.Tyr825Phe)

Purpose@#Autosomal dominant hypocalcemia with hypercalciuria is a genetic disease characterized by hypoparathyroidism with hypercalciuria. We discovered a novel variant (p.Tyr825Phe[Y825F]) of the CASR gene in a neonate with congenital hypoparathyroidism and hypercalciuria and conducted a cell function study to determine whether the CASR-Y825F variant was pathogenic. @*Methods@#To perform a functional study on CaSR-Y825F, we constructed expression vectors expressing wild-type (WT) CASR and CASR-Y825F. After transfection of each expression vector into HEK293 cells, we examined alterations in intracellular signaling. Mitogen-activated protein kinase (MAPK) signaling activity of HEK293 cells expressing CASR-WT or CASR-Y825F was determined. Changes in intracellular calcium ions ([Ca2+]i) by extracellular calcium ion ([Ca2+]e) stimulation were quantitatively compared and analyzed. @*Results@#Cells expressing CASR-Y825F showed elevated of MAPK signaling (phospho-ERK [pERK], phospho-JNK [pJNK], phospho-p38 [pp38]) and increased [Ca2+]i levels at low [Ca2+]e stimulation compared with cells expressing CASR-WT. Additionally, [Ca2+]i levels in HEK293 cells expression CASR-WT and CASR-Y825F were determined at 340 nm/380 nm wavelength ratios using Fura-2 AM. At [Ca2+]e concentrations of 2.5 mM and 3 mM, the ratios of CASR-Y825F cells were higher (2.6 and 3.5, respectively) than those of CASR-WT cells (1.04 and 1.40, respectively). @*Conclusion@#This cell function study proved that the CASR-Y825F expressed in HEK293 cells elevated MAPK signaling (pERK, pJNK, pp38) and increased [Ca2+]i to induce hypocalcemia.

Effectiveness of Cytochrome c Oxidase Subunit 1 Gene Nested Polymerase Chain Reaction Compared to Dermoscopy or Microscopy Alone for the Detection and Diagnosis of Sarcoptes scabiei var. hominis Infection

Background@#While microscopy (MS) evaluation of skin scrapings has a 100% positive predictive value and specificity by definition for scabies diagnosis, it has low sensitivity. Dermoscopy (DS) has not yet been widely accepted for diagnosis, and long-term clinician training is required. @*Objective@#To evaluate the diagnostic validity of cytochrome c oxidase subunit 1 (cox1) gene nested polymerase chain reaction (PCR) as an adjunctive method for diagnosing scabies. @*Methods@#This was a prospective, single institution study, conducted on a total of 302 skin lesions from 50 patients suspected of scabies at Kangdong Sacred Heart Hospital in Seoul, Korea. DS, MS, and cox1 nested PCR were performed on all patients. @*Results@#Of the 302 lesions, 145 (48.0%) were obtained at first visit and 157 (52.0%) were identified in the course of follow-up visits after treatment. For all lesions, DS and MS sensitivity levels were 55.9% (73/136) and 55.2% (75/136), respectively, with cox1 gene nested PCR considered as 100%. The results of DS and MS identification showed no difference between each other and showed significant difference from that of cox1 gene nested PCR. @*Conclusion@#Nested PCR detecting cox1 may be prospectively used to comprehensively diagnose lesions of scabies in clinical practice.

Sequential treatment from mandibulectomy to reconstruction on mandibular oral cancer – Case review II: mandibular anterior and the floor of the mouth lesion of basaloid squamous cell carcinoma and clear cell odontogenic carcinoma

Preoperative patient analysis for oral cancer involves multiple considerations that are based on multiple factors; these include TNM stages, histopathologic findings, and adjacent anatomical structures. Once the decision is made to excise the lesion, the margin of dissection and its extent should be considered along with the best form of reconstruction and airway management. Treatment methods include surgical resection, radiotherapy, and chemotherapy. Although the combined method of treatment is controversial, surgical resection is considered predominantly, and immediate reconstruction after surgical resection follows. The choice of treatment is dictated by the anticipated functional and esthetic results of treatment and also by the availability of a surgeon with the required expertise. Segmental mandibulectomy with primary reconstruction has been shown to have advantages in both functional and esthetic results. A 52-year-old male patient with basaloid squamous cell carcinoma of the floor of the mouth, and the anterior portion of the mandible was treated with surgical procedures that included segmental mandibulectomy with both supraomohyoid neck dissection (SOHND) at Levels I–III and mandible reconstruction with a left fibula free flap. A 55-year-old male patient with clear cell odontogenic carcinoma of the oral cavity underwent segmental mandibulectomy with both SOHND at Levels I–III and mandible reconstruction with a left fibula free flap. The purpose of this study was to review the anatomic and functional results of patients after immediate reconstruction with a fibula free flap following resection of carcinoma in the anterior portion of the mandible and floor of the mouth.

Wake-sleep cycles are severely disrupted by diseases affecting cytoplasmic homeostasis.

The circadian clock is based on a transcriptional feedback loop with an essential time delay before feedback inhibition. Previous work has shown that PERIOD (PER) proteins generate circadian time cues through rhythmic nuclear accumulation of the inhibitor complex and subsequent interaction with the activator complex in the feedback loop. Although this temporal manifestation of the feedback inhibition is the direct consequence of PER's cytoplasmic trafficking before nuclear entry, how this spatial regulation of the pacemaker affects circadian timing has been largely unexplored. Here we show that circadian rhythms, including wake-sleep cycles, are lengthened and severely unstable if the cytoplasmic trafficking of PER is disrupted by any disease condition that leads to increased congestion in the cytoplasm. Furthermore, we found that the time delay and robustness in the circadian clock are seamlessly generated by delayed and collective phosphorylation of PER molecules, followed by synchronous nuclear entry. These results provide clear mechanistic insight into why circadian and sleep disorders arise in such clinical conditions as metabolic and neurodegenerative diseases and aging, in which the cytoplasm is congested.

Bioequivalence of the pharmacokinetics between tofacitinib aspartate and tofacitinib citrate in healthy subjects

Tofacitinib is an oral disease-modifying anti-rheumatic drug to selectively inhibit Janus kinases. Tofacitinib is a representative small molecule inhibitor that is used to treat many diseases including rheumatoid arthritis and various autoimmune conditions.Unlike biological agents, tofacitinib has several advantages, including the ability to be administered orally and a short half-life. This study aimed to evaluate the bioequivalence of the pharmacokinetics (PK) between tofacitinib aspartate 7.13 mg (test formulation) and tofacitinib citrate 8.08 mg (reference formulation; Xeljanz ® ) in healthy subjects. A randomized, open-label, single-dose, 2-sequence, 2-period, 2-treatment crossover trial was conducted in 41 healthy volunteers. A total of 5 mg of tofacitinib as the test or the reference formulation was administered, and serial blood samples were collected up to 14 hours after dosing for PK analyses. The plasma concentration of tofacitinib was determined by ultraperformance liquid chromatography-tandem mass spectrometry. A non-compartmental analysis was used to estimate the PK parameters. A total of 35 subjects completed the study and the study drug was well-tolerated. The mean maximum concentration (Cmax ) and area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast ) for the test formulation were 52.67 ng/mL and 133.86 ng·h/mL, respectively, and 50.61 ng/mL and 133.49 h·ng/mL for the reference formulation, respectively. The geometric mean ratios (90% confidence intervals) of the Cmax and AUClast between the 2 formulations were 1.041 (0.944–1.148) and 1.003 (0.968–1.039), respectively. Tofacitinib aspartate exhibited bioequivalent PK profiles to those of the reference formulation.Trial Registration: ClinicalTrials.gov Identifier: NCT04278391

Does Early Retrograde Intrarenal Surgery Improve the Cost-Effectiveness of Renal Stone Management?

Purpose@#This study aimed to evaluate the cost-effectiveness of treatment with retrograde intrarenal surgery (RIRS) versus repeated shock wave lithotripsy (SWL) in patients with renal calculi. @*Materials and Methods@#The non-retreatment rates (NRRs) and their respective real-world costs for RIRS and SWL were derived through retrospective analysis of health insurance claims data from 2015 to 2017. Decision tree modeling was performed to demonstrate the cost-effectiveness of RIRS. Furthermore, sensitivity analysis was performed to examine the robustness of the results. @*Results@#Analysis of the obtained data showed that NRRs of single SWL ranged from 46% to 56%, whereas NRRs of single RIRS ranged from 75% to 93%. Introducing RIRS early in the treatment sequence was observed to be favorable for the reduction of overall failure (overall NRR, 0.997) compared to the results of repeated SWL (overall NRR, 0.928). The implementation of decision tree modeling revealed that the cost per retreatment-avoided increased with the introduction of RIRS at an earlier time (first line, second line, third line, fourth line: 18640 USD, 10376 USD, 4294 USD, 3377 USD, respectively). Probabilistic modeling also indicated that the introduction of RIRS as the first line of treatment was least likely to be cost-effective, when compared to other options of introducing RIRS as the second, third, or fourth line of treatment. @*Conclusion@#Performing RIRS as early as possible