Advantage of a higher position of the tracheostoma with glottic closure for preventing complications related to tracheostomy tube: a retrospective cohort study.

BACKGROUND: Surgery to prevent aspiration has complications related to tracheostomy tube, such as the trachea-brachiocephalic artery fistula. Glottic closure procedure makes tracheostoma at a position higher than the first ring of the trachea and theoretically has a potential to prevent such complications owing to a longer distance between the tip of tracheostomy tube and the tracheal membrane adjacent to the brachiocephalic artery. Our aim is to evaluate the safety of glottic closure in neurologically impaired patients by comparing outcomes with laryngotracheal separation. METHODS: This study is a single-center retrospective study from 2004 to 2019, using data of 15 and 12 patients who underwent glottic closure (GC) and laryngotracheal separation (LTS). The primary outcome was the incidence of postoperative complications induced by tracheostomy tube placement and adjustment of the tracheostomy tube position to prevent these complications, such as by converting to a length-adjustable tube and/or placing gauze between the skin and tube flange. Additionally, we analyzed the anatomical relationship between the tracheostomy tube tip and brachiocephalic artery and measured the distance between them using postoperative CT images. RESULTS: No patients in either group had trachea-brachiocephalic artery fistula. Erosion or granuloma formation occurred in 1 patient (7%) and 4 patients (33%) in the GC and LTS groups, respectively. Adjustment of the tracheostomy tube was needed in 2 patients (13%) and 6 patients (50%) in the GC and LTS groups. CT revealed a higher proportion of patients with the tracheostomy tube tip superior to the brachiocephalic artery in GC than LTS group. The mean tracheostoma-brachiocephalic artery distance was 40.8 and 32.4 mm in the GC and LTS groups. CONCLUSIONS: Glottic closure reduces the risk of postoperative complications related to a tracheostomy tube. This may be due to the higher position of the tracheostoma at the level of the cricoid cartilage, increasing the distance between the tracheostoma and brachiocephalic artery.

Maximization of calcium and phosphate in neonatal total parenteral nutrition.

BACKGROUND: Appropriate calcium and phosphate supplementation is essential for bone growth in preterm infants. Using Rehabix-K2™ (AY Pharmaceuticals, Tokyo, Japan) and Pleamin-P Injection™ (Fuso Pharmaceutical Industries, Osaka, Japan) as the total parenteral nutrition (TPN) and amino acid solution, respectively, we investigated ways of maximizing calcium and phosphate in the TPN solution. METHODS: Rehabix-K2, Pleamin-P, calcium gluconate, sodium phosphate, 50% glucose, and water were mixed in varying proportions to create 16 formulations. Precipitation assessment was done three times for each of the 16 formulations, and was based on the Japanese Pharmacopeia. RESULT: Precipitation was observed 24 h after mixing when the calcium and phosphate were 60 mEq/L and 30 mmol/L or 80 mEq/L and 40 mmol/L, respectively. No precipitation was observed when the calcium and phosphate were 20 mEq/L and 10 mmol/L, respectively. Precipitation was observed once out of three times, when the calcium and phosphate were 40 mEq/L and 20 mmol/L, respectively, and the amino acids were 2% and 3% (mean pH, 6.13 and 6.26, respectively). No precipitation was observed, however, when the calcium and phosphate were 40 mEq/L and 20 mmol/L, respectively, and the amino acids were 0% and 1% (mean pH, 5.88 and 6.05, respectively). CONCLUSION: Not only the concentration of calcium and phosphate, but also the pH of the TPN solution, are crucial factors for precipitation. Based on these results, a well-balanced TPN solution maximizing calcium and phosphate availability will be able to be formulated.

ENT1, a ribavirin transporter, plays a pivotal role in antiviral efficacy of ribavirin in a hepatitis C virus replication cell system.

We previously showed that equilibrative nucleoside transporter 1 (ENT1) is a primary ribavirin transporter in human hepatocytes. However, because the role of this transporter in the antiviral mechanism of the drug remains unclear, the present study aimed to elucidate the role of ENT1 in ribavirin antiviral action. OR6 cells, a hepatitis C virus (HCV) replication system, were used to evaluate both ribavirin uptake and efficacy. The ribavirin transporter in OR6 cells was identified by mRNA expression analyses and transport assays. Nitrobenzylmercaptopurine riboside (NBMPR) and micro-RNA targeted to ENT1 mRNA (miR-ENT1) were used to reduce the ribavirin uptake level in OR6 cells. Our results showed that ribavirin antiviral activity was associated with its accumulation in OR6 cells, which was also closely associated with the uptake of the drug. It was found that the primary ribavirin transporter in OR6 cells was ENT1 and that inhibition of ENT1-mediated ribavirin uptake by NBMPR significantly attenuated the antiviral activity of the drug as well as its accumulation in OR6 cells. The results also showed that even a small reduction in the ENT1-mediated ribavirin uptake, achieved in this case using miR-ENT1, caused a significant decrease in its antiviral activity, thus indicating that the ENT1-mediated ribavirin uptake level determined its antiviral activity level in OR6 cells. In conclusion, our results show that by facilitating its uptake and accumulation in OR6 cells, ENT1 plays a pivotal role in the antiviral effectiveness of ribavirin and therefore provides an important insight into the efficacy of the drug in anti-HCV therapy.

Identification of a new organic anion transporting polypeptide 1B3 mRNA isoform primarily expressed in human cancerous tissues and cells.

Organic anion transporting polypeptide 1B3 (OATP1B3) is a hepatocyte plasma membrane protein that transports various endogenous and xenobiotic compounds. Although it is exclusively expressed in the human liver under normal conditions, OATP1B3 can be also expressed in various human cancer tissues that have been associated with prognosis and clinical outcomes. However, despite the potential significance of the latter finding, no experimental evidence addressing the molecular entity of cancer-associated OATP1B3 has been provided to date. In this paper, we report the identification of a new OATP1B3 mRNA isoform expressed in human colon and lung cancer tissues, which we named cancer-type OATP1B3 (Ct-OATP1B3). Our results also make known a previously unidentified transcription start site and an alternative promoter region, localized at intron 2, from which Ct-OATP1B3 mRNA is generated. Isoform specific mRNA quantification showed that the Ct-OATP1B3 mRNA level was strikingly higher than that of Lt-OATP1B3 mRNA in human cancer tissues. In addition, the results showed that the translation occurred at three out of four open reading frames. To summarize, our results clearly demonstrate that the newly-identified Ct-OATP1B3 (but not Lt-OATP1B3) is the primary mRNA isoform, at least in the human cancerous samples we have examined. In line with the possibility that its translation products play important biological roles in cancer cells, we strongly believe that the existence of Ct-OATP1B3 should be taken into account during future studies of OATP1B3 associated with cancer prognosis and clinical outcomes.

Catabolism of pemphigus foliaceus autoantibodies by high-dose IVIg therapy.

High-dose intravenous immunoglobulin (HD-IVIg) has several distinguishing therapeutic characteristics. However, a certain number of pemphigus cases have been experienced, which did not respond to HD-IVIg. This is the first case report that the serum level of anti-desmoglein (Dsg) 1 antibody rebounded, critically associated with IgG serum level. We describe a patient with pemphigus foliaceus (PF), unresponsive to oral prednisolone followed by pulse therapy and double-filtration plasmapheresis, in whom clinical remission was induced by 4 courses of HD-IVIg. Anti-Dsg1 antibody levels, serum IgG and disease activity were monitored. Anti-Dsg1 antibody titers rapidly decreased after IVIg treatment when total IgG levels were high; however, the serum level of anti-Dsg1 antibody rebounded as the total IgG level returned to normal. The levels of anti-Dsg1 antibody were decreased for an average of 13.7 days after treatment. The therapeutic effect of IVIg treatment was associated with an increased serum level of total IgG. IVIg therapy reduced the titers of autoantibody by accelerating the catabolism of immunoglobulin induced by high IgG serum levels. IVIg itself appears to accelerate IgG degradation rather than suppress IgG production. Sufficient suppression of antibody production is critical for successful treatment with IVIg.

Epidermal Nevus Syndrome Associated with Dwarfism and Atopic Dermatitis.

Epidermal nevus syndrome (ENS) is a congenital disorder characterized by widespread linear epidermal lesions consisting of epidermal nevus and extracutaneous involvements, especially of the central nervous system and skeletal system. Garcia-Hafner-Happle syndrome, also known as fibroblast growth factor receptor 3 (FGFR3)-ENS, is characterized by a systematized keratinocytic EN of soft and velvety type with neurological abnormalities such as seizures, intellectual impairment, and cortical atrophy. We present a case of a 9-year-old Japanese boy afflicted with Garcia-Hafner-Happle syndrome associated with dwarfism and atopic dermatitis. We show the results of physical examination, DNA analysis, and imaging studies and discuss the mutation underlying the child's disorder.

Striking species difference in the contribution of concentrative nucleoside transporter 2 to nucleoside uptake between mouse and rat hepatocytes.

Concentrative nucleoside transporter 2 (CNT2) (encoded by the SLC28A2 gene) transports various antiviral or antitumor purine nucleoside analogs to be involved in their pharmacokinetics and pharmacological actions. The results of our study showed that mouse hepatocytes hardly expressed CNT2 mRNA and no CNT2-dependent nucleoside uptake was observed, while rat hepatocytes exhibited high CNT2-dependent nucleoside uptake activity levels with abundant CNT2 mRNA expression. We concluded that CNT2 contributes considerably to nucleoside uptake in rat hepatocytes but not in mouse hepatocytes.

Paclitaxel-coated drug-eluting balloon for pulmonary vein stenosis after repair of total anomalous pulmonary venous return with asplenia.

We used a paclitaxel-coated drug-eluting balloon (DEB) for pulmonary vein stenosis (PVS) after repair of total anomalous pulmonary venous return with asplenia. No adverse effect of paclitaxel was revealed and plasma concentration of paclitaxel was not elevated after intervention. Although progression of PVS slowed after dilatation with the DEB, stenosis recurred relentlessly, resulting in patient demise. This strategy may be safe for infantile cases, but requires further effective strategy, such as usage of larger sizes of DEBs. .

Induced Fetal Human Muscle Stem Cells with High Therapeutic Potential in a Mouse Muscular Dystrophy Model.

Duchenne muscular dystrophy (DMD) is a progressive and fatal muscle-wasting disease caused by DYSTROPHIN deficiency. Cell therapy using muscle stem cells (MuSCs) is a potential cure. Here, we report a differentiation method to generate fetal MuSCs from human induced pluripotent stem cells (iPSCs) by monitoring MYF5 expression. Gene expression profiling indicated that MYF5-positive cells in the late stage of differentiation have fetal MuSC characteristics, while MYF5-positive cells in the early stage of differentiation have early myogenic progenitor characteristics. Moreover, late-stage MYF5-positive cells demonstrated good muscle regeneration potential and produced DYSTROPHIN in vivo after transplantation into DMD model mice, resulting in muscle function recovery. The engrafted cells also generated PAX7-positive MuSC-like cells under the basal lamina of DYSTROPHIN-positive fibers. These findings suggest that MYF5-positive fetal MuSCs induced in the late stage of iPSC differentiation have cell therapy potential for DMD.

Bone marrow cell transfer into fetal circulation can ameliorate genetic skin diseases by providing fibroblasts to the skin and inducing immune tolerance.

Recent studies have shown that skin injury recruits bone marrow-derived fibroblasts (BMDFs) to the site of injury to accelerate tissue repair. However, whether uninjured skin can recruit BMDFs to maintain skin homeostasis remains uncertain. Here, we investigated the appearance of BMDFs in normal mouse skin after embryonic bone marrow cell transplantation (E-BMT) with green fluorescent protein-transgenic bone marrow cells (GFP-BMCs) via the vitelline vein, which traverses the uterine wall and is connected to the fetal circulation. At 12 weeks of age, mice treated with E-BMT were observed to have successful engraftment of GFP-BMCs in hematopoietic tissues accompanied by induction of immune tolerance against GFP. We then investigated BMDFs in the skin of the same mice without prior injury and found that a significant number of BMDFs, which generate matrix proteins both in vitro and in vivo, were recruited and maintained after birth. Next, we performed E-BMT in a dystrophic epidermolysis bullosa mouse model (col7a1(-/-)) lacking type VII collagen in the cutaneous basement membrane zone. E-BMT significantly ameliorated the severity of the dystrophic epidermolysis bullosa phenotype in neonatal mice. Type VII collagen was deposited primarily in the follicular basement membrane zone in the vicinity of the BMDFs. Thus, gene therapy using E-BMT into the fetal circulation may offer a potential treatment option to ameliorate genetic skin diseases that are characterized by fibroblast dysfunction through the introduction of immune-tolerated BMDFs.

Genome-wide microhomologies enable precise template-free editing of biologically relevant deletion mutations.

The functional effect of a gene edit by designer nucleases depends on the DNA repair outcome at the targeted locus. While non-homologous end joining (NHEJ) repair results in various mutations, microhomology-mediated end joining (MMEJ) creates precise deletions based on the alignment of flanking microhomologies (µHs). Recently, the sequence context surrounding nuclease-induced double strand breaks (DSBs) has been shown to predict repair outcomes, for which µH plays an important role. Here, we survey naturally occurring human deletion variants and identify that 11 million or 57% are flanked by µHs, covering 88% of protein-coding genes. These biologically relevant mutations are candidates for precise creation in a template-free manner by MMEJ repair. Using CRISPR-Cas9 in human induced pluripotent stem cells (hiPSCs), we efficiently create pathogenic deletion mutations for demonstrable disease models with both gain- and loss-of-function phenotypes. We anticipate this dataset and gene editing strategy to enable functional genetic studies and drug screening.

Severe pemphigus vulgaris: successful combination therapy of plasmapheresis followed by intravenous high-dose immunoglobulin to prevent rebound increase in pathogenic IgG.

A case of severe pemphigus vulgaris (PV), which did not respond to pulse therapy with intravenous (IV) methylprednisolone (1,000 mg/day for 3 days), but was successfully treated with a combination of double-filtration plasmapheresis (DFPP), immediately followed by high-dose IVIg (20 g/day for 5 days), eventually leading to suppression of the rebound increase in pathogenic PV-IgG for 12 months, is reported. Weekly enzyme-linked immunosorbent assay for desmoglein (Dsg) 1 and Dsg3 demonstrates a distinct difference in the alteration curves of serum levels of pathogenic IgG (anti-Dsg1 and Dsg3 antibodies) after DFPP with and without high-dose IVIg. Our experience suggests that combination therapy of DFPP with high-dose IVIg is effective for pathogenic PV-IgG removal and prevention of feedback rebound increases in pathogenic PV-IgG, leading to a long-term amelioration of clinical blistering in the present case.

Preoperative flurbiprofen for pain prevention after tonsillectomy in adults.

STUDY OBJECTIVE: To investigate the analgesic efficacy of preoperative flurbiprofen on postoperative pain after tonsillectomy. DESIGN: Prospective, randomized, nonblinded, non-placebo-controlled study. SETTING: Municipal hospital. PATIENTS: Twenty-five ASA physical status I patients older than 20 years of age, who were scheduled for tonsillectomy. INTERVENTIONS: Patients were randomly allocated to two groups to receive preoperative intravenous (IV) 50 mg flurbiprofen (group F) or not (group C). Anesthesia was induced with IV propofol two mg/kg and maintained with nitrous oxide and sevoflurane. MEASUREMENTS: Pain scores at rest and at swallowing, intraoperative bleeding, vital signs during the postanesthetic period, interval until diclofenac sodium suppository rescue, and the total dose required for 12 hours postoperatively were all recorded. MAIN RESULTS: Pain scores at rest as well as those recorded after swallowing 30 minutes after tonsillectomy were significantly lower in group F than in group C. During the first postoperative 1.5 hours, significantly fewer patients in group F required rescue diclofenac suppository than did group C patients. However, total dose of required rescue during the postoperative 12 hours in group F did not significantly differ from that of group C. There were no significant differences in intraoperative bleeding or in any vital signs during the postanesthetic period either. CONCLUSION: Preoperative flurbiprofen suppressed immediate postoperative pain after tonsillectomy. The analgesic effect, however, disappeared in a few hours and was insufficient for overnight pain relief.

Laryngeal tuberculosis following laryngeal carcinoma.

Laryngeal tuberculosis is a rare entity and the disease related to laryngeal cancer is extremely rare. We describe a case of laryngeal tuberculosis in a 74-year-old man with a history of radiotherapy for laryngeal carcinoma four months earlier. Laryngoscopy demonstrated a white mass on the right vocal fold at the site carcinoma had previously occupied. Recurrence of the cancer was suspected, but the biopsy result showed histological features of tuberculosis. We discuss the derangement of the host's mucosal barrier by the malignancy as a contributing factor in secondary tuberculous infection. Tubercular bacilli may be reactivated due to the immunosuppression associated with the therapy.

Endoscopic transantral orbital floor repair with antral bone grafts.

OBJECTIVE: To evaluate the endoscopic transantral insertion of antral bone grafts into the orbit for repair of orbital floor defects. DESIGN: A retrospective analysis with a mean follow-up of 5.3 months. PATIENTS: Eleven patients who underwent surgical repair of orbital floor fractures. SETTING: Municipal hospital. MAIN OUTCOME MEASURES: Preoperative and postoperative Hess screen tests and the presence of diplopia, enophthalmos, donor site complications, cosmetic deformity, infection, and graft extrusion. RESULTS: Subjectively, 3 patients with diplopia had complete resolution of their symptoms after surgery, and 8 patients had improvement of their symptoms. Objectively, 11 patients had significant improvement in the postoperative Hess area ratio compared with the preoperative Hess area ratio. In 1 patient with a floor defect measuring 2.5 cm, enophthalmos existed after surgery, but reoperation was not performed in this case because diplopia was improved. There were no donor site complications, cosmetic deformity, infection, or graft extrusion. CONCLUSIONS: The endoscopic transantral insertion of antral bone grafts through the floor defect into the orbit is an effective technique that prevents injury to the lower eyelid, carries minimal donor site morbidity, and provides an optimal support function for the globe. It merits consideration in cases of orbital defects less than 2 cm in diameter.

Brain herniation into the middle ear following temporal bone fracture.

Otorrhea of leaked cerebrospinal fluid and meningitis in a 33-year-old male originated from an encephalic herniation into the middle ear following traumatic temporal bone fracture. CT demonstrated a mixed-type fracture consisting of a longitudinal fracture and a posterior oblique fracture of the left temporal bone. The left tegmen tympani was broken into a bellows-like shape and a bone splinter from it had stuck in the epitympanum at the level of the incus body. Surgery via a middle cranial fossa approach confirmed penetration of the brain tissue between the incus and lateral semicircular canal. The diagnosis and management of this condition are discussed in the context of a literature review.

Strong Neck Accumulation of 131I Is a Predictor of Incomplete Low-Dose Radioiodine Remnant Ablation Using Recombinant Human Thyroid-Stimulating Hormone.

The purpose of this study was to identify the factors that predict incomplete low-dose radioiodine remnant ablation (RRA) with recombinant human thyroid-stimulating hormone (rhTSH) and to report the adverse events associated with this treatment. Between 2012 and 2014, 43 consecutive patients with thyroid cancer received low-dose RRA with rhTSH after total thyroidectomy. We retrospectively investigated the adverse events during low-dose RRA and during diagnostic whole body scan (DxWBS) using rhTSH, and analyzed the rate of RRA completion and the associations between RRA completion and various clinical/pathological factors. Complete RRA was seen in 33 (76.7%) patients, and incomplete RRA was observed in 10 (23.3%). Patients with incomplete RRA had stronger neck accumulation of 131I than those with complete RRA (P < 0.001). Adverse events at RRA and DxWBS were seen in 12 and 9 patients, respectively. All events at RRA were grade 1, with one exception (grade 2 vertigo after rhTSH administration). The rate of adverse events at DxWBS was significantly higher in patients with adverse events seen at RRA (risk ratio, 3.778, P = 0.008). Strong neck accumulation of 131I is significant independent predictor of incomplete low-dose RRA. The risk of adverse events at DxWBS was higher in patients who experienced adverse events at RRA than in those who did not.

A usual frameshift and delayed termination codon mutation in keratin 5 causes a novel type of epidermolysis bullosa simplex with migratory circinate erythema.

We report here two unrelated families in Japan and Korea having patients with a unique type of epidermolysis bullosa simplex and a novel mutation in the keratin gene KRT5, i.e., a frameshift and delayed stop codon inconsistent with any subtype described before. The patients showed migratory circinate erythema and multiple vesicles on the circular belt-like areas affected by erythema. Electron microscopy of skin biopsies showed a reduction in the number of keratin intermediate filaments in the basal cells without tonofilament clumping. We identified a novel heterozygous deletion mutation (1649delG of KRT5) in both cases. This deletion is predicted to produce a mutant keratin 5 protein with a frameshift of its terminal 41 amino acids and 35 amino acids longer than the wild-type keratin 5 protein due to a delayed termination codon. As the same abnormal elongated mutant KRT5 gene was found in the independent families, the predicted abnormal elongated keratin protein is likely to lead to an atypical clinical phenotype that has never been reported, possibly by interfering with the functional interaction between keratin and its associated proteins.