Chromatin remodeling factor, INO80, inhibits PMAIP1 in renal tubular cells via exchange of histone variant H2A.Z. for H2A.

Epigenetic modifications such as DNA methylation, histone modifications, and chromatin structures in the kidney contribute towards the progression of chronic kidney disease (CKD). In this study, the role of chromatin remodeling factor inositol requiring 80 (INO80) was investigated. Although INO80 regulates transcription by altering the chromatin structure at the nucleosome level, its role in the kidney remains unknown. We demonstrated that the expression of INO80 in impaired kidneys decreased in rats with unilateral urethral obstruction. We investigated INO80 expression in a proximal tubular cell line and observed that its expression decreased under hypoxic condition. Additionally, INO80 knockdown promoted apoptosis, suggesting that INO80 plays a role in inhibiting tubular cell apoptosis. We identified downstream target genes of INO80 via genome-wide analysis using RNA-sequences and found that the expression of apoptosis-related genes, such as TP53 and E2F1, and pro-apoptotic genes, such as PMAIP1, increased upon INO80 knockdown. ChIP-qPCR of the loci of PMAIP1 showed that the amount of H2A.Z. increased instead of decreasing the amount of H2A when INO80 was knocked down. These results indicated that INO80 plays a role in the exchange of H2A.Z. for H2A in the promoter region of PMAIP1 in tubular cells to inhibit apoptosis during CKD progression.

Hypoxia-inducible lncRNA MIR210HG promotes HIF1α expression by inhibiting miR-93-5p in renal tubular cells.

Chronic hypoxia in the renal tubular interstitium has been reported to contribute to the progression of chronic kidney disease. Recently, long-noncoding RNAs have been shown to be involved in various pathological conditions, including hypoxia, one of which is the MIR210 host gene (MIR210HG). To elucidate the function of MIR210HG in renal hypoxia, we exposed primary cultured renal proximal tubular epithelial cells to hypoxia and examined the temporal profile of MIR210HG expression and the role of MIR210HG interaction with hypoxia-inducible factor1α (HIF1α, encoded by HIF1A). MIR210HG expression was induced by hypoxia. HIF1A silencing and cobalt chloride exposure showed that MIR210HG expression in hypoxia is HIF1α-dependent. MIR210HG silencing significantly reduced both the mRNA and protein levels of HIF1α, pointing to positive feedback regulation. To further investigate the details of this regulation, we turned to the in-silico miRNA targets of MIR210HG. We found that miR-93-5p levels increased when MIR210HG was knocked down. We then showed that miR-93-5p reduced the expression of HIF1A mRNA and MIR210HG. Furthermore, a dual luciferase assay confirmed that miR-93-5p binds to MIR210HG and HIF1A 3' UTR, inhibiting their expression. In conclusion, the long-noncoding RNA MIR210HG is induced shortly after hypoxia, and it promotes HIF1α expression by competing for miR-93-5p and inhibiting it. MIR210HG plays a crucial role in the biological response to hypoxia in renal tubular epithelial cells.

Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits without Conspicuous Mesangial Proliferation, Complicated with Squamous Cell Lung Carcinoma.

We performed a renal biopsy for nephrotic syndrome in a patient with squamous cell lung carcinoma, which can worsen the prognosis. Chemoradiation therapy was effective for the cancer and proteinuria; we thus inferred that the nephrotic syndrome had been closely associated with the carcinoma. A pathological analysis of the kidney showed monoclonality for λ chain, satisfying the diagnostic criteria of proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID); however, conspicuous mesangial proliferation was not observed. This is the first case of PGNMID complicated with lung carcinoma; furthermore, our findings underscore the importance of examining renal lesions and assessing monoclonality in cancer patients.

IL-6-producing Renal Cell Carcinoma Causing Renal and Endocrine Paraneoplastic Syndromes.

An 83-year-old man with stable chronic kidney disease (CKD) exhibited a sudden increase in urinary N-acetyl-ß-D-glucosaminidase and protein excretion, suggesting aggravated kidney damage. Simultaneously, he lost diabetic control, requiring up to 54 units of insulin daily. A detailed examination revealed the presence of renal cell carcinoma, which was surgically resected and confirmed to be interleukin-6-positive by immunohistochemistry. Postoperatively, his uni-nephrectomy necessitated hemodialysis, but the patient's insulin resistance was ameliorated; no medication was required to control diabetes, suggesting that the tumor had caused the insulin resistance. This report describes a case of a tumor secreting interleukin-6, which affects both the control of diabetes and CKD progression.

Arousals in obstructive sleep apnea patients with laryngopharyngeal and gastroesophageal reflux.

OBJECTIVE: We hypothesized that differences exist in the effect of apnea severity and those of laryngopharyngeal reflex (LPR) versus gastroesophageal reflex (GER) on arousals during sleep in patients with obstructive sleep apnea syndrome (OSAS). METHODS: Japanese patients having witnessed snoring or excessive daytime sleepiness with a frequency scale for symptoms of GER of 10 or more or with visualization of inflammatory changes on pharyngolaryngeal endoscopy underwent polysomnography with pH monitoring using double pH catheter in a sleep laboratory. RESULTS: Most reflux events in patients with severe OSAS with LPR (n=16) and GER (n=21) were accompanied with respiratory arousals. On the other hand, among patients with mild-to-moderate OSAS, 64.0% and 24.8% of reflux events were accompanied with spontaneous arousals in those with LPR (n=12) and GER (n=12), respectively, and 9.4% and 8.3% of reflux events were not accompanied by arousals. There were no significant differences in other sleep parameters between mild-to-moderate OSAS patients with LPR versus GER and between severe OSAS patients with LPR versus GER. CONCLUSIONS: Among patients with reflux, the types of arousal differed significantly between those with mild-to-moderate versus severe OSAS. In patients with mild-to-moderate OSAS, LPR induces more spontaneous arousals than does GER.

Multiple system atrophy manifesting as complex sleep-disordered breathing.

A 56-year-old female presented with multiple system atrophy (MSA) and pure obstructive sleep-disordered breathing (SDB) with an apnea hypopnea index of 29.6/h. However, after the elimination of obstructive events, central apneas emerged with a central apnea index (CAI) of 45.3/h as determined by continuous positive airway pressure titration. Adaptive servoventilation titration decreased the CAI; however, it remained at 14.2/h. There are two different underlying causes of SDB in MSA patients, one is upper airway obstruction at the glottic level, and the other is central components owing to the degeneration of the pontomedullary respiratory centers. Clinicians should recognize that whether a patient has central apnea cannot be determined by diagnostic polysomnography but only after the elimination of upper airway obstruction in MSA patients.

Three-dimensional morphological analyses of positional dependence in patients with obstructive sleep apnea syndrome.

BACKGROUND: It is generally considered that patients with obstructive sleep apnea syndrome (OSAS) at increased perioperative risk should be placed in nonsupine positions throughout the recovery process; however, not all patients with OSAS show positional dependence. The authors hypothesized that morphological differences exist in three-dimensional (3D) soft tissue and craniofacial structures of the pharyngeal airway between positional and nonpositional OSAS. METHODS: The subjects of the study were body mass index-matched, age-matched, and apnea hypopnea index-matched positional (n = 10) and nonpositional (n = 10) Japanese OSAS patients and body mass index-matched Japanese control subjects (n = 10). Pharyngeal magnetic resonance imaging and cephalometric radiography were performed during wakefulness. RESULTS: The patients with positional OSAS had a smaller volume of the pharyngeal lateral wall soft tissues, larger maxilla-nasion-mandible angle, and smaller lower facial height than the nonpositional OSAS and the control subjects. The patients with positional OSAS showed a significantly steeper sella-nasion-mandible angle and smaller craniofacial volume than the control subjects. There were no significant differences in tongue volume and 3D pharyngeal anatomical balance between positional and nonpositional OSAS. Multivariate stepwise regression for positional dependence showed that the dominant determinant was the volume of the lateral pharyngeal wall, followed by lower facial height and maxilla-nasion-mandible angle. CONCLUSIONS: Patients with positional OSAS have wider airways in the lateral parts, lower facial height, and more backward position of the lower jaw, which may explain differences in the maintenance of pharyngeal airway patency in the lateral sleep position.

Postoperative monitoring of esophageal pressure in patients with obstructive sleep apnea-hypopnea syndrome who have undergone tonsillectomy with uvulopalatopharyngoplasty.

OBJECTIVES: To realize better postoperative management in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS), we elucidated the need for the postoperative monitoring of esophageal pressure (Pes). METHODS: A prospective randomized controlled study was performed. Adult patients with OSAHS were divided into 2 groups: those administered autoadjusted continuous positive airway pressure (CPAP) before, on, and after the first postoperative night (CPAP group) and those not administered CPAP before or after the surgery (non-CPAP group). Tonsillectomy with uvulopalatopharyngoplasty (UPPP) under general anesthesia was performed on all of the patients. On the first postoperative night, continuous overnight monitoring of Pes and oxygen saturation level was carried out simultaneously with oxygen supplementation in both groups in the patient's room in the general ward. RESULTS: The CPAP group showed a significantly improved mean inspiratory maximal end-apneic Pes swing on the first postoperative night as compared with the non-CPAP group, although there was no significant difference in oxygen desaturation index on the first postoperative night between the 2 groups. CONCLUSIONS: Continuous Pes monitoring and CPAP administration were beneficial in the detection and minimization of respiratory disturbances in patients with OSAHS who underwent tonsillectomy with UPPP under general anesthesia.

Prevalence of upper airway tumors and cysts among patients who snore.

OBJECTIVES: Sleep specialists usually do not pay much attention to the upper airway in patients who snore, because they can make the diagnosis of sleep-disordered breathing without performing nasopharyngeal endoscopy if they have the Epworth Sleepiness Scale scores and the results of polysomnography. The purpose of this study was to determine the prevalence of benign and malignant tumors and cysts in the upper airway in patients who snore. METHODS: A retrospective multicenter trial was performed in 4 sleep laboratories. Adult male and female patients whose chief complaint on their first visit was witnessed snoring were enrolled in this study. All of the patients were evaluated by otolaryngologists using nasopharyngeal endoscopy to detect organic diseases in the upper airway. RESULTS: Among 2,923 patients, 2 patients had malignant tumors, 5 had benign tumors, and 2 had cysts in the upper airway. The prevalence of upper airway benign and malignant tumors and cysts among adult male and female patients was 0.24%. CONCLUSIONS: Routine detailed nasopharyngeal endoscopy should be carried out in each institution so as not to overlook organic diseases in the upper airway among patients who snore.

Comparison of sleep parameters at titration and subsequent compliance between CPAP-pretreated and non-CPAP-pretreated patients with obstructive sleep apnea.

BACKGROUND AND PURPOSE: Obstructive sleep apnea-hypopnea syndrome (OSAHS) patients undergo continuous positive airway pressure (CPAP) treatment for the first time on titration night, and then the effect of overnight CPAP treatment is estimated immediately. The purpose of this study is to compare the effects of CPAP-pretreated and non-pretreated on patients with OSAHS. METHODS: Prospective randomized, controlled parallel study was performed. Seventy patients with OSAHS received autoadjusted CPAP treatment for 2 months and then received the standard manual titration (CPAP-pretreated group). The other 70 did not receive any CPAP treatment before receiving the standard manual titration (non-CPAP-pretreated group). RESULTS: The CPAP-pretreated group had significantly improved sleep efficiency and arousal index in non-rapid eye movement (NREM) sleep compared with the initial CPAP group at titration, whereas there were no significant differences between the two groups in other sleep parameters. Eight patients in the non-CPAP-pretreated group discontinued CPAP treatment 9 months after the titration, whereas one patient in the CPAP-pretreated group discontinued treatment. CONCLUSIONS: A preceding CPAP treatment showed minimal effects on sleep parameters on titration night and subsequent CPAP compliance rate, although it was speculated that this preceding treatment might be of benefit for better compliance in some patients.

[Eosinophil chemoattractants and related factors in nasal polyps].

OBJECTIVE: In vitro studies and animal experiments have shown that cytokines and chemokines are closely related to eosinophil migration, activation, and survival. It remains controversial, however, whether some chemokines or cytokines are actually responsible for the accumulation of eosinophils in nasal polyp tissues. We studied cytokines and chemokines in nasal polyp tissues taken from patients with chronic rhinosinusitis to clarify the pathogenesis of eosinophil accumulation. MATERIALS AND METHODS: Nasal polyp tissues obtained from 20 patients with chronic rhinosinusitis were studied. Concentrations of interleukin (IL-) 5, IL-13, eotaxin, regulated upon activation in normal T cell expressed and secreted (RANTES), and thymus and activation-regulated chemokine (TARC) in homogenates of polyp tissues were measured by ELISA. Nasal polyp tissues were stained by hematoxillin and eosin and were immunostained by an antibody against EG2. The numbers of eosinophils and immunopositive cells for EG2 in the submucosal layer were counted using a microscope. RESULTS: No significant differences were seen in the numbers of eosinophils and EG2-positive cells, or in the concentration of IL-5, eotaxin, TARC, RANTES in nasal polyp tissues between patients with and without atopic predisposition. Significant positive correlations existed, however, between the number of eosinophils and IL-5, eotaxin, and TARC concentration. IL-13 concentration was below detection in all patients. CONCLUSION: We hound that IL-5, eotaxin, and TARC may play an important role in the accumulation of eosinophils in nasal polyps regardless of the presence of atopic predisposition.

Discrepancy in polysomnography scoring for a patient with obstructive sleep apnea hypopnea syndrome.

Overnight polysomnography (PSG) is indispensable for diagnosis of obstructive sleep apnea hypopnea syndrome. However, studies on interscorer agreement on PSG scoring between laboratories are few. The purpose of this study was to examine the reliability of interscorer agreement on PSG scoring among 16 sleep laboratories in Japan. We found a relatively moderate interscorer reliability of the index of oxygen desaturation and arousal during sleep, but a relatively low reliability of the index of transient reduction in and complete cessation of breathing (apnea hypopnea index). The median rate of interscorer coincidence of sleep staging was the lowest for slow wave (deep) sleep (23.5%), followed by those for Stage 1 (59.8%), Wake (73.2%) and Stage 2 (74.2%) in this order, and rapid eye movement was the most reliably identified stage (91.3%). The median rate of interscorer coincidence for all stages was 71.8%. The present study demonstrates that scorers tend to analyze PSG data according to a relatively empirical decision as opposed to a rule-dependent decision. Further detailed scoring manuals are required to decrease the interscorer discrepancy in PSG scoring.

[Temporal bone histopathology exhibiting cochleosaccular degeneration in a patient with profound deafness].

We herein report the histopathological findings of the temporal bone taken from a patient with unilateral profound deafness since early childhood. The patient was a 72-year-old male who died of lung cancer and extensive metastases including the tongue. The patient had a history of profound hearing loss in his left ear since childhood. The histopathological finding of the left temporal bone revealed a severe atrophy of the organ of Corti, a detached and rolled-up tectorial membrane, a moderate loss of the stria vascularis, and a severe loss of spiral ganglion cells. In addition, the macula of the saccule was severely degenerated. The marked degeneration in the inner ear indicated a cochleosaccular disorder, which is a typical temporal bone finding in cases of viral labyrinthitis and hereditary hearing impairment. The present patient was suspected to have suffered cochleosaccular degeneration as a result of an inner ear viral infection during childhood because the number of spiral ganglion cells was significantly reduced because of secondary neural degeneration.