Fractional excretion of total protein in patients with nephrotic syndrome.

BACKGROUND: The urine protein to creatinine ratio (UPCR) correlates well with the 24-h urine protein test (24-h UPT) and is a reliable indicator of proteinuria. However, in nephrotic syndrome, the correlation between the UPCR and the 24-h UPT tends to decrease. To address this, we introduced the fractional excretion of total protein (FETP), which reflects serum total protein and creatinine levels because severe hypoproteinemia and/or elevated serum creatinine levels tend to occur under these conditions. The 24-h UPT corrected for body surface area (BSA) (24-h UPT/BSA) was used to take body size into consideration. The correlation coefficients for 24-h UPT/BSA and FETP and 24-h UPT/BSA and UPCR were calculated. The statistical significance of the differences between these coefficients was also calculated. METHODS: Thirty-six pediatric patients with nephrotic syndrome were included in this study. The FETP was calculated as total protein clearance/creatinine clearance (%). Correlation coefficients were calculated for 24-h UPT/BSA and FETP and 24-h UPT/BSA and UPCR. The statistical significance of the differences between these coefficients was also calculated. RESULTS: The mean ± standard error of FETP was 0.11% ± 0.013%. The correlation coefficients of FETP and UPCR with 24-h UPT/BSA were 0.91 and 0.81, respectively. The FETP demonstrated a significantly stronger correlation with 24-h UPT/BSA than with UPCR (p = 0.01). CONCLUSIONS: The FETP correlated more strongly with 24-h UPT/BSA than with UPCR in patients with nephrotic syndrome. The FETP is a reliable indicator of proteinuria in nephrotic syndrome, especially in patients with severe hypoproteinemia or elevated serum creatinine levels.

Diversity of cortical bone morphology in anuran amphibians.

The cortical bones of mammals, birds, and reptiles are composed of a complex of woven bone and lamellar bone (fibrolamellar bone) organized into a variety of different patterns; however, it remains unclear whether amphibians possess similar structures. Importantly, to understand the evolutionary process of limb bones in tetrapods, it is necessary to compare the bone structure of amphibians (aquatic to terrestrial) with that of amniotes (mostly terrestrial). Therefore, this study compared the cortical bones in the long bones of several frog species before and after metamorphosis. Using micro-computed tomography (CT), we found that the cortical bones in the fibrolamellar bone of Xenopus tropicalis (Pipoidea superfamily) and Lithobates catesbeianus (Ranoidea superfamily) froglets are dense, whereas those of Ceratophrys cranwelli (Hyloidea superfamily) are porous. To clarify whether these features are common to their superfamily or sister group, four other frog species were examined. Histochemical analyses revealed porous cortical bones in C. ornata and Lepidobatrachus laevis (belonging to the same family, Ceratophryidae, as C. cranwelli). However, the cortical bones of Dryophytes japonicus (Hylidae, a sister group of Ceratophryidae in the Hyloidea superfamily), Microhyla okinavensis (Microhylidae, independent of the Hyloidea superfamily), and Pleurodeles waltl, a newt as an outgroup of anurans, are dense with no observed cavities. Our findings demonstrate that at least three members of the Ceratophryidae family have porous cortical bones similar to those of reptiles, birds, and mammals, suggesting that the process of fibrolamellar bone formation arose evolutionarily in amphibians and is conserved in the common ancestor of amniotes.

A Japanese nationwide survey for evaluation of the comprehensibility of alternative audiometry display formats: Insight into otolaryngologists' cognitive processes.

OBJECTIVE: The present study aimed to elucidate opinions regarding comprehensibility of audiometry display formats among otolaryngologists in Japan, and to identify the characteristics of otolaryngologists' cognitive processes for audiometry. METHODS: We conducted a cross-sectional nationwide questionnaire-based mail survey regarding the comprehensibility of audiometry display formats among 543 Japanese otolaryngologists. Of 543 otolaryngologists to whom the questionnaires were mailed, 137 replied to the questions. For the analysis, the sample size used was 112 participants. The questionnaire contained questions regarding the otolaryngologists' occupational characteristics, and assessed their opinions of four comprehensibility aspects of five display formats. RESULTS: Otolaryngologists in clinics indicated that the passage of time and changes in thresholds of each frequency in numeric tables were ordinary or incomprehensible. More than 60% of otolaryngologists with extensive experience in using electronic medical records indicated that both, the passage of time and change in the thresholds in overlaid thresholds on a chart were comprehensible. CONCLUSIONS: Display formats in audiometry influenced the comprehension of pure tone audiometry data. Our results suggest that overlaid thresholds on a chart rather than numeric table or multi-dimensional charts are the primary choice for computerized audiometry display formats in most aspects of audiometry.

The impact of uncertainty in society on the use of traditional, complementary and alternative medicine: a comparative study on visits to alternative/traditional/folk health care practitioners.

BACKGROUND: While traditional, complementary and alternative medicine (TCAM) is gaining increased interest worldwide, the structural factors associated with the usage of TCAM at the social level have not been sufficiently explored. We aim to understand the social structure of uncertainty in society that affects the TCAM usage for men and women. METHODS: We studied 32 countries using data from the International Social Survey Programme and the World Bank. In this study, we defined TCAM usage as visits to an alternative/traditional/folk health care practitioner during the past 12 months. We performed a correlation analysis and used a generalized linear model . RESULTS: The prevalence of TCAM usage in terms of visits to practitioners was 26.1% globally, while usage varied across the 32 countries. Generalized linear models showed that unemployment rate was associated with the prevalence of TCAM usage in terms of visits to practitioners. CONCLUSIONS: At the social-structural level TCAM usage involving visits to practitioners was related to job insecurity. Job insecurity led to a decrease in TCAM usage regarding visits to practitioners. These findings suggest that it is necessary to consider the social-structural factors of uncertainty in society when designing health policies related to TCAM.

External validation of the TRISS, CRASH, and IMPACT prognostic models in severe traumatic brain injury in Japan.

In Japan, a range of patients with traumatic brain injury (TBI) has been recorded in a nationwide database (Japan Neurotrauma Data Bank; JNTDB). This study aimed to externally validate three international prediction models using JNTDB data: Trauma and Injury Severity Score (TRISS), Corticosteroid Randomization After Significant Head Injury (CRASH), and International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT). We also aimed to validate the applicability of these models in the Japanese population. Of 1,091 patients registered in the JNTDB from July 2009 to June 2011, we analyzed data for 635 patients. We examined factors associated with mortality in-hospital and unfavorable outcomes 6 months after TBI by applying the TRISS, CRASH, and IMPACT models. We also conducted an external validation of these models based on these data. The patients' mean age was 60.1 ±21.1 years, and 342 were alive at the time of discharge (53.9%). Univariate analysis revealed eight major risk factors for mortality in-hospital: age, Glasgow Coma Scale (GCS), Injury Severity Score (ISS), systolic blood pressure, heart rate, mydriasis, acute epidural hematoma (AEDH), and traumatic subarachnoid hemorrhage. A similar analysis identified five risk factors for unfavorable outcomes at 6 months: age, GCS, ISS, mydriasis, and AEDH. For mortality in-hospital, the TRISS had a satisfactory area under the curve value (0.75). For unfavorable outcomes at 6 months, the CRASH (basic and computed tomography) and IMPACT (core and core extended) models had satisfactory area under the curve values (0.86, 0.86, 0.81, and 0.85, respectively). The TRISS, CRASH, and IMPACT models were suitable for application to the JNTDB population, indicating these models had high value in Japanese patients with neurotrauma.

Development of an Guideline-Based Decision Support System for Effective Diagnostic Workflow for Oncologic Pathologists.

Accurate and rapid differential diagnosis are required for personalized cancer treatment. However, owing to the numerous molecular tests used for establishing a diagnosis, pathologists need time to investigate and confirm necessary test items. We present a guideline-based decision support system for effective workflow with regards to the molecular tests for pathological differential diagnosis.

[A Resected Case with Early Gastric Cancer That Was Overdiagnosed as Scirrhous Gastric Cancer].

We experienced a case of early gastric cancer. A 69-year-old woman with a thick gastric wall, thickened folds, and undifferentiated cancer cells in biopsy was diagnosed with scirrhous gastric cancer. The patient underwent total gastrectomy for scirrhous gastric cancer and was found to have only an early gastric cancer lesion located on the upper gastric wall. The thick wall diagnosed before surgery was diagnosed as angiodysplasia occupying the submucosal layer.

Application of Muse Cell Therapy for Kidney Diseases.

The kidney plays an essential role in the maintenance of homeostasis in healthy individuals, e.g., by regulating the amount of water and concentration of electrolyte in the body. Owing to the structural complexity, renal dysfunction is caused by a myriad of diseases and conditions, and in severe cases, it progresses to end-stage renal disease in which patients require renal replacement therapy, i.e., maintenance dialysis or kidney transplantation. The currently available therapeutic modalities, with the exception of renal transplantation, cannot recover severely deteriorated renal function. Thus, regenerative medicine holds considerable promise as a potential means for developing next-generation renal therapeutics. Mesenchymal stem cell (MSC) transplantation has been investigated in acute kidney injury and chronic kidney disease models, and clinical studies have already been started for some kinds of kidney diseases. However, most of these studies concluded that the main underlying mechanism of therapeutic effect of MSC transplantation was paracrine. Recently, we reported that Muse cell therapy in a murine model of chronic kidney disease resulted in differentiation of intravenously injected Muse cells into glomerular cells after preferential homing to damaged glomerulus and improvement in renal function. The result suggested the potentiality of Muse cell therapy for glomerular regeneration. Muse cells are a promising cell source for regenerative therapy for kidney diseases.

The prevalence of mental distress before the Great East Japan Earthquake and the associated impact of an aged society: An ecological study.

Various studies have determined that the Great East Japan Earthquake (GEJE) caused mental distress among residents in affected areas. However, previous studies had not considered the prevalence of mental distress before the GEJE, and ignored the impact of an aged society on mental distress. Therefore, we aimed to describe the prevalence of mental distress before the GEJE in Miyagi Prefecture, Japan and elucidate the effect of an aged society on mental distress. We conducted an ecological study, using municipality in Miyagi Prefecture as the study unit. We used the cross-sectional mail survey data conducted in February 2011. We performed a correlation analysis in each of the 39 municipalities in Miyagi Prefecture. The prevalence of serious mental distress was 9.1%. The proportion of the population aged 65 years or older was related to the prevalence of serious mental distress in municipalities with a low proportion of all workers engaged in primary industry and with a high estimated number of inpatients with mental illness. We found that residents in Miyagi Prefecture suffered from poor mental health before the GEJE. Aged society was related to serious mental distress in the areas with advanced industrial structure and more patients with mental illness. We should approach mental health problems in the context of social structure, particularly in an aged society, based on facts about mental distress before the GEJE.

Preoperative sonographic evaluation of the defect size and the diaphragm rim in congenital diaphragmatic hernia - preliminary experience.

BACKGROUND: Sonographic assessment before congenital diaphragmatic hernia repair has rarely been studied. OBJECTIVE: To evaluate the accuracy of preoperative ultrasound in measuring the defect size and in anticipating the presence of a rim and thereby to determine ultrasound's usefulness in informing the surgical approach for definitive repair of congenital diaphragmatic hernia. MATERIALS AND METHODS: We performed a retrospective review of the medical records of seven children with left congenital diaphragmatic hernia who had undergone ultrasound and definitive repair between 2014 and 2017 at our institution. RESULTS: The estimated defect size by ultrasound to the actual defect size measured intraoperatively for each case were as follows: 23 × 25 mm to 20 × 26 mm (case 1); 23 × 30 mm to 20 × 30 mm (case 2); 43 × 25 mm to 30 × 30 mm (case 3); 21 × 23 mm to 20 × 25 mm (case 4); 19 × 24 mm to 10 × 30 mm (case 5); 32 × 33 mm to 30 × 50 mm (case 6); and almost total absence to 40 × 50 mm (case 7). Presence or absence of each part of the diaphragm rim evaluated by ultrasound was almost identical with the actual intraoperative findings. According to the ultrasound findings, we performed a successful thoracoscopic repair in cases 1-5 with relatively small defects and presence of all parts of the rim or absence of only posterolateral rim. CONCLUSION: There was good concordance between ultrasound findings and operative findings regarding the size of the defect and presence or absence of the diaphragm rim.

Social determinants affecting the use of complementary and alternative medicine in Japan: An analysis using the conceptual framework of social determinants of health.

This study aims to use the conceptual framework of social determinants of health (SDH) to elucidate the social determinants that affect the use of complementary and alternative medicine (CAM) from the perspectives of both intermediary and structural determinants. Data were derived from a survey mailed to 1,500 randomly selected residents (20-69 years old; May-July 2009) of Sendai city in Japan. A generalized linear model was used in the analysis, with CAM use over the past one month as the dependent variable, SDH structural and intermediary determinants as independent variables, and demographic characteristics, indicators of health status, and the evaluation of health or healthcare systems as control variables. The prevalence of CAM usage was 62.1%. The generalized linear model showed that middle subjective social status (OR = 1.47; 95% CI: 1.04-2.07) as structural determinants was significantly associated with CAM usage. Adding the intermediary determinants, the same effect was observed. When demographic characteristics, indicators of health status, and the evaluation of health or healthcare systems were introduced as control variables, the associations of the structural determinants disappeared, revealing that hope (OR = 1.25; 95%CI: 1.04-1.50) as intermediary determinants was associated with the use of CAM. Female sex (OR = 1.47; 95% CI: 1.02-2.12) and health anxiety (OR = 1.68; 95% CI: 1.20-2.34) were associated with CAM usage. We found that intermediary rather than structural determinants were associated with CAM usage. Hope as an intermediary determinant was particularly associated with CAM usage.

AKAPs-PKA disruptors increase AQP2 activity independently of vasopressin in a model of nephrogenic diabetes insipidus.

Congenital nephrogenic diabetes insipidus (NDI) is characterized by the inability of the kidney to concentrate urine. Congenital NDI is mainly caused by loss-of-function mutations in the vasopressin type 2 receptor (V2R), leading to impaired aquaporin-2 (AQP2) water channel activity. So far, treatment options of congenital NDI either by rescuing mutant V2R with chemical chaperones or by elevating cyclic adenosine monophosphate (cAMP) levels have failed to yield effective therapies. Here we show that inhibition of A-kinase anchoring proteins (AKAPs) binding to PKA increases PKA activity and activates AQP2 channels in cortical collecting duct cells. In vivo, the low molecular weight compound 3,3'-diamino-4,4'-dihydroxydiphenylmethane (FMP-API-1) and its derivatives increase AQP2 activity to the same extent as vasopressin, and increase urine osmolality in the context of V2R inhibition. We therefore suggest that FMP-API-1 may constitute a promising lead compound for the treatment of congenital NDI caused by V2R mutations.

Prediction of Poor Prognosis After Severe Head Injury in Children Using Logistic Regression.

OBJECTIVES: Head trauma is one of the main causes of death in childhood and often leaves severe disability with serious neurological damage. Appropriate treatment must be provided immediately to improve outcomes. This study was performed to identify factors associated with a poor prognosis at an early stage of severe head injury in children. METHODS: The subjects were registered in the Japan Neurotrauma Data Bank. They were 119 children (mean age, 8 years; male, 67.2%) with severe head injury registered during a period of 4 years (from July 1, 2004 to June 30, 2006 and from July 1, 2009 to June 30, 2011). Univariate and multivariate analyses were performed to examine relationships among factors and outcome 6 months after discharge. Logistic regression analysis was performed to develop models for poor prognosis and death. RESULTS: Outcome was evaluated based on the Glasgow Outcome Scale: 73 children (61.3%) had good recovery, 11 (9.2%) had moderate disability, 8 (6.7%) had severe disability, 4 (3.3%) were in a vegetative state, and 23 (19.3%) had died. Four factors were identified as predictors of a poor prognosis: serum glucose level greater than or equal to 200 mg/dL, Glasgow Coma Scale score on admission less than or equal to 5, presence of mydriasis, and presence of traumatic subarachnoid hemorrhage. Three factors were identified as predictors of death: serum glucose level greater than or equal to 200 mg/dL, Glasgow Coma Scale score on admission less than or equal to 5, and presence of mydriasis. CONCLUSIONS: Using these predictors, subsequent exacerbation may be predicted just after arrival at the hospital and appropriate treatment can be provided immediately.

Psychometric validation of a new measurement instrument for time-oriented patient information in electronic medical records: A questionnaire survey of physicians.

RATIONALE, AIMS, AND OBJECTIVES: Time is an important element in medical data. Physicians record and store information about patients' disease progress and treatment response in electronic medical records (EMRs). Because EMRs use timestamps, physicians can identify patterns over time regarding a patient's disease and treatment (eg, laboratory values and medications). However, analyses of physicians' use and satisfaction with EMRs have focused on functionality, storage, and system operation rather than the use of time-oriented information. This study aimed to understand physicians' needs regarding time-oriented patient information in EMRs in clinical practice. METHODS: The reliability and validity of the items in the questionnaire were evaluated in 87 physicians at a national university hospital. Internal consistency was satisfactory (Cronbach alpha coefficient, 0.87). RESULTS: Four dimensions were identified in exploratory factor analysis. Correlations between the 4 dimensions supported the construct validity of the items. Scores of time-oriented patients' medical history in the 4 dimensions showed a significant association with physician age. Based on confirmatory factor analysis, associations were significant and positive (P < .001). In terms of the needs of physicians regarding time-oriented patient information in EMRs, both time-oriented treatment results followed by time-oriented team information had significant positive associations. CONCLUSION: Our study suggests that 4 specific time-oriented patient information factors in EMRs are needed by physicians. Exploring physicians' needs regarding patient-specific time-oriented information may provide a better understanding of the barriers facing the adoption and use of EMRs (eg, decision-making and practice safety concerns) and lead to better acceptance of EMRs in physicians' clinical practices.

Transfusion-associated hypoxemia in pediatric patients with solid tumors after autologous peripheral blood stem cell transplantation.

BACKGROUND: Although several types of transfusion-related adverse reactions (TRARs) have been reported, one of the most important involves respiratory features during and after blood transfusion. Transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) are the most severe adverse events following blood transfusion, whereas transfusion-associated dyspnea　(TAD) is a less severe respiratory distress. However, there exists little evidence of these factors in pediatric populations. CASE REPORT: Here, two cases of atypical TRARs with respiratory features, in pediatric patients with solid tumors, appearing after transfusion of platelet concentrate following autologous peripheral blood stem cell transplantation are reported. Both patients developed mild hypoxemia during PC transfusion, which continued for approximately 2 weeks. Chest radiography in either patient did not reveal any abnormalities that are included in the criteria of either TRALI or TACO. Both patients recovered following oxygen administration. CONCLUSION: This complication of TRARs with respiratory features may occur more frequently in pediatric populations than realized because it may be under-recognized or under-reported. Accumulation of additional cases, including non-typical cases, is necessary to fully understand the pathology of TRARs, correctly classify these reactions, and improve care of patients receiving blood transfusions.

Beneficial Effects of Systemically Administered Human Muse Cells in Adriamycin Nephropathy.

Multilineage-differentiating stress-enduring (Muse) cells are nontumorigenic endogenous pluripotent-like stem cells that can be collected from various organs. Intravenously administered Muse cells have been shown to spontaneously migrate to damaged tissue and replenish lost cells, but the effect in FSGS is unknown. We systemically administered human bone marrow-derived Muse cells without concurrent administration of immunosuppressants to severe combined immune-deficient (SCID) and BALB/c mouse models with adriamycin-induced FSGS (FSGS-SCID and FSGS-BALB/c, respectively). In FSGS-SCID mice, human Muse cells preferentially integrated into the damaged glomeruli and spontaneously differentiated into cells expressing markers of podocytes (podocin; 31%), mesangial cells (megsin; 13%), and endothelial cells (CD31; 41%) without fusing to the host cells; attenuated glomerular sclerosis and interstitial fibrosis; and induced the recovery of creatinine clearance at 7 weeks. Human Muse cells induced similar effects in FSGS-BALB/c mice at 5 weeks, despite xenotransplant without concurrent immunosuppressant administration, and led to improvement in urine protein, creatinine clearance, and plasma creatinine levels more impressive than that in the FSGS-SCID mice at 5 weeks. However, functional recovery in FSGS-BALB/c mice was impaired at 7 weeks due to immunorejection, suggesting the importance of Muse cell survival as glomerular cells in the FSGS kidney for tissue repair and functional recovery. In conclusion, Muse cells are unique reparative stem cells that preferentially home to damaged glomeruli and spontaneously differentiate into glomerular cells after systemic administration. Introduction of genes to induce differentiation is not required before Muse cell administration; thus, Muse cells may be a feasible therapeutic strategy in FSGS.

[A Patient with Scirrhous Gastric Cancer Diagnosed and Resected Subsequently by Laparotomy Examination Due to Difficulty to Take Cancer Specimen by Endoscopic Biopsy].

Some of scirrhous gastric cancer are difficult to diagnose on the surface view or to take correct biopsy specimen.A 85-yearold man with dysphagia was diagnosed scirrhous gastric cancer endoscopically, but could not be taken a biopsy specimen showing cancer.We informed cases of scirrhous gastric cancer difficult to take correct biopsy specimen and recommended surgical operation to take correct specimen and to start a treatment.Patient underwent total gastrectomy after cancer diagnosis( P0CY0cT4aN0).He can eat more food and survive longer than 1 year without any chemotherapies.Scirrhous gastric cancer needs early diagnosis and treatment to improve patient prognosis.

[A Case of Gastric Remnant Cancer after Proximal Gastrectomy with Jejunum Pouch Interposing Reconstruction].

A 83-year-old man was diagnosed an earlygastric remnant cancer on the site of jejuno-gastrostomyafter proximal gastrectomywith jejunum interposing reconstruction 23 years ago. A total gastrectomywas performed due to the difficultyof endoscopic submucosal resection. The surgical operation took 200 minutes and the blood loss was 180 mL. Histologically, tumor size was 28×22mm invading to submucosal layer with a lymph node metastasis. To reduce the risk of surgical operation for gastric remnant cancer of aged patients, a simple reconstruction method is important for proximal gastrectomy, like a esophagogastrostomyplacing a gastric tube in the mediastinum.

Early RAAS Blockade Exerts Renoprotective Effects in Autosomal Recessive Alport Syndrome.

Alport syndrome is a progressive renal disease caused by mutations in COL4A3, COL4A4, and COL4A5 genes that encode collagen type IV alpha 3, alpha 4, and alpha 5 chains, respectively. Because of abnormal collagen chain, glomerular basement membrane becomes fragile and most of the patients progress to end-stage renal disease in early adulthood. COL4A5 mutation causes X-linked form of Alport syndrome, and two mutations in either COL4A3 or COL4A4 causes an autosomal recessive Alport syndrome. Recently, renin-angiotensin-aldosterone system (RAAS) blockade has been shown to attenuate effectively disease progression in Alport syndrome. Here we present three Japanese siblings and their father all diagnosed with autosomal recessive Alport syndrome and with different clinical courses, suggesting the importance of the early initiation of RAAS blockade. The father was diagnosed with Alport syndrome. His consanguineous parents and his wife were healthy. All three siblings showed hematuria since infancy. Genetic analysis revealed that they shared the same gene mutations in COL4A3 in a compound heterozygous state: c.2330G>A (p.Gly777Ala) from the mother and c.4354A>T (p.Ser1452Cys) from the father. Although RAAS blockade was initiated for the older sister and brother when their renal function was already impaired, it did not attenuate disease progression. In the youngest brother, RAAS blockade was initiated during normal renal function stage. After the initiation, his renal function has been normal with the very mild proteinuria to date at the age of 17 years. We propose that in Alport syndrome, RAAS blockade should be initiated earlier than renal function is impaired.

Wnt5a induces renal AQP2 expression by activating calcineurin signalling pathway.

Heritable nephrogenic diabetes insipidus (NDI) is characterized by defective urine concentration mechanisms in the kidney, which are mainly caused by loss-of-function mutations in the vasopressin type 2 receptor. For the treatment of heritable NDI, novel strategies that bypass the defective vasopressin type 2 receptor are required to activate the aquaporin-2 (AQP2) water channel. Here we show that Wnt5a regulates AQP2 protein expression, phosphorylation and trafficking, suggesting that Wnt5a is an endogenous ligand that can regulate AQP2 without the activation of the classic vasopressin/cAMP signalling pathway. Wnt5a successfully increases the apical membrane localization of AQP2 and urine osmolality in an NDI mouse model. We also demonstrate that calcineurin is a key regulator of Wnt5a-induced AQP2 activation without affecting intracellular cAMP level and PKA activity. The importance of calcineurin is further confirmed with its activator, arachidonic acid, which shows vasopressin-like effects underlining that calcineurin activators may be potential therapeutic targets for heritable NDI.