Irreversible Dysfunction Research Articles

Organic acidurias in adults: late complications and management.

Organic acidurias (synonym, organic acid disorders, OADs) are a heterogenous group of inherited metabolic diseases delineated with the implementation of gas chromatography/mass spectrometry in metabolic laboratories starting in the 1960s and 1970s. Biochemically, OADs are characterized by accumulation of mono-, di- and/or tricarboxylic acids ("organic acids") and corresponding coenzyme A, carnitine and/or glycine esters, some of which are considered toxic at high concentrations. Clinically, disease onset is variable, however, affected individuals may already present during the newborn period with life-threatening acute metabolic crises and acute multi-organ failure. Tandem mass spectrometry-based newborn screening programmes, in particular for isovaleric aciduria and glutaric aciduria type 1, have significantly reduced diagnostic delay. Dietary treatment with low protein intake or reduced intake of the precursor amino acid(s), carnitine supplementation, cofactor treatment (in responsive patients) and nonadsorbable antibiotics is commonly used for maintenance treatment. Emergency treatment options with high carbohydrate/glucose intake, pharmacological and extracorporeal detoxification of accumulating toxic metabolites for intensified therapy during threatening episodes exist. Diagnostic and therapeutic measures have improved survival and overall outcome in individuals with OADs. However, it has become increasingly evident that the manifestation of late disease complications cannot be reliably predicted and prevented. Conventional metabolic treatment often fails to prevent irreversible organ dysfunction with increasing age, even if patients are considered to be "metabolically stable". This has challenged our understanding of OADs and has elicited the discussion on optimized therapy, including (early) organ transplantation, and long-term care.

Early Detection of Subclinical Myocardial Damage in Chronic Aortic Regurgitation and Strategies for Timely Treatment of Asymptomatic Patients.

A series of hemodynamic and pathological responses occur in chronic aortic regurgitation, which eventually result in myocardial fibrosis and irreversible left ventricular dysfunction. According to guidelines, valvular surgery is recommended with the development of symptoms, left ventricular systolic dysfunction, or left ventricular dilatation. The optimal timing of surgical intervention has recently been questioned with documentation of irreversible myocardial damage resulting in incomplete left ventricular recovery and adverse clinical outcomes after surgery. Recognizing the shortcomings of the guidelines, we performed a comprehensive review on the novel diagnostic methods that have been shown to improve the detection of subclinical ventricular dysfunction in chronic aortic regurgitation and to improve prediction of outcomes.

Early treatment for IgG4-related disease may prevent cognitive impairment caused by cerebral vasculitis: A case report and review of the literature

IgG4-related disease (IgG4-RD) is a recently recognized disease entity. A 74-year-old male presented with transient headache. He was diagnosed IgG4-RD by pancreatic biopsy at the age of 72. Magnetic Resonance Imaging (MRI) showed disseminated cerebral microbleeds and microinfarctions in time and space. It suggested cerebral vasculitis, however any causative factor were not confirmed. IgG4-RD rarely causes cerebral vasculitis. This might be a first case of an asymptomatic cerebral vasculitis due to IgG4-RD. Patient was started on oral prednisolone, and no neurological or neuropsychological symptom was clinically observed. The MRI findings improved after treatment, and revealed no indication of newly lesions at 6-months follow-up. Early treatment for IgG4-RD may be recommended to prevent irreversible cognitive dysfunction.

PREDICTION OF LEFT VENTRICULAR SYSTOLIC AND DIASTOLIC FUNCTIONS SIX MONTHS FOLLOWING MITRAL VALVE REPLACEMENT USING NEW ECHO DOPPLER INDICES

The development of left ventricular dysfunction is a major concern in the management of patients withsevere mitral regurgitation. In the initial stages, contractility impairment may be ‘‘invisible’’ by the traditional methodsto assess the ventricular function, because of different loading conditions. This fact can mask the presence of LVdysfunction. Sometimes, LV dysfunction may be ‘‘unmasked’’ only by change in loading conditions after surgicalcorrection, leading to the development of overt LV dysfunction and congestive heart failure. The identification ofcontractile dysfunction at an early stage and surgical correction may avoid the development of irreversible postoperativeLV dysfunction.

Evaluation of Hepatoprotective Effect of Curcumin on Liver Cirrhosis Using a Combination of Biochemical Analysis and Magnetic Resonance-Based Electrical Conductivity Imaging.

In oriental medicine, curcumin is used to treat inflammatory diseases, and its anti-inflammatory effect has been reported in recent research. In this feasibility study, the hepatoprotective effect of curcumin was investigated using a rat liver cirrhosis model, which was induced with dimethylnitrosamine (DMN). Together with biochemical analysis, we used a magnetic resonance-based electrical conductivity imaging method to evaluate tissue conditions associated with a protective effect. The effects of curcumin treatment and lactulose treatment on liver cirrhosis were compared. Electrical conductivity images indicated that liver tissues damaged by DMN showed decreased conductivity compared with normal liver tissues. In contrast, cirrhotic liver tissues treated with curcumin or lactulose showed increased conductivity than tissues in the DMN-only group. Specifically, conductivity of cirrhotic liver after curcumin treatment was similar to that of normal liver tissues. Histological staining and immunohistochemical examination showed significant levels of attenuated fibrosis and decreased inflammatory response after both curcumin and lactulose treatments compared with damaged liver tissues by DMN. The conductivity imaging and biochemical examination results indicate that curcumin's anti-inflammatory effect can prevent the progression of irreversible liver dysfunction.

Investigation of markers for myocardial remodeling during experimental hypobaric hypoxia in the correction with cytoflavin

To reveal the peculiarities of changes in the markers of myocardial remodeling in experimental hypobaric hypoxia. The investigation was conducted on 26 mature male Wistar rats weighing 220-310 g, which were divided into 3 groups: 1) 6 intact animals; 2) 10 rats that were exposed to 30-day simulated hypobaric hypoxia without correction; 3) 10 rats that were given once-daily intraperitoneal injections of cytoflavin solution at a rate of 0.5 ml/100 g of body weight for 30 days before immersion in a hypobaric chamber. The early stages of myocardial remodeling in hypobaric hypoxia were found to be characterized by structural re-systematization of the components of the normal ventricular wall, which was manifested by cardiomyocyte hypertrophy and ischemia; circulatory disorders; fibroblast proliferation that dramatically enhances the extracellular expression of protein matrix, which can lead to the formation of fibrous tissue and irreversible myocardial dysfunction. Elevated matrix metalloproteinase levels are evidence for collagen degradation and cardiac remodeling. In the authors' opinion, the cyto- and angioprotective effects of cytoflavin in rats treated with the latter used in combination therapy are associated with the composition of the drug, the active components of which have mutually potentiating effects, are inducers of the major metabolic pathways in the cells and are also activators of key energy-generating processes. Identification of the molecular mechanisms of myocardial remodeling is of great practical importance. This enables remodeling markers to be considered as a potential therapeutic target in the treatment of hypoxia-induced myocardial injury.

Satisfaction with the semirigid penile prosthesis among couples from a Semiurban Indian population

Introduction: Insertion of penile prosthesis for treatment of irreversible erectile dysfunction (ED) is a common and well-established treatment in the western countries. Even in the times of the newly available oral medications, penile prostheses continue to have such a nonoptional place in the management of severe ED. In this study, we have assessed the satisfaction among semiurban Indian couples following insertion of the semirigid penile prosthesis. Materials and Methods: Between January 2000 and December 2015, 78 men with ED underwent semirigid penile prosthesis implantation (PPI) at our hospital. The satisfaction of patients and partners was evaluated using the ED Inventory of Treatment Satisfaction (EDITS) questionnaire and EDITS partner survey. Results: The mean age of the patients was 44.84 ± 7.30 years. The mean duration of time with ED in the preimplantation period was 38.69 ± 12.44 months. The satisfaction of patients and partners as assessed by EDITS questionnaire and EDITS partner survey was 80.66 ± 4.49 and 75.66 ± 6.57, respectively, at 12 months after surgery and 71.73 ± 8.10 and 65.6 ± 6.49, respectively, at 24 months after surgery. Conclusions: This study showed a high degree of satisfaction among patients as well as their partners with semirigid PPI. More than 80% of the men reported being very satisfied with their penile implantation surgery.

Guiding Lights in Genome Editing for Inherited Retinal Disorders: Implications for Gene and Cell Therapy

Inherited retinal dystrophies (IRDs) are a leading cause of visual impairment in the developing world. These conditions present an irreversible dysfunction or loss of neural retinal cells, which significantly impacts quality of life. Due to the anatomical accessibility and immunoprivileged status of the eye, ophthalmological research has been at the forefront of innovative and advanced gene- and cell-based therapies, both of which represent great potential as therapeutic treatments for IRD patients. However, due to a genetic and clinical heterogeneity, certain IRDs are not candidates for these approaches. New advances in the field of genome editing using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated protein (Cas) have provided an accurate and efficient way to edit the human genome and represent an appealing alternative for treating IRDs. We provide a brief update on current gene augmentation therapies for retinal dystrophies. Furthermore, we discuss recent advances in the field of genome editing and stem cell technologies, which together enable precise and personalized therapies for patients. Lastly, we highlight current technological limitations and barriers that need to be overcome before this technology can become a viable treatment option for patients.

Pine wilt disease causes cavitation around the resin canals and irrecoverable xylem conduit dysfunction

Physiological mechanisms of irreversible hydraulic dysfunction in seedlings infected with pine wilt disease (PWD) are still unclear. We employed cryo-scanning electron microscopy (cryo-SEM) to investigate the temporal and spatial changes in water distribution within the xylem of the main stem of 2-year-old Japanese black pine seedlings infested by pine wood nematodes (PWNs). Our experiment was specifically designed to compare the water relations among seedlings subjected to the following water treatment and PWN combinations: (i) well-watered versus prolonged drought (no PWNs); and (ii) well-watered with PWNs versus water-stressed with PWNs (four treatments in total). Cryo-SEM imaging observations chronicled the development of patchy cavitations in the xylem tracheids of the seedlings influenced by PWD. With the progression of drought, many pit membranes of bordered pits in the xylem of the main stem were aspirated with the decrease in water potential without xylem cavitation, indicating that hydraulic segmentation may exist between tracheids. This is the first study to demonstrate conclusively that explosive and irreversible cavitations occurred around the hydraulically vulnerable resin canals with the progression of PWD. Our findings provide a more comprehensive understanding of stressors on plant-water relations that may eventually better protect trees from PWD and assist with the breeding of trees more tolerant to PWD.

CRISPR-Cas9 HDR system enhances AQP1 gene expression.

Ionizing radiation (IR) isthe primarytherapeutic tool to treat patients with cancerous lesions located in the head and neck. In many patients, IR results in irreversible and severe salivary gland dysfunction or xerostomia. Currently there are no effective treatment options to reduce the effects of xerostomia. More recently, salivary gland gene therapy utilizing the water-specific protein aquaporin 1 (AQP1) has been of great interest to potentially correct salivary dysfunction. In this study, we used CRISPR-Cas9 gene editing along with the endogenous promoter of AQP1 within theHEK293 and MDCK cell lines. The successful integration of the cytomegalovirus (CMV) promoterresultedin a significant increase of AQP1 gene transcription and translation. Additionalfunctional experiments involvingthe MDCK cell line confirmedthat over-expressed AQP1increasedtransmembrane fluid flux indicative of increased intracellular fluid flux. The off-target effect of designed guided RNA sequence was analyzed and demonstrateda high specificity for the Cas9 cleavage. Considering the development of new methods for robust DNA knock-in, our results suggest that endogenous promoter replacement may be a potential treatment forsalivary gland dysfunction.

Chalk-induced Lung Fibrosis — Case Report

Abstract Introduction: Our article underlines the importance of a good professional anamnesis, knowing all the chemical components with which the patient had been exposed to during her active life as a teacher. Case presentation: A 64-year-old female patient, teacher for 27 years, who had been retired for six years, presented cough with white phlegm and shortness of breath occurring during physical exertion, diffuse thoracic pain, and fatigue. Several lung functional tests were performed, which established the diagnosis of irreversible minor mixed ventilatory dysfunction. In order to establish the etiology of the patient’s symptoms, multiple clinical, laboratory, imaging, and functional investigations were performed including a chest radiograph, pulmonary functional testing, bronchial reversibility testing, a thoracic CT scan, fibrobronchoscopy, alveolar-capillary diffusion capacity measurement, otorhinolaryngology examination, thyroid ultrasound, as well as a cardiological consult. Finally, a positive diagnosis was established: bronchial hyperreactivity syndrome, chalk dust-induced diffuse pulmonary fibrosis. Conclusion: An essential part of clinical practice is a proper anamnesis, including detailed information on the professional history and exposure, as well as the composition of the dust/particles with which the patient had been in contact with.

Heart functional and structural compendium of cardiosplenic and cardiorenal networks in acute and chronic heart failure pathology.

Heart failure (HF) secondary to myocardial infarction (MI) is linked to kidney complications that comprise cellular, structural, functional, and survival indicators. However, HF research is focused on left ventricular (LV) pathology. Here, we determined comprehensive functional analysis of the LV using echocardiography in transition from acute heart failure (AHF) to progressive chronic heart failure (CHF) pathology and developed a histological compendium of the cardiosplenic and cardiorenal networks in pathological remodeling. In surgically induced MI using permanent coronary ligation, the LV dysfunction is pronounced, with myocardium necrosis, wall thinning, and 20-30% LV rupture events that indicated AHF and CHF pathological remodeling in C57BL/6 male mice (2-4 mo old, n = 50). Temporal LV function analysis indicated that fractional shortening and strain are reduced from day 1 to day 5 in AHF and sustained to advance to CHF from day 28 to day 56 compared with naïve control mice ( n = 6). During the transition of AHF ( day 1 to day 5) to advanced CHF ( day 28 to day 56), histological and cellular changes in the spleen were definite, with bimodal inflammatory responses in kidney inflammatory biomarkers. Likewise, there was a unidirectional, progressive, and irreversible deposition of compact collagen in the LV along with dynamic changes in the cardiosplenic and cardiorenal networks post-MI. The renal histology and injury markers suggested that cardiac injury triggers irreversible dysregulation that actively alters the cardiosplenic and cardiorenal networks. In summary, the novel strategies or pathways that modulate comprehensive cardiosplenic and cardiorenal networks in AHF and CHF would be effective approaches to study either cardiac repair or cardiac pathology. NEW & NOTEWORTHY The present compendium shows irreversible ventricular dysfunction as assessed by temporal echocardiography while histological and structural measurements of the spleen and kidney added a novel direction to study cardiosplenic and cardiorenal networks in heart failure pathology. Therefore, the consideration of systems biology and integrative approach is essential to develop novel treatments.

Post-Extrasystolic Potentiation asaPredictor of Recovery of LeftVentricularDysfunction After Radiofrequency Catheter Ablation.

This study hypothesizes that post-extrasystolic potentiation reflects left ventricle contractile reserve and therefore may predict an improvement of premature ventricular contraction (PVC)-induced cardiomyopathy after PVC ablation. Post-extrasystolic potentiation is a physiologic phenomenon of blood pressure accentuation after a PVC beat. We performed a retrospective study of patients with a PVC burden of≥10% PVC/24 h and left ventricular ejection fraction (LVEF) of<50% who underwent successful ablation between January 1, 2009, to June 30, 2015. Subjects were classified as having reversible (a final LVEF≥50%) or irreversible (final LVEF<50%) LV dysfunction on a follow-up echocardiogram. A reference (control) group with≥10% PVC but normal LV function was also identified. Sixty-one patients (age 68 ± 11 years, 98% male) were studied: 30 with preserved and 31 with reduced LVEF. During median follow-up of 9.4 months, the LVEF of 17 of 31 reduced EF patients improved (reversible) but 14 did not (irreversible). The post-PVC beat systolic blood pressure (SBP) (mmHg) increase ranged from 12.1 in control subjects (LVEF >50%) to 11.5 in reversible patients to 5 in irreversible patients. In multivariate analysis, the independent predictors of reversible LV function were post-PVC SBP rise (odds ratio [OR]: 4.61; 95% confidence interval [CI]: 1.45 to 15.83 per 5-mm Hg increase; p< 0.001), post-PVC pulse pressure change (OR: 5.2; 95% CI: 2.3 to 18.6 per 5-mm Hg increase; p< 0.001), and PVC QRS duration (OR: 2.78; 95% CI: 1.63 to 10.94 per 10-ms increase; p< 0.001). In patients with LV dysfunction and frequent PVC, post-PVC SBP accentuation may be a marker forsubsequent recovery of LVEF after ablation in presumed PVC-induced cardiomyopathy.

Glutamine ameliorates lipopolysaccharide-induced cardiac dysfunction by regulating the toll-like receptor 4/mitogen-activated protein kinase/nuclear factor-kB signaling pathway.

The inflammatory response of sepsis induced by lipopolysaccharide (LPS) may result in irreversible cardiac dysfunction. Glutamine (GLN) has a multitude of pharmacological effects, including anti-inflammatory abilities. Previous studies have reported that GLN attenuated LPS-induced acute lung injury and intestinal mucosal injury. The present study investigated whether GLN exerts potential protective effects on LPS-induced cardiac dysfunction. Male Sprague-Dawley rats were divided into three groups (15 rats per group), including the control (saline-treated), LPS and LPS+GLN groups. Pretreatment with 1 g/kg GLN was provided via gavage for 5 days in the LPS+GLN group, while the control and LPS groups received the same volume of normal saline. On day 6, a cardiac dysfunction model was induced by administration of LPS (10 mg/kg). After 24 h, the cardiac functions of the rats that survived were detected by echocardiography and catheter-based measurements. The serum levels of tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 were detected by enzyme-linked immunosorbent assay, while the mRNA levels of toll-like receptor (TLR)4, TNF-α, IL-1β and IL-6 were examined by reverse transcription-quantitative polymerase chain reaction. The protein expression of TLR4, mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) were also determined by western blot analysis. The results of echocardiography and catheter-based measurements revealed that GLN treatment attenuated cardiac dysfunction. GLN treatment also attenuated the serum and mRNA levels of the pro-inflammatory cytokines. In addition, the protein levels of TLR4, phosphorylated (p-)extracellular signal-regulated kinase, p-c-Jun N-terminal kinase and p-P38 were reduced upon GLN pretreatment. Furthermore, GLN pretreatment resulted in decreased activation of the NF-κB signaling pathway. In conclusion, GLN has a potential therapeutic effect in the protection against cardiac dysfunction mediated by sepsis through regulating the TLR4/MAPK/NF-κB signaling pathway.

O4-5 - A Rare Case of Continuous Closure of The Aortic Valve in Patient with Acute Fulminant Myocarditis

A 68-year-old male, who was diagnosed as fulminant myocarditis was transferred to our hospital. After admission, intra-aortic balloon pumping (IABP) and percutaneous cardiopulmonary support (PCPS) were introduced due to cardiogenic shock. The 3rd day, echocardiography revealed continuous closure of the aortic valve and spontaneous echo contrast on that. LV vent catheter was inserted to avoid severe pulmonary edema and irreversible LV dysfunction. After 19 days of cardiopulmonary support, His cardiac function improved gradually and he weaned from PCPS. After a termination of deep sedation, Right hemiparesis was appeared and brain CT revealed multiple cerebral infarction. Thrombus on the valve was considered to be the cause of cerebral infarction. This case suggests that the aortic valve opening is important to avoid thromboembolic complications in patients with fulminant myocarditis under PCPS.

(Re-)programming of subtype specific cardiomyocytes.

Adult cardiomyocytes (CMs) possess a highly restricted intrinsic regenerative potential - a major barrier to the effective treatment of a range of chronic degenerative cardiac disorders characterized by cellular loss and/or irreversible dysfunction and which underlies the majority of deaths in developed countries. Both stem cell programming and direct cell reprogramming hold promise as novel, potentially curative approaches to address this therapeutic challenge. The advent of induced pluripotent stem cells (iPSCs) has introduced a second pluripotent stem cell source besides embryonic stem cells (ESCs), enabling even autologous cardiomyocyte production. In addition, the recent achievement of directly reprogramming somatic cells into cardiomyocytes is likely to become of great importance. In either case, different clinical scenarios will require the generation of highly pure, specific cardiac cellular-subtypes. In this review, we discuss these themes as related to the cardiovascular stem cell and programming field, including a focus on the emergent topic of pacemaker cell generation for the development of biological pacemakers and in vitro drug testing.

Long-term kidney transplant survival in patients with continent urinary diversion.

To report the long-term survival of transplanted kidneys in patients with a continent urinary diversion. Between January 1987 and July 2015, 16 patients with a median age of 37 years (range 21-63 years) underwent kidney transplantation on a continent urinary diversion. A total of 14 patients presented irreversible dysfunction of the lower urinary tract, and two patients had required radical cystectomy because of bladder cancer. All continent urinary diversions were carried out before the transplantation. There were nine Kock pouches, five Mainz pouches, one Mainz neobladder and one Hautmann neobladder. A total of 11 patients had a previous non-continent urinary diversion. Of the transplants, 14 came from brain-dead donors and two from related living donors. The median post-transplantation follow up was 171 months (range 30-298 months). Two patients died, while six patients lost their transplant and resumed hemodialysis. Nine patients (56.2%) were alive with a functional transplant at the end of follow up. The most common allograft complication was acute pyelonephritis, but no graft was lost as a result of urinary diversion complications. The kidney transplant survival rate was 73.3% after 10 years, and 66.6% after 15 years. Among patients who still had a functional transplant at the time of the study, creatinine clearance was >30 mL/min for seven patients and <30 mL/min for two patients. The present study is the longest series to date of renal transplantation on continent urinary diversions. The long-term outcome shows that the presence of a continent urinary diversion does not reduce transplant survival.

Deformation Analysis of Myocardial Layers Detects Early Cardiac Dysfunction after Chemotherapy in Bone Marrow Transplantation Patients: A Continuous and Additive Cardiotoxicity Process

Chemotherapy-induced cardiotoxicity has not been extensively validated in bone marrow transplantation (BMT) patients. Speckle-tracking echocardiography is a sensitive method for the detection of subclinical cardiac dysfunction. Cardiac function was prospectively assessed in 80 patients (44 men; mean age, 45±11years) after BMT for non-Hodgkin's lymphoma and acute or chronic myeloid leukemia by means of various echocardiographic techniques. Before chemotherapy for BMT, 89% of the patients had previously been treated with anthracyclines. Patients had normal left ventricular ejection fraction (LVEF). Left ventricular (LV) global longitudinal strain (GLS), subendocardial and subepicardial longitudinal strain, circumferential strain, LV twist, and right ventricular GLS were measured by speckle-tracking, and (2) three-dimensionally derived LVEF and right ventricular ejection fraction were also assessed. Abnormal LVEF was defined as <53%. Studies were performed before (baseline) and 1, 3, 6, and 12months after chemotherapy conditioning followed by BMT. Impaired LV GLS values were observed at 1month after chemotherapy and at 3, 6, and 12months compared with baseline (-20 ±2.2% at baseline, -18.4 ±2.1% at 1month, -17.3 ±2.2% at 3months, -17.1 ±2.1% at 6months, and -17.1 ±2.2% at 12months; P=.001). Early LV GLS changes were driven mostly by changes in subendocardial longitudinal strain (-22.5 ±2.4% at baseline, -20.5 ±2.3% at 1month, -19.2 ±2.3% at 3months, -19.2 ±2.4% at 6months, and -19.1±2.4 at 12months; P=.001), whereas significant subepicardial strain changes were observed at 3months after BMT. Compared with baseline, right ventricular GLS was also impaired early after chemotherapy. Compared with baseline, LVEF was slightly reduced (P=.02) at the end of the follow-up. Among echocardiographic markers, LV GLS at 1month had the strongest predictive value for abnormal LVEF (<53%) at 12months (area under the curve 0.86; 95% CI, 0.76-0.96). A cutoff LV GLS value of -18.4% had sensitivity of 84.6% and specificity of 71.9% for the identification of abnormal LVEF at the end of follow-up. In BMT patients, myocardial deformation analysis detected early and progressive subclinical cardiac dysfunction. Impaired LV GLS had predictive value for the detection of abnormal LVEF at 12-month follow-up. Thus, myocardial deformation study should be applied early after BMT to prevent irreversible cardiac dysfunction by appropriate treatment.

A longitudinal evaluation of health-related quality of life in patients with AL amyloidosis: associations with health outcomes over time.

SummaryLight chain (AL) amyloidosis is a rare disease associated with significant, irreversible organ dysfunction and high case fatality. An observational study was conducted to assess health‐related quality of life (HRQoL) in patients treated for AL amyloidosis between 1994 and 2014 with both high dose melphalan and stem cell transplantation (HDM/SCT) or non‐SCT chemotherapy regimens. The SF‐36v1® Health Survey (SF‐36) was administered to assess HRQoL during clinic visits. Analysis of variance was used to compare pre‐ and post‐treatment HRQoL within each treatment group to an age‐ and gender‐adjusted general population (GP) normative sample. Cox proportional hazard models were fit to examine associations between pre‐treatment levels of HRQoL and mortality within 1 and 5 years after initiating specific treatment regimens (HDM/SCT: n = 402; non‐SCT chemotherapy regimens: n = 172). Among patients who received HDM/SCT, there were significant improvements following treatment in vitality, social functioning, role‐emotional and mental health. Worse pre‐treatment SF‐36 physical component scores were associated with a greater risk of mortality in both treatment groups and follow‐up periods (P ≤ 0·005 for both). [Correction added on 20 October 2017, after first online publication: This P value has been corrected]. Using HRQoL assessments in every physician visit or treatment may provide valuable insights for treating rare conditions like AL amyloidosis.

NFAT3/c4-mediated excitotoxicity in hippocampal apoptosis during radiation-induced brain injury.

Whole brain irradiation (WBI) has become an indispensible tool in the treatment of head and neck cancer, and it has greatly improved patient survival rate and total survival time. In addition, prophylactic cranial irradiation (PCI) has dramatically decreased the incidence of brain metastatic carcinoma. However, WBI may induce temporary functional deficits or even progressive, irreversible cognitive dysfunction that compromises the quality of life for survivors. Unfortunately, the exact molecular mechanisms for cognitive damage remain elusive, and no treatment or preventative measures are available for use in the clinic. In the present study, the nuclear factor of activated T cells isoform 4 (NFAT3/c4) was found to play a vital role in excitotoxic hippocampus cell apoptosis induced by radiation. Sprague–Dawley (SD) rats received 20 Gy WBI, after which we detected NFAT3/c4-mediated excitotoxicity. We found that radiation caused hippocampus excitotoxicity, resulting from overactivation of the N-methyl-D-aspartate receptor (NMDAR) and always accompanied by subsequent elevation of the intracellular calcium level and activation of calcineurin (CaN). P-NFAT3/c4 was the principal downstream target of CaN, including regulation of its nuclear translocation as well as transcriptional activities. Radiation recruited NMDAR/NFAT3/c4 activation and subsequent Bax induction in hippocampus cells. Once treated with the NFAT3/c4 inhibitor 11R-VIVIT peptide pre-irradiation, hippocampal proliferation and neuron survival (dentate gyrus cells in particular) were protected from radiation-induced injury, resulting in inhibition of the apoptosis marker Bax. Our principal aim was to illuminate the role of NFAT3/c4-mediated excitotoxicity in hippocampal apoptosis during radiation-induced brain injury. This study is the first time that radiation-induced activation of NFAT3/c4 has been recorded, and our results suggest that NFAT3/c4 may be a novel target for prevention and treatment of radiation-induced brain injury.