mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.

Transaldolase deficiency predisposes to chronic liver disease progressing from cirrhosis to hepatocellular carcinoma (HCC). Transition from cirrhosis to hepatocarcinogenesis depends on mitochondrial oxidative stress, as controlled by cytosolic aldose metabolism through the pentose phosphate pathway (PPP). Progression to HCC is critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Although AR inactivation blocked susceptibility to hepatocarcinogenesis, it enhanced growth restriction, carbon trapping in the non-oxidative branch of the PPP and failed to reverse the depletion of glucose 6-phosphate (G6P) and liver cirrhosis. Here, we show that inactivation of the TAL-AR axis results in metabolic stress characterized by reduced mitophagy, enhanced overall autophagy, activation of the mechanistic target of rapamycin (mTOR), diminished glycosylation and secretion of paraoxonase 1 (PON1), production of antiphospholipid autoantibodies (aPL), loss of CD161+ NK cells, and expansion of CD38+ Ito cells, which are responsive to treatment with rapamycin in vivo. The present study thus identifies glycosylation and secretion of PON1 and aPL production as mTOR-dependent regulatory checkpoints of autoimmunity underlying liver cirrhosis in TAL deficiency.

Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.

Oxidative stress modulates carcinogenesis in the liver; however, direct evidence for metabolic control of oxidative stress during pathogenesis, particularly, of progression from cirrhosis to hepatocellular carcinoma (HCC), has been lacking. Deficiency of transaldolase (TAL), a rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway (PPP), restricts growth and predisposes to cirrhosis and HCC in mice and humans. Here, we show that mitochondrial oxidative stress and progression from cirrhosis to HCC and acetaminophen-induced liver necrosis are critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Both TAL and AR are confined to the cytosol; however, their inactivation distorts mitochondrial redox homeostasis in opposite directions. The results suggest that AR acts as a rheostat of carbon recycling and NADPH output of the PPP with broad implications for disease progression from cirrhosis to HCC.

Learning curve in robotic transabdominal preperitoneal (rTAPP) ventral hernia repair: a cumulative sum (CUSUM) analysis.

PURPOSE: rTAPP-VHR is a novel technique which may be added to a surgeon's armamentarium. We aim to evaluate the robotic transabdominal preperitoneal ventral hernia repair (rTAPP-VHR) learning curve based on operative times while accounting for peritoneal flap integrity. METHODS: We performed a retrospective analysis of a database collected over a 7-year period. Patients with primary ventral hernias were included and a cumulative sum analysis(CUSUM) was used to create learning curves for three subsets of operative times. A risk-adjusted CUSUM (RA-CUSUM) accounted for repair quality based on peritoneal flap completeness. The flap was considered as incomplete when peritoneal gaps were unable to be closed. RESULTS: 105 patients undergoing rTAPP-VHR were included. Learning curves were created for skin-to-skin, console, and off-console times. Patients were divided into three phases. In terms of skin-to-skin times, both phase 2&3 had a mean 11 min shorter than that of phase 1 (p = 0.0498, p = 0.0245, respectively), with a steady decrease after forty-six cases. An incomplete peritoneal flap was noted in 25/36 patients in phase 1, as compared to 5/24 and 5/45 patients in phase 2&3, respectively. When risk-adjusted for peritoneal flap completeness, gradually decreasing skin-to-skin times were observed after sixty-one cases. In terms of off-console times, the mean across three phases was 14 min, with marked improvement after forty-three cases. CONCLUSIONS: Forty-six cases were needed to achieve steadily decreasing operative times. We can assume that ensuring good-quality repairs, through maintenance of peritoneal flap integrity, was gradually improved after sixty-one cases. Moreover, familiarization with port placements and robotic docking was accomplished after forty-three cases.

Extended approach or usage of nasoseptal flap is a risk factor for olfactory dysfunction after endoscopic anterior skullbase surgery: results from 928 patients in a single tertiary center.

BACKGROUND: The aim of this study was to compare olfactory function change in patients who underwent endoscopic skull-base surgery. METHODOLOGY: A total of 928 patients were included in this retrospective study. Olfactory function was measured using the non- validated Likert scale (0â€"100), the Cross-Cultural Smell Identification Test (CC-SIT) and the butanol threshold test (BTT). Patients were divided into two groups: an endoscopic trans-sellar approach group (ETA, n = 768) and an extended endoscopic endonasal approach group (EEEA, n = 160). The ETA group was sub-divided into Nasoseptal flap (NSF) and no NSF groups. RESULTS: Non-validated olfactory function significantly worsened in the EEEA and ETA-NSF groups compared with that in the ETA- no NSF group for at least 6 months post-operatively. Validated olfactory impairment (BTT and CC-SIT) was also significantly worse in the EEEA and NSF groups compared with that in the ETA-no NSF group 3 months post-operatively. Additionally, the degrees of non-validated and validated olfactory deterioration were not significantly different between the EEEA and ETA-NSF groups. We also found that CC-SIT score changes were significantly impaired in tuberculum sellae meningioma patients than in craniopharyn- gioma patients. CONCLUSIONS: We conclude that NSF was the key factor that led to olfactory impairment after endoscopic skull-base surgery.

Distinctive genomic signature of neural and intestinal organoids from familial Parkinson's disease patient-derived induced pluripotent stem cells.

AIMS: The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is the most common genetic cause of Parkinson's disease (PD). There is compelling evidence that PD is not only a brain disease but also a gastrointestinal disorder; nonetheless, its pathogenesis remains unclear. We aimed to develop human neural and intestinal tissue models of PD patients harbouring an LRRK2 mutation to understand the link between LRRK2 and PD pathology by investigating the gene expression signature. METHODS: We generated PD patient-specific induced pluripotent stem cells (iPSCs) carrying an LRRK2 G2019S mutation (LK2GS) and then differentiated into three-dimensional (3D) human neuroectodermal spheres (hNESs) and human intestinal organoids (hIOs). To unravel the gene and signalling networks associated with LK2GS, we analysed differentially expressed genes in the microarray data by functional clustering, gene ontology (GO) and pathway analyses. RESULTS: The expression profiles of LK2GS were distinct from those of wild-type controls in hNESs and hIOs. The most represented GO biological process in hNESs and hIOs was synaptic transmission, specifically synaptic vesicle trafficking, some defects of which are known to be related to PD. The results were further validated in four independent PD-specific hNESs and hIOs by microarray and qRT-PCR analysis. CONCLUSION: We provide the first evidence that LK2GS also causes significant changes in gene expression in the intestinal cells. These hNES and hIO models from the same genetic background of PD patients could be invaluable resources for understanding PD pathophysiology and for advancing the complexity of in vitro models with 3D expandable organoids.

Anxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac.

Intracellular cAMP and serotonin are important modulators of anxiety and depression. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) also known as Prozac, is widely used against depression, potentially by activating cAMP response element-binding protein (CREB) and increasing brain-derived neurotrophic factor (BDNF) through protein kinase A (PKA). However, the role of Epac1 and Epac2 (Rap guanine nucleotide exchange factors, RAPGEF3 and RAPGEF4, respectively) as potential downstream targets of SSRI/cAMP in mood regulations is not yet clear. Here, we investigated the phenotypes of Epac1 (Epac1(-/-)) or Epac2 (Epac2(-/-)) knockout mice by comparing them with their wild-type counterparts. Surprisingly, Epac2(-/-) mice exhibited a wide range of mood disorders, including anxiety and depression with learning and memory deficits in contextual and cued fear-conditioning tests without affecting Epac1 expression or PKA activity. Interestingly, rs17746510, one of the three single-nucleotide polymorphisms (SNPs) in RAPGEF4 associated with cognitive decline in Chinese Alzheimer's disease (AD) patients, was significantly correlated with apathy and mood disturbance, whereas no significant association was observed between RAPGEF3 SNPs and the risk of AD or neuropsychiatric inventory scores. To further determine the detailed role of Epac2 in SSRI/serotonin/cAMP-involved mood disorders, we treated Epac2(-/-) mice with a SSRI, Prozac. The alteration in open field behavior and impaired hippocampal cell proliferation in Epac2(-/-) mice were alleviated by Prozac. Taken together, Epac2 gene polymorphism is a putative risk factor for mood disorders in AD patients in part by affecting the hippocampal neurogenesis.

Clinical implications of serum galactomannan measurement in patients with acute invasive fungal rhinosinusitis.

BACKGROUND: Acute invasive fungal rhinosinusitis (AIFR) is an aggressive opportunistic infection with a high mortality rate. Recently, non-invasive techniques have been introduced for diagnosis of invasive fungal disease. The purpose of this study is to evaluate the diagnostic significance of serum galactomannan measurement in patients with AIFR. METHODOLOGY: We conducted a retrospective case-control study of 28 patients with AIFR and 36 fungus ball (FB) patients. We evaluated clinical, laboratory, and pathologic findings along with disease course. RESULTS: In 28 patients with AIFR, there were 21 cases of invasive aspergillosis (IA) and 7 cases of invasive mucormycosis (IM). The control group was comprised of 36 patients with FB. The three-group analysis showed a statistically significant difference among the groups. At the cut-off value of 0.48, the sensitivity and specificity were 71.4% and 93.0%, respectively. Comparison of mean serum galactomannan levels in 5 non-survivors and 9 survivors at initial measurement showed no significant difference, but that became significantly different 1 week later. Statistical analysis showed that the levels of serum galactomannan decreased significantly according to the measurement-point in within survivor-group analysis. The difference in between survivor-groups analysis was also significant. CONCLUSION: Serum galactomannan measurement seems useful for early diagnosis and discrimination of fungal species in patients with AIFR. In addition, clinical outcomes may be related to the levels and patterns of serum galactomannan, especially in IA. The appropriate measurement of galactomannan might be helpful in treating the patients at high risk for AIFR.

Ethnicity can predict GLRA1 genotypes in hyperekplexia.

OBJECTIVES: Hyperekplexia is predominantly caused by mutations in the α-1 subunit of the inhibitory glycine receptor (GLRA1). Three quarters of cases show autosomal-recessive inheritance. METHODS: We carefully ascertained reports of ethnicity from our hyperekplexia research cohort. These were compared with all published cases of hyperekplexia with an identified genetic cause. Ethnicities were subgrouped as Caucasian, Asian, Arabic, Turkish, Jewish or Afro-American. RESULTS: We report the ethnicity of 90 cases: 56 cases from our service augmented by 34 cases from the literature. Homozygous deletions of exons 1 to 7 are predominantly seen in people with Turkish backgrounds (n=16/17, p<0.001). In contrast, the dominant point mutation R271 is seen in people of Asian, Caucasian and African-American heritage (n=19) but not in people with Arab or Turkish ethnicities (p<0.001). CONCLUSIONS: Self-declared ethnicity can predict gene-screening outcomes. Cultural practices influence the inheritance patterns and a Caucasian founder is postulated for R271 mutations.

The emerging role of endothelin-1 in the pathogenesis of subchondral bone disturbance and osteoarthritis.

Mounting evidence suggests reconceptualizing osteoarthritis (OA) as an inflammatory disorder. Trauma and obesity, the common risk factors of OA, could trigger the local or systemic inflammatory cytokines cascade. Inflammatory bone loss has been well documented; yet it remains largely unknown about the link between the inflammation and hypertrophic changes of subchondral bone seen in OA, such as osteophytosis and sclerosis. Amid a cohort of inflammatory cytokines, endothelin-1 (ET-1) could stimulate the osteoblast-mediated bone formation in both physiological (postnatal growth of trabecular bone) and pathological conditions (bone metastasis of prostate or breast cancer). Also, ET-1 is known as a mitogen and contributes to fibrosis in various organs, e.g., skin, liver, lung, kidney heart and etc., as a result of inflammatory or metabolic disorders. Subchondral bone sclerosis shared the similarity with fibrosis in terms of the overproduction of collagen type I. We postulated that ET-1 might have a hand in the subchondral bone sclerosis of OA. Meanwhile, ET-1 was also able to stimulate the production of matrix metalloproteinase (MMP)-1 and 13 by articular chondrocytes and synoviocytes, by which it might trigger the enzymatic degradation of articular cartilage. Taken together, ET-1 signaling may play a role in destruction of bone-cartilage unit in the pathogenesis of OA; it warrants further investigations to potentiate ET-1 as a novel diagnostic biomarker and therapeutic target for rescue of OA.

Extraocular muscle injury during endoscopic sinus surgery: a series of 10 cases at a single center.

BACKGROUND: Extraocular muscle (EOM) injury is a rare but serious complication of endoscopic sinus surgery (ESS). The aim of this study is to describe the clinical characteristics and course of EOM injury occurring during ESS. DESIGN: Retrospective case series. METHODS: Medical records and CT images of patients who suffered from EOM injury after ESS between 2006 and 2012 were retrospectively reviewed. Patient demographics, endoscopic anatomy, type of surgery (primary or revision), predisposing risk factors, site and extent of injury on CT imaging, and associated complications were evaluated. In addition, data regarding ophthalmologic management and clinical outcomes were collected. RESULTS: Ten patients with EOM injuries after ESS were included in this study. One patient was undergoing revision ESS. All patients sustained medial rectus muscle injury and one patient suffered concurrent ipsilateral inferior rectus muscle injury. A microdebrider was used in nine cases. Right-sided injury (90% of patients) was more prevalent than left-sided injury, and 70% of injured medial rectus muscles were completely transected. After subsequent strabismus surgery, 8/9 patients regained binocular single vision in primary gaze despite residual diplopia in some gaze positions. CONCLUSION: Although proper ophthalmologic surgery after EOM injury may improve deviation in the primary gaze position, none of the patients regained normal EOM movement. Therefore, prevention of this complication through adequate surgical technique and precautions is important.

The neglected co-star in the dementia drama: the putative roles of astrocytes in the pathogeneses of major neurocognitive disorders.

Alzheimer's disease (AD) and vascular dementia are the major causes of cognitive disorders worldwide. They are characterized by cognitive impairments along with neuropsychiatric symptoms, and that their pathogeneses show overlapping multifactorial mechanisms. Although AD has long been considered the most common cause of dementia, individuals afflicted with AD commonly exhibit cerebral vascular abnormalities. The concept of mixed dementia has emerged to more clearly identify patients with neurodegenerative phenomena exhibiting both AD and cerebral vascular pathologies-vascular damage along with ß-amyloid (Aß)-associated neurotoxicity and τ-hyperphosphorylation. Cognitive impairment has long been commonly explained through a 'neuro-centric' perspective, but emerging evidence has shed light over the important roles that neurovascular unit dysfunction could have in neuronal death. Moreover, accumulating data have been demonstrating astrocytes being the essential cell type in maintaining proper central nervous system functioning. In relation to dementia, the roles of astrocytes in Aß deposition and clearance are unclear. This article emphasizes the multiple events triggered by ischemia and the cytotoxicity exerted by Aß either alone or in association with endothelin-1 and receptor for advanced glycation end products, thereby leading to neurodegeneration in an 'astroglio-centric' perspective.

Evaluation of inferior turbinate outfracture outcomes using computed tomography.

BACKGROUND: Outfracture of the inferior turbinate (IT) presents numerous advantages, but it is generally believed that the lateralized IT will resume its original position. The purpose of this study was to evaluate the outcome of IT outfracture objectively using computed tomography (CT). METHODOLOGY: Fifteen patients who underwent bilateral IT outfracture for the removal of pituitary adenomas by the endonasal approach were enrolled. The angles between the lateral wall of the nasal cavity (NC) and IT on both sides were measured from CT scans before and at least 6 months after operation. In addition, we evaluated the effects of variables including age, thickness of IT attachment site and width of the nasal floor, on the angles. RESULTS: Regardless of the side where a Hardy retractor was placed, the angle between the lateral wall of the NC and IT decreased significantly within 6 months after the outfracture compared to preoperative values on both sides. Other variables showed no significant correlations with the angle between the IT and the lateral wall of the NC. CONCLUSION: The outfracture procedure effectively lateralized the IT and it maintained that position for at least 6 months after the operation.

The effectiveness of home-based individual tele-care intervention for stroke caregivers in South Korea.

PURPOSE: The purpose of this study was to develop effective intervention programmes that can reduce family caregiver burden as they provide care to stroke patients so that family caregivers can adapt to and deal with the new circumstances from the early stages of stroke. We also intended to verify the effectiveness of the developed programme. METHODS: This study employed a quasi-experimental design with a repeated-measures analysis. We included five hospitals specialized in stroke care in Seoul Metropolitan areas. Seventy-three patients from these hospitals agreed to participate in this study. RESULTS: The score of family caregiver burden decreased by 8.07 (±18.67) in the experimental group and increased by 1.65 (±7.47) in the control group, which was a significant difference (t=2.257, P=0.027) between pre- and post-intervention. The family caregiver burden of experimental group was significantly lower than the control group (F=3.649, P=0.033). CONCLUSIONS: The home-based individual tele-care intervention, in addition to the hospital-based group programme, was cost-effective and supportive in reducing family caregivers' burden by providing relevant information for their needs in timely manner.

The value of dual-time-point 18F-FDG PET/CT for identifying axillary lymph node metastasis in breast cancer patients.

OBJECTIVE: The sensitivity of 18-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) for detecting axillary lymph node (ALN) metastases in breast cancer is reported to be low. Several studies have shown, however, that dual-time-point (18)F-FDG PET imaging provides improved accuracy in the diagnosis of certain primary tumours when compared with single-scan imaging. The purpose of this study was to assess whether the use of dual-time-point (18)F-FDG PET/CT scans could improve the diagnostic accuracy of ALN metastasis in breast cancer. METHOD: The study included 171 breast cancer patients who underwent pre-operative (18)F-FDG PET/CT scans at 2 time-points, the first at 1 h after radiotracer injection and the second 3 h after injection. Where (18)F-FDG uptake was in the ALN perceptibly increased, the maximum standardised uptake values for both time-points (SUVmax1 and SUVmax2) and the retention index (RI) were calculated. Correlation between the PET/CT results and post-operative histological results was assessed. RESULTS: The performance of 1 h and 3 h PET/CT scans was equal, with sensitivity 60.3% and specificity 84.7%, in detecting ALN metastasis. Out of 171 patients, 60 had ALNs with increased (18)F-FDG uptake on 1 h or 3 h images. There was no significant difference in RI between the metastatic ALN-positive group and the node-negative group. The area under the receiver operating characteristic (ROC) curve for SUVmax1 was 0.90 (p<0.001) and 0.87 for SUVmax2 (p<0.001). CONCLUSION: Dual time-point imaging did not improve the overall performance of (18)F-FDG PET/CT in detecting ALN metastasis in breast cancer patients.

Predictive capabilities of serum eosinophil cationic protein, percentage of eosinophils and total immunoglobulin E in allergic rhinitis without bronchial asthma.

This study identified cut-off values for allergy markers for use in the diagnosis of allergic rhinitis in the absence of other allergic diseases. Total immunoglobulin E (IgE), eosinophil cationic protein (ECP) and the numbers of eosinophils were measured in serum samples from 442 patients with typical symptoms of allergic rhinitis. A definite diagnosis was made on the basis of the presence of specific IgE levels. Cut-off values with a maximal discrimination to diagnose allergic rhinitis were found to be 98.7 IU/ml, 24.7 µg/ml and 4.0% for total IgE, ECP and eosinophils, respectively. Sensitivity, specificity and odds ratio for these values were 75.2%, 69.7% and 6.93, respectively, for total IgE, 55.7%, 74.4% and 3.70 for ECP, and 57.5%, 72.0% and 3.47 for eosinophils. A composite score representing positive results for all three markers had a positive predictive value of 85.3%, with an odds ratio of 8.55. It was concluded that total serum IgE, ECP and eosinophil percentage are strong predictors of allergic rhinitis and the determination of cut-off values for these markers can aid in the diagnosis of allergic rhinitis in the clinical setting.