ABSTRACT
Cerebellar inhibitory interneurons are important regulators of neural circuit activity for diverse motor and nonmotor functions. The molecular layer interneurons (MLIs), consisting of basket cells (BCs) and stellate cells (SCs), provide dendritic and somatic inhibitory synapses onto Purkinje cells, respectively. They are sequentially generated in an inside-out pattern from Pax2+ immature interneurons, which migrate from the prospective white matter to the ML of the cortex. However, little is known about how MLI subtype identities and pool sizes are determined, nor are their contributions to motor learning well understood. Here, we show that GABAergic progenitors fated to generate both BCs and SCs respond to the Sonic hedgehog (Shh) signal. Conditional abrogation of Shh signaling of either sex inhibited proliferation of GABAergic progenitors and reduced the number of Pax2+ cells, whereas persistent Shh pathway activation increased their numbers. These changes, however, did not affect early born BC numbers but selectively altered the SC pool size. Moreover, genetic depletion of GABAergic progenitors when BCs are actively generated also resulted in a specific reduction of SCs, suggesting that the specification of MLI subtypes is independent of Shh signaling and their birth order and likely occurs after Pax2+ cells settle into their laminar positions in an inside-out sequence. Mutant mice with reduced SC numbers displayed decreased dendritic inhibitory synapses and neurotransmission onto Purkinje cells, resulting in an impaired acquisition of eyeblink conditioning. These findings also reveal an essential role of Shh signaling-dependent SCs in regulating inhibitory dendritic synapses and motor learning.SIGNIFICANCE STATEMENT The cerebellar circuit that enables fine motor learning involves MLIs of BCs and SCs, which provide dendritic and somatic inhibitory synapses onto Purkinje cells. Little is known about how their identities and numbers are determined, nor are their specific contributions to motor learning well understood. We show that MLI subtypes are specified independent of Shh signaling and their birth orders but appear to occur in their terminal laminar positions according to the inside-out sequence. This finding challenges the current view that MLI subtypes are specified sequentially at the progenitor level. We also demonstrate that dendritic inhibition by Shh signaling-dependent SC pool is necessary for motor learning.
Subject(s)
Hedgehog Proteins , Purkinje Cells , Animals , Cerebellum/physiology , Hedgehog Proteins/genetics , Hedgehog Proteins/metabolism , Interneurons/physiology , Mice , Prospective Studies , Purkinje Cells/physiologyABSTRACT
Folic acid exerts both anti-inflammatory and antifibrotic effects. Glycine N-methyltransferase (GNMT), the major folic acid-binding protein in the liver, is a crucial enzyme that regulates the cellular methylation process by maintaining S-adenosylmethionine levels. However, as yet neither the therapeutic effects of folic acid in renal fibrosis nor whether GNMT is involved in these folic acid-associated mechanisms has been investigated. First, the expression of GNMT was examined in human kidneys with or without obstructive nephropathy. Later, wild-type and GNMT knockout (GNMT-/-) mice were subjected to unilateral ureteral obstruction (UUO) and then treated with either folic acid or vehicle for 14 days. Renal tubular injury, inflammation, fibrosis, and autophagy were evaluated by histological analysis and Western blotting. We observed increased expression of GNMT in humans with obstructive nephropathy. Furthermore, UUO significantly increased the expression of GNMT in mice; in addition, it caused renal injury as well as the development of both hydronephrosis and tubular injury. These were all alleviated by folic acid treatment. In contrast, GNMT-/- mice exhibited exacerbated UUO-induced renal injury, but the protective effect of folic acid was not observed in GNMT-/- mice. We propose a novel role for folic acid in the treatment of renal fibrosis, which indicates that GNMT may be a therapeutic target.
Subject(s)
Glycine N-Methyltransferase , Kidney Diseases , Ureteral Obstruction , Animals , Humans , Mice , Fibrosis , Folic Acid/metabolism , Glycine N-Methyltransferase/genetics , Glycine N-Methyltransferase/metabolism , Kidney/metabolism , Kidney Diseases/drug therapy , Kidney Diseases/etiology , Kidney Diseases/metabolism , Liver/metabolism , S-Adenosylmethionine/metabolism , Ureteral Obstruction/complications , Ureteral Obstruction/drug therapy , Ureteral Obstruction/metabolismABSTRACT
OBJECTIVE: Gustatory function is frequently impaired in patients with chronic kidney disease (CKD), and the associated taste dysfunction contributes to compromised nutrition. Whether gustatory dysfunction is an underappreciated risk factor for frailty in patients with CKD remains unclear. The objective of this work was to examine the role of gustatory dysfunction as a risk factor for frailty in patients with CKD. METHODS: We prospectively enrolled patients with stage 3 or higher CKD from a single institute, with their gustatory function assessed using both objective (taste strip method) and subjective approaches, and frailty identified using the Edmonton frail scale, FRAIL scale, and Study of Osteoporotic Fracture (SOF) scale. Multiple regression analyses were performed to investigate whether results from gustatory function tests independently correlated with frailty. RESULTS: Among the enrolled patients with CKD, 14 (17.9%) were found to be frail. We discovered that higher taste strip scores, or better taste function, were significantly associated with a lower frail probability (odds ratio [OR] 0.74 per score, 95% confidence interval [CI] 0.57-0.97), independent of clinical features, while better subjective taste function (OR 0.84 per score, 95% CI 0.74-0.96) and better oral cavity intactness (OR, 0.94; 95% CI, 0.9-0.98) were similarly associated with a lower frail probability among patients with CKD. CONCLUSION: Gustatory dysfunction may be an important risk factor for frailty in patients with CKD. It is tempting to presume that interventions aiming to ameliorate such deficits may bear the potential of reducing frailty severity in this population with a high frailty burden.
Subject(s)
Frail Elderly/statistics & numerical data , Geriatric Assessment/methods , Renal Insufficiency, Chronic/complications , Taste Disorders/complications , Aged , Cohort Studies , Female , Humans , Male , Prospective Studies , Risk Factors , Taste Disorders/diagnosisABSTRACT
T helper (Th)2 cytokines such as interleukin (IL)-4 and IL-13 control immune function by acting on leukocytes. They also regulate multiple responses in non-hematopoietic cells. During pregnancy, IL-4 and IL-13 facilitate alveologenesis of mammary glands. This particular morphogenesis generates alveoli from existing ducts and requires substantial cell proliferation. Using 3D cultures of primary mouse mammary epithelial cells, we demonstrate that IL-4 and IL-13 promote cell proliferation, leading to enlargement of mammary acini with partially filled lumens. The mitogenic effects of IL-4 and IL-13 are mediated by STAT6 as inhibition of STAT6 suppresses cell proliferation and improves lumen formation. In addition, IL-4 and IL-13 stimulate tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). Prolonged treatment with these cytokines leads to increased IRS-1 abundance, which, in turn, amplifies IL-4- and IL-13-stimulated IRS-1 tyrosine phosphorylation. Through signaling crosstalk between IL-4/IL-13 and insulin, a hormone routinely included in mammary cultures, IRS-1 tyrosine phosphorylation is further enhanced. Lowering IRS-1 expression reduces cell proliferation, suggesting that IRS-1 is involved in IL-4- and IL-13-stimulated cell proliferation. Thus, a Th2-dominant cytokine milieu during pregnancy confers mammary gland development by promoting cell proliferation.
Subject(s)
Cell Culture Techniques, Three Dimensional/methods , Epithelial Cells/cytology , Insulin Receptor Substrate Proteins/metabolism , Interleukin-13/metabolism , Interleukin-4/metabolism , Mammary Glands, Animal/cytology , STAT6 Transcription Factor/metabolism , Animals , Cell Proliferation , Epithelial Cells/metabolism , Female , Mammary Glands, Animal/metabolism , Mice , Mice, Inbred ICR , Models, Animal , Phosphorylation , Pregnancy , Signal TransductionABSTRACT
Medulloblastoma (MB) is the most common pediatric CNS malignancy. We identify EAG2 as an overexpressed potassium channel in MBs across different molecular and histological subgroups. EAG2 knockdown not only impairs MB cell growth in vitro, but also reduces tumor burden in vivo and enhances survival in xenograft studies. Mechanistically, we demonstrate that EAG2 protein is confined intracellularly during interphase but is enriched in the plasma membrane during late G2 phase and mitosis. Disruption of EAG2 expression results in G2 arrest and mitotic catastrophe associated with failure of premitotic cytoplasmic condensation. While the tumor suppression function of EAG2 knockdown is independent of p53 activation, DNA damage checkpoint activation, or changes in the AKT pathway, this defective cell volume control is specifically associated with hyperactivation of the p38 MAPK pathway. Inhibition of the p38 pathway significantly rescues the growth defect and G2 arrest. Strikingly, ectopic membrane expression of EAG2 in cells at interphase results in cell volume reduction and mitotic-like morphology. Our study establishes the functional significance of EAG2 in promoting MB tumor progression via regulating cell volume dynamics, the perturbation of which activates the tumor suppressor p38 MAPK pathway, and provides clinical relevance for targeting this ion channel in human MBs.
Subject(s)
Cell Size , Ether-A-Go-Go Potassium Channels/metabolism , Medulloblastoma/physiopathology , Mitosis , Animals , COS Cells , Cell Cycle Checkpoints/genetics , Cell Proliferation , Cells, Cultured , Chlorocebus aethiops , Enzyme Activation/genetics , Ether-A-Go-Go Potassium Channels/genetics , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , HEK293 Cells , Humans , MAP Kinase Signaling System , Medulloblastoma/mortality , Mice , Survival AnalysisABSTRACT
Cucurbitacin E (CuE), an active compound of the cucurbitacin family, possesses a variety of pharmacological functions and chemotherapy potential. Cucurbitacin E exhibits inhibitory effects in several types of cancer; however, its anticancer effects on brain cancer remain obscure and require further interpretation. In this study, efforts were initiated to inspect whether CuE can contribute to anti-proliferation in human brain malignant glioma GBM 8401 cells and glioblastoma-astrocytoma U-87-MG cells. An MTT assay measured CuE's inhibitory effect on the growth of glioblastomas (GBMs). A flow cytometry approach was used for the assessment of DNA content and cell cycle analysis. DNA damage 45ß (GADD45ß) gene expression and CDC2/cyclin-B1 disassociation were investigated by quantitative real-time PCR and Western blot analysis. Based on our results, CuE showed growth-inhibiting effects on GBM 8401 and U-87-MG cells. Moreover, GADD45ß caused the accumulation of CuE-treated G2/M-phase cells. The disassociation of the CDC2/cyclin-B1 complex demonstrated the known effects of CuE against GBM 8401 and U-87-MG cancer cells. Additionally, CuE may also exert antitumour activities in established brain cancer cells. In conclusion, CuE inhibited cell proliferation and induced mitosis delay in cancer cells, suggesting its potential applicability as an antitumour agent.
Subject(s)
Brain Neoplasms/metabolism , G2 Phase Cell Cycle Checkpoints/drug effects , Glioblastoma/metabolism , MAP Kinase Signaling System/drug effects , Triterpenes/pharmacology , Antigens, Differentiation/genetics , Antigens, Differentiation/metabolism , Brain Neoplasms/genetics , Brain Neoplasms/pathology , CDC2 Protein Kinase/genetics , CDC2 Protein Kinase/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Cyclin B1/genetics , Cyclin B1/metabolism , G2 Phase Cell Cycle Checkpoints/genetics , Gene Expression Regulation, Neoplastic/drug effects , Glioblastoma/genetics , Glioblastoma/pathology , Humans , MAP Kinase Signaling System/genetics , Mitosis/drug effects , Mitosis/genetics , Protein Binding/drug effects , RNA InterferenceABSTRACT
Neuronal-glial relationships play a critical role in the maintenance of central nervous system architecture and neuronal specification. A deeper understanding of these relationships can elucidate cellular cross-talk capable of sustaining proper development of neural tissues. In the cerebellum, cerebellar granule neuron precursors (CGNPs) proliferate in response to Purkinje neuron-derived Sonic hedgehog (Shh) before ultimately exiting the cell cycle and migrating radially along Bergmann glial fibers. However, the function of Bergmann glia in CGNP proliferation remains not well defined. Interestingly, the Hh pathway is also activated in Bergmann glia, but the role of Shh signaling in these cells is unknown. In this study, we show that specific ablation of Shh signaling using the tamoxifen-inducible TNCYFP-CreER line to eliminate Shh pathway activator Smoothened in Bergmann glia is sufficient to cause severe cerebellar hypoplasia and a significant reduction in CGNP proliferation. TNCYFP-CreER; SmoF/- (SmoCKO) mice demonstrate an obvious reduction in cerebellar size within two days of ablation of Shh signaling. Mutant cerebella have severely reduced proliferation and increased differentiation of CGNPs due to a significant decrease in Shh activity and concomitant activation of Wnt signaling in SmoCKO CGNPs, suggesting that this pathway is involved in cross-talk with the Shh pathway in regulating CGNP proliferation. In addition, Purkinje cells are ectopically located, their dendrites stunted, and the Bergmann glial network disorganized. Collectively, these data demonstrate a previously unappreciated role for Bergmann glial Shh signaling activity in the proliferation of CGNPs and proper maintenance of cerebellar architecture.
Subject(s)
Cerebellar Cortex/embryology , Hedgehog Proteins/physiology , Neuroglia/physiology , Animals , Astrocytes/metabolism , Cell Differentiation , Cell Division , Cell Proliferation/physiology , Cells, Cultured , Cerebellar Cortex/physiology , Cerebellar Neoplasms/metabolism , Cerebellum/abnormalities , Cerebellum/embryology , Developmental Disabilities/genetics , Hedgehog Proteins/metabolism , Mice , Nervous System Malformations/embryology , Nervous System Malformations/genetics , Neural Stem Cells/cytology , Neural Stem Cells/metabolism , Neurons/metabolism , Purkinje Cells/metabolism , Signal Transduction , Wnt Signaling Pathway/geneticsABSTRACT
Solid-state quantum emitters are in high demand for emerging technologies such as advanced sensing and quantum information processing. Generally, these emitters are not sufficiently bright for practical applications, and a promising solution consists in coupling them to plasmonic nanostructures. Plasmonic nanostructures support broadband modes, making it possible to speed up the fluorescence emission in room-temperature emitters by several orders of magnitude. However, one has not yet achieved such a fluorescence lifetime shortening without a substantial loss in emission efficiency, largely because of strong absorption in metals and emitter bleaching. Here, we demonstrate ultrabright single-photon emission from photostable nitrogen-vacancy (NV) centers in nanodiamonds coupled to plasmonic nanocavities made of low-loss single-crystalline silver. We observe a 70-fold difference between the average fluorescence lifetimes and a 90-fold increase in the average detected saturated intensity. The nanocavity-coupled NVs produce up to 35 million photon counts per second, several times more than the previously reported rates from room-temperature quantum emitters.
ABSTRACT
Cerebellar growth and foliation require the Hedgehog-driven proliferation of granule cell precursors (GCPs) in the external granule layer (EGL). However, that increased or extended GCP proliferation generally does not elicit ectopic folds suggests that additional determinants control cortical expansion and foliation during cerebellar development. Here, we find that genetic loss of the serine-threonine kinase Liver Kinase B1 (Lkb1) in GCPs increased cerebellar cortical size and foliation independent of changes in proliferation or Hedgehog signaling. This finding is unexpected given that Lkb1 has previously shown to be critical for Hedgehog pathway activation in cultured cells. Consistent with unchanged proliferation rate of GCPs, the cortical expansion of Lkb1 mutants is accompanied by thinning of the EGL. The plane of cell division, which has been implicated in diverse processes from epithelial surface expansions to gyrification of the human cortex, remains unchanged in the mutants when compared to wild-type controls. However, we find that Lkb1 mutants display delayed radial migration of post-mitotic GCPs that coincides with increased cortical size, suggesting that aberrant cell migration may contribute to the cortical expansion and increase foliation. Taken together, our results reveal an important role for Lkb1 in regulating cerebellar cortical size and foliation in a Hedgehog-independent manner.
Subject(s)
Cell Movement/physiology , Cytoplasmic Granules/physiology , Protein Serine-Threonine Kinases/physiology , AMP-Activated Protein Kinases , Animals , Cell Differentiation/physiology , Cell Division/physiology , Cerebellar Cortex/cytology , Cerebellar Cortex/enzymology , Cerebellar Cortex/growth & development , Cerebellar Cortex/metabolism , Cytoplasmic Granules/enzymology , Cytoplasmic Granules/metabolism , Hedgehog Proteins/metabolism , Mice , Nerve Tissue Proteins/metabolism , Neurons/cytology , Neurons/enzymology , Neurons/metabolism , Organogenesis/physiology , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Signal Transduction/physiologyABSTRACT
This article mainly focuses on analyzing covariate data from incident and prevalent cohort studies and a prevalent sample with only baseline covariates of interest and truncation times. Our major task in both research streams is to identify the effects of covariates on a failure time through very general single-index survival regression models without observing survival outcomes. With a strict increase of the survival function in the linear predictor, the ratio of incident and prevalent covariate densities is shown to be a non-degenerate and monotonic function of the linear predictor under covariate-independent truncation. Without such a structural assumption, the conditional density of a truncation time in a prevalent cohort is ensured to be a non-degenerate function of the linear predictor. In light of these features, some innovative approaches, which are based on the maximum rank correlation estimation or the pseudo least integrated squares estimation, are developed to estimate the coefficients of covariates up to a scale factor. Existing theoretical results are further used to establish the n -consistency and asymptotic normality of the proposed estimators. Moreover, extensive simulations are conducted to assess and compare the finite-sample performance of various estimators. To illustrate the methodological ideas, we also analyze data from the Worcester Heart Attack Study and the National Comorbidity Survey Replication.
Subject(s)
Models, Statistical , Regression Analysis , Survival Analysis , Analysis of Variance , Comorbidity/trends , Computer Simulation , Incidence , Myocardial Infarction/epidemiology , Prevalence , Statistics as Topic/methodsABSTRACT
BACKGROUND: To prospectively investigate the incidence and relative risks of multiple sclerosis (MS) in patients with type 2 diabetes (T2DM). MATERIALS AND METHODS: Patients with T2DM (n = 614,623) and age- and sex-matched controls (n = 614,021) were followed from 2000 to 2008 to identify cases of newly diagnosed MS (ICD-9-CM: 340). The person-year approach with Poisson assumption was used to evaluate the incidence density. We estimated the covariate-adjusted hazard ratio (HR) of MS incidence in relation to T2DM diabetes using a multiple Cox proportional hazard regression model. RESULTS: Over 9 years of follow-up, 175 T2DM patients were newly diagnosed with MS, and 114 matched controls had the same first-ever diagnosis, representing a covariate-adjusted HR of 1.44 (95% confidence interval [CI], 1.08-1.94). The sex-specific adjusted HR for both men and women with T2DM was also elevated at 1.34 (95% CI, 0.81-2.23) and 1.51 (95% CI, 1.05-2.19), respectively. Women aged ≤50 years had the greatest risk of MS (HR 2.16; 95% CI, 1.02-4.59). CONCLUSION: This study demonstrated a moderate but significant association of T2DM with MS incidence, and the association was not confounded by socio-demographic characteristics or certain MS-related co-morbidities.
Subject(s)
Diabetes Mellitus, Type 2/epidemiology , Multiple Sclerosis/epidemiology , Adult , Age Distribution , Aged , Case-Control Studies , Cohort Studies , Diabetes Mellitus, Type 2/complications , Female , Follow-Up Studies , Humans , Incidence , International Classification of Diseases , Male , Middle Aged , Multiple Sclerosis/diagnosis , Multiple Sclerosis/etiology , Population Surveillance , Proportional Hazards Models , Prospective Studies , Risk Assessment , Risk Factors , Sex Distribution , Taiwan/epidemiologyABSTRACT
Accumulating lines of evidence indicate that high leptin levels are associated with adverse cardiovascular health in obese individuals. Proatherogenic effects of leptin include endothelial cell activation and vascular smooth muscle cell proliferation and migration. Ursolic acid (UA) has been reported to exhibit multiple biological effects including antioxidant and anti-inflammatory properties. In this study, we investigated the effect of UA on leptin-induced biological responses in rat vascular smooth muscle cells (VSMCs). A-10 VSMCs were treated with leptin in the presence or absence of UA. Intracellular reactive oxygen species (ROS) was probed by 2',7'-dichlorofluorescein diacetate. The expression of extracellular signal-regulated kinase (ERK)1/2, phospho-(ERK)1/2, nuclear factor-kappa B (NF-κB) p65 and p50, and matrix metalloproteinase-2 (MMP2) was determined by Western blotting. Immunocytochemistry and confocal laser scanning microscopy were also used for the detection of NF-κB. The secretion of MMP2 was detected by gelatin zymography. UA exhibited antioxidant activities in vitro. In rat VSMCs, UA effectively inhibited cell growth and the activity of MMP2 induced by leptin. These suppressive effects appeared by decreasing the activation of (ERK)1/2, the nuclear expression and translocation of NF-κB, and the production of ROS. UA appeared to inhibit leptin-induced atherosclerosis, which may prevent the development of obesity-induced cardiovascular diseases.
Subject(s)
Antioxidants/pharmacology , Leptin/pharmacology , Muscle, Smooth, Vascular/cytology , Triterpenes/pharmacology , Animals , Cell Proliferation/drug effects , Cell Survival/drug effects , Gene Expression Regulation, Enzymologic/drug effects , Matrix Metalloproteinase 2/metabolism , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , NF-kappa B p50 Subunit/metabolism , Phosphoproteins/metabolism , Rats , Reactive Oxygen Species/metabolism , Transcription Factor RelA/metabolism , Ursolic AcidABSTRACT
BACKGROUND: Arterial stiffness is a determinant of cardiovascular disease in end stage renal disease. Hemodialysis patients may develop anti-platelet factor 4/heparin antibody (PF4-H Ab) because of heparin treatment in dialysis. We tested whether PF4-H Ab was associated with progression of arterial stiffness in a 3-year follow-up. METHODS: We enrolled 74 hemodialysis patients and studied their clinical, biochemical and arterial stiffness measurement with brachial-ankle pulse wave velocity (baPWV) over 3 years. Baseline and changes in baPWV after 3 years (ΔbaPWV) were collected and compared with related clinical and biochemical parameters. PF4-H Ab was evaluated by the enzyme-linked immunosorbent assay and titer ≥ 0.4 was defined to have PF4-H Ab. RESULTS: We found a positive PF4-H Ab status in 25 of 74 patients. Mean baPWV was 16.1 ± 3.8 (m/s) at baseline and 17.6 ± 4.0 (m/s) after 3 years. Mean ΔbaPWV was 3.4 ± 2.2 (m/s) in the PF4-H Ab positive group, and 0.6 ± 1.2 (m/s) in the PF4-H Ab negative group. Baseline baPWV was only significantly associated with age (ß = 0.49, p < 0.01). ΔbaPWV was significantly different between the PF4-H Ab positive and negative groups (p < 0.01). In multivariate regression analysis, only PF4-H Ab was positively associated with ΔbaPWV (ß = 0.71, p < 0.01). CONCLUSIONS: Our study concluded that PF4-H Ab was associated with progression of arterial stiffness in hemodialysis patients.
ABSTRACT
The development of the mammalian cerebellum is orchestrated by both cell-autonomous programs and inductive environmental influences. Here, we describe the main processes of cerebellar ontogenesis, highlighting the neurogenic strategies used by developing progenitors, the genetic programs involved in cell fate specification, the progressive changes of structural organization, and some of the better-known abnormalities associated with developmental disorders of the cerebellum.
Subject(s)
Cerebellum/embryology , Cerebellum/growth & development , Animals , Cerebellum/cytology , Cerebellum/physiopathology , Consensus , Humans , Neurogenesis/physiology , Neurons/cytology , Neurons/physiologyABSTRACT
A new nonparametric approach is developed to estimate the time-dependent accuracy measure curves, which are defined on the cumulative cases and dynamic controls, for censored survival data. Based on an estimable survival process, the main intention of this study is to reduce the finite-sample biases of nearest neighbor estimators. The asymptotic variances of some retrospective accuracy measure estimators are further reduced by applying a smoothing technique to the underlying process of a marker. Meanwhile, practically feasible and theoretically valid procedures are proposed for bandwidth selection in the presented estimators. In addition, the proposed methodology can be reasonably extended to accommodate stratified survival data and survival data with multiple markers. As shown in the simulations, our new estimators outperform the nearest neighbor and inverse censoring weighted estimators. Data from the AIDS Clinical Trials Group study 175 and an angiographic coronary artery disease study are also used to illustrate the proposed methodology. Copyright © 2016 John Wiley & Sons, Ltd.
Subject(s)
Bias , Biomarkers , Computer Simulation , Coronary Artery Disease/diagnosis , Humans , Reproducibility of Results , Retrospective StudiesABSTRACT
Long-term exposure to di-(2-ethylhexyl) phthalate (DEHP) is highly associated with carcinogenicity, fetotoxicity, psychological disorders and metabolic diseases, but the detrimental effects and mechanisms are not fully understood. We investigated the effect of exposing mouse mothers to DEHP, and the underlying mechanism, on blood pressure, obesity and cholesterol metabolism as well as psychological and learning behaviors in offspring. Tail-cuff plethysmography was used for blood pressure measurement; Western blot used was for phosphorylation and expression of protein; hematoxylin and eosin staining, Nissl staining and Golgi staining were used for histological examination. The serum levels of cholesterol, triglycerides and glucose were measured by blood biochemical analysis. Hepatic cholesterol and triglyceride levels were assessed by colorimetric assay kits. Offspring behaviors were evaluated by open-field activity, elevated plus maze, social preference test and Morris water maze. Maternal DEHP exposure deregulated the phosphorylation of endothelial nitric oxide synthase and upregulated angiotensin type 1 receptor in offspring, which led to increased blood pressure. It led to obesity in offspring by increasing the size of adipocytes in white adipose tissue and number of adipocytes in brown adipose tissue. It increased the serum level of cholesterol in offspring by decreasing the hepatic capacity for cholesterol clearance. The impaired social interaction ability induced by maternal DEHP exposure might be due to abnormal neuronal development. Collectively, our findings provide new evidence that maternal exposure to DEHP has a lasting effect on the physiological functions of the vascular system, adipose tissue and nerve system in offspring.
Subject(s)
Adiposity/drug effects , Behavior, Animal/drug effects , Blood Pressure/drug effects , Cholesterol/blood , Diethylhexyl Phthalate/toxicity , Hypertension/chemically induced , Maternal Exposure , Prenatal Exposure Delayed Effects , Social Behavior , Animals , Biomarkers/blood , Brain/drug effects , Brain/pathology , Brain/physiopathology , Female , Hypertension/physiopathology , Liver/drug effects , Liver/metabolism , Maze Learning/drug effects , Mice, Inbred C57BL , Motor Activity/drug effects , PregnancyABSTRACT
PURPOSE: In patients with oral cancer, trismus (maximum interincisal opening [MIO] <35 mm) can develop as a result of surgery and radiotherapy. The aim of this study was to provide an alternative operation to both eradicate oral cancer and prevent postsurgical trismus. MATERIALS AND METHODS: In our retrospective cohort study of oral cancer patients who underwent operations during 2010 to 2014, the predictor variable was the type of operation (alternative operation or traditional operation) and the outcome variable was MIO. All of the cases were allocated by 2 periods: the traditional operations were performed from 2010 to 2011, and the alternative operations were performed from 2011 to 2014. All patients received marginal mandibulectomy, anterolateral thigh free flap, and adjuvant radiotherapy or concurrent chemoradiotherapy. In addition to traditional marginal mandibulectomy, the alternative operation included ipsilateral coronoidectomy and myotomy of the temporalis muscle insertion, masseter muscle, and medial pterygoid muscle. MIO was measured at 10 time points. The adjusted variables included demographic data, diagnostic parameters, treatment, and response. RESULTS: Of the 36 male patients with oral cancer, 16 were placed in the alternative operation group (AOG; mean age, 53.5 ± 11.9 years) and 20 were placed in the traditional operation group (TOG; mean age, 50.7 ± 7.1 years). Regarding the outcome indicator of patient MIO, the preoperative MIO in the AOG was on average 7.5 mm shorter than that in the TOG (P < .01), but it was consistently superior to the MIO in the TOG after the operation. Multivariate analysis of variance showed that patients in the AOG were more likely to have postoperative non-trismus. CONCLUSIONS: The alternative operation exhibited superior postoperative MIO values and similar postoperative complication rates. For the prevention of trismus, it is practical to perform the combined operation simultaneously, cutting all ipsilateral jaw closing muscles and the coronoid process and eradicating the tumor.
Subject(s)
Mouth Neoplasms/therapy , Oral Surgical Procedures/adverse effects , Trismus/prevention & control , Combined Modality Therapy/adverse effects , Combined Modality Therapy/methods , Humans , Male , Middle Aged , Mouth Neoplasms/radiotherapy , Mouth Neoplasms/surgery , Oral Surgical Procedures/methods , Retrospective Studies , Trismus/etiologyABSTRACT
PURPOSE: Use of the skin graft and artificial dermis to reconstruct a defect after the excision of dysplastic lesions of the oral mucosa has been practiced for years. The purpose of this case series was to introduce a novel resolution-that is, an operating procedure using solid-phase concentrated growth factors (SPCGFs) to reconstruct oral mucosa defects-and observe the postoperative results and evaluate its clinical effects. MATERIALS AND METHODS: In this consecutive serial case study of patients with oral dysplastic lesions who underwent operations from April 2015 through July 2015, the primary endpoint of the study was to observe the clinical wound-healing profile at 1 week, 3 weeks, 3 months, and 6 months postoperatively. The secondary endpoint was to observe maximal interincisal opening (MIO) and wound pain preoperatively and at 1 and 3 days, 1 and 3 weeks, and 3 and 6 months postoperatively. The minimum follow-up was 8 months, and the longest was 1 year. RESULTS: All sites had healed with complete epithelialization after 3 weeks postoperatively. All patients had a wound-healing score no higher than 3 at 3 weeks postoperatively. The preoperative MIO was 52 ± 4.64 mm and the 6-month postoperative MIO was 49.2 ± 3.03 mm. No patient reported further pain from 3 weeks postoperatively. No recurrence of the lesion was found at or after the 6-month follow-up period. CONCLUSION: The results of this study show that the use of SPCGFs to reconstruct oral mucosa defects is feasible and practical. The efficacy of SPCGFs needs to be verified by additional studies with higher-level evidence bases in the future.
Subject(s)
Intercellular Signaling Peptides and Proteins/therapeutic use , Mouth Mucosa/surgery , Mouth Neoplasms/surgery , Plastic Surgery Procedures/methods , Aged , Centrifugation , Follow-Up Studies , Humans , Male , Middle Aged , Mouth Mucosa/pathology , Mouth Neoplasms/pathology , Stents , Suture Techniques , Wound HealingABSTRACT
[Purpose] Bicycle saddle height is a critical factor for cycling performance and injury prevention. The present study compared the variance in cadence frequency after exercise fatigue between saddle heights with 25° and 35° knee flexion. [Methods] Two saddle heights, which were determined by setting the pedal at the bottom dead point with 35° and 25° knee flexion, were used for testing. The relative variances of the cadence frequency were calculated at the end of a 5-minute warm-up period and 5 minutes after inducing exercise fatigue. Comparison of the absolute values of the cadence frequency under the two saddle heights revealed a difference in pedaling efficiency. [Results] Five minutes after inducing exercise fatigue, the relative variances of the cadence frequency for the saddle height with 35° knee flexion was higher than that for the saddle height with 25° knee flexion. [Conclusion] The current finding demonstrated that a saddle height with 25° knee flexion is more appropriate for cyclists than a saddle height with 35° knee flexion.
ABSTRACT
Soluble epoxide hydrolase (sEH) is abundantly expressed in kidney and plays a potent role in regulating inflammatory response in inflammatory diseases. However, the role of sEH in progression of chronic kidney diseases such as obstructive nephropathy is still elusive. In current study, wild-type (WT) and sEH deficient (sEH (-/-)) mice were subjected to the unilateral ureteral obstruction (UUO) surgery and the kidney injury was evaluated by histological examination, western blotting, and ELISA. The protein level of sEH in kidney was increased in UUO-treated mice group compared to nonobstructed group. Additionally, UUO-induced hydronephrosis, renal tubular injury, inflammation, and fibrosis were ameliorated in sEH (-/-) mice with the exception of glomerulosclerosis. Moreover, sEH (-/-) mice with UUO showed lower levels of inflammation-related and fibrosis-related protein such as monocyte chemoattractant protein-1, macrophage inflammatory protein-2, interleukin-1ß (IL-1ß), IL-6, inducible nitric oxide synthase, collagen 1A1, and α-actin. The levels of superoxide anion radical and hydrogen peroxide as well as NADPH oxidase activity were also decreased in UUO kidneys of sEH (-/-) mice compared to that observed in WT mice. Collectively, our findings suggest that sEH plays an important role in the pathogenesis of experimental obstructive nephropathy and may be a therapeutic target for the treatment of obstructive nephropathy-related diseases.