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Age-specific characteristics and annual changes of social maturity in adults with Down syndrome (DS) were retrospectively investigated. Forty-six individuals aged 15-58 years were enrolled. Social age (SA) in all domains and subdomains was assessed using the revised S-M social maturity test. Thirty-four cases were evaluated for SA changes over time at 1 year. The SA of adult DS tended to be lower in those under 20 and over 42 years of age. The SA of adults with DS was lowest in the Socialization domain, and this trend was generally common across all age groups. The annual decline of SA was more prominent in the DS-AD group than in the non-DS-AD group. Annual decline of SA in the communication domain had the same discriminative power as that in the whole domains in the discrimination of DS-AD from non-DS-AD. These results are expected to contribute to the development of clinical diagnostic methods for DS-AD in the future.
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BACKGROUND: In cases of adolescent and early adulthood eating disorders, despite the importance of the patients' relationship with their parents, conflict and confusion frequently occur among them. Interpersonal psychotherapy (IPT) is a present-focused psychotherapy that emphasizes the interpersonal context of symptoms. We developed a remote family education and support program exclusively for parents of patients with eating disorders, based on the principle of IPT. The use of IPT is expected to reduce conflicts in the patient-parent relationship. Consequently, parents will be better able to listen to patients, and patients will be better able to express their thoughts and desires. In this study, we describe the protocol for a randomized controlled trial designed to examine the effectiveness of this program in promoting effective communication in their home based on active listening skills of parents of patients with adolescent and early adulthood eating disorders. METHODS: Participants will be parents of patients aged 12-29 years with adolescent and early adulthood eating disorders. Individually randomized, parallel-group trial design will be employed. Seventy participants will be allocated to one of two treatment conditions: (1) remote family education and support program (four, 150 min weekly group sessions) for parents plus treatment-as-usual for patients (consultation by physicians or no treatment), or (2) waiting for the control condition (parents will wait to start the program for 8 weeks) plus treatment-as-usual for patients. The primary outcome measure will be parents' active listening ability as measured by the Active Listening Attitude Scale at 8 weeks after randomization. Additionally, perception of social support (Social Provision Scale-10 item), loneliness (UCLA Loneliness Scale), mental health status (K6), family function (Family Assessment Device), and parent-evaluated eating disorder symptoms (Anorectic Behavior Observation Scale) will be assessed. Data from the intention-to-treat sample will be analyzed 8 weeks after randomization. DISCUSSION: This is the first study to evaluate the effectiveness of a family education and support program for parents of patients with adolescent and early adulthood eating disorders based on IPT. If this type of intervention is effective, although indirect, it could be a new support method for this patient population. TRIAL REGISTRATION: Clinical Trials. gov ID NCT05840614.
For patients with adolescent and early adulthood eating disorders, although the relationship with their parents is an important interpersonal dynamic, conflicts and confusion often arise between patients and their parents. On the other hand, parents who live with individuals with eating disorders are frequently involved in interpersonal disputes, leading to a heavy psychological burden and elevated levels of depression and anxiety. It has been found that highly depressed or anxious parents tend to have difficulty listening carefully to their patients. Additionally, parental anxiety often promotes an overprotective response. Interpersonal psychotherapy (IPT) is a present-focused psychotherapy that emphasizes the interpersonal context of symptoms. In IPT, the patient and therapist work within interpersonal therapeutic domains, such as interpersonal role disputes with different expectations and role transitions. We developed a remote family education and support program exclusively for parents of patients with eating disorders based on IPT principles. In the present study, we describe the protocol for a randomized controlled trial designed to examine the effectiveness of this program in promoting effective communication within their homes, focusing on the active listening skills of parents of patients with adolescent and early adulthood eating disorders.
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Increased low-density lipoprotein levels are risk factors for diabetic neuropathy. Diabetes mellitus is associated with elevated metabolic stress, leading to oxidised low-density lipoprotein formation. Therefore, it is important to investigate the mechanisms underlying the pathogenesis of diabetic neuropathy in diabetes complicated by dyslipidaemia with increased levels of oxidised low-density lipoprotein. Here, we examined the effects of hyperglycaemia and oxidised low-density lipoprotein treatment on Schwann cell death and its underlying mechanisms. Immortalised mouse Schwann cells were treated with oxidised low-density lipoprotein under normo- or hyperglycaemic conditions. We observed that oxidised low-density lipoprotein-induced cell death increased under hyperglycaemic conditions compared with normoglycaemic conditions. Moreover, hyperglycaemia and oxidised low-density lipoprotein treatment synergistically upregulated the gene and protein expression of toll-like receptor 4. Pre-treatment with TAK-242, a selective toll-like receptor 4 signalling inhibitor, attenuated hyperglycaemia- and oxidised low-density lipoprotein-induced cell death and apoptotic caspase-3 pathway. Our findings suggest that the hyperactivation of toll-like receptor 4 signalling by hyperglycaemia and elevated oxidised low-density lipoprotein levels synergistically exacerbated diabetic neuropathy; thus, it can be a potential therapeutic target for diabetic neuropathy.
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AIMS/INTRODUCTION: This study aimed to investigate the diagnostic potential of two simplified tests, a point-of-care nerve conduction device (DPNCheck™) and a coefficient of variation of R-R intervals (CVR-R), as an alternative to traditional nerve conduction studies for the diagnosis of diabetic polyneuropathy (DPN) in patients with diabetes. MATERIALS AND METHODS: Inpatients with type 1 or type 2 diabetes (n = 167) were enrolled. The study population consisted of 101 men, with a mean age of 60.8 ± 14.8 years. DPN severity was assessed using traditional nerve conduction studies, and differentiated based on Baba's classification (BC). To examine the explanatory potential of variables in DPNCheck™ and CVR-R regarding the severity of DPN according to BC, a multiple regression analysis was carried out, followed by a receiver operating characteristic analysis. RESULTS: Based on BC, 61 participants (36.5% of the total) were categorized as having DPN severity of stage 2 or more. The multiple regression analysis yielded a predictive formula with high predictive power for DPN diagnosis (estimated severity of DPN in BC = 2.258 - 0.026 × nerve conduction velocity [m/s] - 0.594 × ln[sensory nerve action potential amplitude (µV)] + 0.528In[age(years)] - 0.178 × ln[CVR-R], r = 0.657). The area under the curve in receiver operating characteristic analysis was 0.880. Using the optimal cutoff value for DPN with severer than stage 2, the predictive formula showed good diagnostic efficacy: sensitivity of 83.6%, specificity of 79.2%, positive predictive value of 51.7% and negative predictive value of 76.1%. CONCLUSIONS: These findings suggest that DPN diagnosis using DPNCheck™ and CVR-R could improve diagnostic efficiency and accessibility for DPN assessment in patients with diabetes.
Subject(s)
Diabetic Neuropathies , Electrocardiography , Neural Conduction , Point-of-Care Systems , Humans , Diabetic Neuropathies/diagnosis , Male , Middle Aged , Neural Conduction/physiology , Electrocardiography/instrumentation , Electrocardiography/methods , Aged , Female , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosisABSTRACT
Aims: We aimed to identify patients who would benefit from basal insulin-supported oral therapy (BOT) with a glinide and an α-glucosidase inhibitor (a fixed-dose combination tablet of mitiglinide 10 mg and voglibose 0.2 mg) in Japanese type 2 diabetic patients. Methods: Patients who were hospitalized to improve hyperglycemia received basal-bolus insulin therapy. After the reduction of glucose toxicity, a 75 g oral glucose tolerance test and a glucagon test were performed. Thereafter, the basal-bolus insulin therapy was switched to BOT with mitiglinide, followed by further addition of voglibose. Interstitial glucose levels were continuously monitored throughout the study period. Diurnal glucose profile was recorded and analyzed. Patients were divided into two groups according to whether their percentage of time in range (TIR, 70-180 mg/dL) under BOT with mitiglinide/voglibose was higher than 70% or not, and the differences in clinical characteristics between the groups were analyzed. Results: Twenty patients were enrolled, and 19 of them completed the study. BOT with mitiglinide/voglibose achieved ≥ 70% of TIR in thirteen patients. The area under the curve of serum C-peptide levels during the oral glucose tolerance test was significantly higher in the patients with ≥ 70% of TIR. The daily insulin dosages and blood glucose profiles were comparable between the two groups. Conclusions: The efficacy of BOT with mitiglinide/voglibose depended on residual insulin secretory abilities. This therapy would be a useful therapeutic option for patients with type 2 diabetes.
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Cancer cells employ glycolysis for their survival and growth (the "Warburg effect"). Consequently, surrounding cells including immune cells in the tumor microenvironment (TME) are exposed to hypoglycemic, hypoxic, and low pH circumstances. Since effector T cells depend on the glycolysis for their survival and functions, the metabolically harsh TME established by cancer cells is unfavorable, resulting in the impairment of effective antitumor immune responses. By contrast, immunosuppressive cells such as regulatory T (Treg) cells can infiltrate, proliferate, survive, and exert immunosuppressive functions in the metabolically harsh TME, indicating the different metabolic dependance between effector T cells and Treg cells. Indeed, some metabolites that are harmful for effector T cells can be utilized by Treg cells; lactic acid, a harmful metabolite for effector T cells, is available for Treg cell proliferation and functions. Deficiency of amino acids such as tryptophan and glutamine in the TME impairs effector T cell activation but increases Treg cell populations. Furthermore, hypoxia upregulates fatty acid oxidation via hypoxia-inducible factor 1α (HIF-1α) and promotes Treg cell migration. Adenosine is induced by the ectonucleotidases CD39 and CD73, which are strongly induced by HIF-1α, and reportedly accelerates Treg cell development by upregulating Foxp3 expression in T cells via A2AR-mediated signals. Therefore, this review focuses on the current views of the unique metabolism of Treg cells dictated by cancer cells. In addition, potential cancer combination therapies with immunotherapy and metabolic molecularly targeted reagents that modulate Treg cells in the TME are discussed to develop "immune metabolism-based precision medicine".
Subject(s)
Neoplasms , T-Lymphocytes, Regulatory , Humans , Immunotherapy/methods , Immunosuppressive Agents/pharmacology , Hypoxia/metabolism , Tumor MicroenvironmentABSTRACT
BACKGROUND: Family members of patients with eating disorders, especially their mothers, experience heavy caregiving burdens associated with supporting the patient. We predict that increasing caregivers' support will have a positive effect on their active listening attitudes, mental health, loneliness, and self-efficacy. This study aimed to investigate differences in mothers' active listening attitudes, mental health, loneliness, and self-efficacy improvements between mothers who did and did not experience increased perceived social support. MAIN BODY: Participants were mothers of patients with eating disorders. Questionnaires for this cohort study were sent to the participants' homes at three time points (baseline, 9 months, and 18 months). The Japanese version of the Social Provision Scale (SPS-10) was used to evaluate social support, the Active Listening Attitude Scale (ALAS) for listening attitude, the UCLA Loneliness Scale (ULS) for loneliness, the General Self-Efficacy Scale (GSES) for self-efficacy, the Beck Depression Inventory (BDI-II) for depression symptoms, and the K6 for psychological distress. An unpaired t-test was used to determine whether participants' status differed between the groups that did and did not experience increased perceived social support. The mean age of the participants was 55.1 ± 6.7 (mean ± SD) years. The duration of their children's eating disorders was 7.6 ± 5.5 years. The degree of improvement for each variable (active listening attitude, loneliness, self-efficacy, depressive symptoms, and mental health) was the difference in each score (ALAS, ULS, GSES, BDI-II, and K6) from T1 to T3. The degree of improvement in active listening attitude and loneliness was significantly greater in the improved social support group than in the non-improved social support group (p < 0.002 and p < 0.012, respectively). CONCLUSIONS: Our findings indicate that increasing mothers' perceptions of social support will be associated with improving their active listening attitudes and loneliness.
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Aims: Muscle atrophy is a diabetic complication, which results in a deterioration in glycemic control in type 2 diabetes mellitus (T2DM) individuals. The psoas muscle mass index (PMI) is a reliable indicator for estimating whole-body muscle mass. We aimed to examine the relationship between clinical parameters and the PMI to clarify the mechanism underlying muscle atrophy in diabetes. Methods: This retrospective, cross-sectional study examined 51 patients (31 men and 20 women) with T2DM and a mean HbA1c value of 9.9 ± 1.7%. These patients were admitted to Aichi Medical University Hospital and underwent abdominal computed tomography imaging from July 2020 to April 2021. Multiple clinical parameters were assessed with the PMI. Results: In a multiple regression analysis adjusted for age and sex, the PMI was correlated with body weight, body mass index, serum concentrations of corrected calcium, aspartate aminotransferase, alanine aminotransferase, creatine kinase, thyroid-stimulating hormone (TSH), urinary C-peptide concentrations, the free triiodothyronine/free thyroxine (FT3/FT4) ratio, and the young adult mean score at the femur neck. Receiver operating characteristic curves were created using TSH concentrations and the FT3/FT4 ratio for diagnosing a low PMI. The area under the curve was 0.593 and 0.699, respectively. The cut-off value with maximum accuracy for TSH concentrations was 1.491 µIU/mL, sensitivity was 56.1%, and specificity was 80.0%. Corresponding values for the FT3/FT4 ratio were 1.723, 78.0, and 66.7%, respectively. Conclusion: TSH concentrations and the FT3/FT4 ratio are correlated with the PMI, and their thresholds may help prevent muscle mass loss in Japanese individuals with T2DM.
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Aim: Patients' and spouses' neurodevelopmental traits may influence marital relationships, which are significantly associated with depressive symptoms. However, no studies have examined marital relationships in persistent depressive disorder (PDD) in terms of neurodevelopmental traits. This study aimed to explore the association between the autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD) traits of female PDD patients and both partners' (patient and husband) marital satisfaction. Methods: A cross-sectional online survey was administered during two predetermined consecutive months at seven institutions. Participants were female outpatients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for PDD and their husbands. The instruments of the study were the following validated surveys: the Quality Marriage Index (QMI), the Autism-Spectrum Quotient Japanese version-21 (AQ-J-21), and the Adult ADHD Self-Report Scale Part A (ASRS Part A). Results: The patients' AQ-J-21 showed a positive significant association with their QMI in all patients who responded to this study's questionnaire, whereas among couples wherein both patient and husband responded, the ASRS Part A exhibited a positive significant association with the patients' QMI. Conversely, the husbands' ASRS Part A exhibited a negative significant association with the patients' QMI. Conclusion: The patients' ASD and ADHD traits may play a positive role in the marital satisfaction of female PDD patients, while their husbands' ADHD traits may play a negative role. For female PDD patients with low marital satisfaction, it may be important to consider whether their husbands have ADHD traits; if so, it may be necessary to develop intervention strategies focused on the traits for improving the low marital satisfaction. However, our conclusions are not sufficiently convincing.
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Background: Prolonged grief disorder (PGD) is a new diagnostic entity. However, treatment for PGD is not yet available. Interpersonal psychotherapy (IPT) may be effective for PGD. Case Presentation: A single 27-year-old Japanese woman lost her brother to suicide. However, she did not express her grief to anyone or visit a psychiatric clinic. After experiencing strong depressive symptoms triggered by work stress, she visited a psychiatric clinic, where she was diagnosed with depression as well as PGD. Through pharmacotherapy, her depressive symptoms improved, but no improvement was noted in her PGD symptoms. She therefore began IPT for PGD at our hospital, 5 years after her brother's suicide and after 4 years of PGD symptoms. In the introductory phase of IPT, she was diagnosed with comorbid persistent depressive disorder (PDD). After this diagnosis, through psychoeducation on PDD, she could identify the symptoms that reflected her personality traits as "PDD symptoms." Furthermore, she could affirm her positive and negative feelings and share them with others. Consequently, the grieving process was facilitated, and her interests and relationships were re-established. Her PGD and PDD symptoms improved. Conclusion: IPT may be effective for PGD comorbid with PDD among Japanese.
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Bereavement-related major depressive disorder (MDD) is a common disorder with both mental and physical effects. Specific psychotherapies for bereavement-related MDD remain unavailable in Japan despite its relatively high prevalence. Interpersonal psychotherapy (IPT) is a treatment with established efficacy for MDD, including bereavement-related MDD. There are, however, few studies of IPT for MDD and none at all for bereavement-related MDD in Japan. The efficacy of IPT for bereavement-related MDD needs confirmation in Japanese culture because the expression of emotions during the grieving and mourning process varies across cultures, and the Japanese-specific cultural custom exists of maintaining a relationship with the deceased in the afterlife mainly via a Buddhist memorial tablet, altar, and grave. We present a case study describing the therapist's adaptation of IPT to Japanese culture to treat bereavement-related MDD in a Japanese man with insufficient response to pharmacotherapy who had suddenly lost his mother to heart disease. His mother's death and a dispute with his father both appeared to have contributed to his sustained bereavement-related MDD. The 16-session treatment course for depressive symptoms was monitored using the Beck Depression Inventory-II. Treatment was scheduled weekly, but some sessions unavoidably took place fortnightly because they were conducted in person during the COVID-19 pandemic. The patient's MDD severity continually decreased, functional disability gradually recovered from the beginning until the 3-month follow-up, and the interpersonal relationships with his deceased mother, his wife, colleague, and father changed after IPT. Case studies are inherently limited, but IPT, in consideration of Japanese cultural characteristics for bereavement-related MDD, can be potentially effective in Japan.
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Morphological analysis of peripheral nerves in mouse models can be used to characterize the pathophysiology of peripheral nerve disease, but obtaining high-quality electron micrographs can be challenging. Here, we present a protocol to obtain electron micrographs of mouse peripheral nerves. We detail the procedures of sampling, fixation, and embedding of peripheral nerves. We then outline the steps for ultrathin sectioning and transmission electron microscopy imaging. Finally, we describe morphological evaluation of nerve fibers in these images using ImageJ and AxonSeg. For complete details on the use and execution of this protocol, please refer to Nakai-Shimoda et al. (2021).
Subject(s)
Histological Techniques , Peripheral Nerves , Animals , Histological Techniques/methods , Mice , Microscopy, Electron, Transmission , Peripheral Nerves/diagnostic imaging , Specimen HandlingABSTRACT
Diabetic peripheral neuropathy (DPN) includes symptoms of thermosensory impairment, which are reported to involve changes in the expression or function, or both, of nociceptive TRPV1 and TRPA1 channels in rodents. In the present study, we did not find changes in the expression or function of TRPV1 or TRPA1 in DPN mice caused by STZ, although thermal hypoalgesia was observed in a murine model of DPN or TRPV1-/- mice with a Plantar test, which specifically detects temperature avoidance. With a Thermal Gradient Ring in which mice can move freely in a temperature gradient, temperature preference can be analyzed, and we clearly discriminated the temperature-dependent phenotype between DPN and TRPV1-/- mice. Accordingly, we propose approaches with multiple behavioral methods to analyze the progression of DPN by response to thermal stimuli. Attention to both thermal avoidance and preference may provide insight into the symptoms of DPN.
Subject(s)
Diabetes Mellitus , Diabetic Neuropathies , Animals , Mice , Diabetic Neuropathies/etiologyABSTRACT
BACKGROUND: Mid-regional pro-adrenomedullin (MR-proADM) is a novel biomarker for cognitive decline based on its association with cerebral small vessel disease (SVD). Cerebral microbleeds (MBs) are characteristic of SVD; however, a direct association between MR-proADM and MBs has not been explored. OBJECTIVE: We aimed to examine whether circulating levels of MR-proADM are associated with the identification of MBs by brain magnetic resonance imaging (MRI) and whether this association could be linked with cognitive impairment. METHODS: In total, 214 participants (mean age: 75.9 years) without history of cerebral infarction or dementia were prospectively enrolled. All participants underwent brain MRI, higher cognitive function testing, blood biochemistry evaluation, lifestyle examination, and blood MR-proADM measurement using a time-resolved amplified cryptate emission technology assay. For between-group comparisons, the participants were divided into two groups according to whether their levels of MR-proADM were normal (<â0.65ânmol/L) or high (≥0.65ânmol/L). RESULTS: The mean MR-proADM level was 0.515±0.127ânmol/L. There were significant between-group differences in age, hypertension, and HbA1c levels (pâ<â0.05). In the high MR-proADM group, the MR-proADM level was associated with the identification of MBs on brain MR images and indications of mild cognitive impairment (MCI). In participants with ≥3 MBs and MCI, high MR-proADM levels remained a risk factor after multivariate adjustment (OR: 2.94; pâ<â0.05). CONCLUSION: High levels of MR-proADM may be a surrogate marker for the early detection of cognitive decline associated with the formation of cerebral MBs. This marker would be valuable during routine clinical examinations of geriatric patients.
Subject(s)
Adrenomedullin , Protein Precursors , Aged , Biomarkers , Cerebral Hemorrhage/complications , Cerebral Hemorrhage/diagnostic imaging , Humans , Prognosis , Risk FactorsABSTRACT
Objective: To investigate the presence of exacerbating factors of persistent perceptual-postural dizziness (PPPD) in patients with vestibular symptoms during the early period after vestibular symptoms onset, and to examine possible predictive factors for developing PPPD later. Methods: One hundred and fifty-five consecutive patients with vestibular symptoms who presented less than 90 days from the onset were included in this study. They filled out the Niigata PPPD Questionnaire (NPQ) that consists of 12 questions on the exacerbating factors of PPPD. The NPQ scores of patients who developed PPPD were compared with those of patients who did not develop PPPD during the follow-up. Results: Seventy-eight of the155 patients (50.3%) showed positive NPQ scores (≥27 points). High NPQ scores were found in patients diagnosed with psychogenic dizziness and vestibular neuritis. During the follow up for an average of 543.3 days after the initial presentation, eight patients (10.3%) developed PPPD. Seven of these eight patients (87.6%) showed positive NPQ scores and all of them had all three exacerbating factors of PPPD at their initial presentation. The NPQ scores of the patients who developed PPPD (40.6 ± 11.6) were significantly higher than those of the patients who did not develop PPPD (26.4 ± 18.3; p <.05). Conclusion: Approximately a half of the patients with vestibular symptoms had exacerbating factors of PPPD in the early stages of the disease. Patients who develop PPPD are likely to have its exacerbating factors in the initial stages after presentation. Level of Evidence: 3.
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Autophagy is the process by which intracellular components are degraded by lysosomes. It is also activated by oxidative stress; hence, autophagy is thought to be closely related to oxidative stress, one of the major causes of diabetic neuropathy. We previously reported that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) induced antioxidant enzymes and protected Schwann cells from oxidative stress. However, the relationship between autophagy and oxidative stress-induced cell death in diabetic neuropathy has not been elucidated. Treatment with tert-butyl hydroperoxide (tBHP) decreased the cell survival rate, as measured by an MTT assay in immortalized Fischer rat Schwann cells 1 (IFRS1). A DHA pretreatment significantly prevented tBHP-induced cytotoxicity. tBHP increased autophagy, which was revealed by the ratio of the initiation markers, AMP-activated protein kinase, and UNC51-like kinase phosphorylation. Conversely, the DHA pretreatment suppressed excessive tBHP-induced autophagy signaling. Autophagosomes induced by tBHP in IFRS1 cells were decreased to control levels by the DHA pretreatment whereas autolysosomes were only partially decreased. These results suggest that DHA attenuated excessive autophagy induced by oxidative stress in Schwann cells and may be useful to prevent or reduce cell death in vitro. However, its potentiality to treat diabetic neuropathy must be validated in in vivo studies.
Subject(s)
Diabetic Neuropathies , Docosahexaenoic Acids , AMP-Activated Protein Kinases/metabolism , Animals , Autophagy , Cell Death , Diabetic Neuropathies/metabolism , Docosahexaenoic Acids/metabolism , Docosahexaenoic Acids/pharmacology , Oxidative Stress , Rats , Rats, Inbred F344 , Schwann Cells/metabolism , Signal Transduction , tert-Butylhydroperoxide/toxicityABSTRACT
BACKGROUND: In this study, we investigated the impact of simple measurement of psoas muscle index (PMI) on the tolerability of sorafenib treatment of switch from sorafenib to regorafenib. METHOD: This retrospective study enrolled 109 patients with Child-Pugh A hepatocellular carcinoma (HCC) treated with sorafenib. Pretreatment PMI was calculated by measuring and multiplying the greatest anterior/posterior and transverse diameters of the psoas muscles on axial computed tomography images at the L3 vertebral level, and normalizing the sum of bilateral psoas muscle areas by the square of the height in meters. We, then, statistically analyzed the association between PMI and adverse events (AEs) to treatment, tolerability of sorafenib, time to treatment failure (TTF), and prognosis in patients stratified according to PMI. RESULT: Patients were divided into high PMI (n = 41) and low PMI (n = 68) groups based on the cutoff PMI values (men: 7.04 cm2/m2; women: 4.40 cm2/m2) determined by receiver operating characteristic curve analysis to determine sorafenib tolerability. Frequencies of all types of severe AEs were higher in the low PMI group (50.0%) than in the high PMI group (29.3%; P = 0.045). The high PMI group (51.2%) had greater tolerance to sorafenib than the low PMI group (25.0%; P = 0.007). Moreover, in multivariable analysis, PMI was associated with sorafenib tolerability (odds ratio 0.26; P = 0.008) and was a prognostic factor affecting TTF (hazard ratio 1.77; P = 0.021). CONCLUSION: PMI might be a predictive marker of tolerance to treatment and TTF in HCC patients receiving sorafenib treatment.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Female , Humans , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Male , Psoas Muscles/diagnostic imaging , Psoas Muscles/pathology , Retrospective Studies , Sorafenib/adverse effectsABSTRACT
Glucose-responsive ATP-sensitive potassium channels (KATP) are expressed in a variety of tissues including nervous systems. The depolarization of the membrane potential induced by glucose may lead to hyperexcitability of neurons and induce excitotoxicity. However, the roles of KATP in the peripheral nervous system (PNS) are poorly understood. Here, we determine the roles of KATP in the PNS using KATP-deficient (Kir6.2-deficient) mice. We demonstrate that neurite outgrowth of dorsal root ganglion (DRG) neurons was reduced by channel closers sulfonylureas. However, a channel opener diazoxide elongated the neurite. KATP subunits were expressed in mouse DRG, and expression of certain subunits including Kir6.2 was increased in diabetic mice. In Kir6.2-deficient mice, the current perception threshold, thermal perception threshold, and sensory nerve conduction velocity were impaired. Electron microscopy revealed a reduction of unmyelinated and small myelinated fibers in the sural nerves. In conclusion, KATP may contribute to the development of peripheral neuropathy.
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Gene expression in eukaryotes is enhanced by the presence of introns in a process known as intron-mediated enhancement (IME), but its mechanism remains unclear. In Saccharomyces cerevisiae, sequences at the 5'-splice sites (SS) and branch point sites (BPS) are highly conserved compared with other higher eukaryotes. Here, the minimum intron sequence essential for IME was investigated using various short introns and a yeast codon-optimized luciferase gene as an IME model. Mutations at the 5'-SS conserved sequence and branch point in the QCR10 intron caused splicing deficiency with either a complete loss or a marked decrease in IME. By contrast, however, the 3'-AG to tG mutant was spliced and retained IME function. Moreover, heterologous introns, which did not show IME in S. cerevisiae, gained splicing competency and IME ability by substitutions to the S. cerevisiae-type 5'-SS and BPS sequences. Intriguingly, several deletion mutants between the 5'-SS and BPS in introns exhibited high levels of IME despite a loss in splicing competency. In most cases, further deletions or substitutions did not recover splicing competency and were found to decrease IME. However, a 16-nt variant consisting of the conserved 5'-SS and BPS sequences and 3'-CAG showed an IME level comparable with that of the wild-type intron. These results indicate that IME can be independent of splicing in S. cerevisiae while intron sequences at the 5'-SS and BPS play an essential role in IME.