Conleysahl9917

Background/Aims Nilotinib is used for treating patients with imatinib-sensitive or -resistant chronic myeloid leukemia (CML); however, nilotinib-resistant cases have been observed in recent years. In addition, a considerable number of patients receiving nilotinib developed diabetes. Metformin is a front-line drug for the treatment of type 2 diabetes, and several studies have shown that diabetes patients treated with metformin have reduced incidence of cancer. This study aimed to define the effect of metformin on CML cells to determine whether metformin overcomes nilotinib resistance, and to identify novel targets for the treatment of nilotinib resistance. Methods We observed the effects of metformin and nilotinib on K562 and KU812 human CML cell lines. Nilotinib-resistant CML cell lines were generated by exposing cells to gradually increasing doses of nilotinib. Then, we investigated the driving force that makes resistance to nilotinib and the effect of metformin on the driving force. Results Sub-toxic doses of metformin enhanced nilotinib efficacy by reducing Bcl-xL expression, which induces apoptosis in CML cells. Next, we generated nilotinib-resistant K562 and KU812 cell lines that overexpressed the c-Jun N-terminal kinase (JNK) gene. JNK silencing by a JNK inhibitor restored sensitivity to nilotinib. Furthermore, metformin was effective in decreasing phosphorylated JNK levels, restoring nilotinib sensitivity. Combined treatment with nilotinib and metformin was more effective than combined treatment with nilotinib and a JNK inhibitor in terms of cell proliferation inhibition. Conclusions This study suggested that combination therapy with metformin and nilotinib may have clinical benefits of enhancing antileukemia efficacy and overcoming resistance to nilotinib.Background/Aims To investigate if BK virus (BKV)-specific T cell immunity measured by an interferon-γ enzyme-linked immunospot (ELISPOT) assay can predict the outcome of BK virus infection in kidney transplant recipients (KTRs). Methods We included 68 KTRs with different viremia status (no viremia [n = 17], BK viremia [n = 27], and cleared viremia [n = 24]) and 44 healthy controls (HCs). The BK viremia group was divided into controller ( 3 months) according to sustained duration of BKV infection. We compared BKV-ELISPOT results against five BKV peptides (large tumor antigen [LT], St, VP1-3). Results BKV-ELISPOT results were higher in three KTRs groups with different BKV infection status than the HCs group (p less then 0.05). In KTR groups, they were higher in cleared viremia group than no viremia or BK viremia group. Within the BK viremia group, controller group had higher LT-ELISPOT results compared to noncontroller group (p = 0.032). Also, KTRs without BK virus-associated nephropathy (BKVN) had higher LT, St, VP1, and VP2-ELISPOT results than those with BKVN (p less then 0.05). Conclusions BKV-ELISPOT assay may be effective in predicting clinical outcomes of BKV infection in terms of clearance of BK virus and development of BKVN.Alcoholic liver disease is a consolidated indication for liver transplantation, but many unsolved issues can be highlighted. Patients with alcohol use disorder develop peculiar comorbidities that can become contraindications for transplantation. Moreover, a number of social and psychological patterns should be evaluated to select candidates with a low risk of alcohol relapse and adequate post-transplant adherence. In this context, the 6-month rule is too rigid to be widely applied. A short period of abstinence (1 to 3 months) is useful to estimate recovery of liver function and, possibly to avoid transplant. Cardiovascular disorders and extra-hepatic malignancies represent the main clinical issues after transplant. Patients transplanted due to alcoholic disease are a major risk for other liver diseases. Severe corticosteroid-resistant alcoholic acute hepatitis is a debated indication for transplant. However, available data indicate that well-selected patients have excellent post-transplant outcomes. Behavioral therapy, continued psychological support and a multidisciplinary team are essential to achieve and maintain complete alcohol abstinence during the transplant process. Alcoholic liver disease is an excellent indication for a liver transplant but patients with alcohol use disorder deserve a personalized approach and dedicated resources.Objective Non-motor symptoms (NMSs) significantly contribute to increased morbidity and poor quality of life in patients with parkinsonian disorders. This study aims to explore the profile of NMSs in patients with progressive supranuclear palsy (PSP) using the validated Non-Motor Symptom Scale (NMSS). Methods Seventy-six patients with PSP were evaluated in this study. Motor symptoms and NMSs were evaluated using the PSP Rating Scale (PSPRS), Unified Parkinson's Disease Rating Scale-III, Montreal Cognitive Assessment, Hamilton Depression (HAMD) and Anxiety Rating Scales, Parkinson's Disease Sleep Scale (PDSS) and NMSS. NMS severity and prevalence were also compared between patients with PSP-Richardson syndrome (PSP-RS) and those with PSP-parkinsonism. Results All subjects in this cohort reported at least 2 NMSs. The most prevalent NMSs in patients with PSP were in the domains of sleep/fatigue, mood/cognition, and sexual function. The least prevalent NMSs were in the domains of cardiovascular including falls, and perceptual problems/hallucinations. Significant correlations were observed between the NMSS scores and HAM-D, PDSS, PSPRS scores and PSPRS sub-scores. The severity of NMSs was unrelated to the duration of illness. Patients with PSP-RS reported a higher severity of drooling, altered smell/taste, depression and altered interest in sex and a higher prevalence of sexual dysfunction. Conclusion NMSs are commonly observed in patients with PSP, and the domains of sleep, mood and sexual function are most commonly affected. These symptoms contribute significantly to disease morbidity, and clinicians should pay adequate attention to identifying and addressing these symptoms.Objective To investigate whether baseline olfactory dysfunction in Parkinson's disease (PD) patients is associated with baseline and longitudinal motor and cognitive function. Methods We recruited 228 drug-naïve PD patients who were followed for a mean of 6 years. Patients underwent the Cross-Cultural Smell Identification Test (CCSIT), a neuropsychological test, and N-(3-[18F]fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane positron emission tomography within 6 months of the baseline evaluation. Olfactory dysfunction was categorized as normosmia (CCSIT score ≥ 9), hyposmia (CCSIT score 5-8), and anosmia (CCSIT score ≤ 4). During the follow-up period, we investigated changes in the levodopa-equivalent dose (LED) and the occurrence of wearing-off, levodopa-induced dyskinesia, and dementia. Results Among the PD patients, 80.7% were hyposmic at the time of diagnosis, and 26.1% were anosmic. Baseline olfactory dysfunction was not associated with either initial parkinsonian motor symptoms or with the longitudinal LED increment and motor complications. Meanwhile, the anosmic group had lower baseline scores on the Korea version of the Boston Naming Test and Stroop color reading test than the normosmic and hyposmic groups. The anosmic group exhibited a higher rate of conversion to dementia than the normosmic [adjusted hazard ratio (HR) 3.99, 95% confidence interval (CI) 1.08-14.72] and hyposmic (adjusted HR 2.48, 95% CI 1.15-5.32) PD groups, regardless of baseline motor deficits and cognitive status. Conclusion Baseline olfactory dysfunction was not associated with motor deficits and complications, but it was associated with cognitive dysfunction and prognosis, suggesting that severe olfactory impairment may reflect early cortical involvement, probably in the frontotemporal region, and rapid spreading of Lewy body pathology.Transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS) have been used for human physiological analyses and treatment of movement disorders. In this review, we present three new TMS utilities for scientific research or clinical application for movement disorders. 1) Confirmation of animal findings. Functional modulation of particular brain areas induced by rTMS can produce changes in task performance. This indicates that the area stimulated by rTMS should play some role in the target task. One example of this use is the study of functional differences between the presupplementary motor area (preSMA) and SMA in a sequential learning task. 2) Utility of cerebellar stimulation. Cerebellar functional changes in basal ganglia disorders are a hot topic in this field. These changes have been studied by cerebellar inhibition using a paired TMS coil experiment. Several researchers have recently used rTMS over the cerebellum as a treatment option for movement disorders. 3) rTMS enhancement of the effects of rehabilitation. The combination of rTMS and conventional rehabilitation may enhance rehabilitation efficacy. For example, rTMS over the lumbar gait (locomotion) center may enhance functional recovery of the gait more robustly than conventional rehabilitation alone in patients with a spinal cord injury.Although the KMT2B gene was identified as a causative gene for early-onset generalized dystonia, the efficacy of deep brain stimulation (DBS) in KMT2B-related dystonia has not been clearly elucidated. Here, we describe a 28-year-old woman who developed generalized dystonia with developmental delay, microcephaly, short stature, and cognitive decline. She was diagnosed with KMT2B- related dystonia using whole-exome sequencing with a heterozygous frameshift insertion of c.515dupC (p.T172fs) in the KMT2B gene. Oral medications and botulinum toxin injection were not effective. The dystonia markedly improved with bilateral pallidal DBS (the Burke-Fahn-Marsden Dystonia Rating Scale score was reduced from 30 to 5 on the dystonia movement scale and from 11 to 1 on the disability scale), and she could walk independently. From this case, we suggest that bilateral globus pallidus internus DBS can be an effective treatment option for patients with KMT2B-related generalized dystonia.A lifetime of general practice brings with it the privilege of acquired wisdom. We swim in uncertainty and have learned to work within its scope.General practice is absolutely central to national and local responses to COVID-19 in Australia, and the nation is building a response on the basis of its very strong system of primary healthcare.Uncharted waters’ is perhaps an understatement of where we are headed at this time. The situation is fluid, with government regulations for our society changing rapidly.INTRODUCTION Emerging infectious disease outbreaks, such as the present coronavirus disease 2019 (COVID-19) pandemic, often have a psychological impact on the well-being of the general population, including survivors and caregivers. Our study aimed to synthesise extant literature regarding the combined psychological responses and coping methods used by the general population in past outbreaks. METHODS We conducted a narrative synthesis of the published literature over the last two decades with a quality appraisal of included articles that reported both psychological responses and coping strategies within infectious disease outbreaks. RESULTS A total of 144 papers were identified from the search, 24 of which were included in the review. Overall, 18 studies examined the psychosocial responses of the general population towards the severe acute respiratory syndrome epidemic, four studies focused on the Ebola epidemic and two studies covered the H1N1 outbreak. Common themes in psychological responses included anxiety/fears, depression, anger, guilt, grief and loss, post-traumatic stress, and stigmatisation, but also a greater sense of empowerment and compassion towards others.