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INTRODUCTION: Affective temperaments are assumed to have biological and neural bases. In the present study, we analyzed 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) images of healthy participants to explore the neural basis of affective temperaments. METHOD: We utilized data of affective temperament measured by the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Autoquestionnaire and 18F-FDG PET images of healthy participants from two of our previous studies. A multiple regression analysis was performed to assess the association between 18F-FDG uptake and temperament scores using Statistical Parametric Mapping 12. RESULTS: The final sample included 62 healthy participants. Whole-brain analysis revealed a cluster of 18F-FDG uptake that was significantly and positively associated with irritable temperament scores in the right cerebellum (Crus II, VIII, and IX). After further adjustment for the other four temperament scores, whole-brain analysis revealed a cluster of 18F-FDG uptake significantly and positively associated with irritable temperament scores in the left insula and right cerebellum (Crus II, VIII, and IX). However, no significant association was found between 18F-FDG uptake and the other four temperaments (depressive, cyclothymic, hyperthymic, and anxious). CONCLUSIONS: The left insula and right cerebellum of the cerebrocerebellar circuit may be one of the neural bases of irritable temperament.
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Bright light exposure (BL) induces neurogenesis in the rat hippocampal dentate gyrus (DG). We had previously conducted a randomized controlled trial (RCT) in which a 4-week period of BL in healthy participants resulted in increased volume of the left DG-head. This study aimed to investigate the effects of BL on the DG in patients with mood disorders. A 4-week RCT was conducted in which patients with mood disorders were randomly assigned to either a BL group (10,000 lx) or dim light exposure group (DL group; 50 lx). All patients underwent clinical assessment and magnetic resonance imaging at baseline and after the intervention. The study registration number is UMIN000019220. Our final sample included 24 patients (BL group, n = 12; DL group, n = 12). A significant effect of time and group was detected in the volumes of the left DG-head (F (1, 22) = 11.6, partial η2 = 0.35, p = 0.003) and left DG-total (left DG-total = left DG-head + left DG-body; [F (1, 22) = 6.5, partial η2 = 0.23, p = 0.02]). Additionally, the BL group demonstrated a significant increase in the volume of the left DG-head (95% CI: -5.4 to -1.6, d = 1.2, p = 0.002) and left DG-total (95% CI: -6.3 to -1.5, d = 1.06, p = 0.005) as well as a positive correlation between the percentage change in the volume of the left DG-total and the percentage change in the scores of the mood visual analog scale (r = 0.58, p = 0.04). In conclusion, our study results suggest that compared to DL, BL leads to a significantly greater increase in the left DG volume in patients with mood disorders. This increase in the left DG volume may be associated with mood improvement in the patients.
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Giro Dentado , Hipocampo , Humanos , Cognición , Giro Dentado/diagnóstico por imagen , Giro Dentado/patología , Hipocampo/patología , Imagen por Resonancia Magnética , Trastornos del Humor/diagnóstico por imagen , Trastornos del Humor/patología , Proyectos de InvestigaciónRESUMEN
ABSTRACT: Herein, we present a case of a female patient with a persistent sore throat, which preceded a hypochondriacal delusion of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Both the sore throat and hypochondriacal delusion persisted together, despite the repeatedly negative results of reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 and a moderate improvement in her depression. Four possibilities for the patient's sore throat were discussed: pain symptoms of somatic symptom disorder, pain symptoms of depression, delusion of pain in her throat, and somatic hallucination as a sore throat. Consequently, somatic hallucinations were considered the most likely. In any case, the present findings suggest that sore throat can precede hypochondriacal delusion of SARS-CoV-2 infection in some noninfected patients. When patients continue to complain of a sore throat despite the negative results of SARS-CoV-2 by the RT-PCR test, we should consider that it might be a somatic hallucination and soon hypochondriacal delusions may occur, leading to the manifestation of other symptoms of psychiatric disorders, such as depression, which may be refractory and/or suicidal.
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COVID-19 , Trastorno Depresivo Resistente al Tratamiento , Faringitis , Femenino , Humanos , Deluciones/etiología , COVID-19/complicaciones , SARS-CoV-2 , Alucinaciones , DolorRESUMEN
Objective The prognostic factors for azacitidine in untreated acute myeloid leukemia (AML) patients ineligible for intensive therapy remain unknown. To identify prognostic factors for azacitidine monotherapy and assist clinicians in deciding whether to use azacitidine monotherapy or other therapies. Methods We retrospectively analyzed 27 patients with AML who were newly treated with azacitidine between 2013 and 2021 at our hospital. We evaluated potential predictors based on the overall survival (OS). Results A univariate analysis found that an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 and platelet count (Plt) <27,000/µL had a significant negative influence on the OS. A multivariate analysis confirmed that both factors had significant independent adverse effects on the OS. An ECOG PS ≥2 and Plt <27,000/µL were thus assigned 1 point each, and a clinical scoring system was created. Log-rank testing showed that the 0-point group (n=12) had a median OS of 680 days [95% confidence interval (CI) 220-898 days] and a 1-year OS rate of 80.8% (95% CI 42.3-94.9%), the 1-point group (n=11) had a median OS of 90 days (95% CI 62-345 days) and a 1-year OS rate of 18.2% (95% CI 2.9-44.2%), and the 2-point group (n=4) had a median OS of 82 days [95% CI 19-not applicable (NA) days] and a 1-year OS rate of 0% (95% CI NA-NA). The p value of 0.00008 indicated that this scoring was useful. Conclusion The ECOG PS and Plt can be used to predict the OS with azacitidine monotherapy in untreated AML patients ineligible for intensive therapy.
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Azacitidina , Leucemia Mieloide Aguda , Humanos , Azacitidina/uso terapéutico , Resultado del Tratamiento , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
OBJECTIVES: The aim of this study was to investigate the association between lithium levels in drinking water and prevalence of Alzheimer's dementia (AD). METHODS: Lithium levels in the drinking water of 808 cities and wards (i.e., 785 Japanese cities of 46 prefectures and 23 wards of Tokyo) in Japan were examined in relation to the prevalence of AD during the 5 years from 2010 to 2014, which was calculated on the basis of the national data base of Ministry of Health, Labor, and Welfare of Japan. Multiple regression analyses were used to investigate the association of lithium levels with the prevalence of AD with adjustment for relevant factors (proportions of one-person households as a family factor and people in primary industry employment as a job factor, annual total sunshine hours as a meteorological factor, and total number of beds of psychiatric hospitals as a medical factor) in total, male, and female elderly populations. RESULTS: The adjusted model showed a significant inverse association of lithium levels with female, but not with male, or total prevalence of AD. CONCLUSIONS: These findings suggest that higher lithium levels in drinking water may be associated with lower prevalence of AD in female, but not male, populations.
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Enfermedad de Alzheimer , Trastorno Bipolar , Agua Potable , Humanos , Femenino , Anciano , Litio , Enfermedad de Alzheimer/epidemiología , Japón/epidemiologíaRESUMEN
BACKGROUND: Transplant-eligible patients with polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes syndrome are treated with induction therapy and autologous stem cell transplantation. Conventional induction therapies may exacerbate neuropathy and a high rate of disease progression within 5 years. Furthermore, only 50% of patients are able to walk independently after the therapies. Daratumumab, lenalidomide, and dexamethasone therapy has been reported as a less neurotoxic, highly effective therapy for patients with polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes syndrome who are ineligible for transplant or whose syndrome is relapsed/refractory, but no reports have provided data from untreated transplant-eligible patients. CASE PRESENTATION: A 34-year-old Japanese woman displayed weakness, pain and edema in the lower limbs, decreased grip strength, amenorrhea, and abdominal distention. She was unable to walk independently. The patient was diagnosed with polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes syndrome and performed four courses of daratumumab, lenalidomide, and dexamethasone therapy, which enabled her to walk independently and did not exacerbate the neuropathy. Hematopoietic stem cells were collected using plerixafor and filgrastim in combination. Autologous stem cell transplantation was performed with high-dose melphalan. At 3-month post-transplantation follow-up, most of her clinical symptoms had disappeared. CONCLUSIONS: Daratumumab, lenalidomide, and dexamethasone therapy followed by autologous stem cell transplantation may be more effective than conventional therapy for newly diagnosed polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes syndrome. Although there was concerns that daratumumab, lenalidomide, and dexamethasone therapy might lead to poor mobilization of hematopoietic stem cells, this was overcome with the combination of plerixafor and filgrastim. The benefit of daratumumab, lenalidomide, and dexamethasone as induction therapy prior to autologous stem cell transplantation should be confirmed in future clinical trials.
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Enfermedades del Sistema Endocrino , Trasplante de Células Madre Hematopoyéticas , Compuestos Heterocíclicos , Polineuropatías , Adulto , Anticuerpos Monoclonales , Dexametasona/uso terapéutico , Femenino , Filgrastim , Movilización de Célula Madre Hematopoyética , Humanos , Lenalidomida , Polineuropatías/tratamiento farmacológico , Trasplante AutólogoRESUMEN
Background: Since our previous investigation on the effects of trace lithium, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA) on deliberate self-harm and suicide attempts in 2018, to our knowledge, no replication study has been conducted on this topic. Subjects and methods: We increased 37 new patients and totally 234 patients were re-analyzed to further investigate the association of suicide-related behaviors with levels of trace lithium, EPA, DHA, and AA in a different way to avoid multicollinearity. Results: Higher lithium levels were significantly associated with fewer suicide attempts and deliberate self-harm, higher EPA levels were significantly associated with fewer deliberate self-harm, and higher AA levels were significantly associated with more deliberate self-harm. Discussion: Although the sample size was only slightly larger than the previous study, the present results were clearly different from the previous ones due to the use of different statistical analyses to avoid multicollinearity. Conclusion: The present findings suggest that naturally absorbed lithium may protect against suicide and deliberate self-harm, while naturally absorbed EPA may protect against deliberate self-harm. However, naturally absorbed AA may be a risk factor for deliberate self-harm.
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INTRODUCTION: Bright light therapy (BLT) has been used for treating seasonal affective disorder, depression and bipolar depression. However, it's precise mechanism remains unclear. Bright light exposure (BL) induces neurogenesis in the adult rat hippocampal dentate gyrus (DG). We hypothesized that BL may induce neurogenesis in the human DG as well. METHOD: A 4-week randomized controlled trial study was conducted, where healthy participants were randomly assigned to a BL group (10,000 lux) or dim light exposure group (DL group; 50 lux). Magnetic resonance imaging was performed at baseline and after 4 weeks. Longitudinal hippocampal subfield segmentation was generated via the FreeSurfer 7.1.1 hippocampal subfields module to evaluate volume of bilateral granule cell and molecular layer of the DG-head and -body. RESULTS: Our final sample size was 20, which consisted of BL group (n = 10) and DL group (n = 10). After age and sex adjustment, significant effects of time and group were detected in the left DG-head volume (p = 0.04). In the BL group, the left DG-head volume significantly increased (p = 0.004), whereas no significant volumetric change was observed in the DL group. CONCLUSIONS: This study revealed that 4-week BL significantly increased left DG-head volume in healthy participants. Thus, neurogenesis might be induced by BL in the human DG, which is a completely new mechanism of BLT.
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Plerixafor and bortezomib have recently been used in autologous stem cell collection to increase the amount of stem cells collected. However, no reports have described the combined use of plerixafor and bortezomib in cases of dialysis-dependent multiple myeloma. The dialysis-dependent multiple myeloma patient in the present study had a small amount of CD34-positive cells with plerixafor and filgrastim, and also with bortezomib and cyclophosphamide. However, by adding plerixafor to bortezomib and cyclophosphamide, collected CD34-positive cells were increased six-fold compared to the previous day. These findings suggest that the combination of plerixafor and bortezomib may be effective in those patients.
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Fármacos Anti-VIH/uso terapéutico , Bencilaminas/uso terapéutico , Ciclamas/uso terapéutico , Movilización de Célula Madre Hematopoyética/métodos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/terapia , Diálisis Renal/métodos , Fármacos Anti-VIH/farmacología , Bencilaminas/farmacología , Ciclamas/farmacología , Femenino , Humanos , Persona de Mediana Edad , Mieloma Múltiple/patologíaRESUMEN
The present study evaluated outcomes and prognostic factors in adult patients with acute myeloid leukemia (AML) after syngeneic hematopoietic stem cell transplantation (HSCT). Among patients in first complete remission (CR1), outcomes of syngeneic HSCT (Syn) were compared with those of autologous HSCT (Auto), allogeneic HSCT from human leukocyte antigen (HLA)-matched sibling donor (MSD), or allogeneic HSCT from HLA-matched unrelated donor (MUD). Among 11,866 patients receiving first HSCT, 26 in the Syn group were analyzed. The 5-year overall survival (OS) rate, the cumulative incidence of relapse, and the cumulative incidence of non-relapse mortality (NRM) were 47.8%, 59.6%, and 4.6%, respectively. The OS was significantly better in patients in CR1 (n = 13) than in patients in non-CR1 (P = 0.012). Furthermore, 39 patients in CR1 each were assigned to the Auto, MSD, and MUD groups using propensity score matching. The 5-year OS in the Syn (68.4%) was not significantly different from those in the Auto (55.9%, P = 0.265), MSD (62.4%, P = 0.419), or MUD (63.7%, P = 0.409) groups. A higher relapse in the Syn than in the MSD and MUD groups was offset by lower NRM. In summary, syngeneic HSCT might be an alternative option for AML patients in CR1.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Adulto , Femenino , Humanos , Leucemia Mieloide Aguda/epidemiología , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Trasplante Autólogo , Trasplante Isogénico , Resultado del Tratamiento , Adulto JovenRESUMEN
Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Trastornos Linfoproliferativos/tratamiento farmacológico , Metotrexato/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bleomicina/administración & dosificación , Ciclofosfamida/administración & dosificación , Dacarbazina/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Quinasas Janus/antagonistas & inhibidores , Estimación de Kaplan-Meier , Linfoma no Hodgkin/mortalidad , Trastornos Linfoproliferativos/inducido químicamente , Trastornos Linfoproliferativos/mortalidad , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Prednisona/administración & dosificación , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Rituximab/administración & dosificación , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Vinblastina/administración & dosificación , Vincristina/administración & dosificaciónRESUMEN
BACKGROUND: Recently, we showed that 4-week mindfulness-based intervention (MBI) followed by 4-week existential approach (EXMIND) was as effective for developing self-compassion as 8-week MBI. This study aims to identify the predictors to EXMIND. METHODS: Of the 63 participants who completed the EXMIND group, 60 participants had baseline, 4-week, and 8-week total scores of the Self-Compassion Scale (SCS). Of the participants, 49 were female and 11 were male, with a mean age of 48.4 years. We investigated the participants' intervention response patterns, then used analysis of variance to compared those patterns by age, gender, and the baseline scores of the Temperament Evaluation of Memphis, Pisa and San Diego Auto-questionnaire, the Temperament and Character Inventory, Mini-Mental State Examination, the Japanese Adult Reading Test, Young Mania Rating Scale, Hamilton Rating Scale for Depression, the Parental Bonding Instrument, and the Purpose in Life Test. In addition, multivariate logistic regression analysis was performed to identify any response pattern predictors. RESULTS: Participants were divided into 4 groups based on response patterns in the changes of total SCS scores of the EXMIND group. The first group consisted of 15 participants who responded positively to MBI, but negatively to the existential approach (A group). The second group consisted of 23 participants who responded negatively to MBI, but positively to the existential approach (B group). The third group consisted of 20 participants who responded positively to both MBI and the existential approach (C group). The fourth group consisted of only 2 participants who responded negatively to both MBI and the existential approach (D group). Participants who responded positively to both MBI and the existential approach (C group) reported more maternal overprotectiveness than the other participants (groups A, B, and D). CONCLUSIONS: The present findings suggest that maternal overprotection may predict consistent improvement of self-compassion during EXMIND therapy.
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Empatía , Existencialismo , Atención Plena , Autoimagen , Adulto , Femenino , Humanos , Masculino , Conducta Materna , Persona de Mediana Edad , Relaciones Madre-Hijo , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
A novel anti-cytomegalovirus (CMV) agent, letermovir (LMV), could reportedly improve the outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) recipients because of its high potential to prevent CMV reactivation. Therefore, 685 Japanese allo-HCT recipients, of whom ~80% had a high risk of CMV reactivation, were retrospectively analyzed to assess the impacts of prophylactic LMV on the incidence of clinically significant CMV (csCMV) infection as well as their transplant outcome. By comparing 114 patients who received LMV prophylaxis for a median 92 days to 571 patients without prophylaxis, we observed that prophylactic LMV could significantly (1) reduce the 180-day cumulative incidence of csCMV infection (44.7 vs. 72.4%, p < 0.001), (2) delay the median time until initiation of CMV antigenemia-guided preemptive therapy (90 vs. 36 days, p < 0.001), (3) shorten the duration of anti-CMV preemptive treatment (21 vs. 25 days, p = 0.006), and (4) improve the overall survival rate at 180 days after transplant (80.4 vs. 73.0%, p = 0.033) with a trend of lower non-relapse mortality (8.9 vs. 14.9%, p = 0.052). Our findings demonstrate that prophylactic LMV treatment is highly effective in preventing the development of csCMV infection and ultimately reduces transplant-related mortality.
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Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Acetatos , Antivirales/uso terapéutico , Citomegalovirus , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/prevención & control , Humanos , Quinazolinas , Estudios RetrospectivosRESUMEN
OBJECTIVES: The aims of the present study thus were (a) to further investigate the association between lithium levels in drinking water and suicide rates by adjusting relevant factors using the so far largest available dataset in Japan, (b) to confirm sex differences, (c) to estimate the effects of long-term exposure to trace lithium, (d) to investigate the effects of drinking bottled instead of tap water, and (e) to exploratorily investigate which lithium levels may be associated with lower suicide rates. METHODS: Mean lithium levels in drinking water of all 808 cities and wards (ie, 785 cities of 46 prefectures and 23 wards of Tokyo) in Japan were examined in relation to mean suicide standardized mortality ratios (SMRs) during the 7 years from 2010 to 2016. Multiple regression analyses adjusted for the size of each population were used to investigate the association of lithium levels with suicide SMRs with adjustments for relevant factors. RESULTS: The adjusted model showed significant inverse associations of lithium levels with total and male SMRs, but not with female SMRs. Neither the proportion of residents who continued to live in the same city nor the consumption of bottled water changed the association between lithium levels and suicide SMRs. Finally, it was 30 µg/L or more that was associated with lower suicide SMRs. CONCLUSIONS: The present findings reconfirm the inverse association between lithium levels in drinking water and suicide rates particularly in the male population.
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Trastorno Bipolar , Agua Potable , Suicidio , Estudios Epidemiológicos , Femenino , Humanos , Japón/epidemiología , Litio/análisis , MasculinoRESUMEN
BACKGROUND: In pharmacological doses, lithium successfully treats bipolar disorder and it can reduce violent crimes committed by individuals with this disorder. AIMS: To investigate whether naturally occurring lithium in drinking water lowers rates of violent crime in the general population. METHOD: We examined lithium levels in the drinking water of the 274 municipalities of Kyushu Island in Japan and compared these with the crime rates in each municipality. RESULTS: We found that lithium levels were significantly and inversely associated with crime rates in 2009. CONCLUSIONS: Our findings suggest that even very low levels of lithium in drinking water may play a role in reducing crime rates in the general population.
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OBJECTIVES: Recently, a 4-week mindfulness-based intervention followed by a 4-week existential approach was found to be as effective for increasing self-compassion as an 8-week mindfulness-based intervention. The purpose of the present study was to identify the factors that predicted change in self-compassion during the 8-week mindfulness-based intervention. METHODS: Fifty-seven of the 61 completers of the 8-week mindfulness-based intervention provided baseline, 4-week, and 8-week self-compassion scale scores. The mean age of the 47 females and 10 males was 49.6 years. Pearson's correlation coefficients were generated on the associations between the change of total self-compassion scale scores from baseline to 8 weeks with age; gender; and the baseline scores on the Temperament Evaluation of Memphis, Pisa and San Diego Auto-questionnaire, Temperament and Character Inventory (TCI), Mini-Mental State Examination, Japanese Adult Reading Test, Young Mania Rating Scale, Hamilton Rating Scale for Depression, Parental Bonding Instrument, and purpose in life (PIL). Multiple regression analysis was performed to identify the predictors of the change in total self-compassion scale scores. RESULTS: Novelty seeking (TCI) was significantly and negatively associated with the change in total self-compassion scale scores, whereas the PIL scores were significantly and positively associated with the change in total self-compassion scale scores. Novelty seeking was not significantly associated with baseline, 4-week, or 8-week total self-compassion scale scores, whereas the PIL scores were significantly and positively associated with baseline, 4-week, and 8-week total self-compassion scale scores. The limitation of the present study was a relatively small number of subjects which deterred a more sophisticated analysis of the pathways involved. CONCLUSIONS: The present findings suggest that more PIL and less novelty seeking predict improvements in self-compassion during mindfulness-based interventions, although novelty seeking might substantially predict the improvement but self-compassion scale and PIL might somewhat conceptually overlap.
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To elucidate dynamic changes in native BCR-ABL and alternatively spliced tyrosine kinase inhibitor (TKI)-resistant but function-dead BCR-ABLIns35bp variant, following commencement or discontinuation of TKI therapy, each transcript was serially quantified in patients with chronic myeloid leukemia (CML) by deep sequencing. Because both transcripts were amplified together using conventional PCR system for measuring International Scale (IS), deep sequencing method was used for quantifying such BCR-ABL variants. At the initial diagnosis, 7 of 9 patients presented a small fraction of cells possessing BCR-ABLIns35bp , accounting for 0.8% of the total IS BCR-ABL, corresponding to actual BCR-ABLIns35bp value of 1.1539% IS. TKI rapidly decreased native BCR-ABL but not BCR-ABLIns35bp , leading to the initial increase in the proportion of BCR-ABLIns35bp . Thereafter, both native BCR-ABL and BCR-ABLIns35bp gradually decreased in the course of TKI treatment, whereas small populations positive for TKI-resistant BCR-ABLIns35bp continued fluctuating at low levels, possibly underestimating the molecular response (MR). Following TKI discontinuation, sequencing analysis of 54 patients revealed a rapid relapse, apparently derived from native BCR-ABL+ clones. However, IS fluctuating at low levels around MR4.0 marked a predominant persistence of cells expressing function-dead BCR-ABLIns35bp , suggesting that TKI resumption was unnecessary. We clarified the possible mechanism underlying mis-splicing BCR-ABLIns35bp , occurring at the particular pseudo-splice site within intron8, which can be augmented by TKI treatment through inhibition of RNA polymerase II phosphorylation. No mutations were found in spliceosomal genes. Therefore, monitoring IS functional BCR-ABL extracting BCR-ABLIns35bp would lead us to a correct evaluation of MR status, thus determining the adequate therapeutic intervention.
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Empalme Alternativo , Proteínas de Fusión bcr-abl/genética , Mutación , Inhibidores de Proteínas Quinasas/farmacología , ARN Polimerasa II/metabolismo , Adulto , Anciano , Femenino , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Sitios Genéticos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Intrones , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , ARN Polimerasa II/antagonistas & inhibidores , Análisis de la Célula IndividualRESUMEN
The effects of stem cell transplantation (SCT) in patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) remain controversial. We analyzed the feasibility of SCT and risk factors associated with outcomes of PTCL-NOS and AITL patients to identify the potential clinical efficacy of SCT. We retrospectively analyzed the data of PTCL-NOS (n = 83) and AITL (n = 112) patients who received autologous (n = 10 and 16, respectively) or allogeneic (n = 12 and 4, respectively) SCT, or no SCT (n = 61 and 92, respectively) between 2008 and 2018. All PTCL-NOS and AITL diagnoses were reconfirmed by an experienced hematopathologist. Median age at PTCL-NOS and AITL diagnoses in the SCT group was younger than that in the no SCT group. Significant risk factors for lower overall survival were intermediate-high and high-risk international prognostic indexes in PTCL-NOS patients (P = 0.0052), and a > 2 modified prognostic index for T-cell lymphoma (P = 0.0079) and no SCT (P = 0.028) in AITL patients. Autologous or allogeneic SCT compared with no SCT in AITL patients resulted in 3-year overall survival of 68.6% and 100% vs. 57.2% (P = 0.018). Strategies should be developed to improve selection of PTCL-NOS and AITL patients suitable for SCT and/or additional novel therapies.