Skeletal-Related Events in Patients With Multiple Myeloma: A Comprehensive Retrospective Cohort Study.

BACKGROUND: Multiple myeloma (MM) patients are at risk of skeletal-related events (SREs) like spinal cord compression, pathologic fractures, bone surgery, and radiation to bone. Real-world data regarding SREs in MM are limited. METHODS: We conducted a large, retrospective, nationwide cohort study using the Korean Health Insurance Review and Assessment Service (HIRA) database from 2007 to 2018. RESULTS: Over a 12-year study period, we identified 6,717 patients who developed symptomatic MM. After a median follow-up of 35.1 months (interquartile range [IQR], 20.8-58.2 months), 43.6% of these patients experienced SREs, and 39.6% had four or more SREs. One in five patients (20.0%) experienced pathologic fractures within the first year of follow-up. The median time to first SRE was 9.6 months (IQR, 1.2-25.8 months), with 3.0 months in the group with prior SREs and 19.8 months in the group without prior SREs. During follow-up, 78.5% of patients received bisphosphonates. Multiple logistic regression analysis revealed several factors associated with an increased risk of SREs, including being female (odds ratio [OR], 1.44), aged 50 or older (OR, 1.87), having cerebrovascular disease (OR, 1.34), undergoing first-line chemotherapy regimens not containing bortezomib or lenalidomide (OR, 1.49), and being in the group with prior SREs and bisphosphonate use (OR, 5.63), compared to the group without prior SREs and without bisphosphonate use. CONCLUSION: This population-based study is the first to report the incidence and risk factors of SREs in Korean MM patients, which can be used to assess their bone health.

Incidence of Venous Thromboembolism: The 3rd Korean Nationwide Study.

BACKGROUND: The incidence of venous thromboembolism (VTE) has gradually increased in the Korean population. This study aimed to evaluate the annual age- and sex-adjusted incidence rates (ASR) of VTE and anticoagulation trends between 2014 and 2018. METHODS: Using the Korean Health Insurance Review and Assessment Service database, we retrospectively identified VTE patients between 2014 and 2018 using both diagnostic and medication anticoagulant codes assigned within 6 months of the initial index event. Anticoagulant patterns were classified as follows: direct oral anticoagulants (DOAC), parenteral anticoagulants, warfarin, and mixed anticoagulation regimens. RESULTS: We identified 95,205 patients with VTE (female, 56.8%). The ASR for VTE per 100,000 person-years increased from 32.8 in 2014 to 53.7 cases in 2018 (relative risk of 1.63; 95% confidence interval, 1.6-1.67). The VTE incidence rates were 25 times higher in the ≥ 80 group than in the 30s group. VTE occurred 1.29 times more often in women than in men. The proportion of DOAC prescriptions increased from 40.5% to 72.8%, whereas warfarin prescriptions decreased from 27% to 5.6% in 2014 and 2018. CONCLUSION: In Korea, the ASRs of VTE continued to increase since 2014, but the rate of increase slowed in 2018. The VTE occurred more often in the elderly and in women. Five years after the introduction of DOACs in 2013, they accounted for 73% of all anticoagulants used to treat VTE.

Evaluation of the need for cytoreduction and its potential carcinogenicity in children and young adults with myeloproliferative neoplasms.

Myeloproliferative neoplasms are rare at a young age, and few reports have described the disease characteristics and outcomes in this group. This study aimed to elucidate the clinical course of essential thrombocythemia (ET) and polycythemia vera (PV) in children and young adults aged <39 years focusing on thromboembolic events (TE) and second primary malignancies (SPMs). A total of 990 patients who were diagnosed from 2008 to 2017 were included by analyzing the Health Insurance Review and Assessment Service database in Korea. The incidence was 2.53 per 1,000,000 for ET (643 patients; 276 male patients; median 31 years) and 1.37 per 1,000,000 for PV (347 patients; 309 male patients; median 32 years). Three ET patients developed secondary acute myelogenous leukemia and three developed secondary myelofibrosis. The 5-year cumulative incidence of TE was 14.2% in ET and 21.3% in PV. Thus, the incidence was higher in PV; in particular, arterial TE (ATE) was evidently higher in PV than in ET. The 5-year cumulative incidence of SPMs was 2.5% in ET and 2.6% in PV. While the use of both aspirin and hydroxyurea reduced the incidence of ATE, hydroxyurea significantly increased the incidence of SPMs. The incidence of ET and PV was very low, and ET was more common than PV in children and young adults. The high incidence of TE in young patients suggests the importance of thrombosis prevention. However, hydroxyurea appears to increase the incidence of SPMs; therefore, the risks and benefits should be considered.

Estimated prevalence and impact of the experience of becoming a victim of exhibitionism and frotteurism in Korea: A general population based study.

Exhibitionism and frotteurism are often considered just nuisance crimes but may cause serious distress to the victims. Previous studies of victim experience have focused on specific groups, such as healthcare professionals or university students. To estimate the prevalence of victimisation by exhibitionism and frotteurism among young general population adults in Korea and to describe the impact of such experiences, trained researchers randomly recruited young adults for face to face interviews at transport hubs and on university campuses. In addition, we posted the questionnaire as a Google survey to a limited number of local websites. Data were analysed descriptively. Of 900 people directly approached, 747 (83%) agreed participation, as did 423 online. These two samples were similar demographically, so combined for analyses. Two hundred and thirty-five (20%) reported experiencing exhibitionism and 130 (11%) frotteurism. Exposure victims were older (means 23.2:21.1 years) and more likely to be women than frotteur victims. All but two exposure and nine frotteur perpetrators were said to be men. Reporting to police was rare (17 exposure, 2 frotteur); most exposure victims (73%) but under half of frotteur victims told family or friends. All but 15% of each group had bad feelings about the experience, varying by experience type. Ten percent of exposure and 20% of frotteur victims described distress lasting months; more reported enduring behaviour changes, like avoiding subways. Although our sample is unlikely to be wholly representative of the general population, our research examines a broader range of people than previous studies. Most victims of these "nuisance crimes" were distressed by them, and, hitherto less well recognised, at least a fifth of such victims may have long-term distress. Further research could establish the extent to which support outside the family or friends' group or treatment would be indicated.

Utility of allogeneic hematopoietic stem cell transplantation using international donors in a homogenous ethnic population: question in the era of various alternative donors.

The advent of various alternative donors in allogeneic hematopoietic stem cell transplantation (HSCT) raises the question of using international donors, especially in ethnically homogenous populations. We analyzed the clinical outcome and medical expense of human leukocyte antigen (HLA)-matched HSCT using domestic and international donors. We analyzed the patients who received allogeneic HSCT at five medical centers in Korea in the last 10 years. Using propensity-score matching, we compared overall survival (OS), relapse-free survival (RFS), and transplantation-related complications. Medical expense was analyzed based on National Health Insurance Service (NHIS) data. A total of 269 patients were analyzed after 3:1 (domestic/international) matching. There was no difference in OS (p = 0.395) and RFS (p = 0.604) between the domestic and international donor groups (5-year OS rate 42.9 and 37.8%, 5-year RFS rate 37.6 and 33.5% for domestic and international groups, respectively). No difference in chronic graft-versus-host disease (GVHD) incidence was observed (34.2% in domestic and 35.9% in international group, p = 0.804). Early infection was more frequent in the domestic group (55.0 vs. 35.8%, p = 0.007), whereas infection after 30 days was more frequent in the international group (28.7 vs. 49.3%, p = 0.001). Mean medical expense was far higher in the international group, by US $51,944 in the entire follow-up period (p < 0.001). We would expect similar outcomes for international and domestic donors in terms of survival and treatment-related complications with HLA-matched HSCT in other ethnically homogenous populations. These findings should be considered together with the high cost of using international donors in the era of various alternative donors.

Current Management of Cancer-associated Venous Thromboembolism: Focus on Direct Oral Anticoagulants.

Cancer-associated venous thromboembolism (CAT) is a common complication associated with high morbidity and mortality. In accordance with major clinical trials comparing low-molecular-weight heparin (LMWH) with a vitamin K antagonist (VKA), LMWH is currently the standard treatment for CAT, owing to its efficacy for thrombosis recurrence and improved safety profile compared to VKA. Over the past few years, direct oral anticoagulants (DOACs) have emerged as potential alternative therapies to LMWH due to their convenient route of administration and predictable pharmacokinetics, but evidence for their use in CAT is inconclusive, as only a small fraction of the study populations in these trials had CAT. Recently, two large head-to-head trials comparing DOACs to LMWH in CAT patients reported comparable efficacies of DOACs with increased bleeding risk. Occasionally, CAT treatment can be challenging due to the heterogeneity of underlying malignancies and comorbidities. Renal insufficiency and gastrointestinal defects are the main obstacles in anticoagulant selection. Careful choice of treatment candidates and proper anticoagulant strategies are critical for the treatment of CAT; hence, more studies are required to address these challenges.

Punicalagin suppresses methicillin resistance of Staphylococcus aureus to oxacillin.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important human pathogen that is cross-resistant to most ß-lactam antibiotics. We investigated whether oxacillin, which is a ß-lactam antibiotic, alone or in combination with punicalagin can affect the penicillin binding protein 2a (PBP2a)-mediated resistance of MRSA. Susceptibility testing of punicalagin with oxacillin was performed using the microdilution and checkerboard assay and the growth curve assay. Binding affinity of punicalagin for cell wall peptidoglycan (PGN) was confirmed by an increased concentration of PGN in bacterial cultures containing punicalagin. The level of PBP2a was analyzed by western blotting. Punicalagin exhibited antimicrobial activity in the viability assay and increased the susceptibility of MRSA to oxacillin. PGN interfered with the antimicrobial activity of punicalagin and prevented the synergistic activity of punicalagin and oxacillin. Increasing the concentration of punicalagin and maintaining a constant concentration of oxacillin resulted in synergistic suppression of the expression of the mec operon (mecA, mecI, and mecR1). The production of PBP2a was suppressed by the addition of punicalagin to oxacillin. Our findings demonstrate that punicalagin potentiates the effect of oxacillin on MRSA by reducing the transcription of mecA (a gene marker for methicillin resistance), which resulted in a reduced level of PBP2a.

Cryptotanshinone Induces Cell Cycle Arrest and Apoptosis of NSCLC Cells through the PI3K/Akt/GSK-3ß Pathway.

Cryptotanshinone (CTT) is a natural product and a quinoid diterpene isolated from the root of the Asian medicinal plant, Salvia miltiorrhizabunge. Notably, CTT has a variety of anti-cancer actions, including the activation of apoptosis, anti-proliferation, and reduction in angiogenesis. We further investigated the anti-cancer effects of CTT using MTS, LDH, and Annexin V assay, DAPI staining, cell cycle arrest, and Western blot analysis in NSCLC cell lines. NSCLC cells treated with CTT reduced cell growth through PI3K/Akt/GSK3ß pathway inhibition, G0/G1 cell cycle arrest, and the activation of apoptosis. CTT induced an increase of caspase-3, caspase-9, poly-ADP-ribose polymerase (PARP), and Bax, as well as inhibition of Bcl-2, survivin, and cellular-inhibitor of apoptosis protein 1 and 2 (cIAP-1 and -2). It also induced G0/G1 phase cell cycle arrest by decreasing the expression of the cyclin A, cyclin D, cyclin E, Cdk 2, and Cdk 4. These results highlight anti-proliferation the latent of CTT as natural therapeutic agent for NSCLC. Therefore, we investigated the possibility of CTT as an anti-cancer agent by comparing with GF, which is a representative anti-cancer drug.

Diagnostic Approaches to Investigate JAK2-Unmutated Erythrocytosis Based on a Single Tertiary Center Experience.

INTRODUCTION: Erythrocytosis is attributed to various clinical and molecular factors. Many cases of JAK2-unmutated erythrocytosis remain undiagnosed. We investigated the characteristics and causes of JAK2-unmutated erythrocytosis. METHODS: We assessed the clinical and laboratory results of patients with erythrocytosis without JAK2 mutations and performed targeted next-generation sequencing (NGS) panels for somatic and germline mutations. RESULTS: In total, 117 patients with JAK2-unmutated erythrocytosis were included. The median hemoglobin and hematocrit levels were 17.9 g/dL and 53.4%, respectively. Erythropoietin levels were not below the reference range. Thrombotic events were reported in 17 patients (14.5%). Among JAK2-unmutated patients, 44 had undergone targeted panel sequencing consisting of myeloid neoplasm-related genes, and 16 had one or more reportable variants in ASXL1 (5/44), TET2, CALR, FLT3, and SH2B3 (2/44). Additional testing for germline causes revealed eight variants in seven genes in eight patients, including NF1, BPGM, EPAS1, PIEZO1, RHAG, SH2B3, and VHL genes. One NF1 pathogenic, one BPGM likely pathogenic, and six variants of undetermined significance were detected. CONCLUSION: Somatic and germline mutations were identified in 36.4% and 33.3 % of the JAK2-unmutated group; most variants had unknown clinical significance. Not all genetic causes have been identified; comprehensive diagnostic approaches are crucial for identifying the cause of erythrocytosis.

A Phase II Study to Evaluate the Efficacy of Bortezomib in Combination with Thalidomide in Treatment-Naïve Waldenstrom Macroglobulinemia Patients.

PURPOSE: Despite the recent success of Bruton's tyrosine kinase (BTK) inhibitors for the treatment of Waldenstrom macroglobulinemia (WM), their indefinite treatment duration ultimately tantamount to substantial financial and emotional burden. On the other hand, fixed duration of proteasome inhibitors (PI) have shown rapid and reasonable response in WM treatment. Despite the well-known synergism between PI and immunomodulatory drugs (IMiD), there is no trials evaluating such combination in WM. MATERIALS AND METHODS: Based on above, we designed this phase II study to investigate the efficacy and safety of 6 cycles of 28-day bortezomib-thalidomide-dexamethasone (VTD) regimen for treatment-naïve WM. RESULTS: A total of 15 patients were enrolled: major response rate was 64.3%, and overall response rate was 78.6%. During the median follow-up of 41 months, median progression-free survival (PFS) was 13 months and overall survival 40 months. For responders, median duration of response was 13 months and median PFS 19 months. The most common adverse event (AE) of any grade was constipation (57.1%). The most common grade ≥ 3 AE was anemia (21.4%). CONCLUSION: All in all, we hereby provide proof-of-concept that PI + IMiD may be an attractive backbone for fixed duration treatment. It should be noted that granting the same level of access to newer drugs globally is virtually impossible. Thus efforts to develop regimens using readily available drugs to yield similar or adequate treatment outcomes should not be disregarded. In this sense, we believe our study holds its place for its novelty and eloquently addresses achieving the daunting societal quest of health equity.

False-positive results of galactomannan assays in patients administered glucose-containing solutions.

Galactomannan (GM) is a polysaccharide cell wall component released by Aspergillus spp., and an immunoenzymatic GM assay is used for the diagnosis of invasive pulmonary aspergillosis. We evaluated the cause of strong positivity for GM in patients with no typical signs of aspergillosis. Repeat assays were performed using different instruments and reagent lots, but there were no differences in results among the assays. Patients with strongly positive GM results were investigated. Medication histories revealed that 14 of 23 patients had been administered total parenteral nutrition solution from one manufacturer and 4 patients had been administered dextrose solution from a different manufacturer before being tested. The results of GM assays conducted on samples of dextrose solution and the glucose fraction of the total parenteral nutrition solution were strongly positive, confirming the causes of the false-positive reactions. We hypothesize that a trace amount of GM was introduced into the glucose-containing solutions because glucoamylase, which is necessary for the saccharification step of glucose synthesis, was derived from Aspergillus niger. To enhance patient care and prevent unnecessary antifungal prescriptions, healthcare providers and manufacturers of healthcare products need to be aware of the possibility of false-positive reactions for GM.

Downregulation of microRNA-330-5p induces manic-like behaviors in REM sleep-deprived rats by enhancing tyrosine hydroxylase expression.

AIM: In our pilot study, we found an increase in tyrosine hydroxylase (Th) mRNA expression in the prefrontal cortex of 72-h REM sleep-deprived (SD) rats, a mania model. Additionally, the expression levels of miR-325-3p, miR-326-3p, and miR-330-5p, the predicted target miRNAs on TH, were significantly decreased. Based on these results, in this study, we investigated whether miRNA-325-3p, miR-326-3p, and miR-330-5p modulate TH and manic-like behaviors in SD rats. METHODS: Manic-like behaviors were assessed using the open field test (OFT) and elevated plus-maze (EPM) test. The direct binding activity of miRNAs to the 3'-untranslated region (3'-UTR) of the Th gene was measured in HEK-293 cells using a luciferase reporter system. We also examined mRNA and protein expression of TH after intracerebroventricular (ICV) injection of miR-330-5p agomir to SD rats, along with manic-like behaviors. RESULTS: We observed an upregulation in mRNA and protein expression of TH and downregulation in miRNA-325-3p, miR-326-3p, and miR-330-5p expressions in the prefrontal cortex of SD rats, together with increased manic-like behaviors. The luciferase reporter assay showed that miR-330-5p could repress TH expression through direct binding to its target site in the 3'-UTR of Th, whereas miR-326-3p and miR-330-5p could not. In addition, ICV injection of miR-330-5p agomir alleviated the increase in TH expression in the prefrontal cortex of SD rats and manic-like behaviors. CONCLUSIONS: TH expression regulation through miR-330-5p may be implicated in the pathophysiology of mania in SD rats.

Hydrolyzed Collagen Tripeptide Promotes Longitudinal Bone Growth in Childhood Rats via Increases in Insulin-Like Growth Factor-1 and Bone Morphogenetic Proteins.

Previous studies have reported that collagen tripeptide (CTP) derived from collagen hydrolysate has various beneficial effects on health by protecting against skin aging and improving bone formation and cartilage regeneration. Collagen-Tripep20TM (CTP20), which is a low-molecular-weight CTP derived from fish skin, contains a bioactive CTP, Gly-Pro-Hyp >3.2% with a tripeptide content >20%. Herein, we investigated the osteogenic effects and mechanisms of CTP20 (<500 Da) on MG-63 osteoblast-like cells and SW1353 chondrocytes. And we measured promoting ratio of the longitudinal bone growth in childhood rats. First, CTP20 at 100 µg/mL elevated the proliferation (15.0% and 28.2%), alkaline phosphatase activity (29.3% and 32.0%), collagen synthesis (1.25- and 1.14-fold), and calcium deposition (1.18- and 1.15-fold) in MG-63 cells and SW1353, respectively. In addition, we found that CTP20 could promote the longitudinal growth and height of the growth plate of the tibia in childhood rats. CTP20 enhanced the protein expression of insulin-like growth factor-1 (IGF-1) in MG-63 and SW1353 cells, and in the growth plate of childhood rats, along with Janus Kinase 2, and signal transducer and activator of transcription 5 activation in MG-63 and SW1353 cells. CTP20 also elevated the expression levels of bone morphogenetic proteins (BMPs) in MG-63 and SW1353 cells and in the growth plates of childhood rats. These results indicate that CTP20 may promote the endochondral ossification and longitudinal bone growth, through enhancing of IGF-1 and BMPs. (Clinical Trial Registration number: smecae 19-09-01).

Increased risk of venous and arterial thromboembolism in patients with colorectal cancer receiving cetuximab-based combination chemotherapy: A population-based study in Korea.

INTRODUCTION: Limited data exist on the risk of venous and arterial thromboembolisms (VTE and ATE) in patients receiving cetuximab plus chemotherapy. We aimed to determine the thromboembolic risk of patients with recurrent/metastatic colorectal cancer (CRC) treated with cetuximab plus chemotherapy compared to chemotherapy alone. METHODS: This population-based study used nationwide claims data from the Health Insurance Review and Assessment Service of South Korea from 2013 to 2020. Patients with recurrent/metastatic CRC treated with first-line oxaliplatin- or irinotecan-based doublets with or without cetuximab and no secondary prevention for VTE and ATE were included. Primary outcomes were the occurrence of any thromboembolic events, VTE, and ATE, which were determined using the cumulative incidence method incorporating death as a competing event. RESULTS: We identified 19,723 patients (cetuximab plus chemotherapy, N = 7630; chemotherapy alone, N = 12,093). The cumulative incidence of any thromboembolic events in patients with cetuximab plus chemotherapy was significantly higher than in those receiving chemotherapy alone (6-month, 5.62 % vs. 3.58 %, P < 0.0001). The rates of VTE (6-month, 5.11 % vs. 3.28 %, P < 0.0001) and ATE (6-month, 0.53 % vs. 0.32 %, P = 0.0218) were also higher in patients receiving cetuximab plus chemotherapy. In multivariable analysis, cetuximab plus chemotherapy was independently associated with developing any thromboembolic events (hazard ratio [HR], 1.63; 95 % confidence interval [CI], 1.42-1.87), VTE (HR, 1.62; 95 % CI, 1.40-1.87), and ATE (HR, 1.77; 95 % CI, 1.16-2.71). CONCLUSIONS: Cetuximab with irinotecan- or oxaliplatin-based doublet chemotherapy was associated with an increased risk of any thromboembolic events, VTE, and ATE; further studies are warranted to examine the underlying mechanisms.

The effect of metformin or dipeptidyl peptidase 4 inhibitors on clinical outcomes in metastatic non-small cell lung cancer treated with immune checkpoint inhibitors.

BACKGROUND: Preclinical data have shown the immunomodulatory effects of metformin and dipeptidyl peptidase 4 (DPP4) inhibitors in patients with diabetes. However, its clinical impact remains unclear in lung cancer. METHODS: Between 2017 and 2021, 466 patients received ICI monotherapy. Patients were categorized into concurrent (MET; metformin or combination of metformin and DPP4 inhibitor) and without concomitant (NMET; nonmetformin/DPP4 inhibitors) administration of metformin and DPP4 inhibitors groups at least 8 weeks before and during ICI therapy. The primary objectives were the objective response rate (ORR) and progression-free survival (PFS). The second objective was to evaluate the overall survival (OS) and the occurrence of immune-related adverse events (irAEs). RESULTS: Among 466 patients, 89 (19.0%) and 377 (81%) were categorized into the MET and NMET groups, respectively. MET group had a significantly higher ORR (MET group: 24.7% vs. NMET group: 14.8%, p = 0.025) and longer PFS than those in the NMET group (MET group 5.1 month vs. NMET group 2.8 months, p = 0.018). After patients were stratified based on the prior line of therapy and PD L1 expression status, the PFS of the second-line therapy and PD L1 ≥50 was significantly higher in the MET than in the NMET group. The proportion of patients experiencing all-grade irAEs was numerically higher in the MET group (19.1%) than in the NMET group (14.3%), without statistical significance (p = 0.382). CONCLUSIONS: Concurrent use of metformin and DPP4 inhibitors with ICIs significantly improved the clinical outcomes without increasing the incidence of irAEs in NSCLC.

Control of fibrosis with enhanced safety via asymmetric inhibition of prolyl-tRNA synthetase 1.

Prolyl-tRNA synthetase 1 (PARS1) has attracted much interest in controlling pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases. However, there are concerns about its catalytic inhibition for potential adverse effects on global protein synthesis. We developed a novel compound, DWN12088, whose safety was validated by clinical phase 1 studies, and therapeutic efficacy was shown in idiopathic pulmonary fibrosis model. Structural and kinetic analyses revealed that DWN12088 binds to catalytic site of each protomer of PARS1 dimer in an asymmetric mode with different affinity, resulting in decreased responsiveness at higher doses, thereby expanding safety window. The mutations disrupting PARS1 homodimerization restored the sensitivity to DWN12088, validating negative communication between PARS1 promoters for the DWN12088 binding. Thus, this work suggests that DWN12088, an asymmetric catalytic inhibitor of PARS1 as a novel therapeutic agent against fibrosis with enhanced safety.

Effects of a hypertension management program by Seongcheon primary health care post in South Korea: an analysis of changes in the level of knowledge of hypertension in the period from 2004 to 2009.

The objective of this study was to examine the effects of a hypertension management program provided by a primary health care post located in a distant rural area in South Korea on the level of knowledge of hypertension. The panel data consisted of a total of 319 people or the entire population aged above 40 years of five villages located in Goseong-gun, Gangwon province, South Korea. Preliminary interviews were conducted with all the residents prior to their enrollment in the health care post's hypertension management program. After 5 years of program operation, follow-up interviews were carried out with the same population. A total of 207 participants who completed both interviews were used in the final analysis. First, only the hypertensive group who participated in the program exhibited a significant difference in the level of knowledge. Second, educational level was associated with the level of knowledge in the entire group. Third, the effects of the program differed by gender, with men demonstrating more significant variations in knowledge upon participating in the program. For effective use of resources, considering that the effects of a hypertension education programs worked differently for groups, more customized hypertension management programs need to be targeted at each group to improve the effectiveness of hypertension education programs.

REM-Sleep Deprivation Induces Mitochondrial Biogenesis in the Rat Hippocampus.

BACKGROUND/AIM: Sleep loss is proposed as a trigger for manic episodes in bipolar disorder in humans. It has been shown that sleep and wakefulness can affect changes in mitochondrial gene expression, oxidative phosphorylation (OXPHOS) activity, and morphology in the brain. In this study, we investigated alterations in mitochondrial bioenergetic function in the brain of rats after 72-h rapid eye movement sleep deprivation (REM-SD). MATERIALS AND METHODS: Alterations in the mitochondrial DNA (mtDNA) copy number were detected in the prefrontal cortex and hippocampus through amplification of mitochondrially encoded NADH dehydrogenase 1 (mt-Nd1) gene using quantitative real-time polymerase chain reaction. The expression levels of mitochondrial biogenesis-related proteins such as peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A), cytochrome c oxidase subunit 4I1 (COX4I1) and sirtuin 3 (SIRT3) were assessed using western blot analysis and immunohistochemistry. RESULTS: We found that REM-SD significantly increased the mtDNA copy number in the hippocampus but not in the prefrontal cortex. In addition, REM-SD increased the protein expression of COX4I1 in the hippocampus. Furthermore, we observed manic-like behaviors in rats exposed to 72-h REM-SD. REM-SD increased locomotion in the open-field test and the time spent in open arms in the elevated plus-maze test. CONCLUSION: REM-SD may induce mitochondrial dysfunction in the brain, which may be involved in the induction of mania.

Interstitial pneumonitis associated with dasatinib treatment for chronic myeloid leukemia or acute lymphoblastic leukemia: case series and a literature review.

Dasatinib, a tyrosine kinase inhibitor, is usually prescribed for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. However, some patients may develop an intolerance to this drug over the years. Among various toxicities related to dasatinib, dasatinib-associated interstitial pneumonitis is not reported frequently in the literature yet. Moreover, published studies have reported only few cases of dasatinib-associated pneumonitis, almost exclusively in chronic myeloid leukemia. In this study, we describe three cases of dasatinib-associated interstitial pneumonitis in patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia (a 56-year-old man, a 34-year-old man, and a 46-year-old woman) at our institution. In all three patients, the time from the initiation of dasatinib therapy to the onset of interstitial pneumonitis varied greatly. Among them, one patient underwent a surgical lung biopsy, which revealed chronic granulomatous inflammation without any causative pathogen. In all patients, dasatinib was discontinued after the diagnosis of interstitial pneumonitis, and two patients were treated with systemic steroids. Although infrequent, dasatinib-induced pneumonitis should be considered a possible diagnosis in dasatinib-treated patients with fever and respiratory symptoms. In addition, hematologists and pulmonologists should be aware of this rare but critical toxicity.