Persistence of Low Back Pain and Predictive Ability of Pain Intensity and Disability in Daily Life among Nursery School Workers in Japan: A Five-Year Panel Study.

Nursery school workers are known for having a high prevalence of low back pain (LBP). The natural history of LBP and the determinants of persistent LBP remain unclear. We examined the prevalence of persistent LBP and whether pain intensity and disability in daily life due to LBP affected the persistence of LBP among these workers. A five-year panel study was conducted for 446 nursery school workers in Japan. LBP, pain intensity, and disability in daily life due to LBP were assessed with a self-administered questionnaire survey. Pain intensity was assessed using the numerical rating scale (NRS). The Roland-Morris Disability Questionnaire (RDQ) was used to assess disability in daily life due to LBP. At baseline, 270 nursery school workers (60.5%) suffered from LBP. The estimated prevalence of persistent LBP was 84.6% (80.3-88.9%), 82.2% (77.7-86.8%), and 82.0% (77.4-86.5%) at 1, 3, and 5 years after the initial study, respectively. NRS scores of 5 or greater predicted the persistence of LBP at 1 and 3 years after the initial survey (adjusted odds ratios: 4.01 (1.27-12.6) and 8.51 (1.87-38.7), respectively), while RDQ scores did not. In conclusion, LBP highly persisted for a long time and pain intensity predicted persistent LBP among nursery school workers in Japan.

Hydrogen bonds connecting the N-terminal region and the DE loop stabilize the monomeric structure of transthyretin.

Transthyretin (TTR) is a homo-tetrameric serum protein associated with sporadic and hereditary systemic amyloidosis. TTR amyloid formation proceeds by the dissociation of the TTR tetramer and the subsequent partial unfolding of the TTR monomer into an aggregation-prone conformation. Although TTR kinetic stabilizers suppress tetramer dissociation, a strategy for stabilizing monomers has not yet been developed. Here, we show that an N-terminal C10S mutation increases the thermodynamic stability of the TTR monomer by forming new hydrogen bond networks through the side chain hydroxyl group of Ser10. Nuclear magnetic resonance spectrometry and molecular dynamics simulation revealed that the Ser10 hydroxyl group forms hydrogen bonds with the main chain amide group of either Gly57 or Thr59 on the DE loop. These hydrogen bonds prevent the dissociation of edge strands in the DAGH and CBEF ß-sheets during the unfolding of the TTR monomer by stabilizing the interaction between ß-strands A and D and the quasi-helical structure in the DE loop. We propose that introducing hydrogen bonds to connect the N-terminal region to the DE loop reduces the amyloidogenic potential of TTR by stabilizing the monomer.

Sepsis-induced disseminated intravascular coagulation: an international estrangement of disease concept.

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by widespread intravascular activation of coagulation, which can be caused by infectious and noninfectious insults, such as trauma, postcardiac arrest syndrome, and malignant diseases. At present, diagnosis and treatment of DIC clearly differ between Japan and Western countries; in Japan, DIC has long been considered a therapeutic target, and much evidence on DIC has been published. However, there has recently been no international consensus on whether DIC should be a therapeutic target with anticoagulant therapy. This review describes the coagulofibrinolytic system abnormalities associated with sepsis and discusses related management strategies. It also explores the reasons why DIC is perceived differently in different regions. There is a major discrepancy between diagnostic and treatment options in Japan, which are based on holistic assessments of trials, as well as the results of post hoc subgroup analyses and observational studies, and those in Western countries, which are based mainly on the results of sepsis mega trials, especially randomized controlled trials. The differences might also be due to various patient factors in each region, especially racial characteristics in thrombolytic mechanisms, and differences in interpretation of evidence for candidate drugs. Hence, Japanese researchers need to distribute their high-quality clinical research data not only to Japan but also to the rest of the world.

Psychosocial work characteristics and low back pain in daycare (nursery) workers in Japan: a prospective cohort study.

BACKGROUND: Low back pain (LBP) is one of the most common musculoskeletal problems affecting daycare (nursery) workers. We aimed to identify the psychosocial factors influencing LBP in daycare workers. METHODS: We conducted a prospective cohort study with a one-year observation period. The baseline sample was a convenience sample of 444 daycare workers from 34 daycare facilities in Nagoya, Japan, and its suburbs. All the data were collected through a questionnaire survey. The question "Where are you currently feeling LBP?" was used to determine whether the subjects suffered from LBP. We examined the prospective relationships of the psychosocial work characteristics, i.e., high job strain, low social support, effort-reward imbalance, and overcommitment, at baseline and LBP after one year. We used multiple logistic regression analyses to calculate the odds ratios of psychosocial work characteristics for the persistence and onset of LBP, adjusted for age, sex, body mass index, smoking, employment status, occupation, and working schedule. RESULTS: At baseline, 270 (60.8%) subjects suffered from LBP. Of 208 who also gave information on LBP one year later, 176 (84.6%) suffered from the persistence of LBP. Low social support at baseline was significantly related to persistent LBP one year later. The incidence of persistent LBP was 89.9% and 80.0% among those with and without low social support at baseline, respectively. The adjusted odds ratio (95% confidence interval) of low social support at baseline for the persistence of LBP was 2.43 (1.01-5.87). Of 150 who were without LBP at baseline and provided information on LBP one year later, 45 (30.0%) suffered from the onset of LBP. None of the psychosocial work characteristics showed significant relationships with the onset of LBP one year later. CONCLUSION: Low social support was related to the persistence, but not to the onset of LBP in a prospective cohort analysis among daycare workers in Japan. High job strain, ERI, or overcommitment did not show a significant prospective effect on LBP.

High-dose cytarabine chemotherapy (≥4 g/m2/day) before allogeneic hematopoietic stem cell transplantation for non-core-binding-factor AML in the first complete remission.

Benefit of high-dose cytarabine (HD-AraC) for acute myeloid leukemia (AML) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unknown. We retrospectively analyzed data from 79 non-core-binding-factor AML patients who underwent allo-HSCT in their first complete remission (CR1). In univariate analysis, HD-AraC (≥4 g/m2/day) before allo-HSCT improved disease-free survival (DFS) (p = .018), overall survival (OS) (p = .029), and cumulative incidence of relapse (CIR) (p = .033). Four-year DFS, OS, and CIR of patients receiving and not receiving HD-AraC were 79% vs. 49%, 82% vs. 56%, and 18% vs. 42%, respectively. In multivariate analysis, HD-AraC was a positive prognostic factor for DFS (hazard ratio (HR) = 0.36, 95% confidence interval (CI): 0.14-0.88), OS (HR = 0.37, 95% CI: 0.14-0.99), and CIR (HR = 0.38, 95% CI; 0.14-1.0). Our study demonstrates that HD-AraC before allo-HSCT at a dose ≥4 g/m2/day is effective for treating AML patients in CR1.

Cold Crystallization of Ferrocene-Hinged π-Conjugated Molecule Induced by the Limited Conformational Freedom of Ferrocene.

Crystallization that proceeds above the glass transition temperature upon heating the glassy or amorphous state is referred to as "cold crystallization", which has often been observed in supercooled phases of molecular materials followed by the transition to the thermodynamically stable crystalline phase. Although this behavior is common for the macromolecules with high structural flexibility among segments preserving the wide temperature range of corresponding glassy phases, cold crystallization of small molecules is relatively rare and there is still less knowledge on the design guideline of such molecules. Here we report a ferrocene-hinged molecule DC12 carrying two units of didodecyl-substituted pentathiophenes at the 1,1'-positions. Due to the rotational freedom of the ferrocene unit, DC12 forms amorphous solid on cooling from its isotropic melt. The amorphous state was realized even by slow cooling such as 0.1 °C min-1. The possible reason for the easy formation of the amorphous phase is the coexistence of various conformations of DC12 originating from the open conformers of the ferrocene. On heating from the amorphous phase, DC12 shows cold crystallization with the estimated activation energy of 61 kJ mol-1. The crystalline phase is composed of the closed form of DC12 molecules packed in a lamellar fashion, and the degree of crystallinity is remarkably high compared with the case of macromolecular materials. The crystallization is triggered by the intermolecular interactions among the dodecyl chains and rotational flexibility of the ferrocene unit. This work provides an unprecedented example that ferrocenes act as heat-controllable rotational hinges in condensed phases. Considering that the cold crystallization phenomenon is related to heat-storage materials, the design strategy presented in this work will be novel to realize both easily formed amorphous phases and highly crystalline phases formed through cold crystallization.

Stochastic model based on preharvest peripheral CD34-positive cell count and collection efficiency predicting processed blood volume in peripheral hematopoietic stem cell apheresis.

BACKGROUND: Processed blood volume (PBV) required to obtain a predefined number of stem cells can be estimated from peripheral blood CD34+ cell concentration, body weight, and collection efficiency (CE). Because CE is indefinite, this study was designed to formulate and validate a new model of PBV based on stochastic CE distribution. STUDY DESIGN AND METHODS: Data were retrospectively collected on 146 peripheral blood stem cell harvests from 114 patients and donors in a single institution from April 2014 to February 2018. The training set consisted of all procedures performed from April 2014 to June 2016 and the validation set of all procedures performed from July 2016 to February 2018. A new algorithm, based on CE2 distribution of the training set, was affirmed using the validation set. The positive predictive value of the model was estimated from the expected percentage of procedures that reached the target CD34-positive dose, with predicted PBV processed as the gold standard. RESULTS: The 10th and 50th percentiles of CE2 were 33.4% and 52.5%, respectively. When PBV was assorted into three categories, defined as greater than 90%, 50% to 90%, and less than 50% of procedures reaching the targeted CD34-positive dose, the positive predictive values of the new model were 100%, 70%, and 100%, respectively. CONCLUSION: The new model was validated with a high positive predictive value and can reliably estimate the required PBV and the success rate corresponding to the PBV. The model can be utilized easily with a Web-based tool.

Recurrent CCND3 mutations in MLL-rearranged acute myeloid leukemia.

In acute myeloid leukemia (AML), MLL (KMT2A) rearrangements are among the most frequent chromosomal abnormalities; however, knowledge of the genetic landscape of MLL-rearranged AML is limited. In this study, we performed whole-exome sequencing (n = 9) and targeted sequencing (n = 56) of samples from pediatric MLL-rearranged AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. Additionally, we analyzed 105 pediatric t(8;21) AML samples and 30 adult MLL-rearranged AML samples. RNA-sequencing data from 31 patients published in a previous study were also reanalyzed. As a result, we identified 115 mutations in pediatric MLL-rearranged AML patients (2.1 mutations/patient), with mutations in signaling pathway genes being the most frequently detected (60.7%). Mutations in genes associated with epigenetic regulation (21.4%), transcription factors (16.1%), and the cohesin complex (8.9%) were also commonly detected. Novel CCND3 mutations were identified in 5 pediatric MLL-rearranged AML patients (8.9%) and 2 adult MLL-rearranged AML patients (3.3%). Recurrent mutations of CCND1 (n = 3, 2.9%) and CCND2 (n = 8, 7.6%) were found in pediatric t(8;21) AML patients, whereas no CCND3 mutations were found, suggesting that D-type cyclins exhibit a subtype-specific mutation pattern in AML. Treatment of MLL-rearranged AML cell lines with CDK4/6 inhibitors (abemaciclib and palbociclib) blocked G1 to S phase cell-cycle progression and impaired proliferation. Pediatric MLL-MLLT3-rearranged AML patients with coexisting mutations (n = 16) had significantly reduced relapse-free survival and overall survival compared with those without coexisting mutations (n = 9) (P = .048 and .046, respectively). These data provide insights into the genetics of MLL-rearranged AML and suggest therapeutic strategies.

[Mitoxantrone, etoposide, and cytarabine combination therapy for acute myeloid leukemia patients failing to achieve a complete remission after induction chemotherapy: a single-center experience].

Optimal salvage chemotherapy has not been established for patients with acute myeloid leukemia (AML) who fail to attain complete remission (CR) after one course of induction chemotherapy. This retrospective study aimed to assess the efficacy and safety of an MEC (mitoxantrone, 6 mg/m2, 1-3 days; etoposide, 80 mg/m2, 1-6 days; cytarabine, 1 g/m2, 1-6 days) regimen in patients with AML who failed to attain CR after one course of induction chemotherapy. Twenty-four patients were included in this study (median age, 58 years; range, 28-79 years). After one course of MEC, 11 patients (45.8%) attained CR. Febrile neutropenia was observed in all patients, and acute infection was observed in 7 patients (29.2%). However, no therapy-related death occurred. All patients eligible for transplantation and who attained CR after MEC salvage chemotherapy underwent allogeneic hematopoietic stem cell transplantation. The MEC regimen exhibited a good response rate with tolerable adverse events. Therefore, the MEC regimen can be safely used as a salvage treatment for patients with AML who failed to attain CR after one course of induction chemotherapy.

Adult-onset primary cyclic autoimmune neutropenia: a case report.

BACKGROUND: A few cases of primary autoimmune neutropenia (AIN) have been reported in adults, but cyclic primary AIN, which is characterized by the periodic oscillation of neutrophils, is uncommon in adults. STUDY DESIGN AND METHODS: Herein, we report a 70-year-old man referred to our hospital with severe neutropenia and thrombocytopenia. He had experienced intermittent episodes of low-extremity purpura for the past 3 months, with cellulitis on the skin of the scalp 1 month previously. RESULTS: The patient presented with severely low neutrophil and platelet (PLT) counts. Myeloid progenitors and megakaryocytes were increased in the marrow, but mature neutrophils were remarkably decreased. Anti-neutrophil antibodies to specific epitopes were detected at neutropenia. Based on these findings, AIN accompanied by autoimmune thrombocytopenia was diagnosed. The patient experienced synchronous fluctuations of neutrophil and PLT counts three times. Despite no treatment, the neutrophil count fluctuated within the range of 0.06 × 109 to 1.65 × 109 /L, and the PLT count fluctuated from 0.7 × 1010 to 20.5 × 1010 /L. We identified an inverse relationship between neutrophil count and anti-neutrophil antibody titers, establishing the conclusive diagnosis of cyclic AIN. After prednisolone treatment, the neutrophil and PLT counts normalized, and the patient has maintained long-term remission. CONCLUSION: We report a rare case of cyclic AIN diagnosed from the inverse association between periodic oscillation of anti-neutrophil antibody titers and neutrophil counts. This clinical course suggests that in AIN patients, laboratory data and recurrent signs of infection should be monitored regularly, including shortly after neutrophil recovery.

A case of non-cardiogenic pulmonary edema provoked by intravenous acetazolamide.

Case: A 61-year-old man was diagnosed with severe chest trauma after a car accident and had had difficulty in weaning from a ventilator because of flail chest and dilated cardiomyopathy. On the 17th day in the intensive care unit, he received i.v. acetazolamide to increase urine output. One hour after the injection, he suddenly developed severe hypoxia. Chest radiography revealed a butterfly shadow. He received other diuretics and a vasodilator, which seemed slowly to resolve the respiratory failure. Five days later, acetazolamide was again given and he experienced the same deterioration. Outcome: We concluded that the episodes were attributed to pulmonary edema provoked by acetazolamide. Conclusion: Acute non-cardiogenic pulmonary edema is an uncommon and lethal adverse effect of acetazolamide. Careful attention may be warranted when administering acetazolamide to critically ill patients.

Peripheral Blood Lymphocyte-to-Monocyte Ratio at Relapse Predicts Outcome for Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma in the Rituximab Era.

BACKGROUND: Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have a poor prognosis, even in the rituximab era. Several studies have reported the clinical importance of the peripheral blood lymphocyte-to-monocyte ratio (LMR) in various malignancies, including lymphoma. However, the prognostic value of the LMR in relapsed/refractory DLBCL has not been well evaluated. The purpose of the present study was to investigate whether the LMR at relapse can predict clinical outcomes for relapsed/refractory DLBCL patients treated with rituximab. PATIENTS AND METHODS: We analyzed data on 74 patients with relapsed/refractory DLBCL, who were initially treated with R-CHOP (rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone) or an R-CHOP-like regimen. RESULTS: There was a significant association between a low LMR (≤ 2.6) and shorter overall survival (OS; P < .001) and progression-free survival (PFS; P < .001) compared with the high LMR group (> 2.6). Multivariate analysis showed that LMR was an independent prognostic factor for OS (P < .001) and PFS (P < .001), as was the international prognostic index (IPI) at relapse for OS. In addition, the LMR had an incremental value for OS and PFS compared with the IPI at relapse. CONCLUSION: The LMR predicts OS and PFS outcomes in relapsed/refractory DLBCL patients treated with rituximab, and might facilitate better stratification among patients in low- and intermediate-risk IPI groups.

Two Cases of Neurolymphomatosis with Fatal Bilateral Vocal Cord Paralysis that were Diagnosed with 18F-fluorodeoxyglucose Positron Emission Tomography (FDG PET)/CT.

Neurolymphomatosis is a rare entity defined as nerve infiltration by neurotropic abnormal lymphocytes which can lead to the development of neuropathy, with typical presentations including pain, hypoesthesia, paresthesis and palsy. We herein report two cases where critical bilateral vocal cord paralysis due to neurolymphomatosis in recurrent nerves occurred in refractory Burkitt lymphoma and adult T-cell lymphoma patients. High-dose methotrexate and intrathecal chemotherapy injection for the nervous lesions were ineffective, and the patients died. Neurolymphomatosis of the recurrent nerve is an emergent and difficult complication and should be suspected when sudden onset of aphasia, hoarseness or shortness of breath is found in refractory lymphoma patients.

Successful treatment with bortezomib and dexamethasone for proliferative glomerulonephritis with monoclonal IgG deposits in multiple myeloma: a case report.

BACKGROUND: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a form of renal involvement by monoclonal IgG deposits that was found in mesangial, subendothelial or subepithelial regions. The distribution of glomerular deposits was completely different from that in monoclonal immunoglobulin deposition disease. PGNMID is reported to be rarely associated with a hematological malignancy. Previously, only five cases of PGNMID with multiple myeloma have been reported. However, the pathogenic relationship between PGNMID and multiple myeloma was unclear because a detailed description was not provided. We report that a patient with PGNMID associated with multiple myeloma was treated with bortezomib and dexamethasone and underwent the second renal biopsy after treatment, showing that chemotherapy was effective for PGNMID clinically and pathologically. CASE PRESENTATION: A 75-year-old man presented with progressive leg edema, had nephrotic range proteinuria, hypoalbuminemia, moderate renal failure, and occult blood in his urine. Electrophoresis results showed serum and urinary monoclonal spikes of IgGκ type immunoglobulin. A renal biopsy specimen showed lobular mesangial proliferation with mesangiolysis, glomerular micro-aneurysm, and endocapillary hypercellularity. Immunofluorescence results revealed strong granular capillary and mesangial staining for IgG1, C3 and κ light chain in glomeruli without tubular deposits of any immunoglobulin. Electron microscopy also showed dense granular deposits in subendothelial and mesangial areas. PGNMID associated with multiple myeloma (IgGκ type) was diagnosed on the basis of a subsequent bone marrow examination. Bortezomib and dexamethasone therapy significantly reduced proteinuria and elevated serum albumin level. Eight months later, the second renal biopsy showed no active lesions and that the IgG1 and κ light chain deposits had drastically disappeared. CONCLUSIONS: This is the first case of PGNMID with multiple myeloma successfully treated with bortezomib and dexamethasone in which comparative renal biopsies were performed before and after treatment. Our findings suggest the pathogenesis of PGNMID and therapeutic options for PGNMID.

An Atypical Clinical Course of Anti-MDA5 Antibody-positive Interstitial Lung Disease in a Patient with Three Deteriorations in 9 years.

Anti-MDA5 antibody-positive patients with clinically amyopathic dermatomyositis (CADM) are at high risk of developing rapidly progressive interstitial lung disease (ILD), which is associated with a high mortality rate. Approximately half of the patients with ILD recover; however, the long-term clinical course of these patients has not been fully reported and is not completely understood. This report describes the atypical clinical course of an anti-MDA5 antibody-positive CADM patient who experienced three deteriorations of ILD in 9 years. These findings indicate that the ILD in anti-MDA5 antibody-positive patients may not only be rapidly progressive, but may also be chronic and recurrent.

Utility of a simple prognostic stratification based on platelet counts and serum albumin levels in elderly patients with diffuse large B cell lymphoma.

Few studies have examined the prognostic impact of blood markers [other than the five factors in the enhanced International Prognostic Index (NCCN-IPI)] in elderly patients with diffuse large B cell lymphoma (DLBCL). We retrospectively analyzed 391 DLBCL patients receiving rituximab plus anthracycline-containing chemotherapy to examine the prognostic impact of simple blood markers. The NCCN-IPI was more accurate for discriminating prognoses than the original IPI. Multivariate analysis identified platelet count (<100,000/µl) and albumin (<3.5 g/dl) levels as significantly associated with lower overall survival (OS), independently of the NCCN-IPI. These parameters stratified patients into three risk groups: platelet-albumin (PA) score low (platelet count ≥100,000/µl, albumin ≥3.5 g/dl, n = 243); intermediate (platelet count <100,000/µl, albumin ≥3.5 g/dl or platelet count ≥100,000/µl, albumin <3.5 g/dl, n = 125); and high (platelet count <100,000/µl, albumin <3.5 g/dl, n = 23). The 5-year OS rates were 81.5, 48.6, and 20.2 %, respectively (p < 0.001). Notably, most patients with a low platelet count (n = 30) were stratified into the high-risk subgroup, suggesting that platelet count was prognostic for high-risk patients with a dismal outcome. In elderly patients (n = 291), the prognostic value of the NCCN-IPI might be diminished because the low-risk category was excluded; however, the PA score was predictive of survival: the 5-year OS rates for PA score low (n = 171), intermediate (n = 101), and high (n = 19) groups were 77.6, 47.9, and 19.0 %, respectively (p < 0.001). Platelet count and albumin levels are useful prognostic factors, and their combined use can predict survival, even in elderly patients.