Severe cervical kyphosis in a young adult with fixed dropped head syndrome, dysphagia, and myelopathy: A case report.

BACKGROUND: Several reports exist on syndromic cervical kyphosis in the elderly, including dropped head syndrome, degenerative spondylosis, and neurological diseases; however, it is rarely reported in young patients especially with complications. CASE PRESENTATION: We describe a case of a 25-year-old man who presented severe cervical kyphosis with dropped head syndrome, horizontal-gaze disorder, dysphagia, and myelopathy. The etiology of this cervical kyphosis was suspected to be as a result of a combination of an underlying developmental disorder and habitual, long-term cervical flexion postures while engaging in smartphone games. Combined anterior and posterior surgeries resulted in good outcomes and improved the patient's quality of life remarkably. CONCLUSION: Cervical kyphosis awareness in young patients is crucial. Moreover, combined anterior and posterior approach provides secure, good results, and with less sequelae.

Repeated infusion of autologous adipose tissue-derived stem cells for Parkinson's disease.

BACKGROUND: Mesenchymal stem cells are expected to have a therapeutic effect on progressive neurodegenerative diseases for which there is currently no fundamental treatment. AIMS OF THE STUDY: The aim is to confirm that repeated infusion of autologous adipose tissue-derived stem cells (ADSCs) can be safely administered to patients with Parkinson's disease, and to investigate the effects of this as a pilot study. METHODS: Three patients with Parkinson's disease received five or six repeated infusions of ADSCs at intervals of approximately one month. Observations were based on medical examinations by a neurologist and interviews with the patient and caregivers. The severity of Parkinson's disease was assessed using the Hoehn & Yahr staging scale and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). RESULTS: No adverse events were observed during the observation period from the start of treatment to six months after the end of the last dose. MDS-UPDRS improved in all three patients. CONCLUSIONS: Repeated administration of Autologous ADSCs for Parkinson's disease was safe and feasible. The results of this pilot study provide insight into the value of further research.

Long Noncoding RNA PVT1 Is Regulated by Bromodomain Protein BRD4 in Multiple Myeloma and Is Associated with Disease Progression.

Long noncoding RNAs (lncRNAs) are deregulated in human cancers and are associated with disease progression. Plasmacytoma Variant Translocation 1 (PVT1), a lncRNA, is located adjacent to the gene MYC, which has been linked to multiple myeloma (MM). PVT1 is expressed in MM and is associated with carcinogenesis. However, its role and regulation remain uncertain. We examined PVT1/MYC expression using real-time PCR in plasma cells purified from 59 monoclonal gammopathy of undetermined significance (MGUS) and 140 MM patients. The MM cell lines KMS11, KMS12PE, OPM2, and RPMI8226 were treated with JQ1, an MYC super-enhancer inhibitor, or MYC inhibitor 10058-F4. The expression levels of PVT1 and MYC were significantly higher in MM than in MGUS (p < 0.0001) and were positively correlated with disease progression (r = 0.394, p < 0.0001). JQ1 inhibited cell proliferation and decreased the expression levels of MYC and PVT1. However, 10054-F4 did not alter the expression level of PVT1. The positive correlation between MYC and PVT1 in patients, the synchronous downregulation of MYC and PVT1 by JQ1, and the lack of effect of the MYC inhibitor on PVT1 expression suggest that the expression of these two genes is co-regulated by a super-enhancer. Cooperative effects between these two genes may contribute to MM pathogenesis and progression.

Overexpression of B-cell lymphoma 6 alters gene expression profile in a myeloma cell line and is associated with decreased DNA damage response.

B-cell lymphoma 6 (BCL6) attenuates DNA damage response (DDR) through gene repression and facilitates tolerance to genomic instability during immunoglobulin affinity maturation in germinal center (GC) B cells. Although BCL6 expression is repressed through normal differentiation of GC B cells into plasma cells, a recent study showed the ectopic expression of BCL6 in primary multiple myeloma (MM) cells. However, the functional roles of BCL6 in MM cells are largely unknown. Here, we report that overexpression of BCL6 in a MM cell line, KMS12PE, induced transcriptional repression of ataxia telangiectasia mutated (ATM), a DDR signaling kinase, which was associated with a reduction in γH2AX formation after DNA damage. In contrast, transcription of known targets of BCL6 in GC B cells was not affected, suggesting a cell type-specific function of BCL6. To further investigate the effects of BCL6 overexpression on the MM cell line, we undertook mRNA sequence analysis and found an upregulation in the genomic mutator activation-induced cytidine deaminase (AID) with alteration in the gene expression profile, which is suggestive of de-differentiation from plasma cells. Moreover, interleukin-6 exposure to KMS12PE led to upregulation of BCL6 and AID, downregulation of ATM, and attenuation of DDR, which were consistent with the effects of BCL6 overexpression in this MM cell line. Taken together, these results indicated that overexpression of BCL6 alters gene expression profile and confers decreased DDR in MM cells. This phenotypic change could be reproduced by interleukin-6 stimulation, suggesting an important role of external stimuli in inducing genomic instability, which is a hallmark of MM cells.

Long non-coding RNA MALAT1 is an inducible stress response gene associated with extramedullary spread and poor prognosis of multiple myeloma.

Extramedullary myeloma (EMM) occurs when myeloma develops outside the bone marrow; it often develops after chemotherapy and is associated with the acquisition of chemo-resistance and a fatal course. The mechanisms underlying extramedullary spread have not yet been fully elucidated. MALAT1 is a highly abundantly and ubiquitously expressed long non-coding RNA that plays important roles in cancer metastasis. The aims of this study were to clarify the association of MALAT1 with EMM and to elucidate the underlying mechanism of EMM formation under chemotherapeutic pressure. MALAT1 expression was significantly higher in multiple myeloma (MM) than in monoclonal gammopathy of undetermined significance. Furthermore, MALAT1 expression was markedly higher in EMM compared with that in corresponding intramedullary myeloma cells. A higher MALAT1 level was associated with shorter overall and progression-free survival. MALAT1 expression level was positively correlated with expression of HSP90AA1, HSP90AB1 and HSP90B1 but not with TP53 expression. MALAT1 was significantly upregulated by bortezomib and doxorubicin. Considering the known functions of MALAT1, our results suggest that it acts as a stress response gene that is upregulated by chemotherapy, thereby linking chemotherapy to EMM formation. Elucidating the biological implication of long non-coding RNA contributes to deeper understanding concerning the pathogenesis and investigation of novel therapeutic targets for MM.

Clinical experience of bendamustine for adult Langerhans cell sarcoma.

A 40-year-old man was diagnosed with Langerhans cell histiocytosis (LCH) in October 2010. His LCH was refractory to conventional chemotherapy, and thus worsened to Langerhans cell sarcoma (LCS) in May 2011. Although we repeated combination chemotherapies, new infiltration of the liver and bone marrow, as well as primary lesions of the bone, lymph nodes, and skin, appeared. These intensive chemotherapies caused candida liver abscesses, invasive aspergillosis, disseminated varicella zoster virus infection and bacterial sepsis. We administered bendamustine for chemotherapy, which resulted in a partial response (PR) with no severe adverse events. Because of pancytopenia caused by secondary myelodysplastic syndrome, we stopped the bendamustine chemotherapy after two courses. PR was maintained for 4 months. We plan to perform allogeneic hematopoietic stem cell transplantation from a sibling donor after a conditioning regimen. Optimal therapy for adult LCH, which is a rare and treatment-resistant disease, has yet to be established. Bendamustine is a potential chemotherapeutic agent for standard treatment of LCS.

Reduction of thoracic aorta motion artifact with high-pitch 128-slice dual-source computed tomographic angiography: a historical control study.

OBJECTIVES: Electrocardiogram-gated imaging combined with multi-detector row computed tomography (MDCT) has reduced cardiac motion artifacts, but it was not practical in the emergency setting. The purpose of this study was to evaluate the ability of a high-pitch, 128-slice dual-source CT (DSCT) scanner to reduce motion artifacts in patients admitted to the emergency room. METHODS: This study comprised 100 patients suspected of having thoracic aorta lesions. We examined 47 patients with the 128-slice DSCT scanner (DSCT group), and 53 patients were examined with a 64-slice MDCT scanner (MDCT group). Six anatomic areas in the thoracic aorta were evaluated. RESULTS: Computed tomography images in the DSCT group were distinct, and significant differences were observed in images of all areas between the 2 groups except for the descending aorta. CONCLUSIONS: The high-pitch DSCT scanner can reduce motion artifacts of the thoracic aorta and enable radiological diagnosis even in patients with tachycardia and without breath hold.

Kikuchi-Fujimoto Disease in Human Leukocyte Antigen Partially Matched Siblings: A Case Study of Familial Susceptibility.

Kikuchi-Fujimoto disease (KFD) is a rare and self-limiting disorder that predominantly affects young individuals of Asian descent. This case report describes familial KFD in partially human leukocyte antigen (HLA)-matched siblings. An adolescent male presented with cervical lymphadenopathy and elevated lactate dehydrogenase (LDH) levels, diagnosed by biopsy as KFD; approximately one year later, his sister presented with similar symptoms. Both siblings were found to carry the HLA-DPB1*0202 allele, which is commonly associated with KFD. These cases highlight a genetic component in KFD and encourage further genetic research to delineate the pathogenesis of the disease.

Real-world efficacy of DA-EPOCH-R/HD-MTX regimen in CD5-positive diffuse large B cell lymphoma: a single-institute analysis.

CD5-positive diffuse large B cell lymphoma (CD5+ DLBCL) is a high-risk lymphoma type. Recently, the PEARL5 (a Phase II trial of DA-EPOCH and Rituximab with HD-MTX therapy for newly diagnosed DLBCL with CD5 expression) study demonstrated the efficacy of the DA-EPOCH-R (cyclophosphamide, etoposide, doxorubicin, vincristine, prednisone, and rituximab)/HD-MTX (high-dose methotrexate) regimen for CD5+ DLBCL. In this report, we revealed the impact of the DA-EPOCH-R/HD-MTX regimen on the clinical course of CD5+ DLBCL in the real-world. We retrospectively compared CD5+ and CD5- DLBCL patients diagnosed from January 2017 to December 2020 and analyzed their clinicopathological characteristics, treatment, and prognosis. There was no difference in age, sex, clinical stage, and cell of origin; however, the CD5-positive group had higher lactate dehydrogenase levels and a worse performance status than the CD5-negative group (p=0.00121 and p=0.0378, respectively). International prognostic index (IPI) was worse in the CD5-positive group than in the CD5-negative group (p=0.0498), but NCCN-IPI (National Comprehensive Cancer Network-IPI) was no different between the two groups. The CD5-positive group was more frequently treated with the DA-EPOCH-R/HD-MTX regimen than the CD5-negative group (p =0.001857). Complete remission rate and 1-year overall survival did not differ between the CD5-positive and -negative groups (90.0% vs 81.4%, p=0.853; 81.8% vs 76.9%, p=0.433). We conclude that the DA-EPOCH-R/HD-MTX regimen is effective for CD5+ DLBCL in this single institute analysis.

Negative Effects of Diffuse Idiopathic Skeletal Hyperostosis on Bone Fusion after Transforaminal Lumbar Interbody Fusion.

STUDY DESIGN: This study adopted a retrospective cohort study design. PURPOSE: This study aimed to clarify the influence of diffuse idiopathic skeletal hyperostosis (DISH) on bone fusion after transforaminal lumbar interbody fusion (TLIF). OVERVIEW OF LITERATURE: The negative effects of DISH on lumbar degenerative diseases have been reported, and DISH may be involved in the onset and severity of lumbar spinal canal stenosis. Patients with DISH have significantly more reoperations after posterior lumbar fusion, including TLIF. However, the effects of DISH on bone fusion after TLIF have not been reported. METHODS: The medical records of patients with intervertebral TLIF from 2012 to 2018 were retrospectively examined. The patients were divided into those with fusion and those with pseudoarthrosis, and the following data were compared: age, sex, DISH, diabetes mellitus, smoking, drinking, albumin levels, body mass index ≥30 kg/m2, and L5/S fixation. Statistical analyses were performed using regression models. RESULTS: In this study, 180 patients (78.6%) had fusion and 49 patients (21.4%) had pseudoarthrosis. The number of patients with DISH was significantly higher in the pseudoarthrosis group than in the fusion group (36.7% and 21.7%, respectively; univariate p=0.031, multivariate p =0.019). No significant differences in age, sex, diabetes mellitus, smoking, drinking, albumin levels, body mass index ≥30 kg/m2, and L5/S fixation were observed between the two groups. The risk factors for bone fusion were statistically analyzed in 57 patients with DISH. DISH with a caudal end below Th11 was an independent risk factor for pseudoarthrosis (univariate p=0.011, multivariate p=0.033). CONCLUSIONS: DISH is an independent risk factor for pseudoarthrosis after one intervertebral TLIF, and DISH with a caudal end below Th11 is associated with a higher risk of pseudoarthrosis than DISH without a caudal end below Th11.

Six new chalcones from Angelica keiskei inducing adiponectin production in 3T3-L1 adipocytes.

Angelica keiskei (Ashitaba in Japanese), a traditional herb in Japan, contains abundant prenylated chalcones. It has been reported that the chalcones from A. keiskei showed such bioactivities as anti-bacterial, anti-cancer and anti-diabetic effects. Xanthoangelol, 4-hydroxyderricin and six new chalcones were isolated in this study from an ethanol extract of A. keiskei by octadecyl silyl (ODS) and silica gel chromatography, and identified by 1D- and 2D-nuclear magnetic resonance (NMR) and high-resolution mass spectrometric analyses. The chalcones from A. keiskei markedly increased the expression of the adiponectin gene and the production of adiponectin in 3T3-L1 adipocytes. These results suggest that the chalcones from A. keiskei might be useful for preventing the metabolic syndrome.

Hypothesis: Intravenous administration of mesenchymal stem cells is effective in the treatment of Alzheimer's disease.

We propose the intravenous administration of autologous adipose-derived stem cells as a new treatment for Alzheimer's disease. We hypothesize that the stem cells will secrete neprilysin in the brain to break down and remove amyloid deposits in the Alzheimer's brain. We have shown a case of skin amyloid deposition that disappeared after stem cell administration and confirmed that the stem cells administered had neprilysin activity. In addition to neprilysin secretion, other mechanisms of action of stem cells include nerve regeneration, nerve repair, growth factor secretion, anti-inflammatory effects, and angiogenesis. The harvesting of adipose-derived stem cells is minimally invasive, and intravenous administration can be safely repeated. We hope that the efficacy of this new treatment will be verified and that it will bring a ray of hope to patients suffering from this incurable disease.

Zona pellucida protein ZP2 is expressed in the oocyte of Japanese quail (Coturnix japonica).

The avian perivitelline layer (PL), a vestment homologous to the zona pellucida (ZP) of mammalian oocytes, is composed of at least three glycoproteins. Our previous studies have demonstrated that the matrix's components, ZP3 and ZPD, are synthesized in ovarian granulosa cells. Another component, ZP1, is synthesized in the liver and is transported to the ovary by blood circulation. In this study, we report the isolation of cDNA encoding quail ZP2 and its expression in the female bird. By RNase protection assay and in situ hybridization, we demonstrate that ZP2 transcripts are restricted to the oocytes of small white follicles (SWF). The expression level of ZP2 decreased dramatically during follicular development, and the highest expression was observed in the SWF. Western blot and immunohistochemical analyses using the specific antibody against ZP2 indicate that the 80 kDa protein is the authentic ZP2, and the immunoreactive ZP2 protein is also present in the oocytes. Moreover, ultrastructural analysis demonstrated that the immunoreactive ZP2 localizes to the zona radiata, the perivitelline space, and the oocyte cytoplasm in the SWF. By means of western blot analysis and immunofluorescence microscopy, we detected a possible interaction of the recombinant ZP2 with ZP3 and that this interaction might lead to the formation of amorphous structure on the cell surface. These results demonstrate for the first time that the avian ZP gene is expressed in the oocyte, and that the ZP2 protein in the oocyte might play a role for the PL formation in the immature follicles of the ovary.

[Clinical profiles of 7 patients with chronic myelogenous leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia treated with dasatinib].

We retrospectively analyzed the clinical outcome of dasatinib in 7 patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) resistant or intolerant to imatinib. Three patients with chronic phase CML and two patients with Ph+ALL achieved major molecular response, however, two CML patients in accelerated phase (AP)/blast crisis (BC), did not. Grade> or =3 pancytopenia was seen in four patients. Among these, two AP/BC-CML patients required interruption/or dose reduction of dasatinib. As for nonhematologic adverse events, pleural effusion was seen in one patient and cytomegalovirus (CMV) colitis was observed in two patients. No patients who had been intolerant to imatinib experienced the same nonhematologic toxicity following treatment with dasatinib. We identified three patients who developed peripheral lymphocytosis, identified as natural killer cells or cytotoxic T-cells based on their large granular lymphocyte (LGL) morphologies and immunophenotypic profiles, out of six patients receiving dasatinib therapy. All three cases that developed LGL lymphocytosis achieved optimal molecular response, two of the patients, however, had pleural effusion and CMV colitis, respectively. Dasatinib inhibits off-target kinases, which may result in unexpected drug responses.

Pembrolizumab-induced Pure Red Cell Aplasia Successfully Treated with Intravenous Immunoglobulin.

We herein report a 64-year-old man who was treated with pembrolizumab for relapsed Hodgkin lymphoma. After the third administration of pembrolizumab, he showed acute anemia with a positive direct anti-globulin test. Because of the markedly erythroid hypoplasia, he was diagnosed with pure red cell aplasia (PRCA) caused by pembrolizumab. He was initially treated with prednisolone, but the reticulocytes decreased after tapering prednisolone. He then received high-dose intravenous immunoglobulin (IVIG) with prednisolone, and PRCA was successfully treated. Although the pathogenesis of PRCA caused by immune checkpoint inhibitors (CPIs) remains unclear, IVIG treatment may be effective for some steroid-refractory CPI-induced PRCA cases.

IgG4-related Disease with a Cardiac Mass.

A 69-year-old man with palpitations and decreased blood pressure was referred. Echocardiography showed a mass in the right atrium and cardiac septum. The serum IgG4 level was 1,450 mg/dL. A biopsy of the cardiac mass showed fibrosis with inflammatory cells and increased IgG4-positive plasma cells and lymphocytes. Flow cytometry and polymerase chain reaction of the immunoglobulin heavy chain did not demonstrate monoclonality. He was diagnosed with IgG4-related disease (IgG4-RD). IgG4-RD with a cardiac mass is rare and it is difficult to distinguish it from malignant lymphoma by a pathological examination alone. We therefore performed a biopsy and analyzed the clonality in order to make an accurate diagnosis of IgG4-RD.

Molecular characterization of egg envelope glycoprotein ZPD in the ovary of Japanese quail (Coturnix japonica).

The egg envelope surrounding avian oocytes exhibits a three-dimensional network of coarse fibers between the granulosa cells and the oocyte. Our previous studies have demonstrated that one of the matrix's components, ZP3, is synthesized in the ovarian granulosa cells. Another component, ZP1, which is critically involved in triggering the sperm acrosome reaction, is synthesized in the liver. We have previously isolated cDNAs encoding quail ZP3 and ZP1, and we now report the isolation of cDNA encoding quail ZPD. By RNase protection assay and in situ hybridization, we have demonstrated that ZPD transcripts are restricted to the granulosa cells of preovulatory follicles. The expression level of ZPD increased progressively during follicular development, and the highest expression was observed in the largest follicles. Western blot analyses using the specific antibody against ZPD indicate that the 40 kDa protein is the authentic ZPD, and the contents of ZPD protein also increased during follicular development. Moreover, we found that the addition of FSH to the culture media enhances the ZPD secretion in the cultured granulosa cells. Two-dimensional gel electrophoresis revealed the presence of several ZPD isoforms with different pI values ranging from 5.5 to 7. Immunohistochemical analyses indicate that the materials recognized with anti-quail ZPD antibody were accumulated in the egg envelope of large yellow follicles. These results demonstrate the presence of ZPD protein in the egg envelope, and that the amount of ZPD in the egg envelope as well as the mRNA in the cells increases at the latter stages of folliculogenesis.

[IgM-lambda multiple myeloma presenting with systemic amyloidosis].

A 59-year-old man was referred to our hospital due to nephrotic syndrome with IgM paraproteinemia. Physical examination demonstrated marked hepatomegaly and anasarca. Serum M-protein was 0.94 g/dl and urinary analysis detected the presence of Bence Jones protein. Bone marrow plasma cell count was 11.2%. Histological examination demonstrated AL-type amyloid deposition in the liver, kidneys, bone marrow, stomach and rectum. These findings led to a diagnosis of IgM multiple myeloma with systemic amyloidosis. Although there was no apparent response to 2 courses of vincristine, doxorubicin and dexamethasone (VAD) regimen, subsequent treatment with bortezomib in combination with dexamethasone resulted in a rapid reduction in M protein to 0.49 g/dl, approximately half the pre-treatment level.