Simultaneous XIAP and cIAP1/2 inhibition by a dimeric SMAC mimetic AZD5582 induces apoptosis in multiple myeloma.

Overexpression of inhibitor of apoptosis (IAP) proteins is associated with poor prognosis. In multiple myeloma (MM), the IAP inhibitors (IAPi), LCL161, have been evaluated in preclinical and clinical settings but are not fully effective. Among IAPs, XIAP has the strongest anti-apoptotic function with direct binding activity to caspases and cIAP1 and cIAP2 are positive regulator of NF-κB signaling. Prior IAPi such as LCL161 has high affinity to cIAP1 and cIAP2 resulting in inferior inhibiting activity against XIAP. A novel dimeric IAPi, AZD5582 (C58H78N8O8), have high binding potency to XIAP with EC50 dose of 15 nM, enabling to simultaneous inhibit XIAP and cIAP1/2. AZD5582 monotherapy showed cell growth inhibition for all MM cell lines, MM1S, RPMI8226, U266 and KMS-5 and induced apoptosis. AZD5582 further showed anti-proliferation effect under the IL-6 additional condition and inhibited JAK-STAT signaling triggered by IL-6. AZD5582 combined with carfilzomib therapy showed a synergistic effect. Enhanced apoptosis was also observed in combination therapy. Synergistic effect was further observed with other conventional therapeutics. Simultaneous XIAP and cIAP1/2 inhibition by the dimeric IAPi AZD5582 is promising. This study provides a rationale of AZD5582 as a new treatment strategy in monotherapy and in combination therapy.

Elevated arginine vasopressin levels surrogate acute lung injury in acute decompensated heart failure.

Activated arginine vasopressin (AVP) pathway worsens congestion in heart failure (HF), but its potential to relieve pulmonary congestion is also reported. The pathophysiological role and prognostic utility of AVP elevation in acute decompensated HF (ADHF) are poorly understood. We prospectively enrolled 52 hospitalized patients for ADHF to investigate the association between acute lung injury (ALI) in ADHF and AVP levels on admission. ALI was defined as respiratory failure leading to death, or requiring a respirator or a more than 12-h non-invasive intermittent positive pressure ventilation (NIPPV) support. In addition, we investigated the prognostic value of AVP levels on admission for cardiovascular death or recurrence of ADHF after discharge. ALI was documented in 7 patients (13.5%) during a median hospital stay of 14 days. And the patients with ALI demonstrated significantly higher AVP levels than those without (32.5 ± 21.6 vs. 6.4 ± 8.7 pg/ml, p = 0.018). Besides, the patients with ALI demonstrated significantly higher heart rates (HR) and lower E/e' on admission (HR: 127 ± 24 vs. 97 ± 28 bpm; E/e': 10.6 ± 3.7 vs. 17.4 ± 6.2, all p < 0.05, respectively). Of note, significant hemodilution assessed by hemoglobin and hematocrit values were observed in the patients with ALI 48 h after admission. A receiver operating characteristic curve analysis showed that higher than 7.2 pg/ml surrogate ALI in ADHF (AUC: 0.897, p = 0.001, Sensitivity: 85.7%, and Specificity: 77.8%). In contrast, increased AVP levels on admission could not predict cardiovascular events after discharge. Elevated AVP levels on admission are associated with ALI in ADHF but not cardiovascular events after discharge.

Association Between Aortic Stiffness and Exercise Tolerance in Patients at the Risk Stage of Heart Failure.

BACKGROUND: The number of patients with heart failure (HF) has increased, and it is crucial to prevent the development of HF in patients at risk of HF. The present study aimed to risk stratify patients in Stage A and B HF based on associations between exercise-induced changes in aortic stiffness and exercise tolerance.Methods and Results: Patients in Stage A and B HF who performed a cardiopulmonary exercise test were enrolled in the study (n=106; median age 65.0 years [interquartile range 52.8-73.0 years]). Exercise tolerance was examined by the percentage of predicted peak oxygen consumption (%V̇O2peak). The ascending aortic pressure waveform was estimated non-invasively. Aortic stiffness was assessed using the augmentation index (AIx) and reflection magnitude (RM). Multivariable regression analysis showed that AIx measured both before and after exercise was significantly associated with %V̇O2peak (ß=-0.221 [P=0.049] and ß=-0.342 [P=0.003], respectively). When participants were divided into %V̇O2peak subgroups using a cut-off value of 60%, RM decreased immediately after exercise and remained lower 5 min after exercise in the group with preserved exercise tolerance, but recovered to baseline levels 5 min after exercise in the group with reduced exercise tolerance. CONCLUSIONS: Exercise-induced increases in aortic stiffness were associated with exercise tolerance in patients at risk of HF, suggesting that exercise-induced changes in aortic stiffness may be useful to stratify high-risk patients.

A Novel Mechanism for Bone Loss: Platelet Count Negatively Correlates with Bone Mineral Density via Megakaryocyte-Derived RANKL.

A potential association between hematopoietic stem cell status in bone marrow and surrounding bone tissue has been hypothesized, and some studies have investigated the link between blood count and bone mineral density (BMD), although their exact relationship remains controversial. Moreover, biological factors linking the two are largely unknown. In our present study, we found no clear association between platelet count and BMD in the female group, with aging having a very strong effect on BMD. On the other hand, a significant negative correlation was found between platelet count and BMD in the male group. As a potential mechanism, we examined whether megakaryocytes, the source of platelet production, secrete cytokines that regulate BMD, namely OPG, M-CSF, and RANKL. We detected the production of these cytokines by megakaryocytes derived from bone marrow mononuclear cells, and found that RANKL was negatively correlated with BMD. This finding suggests that RANKL production by megakaryocytes may mediate the negative correlation between platelet count and BMD. To our knowledge, this is the first report to analyze bone marrow cells as a mechanism for the association between blood count and BMD. Our study may provide new insights into the development and potential treatment of osteoporosis.

Tumor-to-tumor metastasis of diffuse large B cell lymphoma to gastric adenocarcinoma via CXCL12 (SDF-1)/CXCR4 axis: a case report.

BACKGROUND: Tumor-to-tumor metastasis is the rare phenomenon in which one tumor exhibits metastatic deposits from another. To the best of our knowledge, there has been no prior reported case of tumor-to-tumor metastasis of a diffuse large B cell lymphoma (DLBCL) to a primary gastric adenocarcinoma. CASE PRESENTATION: A 70-year-old man presented with chest discomfort. An echocardiogram showed the presence of a right ventricular tumor. A positron emission tomogram showed multiple foci of abnormal activity in right cervical lymph nodes, cardiac wall, and stomach. A right cervical lymph node biopsy specimen revealed histological features of DLBCL. An esophagogastroduodenoscopy showed a large circumferential ulceration on the gastric body. Subsequent biopsy revealed adenocarcinoma cells surrounded by infiltrating lymphoma cells. On immunohistochemical staining, lymphoma cells were positive for CXCR4 and adenocarcinoma cells were positive for CXCL12/SDF-1. The patient was treated with six cycles of R-CHOP chemotherapy regimen, resulting in a complete remission. CONCLUSIONS: This patient's case implies that the interaction between a chemokine and its receptor may be the underlying mechanism for the observed tumor-to-tumor metastasis. Specifically, our case would suggest an involvement of the CXCL12 (SDF-1)/CXCR4 axis in the observed metastasis of DLBCL to primary gastric adenocarcinoma.

Correlation Between Longitudinal Strain in the Apical Segments of the Left Ventricle at End-Systole Obtained by 2-Dimensional Speckle-Tracking Echocardiography and Left Ventricular Relaxation.

BACKGROUND: It is well acknowledged that left ventricular (LV) contractile performance affects LV relaxation via LV elastic recoil. Accordingly, we aimed to investigate whether global longitudinal strain (GLS), particularly longitudinal strain at LV apical segments at end-systole (ALS), obtained by 2-dimensional speckle-tracking echocardiography could be used to assess LV relaxation.Methods and Results:We enrolled 121 patients with suspected or definite coronary artery disease in whom echocardiography and diagnostic cardiac catheterization were performed on the same day. We obtained conventional echo-Doppler parameters and GLS, as well as ALS prior to catheterization. LV functional parameters were obtained from the LV pressure recorded using a catheter-tipped micromanometer. In all patients, GLS and ALS were significantly correlated with the time constant τ of LV pressure decay during isovolumetric relaxation (r=0.63 [P<0.001] and r=0.66 [P<0.001], respectively). Receiver operating characteristic curve analysis for identifying impaired LV relaxation (τ ≥48 ms) revealed that ALS greater than -22.3% was an optimal cut-off value, with 81.7% sensitivity and 82.4% specificity. Even in patients with preserved LV ejection fraction, the same ALS cut-off value enabled the identification of impaired LV relaxation with 70% sensitivity and 87.5% specificity. CONCLUSIONS: The findings indicate that contractile dysfunction at LV apical segments slows LV relaxation via loss of LV elastic recoil, even in patients with preserved LVEF.

[Successful preoperative replacement of prothrombin with prothrombin complex concentrate for Prothrombin Himi].

Dysprothrombinemia is the rarest inherited bleeding disorder that is characterized by a decrease in the prothrombin activity, but normal antigen levels. In this study, we report the case of a compound heterozygote of two mutations in prothrombin; Met337Thr and Arg388His, which has previously been identified as "Prothrombin Himi." A systemic blood coagulation evaluation revealed a prolonged prothrombin time (39%) and activated partial thromboplastin (64.4 sec), with an isolated severe decrease in the prothrombin activity (8.6%). Preoperative replacement of prothrombin with prothrombin complex concentrate, PPSB-HT "Nichiyaku," successfully prevented abnormal postoperative bleeding after laparoscopic hysterectomy for cervical cancer. This is the second reported case of Prothrombin Himi.

Left ventricular contractile performance and heart failure in patients with left ventricular ejection fraction more than 40.

Heart failure (HF) with mid-range left ventricular ejection fraction (LVEF) (HFmrEF) is considered a new category of HF and LVEF < 50%, which is the upper threshold of LVEF for HFmrEF, is thought to represent a mild decrease in LV contractile performance. We aimed to consider an LVEF threshold value to be taken as a surrogate for impairment of LV contractile performance, resulting in new-onset HF. We enrolled 398 patients with LVEF ≥ 40% that underwent cardiac catheterization. Using the LV pressure recording with a catheter-tipped micromanometer, we calculated the inertia force of late systolic aortic flow (IFLSAF), which was sensitive to the slight impairment in LV contractile performance. We evaluated the utility of the IFLSAF for predicting future cardiovascular death or hospitalization for HF. We performed a receiver operating characteristic (ROC) curve analysis to determine the best LVEF threshold value for distinguishing whether the LV maintained the IFLSAF. A multivariate Cox proportional-hazards model revealed that the loss of IFLSAF was significantly associated with the future adverse events (HR: 7.798, 95%CI 2.174-27.969, p = 0.002). According to the ROC curve analysis, an LVEF ≥ 58% indicated that the LV could maintain the IFLSAF. We concluded that the loss of IFLSAF, which could reflect even slight impairment in LV contractile performance, was a reliable indicator for new-onset HF in patients with LVEF ≥ 40%. LVEF ≥ 58% could be taken as a surrogate for the IFLSAF maintenance; this threshold could be useful for risk stratification of new-onset HF in patients with preserved LVEF.

Single administration of resveratrol improves social behavior in adult mouse models of autism spectrum disorder.

Resveratrol (RSV) is a natural polyphenol present in grapes, the skin of peanuts, and several other plants with many health benefits. Autism spectrum disorder (ASD) is a neurodevelopmental disorder that may be linked to neural and synaptic development impairments. The present study aimed to analyze the preventive effects of RSV on the development of ASD-like behavior, using oxytocin receptor gene knockout (Oxtr-KO) and valproic acid-induced ASD (VPA-ASD) model mice. Genetic deficiencies in Oxtr are suggested to be involved in ASD etiology. Twenty-four hours after a single RSV injection to the Oxtr-KO mice, the social impairments caused by OXTR deficiency were ameliorated. RSV also improved social impairments in the VPA-ASD mice. Administration of RSV up-regulated silent information regulator 1 (Sirt1) gene and early growth response factor 3 (Egr3) gene expressions in the amygdala of the Oxtr-KO mice. Our data suggest that RSV may have therapeutic effects on ASD with multiple targets.

[Diffuse large B cell lymphoma with HIV infection presented with disseminated thromboembolism during antiretroviral therapy].

Patients with HIV are at higher risk of developing thrombosis than the general population. We present a rare case of a 57-year-old Japanese man with HIV infection and a malignant lymphoma. He had fever with unknown origin and cervical lymph node swelling 2 months before his hospital visit. Because he was positive for the HIV antibody, he was referred to our HIV special outpatient section. HIV RNA level was found to be 846,680 copies/ml. Therefore, antiretroviral therapy of DTG/ABC/3TC was initiated. However, the high fever continued for 7 days after treatment initiation; moreover, renal dysfunction was progressive. After admission, antibiotic therapy was initiated, due to which the fever subsided. However, renal dysfunction continued to progress. Fourteen days later, he died due to acute renal failure with hyperkalemia. An autopsy revealed a large mass in the spleen, and histological findings revealed a diffuse large B cell lymphoma (DLBCL). Furthermore, thrombi were detected in the right and left ventricles, right atrium, iliac artery, and renal artery. Pathological findings revealed that the thrombus induced the renal failure. These thrombi contained fibrin with inflammatory cell infiltration but not tumor cells. Patients with HIV and malignant lymphoma are at a higher risk of thrombosis. It is important to consider thrombosis during the treatment of patients with HIV.

EPO-R+ myelodysplastic cells with ring sideroblasts produce high erythroferrone levels to reduce hepcidin expression in hepatic cells.

Recently, a new erythroid regulator, erythroferrone (ERFE), which downregulates hepatic hepcidin production, has been identified. However, the relationship between ERFE and abnormal iron metabolism in MDS is unclear. In this study, we examined the level of ERFE mRNA during ex vivo erythroid differentiation using cord blood CD34+ cells and we further analyzed whether ERFE could be produced by MDS cells using a public database (GSE58831). ERFE mRNA was increased during normal erythroid differentiation. An analysis of GSE58831 indicated that ERFE expression in bone marrow (BM) MDS cells was higher than that in healthy volunteer (HV)-derived BM cells. ERFE expression significantly and positively correlated with the expression of erythropoietin (EPO) receptors (EPO-R), ALAS2 (5'-Aminolevulinate Synthase 2), STEAP3 (STEAP family member 3) and the presence of ring sideroblasts or the SF3B1 mutation. These results suggest that EPO-R+ MDS cells with ring sideroblasts or an SF3B1 mutation produce high levels of ERFE that may be associated with a reduction in hepcidin.

Fumarate accumulation involved in renal diabetic fibrosis in Goto-Kakizaki rats.

The Goto-Kakizaki (GK) rat is a spontaneous animal model of type 2 diabetes and early stage of diabetic nephropathy. However, the pathophysiological mechanisms contributing to the progression of diabetic nephropathy in GK rats remain unclear. Kidneys from 15-week old male diabetic GK/Jcl rats and age-matched Wistar rats, which have the same genetic background as GK rats, were used. Proteomic analyses of GK and Wistar kidneys were performed using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Differentially expressed proteins in GK rats were subjected to pathway analysis, and expression levels of hypoxia inducible factor 1α (HIF-1α) and transforming growth factor-ß1 (TGF-ß1), and fumarate accumulation in GK kidneys were examined. Azan staining and immunohistochemical staining of α-smooth muscle actin were performed in relation to fibrosis in GK kidneys. Proteomic analysis using 2D-DIGE, analysis of fumarate content, and expression analysis of HIF-1α, TGF-ß1, and α-smooth muscle actin of GK rat's kidney, suggested the mechanism of fibrosis characterized as two stages in diabetic nephropathy of GK rats. Abnormalities of glucose metabolism such as elevated levels of 2-oxoglutarate dehydrogenase and reduction of fumarate hydratase caused the accumulation of fumarate followed by the upregulation of HIF-1α and TGF-ß1 leading to fibrosis in diabetic nephropathy. Alterations in proteins involved in the tricarboxylic acid cycle are associated with fibrosis through fumarate accumulation in diabetic nephropathy of GK rats.

[Treatment of POEMS syndrome with lenalidomide and dexamethasone].

We report three cases of POEMS syndrome treated with lenalidomide and dexamethasone who presented with peripheral neuropathy. All of them had markedly elevated serum vascular endothelial growth factor (VEGF) levels treated with lenalidomide and dexamethasone for severe peripheral neuropathy, which normalized serum VEGF levels and improved peripheral neuropathy. The standard treatment of POEMS syndrome has not been established, but has been effectively treated with high-dose chemotherapy with autologous stem cell transplantation. Newer agents currently used for plasma cell dyscrasias include bortezomib and immunomodulatory drugs, such as thalidomide and lenalidomide. A randomized controlled trial on thalidomide plus dexamethasone for POEMS syndrome showed reduced serum VEGF levels after therapy; however, the incidence of peripheral neuropathy, a well-known side effect of both thalidomide and bortezomib, increased. Lenalidomide is associated with lower incidence of peripheral neuropathy compared to thalidomide and bortezomib, making it a reasonable treatment option for POEMS syndrome.

Compensatory Increase in Heart Rate Is Responsible for Exercise Tolerance among Male Patients with Permanent Atrial Fibrillation.

Atrial fibrillation (AF) is an exacerbating factor for exercise tolerance due to the loss of atrial kick. However, many patients with permanent AF, which lasts for at least a year without interruption, and preserved left ventricular ejection fraction (LVEF ≥ 50%) are asymptomatic and have good exercise tolerance. In such cases, the possible mechanism that compensates for the decrease in cardiac output accompanying the loss of atrial kick is a sufficient increase in heart rate (HR) during exercise. We investigated the relationship between exercise tolerance and peak HR during exercise using cardiopulmonary exercise testing in 242 male patients with preserved LVEF, 214 with sinus rhythm (SR) and 28 with permanent AF. Peak HR was significantly higher in the AF group than the SR group (148.9 ± 41.9 vs. 132.0 ± 22.0 beats/min, p = 0.001). However, oxygen uptake at peak exercise did not differ between the AF and SR groups (19.4 ± 5.7 vs. 21.6 ± 6.0 mL/kg/min, p = 0.17). In multiple regression analysis, peak HR (ß, 0.091; p < 0.001) and the interaction term constructed by peak HR and presence of permanent AF (ß, 0.05; p = 0.04) were selected as determinants for peak VO2; however, presence of permanent AF was not selected (ß, -0.38; p = 0.31). Therefore, the impact of peak HR on exercise tolerance differed between the AF and SR groups, suggesting that a sufficient increase in HR during exercise is an important factor to preserve exercise tolerance among patients with AF.

Extracellular vesicle miR-7977 is involved in hematopoietic dysfunction of mesenchymal stromal cells via poly(rC) binding protein 1 reduction in myeloid neoplasms.

The failure of normal hematopoiesis is observed in myeloid neoplasms. However, the precise mechanisms governing the replacement of normal hematopoietic stem cells in their niche by myeloid neoplasm stem cells have not yet been clarified. Primary acute myeloid leukemia and myelodysplastic syndrome cells induced aberrant expression of multiple hematopoietic factors including Jagged-1, stem cell factor and angiopoietin-1 in mesenchymal stem cells even in non-contact conditions, and this abnormality was reverted by extracellular vesicle inhibition. Importantly, the transfer of myeloid neoplasm-derived extracellular vesicles reduced the hematopoietic supportive capacity of mesenchymal stem cells. Analysis of extracellular vesicle microRNA indicated that several species, including miR-7977 from acute myeloid leukemia cells, were higher than those from normal CD34(+)cells. Remarkably, the copy number of miR-7977 in bone marrow interstitial fluid was elevated not only in acute myeloid leukemia, but also in myelodysplastic syndrome, as compared with lymphoma without bone marrow localization. The transfection of the miR-7977 mimic reduced the expression of the posttranscriptional regulator, poly(rC) binding protein 1, in mesenchymal stem cells. Moreover, the miR-7977 mimic induced aberrant reduction of hematopoietic growth factors in mesenchymal stem cells, resulting in decreased hematopoietic-supporting capacity of bone marrow CD34(+)cells. Furthermore, the reduction of hematopoietic growth factors including Jagged-1, stem cell factor and angiopoietin-1 were reverted by target protection of poly(rC) binding protein 1, suggesting that poly(rC) binding protein 1 could be involved in the stabilization of several growth factors. Thus, miR-7977 in extracellular vesicles may be a critical factor that induces failure of normal hematopoiesis via poly(rC) binding protein 1 suppression.

Vascular Physiology according to Clinical Scenario in Patients with Acute Heart Failure: Evaluation using the Cardio-Ankle Vascular Index.

Increased aortic stiffness may be an important cause of acute heart failure (AHF). Clinical scenario (CS), which classifies the pathophysiology of AHF based on the initial systolic blood pressure (sBP), was proposed to provide the most appropriate therapy for AHF patients. In CS, elevated aortic stiffness, vascular failure, has been considered as a feature of patients categorized as CS1 (sBP > 140 mmHg at initial presentation). However, whether elevated aortic stiffness, vascular failure, is present in such patients has not been fully elucidated. Therefore, we assessed aortic stiffness in AHF patients using the cardio-ankle vascular index (CAVI), which is considered to be independent of instantaneous blood pressure. Sixty-four consecutive AHF patients (mean age, 70.6 ± 12.8 years; 39 men) were classified with CS, based on their initial sBP: CS1: sBP > 140 mmHg (n = 29); CS2: sBP 100-140 mmHg (n = 22); and CS3: sBP < 100 mmHg (n = 13). There were significant group differences in CAVI (CS1 vs. CS2 vs. CS3: 9.7 ± 1.4 vs. 8.4 ± 1.7 vs. 8.3 ± 1.7, p = 0.006, analysis of variance). CAVI was significantly higher in CS1 than in CS2 (p = 0.02) and CS3 (p = 0.04). CAVI did not significantly correlate with sBP at the time of measurement of CAVI (r = 0.24 and p = 0.06). Aortic stiffness assessed using blood pressure-independent methodology apparently increased in CS1 AHF patients. We conclude that vascular failure is a feature of CS1 AHF initiation.

Evaluation of renal circulation in heart failure using superb microvascular imaging, a microvascular flow imaging system.

PURPOSE: Renal circulation evaluation is essential in understanding the cardiorenal relationship in heart failure (HF), and there is a growing interest in imaging techniques that visualize renal circulation. This study aimed to assess the effectiveness of superb microvascular imaging (SMI) in evaluating renal circulation in HF patients. METHOD: The study included 71 HF patients undergoing cardiac catheterization. Prior to catheterization, renal ultrasound examinations were performed. A control group of 18 subjects without HF was also included. SMI was used to measure the vascular index (VI), which was calculated as the percentage of blood flow signal area in the region of interest. The intrarenal perfusion index (IRPI) was determined as a fluctuation index of VI, reflecting variations in the number of blood cells moving through renal tissue during the cardiac cycle. RESULTS: Using the upper 95% confidence interval of IRPI (0.6) from the control group, HF patients were classified into two groups. Patients with IRPI > 0.6 showed a more congestive profile. Right atrial pressure and biphasic or monophasic Doppler intrarenal flow pattern were independent determinants of IRPI > 0.6. In addition, IRPI remained a significant predictor of estimated glomerular filtration rate (eGFR). CONCLUSION: The parameter IRPI as variations in SMI signal during the cardiac cycle may be a useful evaluation method for renal perfusion impairment in HF.

A Case of Myocardial Infarction with Non-obstructive Coronary Arteries Complicated by a Ventricular Septal Rupture: The Challenge of Achieving Hemodynamic Stability Using Impella Devices.

The prognosis of myocardial infarction with non-obstructive coronary arteries (MINOCA) is reported to be as worse as myocardial infarction with obstructive coronary arteries. However, its mechanical complications are still poorly understood. A 71-year-old woman developed MINOCA after ascending aortic replacement surgery. During treatment, the patient experienced cardiogenic shock due to a ventricular septal rupture (VSR). The introduction of Impella devices reduced the left-to-right shunt and improved the patient's hemodynamics. Finally, a scheduled surgical repair was performed under stable conditions. In this report, we focused on the pathophysiology of MINOCA-related VSR and discussed the effectiveness of Impella devices as a bridge to surgical repair and circulatory backup during the perioperative period.

Cranial hypertrophic pachymeningitis with myelodysplastic syndrome.

Hypertrophic pachymeningitis (HP) is a rare inflammatory disease characterized by thickening of the dura mater. HP develops with several inflammatory diseases. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and IgG4 related disease are reported as 2 major causes. With hematologic diseases, only 3 cases have been reported. We report the case of myelodysplastic syndrome (MDS) developing HP. Our case provides a thought-provoking hypothesis regarding the potential relationship between MDS and HP.