Role of CC chemokine receptor 9 in the progression of murine and human non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The number of patients with non-alcoholic steatohepatitis (NASH) is increasing globally. Recently, specific chemokine receptors have garnered interest as therapeutic targets in NASH. This is the first report to examine the role of the C-C chemokine receptor 9 (CCR9)/C-C chemokine receptor ligand 25 (CCL25) axis, and to reveal its therapeutic potential in NASH. METHODS: Patients with biopsy-proven non-alcoholic liver disease (NAFLD) were recruited and their serum and hepatic chemokine expression was examined. Furthermore, wild-type (WT) and Ccr9-/- mice were fed a high-fat high-cholesterol (HFHC) diet for 24 weeks to establish NASH. RESULTS: Serum CCL25, and hepatic CCR9 and CCL25 expression levels were increased in patients with NASH compared to healthy volunteers. Furthermore, Ccr9-/- mice were protected from HFHC diet-induced NASH progression both serologically and histologically. Flow cytometry and immunohistochemistry analysis showed that CCR9+CD11b+ inflammatory macrophages accumulated in the inflamed livers of HFHC diet-fed mice, while the number was reduced in Ccr9-/- mice. Consistent with human NASH livers, CCR9 was also expressed on hepatic stellate cells (HSCs) in mice with NASH, while CCR9-deficient HSCs showed less fibrogenic potential in vitro. Administration of a CCR9 antagonist hampered further fibrosis progression in mice with NASH, supporting its potential clinical application. Finally, we showed that CCR9 blockade attenuated the development of NAFLD-related hepatocellular carcinoma in HF diet-fed mice injected with diethylnitrosamine. CONCLUSIONS: These results highlight the role of the CCR9/CCL25 axis on macrophage recruitment and fibrosis formation in a murine NASH model, providing new insights into therapeutic strategies for NASH. LAY SUMMARY: Herein, we show that a specific chemokine axis involving a receptor (CCR9) and its ligand (CCL25) contributes to the progression of non-alcoholic steatohepatitis and carcinogenesis in humans and mice. Furthermore, treatment with a CCR9 antagonist ameliorates the development of steatohepatitis and holds promise for the treatment of patients with non-alcoholic steatohepatitis.

Impaired activity of daily living is a risk factor for high medical cost in patients of non-variceal upper gastrointestinal bleeding.

BACKGROUND: Non-variceal upper gastrointestinal bleeding (NVUGIB) is still a common and life-threatening disease, thus it would have a big impact on medical care cost. However, little is known about risk factors for increased medical care cost in NVUGIB patients. AIM: The purpose of the study was to clarify predictor of requiring high medical care cost in NVUGIB patients. Patients who underwent endoscopic hemostasis due to NVUGIB between April 2012 and March 2015 were included in this retrospective study. We analyzed the association between patients' background including activity of daily livings (ADL) and high medical care cost using logistic regression model. Medical care cost was calculated in reference to the "Diagnosis Procedure Combination" which is diagnosis-dominant case-mix system in Japan. The cutoff value of high medical care cost was defined as its first quartile. ADL was assessed according to Katz-6 score. We defined impaired ADL patient who revealed Katz-6 score more than 1. RESULTS: A total of 128 consecutive patients were included in this study. Median medical care cost was 5323 USD (IQR 3661-8172 USD). There were 13 patients (10%) in impaired ADL group. In univariate analysis, age and impaired ADL before admission revealed significant association with high cost. Of these, impaired ADL was an only independent risk factor [odds ratio 15.3 (95% CI 2.49-183)] in multivariate analysis. CONCLUSION: Impairment in ADL before admission was an independent predictor for high medical care cost with NVUGIB patients.

Risk Factor for Vital Signs Fluctuation during Colonoscopy under Conscious Sedation Consisting of Midazolam and Meperidine.

BACKGROUND: Sedatives or analgesics are widely used to relieve a patient's discomfort during colonoscopy (CS). Although cardiopulmonary adverse events are sometimes experienced during the examination, the risk factors for vital signs fluctuation (VSF) have not been fully elucidated. This study thus aimed to identify the risk factors for VSF during the examination, as well as to evaluate the frequency and the degree of VSF. SUMMARY: A total of 755 consecutive subjects who received CS under endoscopist-administrated sedation using midazolam, meperidine, or combination of both were retrospectively analyzed. We assessed the distribution of vital signs during the procedure and frequency of VSF. To identify independent risk factors, we analyzed the association between VSF and subjects' characteristics and procedure information using the multivariate logistic regression model. Consequently, VSF was observed in 17% of all; hypotension and oxygen desaturation was observed in 13 and 5%, respectively. However, we could achieve the purpose of all procedure and, no one required hospitalization or extension of hospital stay. Multivariate analysis revealed that age (OR 1.05 [95% CI 1.04-1.07]), being female (OR 1.78 [95% CI 1.19-2.70]), and use of midazolam (OR 5.06 [95% CI 3.18-8.08]) were independent risk factors for VSF.

The Role of History of Gastro-Duodenal Ulcer in Patients with Upper Gastrointestinal Bleeding.

BACKGROUND: Some scoring systems have been introduced to predict the need for performing urgent endoscopy in patients with upper gastrointestinal bleeding (UGIB). However, in an emergency situation, this intervention is insufficient and cannot easily provide the required treatment. AIM: To identify new risk factors that can predict the need for endoscopic intervention (EI) in UGIB patients. METHODS: This is a retrospective cross-sectional study. Patients with UGIB admitted from April 2011 to August 2014 were included. The proportion of cases requiring EI and clinical factors (age, gender, antiplatelet/anticoagulant therapy, history of gastro-duodenal ulcer (GDU), systolic blood pressure, heart rate, hemoglobin, mean corpuscular volume, blood urea nitrogen-creatinine ratio (BUN/Cr ratio), prothrombin time-international normalized ratio, and Glasgow-Blatchford Score (GBS) were analyzed using logistic regression models. RESULT: Of 378 patients who were included in this study, 180 were found to be with GDU. The proportion of cases requiring EI was significantly higher in those with GDU than in other causes except variceal bleeding (53.5 vs. 37.0%, p < 0.01). Multivariate analysis revealed that a history of GDU was an independent risk factor (OR 1.78, 95% CI 1.06-3.00) in addition to BUN/Cr ratio (OR 1.02, 95% CI 1.00-1.03) and GBS (OR 1.19, 95% CI 1.08-1.33). CONCLUSION: A history of GDU was an independent risk factor for predicting the need for EI in UGIB in addition to BUN/Cr ratio and GBS.

Usefulness of Mean Corpuscular Volume for Detection of Advanced Colorectal Cancer in Patients Older than 85 Years.

BACKGROUND/AIMS: The aim of this study was to elucidate clinical indicators for the detection of advanced colorectal cancer (ACRC). METHODS: This was a retrospective study conducted at a tertiary hospital. This study included 333 patients older than 85 years who underwent colonoscopy from April 2006 to May 2010. The detection rate of ACRC was assessed. Then, we analyzed the association between the detection of ACRC and various background factors including mean corpuscular volume (MCV). We also analyzed the cumulative overall survival of patients with detected ACRC. RESULTS: ACRC was found in 37 patients, resulting in a detection rate of 15%. Multivariate logistic regression analysis revealed that a decreased MCV was an independent predictor for the detection of ACRC (OR 0.88, 95% CI 0.84-0.94), whereas symptoms such as abdominal pain, hematochezia, or anemia were not independent predictors. MCV was an independent predictor irrespective of the location of the tumor. The cumulative survival rates at 3 and 5 years after diagnosis were 78 and 58%, respectively, during a median observational period of 30.3 months. CONCLUSION: This study demonstrated the usefulness of MCV as an indicator of the necessity of colonoscopy for older patients.

Initial Management of Colonic Diverticular Bleeding: Observational Study.

BACKGROUND/AIMS: Although colonic diverticular bleeding (CDB) often ceases spontaneously, re-bleeding occurs in about 30%. Bleeding diverticulum can be treated directly by endoscopic hemostasis; however, it is difficult to perform colonoscopy in all cases with limited medical resource and certain risks. The aim of this study was to clarify who should undergo colonoscopy as well as appropriate methods of initial management in CDB patients. METHODS: A total of 285 patients who were diagnosed as CDB and underwent colonoscopy from March 2004 to October 2015 were retrospectively analyzed. First, the association between re-bleeding and various factors including patients' background and initial management were analyzed. Second, the examination conditions that influenced bleeding point identification were analyzed. RESULTS: Of 285 patients, 187 were men and 98 were women. Median age was 75 years, and the median observation period was 17.5 months. Re-bleeding was observed in 79 patients (28%). A history of CDB (OR 2.1, p = 0.0090) and chronic kidney disease (CKD; OR 2.3, p = 0.035) were risk factors, and bleeding point identification (OR 0.20, p = 0.0037) was a preventive factor for re-bleeding. Bleeding point identification significantly reduced approximately 80% of re-bleeding. Furthermore, extravasation on CT (OR 3.7, p = 0.031) and urgent colonoscopy (OR 5.3, p < 0.001) were predictors for identification of bleeding point. Compared to bleeding point identification of 11% in all patients who underwent colonoscopy, identification rate in those who had extravasation on CT and underwent urgent colonoscopy was as high as 70%. CONCLUSIONS: Contrast-enhanced CT upon arrival is suggested, and patients with extravasation on CT would be good candidates for urgent colonoscopy, as well as patients who have a history of CDB and CKD.

Preparation of cycloheptane ring by nucleophilic cyclopropanation of 1,2-diketones with bis(iodozincio)methane.

The nucleophilic cyclopropanation of hexa-1,5-diene-3,4-diones with bis(iodozincio)methane afforded the Zn alkoxides of cis-dialkenylcyclopropane-1,2-diols stereoselectively. The subsequent oxy-Cope rearrangement afforded the corresponding Zn alkoxides of 5,6-dialkylcyclohepta-3,7-diene-1,3-diols.

Bleb Embolization of Ruptured Cerebral Aneurysms with Coils and n-Butyl Cyanoacrylate Following Proximal Flow Control: Two Case Reports.

Objective: Morphologically challenging cerebral aneurysms cannot be treated through standard endovascular procedures. We report two cases of ruptured aneurysms treated using coils and n-butyl cyanoacrylate (NBCA). Case Presentations: Case 1 was an 80-year-old woman diagnosed with a subarachnoid hemorrhage (SAH). An angiogram revealed a large and wide-necked basilar artery bifurcation aneurysm. Bilateral superior cerebellar and posterior cerebral arteries (PCAs) originated from the aneurysmal wall. A 3-mm-diameter bleb was detected on the aneurysmal fundus. The bleb enlarged 1 month following coil insertion. During the second treatment, we infused a small volume of 33% NBCA into the coil-framed bleb following proximal flow control of the bilateral vertebral arteries (VAs). The complete bleb obliteration was confirmed by the angiogram at 6 months later. The coil shape was followed up via plane X-ray for 5 years. No rebleeding occurred. Case 2 was a 41-year-old woman diagnosed with SAH. An angiogram revealed a dissecting aneurysm of the left PCA (P1 and P2 segments) accompanying a bleb on the P1 segment. Endovascular treatment was performed, and a coil was inserted into the bleb, infusing 33% NBCA into the coil frame following proximal flow control of bilateral VAs and the right internal carotid artery. Angiograms conducted at 3 months, 1 year, and 9 years and an MRA conducted 12 years later revealed a lack of bleb recanalization. Conclusion: We developed a Coil and NBCA technique to obliterate ruptured blebs following proximal flow control. This technique can be considered an effective alternative for treating morphologically challenging cerebral aneurysms.

Enrichment of type I interferon signaling in colonic group 2 innate lymphoid cells in experimental colitis.

Group 2 innate lymphoid cells (ILC2s) serve as frontline defenses against parasites. However, excluding helminth infections, it is poorly understood how ILC2s function in intestinal inflammation, including inflammatory bowel disease. Here, we analyzed the global gene expression of ILC2s in healthy and colitic conditions and revealed that type I interferon (T1IFN)-stimulated genes were up-regulated in ILC2s in dextran sodium sulfate (DSS)-induced colitis. The enhancement of T1IFN signaling in ILC2s in DSS-induced colitis was correlated with the downregulation of cytokine production by ILC2s, such as interleukin-5. Blocking T1IFN signaling during colitis resulted in exaggeration of colitis in both wild-type and Rag2-deficient mice. The exacerbation of colitis induced by neutralization of T1IFN signaling was accompanied by reduction of amphiregulin (AREG) in ILC2s and was partially rescued by exogenous AREG treatment. Collectively, these findings show the potential roles of T1IFN in ILC2s that contribute to colitis manifestation.

[Subarachnoid hemorrhage due to a ruptured intracranial vertebral artery aneurysm associated with cerebrovascular fibromuscular dysplasia: case report].

Fibromuscular dysplasia (FMD) is comprised of a group of nonatherosclerotic and noninflammatory arterial diseases. Cerebrovascular FMD occurs more frequently in women, and the mean age at which it is diagnosed is 50 years. The most common angiographic pattern of cerebrovascular FMD is the "string-of-beads" deformity at the extracranial internal carotid artery. We report the case of a 52-year-old woman who presented with a sudden severe headache and went into a deep coma. She had been complaining of headaches for 2 weeks, but no specific imaging findings were obtained. A computed tomography scan obtained on admission showed a diffuse subarachnoid hemorrhage (SAH) from the cerebellomedullary cistern to the basal cistern with evidence of clot in the fourth and third ventricles. We performed digital subtraction angiography and made the diagnosis of cerebrovascular FMD. Right carotid angiography and left vertebral angiography showed the classic "string-of-beads" pattern with multiple constrictions of the lumen. Left carotid angiography showed a long segment of tubular stenosis. Right vertebral angiography also revealed the "string-of-beads" pattern and a ruptured aneurysm at the intracranial segment, which presented as a diverticulum-like outpouching. The patient was treated with conservative measures but passed away on the 23rd day of hospitalization. An autopsy was not performed. To our knowledge, during the last three decades, there are only four previous reports which showed intracerebral ruptured aneurysms of the vertebral artery or its branch in adults with cerebrovascular FMD. We demonstrate and discuss the radiologic findings here.

Bleeding from an Unruptured Cerebral Aneurysm following the Local Intra-arterial Administration of Urokinase: A Case Report.

A 57-year-old woman with a wide-necked anterior communicating artery (Acom) aneurysm underwent stent-assisted coiling (SAC) due to aneurysm enlargement. Dual antiplatelet therapy was initiated 7 days before the operation, and systemic heparinization was performed while maintaining an activated clotting time (ACT) of approximately 300 s during the procedure. SAC was performed using a laser-cut closed-cell stent and bare platinum coils. At the end of the procedure, the Acom and right anterior cerebral artery (ACA) were occluded by in-stent thrombosis. Following local intra-arterial administration of 480000 U of urokinase, the Acom and right ACA were recanalized, accompanied by extravasation around the Acom aneurysm. A computed tomography (CT) scan revealed a right frontal hematoma, which did not enlarge after the administration of protamine sulfate. The hematoma disappeared spontaneously, and the patient recovered without any neurological deficits. Local administration of urokinase is an effective treatment for in-stent thrombosis. However, because the devices for SAC may cause mechanical injuries to the aneurysms, urokinase should be used cautiously for cerebral aneurysms, even if unruptured.

Unruptured Aneurysmal Shrinkage of the Distal Posterior Inferior Cerebellar Artery Following Stent Jailing of the Arterial Orifice: A Case Report.

A 57-year-old woman who presented with a sudden severe headache and subsequently diagnosed with a subarachnoid hemorrhage was referred to our hospital. CTA revealed a large irregularly shaped dissecting aneurysm of the right vertebral artery (VA) and a small round distal aneurysm of the right posterior inferior cerebellar artery (PICA), which originated just proximal to the VA aneurysm. We diagnosed the VA aneurysm as a ruptured aneurysm and performed endovascular treatment the day the patient was hospitalized. Because the left VA was aplastic, stent-assisted coiling was performed to preserve the blood flow of the right VA, following the administration of antiplatelets and heparin. The proximal part of the laser-cut closed-cell stent jailed the orifice of the right PICA. The postoperative course was uneventful, and she was discharged from the hospital 3 weeks later without any neurological deficits. The follow-up VA angiogram revealed complete disappearance of the distal PICA aneurysm 17 months after stent jailing. Flow reduction by stent jailing of the arterial orifice is considered to be the main mechanism of aneurysmal shrinkage. Jailing of the orifice of the cerebral artery using even a low-metal-coverage stent may cause arterial flow reduction, which may shrink a distal aneurysm.

Epigenetic regulation of T helper cells and intestinal pathogenicity.

Inflammatory bowel diseases (IBDs) are characterized by relapsing and remitting chronic intestinal inflammation. Previous studies have demonstrated the contributions of genetic background, environmental factors (food, microbiota, use of antibiotics), and host immunity in the development of IBDs. More than 200 genes have been shown to influence IBD susceptibility, most of which are involved in immunity. The vertebrate immune system comprises a complex network of innate and adaptive immune cells that protect the host from infection and cancer. Dysregulation of the mutualistic relationship between the immune system and the gut environment results in IBD. Considering the fundamental role of epigenetic regulation in immune cells, epigenetic mechanisms, particularly in T helper (Th) cells, may play a major role in the complex regulation of mucosal immunity. Epigenetic regulation and dysregulation of Th cells are involved in the maintenance of intestinal homeostasis and its breakdown in IBD.

Innate lymphoid cells in organ fibrosis.

Innate lymphoid cells (ILCs) are a recently identified family of lymphoid effector cells. ILCs are mainly clustered into 3 groups based on their unique cytokine profiles and transcription factors typically attributed to the subsets of T helper cells. ILCs have a critical role in the mucosal immune response through promptly responding to pathogens and producing large amount of effector cytokines of type 1, 2, or 3 responses. In addition to the role of early immune responses against infections, ILCs, particularly group 2 ILCs (ILC2), have recently gained attention for modulating remodeling and fibrosis especially in the mucosal tissues. Herein, we overview the current knowledge in this area, highlighting roles of ILCs on fibrosis in the mucosal tissues, especially focusing on the gut and lung. We also discuss some new directions for future research by extrapolating from knowledge derived from studies on Th cells.

Validation of treatment algorithm based on the Japan narrow-band imaging expert team classification for sub-centimeter colorectal polyps.

BACKGROUND AND STUDY AIMS: Although cold polypectomy (CP) is widely used for colorectal polyps < 10 mm, appropriateness of indications for CP or endoscopic mucosal resection (EMR) are still unclear. The aim of this study was to validate the endoscopic treatment algorithm based on the Japan NBI Expert Team (JNET) classification. PATIENTS AND METHODS: Consecutive patients with at least one colorectal non-pedunculated polyp < 10 mm between July 2014 and October 2016 were included in this retrospective study. During the period, EMR was performed for JNET ≥ 2B lesions and CP for JNET < 2A. Among a total of 3966 lesions, 3368 lesions with JNET ≤ 2A were resected by CP in compliance with the treatment algorithm but 565 resections for JNET ≤ 2A were not compliant (by EMR), while all 24 JNET > 2B lesions were removed by EMR in compliance with the algorithm. Polypectomy outcomes were compared between the compliant and non-compliant groups. Histological outcomes were analyzed in accordance with JNET classification. RESULTS: Post-polypectomy bleeding rate in the compliant group (0 %) was lower than that in the non-compliant group (0.53 %, P  < 0.01). Proportion of lesions diagnosed as cancer (38 % vs 0.36 %, P  < 0.01) or submucosal cancer (4.2 % vs 0.03 %, P  = 0.012), and the lesion with free resection margin (91 % vs 64 %, P  < 0.01) was higher in the JNET ≥ 2B than JNET ≤ 2A. CONCLUSION: This study indicated our algorithm would be valid: CP is suitable for most polyps < 10 mm as incidence of post-polypectomy bleeding is low, whereas EMR is recommended for JNET ≥ 2B lesions for histological complete removal.

Hepatoma-derived growth factor as a prognostic marker in completely resected non-small-cell lung cancer.

Hepatoma-derived growth factor (HDGF), unrelated to hepatocyte growth factor, is a heparin-binding protein originally purified from human hepatoma HuH-7 cells. HDGF exhibits mitogenic activities for certain hepatoma cells, fibroblasts and vascular smooth muscle cells, and angiogenic activities through nuclear targeting. Recently, HDGF was found to be a mitogen for lung epithelial cells in vitro and in vivo. This suggests that HDGF may play a critical role in the development and progression of lung cancer. We investigated, immunohistochemically, the relationship between HDGF expression and clinicopathological variables, and the prognostic significance of HDGF in 102 patients with completely resected non-small-cell lung cancer (NSCLC: 70 adenocarcinomas and 32 squamous cell carcinomas). To address the mechanism of action of HDGF, we evaluated the contribution of HDGF to tumor cell proliferation and intratumor angiogenesis using anti-Ki-67 and anti-CD31 antibodies, respectively. HDGF expression was strongly detected in the nucleus of cancer cells; the HDGF-labeling index (LI) was 20-95% (median 64.5%). There was no significant association between HDGF-expression level and clinicopathological variables. Patients with NSCLC showing a high HDGF-LI (> or =65%) had significantly worse overall and disease-free survivals than those with NSCLC showing a low HDGF-LI. Multivariate analysis revealed that HDGF is a significant independent prognostic factor, more powerful than pathological stage. Moreover, HDGF expression correlated with Ki-67-LI and intratumor microvessel density. We consider HDGF as a useful prognostic marker for patients with completely resected NSCLC and it may play a critical role in the pathobiology of lung cancer through its mitogenic and angiogenic activities.

A case of gastric adenocarcinoma of fundic gland type resected by combination of laparoscopic and endoscopic approaches to neoplasia with non-exposure technique (CLEAN-NET).

A male in his eighties attended our hospital for further evaluation of gastric cancer. A gastroscopy revealed a whitish flat elevated lesion (Paris, 0-IIa) of 15 mm in diameter on the greater curvature of the proximal fornix. The preoperative diagnosis was intra-mucosal differentiated gastric cancer, and a novel therapeutic approach, combination of laparoscopic and endoscopic approaches to neoplasia with non-exposure technique (CLEAN-NET) was applied and the lesion was resected in a single piece without any complications. Histopathological findings revealed atypical glandular epithelium proliferated in the mucosa and shallow layer (300 µm) of submucosa. These cells stained positive for pepsinogen-I and the final diagnosis was gastric cancer of fundic gland type (GAFT). There was no lymph-vascular involvement and free horizontal and vertical margins were confirmed. CLEAN-NET could be a therapeutic option for GAFT at low risk of lymph node metastasis because it prevents excess wall defect and exposure of cancer cells into the peritoneal cavity.

Preoperative evaluation of neurovascular compression in patients with trigeminal neuralgia by use of three-dimensional reconstruction from two types of high-resolution magnetic resonance imaging.

OBJECTIVE: To assess the value of three-dimensional (3-D) images reconstructed from 3-D constructive interference in steady state (3-D-CISS) and 3-D fast inflow with steady-state precession (3-D-FISP) images for the visualization of neurovascular compression in patients with trigeminal neuralgia. METHODS: Twenty-four consecutive patients with trigeminal neuralgia underwent preoperative 3-D-FISP and 3-D-CISS imaging. 3-D reconstruction of nerves and vessels was performed with the use of a volume-rendering method. We compared the 3-D reconstructed images with intraoperative findings. RESULTS: 3-D-CISS and 3-D-FISP images scanned from the same position clearly delineated the trigeminal nerve and vessels. 3-D reconstructed images showed the spatial relationship between the trigeminal nerve and causative vessels. The responsible arteries were identified from the 3-D reconstructed images, which closely simulated the microscopic operative view. CONCLUSION: 3-D reconstructions from two types of high-resolution magnetic resonance images (3-D-CISS and 3-D-FISP) are very useful for creating preoperative simulations and in deciding whether to perform surgery in patients with trigeminal neuralgia.

[A case of chronic thromboembolic pulmonary hypertension based on essential thrombocythemia].

We report a case of chronic thromboembolic pulmonary hypertension based on essential thrombocythemia. A 72-year-old woman was admitted to our hospital with dyspnea. The hematologic workup revealed a platelet count of 99.2 x 10(4)/microliter. Chest radiographic examination revealed cardiomegaly with bilateral pulmonary artery enlargement. A perfusion lung scan suggested and pulmonary angiography confirmed--multiple pulmonary embolism. Pulmonary artery pressure was 90/30 (51) mmHg. Thrombolytic therapy was performed successfully, and a diagnosis of essential thrombocythemia was made on the basis of the criteria proposed by the Polycythemia Vera Study Group. The therapy of essential thrombocythemia including ranimustine was effective, and one year later, the essential thrombocythemia and chronic respiratory failure had improved. To our knowledge, this case of chronic thromboembolic pulmonary hypertension based on essential thrombocythemia is a very rare one.