White Blood Cells Of Patients Research Articles

A Bayesian nonparametric model for white blood cells in patients with lower urinary tract symptoms

Lower Urinary Tract Symptoms (LUTS) affect a significant proportion of the population and often lead to a reduced quality of life. LUTS overlap across a wide variety of diseases, which makes the diagnostic process extremely complicated. In this work we focus on the relation between LUTS and Urinary Tract Infection (UTI). The latter is detected through the number of White Blood Cells (WBC) in a sample of urine: WBC≥ 1 indicates UTI and high levels may indicate complications. The objective of this work is to provide the clinicians with a tool for supporting the diagnostic process, deepening the available knowledge about LUTS and UTI. We analyze data recording both LUTS profile and WBC count for each patient. We propose to model the WBC using a random partition model in which we specify a prior distribution over the partition of the patients which includes the clustering information contained in the LUTS profile. Then, within each cluster, the WBC counts are assumed to be generated by a zero-inflated Poisson distribution. The results of the predictive distribution allows to identify the symptoms configuration most associated with the presence of UTI as well as with severe infections.

Fabry Disease Diagnosed Based on the Detection of Urinary Mulberry Bodies.

A 42-year-old Japanese man visited our nephrology department after proteinuria without hematuria was detected in a medical checkup. A physical examination showed no abnormalities. His renal function was normal (serum creatinine concentration: 0.65 mg/dL). The urinary analysis at the first visit revealed fat bodies with a whorl-like appearance; so-called mulberry bodies (Picture 1). These bodies showed a characteristic Maltese Cross configuration under polarized light microscopy (Picture 2), which was highly suggestive of Fabry disease (1). Indeed, the alpha-galactosidase (GLA) activity in the patient's white blood cells was as low as 0.1 nmol/h/mg and his serum globotriaosylceramide level was elevated to 69 nmol/L. A genetic analysis revealed a thymine insertion in exon 5 of the GLA-gene, which confirmed the diagnosis of the classic Fabry disease phenotype (2). In a further examination, left ventricular hypertrophy and whorl-like corneal opacity were observed.

Low-Dose Cyclophosphamide Plus Granulocyte Colony-Stimulating Factor As an Efficacious and Safe Peripheral Blood Stem Cell Mobilizing Regimen in Patients with Hematologic Malignancies

▪Introduction:Collection of adequate numbers of Hematopoietic Stem Cells (HSCs) is a prerequisite for proceeding to autologous bone marrow transplant. However, various studies have showed that approximately 5% to 40% of patients do not meet the minimum threshold of 2×106 CD34+ cells/kg that is associated with timely engraftment and better outcomes. There is little consensus over the optimal mobilization regimen for procurement of peripheral blood CD34 + stem cells (PBSCs). Studies comparing mobilization using high-dose cyclophosphamide(HD-CY) {5-7 g/m2} or intermediate dose cyclophosphamide (ID-CY) {3-4g/m2} plus G-CSF with low dose cyclophosphamide (LD-CY) {1-2g/m2) plus G-CSF have reported higher total PBSC yield with the former but at the cost of higher toxicity [Hiwase et al, Cytotherapy 2007]. Hence the significance of our study to evaluate the efficacy and safety of LD-CY plus G-CSF in the era of novel induction therapies, takes precedence in terms of optimal resource utilization.Methods:We retrospectively analyzed mobilization efficacy and need for supportive care in Myeloma and Lymphoma patients that received LD-CY (2g/m2) plus G-CSF (10µg/kg/day) as the preferred mobilization regimen. Patients treated with novel induction regimens only, with or without radiation were included. LD-CY was given on day 1 with MESNA. G-CSF was started Day +5 from LD-CY and continued until the completion of apheresis. We started to measure peripheral CD34+ (pCD34) when patient's white blood cell count recovered to >1000/µL. When the pCD34 count was ≥10/uL, apheresis was started.Results:Out of 21 patients analyzed, 14 (67%) were Myeloma, predominantly IgG subtype (71%) and 7(33%) Lymphoma predominantly Non-Hodgkins type (71%). Our study population comprised of 53% females, 81% Caucasians with median age of 59 years (30-66). 28.5% patients had radiation treatment in the past. Mean/Median lines of chemotherapy previously received were 2/1 (1-5).71% patients received Lenalidomide (57%) / Thalidomide (14%) based regimens for induction therapies. 52% patients had complete response at the time of chemo mobilization.Successful mobilization (defined as total CD34+ cells collected >2x106/kg) was significantly achieved in 95% patients with mean/ median collection of 12.4/11.5 x106 CD34+ cells/kg (20 out of 21 patients, One sample T- test with significance level, alpha =0.025 [one sided ]showed T statistic 5.36 with p-value <0.0001). First apheresis yielded at least 2 x10 6/kg CD34+ cells in 76 % patients with a mean/median of 5.8/3.8 x106/kg CD34+ cells. 66% of patients were found to be good mobilizers, defined as patients collecting ≥5 x106 CD34+ cells/kg in ≤2 days. 81% patients collected ≥5x106 CD34+ cells/kg and 57 % patients collected ≥10 x106 CD34+ cells/kg. Mean/Median Peak pCD34count was 97.7/60 cells/µL(2-488). Median number of aphereses was 2 (mean 2.6) with the mean and median time to apheresis being 11 days (9-15). None of the patients needed inpatient hospitalization or intravenous antibiotics during mobilization or had any complication related to immunosuppression. 14% and 19% of patients needed packed red blood cell and platelet transfusions respectively during the mobilization period. One Myeloma patient (4.8%) that failed mobilization had previously received five lines of chemotherapy including lenalidomide/thalidomide containing regimens and had stable disease at the time of mobilization. Interestingly, 61% of myeloma patients that successfully mobilized had received lenalidomide containing induction regimen (mean/median no. of cycles- 3.9/4[1-7])Conclusion:Our analysis shows that LD-CY plus G-CSF is efficacious to mobilize sufficient number of stem cells (>2x106 CD34+ cells /kg) in Myeloma and Lymphoma patients treated with novel agents, including the challenging sub-group of lenalidomide treated myeloma patients, with no infectious complications or morbidity noted during the entire period of mobilization. Therefore, we believe LD-CY plus G-CSF may overcome the negative effects of prior lenalidomide exposure on PBSC mobilization [Mark et al, Biol Blood Marrow Transplant 2008] and is superior in terms of optimal resource utilization compared to novel plerixafor based regimens [Chaudhary et al, J Clin Apher 2013]. Prospective studies involving CY based regimens will help elucidate the optimal dose of chemo-mobilization. DisclosuresNo relevant conflicts of interest to declare.

Severe accidental colchicine poisoning by the autumn crocus: A case of successful treatment

The common garden plant autumn crocus contains colchicine and its derivatives. Colchicine poisoning causes abdominal cramps and diarrhea within hours. Several days later, multiorgan failure, pancytopenia, and cardiovascular collapse occur. 1 , 2 Severe colchicine poisoning is associated with high mortality. A 63-year-old woman who accidentally ingested an autumn crocus, which contained ∼0.38 mg colchicine, had severe vomiting and was taken to an emergency center. She presented with symptoms of gastroenterocolitis within 1 hour of ingestion, and bone marrow hypoplasia with pancytopenia developed on the 3 rd day after ingestion. We continued administration of granulocyte colony-stimulating factor (300 μg) for 5 days until we confirmed that the patient's white blood cell count was increasing. Also, there was focal and segmental intestinal ischemia and some cakes of charcoal remained in the intestinal tract. Therefore, we presumed that nonocclusive mesenteric ischemia was caused by hypotension with severe dehydration, although pseudo-obstruction due to the activated charcoal may have been a contributing factor. We were able to promptly intervene to treat paralytic ileus and gastrointestinal edema before anticipated worsening of abdominal compartment syndrome, by conducting open peritoneal drainage. Despite severe poisoning, our patient survived with intensive care. Conclusion: Colchicine intoxication may lead to a sudden and extreme critical course. Therefore, as there is no means to predict prognosis from initial severity of symptoms at onset, we suggest that all patients suspected of colchicine intoxication should be managed in hospital with continuous vital sign monitoring and frequent laboratory testing for at least a few days after ingestion.

A case of acquired immunodeficiency syndrome with ileocecal ulcer

We report a case of a patient with acquired immunodeficiency syndrome (AIDS) and ileocecal ulcer. A 31-year-old man was admitted with chief complaints of decreased body weight and abdominal pain. Colonoscopy revealed a round punched-out ulcer on the ileocecal valve. Initially, we suspected entero-Behçet's disease and simple ulcer as the cause of the ileocecal ulcer. However, after histologic examination of tissue biopsies obtained during colonoscopy, we diagnosed the patient as having cytomegalovirus (CMV) enteritis. Based on the patient's white blood cell depletion and CMV enteritis, we performed a human immunodeficiency virus (HIV) antibody test. The test was positive, and the diagnosis of AIDS was established. The number of patients with AIDS has been increasing in Japan; thus, we should consider the possibility of CMV enteritis and AIDS in young adult patients affected by ileocecal ulcer with no notable history.

Cellular immunotherapy of chronic inflammation and autoimmunity using autologous antigen-specific T regulatory (Treg) cells

Among the most innovative immunotherapies, autologous cellular immunotherapy aims at treating patients with their own immune cells that, before reinjection, have been educated ex vivo to fight disease. Antigen-specific regulatory T cells (Ag-Treg) are recognized as a promising tool for therapeutic intervention in patients with chronic inflammation and autoimmunity. Ovasave ® is an autologous ovalbumin-specific Treg (Ova-Treg) product that is in development for the treatment of severe Crohn's disease patients refractory to available treatments. Ovasave ® has shown a good tolerability and dose-related efficacy in a first-in-man open-labeled phase I/IIa study in refractory Crohn's disease patients. In this study, a 75% response rate and a 38% remission rate on the CDAI (Crohn's Disease Activity Index) were observed at the best dose. In addition, clinical response was correlated with a decrease in vitro proliferation of patient's white blood cells in response to ovalbumin, indicating that decreased proliferation to Ag-Treg specific antigen could be used as a biomarker of clinical response. A randomized controlled phase IIb clinical study with Ovasave will start mid-2014 to confirm the efficacy and tolerability of Ovasave ® in refractory's Crohn's disease patients. Ag-Treg manufacturing has been developed to be highly cost-effective and logistically simple: multiple years of treatment doses are manufactured by one processing from one blood sample. Ovasave ® is the lead product from TxCell's ASTrIA platform Ag-Treg products. From this platform, Col-Treg, an autologous collagen-II specific based product is in the final preclinical stage of development for the treatment of patients with autoimmune uveitis, an orphan chronic inflammatory condition of the eye, with a phase I/IIa clinical study planned for 2015. With Ovasave ® and Col-Treg as novel, personalized cellular immunotherapies for chronic autoimmune inflammatory diseases, Ag-Tregs represent a new therapeutic opportunity for patients who today have few or no treatment options.

Congenital Leukemia Presenting as Fever in a Neonate

BackgroundEmergency department workup of pediatric fever typically focuses on ruling out serious bacterial infection, but other disease processes can cause fever. Congenital leukemia is a rare but important cause of fever in neonates. We review the presentation, pathophysiology, and potential complications of congenital leukemia presenting to the emergency department as pediatric fever. Case ReportWe report a case of a 4-week-old infant brought to the emergency department for fever and “not acting normally.” Complete blood count demonstrated hyperleukocytosis. Subsequent bone marrow biopsy and flow cytometry confirmed the diagnosis of congenital leukemia. The extreme elevation of the patient's white blood cell count put her at high risk for complications, necessitating aggressive treatment, close monitoring, and appropriate consultation for comprehensive care. Why Should an Emergency Physician Be Aware of ThisCongenital leukemia is a rare but serious cause of neonatal fever. While the workup for fever without a source in young pediatric patients primarily focuses on ruling out serious bacterial illness, emergency physicians must be familiar with other potentially life-threatening causes of this complaint.

Enzyme Replacement Therapy With Elosulfase Alfa Decreases Storage of Glycosaminoglycan in White Blood Cells of Patients With Morquio A Syndrome

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disorder caused by a deficient N-acetylgalactosamine-6-sulfate sulfatase activity, leading to cellular storage of undegraded keratan sulfate. Recently enzyme replacement therapy (ERT) was approved for MPS IVA, but some of ERT effects are still unknown. In the present study, we aimed to evaluate the efficacy of elosulfase alfa upon glycosaminoglycan (GAG) storage in peripheral blood white blood cells of patients with MPS IVA treated for 6 months, comparing samples from patients who received weekly infusions of enzyme (ERT-W) versus infusions every other week (ERT-EOW) versus placebo. A significant reduction in GAG storage was observed in both ERT-treated groups, with weekly ERT showing slightly better performance than ERT-EOW.

Androgen receptor mutations and polymorphisms in African American prostate cancer.

The Androgen receptor (AR) plays a central role in the normal development of the prostate gland, in prostate carcinogenesis, and in the progression of prostate cancer (PCa) to advanced metastatic disease. African American (AA) men with PCa present with higher tumor volume, more advanced tumor stage, and higher Gleason score. This could be in part related to the AR expression or activity in the prostate tissue of AA men, or to unique mutations or polymorphisms of the AR. In Caucasian Americans (CAs), AR mutations are rare or infrequent in organ-confined tumors, but occur at a higher rate in advanced, metastatic, or castrate-recurrent disease. In AAs, the prevalence, clinical, and biological significance of AR mutations in PCa are unknown. In this study, we investigated the occurrence of somatic and germline AR mutations in patients with primary PCa in AAs compared with CAs. Due to very limited data available on allelic distribution of E213 (G/A) single nucleotide polymorphism (SNP), we also assessed this in patients with sporadic PCa and in unrelated healthy individuals from both ethnic populations. Somatic missense AR mutations were detected at a higher rate in AAs (17 out of 200 cases) than in CAs (2 out of 100 cases). In AAs, the majority of these mutations (41.1%) were from Gleason 7 tumors, a small portion (23.5%) from Gleason 8 tumors, and the rest (35.2%) from Gleason 6 tumors. Analysis of genomic DNAs extracted from white blood cells of patients with sporadic PCa revealed that the rate of germline AR mutations were also higher (~4 times) in AAs than in CAs. With respect to E213 (G/A) SNP, the E213 A-allele expression was 5.85 times higher in healthy unrelated AA men than in CA men. However, in AAs with somatic AR mutation, the E213 G-allele distribution was almost equal to the A-allele. Silencing of one of the somatic AR mutations (i.e., 597 Ser>Gly) in a primary AA-PCa cell line (e.g., E006AA) revealed that similar AR mutation can be associated simultaneously with both “gain-of-function” phenotype (cell migration and invasion) and a “loss-of-function” phenotype (proliferation). Our data demonstrated a higher susceptibility for genetic alterations in the AR in the form of somatic mutations in sporadic PCa or in the form of germline mutations in AAs as compared with CAs. These data may support the idea that AR-specific hypermutator phenotype in combination with other genes, might serve as a contributing factor to ethnic differences in PCa and potentially different clinical outcome in AAs as a high-risk population.

Marked efficacy of multimodality therapy for ureteral cancer producing granulocyte colony-stmimulating factor

A 69-year-old man was admitted with the chief complaint of macroscopic hematuria. Computerized tomography (CT) and ureteroscopy showed right ureter cancer. Right nephroureterectomy and partial cystectomy were performed. Histological examination revealed urothelial carcinoma of ureter (Grade3, pT3, INFbeta, ly1). The patient underwent two courses of adjuvant chemotherapy with gemcitabine and cisplatin. Three months later, abdominal CT showed a mass in his right obturatorius area. The patient's white blood cell count was 34,140 cells/microl. Additionally serum analysis revealed high value of granulocyte colony stimulating factor (G-CSF), 596 pg/ml with no obvious focus. After being diagnosed with recurrent ureteral cancer producing G-CSF, the patient underwent secondary chemotherapy with gemcitabine and docetaxel. After three courses of chemotherapy, CT revealed a marked decrease in tumor size, and the value of G-CSF declined at 31 pg/nl. Subsequently, radiotherapy (60 Gy) was administered. The patient has been alive for 16 months.

Subtypes of White Blood Cells in Patients with Prostate Cancer or Benign Prostatic Hyperplasia and Healthy Individuals

This study aimed to evaluate the baseline white blood cell (WBC), neutrophil, lymphocyte, monocyte, basophil, eosinophil count, total prostate-specific antigen (TPSA), free PSA (FPSA) level, neutrophil- to-lymphocyte and neutrophil-to-monocyte ratios among patients with prostate cancer and benign prostatic hyperplasia (BPH), as well as healthy individuals. 2005-2012 laboratory files of 160 patients with prostate cancer at Kayseri Training and Research Hospital, Oncology Outpatient Clinic, 285 patients who were pathologically diagnosed with BPH in Urology Outpatient Clinic and 200 healthy individuals who were admitted to Internal Medicine Outpatient Clinic were retrospectively analyzed. Baseline WBC, neutrophil, lymphocyte, monocyte, basophil, eosinophil count, TPSA, FPSA level, neutrophil-to-lymphocyte ratio and neutrophil-to-monocyte ratio were recorded and compared across groups. Patients with prostate cancer had a lower lymphocyte level compared to the patients with BPH and healthy controls (p<0.001). The mean monocyte count, leukocyte-to-monocyte ratio, and leukocyte-to-lymphocyte ratio were higher in patients with prostate cancer, but without significance. The mean WBC and leukocyte count were lower in patients with prostate cancer, but again without statistical significance (p=0.130). The mean TPSA and FPSA were 39.4 and 5.67, respectively in patients with prostate cancer, while they were 5.78 and 1.28 in patients with BPH. There was a significant difference in the mean TPSA and FPSA levels between the patient groups (p<0.001). Our study results showed that patients with prostate cancer had a lower level of lymphocytes, neutrophils and WBCs and a higher level of monocytes with a significant difference in lymphocyte count, compared to healthy controls. We suggest that lymphocyte count may be used in combination with other parameters in the diagnosis of prostate cancer, thanks to its ease of assessment.

Dipeptidyl peptidase IV: serum activity and expression on lymphocytes in different hematological malignancies

The aim of this research was to determine the serum dipeptidyl peptidase IV (DPPIV) activity as well as the percentages of CD26 + lymphocytes and CD26 + overall white blood cells in patients with hematological malignancies: non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), leukemia, plasmacytoma and multiple myeloma, and in healthy individuals. Data from our study showed significantly decreased serum DPPIV activity and a significant decrease in the percentage of: CD26 + lymphocytes, CD26 + overall white blood cells and lymphocytes in patients with NHL in comparison to healthy controls. Patients with leukemia had a statistically significant lower activity of DPPIV in serum and significant decrease in the percentage of CD26 + lymphocytes in relation to healthy controls. Furthermore, significantly decreased DPPIV serum activity associated with a significantly reduced percentage of CD26 + overall white blood cells and percentage of lymphocytes was found in patients with multiple myeloma when compared to the healthy control group. The obtained results indicate that immune disturbances that can occur in hematological malignancies might be related to the decreased expression and activity of CD26/DPPIV that we observed.

Use of CXCR4-antagonist for haematopoietic stem cell mobilization in HIV-infected patients with haematological malignancies

Use of CXCR4-antagonist for haematopoietic stem cell mobilization in HIV-infected patients with haematological malignancies

The alteration of hypoxia inducible factor-1 (HIF-1) and its target genes in mood disorder patients

Recent studies suggest that the dysfunction of neural plasticity is associated with mood disorders. Hypoxia-inducible factor-1 (HIF-1), which is a transcriptional activator of vascular endothelial growth factor (VEGF), activates the cellular response to hypoxia. HIF-1 is ubiquitously expressed in all cells, including peripheral leukocytes. However, little is known about the role of HIF-1 in mood disorder. In the present study, we investigated the mRNA expression levels of HIF-1 (α and β) and its target genes (VEGF, GLUT1, PGK1, PFKFB3, and LDHA) in the peripheral white blood cells of patients with major depressive disorder (MDD) and bipolar disorder (BPD). We found increased expression of HIF- 1α and HIF-1β mRNA, as well as the target genes, VEGF, and PFKFB3 in both MDD and BPD patients in a depressive state compared to healthy control subjects. Furthermore, the mRNA expression levels of GLUT1, PGK1, and LDHA were increased in MDD patients in a depressive state compared to healthy control subjects. We also found increased expression of HIF-1α and LDHA mRNA in MDD patients in a remissive state, whereas the mRNA expression levels of other genes in a remissive state were comparable to those in healthy control subjects. There was no significant difference in mRNA expression levels of the genes examined among patients receiving any type of antidepressant or mood stabilizer. Our data suggest that altered expression of HIF-1 and its target genes mRNA in peripheral blood cells are associated-mainly in a state-dependent manner-with mood disorders (especially with MDD). In addition, altered expression of HIF-1 and its target genes may be associated with the pathophysiology of depression.

Peripheral Blood Levels of Matrix and Inflammatory Mediators are Elevated in Tunisian Patients with Acute Coronary Syndromes

The aim of the present study was to investigate differences of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in the peripheral blood of patients admitted with acute coronary syndrome (ACS), in correlation with the widely accepted markers of inflammatory activity, C-reactive protein, fibrinogen, and white blood cell number. 315 patients with ACS (165 unstable angina pectoris/non-ST-elevation myocardial infarction, 150 ST-elevation myocardial infarction), 111 stable angina (SA) patients, and 296 control subjects were enrolled in the study. All biochemical analyses were carried out using a Hitachi 912 analyzer (Roche). Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were determined in citrate plasma by ELISA methods. White blood cells (WBC) and fibrinogen were also determined. The plasma concentrations of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, C-reactive protein, fibrinogen, and white blood cells in patients with acute coronary syndrome were significantly elevated compared to the control group (p < 0.001). MMP-9/TIMP-1 ratio was significantly higher in SA and ACS patients (p < 0.001) than controls. Strong positive associations were observed between MMP-9 and TIMP-1 (r = 0.213, p < 0.01), MMP-9 and CRP (r = 0.103, p < 0.01), MMP-9 and fibrinogen (r = 0.299, p < 0.01), MMP-9 and WBC (r = 0.135, p < 0.01), TIMP-1 and CRP (r = 0.219, p < 0.01), TIMP-1 and Fibrinogen (r = 0.226, p < 0.01), TIMP-1 and WBC (r = 0.094, p < 0.1), CRP and fibrinogen (r = 0.158, p < 0.01), CRP and WBC (r = 0.156, p < 0.01, and finally between fibrinogen and WBC (r = 0.234, p < 0.01) in the patients with ACS. In conclusion, our observations suggest that ACS shows an increase in both remodeling and inflammation markers. In addition, the strong relationship with MMP-9 and inflammatory mediators such as CRP, fibrinogen, and WBC in ACS patients suggests that MMP-9 might be an additional marker and/or consequence of inflammatory components in ACS.

Leukopenia associated with long-term colchicine administration

A case of leukopenia in a patient receiving colchicine for calcium pyrophosphate dihydrate deposition disease, or pseudogout, is reported. An 85-year-old man experienced leukopenia likely due to colchicine. His medical history included chronic lymphocytic leukemia (CLL), pseudogout, osteoarthritis, and hypertension. In February 2011, his white blood cell (WBC) count was 2700 cells/μL, and his absolute neutrophil count (ANC) was 2200 cells/μL. Colchicine 0.6 mg orally daily was initiated in March for the prophylaxis of pseudogout. His WBC count decreased, and his colchicine dosage was reduced to 0.6 mg every other day. Despite this decreased dosage, his WBC count and ANC were 600 and 100 cells/μL, respectively, in September. In October, the patient received chemotherapy for presumed worsening of his CLL. One month later, his WBC count and ANC were 400 and 200 cells/μL, respectively. Subcutaneous filgrastim was administered, and colchicine was discontinued. At the end of November, he received another cycle of chemotherapy followed by pegfilgrastim. On the day of pegfilgrastim administration, the patient's WBC count and ANC were 2000 and 1300 cells/μL, respectively. Two weeks later, his WBC count was 8800 cells/μL, and his ANC was 8300 cells/μL. Daily colchicine was restarted at the end of December. Two months later, his WBC count and ANC were 800 and 500 cells/μL, respectively. Given the symptomatic relief with colchicine, therapy was continued with close monitoring. A patient with CLL developed leukopenia in association with colchicine administration for pseudogout.

CD59 Deficiency Is Associated with Chronic Hemolysis and Childhood Chronic Immune Mediated Neuropathy

Abstract 3187CD59 deficiency is a common finding in red and white blood cells in patients with chronic hemolysis suffering from paroxysmal nocturnal hemoglobinuria (PNH) where acquired mutation in the PIGA gene leads to membrane loss of GPI-anchored membrane proteins, including CD59. The current study objective was the elucidation of the molecular basis of childhood familial chronic Coombs' negative hemolysis and relapsing polyneuropathy, mimicking chronic inflammatory demyelinating polyradiculoneuropathy in infants of North-African Jewish origin from four unrelated families. A founder mutation was searched using homozygosity mapping followed by exome sequencing. The expression of CD59, CD55 and CD14 was examined in blood cells by flow cytometry followed by western blot of the CD59 protein. A homozygous missense mutation in CD59, was identified in all the patients. The mutation segregated with the disease in the families and had a carrier rate of 1:66 among Jews of North-African origin. The mutated protein was present in the patients' cells in normal amount but was undetectable on the membrane surface.Conclusion: This is the first clinical and molecular characterization of a novel clinical syndrome. CD59 mutation is associated with a failure of proper localization of CD59 protein in the cell surface. This is clinically manifested in infancy by chronic hemolysis and relapsing peripheral demyelinating disease. Disclosures:No relevant conflicts of interest to declare.

Novel aspects of Kindlin‐3 function in humans based on a new case of leukocyte adhesion deficiency III

Kindlin-3 is a novel integrin activator in hematopoietic cells, and its deficiency leads to immune problems and severe bleeding, known as leukocyte adhesion deficiency III (LAD-III). Our current understanding of Kindlin-3 function primarily relies on analysis of animal models or cell lines. To understand the functions of Kindlin-3 in human primary blood cells. We analyzed primary and immortalized hematopoietic cells obtained from a new LAD-III patient with immune problems, bleeding, a history of anemia, and abnormally shaped red blood cells. The patient's white blood cells (WBCs) and platelets showed defects in agonist-induced integrin activation and botrocetin-induced platelet agglutination. Primary leukocytes from this patient exhibited abnormal activation of β(1) integrin. Integrin activation defects were responsible for the observed deficiency in the botrocetin-induced platelet response. Analysis of patient genomic DNA revealed a novel mutation in the Kindlin3 gene. The mutation abolished Kindlin-3 expression in primary WBCs and platelets, owing to abnormal splicing. Kindlin-3 is expressed in red blood cells (RBCs), and its deficiency is proposed to lead to abnormally shaped RBCs. Immortalized patient WBCs expressed a truncated form of Kindlin-3 that was not sufficient to support integrin activation. Expression of Kindlin-3 cDNA in immortalized patient WBCs rescued integrin activation defects, whereas overexpression of the truncated form did not. Kindlin-3 deficiency impairs integrin function, including activation of β(1) integrin. Abnormalities in glycoprotein Ib-IX function in Kindlin-3-deficient platelets are secondary to integrin defects. The region of Kindlin-3 encoded by exon 11 is crucial for its ability to activate integrins in humans.

Granulocyte colony-stimulating factor-producing squamous cell carcinoma of the lower gingiva: a case report

The present study summarizes our experience in treating a patient with a suspected granulocyte colony-stimulating factor (G-CSF)-producing squamous cell carcinoma (SCC) of the lower gingiva, which is a rather rare entity.A 56-year-old woman underwent surgical excision of palate leukoplakia in 1996. In 2009, however, a leukoplakic superficial tumor was detected in the lower left gingiva, for which the patient underwent gingivectomy. This was subsequently diagnosed as SCC. The patient also underwent superselective arterial injection chemotherapy combined with radiotherapy, after local recurrence was observed. The patient was subsequently found to have bone metastasis. After chemotherapy combined with radiotherapy, the patient underwent segmental resection of the lower left jaw, left supraomohyoid neck dissection, and lower jaw reconstruction using titanium plates. Resection of the left femoral tumor and left total knee replacement were also performed. Computed tomography scan performed 1 month after the surgeries revealed multiple lung, liver, spine, and subcutaneous metastases. The patient also exhibited a sudden increase in her white blood cell (WBC) count and a fever that could not be alleviated, despite treatment with antibacterial drugs. A G-CSF-producing tumor was therefore suspected. Serum G-CSF level was high at 250 pg/ml.The patient's WBC count increased to 32 × 103/ml and her general condition suddenly deteriorated, and she died as a result of multiple organ failure. A final diagnosis of G-CSF-producing SCC of the lower gingiva was made based on the patient's clinical course.

Probable rifaximin-induced neutropenia

The development of neutropenia in a patient treated with rifaximin is reported. A 45-year-old Caucasian woman with severe ulcerative colitis arrived at the emergency department with complaints of worsening abdominal pain, nausea, and vomiting and was found to have extensive portal vein and superior mesenteric vein thrombosis with additional thrombi in the distal aortic and left common iliac arteries on an abdominal computed tomography angiography scan. A heparin i.v. drip was started, and the following day the patient underwent thrombectomy and thrombolysis with tissue plasminogen activator of the superior mesenteric vein thrombus. Secondary to rectal bleeding and a decrease of approximately 2 g in the patient's hemoglobin concentration while receiving heparin, the decision was made to forego additional use of tissue plasminogen activator for the portal vein thrombosis, and a transjugular intrahepatic portosystemic shunt (TIPS) procedure was performed to improve portal blood flow. After consultation with the gastroenterology and hepatology departments, the decision was made to initiate rifaximin 400 mg orally every eight hours for the prevention of hepatic encephalopathy after the TIPS procedure. The patient's white blood cell (WBC) count was 6800/μL on the day of rifaximin initiation. On day 4 of rifaximin treatment, the patient's WBC count reached its nadir at 1200/μL. The primary internal medicine team then decided to discontinue rifaximin therapy. During this time, the patient showed no other signs of infection. The patient's WBC count rebounded to 3300/μL three days after discontinuation of rifaximin therapy. A 45-year-old Caucasian woman with severe ulcerative colitis developed neutropenia after the initiation of rifaximin.