The Clinical, Immunohematological, and Molecular Study of Iranian Patients with Severe Congenital Neutropenia

Severe congenital neutropenia (SCN) is a rareE primary immunodeficiency disorder characterized by early onset recurrent infections in association with persistent severe agranulocytosis. To identify the clinical, immunohematological, and molecular characteristics of patients with SCN, 18 Iranian patients with the mean age of 8.8 ± 5.8 years were investigated in this study. All of these patients experienced severe neutropenia; the mean of absolute neutrophil count was 281.4 ± 137.7 cells/mm³. Bone marrow findings were typified by a myeloid maturation arrest at the promyelocyte–myelocyte stage in these patients. Molecular analysis revealed different mutations in the ELA-2 gene of one patient and in the HAX-1 gene of another three patients. The most common presenting complaints in these patients were superficial abscesses, oral ulcers, cutaneous infections, omphalitis, and pneumonia. During the course of illness, all patients developed mucocutaneous manifestations, and 16 cases had respiratory infections. The most commonly manifestations were abscesses, oral ulcers, pneumonia, periodontitis, otitis media, cutaneous infections, mucocutaneous candidiasis, and acute diarrhea. Three patients died because of a severe infection. Although SCN is a rare disorder, early onset of severe and recurrent infections should always raise a suspicion, which deserves further evaluation for detecting such disorder.     

The Clinical Spectrum of Leukocyte Adhesion Deficiency (LAD) III due to Defective CalDAG-GEF1

Introduction  Leukocyte adhesion deficiency (LAD) type III is a rare syndrome characterized by severe recurrent infections, leukocytosis, and increased bleeding tendency. All integrins are normally expressed yet a defect in their activation leads to the observed clinical manifestations. Materials and Methods  Less than 20 patients have been reported world wide and the primary genetic defect was identified in some of them. Here we describe the clinical features of patients in whom a mutation in the calcium and diacylglycerol-regulated guanine nucleotide exchange factor 1 (CalDAG GEF1) was found and compare them to other cases of LAD III and to animal models harboring a mutation in the CalDAG GEF1 gene. Discussion  The hallmarks of the syndrome are recurrent infections accompanied by severe bleeding episodes distinguished by osteopetrosis like bone abnormalities and neurodevelopmental defects.     

Frequency and Clinical Manifestations of Patients with Primary Immunodeficiency Disorders in Iran: Update from the Iranian Primary Immunodeficiency Registry

Primary immunodeficiency disorders (PID) are a heterogeneous group of diseases, characterized by an increased susceptibility to infections. A total of 930 patients (573 males and 357 females) are registered in Iranian PID Registry (IPIDR) during three decades. Predominantly antibody deficiencies were the most common (38.4%), followed by congenital defects of phagocyte number and/or function (28.3%), other well-defined immunodeficiency syndromes (17.7%), combined T- and B-cell immunodeficiencies (11.0%), complement deficiencies (2.4%), and diseases of immune dysregulation (2.3%). Common variable immunodeficiency was the most frequent disorder (20.8%), followed by chronic granulomatous disease, ataxia-telangiectasia, btk deficiency, selective IgA deficiency, and T-B-severe combined immunodeficiency. The frequency of other PID disorders was less than 50 in number (<5%). There is an increasing trend in recognition of more PID in the recent years. Construction of such registry is not only important for its epidemiological aspect but also for its role in increasing the physician's knowledge about such disorders.     

怡开对白细胞粘附和血液流变性影响的研究

目的 :深入探讨怡开改善微循环及血液流变学的作用机理。方法 :利用活体肠系膜微循环观察、血液粘度和红细胞变形性测定方法。结果 :对照组用内毒素后明显引起静脉内白细胞粘附、游出和血小板聚集 ,血流减慢 ,内皮水肿、内皮细胞间间隙增大、血管内皮损伤、出血等对血管内皮有明显的损伤作用。用PK预防的大鼠明显减轻内毒素引起的白细胞粘附、游出和血小板聚集 ,未见血管内皮水肿和血栓形成 ,出血比对照组轻。结论 :用PK预防的大鼠能明显减轻白细胞粘附、游出和血小板聚集等 ,减轻血管内皮水肿和血栓形成 ,对血管内皮的损伤有一定预防作用     

18例儿童特发性肺含铁血黄素沉着症的临床分析

目的 探讨儿童特发性肺含铁血黄素沉着症（IPH）的临床特点。方法 结合以前相关研究对确诊为IPH的18例患儿的临床表现、治疗及预后进行分析。结果 IPH好发于学龄前儿童,主要症状为面色苍白、咳嗽及咯血等,主要体征为呼吸音增粗。糖皮质激素治疗能有效改善患儿的症状,减轻肺部病变。结论 IPH临床表现多样,易被漏诊,长疗程激素治疗是本病治疗的重要方法。     

The prevalence of Selective Immunoglobulin M Deficiency (SIgMD) in Iranian volunteer blood donors

BackgroundSelective Immunoglobulin M Deficiency (SIgMD) is known as a rare primary immunodeficiency characterized by an isolated deficiency of serum IgM. Other immunoglobulin levels and T-cell immunity are usually normal; although IgE may be elevated. SIgMD can be asymptomatic or with various bacterial and viral infections. It can also be associated with autoimmune diseases or malignancies. In the present study, we report for the first time, the prevalence of SIgMD in Iranian healthy adult population.Materials and MethodsA total of 3436 healthy donors were examined in the study; from August, 2006 to April, 2008. Serum IgM concentration was measured using the nephelometric method. We considered serum IgM less than 30 mg/dl as IgM deficiency.ResultsAmong 3436 participants, 65% were male and 34% were female; aging from 17 to 72 years (38.18 ± 10.78). Thirteen individuals were detected as IgM deficient subjects with the male to female ratio of 11/2, the prevalence of 0.37% and the frequency of 1/265. The mean serum IgM level was 24 ± 4.56 (16–29 mg/dl) in these cases. Among 13 IgM-deficient subjects, 7 cases were available for evaluating the clinical manifestations. In addition to atopic dermatitis which was the most common symptom in these patients, others were allergic rhinitis, food allergy, urinary tract infection and skin fungal infection. Two patients had no history of infectious disease or atopic conditions.ConclusionIn the present study we could determine the prevalence of SIgMD in our adult population (0.37%). The most common comorbid condition was atopy. Neither severe or life-threatening infections, nor autoimmune diseases (based on their history; the antibody screening was not performed as part of this study) or malignancies were found in these patients. Further evaluation is recommended to elucidate the prevalence of SIgMD among patients with recurrent infections.     

sICAM-1和PCT在急性胰腺炎诊治中的临床价值

目的：探讨细胞间黏附分子-1（sICAM-1）和降钙素原（PCT）水平在急性胰腺炎（AP）发病中的作用及诊断意义。方法：将77例急性胰腺炎（AP）患者分为轻型急性胰腺炎（MAP）31例,重症型急性胰腺炎（SAP）46例,并对SAP按有无感染分为SAP-1（感染性）25例和SAP-2（非感染性）21例;分别取其7d内的空腹静脉血,用ELISA测定血清sICAM-1水平,用双抗体夹心化学发光法测定血清PCT水平,并与正常对照组进行比较。结果：SAP-1和SAP-2组的sICAM-1水平高于MAP组,差异有统计学意义（P〈0.01）,所有的AP患者与正常对照组比较,也存在显著差异;SAP-1组的PCT水平与MAP组、SAP-2组和正常对照组比较,差异有统计学意义（P〈0.01）。结论：sICAM-1和PCT的水平变化与AP的发生、发展过程密切相关,认为其可以作为AP早期诊断及预后判断有价值的指标。     

Deficiency of Biotinyl-AMP Synthetase Activity in Fibroblasts of Patients with Holocarboxylase Synthetase Deficiency

A simple, rapid assay was developed to diagnose holocarboxylase synthetase deficiency. Holocarboxylase synthetase first catalyzes the formation of biotinyl-AMP from biotin and ATP, an activity designated as biotinyl-AMP synthetase. In the second step of the reaction, biotin is transferred from biotinyl-AMP to the enzymatically inactive apocarboxylase to form an active holocarboxylase. The assay for holocarboxylase synthetase activity therefore requires a protein apocarboxylase substrate which is not readily available. In the assay for biotinyl-AMP synthetase, hydroxylamine reacts nonenzymatically with the product of the enzymatic reaction, biotinyl-AMP, to form biotinylhydroxamate. At the end of the reaction, unreacted radioactive biotin substrate, which is negatively charged at neutral pH, is bound to an anion-exchange resin and a neutral radioactive biotinylhydroxamate product in the supernatant is counted. In fibroblasts from 11 patients with proven holocarboxylase synthetase deficiency, the mean biotinyl-AMP synthetase activity at 25 nM biotin was 4% of the control mean with a range of 0.2 to 8%. This is an improved assay because it does not require preparation of an apocarboxylase substrate and is suitable for the diagnosis of patients with holocarboxylase synthetase deficiency.     

Characterization of 11 New Cases of Leukocyte Adhesion Deficiency Type 1 with Seven Novel Mutations in the ITGB2 Gene

Background

Leukocyte adhesion deficiency type 1 (LAD I) is an autosomal recessive disorder caused by mutations in the ITGB2 gene, encoding the β2 integrin family. Severe recurrent infections, impaired wound healing, and periodontal diseases are the main features of disease.

Methods

In order to investigate clinical and molecular manifestations of new LAD I cases, 11 patients diagnosed in one center during 7 years were studied. Patients were screened for the ITGB2 gene mutations, using polymerase chain reaction, followed by single-strand conformation polymorphism and sequencing.

Results

The most common first presenting feature of the patients was omphalitis. The mean age of cord separation was 19.9?±?1 days. The most common clinical manifestations of the patients during the follow-up period included omphalitis, skin ulcers with poor healing, sepsis, and otitis media. During the follow-up, eight patients died. Eight homozygous changes, including seven novel mutations, were detected: two splicing (IVS4?6C>A, IVS7+1G>A), three missense (Asp128Tyr, Ala239Thr, and Gly716Ala), and three frameshift deletions (Asn282fsX41, Tyr382fsX9, and Lys636fsX22).

Conclusion

Our results indicate that different mutations underlie the development of LAD I. Definitive molecular diagnosis is valuable for genetic counseling and prenatal diagnosis. Regarding clinical presentations, it seems that omphalitis is the most consistent finding seen in LAD I infants.     

Mutation spectra of the ITGB2 gene in Iranian families with leukocyte adhesion deficiency type 1

Leukocyte adhesion deficiency type 1 (LAD1) is an autosomal recessive disorder clinically characterized by severe, recurrent bacterial infections, impaired pus formation and wound healing. It is caused by mutation in the ITGB2 gene, encoding the β₂ integrin subunit of the leukocyte adhesion cell molecule. This study aimed to identify disease causing mutations in 19 consanguineous families diagnosed with LAD1.Blood samples were collected after informed and written consent was obtained. Genomic DNA was extracted from peripheral blood of patients and their parents. PCR amplification of the ITGB2 gene was done using specific primers followed by sequencing for mutation detection.A total number of 14 alterations scattered throughout the ITGB2 gene were ascertained in which 10 mutations were previously reported, including c.329−6C>A, c.382G>T, c.715G>A, c.843delC, c.897+1G>A, c.1062A>T, c.1143delC, c.1877+2T>C, c.1907delA and c.2147G>C. Four novel likely pathogenic mutations consisting of c.576dupC (Asn193GlnfsX72), c.706G>A (Gly236Arg), c.897+1G>T and c.1030G>T (Glu344¹), were identified. The majority of these mutations were located in exon six, suggesting this exon as a hotspot region probably.This study emphasis on allelic heterogeneity of the ITGB2 gene in Iranian patients diagnosed with LAD1. Our results suggest that every population should develop a mutation database for rare genetic disorders to take advantage in genetic counseling clinic as well as genetic testing for rapid diagnostic purposes.     

Quality of Life and its Related Factors Among Iranian Patients with Metastatic Gastrointestinal Tract Cancer: A Cross-sectional Study

Context:

Quality of life (QoL) is an important issue in all cancer patients; especially in patients with metastatic cancer. But there is very little information available about QoL in patients with metastatic gastrointestinal cancer.

Aims:

The aim of this study was to evaluate the quality of life and its associated factors among Iranian patients with metastatic gastrointestinal tract cancer.

Materials and Methods:

In this cross-sectional study, a total of 250 patients with metastatic gastrointestinal tract cancer were recruited from the one oncology center related to the Mazandaran University of Medical Sciences, Sari, between March 2012 and August 2013. Their QoL was evaluated using the EORTC QLQ-C30 questionnaire (Persian version).

Results:

In this study, the overall QoL score of patients with gastrointestinal tract cancer was 57.63, which was relatively optimal. There was a statistically significant relationship between symptoms scale and general health status domains of quality of life with age (P < 0.05). Also, there was a significant association between patients’ gender and their social functioning (P = 0.017) and also their emotional functioning (P = 0.015).

Conclusions:

The findings suggest that in patients with metastatic gastrointestinal cancers, the most affected functions in their QoL were social and emotional functioning which get worse with age. Thus, providing psychological counseling and psychotherapy services to deliver culturally appropriate mental health care and social support for these patients and their families’ which can lead to the improvement of QoL in these patients is strongly recommended.     

Surface Patterning and Adhesion of Neuroblastoma X Glioma (NG108-15) Cells

A variable height flow cell was used to measure the adhesion properties of the neural cell line of neuroblastoma X glioma (NG108-15) cells cultured on substrates of organosilane self-assembled monolayers (SAMs). The SAMs tested in this study were 13F, 15F, PEG 550, OTS, DETA and APTS. Utilizing deep UV lithography, patterning of the SAMs create three regions for cell attachment; the original SAM, the backfilled SAM, and the interface between the two. Upon plating, the cell soma show no preference for any of the three regions. One exception was on PEG 550, which was found to resist cell adhesion upon normal plating conditions. The cell processes of the NG108-15 cells show a preference for growth at the interface between two patterned surfaces. A factor of three increase in adhesive properties was found for the patterned surfaces over an uncoated glass surface. Design rules of a single whole cell biosensor using the NG108-15 cells can be developed based on these findings.     

Function of Junctional Adhesion Molecules (JAMs) in Leukocyte Migration and Homeostasis

Homeostasis is a word widely used in the scientific community to refer to the property of a system to maintain its uniformity and functionality. In living organisms, the word refers to the concept enunciated 150 years ago by C. Bernard by which external variations must be compensated for in order to maintain internal conditions compatible with life. This is especially true in the case of highly dynamic system such as the hematopoietic system that requires the coordinated control of cell proliferation and death within specialized microenvironments that are anatomically distinct. As a consequence, hematopoietic cell adhesion and migration must be tightly controlled in order for hematopoietic cells to reach and to be maintained in appropriate microenvironments. The junctional adhesion molecules (JAMs) are adhesion molecules that belong to the immunoglobulin superfamily (IgSf) and that have been initially identified as important players controlling vascular permeability and leukocyte transendothelial migration. This involves the regulated localization of the JAMs at lateral endothelial cell/cell borders and their interaction with leukocyte integrins. More recently, some of the JAM family members have also been found to be expressed by stromal cells and to regulate chemokine secretion within lymphoid organs, acting not only on leukocyte transendothelial migration, but also on hematopoietic cell retention within specialized microenvironments. This review summarizes recent progress in understanding the role of the JAMs in leukocyte adhesion and migration to tentatively draw an integrated view of the homeostatic function of the JAMs within the hematopoietic system.     

Isolation of a type 3 vaccine-derived poliovirus (VDPV) from an Iranian child with X-linked agammaglobulinemia

Type 3 immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) were isolated from a 15-month-old Iranian boy with acute flaccid paralysis (AFP) who was subsequently diagnosed with X-linked agammaglobulinemia (XLA). VP1 nucleotide sequences of the two isolates differed from Sabin 3 by 2.0% and 2.1% and from each other by 0.6%. Although the key determinant of attenuation and temperature sensitivity in the 5'-untranslated region (U(472)-->C) had reverted, a second capsid-region determinant (VP3:Phe(091)) was unchanged, but a presumptive suppressor (VP1:Ala(054)-->Val) was found. The isolates were Sabin 3/Sabin 1 recombinants, sharing a single recombination breakpoint in the 2C region. Although the two isolates were antigenically distinct from Sabin 3, only one amino acid replacement was found in the neutralizing antigenic sites (VP3:Ser(059)-->Asn in site 3). The patient was placed on intravenous immunoglobulin (IVIG) therapy within 9 days of onset of AFP, and iVDPV excretion ceased thereafter, but the patient remained severely paralyzed until his death approximately 11 months after paralysis. No secondary AFP cases were found, and none of the seven tested contacts of the patient were found to be infected with poliovirus.     

Microrheology disorders and their biochemical correlates in patients with diabetes mellitus and initial manifestations of hypertension

Similar disorders in microrheology manifesting in increased rigidity of leukocytes and correlating with high blood levels of globulins and C-reactive protein were detected in patients with diabetes mellitus and initial manifestations of hypertension. It was found that statistical relationships between aggregate properties of erythrocytes and biochemical parameters of the plasma are not universal and depend on the disease. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 2, pp. 148–150, February, 2008     

血栓性疾病患者血浆可溶性细胞间粘附分子1水平与微血栓形成

目的为进一步探讨血栓性疾病患者血流中微血栓形成的发生机理。方法采用酶联免疫吸附（ＥＬＩＳＡ）法,检测４３例血栓性疾病（脑血栓１９例,肺栓塞１７例,下肢静脉血栓７例）患者血浆可溶性细胞间粘附分子１（ｓＩＣＡＭ－１）水平。结果血栓性疾病患者血浆ｓＩＣＡＭ－１水平明显高于正常健康组（白色微小血栓形成组Ｐ<０．０１,单纯红细胞聚集组Ｐ＜０．０５）,尤以白色微小血栓形成组最为显著。结论血栓性疾病患者血浆ｓＩＣＡＭ－１水平与微血栓形成密切相关,因此检测血浆ｓＩＣＡＭ－１水平,对血栓性疾病的早期诊断、疾病预防和药物疗效观察有意义,是一个重要标志物。     

Factor V Deficiency in Korean Patients: Clinical and Laboratory Features,Treatment, and Outcome

Due to rarity of factor V (FV) deficiency, there have been only a few case reports in Korea. We retrospectively analysed the clinical-laboratory features of FV deficiency in 10 Korean patients. Between January 1987 and December 2013, 10 case reports published in a Korean journal or proceedings of Korea Society on Thrombosis and Hemostasis were reviewed. Severity is defined as mild (> 5% of factor activity), moderate (1%–5%), and severe (< 1%). The median age at diagnosis, six males and four females, was 26 years (range, 1 month-73 years). Six of 10 patients were classified as moderate, three as mild, and one as severe disease. Eight patients were diagnosed as inherited FV deficiency. The most frequent symptoms were mucosal tract bleedings (40%) such as epistaxis, and menorrhagia in female. Hemarthroses and postoperative bleeding occurred in one and four patients, respectively. Life-threatening bleeding episodes occurred in the peritoneal cavity (n = 2), central nerve system (n = 1), and retroperitoneal space (n = 1). No lethal haemorrhages happened to patients with mild disease. The majority of bleeding episodes were controlled with local measures and fresh-frozen plasma replacement. Two acquired FV deficient-patients showing life-threatening haemorrhages received the immunosuppressive therapy, but one of them died from postoperative bleeding complications. Despite the small sample size of this study due to rarity of the disease, we found that Korean patients with FV deficiency had similar clinical manifestations and treatment outcomes shown in previous studies.     

2型糖尿病视网膜病变患者血清sVCAM-1水平的变化和意义

研究糖尿病视网膜病变不同时期血清可溶性血管内皮细胞粘附分子-1(sVCAM-1)与视网膜病变严重程度、诊断病程、血清胰岛素和血糖的相关性.采用ELISA法检测85例2型糖尿病视网膜病变患者血清sVCAM-1含量, 由同一眼科医师通过眼底镜或荧光造影检查, 将患者分为无视网膜病变组(NDR)、背景期视网膜病变组(BDR)和增殖期视网膜病变组(PDR).结果显示, 三组糖尿病患者血清sVCAM-1水平均高于对照组, 其中PDR组、BDR组血清sVCAM-1水平与对照组和NDR组比较, 均有显著性差异(P＜0.01), NDR组与对照组比较也存在显著性差异(P＜0.01).糖尿病患者血清sVCAM-1水平与血糖、血清胰岛素、诊断病程均无相关性(P＞0.05).研究表明, 糖尿病视网膜病变不同时期血清sVCAM-1水平的变化可作为判断视网膜病变发展和严重程度的指标, 为临床早期发现和治疗糖尿病视网膜病变提供较好的依据.