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The development of a congenital heart defect (CHD) is multifactorial, with many cases having an unknown etiology. This study explored whether maternal race and lived environment were associated with an infant being born with a critical CHD. A cross-sectional, case-control design was conducted utilizing secondary data analysis. The CHD group (N = 199) consisted of infants diagnosed with a critical CHD within the first year of life identified from hospital databases. The non-CHD group (N = 548) was a random sample of infants selected from the state's vital statistics database. The primary outcome was a critical CHD diagnosis. Maternal race, residential rurality, and the Social Vulnerability Index (SVI) were assessed for associations with a critical CHD using bivariate and multilevel regression models. Bivariate findings reported significance among residential rurality (p < 0.001), SVI ranking overall (p = 0.017), and SVI by theme (theme 1 p =  0.004, theme 2 p < 0.001, theme 3 p = 0.007, and theme 4 p = 0.049) when comparing infants with and without a critical CHD diagnosis. Results of multilevel logistic regression analyses further identified living in a rural residential area compared to urban areas (OR = 7.32; p < 0.001) as a predictor for a critical CHD diagnosis. The findings of lived environmental level associations provides information needed for continued investigation as the burden of a critical CHD continues to impact families, suggesting further research efforts are needed to improve health disparities., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing. PKHD1L1 was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants in PKHD1L1 also cause hearing loss in humans. Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified in PKHD1L1 that were predicted to be damaging using in silico pathogenicity prediction methods. In vitro functional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant. In silico molecular modeling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure. In vitro functional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G>A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids. In silico molecular modeling exposed key structural features that might suggest PKHD1L1 protein destabilization. Multiple lines of evidence collectively associate PKHD1L1 with nonsyndromic mild-moderate to severe sensorineural hearing loss. PKHD1L1 testing in individuals with mild-moderate hearing loss may identify further affected families., (© 2024. The Author(s).)

Currently there is a limited understanding for the optimal combination of immune checkpoint inhibitor and chemotherapy for patients with metastatic triple-negative breast cancer (mTNBC). Here we evaluate the safety, efficacy, and immunogenicity of a phase I trial for patients with mTNBC treated with pembrolizumab plus doxorubicin. Patients without prior anthracycline use and 0-2 lines of prior systemic chemotherapies received pembrolizumab and doxorubicin every 3 weeks for 6 cycles followed by pembrolizumab maintenance until disease progression or intolerance. The primary objectives were safety and objective response rate per RECIST 1.1. Best responses included one complete response (CR), five partial responses (PR), two stable disease (SD), and one progression of disease (PD). Overall response rate was 67% (95% CI 13.7%, 78.8%) and clinical benefit rate at 6 months was 56% (95% CI 21.2%, 86.3%). Median PFS was 5.2 months (95% CI 4.7, NA); median OS was 15.6 months (95% CI 13.3, NA). Grade 3-4 AEs per CTCAE 4.0 were neutropenia n = 4/10 (40%), leukopenia n = 2/10 (20%), lymphopenia n = 2/10 (20%), fatigue n = 2/10 (20%), and oral mucositis n = 1/10 (10%). Immune correlates showed increased frequencies of circulating CD3 + T cells (p = 0.03) from pre-treatment to cycle 2 day 1 (C2D1). An expansion of a proliferative exhausted-like PD-1 + CD8 + T cell population was identified in 8/9 patients, and exhausted CD8 + T cells were significantly expanded from pre-treatment to C2D1 in the patient with CR (p = 0.01). In summary, anthracycline-naïve patients with mTNBC treated with the combination of pembrolizumab and doxorubicin showed an encouraging response rate and robust T cell response dynamics.Trial registration: NCT02648477., (© 2023. The Author(s).)

Cancer immunotherapy relies on improving T cell effector functions against malignancies, but despite the identification of several key transcription factors (TFs), the biological functions of these TFs are not entirely understood. We developed and utilized a novel, clinically relevant murine model to dissect the functional properties of crucial T cell transcription factors during anti-tumor responses. Our data showed that the loss of TCF-1 in CD8 T cells also leads to loss of key stimulatory molecules such as CD28. Our data showed that TCF-1 suppresses surface NKG2D expression on naïve and activated CD8 T cells via key transcriptional factors Eomes and T-bet. Using both in vitro and in vivo models, we uncovered how TCF-1 regulates critical molecules responsible for peripheral CD8 T cell effector functions. Finally, our unique genetic and molecular approaches suggested that TCF-1 also differentially regulates essential kinases. These kinases, including LCK, LAT, ITK, PLC-γ1, P65, ERKI/II, and JAK/STATs, are required for peripheral CD8 T cell persistent function during alloimmunity. Overall, our molecular and bioinformatics data demonstrate the mechanism by which TCF-1 modulated several critical aspects of T cell function during CD8 T cell response to cancer. Summary Figure: TCF-1 is required for persistent function of CD8 T cells but dispensable for anti-tumor response. Here, we have utilized a novel mouse model that lacks TCF-1 specifically on CD8 T cells for an allogeneic transplant model. We uncovered a molecular mechanism of how TCF-1 regulates key signaling pathways at both transcriptomic and protein levels. These key molecules included LCK, LAT, ITK, PLC-γ1, p65, ERK I/II, and JAK/STAT signaling. Next, we showed that the lack of TCF-1 impacted phenotype, proinflammatory cytokine production, chemokine expression, and T cell activation. We provided clinical evidence for how these changes impact GVHD target organs (skin, small intestine, and liver). Finally, we provided evidence that TCF-1 regulates NKG2D expression on mouse naïve and activated CD8 T cells. We have shown that CD8 T cells from TCF-1 cKO mice mediate cytolytic functions via NKG2D., (© 2022. The Author(s).)

Over the past 20 years, hydroxyurea (HU) has emerged as an effective therapeutic agent in thalassemic patients to improve anemia and decrease the transfusion dependency. We evaluated long-term safety and clinical response to HU in patients with non-transfusion-dependent β-thalassemia (NTDT). In this retrospective study, medical records of 181 patients with NTDT were evaluated during October to December 2020 in Southern Iran. No requirement to blood transfusion was considered as sustained transfusion independence response. All patients were regularly examined and monitored for the occurrence of any adverse event (AE) of HU. The mean duration of HU consumption ± SD was 18.2 ± 4.0 (8-22) years. Overall, 149 patients (82.3%) had sustained transfusion independence response. β-globin gene mutations and XmnI polymorphisms were not significantly associated with clinical response (P > 0.05). Mild and transient AEs were reported in 60 patients (33%) with no requirement to drug interruption. Hydroxyurea with the dose of 8-15 mg/kg can be used as a safe and effective treatment in NTDT patients. It was well tolerated in long term without any serious complication or secondary malignancy. No relationship between XmnI or β-globin gene mutations with HU response was observed in this geographic area of the world., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Alloimmunization is a serious complication in β-thalassemia major patients as a result of repeated blood transfusion. The immune checkpoint receptors play an important role in regulating immune system homeostasis and the function of the immune cells. This study aimed to evaluate the expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte activation gene 3 (LAG-3), and T-cell immunoglobulin and mucin domain-containing protein-3 (TIM-3) immune checkpoint molecules in β-thalassemia major patients with and without alloantibody. For this purpose, 68 β-thalassemia major patients with (34 patients) and without (34 patients) alloantibody as well as 20 healthy controls were enrolled. The expression of these genes was evaluated in different groups of patients by SYBR Green real-time PCR method. Our results showed that the mean expression of LAG-3 was significantly increased in thalassemia patients compared to the control group (*P < 0.001). However, there was no significant difference in expression of the CTLA-4 and TIM-3 as well as LAG-3 genes between patients with and without alloantibody (P > 0.05). A positive correlation was observed between the level of LAG-3 expression with markers associated with Treg function including FOXP3 and GDF-15 genes in β-thalassemia major patients. Taken together, the LAG-3 molecule might have a more prominent role in the abnormality of the immune system in thalassemia patients especially the function of regulatory T cells (Tregs), prior to the CTLA-4 and TIM-3 genes., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Thalassemia intermedia is a subgroup of β-thalassemia which originates from mutations in the beta-globin gene. Zinc and copper play important roles in the metabolism. Due to its significant therapeutic effects, curcumin has led many studies to focus on curcumin. In a double-blind clinical trial study, 30 patients with beta-thalassemia intermedia with an age range of 20 to 35 years were randomly selected 1:1 to receive either curcumin or placebo for 3 months. Before and after the intervention period, 5 ml of blood was taken to determine the serum levels of zinc and copper. The laboratory tests were checked at baseline and at the end of the treatment. While the serum levels of zinc and zinc/copper significantly increased, the serum levels of copper decreased after 3 months of curcumin intake. In addition, on the basis of baseline characteristics, a negative correlation was found between zinc and body mass index and positive correlations were identified between copper with triglyceride and high-density lipoprotein. Also, the level of ferritin protein in the curcumin group compared to the placebo group showed a significant decrease after 3 months of curcumin use. Therefore, it could be concluded that curcumin might exert a net protective effect on copper toxicity in thalassemia intermedia patients. The investigation also implicated that curcumin represents an approach to regulating zinc homeostasis and may be useful as a complementary treatment of patients with thalassemia intermedia, especially in patients with zinc deficiency or low serum zinc/copper ratio. Clinical Trial Registration Number: IRCT20190902044668N1.

Oxidative stress is a major mechanism contributing to the progression of β-thalassemia. To assess the effect of vitamin E and N-acetyl cysteine (NAC) as antioxidant agents on total oxidative stress (TOS) status and total antioxidant capacity (TAC) in patients with transfusion-dependent β-thalassemia (TDT). In this open-label randomized controlled trial, from May to August 2019, 78 eligible patients with TDT over the age of 18 were enrolled. All patients were registered at the Thalassemia Clinic of Shiraz University of Medical Sciences in Southern Iran. Patients were randomly allocated to the NAC group (10 mg/kg/day, orally), vitamin E group (10 U/kg/day, orally), and control group. The duration of the study was 3 months. The mean age of the participants was 28.5 ± 5.1 (range: 18-41) years. At the end of the study, TOS significantly decreased only in the vitamin E group (mean difference (MD), 95% confidence interval (CI): 0.27 (0.03-0.50), P = 0.026). TAC significantly decreased in both supplemented groups at the 3rd month of treatment (NAC group: MD (95% CI): 0.11 (0.04-0.18), P = 0.002 and vitamin E group: 0.09 (0.01-0.16), P = 0.022 respectively). Hemoglobin did not significantly change at the end of the study in each group (P > 0.05). Mild transient adverse events occurred in 4 patients of the NAC group and 5 patients of the vitamin E group with no need to discontinue the treatment. Vitamin E can be a safe and effective supplement in improving oxidative stress in patients with TDT. Moreover, it seems that a longer duration of using antioxidant supplements needs to make clinical hematologic improvement in TDT patients.

Purpose: To evaluate the association of time intervals between various steps of the intracytoplasmic sperm injection (ICSI) cycle with oocyte quality and reproductive outcomes., Methods: We conducted a prospective study among patients undergoing ICSI cycles in an academic hospital between May 2017 and January 2019. The time intervals between the various steps of cycles were recorded. The ICSI cycles were categorized according to the different time intervals; human chorionic gonadotropin (hCG) injection to oocyte pick up (hCG-OPU) (≤ 36 h and > 36 h), OPU-denudation (≤ 2 h and > 2 h), and denudation-ICSI (≤ 2 h and > 2 h). The main outcome measures were oocyte dysmorphisms, fertilization, cleavage, biochemical, and clinical pregnancy rates., Results: A total of 613 ICSI cycles using fresh autologous oocytes were included in this study. After adjusting for confounders, the hCG-OPU interval was associated with the presence of cytoplasmic granulation, inclusion body, and also the total number of morphologically abnormal premature oocytes in the cycle (P = 0.02, P = 0.04, P = 0.008, respectively). OPU-denudation interval was associated with cytoplasmic granulation and extended perivitelline space of the oocytes (P = 0.006 and P = 0.03, respectively). The denudation-ICSI interval was only associated with cytoplasmic granulation (P = 0.01). However, hCG-OPU, OPU-denudation, and denudation-ICSI intervals were not significantly associated with fertilization, cleavage, biochemical, and clinical pregnancy rates., Conclusions: All the studied time intervals between various steps of ICSI procedure could affect oocyte quality, but the oocyte dysmorphisms were mainly associated with hCG-OPU interval. However, the time intervals were not associated with fertilization, cleavage, and pregnancy outcomes.

In the original article published, the values given in the variables are incorrect.

Silent brain lesions might be associated with overt cerebrovascular accident over time in beta thalassemia major (BTM) and intermediate (BTI). Aspirin may be protective in these patients. We evaluated brain magnetic resonance imaging (MRI) in thalassemia patients to see whether aspirin is protective or not. A historical cohort study was conducted on 35 thalassemia patients, 22 BTI, and 13 BTM patients at Shiraz Hematology Research Center in 2018. Median age of the patients was 32 years and ranged from 8 to 42 years. Twenty-four patients (68.6%) were females. Overall frequency of white matter lesions (WMLs) in the first MRI was 10 patients (28.6%). After 3 years, 3 patients developed new lesions and the frequency of WMLs was 13 patients (37.1%) in the second MRI. Moreover, in 3 patients, number of WMLs increased. Patients with new lesions or more lesions compared to the baseline were significantly older than the other group (median age 36.5 years vs. 31 years, P = 0.046). Regarding aspirin consumption, only 1 patient (16.7%) of patients with new lesions was using aspirin compared to 10 (34.5%) of the other group (P = 0.640). The high-risk patients with thrombocytosis, splenectomy, severe iron overload, and older age (> 30 years) should be under close follow-up and evaluated on a regular periodic basis as well as brain MRI at least once every 3 years. Aspirin could be protective against new or progressive brain lesions so that low-dose aspirin is recommended in high-risk thalassemia patients.

Recently, resveratrol showed induction of γ-globin mRNA synthesis in human erythroid precursors and reducing oxidative stress in red cells of thalassemia patients in many in vitro studies. We aimed to investigate the efficacy and safety of resveratrol, for the first time, in non-transfusion-dependent beta-thalassemia intermedia (B-TI) in Southern Iran. In this double-blind randomized clinical trial, 54 patients with B-TI were investigated during 6 months between October 2016 and March 2017. Patients were randomly allocated into three groups by simple randomization method. Group 1 (hydroxyurea (HU) and placebo, 18 patients), group 2 (resveratrol/piperine and placebo, 16 patients), and group 3(HU and resveratrol/piperine, 20 patients). Primary end point was considered as change in hemoglobin (Hb) levels and need for blood transfusion. Drug safety was considered as a secondary end point. Mean age of the patients was 28.2 ± 5.6 (18-42) years. Response rate was not significantly different among the three groups (P > 0.05). Higher percentages of adverse events were detected in groups 2 (31.3%) and 3 (25%) compared to group 1 (5.6%). However, the difference was not statistically significant (P > 0.05). All reported adverse events were gastrointestinal symptoms. Resveratrol showed a similar efficacy with HU in the small population of non-transfusion B-TI patients during a 6-month follow-up. Complications, mostly gastrointestinal, were observed more frequently in resveratrol groups compared to the HU group. Although it was not statistically significant, more attention should be given to safety and efficacy of resveratrol as an oral HbF-augmenting agent.

Objectives: This study was conducted to assess bone mineral density (BMD) and bone mineral content (BMC) of patients with hemoglobin H (HbH) disease., Methods: BMD and BMC were measured by dual energy X-ray absorptiometry of the lumbar spines and femur neck in 21 patients with Hb H disease over the age of 10 years. An association of BMD with sex, age, hemoglobin, calcium, phosphorus, and serum ferritin level was also evaluated., Results: Prevalence of BMD below the expected range for age in the lumbar spine and femur neck region in patients with HbH disease were 33.3 and 14.3 %, respectively. Lumbar BMD was significantly lower in the patients compared to healthy individuals (median (min-max) 0.725 (0.595-0.924) vs. 1.061 (0.645-1.238), P < 0.001)). There was no significant relationship between BMD in the lumbar and femur neck with any of the evaluated variables (P value >0.05)., Conclusion: Data regarding bone density in HbH disease is limited; osteoporosis as a common complication of β-thalassemia intermedia syndrome should be considered even in HbH which shows its prevalence is less than β-thalassemia intermedia.

The aim of this study is to determine the frequency of silent cerebral ischemia (SCI) in a group of patients with β-thalassemia major and correlate them with demographic parameters, blood and spleen status, volume and frequency of transfusions. In this cross-sectional study, 40 β-thalassemic patients over 10 years old who had no neurologic deficit were studied. Brain MRI was performed to detect SCI. Silent cerebral ischemia was classified according to number and size. Silent cerebral ischemia was found in 15 patients (37.5 %). Mean number of SCI was 6.73 ± 10.33 (1-40), and mean size of the brain lesions was 3.07 ± 2.81 mm (1-11 mm). The patients with SCI were significantly older (31.1 ± 6.5 vs. 25 ± 6.8 years, P = 0.009), and most of them were splenectomized (80% vs. 36 %, P = 0.01). Interestingly, 10 out of 15 patients with SCI had platelet count less than 500,000/mm(3). Eight of these patients (80 %) were splenectomized. Other variables had no statistically significant association with the presence of SCI. Older age and splenectomized multitransfused β-thalassemic patients even with normal platelet count have a higher incidence of SCI. The effect of splenectomy is more significant in statistical analysis. In splenectomized patients with a high platelet count and even with normal platelet count, aspirin therapy is indicated. Based on the results, it seems that regular blood transfusions are not going to have a significant effect on the number and size of SCI.

We assessed the prevalence of testicular microlithiasis by scrotal ultrasonography in β-thalassemia major patients older than 10 years and evaluated the association with serum ferritin levels, calcium (Ca), phosphate (Ph), and parathyroid hormone levels (PTH). In this cross-sectional study, 132 male β-thalassemia major patients from 300 male patients older than 10 years old were randomly evaluated by scrotal ultrasonography. Parathyroid hormone, calcium, phosphate, and serum ferritin levels were also evaluated. All of the patients were urologically asymptomatic. One hundred healthy age-matched subjects were selected as control group. Testicular microlithiasis was found in 16 patients and 1 individual in control group (12.1 vs 1 %; p = 0.003). Testicular microlithiasis was associated with age and high serum ferritin levels, but there was no association between Ca, Ph, and PTH levels; blood transfusion; and oral or subcutaneous iron chelation therapy. Also, there was no significant correlation between hyperparathyroidism, history of viral hepatitis, and splenectomy with testicular microlithiasis. The frequency of testicular microlithiasis in β-thalassemia major patients was higher than previously reported. A correlation was found between testicular microlithiasis with age and serum ferritin levels, so regular and adequate iron chelator therapy (at least 10-12 h per day for 5-6 days a week) is recommended. We suggest a close observation and treatment with iron-chelating agents of these patients. Since testicular microlithiasis is occasionally associated with germ cell tumors, clinical and sonographic follow-up is recommended.

Intracranial hemorrhage (ICH) is one of the most severe and life-threatening manifestations occurring in the patients with factor XIII (F XIII) deficiency. The aim of this study was to describe the ICH pattern in the patients suffering from F XIII deficiency. In this case series, we investigated 38 patients with severe F XIII deficiency in south of Iran from January to May 2012. ICH pattern, neurologic complications, efficacy of treatment, and incidence of recurrence were reported. The site of ICH was intraparenchymal in 35 patients (92.1 %), subdural in 2 patients (5.2 %), and epidural hemorrhage in 1 patient (2.6 %). Besides, neurologic complications occurred in 21 patients (55.2 %), including locomotor disability in 8, psychological impairment in 7, mental disorders in 5, speech impairment in 4, and visual impairment in 2. Prophylaxis was started with a dose of 10 IU/kg Fibrogammin every 4-6 weeks for all the patients, except for one. All the patients on prophylaxis showed good response without any episodes of recurrence, except for one. The most frequent site of ICH in our patients was intraparenchymal. It seems that long-term prophylactic treatment with a dose of 10 IU/kg Fibrogammin could be effective in the prevention of CNS bleeding in the patients with F XIII deficiency. Moreover, all the patients with severe F XIII deficiency even without severe bleeding symptoms are recommended to undergo prophylactic treatment.

A gold nanoparticles modified fused silica fiber was developed and used for the head space solid phase micro-extraction (HS-SPME) of polycyclic aromatic hydrocarbons (PAHs), including naphthalene, anthracene, acenaphthylene, phenanthrene, fluoranthene and pyrene. The effects of different parameters influencing the extraction efficiency including extraction temperature, extraction time, ionic strength, stirring rate and sample volume were examined and optimized. Linear ranges of 1-300 μg L(-1) for naphthalene, 0.5-250 μg L(-1) for anthracene, acenaphthylene and phenanthrene and 0.05-200 μg L(-1) for fluoranthene and pyrene were obtained. Detection limits were in the range of 10-200 μg L(-1). Single fiber repeatability and fiber to fiber reproducibility were less than 2.5 %-6.0 % and 8.5 %-13.6 %, respectively. Seawater samples were analyzed as real samples and good recoveries (91.9 %-105.3 %) were obtained for target analytes.

We aimed to determine the frequency of asymptomatic brain lesions in a group of patients with β-thalassemia intermedia (β-TI) and to evaluate correlation of asymptomatic brain lesions with splenectomy, thrombocytosis, blood transfusions, and clinical parameters. Ninety five neurologically intact patients with β-TI were randomly enrolled in this cross-sectional study. Diffusion-weighted imaging brain MRI was performed in every patient to detect cerebral white matter lesions (WML). We found an overall frequency of 15 (15.8 %) for WMLs, 14 (23.7 %) in splenectomized, and 1 (2.8 %) in nonsplenectomized patients. The presence of WML was significantly associated with splenectomy (P = 0.008) and thrombocytosis (P = 0.009). However, after adjustment for splenectomy, thrombocytosis was not significantly associated with the presence of WML (P > 0.05). The number of patients with regular blood transfusions and normal MRI was not significantly higher compared to those with abnormal findings (52.5 % vs. 26.7 %; P = 0.092). In untransfused patients, hydroxyurea (HU) administration was associated with a lower incidence of WML (P < 0.001). Although in univariate analysis either splenectomy or thrombocytosis showed significant correlation with the presence of single or multiple WMLs, thrombocytosis by itself did not significantly contribute in developing asymptomatic brain lesions. The lack of significant correlation between lesions and regular blood transfusions could be related to the treatment with HU in untransfused patients, which increased fetal hemoglobin levels and improved the morphology and the pathological indices of the red blood cells. Larger prospective studies are suggested for the accurate evaluation of the correlation of these factors with developing asymptomatic brain lesions.

Intra-articular hemorrhage is the clinical hallmark of hemophilia. Synoviorthesis, the intra-articular injection of chemical or radioactive substances in order to produce fibrosis of the hypertrophied synovium, has proved effective in the treatment of chronic hemophilic synovitis. Between December 2006 and July 2007, we treated 21 patients with hemophilic arthropathy by synoviorthesis with rifampicin once a week. The procedures were performed on 14 knees, five elbows, four ankles, and one shoulder (24 joints and 113 injections). The mean age was 16.7 years (range, 7-49 years). According to the Fernandez-Palazzi classification, synoviorthesis was considered satisfactory (excellent or good) in 21 (87.5%) joints and unsatisfactory (fair or poor) in three (12.5%). A mean reduction of 6.3 bleeding episodes per month was obtained (P < 0.0001). The mean pain score was reduced from 2.62 (range, 2-3; SD, 0.49) before treatment to 0.79 (range, 0-2; SD, 0.65) after treatment. The mean World Federation of Hemophilia (WFH) score was 5.45 (range, 2-8) before synoviorthesis and 3.5 (range, 1-7) after treatment. This method effectively reduced hemarthrosis and pain and also improved the range of motion in patients with hemophilic arthropathy. Chemical synoviorthesis with rifampicin appears to be efficient, inexpensive, and simple and also especially practical in developing countries where radioactive agents are not easily available.

Patients with bleeding disorders are at a high risk of bleeding complications during surgical procedures. Cyanoacrylates have been used successfully in many procedures and surgeries. This study was undertaken to evaluate the effectiveness of Glubran 2 and Glubran tissue skin adhesive (Glubran Tiss) in patients with hereditary bleeding disorders who underwent circumcision or dental extraction. Seven patients with congenital bleeding disorders who underwent circumcision or dental extraction were evaluated during 2009. A historical control group was considered for comparison. Glubran 2 acrylic glue was applied in cases of dental extraction and Glubran Tiss in circumcision. The patients were followed up for 6 months to detect complications. Five patients had hemophilia A, one patient had hemophilia B, and one patient had Bernard-Soulier syndrome; six were boys or men and one was a girl. Mean age was 15±8 years (range 5 to 25 years). The results in all patients under circumcision were good with significantly less factor consumption (P=0.043). But in patients who underwent dental extraction, Glubran was effective only in a 5-year-old girl with mandibular premolar tooth extraction, but not successful in a 21-year-old man with extraction of maxillary wisdom tooth. After 6 months of follow-up, no complications were observed in any patients. Our experiences in this small series of patients suggest that adjunct use of Glubran Tiss, in addition to systemic replacement therapy, can be effective in the control of bleeding in patients with hemophilia who undergo circumcision, and helps to lessen factor consumption. But, further studies with larger sample size are needed. However, our experience in using Glubran in dental extraction was not successful.

Heart complications are among the serious problems of patients with β-thalassemia intermedia. This study aimed to evaluate myocardial function in these patients. Clinical parameters and both standard Doppler and pulsed Doppler tissue imaging parameters were compared in 51 β-thalassemia intermedia patients (mean age, 17.05 ± 5.8 years) and 20 normal subjects (mean age, 17.81 ± 7.35 years, p = 0.98). In 11 patients (21.5%), pulmonary artery hypertension was detected. M-mode echocardiographic findings such as ejection fraction and fractional shortening did not show statistically significant changes (p > 0.005). Pulsed Doppler showed a significant difference in the early (E) to late diastolic (A) velocity ratio of the tricuspid and mitral valve between the patients and the control subjects (p < 0.05). In the pulsed tissue Doppler study, the peak systolic velocity of the septum (Ss), the peak atrial velocity of the septum (Aas), the peak systolic velocity of the tricuspid annulus (St), the peak early diastolic velocity of the tricuspid annulus (Eat), and the peak late diastolic velocity of the tricuspid annulus (Aat) were increased significantly (p < 0.05). The pulse tissue Doppler of the lateral mitral annulus did not change significantly (p > 0.005). The peak systolic velocity of the posterior wall and the peak late diastolic velocity of the anterior wall changed significantly (p < 0.05). This study showed that β-thalassemia intermedia patients with normal M-mode and two-dimensional echocardiography had statistically significant changes in pulsed Doppler and pulsed tissue Doppler imaging.

Factor XI (FXI)-deficiency is a rare coagulation disorder inherited as an autosomal recessive trait, which is most common in Ashkenazi Jews, but also found in other groups like Moslems. We have reviewed for the first time cases of FXI deficiency in southern Iran in order to analyze their mutations related to factor XI, the main clinical and biological features, levels of circulating factor XI, and bleeding history. All 15 exons and exon-intron boundaries of F11 were polymerase chain reaction amplified using sets of primers designed on the basis of the known genomic sequence of the gene. Among bleeding disorder cases, five were FXI-deficient. FXI clotting activity ranged 0.39-16%. All were severely deficient. In all analyzed patients, functional level of FXI was markedly reduced, confirming the diagnosis of quantitative FXI deficiency. Sequencing of F11 identified three mutations: (1) a highly prevalent type II nonsense mutation (Glu117stop) in a homozygous patient, (2) a previously reported missense (Glu547Lys), and (3) novel missense (Gly372Ala) mutation. No causative mutation was found in the sequenced regions of other patients. One novel mutation and two previously described mutations were identified in patients living in southern Iran. No recurrent mutation was found, perhaps because there is a more intense population mixing in southern Iran. Screening a higher number of FXI-deficient patients will also be necessary to reveal the existence of a founder effect for these mutations in the Iranian population.

In this study, the immunologic abnormalities of Iranian beta-thalassemia major patients were characterized, considering their clinical parameters including splenectomy status and iron overload. Serum samples and peripheral blood mononuclear cells were collected from 28 patients and 30 age- and sex-matched healthy individuals. Patients with thalassemia showed significantly increased absolute lymphocyte counts compared with the control group. An increased number of activated T cells and higher levels of serum neopterin were also observed in thalassemia patients, which suggest chronic stimulation of immune system. On the contrary, T-cell proliferation and interleukin 2 (IL-2), interferon gamma (IFN-gamma), and IL-4 production were suppressed in patients compared to controls. Patients with high serum ferritin levels produced significantly less IFN-gamma and IL-2, indicating the immunosuppressive effect of iron overload in beta-thalassemia patients. The serum levels of tumor necrosis factor alpha and absolute counts and percentages of B and T cells were higher in splenectomized patients; however, serum levels of neopterin significantly decreased in splenectomized patients compared to the non-splenectomized group. Taken together, T lymphocytes express activated phenotype in polytransfused beta-thalassemia major patients, while T cell proliferation and effector function are significantly suppressed. Multiple blood transfusion and continuous immune stimulation could be responsible for making such a double-faced immune response.

Beta-thalassemia trait (BTT) is a common genetic disorder in Mediterranean countries including Iran. Previous studies have shown the protective effect of BTT on myocardial infarction that may be due to lower cholesterol levels or lower arterial blood pressure in BTT subjects. This study was designed to analyze the effect of BTT on arterial blood pressure in young adults. Four-hundred and eight subjects who were referred to our clinic for premarriage screening of BTT (208 BTT as the case group and 200 normal subjects as the control group) were recruited. BTT was diagnosed by complete blood count, hemoglobin electrophoresis, and column chromatography. Blood pressure was measured twice with 20-min intervals by a medical barometer in the sitting position from left arm, and the average blood pressure was recorded as subject's blood pressure level. Mean systolic blood pressure in the control group was 122.8 mmHg as compared to 117.0 mmHg in the case group (P value = 0.249). Mean diastolic pressure was the same in both groups (76.7 mmHg in control group as compared with 77.5 mmHg in the case group) (P value = 0.433). Analysis of blood pressure by gender showed that male BTT subjects had a 10-mmHg lower systolic blood pressure than normal subjects (120.8 mmHg in the case group as compared with 130.7 mmHg in the control group). BTT has a protective effect on the development of hypertension in young male adults.