Detection of 13 Novel Variants and Investigation of Mutation Distribution by Next Generation Sequencing in Hemoglobinopathies: A Single Center Experience.

Hemoglobinopathies are the most common monogenic disorders in the world. Traditional diagnostic algorithms generated by conventional methods for thalassemia can be labor-intensive and time-consuming due to the complexities of the genes involved and the variability in disease-causing mutations. With the advantages of next-generation sequencing (NGS) technology, molecular analysis of highly complex diseases such as hemoglobinopathies has become easier. Next-generation sequencing is a highly sensitive and effective method due to its capacity to sequence many gene regions simultaneously while allowing good read depths. In this study, single nucleotide changes, small deletions and copy number variations in HBA1, HBA2 and HBB in 914 patients with suspected hemoglobinopathy were analysed with NGS. At least one HBA1, HBA2, HBB or HBD variant was detected in 483 (52.8%) patients. Ten novel variants were detected in HBA1 and HBA2, three in HBB, and one in HBD. From these variants, c.*76T > A, c.301-24 G > A, c.301-24G > C c.-41C > G, c.-37-40C > G, c.-9G > C, c. 95 + 9C > T, c.95 + 26C > A, c.95 + 38C > T and c.*18C > G variants were located in α-globin genes, c.-25T > C, c.*103T > C and c92 + 39A > G variants were located in ß-globin genes, and c.-43C > A was located in HBD. This is the first comprehensive study using NGS for the molecular diagnosis of hemoglobinopathies in Turkey. Accurate molecular diagnosis is of critical importance in hemoglobinopathies which are a public health problem due to their increased prevalence, high burden to society, and lack of curative treatment. Currently, NGS appears to be an advanced option over conventional methods to detect all variants occurring by molecular mechanisms and simultaneously analyse many genomic sequences.

Effects of Delayed-Onset Muscle Pain on Respiratory Muscle Function.

BACKGROUND: Delayed-onset muscle soreness (DOMS) has been widely examined in the peripheral muscles; however, studies showing the potential effects of DOMS on respiratory function are limited. HYPOTHESIS: DOMS in trunk muscles has a negative effect on respiratory function parameters, respiratory muscle strength, respiratory muscle endurance, and exercise capacity. STUDY DESIGN: Prospective cohort study. LEVEL OF EVIDENCE: Level 2. METHODS: In 24 healthy participants with a mean age of 21 ± 2 years, DOMS was induced for the trunk muscles with a load equal to 80% of the maximum repetitive voluntary contraction. Pulmonary function parameters, respiratory muscle strength and endurance, exercise capacity, pain, fatigue, and dyspnea perception severity were recorded before DOMS and at 24 and 48 hours after DOMS. RESULTS: After DOMS, decreases were observed in respiratory function parameters, namely, forced vital capacity, forced expiratory volume in the first second, vital capacity, and 25% to 75% flow rate value of forced expiratory volume (25% to 75%) (P = 0.02, P = 0.02, P < 0.01, P = 0.01, respectively). Maximal inspiratory pressure and exercise capacity also decreased (P = 0.02, P < 0.01, respectively). No difference was observed between all 3 measurements of maximal expiratory pressure (MEP) and MEP% values (P1 = P2 = P3 ≥ 0.99). The results of the respiratory muscle endurance tests did not reveal a significant difference in terms of load and time in all 3 conditions (P > 0.05). CONCLUSION: After DOMS, there was a 4% to 7.5% decrease in respiratory function parameters, and a 6.6% decrease in respiratory muscle strength. CLINICAL RELEVANCE: The occurrence of DOMS before a competition can have a detrimental impact on pulmonary performance. Hence, it is imperative to consider this factor when devising training and exercise programs. In addition, the development of treatment protocols becomes crucial if DOMS arises.

Utility of a targeted next-generation sequencing-based genetic screening panel in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome.

Objectives: This study aims to investigate a genetic panel in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome and examine its performance for an accurate differential diagnosis. Patients and methods: Between January 2021 and January 2022, a total of 104 children with PFAPA syndrome (63 males, 41 females; mean age: 4.8±2.3 years; range, 1.2 to 8.9 years) were retrospectively analyzed. Next-generation sequencing test was performed using a custom QIAGEN- QIAseq™ Targeted DNA Panel which includes six genes namely ELANE, LPIN2, MEFV, MVK, NLRP3, and TNFRSF1A. Results: Of 104 patients, 38 (36.5%) had variants in the genetic panel. The most common variants were found in the MEFV gene (n=35, 33.6%), the most frequent genotype was E148Q heterozygosity (n=16). Four and two patients were eventually diagnosed with Familial Mediterranean fever (FMF) and hyperimmunoglobulin D syndrome (HIDS), since they had confirmative biallelic pathogenic in the MEFV and MVK genes, respectively. Conclusion: A genetic panel, including MEFV and MVK genes, may be useful in patients, clinically resembling PFAPA, since they may have HIDS or FMF, but lack typical features of the exact disease. Nonetheless, we believe that distinct genetic panels should be developed for different populations.

A recurrent homozygous LMNA missense variant p.Thr528Met causes atypical progeroid syndrome characterized by mandibuloacral dysostosis, severe muscular dystrophy, and skeletal deformities.

Atypical progeroid syndromes (APS) are premature aging syndromes caused by pathogenic LMNA missense variants, associated with unaltered expression levels of lamins A and C, without accumulation of wild-type or deleted prelamin A isoforms, as observed in Hutchinson-Gilford progeria syndrome (HGPS) or HGPS-like syndromes. A specific LMNA missense variant, (p.Thr528Met), was previously identified in a compound heterozygous state in patients affected by APS and severe familial partial lipodystrophy, whereas heterozygosity was recently identified in patients affected by Type 2 familial partial lipodystrophy. Here, we report four unrelated boys harboring homozygosity for the p.Thr528Met, variant who presented with strikingly homogeneous APS clinical features, including osteolysis of mandibles, distal clavicles and phalanges, congenital muscular dystrophy with elevated creatine kinase levels, and major skeletal deformities. Immunofluorescence analyses of patient-derived primary fibroblasts showed a high percentage of dysmorphic nuclei with nuclear blebs and typical honeycomb patterns devoid of lamin B1. Interestingly, in some protrusions emerin or LAP2α formed aberrant aggregates, suggesting pathophysiology-associated clues. These four cases further confirm that a specific LMNA variant can lead to the development of strikingly homogeneous clinical phenotypes, in these particular cases a premature aging phenotype with major musculoskeletal involvement linked to the homozygous p.Thr528Met variant.

An unusual manifestation in a pediatric patient with MAFB mutation: Sacroiliitis in multicentric carpotarsal osteolysis syndrome.

Multicentric carpotarsal osteolysis (MCTO) syndrome, is typically characterized by progressive bone resorption in especially carpal and tarsal bones, in addition to abnormal facial appearance and proteinuria. This disorder is caused by monoallelic pathogenic MAFB mutations, which result in excessive osteoclastogenesis via aberrant receptor activator of nuclear factor kappa-B ligand activation. Most cases are sporadic with de-novo mutations, and it is still unclear why carpal and tarsal bones are predominantly affected. The early phases of MCTO resemble juvenile idiopathic arthritis (JIA) with ankle and wrist swelling and pain, even with inflammatory changes in magnetic resonance imaging. Herein we report a pediatric patient, previously treated with antirheumatic drugs, and eventually diagnosed with MCTO. This case was a descriptive case with exophthalmos, significant proteinuria, and total loss of carpal and tarsal bones at the time of genetic diagnosis. Similar to the literature, our case had typical radiological findings despite methotrexate and anti-tumor necrosis factor-alpha treatment. However, while arthritis affecting joints other than wrists and ankles has not been reported so far in the literature, our case had bilateral sacroiliitis which completely resolved after adalimumab treatment. We cannot be sure if sacroiliitis was incidental or occurred as a component of the disease, nonetheless, we think that sharing our experience may lead to easy and early recognition of MCTO, with more knowledge on rare manifestations of MCTO, and thus we may be able to clarify the benefits of denosumab, which is the most promising agent in early phases of the disease.

The Role of miR-26a, miR-29a and miR-448-3p in the Development of Cerebral Aneurysm.

AIM: To elucidate the role of microRNAs (miRNAs) in the development of cerebral aneurysms. MATERIAL AND METHODS: This study compared the expression levels of miR-26a, miR-29a and miR-448-3p in 50 samples each of cerebral aneurysm tissues and normal superficial temporal artery tissues. The miRNA expression levels were also compared in terms of aneurysm location and rupture status, i.e., presence or absence of rupture. RESULTS: Expression levels of miR-26a, miR-29a and miR-448-3p were increased in aneurysm tissues compared with normal vascular tissues. No significant difference was found in the miRNA expression levels with respect to aneurysm location or rupture status. CONCLUSION: This study showed that miR-26a, miR-29a and miR-448-3p overexpression could play an important role in intracranial aneurysm development independent of aneurysm location and rupture status. miR-26a, miR-29a and miR-448-3p could act as potential therapeutic targets in patients with intracranial aneurysms; however, further studies are needed on this issue.

Developmental genomics of limb malformations: Allelic series in association with gene dosage effects contribute to the clinical variability.

Genetic heterogeneity, reduced penetrance, and variable expressivity, the latter including asymmetric body axis plane presentations, have all been described in families with congenital limb malformations (CLMs). Interfamilial and intrafamilial heterogeneity highlight the complexity of the underlying genetic pathogenesis of these developmental anomalies. Family-based genomics by exome sequencing (ES) and rare variant analyses combined with whole-genome array-based comparative genomic hybridization were implemented to investigate 18 families with limb birth defects. Eleven of 18 (61%) families revealed explanatory variants, including 7 single-nucleotide variant alleles and 3 copy number variants (CNVs), at previously reported "disease trait associated loci": BHLHA9, GLI3, HOXD cluster, HOXD13, NPR2, and WNT10B. Breakpoint junction analyses for all three CNV alleles revealed mutational signatures consistent with microhomology-mediated break-induced replication, a mechanism facilitated by Alu/Alu-mediated rearrangement. Homozygous duplication of BHLHA9 was observed in one Turkish kindred and represents a novel contributory genetic mechanism to Gollop-Wolfgang Complex (MIM: 228250), where triplication of the locus has been reported in one family from Japan (i.e., 4n = 2n + 2n versus 4n = 3n + 1n allelic configurations). Genes acting on limb patterning are sensitive to a gene dosage effect and are often associated with an allelic series. We extend an allele-specific gene dosage model to potentially assist, in an adjuvant way, interpretations of interconnections among an allelic series, clinical severity, and reduced penetrance of the BHLHA9-related CLM spectrum.

Clinical presentation of children with Deficiency of Adenosine deaminase 2: A case series.

Deficiency of Adenosine deaminase 2 (DADA2) is a monogenic inflammatory disease, caused by mutations in ADA2 gene, which encodes an extracellular enzyme acting as a monocyte differentiation factor. DADA2 is first described with the clinical picture resembling polyarteritis nodosa, including livedo racemose, recurrent fever, musculoskeletal complaints. Besides, some patients have cytopenia, lymphoproliferation and mild to moderate immunodeficiency. The most crucial complication of DADA2 is neurological involvement, especially arterial stroke, which necessitates continuous treatment with anti-tumor necrosis factor α (anti-TNFα) treatment for preventing further stroke attacks. Herein, we report 5 DADA2 patients from 5 unrelated families, all had G47R mutation in at least one allele. All patients had livedo racemose, and 4 patients suffered from recurrent fever. Besides, musculoskeletal complaints and gastrointestinal symptoms were present in 4 and 3 patients, respectively. One patient had chronic arthritis and only one patient had a history of recurrent stroke without any sequela. Hematological and immunological involvement occurred in 3 and 4 patients, respectively, whereas only one had significant panhypogammaglobulinemia, requiring replacement therapy. We started etanercept treatment to all patients, which resulted the complete resolution of systemic inflammatory attacks and skin lesions and provided neurologically symptom free during their follow-up. With this report, we emphasize the importance of early referral of the patients with suspected livedo racemose to avoid the delay of DADA2 diagnosis for favorable outcome.

Diagnostic Value of Microarray Method in Autism Spectrum Disorder, Intellectual Disability, and Multiple Congenital Anomalies and Some Candidate Genes for Autism: Experience of Two Centers.

Objective: This study aimed to demonstrate the diagnostic value of microarray testing in autism spectrum disorder, intellectual disability, and multiple congenital anomalies of unknown etiology, as well as to report some potential candidate genes for autism. Methods: Microarray analysis records between January 2016 and December 2017 from two Genetic Diagnostic Centers in Turkey, Kanuni Sultan Suleyman and Adana Numune Training and Research Hospital, were compiled. Detected copy number variations (CNVs) were classified as benign, likely benign, variants of uncertain significance (VUS), likely pathogenic, and pathogenic according to American College of Medical Genetics and Genomics guidelines. The clinical findings of the some patients and the literature data were compared. Results: In 109 (24.5%) of 445 patients, a total of 163 CNVs with reporting criterion feature were detected. Sixty-nine (42%) and 8 (5%) of these were evaluated as pathogenic and likely pathogenic, respectively. Fifteen (9%) CNVs were also evaluated as VUS. Pathogenic or likely pathogenic CNVs were detected in 61 (13.6%) of 445 patients. Conclusions: We found that the probability of elucidating the etiology of microarray method in autism spectrum disorder, intellectual disability, and multiple congenital anomalies is 13.6% with a percentage similar to the literature. We suggest that the MYT1L, PXDN, TPO, and AUTS2 genes are all strong candidate genes for autism spectrum disorders. We detailed the clinical findings of the cases and reported that some CNV regions in the genome may be associated with autism.

Diagnostic value of plasma lysosphingolipids levels in a Niemann-Pick disease type C patient with transient neonatal cholestasis.

OBJECTIVES: Niemann-Pick disease type C (NPC) is a lysosomal storage disease due to impaired intracellular lipid trafficking caused by biallelic pathogenic variants in NPC1 or NPC2 genes. NPC is classified according to the age of onset of neurological manifestations. Cholestatic liver disease can be transient or lead to liver failure. Accompanying neurological findings can be observed at any age. In this report, an infant with a homozygous pathogenic variant in NPC1 gene whose diagnosis was eventually confirmed by specific biomarkers is described. CASE PRESENTATION: A sixteen-day-old male was admitted to hospital with prolonged jaundice. He had mild hepatosplenomegaly, conjugated hyperbilirubinemia, elevated liver transaminases, and mild hypoalbuminemia. Cholestasis resolved spontaneously and patient was readmitted due to progressive hepatosplenomegaly without any neurologic findings when he was 8 months old. Molecular investigations detected homozygous c.1123A > C (p.Thr375Pro) pathogenic variant in NPC1 gene. NPC-specific lysosomal biomarkers such as Lysosphingomyelin and Lysosphingomyelin-509 were elevated, confirming the diagnosis. CONCLUSIONS: The clinical features of NPC are highly heterogeneous, from disease severity or age of onset to disease progression. Patients presenting with transient neonatal cholestasis and should be regularly followed for neurodevelopmental status and visceromegaly. In the case of variants of unknown significance in NPC1 gene, lysosomal biomarkers play an important role when genetic analyses are inconclusive.

High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population.

Neurodevelopmental disorders (NDDs) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDDs is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDDs; however, the majority of NDDs remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDDs. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROHs) - reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey.

Validity and Reliability of the Turkish Version of the London Chest Activity of Daily Living Scale in Obstructive Lung Diseases.

OBJECTIVES: The London Chest Activity of Daily Living Scale (LCADL) is a simple, useful, and comprehensive measure of dyspnea perception in activities of daily living. This study was conducted to determine the validity and reliability of the Turkish version of the LCADL. MATERIALS AND METHODS: A total of 64 patients with obstructive lung disease (24 chronic obstructive pulmonary disease, 20 asthma, and 20 bronchiectasis patients) were included. The Turkish LCADL was evaluated for interobserver reliability, test-retest reliability, and criterion validity. Two different observers applied the scale with an interval of 10 minutes to assess interobserver reliability. The second observer applied the scale twice at an interval of 10-15 days to assess test-retest reliability. Criterion validity was assessed using the 6-minute walk test (6MWT), Nottingham Health Profile (NHP), and Saint George Respiratory Questionnaire (SGRQ). RESULTS: The interobserver reliability of the scale was very high (rs=0.985, p<0.050). Cronbach's alpha coefficient for total score was 0.976 and intraclass correlation coefficient was 0.953. These results indicate that the Turkish LCADL has high reliability. The correlation between LCADL and 6MWT was moderate 0.503 (p=0.002). The LCADL total score was weakly correlated with NHP total score (rs=0.370, p=0.040) and SGRQ total score (rs=0.367, p=0.004). CONCLUSION: The Turkish version of the LCADL scale is reliable and valid in obstructive lung disease. The LCADL scale will be beneficial in existing pulmonary rehabilitation programs aiming to improve functional status. We believe that using the Turkish LCADL scale as an outcome measure in pulmonary rehabilitation programs will serve as an indicator of rehabilitation efficacy for individual patients.

Physical activity of patients with bronchiectasis compared with healthy counterparts: A cross-sectional study.

BACKGROUND: A few studies have implied that patients with bronchiectasis have a more inactive lifestyle than healthy counterparts do. The main objective of this study was to compare physical activity (PA) levels subjectively and objectively between patients with bronchiectasis and healthy individuals using an accelerometer and a questionnaire. METHODS: The study included 41 patients with bronchiectasis aged 18-65 years and 35 healthy age- and sex-matched control subjects. The PA level was assessed objectively using a multisensorial PA monitor, the SenseWear Armband (SWA), and subjectively with the International Physical Activity Questionnaire (IPAQ). All participants performed the incremental shuttle walk test (ISWT) for the assessment of exercise capacity. Pulmonary function, dyspnea, severity of bronchiectasis, respiratory and peripheral muscle strength, and quality of life were assessed. RESULTS: The pulmonary function test parameters, respiratory and peripheral muscle strength, exercise capacity, step count, moderate- and vigorous-intensity PA duration were significantly lower in patients with bronchiectasis than in the healthy control group (p < 0.05). Sedentary, moderate, vigorous, and total PA duration measured using the SWA were higher than those obtained using the IPAQ (p < 0.05). CONCLUSIONS: Patients with bronchiectasis have a reduced PA level compared with healthy counterparts. The IPAQ (based on the subjective estimation of PA) outcomes differed from the SWA outcomes, reinforcing the necessity for a disease-specific PA questionnaire. IPAQ underestimates the physical activity level compared with objective measurements.

High-intensity inspiratory muscle training in bronchiectasis: A randomized controlled trial.

BACKGROUND AND OBJECTIVE: Inspiratory muscle training (IMT) enhances velocity of inspiratory muscle contraction and modifies inspiratory and expiratory time. This study aimed to examine the impact of high-intensity IMT (H-IMT) on exercise capacity in bronchiectasis. METHODS: Forty-five patients were included. Lung function, respiratory muscle strength and endurance, exercise capacity, dyspnoea, fatigue and quality of life (QOL) were evaluated. Patients were randomized into two groups: H-IMT and control groups. Twenty-three patients underwent H-IMT for 8 weeks, using threshold loading with a target workload of maximal inspiratory pressure (MIP) of at least 70%, with 3-min cycles (as 2-min training: 1-min rest intervals) for 21 min. There was a total period of 14 min of loaded breathing and 7 min of recovery. The control group (n = 22) underwent low-intensity IMT at 10% of the initial MIP and was maintained at the same intensity until the end of the training. RESULTS: After training, both MIP and maximal expiratory pressure (MEP) and the incremental shuttle walk distance were increased in the H-IMT group compared with the control group (P < 0.05). There was a significant difference in constant threshold load, time and pressure-time units in the H-IMT group (P < 0.05) but not in the control group (P > 0.05). A significant decrease was found in fatigue in both groups (P < 0.05). The Leicester Cough Questionnaire social score for the H-IMT group decreased significantly after the treatment (P < 0.05). CONCLUSION: The H-IMT increased exercise capacity in patients with non-cystic fibrosis bronchiectasis. It has also positive effects on respiratory muscle strength and endurance, and social aspects of QOL.

Extrapulmonary features of bronchiectasis: muscle function, exercise capacity, fatigue, and health status.

BACKGROUND: There are limited number of studies investigating extrapulmonary manifestations of bronchiectasis. The purpose of this study was to compare peripheral muscle function, exercise capacity, fatigue, and health status between patients with bronchiectasis and healthy subjects in order to provide documented differences in these characteristics for individuals with and without bronchiectasis. METHODS: Twenty patients with bronchiectasis (43.5 ± 14.1 years) and 20 healthy subjects (43.0 ± 10.9 years) participated in the study. Pulmonary function, respiratory muscle strength (maximal expiratory pressure - MIP - and maximal expiratory pressure - MEP), and dyspnea perception using the Modified Medical Research Council Dyspnea Scale (MMRC) were determined. A six-minute walk test (6MWT) was performed. Quadriceps muscle, shoulder abductor, and hand grip strength (QMS, SAS, and HGS, respectively) using a hand held dynamometer and peripheral muscle endurance by a squat test were measured. Fatigue perception and health status were determined using the Fatigue Severity Scale (FSS) and the Leicester Cough Questionnaire (LCQ), respectively. RESULTS: Number of squats, 6MWT distance, and LCQ scores as well as lung function testing values and respiratory muscle strength were significantly lower and MMRC and FSS scores were significantly higher in patients with bronchiectasis than those of healthy subjects (p < 0.05). In bronchiectasis patients, QMS was significantly associated with HGS, MIP and MEP (p < 0.05). The 6MWT distance was significantly correlated to LCQ psychological score (p < 0.05). The FSS score was significantly associated with LCQ physical and total and MMRC scores (p < 0.05). The LCQ psychological score was significantly associated with MEP and 6MWT distance (p < 0.05). CONCLUSIONS: Peripheral muscle endurance, exercise capacity, fatigue and health status were adversely affected by the presence of bronchiectasis. Fatigue was associated with dyspnea and health status. Respiratory muscle strength was related to peripheral muscle strength and health status, but not to fatigue, peripheral muscle endurance or exercise capacity. These findings may provide insight for outcome measures for pulmonary rehabilitation programs for patients with bronchiectasis.

PAI-1 4G/5G gene polymorphism is associated with angiographic patency in ST-elevation myocardial infarction patients treated with thrombolytic therapy.

BACKGROUND: In this study, we examined the relationship between PAI-1 4G/5G polymorphism and patency of the infarct-related artery after thrombolysis in patients with ST-elevation myocardial infarction (STEMI). METHODS: Acute STEMI patients who received thrombolytic therapy within first 12 h were included in our study. The PAI-1 4G/5G promoter region insertion/deletion polymorphism was studied from venous blood samples. Patients with the PAI-1 4G/5G gene polymorphism were included in group 1 and the others were included in group 2. Coronary angiography was performed in all patients in the first 24 h after receiving thrombolytic therapy. Thrombolysis in myocardial infarction (TIMI) 0-1 flow in the infarct-related artery was considered as 'no flow', TIMI 2 flow as 'slow flow', and TIMI 3 flow as 'normal flow'. RESULTS: A total of 61 patients were included in our study. Thirty patients (49.2%) were positive for the PAI-1 4G/5G gene polymorphism, whereas 31 of them (50.8%) were in the control group. There were significantly more patients with 'no flow' (14 vs. 6; P=0.02) and less patients with 'normal flow' (8 vs. 19; P=0.02) in group 1. In addition, time to thrombolytic therapy (TTT) was maximum in the 'no flow' group and minimum in the 'normal flow' group (P=0.005). In the logistic regression analysis, TTT (odds ratio: 0.9898; 95% confidence interval: 0.982-0.997; P=0.004) and the PAI-1 4G/5G gene polymorphism (odds ratio: 4.621; 95% confidence interval: 1.399-15.268; P<0.01) were found to be independently associated with post-thrombolytic 'no flow'. CONCLUSION: The PAI-1 4G/5G gene polymorphism and TTT are associated independently with 'no flow' after thrombolysis in patients with STEMI.

Clonal monosomy 7 in a megakaryoblastic leukemia developed on the basis of Fanconi anemia.

A 13-year-old girl with a history of Fanconi anemia developed acute myeloid leukemia of the M7 subtype with a 45,XX,-7 karyotype, which is rare in M7 subtype. Treatment protocols were set up, but she died of sepsis and osteomyelitis during induction.