Role of Genomic Biomarkers in Increasing Fetal Hemoglobin Levels Upon Hydroxyurea Therapy and in β-Thalassemia Intermedia: A Validation Cohort Study

Hemoglobinopathies exhibit a remarkable phenotypic diversity in terms of disease severity, while individual genetic background plays a key role in differential response to drug treatment. In the last decade, genomic variants in genes located within, as well as outside the human β-globin cluster have been shown to be significantly associated with Hb F increase, in relation to hydroxyurea (HU) therapy in patients with these diseases. Here, we aim to determine the effect of genomic variants located in genes, such as MAP3K5, ASS1, NOS2A, TOX, PDE7B, NOS1, FLT1 and ARG2, previously shown to modulate fetal hemoglobin (Hb F) levels in patients with β type hemoglobinopathies and reflecting disease severity and response to HU therapy in an independent cohort of Greek patients with these diseases. We recruited and genotyped 45 β-thalassemia patients (β-thal), either transfusion-dependent (TDT) or non transfusion-dependent (NTDT), 42 Hb S (HBB: c.20A>T)-β-thal compound heterozygotes, who were treated with HU, as well as 53 healthy individuals, all of Hellenic origin. Our study showed that genomic variants of the MAP3K5, NOS2A and ARG2 gene are associated with HU therapy efficacy in Hb S-β-thal compound heterozygotes. We have also shown that FLT1 and ARG2 genomic variants are associated with the mild phenotype of NTDT patients. Our findings provide evidence that MAP3K5, NOS2A, ARG2 and FLT1 genomic variants could be considered as genomic biomarkers to predict HU therapy efficacy in Hb S-β-thal compound heterozygotes and also to describe disease severity in patients with β type hemoglobinopathies.     

Danazol therapy in patients with chronic idiopathic thrombocytopenic purpura: long-term results

BACKGROUND: Adults with chronic idiopathic thrombocytopenic purpura (ITP) in whom standard-dose corticosteroids and splenectomy have failed or who have contraindications to these therapies often require further treatment for life-threatening thrombocytopenia or bleeding. We studied whether danazol, an attenuated androgen, is useful in this setting. METHODS: To assess both clinical outcome and tolerance issues, 57 patients who had refractory chronic ITP (n = 27) or who had contraindications to splenectomy or corticosteroids or who refused these therapeutic options (n = 30) were studied. RESULTS: Thirty-eight patients experienced a partial or complete response to therapy (67%), among whom 27 (46%) remained in remission at a median (+/- SD) of 119 +/- 45 months. Treatment tolerance was acceptable, although severe adverse events were reported in 9 patients (16%). CONCLUSION: Our findings suggest that danazol therapy may be beneficial in the management of refractory chronic ITP or when there are contraindications to splenectomy or corticosteroids (or both).     

Maternal hemoglobin at 27–29 weeks’ gestation and severity of pre-eclampsia

Objective: To examine the relationship between maternal hemoglobin concentration (Hb) at 27–29 weeks’ gestation and severity of pre-eclampsia (PE).

Methods: This was a retrospective study of maternal Hb at 27–29 week in 497 pregnancies that developed PE and 497 healthy controls with normal pregnancy outcomes. Multiple regression analysis was used to examine the association between HB and maternal characteristics and severity of PE classified according to gestation at delivery, birth weight and prevalence of abnormal peripartum maternal creatinine, aspartate transaminase and platelet count.

Results: There was no significant difference in median Hb between the PE and control groups. Multiple regression analysis in the PE group showed that significant prediction for Hb was provided by Afro-Caribbean race, gestation at delivery, maternal platelet count <2.5th percentile and birth weight, but not serum creatinine or aspartate transaminase above the 97.5th percentile. Increased Hb was observed in both small and large for gestational age neonates.

Conclusion: In PE, Hb at 27–29 weeks is influenced by birth weight, maternal characteristics and platelet count.     

Failure rate of self-ligating and edgewise brackets bonded with conventional acid etching and a self-etching primer: a prospective in vivo study

The purpose of this study was to comparatively assess the failure rate of self-ligating and edgewise brackets bonded with a self-etching adhesive and conventional phosphoric acid in patients followed for 12 months of active treatment. Sixty-two patients with complete permanent dentitions, similar treatment plans, and mechanotherapy were selected for the study. GAC Microarch edgewise brackets and ORMCO Damon2 brackets were bonded using a split mouth design, using the 3M Transbond Plus Self-etching primer (SEP) and Transbond XT paste; and conventional acid etching, with Orthosolo primer and Enlight paste, applied at an alternate sequence so that the adhesives were equally distributed on the maxillary and mandibular right and left quadrants. Data analysis was conducted with the use of logistic regression modeling. No difference in failure incidence was noted for either bracket-adhesive and mandibular or maxillary arch combinations, whereas a statistically significant difference was shown for right-sided appliances. On the basis of the results of this study, bonding of self-ligating brackets with SEP does not demonstrate higher probability for failure relative to standard bonding procedures and conventional brackets.     

Rituximab-induced nonspecific interstitial pneumonia like reaction in a patient with idiopathic thrombocytopenic purpura

Rituximab, a chimeric anti-CD20 IgG1 monoclonal antibody, is an effective treatment for haematological autoimmune diseases such as idiopathic thrombocytopenic purpura (ITP). A 72-year-old man was diagnosed with idiopathic thrombocytopenic purpura (ITP). After receiving 4 cycles of rituximab in one month complete response was achieved. However, three weeks after the last infusion he presented to the haematology department with fever, productive cough and dyspnea and severe hypoxemia. HRCT of the thorax revealed patchy areas of ground glass opacities throughout both lungs and small peripheral consolidations were seen. Transbronchial biopsy showed interstitial thickening and type II pneumocyte activation with interstitial pneumonia. Bronchoalveolar lavage showed increased eosinophils. The patient was treated with three pulses of 1 gr iv methylprednisolone and then gradually switched to 15 mg of prednisolone for 3 months. The dyspnea and tachypnea gradually improved, in addition to blood oxygenation and a follow up HRCT 3 months later showed a significant resolution of lesions.Severe lung toxicity like acute respiratory distress syndrome, cryptogenic organizing pneumonia, pneumonitis, and interstitial lung disease are very rare, with most of the knowledge coming from case reports. Rituximab-induced interstitial lung disease (R-ILD) is a rare complication. To the best of our knowledge, 23 cases of R-ILD have been reported in the literature; 22 of them were treated with R-CHOP for NHL and only one was receiving rituximab for ITP. We report the second case to develop this complication for a non-malignant disorder.     

Performance of Greek demented and nondemented subjects on the Greek version of the Mattis Dementia Rating Scale. A validation study

A translated version of the Mattis Dementia Rating Scale (DRS) into Greek ((DRS-GR) was applied to a sample of Greek population (N = 356) comprising normal middle-aged and elderly subjects (controls), as well as patients suffering from Parkinson's (PD) and Alzheimer's disease (AD) to test its reliability and validity. A well-known dementia screening instrument, the Mini Mental State Examination test (MMSE), and a nonverbal measure of abstract reasoning, the Raven Coloured Progressive Matrices, were employed as measures of DRS-GR concurrent validity. Reliability analysis was satisfactory with Cronbach's alpha reaching 0.82 and item to total correlations yielding high coefficients for most items. DRS-GR scores were influenced by age and education, but not by gender. Correlation between MMSE and the total DRS-GR score was significant in patients and normal controls, but correlation between DRS-GR and RCPM was significant in AD and nondemented PD only. Specificity and sensitivity for dementia screening, calculated on a Receiver Operating Characteristic curve, with a cut-off score the mean value minus two standard deviations, corrected for age and education, was 96% and 80%, respectively. Our preliminary findings show that DRS-GR is a reliable and well-adapted instrument for clinical application in the Greek population.     

Sacroiliac joints: anatomical variants on CT

The purpose of this work was to examine the type and prevalence of anatomical variants of the sacroiliac joints (SJs) in patients without SJ disease on CT examinations. The study comprised 534 consecutive patients undergoing pelvic CT with various indications not related to diseases that could involve the SJ. Images printed on bone window settings were evaluated with reference to any deviation from the usual appearance of the SJ. Physical data and history of low back pain were recorded in each patient. Six types of anatomical variants were observed: accessory joints in 102 patients (19.1%), "iliosacral complex" in 31 (5.8%), bipartite iliac bony plate in 22 (4.1%), crescent-like iliac bony plate in 20 (3.7%), semicircular defects at the sacral or iliac side in 16 (3%), and ossification centers in 3 patients (0.6%). Accessory joints were more common in obese than in normal-weight individuals (p < 0.05) and in older than younger (<60 years) patients (p < 0.001) and presented degenerative alterations especially in patients with episodes of low back pain. Three of these variants (iliosacral complex, bipartite iliac bony plate, and crescent-like iliac bony plate) had higher incidence in women than in men (p < 0.05) and were not associated with degenerative changes. Knowledge of the normal variations in the SJ appearance broadens the understanding of SJ anatomy, facilitating image interpretation.     

Cdt1 overexpression drives colorectal carcinogenesis through origin overlicensing and DNA damage

Chromatin licensing and DNA replication factor 1 (CDT1), a protein of the pre-replicative complex, is essential for loading the minichromosome maintenance complex (MCM) helicases onto the origins of DNA replication. While several studies have shown that dysregulation of CDT1 expression causes re-replication and DNA damage in cell lines, and CDT1 is highly expressed in several human cancers, whether CDT1 deregulation is sufficient to enhance tumorigenesis in vivo is currently unclear. To delineate its role in vivo, we overexpressed Cdt1 in the mouse colon and induced carcinogenesis using azoxymethane/dextran sodium sulfate (AOM/DSS). Here, we show that mice overexpressing Cdt1 develop a significantly higher number of tumors with increased tumor size, and more severe dysplastic changes (high-grade dysplasia), compared with control mice under the same treatment. These tumors exhibited an increased growth rate, while cells overexpressing Cdt1 loaded greater amounts of Mcm2 onto chromatin, demonstrating origin overlicensing. Adenomas overexpressing Cdt1 showed activation of the DNA damage response (DDR), apoptosis, formation of micronuclei, and chromosome segregation errors, indicating that aberrant expression of Cdt1 results in increased genomic and chromosomal instability in vivo, favoring cancer development. In line with these results, high-level expression of CDT1 in human colorectal cancer tissue specimens and colorectal cancer cell lines correlated significantly with increased origin licensing, activation of the DDR, and microsatellite instability (MSI). © 2022 The Pathological Society of Great Britain and Ireland.