Bone marrow transplantation as therapy for ataxia-telangiectasia: a systematic review

Ataxia-Telangiectasia (A-T) is a rare autosomal recessive disorder, first reported in 1926, caused by a deficiency of ATM (Ataxia-Telangiectasia Mutated) protein. The disease is characterized by progressive cerebellar neurodegeneration, immunodeficiency, leukemia, and lymphoma cancer predisposition. Immunoglobulin replacement, antioxidants, neuroprotective factors, growth, and anti-inflammatory hormones are commonly used for A-T treatment, but, to date, there is no known cure. Bone marrow transplantation (BMT) is a successful therapy for several forms of diseases and it is a valid approach for tumors, hemoglobinopathies, autoimmune diseases, inherited disorders of metabolism, and other pathologies. Some case reports of A-T patients have shown that BMT is becoming a good option, as a correct engraftment of healthy cells can restore some aspects of immunologic capacity. However, due to a high risk of mortality as a result of a clinical and cellular hypersensitivity to ionizing radiation and radiomimetic drugs, a specific non-myeloablative conditioning is required before BMT. Although BMT might be considered as one promising therapy for the treatment of immunological defects and cancer prevention in selected A-T patients, the therapy is currently not recommended or recognized and the eligibility of A-T patients for BMT is a point to deepen and deliberate

Longitudinal umbilical vein blood flow changes in normal and growth-retarded fetuses

Objective. To explore whether the umbilical vein blood flow of growth-retarded fetuses with normal Doppler parameters changes over time differently to that of normally grown fetuses. Methods. Fifteen consecutive women whose fetus was diagnosed to be growth restricted were compared with 30 women whose fetus was normally grown. Two ultrasonographic evaluations were conducted at 2-weekly intervals (± 2 days) in all cases. At each sonographic evaluation, umbilical vein blood flow parameters were obtained by digital color Doppler velocity profile integration. To allow comparisons among fetuses, the umbilical vein blood flow per minute was normalized for abdominal circumference. Results. The absolute vein blood flow was lower in growth-retarded than in normally grown fetuses (209 ml/min ± 73 vs. 313 ml/min ± 72, p < 0.01). The median (range) umbilical vein blood flow normalized for abdominal circumference was significantly lower in growth-retarded than in normally grown fetuses at the first [0.70 (0.32; 1.15) vs. 1.11 (0.65; 2.07), p < 0.05] and at the second [0.71(0.30; 1.09) vs. 1.14 (0.69; 2.05), p < 0.05] sonographic evaluation. The difference in umbilical vein blood flow normalized for abdominal circumference between the second and the first examination was significantly lower in growth-retarded than in appropriate for gestational age fetuses [-0.005 (-0.08; 0.06) vs. 0.02 (-0.08; 0.1), p < 0.05]. Conclusion. This study demonstrates that umbilical vein blood flow normalized for biometric parameters is lower in growth-retarded fetuses than in healthy fetuses even in the absence of umbilical artery Doppler abnormalities

Cell Shortening and Calcium Homeostasis Analysis in Adult Cardiomyocytes via a New Software Tool

Intracellular calcium (Ca2+) is the central regulator of heart contractility. Indeed, it couples the electrical signal, which pervades the myocardium, with cardiomyocytes contraction. Moreover, alterations in calcium management are the main factors contributing to the mechanical and electrical dysfunction observed in failing hearts. So, simultaneous analysis of the contractile function and intracellular Ca2+ is indispensable to evaluate cardiomyocytes activity. Intracellular Ca2+ variations and fraction shortening are commonly studied with fluorescent Ca2+ indicator dyes associated with microscopy techniques. However, tracking and dealing with multiple files manually is time-consuming and error-prone and often requires expensive apparatus and software. Here, we announce a new, user-friendly image processing and analysis tool, based on ImageJ-Fiji/MATLAB® software, to evaluate the major cardiomyocyte functional parameters. We succeeded in analyzing fractional cell shortening, Ca2+ transient amplitude, and the kinematics/dynamics parameters of mouse isolated adult cardiomyocytes. The proposed method can be applied to evaluate changes in the Ca2+ cycle and contractile behavior in genetically or pharmacologically induced disease models, in drug screening and other common applications to assess mammalian cardiomyocyte functions

The centrosomal kinase NEK2 is a novel splicing factor kinase involved in cell survival

NEK2 is a serine/threonine kinase that promotes centrosome splitting and ensures correct chromosome segregation during the G2/M phase of the cell cycle, through phosphorylation of specific substrates. Aberrant expression and activity of NEK2 in cancer cells lead to dysregulation of the centrosome cycle and aneuploidy. Thus, a tight regulation of NEK2 function is needed during cell cycle progression. In this study, we found that NEK2 localizes in the nucleus of cancer cells derived from several tissues. In particular, NEK2 co-localizes in splicing speckles with SRSF1 and SRSF2. Moreover, NEK2 interacts with several splicing factors and phosphorylates some of them, including the oncogenic SRSF1 protein. Overexpression of NEK2 induces phosphorylation of endogenous SR proteins and affects the splicing activity of SRSF1 toward reporter minigenes and endogenous targets, independently of SRPK1. Conversely, knockdown of NEK2, like that of SRSF1, induces expression of pro-apoptotic variants from SRSF1-target genes and sensitizes cells to apoptosis. Our results identify NEK2 as a novel splicing factor kinase and suggest that part of its oncogenic activity may be ascribed to its ability to modulate alternative splicing, a key step in gene expression regulation that is frequently altered in cancer cells

Phosphodiesterase inhibitors: Could they be beneficial for the treatment of COVID-19?

In March 2020, the World Health Organization declared the severe acute respiratory syndrome corona virus 2 (SARS-CoV2) infection to be a pandemic disease. SARS-CoV2 was first identified in China and, despite the restrictive measures adopted, the epidemic has spread globally, becoming a pandemic in a very short time. Though there is growing knowledge of the SARS-CoV2 infection and its clinical manifestations, an effective cure to limit its acute symptoms and its severe complications has not yet been found. Given the worldwide health and economic emergency issues accompanying this pandemic, there is an absolute urgency to identify effective treatments and reduce the post infection outcomes. In this context, phosphodiesterases (PDEs), evolutionarily conserved cyclic nucleotide (cAMP/cGMP) hydrolyzing enzymes, could emerge as new potential targets. Given their extended distribution and modulating role in nearly all organs and cellular environments, a large number of drugs (PDE inhibitors) have been developed to control the specific functions of each PDE family. These PDE inhibitors have already been used in the treatment of pathologies that show clinical signs and symptoms completely or partially overlapping with post-COVID-19 conditions (e.g., thrombosis, inflammation, fibrosis), while new PDE-selective or pan-selective inhibitors are currently under study. This review discusses the state of the art of the different pathologies currently treated with phosphodiesterase inhibitors, highlighting the numerous similarities with the disorders linked to SARS-CoV2 infection, to support the hypothesis that PDE inhibitors, alone or in combination with other drugs, could be beneficial for the treatment of COVID-19

Umbilical vein blood flow in fetuses with normal and lean umbilical cord

Objective: To evaluate whether umbilical vascular coiling is correlated with the umbilical vein blood flow profile and to investigate if this is different between fetuses with a lean and those with a normal umbilical cord. Methods: Consecutive women with a singleton gestation who delivered at term and who underwent an ultrasound examination within 24 h from delivery were studied. Umbilical cord and vessel areas were calculated. Umbilical vein blood flow parameters were obtained by digital color Doppler velocity profile integration. After delivery, the umbilical coiling index was calculated. Results: One hundred and sixteen women were studied. Twelve (10.3%) had a lean umbilical cord (area < 10th centile). A significant correlation was found between the umbilical coiling index and the umbilical vein blood flow (r = 0.67, P < 0.001). A significant difference between fetuses with and without a lean cord was found in terms of: umbilical coiling index (0.18 ± 0.08 vs. 0.29 ± 0.09, P < 0.005), cord area (87.6 ± 5.1 mm2 vs. 200.6 ± 34.6 mm2, P < 0.001), Wharton's jelly amount (25.7 ± 10.3 mm2 vs. 122.1 ± 33.4 mm2, P < 0.001), umbilical vein blood flow (93.7 ± 17.8 ml/kg per min vs. 126.0 ± 23.4 ml/kg per min, P < 0.001), and umbilical vein blood flow mean velocity (6.6 ± 2.7 cm/s vs. 9.0 ± 3.6 cm/s, P < 0.05). The proportion of fetuses with an umbilical vein blood flow < 80 ml/kg per min was higher when the cord was lean than when it was normal (25% vs. 1.9%, P < 0.01). Conclusions: Lean umbilical cords differ from normal cords not only from a structural point of view but also in the umbilical vein blood flow characteristics. This could explain the increased incidence of intrapartum complications and fetal growth restriction among fetuses with a lean and/or hypocoiled cord

Ductus venosus blood flow velocity characteristics of fetuses with single umbilical artery

Objectives: Sonographic Doppler evaluation of the fetal ductus venosus has been proved to be useful in the evaluation of fetal cardiac function. The aim of this study was to investigate the ductus venosus blood flow profile in fetuses with single umbilical artery and to correlate it with the umbilical cord morphology. Methods: Fetuses at > 20 weeks' gestation with single umbilical artery who were otherwise healthy were consecutively enrolled into the study. The sonographic examination included evaluation of the following Doppler parameters: umbilical artery resistance index, maximum blood flow velocity of the ductus venosus during ventricular systole (S-peak) and atrial contraction (A-wave), ductus venosus time-averaged maximum velocity (TAMXV), and pulsatility index for veins (PIV). The cross-sectional area of the umbilical cord and its vessels were measured in all cases. The Doppler and morphometric values obtained were plotted on reference ranges. Results: A total of 88 fetuses with single umbilical artery were scanned during the study period. Of these 52 met the inclusion criteria. The S-peak velocity, A-wave velocity, and TAMXV were below the 5th centile for gestational age in 57.7%, 59.6%, and 57.7% of cases, respectively. The PIV was within the normal range in 80.1% of cases. The umbilical vein cross-sectional area of fetuses with single umbilical artery was above the 95th centile for gestational age in 34.6% cases. Conclusions: The ductus venosus blood flow pattern is different in fetuses with single umbilical artery from that in those with a three-vessel cord. This difference may be caused in part by the particular morphology of umbilical cords with a single artery. Copyright © 2003 ISUOG. Published by John Wiley & Sons, Ltd

Prenatal diagnosis of a lean umbilical cord: A simple marker for the fetus at risk of being small for gestational age at birth

Objective. The purpose of this study was to investigate whether the prenatal diagnosis of a 'lean' umbilical cord in otherwise normal fetuses identifies fetuses at risk of being small for gestational age (SGA) at birth and of having distress in labor. The umbilical cord was defined as lean when its cross-sectional area on ultrasound examination was below the 10th centile for gestational age. Method. Pregnant women undergoing routine sonographic examination were included in the study. Inclusion criteria were gestational age greater than 20 weeks, intact membranes, and singleton gestation. The sonographic cross-sectional area of the umbilical cord was measured in a plane adjacent to the insertion into the fetal abdomen. Umbilical artery Doppler waveforms were recorded during fetal apnea and fetal anthropometric parameters were measured. Results. During the study period, 860 patients met the inclusion criteria, of whom 3.6% delivered a SGA infant. The proportion of SGA infants was higher among fetuses who had a lean umbilical cord on ultrasound examination than among those with a normal umbilical cord (11.5% vs. 2.6%, p < 0.05). Fetuses with a lean cord had a risk 4.4-fold higher of being SGA at birth than those with a normal umbilical cord. After 25 weeks of gestation, this risk was 12.4 times higher when the umbilical cord was lean than when it was of normal size. The proportion of fetuses with meconium-stained amniotic fluid at delivery was higher among fetuses with a lean cord than among those with a normal umbilical cord (14.6% vs. 3.1%, p < 0.001). The proportion of infants who had a 5-min Apgar score < 7 was higher among those who had a lean cord than among those with normal umbilical cord (5.2% vs. 1.3%, p < 0.05). Considering only patients admitted in labor with intact membranes and who delivered an appropriate-for-gestational-age infant, the proportion of fetuses who had oligohydramnios at the time of delivery was higher among those who had a lean cord than among those with a normal umbilical cord (17.6% versus 1.3%, p < 0.01). Conclusion. We conclude that fetuses with a lean umbilical cord have an increased risk of being small for gestational age at birth and of having signs of distress at the time of delivery