Prolonged survival in patients with treatment-related leukemia

We summarize the findings in 2 patients with treatment-related acute leukemia, who have had prolonged disease-free survival (62 and 84 months, respectively). The 1st patient developed acute myelogenous leukemia after receiving whole pelvic radiation and chlorambucil daily for 7 yr, as treatment for Stage III ovarian carcinoma; and the 2nd patient received cyclophosphamide, doxorubicin, vincristine and prednisone for Stage IV non-Hodgkin's lymphoma and subsequently developed acute monoblastic leukemia. The most remarkable finding is the unusually prolonged survival of both these patients with what is generally considered to be a very poor prognostic type of leukemia (mean survival less than 6 months). One predictive factor may have been the normal chromosomes in 1 patient. Since prolonged survival is possible in treatment-related leukemia, it is recommended that aggressive induction chemotherapy be at least considered for all such patients.     

Exploring genotype‐phenotype relationships in the CDKL5 deficiency disorder using an international dataset

Characterized by early‐onset seizures, global developmental delay and severe motor deficits, CDKL5 deficiency disorder is caused by pathogenic variants in the cyclin‐dependent kinase‐like 5 gene. Previous efforts to investigate genotype‐phenotype relationships have been limited due to small numbers of recurrent mutations and small cohort sizes. Using data from the International CDKL5 Disorder Database we examined genotype‐phenotype relationships for 13 recurrent CDKL5 variants and the previously analyzed historic variant groupings. We have applied the CDKL5 Developmental Score (CDS) and an adapted version of the CDKL5 Clinical Severity Assessment (CCSA), to grade the severity of phenotype and developmental outcomes for 285 individuals with CDKL5 variants. Comparisons of adapted CCSA and CDS between recurrent variants and variant groups were performed using multiple linear regression adjusting for age and sex. Individuals with the missense variant, p.Arg178Trp, had the highest mean adapted CCSA and lowest mean developmental scores. Other variants producing severe phenotypes included p.Arg559* and p.Arg178Gln. Variants producing milder phenotypes included p.Arg134*, p.Arg550*, and p.Glu55Argfs*20. There are observed differences in phenotype severity and developmental outcomes for individuals with different CDKL5 variants. However, the historic variant groupings did not seem to reflect differences in phenotype severity or developmental outcomes as clearly as analyzed by individual variants.     

Antigen presentation,autoantibody production,and therapeutic targets in autoimmune liver disease

The liver is an important immunological organ that controls systemic tolerance. The liver harbors professional and unconventional antigen-presenting cells that are crucial for tolerance induction and maintenance. Orchestrating the immune response in homeostasis depends on a healthy and well-toned immunological liver microenvironment, which is maintained by the crosstalk of liver-resident antigen-presenting cells and intrahepatic and liver-infiltrating leukocytes. In response to pathogens or autoantigens, tolerance is disrupted by unknown mechanisms. Intrahepatic parenchymal and nonparenchymal cells exhibit unique antigen-presenting properties. The presentation of microbial and endogenous lipid-, metabolite- and peptide-derived antigens from the gut via conventional and nonconventional mechanisms can educate intrahepatic immune cells and elicit effector responses or tolerance. Perturbation of this balance results in autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. Although the exact etiologies of these autoimmune liver diseases are unknown, it is thought that the disruption of tolerance towards self-antigens and microbial metabolites and lipids, as well as alterations in bile acid composition, may result in changes in effector cell activation and polarization and may reduce or impair protective anti-inflammatory regulatory T and B cell responses. Additionally, the canonical and noncanonical transmission of antigens and antigen:MHC complexes via trogocytosis or extracellular vesicles between different (non) immune cells in the liver may play a role in the induction of hepatic inflammation and tolerance. Here, we summarize emerging aspects of antigen presentation, autoantibody production, and the application of novel therapeutic approaches in the characterization and treatment of autoimmune liver diseases.     

Pulmonary function indices in children with sickle cell anemia in Enugu,south-east Nigeria

Objectives:

To determine the pulmonary function indices of children with sickle cell anemia (SCA) attending the pediatric sickle cell clinic at the University of Nigeria Teaching Hospital, Enugu, south-east Nigeria and to compare these indices with the results obtained from other regions.

Methods:

A case control study of lung function in children with SCA aged 6-20 years. The study was carried out in the University of Nigeria/University of Nigeria Teaching Hospital, Enugu State, Nigeria between October 2014 and January 2015. Measurements of the peak expiratory flow rate, forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) were evaluated.

Results:

A total of 80 subjects were recruited into the study, comprising 40 homozygous HbSS (hemoglobin SS) patients and an equal number of controls. Children with SCA had statistically lower values of FEV1 (1.6±0.52), FVC (1.76±0.95), and peak expiratory flow rate (PEFR) (309.00±82.64) when compared with normal hemoglobin genotype FEV1 (12.01±0.53), FVC (2.12±0.54), and PEFR (364.10±87.85). The mean FVC, FEV1/FVC, and PEFR were also higher in the male control group compared with the HbSS male group, but these differences were not statistically significant. Female controls had significantly larger FEV1, FVC, and PEFR values compared with the HbSS females.

Conclusion:

The lung function indices were significantly lower in children and adolescents with SCA compared with the matched controls with a hemoglobin genotype AA.Sickle cell anemia (SCA) is a genetic hematological disorder characterized by red blood cells that assume an abnormal, rigid, sickle shape.1 This hereditary disorder contributes the equivalent of 3.4% mortality in children aged <5 years worldwide or 6.4% in Africa.2 The prevalence of SCA in Nigeria ranges from 0.4-3%.3 Approximately 85% of sickle cell disorders and >70% of all affected births occur in Africa.4 It is worth noting that at least 5.2% of the world population carry a significant trait. The clinical consequence of SCA results from obstruction of the microvasculature by the sickle cells and red blood cell hemolysis, which causes multi-systemic manifestation. The lungs are affected in a variety of ways by these pulmonary insults, and recurrence overtime may leave the lungs with chronic interstitial, parenchymal, or vascular damage that compromises pulmonary function.5,6 It has been documented that the prevalence of hypoxemia among SCA children was 13%.4 This prevalence was attributable to the chronic anemic state, micro vascular occlusion of the circulation by sickle hemoglobin, and constant pertubation of the endothelial membrane, and consequent elaboration of endothelial molecules, which are commonly seen among SCA children, especially those with various types of vaso-occlusive episodes.7 This is defined as bone and joint pain or multiple sites of pain needing analgesics or hospitalization.8 Acute and chronic pulmonary complications occur frequently in patients with SCA, and contribute to morbidity and mortality later in life. Although the pathogenesis of chronic pulmonary disease in sickle cell disease (SCD) has not been clearly defined, recurrent microvascular obstruction resulting in the development of pulmonary hypertension, endothelial dysfunction, and parenchymal fibrosis are probably the primary mechanisms.6 There is increasing evidence that repeated episodes of acute chest syndrome (ACS) may cause permanent damage to the pulmonary parenchyma and vasculature. Repeated attacks of ACS are a major risk factor for the development of sickle cell chronic lung disease. Studies of lung function in SCD have also demonstrated a restrictive defect,8,9 while a reduction in the total lung capacity (TLC) of 50% has been reported in advanced forms. Acute chest syndrome refers to a spectrum of pulmonary pathology having in common, chest pain, fever, dyspnea with abnormal clinical, and radiologic chest signs as well as leucocytosis.10,11 It is the most common cause of death in children with sickle cell anemia over 10 years of age.12 The etiology of ACS is not clear, lung and bone infarction, infection, and acute pulmonary sequestration, among other possible causes have been proposed.10 In children with sickle anemia in steady state, the major abnormality in pulmonary function is a restrictive pathology, characterized by a slight decrease in total lung capacity, with attendant ventilation perfusion mismatch.10 This can cause a defect in diffusion capacity for carbon monoxide.10 These abnormalities worsen with age and are associated with increases in pulmonary-artery pressures.11 Whereas some studies have documented impaired lung function in SCA (hemoglobin SS) patients,8-10 previous studies8-10 reported what appears to be contrasting findings when the lung function in children with SCA and those of healthy controls with normal hemoglobin genotype were compared. It is therefore necessary that ventilatory function studies be undertaken in this parts of the world to see if there is any difference with known values in other part of the world. In this study, we determine the impact of SCA on the pulmonary function indices in patients attending the pediatric sickle cell clinic at the University of Nigeria Teaching Hospital (UNTH) Enugu, south-east Nigeria and compare it with matched controls and other studies. Many studies have described and assessed the pattern of pulmonary function in SCD from childhood to adulthood, but much is not known on this topic in South Eastern Nigeria. Most of the original studies are from western Nigeria.13,14 This study could therefore corroborate or refute regional or ethnic differences in lung function in children with SCD. The study hypothesis seeks to answer the following questions? Do children with SCA attending UNTH Enugu present with any alteration in lung function? If they do, is there any gender and age difference? Are these lung volume findings similar to that obtained from other region?     

Helicobacter pylori-Associated Upper Gastrointestinal Disease in Saudi Arabia: A Pathologic Evaluation of 298 Endoscopic Biopsies from 201 Consecutive Patients

In a prospective study, histopathological examination 298 upper gastrointestinal (UGI) biopsies, obtained from 201 consecutive patients, was made. Patients were referred with mild to severe dyspeptic symptoms. The aim of the study was to compare the rate of identification of Helicobacter pylori (H. pylori) in the histologically normal gastric mucosa with that in histologically confirmed gastritis or peptic ulcer disease. The gastroduodenal mucosa was histologically normal in 35 patients (17.4%); among those patients, H. pylori was identified in only three (9%). Chronic gastritis was histologically confirmed in 162 patients (80.6%). H. pylori was identified in 123 (76%) of those patients. The difference was statistically significant (p less than 0.00001). Furthermore, when cases with a histological diagnosis of superficial chronic active gastritis (SCAG) are considered separately, the identification rate of H. pylori increases to 88% (121 of 137). When this rate is compared with that of 8% (two of 25), found in superficial chronic quiescent gastritis (SCQG), the difference is highly significant (p less than 0.00001). Of 38 endoscopically diagnosed peptic ulcers, H. pylori was identified in the gastric mucosa of 34 (89%). The organisms were always seen in the antral gastric mucosa, but never in duodenal mucosa. Identification of H. pylori correlates significantly with the histologic activity of chronic gastritis, in both peptic ulcer disease and non-ulcer dyspepsia.     

Replication of RYR3 gene polymorphism association with cIMT among HIV-infected whites

To replicate the association of variants in RYR3 gene with common carotid intima-media thickness (cIMT), a surrogate marker of atherosclerosis, we genotyped single nucleotide polymorphisms (SNPs) rs2229116 and rs7177922 in a sub-population of 244 HIV-positive and HIV-negative men. SNP rs2229116 was associated with common cIMT in HIV infected white men after adjusting for age and use of stavudine (d4T). The association was more evident at younger ages and decreased among older individuals.     

Effects of resistance exercise training on resting and post-exercise forearm blood flow and wave reflection in overweight and obese women

The vascular responses to acute resistance exercise and resistance exercise training (RET) in overweight women are unclear. Therefore, the purpose of this study was to examine the vasodilatory and wave reflection responses to acute resistance exercise before and after RET. In all, 24 overweight/obese (28.5±0.6?kg?m(-2)) women (44±1 years of age) volunteered for this study. Forearm blood flow (FBF), vasodilatory capacity in response to reactive hyperemia (peak FBF) and wave reflection (radial tonometry) were measured, before and 15?min after five sets of leg press at 10-repetition maximum (RM). Measures of pulse wave reflection included the augmentation index (AIx) and the time of the reflected wave (Tr). Measurements were collected at baseline, after a 4-week control period (before RET) and after 12 weeks of whole-body RET using three sets of five exercises at 50-60% of 1-RM. There were no differences in vascular measurements at baseline or before RET for any variable. Resting FBF (66.7%) and peak FBF (51.6%) increased significantly (P<0.05) after RET compared with before RET. Post-exercise FBF (48.9%) and peak FBF (41.1%) also increased significantly (P<0.05) after RET compared with before RET. Post-exercise AIx decreased significantly (P<0.05), whereas Tr increased significantly (P<0.05) compared with rest at all time points. However, AIx and Tr were unaltered by RET. The 12-week whole-body RET increased the resting and post-exercise FBF as well as vasodilatory capacity without changing wave reflection in premenopausal overweight women. RET may be an important non-pharmacological therapy for reducing cardiovascular risk in overweight and obese premenopausal women.