Increased serum levels of macrophage colony-stimulating factor (M–CSF) in α-and β-thalassaemia syndromes: correlation with anaemia and monocyte activation

Abstract: Serum levels of M–CSF were determined by an ELISA method in 29 and 34 patients with HbH disease (α₁/α₂ or α₁/HbCS) or β⁰-thal/HbE, respectively, in 28 haematologically normal subjects and in five patients with anaemia due to iron deficiency or myelodysplasia. In HbH disease and β⁰-thal/HbE, M–CSF concentrations were significantly higher than those in the normal subjects [986 ± 138 and 1385 ± 133, respectively, vs. 500 ± 33 pg/ml (mean ± SEM); p <0.01, and p <0.001, respectively]. By contrast, in patients with anaemia due to iron deficiency, M–CSF levels were within the normal range. In HbH disease and in β⁰-thal/HbE, M–CSF levels correlated inversely with mean basal Hb values (r = –0.39, p = 0.05 and r = –0.60, p <0.001, respectively). In addition, in some of the HbH and β⁰-thal/HbE patients, monocyte ADCC activities towards red cells were tested and found to be approximately twice as high as those in normal controls [38.3±5.7 and 30.7 ± 4.6 vs. 17.8 ± 1.8 % specific lysis (mean ± SEM), respectively; p <0.01 and p <0.02, respectively]. When thalassaemic patients and normal controls were considered together there was a significant correlation between M–CSF levels and monocyte ADCC activities (r = 0.51, p <0.02). The results suggest that in HbH disease and in β⁰-thal/HbE, raised serum M–CSF contributes to the anaemia by enhancing the effector function of mononuclear phagocytes towards red cells.     

De novo chromosomal translocation t(3;5)(q13;q35) in an infertile man

Chromosomal rearrangements are rare structural abnormalities that are usually associated with male infertility or sterility. We describe here the clinical and cytogenetic studies carried out in a couple with repeated abortions. Cytogenetic analysis of the male partner showed a de novo chromosomal translocation t(3;5)(q13;q35) which could be involved in the meiotic errors resulting in reproductive failure.     

Nucleotide deletion in RHCE*cE (907delC) is responsible for a D- - haplotype in Hispanics

BACKGROUND: Lack of Cc and Ee expression is associated with either hybrid alleles in which regions of RHCE are replaced by RHD or nucleotide deletion(s) in RHCE. The former have been found as D– – phenotypes, and the latter as Rh_null when accompanied by deletion of RHD. We investigated RH in eight samples, three presenting as D– –, whose c–E– red blood cell (RBC) typing was discordant with the RHCE genotype that predicted c+E+. STUDY DESIGN AND METHODS: Serologic and molecular testing was performed by standard methods. CASES AND RESULTS: RBCs from Patient 1 were D+C?E?c+e+^w but DNA testing predicted E+. RBCs from Patients 2, 3, and 4 typed as D+C?E?c?e? but DNA testing predicted c+E+. All had alloantibodies strongly reactive with all RBCs tested except D– – and Rh_null. Patient 5 had anti‐c and anti‐E but DNA testing predicted she was c+E+. RBCs from three donors typed D+C+E?c?e+ with DNA testing predicting c+E+. All had RHCE*cE with deletion of nucleotide 907C in Exon 6 predicted to cause a premature stop codon at Amino Acid 303 (Leu303Stop). HphI polymerase chain reaction–restriction fragment length polymorphism was used to confirm the deletion and to screen 100 Hispanic, 100 Caucasian, and 100 African American donor samples. One additional example was found. CONCLUSIONS: A novel allele, RHCE*cE 907delC (ISBT provisional designation RHCE*03N.02), silences c and E and in the homozygous state resulted in a D– – phenotype and production of anti‐Rh17. All eight probands were Hispanic. The allele is associated with discrepant molecular typing, with an approximate frequency of 0.005 in Hispanics.     

Addressing gaps in pharmacovigilance practices in the antiretroviral therapy program in the Eastern Cape Province, South Africa

BackgroundThe use of antiretrovirals (ARVs) is associated with considerable concern regarding adverse drug reactions (ADRs), including both short- and long-term complications. Currently, there is a general underreporting of ADRs in South Africa. In May 2007, the Eastern Cape regional training centre introduced a pharmacovigilance plan for antiretroviral therapy (ART) to improve reporting practices in the area.ObjectivesThe aim of this study was to gain insight on attitudes and experiences regarding ADR detection and reporting among health care providers (HCPs) shortly after the first formal pharmacovigilance plan for ART was introduced.MethodsThree focus-group discussions were conducted with 12 HCPs. There were 7 nurses, 3 pharmacists, 1 doctor, and 1 auxiliary staff, all recruited from public hospitals and local health authorities in 2 towns in the Eastern Cape Province, South Africa.ResultsIt was observed that senior HCPs knew that ADRs from ARVs should be reported formally, whereas junior staff did not demonstrate the same knowledge. The participants thought that underreporting from the primary health care level was a major problem. HCPs identified various reasons for underreporting ADRs: problems with filling out the reporting form, lack of training, high workload, lack of feedback, and fears of not being taken seriously. Lack of adequate training in pharmacovigilance led to lack of confidence among the professional nurses in managing ADRs.ConclusionsIncreased focus on pharmacovigilance with adequate, continuous training, especially for nurses managing down-referred patients in primary health care on identification and management of ADRs, and practical use of the ADR form may be necessary to improve pharmacovigilance practices in the area.     

The dawn of precision medicine in HIV: state of the art of pharmacotherapy

ABSTRACT

Introduction: Combination antiretroviral therapy (ART) reduces viral load to under the limit of detection, successfully decreasing HIV-related morbidity and mortality. Due to viral mutations, complex drug combinations and different patient response, there is an increasing demand for individualized treatment options for patients.

Areas covered: This review first summarizes the pharmacokinetic and pharmacodynamic profile of clinical first-line drugs, which serves as guidance for antiretroviral precision medicine. Factors which have influential effects on drug efficacy and thus precision medicine are discussed: patients’ pharmacogenetic information, virus mutations, comorbidities, and immune recovery. Furthermore, strategies to improve the application of precision medicine are discussed.

Expert opinion: Precision medicine for ART requires comprehensive information on the drug, virus, and clinical data from the patients. The clinically available genetic tests are a good starting point. To better apply precision medicine, deeper knowledge of drug concentrations, HIV reservoirs, and efficacy associated genes, such as polymorphisms of drug transporters and metabolizing enzymes, are required. With advanced computer-based prediction systems which integrate more comprehensive information on pharmacokinetics, pharmacodynamics, pharmacogenomics, and the clinically relevant information of the patients, precision medicine will lead to better treatment choices and improved disease outcomes.     

Circadian Patterns of ST Elevation Myocardial Infarction in the New Millennium

Objective

Nearly four decades ago, a circadian pattern of acute myocardial infarction (AMI) with a peak in the early morning waking hours was described. The goal of the present study was to determine whether major changes in lifestyle and significant advances in medical therapy have altered this pattern in the intervening years.

Design

Retrospective chart review.

Setting

Tertiary care hospital in central Wisconsin.

Methods

We examined circadian patterns of ST elevation myocardial infarction (STEMI) in 519 patients diagnosed with STEMI over a 5-year period. Time of symptom onset was obtained from patient self-reports in the medical record and was recorded over 24 hours.

Results

We observed a circadian pattern of STEMI occurrence with a morning peak at approximately 11:30 AM. This pattern was highly significant in patients who were not using beta-blockers (P <0.0001) and had no history of diabetes (P <0.0001), but was otherwise absent. The circadian pattern appeared to be attenuated in patients of a younger age, female gender, or who used statins or aspirin. Peak STEMI occurrence was earlier in smokers than non-smokers.

Conclusions

Despite significant lifestyle changes and medical advances in the nearly four decades since a circadian pattern of AMI occurrence was first described, patients with STEMI had a circadian pattern of symptom onset with a morning peak. Use of beta-blockers and a history of diabetes mellitus abolished this pattern. Other modifying factors, including medications, age, and gender attenuated, but did not abolish, the circadian pattern.