Successful Treatment of Congenital Erythropoietic Porphyria Using Matched Unrelated Hematopoietic Stem Cell Transplantation

Congenital erythropoietic porphyria (CEP), or Günther's disease, is an inborn error of metabolism produced by a deficiency of uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme biosynthesis pathway. This enzymatic defect induces the accumulation of isomer I porphyrins in erythrocytes, skin, and tissues, producing various clinical manifestations. Severe cases are characterized by extreme photosensitivity, causing scarring and mutilations, and by hemolytic anemia, reducing life expectancy. CEP is caused by mutations in the UROS gene, and one of the most severe forms of the disease is associated with a cysteine to arginine substitution at residue 73 of the protein (C73R). CEP has been successfully treated only by the transplantation of hematopoietic precursors. We report the case of a male infant with severe postdelivery symptoms diagnosed with CEP and found to be homozygous for the C73R mutation. He underwent successful allogeneic bone marrow transplantation from a matched unrelated donor at 7 months of age. The hemolytic anemia was corrected and the porphyrin overproduction was significantly reduced. The patient remained asymptomatic after 1 year. This new case confirms that patients with severe CEP can benefit from early postnatal hematopoietic stem cell transplantation.     

Hematopoietic Cell Transplantation Comorbidity Index Predicts Outcomes in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes Receiving CD34+ Selected Grafts for Allogeneic Hematopoietic Cell Transplantation

To evaluate the association between the hematopoietic cell transplantation-comorbidity index (HCT-CI) and the recently developed age-adjusted HCT-CI (HCT-CI/age) and transplant outcomes in the setting of CD34-selected allogeneic HCT, we analyzed a homogeneous population of patients undergoing allogeneic HCT with CD34-selected grafts for acute myeloid leukemia and myelodysplastic syndrome (n?=?346). Median HCT-CI and HCT-CI/age scores were 2 (percentile 25 to 75, 1 to 4) and 3 (percentile 25 to 75, 1 to 5), respectively. Higher HCT-CI and HCT-CI/age scores were associated with higher nonrelapse mortality (NRM) and lower overall survival (OS). The HCT-CI distinguished 2 risk groups (0 to 2 versus ≥3), whereas, with the HCT-CI/age, there was a progressive increase in NRM and decrease in OS with increasing scores in all 4 groups (0 versus 1 to 2 versus 3 to 4 versus ≥5). Higher scores in both models were associated with lower chronic graft-versus-host disease relapse-free survival but not with higher relapse. Both models showed a promising predictive accuracy for NRM (c??= .616 for HCT-CI and c??=?.647 for HCT-CI/age). In conclusion, the HCT-CI and HCT-CI/age predict transplant outcomes in CD34-selected allo-HCT, including NRM, OS, and chronic graft-versus-host disease relapse-free survival and may be used to select appropriate patients for this approach.     

Harm Reduction Behaviors Among Young Polysubstance Users at Raves

ABSTRACT. Background: Raves may be considered recreational settings in which drug use and health risks related to polydrug use are higher than in others. Harm reduction behaviors implemented by ravers are of particular relevance in reducing such risks. This study analyzes harm reduction behaviors and their relationship to raver polysubstance use patterns. Methods: Cross-sectional study of 248 ravers recruited at underground raves in Andalusia (Spain). A questionnaire was developed to collect information about their sociodemographics, drug use, and harm reduction behaviors. Results: The results show that ravers employ harm reduction behaviors for minimizing drug-related harm. Nevertheless, only a small minority of the participants frequently employed harm reduction behavior for polysubstance use as well. Ravers identified as high polysubstance users protected themselves significantly less than those identified as low polysubstance users. Conclusions: This study provides empirical information that may be useful for harm reduction intervention in a hidden and hard-to-reach population like rave attendees. The results point to the need to inform and increase harm reduction behavior specifically aimed at polysubstance use by ravers, especially among more frequent users. Future directions for research are also suggested.     

Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene

OBJECTIVES: There is increasing evidence that polymorphism of the ABCB1 (MDR1) gene contributes to interindividual variability in bioavailability and tissue distribution of P-glycoprotein substrates. The aim of the present study was to (1) identify and describe novel variants in the ABCB1 gene, (2) understand the extent of variation in ABCB1 at the population level, (3) analyze how variation in ABCB1 is structured in haplotypes, and (4) functionally characterize the effect of the most common amino acid change in P-glycoprotein. METHODS AND RESULTS: Forty-eight variant sites, including 30 novel variants and 13 coding for amino acid changes, were identified in a collection of 247 ethnically diverse DNA samples. These variants comprised 64 statistically inferred haplotypes, 33 of which accounted for 92% of chromosomes analyzed. The two most common haplotypes, ABCB1*1 and ABCB1*13, differed at six sites (three intronic, two synonymous, and one non-synonymous) and were present in 36% of all chromosomes. Significant population substructure was detected at both the nucleotide and haplotype level. Linkage disequilibrium was significant across the entire ABCB1 gene, especially between the variant sites found in ABCB1*13, and recombination was inferred. The Ala893Ser change found in the common ABCB1*13 haplotype did not affect P-glycoprotein function. CONCLUSION: This study represents a comprehensive analysis of ABCB1 nucleotide diversity and haplotype structure in different populations and illustrates the importance of haplotype considerations in characterizing the functional consequences of ABCB1 polymorphisms.     

Oswestry Disability Index is a better indicator of lumbar motion than the Visual Analogue Scale

Background contextLumbar pathology is often associated with axial pain or neurologic complaints. It is often presumed that such pain is associated with decreased lumbar motion; however, this correlation is not well established. The utility of various outcome measures that are used in both research and clinical practice have been studied, but the connection with range of motion (ROM) has not been well documented.PurposeThe current study was performed to assess objectively the postulated correlation of lumbar complaints (based on standardized outcome measures) with extremes of lumbar ROM and functional ROM (fROM) with activities of daily living (ADLs) as assessed with an electrogoniometer.Study design/settingThis study was a clinical cohort study.Patient sampleSubjects slated to undergo a lumbar intervention (injection, decompression, and/or fusion) were enrolled voluntarily in the study.Outcome measuresThe two outcome measures used in the study were the Visual Analogue Scale (VAS) for axial extremity, lower extremity, and combined axial and lower extremity, as well as the Oswestry Disability Index (ODI).MethodsPain and disability scores were assessed with the VAS score and ODI. A previously validated electrogoniometer was used to measure ROM (extremes of motion in three planes) and fROM (functional motion during 15 simulated activities of daily living). Pain and disability scores were analyzed for statistically significant association with the motion assessments using linear regression analyses.ResultsTwenty-eight men and 39 women were enrolled, with an average age of 55.6 years (range, 18–79 years). The ODI and VAS were associated positively (p<.001). Combined axial and lower extremity VAS scores were associated with lateral and rotational ROM (p<.05), but not with flexion/extension or any fROM. Similar findings were noted for separately analyzed axial and lower extremity VAS scores. On the other hand, the ODI correlated inversely with ROM in all planes, and fROM in at least one plane for 10 of 15 ADLs (p<.05).ConclusionsExtremes of lumbar motion and motions associated with ADLs are of increasing clinical interest. Although the ODI and VAS are associated with each other, the ODI appears to be a better predictor of these motion parameters than the VAS (axial extremity, lower extremity, or combined) and may be more useful in the clinical setting when considering functional movement parameters.