Hemopoietic cell transplantation as curative therapy of myelodysplastic syndromes and myeloproliferative disorders

Hemopoietic cell transplantation (HCT) is presently the only therapy with curative potential for myelodysplastic syndromes (MDS) and myeloproliferative disorders (MPD). Among patients with less advanced MDS, 3-year survival figures of 65-80% are achieved with human leukocyte antigen (HLA)-identical related and unrelated donors. The probability of relapse is less than 5%. Among patients with advanced MDS (> or = 5% marrow blasts), about 35-50% of patients transplanted from related donors, and 25-40% transplanted from unrelated donors are surviving in remission beyond 3 years. The incidence of post-transplant relapse is 10-35%. Criteria of the International Prognostic Scoring System (IPSS) predict relapse and survival following HCT. In patients with myelofibrosis, allogeneic transplantation is successful in 50-80%, if performed during the fibrosis stage. The success rate declines to 25-40%, if the transplant is performed after leukemic transformation has occurred. About 40% of patients with chronic myelomonocytic leukemia survive in remission after transplantation. Results obtained with low/reduced-intensity conditioning regimens are encouraging because of a low incidence of early mortality. However, retrospective analyses comparing low intensity and conventional conditioning regimens have yielded inconclusive results regarding long-term outcome. Co-morbid conditions present at the time of transplantation have a major negative effect on transplant outcome. Controlled prospective trials are needed.     

Group A streptococcal infections of the skin: molecular advances but limited therapeutic progress

PURPOSE OF REVIEW: With the sequencing of several Streptococcus pyogenes (group A Streptococcus) genomes have come major advances in understanding the pathogenesis of group A Streptococcus-associated diseases. This review focuses on group A Streptococcus skin infections and summarizes data published in the English language medical literature in 2004 and 2005. RECENT FINDINGS: Group A Streptococcus shows enormous and evolving molecular diversity driven by horizontal transmission between group A Streptococcus strains and between group A Streptococcus and other streptococci. Acquisition of prophages accounts for much of the diversity, conferring both virulence through phage-associated virulence factors and increased bacterial survival against host defences. Studies of group A Streptococcus isolates outside the US also question the generalizability of classic group A Streptococcus M serotype associations with specific disease entities such as acute rheumatic fever and necrotizing fasciitis. The distinction between throat and skin group A Streptococcus has become blurred. Although there have been few advances in treatment of group A Streptococcus skin infections, developments towards group A Streptococcus vaccines are promising. SUMMARY: The diversity of group A Streptococcus remains a challenge for vaccine development. As acute rheumatic fever and streptococcal pyoderma occur predominantly in disadvantaged populations, international funding support will be necessary for any group A Streptococcus vaccine to have a sustained impact on the global burden of disease.     

Genetic association of the serotonin transporter in pulmonary arterial hypertension

RATIONALE: The bone morphogenetic receptor type II gene is the major genetic determinant for the inherited form of pulmonary arterial hypertension. However, deleterious mutations of this gene are not observed in the majority of subjects who develop the condition spontaneously and familial disease displays age- and sex-dependent penetrance, indicating the requirement for additional environmental and/or genetic modifiers for disease development. METHODS: We investigated polymorphic variation of the serotonin transporter gene, a biological candidate for predisposition to this vascular disorder. RESULTS: No significant evidence of association between alleles of the serotonin transporter gene and pulmonary hypertension was detected, nor did we observe a relationship with age of onset in familial and idiopathic disease. CONCLUSIONS: Variation of the serotonin transporter gene appears unlikely to confer significant susceptibility to pulmonary arterial hypertension. This study emphasizes the need for adequately powered cohorts for association analyses to identify not only genetic determinants of disease susceptibility but also inherited modifiers for disease development.     

Recent advances in the use of serological bone formation markers to monitor callus development and fracture healing

The failure of an osseous fracture to heal, or the development of a nonunion, is common; however, current diagnostic measures lack the capability of early and reliable detection of such events. Analyses of radiographic imaging and clinical examination, in combination, remain the gold standard for diagnosis; however, these methods are not reliable for early detection. Delayed diagnosis of a nonunion is costly from both the patient and treatment standpoints. In response, repeated efforts have been made to identify bone metabolic markers as diagnostic or prognostic tools for monitoring bone healing. Thus far, the evidence regarding a correlation between the kinetics of most bone metabolic markers and nonunion is very limited. With the aim of classifying the role of biological pathways of bone metabolism and of understanding bone conditions in the development of osteoporosis, advances have been made in our knowledge of the molecular basis of bone remodeling, fracture healing, and its failure. Procollagen type I amino-terminal propeptide has been shown to be a reliable bone formation marker in osteoporosis therapy and its kinetics during fracture healing has been recently described. In this article, we suggest that procollagen type I amino-terminal propeptide presents a good opportunity for early detection of nonunion. We also review the role and potential of serum PINP, as well as other markers, as indications of fracture healing.     

Thoracic radiology of infections emerging after natural disasters

When natural disasters demolish shelter, destroy sources of clean drinking water, and disrupt the availability of medical care, vast numbers of people are placed at increased risk of disease. The infectious diseases that propagate under these conditions are usually common ones. Occasionally, a natural disaster alters the local environment in ways that markedly increase the prevalence of a disease that is endemic to a geographic region, occurring only as isolated cases under normal conditions. Many of these infections may affect the thorax. In this article, we discuss the radiologic findings of 4 infectious diseases, coccidioidomycosis, leptospirosis, melioidosis, and Chagas disease, which may flourish after natural disasters strike areas where they are endemic.     

Polymorphisms in human connexin40 gene promoter are associated with increased risk of hypertension in men

OBJECTIVE: Gap junctions, formed by connexins (Cx), are important in the regulation of vascular tone. Previously, we reported two closely linked polymorphisms (-44G --> A and +71A --> G) within regulatory regions of the gene for Cx40, a major connexin in the vascular wall and the kidney. In the present study, we examined the hypothesis that these polymorphic variants are associated with hypertension and that they interact with blood pressure in healthy individuals. METHODS: Cx40 genotypes were determined in 191 subjects with essential hypertension, 198 normotensive individuals, and a healthy control population (178 twin pairs, 108 monozygotic, 70 dizygotic). RESULTS: We found a significant contribution of the minor Cx40 allele or genotype (-44AA/+71GG) to the risk of hypertension in men (P = 0.013 or P = 0.035; odds ratio, 1.87 or 2.10, respectively), but not in women. Moreover, in the healthy control population a significant effect of Cx40 genotype and sex on systolic blood pressure was found (P < 0.05 and P < 0.0001, respectively). Women carrying the minor Cx40 genotype had significantly higher systolic blood pressure compared with non-carriers (P < 0.05). In men, systolic blood pressure in carriers of the minor Cx40 genotype was not significantly different from the other two genotypes, possibly because of the small number of men in this group. However, men carrying the -44GA/+71AG genotype had higher standing systolic blood pressure compared with the more common Cx40 genotype (-44GG; P = 0.033). CONCLUSION: These findings suggest that the Cx40 polymorphisms may form a genetic susceptibility factor for essential hypertension in men.