The degree of matching at HLA-DPB1 predicts for acute graft-versus-host disease and disease relapse following haematopoietic stem cell transplantation

The importance of matching for HLA-DPB1 in unrelated donor haematopoietic stem cell (HSC) transplantation is little understood. Most transplant centres do not, currently, prospectively match for DPB1, but emerging data show that DPB1 matching does play a role in determining outcome. We studied the impact of HLA-DPB1 matching on outcome in 143 recipients of T-cell depletion transplants, who matched with their respective unrelated donors (allelic level) at HLA-A, -B, -C, -DRB1 and -DQB1. Of those matched at DPB1, 47.2% (17/36) developed acute graft-versus-host disease (aGvHD) as compared to 66.3% (55/83) of those who were mismatched. This led to a 19.1% (95% CI 0.1-38.3%) increase in the chance of developing aGvHD in mismatched patients (P=0.049). Relapse of the original disease occurred in 51 recipients; 23 of 37 (62%) matched at both DPB1 alleles, 28 of 82 (34%) were mismatched at one or two DPB1 alleles. Thus, there was a significantly higher relapse rate (P=0.0011) in transplant recipients who matched at both DPB1 alleles. In conclusion, a donor/recipient DPB1 match was associated with a significantly lower incidence of aGvHD and a significantly higher incidence of disease relapse. This study provides further evidence for an immunogenic role of HLA-DPB1 in HSC transplants.     

Massive Plasmodium falciparum visceral sequestration: a cause of maternal death in Africa

Sequestration of Plasmodium falciparum-infected erythrocytes (PfIE) in the capillaries of the central nervous system (CNS) is the pathognomonic feature of cerebral malaria, a condition frequently leading to death. Sequestration of PfIE in the placental intervillous spaces is the characteristic feature of malaria in pregnancy and is associated with low birthweight and prematurity. Although both patterns of sequestration are thought to result from the expression of different parasite proteins involved in cytoadhesion to human receptors, scant information exists on whether both conditions can coexist and whether this can lead to death. We conducted a prospective autopsy study including all consecutive pregnancy-related deaths in a tertiary-level referral hospital in Maputo, Mozambique, between October 2002 and December 2006. Extensive sampling of all major viscera was performed. All cases showing parasites in any of the viscera were included in the analysis. From 317 complete autopsies PfIEs were identified in ten women (3.2%). All cases showed massive accumulation of PfIE in small capillaries of the CNS but also in most visceral capillaries (heart, lung, kidney, uterus). Placental tissue, available in four cases, showed a massive accumulation of maternal PfIE in the intervillous space. Coma (six women) and dyspnoea (five women) were the most frequent presenting clinical symptoms. In conclusion, massive visceral sequestration of PfIE with significant involvement of the CNS is an infrequent but definite direct cause of maternal death in endemic areas of Africa. The PfIE sequestered in cerebral capillaries and the placenta coexist in these fatal cases.     

Role of G protein-coupled receptor kinase 2 and arrestins in beta-adrenergic receptor internalization

G protein-coupled receptors (GPCRs) mediate the action of messengers that are key modulators of the function, growth, and differentiation of cardiac and vascular cells. A general feature of GPCRs is the existence of complex regulatory mechanisms that modulate receptor responsiveness and underlie important physiologic phenomena such as signal integration and desensitization. The molecular mechanisms of desensitization have been investigated with the beta2-adrenergic receptor (beta2AR) used as the main model system. Rapid regulation of betaAR and other GPCRs appears to involve agonist-promoted receptor phosphorylation by G protein-coupled receptor kinases (GRKs). This is followed by binding of uncoupling proteins termed arrestins and transient receptor internalization, which plays a key role in resensitizing GPCR by allowing its dephosphorylation and recycling. Recent data indicate that, besides the uncoupling function, GRK2 and beta-arrestin also directly participate in beta2AR sequestration, thus providing the trigger for its resensitization. A detailed knowledge of the role of GRKs and arrestins in betaAR internalization would make their physiologic role in the modulation of cellular responses to messengers better understood.     

Intracranial arterial stenoses: current viewpoints, novel approaches, and surgical perspectives

Ten percent of all strokes occurring in the USA are caused by intracranial arterial stenosis (IAS). Symptomatic IAS carries one of the highest rates of recurrent stroke despite intensive medical therapy (25 % in high-risk groups). Clinical results for endovascular angioplasty and stenting have been disappointing. The objectives of this study were to review the contemporary understanding of symptomatic IAS and present potential alternative treatments to resolve factors not addressed by current therapies. We performed a literature review on IAS pathophysiology, natural history, and current treatment. We present an evaluation of the currently deficient aspects in its treatment and explore the role of alternative surgical approaches. There is a well-documented interrelation between hemodynamic and embolic factors in cerebral ischemia caused by IAS. Despite the effectiveness of medical therapy, hemodynamic factors are not addressed satisfactorily by medications alone. Collateral circulation and severity of stenosis are the strongest predictors of risk for stroke and death. Indirect revascularization techniques, such as encephaloduroarteriosynangiosis, offer an alternative treatment to enhance collateral circulation while minimizing risk of hemorrhage associated with hyperemia and endovascular manipulation, with promising results in preliminary studies on chronic cerebrovascular occlusive disease. Despite improvements in medical management for IAS, relevant aspects of its pathophysiology are not resolved by medical treatment alone, such as poor collateral circulation. Surgical indirect revascularization can improve collateral circulation and play a role in the treatment of this condition. Further formal evaluation of indirect revascularization for IAS is a logical and worthy step in the development of intracranial atherosclerosis treatment strategies.     

Quels marqueurs osseux chez les patients hémodialysés : phosphatases alcalines osseuses ou ß-CrossLaps ?

BackgroundBone turnover (BT) abnormalities are frequently observed in patients with chronic kidney disease. Bone biopsy remains the gold standard for diagnosis; however, its invasive nature has led to its decreased utilisation. The serum parathyroid hormone (PTH) level is not a reliable bone marker (BM) for BT assessment. The latest international recommendations suggest the use of total alkaline phosphatase (t-ALP) or bone-specific alkaline phosphatase (b-ALP), but not ß-CrossLaps (CTX). We compared b-ALP, t-ALP, and CTX levels in patients on haemodialysis (HD).MethodsAll HD patients at a single institution following a standard 3 × 4 to 3 × 5 hours schedule were included in the study, provided they were free from liver disease. Serum intact PTH, t-ALP, b-ALP, and CTX values were compared at baseline and after 18 months of treatment. A kinetic study was performed for pre- and postdialysis CTX values over a 2-week period. We described the longitudinal evolution of these BMs in two typical patients.ResultsA total of 98 patients on HD (46% female) were evaluated. The mean age was 69.8 ± 11 years and the mean duration of dialysis was 54.4 ± 61 months. At baseline, CTX (2.1 ± 1 μg/L) correlated well with b-ALP (18 ± 11 μg/L; r = 0.64; P < 0.001) and PTH (221 ± 165 pg/mL; r = 0.62; P < 0.001). The changes in these values at 18 months were also correlated (ΔCTX compared with Δb-ALP: r = 0.51; P < 0.001; Δb-ALP compared with ΔPTH: r = 0.37, P < 0.01). b-ALP and t-ALP (245 ± 132 U/L) were closely correlated (r = 0.78), as was their variation over 18 months (r = 0.67), but t-ALP did not correlate with PTH, and correlated poorly with CTX (r = 0.38). The CTX reduction ratio during standard dialysis was approximately 70 to 75% over each session, although predialysis values remained stable.ConclusionIn HD patients, mean CTX values are five times higher than the normal range. CTX appears to be an alternative to b-ALP for assessing BT. b-ALP remains the standard BM, despite being expensive, infrequently available in many laboratories, and not useful for patients with liver disease.     

Leukodystrophy and CSF Purine Abnormalities Associated with Isolated 3-Methylcrotonyl-CoA Carboxylase Deficiency

We report the first case of isolated biotin resistant 3-methylcrotonyl-CoA carboxylase (MCC) deficiency in Argentina. The diagnosis was established at 14 months of age by urinary organic-acid analysis and confirmed by enzyme assay in fibroblasts. The patient suffered from severe psychomotor retardation, hypotonia, areflexia, and failure to thrive, and died unexpectedly at 3 years 4 months of life. Brain MRI at 14 months showed signals of the white matter on cerebral T₂-weighted, which were indicative of confluent and multiple foci of leukodystrophy, a pattern not previously described in this entity. In addition, high levels of oxypurines were detected in cerebrospinal fluid. This might be related to energetic consequences of the enzyme deficiency in the brain. This case extends the phenotype of isolated MCC deficiency in infancy and suggests this entity should be considered to be one of the possible causes of metabolic leukodystrophies.     

Admission screening by thyroid function tests in an acute general care teaching hospital.

To determine the incidence of unrecognized thyroid disease among admissions to a large acute care university teaching hospital, 364 samples taken on consecutive admissions were assayed for thyroid-stimulating hormone (TSH) and free thyroxine index (FTI). Patients with abnormal test results were further evaluated by determination of antimicrosomal and antithyroglobulin antibodies, and charts were reviewed for evidence of prior diagnosis of thyroid disease, especially severe illness, drug treatment that might affect thyroid function tests, and prior diagnosis of thyroid disease. Results of subsequent thyroid function tests performed during the patient's hospitalization were correlated with the admission serum assays, and data on subsequent testing during the following 6 months were also obtained. A total of 3.9% of patients had significantly depressed TSH, and 11.1% of values were significantly elevated. A total of 11.3% of patients had significantly low FTI values, and 1% had significantly elevated values. A total of 7.4% appeared to have the euthyroid sick syndrome, 5.8% appeared to have unrecognized or undertreated primary thyroid failure, 6% had apparent subclinical hypothyroidism, 2% were thyrotoxic, and 2.8% (all women) had suppressed TSH levels for inapparent reasons. Limiting testing to patients over 49 years of age, or to women, would have missed many individuals with abnormal test results. Considering widespread availability of tests, relative costs, and value of the information obtained, it is suggested that the FTI determination would provide an appropriate screening test for patients in a population such as this entering a large, acute care general hospital.