Insight into the complex pathophysiology of sickle cell anaemia and possible treatment

Sickle cell anaemia (SCA) is the consequence of abnormal haemoglobin production due to an inherited point mutation in the β‐globin gene. The resulting haemoglobin tetramer is poorly soluble when deoxygenated, and when this is prolonged, intracellular gelation of sickle haemoglobin occurs, followed by haemoglobin polymerisation. If many cycles of sickling and unsickling occur, the red cell membrane will be disrupted leading to haemolysis and vaso‐occlusive events. Recent studies have also shown that leucocyte adhesion molecules and nitric oxide (NO) depletion are involved in endothelial damage. New insights in SCA pathophysiology and vascular biology have shown that cell‐derived microparticle (MP) generation is also involved in the vaso‐occlusion. Endothelial damage is perpetuated by impaired production or increased consumption of protective modulators such as protein C, protein S and NO. New therapeutic interventions should address these aspects of SCA pathogenesis. To date, the only US‐FDA‐approved therapy to prevent painful vaso‐occulsive episodes is hydroxyurea that reduces haemoglobin polymerisation in sickle cells by increasing the production of foetal haemoglobin and L‐glutamine. However, several new drugs have been tested in the last years in randomised clinical trials. We here report an update on the current status of knowledge on SCA.     

Multifocal Infantile Myofibromatosis and Generalized Fibromuscular Dysplasia in a Child: Evidence for a Common Pathologic Process?

Infantile myofibromatosis (IM) is a condition characterized by the formation of spindle cell tumors of skin, soft tissue, and viscera. Although small vessel involvement by the process is a frequently identified and indeed diagnostically useful histological finding, involvement of large vessels is not widely reported. Fibromuscular dysplasia (FMD) is a noninflammatory arteriopathy characterized by intimal, medial, and/or adventitial fibroplasias leading to luminal compromise and aneurysm formation. Although venous disease has been reported, involvement of arterioles and viscera has not been identified. We report a patient in whom IM was diagnosed, on the basis of multiple soft tissue tumors present from birth, who subsequently developed generalized and ultimately fatal FMD. These two conditions exhibit overlapping pathologic features, including pronounced intimal fibroplasia. Their occurrence in a single individual may provide insights into the pathogenesis of both conditions, suggesting that they represent part of the same spectrum of vascular myofibroblastic proliferations.     

The role of primary prophylactic factor replacement therapy in children with severe factor X deficiency

Severe factor X (FX) deficiency is one of the severest inherited coagulation disorders. Clinical manifestations include umbilical cord, mucosal, joint and central nervous system bleeding. Four Irish children with severe FX deficiency presented with umbilical cord bleeding. One developed an intraperitoneal haemorrhage and another an intracranial bleed. Prophylaxis, using intermediate purity Factor IX concentrate, was commenced within the first month of life, necessitating the insertion of central venous access devices in two of the children. All children have normal joint function, suggesting that prophylaxis commenced early in life reduces the incidence of arthropathy and improves quality of life.     

Increased angiogenesis in bone marrow of children with acute lymphoblastic leukaemia has no prognostic significance

The importance of angiogenesis for the growth and viability of solid tumours has been established. Similarly, prognostic information may be gained from the extent of angiogenesis in these tumours. Haematopoietic malignancies should have equal requirements for angiogenesis and important prognostic information may be derived from quantification of bone marrow angiogenic activity. We retrospectively investigated 82 bone marrow trephine biopsies from 41 children with acute lymphoblastic leukaemia (ALL) at diagnosis and following treatment. Nine normal bone marrow trephines from age-matched children were also analysed as controls. The microvessels were stained immunohistochemically with anti-Factor VIII-related antigen (antivWF) and antithrombomodulin (anti-THR). Angiogenesis was quantified manually by two independent observers and was highly reproducible (Pearson's r = 0.91). Staining with anti-vWF and anti-THR was highly specific for microvessels and thetwo stains closely correlated (r = 0.68). Microvessel densities (MVD) at presentation were significantly increased in the majority of patients in comparison with controls (P < 0.0001) and MVD dropped towards normal in remission (P < 0.0001). Of interest, the difference in total vessel counts between leukaemic and normal/remission marrows was contributed solely by small microvessels. There was no significant difference in MVD at presentation or remission from children in poor prognostic groups or those who subsequently relapsed. Similarly, we could not find an association with age, sex, cytogenetic abnormality or disease phenotype.     

Differing roles for the dominant and non-dominant hands in the hand laterality task

Determining the handedness of visually presented stimuli is thought to involve two separate stages--a rapid, implicit recognition of laterality followed by a confirmatory mental rotation of the matching hand. In two studies, we explore the role of the dominant and non-dominant hands in this process. In Experiment 1, participants judged stimulus laterality with either their left or right hand held behind their back or with both hands resting in the lap. The variation in reactions times across these conditions reveals that both hands play a role in hand laterality judgments, with the hand which is not involved in the mental rotation stage causing some interference, slowing down mental rotations and making them more accurate. While this interference occurs for both lateralities in right-handed people, it occurs for the dominant hand only in left-handers. This is likely due to left-handers' greater reliance on the initial, visual recognition stage than on the later, mental rotation stage, particularly when judging hands from the non-dominant laterality. Participants' own judgments of whether the stimuli were 'self' and 'other' hands in Experiment 2 suggest a difference in strategy for hands seen from an egocentric and allocentric perspective, with a combined visuo-sensorimotor strategy for the former and a visual only strategy for the latter. This result is discussed with reference to recent brain imaging research showing that the extrastriate body area distinguishes between bodies and body parts in egocentric and allocentric perspective.     

Individual differences in amygdala and ventromedial prefrontal cortex activity are associated with evaluation speed and psychological well-being

Using functional magnetic resonance imaging, we examined whether individual differences in amygdala activation in response to negative relative to neutral information are related to differences in the speed with which such information is evaluated, the extent to which such differences are associated with medial prefrontal cortex function, and their relationship with measures of trait anxiety and psychological well-being (PWB). Results indicated that faster judgments of negative relative to neutral information were associated with increased left and right amygdala activation. In the prefrontal cortex, faster judgment time was associated with relative decreased activation in a cluster in the ventral anterior cingulate cortex (ACC, BA 24). Furthermore, people who were slower to evaluate negative versus neutral information reported higher PWB. Importantly, higher PWB was strongly associated with increased activation in the ventral ACC for negative relative to neutral information. Individual differences in trait anxiety did not predict variation in judgment time or in amygdala or ventral ACC activity. These findings suggest that people high in PWB effectively recruit the ventral ACC when confronted with potentially aversive stimuli, manifest reduced activity in subcortical regions such as the amygdala, and appraise such information as less salient as reflected in slower evaluative speed.     

Successful use of protease inhibitors in HIV-infected haemophilia patients

The haemophilias are a group of inherited haemostatic disorders that require regular clotting factor replacement therapy in the severe and moderately severe subgroups. Prior to the introduction of adequate viral inactivation methods in 1985, haemophilia patients were at exceptionally high risk of contracting blood-borne viruses from factor concentrates as each batch was derived from the plasma of thousands of donors. As a result, approximately 60% of these patients were infected with HIV between 1979 and 1985, and HIV infection now contributes significantly to the morbidity and mortality seen in this group.
Protease inhibitors (PIs) have been shown to significantly log reduce viral loads and increase CD4 cell counts in HIV-infected individuals. Recently, there has been concern about their use in HIV-infected haemophilia patients following increased bleeding episodes in some patients during PI therapy. We prospectively studied the effect of PI therapy in 20 HIV-infected haemophilia patients at our centre over a 6-month period. The mean increase in CD4 cell count was 70 × 10⁶/l and the mean log decrease in viral load was 1.59 over the study period. Gastrointestinal side-effects (nausea and vomiting in five, diarrhoea in two) were the most frequent and resulted in discontinuation of the medication in two patients. Factor concentrate usage for the group on and off study was similar. One severe FVIII patient reported a single episode of an unusual bleed which responded promptly to FVIII concentrate infusion. The significant clinical and laboratory benefits in terms of HIV disease and the paucity of added bleeding complications suggest that PI therapy should not be withheld from HIV-infected haemophilics. Further prospective studies evaluating the efficacy and possible haemostatic complications related to these promising inhibitors of the HIV protease are needed.