Neonatal sepsis is an important cause of morbidity and mortality as a result of multiple organ system failure, particularly in neonates requiring total parenteral nutrition. Suitable therapies and support are needed both to prevent sepsis and to prevent multiple organ failure. After bacterial infection, pro-inflammatory cytokines trigger the antimicrobial activity of macrophages and neutrophils, resulting in production of reactive species such as H2O2, NO, superoxide and peroxynitrite. However, excess production can lead to host tissue damage. Incubation of either hepatocytes or heart mitochondria from neonatal rats with these reactive species, or with cytokines, leads to impairment of mitochondrial oxidative function, and in an animal model of neonatal sepsis similar results to the in vitro findings have been demonstrated. Recent in vivo studies, using indirect calorimetry of suckling rat pups, show that during endotoxaemia there is a profound hypometabolism, associated with hypothermia. Having determined that cellular oxidative function may be impaired during sepsis, it is of great importance to try to identify therapeutic measures. Much interest has been shown in glutamine, which may become essential during sepsis. It has been shown that hepatic glutamine is rapidly depleted during endotoxaemia. When hepatocytes from endotoxaemic rats were incubated with glutamine, there was a restoration of mitochondrial structure and metabolism. In vivo, intraperitoneal injection of glutamine into endotoxic suckling rats partially reversed hypometabolism, markedly reduced the incidence of hypothermia and improved clinical status. These results suggest that glutamine has a beneficial effect during sepsis in neonates.

Thalassaemias result from mutations of the globin genes that cause reduced or absent haemoglobin production and thus interfere with the critical function of oxygen delivery. They represent the most common single-gene disorders, with 4.83% of the world population carrying globin gene variants. Reduced or absent α-globin (α-thalassaemia) or β-globin (β-thalassaemia) leads to anaemia and multifaceted clinical syndromes. In this second of two reviews on the pathophysiology of haemoglobinopathies, we describe the clinical features, pathophysiology and molecular basis of α- and β-thalassaemias. We then discuss current targeted therapies, including the new oral iron chelators, which, along with chronic transfusions, constitute the mainstay of symptomatic therapy for the majority of patients. Finally, we describe potentially curative therapies, such as bone marrow transplant, and discuss some of the outstanding research studies and questions, including the upcoming field of gene therapy for β-thalassaemia. An accompanying article on haemoglobinopathies (Part I) focuses on sickle cell disease.

In sickle cell disease, a single base pair substitution in the gene encoding the β-globin chain of the haemoglobin molecule gives rise to a surprisingly broad spectrum of pathophysiological and clinical manifestations. Inflammation, endothelial activation, red blood cell membrane abnormalities and altered availability of vasoactive factors characterise this disorder. Clinically, patients suffer from a host of seemingly unrelated maladies, from pain episodes to strokes, life-threatening infections and pulmonary hypertension. Deepened understanding of this complex disease now allows us to begin to turn away from simple supportive treatments, and move towards therapies aimed at specific pathophysiological targets. This article, the first of two reviews on the pathophysiology of haemoglobinopathies, discusses the molecular basis of sickle cell disease, and elaborates on the many factors that exacerbate or ameliorate the disease process. It then focuses on the promising targeted therapies currently in use or under investigation. An accompanying article on haemoglobinopathies (Part II) focuses on thalassaemias.