Inherited deficiencies of human methylmalonyl CaA mutase activity: reduced affinity of mutant apoenzyme for adenosylcobalamin.

We have studied the affinity of methylmalonyl CoA mutase for its required cofactor, adenosylcobalamin, in extracts of control and mutant human cultured fibroblasts. Control enzyme has an apparent K_m for adenosylcobalamin of 6–7 × 10^?8 M. Five mutant cell lines from patients with methylmalonicacidemia due to a mutase apoenzyme defect were studied. Three have undetectable mutase activity (<0.15% of control) at all cofactor concentrations. Two others, however, have markedly altered K_m's for adenosylcobalamin of 2.8 × 10^?4 M and 1.7 × 10^?5 M. These mutant lines synthesize adenosylcobalamin normally and, by complementation analysis, are genetically identical to all other mutase apoenzyme mutants tested. We conclude that the mutase deficiency in these two cell lines results from structurally altered mutase apoenzymes with markedly reduced affinities for adenosylcobalamin.     

SPLENECTOMY IN BLOOD DYSCRASIA

The decision for splenectomy must be based on a knowledge of the three functions of the spleen: Hematopoiesis (usually ceasing during fetal life but sometimes resuming when bone marrow function fails); filtration of abnormal and senescent cells and control of bone marrow activity, most probably humoral.When bone marrow function fails, splenectomy is contraindicated since splenic hematopoiesis becomes a vital function. On the other hand, when a large proportion of erythrocytes are abnormally shaped (spherocytes), although otherwise adequate, the spleen may trap these cells in its filter and destroy large numbers. Splenectomy is beneficial in almost every case of congenital spherocytosis, but in only half the cases of the acquired defect.In panhematocytopenia, thrombocytopenia and neutropenia, all apparently due to depression of hematopoiesis by endocrine or other action of the spleen, splenectomy may be beneficial if medical therapy fails.A surgeon undertaking splenectomy should recognize two special problems: (1) The presence of accessory spleens, which if not removed may negate the effects of the operation, and (2) the apparently high rate of infection in infants and children who have undergone splenectomy.     

Liposomal delivery of a phosphodiesterase 3 inhibitor rescues low oxygen-induced ATP release from erythrocytes of humans with type 2 diabetes

ATP release from erythrocytes in response to low oxygen tension requires an increase in cAMP, the level of which is regulated by phosphodiesterase 3 (PDE3). Such release is defective in erythrocytes of humans with type 2 diabetes (DM2). This study tested a hypothesis that direct delivery of the clinically useful PDE3 inhibitor, cilostazol, to erythrocytes of humans with type 2 diabetes using liposomes would restore low-oxygen tension-induced ATP release. Cilostazol was incorporated into liposomes prepared from dimyristoylphosphatidylcholine (DMPC). Liposome-delivery of cilostazol restored ATP release from DM2 erythrocytes to levels which were not different from that released from non-cilostazol treated healthy erythrocytes under the same conditions. There were no observed adverse effects of the liposomes on either healthy or DM2 erythrocytes. The directed liposomal delivery of PDE inhibitors to erythrocytes may help prevent or slow the development of peripheral vascular disease in individuals with DM2 by restoring an important physiological controller of microvascular perfusion while minimizing side effects associated with systemic delivery of some of these inhibitors.     

There is an obstetrical dilemma: Misconceptions about the evolution of human childbirth and pelvic form

Compared to other primates, modern humans face high rates of maternal and neonatal morbidity and mortality during childbirth. Since the early 20th century, this “difficulty” of human parturition has prompted numerous evolutionary explanations, typically assuming antagonistic selective forces acting on maternal and fetal traits, which has been termed the “obstetrical dilemma.” Recently, there has been a growing tendency among some anthropologists to question the difficulty of human childbirth and its evolutionary origin in an antagonistic selective regime. Partly, this stems from the motivation to combat increasing pathologization and overmedicalization of childbirth in industrialized countries. Some authors have argued that there is no obstetrical dilemma at all, and that the difficulty of childbirth mainly results from modern lifestyles and inappropriate and patriarchal obstetric practices. The failure of some studies to identify biomechanical and metabolic constraints on pelvic dimensions is sometimes interpreted as empirical support for discarding an obstetrical dilemma. Here we explain why these points are important but do not invalidate evolutionary explanations of human childbirth. We present robust empirical evidence and solid evolutionary theory supporting an obstetrical dilemma, yet one that is much more complex than originally conceived in the 20th century. We argue that evolutionary research does not hinder appropriate midwifery and obstetric care, nor does it promote negative views of female bodies. Understanding the evolutionary entanglement of biological and sociocultural factors underlying human childbirth can help us to understand individual variation in the risk factors of obstructed labor, and thus can contribute to more individualized maternal care.