Sarcopenia--consequences, mechanisms, and potential therapies.

Increasingly, the worldwide population is growing older. Sarcopenia occurs with age and is characterized by loss of muscle mass, strength and endurance. Mechanisms that underlie this process are beginning to be understood. These include age-related loss and atrophy of individual muscle fibers, decreased synthesis of muscle proteins, and reduced mitochondrial function. The role of decreased anabolic hormone production in causing these changes remains to be clearly defined. Anabolic hormone replacement is a potential strategy currently being investigated for treatment of sarcopenia. Combinations of aerobic, resistance, and stretching exercise programs have well established beneficial effects. Further understanding of the molecular processes involved in the aging of muscle both at the level of gene expression and protein modification will be important for discovering novel treatment strategies.

Acute leukemia during pregnancy: a single institutional experience with 17 cases.

We reviewed the medical records of 17 consecutive patients with concomitant acute leukemia and pregnancy seen at our institution over a 37-year period. Fifteen cases each were either newly diagnosed or classified as acute myeloid leukemia (AML). Seven diagnoses (41%) occurred in the first, 7 (41%) in the second, and 3 (18%) in the third trimester. In general, nine patients received chemotherapy while pregnant-eight in the second trimester and one in the third. The overall complete remission rate among the 13 patients with newly diagnosed AML was 69%, compared with 86% in those who were pregnant during chemotherapy. Long-term survival was documented in five of the nine complete responders. Three of four patients who elected to delay treatment until after delivery died within days of starting chemotherapy. Unintentional fetal loss occurred in four patients (29%), including two without exposure to chemotherapy. There were no instances of congenital malformation. The results from the current study confirm that pregnancy per se may not affect the outcome of chemotherapy in AML. In addition, it is suggested that treatment delays may compromise maternal outcome without improving pregnancy outcome.

Neuronal apoptosis: current understanding of molecular mechanisms and potential role in ischemic brain injury.

Apoptosis is a rediscovered mechanism of cell death crucial in normal development. Recent exploration of the genetic mechanisms of apoptosis has broadened our insight into the regulation of cell death in development as well as disease states. We present an overview on current understanding of the genetic molecular events in apoptosis in all, or most cell types, with emphasis on events observed in a well-characterized model of neuronal death in vitro. The second part of this article reviews recent studies in in vivo stroke models on the mechanism of cell death relevant to apoptosis after cerebral ischemia. Further delineation of the mechanisms of cell death, especially those that trigger apoptosis, is likely to redirect our approaches in the development of new therapeutic interventions for ischemic stroke.

Role of BCL-2 in the survival and function of developing and mature sympathetic neurons.

Sympathetic neurons, when placed in culture during the period of naturally occurring cell death, will die by apoptosis when deprived of nerve growth factor (NGF). In this system, the mRNA levels of the BCL-2 family members decrease after NGF deprivation and during apoptosis. Sympathetic neurons from BCL-2-deficient mice died more rapidly after NGF deprivation than neurons from wild-type littermates. Sympathetic neurons of adult animals are relatively independent of NGF for survival. If sympathetic neurons are maintained in vitro for several weeks, loss of acute trophic factor dependence develops with a time course similar to that seen in the intact animal. Examination of neurons from BCL-2-deficient mice showed that BCL-2 expression is not required for the development of trophic factor independence. Therefore, BCL-2 is an important regulator of the survival of sympathetic neurons after NGF deprivation during the period of naturally occurring programmed neuronal death, but BCL-2 is not involved in the development of trophic factor independence in mature sympathetic neurons.

Superoxide dismutase delays neuronal apoptosis: a role for reactive oxygen species in programmed neuronal death.

Sympathetic neurons in culture die by apoptosis when deprived of nerve growth factor (NGF). We used this model of programmed cell death to study the mechanisms that mediate neuronal apoptosis. Cultured sympathetic neurons were injected with copper/zinc superoxide dismutase protein (SOD) or with an expression vector containing an SOD cDNA. In both cases apoptosis was delayed when the neurons were deprived of NGF. The delay was similar to that seen when a bcl-2 expression vector was injected. SOD, injected 8 hr after NGF deprivation, provided no protection, indicating that superoxide production may occur early in response to trophic factor deprivation. We have demonstrated, with a redox-sensitive dye, an increase in reactive oxygen species (ROS) that peaked at 3 hr after sympathetic neurons were deprived of NGF. If NGF was added back to the culture medium after the period of peak ROS generation, apoptosis was completely prevented, suggesting that ROS production serves as an early signal, rather than a toxic agent, to mediate apoptosis.

Molecular genetics of neuronal survival.

The past year has witnessed remarkable progress towards understanding the molecular genetics of neuronal survival. Gene-targeting experiments in mice have confirmed the long-standing idea that the nerve growth factor model of neuronal survival--that is, neuronal dependence on target-derived molecules during a critical period in development--is broadly applicable. Furthermore, a variety of biochemical and genetic techniques applied to both mammals and invertebrates have identified new genes involved in regulating cell survival during development.