Latrepirdine is a potent activator of AMP-activated protein kinase and reduces neuronal excitability.

Latrepirdine/Dimebon is a small-molecule compound with attributed neurocognitive-enhancing activities, which has recently been tested in clinical trials for the treatment of Alzheimer's and Huntington's disease. Latrepirdine has been suggested to be a neuroprotective agent that increases mitochondrial function, however the molecular mechanisms underlying these activities have remained elusive. We here demonstrate that latrepirdine, at (sub)nanomolar concentrations (0.1 nM), activates the energy sensor AMP-activated protein kinase (AMPK). Treatment of primary neurons with latrepirdine increased intracellular ATP levels and glucose transporter 3 translocation to the plasma membrane. Latrepirdine also increased mitochondrial uptake of the voltage-sensitive probe TMRM. Gene silencing of AMPKα or its upstream kinases, LKB1 and CaMKKß, inhibited this effect. However, studies using the plasma membrane potential indicator DisBAC2(3) demonstrated that the effects of latrepirdine on TMRM uptake were largely mediated by plasma membrane hyperpolarization, precluding a purely 'mitochondrial' mechanism of action. In line with a stabilizing effect of latrepirdine on plasma membrane potential, pretreatment with latrepirdine reduced spontaneous Ca(2+) oscillations as well as glutamate-induced Ca(2+) increases in primary neurons, and protected neurons against glutamate toxicity. In conclusion, our experiments demonstrate that latrepirdine is a potent activator of AMPK, and suggest that one of the main pharmacological activities of latrepirdine is a reduction in neuronal excitability.

Dyssegmental dwarfism: a histologic study of osseous and nonosseous cartilage.

Dyssegmental dwarfism is probably an autosomal recessive, lethal, generalized chondrodysplasia; it is characterized by anisospondyly , shortening of long bones, and narrow chest. Maturation of chondrocytes at the epiphyseal plates is disturbed. The pathologic features of osseous and nonosseous cartilage in a stillborn female infant with dyssegmental dwarfism are described. The cartilage matrix of tubular bones, vertebrae, ilia , ribs, nose, larynx, and trachea showed acellular areas with accumulation of acid mucopolysaccharides and no increase in collagen fibers. The findings, although not pathognomonic, suggest that this type of dwarfism may be a generalized connective tissue disorder. The abnormal synthesis, structure, or secretion of the components of the cartilaginous matrix may lead to accumulation of acellular material in both skeletal and respiratory tract cartilage.

Small intestinal atresia and segmental absence of muscle coats.

The case of a newborn infant with small-intestine atresia coexisting with segmental absence of muscle coats leading to perforation and meconium peritonitis is presented. The theories of pathogenesis of the simultaneous occurrence of segmental absence of gut musculature and atresia are briefly reviewed. A possible etiologic role of vascular accident in utero for both conditions is discussed.

Sinusoidal fetal heart rate pattern with vasa previa in twin pregnancy.

A case of vasa previa in twin pregnancy associated with a sinusoidal heart rate was observed. A review of the world literature revealed eight previously reported cases of vasa previa in twins. No first twin survived, and 62.5% of second twins eventually died from partial or complete exsanguination. This is the first reported case of sinusoidal fetal heart rate in association with vasa previa. Continuous fetal monitoring suggested the diagnosis of funic presentation and of fetal bleeding. A high index of suspicion, use of amnioscopy, ability to detect fetal blood in the vaginal pool, continuous fetal heart rate monitoring and ultrasonography may help in reducing the high perinatal mortality associated with vasa previa.