Deletion of eIF2beta suppresses testicular cancer incidence and causes recessive lethality in agouti-yellow mice.

The agouti-yellow (A(y)) deletion is the only genetic modifier known to suppress testicular germ cell tumor (TGCT) susceptibility in mice or humans. The A(y) mutation deletes Raly and Eif2s2, and induces the ectopic expression of agouti, all of which are potential TGCT-modifying mutations. Here we report that the reduced TGCT incidence of heterozygous A(y) males and the recessive embryonic lethality of A(y) are caused by the deletion of Eif2s2, the beta subunit of translation initiation factor eIF2.

Chromosome X modulates incidence of testicular germ cell tumors in Ter mice.

Germ cell tumor development in humans has been proposed to be part of testicular dysgenesis syndrome (TDS), which manifests as undescended testes, sterility, hypospadias, and, in extreme cases, as germ cell tumors. Males of the Ter mouse strain show interesting parallels to TDS because they either lack germ cells and are sterile or develop testicular germ cell tumors. We found that these defects in Ter mice are due to mutational inactivation of the Dead-end (Dnd1) gene.

Trans-generational epistasis between Dnd1Ter and other modifier genes controls susceptibility to testicular germ cell tumors.

The genetic basis for susceptibility to testicular germ cell tumors (TGCTs) has been remarkably elusive. Although TGCTs are the most common cancer in young men and have an unusually strong familial risk, only one low-frequency susceptibility gene has been identified for this highly multigenic trait. In tests to determine whether pairs of genetic variants act epistatically to modulate susceptibility in the 129/Sv mouse model of spontaneous TGCTs, we discovered an unusual mode of inheritance that involved interactions between different genes in different generations.

The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours.

In mice, the Ter mutation causes primordial germ cell (PGC) loss in all genetic backgrounds. Ter is also a potent modifier of spontaneous testicular germ cell tumour (TGCT) susceptibility in the 129 family of inbred strains, and markedly increases TGCT incidence in 129-Ter/Ter males. In 129-Ter/Ter mice, some of the remaining PGCs transform into undifferentiated pluripotent embryonal carcinoma cells, and after birth differentiate into various cells and tissues that compose TGCTs.

Enhancers and suppressors of testicular cancer susceptibility in single- and double-mutant mice.

Susceptibility to spontaneous testicular germ cell tumors (TGCTs), a common cancer affecting young men, shows unusual genetic complexity. Despite remarkable progress in the genetics analysis of susceptibility to many cancers, TGCT susceptibility genes have not yet been identified. Various mutations that are inherited as Mendelian traits in laboratory mice affect susceptibility to spontaneous TGCTs on the 129/Sv inbred genetic background.

Testicular cancer susceptibility in the 129.MOLF-Chr19 mouse strain: additive effects, gene interactions and epigenetic modifications.

Testicular germ cell tumors (TGCTs) are the most common solid cancers affecting young men. Although the evidence for genetic predisposition to TGCTs in humans is compelling, the genetic control of susceptibility is poorly understood. The 129S1/SvImJ (129/Sv) inbred strain of mice is an excellent model for studying TGCT susceptibility.

The rectus myofascial wrap in the management of urethral sphincter incompetence.

Objective: To review our experience with a modified rectus/pyramidalis myofascial sling, described more than a century ago for treating refractory urinary incontinence in children with neurogenic sphincteric incompetence.

Patients And Methods: Thirty-seven patients (23 females and 14 males, aged 8-21 years) presented with urinary incontinence which failed to respond to medical treatment. In 36 patients the cause of the incontinence was a neurogenic bladder; one patient had sustained a traumatic injury to the bladder neck and urethra.

Clozapine preferentially increases dopamine release in the rhesus monkey prefrontal cortex compared with the caudate nucleus.

Despite substantial differences between species in the organization and elaboration of the cortical dopamine innervation, little is known about the pharmacological response of cortical or striatal sites to antipsychotic medications in nonhuman primates. To examine this issue, rhesus monkeys were chronically implanted with guide cannulae directed at the principal sulcus, medial prefrontal cortex, premotor cortex, and caudate nucleus. Alterations in dopamine release in these discrete brain regions were measured in response to administration of clozapine or haloperidol.

Dopamine D4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys.

D4 dopamine receptors (DRs) are enriched in the primate prefrontal cortex, a brain region implicated in cognitive processes, and mesoprefrontal dopaminergic systems appear to be involved in modulating some cognitive functions of the prefrontal cortex. Despite anatomical localization of D4 DRs within the frontal cortex, the role of these receptors, specifically, in the regulation of cognition or behavior in primates is unknown. In these studies, we sought to learn whether specific antagonism of D4 DRs would affect performance of a task dependent on the frontostriatal system.

Synchrony in telomere length of the human fetus.

Telomere length, measured by terminal restriction fragments, was examined in tissues from human fetuses of gestational ages estimated as 15-19 weeks. The length of telomeres was similar in most fetal tissues. However, there were significant variations in telomere length among fetuses, with no apparent relationship between gestational age and telomere length.

Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine.

The effects of the psychotomimetic drug phencyclidine on the neurochemistry and function of the prefrontal cortex in vervet monkeys were investigated. Monkeys treated with phencyclidine twice a day for 14 days displayed performance deficits on a task that was sensitive to prefrontal cortex function; the deficits were ameliorated by the atypical antipsychotic drug clozapine. Repeated exposure to phencyclidine caused a reduction in both basal and evoked dopamine utilization in the dorsolateral prefrontal cortex, a brain region that has long been associated with cognitive function.

Subchronic phencyclidine administration reduces mesoprefrontal dopamine utilization and impairs prefrontal cortical-dependent cognition in the rat.

Repeated ingestion of phencyclidine by humans induces enduring schizophrenic symptomatology, particularly cognitive dysfunction. In the presently described series of experiments, the neurochemical and cognitive consequences of subchronic phencyclidine administration in the rat were explored. Repeated phencyclidine exposure led to a selective reduction in basal and stress-evoked dopamine utilization in the prefrontal cortex.

Preferential activation of dopamine overflow in prefrontal cortex produced by chronic clozapine treatment.

The effect of chronic treatment with clozapine on extracellular dopamine levels in the rat striatum, nucleus accumbens and medial prefrontal cortex (mPFC) was examined using intracerebral microdialysis. Clozapine (20 mg/kg/day x 21 days in drinking water) increased basal dopamine release in the mPFC but had no effect in the striatum or nucleus accumbens. After chronic treatment, an acute dose of clozapine (20 mg/kg i.

Distinct actions of endogenous excitatory amino acids on the outflow of dopamine in the nucleus accumbens.

Intracerebral microdialysis was utilized to assess the effect of endogenous excitatory amino acids (EAA), l-glutamate (GLU) and l-aspartate (ASP), on the extracellular levels of dopamine in the rat nucleus accumbens. Both ASP and GLU produced a release response at a concentration range of 1 to 10 mM. GLU was generally less efficacious in increasing dopamine outflow; at 5 and 10 mM, the maximum effect exerted by GLU was significantly less than that observed with ASP.