Although surgical transmission of Creutzfeldt-Jakob disease (CJD) has been demonstrated, these iatrogenic cases account for only a small proportion of all CJD cases. The majority are sporadic CJD (sCJD) cases of unknown cause. This study investigated whether some cases classified as sCJD might have an unrecognized iatrogenic basis through surgical or other medical proceduresThis study compared medical risk factors from 431 sCJD cases referred 1998 to 2006 with 454 population control subjects. Possible geographic and temporal links between neurological and gynecological operations in 857 sCJD cases referred from 1990 to 2006 were investigatedA reported history of ever having undergone surgery was associated with increased risk for sCJD (odds ratio, 2.0; 95% confidence interval, 1.3-2.1; p = 0.003). Increased risk was not associated with surgical categories chosen a priori but was confined to the residual category "other surgery," in which the increase in risk appeared most marked for three subcategories: skin stitches, nose/throat operations, and removal of growths/cysts/moles. No convincing evidence was found of links (same hospital, within 2 years) between cases undergoing neurosurgery or gynecological surgeryIt is unlikely that a high proportion of UK sCJD cases are the result of transmission during surgery, but we cannot exclude the possibility that such transmission occurs occasionally. A study based on accurate surgical histories obtained from medical records is required to determine whether the increased risk associated with reported surgical history reflects a causal association or recall bias. Ann Neurol 2007
Human immunodeficiency virus-1 (HIV-1) causes mild to severe cognitive impairment and dementia. The transactivator viral protein, Tat, is implicated in neuronal death responsible for neurological deficits. Several clades of HIV-1 are unequally distributed globally, of which HIV-1 B and C together account for the majority of the viral infections. HIV-1-related neurological deficits appear to be most common in clade B, but not clade C prevalent areas. Whether clade-specific differences translate to varied neuropathogenesis is not known, and this uncertainty warrants an immediate investigation into neurotoxicity on human neurons of Tat derived from different viral cladesWe used human fetal central nervous system progenitor cell-derived astrocytes and neurons to investigate effects of B- and C-Tat on neuronal cell death, chemokine secretion, oxidative stress, and mitochondrial membrane depolarization by direct and indirect damage to human neurons. We used isogenic variants of Tat to gain insights into the role of the dicysteine motif (C30C31) for neurotoxic potential of TatOur results suggest clade-specific functional differences in Tat-induced apoptosis in primary human neurons. This study demonstrates that C-Tat is relatively less neurotoxic compared with B-Tat, probably as a result of alteration in the dicysteine motif within the neurotoxic region of B-TatThis study provides important insights into differential neurotoxic properties of B- and C-Tat, and offers a basis for distinct differences in degree of HIV-1-associated neurological deficits observed in patients in India. Additional studies with patient samples are necessary to validate these findings. Ann Neurol 2007
Marijuana and alcohol are most widely abused drugs among women of reproductive age. Neurocognitive deficits have been reported in children whose mothers used marijuana during pregnancy. Maternal consumption of ethanol is known to cause serious developmental deficitsInfant rats and mice received systemic injections of [Delta]9-tetrahydrocannabinol (THC; 1-10mg/kg) or the synthetic cannabinoid WIN 55,212-2 (1-10mg/kg), alone or in combination with subtoxic and toxic ethanol doses, and apoptotic neurodegeneration was studied in the brainsAcute administration of THC (1-10mg/kg), the principal psychoactive cannabinoid of marijuana, markedly enhanced proapoptotic properties of ethanol in the neonatal rat brain. THC did not induce neurodegeneration when administered alone. Neuronal degeneration became disseminated and severe when THC was combined with a mildly intoxicating ethanol dose (3gm/kg), with the effect of this drug combination resembling the massive apoptotic death observed when administering ethanol alone at much higher doses. The detrimental effect of THC was mimicked by the synthetic cannabinoid WIN 55,212-2 (1-10mg/kg) and counteracted by the CB1 receptor antagonist SR141716A (0.4mg/kg). THC enhanced the proapoptotic effect of the GABAA agonist phenobarbital and the N-methyl-D-aspartate receptor antagonist dizocilpine. Interestingly, infant CB1 receptor knock-out mice were less susceptible to the neurotoxic effect of ethanol. Furthermore, the CB1 receptor antagonist SR141716A ameliorated neurotoxicity of ethanolThese observations indicate that CB1 receptor activation modulates GABAergic and glutamatergic neurotransmission and primes the developing brain to suffer apoptotic neuronal death. Ann Neurol 2007