Chemotherapy-induced cognitive impairments: White matter pathologies.

Whilst chemotherapeutic agents show promising results in the amelioration of cancerous tumors, patients often experience cognitive disturbances associated with chemotherapy long after treatment has ceased. Research has suggested that the structural integrity of white matter fibres in the brain are susceptible to the harmful effects of chemotherapy. Post-chemotherapy, white matter tracts often display altered morphology with a reduction in glial cells such as oligodendrocytes. Demyelination, gliosis and leukoencephalopathy during or post chemotherapy is associated with changes in processing speed and IQ. Thus, understanding the relationship between chemotherapy, white matter damage and cognition is warranted. This review presents evidence for chemotherapy induced white matter damage highlighting the importance of implementing behavioral and pharmological strategies to prevent or reverse such acute toxicity in the brain.

A phylogenetic approach to following West Nile virus in Connecticut.

The 1999 outbreak of West Nile (WN) virus in the northeastern United States was the first known natural occurrence of this flavivirus in the Western Hemisphere. In 1999 and 2000, 82 independent Connecticut WN virus isolates were cultured from nine species of birds, five species of mosquitoes, and one striped skunk. Nucleotide sequences obtained from these isolates identified 30 genetic changes, compared with WN-NY99, in a 921-nt region of the viral genome beginning at nucleotide position 205 and ending at 1125. This region encodes portions of the nucleocapsid and envelope proteins and includes the entire coding regions for the premembrane and membrane proteins. Amino acid changes occurred at seven loci in six isolates relative to the WN-NY99 strain. Although 34 of the isolates showed sequences identical to the WN-NY99 isolate, we were able to show geographical-based clusters of mutations. In particular, 26 isolates were characterized by mutation of C to T at position 858. This group apparently originated in Stamford, CT and disseminated to sites located as far as 54 miles from Stamford. Sequences of WN virus isolated from both brain and heart tissues from the same avian host were identical in all 14 tested individual birds, suggesting that the mutations we have documented are real and not caused by culture, RNA extraction, or PCR procedures. We conclude that this portion of the viral genome will enable us to follow the geographical and temporal movement of variant WN virus strains as they adapt to North America.

West Nile virus surveillance in Connecticut in 2000: an intense epizootic without high risk for severe human disease.

In 1999, Connecticut was one of three states in which West Nile (WN) virus actively circulated prior to its recognition. In 2000, prospective surveillance was established, including monitoring bird deaths, testing dead crows, trapping and testing mosquitoes, testing horses and hospitalized humans with neurologic illness, and conducting a human seroprevalence survey. WN virus was first detected in a dead crow found on July 5 in Fairfield County. Ultimately, 1,095 dead crows, 14 mosquito pools, 7 horses, and one mildly symptomatic person were documented with WN virus infection. None of 86 hospitalized persons with neurologic illness (meningitis, encephalitis, Guillain-Barré-like syndrome) and no person in the seroprevalence survey were infected. Spraying in response to positive surveillance findings was minimal. An intense epizootic of WN virus can occur without having an outbreak of severe human disease in the absence of emergency adult mosquito management.

Allele-specific interactions between the yeast RFC1 and RFC5 genes suggest a basis for RFC subunit-subunit interactions.

Replication factor C (RFC) is an essential, multi-subunit ATPase that functions in DNA replication, DNA repair, and DNA metabolism-related checkpoints. In order to investigate how the individual RFC subunits contribute to these functions in vivo, we undertook a genetic analysis of RFC genes from budding yeast. We isolated and characterized mutations in the RFC5 gene that could suppress the cold-sensitive phenotype of rfc1-1 mutants. Analysis of the RFC5 suppressors revealed that they could not suppress the elongated telomere phenotype, the sensitivity to DNA damaging agents, or the mutator phenotype of rfc1-1 mutants. Unlike the checkpoint-defective rfc5-1 mutation, the RFC5 suppressor mutations did not interfere with the methylmethane sulfonate- or hydroxyurea-induced phosphorylation of Rad53p. The Rfc5p suppressor substitutions mapped to amino acid positions in the conserved RFC box motifs IV-VII. Comparisons of the structures of related RFC box-containing proteins suggest that these RFC motifs may function to coordinate interactions between neighboring subunits of multi-subunit ATPases.

Destabilized PCNA trimers suppress defective Rfc1 proteins in vivo and in vitro.

Replication factor C (RFC) and the proliferating cell nuclear antigen (PCNA) are two essential DNA polymerase accessory proteins that are required for numerous aspects of DNA metabolism including DNA replication, DNA repair, and telomere metabolism. PCNA is a homotrimeric ring-shaped sliding DNA clamp that can facilitate DNA replication by tethering DNA polymerase delta or DNA polymerase epsilon to the DNA template. RFC is the 5-subunit multiprotein complex that loads PCNA onto DNA at primer-template junctions in an ATP-dependent reaction. All five of the RFC subunits share a set of related sequences (RFC boxes) that include nucleotide-binding consensus sequences. We report here that a mutation in the gene encoding the large subunit of yeast RFC gives rise to DNA metabolism defects that can be observed in vivo and in vitro. The rfc1-1 substitution (D513N) lies within the widely conserved RFC box VIII consensus sequence and results in phenotypes including DNA replication defects, increased sensitivity to DNA damaging agents, and elongated telomeres. Mutant Rfc1-1 complexes exhibit in vitro DNA replication defects that are sensitive to ATP concentrations, and these defects can be suppressed by mutant PCNA proteins which contain substitutions that destabilize the homotrimeric sliding DNA clamp.

Economic humidity control: an alternative to reheat.

Heat pipe technology will have a significant impact on the power consumption of many manufacturing industries, the installation costs of new or replacement air conditioning systems, and on electric utility peak demands.

Clinically significant adverse effects in a Phase 1 testing program.

Twelve years' experience with a Phase I drug testing program in normal prison volunteers is reported. Involved in 805 protocol studies were 29,162 participants over 614,534 subject days. During this period there were 64 significant medical events of which 58 were adverse drug reactions and 6 were complications. One subject has residual hip changes due to an infectious complication, another on placebo died from cerebrovascular hemorrhage while asleep. There was complete recovery from all adverse drug reactions and the other 4 complications encountered. Thus a clinically significant medical event occurred once every 9,602 days subject exposure or about once every 26.3 years of individual subject participation.