Hsp22 (HspB8/H11) knockdown induces Sam68 expression and stimulates proliferation of glioblastoma cells.

Sam68 (Src-associated protein in mitosis 68 kDa) is a multifunctional protein, known to govern cellular signal transduction, transcription, RNA metabolism, proliferation, apoptosis, and HIV-1 replication. Although intrinsic mechanisms that modulate Sam68 function are beginning to emerge, the regulatory events contributing to its expression remain elusive. We previously reported that heat shock protein-22 (Hsp22) antagonizes Sam68 function in rev-response element (RRE)-mediated gene expression. We now demonstrate that Sam68 levels correlate inversely with Hsp22 in a variety of cells, including U87, Jurkat, 293T, and U-937. In U87 glioblastoma cells, which contained high levels of Hsp22 than other cell lines tested, Hsp22 knockdown dramatically increased both Sam68 mRNA and protein, altered cellular morphology, and enhanced cell proliferation. This heightened proliferation was associated with a sharp decrease in G(0) /G(1) and a corresponding increase in S and G(2) /M phases in exponentially growing cultures. The increased S phase population in turn correlated with enhanced expression of cell cycle regulatory proteins such as cyclin E, cyclin A, ribonucleotide reductase (RNR), and proliferating cell nuclear antigen (PCNA), which are required for the transition of cells from G(1) to S phase. Collectively, our results demonstrate for the first time that Hsp22 regulates Sam68 expression and the ratio of Sam68 to Hsp22 may determine the proliferative potential of glioblastoma cells.

Autoimmune hemolytic anemia: mixed type-a case report.

Mixed autoimmune haemolytic anemia (AIHA) is defined by the presence of both warm and cold auto antibodies. Diagnosis is based on detection of autoantibodies by monospecific direct antiglobulin test showing a pattern of IgG and complement C3d and presence of cold agglutinins. We report a rare case of primary mixed AIHA in a 12 year old girl who responded to corticosteroids.

Anti-intercellular adhesion molecule-1 antibody's effect on noise damage.

OBJECTIVES/HYPOTHESIS: The purpose of this study was to investigate possible preventive effects of anti-intercellular adhesion molecule-1 antibody (anti-ICAM-1 Ab) on noise-induced cochlear damage as assessed by changes in auditory thresholds and cochlear blood flow. STUDY DESIGN: A controlled animal study. Pretreated rats with anti-ICAM-1 Ab or saline control, followed with exposure to 72 continuous hours of broad band noise (107 dB SPL), and 24 hours after noise exposure treated again with anti-ICAM-1 Ab or saline. METHODS: Eighteen healthy male Fischer rats (200-250 g) were used. Sixteen were randomly selected to study noise-induced temporary threshold shifts. The remaining two rats were used to study cochlear blood flow (CBF), using laser Doppler flowmetry and blood pressure measurements. RESULTS: Rats treated with anti-ICAM-1 Ab (1.875 mg/kg, intravenously) showed attenuated temporary threshold shifts (TTS) compared to controls. Both groups showed a partial threshold recovery 72 hours following noise exposure, normal for this noise exposure paradigm. Comparisons of baseline and post-treatment measurements of CBF and mean arterial blood pressure revealed no significant changes. Anti-ICAM-1 Ab animals displayed significantly lower mean auditory threshold shifts at all five test frequencies (P < .05) when compared to control. CONCLUSIONS: Blocking the cascade of reactive oxygen species (ROS) generation by using anti-ICAM-Ab protects against noise-induced hearing loss.

Effect of SOD1 overexpression on age- and noise-related hearing loss.

Reactive oxygen species (ROS) have been implicated in hearing loss associated with aging and noise exposure. Superoxide dismutases (SODs) form a first line of defense against damage mediated by the superoxide anion, the most common ROS. Absence of Cu/Zn SOD (SOD1) has been shown to potentiate hearing loss related to noise exposure and age. Conversely, overexpression of SOD1 may be hypothesized to afford a protection from age- and noise-related hearing loss. This hypothesis may be tested using a transgenic mouse model carrying the human SOD1 gene. Contrary to expectations, here, we report that no protection against age-related hearing loss was observed in mice up to 7 months of age or from noise-induced hearing loss when 8 week old mice were exposed to broadband noise (4-45 kHz, 110 dB for 1 h). Mitochondrial DNA deletion, an index of aging, was elevated in the acoustic nerve of transgenic mice compared to nontransgenic littermates. The results indicate the complexity of oxidative metabolism in the cochlea is greater than previously hypothesized.

Molecular mechanisms of age-related hearing loss.

Age-related hearing loss, known as presbyacusis, is characterized by the progressive deterioration of auditory sensitivity associated with aging and is the most common cause of adult auditory deficiency in the United States. Presbyacusis is defined as a progressive, bilateral, high-frequency hearing loss that is manifested on audiometric assessment by a moderately sloping pure tone audiogram. This condition affects approximately 23% of the population between 65 and 75 years of age and 40% of the population older than 75 years of age. In 1980, it was estimated that 11% of the population was 76 years or older and this number is expected to nearly double by the year 2030 [, Otolaryngol. Head Neck Surg. 100, 262]. When coupled with the fact that the population over 65 years of age is experiencing the most rapid progression of hearing loss, the potential socioeconomic ramifications are staggering. Interestingly, presbyacusis varies in its frequency across differing societies. This discrepancy has been attributed to many factors such as genetics, diet, socioeconomic factors, and environmental variables [, Otolaryngol. Head Neck Surg. 100, 266;. Scand. Audiol. 26 (1997) 133]. The purpose of this discussion is to illuminate the various molecular mechanisms underlying this age-related hearing loss and to offer insights into potential ways to mitigate the effects of aging on hearing impairment.