Cartilage-specific ablation of XBP1 signaling in mouse results in a chondrodysplasia characterized by reduced chondrocyte proliferation and delayed cartilage maturation and mineralization.

OBJECTIVE: To investigate the in vivo role of the IRE1/XBP1 unfolded protein response (UPR) signaling pathway in cartilage. DESIGN: Xbp1(flox/flox).Col2a1-Cre mice (Xbp1(CartΔEx2)), in which XBP1 activity is ablated specifically from cartilage, were analyzed histomorphometrically by Alizarin red/Alcian blue skeletal preparations and X-rays to examine overall bone growth, histological stains to measure growth plate zone length, chondrocyte organization, and mineralization, and immunofluorescence for collagen II, collagen X, and IHH. Bromodeoxyuridine (BrdU) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses were used to measure chondrocyte proliferation and cell death, respectively. Chondrocyte cultures and microdissected growth plate zones were analyzed for expression profiling of chondrocyte proliferation or endoplasmic reticulum (ER) stress markers by Quantitative PCR (qPCR), and of Xbp1 mRNA splicing by RT-PCR to monitor IRE1 activation. RESULTS: Xbp1(CartΔEx2) displayed a chondrodysplasia involving dysregulated chondrocyte proliferation, growth plate hypertrophic zone shortening, and IRE1 hyperactivation in chondrocytes. Deposition of collagens II and X in the Xbp1(CartΔEx2) growth plate cartilage indicated that XBP1 is not required for matrix protein deposition or chondrocyte hypertrophy. Analyses of mid-gestation long bones revealed delayed ossification in Xbp1(CartΔEx2) embryos. The rate of chondrocyte cell death was not significantly altered, and only minimal alterations in the expression of key markers of chondrocyte proliferation were observed in the Xbp1(CartΔEx2) growth plate. IRE1 hyperactivation occurred in Xbp1(CartΔEx2) chondrocytes but was not sufficient to induce regulated IRE1-dependent decay (RIDD) or a classical UPR. CONCLUSION: Our work suggests roles for XBP1 in regulating chondrocyte proliferation and the timing of mineralization during endochondral ossification, findings which have implications for both skeletal development and disease.

Improved motor function in tetraplegics following neuromuscular stimulation-assisted arm ergometry.

The effectiveness of neuromuscular stimulation (NMS)-assisted arm ergometry for strengthening triceps brachii was evaluated in 34 cervical spinal cord injured persons. Group I (n = 12) received eight weeks of NMS-assisted ergometry. Group II (n = 11) received four weeks of NMS-assisted ergometry followed by four weeks of arm ergometry alone. Group III (N = 11) received only arm ergometry (control group). Seventeen of 24 muscles in Group I subjects had improved manual muscle test scores after eight weeks, compared with 10 of 22 Group II muscles and five of 22 Group III muscles. Including only muscles with initial scores < or = 3, Group I demonstrated significant improvements versus Group III after four weeks (p < .003) and after eight weeks (p < .0005) of exercise. A difference was also found between Groups II and III (p < .03) after eight weeks. These results suggest that NMS-assisted ergometry is effective for strengthening voluntary triceps muscle contractions in tetraplegics.

Drinking and driving among American youth: beliefs and behaviors.

Data from research on traffic accident populations clearly indicate that a large proportion of accidents involve drivers under the age of twenty-five. Even after differential exposure to traffic accidents has been controlled for, young drivers remain over-represented in both alcohol-related and non-alcohol-related traffic crashes. The relative risk of crash involvement begins to increase markedly among drivers at even relatively low blood alcohol concentrations. Data from general population surveys confirm these findings. When persons under 25 years of age are compared as a group with those 25 and older, a larger proportion of the young persons in the general population both approved of and reported that they engaged in drinking and driving behavior. However, the actual proportion of young persons in the general population who indicated that they had ever been arrested for driving while impaired, or that they had had a traffic accident as a result of drinking, was quite small. The somewhat limited data available on social, psychological and behavioral correlates of youthful drinking and driving problems indicate some association between feelings of rebellion, hostility and alienation (as measured by attitudes toward parents, school, and society), and increased numbers of traffic violations and accidents.