FALL-39

PR-39, a proline/arginine-rich peptide antibiotic, has been purified from pig intestine and later shown to originate in the bone marrow. Intending to isolate a clone for a human counterpart to PR-39, we synthesized a PCR probe derived from the PR-39 gene. However, when this probe was used to screen a human bone marrow cDNA library, eight clones were obtained with information for another putative human peptide antibiotic, designated FALL-39 after the first four residues. FALL-39 is a 39-residue peptide lacking cysteine and tryptophan. All human peptide antibiotics previously isolated (or predicted) belong to the defensin family and contain three disulfide bridges. The clone for prepro-FALL-39 encodes a cathelin-like precursor protein with 170 amino acid residues. We have postulated a dibasic processing site for the mature FALL-39 and chemically synthesized the putative peptide. In basal medium E, synthetic FALL-39 was highly active against Escherichia coli and Bacillus megaterium. Residues 13-34 in FALL-39 can be predicted to form a perfect amphiphatic helix, and CD spectra showed that medium E induced 30% helix formation in FALL-39. RNA blot analyses disclosed that the gene for FALL-39 is expressed mainly in human bone marrow and testis.

The peptide antibiotic PR-39 was originally isolated from the upper part of pig intestine. It has antibacterial activity against Gram negative bacteria at concentrations comparable with tetracycline. Studies of the mechanism of action showed that PR-39 inhibits both DNA and protein synthesis. Recently, PR-39 was found in wound fluid and was shown to have inductive activity on matrix components as part of the wound repair process. We have now sequenced the complete gene and possible mediators of its expression will be discussed. Our attempts to characterize the human counterpart of PR-39 by probing for the well conserved prepro-part led to a different peptide antibiotic. A clone containing the coding information for this new peptide was isolated from a human bone marrow cDNA library. The putative human peptide antibiotic was designated FALL-39 after the first four residues and the total number of residues. All human peptide antibiotics previously isolated (or predicted) belong to the defensin family with three disulfide bridges, while FALL-39 lacks cysteine. The clone for the prepro-FALL-39 encodes a cathelin-like precursor protein with 170 amino acid residues. We have postulated a dibasic processing site for the mature FALL-39 and chemically synthesized the peptide. In the presence of the basal medium E, synthetic FALL-39 was highly active against Escherichia coli D21 and Bacillus megaterium Bm11. Residues 13-34 in FALL-39 can be predicted to form a perfect amphipatic helix and CD spectra showed that medium E induced 30% helix formation in FALL-39. By Northern blot analyses the transcript was located in bone marrow and testis. The structure of the gene and the chromosomal location is under investigation.

Background/objectives: To assess whether vitamin D supplementation prevents specific fall subtypes and sequelae (e.g., fracture). Design: Secondary analyses of STURDY (Study to Understand Fall Reduction and Vitamin D in You)-a response-adaptive, randomized clinical trial. Setting: Two community-based research units. Participants: Six hundred and eighty-eight participants ≥70 years old with elevated fall risk and baseline serum 25-hydroxyvitamin D levels of 10-29 ng/ml. Intervention: 200 IU/day (control), 1000 IU/day, 2000 IU/day, or 4000 IU/day of vitamin D3. Measurements: Outcomes included repeat falls and falls that were consequential, were injurious, resulted in emergency care, resulted in fracture, and occurred either indoors or outdoors. Results: After adjustment for multiple comparisons, the risk of fall-related fracture was greater in the pooled higher doses (≥1000 IU/day) group compared with the control (hazard ratio [HR] = 2.66; 95% confidence interval [CI]:1.18-6.00). Although not statistically significant after multiple comparisons adjustment, time to first outdoor fall appeared to differ between the four dose groups (unadjusted p for overall difference = 0.013; adjusted p = 0.222), with risk of a first-time outdoor fall 39% lower in the 1000 IU/day group (HR = 0.61; 95% CI: 0.38-0.97; unadjusted p = 0.036; adjusted p = 0.222) and 40% lower in the 2000 IU/day group (HR = 0.60; 95%CI 0.38-0.97; p = 0.037; adjusted p = 0.222), each versus control. Conclusion: Vitamin D supplementation doses ≥1000 IU/day might have differential effects on fall risk based on fall location and fracture risk, with the most robust finding that vitamin D doses between 1000 and 4000 IU/day might increase the risk of first time falls with fractures. Replication is warranted, given the possibility of type 1 error.