The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

Collagen is the most abundant protein in animals. This fibrous, structural protein comprises a right-handed bundle of three parallel, left-handed polyproline II-type helices. Much progress has been made in elucidating the structure of collagen triple helices and the physicochemical basis for their stability. New evidence demonstrates that stereoelectronic effects and preorganization play a key role in that stability. The fibrillar structure of type I collagen—the prototypical collagen fibril—has been revealed in detail. Artificial collagen fibrils that display some properties of natural collagen fibrils are now accessible using chemical synthesis and self-assembly. A rapidly emerging understanding of the mechanical and structural properties of native collagen fibrils will guide further development of artificial collagenous materials for biomedicine and nanotechnology.

/pdf/collagen-structure-and-stability-4a8qztbno6.pdf

Collagen Structure and Stability

Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

http://media.onj.nu/2013/08/AAOMS-Position-paper-ONJ_2014.pdf

American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update.

In principle, transplantation of mesenchymal progenitor cells would attenuate or possibly correct genetic disorders of bone, cartilage and muscle, but clinical support for this concept is lacking. Here we describe the initial results of allogeneic bone marrow transplantation in three children with osteogenesis imperfecta, a genetic disorder in which osteoblasts produce defective type I collagen, leading to osteopenia, multiple fractures, severe bony deformities and considerably shortened stature. Three months after osteoblast engraftment (1.5-2.0% donor cells), representative specimens of trabecular bone showed histologic changes indicative of new dense bone formation. All patients had increases in total body bone mineral content ranging from 21 to 29 grams (median, 28), compared with predicted values of 0 to 4 grams (median, 0) for healthy children with similar changes in weight. These improvements were associated with increases in growth velocity and reduced frequencies of bone fracture. Thus, allogeneic bone marrow transplantation can lead to engraftment of functional mesenchymal progenitor cells, indicating the feasibility of this strategy in the treatment of osteogenesis imperfecta and perhaps other mesenchymal stem cell disorders as well.

Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta

Chapter 17 – Osteogenesis Imperfecta

CaMKII inhibition due to TRIC-B loss-of-function dysregulates SMAD signalling in osteogenesis imperfecta.

We have developed a strategy for the detection, localization, and sequencing of point mutations in the mRNA coding for the two chains of type I collagen. Point mutations are detected by RNase A cleavage of mismatches in RNA/RNA hybrids between patient mRNA and labeled antisense riboprobes. The mRNAs coding for the fibrillar collagens pose special problems for hybrid analysis because of their large size and the GC-rich and repetitive nature of their sequences. Because the central helical portion of the fibrillar collagens is composed of a repeating unit of three amino acids, gly-XY, the mRNA has over 300 repeats of 9 nucleotides (nt) with high homology. To contend with the length of the fibrillar collagen mRNAs, the entire cDNAs for the al(1) and a2(I) chains of type I collagen were subcloned in overlapping segments into pGEM vectors (FIG. 1). Inserts were oriented such that antisense riboprobes were transcribed from the T7 promoter. Futhermore, the lengths of the riboprobes were limited to about 1 kb or less, due to the practical limitations of gel analysis. If a longer probe is used, it is difficult to resolve cleavage fragments that are near fulllength in size from full-length probe protection. To maximize specificity despite the extremely repetitive sequences, the probes were hybridized to patient mRNA near the melting temperature of the hybrids. RNA/RNA hybrid analysis was performed essentially according to the methodology developed by Gibbs and Caskey.' A crucial feature of this methodology is the use of mAP membrane after hybridization to separate poly( A+) mRNA containing the RNA/RNA hybrids of interest from unhybridized probe and to yield a lower background. Mismatches in the RNA/RNA hybrids were cleaved with RNase A, and the labeled riboprobe cleavage products were examined electrophoretically. The sensitivity and specificity of the system were demonstrated by the detection and localization of a known point mutation in the codon for al(1) gly 988' from a proband with lethal type I1 osteogenesis imperfecta (01). Total RNA from the 01 proband was hybridized with a pair of overlapping riboprobes [FIG. 1, EX and EPC in al(I)]. both of which should allow detection of the mismatch. In addition, the probes have a common 5' end but extend a variable distance at their 3' ends. Thus, these probes should also allow localization of the mismatch with respect to their ends. As expected, a 603-nt fragment was generated from the common 5' end, and 198-nt

Characterization of Point Mutations in Type I Collagen by RNA/RNA Hybrid Analysis

Bone tissue in murine atypical type VI osteogenesis imperfecta has changes in vascular pores and matrix organization, plus classic OI hypermineralization

Joan C. Marini

Papers

Chapter 17 – Osteogenesis Imperfecta

CaMKII inhibition due to TRIC-B loss-of-function dysregulates SMAD signalling in osteogenesis imperfecta.

Characterization of Point Mutations in Type I Collagen by RNA/RNA Hybrid Analysis

Bone tissue in murine atypical type VI osteogenesis imperfecta has changes in vascular pores and matrix organization, plus classic OI hypermineralization

News&views 骨小児におけるビスホスホネート製剤の使用--引き続き注意が要される

Joan C. Marini

Papers

Chapter 17 – Osteogenesis Imperfecta

CaMKII inhibition due to TRIC-B loss-of-function dysregulates SMAD signalling in osteogenesis imperfecta.

Characterization of Point Mutations in Type I Collagen by RNA/RNA Hybrid Analysis

Bone tissue in murine atypical type VI osteogenesis imperfecta has changes in vascular pores and matrix organization, plus classic OI hypermineralization

News&views 骨 小児におけるビスホスホネート製剤の使用--引き続き注意が要される

News&views 骨小児におけるビスホスホネート製剤の使用--引き続き注意が要される