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The anterior skull base undergoes a progressive ossification after birth. This has implications on the epidural dissection of early trans-craniofacial osteotomy procedures such as monobloc advancements. Our purpose was to determine the rate of ossification in syndromic synostosis patients relative to a normal cohort to establish when maturation of the anterior skull base is complete. The authors analyzed CT scans from 35 patients with Crouzon, Apert or Pfeiffer syndrome, and 84 patients without any craniofacial anomaly between the ages of 0 and 6 years. The non-ossified anterior skull base area was measured using 3D Slicer. The authors compared the sizes of the defects at different ages between the three syndromes and with the control group using Mann-Whitney test. Significance was set at P < 0.05. All patients less than 12 months of age had a measurable defect anterior to the cribriform whereas patients greater than five years of age had full ossification of the anterior skull base with no evidence of defect. The relationship of defect size and age at scan was non-linear, with most defects closing rapidly in the first six months. The temporal closure pattern of the defect was similar between the three syndromes and the control group with no significant difference. Our findings indicate that syndromic children undergo skull base maturation at the same rate as non-syndromic cases, with the majority ossified by three years of age. Anterior skull base surgeries performed before three years should optimize visualization of this area during dissection.

We have demonstrated previously that chondral damage is associated with increased knee surface velocities following ligament and meniscus injuries in sheep. We tested the hypothesis that cartilage damage scores would correlate with a new bone surface interaction measure that captures complex changes in tibiofemoral alignment, “proximity disturbance” (PD). Six sheep underwent combined anterior cruciate and medial collateral ligament transection (ACL/MCLx), five complete lateral meniscectomy (Mx), and four sham arthrotomy (Sham). Tibiofemoral subchondral bone surfaces were modeled, and the post-operative changes in relative separation of the surfaces (i.e., “proximity”) were derived from subject-specific in vivo 3D stifle kinematics. Surface areas of regions of near contact were determined, and PD was calculated as the range of change in tibiofemoral proximity, divided by normalized overlapping proximity surface areas between baseline and post-operative time points. Cartilage morphology was graded at dissection. ACL/MCLx PD was significantly elevated relative to Mx and Shams, and correlated with cartilage damage (r2 = 0.88–0.98). Although not statistically significant, Mx PD values tended to be higher than those of Shams, and correlated with cartilage damage. Results from both injury models suggest that increasing change in tibiofemoral surface alignment may be increasingly deleterious to long-term cartilage health in sheep. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1371–1380, 2014.

Summary:. Mucormycosis is a rare fungal infection caused by ubiquitous fungi in the order Mucorales. It is the most rapidly progressing fulminant fungal infection that mimics necrotizing soft-tissue infections. Overwhelming fungal sepsis develops quickly and mortality rates approach 70%. Culture negative necrotizing infections and cutaneous necrosis following a vascular pattern should raise suspicion for this rare entity. We describe avoiding mortality in a case of orbitomaxillofacial mucormycosis multifactorially treated with: radical serial debridement, topical amphotericin B irrigation and dressings, parenteral amphotericin B, and hyperbaric oxygen therapy. Tissue biopsy was central to confirming the diagnosis and directing multimodal management that ultimately prevented dissemination to the central nervous system and mortality.

Chromosome 9 is highly structurally polymorphic. It contains the largest autosomal block of heterochromatin, which is heteromorphic in 6–8% of humans, whereas pericentric inversions occur in more than 1% of the population. The finished euchromatic sequence of chromosome 9 comprises 109,044,351 base pairs and represents >99.6% of the region. Analysis of the sequence reveals many intra- and interchromosomal duplications, including segmental duplications adjacent to both the centromere and the large heterochromatic block. We have annotated 1,149 genes, including genes implicated in male-to-female sex reversal, cancer and neurodegenerative disease, and 426 pseudogenes. The chromosome contains the largest interferon gene cluster in the human genome. There is also a region of exceptionally high gene and G + C content including genes paralogous to those in the major histocompatibility complex. We have also detected recently duplicated genes that exhibit different rates of sequence divergence, presumably reflecting natural selection.

The finished sequence of human chromosome 10 comprises a total of 131,666,441 base pairs. It represents 99.4% of the euchromatic DNA and includes one megabase of heterochromatic sequence within the pericentromeric region of the short and long arm of the chromosome. Sequence annotation revealed 1,357 genes, of which 816 are protein coding, and 430 are pseudogenes. We observed widespread occurrence of overlapping coding genes (either strand) and identified 67 antisense transcripts. Our analysis suggests that both inter- and intrachromosomal segmental duplications have impacted on the gene count on chromosome 10. Multispecies comparative analysis indicated that we can readily annotate the protein-coding genes with current resources. We estimate that over 95% of all coding exons were identified in this study. Assessment of single base changes between the human chromosome 10 and chimpanzee sequence revealed nonsense mutations in only 21 coding genes with respect to the human sequence.

Chromosome 13 is the largest acrocentric human chromosome. It carries genes involved in cancer including the breast cancer type 2 (BRCA2) and retinoblastoma (RB1) genes, is frequently rearranged in B-cell chronic lymphocytic leukaemia, and contains the DAOA locus associated with bipolar disorder and schizophrenia. We describe completion and analysis of 95.5 megabases (Mb) of sequence from chromosome 13, which contains 633 genes and 296 pseudogenes. We estimate that more than 95.4% of the protein-coding genes of this chromosome have been identified, on the basis of comparison with other vertebrate genome sequences. Additionally, 105 putative non-coding RNA genes were found. Chromosome 13 has one of the lowest gene densities (6.5 genes per Mb) among human chromosomes, and contains a central region of 38 Mb where the gene density drops to only 3.1 genes per Mb.

We have demonstrated previously that chondral damage is associated with increased knee surface velocities following ligament and meniscus injuries in sheep. We tested the hypothesis that cartilage damage scores would correlate with a new bone surface interaction measure that captures complex changes in tibiofemoral alignment, "proximity disturbance" (PD). Six sheep underwent combined anterior cruciate and medial collateral ligament transection (ACL/MCLx), five complete lateral meniscectomy (Mx), and four sham arthrotomy (Sham). Tibiofemoral subchondral bone surfaces were modeled, and the post-operative changes in relative separation of the surfaces (i.e., "proximity") were derived from subject-specific in vivo 3D stifle kinematics. Surface areas of regions of near contact were determined, and PD was calculated as the range of change in tibiofemoral proximity, divided by normalized overlapping proximity surface areas between baseline and post-operative time points. Cartilage morphology was graded at dissection. ACL/MCLx PD was significantly elevated relative to Mx and Shams, and correlated with cartilage damage (r(2) = 0.88-0.98). Although not statistically significant, Mx PD values tended to be higher than those of Shams, and correlated with cartilage damage. Results from both injury models suggest that increasing change in tibiofemoral surface alignment may be increasingly deleterious to long-term cartilage health in sheep.

Obtaining accurate values of joint tissue loads in human subjects and animals in vivo requires exact 3D-reproduction of joint kinematics and comparisons of in vivo motions between subjects and animals, and also necessitates an accurate reference position. For the knee, passive flexion-extension of isolated joints by hand has been assumed to produce bony motions similar to those of normal gait. We hypothesized that passive flexion-extension kinematics would not accurately reproduce in vivo gait, and, further, that such kinematics would vary significantly between testers. In vivo gait motions of four ovine stifle joints were measured in six degrees of freedom, as were passive flexion-extension motions after sacrifice. Passive flexion-extension motions were performed by three testers on the same stifle joints used in vitro. Results showed statistically significant differences in all degrees of freedom, with the largest differences in the proximal-distal and internal-external directions. Differences induced by muscle loads and kinetic factors in vivo were most evident during stance and hoof-off phases of gait. The in vitro passive paths generated by hand created motions with large variability both between and within individual testers. The user dependence and "area" of motion of passive flexion-extension indicates that passive flexion-extension is contained in a volume of motion, rather than constrained to a unique path. The assumption that the passive path has relevance to precise bone positions during normal in vivo gait is not supported by these results. Thus, using passive flexion-extension as a reference between joints may introduce large motion variability in the observed outcome, and large potential errors in determining joint tissue loads.

SUMMARY Although it is well known that many mutations influence phenotypic variability as well as the mean, the underlying mechanisms for variability effects are very poorly understood. The brachymorph (bm) phenotype results from an autosomal recessive mutation in the phosphoadenosine-phosphosulfate synthetase 2 gene (Papps2). A major cranial manifestation is a dramatic reduction in the growth of the chondrocranium which results from undersulfation of glycosaminoglycans (GAGs) in the cartilage matrix. We found that this reduction in the growth of the chondrocranium is associated with an altered pattern of craniofacial shape variation, a significant increase in phenotypic variance and a dramatic increase in morphological integration for craniofacial shape. Both effects are largest in the basicranium. The altered variation pattern indicates that the mutation produces developmental influences on shape that are not present in the wildtype. As the mutation dramatically reduces sulfation of GAGs, we infer that this influence is variation among individuals in the degree of sulfation, or variable expressivity of the mutation. This variation may be because of genetic variation at other loci that influence sulfation, environmental effects, or intrinsic effects. We infer that chondrocranial development exhibits greater sensitivity to variation in the sulfation of chondroitin sulfate when the degree of sulfation is low. At normal levels, sulfation probably contributes minimally to phenotypic variation. This case illustrates canalization in a particular developmentalgenetic context.

The reference sequence for each human chromosome provides the framework for understanding genome function, variation and evolution. Here we report the finished sequence and biological annotation of human chromosome 1. Chromosome 1 is gene-dense, with 3,141 genes and 991 pseudogenes, and many coding sequences overlap. Rearrangements and mutations of chromosome 1 are prevalent in cancer and many other diseases. Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, and also in regions where no function is evident. Fine-scale recombination occurs in hotspots of varying intensity along the sequence, and is enriched near genes. These and other studies of human biology and disease encoded within chromosome 1 are made possible with the highly accurate annotated sequence, as part of the completed set of chromosome sequences that comprise the reference human genome.

Publisher Summary This chapter deals with variability at a specific level, the organismal phenotype. The study of variability at the phenotypic level is concerned with how the architecture of development structures the translation of genetic variation and environmental effects into phenotypic variation. This is important because natural selection acts on phenotypes, but the results are interpreted and transmitted from generation to generation at the genetic level. It is interesting precisely because the relationship between variation at the genetic level and variation at the phenotypic level can be very complex. If the relationship between genetic and phenotypic variation were straightforward, the study of development would be largely irrelevant to evolutionary biology. Getting at the developmental genetic basis for variability is different from the developmental genetic basis of phenotypic variation in specific developmental contexts. The study of the evolutionary developmental biology of variation is still at a very early stage, but its conceptual framework is well developed. The study of the developmental basis for phenotypic variability addresses a higher level of abstraction in that it deals with the tendency of developmental systems to change, amplify, or reduce the expression of genetic variation at the phenotypic level. This area of study is difficult because variability arises from emergent properties of complex developmental systems. Understanding how variability arises from developmental systems requires approaches that focus on the patterns and nature of the interactions among elements in the system.

Chromosome 6 is a metacentric chromosome that constitutes about 6% of the human genome. The finished sequence comprises 166,880,988 base pairs, representing the largest chromosome sequenced so far. The entire sequence has been subjected to high-quality manual annotation, resulting in the evidence-supported identification of 1,557 genes and 633 pseudogenes. Here we report that at least 96% of the protein-coding genes have been identified, as assessed by multi-species comparative sequence analysis, and provide evidence for the presence of further, otherwise unsupported exons/genes. Among these are genes directly implicated in cancer, schizophrenia, autoimmunity and many other diseases. Chromosome 6 harbours the largest transfer RNA gene cluster in the genome; we show that this cluster co-localizes with a region of high transcriptional activity. Within the essential immune loci of the major histocompatibility complex, we find HLA-B to be the most polymorphic gene on chromosome 6 and in the human genome.

The finished sequence of human chromosome 20 comprises 59,187,298 base pairs (bp) and represents 99.4% of the euchromatic DNA. A single contig of 26 megabases (Mb) spans the entire short arm, and five contigs separated by gaps totalling 320 kb span the long arm of this metacentric chromosome. An additional 234,339 bp of sequence has been determined within the pericentromeric region of the long arm. We annotated 727 genes and 168 pseudogenes in the sequence. About 64% of these genes have a 5' and a 3' untranslated region and a complete open reading frame. Comparative analysis of the sequence of chromosome 20 to whole-genome shotgun-sequence data of two other vertebrates, the mouse Mus musculus and the puffer fish Tetraodon nigroviridis, provides an independent measure of the efficiency of gene annotation, and indicates that this analysis may account for more than 95% of all coding exons and almost all genes.

Nature 441, 315–321 (2006) We inadvertently omitted the names of the following authors: R. Banerjee, S. P. Bryant, D. C. Burford, W. D. H. Burrill, S. M. Clegg, P. Dhami, O. Dovey, L. M. Faulkner, S. M. Gribble, C. F. Langford, R. D. Pandian, K. M. Porter and E. Prigmore.