Internal fixation implants for intracapsular hip fractures in older adults: Review

Background Hip fractures are a major healthcare problem, presenting a huge challenge and burden to patients, healthcare systems and society. The increased proportion of older adults in the world population means that the absolute number of hip fractures is rising rapidly across the globe. The majority of hip fractures are treated surgically. This review evaluates evidence for types of internal fixation implants used in joint‐preserving surgery for intracapsular hip fractures. Objectives To determine the relative effects (benefits and harms) of different implants for the internal fixation of intracapsular hip fractures in older adults. Search methods We searched CENTRAL, MEDLINE, Embase, Web of Science, Cochrane Database of Systematic Reviews, Epistemonikos, Proquest Dissertations and Theses, and National Technical Information Service in July 2020. We also searched clinical trials databases, conference proceedings, reference lists of retrieved articles and conducted backward‐citation searches. Selection criteria We included randomised controlled trials (RCTs) and quasi‐RCTs comparing implants used for internal fixation of fragility intracapsular proximal femoral fractures in older adults. Types of implants were smooth pins (these include pins with fold‐out hooks), screws, or fixed angle plates. We excluded studies in which all or most fractures were caused by specific pathologies other than osteoporosis or were the result of a high energy trauma. Data collection and analysis Two review authors independently assessed studies for inclusion. One review author extracted data and assessed risk of bias which was checked by a second review author. We collected data for seven outcomes: activities of daily living (ADL), delirium, functional status, health‐related quality of life (HRQoL), mobility, mortality (reported within four months of surgery as early mortality, and at 12 months since surgery), and unplanned return to theatre for treating a complication resulting directly or indirectly from the primary procedure (such as deep infection or non‐union). We assessed the certainty of the evidence for these outcomes using GRADE. Main results We included 38 studies (32 RCTs, six quasi‐RCTs) with 8585 participants with 8590 intracapsular fractures. The mean ages of participants in the studies ranged from 60 to 84 years; 73% were women, and 38% of fractures were undisplaced. We report here the findings of the four main comparisons, which were between different categories of implants. We downgraded the certainty of the outcomes for imprecision (when data were available from insufficient numbers of participants or the confidence interval (CI) was wide), study limitations (e.g. high or unclear risks of bias), and inconsistency (when we noted substantial levels of statistical heterogeneity). Smooth pins versus fixed angle plate (four studies, 1313 participants) We found very low‐certainty evidence of little or no difference between the two implant types in independent mobility with no more than one walking stick (1 study, 112 participants), early mortality (1 study, 383 participants), mortality at 12 months (2 studies, 661 participants), and unplanned return to theatre (3 studies, 736 participants). No studies reported on ADL, delirium, functional status, or HRQoL. Screws versus fixed angle plates (11 studies, 2471 participants) We found low‐certainty evidence of no clinically important differences between the two implant types in functional status using WOMAC (MD ‐3.18, 95% CI ‐6.35 to ‐0.01; 2 studies, 498 participants; range of scores from 0 to 96, lower values indicate better function), and HRQoL using EQ‐5D (MD 0.03, 95% CI 0.00 to 0.06; 2 studies, 521 participants; range ‐0.654 (worst), 0 (dead), 1 (best)). We also found low‐certainty evidence showing little or no difference between the two implant types in mortality at 12 months (RR 1.04, 95% CI 0.83 to 1.31; 7 studies, 1690 participants), and unplanned return to theatre (RR 1.10, 95% CI 0.95 to 1.26; 11 studies, 2321 participants). We found very low‐certainty evidence of little or no difference between the two implant types in independent mobility (1 study, 70 participants), and early mortality (3 studies, 467 participants). No studies reported on ADL or delirium. Screws versus smooth pins (seven studies, 1119 participants) We found low‐certainty evidence of no or little difference between the two implant types in mortality at 12 months (RR 1.07, 95% CI 0.85 to 1.35; 6 studies, 1005 participants; low‐certainty evidence). We found very low‐certainty evidence of little or no difference between the two implant types in early mortality (3 studies, 584 participants) and unplanned return to theatre (5 studies, 862 participants). No studies reported on ADL, delirium, functional status, HRQoL, or mobility. Screws or smooth pins versus fixed angle plates (15 studies, 3784 participants) In this comparison, we combined data from the first two comparison groups. We found low‐certainty evidence of no or little difference between the two groups of implants in mortality at 12 months (RR 1.04, 95% CI.083 to 1.31; 7 studies, 1690 participants) and unplanned return to theatre (RR 1.02, 95% CI 0.88 to 1.18; 14 studies, 3057 participants). We found very low‐certainty evidence of little or no difference between the two groups of implants in independent mobility (2 studies, 182 participants), and early mortality (4 studies, 850 participants). We found no additional evidence to support the findings for functional status or HRQoL as reported in 'Screws versus fixed angle plates'. No studies reported ADL or delirium. Authors' conclusions There is low‐certainty evidence that there may be little or no difference between screws and fixed angle plates in functional status, HRQoL, mortality at 12 months, or unplanned return to theatre; and between screws and pins in mortality at 12 months. The limited and very low‐certainty evidence for the outcomes for which data were available for the smooth pins versus fixed angle plates comparison, as well as the other outcomes for which data were available for the screws and fixed angle plates, and screws and pins comparisons means we have very little confidence in the estimates of effect for these outcomes. Additional RCTs would increase the certainty of the evidence. We encourage such studies to report outcomes consistent with the core outcome set for hip fracture, including long‐term quality of life indicators such as ADL and mobility

Surgical interventions for treating extracapsular hip fractures in older adults: a network meta‐analysis: Review

Background Hip fractures are a major healthcare problem, presenting a challenge and burden to individuals and healthcare systems. The number of hip fractures globally is rising. The majority of extracapsular hip fractures are treated surgically. Objectives To assess the relative effects (benefits and harms) of all surgical treatments used in the management of extracapsular hip fractures in older adults, using a network meta‐analysis of randomised trials, and to generate a hierarchy of interventions according to their outcomes. Search methods We searched CENTRAL, MEDLINE, Embase, Web of Science and five other databases in July 2020. Selection criteria We included randomised controlled trials (RCTs) and quasi‐RCTs comparing different treatments for fragility extracapsular hip fractures in older adults. We included internal and external fixation, arthroplasties and non‐operative treatment. We excluded studies of hip fractures with specific pathologies other than osteoporosis or resulting from high‐energy trauma. Data collection and analysis Two review authors independently assessed studies for inclusion. One review author completed data extraction which was checked by a second review author. We collected data for three outcomes at different time points: mortality and health‐related quality of life (HRQoL) ‐ both reported within 4 months, at 12 months and after 24 months of surgery, and unplanned return to theatre (at end of study follow‐up). We performed a network meta‐analysis (NMA) with Stata software, using frequentist methods, and calculated the differences between treatments using risk ratios (RRs) and standardised mean differences (SMDs) and their corresponding 95% confidence intervals (CIs). We also performed direct comparisons using the same codes. Main results We included 184 studies (160 RCTs and 24 quasi‐RCTs) with 26,073 participants with 26,086 extracapsular hip fractures in the review. The mean age in most studies ranged from 60 to 93 years, and 69% were women. After discussion with clinical experts, we selected nine nodes that represented the best balance between clinical plausibility and efficiency of the networks: fixed angle plate (dynamic and static), cephalomedullary nail (short and long), condylocephalic nail, external fixation, hemiarthroplasty, total hip arthroplasty (THA) and non‐operative treatment. Seventy‐three studies (with 11,126 participants) with data for at least two of these treatments contributed to the NMA. We selected the dynamic fixed angle plate as a reference treatment against which other treatments were compared. This was a common treatment in the networks, providing a clinically appropriate comparison. We downgraded the certainty of the evidence for serious and very serious risks of bias, and because some of the estimates included the possibility of transitivity owing to the proportion of stable and unstable fractures between treatment comparisons. We also downgraded if we noted evidence of inconsistency in direct or indirect estimates from which the network estimate was derived. Most estimates included the possibility of benefits and harms, and we downgraded the evidence for these treatments for imprecision. Overall, 20.2% of participants who received the reference treatment had died by 12 months after surgery. We noted no evidence of any differences in mortality at this time point between the treatments compared. Effect estimates of all treatments included plausible benefits as well as harms. Short cephalomedullary nails had the narrowest confidence interval (CI), with 7 fewer deaths (26 fewer to 15 more) per 1000 participants, compared to the reference treatment (risk ratio (RR) 0.97, 95% CI 0.87 to 1.07). THA had the widest CI, with 62 fewer deaths (177 fewer to 610 more) per 1000 participants, compared to the reference treatment (RR 0.69, 95% CI 0.12 to 4.03). The certainty of the evidence for all treatments was low to very low. Although we ranked the treatments, this ranking should be interpreted cautiously because of the imprecision in all the network estimates for these treatments. Overall, 4.3% of participants who received the reference treatment had unplanned return to theatre. Compared to this treatment, we found very low‐certainty evidence that 58 more participants (14 to 137 more) per 1000 participants returned to theatre if they were treated with a static fixed angle plate (RR 2.48, 95% CI 1.36 to 4.50), and 91 more participants (37 to 182 more) per 1000 participants returned to theatre if treated with a condylocephalic nail (RR 3.33, 95% CI 1.95 to 5.68). We also found that these treatments were ranked as having the highest probability of unplanned return to theatre. In the remaining treatments, we noted no evidence of any differences in unplanned return to theatre, with effect estimates including benefits as well as harms. The certainty of the evidence for these other treatments ranged from low to very low. We did not use GRADE to assess the certainty of the evidence for early mortality, but our findings were similar to those for 12‐month mortality, with no evidence of any differences in treatments when compared to dynamic fixed angle plate. Very few studies reported HRQoL and we were unable to build networks from these studies and perform network meta‐analysis. Authors' conclusions Across the networks, we found that there was considerable variability in the ranking of each treatment such that there was no one outstanding, or subset of outstanding, superior treatments. However, static implants such as condylocephalic nails and static fixed angle plates did yield a higher risk of unplanned return to theatre. We had insufficient evidence to determine the effects of any treatments on HRQoL, and this review includes data for only two outcomes. More detailed pairwise comparisons of some of the included treatments are reported in other Cochrane Reviews in this series. Short cephalomedullary nails versus dynamic fixed angle plates contributed the most evidence to each network, and our findings indicate that there may be no difference between these treatments. These data included people with both stable and unstable extracapsular fractures. At this time, there are too few studies to draw any conclusions regarding the benefits or harms of arthroplasty or external fixation for extracapsular fracture in older adults. Future research could focus on the benefits and harms of arthroplasty interventions compared with internal fixation using a dynamic implant

V_H replacement in rearranged immunoglobulin genes

Examples suggesting that all or part of the V<sub>H</sub> segment of a rearranged V<sub>H</sub>DJ<sub>H</sub> may be replaced by all or part of another V<sub>H</sub> have been appearing since the 1980s. Evidence has been presented of two rather different types of replacement. One of these has gained acceptance and has now been clearly demonstrated to occur. The other, proposed more recently, has not yet gained general acceptance because the same effect can be produced by polymerase chain reaction artefact. We review both types of replacement including a critical examination of evidence for the latter. The first type involves RAG proteins and recombination signal sequences (RSS) and occurs in immature B cells. The second was also thought to be brought about by RAG proteins and RSS. However, it has been reported in hypermutating cells which are not thought to express RAG proteins but in which activation-induced cytidine deaminase (AID) has recently been shown to initiate homologous recombination. Re-examination of the published sequences reveals AID target sites in V<sub>H</sub>-V<sub>H</sub> junction regions and examples that resemble gene conversion

On the Banach lattice structure of L-w(1) of a vector measure on a delta-ring

We study some Banach lattice properties of the space L-w(1)(v) of weakly integrable functions with respect to a vector measure v defined on a delta-ring. Namely, we analyze order continuity, order density and Fatou type properties. We will see that the behavior of L-w(1)(v) differs from the case in which is defined on a sigma-algebra whenever does not satisfy certain local sigma-finiteness property.J. M. Calabuig and M. A. Juan were supported by the Ministerio de Economia y Competitividad (project MTM2008-04594). O. Delgado was supported by the Ministerio de Economia y Competitividad (project MTM2009-12740-C03-02). E. A. Sanchez Perez was supported by the Ministerio de Economia y Competitividad (project MTM2009-14483-C02-02).Calabuig Rodriguez, JM.; Delgado Garrido, O.; Juan Blanco, MA.; Sánchez Pérez, EA. (2014). On the Banach lattice structure of L-w(1) of a vector measure on a delta-ring. Collectanea Mathematica. 65(1):67-85. doi:10.1007/s13348-013-0081-8S6785651Brooks, J.K., Dinculeanu, N.: Strong additivity, absolute continuity and compactness in spaces of measures. J. Math. Anal. Appl. 45, 156–175 (1974)Calabuig, J.M., Delgado, O., Sánchez Pérez, E.A.: Factorizing operators on Banach function spaces through spaces of multiplication operators. J. Math. Anal. Appl. 364, 88–103 (2010)Calabuig, J.M., Juan, M.A., Sánchez Pérez, E.A.: Spaces of $$p$$ -integrable functions with respect to a vector measure defined on a $$\delta$$ -ring. Oper. Matrices 6, 241–262 (2012)Curbera, G.P.: El espacio de funciones integrables respecto de una medida vectorial. Ph. D. thesis, University of Sevilla, Sevilla (1992)Curbera, G.P.: Operators into $$L^1$$ of a vector measure and applications to Banach lattices. Math. Ann. 293, 317–330 (1992)Curbera, G.P., Ricker, W.J.: Banach lattices with the Fatou property and optimal domains of kernel operators. Indag. Math. (N.S.) 17, 187–204 (2006)G. P. Curbera and W. J. Ricker, Vector measures, integration and applications. In: Positivity (in Trends Math.), Birkhäuser, Basel, pp. 127–160 (2007)Curbera, G.P., Ricker, W.J.: The Fatou property in $$p$$ -convex Banach lattices. J. Math. Anal. Appl. 328, 287–294 (2007)Delgado, O.: $$L^1$$ -spaces of vector measures defined on $$\delta$$ -rings. Arch. Math. 84, 432–443 (2005)Delgado, O.: Optimal domains for kernel operators on $$[0,\infty )\times [0,\infty )$$ . Studia Math. 174, 131–145 (2006)Delgado, O., Soria, J.: Optimal domain for the Hardy operator. J. Funct. Anal. 244, 119–133 (2007)Delgado, O., Juan, M.A.: Representation of Banach lattices as $$L_w^1$$ spaces of a vector measure defined on a $$\delta$$ -ring. Bull. Belg. Math. Soc. Simon Stevin 19(2), 239–256 (2012)Diestel, J., Uhl, J.J.: Vector measures (Am. Math. Soc. surveys 15). American Mathematical Society, Providence (1997)Dinculeanu, N.: Vector measures, Hochschulbcher fr Mathematik, vol. 64. VEB Deutscher Verlag der Wissenschaften, Berlin (1966)Fernández, A., Mayoral, F., Naranjo, F., Sáez, C., Sánchez Pérez, E.A.: Spaces of $$p$$ -integrable functions with respect to a vector measure. Positivity 10, 1–16 (2006)Fremlin, D.H.: Measure theory, broad foundations, vol. 2. Torres Fremlin, Colchester (2001)Jiménez Fernández, E., Juan, M.A., Sánchez Pérez, E.A.: A Komlós theorem for abstract Banach lattices of measurable functions. J. Math. Anal. Appl. 383, 130–136 (2011)Lewis, D.R.: On integrability and summability in vector spaces. Ill. J. Math. 16, 294–307 (1972)Lindenstrauss, J., Tzafriri, L.: Classical Banach spaces II. Springer, Berlin (1979)Luxemburg, W.A.J., Zaanen, A.C.: Riesz spaces I. North-Holland, Amsterdam (1971)Masani, P.R., Niemi, H.: The integration theory of Banach space valued measures and the Tonelli-Fubini theorems. I. Scalar-valued measures on $$\delta$$ -rings. Adv. Math. 73, 204–241 (1989)Masani, P.R., Niemi, H.: The integration theory of Banach space valued measures and the Tonelli-Fubini theorems. II. Pettis integration. Adv. Math. 75, 121–167 (1989)Thomas, E.G.F.: Vector integration (unpublished) (2013)Turpin, Ph.: Intégration par rapport à une mesure à valeurs dans un espace vectoriel topologique non supposé localement convexe, Intègration vectorielle et multivoque, (Colloq., University Caen, Caen, 1975), experiment no. 8, Dèp. Math., UER Sci., University Caen, Caen (1975)Okada, S., Ricker, W.J., Sánchez Pérez, E.A.: Optimal domain and integral extension of operators acting in function spaces (Oper. Theory Adv. Appl.), vol. 180. Birkhäuser, Basel (2008)Zaanen, A.C.: Riesz spaces II. North-Holland, Amsterdam (1983

DNA Sequence Variation among Conspecific Accessions of the Legume Coursetia caribaea Reveals Geographically Localized Clades Here Ranked as Species

 This is the author accepted manuscript. The final version is available from ASPT via the DOI in this recordCoursetia caribaea is geographically and morphologically the most variable species in the genus Coursetia and in the tribe Robinieae (Leguminosae, Papilionoideae). Because of potentially undetected species, we assessed the phylogenetic relationships among the eight taxonomic varieties of C. caribaea. Sampling included nuclear ribosomal internal transcribed spacer sequences from 489 Robinieae accessions representing all varieties of C. caribaea and 38 of the 40 species of Coursetia, in addition to chloroplast trnD-trnT sequences from 186 accessions. Separate and combined phylogenetic analyses resolved a clade of conspecific accessions of the Bolivian C. caribaea var. astragalina as sister to the central Andean Coursetia grandiflora clade. Also distantly related to Coursetia caribaea var. caribaea accessions were those of the coastal Oaxacan C. caribaea var. pacifica, which formed the sister clade to accessions of the central Andean C. caribaea var. ochroleuca. The estimated mean ages of the stem clades for these three lineages, 11, 7.7, and 7.7 Ma, respectively, contrasted to the estimated mean ages of the corresponding crown clades of 0, 0, and 1.5 Ma. The contrasting stem and crown ages suggest that these taxa, appropriately ranked as species, Coursetia astragalina , Coursetia diversifolia , and Coursetia ochroleuca , each have persisted over evolutionary time frames as distinct geographically localized populations in seasonally dry tropical forests and woodlands.USDA National Institute of Food and Agricultur

Kothe dual of Banach lattices generated by vector measures

We study the Kothe dual spaces of Banach function lattices generated by abstract methods having roots in the theory of interpolation spaces. We apply these results to Banach spaces of integrable functions with respect to Banach space valued countably additive vector measures. As an application we derive a description of the Banach dual of a large class of these spaces, including Orlicz spaces of integrable functions with respect to vector measuresThe first author was supported by the Foundation for Polish Science (FNP). The second author was supported by the Ministerio de Economia y Competitividad (Spain) under Grant #MTM2012-36740-C02-02.Mastylo, M.; Sánchez Pérez, EA. (2014). Kothe dual of Banach lattices generated by vector measures. Monatshefte fur Mathematik. 173(4):541-557. https://doi.org/10.1007/s00605-013-0560-8S5415571734Aronszajn, N., Gagliardo, E.: Interpolation spaces and interpolation methods. Ann. Mat. Pura. Appl. 68, 51–118 (1965)Bartle, R.G., Dunford, N., Schwartz, J.: Weak compactness and vector measures. Canad. J. Math. 7, 289–305 (1955)Brudnyi, Yu.A., Krugljak, N.Ya.: Interpolation functors and interpolation spaces $$I$$ I . North-Holland, Amsterdam (1991)Curbera, G.P.: Operators into $$L^1$$ L 1 of a vector measure and applications to Banach lattices. Math. Ann. 293, 317–330 (1992)Curbera, G.P., Ricker, W.J.: The Fatou property in $$p$$ p -convex Banach lattices. J. Math. Anal. Appl. 328, 287–294 (2007)Delgado, O.: Banach function subspaces of $$L^1$$ L 1 of a vector measure and related Orlicz spaces. Indag. Math. 15(4), 485–495 (2004)Diestel, J., Jr., Uhl, J.J.: Vector measures, Amer. Math. Soc. Surveys 15, Providence, R.I. (1977)Fernández, A., Mayoral, F., Naranjo, F., Sánchez-Pérez, E.A.: Spaces of $$p$$ p -integrable functions with respect to a vector measure. Positivity 10, 1–16 (2006)Ferrando, I., Rodríguez, J.: The weak topology on $$L_p$$ L p of a vector measure. Topol. Appl. 155, 1439–1444 (2008)Ferrando, I., Sánchez Pérez, E.A.: Tensor product representation of the (pre)dual of the $$L_p$$ L p -space of a vector measure. J. Aust. Math. Soc. 87, 211–225 (2009)Galaz-Fontes, F.: The dual space of $$L^p$$ L p of a vector measure. Positivity 14(4), 715–729 (2010)Kamińska, A.: Indices, convexity and concavity in Musielak-Orlicz spaces, dedicated to Julian Musielak. Funct. Approx. Comment. Math. 26, 67–84 (1998)Kantorovich, L.V., Akilov, G.P.: Functional analysis, 2nd edn. Pergamon Press, New York (1982)Krein, S.G., Petunin, Yu.I., Semenov, E.M.: Interpolation of linear operators. In: Translations of mathematical monographs, 54. American Mathematical Society, Providence, R.I., (1982)Lewis, D.R.: Integration with respect to vector measures. Pacific. J. Math. 33, 157–165 (1970)Lewis, D.R.: On integrability and summability in vector spaces. Ill. J. Math. 16, 583–599 (1973)Lindenstrauss, J., Tzafriri, L.: Classical Banach spaces II. Springer, Berlin (1979)Lozanovskii, G.Ya.: On some Banach lattices, (Russian). Sibirsk. Mat. Z. 10, 419–430 (1969)Musielak, J.: Orlicz spaces and modular spaces. In: Lecture Notes in Math. 1034, Springer-Verlag, Berlin (1983)Okada, S.: The dual space of $$L^1(\mu )$$ L 1 ( μ ) of a vector measure $$\mu$$ μ . J. Math. Anal. Appl. 177, 583–599 (1993)Okada, S., Ricker, W.J., Sánchez Pérez, E.A.: Optimal domain and integral extension of operators acting in function spaces, operator theory. Adv. Appl., vol. 180, Birkhäuser, Basel (2008)Rao, M.M., Zen, Z.D.: Applications of Orlicz spaces. Marcel Dekker, Inc., New York (2002)Rivera, M.J.: Orlicz spaces of integrable functions with respect to vector-valued measures. Rocky Mt. J. Math. 38(2), 619–637 (2008)Sánchez Pérez, E.A.: Compactness arguments for spaces of $$p$$ p -integrable functions with respect to a vector measure and factorization of operators through Lebesgue-Bochner spaces. Ill. J. Math. 45(3), 907–923 (2001)Sánchez Pérez, E.A.: Vector measure duality and tensor product representation of $$L_p$$ L p spaces of vector measures. Proc. Amer. Math. Soc. 132, 3319–3326 (2004)Zaanen, A.C.: Integration. North Holland, Amsterdam (1967

Computer-supported feedback message tailoring: Theory-informed adaptation of clinical audit and feedback for learning and behavior change

Background: Evidence shows that clinical audit and feedback can significantly improve compliance with desired practice, but it is unclear when and how it is effective. Audit and feedback is likely to be more effective when feedback messages can influence barriers to behavior change, but barriers to change differ across individual health-care providers, stemming from differences in providers' individual characteristics. Discussion: The purpose of this article is to invite debate and direct research attention towards a novel audit and feedback component that could enable interventions to adapt to barriers to behavior change for individual health-care providers: computer-supported tailoring of feedback messages. We argue that, by leveraging available clinical data, theory-informed knowledge about behavior change, and the knowledge of clinical supervisors or peers who deliver feedback messages, a software application that supports feedback message tailoring could improve feedback message relevance for barriers to behavior change, thereby increasing the effectiveness of audit and feedback interventions. We describe a prototype system that supports the provision of tailored feedback messages by generating a menu of graphical and textual messages with associated descriptions of targeted barriers to behavior change. Supervisors could use the menu to select messages based on their awareness of each feedback recipient's specific barriers to behavior change. We anticipate that such a system, if designed appropriately, could guide supervisors towards giving more effective feedback for health-care providers. Summary: A foundation of evidence and knowledge in related health research domains supports the development of feedback message tailoring systems for clinical audit and feedback. Creating and evaluating computer-supported feedback tailoring tools is a promising approach to improving the effectiveness of clinical audit and feedback

Locus-Specific Ribosomal RNA Gene Silencing in Nucleolar Dominance

The silencing of one parental set of rRNA genes in a genetic hybrid is an epigenetic phenomenon known as nucleolar dominance. We showed previously that silencing is restricted to the nucleolus organizer regions (NORs), the loci where rRNA genes are tandemly arrayed, and does not spread to or from neighboring protein-coding genes. One hypothesis is that nucleolar dominance is the net result of hundreds of silencing events acting one rRNA gene at a time. A prediction of this hypothesis is that rRNA gene silencing should occur independent of chromosomal location. An alternative hypothesis is that the regulatory unit in nucleolar dominance is the NOR, rather than each individual rRNA gene, in which case NOR localization may be essential for rRNA gene silencing. To test these alternative hypotheses, we examined the fates of rRNA transgenes integrated at ectopic locations. The transgenes were accurately transcribed in all independent transgenic Arabidopsis thaliana lines tested, indicating that NOR localization is not required for rRNA gene expression. Upon crossing the transgenic A. thaliana lines as ovule parents with A. lyrata to form F1 hybrids, a new system for the study of nucleolar dominance, the endogenous rRNA genes located within the A. thaliana NORs are silenced. However, rRNA transgenes escaped silencing in multiple independent hybrids. Collectively, our data suggest that rRNA gene activation can occur in a gene-autonomous fashion, independent of chromosomal location, whereas rRNA gene silencing in nucleolar dominance is locus-dependent

Anatomical Network Comparison of Human Upper and Lower, Newborn and Adult, and Normal and Abnormal Limbs, with Notes on Development, Pathology and Limb Serial Homology vs. Homoplasy

How do the various anatomical parts (modules) of the animal body evolve into very different integrated forms (integration) yet still function properly without decreasing the individual's survival? This long-standing question remains unanswered for multiple reasons, including lack of consensus about conceptual definitions and approaches, as well as a reasonable bias toward the study of hard tissues over soft tissues. A major difficulty concerns the non-trivial technical hurdles of addressing this problem, specifically the lack of quantitative tools to quantify and compare variation across multiple disparate anatomical parts and tissue types. In this paper we apply for the first time a powerful new quantitative tool, Anatomical Network Analysis (AnNA), to examine and compare in detail the musculoskeletal modularity and integration of normal and abnormal human upper and lower limbs. In contrast to other morphological methods, the strength of AnNA is that it allows efficient and direct empirical comparisons among body parts with even vastly different architectures (e.g. upper and lower limbs) and diverse or complex tissue composition (e.g. bones, cartilages and muscles), by quantifying the spatial organization of these parts-their topological patterns relative to each other-using tools borrowed from network theory. Our results reveal similarities between the skeletal networks of the normal newborn/adult upper limb vs. lower limb, with exception to the shoulder vs. pelvis. However, when muscles are included, the overall musculoskeletal network organization of the upper limb is strikingly different from that of the lower limb, particularly that of the more proximal structures of each limb. Importantly, the obtained data provide further evidence to be added to the vast amount of paleontological, gross anatomical, developmental, molecular and embryological data recently obtained that contradicts the long-standing dogma that the upper and lower limbs are serial homologues. In addition, the AnNA of the limbs of a trisomy 18 human fetus strongly supports Pere Alberch's ill-named "logic of monsters" hypothesis, and contradicts the commonly accepted idea that birth defects often lead to lower integration (i.e. more parcellation) of anatomical structures