Trisomy 17 in a baboon (Papio hamadryas) with polydactyly, patent foramen ovale and pyelectasis

Trisomy 13 in humans is the third most common autosomal abnormality at birth, after trisomy 21 and trisomy 18. It has a reported incidence of between 1:5,000 and 1:30,000 live births. It is associated with multiple abnormalities, many of which shorten lifespan. We describe here the first reported case of a baboon (Papio hamadryas) with trisomy of chromosome 17, which is homologous to human chromosome 13. The trisomic infant was born to a consanguineous pair of baboons and had morphological characteristics similar to those observed in human trisomy 13, including bilateral polydactyly in the upper limbs, a patent foramen ovale, and pyelectasis. Molecular DNA analysis using human chromosome 13 markers was consistent with the affected infant inheriting two copies of chromosome 17 derived from the same parental chromosome. This trisomy was, therefore, due to either an error in meiosis II or the result of postzygotic nondisjunction. The parental origin, however, could not be determined.     

The complex biogeographic history of a widespread tropical tree species

Many tropical forest tree species have broad geographic ranges, and fossil records indicate that population disjunctions in some species were established millions of years ago. Here we relate biogeographic history to patterns of population differentiation, mutational and demographic processes in the widespread rainforest tree Symphonia globulifera using ribosomal (ITS) and chloroplast DNA sequences and nuclear microsatellite (nSSR) loci. Fossil records document sweepstakes dispersal origins of Neotropical S. globulifera populations from Africa during the Miocene. Despite historical long-distance gene flow, nSSR differentiation across 13 populations from Costa Rica, Panama, Ecuador (east and west of Andes) and French Guiana was pronounced (F(ST)= 0.14, R(ST)= 0.39, P < 0.001) and allele-size mutations contributed significantly (R(ST) > F(ST)) to the divergences between cis- and trans-Andean populations. Both DNA sequence and nSSR data reflect contrasting demographic histories in lower Mesoamerica and Amazonia. Amazon populations show weak phylogeographic structure and deviation from drift-mutation equilibrium indicating recent population expansion. In Mesoamerica, genetic drift was strong and contributed to marked differentiation among populations. The genetic structure of S. globulifera contains fingerprints of drift-dispersal processes and phylogeographic footprints of geological uplifts and sweepstakes dispersal.     

HDL metabolism in context: looking on the bright side

PURPOSE OF REVIEW: To review new data concerning HDL metabolism and cardiovascular disease, the concept of HDL 'functionality', and HDL kinetics in the metabolic syndrome. RECENT FINDINGS: HDL-apoA-I and apoA-II may be better predictors of cardiovascular disease than HDL-cholesterol. Cholesteryl ester transfer protein inhibition with torcetrapib does not benefit cardiovascular disease; whether this is related to 'congestion' of HDL transport or a specific off-target vasopressor effect remains unclear. Accelerated catabolism of HDL particles in metabolic syndrome could be due to increased hepatic secretion of apoB and apoC-III, hepatic steatosis, and low plasma adiponectin. The role of serum amyloid A and homocysteine is uncertain. In metabolic syndrome, therapies that could favourably alter HDL transport include weight loss, fish oils, higher dose statins, and fibrates; 'balancing feedback' may offset reduced catabolism of HDL, fenofibrate being the only agent hitherto shown to increase apoA-I production. SUMMARY: Elevating HDL-apoA-I and apoA-II may be a more important therapeutic objective than increased HDL-cholesterol. Recent studies underscore the potential value of studying HDL functionality, particularly in the metabolic syndrome. Reverse cholesterol transport can only be reliably probed at present by studying the kinetics of HDL particles or apolipoproteins; new methods are needed for investigating cellular and whole body cholesterol turnover. In metabolic syndrome, HDL-raising therapies have differential impact on HDL kinetics, the optimal endpoint being to increase transport and concentration with unchanged or accelerated catabolism.     

Mutation of the LXCXE Binding Cleft of pRb Facilitates Transformation by ras In Vitro but Does Not Promote Tumorigenesis In Vivo

Background

The Retinoblastoma protein (pRB) is a key tumor suppressor that is functionally inactivated in most cancers. pRB regulates the cell division cycle and cell cycle exit through protein–protein interactions mediated by its multiple binding interfaces. The LXCXE binding cleft region of pRB mediates interactions with cellular proteins that have chromatin regulatory functions. Chromatin regulation mediated by pRB is required for a stress responsive cell cycle arrest, including oncogene induced senescence. The in vivo role of chromatin regulation by pRB during senescence, and its relevance to cancer is not clear.

Methodology/Principal Findings

Using gene-targeted mice, uniquely defective for pRB mediated chromatin regulation, we investigated its role during transformation and tumor progression in response to activation of oncogenic ras. We report that the pRB^∆L mutation confers susceptibility to escape from HrasV12 induced senescence and allows transformation in vitro, although these cells possess high levels of DNA damage. Intriguingly, LSL-Kras, Rb1 ^∆L/∆L mice show delayed lung tumor formation compared to controls. This is likely due to the increased apoptosis seen in the early hyperplastic lesions shortly following ras activation that inhibits tumor progression. Furthermore, DMBA treatment to induce sporadic ras mutations in other tissues also failed to reveal greater susceptibility to cancer in Rb1 ^∆L/∆L mice.

Conclusions/Significance

Our data suggests that chromatin regulation by pRB can function to limit proliferation, but its loss fails to contribute to cancer susceptibility in ras driven tumor models because of elevated levels of DNA damage and apoptosis.     

Redundancy or heterogeneity in the electric activity of the biceps brachii muscle? Added value of PCA-processed multi-channel EMG muscle activation estimates in a parallel-fibered muscle

Conventional bipolar EMG provides imprecise muscle activation estimates due to possibly heterogeneous activity within muscles and due to improper alignment of the electrodes with the muscle fibers. Principal component analysis (PCA), applied on multi-channel monopolar EMG yielded substantial improvements in muscle activation estimates in pennate muscles. We investigated the degree of heterogeneity in muscle activity and the contribution of PCA to muscle activation estimates in biceps brachii (BB), which has a relatively simply parallel-fibered architecture. EMG-based muscle activation estimates were assessed by comparison to elbow flexion forces in isometric, two-state isotonic contractions in eleven healthy male subjects. Monopolar EMG was collected over the entire surface of the BB with about 63 electrodes. Estimation quality of different combinations of EMG channels showed that heterogeneous activation was found mainly in medio-lateral direction, whereas adding channels in the longitudinal direction added largely redundant information. Multi-channel bipolar EMG amplitude improved muscle activation estimates by 5–14% as compared to a single bipolar. PCA-processed monopolar EMG amplitude yielded a further improvement of (12–22%). Thus multi-channel EMG, processed with PCA, substantially improves the quality of muscle activation estimates compared conventional bipolar EMG in BB.     

Cost-Effectiveness of Quantiferon?-TB Gold-In-Tube Versus Tuberculin Skin Testing for Contact Screening and Treatment of Latent Tuberculosis Infection in Brazil

Background

Latent tuberculosis infection (LTBI) is a reservoir for new TB cases. Isoniazid preventive therapy (IPT) reduces the risk of active TB by as much as 90%, but LTBI screening has limitations. Unlike tuberculin skin testing (TST), interferon-gamma release assays are not affected by BCG vaccination, and have been reported to be cost-effective in low-burden countries. The goal of this study was to perform a cost-effectiveness analysis from the health system perspective, comparing three strategies for LTBI diagnosis in TB contacts: tuberculin skin testing (TST), QuantiFERON®-TB Gold-in-Tube (QFT-GIT) and TST confirmed by QFT-GIT if positive (TST/QFT-GIT) in Brazil, a middle-income, high-burden country with universal BCG coverage.

Methodology/Principal Findings

Costs for LTBI diagnosis and treatment of a hypothetical cohort of 1,000 adult immunocompetent close contacts were considered. The effectiveness measure employed was the number of averted TB cases in two years. Health system costs were US$ 105,096 for TST, US$ 121,054 for QFT-GIT and US$ 101,948 for TST/QFT-GIT; these strategies averted 6.56, 6.63 and 4.59 TB cases, respectively. The most cost-effective strategy was TST (US$ 16,021/averted case). The incremental cost-effectiveness ratio was US$ 227,977/averted TB case for QFT-GIT. TST/QFT-GIT was dominated.

Conclusions

Unlike previous studies, TST was the most cost-effective strategy for averting new TB cases in the short term. QFT-GIT would be more cost-effective if its costs could be reduced to US$ 26.95, considering a TST specificity of 59% and US$ 18 considering a more realistic TST specificity of 80%. Nevertheless, with TST, 207.4 additional people per 1,000 will be prescribed IPT compared with QFT.     

Cytomegaloviral hypophysitis in a simian immunodeficiency virus‐infected rhesus macaque (Macacca mulatta)

Rhesus macaques experimentally infected with Simian Immunodeficiency Virus (SIV) experience immunosuppression and often opportunistic infection. Among the most common opportunistic infections are rhesus cytomegalovirus (RhCMV), a ubiquitous betaherpesvirus that undergoes continuous low‐level replication in immunocompetent monkeys. Upon SIV‐mediated immunodeficiency, RhCMV reactivates and results in lesions in numerous organ systems including the nervous and reproductive systems. We report the first case of cytomegaloviral hypophysitis in a SIV‐immunocompromised rhesus macaque.     

Tachykinin-related peptide precursors in two cockroach species

Tachykinins and tachykinin-related peptides (TKRPs) play major roles in signaling in the nervous system and intestine of both invertebrates and vertebrates. Here we have identified cDNAs encoding precursors of multiple TKRPs from the cockroaches Leucophaea maderae and Periplaneta americana. All nine LemTKRPs that had been chemically isolated in earlier experiments could be identified on the precursor of L. maderae. Four previously unidentified LemTKRPs were found in addition on the precursor. The P. americana cDNA displayed an open reading frame very similar to that of L. maderae with 13 different TKRPs. MALDI-TOF mass spectra from tissues of both species confirms the presence of all the TKRPs encoded on the precursor plus two additional peptides that are cleavage products of the N-terminally extended TKRPs. A tissue-specific distribution of TKRPs was observed in earlier experiments at isolation from brain and midgut of L. maderae. Our data do not suggest a differential gene expression but a different efficacy in processing of LemTKRP-2 and Lem/PeaTKRP-3 in the brain and intestine, respectively. This results in a gut-specific accumulation of these extended peptides, whereas in the brain their cleavage products, LemTKRP-1 and LemTKRP-3(11-19), are most abundant. Mass spectrometric analysis demonstrated the occurrence of the different TKRPs in single glomeruli of the tritocerebrum and in cells of the optical lobe.     

13C NMR of methylated lysines of fd gene 5 protein: evidence for a conformational change involving lysine 24 upon binding of a negatively charged lanthanide chelate

Helical complexes formed between fd DNA and reductively methylated fd gene 5 protein were indistinguishable by electron microscopy from complexes formed with the nonmethylated protein. 13C NMR spectroscopy of 13C-enriched N epsilon, N epsilon-dimethyllsyl residues of the protein showed that three of these residues (Lys-24, Lys-46, and Lys-69) were selectively perturbed by binding of the oligomer d(pA)7. These were the same lysyl residues that we previously found to be most protected from methylation by binding of the protein to poly[r(U)] [Dick, L. R., Sherry, A. D., Newkirk, M. M., & Gray D. M. (1988) J. Biol. Chem. 263, 18864-18872]. Thus, these lysines are probably directly involved in the nucleic acid binding function of the protein. Negatively charged chelates of lanthanide ions were used to perturb the 13C NMR resonances of labeled lysyl and amino-terminal residues of the gene 5 protein. The terbium chelate was found to bind tightly (Ka approximately 10(5) M-1) to the protein with a stoichiometry of 1 chelate molecule per protein dimer. 13C resonances of Lys-24, Lys-46, and Lys-69 were maximally shifted by the terbium chelate and were maximally relaxed by the gadolinium chelate. Also, the terbium chelate was excluded by the oligomer d(pA)7. Computer fits of the induced chemical shifts of 13C resonances with those expected for various positions of the terbium chelate failed to yield a possible chelate binding site unless the chemical shift for Lys-24 was excluded from the fitting process.(ABSTRACT TRUNCATED AT 250 WORDS)