A genomic analysis identifies a novel component in the genetic structure of sub-Saharan African populations

Studies of large sets of SNP data have proven to be a powerful tool in the analysis of the genetic structure of human populations. In this work, we analyze genotyping data for 2,841 SNPs in 12 Sub-Saharan African populations, including a previously unsampled region of south-eastern Africa (Mozambique). We show that robust results in a world-wide perspective can be obtained when analyzing only 1,000 SNPs. Our main results both confirm the results of previous studies, and show new and interesting features in Sub-Saharan African genetic complexity. There is a strong differentiation of Nilo-Saharans, much beyond what would be expected by geography. Hunter-gatherer populations (Khoisan and Pygmies) show a clear distinctiveness with very intrinsic Pygmy (and not only Khoisan) genetic features. Populations of the West Africa present an unexpected similarity among them, possibly the result of a population expansion. Finally, we find a strong differentiation of the south-eastern Bantu population from Mozambique, which suggests an assimilation of a pre-Bantu substrate by Bantu speakers in the region.

The effect of femoral component rotation on the five-year outcome of cemented mobile bearing total knee arthroplasty.

PURPOSE: Performing total knee replacement, accurate alignment and neutral rotation of the femoral component are widely believed to be crucial for the ultimate success. Contrary to absolute bone referenced alignment, using a ligament balancing technique does not automatically rotate the femoral component parallel to the transepicondylar axis. In this context we established the hypothesis that rotational alignment of the femoral component parallel to the transepicondylar axis (0° ± 3°) results in better outcome than alignment outside of this range. METHODS: We analysed 204 primary cemented mobile bearing total knee replacements five years postoperatively. Femoral component rotation was measured on axial radiographs using the condylar twist angle (CTA). Knee society score, range of motion as well as subjective rating documented outcome. RESULTS: In 96 knees the femoral component rotation was within the range 0 ± 3° (neutral rotation group), and in 108 knees the five-year postoperative rotational alignment of the femoral component was outside of this range (outlier group). Postoperative CTA showed a mean of 2.8° (±3.4°) internal rotation (IR) with a range between 6° external rotation (ER) and 15° IR (CI 95). No difference with regard to subjective and objective outcome could be detected. CONCLUSION: The present work shows that there is a large given natural variability in optimal rotational orientation, in this study between 6° ER and 15° IR, with numerous co-factors determining correct positioning of the femoral component. Further studies substantiating pre- and postoperative determinants are required to complete the understanding of resulting biomechanics in primary TKA.

Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial.

Glioblastoma (GBM) is a morphologically heterogeneous tumor type with a median survival of only 15 months in clinical trial populations. However, survival varies greatly among patients. As part of a central pathology review, we addressed the question if patients with GBM displaying distinct morphologic features respond differently to combined chemo-radiotherapy with temozolomide. Morphologic features were systematically recorded for 360 cases with particular focus on the presence of an oligodendroglioma-like component and respective correlations with outcome and relevant molecular markers. GBM with an oligodendroglioma-like component (GBM-O) represented 15% of all confirmed GBM (52/339) and was not associated with a more favorable outcome. GBM-O encompassed a pathogenetically heterogeneous group, significantly enriched for IDH1 mutations (19 vs. 3%, p = 0.003) and EGFR amplifications (71 vs. 48%, p = 0.04) compared with other GBM, while co-deletion of 1p/19q was found in only one case and the MGMT methylation frequency was alike (47 vs. 46%). Expression profiles classified most of the GBM-O into two subtypes, 36% (5/14 evaluable) as proneural and 43% as classical GBM. The detection of pseudo-palisading necrosis (PPN) was associated with benefit from chemotherapy (p = 0.0002), while no such effect was present in the absence of PPN (p = 0.86). In the adjusted interaction model including clinical prognostic factors and MGMT status, PPN was borderline nonsignificant (p = 0.063). Taken together, recognition of an oligodendroglioma-like component in an otherwise classic GBM identifies a pathogenetically mixed group without prognostic significance. However, the presence of PPN may indicate biological features of clinical relevance for further improvement of therapy.

Teichoic acids are not required for Streptococcus pneumoniae and Staphylococcus aureus cell walls to trigger the release of tumor necrosis factor by peripheral blood monocytes.

In gram-negative bacteria, the outer membrane lipopolysaccharide is the main component triggering cytokine release from peripheral blood mononuclear cells (PBMCs). In gram-positive bacteria, purified walls also induce cytokine release, but stimulation requires 100 times more material. Gram-positive walls are complex megamolecules reassembling distinct structures. Only some of them might be inflammatory, whereas others are not. Teichoic acids (TA) are an important portion (> or =50%) of gram-positive walls. TA directly interact with C3b of complement and the cellular receptor for platelet-activating factor. However, their contribution to wall-induced cytokine-release by PBMCs has not been studied in much detail. In contrast, their membrane-bound lipoteichoic acids (LTA) counterparts were shown to trigger inflammation and synergize with peptidoglycan (PGN) for releasing nitric oxide (NO). This raised the question as to whether TA are also inflammatory. We determined the release of tumor necrosis factor (TNF) by PBMCs exposed to a variety of TA-rich and TA-free wall fragments from Streptococcus pneumoniae and Staphylococcus aureus. TA-rich walls from both organisms induced measurable TNF release at concentrations of 1 microg/ml. Removal of wall-attached TA did not alter this activity. Moreover, purified pneumococcal and staphylococcal TA did not trigger TNF release at concentrations as high as > or =100 microg/ml. In contrast, purified LTA triggered TNF release at 1 microg/ml. PGN-stem peptide oligomers lacking TA or amino-sugars were highly active and triggered TNF release at concentrations as low as 0.01 microg/ml (P. A. Majcherczyk, H. Langen, et al., J. Biol. Chem. 274:12537-12543,1999). Thus, although TA is an important part of gram-positive walls, it did not participate to the TNF-releasing activity of PGN.

Charge dependent substrate activity of C3' and N3 functionalized, organometallic technetium and rhenium-labeled thymidine derivatives toward human thymidine kinase 1.

Human cytosolic thymidine kinase (hTK1) has proven to be a suitable target for the noninvasive imaging of cancer cell proliferation using radiolabeled thymidine analogues such as [(18)F]3'-fluoro-3'-deoxythymidine ([(18)F]FLT). A thymidine analogue for single photon emission computed tomography (SPECT), which incorporates the readily available and inexpensive nuclide technetium-99m, would be of considerable practical interest. hTK1 is known to accommodate modification of the structure of the natural substrate thymidine at the positions N3 and C3' and, to a lesser extent, C5. In this work, we used the copper-catalyzed azide-alkyne cycloaddition to synthesize two series of derivatives in which thymidine is functionalized at either the C3' or N3 position with chelating systems suitable for the M(CO)(3) core (M = (99m)Tc, Re). The click chemistry approach enabled complexes with different structures and overall charges to be synthesized from a common precursor. Using this strategy, the first organometallic hTK1 substrates in which thymidine is modified at the C3' position were identified. Phosphorylation of the organometallic derivatives was measured relative to thymidine. We have shown that the influence of the overall charge of the derivatives is dependent on the position of functionalization. In the case of the C3'-functionalized derivatives, neutral and anionic substrates were most readily phosphorylated (20-28% of the value for the parent ligand thymidine), whereas for the N3-functionalized derivatives, cationic and neutral complexes were apparently better substrates for the enzyme (14-18%) than anionic derivatives (9%).

C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L.

Interaction between CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, and its ligand CD40L, a 39-kDa glycoprotein, is essential for the development of humoral and cellular immune responses. Selective blockade or activation of this pathway provides the ground for the development of new treatments against immunologically based diseases and malignancies. Like other members of the TNF superfamily, CD40L monomers self-assemble around a threefold symmetry axis to form noncovalent homotrimers that can each bind three receptor molecules. Here, we report on the structure-based design of small synthetic molecules with C3 symmetry that can mimic CD40L homotrimers. These molecules interact with CD40, compete with the binding of CD40L to CD40, and reproduce, to a certain extent, the functional properties of the much larger homotrimeric soluble CD40L. Architectures based on rigid C3-symmetric cores may thus represent a general approach to mimicking homotrimers of the TNF superfamily.

Meningococcal disease in a kidney transplant recipient with mannose-binding lectin (MBL) deficiency

Background: There is an increasing amount of data associating MBL deficiency with a higher susceptibility to meningococca[ disease. In addition, meningococca[ disease has been reported in patients with various immunosuppressive conditions. However, to our knowledge, only three cases of meningococca[ disease have been reported in solid organ recipients (SOT). Methods & Results: A 32 year-old male patient underwent cadaveric kidney transplantation for endstage renal disease of unknown origin. On day 71 post-transplantation he developed fever (39.6°C), shaking chilis, and tachycardia without hypotension. At this time, immunosuppression consisted of tacro[imus, prednisone 10mg daily and mycopheno[ ate mofeti[ 2 g daily. Physical examination on admission was normal, except for two small petechia[ lesions on the forearm. No meningeal signs were present. Three sets of blood cultures grew Neisseria meningitidis group C susceptible to ceftriaxone (MIC=0.003mg/[). Antibiotic therapy consisted in intravenous ceftriaxone 2 g per day for a total duration of 7 days. Serum immunog[obu[in levels, C3, C4 and CHS0 were normal However, using a method to screen for the functional activity of a[[ three pathways of complement (Wies[ab, Lund, Sweden), no activation via the MBL pathway could be detected (0%). A subsequent quantification of MBL pathway components revealed normal levels of MASP 2 but undetectab[e amounts of MBL (below 10 ng/m[, normal range: >500 ng/m[). Conclusion: Since the exact incidence and the possible relationship between meningococca[ disease and organ transplantation is not we[[ understood, we strongly encourage transplantation centers to report additional cases. The potential clinical usefu[ ness of screening SOT candidates for MBL deficiency in relation to infectious complications after transplantation remains to be determined.

Total shoulder arthroplasty: downward inclination of the glenoid component to balance supraspinatus deficiency.

HYPOTHESIS: Supraspinatus deficiency associated with total shoulder arthroplasty (TSA) provokes eccentric loading and may induce loosening of the glenoid component. A downward inclination of the glenoid component has been proposed to balance supraspinatus deficiency. METHODS: This hypothesis was assessed by a numeric musculoskeletal model of the glenohumeral joint during active abduction. Three cases were compared: TSA with normal muscular function, TSA with supraspinatus deficiency, and TSA with supraspinatus deficiency and downward inclination of the glenoid. RESULTS: Supraspinatus deficiency increased humeral migration and eccentric loading. A downward inclination of the glenoid partly balanced the loss of stability, but this potential advantage was counterbalanced by an important stress increase within the glenoid cement. The additional subchondral bone reaming required to incline the glenoid component indeed reduced the bone support, increasing cement deformation and stress. CONCLUSION: Glenoid inclination should not be obtained at the expense of subchondral bone support.

Fetal MRI as complement to US in the diagnosis and characterization of anomalies of the genito-urinary tract.

The purpose of this study is to compare the accuracy of prenatal ultrasound (US) and prenatal magnetic resonance imaging (MRI) in the diagnosis and characterization of congenital abnormalities of the genito-urinary tract and to determine if the additional information obtained by MRI may influence the management of the fetus. We retrospectively evaluate 15 cases of congenital genito-urinary tract anomalies detected by prenatal US and with echographic inconclusive diagnosis. We compare the MRI findings with the US findings and the final diagnosis, obtained from neonatal outcomes, imaging studies and pathology records. Fetal US diagnosis was correct in 9 cases (60%) and MRI in 13 cases (86.7%). Prenatal MRI revealed additional information to US in 9 cases (60%), which modified the initial US diagnosis in 5 cases (33.3%) and changed the therapeutic approach in 5 fetuses (33.3%). Fetal MRI was better than US in cases of oligoamnios and in fetuses with genito-urinary pathology concerning the pelvic and perineum region. We believe that MRI should be considered as a complementary diagnostic method in cases of echographic suspicion of congenital pathology of the genito-urinary tract and inconclusive prenatal US.

2010- 2014 Iowa Transportation Improvement Program

The Iowa Transportation Improvement Program (Program) is published to inform Iowans of planned investments in our state’s transportation system. The Iowa Transportation Commission (Commission) and Iowa Department of Transportation (Iowa DOT) are committed to programming those investments in a fiscally responsible manner. A major component of the 2010-2014 Program is the full integration of funding allocated to the Iowa DOT from the American Recovery and Reinvestment Act of 2009 (Recovery Act). To date, the Recovery Act has provided over $400 million of additional federal funding for transportation in Iowa, including funding that is allocated to local governments and entities. Recovery Act funding will result in a record year for transportation construction in Iowa and the creation and retention of jobs. Opportunities for additionalRecovery Act transportation funding remain and will be pursued as they becomeavailable. While Recovery Act funding will make a one-time significant impact in addressing Iowa’s backlog of needs, it is important to note that there remains a large shortfall in sustained annual transportation investment to meet Iowa’s current and future critical transportation needs. In recognition of this shortfall, Governor Culver introduced and the legislature passed an I-JOBS proposal. I-JOBS will result in an additional $50 million of state funding to reduce structurally deficient and functionally obsolete bridges on the primary road system and approximately $10 million in funding for other modes of transportation including $3 million of new funding to support the expansion of passenger rail service in Iowa. I-JOBS, and the continuing gradual increase in funding due to TIME-21, will complement and extend the benefits of Recovery Act funding and set the stage for addressing the shortfall in annual funding in the next few years. Iowa’s transportation system is multi-modal; therefore, the Program encompasses investments in aviation, transit, railroads, trails, and highways. A major component of the Program is the highway section. The FY2010-2014 highway section is financially balanced and was developed to achieve several objectives. The Commission’s primary highway investment objective is stewardship (i.e. safety, maintenance and preservation) of Iowa’s existing highway system. The highway section includes an annual average of $104 million for preserving the interstate system; an annual average of $78 million for non-interstate pavement preservation; an annual average of $36 million for non-interstate bridges; and an annual average of $14 million for safety projects. Another objective is to maintain the scheduled completion of interstate and non-interstate capacity and economic development projects that were identified in the previous Program and this Program does so. The final Commission objective is to further address capacity and economic development needs and the Commission has done so by adding several such projects to the Program. Construction improvements are partially funded through the current federal transportation act, Safe, Accountable, Flexible, Efficient Transportation Equity Act: A Legacy for Users (SAFETEA-LU). The act will expire September 30, 2009. With the expiration of SAFETEA-LU, there is significant uncertainty in the forecast of federal revenues in the out-years of this Program. The Commission and Iowa DOT will monitor federal actions closely and make adjustments to the Program as necessary. The Iowa DOT and Commission appreciate the public’s involvement in the state’s transportation planning process. Comments received personally, by letter, or through participation in the Commission’s regular meetings or public input meetings held around the state each year are invaluable in providing guidance for the future of Iowa’s transportation system. It should be noted that this document is a planning guide. It does not represent a binding commitment or obligation of the Commission or Iowa DOT, and is subject to change. You are invited to visit the Iowa DOT’s Web site at iowadot.gov for additional and regular updates about the department’s programs and activities.

FAM161A, associated with retinitis pigmentosa, is a component of the cilia-basal body complex and interacts with proteins involved in ciliopathies.

Retinitis pigmentosa (RP) is a retinal degenerative disease characterized by the progressive loss of photoreceptors. We have previously demonstrated that RP can be caused by recessive mutations in the human FAM161A gene, encoding a protein with unknown function that contains a conserved region shared only with a distant paralog, FAM161B. In this study, we show that FAM161A localizes at the base of the photoreceptor connecting cilium in human, mouse and rat. Furthermore, it is also present at the ciliary basal body in ciliated mammalian cells, both in native conditions and upon the expression of recombinant tagged proteins. Yeast two-hybrid analysis of binary interactions between FAM161A and an array of ciliary and ciliopathy-associated proteins reveals direct interaction with lebercilin, CEP290, OFD1 and SDCCAG8, all involved in hereditary retinal degeneration. These interactions are mediated by the C-terminal moiety of FAM161A, as demonstrated by pull-down experiments in cultured cell lines and in bovine retinal extracts. As other ciliary proteins, FAM161A can also interact with the microtubules and organize itself into microtubule-dependent intracellular networks. Moreover, small interfering RNA-mediated depletion of FAM161A transcripts in cultured cells causes the reduction in assembled primary cilia. Taken together, these data indicate that FAM161A-associated RP can be considered as a novel retinal ciliopathy and that its molecular pathogenesis may be related to other ciliopathies.