Naked1 Antagonizes Wnt Signaling by Preventing Nuclear Accumulation of β-Catenin

Cyto-nuclear shuttling of β-catenin is at the epicenter of the canonical Wnt pathway and mutations in genes that result in excessive nuclear accumulation of β-catenin are the driving force behind the initiation of many cancers. Recently, Naked Cuticle homolog 1 (Nkd1) has been identified as a Wnt-induced intracellular negative regulator of canonical Wnt signaling. The current model suggests that Nkd1 acts between Disheveled (Dvl) and β-catenin. Here, we employ the zebrafish embryo to characterize the cellular and biochemical role of Nkd1 in vivo. We demonstrate that Nkd1 binds to β-catenin and prevents its nuclear accumulation. We also show that this interaction is conserved in mammalian cultured cells. Further, we demonstrate that Nkd1 function is dependent on its interaction with the cell membrane. Given the conserved nature of Nkd1, our results shed light on the negative feedback regulation of Wnt signaling through the Nkd1-mediated negative control of nuclear accumulation of β-catenin

Pαx6 Expression in Postmitotic Neurons Mediates the Growth of Axons in Response to SFRP1

During development, the mechanisms that specify neuronal subclasses are coupled to those that determine their axonal response to guidance cues. Pax6 is a homedomain transcription factor required for the specification of a variety of neural precursors. After cell cycle exit, Pax6 expression is often shut down in the precursor progeny and most postmitotic neurons no longer express detectable levels of the protein. There are however exceptions and high Pax6 protein levels are found, for example, in postmitotic retinal ganglion cells (RGCs), dopaminergic neurons of the olfactory bulb and the limbic system in the telencephalon. The function of Pax6 in these differentiating neurons remains mostly elusive. Here, we demonstrate that Pax6 mediates the response of growing axons to SFRP1, a secreted molecule expressed in several Pax6-positive forebrain territories. Forced expression of Pax6 in cultured postmitotic cortical neurons, which do not normally express Pax6, was sufficient to increment axonal length. Growth was blocked by the addition of anti-SFRP1 antibodies, whereas exogenously added SFRP1 increased axonal growth of Pax6-transfected neurons but not that of control or untransfected cortical neurons. In the reverse scenario, shRNA-mediated knock-down of Pax6 in mouse retinal explants specifically abolished RGCs axonal growth induced by SFRP1, but had no effect on RGCs differentiation and it did not modify the effect of Shh or Netrin on axon growth. Taken together these results demonstrate that expression of Pax6 is necessary and sufficient to render postmitotic neurons competent to respond to SFRP1. These results reveal a novel and unexpected function of Pax6 in postmitotic neurons and situate Pax6 and SFRP1 as pair regulators of axonal connectivity

PKD1 and PKD2 mutations in Slovenian families with autosomal dominant polycystic kidney disease

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder caused by mutations in at least two different loci. Prior to performing mutation screening, if DNA samples of sufficient number of family members are available, it is worthwhile to assign the gene involved in disease progression by the genetic linkage analysis. METHODS: We collected samples from 36 Slovene ADPKD families and performed linkage analysis in 16 of them. Linkage was assessed by the use of microsatellite polymorphic markers, four in the case of PKD1 (KG8, AC2.5, CW3 and CW2) and five for PKD2 (D4S1534, D4S2929, D4S1542, D4S1563 and D4S423). Partial PKD1 mutation screening was undertaken by analysing exons 23 and 31–46 and PKD2 . RESULTS: Lod scores indicated linkage to PKD1 in six families and to PKD2 in two families. One family was linked to none and in seven families linkage to both genes was possible. Partial PKD1 mutation screening was performed in 33 patients (including 20 patients from the families where linkage analysis could not be performed). We analysed PKD2 in 2 patients where lod scores indicated linkage to PKD2 and in 7 families where linkage to both genes was possible. We detected six mutations and eight polymorphisms in PKD1 and one mutation and three polymorphisms in PKD2. CONCLUSION: In our study group of ADPKD patients we detected seven mutations: three frameshift, one missense, two nonsense and one putative splicing mutation. Three have been described previously and 4 are novel. Three newly described framesfift mutations in PKD1 seem to be associated with more severe clinical course of ADPKD. Previously described nonsense mutation in PKD2 seems to be associated with cysts in liver and milder clinical course

Polycystic kidney diseases: From molecular discoveries to targeted therapeutic strategies

Polycystic kidney diseases (PKDs) represent a large group of progressive renal disorders characterized by the development of renal cysts leading to end-stage renal disease. Enormous strides have been made in understanding the pathogenesis of PKDs and the development of new therapies. Studies of autosomal dominant and recessive polycystic kidney diseases converge on molecular mechanisms of cystogenesis, including ciliary abnormalities and intracellular calcium dysregulation, ultimately leading to increased proliferation, apoptosis and dedifferentiation. Here we review the pathobiology of PKD, highlighting recent progress in elucidating common molecular pathways of cystogenesis. We discuss available models and challenges for therapeutic discovery as well as summarize the results from preclinical experimental treatments targeting key disease-specific pathways

Cross-education does not accelerate the rehabilitation of neuromuscular functions after ACL reconstruction: a randomized controlled clinical trial

Purpose: Cross-education reduces quadriceps weakness 8 weeks after anterior cruciate ligament (ACL) surgery, but the long-term effects are unknown. We investigated whether cross-education, as an adjuvant to the standard rehabilitation, would accelerate recovery of quadriceps strength and neuromuscular function up to 26 weeks post-surgery. Methods: Group allocation was randomized. The experimental (n = 22) and control (n = 21) group received standard rehabilitation. In addition, the experimental group strength trained the quadriceps of the non-injured leg in weeks 1–12 post-surgery (i.e., cross-education). Primary and secondary outcomes were measured in both legs 29 ± 23 days prior to surgery and at 5, 12, and 26 weeks post-surgery. Results: The primary outcome showed time and cross-education effects. Maximal quadriceps strength in the reconstructed leg decreased 35% and 12% at, respectively, 5 and 12 weeks post-surgery and improved 11% at 26 weeks post-surgery, where strength of the non-injured leg showed a gradual increase post-surgery up to 14% (all p ≤ 0.015). Limb symmetry deteriorated 9–10% more for the experimental than control group at 5 and 12 weeks post-surgery (both p ≤ 0.030). One of 34 secondary outcomes revealed a cross-education effect: Voluntary quadriceps activation of the reconstructed leg was 6% reduced for the experimental vs. control group at 12 weeks post-surgery (p = 0.023). Both legs improved force control (22–34%) and dynamic balance (6–7%) at 26 weeks post-surgery (all p ≤ 0.043). Knee joint proprioception and static balance remained unchanged. Conclusion: Standard rehabilitation improved maximal quadriceps strength, force control, and dynamic balance in both legs relative to pre-surgery but adding cross-education did not accelerate recovery following ACL reconstruction

Wealth, household heterogeneity and livelihood diversification of Fulani pastoralists in the Kachia Grazing Reserve, northern Nigeria, during a period of social transition

A mixed methods study was undertaken in the Kachia Grazing Reserve of northern Nigeria. Surveys in March, June and October 2011 included focus group discussions, key informant and in-depth household interviews, concerning livelihood practices, animal health, ownership, and productivity. In May 2011, 249 Fulani families fleeing post-election violence entered the reserve with their livestock, increasing the number of households by one third.Despite being settled within a grazing reserve, over half of households sent all their cattle away on seasonal transhumance and another third sent some away. Cattle accounted for 96% of total tropical livestock units (TLU), of which 26% were cattle kept permanently outside the reserve. While all households cited livestock as their main source of income, 90% grew crops and 55% derived income from off-farm activities. A multiple correspondence analysis showed that for each extra member of a household its TLU value increased by 2.0 [95% CI, 1.4-2.7], while for each additional marriage its TLU increased by 15.7 [95% CI, 7.1-24.3]. A strong association was also observed between small herds, small households with only one wife, alongside marked geographical wealth differences within the reserve. New immigrant families had larger household sizes (33) and livestock holdings (122 TLU) than old settlers (22 people and 67 TLU). Prior to the mass immigration, the distribution of TLU per person was unimodal: 41% of households were classified as 'poor' and 27% as 'medium', whereas post-immigration it was bi-modal, with 26% classified as 'very poor' and 28% as 'medium'.While cattle remain the principal source of Fulani income and wealth, the inhabitants of Kachia Grazing Reserve have diversified their livelihood strategies to respond to changing circumstances and stress, especially the limited availability of grazing within the reserve and political insecurity outside, resulting in continued transhumance, the maintenance of smaller livestock holdings and pushing households into poverty

VALIDITY OF THE DUTCH MODIFIED PAINDETECT QUESTIONNAIRE (MPDQ-NL) FOR PATIENTS WITH HIP OR KNEE OSTEOARTHRITIS

The etiology of pain in osteoarthritis (OA) is complex and multifactorial. A growing number of studies suggest that modification of pain-transmission in the peripheral and central nervous system, leading to sensitization, plays a role in OA pain. Sensitization seems to be associated with neuropathic pain-like symptoms and assessment of these symptoms can help to identify patients who could benefit from additional treatment options. Several questionnaires are available to distinguish neuropathic from nociceptive pain symptoms

High Prevalence of Pseudotumors in Patients with a Birmingham Hip Resurfacing Prosthesis A Prospective Cohort Study of One Hundred and Twenty-nine Patients

<p>Background: Recently, concern has emerged about pseudotumors (lesions that are neither malignant nor infective in the soft tissues surrounding total hip arthroplasty components) after hip arthroplasties with metal-on-metal bearings. Patients treated in our hospital for degenerative arthritis of the hip with a Birmingham Hip Resurfacing (BHR) prosthesis were invited to return for follow-up evaluation. The prevalence and clinical relevance of pseudotumors were investigated. Risk factors for pseudotumor formation were sought.</p><p>Methods: A single-center cross-sectional prospective cohort study was conducted and included all patients who received a BHR from 2005 to 2010 in Martini Hospital, Groningen, The Netherlands. Data were collected on patient and surgical characteristics, clinical hip outcome scores (Harris hip score and Oxford score), serum metal ion levels (cobalt and chromium), and radiographs. A computed tomographic scan (without metal suppression) was made. In patients who had a revision, tissue samples were histologically examined.</p><p>Results: Originally, there were 129 patients with 149 BHRs. Four patients (six hips; 4%) were lost to follow-up. Our final cohort consisted of 125 patients (143 hips). From this final cohort, eleven patients (twelve hips) had a revision, and three of them (three hips) had the revision before the present study was conducted. Seven patients (eight hips; 5.6%) had a revision because of a symptomatic pseudotumor. Survival analysis showed an implant survival rate of 87.5% at five years (failure was defined as a revision for any reason). A pseudotumor was found on computed tomography in thirty-nine patients (forty hips; 28%). Of those patients, ten (eleven hips; 28%) had complaints involving groin pain and discomfort, a noticeable mass, or paresthesia. Symptomatic pseudotumors were significantly larger than asymptomatic pseudotumors (a mean volume of 53.3 cm(3) compared with 16.3 cm(3); p = 0.05). A serum cobalt level of >85 nmol/L was a predictor for pseudotumor formation (odds ratio, 4.9).</p><p>Conclusions: Pseudotumor formation occurred in 28% of hips after an average follow-up of forty-one months. Most pseudotumors (72.5%) were asymptomatic. Larger pseudotumors were associated with more complaints. Survival analysis showed an implant survival of 87.5% at five years. Failure occurred in 5.6% (eight) of 143 hips because of a symptomatic pseudotumor.</p>