PARP1 allows proper telomere replication through TRF1 poly (ADP-ribosyl)ation and helicase recruitment.

Telomeres are nucleoprotein structures at eukaryotic chromosome termini. Their stability is preserved by a six-protein complex named shelterin. Among these, TRF1 binds telomere duplex and assists DNA replication with mechanisms only partly clarified. Here we found that poly (ADP-ribose) polymerase 1 (PARP1) interacts and covalently PARylates TRF1 in S-phase modifying its DNA affinity. Therefore, genetic and pharmacological inhibition of PARP1 impairs the dynamic association of TRF1 and the bromodeoxyuridine incorporation at replicating telomeres. Inhibition of PARP1 also affects the recruitment of WRN and BLM helicases in TRF1 containing complexes during S-phase, triggering replication-dependent DNA-damage and telomere fragility. This work unveils an unprecedented role for PARP1 as a "surveillant" of telomere replication, which orchestrates protein dynamics at proceeding replication fork.

Multiscale analysis of bamboo deformation mechanisms following NaOH treatment using X-ray and correlative microscopy.

For hundreds of years, bamboo has been employed for a variety of applications ranging from load-bearing structures to textiles. Thanks to its hierarchical structure that is functionally graded and naturally optimised, bamboo displays a variation in properties across its stem that ensures exceptional flexural performance. Often, alkaline solutions are employed for the treatment of bamboo in order to alter its natural elastic behaviour and make it suitable for particular applications. In this work we study the effect of NaOH solutions of five different concentrations (up to 25%) on the elastic properties of bamboo. By exploiting the capabilities of modern experimental techniques such as in situ synchrotron X-ray scattering and Digital Image Correlation, we present detailed analysis of the deformation mechanisms taking place in the main constituents of bamboo, i.e. fibres and matrix (Parenchyma). The principal achievement of this study is the elucidation of the deformation mechanisms at the fibre scale, where the relative sliding of fibrils plays a crucial role in the property modification of the whole bamboo stem. Furthermore, we shed light on the parenchyma toughness variation as a consequence of alkali treatments. STATEMENT OF SIGNIFICANCE: Alkaline solutions are often employed for the treatment of bamboo in order to alter its natural elastic behaviour. In this work we study the effect of alkaline solutions on the elastic properties of bamboo. Using state of the art experimental techniques allowed shedding light on the deformation mechanisms occurring in the bamboo main constituents, i.e. fibres and matrix (parenchyma cells). Enhancement of fibre stiffness was experienced when up to 20% NaOH solution was employed, while for higher concentration a decay was observed. This effect was imputed to the modification of adhesion between fibrils induced by disruption of ligand elements (e.g. lignin). Modification of the matrix toughness was also experienced, that indicated an improved resistance to cracking when the concentration of NaOH is 25%, while reduction of toughness was revealed for lower concentrations.

Strain softening of nano-scale fuzzy interfaces causes Mullins effect in thermoplastic polyurethane.

The strain-induced softening of thermoplastic polyurethane elastomers (TPUs), known as the Mullins effect, arises from their multi-phase structure. We used the combination of small- and wide- angle X-ray scattering (SAXS/WAXS) during in situ repeated tensile loading to elucidate the relationship between molecular architecture, nano-strain, and macro-scale mechanical properties. Insights obtained from our analysis highlight the importance of the 'fuzzy interface' between the hard and soft regions that governs the structure evolution at nanometre length scales and leads to macroscopic stiffness reduction. We propose a hierarchical Eshelby inclusion model of phase interaction mediated by the 'fuzzy interface' that accommodates the nano-strain gradient between hard and soft regions and undergoes tension-induced softening, causing the Mullins effect that becomes apparent in TPUs even at moderate tensile strains.

The modern, hybrid total hip arthroplasty for primary osteoarthritis at the Hospital for Special Surgery.

We describe our technique and rationale using hybrid fixation for primary total hip arthroplasty (THA) at the Hospital for Special Surgery. Modern uncemented acetabular components have few screw holes, or no holes, polished inner surfaces, improved locking mechanisms, and maximised thickness and shell-liner conformity. Uncemented sockets can be combined with highly cross-linked polyethylene liners, which have demonstrated very low wear and osteolysis rates after ten to 15 years of implantation. The results of cement fixation with a smooth or polished surface finished stem have been excellent, virtually eliminating complications seen with cementless fixation like peri-operative femoral fractures and thigh pain. Although mid-term results of modern cementless stems are encouraging, the long-term data do not show reduced revision rates for cementless stems compared with cemented smooth stems. In this paper we review the conduct of a hybrid THA, with emphasis on pre-operative planning, surgical technique, hypotensive epidural anaesthesia, and intra-operative physiology.

ß-arrestin-1 is a nuclear transcriptional regulator of endothelin-1-induced ß-catenin signaling.

Despite the fundamental pathophysiological importance of ß-catenin in tumor progression, the mechanism underlying its final transcriptional output has been partially elucidated. Here, we report that ß-arrestin-1 (ß-arr1) is an epigenetic regulator of endothelin (ET)-1-induced ß-catenin signaling in epithelial ovarian cancer (EOC). In response to ET A receptor (ETAR) activation by ET-1, ß-arr1 increases its nuclear translocation and direct binding to ß-catenin. This in turn enhanced ß-catenin nuclear accumulation and transcriptional activity, which was prevented by expressing a mutant ß-arr1 incapable of nuclear distribution. ß-arr1-ß-catenin interaction controls ß-catenin target gene expressions, such as ET-1, Axin 2, Matrix metalloproteinase 2, and Cyclin D1, by promoting histone deacetylase 1 (HDAC1) dissociation and the recruitment of p300 acetyltransferase on these promoter genes, resulting in enhanced H3 and H4 histone acetylation, and gene transcription, required for cell migration, invasion and epithelial-to-mesenchymal transition. These effects are abrogated by ß-arr1 silencing or by mutant ß-arr1, as well as by ß-catenin or p300 silencing, confirming that nuclear ß-arr1 forms a functional complex capable of regulating epigenetic changes in ß-catenin-driven invasive behavior. In a murine orthotopic model of metastatic human EOC, silencing of ß-arr1 or mutant ß-arr1 expression, as well as ETAR blockade, inhibits metastasis. In human EOC tissues, ß-arr1-ß-catenin nuclear complexes are selectively enriched at ß-catenin target gene promoters, correlating with tumor grade, confirming a direct in vivo ß-arr1-ß-catenin association at specific set of genes involved in EOC progression. Collectively, our study provides insights into how a ß-arr1-mediated epigenetic mechanism controls ß-catenin activity, unraveling new components required for its nuclear function in promoting metastasis.

Meta-analysis of cause of death following total joint replacement using different thromboprophylaxis regimens.

We performed a meta-analysis of modern total joint replacement (TJR) to determine the post-operative mortality and the cause of death using different thromboprophylactic regimens as follows: 1) no routine chemothromboprophylaxis (NRC); 2) Potent anticoagulation (PA) (unfractionated or low-molecular-weight heparin, ximelagatran, fondaparinux or rivaroxaban); 3) Potent anticoagulation combined (PAC) with regional anaesthesia and/or pneumatic compression devices (PCDs); 4) Warfarin (W); 5) Warfarin combined (WAC) with regional anaesthesia and/or PCD; and 6) Multimodal (MM) prophylaxis, including regional anaesthesia, PCDs and aspirin in low-risk patients. Cause of death was classified as autopsy proven, clinically certain or unknown. Deaths were grouped into cardiopulmonary excluding pulmonary embolism (PE), PE, bleeding-related, gastrointestinal, central nervous system, and others (miscellaneous). Meta-analysis based on fixed effects or random effects models was used for pooling incidence data. In all, 70 studies were included (99 441 patients; 373 deaths). The mortality was lowest in the MM (0.2%) and WC (0.2%) groups. The most frequent cause of death was cardiopulmonary (47.9%), followed by PE (25.4%) and bleeding (8.9%). The proportion of deaths due to PE was not significantly affected by the thromboprophylaxis regimen (PA, 35.5%; PAC, 28%; MM, 23.2%; and NRC, 16.3%). Fatal bleeding was higher in groups relying on the use of anticoagulation (W, 33.8%; PA, 9.4%; PAC, 10.8%) but the differences were not statistically significant. Our study demonstrated that the routine use of PA does not reduce the overall mortality or the proportion of deaths due to PE.

[Cemented stems in hip arthroplasty: history and evolution]. / Vástagos cementados en la artroplastía de cadera: historia y evolución.

Despite the favorable results in cemented femoral fixation, there is a growing tendency to use uncemented stems. Due to the successful results of cementless acetabular fixation, the most versatile and easy implantation technique, to the misinformation about the "cement disease" and the poor performance of cemented stems with a rough surface. However, the advantages of cemented femoral fixation are numerous: it can be implemented successfully in femurs of diverse morphology and quality of bone, the surgeon can position the implant with the desired femoral anteversion, without it being determined by th natural femoral anteversion, very low incidence of intraoperative and postoperative fractures, allows the addition of antibiotics in patients with a history or predisposition to infection and minimal risk of postoperative leg pain during walking.

PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy.

New anti-telomere strategies represent important goals for the development of selective cancer therapies. In this study, we reported that uncapped telomeres, resulting from pharmacological stabilization of quadruplex DNA by RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate), trigger specific recruitment and activation of poly-adenosine diphosphate (ADP) ribose polymerase I (PARP1) at the telomeres, forming several ADP-ribose polymers that co-localize with the telomeric repeat binding factor 1 protein and are inhibited by selective PARP(s) inhibitors or PARP1-specific small interfering RNAs. The knockdown of PARP1 prevents repairing of RHPS4-induced telomere DNA breaks, leading to increases in chromosome abnormalities and eventually to the inhibition of tumor cell growth both in vitro and in xenografts. More interestingly, the integration of a TOPO1 inhibitor on the combination treatment proved to have a high therapeutic efficacy ensuing a complete regression of the tumor as well as a significant increase in overall survival and cure of mice even when treatments started at a very late stage of tumor growth. Overall, this work reveals the unexplored link between the PARP1 and G-quadruplex ligands and demonstrates the excellent efficacy of a multi-component strategy based on the use of PARP inhibitors in telomere-based therapy.

La planificación preoperatoria del reemplazo protésico en las fracturas de cadera del anciano / Preoperative planning of prosthetic replacement in hip fractures in the elderly

Existen numerosas publicaciones sobre la planificación preoperatoria en los reemplazos de cadera electivos con resultados satisfactorios. Sin embargo, ninguna de ellas se ha enfocado para el tratamiento de las fracturas de cadera. La planificación aumenta su importancia en estos pacientes debido a que la reconstrucción de la biomecánica de la cadera se ve dificultada por la ausencia de un fémur intacto.En este trabajo se describe un método de planificación preoperatoria basado en la reproducción de la biomecánica de la cadera contralateral no fracturada, siempre y cuando ésta sea anatómicamente normal. El plan registra medidas radiológicas que se reproducen durante la cirugía para lograr una reconstrucción de la biomecánica normal de la cadera fracturada (AU)

There are numerous reports on successful results for total hip replacement being achieved through preoperative planning. However, none of these reports have been focused on the treatment of hip fractures. Preoperative planning has increased importance in this group of patients as the correct biomechanical reconstruction of the hip is made more difficult by the absence of an intact femur.This report describes a method for preoperative planning based on the reproduction of the biomechanics of the intact contralateral hip, if and when it is anatomically normal. The plan is based on radiological measurements that are reproduced during surgery to achieve normal biomechanical reconstruction for the fractured hip (AU)

Delineating v-Src downstream effector pathways in transformed myoblasts.

In this study, we delineate the intracellular signalling pathways modulated by a conditional v-Src tyrosine kinase that lead to unrestrained proliferation and block of differentiation of primary avian myoblasts. By inhibiting Ras-MAPK kinase and phosphatidylinositol 3-kinase with different means, we find that both pathways play crucial roles in controlling v-Src-sustained growth factor and anchorage independence for proliferation. The Ras-MAPK kinase pathway also contributes to block of differentiation independently of cell proliferation since inhibition of this pathway both in proliferating and growth-arrested v-Src-transformed myoblasts induces expression of muscle-specific genes, fusion into multinucleated myotubes and assembly of specialized contractile structures. Importantly, we find that the p38 MAPK pathway is inhibited by v-Src in myoblasts and its forced activation results in growth inhibition and expression of differentiation, indicating p38 MAPK as a critical target of v-Src in growth transformation and myogenic differentiation. Furthermore, we show that downregulation of p38 MAPK activation may occur via Ras-MAPK kinase, thus highlighting a cross-regulation between the two pathways. Finally, we report that the simultaneous inhibition of MAPK kinase and calpain, combined to activation of p38 MAPK, are sufficient to reconstitute largely the differentiation potential of v-Src-transformed myoblasts.

A new technique to improve cup inclination accuracy in primary total hip arthroplasty.

Accurate inclination and anteversion of the acetabular component is paramount to achieve a stable total hip arthroplasty, prevent prosthetic dislocation and minimize long- term wear. We present and evaluate a simple new technique to improve consistency in cup inclination during primary total hip arthroplasty, based on information available from the preoperative plan. The technique consists of assessing the distance and relationship between the inferomedial border of the acetabular cup and the inferomedial margin of the teardrop, with the use of a measuring probe. This simple surgical gesture improved consistency in cup inclination during total hip arthroplasty.;

Thromboembolic disease in hip replacement surgery.

Total hip replacement surgery carries the risk of thromboembolic complications, which could be fatal. Over the last three decades however, the risk has decreased considerably thanks to progress made in the understanding of the physiopathogenetic mechanism of thromboembolic disease and perioperative prophylaxis. It is the purpose of this study to discuss the main medical and surgical preventive measures that must be carried out before, during and immediately after surgery. The old concept of deciding thromboembolic prophylaxis after surgery is now obsolete.

Total hip replacement in identical twins with Scheie Mucopolysaccharidosis.

Investigation performed at the Hospital for Special Surgery, New York, USA Scheie Syndrome is an autosomal recessive metabolic storage disease with distinct skeletal findings known as "dysostosis multiplex". This paper reports on identical twins with Scheie Syndrome who required total hip arthroplasty for early osteoarthritis of the hip. The surgical approach and exposure was particularly demanding due to the stiffness imposed by the soft tissues arising from infiltration of glycosaminoglycans. The small femoral head and acetabulum limited the diameter of the acetabular component and subsequently the prosthetic head diameter that could be safely utilized without compromising the thickness of the polyethylene liner. Twenty-two millimeter heads with a standard polyethylene insert were therefore utilized in the two arthroplasties performed in 1998 in the first twin, and a 28 mm head with a highly cross linked polyethylene liner, in the arthroplasty performed on the second twin in 2003. This is a relevant issue considering that these patients required an arthroplasty at a young age. Hip arthroplasty relieved pain, improved ambulation and provided a better range of motion in our two patients. There were no peri-operative complications. Long-term survivorship of total hip replacement in this population is not yet known. (Hip International 2005; 15: 55-8).

Age affects the perception of limb length discrepancy in patients with and without a total hip arthroplasty.

The amount of lengthening or shortening that can be detected by patients before and after total hip arthroplasty has not been yet quantified. We studied the ability to detect limb length inequality in 194 patients with and without a total hip arthroplasty, match-paired for age and sex. None of the participants had clinical signs of lumbosacral pathology, spinal deformity, or fixed pelvic obliquity; and all had equal functional and actual limb length. The participants walked with shoes, with and without the addition of fixed insoles, to simulate 2.5, 5, 10 and 15 millimeters of shortening and lengthening of the tested limb. Lengthening and shortening were similarly detected. Younger individuals detected the differences better than older ones (p=0.001), and there was a significant correlation between the decade of life and the ability to detect a limb length discrepancy (r=-0.22; p=0.002). This study demonstrates that perception of limb length is affected by the age, with older individuals having less awareness of changes in limb length than younger ones. (Hip International 2004; 14: 249-53).

Treatment of hemorrhagic radiation proctitis with 4 percent formalin.

PURPOSE: The purpose of this study was to review our results in patients undergoing treatment with 4 percent formalin for radiation-induced injury to the rectum. METHODS: A retrospective review of office charts was performed, identifying all patients undergoing formalin treatment. Patient gender, initial malignancy, prior treatments, response to treatment with formalin, complications, and length of follow-up were reviewed. All patients had flexible endoscopy to assess for proximal sources of bleeding. The indication for treatment was a symptomatic patient with endoscopic evidence of radiation injury. A cotton pledget was used for direct application of 4 percent formalin to the affected area via a rigid proctoscope or anoscope. The treatment was repeated if blanching did not occur or if bleeding continued. Patients were followed up at three-week to four-week intervals and treatment was repeated based on the above indications. Treatments were continued until cessation of bleeding occurred or, when treatment failed, operative treatment was required. RESULTS: Thirty-six patients were identified. Three were lost to follow-up. Symptoms included bleeding in all but one patient, who presented with an ulcer. There were 33 (26 male) patients. Seventeen (51.5 percent) patients had prior treatment. The number of formalin treatments ranged from 1 to 13, with a mean of 3.4. The follow-up ranged from 1 to 60 months, with a mean of 18 months. Twenty-nine (88 percent) patients had improvement or cessation of symptoms. Four (12 percent) patients failed treatment. Two patients were noted to have full-thickness ulcers and both failed formalin treatment. No complications were noted related to formalin treatment. CONCLUSION: We conclude that formalin therapy is a safe and effective form of treatment that can be performed in the office with minimal discomfort and no complications. It can be performed multiple times until results are achieved. Formalin therapy may be useful as a first-line treatment for chronic radiation proctitis, however, a prospective controlled trial comparing modalities is required to prove this to be true.

Inflatable pillows as axillary support devices during surgery performed in the lateral decubitus position under epidural anesthesia.

UNLABELLED: The lateral decubitus position can cause dependent shoulder discomfort or result in traction on the brachial plexus. We measured pressure beneath the dependent shoulder and lateral angulation of the cervical spine in patients positioned in the lateral decubitus position for total hip replacement under epidural anesthesia. Inflatable pillows (Shoulder-Float) beneath the chest wall and head reduced pressure beneath the dependent shoulder from 66 to 12 mm Hg (P < 0.001) and lateral angulation of the cervical spine from 14 degrees to 4 degrees (P < 0.001). In a randomized crossover study of a further 15 patients, the use of inflatable pillows resulted in significantly less pressure beneath the dependent shoulder and chest wall than either a gel-pad or a 1000-mL lactated Ringer's bag. Inflatable pillows placed beneath the chest wall and head in the lateral decubitus position provided lower pressure beneath the dependent shoulder than other support devices and facilitated alignment of the cervical spine. IMPLICATIONS: When patients lie on their side, this results in pressure beneath the shoulder and tilting of the head and neck to one side. These problems were effectively corrected with an inflatable pillow (Shoulder-Float).

Effective bactericidal activity of tobramycin and vancomycin eluted from acrylic bone cement.

We studied the bioactivity of vancomycin and tobramycin eluted from methylmethacrylate bone cement. Aliquots of the drainage were obtained at 1, 6, 12 and 24 hours following total hip prosthetic implantation with vancomycin-tobramycin-loaded cement in 3 patients. The samples were analyzed with fluorescence polarization immunoassay and bioassay, using group B streptococcus for vancomycin and Escherichia coli for tobramycin. These bacteria were selected due to the effectiveness of vancomycin and poor effectiveness of tobramycin against group B streptococcus and conversely with E. coli. The immunodetection of vancomycin averaged 14 (1 hour), 9 (6 hours), 10 (12 hours) and 11 microg/mL (24 hours). The bioassay averaged 47, 36, 79 and 41 microg/mL (p = 0.03). The immunodetection of tobramycin averaged 43, 21, 18 and 14 microg/mL; and bioassay 30, 15, 15 and 12 microg/mL (p = 0.1). Both antibiotics eluted with a highly effective bactericidal activity. Our findings indicate that the presence of tobramycin has a synergistic-like effect on the bactericidal activity of vancomycin, which has not been previously reported. We recommend a combination of vancomycin and tobramycin with cement for the treatment of orthopedic infections caused by gram-positive organisms.

The effect of preoperative donation of autologous blood on deep-vein thrombosis after total hip arthroplasty.

We have assessed the effect of the donation of autologous blood and the preoperative level of haemoglobin on the prevalence of postoperative thromboembolism in 2043 patients who had a total hip arthroplasty. The level of haemoglobin was determined seven to ten days before surgery and all patients had venography of the operated leg on the fifth postoperative day. The number of patients who had donated autologous blood (1037) was similar to that who had not (1006). A significant decrease in the incidence of deep-vein thrombosis (DVT) was noted in those who had donated blood preoperatively (9.0%) compared with those who had not (13.5%) (p = 0.003). For all patients, the lower the preoperative level of haemoglobin the less likely it was that a postoperative DVT would develop. Of those who had donated blood, 0.3% developed a postoperative pulmonary embolism compared with 0.7% in those who had not, but this difference was not statistically significant. No significant difference was found in the requirements for transfusion between the two groups.

Pigmented villonodular synovitis of the hip: 2- to 23-year followup study.

Pigmented villonodular synovitis affecting the hip is rare. Seven new patients are presented and 117 cases from the literature are reviewed. Among the new patients, two refused treatment; in one patient, severe bone loss was observed after a radiographic followup of 21 years; the second patient showed no radiographic changes 2 years after diagnosis. One patient underwent a synovectomy and had a recurrence 9 years later, requiring a total hip replacement. The remaining four patients underwent synovectomy and primary total hip replacement with no recurrences detected after an average followup of 13 years (range, 2-23 years). Among 117 cases published, 62 patients (53%) did not have enough information for analysis. A metaanalysis using the remaining 55 patients was done. In nine patients (16%; nine of 55) the diagnosis was made with a preoperative biopsy. Treatment consisted of synovectomy in 26 patients (47%; 26 of 55), arthroplasty in 24 (43%; 24 of 55), arthrodesis in two (4%; two of 55), and hindquarter amputation in a patient misdiagnosed as having synovial sarcoma (2%; one of 55). Two patients (4%; two of 55) were not treated. Ten patients had a recurrence (19%; 10 of 53); nine in the synovectomy group (35 %; nine of 26) and one in the joint replacement group (4%; one of 24). Synovectomy is recommended for patients with preserved articular cartilage and total hip replacement is recommended for patients with secondary osteoarthritis. Removal of all macroscopic tumors including careful curetting of the osteolytic lesions should be done as they may constitute a source of recurrence.