RESUMO
The classical Non-Homologous End Joining (c-NHEJ) pathway is the predominant process in mammals for repairing endogenous, accidental or programmed DNA Double-Strand Breaks. c-NHEJ is regulated by several accessory factors, post-translational modifications, endogenous chemical agents and metabolites. The metabolite inositol-hexaphosphate (IP6) stimulates c-NHEJ by interacting with the Ku70-Ku80 heterodimer (Ku). We report cryo-EM structures of apo- and DNA-bound Ku in complex with IP6, at 3.5 Å and 2.74 Å resolutions respectively, and an X-ray crystallography structure of a Ku in complex with DNA and IP6 at 3.7 Å. The Ku-IP6 interaction is mediated predominantly via salt bridges at the interface of the Ku70 and Ku80 subunits. This interaction is distant from the DNA, DNA-PKcs, APLF and PAXX binding sites and in close proximity to XLF binding site. Biophysical experiments show that IP6 binding increases the thermal stability of Ku by 2°C in a DNA-dependent manner, stabilizes Ku on DNA and enhances XLF affinity for Ku. In cells, selected mutagenesis of the IP6 binding pocket reduces both Ku accrual at damaged sites and XLF enrolment in the NHEJ complex, which translate into a lower end-joining efficiency. Thus, this study defines the molecular bases of the IP6 metabolite stimulatory effect on the c-NHEJ repair activity.
Assuntos
Proteínas de Ligação a DNA , Ácido Fítico , Animais , DNA/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , Proteínas de Ligação a DNA/genética , Autoantígeno Ku/metabolismo , Mamíferos/genética , HumanosRESUMO
PURPOSE: Whether photographs included in the operative report of knee arthroscopies can make the surgeon liable in the event of a legal investigation remains unknown. The main objective of this study was to establish inter-observer reliability in determining the presence or absence of lesions of the cartilage, meniscus and anterior cruciate ligament (ACL). Secondary objective was to assess the inter-observer reliability in classifying lesions. METHOD: A retrospective observational study was conducted in a continuous serie of 60 patients who underwent knee arthroscopy from the same operator. The photographs of each patient's operative report were presented separately to three experts, blinded to each other. Each expert had to decide on the presence or absence of injuries to the following structures: meniscal, cartilage and ACL and then, classify it. Primary and secondary endpoints were evaluated using the Fleiss' kappa index. RESULTS: Inter-observer reliability for lesion detection was between 0.4 and 0.61 for all structures with three exceptions: for cartilage, it was low (0.15) at the lateral tibial plateau and poor (-0.01) at the external condyle. On the contrary, the concordance was almost perfect (0.8) for the ACL. For classifying cartilaginous and meniscal lesions, inter-observer reliability was poor (from 0.03 to 0.14), except for at the lateral meniscus (0.65). CONCLUSION: Inter-observer reliability of arthroscopic knee diagnoses is poor when photographs alone are used. In the event of a legal investigation following knee arthroscopy, the photographs included in the operative report should not be used alone to hold the surgeon liable.
Assuntos
Lesões do Ligamento Cruzado Anterior , Lesões do Menisco Tibial , Humanos , Lesões do Ligamento Cruzado Anterior/diagnóstico , Lesões do Ligamento Cruzado Anterior/cirurgia , Lesões do Ligamento Cruzado Anterior/complicações , Artroscopia/efeitos adversos , Reprodutibilidade dos Testes , Lesões do Menisco Tibial/diagnóstico por imagem , Lesões do Menisco Tibial/cirurgia , Articulação do Joelho/cirurgia , Meniscos Tibiais/cirurgia , Estudos RetrospectivosRESUMO
Knee popping is a frequent symptom among knee disorders which requires further investigation in case of a recent evolution of the symptom or pathological associated ones. This article reports a rare presentation of pigmented villonodular synovitis (PVNS), identified as the cause of knee popping symptoms, by performing MRI sequences at various degrees of knee flexion for a patient complaining from a gradual onset of knee popping, occurring when bending the knee over 120° of flexion. MRI sequences were performed just before the popping occurs (flexion 90°) and right after it had occurred (flexion 120°). The latter confirmed the origin of the symptom as the lesion moved forward, passing brutally through the interstice between the PCL and the ACL at 120° of flexion, explaining the popping. Treatment decision was to perform an arthroscopic resection of the lesion. Diagnosis of isolated PVNS was confirmed after anatomopathological analysis.
RESUMO
PURPOSE: High tibial osteotomy (HTO) is used to treat young and active patients with knee osteoarthritis (OA) and varus deformity. The medial compartment OA alters the patients' gait. METHODS: A prospective study was carried out in 21 consecutive patients operated for HTO due to knee OA with varus deformity. There were 14 men and 7 women, with a median age of 51.9 years (38-64). Their gait was analyzed preoperatively and at 1 year postoperatively, and compared to a healthy control group. Clinical assessment (KOOS, WOMAC, Lysholm, and SF-36 scores) was also performed preoperatively and postoperatively. RESULTS: Patients with medial compartment OA had altered gait relative to the control population. Their walking speed was slower, step length was shorter, and single-leg stance time was shorter, while the double-leg stance time was longer (P < 0.001). Step width was not different between the two groups preoperatively (n.s.), but it was wider in the patient group postoperatively (P = 0.003). There were no differences in the patients' gait parameters before and after the osteotomy (n.s.). However, there was an improved perception of walking so that it is no longer different from controls (n.s.). The KOOS, WOMAC, Lysholm and SF-36 scores improved after HTO. The preoperative median of 7° varus (1-11) was corrected to 3° valgus (0-6). CONCLUSION: Medial compartment OA with varus deformity leads to gait modifications. HTO does not alter the time-distance parameters of gait; however, patients have improved perception of their walking ability. HTO leads to excellent results for knee function, and improves quality of life without modifying the gait pattern. LEVEL OF EVIDENCE: II.
Assuntos
Marcha/fisiologia , Genu Varum/cirurgia , Articulação do Joelho/fisiopatologia , Osteoartrite do Joelho/fisiopatologia , Osteotomia/métodos , Tíbia/cirurgia , Adulto , Feminino , Genu Varum/fisiopatologia , Humanos , Articulação do Joelho/cirurgia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/cirurgia , Estudos Prospectivos , Qualidade de VidaRESUMO
PURPOSE: The aim of this study was to analyse the clinical and radiographic results of 208 e-Motion® posterior cruciate-retaining, mobile bearing prostheses (BBraun-Aesculap, Tuttlingen, Germany) fitted using computer navigation, for knee osteoarthritis with a genu varum greater than 10°. METHODS: One hundred ninety-two patients were operated on with 208 e-Motion® prostheses fitted, between January 2006 and December 2011, using the OrthoPilot® computer navigation system. Average pre-operative IKS score was 70 ± 27 points (6-143) with a function score of 38 ± 20.5 (0-90) and a knee score of 32.5 ± 13 (0-63). Average flexion was 116.5° ± 13° (65-140°). Average pre-operative HKA angle was 166° ± 3° (154-169°). RESULTS: 2Results are available for 134 patients, with a total of 150 knees operated on (38 lost to follow-up and 20 deceased). Average follow-up was 104.5 months (60-116 months). On last follow-up, the average IKS was 180 ± 22 points (95-200) with 86.5 ± 16 points (25-100) for the function score and 93.5 ± 8 points (55-100) for the knee score. Knee flexion was 116° ± 10.5° (80-135°) and average HKA angle was 179° ± 2° (175-184°). The pre-operative objective was achieved in 90.5% of knees. CONCLUSION: The e-Motion® mobile bearing posterior cruciate-retaining prosthesis, fitted using computer navigation, offers excellent results after an average of 8.5 years follow-up. These results are at least equivalent, even superior, to those of the posterior-stabilised prostheses usually used for this type of deformity.
Assuntos
Artroplastia do Joelho/métodos , Genu Varum/cirurgia , Prótese do Joelho/efeitos adversos , Osteoartrite do Joelho/cirurgia , Cirurgia Assistida por Computador/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Artroplastia do Joelho/instrumentação , Feminino , Seguimentos , Humanos , Articulação do Joelho/cirurgia , Masculino , Pessoa de Meia-Idade , Falha de Prótese , Amplitude de Movimento Articular , Resultado do TratamentoRESUMO
PURPOSE: Cysts of the proximal tibiofibular articulation are rare and their optimal treatment remains unclear. The objective of this study was to evaluate the results and complications of the treatment of synovial ganglion cysts of the proximal tibiofibular articulation by simple excision or by excision and fusion of the proximal tibiofibular joint with a limited fibula excision. METHODS: Between January 2005 and December 2016, seven male patients with an average age of 46 years were treated for a ganglion cyst of the proximal tibiofibular articulation. Nine procedures were performed in total. Four patients underwent primary cyst excision, two underwent revision cyst excision and three underwent revision cyst excision with arthrodesis of the proximal tibiofibular joint and partial excision of the fibula (two patients underwent two procedures). RESULTS: Average follow-up was 79 months. The recurrence rate was 25% for simple cyst excision, 100% for revision cyst excision and 0% for cyst excision with arthrodesis. Average kitaoka score was 98 for simple cyst excision and 100 for cyst excision with arthrodesis (P = 0.34); resting visual analogue scores (VAS) were zero in both groups. With activity VAS was 0 for simple cyst excision and 1.6 in the arthrodesis group (P = 0.33). Two of the three arthrodesis patients went on to successful fusion. The third patient has an asymptomatic pseudarthrosis. CONCLUSION: Simple primary cyst excision has a high failure rate at 25%. Revision cyst excision without fusion failed in all cases. We therefore recommend arthrodesis with limited fibula excision.
Assuntos
Artrodese/métodos , Fíbula/cirurgia , Cistos Glanglionares/cirurgia , Articulação do Joelho/patologia , Adulto , Artrodese/efeitos adversos , Estudos de Coortes , Humanos , Articulação do Joelho/cirurgia , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Recidiva , Reoperação/estatística & dados numéricos , Resultado do Tratamento , Escala Visual AnalógicaRESUMO
The outcome of CRISPR-Cas-mediated genome modifications is dependent on DNA double-strand break (DSB) processing and repair pathway choice. Homology-directed repair (HDR) of protein-blocked DSBs requires DNA end resection that is initiated by the endonuclease activity of the MRE11 complex. Using reconstituted reactions, we show that Cas9 breaks are unexpectedly not directly resectable by the MRE11 complex. In contrast, breaks catalyzed by Cas12a are readily processed. Cas9, unlike Cas12a, bridges the broken ends, preventing DSB detection and processing by MRE11. We demonstrate that Cas9 must be dislocated after DNA cleavage to allow DNA end resection and repair. Using single molecule and bulk biochemical assays, we next find that the HLTF translocase directly removes Cas9 from broken ends, which allows DSB processing by DNA end resection or non-homologous end-joining machineries. Mechanistically, the activity of HLTF requires its HIRAN domain and the release of the 3'-end generated by the cleavage of the non-target DNA strand by the Cas9 RuvC domain. Consequently, HLTF removes the H840A but not the D10A Cas9 nickase. The removal of Cas9 H840A by HLTF explains the different cellular impact of the two Cas9 nickase variants in human cells, with potential implications for gene editing.
Assuntos
Proteína 9 Associada à CRISPR , Sistemas CRISPR-Cas , Quebras de DNA de Cadeia Dupla , DNA , Humanos , Proteína 9 Associada à CRISPR/metabolismo , Proteína 9 Associada à CRISPR/genética , DNA/metabolismo , DNA/genética , Proteína Homóloga a MRE11/metabolismo , Proteína Homóloga a MRE11/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas Associadas a CRISPR/metabolismo , Proteínas Associadas a CRISPR/genética , Edição de Genes , Endonucleases/metabolismo , Endonucleases/genética , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Endodesoxirribonucleases/metabolismo , Endodesoxirribonucleases/genética , Reparo do DNA por Junção de Extremidades , Clivagem do DNA , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genéticaRESUMO
We describe a series of new chalcogen-bonded cocrystals featuring 1,2-bis(selenocyanatomethyl)benzene (DSN) and 1,2,4,5-tetrakis(selenocyanatomethyl)-benzene (TSN) as the donor moieties and a variety of Lewis bases such as onium halides, N-oxides, and pyridine-containing heterocycles as the acceptors. Single-crystal X-ray diffraction demonstrates that, in every case, the selenocyanates consistently interact with the acceptor molecules through strong and directional Se···X chalcogen-bonds (ChBs) (X = halides, oxygen, and nitrogen). 77Se solid-state nuclear magnetic resonance spectroscopy was applied to measure selenium chemical shift tensor magnitudes and to explore potential correlations between these tensor elements and the local ChB geometry. In every case, the isotropic 77Se chemical shift decreases, and the chemical shift tensor span increases upon cocrystallization of DSN with the various ChB acceptors. This work contributes to a growing body of knowledge concerning the predictability and robustness of chalcogen bonds in crystal engineering as well as the NMR response to the establishment of chalcogen bonds. In particular, among the systems studied here, highly linear chalcogen bonds are formed exclusively at the stronger σ-hole of each and every selenium atom regardless of the size, charge, or denticity of the electron donor moiety.
RESUMO
BACKGROUND: COVID-19 changed the way we practice oncology in multiple ways. Because most cancer patients are comorbid or immunocompromised, we are trying as much as possible to reduce their risk of infection. Marginal just 2 years ago, telemedicine quickly became preeminent with the pandemic to reduce hospital exposure. However, using only virtual visits in oncology patients risk delaying cancer diagnosis or the identification of a complication. CASE SERIES: We present here four cases where a serious medical problem evident on physical exam was overlooked during a virtual visit. Two of our patients experienced a delay in cancer diagnosis thus putting them at risk of local or distant spread. The two others were established oncology patients where a serious medical complication was missed on a virtual visit. CONCLUSIONS: Now more than a year into the pandemic, telemedicine has clearly been a useful tool by limiting unnecessary hospital visits. Yet, as our cases illustrate, its use in oncology without clear boundary can undermine the quality of care. Now that effective vaccines are reducing the transmission and the severity of infection, most oncology patients can be evaluated by a real-time visit.
Assuntos
COVID-19 , Neoplasias , Telemedicina , COVID-19/epidemiologia , Humanos , Neoplasias/diagnóstico , Neoplasias/terapia , Pandemias/prevenção & controle , SARS-CoV-2RESUMO
Anterior cruciate ligament (ACL) rupture is a common affliction in the athletic population. In pediatric patients, the immature skeleton with active growth plates is an issue that makes ACL reconstruction surgery technically challenging. The rerupture rate after ACL reconstruction is higher in the pediatric population than in the adult population. The addition of anterolateral ligament (ALL) reconstruction has been shown to be an effective way to reduce the rate of graft rupture and to control rotatory instability (pivot shift). Therefore, it appears necessary to combine ACL and ALL reconstruction in the pediatric population. We describe the surgical steps for combined ACL and ALL reconstruction adapted for young patients with active growth plates.
RESUMO
The strategy for surgical treatment of chronic ankle instability is becoming increasingly refined. In instances of isolated symptomatic non-repairable anterior talofibular ligament (ATFL) injury, there is a surgical indication for isolated ATFL reconstruction. However, we feel that the typical gracilis tendon graft is not always appropriate. Interest in using the plantaris tendon as a graft has picked up since a biomechanics study found the tensile strength of a quadrupled plantaris tendon is comparable to that of the ATFL. Here, we describe an original arthroscopic technique for isolated ATFL reconstruction using a quadrupled plantaris tendon (PT4) graft.
Assuntos
Traumatismos do Tornozelo , Instabilidade Articular , Ligamentos Laterais do Tornozelo , Traumatismos do Tornozelo/diagnóstico por imagem , Traumatismos do Tornozelo/cirurgia , Articulação do Tornozelo/diagnóstico por imagem , Articulação do Tornozelo/cirurgia , Humanos , Instabilidade Articular/cirurgia , Ligamentos Laterais do Tornozelo/cirurgia , Tendões/cirurgiaRESUMO
OBJECTIVE: We determined secular changes in the incidence of hospitalizations due to herpes zoster (HZh) and assessed the validity of HZ International Classification of Diseases (ICD) code algorithms for identifying HZh in a region of Quebec, Canada. METHODS: We performed a validation study as part of a retrospective cohort study of adult HZ patients hospitalized at Centre Hospitalier Universitaire de Sherbrooke during 2000-2017. Cases were identified using ICD codes from an inpatient administrative database. HZ cases identified by ICD-9 (053.xx) and ICD-10 (B02.x) codes were chart-confirmed, and performance characteristics of ICD code algorithms were calculated (positive predictive value [PPV] and sensitivity). RESULTS: Overall, 1314 hospitalizations with HZ diagnosis (HZh) with or without complications were identified during 2000-2017. Among the hospitalizations, 526 (44.4%) were due to active HZ disease or a complication related to a recent or previous HZ episode. These hospitalizations were due to active disease at the time of admission (340/526, 64.6%), HZ that developed during hospitalization (120/526, 22.8%), or a complication directly related to a recent or previous HZ episode (66/526, 12.6%). PPV was significantly higher when HZ was the primary diagnosis (276/310, 89%, 95% confidence interval [CI]: 85-92%) than when HZ was a secondary diagnosis (254/928, 27%, 95% CI: 25-30%) (pâ¯<â¯0.0001), and the PPV of a first secondary diagnosis (84/140, 60.0%, 95% CI: 51.3-68.2%) was higher than that of other secondary diagnoses (203/794, 25.6%, 95% CI: 22.6-28.8%) (pâ¯<â¯0.0001). An algorithm combining ICD codes and antiviral usage demonstrated the best sensitivity (86.3%, 95% CI: 83.1-89.1%) and PPV to identify HZh (100%, 95% CI: 99.2-100%). Poisson regression revealed no significant changes in HZh over time (incidence rate ratio: 0.98, 95% CI: 0.92-1.04%; pâ¯=â¯0.5). CONCLUSION: HZh incidence was stable over time. Prescription of antivirals might be a useful addition to ICD codes to identify HZh cases from administrative databases.
Assuntos
Herpes Zoster , Classificação Internacional de Doenças , Adulto , Algoritmos , Bases de Dados Factuais , Herpes Zoster/diagnóstico , Herpes Zoster/epidemiologia , Hospitalização , Humanos , Quebeque/epidemiologia , Estudos RetrospectivosRESUMO
BACKGROUND: Few data are available on the 20-year outcomes of anterior cruciate ligament (ACL) reconstruction. The purpose of this study was to assess the prevalence and risk factors of knee osteoarthritis at least 20 years after ACL reconstruction. HYPOTHESIS: Factors associated with progression to knee osteoarthritis include meniscal lesions, level of physical activity, injury-to-surgery time, body mass index, residual laxity, tunnel position and cartilage injury. MATERIAL AND METHODS: One hundred and eighty two patients were included in a multicentre retrospective study conducted in the setting of a SoFCOT symposium. Females contributed two-thirds of the study population. ACL reconstruction was performed arthroscopically in 82% of cases, and a bone-patellar tendon-bone transplant was used in 92.8% of cases. Mean age at surgery was 26±7years. Clinical outcomes were assessed based on the objective and subjective IKDC scores and on the KOOS. Radiographic evidence of osteoarthritis was classified according to the IKDC. Factors evaluated for their ability to predict progression to osteoarthritis included age, sex, body mass index, level of physical activity, injury-to-surgery time, meniscectomy, cartilage injury, tunnel position and residual laxity. RESULTS: At last follow-up, the objective IKDC score was A (normal) for 48%, B for 35%, and C or D for 17% of the knees. The mean subjective IKDC score was 82.7±13.1. Moderate-to-severe osteoarthritis was present in 29% of cases. The following risk factors for osteoarthritis were identified: medial or lateral meniscectomy, residual laxity, age >30years at surgery, and engaging in a pivoting sport. Meniscectomy was a major contributor to the development of osteoarthritis (17% of knees without vs. 46% with meniscectomy). Finally, the ACL re-tear rate was 13%. CONCLUSION: ACL reconstruction provides satisfactory knee stability. The risk of subsequent osteoarthritis depends chiefly on the status of the menisci. Residual laxity is also associated with the development of osteoarthritis. LEVEL OF EVIDENCE: IV, retrospective cohort study.
Assuntos
Lesões do Ligamento Cruzado Anterior , Reconstrução do Ligamento Cruzado Anterior , Osteoartrite do Joelho , Adulto , Lesões do Ligamento Cruzado Anterior/epidemiologia , Lesões do Ligamento Cruzado Anterior/cirurgia , Feminino , Seguimentos , Humanos , Articulação do Joelho/cirurgia , Osteoartrite do Joelho/epidemiologia , Osteoartrite do Joelho/etiologia , Osteoartrite do Joelho/cirurgia , Estudos RetrospectivosRESUMO
OBJECTIVE: To describe successful therapeutic strategies in statin-induced anti-HMGCR myopathy. METHODS: Retrospective data from a cohort of 55 patients with statin-induced anti-HMGCR myopathy, sequentially stratified by the presence of proximal weakness, early remission, and corticosteroid and IVIG use at treatment induction, were analyzed for optimal successful induction and maintenance of remission strategies. RESULTS: A total of 14 patients achieved remission with a corticosteroid-free induction strategy (25%). In 41 patients treated with corticosteroids, only 4 patients (10%) failed an initial triple steroid/IVIG/steroid-sparing immunosuppressant (SSI) induction strategy. Delay in treatment initiation was independently associated with lower odds of successful maintenance with immunosuppressant monotherapy (OR 0.92, 95% CI 0.85 to 0.97, P = 0.015). While 22 patients (40%) presented with normal strength, only 9 had normal strength at initiation of treatment. CONCLUSION: While corticosteroid-free treatment of anti-HMGCR myopathy is now a safe option in selected cases, initial triple steroid/IVIG/SSI was very efficacious in induction. Delays in treatment initiation and, as a corollary, delays in achieving remission decrease the odds of achieving successful maintenance with an SSI alone. Avoiding such delays, most notably in patients with normal strength, may reset the natural history of anti-HMGCR myopathy from a refractory entity to a treatable disease.
Assuntos
Doenças Autoimunes/induzido quimicamente , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Imunossupressores/uso terapêutico , Miosite/induzido quimicamente , Miosite/etiologia , Corticosteroides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/tratamento farmacológico , Feminino , Humanos , Hidroximetilglutaril-CoA Redutases/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Quimioterapia de Indução/métodos , Quimioterapia de Manutenção/métodos , Masculino , Pessoa de Meia-Idade , Miosite/imunologia , Estudos RetrospectivosRESUMO
The halogen bond has previously been explored as a versatile tool in crystal engineering and anion coordination chemistry, with mechanochemical synthetic techniques having been shown to provide convenient routes towards cocrystals. In an effort to expand our knowledge on the role of halogen bonding in anion coordination, here we explore a series of cocrystals formed between 3-iodoethynylpyridine and 3-iodoethynylbenzoic acid with halide salts. In total, we report the single-crystal X-ray structures of six new cocrystals prepared by mechanochemical ball milling, with all structures exhibiting C≡C-Iâ â â X- (X=Cl, Br) halogen bonds. Whereas cocrystals featuring a pyridine group favoured the formation of discrete entities, cocrystals featuring a benzoic acid group yielded an alternation of halogen and hydrogen bonds. The compounds studied herein were further characterized by 13C and 31P solid-state nuclear magnetic resonance, with the chemical shifts offering a clear and convenient method of identifying the occurrence of halogen bonding, using the crude product obtained directly from the mechanochemical ball milling. Whereas the 31P chemical shifts were quickly able to identify the occurrence of cocrystallization, 13C solid-state NMR was diagnostic of both the occurrence of halogen bonding and of hydrogen bonding.
RESUMO
Invited for this month's cover picture is the group of Professor David Bryce at the University of Ottawa. The cover picture shows a stylized depiction of the mechanochemical halogen-bond induced cocrystallization of 3-iodoethynylpyridine with tetraphenylphosphonium bromide. Read the full text of their Full Paper at 10.1002/open.201900194.
RESUMO
BACKGROUND: Anterior cruciate ligament (ACL) reconstruction is important to prevent knee osteoarthritis. Neither of the 2 most common graft techniques-the patellar tendon (PT) or hamstring tendon (HS) graft-has demonstrated superiority in terms of the long-term osteoarthritis rate. HYPOTHESIS: Based on the International Knee Documentation Committee (IKDC) radiographic grading system, PT grafts decrease the incidence of osteoarthritis by providing better knee stability as compared with HS grafts over 12 years of follow-up. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: All adults with a first ACL rupture who underwent surgery with a PT or HS graft technique between January 2002 and December 2003 were included in the 2014 French Society of Orthopedic Surgery and Traumatology Symposium database. Baseline characteristics were collected. The primary endpoint was the occurrence of moderate to severe osteoarthritis in each group. The secondary endpoints included clinical subjective evaluations by the IKDC score and Knee injury and Osteoarthritis Outcome Score. To control the differences in baseline characteristics, the data were analyzed with propensity score matching. RESULTS: In the cohort, 541 patients from 18 centers were included: 311 PT and 230 HS ACL reconstructions. The baseline characteristics were similar after inverse probability weighting treatment (IPWT). The occurrence of osteoarthritis was similar after IPWT (19.3% for PT and 19.6% for HS, P = .94). Age at surgery >29 years and IKDC osteoarthritis stage B at the index surgery were identified as risk factors for moderate to severe osteoarthritis. Most functional outcomes were significantly higher in the HS group; however, the difference between groups remained <10 points. Of the 106 patients who needed a medial meniscectomy, the proportion of patients with moderate to severe osteoarthritis was much higher in the HS group (43.5% vs 18.3%, P = .006). However, after IPWT, the difference was not statistically significant. CONCLUSION: At 12 years of follow-up, neither graft technique was superior to the other in terms of the rate of osteoarthritis.
Assuntos
Reconstrução do Ligamento Cruzado Anterior/métodos , Tendões dos Músculos Isquiotibiais/transplante , Osteoartrite do Joelho/etiologia , Ligamento Patelar/transplante , Adulto , Reconstrução do Ligamento Cruzado Anterior/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/cirurgia , Adulto JovemRESUMO
PARP inhibitors (PARPi), such as Olaparib, have shown promising results in high-grade serous (HGS) epithelial ovarian cancer (EOC) treatment. PARPi sensitivity has been mainly associated with homologous recombination (HR) deficiency, but clinical trials have shown that predicting actual patient response is complex. Here, we investigated gene expression microarray, HR functionality and Olaparib sensitivity of 18 different HGS EOC cell lines and demonstrate that PARPi sensitivity is not only associated with HR defects. Gene target validation show that down regulation of genes in the nucleotide excision repair (NER) and mismatch repair (MMR) pathways (ERCC8 and MLH1, respectively) increases PARPi response. The highest sensitivity was observed when genes in both the HR and either NER or MMR pathways were concomitantly down regulated. Using clinical samples, patients with these concurrent down regulations could be identified. Based on these results, a novel model to predict PARPi sensitivity is herein proposed. This model implies that the extreme responders identified in clinical trials have deficiencies in HR and either NER or MMR.
Assuntos
Reparo do DNA/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ftalazinas/farmacologia , Piperazinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Gradação de Tumores , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Interferência de RNA , Transdução de Sinais/genéticaRESUMO
We report a comprehensive proton NMR relaxation study of the water confined in the evolving porous structure of hardened gypsum prepared with different water-to-plaster ratios (w/p) and increasing additions of crushed gypsum. This study gives some new information on the microstructure, the water distribution, and the hydration kinetics without any drying or perturbing preparation. The bi-exponential transverse magnetization decay reveals the existence of two water populations in slow exchange. However, the different behaviors of these populations during saturation and desaturation experiments show evidence of a fast exchange of each population with the surface. Two modes of organization of the microstructure of this material are identified through an original model of exchange as a function of the water-to-plaster ratio (0.4 < or = w/p < or = 0.6 and 0.7 < or = w/p < or = 1). A clear gap is shown in the exchange rate value above w/p = 0.6 that could be representative of a percolation threshold. Both the method and the theory presented can be applied more widely to other porous media with reactive surface areas.
RESUMO
A new multi-scale experimental approach is proposed to continuously relate the microstructure and the macroscopic mechanical properties of plaster pastes during their settings. (1)H NMR relaxometry is used to follow continuously and not destructively, the degree of hydration and the microstructure evolution during the setting and hardening of plaster paste. Transmission of shear and compressional ultrasonic velocities enable the determination of macroscopic mechanical properties of the material during the setting. On the basis of similar behaviors of Young's modulus and NMR-population of confined water as function of the degree of hydration, we conclude that NMR gives a better understanding of the evolution of the microstructure at the origin of a better control of the macroscopic mechanical properties.