Background:. Analyzing outcomes and the minimal clinically important difference (MCID) after anterior cruciate ligament reconstruction (ACLR) is of increased interest in the orthopaedic literature. ...The purposes of this study were to report outcomes after ACLR at medium to long-term follow-up, identify the threshold preoperative outcome values that would be predictive of achieving the MCID postoperatively, and analyze outcome maintenance at medium to long-term follow-up after ACLR. Methods:. Active athletes who underwent ACLR were identified in an institutional ACL registry. Patient-reported outcome measures (PROMs) were administered preoperatively and at the 2-year and >5-year postoperative follow-up; measures included the International Knee Documentation Committee (IKDC) form, the 12-item Short Form Health Survey (SF-12) Physical Component Summary (PCS) and Mental Component Summary (MCS), and Lysholm scale. We calculated the MCID from baseline to each of the 2 follow-up periods (2-year and mean 7.7-year). Logistic regression was performed to investigate factors associated with achievement of the MCID. Results:. A total of 142 patients (mean follow-up, 7.7 years range, 6.6 to 9.1 years) underwent ACLR. The mean age and body mass index at the time of surgery were 27.2 ± 13.0 years and 23.2 ± 3.0 kg/m2, respectively. Final postoperative outcome scores improved significantly from baseline for the IKDC (50.9 ± 14.7 to 87.9 ± 11.2), SF-12 PCS (41.6 ± 8.9 to 55.6 ± 3.2), and Lysholm scale (62.2 ± 17.6 to 90.5 ± 10.3) (p < 0.0001), while the SF-12 MCS did not improve significantly (54.2 ± 8.0 to 54.4 ± 6.0) (p = 0.763). Between 2- and >5-year follow-up, the SF-12 PCS showed significant improvement (54.6 ± 4.5 to 55.6 ± 3.2; p = 0.036), while no change was noted in the IKDC (87.6 ± 11.1 to 87.9 ± 11.2), SF-12 MCS (55.5 ± 5.3 to 54.4 ± 6.0), and Lysholm scale (89.8 ± 10.6 to 90.5 ± 10.3) (p ≥ 0.09). At the time of final follow-up, the MCID was achieved by 94.7% of patients for the IKDC, 80.8% for the Lysholm, 79.0% for the SF-12 PCS, and 28.2% for the SF-12 MCS. At 2-year follow-up, 95.3% of patients were either “very” or “somewhat” satisfied with their surgery, compared with 88.6% at the time of final follow-up. Conclusions:. We found a high level of maintained function following ACLR. The IKDC, SF-12 PCS, and Lysholm scores improved significantly after ACLR at the time of final follow-up and were not significantly different between follow-up periods. Approximately 95% and 89% of patients reported being satisfied with the outcome of surgery at the 2-year and final follow-up, respectively. Level of Evidence:. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS) are defined by somatic mutations in genes associated with myeloid neoplasms (MN) at a ...variant allele fraction (VAF) ≥ 0.02, in the absence and presence of cytopenia, respectively. CHIP/CCUS is highly prevalent in adults and defining predictors of MN risk would aid clinical management and research.
We analyzed sequenced exomes of healthy UK Biobank (UKB) participants (n = 438,890) in separate derivation and validation cohorts. Genetic mutations, laboratory values, and MN outcomes were used in conditional probability-based recursive partitioning and Cox regression to determine predictors of incident MN. Combined statistical weights defined a clonal hematopoiesis risk score (CHRS). Independent CHIP/CCUS patient cohorts were used to test prognostic capability of the CHRS in the clinical setting.
Recursive partitioning distinguished CHIP/CCUS cases with 10-year probabilities of MN ranging from 0.0078 - 0.85. Multivariable analysis validated partitioning variables as predictors of MN. Key features, including single
mutations, high risk mutations, ≥ 2 mutations, VAF ≥ 0.2, age ≥ 65 years, CCUS vs CHIP and red blood cell indices, influenced MN risk in variable direction. The CHRS defined low risk (n = 10018, 88.4%), intermediate risk (n = 1196, 10.5%), and high risk (n = 123, 1.1%) groups. In clinical cohorts, most MN events occurred in high risk CHIP/CCUS patients.
The CHRS provides simple prognostic framework for CHIP/CCUS, distinguishing a high risk minority from the majority of CHIP/CCUS which has minimal risk for progression to MN.
2,4-Diaryl-2,5-dihydropyrroles are reported as potent inhibitors of the mitotic kinesin KSP.
The evolution of 2,4-diaryl-2,5-dihydropyrroles as inhibitors of KSP is described. Introduction of basic ...amide and urea moieties to the dihydropyrrole nucleus enhanced potency and aqueous solubility, simultaneously, and provided compounds that caused mitotic arrest of A2780 human ovarian carcinoma cells with EC
50s
<
10
nM. Ancillary hERG activity was evaluated for this series of inhibitors.
Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first ...generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound.
Previous work has shown that hyperaccumulator levels of some metals can defend plants against herbivores, but the possibility of defense by metal concentrations at accumulator or normal levels is ...unexplored. This study tested the hypothesis that metals can defend plants at low concentrations. We determined the relative toxicities of eight metals commonly acquired by plants: Cd, Co, Cr, Cu, Mn, Ni, Pb, and Zn. Larvae of the diamondback moth (Plutella xylostella), a representative crucifer specialist, were fed with artificial diet amended with concentrations of metal varying from 2 to 3,000 microg/g. Different concentration ranges were used for each of the eight metals, and larval survival at 10-14 days was calculated for each concentration. All metals were toxic to diamondback moth larvae at hyperaccumulator levels. All metals, however, were also toxic to larvae at accumulator concentrations, far below those found in hyperaccumulating plants. Five metals (Cd, Mn, Ni, Pb, and Zn) were toxic below accumulator levels, Cd and Pb were toxic near the concentration ranges of normal plants, and Zn was toxic at a concentration within the normal range. Our results indicate that uptake of certain metals may provide a defensive benefit for plants, and that elemental defenses may be effective at concentrations far lower than previously hypothesized. This study implies that elemental defenses are more widespread in plants than previously believed, and that the ecological consequences of even low levels of metal accumulation need to be explored.
Women diagnosed with ovarian tumors of low malignant potential have an excellent prognosis. Because few will receive adjuvant therapy, the benefit of surgical staging has recently been challenged. ...The purpose of this study was to compare the outcome of surgically staged patients with low malignant potential tumors with those who were not staged.
Between 1984 and 2003, all women with ovarian low malignant potential tumors were identified at 3 institutions. Data were extracted from clinical records.
One hundred eighty-three (74%) of 248 women were surgically staged. Forty of 183 staged patients had clinically obvious extraovarian disease. Forty (28%) of the remaining 143 women with disease apparently confined to the ovary were upstaged. Cytologic washings were positive in 28 cases, 10 had microscopic implants detected by peritoneal or omental biopsy, and 2 were upstaged to stage IIIC solely on the basis of nodal metastases. One hundred eighteen women underwent pelvic node dissection (median: 5 nodes), and 86 underwent para-aortic node dissection (median: 2 nodes). Overall, 9 (1%) metastases were detected in 832 submitted pelvic nodes. All 314 para-aortic nodes were negative. Intraoperative blood loss (P <.001) and length of hospital stay (P <.001) were increased in women without gross disease who were surgically staged. Eight (3%) of 248 patients received adjuvant platinum-based chemotherapy, but neither of the women upstaged to IIIC based on the results of their nodal dissection were treated. Fifteen (6%) recurrences developed and 1 (0.4%) death occurred after a median follow-up of 28 (range, 1-208) months.
Routine pelvic and para-aortic lymph node dissection is not necessary in the majority of women with ovarian low malignant potential tumors.
We investigated how water and nutrient availability affect radiation-use efficiency (epsilon) and assessed leaf gas exchange as a possible mechanism for shifts in epsilon. We measured aboveground net ...primary production (ANPP) and annual photosynthetically active radiation (PAR) capture to calculate epsilon as well as leaf-level physiological variables (light-saturated net photosynthesis, A(sat); stomatal conductance, g(s); leaf internal CO2 concentration, C(i); foliar nitrogen concentration, foliar N; and midday leaf water potential, psi(leaf) during the second (2001) and third (2002) growing seasons in sweetgum (Liquidambar styraciflua L.) and sycamore (Platanus occidentalis L.) stands receiving a factorial combination of irrigation and fertilization at the Savannah River Site, South Carolina. Irrigation and fertilization increased PAR capture (maximum increase 60%) in 2001 and 2002 for both species and annual PAR capture was well correlated with ANPP (mean r2 = 0.77). A decreasing trend in epsilon was observed in non-irrigated stands for sweetgum in 2001 and for sycamore in both years, although this was only significant for sycamore in 2002. Irrigated stands maintained higher gas exchange rates than non-irrigated stands for sweetgum in 2001 and for sycamore in both years, although foliar N and psi(leaf) were generally unaffected. Because C(i) decreased in proportion to gs in non-irrigated stands, it appeared that greater stomatal limitation of photosynthesis was associated with decreased A(sat). On several measurement dates for sweetgum in 2001 and for sycamore in both years, epsilon was positively correlated with gas exchange variables (A(sat), g(s), C(i)) (r ranged from 0.600 to 0.857). These results indicate that PAR capture is well correlated with ANPP and that gas exchange rates modified by irrigation can influence the conversion of captured light energy to biomass.
Synthetic oligonucleotides with a fluorescent coumarin group replacing a basepair have been used in recent time-resolved Stokes-shift experiments to measure DNA dynamics on the femtosecond to ...nanosecond timescales. Here, we show that the APE1 endonuclease cleaves such a modified oligonucleotide at the abasic site opposite the coumarin with only a fourfold reduction in rate. In addition, a noncatalytic mutant (D210N) binds tightly to the same oligonucleotide, albeit with an 85-fold reduction in binding constant relative to a native oligonucleotide containing a guanine opposite the abasic site. Thus, the modified oligonucleotide retains substantial biological activity and serves as a useful model of native DNA. In the complex of the coumarin-containing oligonucleotide and the noncatalytic APE1, the dye’s absorption spectrum is shifted relative to its spectrum in either water or within the unbound oligonucleotide. Thus the dye occupies a site within the DNA:protein complex. This result is consistent with modeling, which shows that the complex accommodates coumarin at the site of the orphaned base with little distortion of the native structure. Stokes-shift measurements of the complex show surprisingly little change in the dynamics within the 40 ps–40
ns time range.
Lipoic acid and its reduced derivative, dihydrolipoic acid (DHLA) are highly promising antioxidant agents, which are potent attenuators of reactive species-mediated damage in vitro and in animal ...studies. Lipoic acid is a universal antioxidant, effective in lipophilic and aqueous environments. In contrast to an equivalent endogenous agent, such as oxidised glutathione (GSSG), lipoic acid acts as an antioxidant in its oxidised form. Lipoic acid has been evaluated in diabetic polyneuropathy, a condition which is thought to result in part from oxidant damage caused by long-term hyperglycaemia. Diabetic patients are prone to incur enhanced cellular free radical formation and reduced antioxidant defence. Treatment with lipoic acid has improved nerve conduction velocity during studies in diabetic animals. Trials in diabetic patients have often observed some relief of neuropathic symptoms during treatment with lipoic acid, but consistent objective benefits have been difficult to establish. Lipoic acid is now used in Germany for the treatment of diabetic neuropathy and definitive evidence of efficacy should arise from postmarketing surveillance studies. It is possible that lipoic acid may be more effective as a long-term dietary supplement aimed at the prophylactic protection of diabetics from complications.
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