Cisplatin-DNA damage in p21WAF1/Cip1 deficient mouse keratinocytes exposed to cisplatin

In response to DNA damage, cell cycle arrest, apoptosis, and DNA repair are mediated by a TP53 pathway that induces p21(WAF1/Cip1). The chemotherapeutic drug cis-diamminedichloroplatinum-II (cisplatin) damages cellular DNA by forming cis-diammineplatinum-N(7)-d[GpG] and cis-diammine-platinum-N(7)-d[ApG] adducts. To investigate the role of p21, skin keratinocytes from p21(WAF1/Cip1) wild-type (+/+), heterozygous (+/-), and null (-/-) mice, cultured in calcium levels designed to maintain a proliferating state, were exposed to 5 microM cisplatin continuously for 0, 8, 24, 48 and 72 h. At all time points the (+/-) cells had the fewest Pt-DNA adducts, and at 24 h mean Pt-DNA adduct levels were 541, 153 and 779 fmol adduct/mug DNA for p21(WAF1/Cip1) (+/+), (+/-) and (-/-) cells, respectively [P < 0.05 for (+/+) versus (+/-) and (-/-) versus (+/-)]. In order to understand underlying events, we examined p21(WAF1/Cip1) messenger RNA (mRNA), cell cycle arrest, and apoptosis in these cells. At 48 h of cisplatin exposure p21(WAF1/Cip1) mRNA expression was 2-fold higher in the (+/+) cells, compared to the (+/-) cells. At 24 h, the % of cells in S-phase in cisplatin-exposed cultures, compared to unexposed cultures, was decreased by 51, 40 and 11% in p21(WAF1/Cip1) (+/+), (+/-) and (-/-) cells, respectively (P = 0.04, ANOVA). At 24, 48 and 72 h the % of cisplatin-exposed (+/+) cells in apoptosis was 9.4-10.5%, while the cisplatin-exposed (+/-) and (-/-) cells had 1.2-3.7% of cells in apoptosis. The data support the interpretation that DNA replication arrest and apoptosis do not completely explain the low levels of Pt-DNA adducts in the (+/-) cells, and suggest that p21(WAF1/Cip1) controls activity resulting in either low Pt-DNA adduct formation or enhanced Pt-DNA adduct removal.     

Clinical characteristics of impaired trunk control in children with spastic cerebral palsy

This study aimed to identify clinical characteristics of impaired trunk control in hundred children with spastic CP (mean age 11.4 ± 2.1 years, range 8–15 years). Assessment of trunk control was performed with the Trunk Control Measurement Scale (TCMS). Trunk control was clearly impaired, indicated by a median total TCMS score of 38.5 out of 58 (66%). Median subscale scores were 18 out of 20 (90%) for the subscale static sitting balance, 16 out of 28 (57%) for the subscale selective movement control and 6 out of 10 (60%) for the subscale dynamic reaching. Total TCMS and subscale scores differed significantly between topographies and severity of motor impairment according to the Gross Motor Function Classification System (GMFCS). Children with hemiplegia obtained the highest scores, followed by children with diplegia and children with quadriplegia obtained the lowest scores. TCMS scores significantly decreased with increasing GMFCS level. In conclusion, trunk control is impaired in children with CP to a various extent, depending on the topography and severity of the motor impairment. The findings of this study also provide specific clues for treatment interventions targeting trunk control to improve their functional abilities.     

Does somatosensory discrimination activate different brain areas in children with unilateral cerebral palsy compared to typically developing children? An fMRI study

Aside from motor impairment, many children with unilateral cerebral palsy (CP) experience altered tactile, proprioceptive, and kinesthetic awareness. Sensory deficits are addressed in rehabilitation programs, which include somatosensory discrimination exercises. In contrast to adult stroke patients, data on brain activation, occurring during somatosensory discrimination exercises, are lacking in CP children. Therefore, this study investigated brain activation with functional magnetic resonance imaging (fMRI) during passively guided somatosensory discrimination exercises in 18 typically developing children (TD) (age, M = 14 ± 1.92 years; 11 girls) and 16 CP children (age, M = 15 ± 2.54 years; 8 girls). The demographic variables between both groups were not statistically different. An fMRI compatible robot guided the right index finger and performed pairs of unfamiliar geometric shapes in the air, which were judged on their equality. The control condition comprised discrimination of music fragments. Both groups exhibited significant activation (FDR, p < .05) in frontoparietal, temporal, cerebellar areas, and insula, similar to studies in adults. The frontal areas encompassed ventral premotor areas, left postcentral gyrus, and precentral gyrus; additional supplementary motor area (SMA_proper) activation in TD; as well as dorsal premotor, and parietal operculum recruitment in CP. On uncorrected level, p < .001, TD children revealed more left frontal lobe, and right cerebellum activation, compared to CP children. Conversely, CP children activated the left dorsal cingulate gyrus to a greater extent than TD children. These data provide incentives to investigate the effect of somatosensory discrimination during rehabilitation in CP, on clinical outcome and brain plasticity.     

8p21.3 deletions are rare causes of non-syndromic autism spectrum disorder

neurogenetics - A de novo 0.95 Mb 8p21.3 deletion had been identified in an individual with non-syndromic autism spectrum disorder (ASD) through high-resolution copy number variant analysis....     

Effects of Odanacatib on Bone Structure and Quality in Postmenopausal Women With Osteoporosis: 5-Year Data From the Phase 3 Long-Term Odanacatib Fracture Trial (LOFT) and its Extension

Odanacatib (ODN), a selective oral inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this analysis, the effects of ODN on bone remodeling/modeling and structure were examined in the randomized, double-blind, placebo-controlled, event-driven, Phase 3, Long-term Odanacatib Fracture Trial (LOFT; NCT00529373) and planned double-blind extension in postmenopausal women with osteoporosis. A total of 386 transilial bone biopsies, obtained from consenting patients at baseline (ODN n = 17, placebo n = 23), month 24 (ODN n = 112, placebo n = 104), month 36 (ODN n = 42, placebo n = 41), and month 60 (ODN n = 27, placebo n = 20) were assessed by dynamic and static bone histomorphometry. Patient characteristics at baseline and BMD changes over 5 years for this subset were comparable to the overall LOFT population. Qualitative assessment of biopsies revealed no abnormalities. Consistent with the mechanism of ODN, osteoclast number was higher with ODN versus placebo over time. Regarding bone remodeling, dynamic bone formation indices in trabecular, intracortical, and endocortical surfaces were generally similar in ODN-treated versus placebo-treated patients after 2 years of treatment. Regarding periosteal modeling, the proportion of patients with periosteal double labels and the bone formation indices increased over time in the ODN-treated patients compared with placebo. This finding supported the observed numerical increase in cortical thickness at month 60 versus placebo. In conclusion, ODN treatment for 5 years did not reduce bone remodeling and increased the proportion of patients with periosteal bone formation. These results are consistent with the mechanism of action of ODN, and are associated with continued BMD increases and reduced risk of fractures compared with placebo in the LOFT Phase 3 fracture trial. © 2020 American Society for Bone and Mineral Research.     

Circulating delta‐like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus‐based immunosuppression

Cardiac allograft vasculopathy (CAV) causes heart failure after heart transplantation (HTx), but its pathogenesis is incompletely understood. Notch signaling, possibly modulated by everolimus (EVR), is essential for processes involved in CAV. We hypothesized that circulating Notch ligands would be dysregulated after HTx. We studied circulating delta‐like Notch ligand 1 (DLL1) and periostin (POSTN) and CAV in de novo HTx recipients (n = 70) randomized to standard or EVR‐based, calcineurin inhibitor‐free immunosuppression and in maintenance HTx recipients (n = 41). Compared to healthy controls, plasma DLL1 and POSTN were elevated in de novo (P < .01; P < .001) and maintenance HTx recipients (P < .001; P < .01). Use of EVR was associated with a treatment effect for DLL1. For de novo HTx recipients, a change in DLL1 correlated with a change in CAV at 1 (P = .021) and 3 years (P = .005). In vitro, activation of T cells increased DLL1 secretion, attenuated by EVR. In vitro data suggest that also endothelial cells and vascular smooth muscle cells (VSMCs) could contribute to circulating DLL1. Immunostaining of myocardial specimens showed colocalization of DLL1 with T cells, endothelial cells, and VSMCs. Our findings suggest a role of DLL1 in CAV progression, and that the beneficial effect of EVR on CAV could reflect a suppressive effect on DLL1. Trial registration numbers— SCHEDULE trial: ClinicalTrials.gov NCT01266148; NOCTET trial: ClinicalTrials.gov NCT00377962.     

Patellofemoral arthroplasty influences tibiofemoral kinematics: the effect of patellar thickness

Purpose

Although controversy still remains, isolated patellofemoral arthroplasty recently gained in popularity as a treatment option for patellofemoral osteoarthritis. It has compared to total knee arthroplasty the advantage of preserving the tibiofemoral articulation, which in theory would allow the preservation of natural tibiofemoral kinematics. Today, however, no data exist to support this assumption. This study was therefore performed in order to investigate the effect of isolated patellofemoral arthroplasty on the native three-dimensional tibiofemoral kinematic behaviour and whether a change in patellar thickness would have an influence.

Methods

Six fresh-frozen cadavers were fixed on a custom-made mechanical knee rig. Full 3D kinematics was analysed during passive flexion–extension cycles, open chain extension, with and without mechanical resistance, as well as deep knee squats, using infrared motion capture cameras and retroflective markers. Measurements were taken for the native knee and after prosthetic trochlear resurfacing with and without patellar resurfacing in three different patellar thicknesses.

Results

Compared to the natural knee, patellofemoral arthroplasty resulted in significant changes in tibiofemoral kinematics, which were most pronounced in the most loaded motor tasks. Increased internal tibial rotation was noted in the mid- and high flexion ranges, reaching at 120° of flexion a mean difference of 4.5° ± 4.3° (p < 0.0001) during squat motion, over the whole flexion range during open chain motion and in deeper flexion beyond 50° (mean at 70°, 1.9° ± 3.7°) during resisted open chain. During squats, also, a more posterior translation of the lateral femoral condyle was observed. The effect was accentuated in case of patella overstuffing, whereas kinematics was closer to normal with patellar thinning.

Conclusion

Isolated patellofemoral arthroplasty alters natural tibiofemoral kinematics, and the effects become more pronounced in case of increased patellar thickness. Therefore, it might be recommended to aim for a slight over-resection of patellar bone if sufficient bone stock is available.     

How does brain activation differ in children with unilateral cerebral palsy compared to typically developing children,during active and passive movements,and tactile stimulation? An fMRI study

The aim of the functional magnetic resonance imaging (fMRI) study was to investigate brain activation associated with active and passive movements, and tactile stimulation in 17 children with right-sided unilateral cerebral palsy (CP), compared to 19 typically developing children (TD). The active movements consisted of repetitive opening and closing of the hand. For passive movements, an MRI-compatible robot moved the finger up and down. Tactile stimulation was provided by manually stroking the dorsal surface of the hand with a sponge cotton cloth. In both groups, contralateral primary sensorimotor cortex activation (SM1) was seen for all tasks, as well as additional contralateral primary somatosensory cortex (S1) activation for passive movements. Ipsilateral cerebellar activity was observed in TD children during all tasks, but only during active movements in CP children. Of interest was additional ipsilateral SM1 recruitment in CP during active movements as well as ipsilateral S1 activation during passive movements and tactile stimulation. Another interesting new finding was the contralateral cerebellum activation in both groups during different tasks, also in cerebellar areas not primarily linked to the sensorimotor network. Active movements elicited significantly more brain activation in CP compared to TD children. In both groups, active movements displayed significantly more brain activation compared to passive movements and tactile stimulation.