Background The kinetic chain of the throwing motion functions to optimize efficiency of proximal segments to decrease force loads seen
at smaller, distal segments such as the ulnar collateral ...ligament. Several studies have shown that shoulder internal rotation
forms the physiologic counter to the valgus torque generated during the late cocking phase of throwing. Previous studies have
implicated decreased glenohumeral internal rotation as a cause of shoulder internal impingement. To date, an association between
pathologic glenohumeral internal rotation deficit and elbow injury has not been exhibited.
Hypothesis Throwers with ulnar collateral ligament insufficiency will exhibit significantly increased glenohumeral internal rotation
deficit.
Study Design Case control study; Level of evidence, 3.
Methods Twenty-nine baseball players with ulnar collateral ligament insufficiency were demographically matched with 29 control baseball
players who had no history of shoulder, elbow, or cervical spine injury. The investigators measured passive glenohumeral internal
and external rotation, elbow flexion and extension, and forearm pronation and supination. The Mann-Whitney test was used to
analyze continuous variables.
Results There were no significant differences between the groups in terms of demographics. There was a significant difference in
dominant arm internal rotation, with injured players having significantly less ( P < .004), and in glenohumeral internal rotation deficit between players with ulnar collateral ligament insufficiency and those
who were asymptomatic (28.5° vs 12.7°; P < .001). Also, total range of motion was significantly decreased in the injured group. There were no significant differences
in elbow or forearm range of motion between the groups.
Conclusion Our results indicate that pathologic glenohumeral internal rotation deficit may be associated with elbow valgus instability.
This has important clinical implications both in terms of preventing ulnar collateral ligament injury and with regard to rehabilitating
throwers after ulnar collateral ligament reconstruction.
Most deaths from breast cancer result from tumor recurrence, but mechanisms underlying tumor relapse are largely unknown. We now report that Par-4 is downregulated during tumor recurrence and that ...Par-4 downregulation is necessary and sufficient to promote recurrence. Tumor cells with low Par-4 expression survive therapy by evading a program of Par-4-dependent multinucleation and apoptosis that is otherwise engaged following treatment. Low Par-4 expression is associated with poor response to neoadjuvant chemotherapy and an increased risk of relapse in patients with breast cancer, and Par-4 is downregulated in residual tumor cells that survive neoadjuvant chemotherapy. Our findings identify Par-4-induced multinucleation as a mechanism of cell death in oncogene-addicted cells and establish Par-4 as a negative regulator of breast cancer recurrence.
•Par-4 is downregulated during tumor recurrence in mice•Par-4 downregulation is necessary and sufficient for mammary tumor recurrence•Par-4 downregulation promotes survival of residual tumor cells following therapy•Par-4-induced multinucleation is a mechanism of death in oncogene-addicted cells
Purpose
To determine whether femoral nerve blockade (FNB) at the time of primary ACL reconstruction is associated with meeting isokinetic extension strength return to sport criteria near completion ...of physical therapy and whether FNB affects 1-year or 2-year risk of ipsilateral ACL graft rupture or contralateral native ACL injury.
Methods
Three-hundred and sixty patients (
n
= 244 with FNB,
n
= 116 no FNB) underwent primary ACL reconstruction. All patients completed rehabilitation and underwent functional strength testing towards the end of knee rehabilitation (mean 5.6 months post-surgery). Association between FNB and isokinetic extension strength limb symmetry index (LSI) (goal LSI ≥ 90% for return to sport) as well as risk of recurrent ACL injury within first or second year after surgery was evaluated.
Results
Ipsilateral or contralateral ACL injury within 2 years occurred in 11.2% of patients with FNB and 5.7% without FNB (
p
= 0.01). Patients with FNB had higher incidence of ipsilateral graft rupture within the first year after surgery but no difference in graft rupture during the second. Two-year risk of contralateral ACL injury was similar in both groups. At the time of initial testing, patients who received FNB had lower fast isokinetic extension LSI versus patients without FNB and were less likely achieve a goal ≥ 90% LSI; slow extension LSI was unaffected.
Conclusion
Use of FNB at the time of primary ACL reconstruction can negatively affect achievement of isokinetic extension strength return to sport criteria. FNB increases risk of graft rupture within the first year after surgery but does not affect re-injury risk during the second. FNB may not be appropriate for use in patients already at high risk of ACL re-injury.
Level of evidence
III.
Loss-of-function mutations of Na(V)1.7 lead to congenital insensitivity to pain, a rare condition resulting in individuals who are otherwise normal except for the inability to sense pain, making ...pharmacological inhibition of Na(V)1.7 a promising therapeutic strategy for the treatment of pain. We characterized a novel mouse model of Na(V)1.7-mediated pain based on intraplantar injection of the scorpion toxin OD1, which is suitable for rapid in vivo profiling of Na(V)1.7 inhibitors. Intraplantar injection of OD1 caused spontaneous pain behaviors, which were reversed by co-injection with Na(V)1.7 inhibitors and significantly reduced in Na(V)1.7(-/-) mice. To validate the use of the model for profiling Na(V)1.7 inhibitors, we determined the Na(V) selectivity and tested the efficacy of the reported Na(V)1.7 inhibitors GpTx-1, PF-04856264 and CNV1014802 (raxatrigine). GpTx-1 selectively inhibited Na(V)1.7 and was effective when co-administered with OD1, but lacked efficacy when delivered systemically. PF-04856264 state-dependently and selectively inhibited Na(V)1.7 and significantly reduced OD1-induced spontaneous pain when delivered locally and systemically. CNV1014802 state-dependently, but non-selectively, inhibited Na(V) channels and was only effective in the OD1 model when delivered systemically. Our novel model of Na(V)1.7-mediated pain based on intraplantar injection of OD1 is thus suitable for the rapid in vivo characterization of the analgesic efficacy of Na(V)1.7 inhibitors.
Reinventing Neuroaging Research in the Digital Age Huentelman, Matt J.; Talboom, Joshua S.; Lewis, Candace R. ...
Trends in neurosciences (Regular ed.),
January 2020, 2020-Jan, 2020-01-00, Letnik:
43, Številka:
1
Journal Article
Recenzirano
The worldwide average human lifespan has increased over the past century. These changing demographics demand a reinvention of experimental approaches to study the brain and aging, with the aim of ...better matching cognitive healthspan with human lifespan. Past studies of cognitive aging included sample sizes that tended to be underpowered, were not sufficiently representative of national population characteristics, and often lacked longitudinal assessments. As a step to address these shortcomings, we propose a framework that encourages interaction between electronic-based and face-to-face study designs. We argue that this will achieve the necessary synergy to accelerate progress in the discovery and application of personalized interventions to optimize brain and cognitive health.
A better understanding of differential cognitive aging trajectories is essential to advise policy and the public about dementia risk reduction that enables cognitive healthspan to better match human lifespan.A major impediment to most studies of brain and cognitive aging is the ability to achieve sample sizes that are large, representative of the heterogeneous national population, and longitudinal.Internet and smartphone usage continues to rise dramatically in many countries, and this fact holds across a range of socioeconomic and demographic characteristics.Recent work demonstrates that internet or smartphone app-based approaches can be used to recruit large research cohorts to assess cognitive performance.We propose research approaches that merge electronic-based cohorts and face-to-face research to power the longitudinal study of cognitive aging in the evolving digital age.
Purpose
To determine whether articular cartilage damage noted at the time of primary anterior cruciate ligament reconstruction (ACLR) affects the likelihood of achieving ≥ 90% symmetry for isokinetic ...extension strength at 6 months after surgery or risk of recurrent ACL injury.
Methods
Five hundred and eight patients underwent primary ACLR and diagnostic arthroscopy. All identified cartilage lesions were graded using the Outerbridge system. All patients underwent isokinetic strength testing. The association between cartilage Outerbridge grade and a ≥ 90% Limb Symmetry Index (LSI) and recurrent ACL injury risk at mean 38.7 month follow-up (SD 31.8) was evaluated via multivariate regression analysis.
Results
Grade 2 or higher damage was present in 394 (77.5%) of patients, grade 3 or higher in 143 (28.1%) and grade 4 in 83 (16.4%) at time of ACLR. Ipsilateral ACLR graft rupture occurred in 31 (6.1%) of patients. Contralateral ACL injury occurred in 19 (3.7%). Patients with grade 2 or higher damage were significantly less likely to meet an LSI goal of ≥ 90% for fast (300°/s) isokinetic extension. There was no association with slow isokinetic extension. Cartilage lesion severity at or beyond grade 2 had a similar effect on isokinetic testing results regardless of compartment involvement or performance of microfracture. Patients with grade 2–4 cartilage damage were less likely to sustain a second ipsilateral ACL injury or a contralateral native ACL injury.
Conclusions
Cartilage damage seen at time of ACL reconstruction is common and associated with lower likelihood of achieving ≥ 90% symmetry for isokinetic extension strength at 6 months after surgery. However, lower recurrent ACL injury rates are seen in patients with concurrent cartilage damage. These data may inform future clinical decisions regarding operative managment of recurrent ACL injuries.
Level of evidence
III.
Human genetic studies have implicated the voltage-gated sodium channel Na
1.7 as a therapeutic target for the treatment of pain. A novel peptide, μ-theraphotoxin-Pn3a, isolated from venom of the ...tarantula Pamphobeteus nigricolor, potently inhibits Na
1.7 (IC
0.9 nM) with at least 40-1000-fold selectivity over all other Na
subtypes. Despite on-target activity in small-diameter dorsal root ganglia, spinal slices, and in a mouse model of pain induced by Na
1.7 activation, Pn3a alone displayed no analgesic activity in formalin-, carrageenan- or FCA-induced pain in rodents when administered systemically. A broad lack of analgesic activity was also found for the selective Na
1.7 inhibitors PF-04856264 and phlotoxin 1. However, when administered with subtherapeutic doses of opioids or the enkephalinase inhibitor thiorphan, these subtype-selective Na
1.7 inhibitors produced profound analgesia. Our results suggest that in these inflammatory models, acute administration of peripherally restricted Na
1.7 inhibitors can only produce analgesia when administered in combination with an opioid.
People with sickle cell disease (SCD) are at risk of cognitive dysfunction independent of stroke. Diminished functional connectivity in select large-scale networks and white matter integrity reflect ...the neurologic consequences of SCD. Because chronic transfusion therapy is neuroprotective in preventing stroke and strengthening executive function abilities in people with SCD, we hypothesized that red blood cell (RBC) transfusion facilitates the acute reversal of disruptions in functional connectivity while white matter integrity remains unaffected.
Children with SCD receiving chronic transfusion therapy underwent a brain MRI measuring white matter integrity with diffusion tensor imaging and resting-state functional connectivity within 3 days before and after transfusion of RBCs. Cognitive assessments with the NIH Toolbox were acquired after transfusion and then immediately before the following transfusion cycle.
Sixteen children with a median age of 12.5 years were included. Global assessments of functional connectivity using homotopy (
= 0.234) or modularity (
= 0.796) did not differ with transfusion. Functional connectivity within the frontoparietal network significantly strengthened after transfusion (median intranetwork
-score 0.21 0.17-0.30 before transfusion, 0.29 0.20-0.36 after transfusion,
< 0.001), while there was not a significant change seen within the sensory motor, visual, auditory, default mode, dorsal attention, or cingulo-opercular networks. Corresponding to the change within the frontoparietal network, there was a significant improvement in executive function abilities after transfusion (median executive function composite score 87.7 81.3-90.7 before transfusion, 90.3 84.3-93.7 after transfusion,
= 0.021). Participants with stronger connectivity in the frontoparietal network before transfusion had a significantly greater improvement in the executive function composite score with transfusion (
= 0.565, 95% CI 0.020-0.851,
= 0.044). While functional connectivity and executive abilities strengthened with transfusion, there was not a significant change in white matter integrity as assessed by fractional anisotropy and mean diffusivity within 16 white matter tracts or globally with tract-based spatial statistics.
Strengthening of functional connectivity with concomitant improvement in executive function abilities with transfusion suggests that functional connectivity MRI could be used as a biomarker for acutely reversible neurocognitive injury as novel therapeutics are developed for people with SCD.
Abstract
Human genetic studies have implicated the voltage-gated sodium channel Na
V
1.7 as a therapeutic target for the treatment of pain. A novel peptide, μ-theraphotoxin-Pn3a, isolated from venom ...of the tarantula
Pamphobeteus nigricolor,
potently inhibits Na
V
1.7 (IC
50
0.9 nM) with at least 40–1000-fold selectivity over all other Na
V
subtypes. Despite on-target activity in small-diameter dorsal root ganglia, spinal slices, and in a mouse model of pain induced by Na
V
1.7 activation, Pn3a alone displayed no analgesic activity in formalin-, carrageenan- or FCA-induced pain in rodents when administered systemically. A broad lack of analgesic activity was also found for the selective Na
V
1.7 inhibitors PF-04856264 and phlotoxin 1. However, when administered with subtherapeutic doses of opioids or the enkephalinase inhibitor thiorphan, these subtype-selective Na
V
1.7 inhibitors produced profound analgesia. Our results suggest that in these inflammatory models, acute administration of peripherally restricted Na
V
1.7 inhibitors can only produce analgesia when administered in combination with an opioid.
Spider venoms are rich sources of peptidic ion channel modulators with important therapeutical potential. We screened a panel of 60 spider venoms to find modulators of ion channels involved in pain ...transmission. We isolated, synthesized and pharmacologically characterized Cd1a, a novel peptide from the venom of the spider Ceratogyrus darlingi. Cd1a reversibly paralysed sheep blowflies (PD50 of 1318 pmol/g) and inhibited human Cav2.2 (IC50 2.6 μM) but not Cav1.3 or Cav3.1 (IC50 > 30 μM) in fluorimetric assays. In patch-clamp electrophysiological assays Cd1a inhibited rat Cav2.2 with similar potency (IC50 3 μM) without influencing the voltage dependence of Cav2.2 activation gating, suggesting that Cd1a doesn't act on Cav2.2 as a classical gating modifier toxin. The Cd1a binding site on Cav2.2 did not overlap with that of the pore blocker ω-conotoxin GVIA, but its activity at Cav2.2-mutant indicated that Cd1a shares some molecular determinants with GVIA and MVIIA, localized near the pore region. Cd1a also inhibited human Nav1.1-1.2 and Nav1.7-1.8 (IC50 0.1-6.9 μM) but not Nav1.3-1.6 (IC50 > 30 μM) in fluorimetric assays. In patch-clamp assays, Cd1a strongly inhibited human Nav1.7 (IC50 16 nM) and produced a 29 mV depolarising shift in Nav1.7 voltage dependence of activation. Cd1a (400 pmol) fully reversed Nav1.7-evoked pain behaviours in mice without producing side effects. In conclusion, Cd1a inhibited two anti-nociceptive targets, appearing to interfere with Cav2.2 inactivation gating, associated with the Cav2.2 α-subunit pore, while altering the activation gating of Nav1.7. Cd1a was inactive at some of the Nav and Cav channels expressed in skeletal and cardiac muscles and nodes of Ranvier, apparently contributing to the lack of side effects at efficacious doses, and suggesting potential as a lead for development of peripheral pain treatments.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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