Mechanosensory encoding in ex vivo muscle-nerve preparations.

Our objective was to evaluate an ex vivo muscle-nerve preparation used to study mechanosensory signalling by low threshold mechanosensory receptors (LTMRs). Specifically, we aimed to assess how well the ex vivo preparation represents in vivo firing behaviours of the three major LTMR subtypes of muscle primary sensory afferents, namely type Ia and II muscle spindle (MS) afferents and type Ib tendon organ afferents. Using published procedures for ex vivo study of LTMRs in mouse hindlimb muscles, we replicated earlier reports on afferent firing in response to conventional stretch paradigms applied to non-contracting, that is passive, muscle. Relative to in vivo studies, stretch-evoked firing for confirmed MS afferents in the ex vivo preparation was markedly reduced in firing rate and deficient in encoding dynamic features of muscle stretch. These deficiencies precluded conventional means of discriminating type Ia and II afferents. Muscle afferents, including confirmed Ib afferents were often indistinguishable based on their similar firing responses to the same physiologically relevant stretch paradigms. These observations raise uncertainty about conclusions drawn from earlier ex vivo studies that either attribute findings to specific afferent types or suggest an absence of treatment effects on dynamic firing. However, we found that replacing the recording solution with bicarbonate buffer resulted in afferent firing rates and profiles more like those seen in vivo. Improving representation of the distinctive sensory encoding properties in ex vivo muscle-nerve preparations will promote accuracy in assigning molecular markers and mechanisms to heterogeneous types of muscle mechanosensory neurons.

Attenuation of muscle spindle firing with artificially increased series compliance during stretch of relaxed muscle.

Muscle spindles relay vital mechanosensory information for movement and posture, but muscle spindle feedback is coupled to skeletal motion by a compliant tendon. Little is known about the effects of tendon compliance on muscle spindle feedback during movement, and the complex firing of muscle spindles makes these effects difficult to predict. Our goal was to investigate changes in muscle spindle firing using added series elastic elements (SEEs) to mimic a more compliant tendon, and to characterize the accompanying changes in firing with respect to muscle-tendon unit (MTU) and muscle fascicle displacements (recorded via sonomicrometry). Sinusoidal, ramp-and-hold and triangular stretches were analysed to examine potential changes in muscle spindle instantaneous firing rates (IFRs) in locomotor- and perturbation-like stretches as well as serial history dependence. Added SEEs effectively reduced overall MTU stiffness and generally reduced muscle spindle firing rates, but the effect differed across stretch types. During sinusoidal stretches, peak and mean firing rates were not reduced and IFR was best-correlated with fascicle velocity. During ramp stretches, SEEs reduced the initial burst, dynamic and static responses of the spindle. Notably, IFR was negatively related to fascicle displacement during the hold phase. During triangular stretches, SEEs reduced the mean IFR during the first and second stretches, affecting the serial history dependence of mean IFR. Overall, these results demonstrate that tendon compliance may attenuate muscle spindle feedback during movement, but these changes cannot be fully explained by reduced muscle fascicle length or velocity, or MTU force.

Biophysical model of muscle spindle encoding.

Muscle spindles encode mechanosensory information by mechanisms that remain only partially understood. Their complexity is expressed in mounting evidence of various molecular mechanisms that play essential roles in muscle mechanics, mechanotransduction and intrinsic modulation of muscle spindle firing behaviour. Biophysical modelling provides a tractable approach to achieve more comprehensive mechanistic understanding of such complex systems that would be difficult/impossible by more traditional, reductionist means. Our objective here was to construct the first integrative biophysical model of muscle spindle firing. We leveraged current knowledge of muscle spindle neuroanatomy and in vivo electrophysiology to develop and validate a biophysical model that reproduces key in vivo muscle spindle encoding characteristics. Crucially, to our knowledge, this is the first computational model of mammalian muscle spindle that integrates the asymmetric distribution of known voltage-gated ion channels (VGCs) with neuronal architecture to generate realistic firing profiles, both of which seem likely to be of great biophysical importance. Results predict that particular features of neuronal architecture regulate specific characteristics of Ia encoding. Computational simulations also predict that the asymmetric distribution and ratios of VGCs is a complementary and, in some instances, orthogonal means to regulate Ia encoding. These results generate testable hypotheses and highlight the integral role of peripheral neuronal structure and ion channel composition and distribution in somatosensory signalling.

Moonlight surgery: no influence of moon phase or Friday 13th on outcomes of total knee arthroplasty.

OBJECTIVES: The purpose of the present study was to investigate associations between revision-free survival and functional scores of total knee arthroplasty (TKA) and moon phase on the day of surgery, as well as operations performed on a Friday 13th. PARTICIPANTS: The data of all patients that received TKA between 2003 and 2019 were extracted from the Tyrol arthroplasty registry. Patients that had undergone previous total or partial knee arthroplasty as well as patients that had missing pre- or post-operative WOMAC were excluded. Patients were allocated to one of the following four groups according to moon phase on the day of surgery: new, waxing, full and waning. Patients operated on a Friday 13th were also identified and compared to patients operated on any other days/dates. A total of 5923 patients met the inclusion criteria, with mean age of 69 ± 9 years, and comprising 62% women. RESULTS: There were no significant differences in revision-free survival among the four moon phase groups (p = 0.479), and no significant differences in preoperative and postoperative total WOMAC (p = 0.260, p = 0.122), There were no significant differences in revision-free survival patients operated on Friday 13th vs. other days/dates (p = 0.440). The preoperative total WOMAC was significantly worse for patients operated on a Friday 13th (p = 0.013), which was observed in the pain (p = 0.032) and function (p = 0.010) subscales. There were no significant differences in postoperative total WOMAC at 1 year follow-up (p = 0.122). CONCLUSIONS: Neither moon phase on the day of surgery nor Friday 13th were associated with revision-free survival or clinical scores of TKA. Patients operated on a Friday 13th had significantly worse preoperative total WOMAC but similar postoperative total WOMAC at 1-year follow-up. These findings could help reassure patients that TKA renders consistent outcomes regardless of the preoperative pain or function, and in spite of bad omens or moon phases.

Structural Preservation Does Not Ensure Function at Sensory Ia-Motoneuron Synapses following Peripheral Nerve Injury and Repair.

Injury that severs peripheral nerves often results in long-lasting motor behavioral deficits and in reorganization of related spinal motor circuitry, neither of which reverse even after nerve regeneration. Stretch areflexia and gait ataxia, for example, emerge from a combination of factors including degeneration of Ia-motoneuron synapses between peripherally damaged Ia muscle spindle afferents and motoneurons. Based on evidence that nerve injury acts via immune responses to induce synapse degeneration, we hypothesized that suppressing inflammatory responses would preserve Ia-motoneuron connectivity and aid in restoring normal function. We tested our hypothesis by administering the anti-inflammatory agent minocycline in male and female rats following axotomy of a peripheral nerve. The connectivity of Ia-motoneuron synapses was then assessed both structurally and functionally at different time points. We found that minocycline treatment overcame the physical loss of Ia contacts on motoneurons which are otherwise lost after axotomy. While necessary for functional recovery, synaptic preservation was not sufficient to overcome functional decline expressed as smaller than normal stretch-evoked synaptic potentials evoked monosynaptically at Ia-motoneuron connections and an absence of the stretch reflex. These findings demonstrate a limited capacity of minocycline to rescue normal sensorimotor behavior, illustrating that structural preservation of synaptic connectivity does not ensure normal synaptic function.SIGNIFICANCE STATEMENT Here we demonstrate that acute treatment with the semisynthetic tetracycline anti-inflammatory agent minocycline permanently prevents the comprehensive loss of synaptic contacts made between sensory neurons and spinal motoneurons following peripheral nerve injury and eventual regeneration. Treatment failed, however, to rescue normal function of those synapses or the reflex circuit they mediate. These findings demonstrate that preventing synaptic disconnection alone is not sufficient to restore neural circuit operation and associated sensorimotor behaviors.

Attenuation of muscle spindle firing with artificially increased series compliance during stretch of relaxed muscle.

Muscle spindles relay vital mechanosensory information for movement and posture, but muscle spindle feedback is coupled to skeletal motion by a compliant tendon. Little is known about the effects of tendon compliance on muscle spindle feedback during movement, and the complex firing of muscle spindles make these effects difficult to predict. Our goal was to investigate changes in muscle spindle firing using added series elastic elements (SEEs) to mimic a more compliant tendon, and to characterize the accompanying changes in firing with respect to muscle-tendon unit (MTU) and muscle fascicle displacements (recorded via sonomicrometry). Sinusoidal, ramp-hold-release, and triangular stretches were analyzed to examine potential changes in muscle spindle instantaneous firing rates (IFRs) in locomotor- and perturbation-like stretches as well as history dependence. Added SEEs effectively reduced overall MTU stiffness and generally reduced muscle spindle firing rates, but the effect differed across stretch types. During sinusoidal stretches, peak firing rates were reduced and IFR was strongly correlated with fascicle velocity. During ramp stretches, SEEs reduced the dynamic and static responses of the spindle during lengthening but had no effect on initial bursts at the onset of stretch. Notably, IFR was negatively related to fascicle displacement during the hold phase. During triangular stretches, SEEs reduced the mean IFR during the first and second stretches, affecting the history dependence of mean IFR. Overall, these results demonstrate that tendon compliance may attenuate muscle spindle feedback during movement, but these changes cannot be fully explained by reduced muscle fascicle length and velocity.

Incidence of alpine skiing and snowboarding injuries.

BACKGROUND: The incidence of injuries on alpine ski slopes have been assessed using various methods. A decline in injury rate has been observed throughout the literature; however, the actual incidence remains unclear. The purpose of this study was therefore to evaluate the incidence of skiing and snowboarding injuries using large-sample data from an entire geographic state. METHODS: Data on alpine injuries over the course of five winter seasons between 2017 and 2022 were prospectively collected from the emergency service dispatch center of Tyrol (Austria). The incidence of injuries was assessed in relation to the number of skier days, which was obtained from the chamber of commerce. RESULTS: A total of 43,283 cases were identified, and a total of 98.1 Mio skier days were registered during the inclusion period of our study, resulting in an overall incidence of 0.44 injuries per 1,000 skier days. This is significantly less than reported from previous studies. From 2017/18 to 2021/22 there was a slight increase in injuries per 1000 skier days with an exception only for the COVID-19 related season 2020/21. CONCLUSION: Our study showed a significant reduction in the incidence of alpine skiing and snowboarding injuries in comparison with previous studies and should be considered a benchmark for future studies. Long-term studies on the efficacy of safety gear, as well as the influence of ski patrol and air-borne rescues on patient outcome are warranted.

Total knee arthroplasty without patella resurfacing leads to worse results in patients with patellafemoral osteoarthritis Iwano Stages 3-4: a study based on arthroplasty registry data.

PURPOSE: To determine whether the preoperative degree of degeneration of the patellofemoral joint really affects the outcome of total knee arthroplasty (TKA) surgery without patella resurfacing and thus to establish a parameter that might serve as a guiding factor to decide whether or not to perform retropatellar resurfacing. It was hypothesized that patients with preoperative mild patellofemoral osteoarthritis (Iwano Stages 0-2) would significantly differ from patients with preoperative severe patellofemoral osteoarthritis (Iwano Stages 3-4) in terms of patient-reported outcome (Hypothesis 1) and revision rates/survival (Hypothesis 2) after TKA without patella resurfacing. METHODS: Application of a retrospective-comparative design on the basis of Arthroplasty Registry data that included patients with primary TKA without patella resurfacing. Patients were allocated to the following groups based on preoperative radiographic stage of patellofemoral joint degeneration: (a) mild patellofemoral osteoarthritis (Iwano Stage ≤ 2) and (b) severe patellofemoral osteoarthritis (Iwano Stages 3-4). The Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC) score was assessed preoperative and 1 year postoperative (0: best, 100 worst). In addition, implant survival was calculated from the Arthroplasty Registry data. RESULTS: In 1209 primary TKA without patella resurfacing, postoperative WOMAC total and WOMAC subscores did not differ significantly between groups, but potentially suffered from type 2 error. Three-year survival was 97.4% and 92.5% in patients with preoperative mild and severe patellofemoral osteoarthritis, respectively (p = 0.002). Five-year survival was 95.8% vs. 91.4% (p = 0.033) and 10-year survival was 93.3% vs. 88.6% (p = 0.033), respectively. CONCLUSIONS: From the study findings, it is concluded that patients with preoperative severe patellofemoral osteoarthritis have significantly higher risks for reoperation than do those with preoperative mild patellofemoral osteoarthritis-when treated with TKA without patella resurfacing. Hence, it is recommended that patella resurfacing be applied in patients with severe Iwano Stage 3 or 4 patellofemoral osteoarthritis during TKA. LEVEL OF EVIDENCE: III, Retrospective comparative.

Mechanosensory encoding dysfunction emerges from cancer-chemotherapy interaction.

Persistent sensory, motor and cognitive disabilities comprise chemotherapy-induced neural disorders (CIND) that limit quality of life with little therapeutic relief for cancer survivors. Our recent preclinical study provides new insight into a condition impacting the severity of chronic CIND. We find that sensorimotor disability observed following cancer treatment exceeds that attributable to chemotherapy alone. A possible explanation for intensified disability emerged from evidence that codependent effects of cancer and chemotherapy amplify defective firing in primary sensory neurons supplying one type of low threshold mechanosensory receptor (LTMR). Here we test whether cancer's modification of chemotherapy-induced sensory defects generalizes across eight LTMR submodalities that collectively generate the signals of origin for proprioceptive and tactile perception and guidance of body movement. Preclinical study enabled controlled comparison of the independent contributions of chemotherapy and cancer to their clinically relevant combined effects. We compared data sampled from rats that were otherwise healthy or bearing colon cancer and treated, or not, with human-scaled, standard-of-care chemotherapy with oxaliplatin. Action potential firing patterns encoding naturalistic mechanical perturbations of skeletal muscle and skin were measured electrophysiologically in vivo from multiple types of LTMR neurons. All expressed aberrant encoding of dynamic and/or static features of mechanical stimuli in healthy rats treated with chemotherapy, and surprisingly also by some LTMRs in cancer-bearing rats that were not treated. By comparison, chemotherapy and cancer in combination worsened encoding aberrations, especially in slowly adapting LTMRs supplying both muscle and glabrous skin. Probabilistic modeling best predicted observed encoding defects when incorporating interaction effects of cancer and chemotherapy. We conclude that for multiple mechanosensory submodalities, the severity of encoding defects is modulated by a codependence of chemotherapy side effects and cancer's systemic processes. We propose that the severity of CIND might be reduced by therapeutically targeting the mechanisms, yet to be determined, by which cancer magnifies chemotherapy's neural side effects as an alternative to reducing chemotherapy and its life-saving benefits.

Emergency Service Assistance for Injuries on Alpine Ski Slopes: A Cross-Sectional Study.

OBJECTIVES: Injuries on alpine ski slopes have been described in cohorts of a reasonable sample size, but constant improvements in safety gear, increased use of airborne rescue, and safety measures during the coronavirus disease 2019 (COVID-19) pandemic mandate re-evaluation. Therefore, the purpose of this study was to evaluate skiing and snowboarding injuries, effectiveness of airborne rescue, and impact of the COVID-19 pandemic on a large sample size. METHODS: Data on alpine injuries were prospectively collected from the state emergency services dispatch center in the state of Tyrol (Austria). A total of 10,143 patients were identified, with an average age of 33.5 years (SD = 20.36). The ski patrol was involved in 8,606 cases (84.9%) and some patients (n = 1,536; 15.1%) required helicopter rescue. RESULTS: A total of 10,143 patients were identified from the dataset of the emergency dispatch center. The most frequently injured region was the knee (30.2%), and it was followed by the shoulder (12.9%), the lower leg (9.5%), and the head/skull (9.5%). CONCLUSION: The present findings indicate that the most frequent site of injuries on alpine slopes is the knee, and life-threatening injuries are rare. Airborne rescue is very time-effective, however clinical studies with patient follow-up should be emphasized to determine the impact of airborne rescue on patient outcome. The present findings indicate that the duration of all rescue operations has been prolonged as a result of the introduction of safety measures during the COVID-19 pandemic.

Sex differences in appropriate insertion depth for intraosseous access in adults: An exploratory radiologic single-center study.

BACKGROUND: Intraosseous access is a recommended alternative to venous access in emergencies. For its application, knowledge of the correct insertion depth is indispensable. We aimed to determine sex-specific differences on the appropriate insertion depth for intraosseous access in adults at the insertion sites most frequently used, namely the proximal and distal tibia and the proximal humerus. METHODS: In this exploratory retrospective study, we measured thickness of soft tissue cover, cortex and cancellous bone along the puncture line on magnetic resonance images or computed tomography scans. Inclusion criteria were both sexes, 18-90 years of age and appropriate image quality. Primary outcome was the appropriate insertion depth to reach the cancellous bone for each sex. This was defined as the corridor between (i) the sum of the soft tissue cover and the cortex and (ii) the sum of (i) plus the diameter of the cancellous bone. Secondary outcomes were the differences in thickness of each layer between sexes. RESULTS: In 179 females and males, the appropriate insertion depth was 32.5-45.5 mm and 20.5-42.0 mm in the proximal tibia, 14.5-30.5 mm and 16.5-34.5 mm in the distal tibia, and 27.5-52.5 mm and 26.0-56.5 mm in the proximal humerus. Although females had a thicker soft tissue cover (+6.8 mm [95% CI 3.7-10.1], p < 0.01) in the proximal tibia, extrapolation by correlation analysis showed no clinically relevant difference between the sexes. CONCLUSION: In adults, there are no sex-specific differences in the appropriate insertion depth for intraosseous access in the proximal or distal tibia or in the proximal humerus.

External validation of the Tyrolean hip arthroplasty registry.

PURPOSE: Arthroplasty registries gained increasing importance to the re-certification of orthopaedic implants according to the European Union (EU) Medical Device Regulation (MDR) adopted in 2017. Until recently, several European countries only had regional arthroplasty registries. Whether regional registries deliver data quality comparable with national registries remained unclear. Therefore, the purpose of this study was to validate the Austrian Tyrolean Hip Arthroplasty Registry (THAR) and to evaluate if this regional registry showed adequate adherence, completeness and correctness when compared with well-established national registries. METHODS: A consecutive series of 1100 primary total hip arthroplasties were identified from our institution's medical database. Patients were interviewed by phone and completed questionnaires after a mean follow-up period of 8.05 years and were asked if they had had revision surgeries. The data were compared to the corresponding dataset from the THAR. RESULTS: Adherence was 97.91% for primary total hip arthroplasty. Clinical follow-up identified 10 missing cases, resulting in adherence of 81.48% for revisions. Completeness of patient-reported outcome measurements was 78.55% before surgery and 84.45% 1 year after surgery. Correctness was 99.7% for demographic data, 99.54% for implant specifications, and 99.35% for mode of fixation. CONCLUSION: The data of this study showed that regional arthroplasty registries can deliver data quality comparable with well-established national registries. The main reason for unrecorded revision cases and wrongly recoded implants was human error. Further digitalization with more automatic data submission may have the potential to reduce these failure rates in the future. Overall, the THAR represents a valid data source for re-certification of medical implants according to the EU's MDR.

Bonit Coating Leads to Macroscopic Bone Ingrowth at 8 Weeks After Primary Total Hip Arthroplasty.

Primary total hip arthroplasty with cementless stems has numerous advantages over cemented total hip arthroplasty in patients with good bone quality. To enhance osseointegration with ingrowth into the implant, various surface treatments have been proposed. Multiple biomechanical studies in animals have shown that bioactive coatings enhance osseointegration and increase construct stability. Bony ingrowth in humans can only be assessed in rare instances of periprosthetic femoral fractures. In this case report, we describe the findings after a periprosthetic fracture mandating stem exchange in a patient who experienced a fall 8 weeks after implantation. The retrieved proximal Bonit (DOT GmbH, Rostock, Germany) coated stem showed substantial macroscopically visible trabecular bone. This finding supports results from animal studies that showed enhanced metaphyseal bone ingrowth with Bonit coating of implants.

Detection of epimuscular myofascial forces by Golgi tendon organs.

Skeletal muscles embed multiple tendon organs, both at the proximal and distal ends of muscle fibers. One of the functions of such spatial distribution may be to provide locally unique force feedback, which may become more important when stresses are distributed non-uniformly within the muscle. Forces exerted by connections between adjacent muscles (i.e. epimuscular myofascial forces) may cause such local differences in force. The aim of this exploratory study was to investigate the effects of mechanical interactions between adjacent muscles on sensory encoding by tendon organs. Action potentials from single afferents were recorded intra-axonally in response to ramp-hold release (RHR) stretches of a passive agonistic muscle at different lengths or relative positions of its passive synergist. The tendons of gastrocnemius (GAS), plantaris (PL) and soleus (SO) muscles were cut from the skeleton for attachment to servomotors. Connective tissues among these muscles were kept intact. Lengthening GAS + PL decreased the force threshold of SO tendon organs (p = 0.035). The force threshold of lateral gastrocnemius (LG) tendon organs was not affected by SO length (p = 0.371). Also displacing LG + PL, kept at a constant muscle-tendon unit length, from a proximal to a more distal position resulted in a decrease in force threshold of LG tendon organs (p = 0.007). These results indicate that tendon organ firing is affected by changes in length and/or relative position of adjacent synergistic muscles. We conclude that tendon organs can provide the central nervous system with information about local stresses caused by epimuscular myofascial forces.

Imbalanced Subthreshold Currents Following Sepsis and Chemotherapy: A Shared Mechanism Offering a New Therapeutic Target?

Both sepsis and treatment of cancer with chemotherapy are known to cause neurologic dysfunction. The primary defects seen in both groups of patients are neuropathy and encephalopathy; the underlying mechanisms are poorly understood. Analysis of preclinical models of these disparate conditions reveal similar defects in ion channel function contributing to peripheral neuropathy. The defects in ion channel function extend to the central nervous system where lower motoneurons are affected. In motoneurons the defect involves ion channels responsible for subthreshold currents that convert steady depolarization into repetitive firing. The inability to correctly translate depolarization into steady, repetitive firing has profound effects on motor function, and could be an important contributor to weakness and fatigue experienced by both groups of patients. The possibility that disruption of function, either instead of, or in addition to neurodegeneration, may underlie weakness and fatigue leads to a novel approach to therapy. Activation of serotonin (5HT) receptors in a rat model of sepsis restores the normal balance of subthreshold currents and normal motoneuron firing. If an imbalance of subthreshold currents also occurs in other central nervous system neurons, it could contribute to encephalopathy. We hypothesize that pharmacologically restoring the proper balance of subthreshold currents might provide effective therapy for both neuropathy and encephalopathy in patients recovering from sepsis or treatment with chemotherapy.

Mid-Term Results After 517 Primary Total Hip Arthroplasties With a Shortened and Shoulderless Double-Taper Press-Fit Stem: High Rates of Aseptic Loosening.

BACKGROUND: Shorter double-taper stems with reduced lateral shoulders facilitate implantation via the muscle-sparing direct anterior approach and are becoming increasingly popular. We observed an unusually high number of cases of aseptic loosening with the use of a modified stem. Therefore, the aim of this prospective single-center study was to assess safety and efficacy of this cementless stem. METHODS: A total of 486 consecutive patients receiving 517 primary total hip arthroplasties using the MonoconMIS stem were prospectively followed up for a mean period of 5.29 years (standard deviation [SD], 1.47). Surgical and clinical data, complications, and revision surgeries were analyzed. The Western Ontario and McMaster Universities Arthritis Index (WOMAC) score was recorded before surgery and at one year and five years after surgery. RESULTS: The overall 5-year implant survival rate was 95.2%. The individual component survival rates were 96.1% for the stem, 99.4% for the acetabular cup, and 99.0% for the isolated mobile component exchange. The most common reasons for revision were periprosthetic fracture (1.5%), aseptic stem loosening (1.4%), and infection (1.0%). The WOMAC score improved significantly from 49.57 (SD, 21.42) at baseline to 13.33 (SD, 16.47) at one year and 9.84 (SD, 14.45) at five years after surgery. Aseptic stem loosening occurred only in patients with Dorr type A proximal femur morphology. CONCLUSION: The evaluated femoral stem is associated with revision rates higher than what has been reported for other implants. The WOMAC scores suggest adequate efficacy. Our data do not support the use of the MonoconMIS for primary total hip arthroplasty in patients with Dorr type A proximal femur morphology.

Neural circuit mechanisms of sensorimotor disability in cancer treatment.

Cancer survivors rank sensorimotor disability among the most distressing, long-term consequences of chemotherapy. Disorders in gait, balance, and skilled movements are commonly assigned to chemotoxic damage of peripheral sensory neurons without consideration of the deterministic role played by the neural circuits that translate sensory information into movement. This oversight precludes sufficient, mechanistic understanding and contributes to the absence of effective treatment for reversing chemotherapy-induced disability. We rectified this omission through the use of a combination of electrophysiology, behavior, and modeling to study the operation of a spinal sensorimotor circuit in vivo in a rat model of chronic, oxaliplatin (chemotherapy)-induced neuropathy (cOIN). Key sequential events were studied in the encoding of propriosensory information and its circuit translation into the synaptic potentials produced in motoneurons. In cOIN rats, multiple classes of propriosensory neurons expressed defective firing that reduced accurate sensory representation of muscle mechanical responses to stretch. Accuracy degraded further in the translation of propriosensory signals into synaptic potentials as a result of defective mechanisms residing inside the spinal cord. These sequential, peripheral, and central defects compounded to drive the sensorimotor circuit into a functional collapse that was consequential in predicting the significant errors in propriosensory-guided movement behaviors demonstrated here in our rat model and reported for people with cOIN. We conclude that sensorimotor disability induced by cancer treatment emerges from the joint expression of independent defects occurring in both peripheral and central elements of sensorimotor circuits.

Axon initial segment geometry in relation to motoneuron excitability.

The axon initial segment (AIS) responsible for action potential initiation is a dynamic structure that varies and changes together with neuronal excitability. Like other neuron types, alpha motoneurons in the mammalian spinal cord express heterogeneity and plasticity in AIS geometry, including length (AISl) and distance from soma (AISd). The present study aimed to establish the relationship of AIS geometry with a measure of intrinsic excitability, rheobase current, that varies by 20-fold or more among normal motoneurons. We began by determining whether AIS length or distance differed for motoneurons in motor pools that exhibit different activity profiles. Motoneurons sampled from the medial gastrocnemius (MG) motor pool exhibited values for average AISd that were significantly greater than that for motoneurons from the soleus (SOL) motor pool, which is more readily recruited in low-level activities. Next, we tested whether AISd covaried with intrinsic excitability of individual motoneurons. In anesthetized rats, we measured rheobase current intracellularly from MG motoneurons in vivo before labeling them for immunohistochemical study of AIS structure. For 16 motoneurons sampled from the MG motor pool, this combinatory approach revealed that AISd, but not AISl, was significantly related to rheobase, as AIS tended to be located further from the soma on motoneurons that were less excitable. Although a causal relation with excitability seems unlikely, AISd falls among a constellation of properties related to the recruitability of motor units and their parent motoneurons.

Effects of route of administration on neural exposure to platinum-based chemotherapy treatment: a pharmacokinetic study in rat.

The persisting need for effective clinical treatment of chemotherapy-induced neurotoxicity (CIN) motivates critical evaluation of preclinical models of CIN for their translational relevance. The present study aimed to provide the first quantitative evaluation of neural tissue exposed in vivo to a platinum-based anticancer compound, oxaliplatin (OX) during and after two commonly used dosing regimens: slow IV infusion used clinically and bolus IP injection used preclinically. Inductively-coupled plasma mass spectrometry analysis of dorsal root ganglia indicated that while differences in the temporal dynamics of platinum distribution exist, key drivers of neurotoxicity, e.g. peak concentrations and exposure, were not different across the two routes of administration. We conclude that the IP route of OX administration achieves clinically relevant pharmacokinetic exposure of neural tissues in a rodent model of CIN.

Does the type of surgical approach affect the clinical outcome of total knee arthroplasty?

BACKGROUND: The aim of the study was to investigate the issue of medial midvastus (MMV) vs. medial parapatellar (MPP) approaches in total knee arthroplasty (TKA). It was hypothesized that the two surgical approaches would produce significantly different results with respect to patient-reported knee score outcome (hypothesis 1), short-term postoperative range of motion (ROM) (hypothesis 2), long-term postoperative ROM (hypothesis 3) and prosthesis survival (hypothesis 4). METHODS: A retrospective comparative study design was applied. Data sets were obtained from the state arthroplasty registry. The Western Ontario and McMaster Universities osteoarthritis index (WOMAC) data were analyzed from preoperative and 1 year postoperatively. The ROM data were analyzed for the time points preoperative, postoperative days 4 and 10 and 1 year. RESULTS: Available were 627 cases (407 MMV vs. 220 MPP) and 1 year postoperatively there were no significant differences between groups regarding the WOMAC scores (hypothesis 1). Early postoperatively on days 4 and 10 after TKA there were no differences between groups (p = 0.305 and p = 0.383, respectively, hypothesis 2). Likewise, ROM did not significantly differ between the groups 1 year after TKA (p = 0.338, hypothesis 3). The 5­year prosthesis survival did not differ between the groups and showed 94.46% (95% confidence interval, CI 90.69-96.73%) in the MMV group and 94.33% (95% CI 89.96-96.83%) in the MPP group (p = 0.664, hypothesis 4). CONCLUSION: Both surgical approaches produce equivalent clinical results in terms of early postoperative ROM, late postoperative ROM and 1­year WOMAC. The same prosthesis survival rates can be expected.