A randomized, double-blind, placebo-controlled phase 2 study to assess safety, tolerability, and efficacy of RT001 in patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: RT001 is a deuterated synthetic homologue of linoleic acid, which makes membrane polyunsaturated fatty acids resistant to lipid peroxidation, a process involved in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). METHODS: We conducted a randomized, multicenter, placebo-controlled clinical trial. Patients with ALS were randomly allocated to receive either RT001 or placebo for 24 weeks. After the double-blind period, all patients received RT001 during an open-label phase for 24 weeks. The primary outcome measures were safety and tolerability. Key efficacy outcomes included the ALS Functional Rating Scale (ALSFRS-R), percent predicted slow vital capacity, and plasma neurofilament light chain concentration. RESULTS: In total, 43 patients (RT001 = 21; placebo = 22) were randomized. RT001 was well tolerated; one patient required dose reduction due to adverse events (AEs). Numerically, there were more AEs in the RT001 group compared to the placebo group (71% versus 55%, p = 0.35), with gastrointestinal symptoms being the most common (43% in RT001, 27% in placebo, p = 0.35). Two patients in the RT001 group experienced a serious AE, though unrelated to treatment. The least-squares mean difference in ALSFRS-R total score at week 24 of treatment was 1.90 (95% confidence interval = -1.39 to 5.19) in favor of RT001 (p = 0.25). The directions of other efficacy outcomes favored RT001 compared to placebo, although no inferential statistics were performed. CONCLUSIONS: Initial data indicate that RT001 is safe and well tolerated. Given the exploratory nature of the study, a larger clinical trial is required to evaluate its efficacy.

An expanded access protocol of RT001 in amyotrophic lateral sclerosis-Initial experience with a lipid peroxidation inhibitor.

INTRODUCTION/AIMS: Lipid peroxidation is thought to play a biologically important role in motor neuron death in amyotrophic lateral sclerosis (ALS). 11,11 Di-deuterated linoleic ethyl ester (RT001) prevents lipid peroxidation in cellular and mitochondrial membranes. Herein we report on the use of RT001 under expanded access (EA). METHODS: We provided RT001 to patients with ALS via EA at a single site. The starting dose was 2.88 g/day, which was increased to to 8.64 g/day as tolerated. Participants were not eligible for alternative clinical trials. Participants were followed for adverse events and pharmacokinetic (PK) parameters were measured approximately 3 months after RT001 initiation. RESULTS: Sixteen participants received RT001 (5.6 ± 1.6 g/day; dose range, 1.92 to 8.64 g/day) for a mean period of 10.8 ± 7.1 months. After 3 months of treatment, PK studies showed that RT001 was absorbed, metabolized, and incorporated into red blood cell membranes at concentrations expected to be therapeutic based on in vitro models. The most common adverse events were gastrointestinal, including diarrhea, which occurred in 25% of the participants, and were considered possibly related to RT001. One participant (6%) discontinued due to an adverse event. Ten serious adverse events occurred: these events were recognized complications of ALS and none were attributed to treatment with RT001. DISCUSSION: RT001 was administered safely to a small group of people living with ALS in the context of an EA protocol. Currently, there is an ongoing randomized, double-blind, controlled study of RT001 in ALS.

CT more accurately detects foreign bodies within the equine foot than MRI or digital radiography.

Identification and characterization of foreign bodies in the distal limb of horses poses a diagnostic challenge. The aims of this prospective experimental cadaver study were to describe the appearance of five foreign body materials within the equine hoof using CT, MRI, and digital radiography (DR) and to compare interrater agreement among three reviewers. Fifty foreign bodies consisting of five materials were implanted at a solar location or a coronary location in 25 equine cadaver feet. The images were reviewed by three equine veterinarians experienced in advanced imaging interpretation, who were blinded to the material of the foreign body. Foreign bodies were graded on visibility and appearance. Sensitivity and specificity were calculated for accurate identification of the different materials. Interrater agreement was assessed using Fleiss' kappa. Computed tomography had higher visibility score, sensitivity/specificity, and interrater agreement for detection of all materials; particularly slate, glass, and dry wood, compared to the other imaging modalities. Soaked wood and plastic had lower sensitivity (31-33%) on CT with a similar attenuation of the two materials. Foreign bodies were often visible on MRI, although with similar appearance and unclear details. On DR, only slate and glass were visible. The interrater agreement for identifying the correct material was almost perfect for slate, glass, and dry wood (κ = 0.92-1.00) and poor for plastic and soaked wood (κ < 0.20) on CT. Interrater agreement was poor for all materials on MRI and DR (κ < 0.20), with the except for fair (κ = 0.28) for slate on DR and moderate (κ = 0.28) for soaked wood on MRI.

Use of wound infusion catheters for delivery of local anesthetic following standing partial ostectomy of thoracolumbar vertebral spinous processes in horses is not associated with increased surgical site infections.

Background: Wound infusion catheters (WICs) have been used in humans and some veterinary species for post-operative local anesthetic administration following a variety of surgical procedures, aiming to reduce post-operative analgesia requirements and improve patient comfort. Benefit in reduction in pain, post-operative analgesia requirements and length of hospital stay are well documented in humans, but use of WICs may not have been widely adopted in veterinary species due to the concern of increased complications, such as dehiscence or surgical site infection (SSI), creating a barrier to their use. This study aimed to evaluate the use of WICs in horses undergoing standing partial ostectomy surgeries, document complications and investigate if the incidence of SSI was equivalent between those horses that did and did not have a WIC. Methods: Clinical records were searched between January 2010-December 2023 for horses undergoing standing partial ostectomy surgery of thoracolumbar vertebral spinous processes at one institution. Population variables (age, breed, bodyweight), placement of a WIC or not, post-operative complications, analgesia protocols and surgical time were recorded. Horses received up to 0.1 mg kg-1 bupivacaine (0.5 mg mL-1) every 6-8 h via the WIC where one was placed. To compare SSI complication incidence between using or not using a WIC, a proportional independent equivalence test was used. Results: There were 64 horses included in the final analysis with a WIC placed in 29/64 horses (45.3%) and 35/64 (54.7%) having no WIC placed at surgery. Incidence of short-term SSI was 11.4% (no WIC used) and 13.8% (WIC used), respectively. The difference in proportion of SSI between the presence or absence of a WIC was not significant [-0.024 (90% CI -0.181; 0.133); p = 0.94]. Conclusion: The incidence of SSIs was equivalent between groups whether a WIC was used or not. WICs should be considered as part of a multi-modal analgesic approach in the post-operative period. Further research into local anesthetic dosing and its impact on rescue analgesia requirements and pain-scores is warranted.

Arterial Blood Gas, Electrolyte and Acid-Base Values as Diagnostic and Prognostic Indicators in Equine Colic.

The study aimed to investigate if arterial blood analysis in conscious horses presenting with signs of colic and breathing ambient air had diagnostic or prognostic value. Arterial blood samples from 352 horses presenting with colic at a university equine referral hospital were analysed for pH, partial pressure of carbon dioxide (PaCO2), partial pressure of oxygen (PaO2), concentrations of sodium (Na+), potassium (K+), ionised calcium (Ca2+) and chloride (Cl-), actual and standardised plasma bicarbonate concentration (HCO3- (P) and HCO3- (P, st)), blood and extracellular fluid base excess (Base (B) and Base (ecf)) and anion gap (AG). Results were compared to previously reported values for healthy horses, and comparisons were made between final diagnosis, treatment and survival to hospital discharge. Significant differences were found between colic cases and healthy reference values between some primary aetiologies. Overall, surgical and non-surgical colic cases differed in Ca2+ and Cl- concentrations and Ca2+ differed between cases that survived to discharge and those that did not. PaO2 differed between small intestinal surgical cases that survived and those that did not. From these results, we developed regression models that demonstrated excellent or good predictive value in identifying the likelihood of surgical versus medical management and survival to hospital discharge.

Histological Evaluation of Resected Tissue as a Predictor of Survival in Horses with Strangulating Small Intestinal Disease.

Strangulating small intestinal disease (SSID) in horses carries a poor prognosis for survival, especially following resection of ischaemic tissue. The margins of a resection are principally based on visual appraisal of the intestine during surgery. We hypothesized that histological evaluation of resected tissue may identify occult changes indicative of prognosis. Small intestinal samples from 18 horses undergoing resection for SSID and 9 horses euthanised for reasons unrelated to gastrointestinal pathology were utilised. Histological appearance was used to generate a 'total damage score' (TDS) for the control tissue, grossly normal tissue at oral and aboral extremities (sections OR1 and AB1) of the resected intestine, and oral and aboral extremities of visually abnormal tissue (sections OR2 and AB2) from SSID horses. The relationship between TDS and long-term post-operative survival was investigated. TDS was not different between control tissues and OR1 and AB1 sections. Five surgical cases were alive at follow-up, the longest follow-up time being 2561 days. Based on the median scores for SSID cases versus controls, cut-off values were generated to evaluate post-operative survival versus TDS. Only OR2 TDS was significantly associated with survival, with a higher (worse) score indicating longer survival. More severe tissue insult may expedite rapid progression to surgery, improving post-operative outcomes.

Double blind trial of a deuterated form of linoleic acid (RT001) in Friedreich ataxia.

OBJECTIVES: Friedreich ataxia is (FRDA) an autosomal recessive neurodegenerative disorder associated with intrinsic oxidative damage, suggesting that decreasing lipid peroxidation (LPO) might ameliorate disease progression. The present study tested the ability of RT001, a deuterated form of linoleic acid (D2-LA), to alter disease severity in patients with FRDA in a double-blind placebo-controlled trial. METHODS: Sixty-five subjects were recruited across six sites and received either placebo or active drug for an 11-month study. Subjects were evaluated at 0, 4, 9, and 11 months, with the primary outcome measure being maximum oxygen consumption (MVO2) during cardiopulmonary exercise testing (CPET). A key secondary outcome measure was a composite statistical test using results from the timed 1-min walk (T1MW), peak workload, and MVO2. RESULTS: Forty-five subjects completed the protocol. RT001 was well tolerated, with no serious adverse events related to drug. Plasma and red blood cell (RBC) membrane levels of D2-LA and its primary metabolite deuterated arachidonic acid (D2-AA) achieved steady-state concentrations by 4 months. No significant changes in MVO2 were observed for RT001 compared to placebo. Similarly, no differences between the groups were found in secondary or exploratory outcome measures. Post hoc evaluations also suggested minimal effects of RT001 at the dosages used in this study. INTERPRETATIONS: The results of this study provide no evidence for a significant benefit of RT001 at the dosages tested in this Friedreich ataxia patient population.

Stem cell-based therapies for bone repair.

This article provides an overview of the cellular and molecular events involved in bone repair and the current approaches to using stem cells as an adjunct to this process. The article emphasizes the key role of osteoprogenitor cells in the formation of bone and where the clinical applications of current research may lend themselves to large animal orthopaedics. The processes involved in osteogenic differentiation are presented and strategies for bone formation, including induction by osteogenic factors, bioscaffolds, and gene therapy, are reviewed.

Neurovascular variations in the proximal plantar metatarsal region of the horse.

BACKGROUND: Neurovascular variation may be relevant when performing surgical techniques to the proximal plantar metatarsal region. OBJECTIVES: To document variations in the neurovascular anatomy of the proximal plantar metatarsal region and study the relationship of the neurovascular components to each other and other structures located in this area. STUDY DESIGN: Descriptive anatomical study. METHODS: Paired cadaver hind limbs from 15 horses were dissected from the distal tibia to the metatarsophalangeal joint. Deep branch of the lateral plantar nerve (DBLPN) length, location of its origin from the lateral plantar nerve (LPN), individual DBLPN ramifications into the suspensory ligament (SL) and relationship of the DBLPN to the plantar arch and accessory ligament of the deep digital flexor tendon (ALDDFT) were recorded. RESULTS: Mean DBLPN length was 5.8 ± 1.7 cm with the nerve arising 3.7 ± 1.5 cm proximal to the head of the fourth metatarsal bone (MTIV). There was a median of three individual DBLPN ramifications (range 2-6) entering the SL. There were no significant left/right differences. In 57% (CI 39%-74%; n = 17) limbs, the deep plantar arch was superficial to the DBLPN, whereas in 33% (CI 16%-50%; n = 10) limbs, the DBLPN passed between the venous and arterial components of the arch. In 10% (CI 1%-20%; n = 3) limbs, the deep plantar arch was deep to the DBLPN. In 67% (CI 50%-84%; n = 20) limbs, the DBLPN was superficial to the ALDDFT, whereas in 33% (CI 16%-50%; n = 10) limbs, the nerve ran deep to the ALDDFT. An additional branch from the LPN was noted in one limb. MAIN LIMITATIONS: Limbs were used from horses with unknown clinical history. CONCLUSIONS: Anatomical variation, in particular the relationship of the DBLPN and deep metatarsal fascia to the deep plantar arch and the ALDDFT is an important consideration when undertaking surgical approaches to the proximal plantar metatarsal region.

Epidural administration of opioid analgesics improves quality of recovery in horses anaesthetised for treatment of hindlimb synovial sepsis.

BACKGROUND: Opioid epidural analgesia has been shown to provide effective analgesia in horses. There is a lack of evidence regarding the effect of opioid epidural analgesia on quality of recovery in horses. OBJECTIVES: Identify whether opioid epidural analgesia influences quality of recovery in horses undergoing general anaesthesia required for management of hindlimb synovial sepsis. STUDY DESIGN: Single-centre retrospective cross-sectional study. METHODS: Data were obtained from the clinical records of horses which had undergone arthroscopic or tenoscopic surgery for management of hindlimb synovial sepsis over a 9-year period in a referral hospital population. Multivariable logistic regression analysis was used to identify the perioperative factors that impact on quality of recovery. RESULTS: Records from 149 horses, undergoing 170 general anaesthetics were included. Multivariable logistic regression analysis showed that opioid epidural analgesia (OR 3.0, 95% CI 1.2 to 7.2, P = .02) was associated with good quality of recovery, whereas Cob breeds (OR 0.16, 95% CI 0.06 to 0.46, P = .001), age (in years) (OR 0.90, 95% CI 0.83 to 0.97, P = .004) increasing intraoperative dosages (in mg/kg) of thiopental (OR 0.64, 95% CI 0.46 to 0.90, P = .01) or ketamine (OR 0.42, 95% CI 0.18 to 0.98, P = .04) were associated with poor quality of recovery. MAIN LIMITATIONS: Certain variables that may influence quality of recovery, such as patient temperament and hindlimb orthopaedic co-morbidities were not recorded. The clinical prediction model obtained is only applicable to the specific facilities, population and perianaesthetic management practiced at our institution. CONCLUSIONS: Opioid epidural analgesia is significantly associated with good quality of recovery in horses undergoing general anaesthesia required for management of hindlimb synovial sepsis. Other risk factors, such as increasing age, cob breed, use of higher intraoperative dosages (in mg/kg) of ketamine and/or thiopental, were associated with poor quality of recovery.

RT001 in Progressive Supranuclear Palsy-Clinical and In-Vitro Observations.

BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive movement disorder associated with lipid peroxidation and intracerebral accumulation of tau. RT001 is a deuterium reinforced isotopologue of linoleic acid that prevents lipid peroxidation (LPO) through the kinetic isotope effect. METHODS: The effects of RT001 pre-treatment on various oxidative and bioenergetic parameters were evaluated in mesenchymal stem cells (MSC) derived from patients with PSP compared to controls. In parallel, 3 patients with PSP were treated with RT001 and followed clinically. RESULTS: MSCs derived from PSP patients had a significantly higher rate of LPO (161.8 ± 8.2% of control; p < 0.001). A 72-h incubation with RT001 restored the PSP MSCs to normal levels. Mitochondrial reactive oxygen species (ROS) overproduction in PSP-MSCs significantly decreased the level of GSH compared to control MSCs (to 56% and 47% of control; p < 0.05). Incubation with RT001 significantly increased level of GSH in PSP MSCs. The level of mitochondrial DNA in the cells was significantly lower in PSP-MSCs (67.5%), compared to control MSCs. Changes in mitochondrial membrane potential, size, and shape were also observed. Three subjects with possible or probable PSP were treated with RT001 for a mean duration of 26 months. The slope of the PSPRS changed from the historical decline of 0.91 points/month to a mean decline of 0.16 points/month (+/-0.23 SEM). The UPDRS slope changed from an expected increase of 0.95 points/month to an average increase in score of 0.28 points/month (+/-0.41 SEM). CONCLUSIONS: MSCs derived from patients with PSP have elevated basal levels of LPO, ROS, and mitochondrial dysfunction. These findings are reversed after incubation with RT001. In PSP patients, the progression of disease may be reduced by treatment with RT001.

Mouse microRNA signatures in joint ageing and post-traumatic osteoarthritis.

OBJECTIVE: This study investigated mice serum and joint microRNA expression profiles in ageing and osteoarthritis to elucidate the role of microRNAs in the development and progression of disease, and provide biomarkers for ageing and osteoarthritis. DESIGN: Whole joints and serum samples were collected from C57BL6/J male mice and subjected to small RNA sequencing. Groups used included; surgically-induced post-traumatic osteoarthritis, (DMM; 24 months-old); sham surgery (24 months-old); old mice (18 months-old); and young mice (8 months-old). Differentially expressed microRNAs between the four groups were identified and validated using real-time quantitative PCR. MicroRNA differential expression data was used for target prediction and pathway analysis. RESULTS: In joint tissues, miR-140-5p, miR-205-5p, miR-682, miR-208b-3p, miR-499-5p, miR-455-3p and miR-6238 were differentially expressed between young and old groups; miR-146a-5p, miR-3474, miR-615-3p and miR-151-5p were differentially expressed between DMM and Sham groups; and miR-652-3p, miR-23b-3p, miR-708-5p, miR-5099, miR-23a-3p, miR-214-3p, miR-6238 and miR-148-3p between the old and DMM groups. The number of differentially expressed microRNAs in serum was higher, some in common with joint tissues including miR-140-5p and miR-455-3p between young and old groups; and miR-23b-3p, miR-5099 and miR-6238 between old and DMM groups.We confirmed miR-140-5p, miR-499-5p and miR-455-3p expression to be decreased in old mouse joints compared to young, suggesting their potential use as biomarkers of joint ageing in mice. CONCLUSIONS: MiR-140-5p, miR-499-5p and miR-455-3p could be used as joint ageing biomarkers in mice. Further research into these specific molecules in human tissues is now warranted to check their potential suitability as human biomarkers of ageing.

The first evaluation of a novel vitamin K antagonist, tecarfarin (ATI-5923), in patients with atrial fibrillation.

BACKGROUND: Tecarfarin (ATI-5923) is a novel oral vitamin K antagonist. Unlike warfarin, it is metabolized by esterases, escaping metabolism by the cytochrome P450 system and thereby avoiding cytochrome P450-mediated drug-drug or drug-food interactions as well as genetic variations found in the cytochrome P450 system. Both tecarfarin and warfarin can be monitored with the international normalized ratio. We hypothesized that the time in therapeutic range for tecarfarin will exceed values usually experienced with warfarin. METHODS AND RESULTS: This was a 6- to 12-week open-label, multicenter, phase IIA study of 66 atrial fibrillation patients with a mild to moderate risk of stroke to determine the safety and tolerability of tecarfarin and to ascertain an optimal tecarfarin dosing regimen. Sixty-four subjects (97%) were taking warfarin at enrollment and were switched to tecarfarin. After the initial 3 weeks of tecarfarin treatment, the mean interpolated time in therapeutic range was 71.4%. Only 10.9% of patients had time in therapeutic range of <45%. Times in extreme international normalized ratio ranges of <1.5 and >4.0 were 1.2% and 1.2%, respectively. The median daily dose (for an individual patient) to maintain an international normalized ratio between 2 and 3 was 15.6 mg (range, 6 to 29 mg). CONCLUSIONS: This is the first study of tecarfarin in patients with atrial fibrillation. It appears that tecarfarin may possess advantages over the currently available standard of care, warfarin, by improving time in therapeutic range. Adequately powered prospective trials are warranted to definitively compare tecarfarin with warfarin in clinical settings for which warfarin is indicated.

The infantile neuroaxonal dystrophy rating scale (INAD-RS).

BACKGROUND: INAD is an autosomal recessive neurogenetic disorder caused by biallelic pathogenic variants in PLA2G6. The downstream enzyme, iPLA2, plays a critical role in cell membrane homeostasis by helping to regulate levels of phospholipids. The clinical presentation occurs between 6 months and 3 years with global developmental regression, hypotonia, and progressive spastic tetraparesis. Progression is often rapid, resulting in severe spasticity, visual impairment, and cognitive decline, with many children not surviving past the first decade of life. To date, no accepted tool for assessing the severity of INAD exists; other commonly used scales (e.g. CHOP-INTEND, Modified Ashworth, Hammersmith Functional Motor Scale) do not accurately gauge the current severity of INAD, nor are they sensitive/specific enough to monitor disease progression. Finally, these other scales are not appropriate, because they do not address the combination of CNS, peripheral nerve, and visual pathology that occurs in children with INAD. METHODS: We have developed and validated a structured neurological examination for INAD (scored out of 80). The examination includes six main categories of pediatric developmental evaluation: 1) gross motor-and-truncal-stability skills, 2) fine motor skills, 3) bulbar function, 4) ocular function, 5) temporo-frontal function, and, 6) Functional evaluation of the autonomic nervous system. A cohort of patients diagnosed with INAD were followed prospectively to validate the score against disease severity and disease progression. RESULTS: We show significant correlation between the total neurological assessment score and months since symptom onset with a statistically significant (p = 6.7 × 10- 07) correlation between assessment score and disease onset. As hypothesized, the coefficient of months-since-symptom-onset is strongly negative, indicating a negative correlation between total score and months since symptom onset. CONCLUSION: We have developed and validated a novel neurological assessment score in INAD that demonstrates strong correlation with disease severity and disease progression.

Post-traumatic osteoarthritis development is not modified by postnatal chondrocyte deletion of Ccn2.

CCN2 is a matricellular protein involved in several crucial biological processes. In particular, CCN2 is involved in cartilage development and in osteoarthritis. Ccn2 null mice exhibit a range of skeletal dysmorphisms, highlighting its importance in regulating matrix formation during development; however, its role in adult cartilage remains unclear. The aim of this study was to determine the role of CCN2 in postnatal chondrocytes in models of post-traumatic osteoarthritis (PTOA). Ccn2 deletion was induced in articular chondrocytes of male transgenic mice at 8 weeks of age. PTOA was induced in knees either surgically or non-invasively by repetitive mechanical loading at 10 weeks of age. Knee joints were harvested, scanned with micro-computed tomography and processed for histology. Sections were stained with Toluidine Blue and scored using the Osteoarthritis Research Society International (OARSI) grading system. In the non-invasive model, cartilage lesions were present in the lateral femur, but no significant differences were observed between wild-type (WT) and Ccn2 knockout (KO) mice 6 weeks post-loading. In the surgical model, severe cartilage degeneration was observed in the medial compartments, but no significant differences were observed between WT and Ccn2 KO mice at 2, 4 and 8 weeks post-surgery. We conclude that Ccn2 deletion in chondrocytes does not modify the development of PTOA in mice, suggesting that chondrocyte expression of CCN2 in adults is not a crucial factor in protecting cartilage from the degeneration associated with PTOA.This article has an associated First Person interview with the first author of the paper.

Treatment of infantile neuroaxonal dystrophy with RT001: A di-deuterated ethyl ester of linoleic acid: Report of two cases.

BACKGROUND: Infantile neuroaxonal dystrophy (INAD) is a rare, autosomal recessive disease due to defects in PLA2G6 and is associated with lipid peroxidation. RT001 is a di-deuterated form of linoleic acid that protects lipids from oxidative damage. METHODS: We evaluated the pharmacokinetics (PK), safety, and effectiveness of RT001 in two subjects with INAD (subject 1: 34 months; subject 2: 10 months). After screening and baseline evaluations, subjects received 1.8 g of RT001 BD. PK analysis and clinical evaluations were made periodically. MAIN FINDINGS: Plasma levels of deuterated linoleic acid (D2-LA), deuterated arachidonic acid (D2-AA), D2-LA to total LA, and D2-AA to total AA ratios were measured. The targeted plasma D2-LA ratio (>20%) was achieved by month 1 and maintained throughout the study. RBC AA-ratios were 0.11 and 0.18 at 6 months for subjects 1 and 2; respectively. No treatment-related adverse events occurred. Limited slowing of disease progression and some return of lost developmental milestones were seen. CONCLUSIONS: Oral RT001 was administered safely in two subjects with INAD. Early findings suggest that the compound was well tolerated, metabolized and incorporated in the RBC membrane. A clinical trial is underway to assess efficacy.

The natural history of infantile neuroaxonal dystrophy.

BACKGROUND: Infantile neuroaxonal dystrophy (INAD) is a rapidly progressive neurodegenerative disorder of early onset causing premature death. It results from biallelic pathogenic variants in PLA2G6, which encodes a calcium-independent phospholipase A2. OBJECTIVE: We aim to outline the natural history of INAD and provide a comprehensive description of its clinical, radiological, laboratory, and molecular findings. MATERIALS AND METHODS: We comprehensively analyzed the charts of 28 patients: 16 patients from Riyadh, Saudi Arabia, 8 patients from North and South America and 4 patients from Europe with a molecularly confirmed diagnosis of PLA2G6-associated neurodegeneration (PLAN) and a clinical history consistent with INAD. RESULTS: In our cohort, speech impairment and loss of gross motor milestones were the earliest signs of the disease. As the disease progressed, loss of fine motor milestones and bulbar dysfunction were observed. Temporo-frontal function was among the last of the milestones to be lost. Appendicular spastic hypertonia, axial hypotonia, and hyperreflexia were common neurological findings. Other common clinical findings include nystagmus (60.7%), seizures (42.9%), gastrointestinal disease (42.9%), skeletal deformities (35.7%), and strabismus (28.6%). Cerebellar atrophy and elevations in serum AST and LDH levels were consistent features of INAD. There was a statistically significant difference when comparing patients with non-sense/truncating variants compared with missense/in-frame deletions in the time of initial concern (p = 0.04), initial loss of language (p = 0.001), initial loss of fine motor skills (p = 0.009), and initial loss of bulbar skills (p = 0.007). CONCLUSION: INAD is an ultra-rare neurodegenerative disorder that presents in early childhood, with a relentlessly progressive clinical course. Knowledge of the natural history of INAD may serve as a resource for healthcare providers to develop a targeted care plan and may facilitate the design of clinical trials to treat this disease.

Plasma and Red Blood Cell Membrane Accretion and Pharmacokinetics of RT001 (bis-Allylic 11,11-D2-Linoleic Acid Ethyl Ester) during Long Term Dosing in Patients.

RT001 is the di-deutero isotopologue of linoleic acid ethyl ester (D2-LA). Resistance to oxidative damage at the carbon-deuterium bond depends upon the concentration of D2-LA as a percentage of total LA. We report here on the plasma and red cell (RBC) pharmacokinetics (PK) of D2-LA, and its metabolite 13,13-D2-arachidonic acid (D2-AA), in patients with multiple neurodegenerative diseases (total of 59 participants). In Friedreich's ataxia patients, D2-LA was absorbed and transported similarly to dietary LA, peaking at about 6 h after oral dosing. Plasma D2-LA concentrations approached steady state after 28 days of dosing. After 6 months of daily dosing in subjects with other disorders, D2-LA and D2-AA levels were at or above the 20% of total (D2-LA/total LA, or D2-AA/total AA) therapeutic targets for most subjects. We conclude that chronic dosing of RT001 and associated dietary guidance can be maintained over many months to achieve target plasma and RBC levels, forming a basis for therapeutic dosing across a broad range of conditions. RT001 has been safe and well-tolerated in 59 different participants treated across 10 different neurodegenerative diseases in multiple clinical trials for up to 36 months with no significant drug related adverse events limiting use.

Rapid effects of hypoxia on H+ homeostasis in articular chondrocytes.

Articular chondrocytes experience low oxygen (O(2)) levels compared with many other tissues, and values fall further in disease states. Chondrocyte intracellular pH (pH(i)) is a powerful modulator of matrix synthesis and is principally regulated by Na(+)-H(+) exchange (NHE). In equine chondrocytes, NHE is inhibited when cells are incubated for 3 h at low O(2), leading to intracellular acidosis. O(2)-dependent changes in reactive oxygen species (ROS) levels appear to underlie this effect. The present study examines whether hypoxia can influence chondrocyte NHE activity and pH(i) over shorter timescales using the pH-sensitive fluoroprobe BCECF in cells isolated not only from equine cartilage but also from bovine tissue. O(2) levels in initially oxygenated solutions gassed with N(2) fell to approximately 1% within 2 h. A progressive fall in pH(i) and acid extrusion capacity was observed, with statistically significant effects (P < 0.05) apparent within 3 h. For equine and bovine cell populations subjected to step change in O(2) by resuspension in hypoxic (1%) solutions, a decline in acid extrusion and pH(i) was observed within 10 min and continued throughout the recording period. This effect represented inhibition of the NHE-mediated fraction of acid extrusion. Cells subjected to hypoxic solutions supplemented with CoCl(2) (100 microM) or antimycin A (100 microM) to raise levels of ROS did not acidify. The conserved nature and rapidity of the response to hypoxia has considerable implications for chondrocyte homeostasis and potentially for the maintenance of cartilage integrity.

A preliminary assessment of the effects of ATI-2042 in subjects with paroxysmal atrial fibrillation using implanted pacemaker methodology.

AIMS: ATI-2042 (budiodarone) is a chemical analogue of amiodarone with a half life of 7 h. It is electrophysiologically similar to amiodarone, but may not have metabolic and interaction side effects. The sophisticated electrocardiograph logs of advanced DDDRP pacemakers were used to monitor the efficacy of ATI-2042. The aim of this study was to determine the preliminary efficacy and safety of ATI-2042 in patients with paroxsymal atrial fibrillation (PAF) and pacemakers. METHODS AND RESULTS: Six women with AF burden (AFB) between 1 and 50% underwent six sequential 2-week study periods. Patients received 200 mg bid of ATI-2042 during Period 2 (p2), 400 mg bid during p3, 600 mg bid during p4, 800 mg bid during p5, and no drug during baseline and washout (p1 and p6). Pacemaker data for the primary outcome measure AFB were downloaded during each period. Mean AFB decreased between baseline and all doses: AFB at baseline (SD) was 20.3 +/- 14.6% and mean AFB at 200 mg bid was 5.2 +/- 4.2%, at 400 mg bid 5.2 +/- 5.2%, at 600 mg bid 2.8 +/- 3.4%, and at 800 mg bid 1.5 +/- 0.5%. The mean reductions in AFB at all doses of ATI-2042 were statistically significant (P < 0.005). Atrial fibrillation burden increased in washout. Atrial fibrillation episodes tended to increase with ATI-2042, but this was offset by substantial decreases in episode duration. ATI-2042 was generally well tolerated. CONCLUSION: ATI-2042 effectively reduced AFB over all doses studied by reducing mean episode duration. A large-scale study will be required to confirm this effect.