Localization and Network Connectivity of Lesions Causing Limb Ataxia in Patients With Stroke.

BACKGROUND AND OBJECTIVES: Ataxia is primarily considered to originate from the cerebellum. However, it can manifest without obvious cerebellar damage, such as in anterior circulation stroke, leaving the mechanisms of ataxia unclear. The aim of this study was to investigate whether stroke lesions causing limb ataxia localize to a common brain network. METHODS: In this prospective cohort study, adult patients with new-onset stroke with visible lesions on CT or MRI from Turku University Hospital, Finland, were clinically examined (1) after their stroke while still admitted to the hospital (baseline) and (2) 4 months later (follow-up) to assess limb ataxia. Lesion locations and their functional connectivity, computed using openly available data from 1,000 healthy volunteers from the Brain Genome Superstruct Project, were compared voxel-by-voxel across the whole brain between patients with and without ataxia, using voxel-based lesion-symptom mapping and lesion network mapping. The findings were confirmed in an independent stroke patient cohort with identical clinical assessments. RESULTS: One hundred ninety-seven patients (mean age 67.2 years, 39%female) were included in this study. At baseline, 35 patients (68.3 years, 34%female) had and 162 (67.0 years, 40%female) did not have new-onset acute limb ataxia. At follow-up, additional 4 patients had developed late-onset limb ataxia, totalling to 39 patients (68.6 years, 36%female) with limb ataxia at any point. One hundred eighteen patients (66.2 years, 40%female) did not have ataxia at any point (n = 40 with missing follow-up data). Lesions in 54% of the patients with acute limb ataxia were located outside the cerebellum and cerebellar peduncles, and we did not find an association between specific lesion locations and ataxia. Lesions causing acute limb ataxia, however, were connected to a common network centered on the intermediate zone cerebellum and cerebellar peduncles (lesion connectivity in patients with vs without acute limb ataxia, pFWE < 0.05). The results were similar when comparing patients with and without ataxia at any point, and when excluding lesions in the cerebellum and cerebellar peduncles (pFWE < 0.05). The findings were confirmed in the independent stroke dataset (n = 96), demonstrating an OR of 2.27 (95% CI 1.32-3.91) for limb ataxia per standard deviation increase in limb ataxia network damage score. DISCUSSION: Lesions causing limb ataxia occur in heterogeneous locations but localize to a common brain network.

Síndrome de leiomiomatose cutânea e uterina múltipla: relato de três casos clínicos / Multiple cutaneous and uterine leiomyomatosis syndrome: report of three clinical cases

A síndrome de Reed ocorre em mulheres com múltiplos leiomiomas cutâneos e leiomiomatose uterina. Relatam-se três casos de pacientes do sexo feminino, acompanhadas em hospital universitário, com pápulas e nódulos eritêmato-acas- tanhados dolorosos em membros superiores e tórax, agravados por frio, pressão e estresse, e associados a miomatose uterina. Foram realizados diversos tratamentos prévios, sem sucesso, tais como: aplicação de corticoterapia e toxina botulínica intralesional, bloqueadores de canais de cálcio, neuromoduladores e analgésicos orais. Foi, então, realizado tratamento cirúrgico, com melhora dos sintomas. O co- nhecimento e o esclarecimento dessa síndrome é fundamental para estabelecer a relação com miomatose uterina e câncer de células renais, para que, então, a partir da lesão de pele, se faça o rastreio das demais neoplasias, diagnóstico precoce e a educação em saúde.

Reed syndrome occurs in women with multiple cutaneous leiomyomas and uterine leiomyomatosis. We report the case of three female patients followed at a university hospital with painful erythematous-brown papules and nodules on the upper limbs and chest, aggravated by cold, pressure, stress, and associated with uterine myoma- tosis. Several previous unsuccessful treatments were performed, such as the applica- tion of corticotherapy and intralesional botulinum toxin, calcium channel blockers, neuromodulators, and analgesics. Surgical treatment was performed with the im- provement of symptoms. Knowledge and clarification of this syndrome are essential to establish a relationship between uterine myomatosis and renal cell neoplasm, so that, after the skin lesion, screening for other neoplasms, early diagnosis, and health education can be carried out.

Association of Lipoprotein(a) Levels With Incidence of Major Adverse Limb Events.

Importance: High lipoprotein(a) (Lp[a]) levels are involved in the development of cardiovascular events, particularly in myocardial infarction, stroke, and peripheral artery disease. Studies assessing the Lp(a) levels associated with adverse lower-limb events are lacking. Objective: To assess the association between Lp(a) levels and incidence of major adverse limb events in unselected hospitalized patients. Design, Setting, and Participants: This large retrospective monocentric cohort study was conducted from January 1, 2000, to December 31, 2020. Data were derived from the clinical information system of the Hôpital Européen Georges-Pompidou, a Paris-based university hospital. Patients who underwent at least 1 Lp(a) measurement at the center during the study period were included. Patients who had no follow-up data or who had the first Lp(a) measurement after the study outcome had occurred were excluded. Data analyses were performed from May 2021 to January 2022. Main Outcomes and Measures: The primary outcome was the first inpatient major adverse limb event, defined as a major amputation, peripheral endovascular revascularization, or peripheral surgical revascularization, during follow-up. Secondary outcomes included individual components of the primary outcome. Lipoprotein(a) levels were categorized as follows: normal (<50 mg/dL), high (50 to <134 mg/dL), and very high (≥134 mg/dL); to convert Lp(a) values to milligrams per liter, multiply by 0.1. Results: A total of 16 513 patients (median [IQR] age, 58.2 [49.0-66.7] years; 9774 men [59.2%]) were included in the cohort. The median (IQR) Lp(a) level was 24 (10.0-60.0) mg/dL. The 1-year incidence of major adverse limb event was 2.44% in the overall population and 4.54% among patients with very high Lp(a) levels. High (adjusted accelerated failure time [AFT] exponential estimate: 0.43; 95% CI, 0.24-0.78; Benjamini-Hochberg-corrected P = .01) and very high (adjusted AFT exponential estimate: 0.17; 95% CI, 0.07-0.40; Benjamini-Hochberg-corrected P < .001) Lp(a) levels were independently associated with an increased risk of major adverse limb event. Conclusions and Relevance: Results of this study showed that higher Lp(a) levels were independently associated with an increased risk of a major adverse limb event in hospitalized patients. The Lp(a) measurement needs to be taken into account to improve lower-limb vascular risk assessment.

Evaluation of Muscle Mass and Stiffness with Limb Ultrasound in COVID-19 Survivors.

BACKGROUND: acute illnesses, like COVID-19, can act as a catabolic stimulus on muscles. So far, no study has evaluated muscle mass and quality through limb ultrasound in post-COVID-19 patients. METHODS: cross sectional observational study, including patients seen one month after hospital discharge for SARS-CoV-2 pneumonia. The patients underwent a multidimensional evaluation. Moreover, we performed dominant medial gastrocnemius ultrasound (US) to characterize their muscle mass and quality. RESULTS: two hundred fifty-nine individuals (median age 67, 59.8% males) were included in the study. COVID-19 survivors with reduced muscle strength had a lower muscle US thickness (1.6 versus 1.73 cm, p =0.02) and a higher muscle stiffness (87 versus 76.3, p = 0.004) compared to patients with normal muscle strength. Also, patients with reduced Short Physical Performance Battery (SPPB) scores had a lower muscle US thickness (1.3 versus 1.71 cm, p = 0.01) and a higher muscle stiffness (104.9 versus 81.07, p = 0.04) compared to individuals with normal SPPB scores. The finding of increased muscle stiffness was also confirmed in patients with a pathological value (≥ 4) at the sarcopenia screening tool SARC-F (103.0 versus 79.55, p < 0.001). Muscle stiffness emerged as a significant predictor of probable sarcopenia (adjusted OR 1.02, 95% C.I. 1.002 - 1.04, p = 0.03). The optimal ultrasound cut-offs for probable sarcopenia were 1.51 cm for muscle thickness (p= 0.017) and 73.95 for muscle stiffness (p = 0.004). DISCUSSION: we described muscle ultrasound characteristics in post COVID-19 patients. Muscle ultrasound could be an innovative tool to assess muscle mass and quality in this population. Our preliminary findings need to be confirmed by future studies comparing muscle ultrasound with already validated techniques for measuring muscle mass and quality.

Interventional- and amputation-stage muscle proteomes in the chronically threatened ischemic limb.

BACKGROUND: Despite improved surgical approaches for chronic limb-threatening ischemia (CLTI), amputation rates remain high and contributing tissue-level factors remain unknown. The purpose of this study was twofold: (1) to identify differences between the healthy adult and CLTI limb muscle proteome, and (2) to identify differences in the limb muscle proteome of CLTI patients prior to surgical intervention or at the time of amputation. METHODS AND RESULTS: Gastrocnemius muscle was collected from non-ischemic controls (n = 19) and either pre-interventional surgery (n = 10) or at amputation outcome (n = 29) CLTI patients. All samples were subjected to isobaric tandem-mass-tag-assisted proteomics. The mitochondrion was the primary classification of downregulated proteins (> 70%) in CLTI limb muscles and paralleled robust functional mitochondrial impairment. Upregulated proteins (> 38%) were largely from the extracellular matrix. Across the two independent sites, 39 proteins were downregulated and 12 upregulated uniformly. Pre-interventional CLTI muscles revealed a robust upregulation of mitochondrial proteins but modest functional impairments in fatty acid oxidation as compared with controls. Comparison of pre-intervention and amputation CLTI limb muscles revealed mitochondrial proteome and functional deficits similar to that between amputation and non-ischemic controls. Interestingly, these observed changes occurred despite 62% of the amputation CLTI patients having undergone a prior surgical intervention. CONCLUSIONS: The CLTI proteome supports failing mitochondria as a phenotype that is unique to amputation outcomes. The signature of pre-intervention CLTI muscle reveals stable mitochondrial protein abundance that is insufficient to uniformly prevent functional impairments. Taken together, these findings support the need for future longitudinal investigations aimed to determine whether mitochondrial failure is causally involved in amputation outcomes from CLTI.

Limb loss experience evoked by electric cortical stimulation.

Limb loss experience is a type of body illusion characterized by the sensation of a missing limb or body part. We aimed to investigate the brain areas involved in this unusual somatosensory experience evoked by electric cortical stimulation with stereo-electroencephalography electrodes. We retrospectively reviewed the data of patients with medical intractable epilepsy, from October 2015 to December 2020, who underwent stereo-electroencephalography implantation and electric cortical stimulation in order to locate the epileptogenic zone and obtain a functional map. We included patients who reported experiences of limb loss during the process of electric cortical stimulation for functional mapping. Three patients reported experiences of limb loss in the process of electric cortical stimulation. Limb loss experience (including the right hand, right upper limb and right side of the body) occurred when the cortex of the left posterior insula, posterior dorsal cingulate and parietal operculum were stimulated. Limb loss experience can be evoked by electric cortical stimulation of the posterior insula, parietal operculum, and posterior cingulate cortex, and provides additional evidence that these cortices play a role in the integration of body sensory perception.

The Emergence of Stereotyped Kinematic Synergies when Mice Reach to Grasp Following Stroke.

Reaching tasks are commonly used in preclinical and clinical studies to assess the acquisition of fine motor skills and recovery of function following stroke. These tasks are often used to assess functional deficits in the absence of quantifying the quality of movement which requires kinematic analysis. To meet this need, this study uses a kinematic analysis in mice performing the Montoya staircase task at 5 and 14 days following a cortical photothrombosis-induced stroke. Following stroke, the mice had reaching impairments associated with sustained deficits including longer, unsmooth, and less individuated paw trajectories. Two weeks after stroke we also detected the emergence of abnormal elbow and shoulder angles, flexion/extensions, and stereotyped kinematic synergies. These data suggest that proximal and distal segments acting in concert is paramount during post-stroke reaching and encourage further analysis of synergies within the translational pipeline of preclinical to clinical studies.

Clinical characteristics of periodic limb movements during sleep categorized by continuous positive airway pressure titration polysomnography in patients with obstructive sleep apnea.

PURPOSE: The presence of periodic limb movements during sleep (PLMS) varies among patients with obstructive sleep apnea (OSA) undergoing treatment with continuous positive airway pressure (CPAP). The factors associated with this variation are unknown. METHODS: PLMS were defined as a periodic leg movements index of > 15/h. Patients with OSA and PLMS were categorized into four groups depending on diagnostic and CPAP titration polysomnography (PSG). A multinomial logistic regression analysis was performed using a non-PLMS group as the reference category. RESULTS: This study included 861 patients with OSA who underwent a full-night CPAP titration PSG. The proportions of the subjects with PLMS on both PSGs (persistent PLMS), those with CPAP-emergent PLMS, and those with CPAP-resolved PLMS were 12.9%, 9.2%, and 3.9%, respectively. Compared with the non-PLMS group, the persistent group was more likely to be of older age and male sex and has a higher body mass index and restless legs syndrome (RLS). Patients in the CPAP-emergent group were also older and more likely to have RLS as well as more severe apnea. Patients in the CPAP-resolved group were more likely to be women, of older age, have a higher body mass index, but less severe apnea. CONCLUSIONS: PLMS elicited by CPAP are more likely to occur in older patients with more severe sleep apnea and comorbid RLS, whereas OSA patients in which PLMS resolve after CPAP are more likely to be women and have milder sleep apnea. Persistent PLMS share clinical characteristics with PLMS in general population.

Silencing long ascending propriospinal neurons after spinal cord injury improves hindlimb stepping in the adult rat.

Long ascending propriospinal neurons (LAPNs) are a subpopulation of spinal cord interneurons that directly connect the lumbar and cervical enlargements. Previously we showed, in uninjured animals, that conditionally silencing LAPNs disrupted left-right coordination of the hindlimbs and forelimbs in a context-dependent manner, demonstrating that LAPNs secure alternation of the fore- and hindlimb pairs during overground stepping. Given the ventrolateral location of LAPN axons in the spinal cord white matter, many likely remain intact following incomplete, contusive, thoracic spinal cord injury (SCI), suggesting a potential role in the recovery of stepping. Thus, we hypothesized that silencing LAPNs after SCI would disrupt recovered locomotion. Instead, we found that silencing spared LAPNs post-SCI improved locomotor function, including paw placement order and timing, and a decrease in the number of dorsal steps. Silencing also restored left-right hindlimb coordination and normalized spatiotemporal features of gait such as stance and swing time. However, hindlimb-forelimb coordination was not restored. These data indicate that the temporal information carried between the spinal enlargements by the spared LAPNs post-SCI is detrimental to recovered hindlimb locomotor function. These findings are an illustration of a post-SCI neuroanatomical-functional paradox and have implications for the development of neuronal- and axonal-protective therapeutic strategies and the clinical study/implementation of neuromodulation strategies.

Powered hip exoskeleton improves walking economy in individuals with above-knee amputation.

Above-knee amputation severely reduces the mobility and quality of life of millions of individuals. Walking with available leg prostheses is highly inefficient, and poor walking economy is a major problem limiting mobility. Here we show that an autonomous powered hip exoskeleton assisting the residual limb significantly improves metabolic walking economy by 15.6 ± 2.9% (mean ± s.e.m.; two-tailed paired t-test, P = 0.002) in six individuals with above-knee amputation walking on a treadmill. The observed metabolic cost improvement is equivalent to removing a 12-kg backpack from a nonamputee individual. All participants were able to walk overground with the exoskeleton, including starting and stopping, without notable changes in gait balance or stability. This study shows that assistance of the user's residual limb with a powered hip exoskeleton is a viable solution for improving amputee walking economy. By significantly reducing the metabolic cost of walking, the proposed hip exoskeleton may have a considerable positive impact on mobility, improving the quality of life of individuals with above-knee amputations.

Relationship between arm-to-leg and limbs-to-trunk body composition ratio and cardiovascular disease risk factors.

We aimed to analyze the relationship of the distribution of body fat mass (FM) and fat-free mass (FFM) in the limbs and trunk with the prevalence of cardiovascular disease risk factors (CVD-RF). In total, 13,032 adults were selected from the KNHANES (2008-2011). The prevalence of hypertension, diabetes mellitus (DM), dyslipidemia, and metabolic syndrome (MetS) according to the arm-to-leg ratio and limbs-to-trunk ratio for FM and FFM was compared, respectively. The higher the arm-to-leg FM ratio, the higher the prevalence of CVD-RF (DM-male-OR 7.04, 95% CI 4.22-11.74; DM-female-OR 10.57, 95% CI 5.80-19.26; MetS-male-OR 4.47, 95% CI 3.41- 5.86; MetS-female-OR 8.73, 95% CI 6.38-11.95). The higher the limbs-to-trunk FM ratio (DM-male-OR 0.12, 95% CI 0.07-0.21; DM-female-OR 0.12, 95% CI 0.06-0.23; MetS-male-OR 0.06, 95% CI 0.04-0.08; MetS-female-OR 0.02, 95% CI 0.01-0.04), the higher the limbs-to-trunk FFM ratio (DM-male-OR 0.19, 95% CI 0.11-0.31; DM-female-OR 0.46, 95% CI 0.30-0.70; MetS-male-OR 0.39, 95% CI 0.31-0.50; MetS-female-OR 0.62, 95% CI 0.50-0.78), and the higher the arm-to-leg FFM ratio (MetS-male-OR 0.75, 95% CI 0.59-0.94; MetS-female-OR 0.73, 95% CI 0.58-0.92), the lower the prevalence of CVD-RF. The higher the FM of the legs compared to the arms, FFM of the arms compared to the legs, and FM or FFM of the limbs compared to the trunk, the lower the prevalence of CVD-RF.

Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity.

LMX1B haploinsufficiency causes Nail-patella syndrome (NPS; MIM 161200), characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma. Accordingly in mice, Lmx1b has been shown to play crucial roles in the development of the limb, kidney and eye. Although one functional allele of Lmx1b appears adequate for development, Lmx1b null mice display ventral-ventral distal limbs with abnormal kidney, eye and cerebellar development, more disruptive, but fully concordant with NPS. In Lmx1b functional knockouts (KOs), Lmx1b transcription in the limb is decreased nearly 6-fold, indicating autoregulation. Herein, we report on two conserved Lmx1b-associated cis-regulatory modules (LARM1 and LARM2) that are bound by Lmx1b, amplify Lmx1b expression with unique spatial modularity in the limb, and are necessary for Lmx1b-mediated limb dorsalization. These enhancers, being conserved across vertebrates (including coelacanth, but not other fish species), and required for normal locomotion, provide a unique opportunity to study the role of dorsalization in the fin to limb transition. We also report on two NPS patient families with normal LMX1B coding sequence, but with loss-of-function variations in the LARM1/2 region, stressing the role of regulatory modules in disease pathogenesis.

Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder.

The Rubinstein-Taybi syndrome (RSTS) is a rare congenital developmental disorder characterized by a typical facial dysmorphism, distal limb abnormalities, intellectual disability, and many additional phenotypical features. It occurs at between 1/100,000 and 1/125,000 births. Two genes are currently known to cause RSTS, CREBBP and EP300, mutated in around 55% and 8% of clinically diagnosed cases, respectively. To date, 500 pathogenic variants have been reported for the CREBBP gene and 118 for EP300. These two genes encode paralogs acting as lysine acetyltransferase involved in transcriptional regulation and chromatin remodeling with a key role in neuronal plasticity and cognition. Because of the clinical heterogeneity of this syndrome ranging from the typical clinical diagnosis to features overlapping with other Mendelian disorders of the epigenetic machinery, phenotype/genotype correlations remain difficult to establish. In this context, the deciphering of the patho-physiological process underlying these diseases and the definition of a specific episignature will likely improve the diagnostic efficiency but also open novel therapeutic perspectives. This review summarizes the current clinical and molecular knowledge and highlights the epigenetic regulation of RSTS as a model of chromatinopathy.

Electrophysiological characteristics of patients with nitrous oxide abuse.

Objective: In the young generations with nitrous oxide abuse (N2O), featured electrophysiological response of the peripheral neuropathy caused by nitrous oxide remains to be defined.Methods: Patients with nitrous oxide abuse (20 cases), two variants of Guillain-Barré syndrome (GBS), that is, acute inflammatory demyelinating polyradiculoneuropathy (GBS-AIDP, 19 cases) and acute motor axonal neuropathy (GBS-AMAN, 18 cases), as well as diabetic peripheral neuropathy (DPN, 20 cases) were enrolled into this study. Electrophysiological parameters including distal motor latency (DML), motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), amplitudes of compound muscle action potential (CMAP), and sensory nerve action potential (SNAP) were measured and analyzed by comparing the parameters between the aforementioned patients groups as well as normal control group (20 subjects).Results: Compared to normal control subjects, patients with nitrous oxide abuse showed prolonged DML, slower MNCV and SNCV in the limbs, lower amplitudes of CMAP in the median, tibial and peroneal nerves, and lower SNAP in median and ulnar nerves. Abnormalities of MNCV and amplitudes of CMAP in the lower limbs were significantly higher than that in the upper limbs . Abnormal electrophysiological features of patients with nitrous oxide abuse were dramatically different from those in GBS-AIDP or DPN patients, but similar to those in GBS-AMAN patients.Conclusions: Nitrous oxide abuse could cause abnormal electrophysiological response in the limbs. Some of the parameters (DML, MNCV, SNCV, CMAP and SNAP) appeared significantly different between the patients with nitrous oxide abuse, GBS with AIDP or AMAN, and DPN patients.Significance: Electrophysiological examination could be considered as an important supporting factor in differential diagnosis for nitrous oxide abuse, GBS with AIDP or AMAN, and DPN.

Characterization of Fasciculation Potentials (FPs) in Amyotrophic Lateral Sclerosis (ALS) and Peripheral Nerve Hyperexcitability Syndromes (PNH).

This study is aimed at investigating the features of fasciculation potentials (FPs) in amyotrophic lateral sclerosis (ALS) and peripheral nerve hyperexcitability syndromes (PNH). Needle electrophysiologic examination (EMG) was performed for 5-15 muscles in the ALS and PNH patients. The spontaneous activity of fasciculations and fibrillations/sharp-waves (fibs-sw) was recorded. The distribution, firing frequency, and waveform parameters of FPs in muscles were calculated and compared. In total, 361 muscles in ALS patients and 124 muscles in PNH patients were examined, with the FP detection rates of 45.1% and 53.2%. Moreover, the ALS patients with the upper limb onset had the highest FP detection rate. Fasciculations occurred more frequently in the upper limbs than in the lower limbs in ALS and PNH. The detection rate of fibs-sw in the bulbar muscle was relatively low, which could be elevated when combining fibs-sw and FPs. Benign FPs in PNH were of smaller amplitude, shorter duration, and fewer phases/turns, compared with malignant FPs in ALS. The FP area in PNH was significantly smaller than that in ALS. The incidence of polyphasic FPs in ALS was distinctly greater than that in PNH. The firing frequency of FPs in PNH was higher than that in ALS. There was no significant difference in the amplitude, duration, phases and turns, and area of FPs between groups with and without fibs-sw in the muscles of normal strength in ALS. Conclusively, it is necessary to detect the FPs in the thoracic and bulbar muscles of patients suspected having ALS. FP parameters in ALS are significantly different from PNH.

Hydrogen alleviates acute lung injury induced by limb ischaemia/reperfusion in mice.

AIMS: Limb ischaemia/reperfusion (LIR) occurs in various clinical conditions including critical limb ischaemia, abdominal aortic aneurysm, and traumatic arterial injury. Reperfusion of the acutely ischemic limb can lead to a systemic inflammation response and multiple organ dysfunction syndrome, further resulting in significant morbidity and mortality. Molecular hydrogen exhibits therapeutic activity for the treatment and prevention of many diseases. Our study investigated the possible therapeutic effects of hydrogen and its mechanism of action in a LIR-induced acute lung injury (ALI) model. MATERIALS AND METHODS: Limb ischaemia/-reperfusion model was established in mice. The hydrogen-saturated saline was administered by intraperitoneal injection. Protein level of nuclear factor erythroid 2-related factor 2 (Nrf2), haem oxygenase-1 (HO1) and nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1 (NQO1) was evaluated by immunohistochemistry staining and western blotting. Autophagy-related molecules were evaluated by western blotting. Malondialdehyde (MDA) and superoxide dismutase (SOD) were determined by assay kits. Quantification of ceramides in lung was performed by high-performance liquid chromatography-tandem mass spectrometry. KEY FINDINGS: Molecular hydrogen exhibited a protective effect on the LIR-induced ALI model. Hydrogen decreased malondialdehyde and increased superoxide dismutase activity in lung tissues. Additionally, hydrogen activated Nrf2 signalling in lung tissues. Hydrogen could inhibit the upregulation of autophagy in the present rodent model. Furthermore, ceramide was accumulated in lung tissues because of LIR; however, hydrogen altered the accumulation status. SIGNIFICANCE: Molecular hydrogen was found to be therapeutically effective in the LIR-induced ALI model; the mechanisms of action included modulation of antioxidation and autophagy.

Essential roles of matrix metalloproteinases in axolotl digit regeneration.

Among vertebrates, urodele amphibians possess a unique ability to regenerate various body parts including limbs. However, reports of their digit regeneration remain scarce, especially information about the related genes. In this study, it was evident that matrix metalloproteinases (mmps) including mmp9, mmp3/10a, and mmp3/10b, which play a crucial role in tissue remodeling, are highly expressed during early stages of digit regeneration in axolotl. Using in situ hybridization, we revealed that wound epidermis and blastema are two major origins of the MMPs during the regeneration process. Additionally, we found that the inhibition of MMPs with GM6001 (a wide-spectrum inhibitor of MMPs) in vivo after amputation disturbed normal digit regeneration process and resulted in malformed regenerates. Furthermore, inhibition of MMPs hindered blastema formation and decreased cell apoptosis at early stages in the digit regenerates. All these points suggest that MMPs are required for digit regeneration, as they play a significant role in the regulation of blastema formation.

An analysis of the CatWalk XT and a composite score to assess neurofunctional deficits after photothrombosis in mice.

The purpose of this study was to evaluate CatWalk's capability for assessing the functional outcome after photothrombotic stroke affecting the motor cortex of mice. Mice were tested up to 21 days after photothrombosis or sham surgery using CatWalk, and a composite score assessing functional deficits (neuroscore). The neuroscore demonstrated deficits of the contralateral forelimb for more than two weeks after stroke. There were no asymmetric or coordinative dysfunctions of limbs detected by CatWalk. However, CatWalk data revealed impairment of locomotion speed and its depending parameters for one-week after stroke in strong correlation to the neuroscore. Data suggest that the composite neuroscore allows to more sensitively and precisely specify and quantify photothrombosis-induced hemisyndromes than CatWalk.

＜Editors' Choice＞ Treatment strategy for upper cervical epidural abscess: a literature review.

We aimed to determine available evidences in the literature regarding surgical approaches and methods, timing of surgical interventions, duration of perioperative antibiotics, and duration of nonsurgical treatments (antibiotics administration) in patients with upper cervical (occiput-C2) epidural abscess (UCEA). We performed a literature review of the articles on surgical interventions and antibiotic therapy to treat UCEA, searching the PubMed database for relevant articles published in the English language (as of March 2020). In total, 53 patients with UCEA were identified. Permanent limb paralysis or death was observed in 1/15 (6.7%) patients who received the transoral approach and 2/15 (13.3%) patients who received the transcervical approach, 1/26 (3.8%) patients who underwent surgery before the onset of paralysis, and 2/4 (50.0%) patients who underwent surgery after the onset of paralysis. In 85%-89% of cases, antibiotic administration was continued for 6-12 weeks, which was determined by the confirmation of reduced inflammatory response and/or abscess disappearance on imaging. Differences in surgical approaches may not be associated with the incidence of permanent limb paralysis or death. Surgical interventions before limb paralysis onset are recommended in UCEA patients. In perioperative and nonoperative treatments, antibiotic administration for 6-12 weeks may be supported based on the confirmation of reduced inflammatory response and/or abscess disappearance on imaging. Further investigations are needed.

Current Status of Angiogenic Cell Therapy and Related Strategies Applied in Critical Limb Ischemia.

Critical limb ischemia (CLI) constitutes the most severe form of peripheral arterial disease (PAD), it is characterized by progressive blockade of arterial vessels, commonly correlated to atherosclerosis. Currently, revascularization strategies (bypass grafting, angioplasty) remain the first option for CLI patients, although less than 45% of them are eligible for surgical intervention mainly due to associated comorbidities. Moreover, patients usually require amputation in the short-term. Angiogenic cell therapy has arisen as a promising alternative for these "no-option" patients, with many studies demonstrating the potential of stem cells to enhance revascularization by promoting vessel formation and blood flow recovery in ischemic tissues. Herein, we provide an overview of studies focused on the use of angiogenic cell therapies in CLI in the last years, from approaches testing different cell types in animal/pre-clinical models of CLI, to the clinical trials currently under evaluation. Furthermore, recent alternatives related to stem cell therapies such as the use of secretomes, exosomes, or even microRNA, will be also described.