Search

Abstract Background Morquio A syndrome is a rare, autosomal recessive, progressively debilitating disorder, with multi-system impairments and high medical burden. Quebec, Canada has a large Morquio A population, which is considered unique due to the presence of founder pathogenic variants. The objectives of this study were to document the genetic and clinical heterogeneity of patients with Morquio A in Quebec, to better characterize the phenotype of those with the French Canadian founder pathogenic variant (NM_000512.5: c.1171A>G, p.Met391Val), and to describe the natural history of the patients treated with elosulfase alfa enzyme replacement therapy. Patients with Morquio A were genotyped for pathogenic variants in the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. Clinical data were retrospectively collected from medical charts of patients and included medical history, height, physical examination, respiratory function tests, electrocardiogram, echocardiogram, endurance in the 6-min walk test (6MWT), and activities of daily living (ADL) as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ). Longitudinal data were collected retrospectively and prospectively for patients treated with elosulfase alfa. Results A total of 33 patients, aged 5–63 years, were included in the analysis. Patients with the founder pathogenic variant (n = 17) generally exhibited a non-classical form of Morquio A. As compared with patients with a non-founder pathogenic variant (n = 16), these patients were generally taller, had greater endurance and were better able to perform ADL. However, they still had significant musculoskeletal disease. Most of the 26 patients treated with elosulfase alfa, regardless of pathogenic variant, showed improvements in endurance and ADL. After 5 to 12 months of treatment, the mean improvement from baseline in the 6MWT was 23% and 10 of 14 patients improved in at least one MPS-HAQ domain. Endurance and ADL generally continued to improve or maintained stable in the long term (up to 7 years). Four out of 19 treated patients with echocardiogram data at follow-up showed progression of cardiac disease. Conclusions In Quebec, Canada, Morquio A frequently manifests as a non-classical form of the syndrome due to a founder effect. Patients treated with elosulfase alfa generally show long-term improvement or stability in endurance and function, regardless of pathogenic variant.

Abstract Purpose Anterior cruciate ligament (ACL) rupture is a common injury and psychological parameters measured at 6–8 months are said to be almost more predictive for return to sport (RTS) than physiological. Purpose was 1) to evaluate the correlation between knee apprehension using ACL‐RSI and physical factors after ACL reconstruction (ACLR), 2) to assess the correlation between ACL‐RSI and patient parameters (age, pivot‐sport, BMI), and 3) to evaluate ACL‐RSI over time. Methods Patients with ACLR with or without meniscal repair between 2013 and 2020 were retrospectively analyzed. Including criteria were RTS testing battery, assessed at least 6 months after surgery, including physical parameters (strength, triple hop test, side hop test, and bilateral knee stability) and psychological parameters (ACL‐RSI). 5 subgroups were analyzed to assessed factors such as age, BMI, pivot sport, time interval between two RTS testing battery. Results Three hundred three patients (212 male, 91 female) presenting ACLR were included. Mean age at surgery was 27 (± 8) years. 258 patients practiced pivot‐sport activity and 45 non‐pivot‐sport activity. The mean interval between ACL rupture and surgery was 6.5 (± 4.5) months. RTS testing battery were performed at 8 (± 7) months after ACLR. Mean ACL‐RSI was 58 (± 28). 1) ACL‐RSI was not influenced by muscle strength, coordination and stability of the knee. 2) ACL‐RSI was significantly better in lower BMI and non‐pivot‐sport activities. No correlation was found between graft type, age, sex, and ACL‐RSI assessment. 3) For patients who performed two RTS testing battery at 8 and 12 months, ACL‐RSI did not significantly increase over time (56 to 64 points, p = 0.22) in spite of significant increased quadriceps (127 to 151 Nm/kg, p = 0.005) and hamstring (93 to 105 Nm/kg, p = 0.05) strength. Conclusions Psychological readiness before RTS, measured upon ACL‐RSI does not correlate with any physical parameter at 8–12 months postoperatively. Although quadriceps and hamstring strength increased significantly over time, ACL‐RSI does not and must therefore be routinely assessed.

Summary: Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

Abstract Background Osteochondritis dissecans is a condition wherein there is a subchondral bone lesion that causes pain, inflammation, and cartilage damage. Dominant Familial Osteochondritis Dissecans is a rare and severe form of osteochondritis dissecans (OCD). It is caused by heterozygous pathogenic variants in the gene encoding Aggrecan; ACAN. Aggrecan, a proteoglycan, is an essential component of the articular and growth plate cartilage. Methods Herein, we report three individuals from one family; the proband who presented with short stature, a lower limb bone exostosis, and bilateral knee and elbow OCD at the age of 13 years old. His twin brother presented with isolated short stature and his father with short stature and lumbar disc herniation. Results Next‐generation sequencing of the ACAN gene in the proband identified a frameshift variant which is also present in the brother and father with short stature. The proband was treated surgically with bilateral elbow microfracture, after the failure of conservative therapy. Conclusion To the best of our knowledge, this is the first patient with an aggrecanopathy who presents with osteochondritis dissecans due to a frameshift variant. This family presents with variable expressivity which might be attributed to modifier genes.

Osteoporosis is a multifactorial disorder characterized by low bone mass and strength, leading to increased risk of fracture. The WNT pathway plays a critical role in bone remodeling by enhancing osteoblastic differentiation, which promotes bone formation, and inhibiting osteoclastic differentiation, decreasing bone resorption. Therefore, genetic alterations of this pathway will lead to impaired bone homeostasis and could contribute to varying response to treatment. We present the case of two brothers with early osteoporosis who were found to have a heterozygous variant of unknown significance in the WNT1 gene, c.1060_1061delCAinsG (p.H354Afs*39). This finding demonstrates that frameshift variants in WNT1 may also act in a dominant fashion leading to decreased bone mass.

Calvarial Doughnut Lesions with Bone Fragility (CDL) is an autosomal dominant genetic disease, characterized by low bone mineral density, multiple fractures starting in childhood, and sclerotic doughnut-shaped lesions in the cranial bones. Aubé and colleagues described in 1988 a French-Canadian family of 12 affected members who had a clinical diagnosis of doughnut lesions of the skull, with pathological fractures, osteopenia, “bone in bone” in the vertebral bodies and squaring of metatarsal and metacarpal bones. Herein we study new members of this family. Sequential genetic testing identified a nonsense variant c.148C>T, p. Arg50⁎ in SGMS2 previously reported in other families. SGMS2 encodes Sphingomyelin Synthase 2, which produces Sphingomyelin (SM), a major lipid component of the plasma membrane that plays a role in bone mineralization. The nonsense variant is associated with milder phenotype. The proband presents with bone in bone vertebral appearance that had been defined uniquely in the first cases described in the same family. The proband's son was identified to carry the same variant, which makes him the sixth generation with the diagnosis of CDL. We also report that the same pathogenic variant was identified in another previously described family, from France. These reports further confirm the genetic basis of CDL, the recurrence of the same variant (p.Arg50*) in individuals of the same ancestry, and the variable penetrance of some of the clinical findings.

In regular times, implementing exercise-based injury prevention programs into the training routine of high-level and professional athletes represents a key and challenging aspect to decrease injury risk. Barriers to implementing such prevention programs have previously been identified such as lack of resources, logistic issues or motivation. The COVID-19 pandemic associated with restrictions on daily life dramatically impacted sports participation from training to competition. It is therefore reasonable to assume that such lockdown-like context has exacerbated the challenge to implement exercise-based injury prevention programs, potentially leading to a greater musculoskeletal injury risk. In this narrative review, recommendations are proposed for building an expertise- and evidence-based Standard Operating Procedure for injury prevention in lockdown-like contexts for high-level and professional athletes. The following recommendations can be provided: (1) assess the global and sport-specific risks in the light of the ongoing cause of isolation; (2) adapt remote training materials and programs; (3) ensure regular quality communication within the staff, between athletes and the staff as well as between athletes; (4) follow the athlete's mental well-being; and (5) plan for a safe return-to-sports as well as for an ongoing monitoring of the load-recovery balance. These key domains should further be addressed to comply with local policies, which are subject to change over time in each individual country. The use of these recommendations may improve the readiness of athletes, coaches, physicians and all sports stakeholders for future lockdown-like contexts.

A chemical analysis of water quality cannot detect some toxicants due to time constraints, high costs, and limited interactions for detection. Bioassays would offer a complementary means to assess pollution levels in water. Euglena is a flagellate green alga and an excellent system for toxicity testing thanks to its ease of culture, rapid growth, and quick response to environmental stresses. Herein, we examined the sensitivity of E. agilis to seven heavy metals by analyzing six end-point parameters: motility, velocity, cell compactness, upward swimming, r-value, and alignment. Notably, the velocity of E. agilis was most sensitive to cadmium (96.28 mg·L−1), copper (6.51 mg·L−1), manganese (103.28 mg·L−1), lead (78.04 mg·L−1), and zinc (101.90 mg·L−1), while r-values were most sensitive to arsenic (12.84 mg·L−1) and mercury (4.26 mg·L−1). In this study, velocity and r-values are presented as useful biomarkers for the assessment of metal toxicity in Euglena. The metals As, Cd, Cu, and Pb were suitable for this test. The advantages of the ecotoxicity test are its rapidity: It takes 10 min to obtain results, as opposed to the typical 3–4 d of exposure time with intensive labor. Moreover, this test can be performed at room temperature under dark conditions.

Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and influence disease. Lysine acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here, we report that cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development. Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis, and scant H4K16 propionylation. Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation. Moreover, we describe KAT8 variants in 9 patients with intellectual disability, seizures, autism, dysmorphisms, and other anomalies. The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation. Valproate was effective for treating epilepsy in at least 2 of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies., Introduction Hundreds of epigenetic regulators have been identified and characterized, but much less is known about their pathophysiological roles. Lysine acetyltransferases (KATs) form a prominent group of chromatin regulators, catalyze [...]

Despite their widespread use in the chemical industries, hydrogenation reactions remain challenging. Indeed, the nature of reagents and catalysts induce intrinsic safety challenges, in addition to demanding process development involving a 3-phase system. Here, to address common issues, we describe a successful process intensification study using a meso-scale flow reactor applied to a hydrogenation reaction of ethyl cinnamate at kilo lab scale with heterogeneous catalysis. This method relies on the continuous pumping of a catalyst slurry, delivering fresh catalyst through a structured flow reactor in a continuous fashion and a throughput up to 54.7 g/h, complete conversion and yields up to 99%. This article describes the screening of equipment, reactions conditions and uses statistical analysis methods (Monte Carlo/DoE) to improve the system further and to draw conclusions on the key influential parameters (temperature and residence time).

Visceral leishmaniasis is a protozoan disease associated with high fatality rate in developing countries. Although the drug pipeline is constantly improving, available treatments are costly and live-threatening side effects are not uncommon. Moreover, an approved vaccine against human leishmaniasis does not exist yet. Using whole antigens from Leishmania donovani promastigotes (LdAg), we investigated the protective potential of a novel adjuvant-free vaccine strategy. Immunization of mice with LdAg via the intradermal or the intranasal route prior to infection decreases the parasitic burden in primary affected internal organs, including the liver, spleen, and bone marrow. Interestingly, the intranasal route is more efficient than the intradermal route, leading to better parasite clearance and remarkable induction of adaptive immune cells, notably the helper and cytotoxic T cells. In vitro restimulation experiments with Leishmania antigens led to significant IFN-γ secretion by splenocytes; therefore, exemplifying specificity of the adaptive immune response. To improve mucosal delivery and the immunogenic aspects of our vaccine strategy, we used polysaccharide-based nanoparticles (NP) that carry the antigens. The NP-LdAg formulation is remarkably taken up by dendritic cells and induces their maturation in vitro, as revealed by the increased expression of CD80, CD86 and MHC II. Intranasal immunization with NP-LdAg does not improve the parasite clearance in our experimental timeline; however, it does increase the percentage of effector and memory T helper cells in the spleen, suggesting a potential induction of long-term memory. Altogether, this study provides a simple and cost-effective vaccine strategy against visceral leishmaniasis based on LdAg administration via the intranasal route, which could be applicable to other parasitic diseases.

This work aims to evaluate whether nanoassemblies (NanoSb) made from antimony(V) complexes with octanoyl-N-methylglucamide (SbL8) or decanoyl-N-methylglucamide (SbL10) would effectively target the infection sites in visceral and cutaneous leishmaniases (VL and CL). NanoSb were investigated regarding stability at different pHs, accumulation of Sb in the macrophage host cell and liver, and in vitro and in vivo activities in models of leishmaniasis. The kinetic stability assay showed that NanoSb are stable at neutral pH, but release incorporated lipophilic substance after conformational change in media that mimic the gastric fluid and the parasitophorous vacuole. NanoSb promoted greater accumulation of Sb in macrophages and in the liver of mice after parenteral administration, when compared to conventional antimonial Glucantime®. SbL10 was much more active than Glucantime® against intramacrophage Leishmania amastigotes and less cytotoxic than SbL8 against macrophages. The in vitro SbL10 activity was further enhanced with co-incorporated miltefosine. NanoSb showed high antileishmanial activity in the L. donovani murine VL after parenteral administration and moderate activity in the L. amazonensis murine CL after topical treatment. This study supports the ability of NanoSb to effectively deliver a combination of Sb and co-incorporated drug to host cell and infected tissues, in a better way than Glucantime® does.