Tracking of MVPA across childhood and adolescence

\ua9 2024 The AuthorsObjectives: Tracking of physical activity from childhood onwards is an important public health issue, but evidence on tracking is limited. This study quantified the tracking of Moderate-Vigorous Physical Activity (MVPA) across childhood and adolescence in a recent cohort from England. Design: Longitudinal, with a socio-economically representative sample from North-East England, over an 8-year period. Methods: Measures of time spent in MVPA, with an Actigraph GT1M accelerometer, were made at age 7–8y (n = 622, T1), age 9–10y (n = 585, T2), age 12–13y (n = 525, T3) and age 14–16y (n = 361, T4). Tracking of MVPA was assessed using rank order correlations between time spent in MVPA T1–T2, T1–T3, and T1–T4, and by using Cohen\u27s kappa to examine tracking of meeting the MVPA guideline (mean of 60 min/d). We examined whether tracking varied by sex, socio-economic status (SES), initial MVPA, or initial body fatness. Results: Rank order correlations were all statistically significant at p < 0.01 and moderate: 0.58 between T1 and T2; 0.42 between T1 and T3; 0.41 between T1 and T4. Cohen\u27s kappas for meeting the global MVPA guideline were all significant, weakening from moderate to low over the 8 years. Tracking was stronger in higher SES compared to lower SES groups, and there was some evidence that it was stronger in girls than boys, but the other explanatory variables had little influence on tracking. Conclusions: Tracking of MVPA from mid-childhood to mid-adolescence in this cohort was moderate. This study suggests there is a need to establish high MVPA by mid-childhood, and to mitigate the age-related reduction in MVPA which occurs from mid-childhood

Spinal Muscular Atrophy autophagy profile is tissue-dependent: differential regulation between muscle and motoneurons

Motoneurona; Neurodegeneració; Malaltia neuromuscularMotoneurona; Neurodegeneración; Enfermedad neuromuscularMotoneuron; Neurodegeneration; Neuromuscular diseaseSpinal muscular atrophy (SMA) is a neuromuscular genetic disease caused by reduced survival motor neuron (SMN) protein. SMN is ubiquitous and deficient levels cause spinal cord motoneurons (MNs) degeneration and muscle atrophy. Nevertheless, the mechanism by which SMN reduction in muscle contributes to SMA disease is not fully understood. Therefore, studies evaluating atrophy mechanisms in SMA muscles will contribute to strengthening current knowledge of the pathology. Here we propose to evaluate autophagy in SMA muscle, a pathway altered in myotube atrophy. We analized autophagy proteins and mTOR in muscle biopsies, fibroblasts, and lymphoblast cell lines from SMA patients and in gastrocnemius muscles from a severe SMA mouse model. Human MNs differentiated from SMA and unaffected control iPSCs were also included in the analysis of the autophagy. Muscle biopsies, fibroblasts, and lymphoblast cell lines from SMA patients showed reduction of the autophagy marker LC3-II. In SMA mouse gastrocnemius, we observed lower levels of LC3-II, Beclin 1, and p62/SQSTM1 proteins at pre-symptomatic stage. mTOR phosphorylation at Ser2448 was decreased in SMA muscle cells. However, in mouse and human cultured SMA MNs mTOR phosphorylation and LC3-II levels were increased. These results suggest a differential regulation in SMA of the autophagy process in muscle cells and MNs. Opposite changes in autophagy proteins and mTOR phosphorylation between muscle cells and neurons were observed. These differences may reflect a specific response to SMN reduction, which could imply diverse tissue-dependent reactions to therapies that should be taken into account when treating SMA patients.The authors wish to thank the consenting parents and patients. This work was supported by grants from Instituto de Salud Carlos III, Fondo de Inversiones Sanitarias, Unión Europea, Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa” (PI17/00231, PI20/00098), AGAUR (2014 SGR 1087), and Fundació La Marató TV3 (73/C/2020). AG is a Serra Hunter Fellow from Generalitat de Catalunya, AS holds a fellowship from Universitat de Lleida and M.J.P-G was awarded the Marie-Curie fellowship (BP-B 00083). We thank Elaine Lilly, PhD, for English language revision of the manuscript

Identification, characterization and expression of novel Sex Hormone Binding Globulin alternative first exons in the human prostate

<p>Abstract</p> <p>Background</p> <p>The human Sex Hormone Binding Globulin (SHBG) gene, located at 17p13.1, comprises, at least, two different transcription units regulated by two different promoters. The first transcription unit begins with the exon 1 sequence and is responsible for the production of plasma SHBG by the hepatocytes, while the second begins with an alternative exon 1 sequence, which replaces the exon 1 present in liver transcripts. Alternative exon 1 transcription and translation has only been demonstrated in the testis of transgenic mice containing an 11-kb human SHBG transgene and in the human testis. Our goal has been to further characterize the 5' end of the SHBG gene and analyze the presence of the SHBG alternative transcripts in human prostate tissue and derived cell lines.</p> <p>Results</p> <p>Using a combination of <it>in silico </it>and <it>in vitro </it>studies, we have demonstrated that the SHBG gene, along with exon 1 and alternative exon 1 (renamed here exon 1A), contains four additional alternative first exons: the novel exons 1B, 1C, and 1E, and a previously identified exon 1N, which has been further characterized and renamed as exon 1D. We have shown that these four alternative first exons are all spliced to the same 3' splice site of SHBG exon 2, and that exon 1A and the novel exon 1B can be spliced to exon 1. We have also demonstrated the presence of SHBG transcripts beginning with exons 1B, 1C and 1D in prostate tissues and cell lines, as well as in several non-prostatic cell lines. Finally, the alignment of the SHBG mammalian sequences revealed that, while exons 1C, 1D and 1E are very well conserved phylogenetically through non-primate mammal species, exon 1B probably aroused in apes due to a single nucleotide change that generated a new 5' splice site in exon 1B.</p> <p>Conclusion</p> <p>The identification of multiple transcription start sites (TSS) upstream of the annotated first exon of human SHBG, and the detection of the alternative transcripts in human prostate, concur with the prediction of the ENCODE (ENCyclopedia of DNA Elements) project, and suggest that the regulation of SHBG is much more complex than previously reported.</p

Collaborative model for diagnosis and treatment of very rare diseases: experience in Spain with thymidine kinase 2 deficiency

Malaltia mitocondrial; Medicina mitocondrial; Deficiència de timidina cinasa 2 (TK2d)Mitochondrial disease; Mitochondrial medicine; Thymidine kinase 2 deficiency (TK2d)Enfermedad mitocondrial; Medicina mitocondrial; Deficiencia de timidina cinasa 2 (TK2d)Background Mitochondrial diseases are difficult to diagnose and treat. Recent advances in genetic diagnostics and more effective treatment options can improve patient diagnosis and prognosis, but patients with mitochondrial disease typically experience delays in diagnosis and treatment. Here, we describe a unique collaborative practice model among physicians and scientists in Spain focused on identifying TK2 deficiency (TK2d), an ultra-rare mitochondrial DNA depletion and deletions syndrome. Main Body This collaboration spans research and clinical care, including laboratory scientists, adult and pediatric neuromuscular clinicians, geneticists, and pathologists, and has resulted in diagnosis and consolidation of care for patients with TK2d. The incidence of TK2d is not known; however, the first clinical cases of TK2d were reported in 2001, and only ~ 107 unique cases had been reported as of 2018. This unique collaboration in Spain has led to the diagnosis of more than 30 patients with genetically confirmed TK2d across different regions of the country. Research affiliate centers have led investigative treatment with nucleosides based on understanding of TK2d clinical manifestations and disease mechanisms, which resulted in successful treatment of a TK2d mouse model with nucleotide therapy in 2010. Only 1 year later, this collaboration enabled rapid adoption of treatment with pyrimidine nucleotides (and later, nucleosides) under compassionate use. Success in TK2d diagnosis and treatment in Spain is attributable to two important factors: Spain’s fully public national healthcare system, and the designation in 2015 of major National Reference Centers for Neuromuscular Disorders (CSURs). CSUR networking and dissemination facilitated development of a collaborative care network for TK2d disease, wherein participants share information and protocols to request approval from the Ministry of Health to initiate nucleoside therapy. Data have recently been collected in a retrospective study conducted under a Good Clinical Practice–compliant protocol to support development of a new therapeutic approach for TK2d, a progressive disease with no approved therapies. Conclusions The Spanish experience in diagnosis and treatment of TK2d is a model for the diagnosis and development of new treatments for very rare diseases within an existing healthcare system.This study was sponsored by Zogenix, Inc., and ERN EURO-NMD. The sponsors reviewed the drafts and provided medical writing support for draft preparation

Exercise to treat psychopathology and other clinical outcomes in schizophrenia: A systematic review and meta-analysis

Background Psychopathology and side effects of antipsychotic drugs contribute to worsening physical health and long-term disability, and increasing the risk of mortality in these patients. The efficacy of exercise on these factors is not fully understood, and this lack of knowledge may hamper the routine application of physical activity as part of the clinical care of schizophrenia. Aims To determine the effect of exercise on psychopathology and other clinical markers in patients with schizophrenia. We also looked at several moderators. Method MEDLINE, Web of Science, Scopus, CINAHL, SPORTDiscus, PsycINFO, and Cochrane Library databases were systematically searched from inception to October 2022. Randomized controlled trials of exercise interventions in patients 18-65 years old diagnosed with schizophrenia disorder were included. A multilevel random-effects meta-analysis was conducted to pool the data. Heterogeneity at each level of the meta-analysis was estimated via Cochran's Q, I2, and R2. Results Pooled effect estimates from 28 included studies (1,460 patients) showed that exercise is effective to improve schizophrenia psychopathology (Hedges' g = 0.28, [95% CI 0.14, 0.42]). Exercise presented stronger effects in outpatients than inpatients. We also found exercise is effective to improve muscle strength and self-reported disability. Conclusions Our meta-analysis demonstrated that exercise could be an important part in the management and treatment of schizophrenia. Considering the current evidence, aerobic and high-intensity interval training exercises may provide superior benefits over other modalities. However, more studies are warranted to determine the optimal type and dose of exercise to improve clinical outcomes in people with schizophrenia.12 página

Acció dels andrògens en el testicle: un paper per a la meiosi

La funció que duen a terme els andrògens en l'espermatogènesi és, encara en certa mesura, enigmàtica: mentre que llur implicació és absolutament vital en la iniciació i en el manteniment del procés espermatogènic normal, la seva funció específica encara no està definida de manera precisa. Els andrògens, com les altres hormones esteroïdals, actuen a través del seu corresponent receptor anomenat receptor d'andrògens (AR). Fins avui, no hi ha gaire evidència que recolzi l'existència de diverses isoformes de l'AR com en el cas del sistema estrògensreceptor d'estrògens. Per tant, la pregunta de com els andrògens duen a terme la seva acció en l'espermatogènesi s'ha d'abordar definint dos processos: en primer lloc, s'han d'identifi- car amb total certesa els tipus cell. ulars testiculars capaços de respondre directament a l'estimulació androgènica. De manera específica, la qüestió per resoldre és quins són els tipus cellulars que expressen l'AR en el testicle. En segon lloc, sabent també que el complex del lligand unit a l'AR actua com a factor de transcripció, caldrà determinar quins són els gens que estaran activats o reprimits en les cèll. ules que tenen AR en resposta a l'estimulació androgènica. Fins que aquestes dues preguntes no estiguin contestades amb tota certesa, el mecanisme pel qual els andrògens regulen l'espermatogènesi serà, en el millor dels casos, especulatiu. En aquesta revisió presentem evidència que els andrògens actuen únicament a les cèll. ules somàtiques del testicle, com són les cèll. ules de Sertoli, les de Leydig, les mioides peritubulars i les cèll. ules del múscul llis que envolten els vasos sanguinis. A més a més, també discutim la possibilitat que els andrògens siguin indispensables per a l'inici de la meiosi, encara que continua essent desconegut el mecanisme pel qual els andrògens actuen en aquest procés.The role that androgens play in spermatogenesis still remains enigmatic: whereas their involvement is absolutely vital to the initiation and maintenance of the normal spermatogenic process, their specific role is yet to be defined. Androgens, like other steroid hormones, act via their corresponding receptor termed the androgen receptor (AR). To date, there is little evidence to support the notion that there are multiple forms of AR as is the case for the estrogen-estrogen receptor system. Thus, the question of how androgens manifest their action on spermatogenesis becomes one of defining two processes: First, the cell types within the testis that are capable of responding directly to androgen stimulation must be identified with absolute certainty. Specifically, this question can be stated as what cell types in the testis express AR. Second, given that the ligand-bound AR serves as a transcription factor, the question then becomes what are the genes turned on or off in AR positive cells in response to androgen stimulation? Until these two questions are unequivocally answered, the mechanism of how androgens regulate spermatogenesis will remain speculative at best. In this review we present evidence that androgens act solely at the level of the somatic cells of the testis, including Sertoli cells, Leydig cells, peritubular myoid cells and smooth muscle cells surrounding blood vessels. In addition, we discuss the likely possibility that androgens are indispensable for the onset of meiosis, albeit how they accomplish this remains a mystery

Tracking of MVPA across childhood and adolescence

Objectives: Tracking of physical activity from childhood onwards is an important public health issue, but evidence on tracking is limited. This study quantified the tracking of Moderate-Vigorous Physical Activity (MVPA) across childhood and adolescence in a recent cohort from England. Design: Longitudinal, with a socio-economically representative sample from North-East England, over an 8-year period. Methods: Measures of time spent in MVPA, with an Actigraph GT1M accelerometer, were made at age 7–8y (n = 622, T1), age 9–10y (n = 585, T2), age 12–13y (n = 525, T3) and age 14–16y (n = 361, T4). Tracking of MVPA was assessed using rank order correlations between time spent in MVPA T1–T2, T1–T3, and T1–T4, and by using Cohen's kappa to examine tracking of meeting the MVPA guideline (mean of 60 min/d). We examined whether tracking varied by sex, socio-economic status (SES), initial MVPA, or initial body fatness. Results: Rank order correlations were all statistically significant at p < 0.01 and moderate: 0.58 between T1 and T2; 0.42 between T1 and T3; 0.41 between T1 and T4. Cohen's kappas for meeting the global MVPA guideline were all significant, weakening from moderate to low over the 8 years. Tracking was stronger in higher SES compared to lower SES groups, and there was some evidence that it was stronger in girls than boys, but the other explanatory variables had little influence on tracking. Conclusions: Tracking of MVPA from mid-childhood to mid-adolescence in this cohort was moderate. This study suggests there is a need to establish high MVPA by mid-childhood, and to mitigate the age-related reduction in MVPA which occurs from mid-childhood

Collaborative model for diagnosis and treatment of very rare diseases: experience in Spain with thymidine kinase 2 deficiency

[EN]Background: Mitochondrial diseases are difficult to diagnose and treat. Recent advances in genetic diagnostics and more effective treatment options can improve patient diagnosis and prognosis, but patients with mitochondrial disease typically experience delays in diagnosis and treatment. Here, we describe a unique collaborative practice model among physicians and scientists in Spain focused on identifying TK2 deficiency (TK2d), an ultra-rare mitochondrial DNA depletion and deletions syndrome. Main Body: This collaboration spans research and clinical care, including laboratory scientists, adult and pediatric neuromuscular clinicians, geneticists, and pathologists, and has resulted in diagnosis and consolidation of care for patients with TK2d. The incidence ofTK2d is not known; however, the first clinical cases ofTK2d were reported in 2001, and only similar to 107 unique cases had been reported as of 2018. This unique collaboration in Spain has led to the diagnosis of more than 30 patients with genetically confirmed TK2d across different regions of the country. Research affiliate centers have led investigative treatment with nucleosides based on understanding ofTK2d clinical manifestations and disease mechanisms, which resulted in successful treatment of a TK2d mouse model with nucleotide therapy in 2010. Only 1 year later, this collaboration enabled rapid adoption of treatment with pyrimidine nucleotides (and later, nucleosides) under compassionate use. Success in TK2d diagnosis and treatment in Spain is attributable to two important factors: Spain's fully public national healthcare system, and the designation in 2015 of major National Reference Centers for Neuromuscular Disorders (CSURs). CSUR networking and dissemination facilitated development of a collaborative care network for TK2d disease, wherein participants share information and protocols to request approval from the Ministry of Health to initiate nucleoside therapy. Data have recently been collected in a retrospective study conducted under a Good Clinical Practice-compliant protocol to support development of a new therapeutic approach for TK2d, a progressive disease with no approved therapies. Conclusions: The Spanish experience in diagnosis and treatment of TK2d is a model for the diagnosis and development of new treatments for very rare diseases within an existing healthcare system.This study was sponsored by Zogenix, Inc., and ERN EURO-NMD. The sponsors reviewed the drafts and provided medical writing support for draft preparation

Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

Next-generation sequencing; Phenotype–genotype correlations; Spinal muscular atrophySeqüenciació de nova generació; Correlacions fenotip-genotip; Atròfia muscular espinalSecuenciación de nueva generación; Correlaciones fenotipo-genotipo; Atrofia muscular espinalSpinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic loss or pathogenic variants in the SMN1 gene. Copy number and modifier intragenic variants in SMN2, an almost identical paralog gene of SMN1, are known to influence the amount of complete SMN proteins. Therefore, SMN2 is considered the main phenotypic modifier of SMA, although genotype–phenotype correlation is not absolute. We present eleven unrelated SMA patients with milder phenotypes carrying the c.859G>C-positive modifier variant in SMN2. All were studied by a specific NGS method to allow a deep characterization of the entire SMN region. Analysis of two homozygous cases for the variant allowed us to identify a specific haplotype, Smn2-859C.1, in association with c.859G>C. Two other cases with the c.859G>C variant in their two SMN2 copies showed a second haplotype, Smn2-859C.2, in cis with Smn2-859C.1, assembling a more complex allele. We also identified a previously unreported variant in intron 2a exclusively linked to the Smn2-859C.1 haplotype (c.154-1141G>A), further suggesting that this region has been ancestrally conserved. The deep molecular characterization of SMN2 in our cohort highlights the importance of testing c.859G>C, as well as accurately assessing the SMN2 region in SMA patients to gain insight into the complex genotype–phenotype correlations and improve prognostic outcomes.This research was funded by grants from Biogen (ESP-SMG-17-11256), Roche, GaliciAME and Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias and co-funded with ERDF funds (grant no. FIS PI18/000687). A grant from Horizon 2020 IMI2 Screen4Care is acknowledged by E.B., and L.T., E.F.T., R.J., J.S., L.C.-C., F.M., E.B., and L.T. are members of the ERN NMD Network for Rare Diseases. E.F.T. is a member of the ERN ITHACA Network for Rare Diseases

Muscle imaging in laminopathies: Synthesis study identifies meaningful muscles for follow-up

Introduction: Particular fibroadipose infiltration patterns have been recently described by muscle imaging in congenital and later onset forms of LMNA-related muscular dystrophies (LMNA-RD). Methods: Scores for fibroadipose infiltration of 23 lower limb muscles in 34 patients with LMNA-RD were collected from heat maps of 2 previous studies. Scoring systems were homogenized. Relationships between muscle infiltration and disease duration and age of onset were modeled with random forests. Results: The pattern of infiltration differs according to disease duration but not to age of disease onset. The muscles whose progression best predicts disease duration were semitendinosus, biceps femoris long head, gluteus medius, and semimembranosus. Discussion: In LMNA-RD, our synthetic analysis of lower limb muscle infiltration did not find major differences between forms with different ages of onset but allowed the identification of muscles with characteristic infiltration during disease progression. Monitoring of these specific muscles by quantitative MRI may provide useful imaging biomarkers in LMNA-RD. Muscle Nerve 58:812-817, 201