Despite lost contractility, a sub-population of rat muscle fibers maintains an assessable excitation-contraction coupling mechanism after long-standing denervation

J Neuropathol Exp Neurol. 2009 Dec;68(12):1256-68. A subpopulation of rat muscle fibers maintains an assessable excitation-contraction coupling mechanism after long-standing denervation despite lost contractility. Squecco R, Carraro U, Kern H, Pond A, Adami N, Biral D, Vindigni V, Boncompagni S, Pietrangelo T, Bosco G, Fanò G, Marini M, Abruzzo PM, Germinario E, Danieli-Betto D, Protasi F, Francini F, Zampieri S. Source Interuniversitary Institute of Myology, Chieti, Italy. Abstract To define the time course and potential effects of electrical stimulation on permanently denervated muscle, we evaluated excitation-contraction coupling (ECC) of rat leg muscles during progression to long-term denervation by ultrastructural analysis, specific binding to dihydropyridine receptors, ryanodine receptor 1 (RYR-1), Ca channels and extrusion Ca pumps, gene transcription and translation of Ca-handling proteins, and in vitro mechanical properties and electrophysiological analyses of sarcolemmal passive properties and L-type Ca current (ICa) parameters. We found that in response to long-term denervation: 1) isolated muscle that is unable to twitch in vitro by electrical stimulation has very small myofibers but may show a slow caffeine contracture; 2) only roughly half of the muscle fibers with "voltage-dependent Ca channel activity" are able to contract; 3) the ECC mechanisms are still present and, in part, functional; 4)ECC-related gene expression is upregulated; and 5) at any time point, there are muscle fibers that are more resistant than others to denervation atrophy and disorganization of the ECC apparatus. These results support the hypothesis that prolonged "resting" [Ca] may drive progression of muscle atrophy to degeneration and that electrical stimulation-induced [Ca] modulation may mimic the lost nerve influence, playing a key role in modifying the gene expression of denervated muscle. Hence, these data provide a potential molecular explanation for the muscle recovery that occurs in response to rehabilitation strategies developed based on empirical clinical observations. PMID: 19915489 [PubMed - indexed for MEDLINE

Gender differences in chronic obstructive pulmonary disease: an analysis of hospitalization indicators

Compared to the last two decades, an increase in chronic obstructive pulmonary disease (COPD) prevalence, morbidity, mortality and disability has clearly emerged among women both in Europe and in all other countries. Despite this evidence, in the international guidelines for COPD there are no sex-specific recommendations. The aim of this study is to evaluate gender differences in patients hospitalized for COPD in Puglia (Italy), with regard to number of admissions, mean age, average length of stay in hospital (ALOS), hospital mortality, re-hospitalization and presence of comorbidities. To identify COPD hospitalized patients, we relied on the Puglia Hospital Discharge Register Database. We included all patients discharged with principal diagnosis of COPD with or without exacerbation (respectively ICD-9-CM codes 491.21 and 491.20) between 2005 and 2016. There has been an increase in the proportion of women’s hospitalizations for COPD, from 2005 [31.9%, 95% confidence interval (CI) 31.1-32.7] to 2016 (37.9%, 95%CI 36.0-40.0). Women need longer hospitalization and in 2016 the proportion of women’s re-hospitalization was greater compared to men. Despite these data, women are less treated with respiratory therapy (ICD-9- CM 93.9x) than men in all the examined years and wards. The prevalence of most common comorbidities is higher among women. The number of COPD hospitalized patients had been reduced in Puglia between 2005 and 2016, with an important increase of female COPD patients, female average age, ALOS and re-hospitalization. Women are treated less and have more comorbidities with a negative impact on clinical progression of COPD, survival and quality of life

High Risk of Secondary Infections Following Thrombotic Complications in Patients With COVID-19

Background. This study’s primary aim was to evaluate the impact of thrombotic complications on the development of secondary infections. The secondary aim was to compare the etiology of secondary infections in patients with and without thrombotic complications. Methods. This was a cohort study (NCT04318366) of coronavirus disease 2019 (COVID-19) patients hospitalized at IRCCS San Raffaele Hospital between February 25 and June 30, 2020. Incidence rates (IRs) were calculated by univariable Poisson regression as the number of cases per 1000 person-days of follow-up (PDFU) with 95% confidence intervals. The cumulative incidence functions of secondary infections according to thrombotic complications were compared with Gray’s method accounting for competing risk of death. A multivariable Fine-Gray model was applied to assess factors associated with risk of secondary infections. Results. Overall, 109/904 patients had 176 secondary infections (IR, 10.0; 95% CI, 8.8–11.5; per 1000-PDFU). The IRs of secondary infections among patients with or without thrombotic complications were 15.0 (95% CI, 10.7–21.0) and 9.3 (95% CI, 7.9–11.0) per 1000-PDFU, respectively (P = .017). At multivariable analysis, thrombotic complications were associated with the development of secondary infections (subdistribution hazard ratio, 1.788; 95% CI, 1.018–3.140; P = .043). The etiology of secondary infections was similar in patients with and without thrombotic complications. Conclusions. In patients with COVID-19, thrombotic complications were associated with a high risk of secondary infections

SARS-CoV-2 vaccination modelling for safe surgery to save lives : data from an international prospective cohort study

Background: Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods: The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18-49, 50-69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty. Results: NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year. Conclusion: As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population.Peer reviewe

Adaptation of Mouse Skeletal Muscle to Long-Term Microgravity in the MDS Mission

The effect of microgravity on skeletal muscles has so far been examined in rat and mice only after short-term (5–20 day) spaceflights. The mice drawer system (MDS) program, sponsored by Italian Space Agency, for the first time aimed to investigate the consequences of long-term (91 days) exposure to microgravity in mice within the International Space Station. Muscle atrophy was present indistinctly in all fiber types of the slow-twitch soleus muscle, but was only slightly greater than that observed after 20 days of spaceflight. Myosin heavy chain analysis indicated a concomitant slow-to-fast transition of soleus. In addition, spaceflight induced translocation of sarcolemmal nitric oxide synthase-1 (NOS1) into the cytosol in soleus but not in the fast-twitch extensor digitorum longus (EDL) muscle. Most of the sarcolemmal ion channel subunits were up-regulated, more in soleus than EDL, whereas Ca2+-activated K+ channels were down-regulated, consistent with the phenotype transition. Gene expression of the atrophy-related ubiquitin-ligases was up-regulated in both spaceflown soleus and EDL muscles, whereas autophagy genes were in the control range. Muscle-specific IGF-1 and interleukin-6 were down-regulated in soleus but up-regulated in EDL. Also, various stress-related genes were up-regulated in spaceflown EDL, not in soleus. Altogether, these results suggest that EDL muscle may resist to microgravity-induced atrophy by activating compensatory and protective pathways. Our study shows the extended sensitivity of antigravity soleus muscle after prolonged exposition to microgravity, suggests possible mechanisms accounting for the resistance of EDL, and individuates some molecular targets for the development of countermeasures

2015/16 seasonal vaccine effectiveness against hospitalisation with influenza a(H1N1)pdm09 and B among elderly people in Europe: Results from the I-MOVE+ project

We conducted a multicentre test-negative caseâ\u80\u93control study in 27 hospitals of 11 European countries to measure 2015/16 influenza vaccine effectiveness (IVE) against hospitalised influenza A(H1N1)pdm09 and B among people aged â\u89¥ 65 years. Patients swabbed within 7 days after onset of symptoms compatible with severe acute respiratory infection were included. Information on demographics, vaccination and underlying conditions was collected. Using logistic regression, we measured IVE adjusted for potential confounders. We included 355 influenza A(H1N1)pdm09 cases, 110 influenza B cases, and 1,274 controls. Adjusted IVE against influenza A(H1N1)pdm09 was 42% (95% confidence interval (CI): 22 to 57). It was 59% (95% CI: 23 to 78), 48% (95% CI: 5 to 71), 43% (95% CI: 8 to 65) and 39% (95% CI: 7 to 60) in patients with diabetes mellitus, cancer, lung and heart disease, respectively. Adjusted IVE against influenza B was 52% (95% CI: 24 to 70). It was 62% (95% CI: 5 to 85), 60% (95% CI: 18 to 80) and 36% (95% CI: -23 to 67) in patients with diabetes mellitus, lung and heart disease, respectively. 2015/16 IVE estimates against hospitalised influenza in elderly people was moderate against influenza A(H1N1)pdm09 and B, including among those with diabetes mellitus, cancer, lung or heart diseases

Effects of sphingomyelin derivatives on innervated and denervated rat soleus muscle

Present work is aimed at studying the effects of natural bioactive sphingomyelin derivatives, on normal and denervated slow-twitch skeletal muscle. The effects on fibre cross sectional area and myosin heavy chains composition of sphingosine (SPH), sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC) were studied. Denervation was bilaterally performed cutting the sciatic nerve at the level of trochanter in adult rats. A group of animals was used as controls. Sphingolipids were continuously released by a mini-osmotic pumps implanted subcutaneously in the scapular region and connected by a catheter to the left (control or denervated) soleus muscles. Supplementation of SPC to adult control soleus muscle, produced significant atrophy of fibres and small changes to fibre type composition. No significant effects of SPH and S1P were found. In contrast, SPH and, to a smaller extent, S1P reduced the atrophy and the slow-to-fast transformation produced by 7-14 days of denervation. Preliminary results indicate that these sphingolipids may exert their action by reducing the overall muscle apoptosis and by activating satellite cells

Nerve influence on rat fast-twitch skeletal muscle regeneration

The degeneration-regeneration process induced by bupivacaine injection has been studied in rat extensor digitorum longus (EDL) muscle in the presence or absence of nerve, the presence of tetrodotoxin (TTX)-induced block of nerve impulse conduction, and the presence of vinblastine- induced block of nerve axoplasmic flow associated to TTX block. Seven and 14 days after bupivacaine injection, myosin heavy chain (MHC) expression was analysed by immunohistochemistry and Western blot. Type 1 MHC isoform expression was almost completely dependent on nerve impulse discharge. Expression of the type 2A showed a zonal distribution in denervated muscles, and a marked down-regulation in the TTX-paralysed, but not in TTXvinblastine- treated muscles. These results show that expression of type 2A isoform in innervated- regenerated fast muscle is mainly due to neuromotor activity. They also suggest that 2A isoform expression is inhibited by a chemical factor carried by axoplasmic flow

Role of sphingosylphosphorylcholine on skeletal muscle denervation and regeneration

Present work is aimed at studying the role of sphingosylphosphorylcholine (SPC), a natural bioactive sphingomyelin derivative, on denervation and regeneration of skeletal muscle. SPC is known to participate in growth, proliferation and survival of various cell systems. The experiments were performed in adult rats. SPC was continuously released by a mini-osmotic pumps connected by a catheter to control, denervated or regenerating (after bupivacaine injection) soleus muscles. Supplementation of SPC to adult muscles, produced significant atrophy of fibres and light changes to fibre type composition. In contrast, SPC did not influence denervation atrophy. During regeneration, SPC produced alterations on fibre dimensions and on myosin expression. In conclusion, it appears that SPC exerts distinctive actions depending on definite condition of skeletal muscl