Mitochondria provide ATP through the process of oxidative phosphorylation, physically located in the inner mitochondrial membrane (IMM). The mitochondrial contact site and organising system (MICOS) ...complex is known as the 'mitoskeleton' due to its role in maintaining IMM architecture.
encodes MIC26, a component of MICOS, whose exact function in its maintenance or assembly has still not been completely elucidated.
We have studied a family in which the most affected subject presented progressive developmental delay, lactic acidosis, muscle weakness, hypotonia, weight loss, gastrointestinal and body temperature dysautonomia, repetitive infections, cognitive impairment and autistic behaviour. Other family members showed variable phenotype presentation. Whole exome sequencing was used to screen for pathological variants. Patient-derived skin fibroblasts were used to confirm the pathogenicity of the variant found in
. Knockout models in
and
were employed to validate MIC26 involvement in MICOS assembly and mitochondrial function.
A likely pathogenic c.350T>C transition was found in
predicting an I117T substitution in MIC26. The mutation caused impaired processing of the protein during import and faulty insertion into the IMM. This was associated with altered MICOS assembly and cristae junction disruption. The corresponding mutation in MIC26 or complete loss was associated with mitochondrial structural and functional deficiencies in yeast and
models.
This is the first case of pathogenic mutation in
, causing altered MICOS assembly and neuromuscular impairment. MIC26 is involved in the assembly or stability of MICOS in humans, yeast and flies.
Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this ...STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US.
STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes vg/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed).
From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p<0·0001). 31 (97%, 95% CI 91–100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8–44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 67% of 33), upper respiratory infection (11 33%), and increased alanine aminotransferase (nine 27%). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study.
STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline.
Novartis Gene Therapies.
OBJECTIVES:Prolonged emergency department to ICU waiting time may delay intensive care treatment, which could negatively affect patient outcomes. The aim of this study was to investigate whether ...emergency department to ICU time is associated with hospital mortality.
DESIGN, SETTING, AND PATIENTS:We conducted a retrospective observational cohort study using data from the Dutch quality registry National Intensive Care Evaluation. Adult patients admitted to the ICU directly from the emergency department in six university hospitals, between 2009 and 2016, were included. Using a logistic regression model, we investigated the crude and adjusted (for disease severity; Acute Physiology and Chronic Health Evaluation IV probability) odds ratios of emergency department to ICU time on mortality. In addition, we assessed whether the Acute Physiology and Chronic Health Evaluation IV probability modified the effect of emergency department to ICU time on mortality. Secondary outcomes were ICU, 30-day, and 90-day mortality.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:A total of 14,788 patients were included. The median emergency department to ICU time was 2.0 hours (interquartile range, 1.3–3.3 hr). Emergency department to ICU time was correlated to adjusted hospital mortality (p < 0.002), in particular in patients with the highest Acute Physiology and Chronic Health Evaluation IV probability and long emergency department to ICU time quintilesodds ratio, 1.29; 95% CI, 1.02–1.64 (2.4–3.7 hr) and odds ratio, 1.54; 95% CI, 1.11–2.14 (> 3.7 hr), both compared with the reference category (< 1.2 hr). For 30-day and 90-day mortality, we found similar results. However, emergency department to ICU time was not correlated to adjusted ICU mortality (p = 0.20).
CONCLUSIONS:Prolonged emergency department to ICU time (> 2.4 hr) is associated with increased hospital mortality after ICU admission, mainly driven by patients who had a higher Acute Physiology and Chronic Health Evaluation IV probability. We hereby provide evidence that rapid admission of the most critically ill patients to the ICU might reduce hospital mortality.
Resolution of inflammation is orchestrated by specialized proresolving lipid mediators (SPMs), and this would be impaired in some cardiovascular diseases. Among SPMs, resolvins (Rv) have beneficial ...effects in cardiovascular pathologies, but little is known about their effect on cardiovascular damage in hypertension.
Aorta, small mesenteric arteries, heart, and peritoneal macrophages were taken from C57BL/6J mice, infused or not with angiotensin II (AngII; 1.44 mg/kg/day, 14 days) in presence or absence of resolvin D2 (RvD2) (100 ng/mice, every second day) starting 1 day before or 7 days after AngII infusion.
Enzymes and receptors involved in SPMs biosynthesis and signaling were increased in aorta or heart from AngII-infused mice. We also observed a differential regulation of SPMs in heart from these mice. Preventive treatment with RvD2 partially avoided AngII-induced hypertension and protected the heart and large and small vessels against functional and structural alterations induced by AngII. RvD2 increased the availability of vasoprotective factors, modified SPMs profile, decreased cardiovascular fibrosis, and increased the infiltration of pro-resolving macrophages. When administered in hypertensive animals with established cardiovascular damage, RvD2 partially improved cardiovascular function and structure, decreased fibrosis, reduced the infiltration of neutrophils, and shifted macrophage phenotype toward a pro-resolving phenotype.
There is a disbalance between proinflammatory and resolution mediators in hypertension. RvD2 protects cardiovascular function and structure when administered before and after the development of hypertension by modulating vascular factors, fibrosis and inflammation. Activating resolution mechanisms by treatment with RvD2 may represent a novel therapeutic strategy for the treatment of hypertensive cardiovascular disease.
Abstract Objectives This article presents a novel approach based on computer-aided diagnostic (CAD) scheme and wavelet transforms to aid pneumonia diagnosis in children, using chest radiograph ...images. The prototype system, named Pneumo-CAD, was designed to classify images into presence (PP) or absence of pneumonia (PA). Materials and methods The knowledge database for the Pneumo-CAD comprised chest images confirmed as PP or PA by two radiologists trained to interpret chest radiographs according to the WHO guidelines for the diagnosis of pneumonia in children. The performance of the Pneumo-CAD was evaluated by a subset of images randomly selected from the knowledge database. The retrieval of similar images was made by feature extraction using wavelets transform coefficients of the image. The energy of the wavelet coefficients was used to compose the feature vector in order to support the computational classification of images as PP or PA. Methodology I worked with a rank-weighted 15-nearest-neighbour scheme, while methodology II employed a distance-dependent weighting for image classification. The performance of the prototype system was assessed by the ROC curve. Results Overall, the Pneumo-CAD using the Haar wavelet presented the best accuracy in discriminating PP from PA for both, methodology I (AUC = 0.97) and methodology II (AUC = 0.94), reaching sensitivity of 100% and specificity of 80% and 90%, respectively. Conclusion Pneumo-CAD could represent a complementary tool to screen children with clinical suspicion of pneumonia, and so to contribute to gather information on the burden of-pneumonia estimates in order to help guide health policies toward preventive interventions.
Pertussis is associated with significant disease burden in children worldwide. In addition to its cyclical nature, resurgences of pertussis cases, hospitalizations and deaths have been reported by ...many countries. We describe the dynamics of pertussis in Brazil, a middle-income country that has experienced a resurgence and that provides good quality data to allow building a dynamic transmission disease model.
We conducted a descriptive analysis of pertussis burden considering data from the national disease surveillance system, national hospitalization information system and national mortality registry. Study period was 2000–2016. Absolute numbers and rates per 100,000 inhabitants over time, by age sub-groups and geographical regions are presented.
From 2000 to 2016, a total of 37,299 reported pertussis cases, 25,240 hospitalizations, and 601 deaths due to pertussis were reported. Although the outcomes – pertussis cases, hospitalizations, and deaths – come from independent information systems, our results document low disease burden with periodic increases every 3–4 years during the years 2000–2010, followed by a sharp increase which peaked in 2014. In both periods, disease burden is concentrated in young children, while its more serious outcomes – hospitalizations and deaths, are concentrated in infants. Pre-outbreak and outbreak disease burden as well as timing of peak during the outbreak period vary by states and within geographical regions, representing valuable resources of data for modelling purposes.
Consistent disease burden patterns were observed over time in Brazil using a variety of data sources. Given the scarcity of good epidemiological data on pertussis available from low- and middle-income countries, our reported data provide valuable information for the assessment of the public health impact and cost-effectiveness modelling studies of newer strategies to prevent and control pertussis. These data were used to build and calibrate a national dynamic transmission model, which was used to evaluate the cost-effectiveness of maternal immunization.
Clinical Trial registry name and registration number: Not applicable.
•TiO2−MWCNT did not caused cytotoxicity on fish cell line up to 100 mg L−1.•TiO2−MWCNT can be internalised by cells probed using Raman microspectroscopy.•TiO2 particles stays attached on MWCNT ...surface after protein corona formation.
Titanium dioxide nanoparticles-multiwalled carbon nanotubes (TiO2−MWCNT) nanohydrid has an enhanced photocatalytic activity across the visible light with promising applications in environmental remediation, solar energy devices and antimicrobial technologies. However, it is necessary to evaluate the toxicological effects of TiO2−MWCNT towards safe and sustainable development of nanohybrids. In this work, we studied the cytotoxicity, protein corona formation and cellular internalisation of TiO2−MWCNT on fibroblasts derived from gonadal rainbow trout tissue (RTG-2) for the first time. This nanohydrid did not show any toxicity effect on RTG-2 cells up to 100 mg L−1 after 24 h of exposure as monitored by alamar blue, neutral red and trypan blue assays (in presence or absence of foetal bovine serum, FBS). Futhermore, cryo-transmission electron microscopy analysis demonstrated that TiO2 particles is attached on nanotube surface after FBS-protein corona formation in cell culture medium. Raman spectroscopy imaging showed that TiO2−MWCNT can be internalised by RTG-2 cells. This work is a novel contribution towards better understanding the nanobiointeractions of nanohydrids linked to their in vitro effects on fish cells in aquatic nanoecotoxicology.
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PspA is one of the most well studied pneumococcal proteins and a promising candidate for a future protein-based anti-pneumococcal vaccine. Nevertheless, its structural and serological variability ...suggests the inclusion of more than one PspA molecule in order to broaden protection. Since different PspAs exhibit variable levels of cross-reactivity, the selection of the protein combination with the highest coverage potential is an essential step for PspA-based vaccine development. This work investigated the level of cross-reactivity within family 1 PspAs, and established a complement based antibody mediated opsonophagocytic assay for measuring the level of cross-protection. Among a panel of ten family 1 PspA molecules, two of them, one belonging to clade 1 and another from clade 2, induced antibodies capable of enhancing complement deposition and mediating the phagocytic killing by mouse peritoneal macrophages of all pneumococci bearing PspA family 1 strains tested, regardless of their serotype. Therefore, we suggest the inclusion of either one in a PspA-based vaccine, as a representative of family 1. Furthermore, our results suggest that opsonophagocytosis by mouse peritoneal cells can be an efficient means of evaluating the induction of protective immune responses in mice across a large number of strains.
The aim of this study was to evaluate the cephalometric outcome of bone-anchored maxillary protraction (BAMP) in individuals with unilateral complete cleft lip and palate (UCLP).
The experimental ...group (EG) comprised 23 individuals (17 males and 6 females) with UCLP and a mean age of 11.7 years. At least 6 months after secondary alveolar bone grafting, Bollard miniplates were installed in the posterior region of the maxilla and in the anterior region of the mandible. Class III elastics were recommended to be worn for 24 hours/day for a mean time of 18 months. Cone beam computed tomography (CBCT) was obtained before (T1) and after treatment (T2). The control group (CG) consisted of 23 individuals with UCLP matched by initial age and gender with the EG and without any orthopaedic or surgical intervention performed between T1 and T2. The interval between T1 and T2 observations was 18 months for both groups. Twenty-one cephalometric variables were analysed. Intra- and intergroup comparisons were performed using paired and independent t-tests, respectively (P < 0.05).
BAMP caused a greater maxillary protrusion (SNA) and a greater decrease of Class III maxillomandibular discrepancy (ANB and Wits appraisal) compared with the CG. BAMP also caused a counterclockwise rotation of the occlusal plane (Occ Plane to FH) and an improvement in the molar relationship compared with controls.
BAMP therapy demonstrated a significant orthopaedic maxillary protraction and an improvement in the Class III skeletal pattern in UCLP.
This study was designed to verify whether different lactation conditions influenced nervous system development. The authors used motor tasks to verify changes in exploratory activity and muscle ...strength of weaned rats from different litter sizes and evaluated the applicability of the grid-walking test for assessing motor abnormalities caused by undernutrition. Alterations in litter size during the suckling period perturbed the nutritional status of pups, which exhibited body weight differences between the groups. Large-litter (L) pups showed significant delays in achieving developmental milestones and neurological reflexes compared to the small-litter (S) and medium-litter (M) pups. The S, M, and L group pups exhibited similar exploratory responses and muscle strength. In the grid-walking and foot-fault tests, the L group pups traveled shorter distances and, consequently, had less footsteps. However, the percentages of foot faults in the L group were higher than S and M groups. These results reflect delayed maturation of structures responsible for sensorimotor responses, such as the cerebellum, because much cerebellar maturation takes place postnatally. This is the first study to report that early undernutrition in pups resulted in suboptimal performances on the grid-walking and foot-fault tests and that the former test was sensitive to alterations caused by nutritional deficiency.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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