Role of cardiac magnetic resonance in stratifying arrhythmogenic risk in mitral valve prolapse patients: a systematic review and meta-analysis.

OBJECTIVES: To perform a systematic review and meta-analysis of studies investigating the diagnostic value of cardiac magnetic resonance (CMR) features for arrhythmic risk stratification in mitral valve prolapse (MVP) patients. MATERIALS AND METHODS: EMBASE, PubMed/MEDLINE, and CENTRAL were searched for studies reporting MVP patients who underwent CMR with assessment of: left ventricular (LV) size and function, mitral regurgitation (MR), prolapse distance, mitral annular disjunction (MAD), curling, late gadolinium enhancement (LGE), and T1 mapping, and reported the association with arrhythmia. The primary endpoint was complex ventricular arrhythmias (co-VAs) as defined by any non-sustained ventricular tachycardia, sustained ventricular tachycardia, ventricular fibrillation, or aborted sudden cardiac death. Meta-analysis was performed when at least three studies investigated a CMR feature. PROSPERO registration number: CRD42023374185. RESULTS: The meta-analysis included 11 studies with 1278 patients. MR severity, leaflet length/thickness, curling, MAD distance, and mapping techniques were not meta-analyzed as reported in < 3 studies. LV end-diastolic volume index, LV ejection fraction, and prolapse distance showed small non-significant effect sizes. LGE showed a strong and significant association with co-VA with a LogORs of 2.12 (95% confidence interval (CI): [1.00, 3.23]), for MAD the log odds-ratio was 0.95 (95% CI: [0.30, 1.60]). The predictive accuracy of LGE was substantial, with a hierarchical summary ROC AUC of 0.83 (95% CI: [0.69, 0.91]) and sensitivity and specificity rates of 0.70 (95% CI: [0.41, 0.89]) and 0.80 (95% CI: [0.67, 0.89]), respectively. CONCLUSIONS: Our study highlights the role of LGE as the key CMR feature for arrhythmia risk stratification in MVP patients. MAD might complement arrhythmic risk stratification. CLINICAL RELEVANCE STATEMENT: LGE is a key factor for arrhythmogenic risk in MVP patients, with additional contribution from MAD. Combining MRI findings with clinical characteristics is critical for evaluating and accurately stratifying arrhythmogenic risk in MVP patients. KEY POINTS: MVP affects 2-3% of the population, with some facing increased risk for arrhythmia. LGE can assess arrhythmia risk, and MAD may further stratify patients. CMR is critical for MVP arrhythmia risk stratification, making it essential in a comprehensive evaluation.

Negative Symptoms and Cognitive Deficits in Primary Psychoses: an Observational Study in a Psychiatric Rehabilitation Centre.

Negative symptoms (NSs) and cognitive deficits (CDs) negatively affect patients' quality of life with primary psychosis. Our observational study evaluated the percentage of NSs in a group of inpatients of a psychiatric rehabilitation facility and the variation of the interaction with CDs during the COVID-19 pandemic. The results showed a significant correlation between NSs and CDs in the first observation period (PANSS - FSNS p=0.001; BNSS p=0.023; Epitrack p=0.00) and a stabilization of the results between the first and second observation periods (PANSS - FSNS: p=0.094; BNSS p=0.466; Epitrack p=0.026).

Decreased amount of vimentin N-terminal truncated proteolytic products in parkin-mutant skin fibroblasts.

Vimentin, a member of cytoskeleton intermediate filaments proteins, plays a critical role in cell structure and dynamics. The present proteomic study reveals reduced amount of six different lengths, N-terminal truncated proteolytic products of vimentin, in the primary skin fibroblasts from two unrelated PD patients, as compared to control fibroblasts. The decreased amount of N-terminal truncated forms of vimentin in parkin-mutant fibroblasts, could contribute to impairment of cellular function, potentially contributing to the pathogenesis of Parkinson disease.

Rapid evolution of female-biased genes among four species of Anopheles malaria mosquitoes.

Understanding how phenotypic differences between males and females arise from the sex-biased expression of nearly identical genomes can reveal important insights into the biology and evolution of a species. Among Anopheles mosquito species, these phenotypic differences include vectorial capacity, as it is only females that blood feed and thus transmit human malaria. Here, we use RNA-seq data from multiple tissues of four vector species spanning the Anopheles phylogeny to explore the genomic and evolutionary properties of sex-biased genes. We find that, in these mosquitoes, in contrast to what has been found in many other organisms, female-biased genes are more rapidly evolving in sequence, expression, and genic turnover than male-biased genes. Our results suggest that this atypical pattern may be due to the combination of sex-specific life history challenges encountered by females, such as blood feeding. Furthermore, female propensity to mate only once in nature in male swarms likely diminishes sexual selection of post-reproductive traits related to sperm competition among males. We also develop a comparative framework to systematically explore tissue- and sex-specific splicing to document its conservation throughout the genus and identify a set of candidate genes for future functional analyses of sex-specific isoform usage. Finally, our data reveal that the deficit of male-biased genes on the X Chromosomes in Anopheles is a conserved feature in this genus and can be directly attributed to chromosome-wide transcriptional regulation that de-masculinizes the X in male reproductive tissues.

Altered protein expression pattern in skin fibroblasts from parkin-mutant early-onset Parkinson's disease patients.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder caused primarily by selective degeneration of the dopaminergic neurons in substantia nigra. In this work the proteomes extracted from primary fibroblasts of two unrelated, hereditary cases of PD patients, with different parkin mutations, were compared with the proteomes extracted from commercial adult normal human dermal fibroblasts (NHDF) and primary fibroblasts from the healthy mother of one of the two patients. The results show that the fibroblasts from the two different cases of parkin-mutant patients display analogous alterations in the expression level of proteins involved in different cellular functions, like cytoskeleton structure-dynamics, calcium homeostasis, oxidative stress response, protein and RNA processing.

Regulation of the biogenesis of OXPHOS complexes in cell transition from replicating to quiescent state: involvement of PKA and effect of hydroxytyrosol.

A study is presented on the expression of mitochondrial oxidative phosphorylation complexes in exponentially growing and serum-starved, quiescent human fibroblast cultures. The functional levels of respiratory complexes I and III and complex V (adenosine triphosphate (ATP) synthase) were found to be severely depressed in serum-starved fibroblasts. The depression of oxidative phosphorylation system (OXPHOS) complexes was associated with reduced levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and the down-stream nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factors (TFAM). In serum-starved fibroblasts decrease of the catalytic activity of AMP cyclic dependent protein kinase (PKA) and phosphorylation of cAMP response element-binding protein (CREB), the transcription coactivator of the PGC-1α gene, was found. Hydroxytyrosol prevented the decline in the expression of the PGC-1α transcription cascade of OXPHOS complexes in serum-starved fibroblast cultures. The positive effect of HT was associated with activation of PKA and CREB phosphorylation. These results show involvement of PKA, CREB and PGC-1α in the regulation of OXPHOS in cell transition from the replicating to the quiescent state.

The mechanism of alternative splicing of the X-linked NDUFB11 gene of the respiratory chain complex I, impact of rotenone treatment in neuroblastoma cells.

A study is presented on the regulation of alternative splicing (AS) of the Ndufb11 gene of complex I of the mitochondrial respiratory chain and the impact on this process of rotenone treatment in neuroblastoma cells. In physiological conditions the Ndufb11 gene produces at high level a short transcript isoform encoding for a 153 aa protein. This subunit is essential for the assembly of a functional and stable mammalian complex I. The gene produces also, at low level, a longer transcript isoform encoding for a 163 aa protein whose role is unknown. Evidence is presented here showing that the level of the two isoforms is regulated by three DGGGD ESS elements located in exon 2 which can bind the hnRNPH1 protein. In neuronal cells rotenone treatment affects the Ndufb11 alternative splicing pathway, with the increase of the 163/153 mRNAs ratio. This effect appears to be due to the down-regulation of the hnRNPH1 protein. Since rotenone induces apoptosis in neuronal cells, the post-transcriptional regulation of the Ndufb11 gene can be involved in the programmed cell death process.

Cytokine gene polymorphisms associate with microbiogical agents in periodontal disease: our experience.

Periodontics has evolved from a simplistic model to a more complex interplay between infection and host response. Genetic factors have been a new addition to the list of risk factors for periodontal diseases. The processes leading to destruction and regeneration of the destroyed tissues are of great interest to both researchers and clinicians. The selective susceptibility of subjects for periodontitis has remained an enigma and wide varieties of risk factors have been implicated for the manifestation and progression of periodontitis. Emerging pathway models suggest that gene-environment interactions are etiologically important in disease pathogenesis. The current practical utility of genetic knowledge in periodontitis is limited. Allelic variants at multiple gene loci probably influence periodontitis susceptibility. The pro-inflammatory cytokine interleukin-1 (IL-1) is a key modulator of host responses to microbial infection and a major modulator of extracellular matrix catabolism and bone resorption, and polymorphisms in the IL-1 gene cluster have been associated with an increased risk of developing severe adult periodontitis. The aim of this study was to test if polymorphisms of genes of IL-1α(+4845) and IL-1ß(+3954) were linked with periodontitis, in a case-control study population, delimited to a specific geographic area, in association with microbiological findings. The polymorphisms observed in IL-1α(+4845) and IL-1ß(+3954) single nucleotide polymorphisms (SNPs), was significantly different among the study groups (healthy controls, mild, moderate and severe periodontitis with p<0.05, d.f.=1. We found a significant correlation between the severe form of periodontitis and the presence of composite genotype (p < 0.05, d.f.=1, calculated among healthy vs. severe). Furthermore a statistically significant association between the presence of bacteria and periodontitis was detected (p<0.05, d.f.=1). In the current investigation findings were concordant with literature observations.

Cardiac magnetic resonance of hypertrophic heart phenotype: A review.

Hypertrophic heart phenotype is characterized by an abnormal left ventricular (LV) thickening. A hypertrophic phenotype can develop as adaptive response in many different conditions such as aortic stenosis, hypertension, athletic training, infiltrative heart muscle diseases, storage disorders and metabolic disorders. Hypertrophic cardiomyopathy (HCM) is the most frequent primary cardiomyopathy (CMP) and a genetical cause of cardiac hypertrophy. It requires the exclusion of any other cause of LV hypertrophy. Cardiac magnetic resonance (CMR) is a comprehensive imaging technique that allows a detailed evaluation of myocardial diseases. It provides reproducible measurements and myocardial tissue characterization. In clinical practice CMR is increasingly used to confirm the presence of ventricular hypertrophy, to detect the underlying cause of the phenotype and more recently as an efficient prognostic tool. This article aims to provide a detailed overview of the applications of CMR in the setting of hypertrophic heart phenotype and its role in the diagnostic workflow of such condition.

Dysfunction of mitochondrial respiratory chain complex I in neurological disorders: genetics and pathogenetic mechanisms.

This chapter covers genetic and biochemical aspects of mitochondrial bioenergetics dysfunction in neurological disorders associated with complex I defects. Complex I formation and functionality in mammalian cells depends on coordinated expression of nuclear and mitochondrial genes, post-translational subunit modifications, mitochondrial import/maturation of nuclear encoded subunits, subunits interaction and stepwise assembly, and on proteolytic processing. Examples of complex I dysfunction are herein presented: homozygous mutations in the nuclear NDUFS1 and NDUFS4 genes for structural components of complex I; an autosomic recessive form of encephalopathy associated with enhanced proteolytic degradation of complex I; familial cases of Parkinson associated to mutations in the PINK1 and Parkin genes, in particular, homoplasmic mutations in the ND5 and ND6 mitochondrial genes of the complex I, coexistent with mutation in the PINK1 gene. This knowledge, besides clarifying molecular aspects of the pathogenesis of hereditary diseases, can also provide hints for understanding the involvement of complex I in neurological disorders, as well as for developing therapeutical strategies.

Rat embryo exposure to all-trans retinoic acid results in postnatal oxidative damage of respiratory complex I in the cerebellum.

The results of the present work show that the exposure of pregnant rats to low doses of all-trans-retinoic acid (ATRA) (2.5 mg/kg body weight) results in postnatal dysfunction of complex I of the respiratory chain in the cerebellum of the offspring. ATRA had no effect on the postnatal expression of complex I and did not exert any direct inhibitory effect on the enzymatic activity of the complex. The ATRA embryonic exposure resulted, however, in a marked increase in the level of carbonylated proteins in the mitochondrial fraction of the cerebellum, in particular of complex I subunits. The postnatal increase of the carbonylated proteins correlated directly with the inhibition of the activity of complex I. ATRA had, on the other hand, no effect on oxygen free-radical scavengers. It is proposed that embryonic exposure to ATRA results in impairment of protein surveillance in the cerebellum, which persists after birth and results in accumulation of oxidatively damaged complex I.

cAMP-dependent protein kinase regulates post-translational processing and expression of complex I subunits in mammalian cells.

Work is presented on the role of cAMP-dependent protein phosphorylation in post-translational processing and biosynthesis of complex I subunits in mammalian cell cultures. PKA-mediated phosphorylation of the NDUFS4 subunit of complex I promotes in cell cultures in vivo import/maturation in mitochondria of the precursor of this protein. The import promotion appears to be associated with the observed cAMP-dependent stimulation of the catalytic activity of complex I. These effects of PKA are counteracted by activation of protein phosphatase(s). PKA and the transcription factor CREB play a critical role in the biosynthesis of complex I subunits. CREB phosphorylation, by PKA and/or CaMKs, activates at nuclear and mitochondrial level a transcriptional regulatory cascade which promotes the concerted expression of nuclear and mitochondrial encoded subunits of complex I and other respiratory chain proteins.

The allosteric protein interactions in the proton-motive function of mammalian redox enzymes of the respiratory chain.

Insight into mammalian respiratory complexes defines the role of allosteric protein interactions in their proton-motive activity. In cytochrome c oxidase (CxIV) conformational change of subunit I, caused by O2 binding to heme a32+-CuB+ and reduction, and stereochemical transitions coupled to oxidation/reduction of heme a and CuA, combined with electrostatic effects, determine the proton pumping activity. In ubiquinone-cytochrome c oxidoreductase (CxIII) conformational movement of Fe-S protein between cytochromes b and c1 is the key element of the proton-motive activity. In NADH-ubiquinone oxidoreductase (CxI) ubiquinone binding and reduction result in conformational changes of subunits in the quinone reaction structure which initiate proton pumping.

Pathogenetic mechanisms in hereditary dysfunctions of complex I of the respiratory chain in neurological diseases.

This paper covers genetic and biochemical aspects of mitochondrial bioenergetics dysfunction in hereditary neurological disorders associated with complex I defects. Three types of hereditary complex I dysfunction are dealt with: (i) homozygous mutations in the nuclear genes NDUFS1 and NDUFS4 of complex I, associated with mitochondrial encephalopathy; (ii) a recessive hereditary epileptic neurological disorder associated with enhanced proteolytic degradation of complex I; (iii) homoplasmic mutations in the ND5 and ND6 mitochondrial genes of the complex, coexistent with mutation in the nuclear PINK1 gene in familial Parkinsonism. The genetic and biochemical data examined highlight different mechanisms by which mitochondrial bioenergetics is altered in these hereditary defects of complex I. This knowledge, besides clarifying molecular aspects of the pathogenesis of hereditary diseases, can also provide hints for understanding the involvement of complex I in sporadic neurological disorders and aging, as well as for developing therapeutical strategies.

cAMP/Ca2+ response element-binding protein plays a central role in the biogenesis of respiratory chain proteins in mammalian cells.

In mammalian cells, promotion of mitochondrial biogenesis by various agents involves cAMP and Ca(2+)-mediated signal transduction pathways. Recruitment of these pathways results in phosphorylation by cAMP and Ca(2+)-dependent protein kinases of cAMP/Ca(2+) response element-binding protein (CREB). Phosphorylation of CREB, bound to transcriptional complexes of target genes, activates a down-stream cascade of transcriptional complexes, which involve in sequence, the nuclear factors TORCs, PGC-1, NRF1 and NRF2, and the mitochondrial factor mitochondrial transcriptional factor A. CREB also binds directly to the D-loop of mitochondrial DNA and activates its expression. Activation of this network of transcriptional complexes results in concerted promotion of the expression of nuclear and mitochondrial genes encoding subunits of oxidative phosphorylation complexes.

Maxillary constriction treated by a new palatal distractor device: surgical and occlusal evaluations of 10 patients.

PURPOSE: To study the changes in maxillary dimensions after the application of a new distractor on 10 adult patients affected by severe palatal constriction. MATERIALS AND METHODS: The palatal distractor device was made of a Rematitan titanium expansion screw (Dentaurum) welded to 2 titanium miniplates (LEIBINGER) on patient's models. The device was applied using four 8-mm screws, activated 0.20 mm 4 times a day, and blocked for 4 months. The intermolar, interpremolar, and intercanine distances were measured before the palatal distractor device application and 1 week and 4 months after activation. Changes in dental angulation in the frontal plane, the intermolar, and the interpremolar angle variations were measured. RESULTS: There was an increase of the arch perimeter, well correlated with the expansion at dental level, resulting in teeth crowding resolution. The changes in dental angulation in the frontal plane were minimal, indicating mainly a skeletal movement. CONCLUSIONS: The device produces mainly a skeletal movement and a minimal dental angulation movement.

Allosteric Cooperativity in Proton Energy Conversion in A1-Type Cytochrome c Oxidase.

Cytochrome c oxidase (CcO), the CuA, heme a, heme a3, CuB enzyme of respiratory chain, converts the free energy released by aerobic cytochrome c oxidation into a membrane electrochemical proton gradient (ΔµH+). ΔµH+ derives from the membrane anisotropic arrangement of dioxygen reduction to two water molecules and transmembrane proton pumping from a negative (N) space to a positive (P) space separated by the membrane. Spectroscopic, potentiometric, and X-ray crystallographic analyses characterize allosteric cooperativity of dioxygen binding and reduction with protonmotive conformational states of CcO. These studies show that allosteric cooperativity stabilizes the favorable conformational state for conversion of redox energy into a transmembrane ΔµH+.

Mammalian complex I: a regulable and vulnerable pacemaker in mitochondrial respiratory function.

In this paper the regulatory features of complex I of mammalian and human mitochondria are reviewed. In a variety of mitotic cell-line cultures, activation in vivo of the cAMP cascade, or direct addition of cAMP, promotes the NADH-ubiquinone oxidoreductase activity of complex I and lower the cellular level of ROS. These effects of cAMP are found to be associated with PKA-mediated serine phosphorylation in the conserved C-terminus of the subunit of complex I encoded by the nuclear gene NDUFS4. PKA mediated phosphorylation of this Ser in the C-terminus of the protein promotes its mitochondrial import and maturation. Mass-spectrometry analysis of the phosphorylation pattern of complex I subunits is also reviewed.

Outcome of 47 consecutive sinus lift operations using aragonitic calcium carbonate associated with autologous platelet-rich plasma: clinical, histologic, and histomorphometrical evaluations.

BACKGROUND: The reconstruction of the maxillary bone frequently represents a real challenge for maxillofacial surgeons especially regarding the best choice of a suitable material to produce the required bone augmentation. AIM: In this study, we summarize our clinical experience on 47 sinus lifts with lateral approach using a mixture of aragonitic calcium carbonate and autologous platelet-rich plasma compared with that of a previous published study in which bovine bone (LADDEC) and autologous bone were used in 50 sinus lift operations (Br J Oral Maxillofac Surg 2005;43:309-313). MATERIALS AND METHODS: We subjected 34 patients to sinus lift operation, for a total of 47 sinus lifts, using natural coral as osteoconductive material. This material, combined with autologous platelet-rich plasma, was placed onto the maxillary sinus floor, after carefully lifting the endosteum. Cases were clinically, radiographically, and histologically analyzed. Histomorphometrical analysis, tests of microhardness, and x-ray microanalysis were conducted comparing the various sample to controls obtained from the same patients. RESULTS AND CONCLUSIONS: Histomorphometrical analysis, microhardness test, and x-ray microanalysis demonstrated that the newly formed bone showed morphologic and structural characteristics that were similar for all the grafting materials compared (bovine bone, autologous bone, and coral). Although all the grafting materials did yield good results of maturation of the newly formed bone, best results were achieved using autologous bone.

The mechanism of coupling between oxido-reduction and proton translocation in respiratory chain enzymes.

The respiratory chain of mitochondria and bacteria is made up of a set of membrane-associated enzyme complexes which catalyse sequential, stepwise transfer of reducing equivalents from substrates to oxygen and convert redox energy into a transmembrane protonmotive force (PMF) by proton translocation from a negative (N) to a positive (P) aqueous phase separated by the coupling membrane. There are three basic mechanisms by which a membrane-associated redox enzyme can generate a PMF. These are membrane anisotropic arrangement of the primary redox catalysis with: (i) vectorial electron transfer by redox metal centres from the P to the N side of the membrane; (ii) hydrogen transfer by movement of quinones across the membrane, from a reduction site at the N side to an oxidation site at the P side; (iii) a different type of mechanism based on co-operative allosteric linkage between electron transfer at the metal redox centres and transmembrane electrogenic proton translocation by apoproteins. The results of advanced experimental and theoretical analyses and in particular X-ray crystallography show that these three mechanisms contribute differently to the protonmotive activity of cytochrome c oxidase, ubiquinone-cytochrome c oxidoreductase and NADH-ubiquinone oxidoreductase of the respiratory chain. This review considers the main features, recent experimental advances and still unresolved problems in the molecular/atomic mechanism of coupling between the transfer of reducing equivalents and proton translocation in these three protonmotive redox complexes.