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Laura Marie Lombardi Steven Andrew Baker Huda Yahya Zoghbi 《The Journal of clinical investigation》2015,125(8):2914-2923
Two severe, progressive neurological disorders characterized by intellectual disability, autism, and developmental regression, Rett syndrome and MECP2 duplication syndrome, result from loss and gain of function, respectively, of the same critical gene, methyl-CpG–binding protein 2 (MECP2). Neurons acutely require the appropriate dose of MECP2 to function properly but do not die in its absence or overexpression. Instead, neuronal dysfunction can be reversed in a Rett syndrome mouse model if MeCP2 function is restored. Thus, MECP2 disorders provide a unique window into the delicate balance of neuronal health, the power of mouse models, and the importance of chromatin regulation in mature neurons. In this Review, we will discuss the clinical profiles of MECP2 disorders, the knowledge acquired from mouse models of the syndromes, and how that knowledge is informing current and future clinical studies. 相似文献
3.
Marcel Wchter Jan W. Kantelhardt Maria R. Bonsignore Izolde Bouloukaki Pierre Escourrou Ingo Fietze Ludger Grote Damian Korzybski Carolina Lombardi Oreste Marrone Ivana Paranicova Athanasia Pataka Silke Ryan Sophia E. Schiza Pawel Sliwinski Paschalis Steiropoulos Johan Verbraecken Thomas Penzel 《Journal of sleep research》2020,29(2)
In obstructive sleep apnea, patients’ sleep is fragmented leading to excessive daytime sleepiness and co‐morbidities like arterial hypertension. However, traditional metrics are not always directly correlated with daytime sleepiness, and the association between traditional sleep quality metrics like sleep duration and arterial hypertension is still ambiguous. In a development cohort, we analysed hypnograms from mild (n = 209), moderate (n = 222) and severe (n = 272) obstructive sleep apnea patients as well as healthy controls (n = 105) from the European Sleep Apnea Database. We assessed sleep by the analysis of two‐step transitions depending on obstructive sleep apnea severity and anthropometric factors. Two‐step transition patterns were examined for an association to arterial hypertension or daytime sleepiness. We also tested cumulative distributions of wake as well as sleep‐states for power‐laws (exponent α) and exponential distributions (decay time τ) in dependency on obstructive sleep apnea severity and potential confounders. Independent of obstructive sleep apnea severity and potential confounders, wake‐state durations followed a power‐law distribution, while sleep‐state durations were characterized by an exponential distribution. Sleep‐stage transitions are influenced by obstructive sleep apnea severity, age and gender. N2 → N3 → wake transitions were associated with high diastolic blood pressure. We observed higher frequencies of alternating (symmetric) patterns (e.g. N2 → N1 → N2, N2 → wake → N2) in sleepy patients both in the development cohort and in a validation cohort (n = 425). In conclusion, effects of obstructive sleep apnea severity and potential confounders on sleep architecture are small, but transition patterns still link sleep fragmentation directly to obstructive sleep apnea‐related clinical outcomes like arterial hypertension and daytime sleepiness. 相似文献
4.
Ferdinando Carlo Sasso Pia Clara Pafundi Alfredo Caturano Raffaele Galiero Erica Vetrano Riccardo Nevola Salvatore Petta Anna Ludovica Fracanzani Carmine Coppola Vito Di Marco Antonio Solano Rosa Lombardi Mauro Giordano Antonio Craxi Alessandro Perrella Celestino Sardu Raffaele Marfella Teresa Salvatore Luca Rinaldi 《Nutrition, metabolism, and cardiovascular diseases : NMCD》2021,31(8):2345-2353
Background and aimsBeyond type 2 diabetes, even a condition of prediabetes is associated with an increased cardiovascular (CV) risk, and HCV infection coexistence represents an exacerbating factor. CV prognosis improvement in prediabetes represents a challenge, due to the increasing prevalence of this metabolic condition worldwide. Hence, we aimed to prospectively assess how direct acting antivirals (DAAs) could affect major cardiovascular events (MACE) in a prediabetic HCV positive cohort.Methods and resultsIn this prospective multicenter study, we enrolled HCV patients with overt prediabetes. We compared a subgroup of patients treated with DAAs with untreated prediabetic controls. We recorded all CV events occurred during an overall median follow-up of 24 months (IQR 19–34). 770 HCV positive prediabetic patients were enrolled, 398 untreated controls and 372 DAAs treated patients. Overall, the CV events annual incidence was much higher among prediabetic treated patients (1.77 vs. 0.62, p < 0.001), and HCV clearance demonstrated to significantly reduce CV events (RR: 0.411, 95%CI 0.148–1.143; p < 0.001), with an estimated NNT for one additional patient to benefit of 52.1. Moreover, an independent association between a lower rate of CV events and HCV clearance after DAAs was observed (OR 4.67; 95%CI 0.44–53.95; p = 0.016).ConclusionsHCV eradication by DAAs allows a significant reduction of MACEs in the prediabetic population, and therefore represents a primary objective, regardless of the severity of liver disease and CV risk factors. 相似文献
5.
H. Jang Y.-J. Ma E.Y. Chang S. Fazeli R.R. Lee A.F. Lombardi G.M. Bydder J. Corey-Bloom J. Du 《AJNR. American journal of neuroradiology》2021,42(5):868
BACKGROUND AND PURPOSE:MR imaging has been widely used for the noninvasive evaluation of MS. Although clinical MR imaging sequences are highly effective in showing focal macroscopic tissue abnormalities in the brains of patients with MS, they are not specific to myelin and correlate poorly with disability. We investigated direct imaging of myelin using a 2D adiabatic inversion recovery ultrashort TE sequence to determine its value in assessing disability in MS.MATERIALS AND METHODS:The 2D inversion recovery ultrashort TE sequence was evaluated in 14 healthy volunteers and 31 patients with MS. MPRAGE and T2-FLAIR images were acquired for comparison. Advanced Normalization Tools were used to correlate inversion recovery ultrashort TE, MPRAGE, and T2-FLAIR images with disability assessed by the Expanded Disability Status Scale.RESULTS:Weak correlations were observed between normal-appearing white matter volume (R = –0.03, P = .88), lesion load (R = 0.22, P = .24), and age (R = 0.14, P = .44), and disability. The MPRAGE signal in normal-appearing white matter showed a weak correlation with age (R = –0.10, P = .49) and disability (R = –0.19, P = .31). The T2-FLAIR signal in normal-appearing white matter showed a weak correlation with age (R = 0.01, P = .93) and disability (R = 0.13, P = .49). The inversion recovery ultrashort TE signal was significantly negatively correlated with age (R = –0.38, P = .009) and disability (R = –0.44; P = .01).CONCLUSIONS:Direct imaging of myelin correlates with disability in patients with MS better than indirect imaging of long-T2 water in WM using conventional clinical sequences.MS is the most common demyelinating disease of the brain.1 Demyelination affects many aspects of neurologic function, including speech, balance, and cognitive awareness. Across time, this frequently leads to severe and irreversible clinical disability. MR imaging has been widely used for accurate diagnosis of MS, with current techniques focused on imaging the long-T2 water components in WM and GM.2-4 MS lesions often appear hypointense with T1-weighted gradient recalled-echo sequences2 and hyperintense with T2-weighted FSE and T2-weighted FLAIR sequences.3 Active lesions can be highlighted with gadolinium-enhanced imaging.4 The magnetization transfer ratio has been used as an indirect marker of myelin disorder in regions of normal-appearing WM (NAWM).5 There are also several other advanced imaging techniques for indirect myelin imaging via assessment of myelin water, such as multicomponent T2 or T2* analysis6,7 and direct visualization of components with short transverse relaxation times.8,9While conventional MR imaging sequences are highly effective in detecting focal macroscopic brain tissue abnormalities, they are not specific for pathologic substrates of MS lesions such as demyelination and remyelination, and they may not correlate well with patients'' neurologic deficits. Current MR imaging techniques correlate only modestly with disability assessed by the Expanded Disability Status Scale (EDSS).10-15 The total lesion load showed statistically significant-but-weak correlations with the EDSS score in several large-scale studies (R = 0.1–0.3).10-12 Composite scores including relaxation times of different tissues and/or volumetric measures generally correlate more strongly with the EDSS score, with a maximum observed correlation of R = 0.34 (P < .001).13 Lesions seen with gadolinium-enhanced imaging are only moderately correlated with disability in the first 6 months and are not predictive of changes in the EDSS score in the subsequent 1 or 2 years.14 A large-scale multicenter study reported very limited correlation between the EDSS score and normalized brain volume (R = –0.18), cross-sectional area (R = –0.26), magnetization transfer ratio of whole-brain tissue (R = –0.16), and GM (R = –0.17).15The poor performance of conventional MR imaging sequences in assessing disability highlights the need for novel MR imaging techniques that can directly image myelin lipid and enable direct assessment of both myelin damage and repair. However, myelin has an extremely short transverse relaxation time and is not directly detectable with conventional MR images, which typically have TEs of several milliseconds or longer. Ultrashort TE (UTE) sequences can directly detect signal from myelin with ultrashort T2 (ie, excluding water with longer T2s).16-21 In this study, we describe imaging of WM using a 2D adiabatic inversion recovery prepared UTE (IR-UTE) sequence in healthy volunteers and patients with MS and evaluate its performance in assessing disability in patients with MS compared with 2 conventional clinical sequences. 相似文献
6.
Emilie Ronin Charlotte Pouchy Maryam Khosravi Morgane Hilaire Sylvie Grgoire Armanda Casrouge Sahar Kassem David Sleurs Gaëlle H. Martin Nomie Chanson Yannis Lombardi Guilhem Lalle Harald Wajant Cdric Auffray Bruno Lucas Gilles Marodon Yenkel Grinberg-Bleyer Benoît L. Salomon 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(13)
7.
Nicla La Verde Agostino Riva Maria Silvia Cona Arianna Gabrieli Monica Cattaneo Cinzia Fasola Giuseppe Lipari Claudia De Stradis Valentina Favorito Benedetta Lombardi Stocchetti Davide Chizzoniti Alice Covizzi Eliana Rulli Francesca Galli Lorenzo Ruggieri Anna Gambaro Sabrina Ferrario Davide Dalu Maciej S. Tarkowski 《International journal of cancer. Journal international du cancer》2023,152(4):661-671
Previous studies on the immunogenicity of SARS-CoV-2 mRNA vaccines showed a reduced seroconversion in cancer patients. The aim of our study is to evaluate the immunogenicity of two doses of mRNA vaccines in solid cancer patients with or without a previous exposure to the virus. This is a single-institution, prospective, nonrandomized study. Patients in active treatment and a control cohort of healthy people received two doses of BNT162b2 (Comirnaty, BioNTech/Pfizer, The United States) or mRNA-1273 (Spikevax, Moderna). Vaccine was administered before starting anticancer therapy or on the first day of the treatment cycle. SARS-CoV-2 antibody levels against S1, RBD (to evaluate vaccine response) and N proteins (to evaluate previous infection) were measured in plasma before the first dose and 30 days after the second one. From January to June 2021, 195 consecutive cancer patients and 20 healthy controls were enrolled. Thirty-one cancer patients had a previous exposure to SARS-CoV-2. Cancer patients previously exposed to the virus had significantly higher median levels of anti-S1 and anti-RBD IgG, compared to healthy controls (P = .0349) and to cancer patients without a previous infection (P < .001). Vaccine type (anti-S1: P < .0001; anti-RBD: P = .0045), comorbidities (anti-S1: P = .0274; anti-RBD: P = .0048) and the use of G-CSF (anti-S1: P = .0151) negatively affected the antibody response. Conversely, previous exposure to SARS-CoV-2 significantly enhanced the response to vaccination (anti-S1: P < .0001; anti-RBD: P = .0026). Vaccine immunogenicity in cancer patients with a previous exposure to SARS-CoV-2 seems comparable to that of healthy subjects. On the other hand, clinical variables of immune frailty negatively affect humoral immune response to vaccination. 相似文献
8.
A Grimaldi D Santini S Zappavigna A Lombardi G Misso M Boccellino V Desiderio P P Vitiello G Di Lorenzo A Zoccoli F Pantano M Caraglia 《Cancer biology & therapy》2015,16(4):567-579
Renal cell carcinoma is an aggressive disease often asymptomatic and weakly chemo-radiosensitive. Currently, new biologic drugs are used among which everolimus, an mTOR inhibitor, that has been approved for second-line therapy. Since mTOR is involved in the control of autophagy, its antitumor capacity is often limited. In this view, chloroquine, a 4-alkylamino substituted quinoline family member, is an autophagy inhibitor that blocks the fusion of autophagosomes and lysosomes. In the present study, we evaluated the effects of everolimus alone or in combination with chloroquine on renal cancer cell viability and verified possible synergism. Our results demonstrate that renal cancer cells are differently sensitive to everolimus and chloroquine and the pharmacological combination everolimus/chloroquine was strongly synergistic inducing cell viability inhibition. In details, the pharmacological synergism occurs when chloroquine is administered before everolimus. In addition, we found a flow autophagic block and shift of death mechanisms to apoptosis. This event was associated with decrease of Beclin-1/Bcl-2 complex and parallel reduction of anti-apoptotic protein Bcl-2 in combined treatment. At last, we found that the enhancement of apoptosis induced by drug combination occurs through the intrinsic mitochondrial apoptotic pathway activation, while the extrinsic pathway is involved only partly following its activation by chloroquine. These results provide the basis for new therapeutic strategies for the treatment of renal cell carcinoma after appropriate clinical trial. 相似文献
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Antifungal therapy in the oral cavity 总被引:1,自引:0,他引:1