Summary Background Most previous studies of the use of cervical pessaries were either retrospective or case controlled and their results showed that this intervention might be a preventive strategy ...for women at risk of preterm birth; no randomised controlled trials have been undertaken. We therefore undertook a randomised, controlled trial to investigate whether the insertion of a cervical pessary in women with a short cervix identified by use of routine transvaginal scanning at 20–23 weeks of gestation reduces the rate of early preterm delivery. Methods The Pesario Cervical para Evitar Prematuridad (PECEP) trial was undertaken in five hospitals in Spain. Pregnant women (aged 18–43 years) with a cervical length of 25 mm or less were randomly assigned according to a computer-generated allocation sequence by use of central telephone in a 1:1 ratio to the cervical pessary or expectant management (without a cervical pessary) group. Because of the nature of the intervention, this study was not masked. The primary outcome was spontaneous delivery before 34 weeks of gestation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00706264. Findings 385 pregnant women with a short cervix were assigned to the pessary (n=192) and expectant management groups (n=193), and 190 were analysed in each group. Spontaneous delivery before 34 weeks of gestation was significantly less frequent in the pessary group than in the expectant management group (12 6% vs 51 27%, odds ratio 0·18, 95% CI 0·08–0·37; p<0·0001). No serious adverse effects associated with the use of a cervical pessary were reported. Interpretation Cervical pessary use could prevent preterm birth in a population of appropriately selected at-risk women previously screened for cervical length assessment at the midtrimester scan. Funding Instituto Carlos III.
Fatty acid metabolism in the hypothalamus has an important role in food intake, but its specific role in AgRP neurons is poorly understood. Here, we examined whether carnitinea palmitoyltransferase ...1A (CPT1A), a key enzyme in mitochondrial fatty acid oxidation, affects energy balance.
To obtain Cpt1aKO mice and their control littermates, Cpt1a
mice were crossed with tamoxifen-inducible AgRP
mice. Food intake and body weight were analyzed weekly in both males and females. At 12 weeks of age, metabolic flexibility was determined by ghrelin-induced food intake and fasting-refeeding satiety tests. Energy expenditure was analyzed by calorimetric system and thermogenic activity of brown adipose tissue. To study fluid balance the analysis of urine and water intake volumes; osmolality of urine and plasma; as well as serum levels of angiotensin and components of RAAS (renin-angiotensin-aldosterone system) were measured. At the central level, changes in AgRP neurons were determined by: (1) analyzing specific AgRP gene expression in RiboTag-Cpt1aKO mice obtained by crossing Cpt1aKO mice with RiboTag mice; (2) measuring presynaptic terminal formation in the AgRP neurons with the injection of the AAV1-EF1a-DIO-synaptophysin-GFP in the arcuate nucleus of the hypothalamus; (3) analyzing AgRP neuronal viability and spine formations by the injection AAV9-EF1a-DIO-mCherry in the arcuate nucleus of the hypothalamus; (4) analyzing in situ the specific AgRP mitochondria in the ZsGreen-Cpt1aKO obtained by breeding ZsGreen mice with Cpt1aKO mice. Two-way ANOVA analyses were performed to determine the contributions of the effect of lack of CPT1A in AgRP neurons in the sex.
Changes in food intake were just seen in male Cpt1aKO mice while only female Cpt1aKO mice increased energy expenditure. The lack of Cpt1a in the AgRP neurons enhanced brown adipose tissue activity, mainly in females, and induced a substantial reduction in fat deposits and body weight. Strikingly, both male and female Cpt1aKO mice showed polydipsia and polyuria, with more reduced serum vasopressin levels in females and without osmolality alterations, indicating a direct involvement of Cpt1a in AgRP neurons in fluid balance. AgRP neurons from Cpt1aKO mice showed a sex-dependent gene expression pattern, reduced mitochondria and decreased presynaptic innervation to the paraventricular nucleus, without neuronal viability alterations.
Our results highlight that fatty acid metabolism and CPT1A in AgRP neurons show marked sex differences and play a relevant role in the neuronal processes necessary for the maintenance of whole-body fluid and energy balance.
Covalent organic frameworks (COFs) are crystalline porous organic polymers built from covalent organic blocks that can be photochemically active when incorporating organic semiconducting units, such ...as triazine rings or diacetylene bridges. The bandgap, charge separation capacity, porosity, wettability, and chemical stability of COFs can be tuned by properly choosing their constitutive building blocks, by extension of conjugation, by adjustment of the size and crystallinity of the pores, and by synthetic post-functionalization. This review focuses on the recent uses of COFs as photoactive platforms for the hydrogen evolution reaction (HER), in which usually metal nanoparticles (NPs) or metallic compounds (generally Pt-based) act as co-catalysts. The most promising COF-based photocatalytic HER systems will be discussed, and special emphasis will be placed on rationalizing their structure and light-harvesting properties in relation to their catalytic activity and stability under turnover conditions. Finally, the aspects that need to be improved in the coming years will be discussed, such as the degree of dispersibility in water, the global photocatalytic efficiency, and the robustness and stability of the hybrid systems, putting emphasis on both the COF and the metal co-catalyst.
Introduction and objective: in recent years, the number of oral antineoplastic and immunomodulating drugs in oncohematology has increased enormously. Often, these drugs must be administered to ...patients with enteral tube feeding or swallowing disorders, which causes safety problems when handling these drugs (many of them are classified as hazardous drugs). In addition, it is important to note that the administration of these drugs can also interact with enteral nutrition (EN). The objective of this study was to review and update the recommendations for the administration and handling of oral antineoplastic and immunomodulating drugs. Methods: a Working Group made up of pharmacists from the Pharmacy Group of The Spanish Society of Clinical Nutrition and Metabolism (SENPE) and the Clinical Nutrition Group of The Spanish Society of Hospital Pharmacy (SEFH) was created. A bibliographic review was carried out between 2015 and 2020 on the administration and handling of oral antineoplastic and immunomodulating drugs in oncohematology. The information about pharmaceutical specialties, dosage, presentation, brand names, instructions for oral or enteral tube administration, interactions with EN, precautions, and remarks for handling and administration was analyzed. Results: a total of 77 active principles and 84 pharmaceutical forms were included. Recommendations and instructions for oral, nasogastric tube, and gastrostomy administration, handling of the antineoplastic and immunomodulating drugs, and interactions with EN were described. Conclusions: the handling and administration information about the oral antineoplastic and immunomodulating drugs currently used in oncohematology for people with enteral accesses or swallowing disorders is limited. It is important to perform post-marketing studies to ensure a safe and effective administration of these drugs.
Analogously to enzymatic catalysis, where the active metal sites and their environment are controlled by protein residues, the catalytic properties of metal nanoparticles (NPs) can be tuned by ...carefully selecting their surface‐coordinated species. In artificial photosynthesis, surface‐functionalization emerged in the last decade, grounded on the development of reliable methods for tailored synthesis, advanced characterization and theoretical modeling of metal NPs, altogether with the aim of transferring to the nanoscale the mechanistic knowledge acquired from molecular complexes. Metal NPs surface‐functionalization modulates the energetics of key catalytic intermediates, introduces second coordination sphere effects, influences the catalyst‐electrolyte interface, and determines the metal NPs surface coverage and, accordingly, the number of accessible active sites. In photoactivated systems, metal NPs surface‐functionalization may play a key role in modulating the charge transfers and recombination processes between the light absorber and the active sites and in the light absorber itself. Thus, after a presentation of the most relevant synthetic methods to produce well‐defined surface‐functionalized metal NPs, a critical analysis of why the above effects are the cornerstone in enhancing their catalytic performance in the key processes of artificial photosynthesis, namely the oxygen evolution reaction, the hydrogen evolution reaction, and the CO2 reduction reaction, is given.
Nanoparticle surface‐functionalization is an emerging strategy to enhance the catalysis of artificial photosynthesis. This review presents a critical analysis of the most remarkable examples reported to date with the aim to shed light on the role of surface ligands in each of the followingreactions: oxygen evolution reaction, hydrogen evolution reaction, and CO2 reduction reaction.
Purpose: On the 14th of March 2020, the Spanish government decreed a state of alarm due to the coronavirus disease 2019 (COVID-19) pandemic, directly affecting healthcare. This situation led to ...delayed diagnosis of several serious diseases, and its impact on many diseases such as the onset of type 1 diabetes mellitus (T1DM) remains unknown. The aim of this study is to determine the impact of the COVID-19 pandemic on the onset of T1DM in children.Methods: A descriptive-observational study was performed using data from children younger than 18 years (n=115) admitted with diagnosis of T1DM. We compared the 8 months from May–December 2020 to the same timeframe in 2019.Results: Our data show an increase of newly attended cases of T1DM in 2020, due to referral of Catalan children with onset of diabetes to our centre. Moreover, fewer patients presented with simple hyperglycaemia at the onset of the COVID-19 period. Delay in consulting the hospital, decreased access to the healthcare system, and avoidance of hospitals to minimize exposure to COVID-19 could have contributed to this finding. There were no differences in the number of days of hospitalization (including days in the paediatric intensive care uniy) between the years.Conclusion: The effects of the lockdown during the COVID-19 pandemic not only delayed the diagnosis of diabetes, but also its allowed time for its severity to increase. Future studies should focus on the influence of new variants of COVID-19 on the onset of T1DM during the postvaccination period.
Cyclin-dependent kinase 4 (CDK4) is well-known for its role in regulating the cell cycle, however, its role in cancer metabolism, especially mTOR signaling, is undefined. In this study, we ...established a connection between CDK4 and lysosomes, an emerging metabolic organelle crucial for mTORC1 activation. On the one hand, CDK4 phosphorylated the tumor suppressor folliculin (FLCN), regulating mTORC1 recruitment to the lysosomal surface in response to amino acids. On the other hand, CDK4 directly regulated lysosomal function and was essential for lysosomal degradation, ultimately regulating mTORC1 activity. Pharmacologic inhibition or genetic inactivation of CDK4, other than retaining FLCN at the lysosomal surface, led to the accumulation of undigested material inside lysosomes, which impaired the autophagic flux and induced cancer cell senescence
and in xenograft models. Importantly, the use of CDK4 inhibitors in therapy is known to cause senescence but not cell death. To overcome this phenomenon and based on our findings, we increased the autophagic flux in cancer cells by using an AMPK activator in combination with a CDK4 inhibitor. The cotreatment induced autophagy (AMPK activation) and impaired lysosomal function (CDK4 inhibition), resulting in cell death and tumor regression. Altogether, we uncovered a previously unknown role for CDK4 in lysosomal biology and propose a novel therapeutic strategy to target cancer cells. SIGNIFICANCE: These findings uncover a novel function of CDK4 in lysosomal biology, which promotes cancer progression by activating mTORC1; targeting this function offers a new therapeutic strategy for cancer treatment.
Regional Overlap of Pathologies in Lewy Body Disorders Colom-Cadena, Martí; Grau-Rivera, Oriol; Planellas, Lluís ...
Journal of neuropathology and experimental neurology,
03/2017, Letnik:
76, Številka:
3
Journal Article, Web Resource
Recenzirano
Odprti dostop
Lewy body disorders (LBD) are common neurodegenerative diseases characterized by the presence of aggregated α-synuclein in Lewy bodies and Lewy neurites in the central and peripheral nervous systems. ...The brains of patients with LBD often display other comorbid pathologies, i.e. insoluble tau, β-amyloid aggregates, TAR DNA-binding protein 43 (TDP-43) deposits, and argyrophilic grain disease (AGD). The incidence and physiological relevance of these concurrent pathological findings remain controversial. We performed a semiquantitative detailed mapping of α-synuclein, tau, β-amyloid (Aβ), TDP-43, and AGD pathologies in 17 areas in 63 LBD cases (44 with Parkinson disease PD, 28 with dementia, and 19 with dementia with Lewy bodies). APOE and MAPT genetic variants were also investigated. A majority of LBD cases had 2 or 3 concomitant findings, particularly Alzheimer disease-related pathology. Pathological stages of tau, β-amyloid and α-synuclein pathologies were increased in cases with dementia. Aβ score was the best correlate of the time to dementia in PD. In addition, β-amyloid deposition correlated with α-synuclein load in all groups. MAPT H1 haplotype did not influence any assessed pathology in PD. These results highlight the common concurrence of pathologies in patients with LBD that may have an impact on the clinical expression of the diseases.
Mutations in chromatin regulators are widespread in cancer. Among them, the histone H3 lysine 27 methyltransferase Polycomb Repressive Complex 2 (PRC2) shows distinct alterations according to tumor ...type. This specificity is poorly understood. Here, we model several PRC2 alterations in one isogenic system to reveal their comparative effects. Focusing then on lymphoma-associated EZH2 mutations, we show that Ezh2
induces aberrant H3K27 methylation patterns even without wild-type Ezh2, which are alleviated by partial PRC2 inhibition. Remarkably, Ezh2
rewires the response to PRC2 inhibition, leading to induction of antigen presentation genes. Using a unique longitudinal follicular lymphoma cohort, we further link EZH2 status to abnormal H3K27 methylation. We also uncover unexpected variability in the mutational landscape of successive biopsies, pointing to frequent co-existence of different clones and cautioning against stratifying patients based on single sampling. Our results clarify how oncogenic PRC2 mutations disrupt chromatin and transcription, and the therapeutic vulnerabilities this creates.
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