Assessment of nutritional status and bone health in neurologically impaired children: a challenge in pediatric clinical practice

NTRODUCTION: neurologically impaired children frequently experience nutritional disorders and bone health complications. Our aim was firstly to analyze a method to interpret bone mineral density (BMD) accurately in neurologically impaired children. Secondly, to determine its relationship with the nutritional status and micronutrient levels in order to identify which factors are associated with low BMD. METHODS: a observational multicenter study was conducted in children with moderate-to-severe neurological impairment. Data collected included: medical records, anthropometric measures, hematologic and biochemical evaluation. BMD was measured with Dual-energy X-ray absorptiometry and z-scores were calculated adjusting for sex and chronological age. Secondly, BMD z-scores were calculated applying height age (age at which the child's height would be in 2nd percentile) instead of chronological age. RESULTS: fifty-two children were included (aged 4-16 years). Seventeen patients (32.7%) received feeding by gastrostomy tube. Height and BMI z-score were below 2SD in 64% and 31% of patients respectively, with normal mid upper arm circumference and skinfold thickness measurements. Low vitamin-D levels were found in 42% of cases. 50% of patients evidenced low BMD when calculated for chronological age, whereas only 34.5% showed BMD z-score <-2 when calculated for height age. No correlation was observed between BMD and vitamin-D levels, weight and height z-scores or age when BMD was calculated applying height age. CONCLUSIONS: the prevalence of low BMD is high in neurologically impaired children, and it is probably multifactorial. In these children, we suggest adjusting BMD for height age, in order not to over diagnose low BMD

Prospective analysis of psychological differences between adult and elderly cancer patients during postoperaritve adjuvant chemotherapy

PURPOSE: Despite the burgeoning geriatric population with cancer and the importance of understanding how age may be related to mental adjustment and quality of life so far, differences in coping strategies and psychological harm between the elderly and adults are hardly being taken into account to modify the approach to this population. The aim of this prospective study is to describe the differences in psychological characteristics between older and adult cancer patients and examine dissimilarities in their psychological evolution during adjuvant chemotherapy. METHODS: Adults (18-69 years old) and older patients (≥ 70) with newly diagnosed non-metastatic resected cancer admitted to receive adjuvant chemotherapy were recruited. Patients completed the following questionnaires: mini-mental adjustment to cancer, brief symptom inventory, shared decision-making questionnaire-patient's version, multidimensional scale of perceived social support, EORTC quality-of-life instrument, life orientation test-revised, and satisfaction with life scale. RESULTS: 500 cancer patients (394 adults and 106 older) were evaluated. The impact of the diagnosis was less negative among older patients, with no differences in coping strategies, quality of life, or search for support. Regarding psychological changes from the beginning to the end of the adjuvant treatment, both age groups reported more somatic symptoms, increased psychological difficulty, reduced coping strategies, and a significant decrease in quality of life at the end of postoperative chemotherapy. CONCLUSION: Although there were clear psychological differences between adults and senior cancer patients, their evolution during adjuvant chemotherapy was similar, with deterioration in quality of life and coping. This negative psychological impact of adjuvant chemotherapy should be taken into account when considering interventions

Dignity and psychosocial related variables in elderly advanced cancer patients

Abstract Introduction: Most cancers occur in older individuals, who are more vulnerable due to functional impairment, multiple comorbidities, cognitive impairment, and lack of socio‑familial support. These can undermine patients' sense of dignity. This study seeks to compare dignity scores in older patients with advanced cancer on sociodemographic and clinical variables and analyze the predictive value of anxiety, depression, functional limitations, and social support on dignity scores. Methods: A prospective, multicenter, observational study conducted with participation of 15 hospitals in Spain from February 2020 to October 2021. Patients with newly‑diagnosed, advanced cancer completed the dignity (PPDS), anxiety and depression (BSI), Social Support (Duke-UNC‑11), and functional limitations (EORTC‑C30) scales. Lineal regression analyses explored the effects of anxiety, depression, functional status, and social support on dignity, adjusting for sociodemographic and clinical variables. Results: A total of 180 subjects participated in this study. The results of the correlation analysis revealed that dignity correlated negatively with anxiety, depression, and sex, and positively with social support, functional status, and longer estimated survival. Thus, women, and more anxious and depressed individuals scored lower on the dignity scale, whereas patients with more social support, fewer functional limitations, and longer estimated survival scored higher. Conclusion: In conclusion, being female, having a lower educational level, lower estimated survival, depression, anxiety, less social support, and limited functionality are correlated with less dignity in the elderly with advanced cancer. It is a priority to manage both physical and psychological symptoms in patients with unresectable advanced cancer to mitigate psychological distress and increase their sense of dignit

RNASeq analysis reveals biological processes governing the clinical behaviour of endometrioid and serous endometrial cancers

BACKGROUND: Endometrial carcinoma comprises a group of tumors with distinct histologic and molecular features, and clinical behavior. Here we sought to define the biological processes that govern the clinical behavior of endometrial cancers. METHODS: Sixteen prototype genes representative of different biological processes that would likely play a role in endometrial and other hormone-driven cancers were defined. RNA-sequencing gene expression data from 323 endometrial cancers from The Cancer Genome Atlas were used to determine the transcription module of each prototype gene. The expression of prototype genes and modules and their association with outcome was assessed in univariate and multivariate survival analyses. The association of MSH6 expression with outcome was validated in an independent cohort of 243 primary endometrial cancers using immunohistochemistry. RESULTS: We observed that the clinical behavior of endometrial carcinomas as a group was associated with hormone receptor signaling, PI3K pathway signaling and DNA mismatch repair processes. When analyzed separately, in endometrioid carcinomas, hormone receptor, PI3K and DNA mismatch repair modules were significantly associated with outcome in univariate analysis, whereas the clinical behavior of serous cancers was likely governed by apoptosis and Wnt signaling. Multivariate survival analysis revealed that MSH6 expression was associated with outcome of endometrial cancer patients independently from traditional prognostic clinicopathologic parameters, which was confirmed in an independent cohort at the protein level. CONCLUSION: Endometrioid and serous endometrial cancers are underpinned by distinct molecular pathways. MSH6 expression levels may be associated with outcome in endometrial cancers as a group

VID22 counteracts G-quadruplex-induced genome instability

Genome instability is a condition characterized by the accumulation of genetic alterations and is a hallmark of cancer cells. To uncover new genes and cellular pathways affecting endogenous DNA damage and genome integrity, we exploited a Synthetic Genetic Array (SGA)-based screen in yeast. Among the positive genes, we identified VID22, reported to be involved in DNA double-strand break repair. vid22Δ cells exhibit increased levels of endogenous DNA damage, chronic DNA damage response activation and accumulate DNA aberrations in sequences displaying high probabilities of forming G-quadruplexes (G4-DNA). If not resolved, these DNA secondary structures can block the progression of both DNA and RNA polymerases and correlate with chromosome fragile sites. Vid22 binds to and protects DNA at G4-containing regions both in vitro and in vivo. Loss of VID22 causes an increase in gross chromosomal rearrangement (GCR) events dependent on G-quadruplex forming sequences. Moreover, the absence of Vid22 causes defects in the correct maintenance of G4-DNA rich elements, such as telomeres and mtDNA, and hypersensitivity to the G4-stabilizing ligand TMPyP4. We thus propose that Vid22 is directly involved in genome integrity maintenance as a novel regulator of G4 metabolism.Associazione Italiana per la Ricerca sul Cancro (AIRC) [15631, 21806 to M.M.F.]; MIUR [PRIN 2015-2015SJLMB9; PRIN 2017-2017KSZZJW to M.M.F.]; Telethon [GGP15227 to M.M.F.]; F.L. was supported by the University of Milano: ‘‘Piano di Sviluppo dell’Ateneo per la Ricerca. Linea B: Supporto per i Giovani Ricercatori’’; M.C.B. was supported by Fondazione Veronesi; Research at the laboratory of A.A. was funded by the Spanish Ministry of Economy and Competitiveness [BFU2016-75058-P]; B.G.G. was funded by the Spanish Association Against Cancer; MIUR [PRIN2017-2017Z55KC to T.B.]; M.C., D.S.H. are supported by MIUR [PRIN 2017] and CNRbiomics [PIR01_00017]; H2020 Projects ELIXIR-EXCELERATE, EOSC-Life, EOSC-Pillar and Elixir-IIB; G.W.B. was supported by the Canadian Institutes of Health Research[FDN-159913]. Funding for open access charge: Associazione Italiana per la Ricerca sul Cancro (AIRC) [21806]

Immunomodulation by Different Types of N-Oxides in the Hemocytes of the Marine Bivalve Mytilus galloprovincialis

The potential toxicity of engineered nanoparticles (NPs) for humans and the environment represents an emerging issue. Since the aquatic environment represents the ultimate sink for NP deposition, the development of suitable assays is needed to evaluate the potential impact of NPs on aquatic biota. The immune system is a sensitive target for NPs, and conservation of innate immunity represents an useful basis for studying common biological responses to NPs. Suspension-feeding invertebrates, such as bivalves, are particularly at risk to NP exposure, since they have extremely developed systems for uptake of nano and microscale particles integral to intracellular digestion and cellular immunity. Evaluation of the effects of NPs on functional parameters of bivalve immunocytes, the hemocytes, may help understanding the major toxic mechanisms and modes of actions that could be relevant for different NP types in aquatic organisms.In this work, a battery of assays was applied to the hemocytes of the marine bivalve Mytilus galloprovincialis to compare the in vitro effects of different n-oxides (n-TiO2, n-SiO2, n-ZnO, n-CeO2) chosen on the basis of their commercial and environmental relevance. Physico-chemical characterization of both primary particles and NP suspensions in artificial sea water-ASW was performed. Hemocyte lysosomal and mitochondrial parameters, oxyradical and nitric oxide production, phagocytic activity, as well as NP uptake, were evaluated. The results show that different n-oxides rapidly elicited differential responses hemocytes in relation to their chemical properties, concentration, behavior in sea water, and interactions with subcellular compartments. These represent the most extensive data so far available on the effects of NPs in the cells of aquatic organisms. The results indicate that Mytilus hemocytes can be utilized as a suitable model for screening the potential effects of NPs in the cells of aquatic invertebrates, and may provide a basis for future experimental work for designing environmentally safer nanomaterials

Comparative efficacy of two primary care interventions to assist withdrawal from long term benzodiazepine use: A protocol for a clustered, randomized clinical trial

<p>Abstract</p> <p>Background</p> <p>Although benzodiazepines are effective, long-term use is not recommended because of potential adverse effects; the risks of tolerance and dependence; and an increased risk of hip fractures, motor vehicle accidents, and memory impairment. The estimated prevalence of long-term benzodiazepine use in the general population is about 2,2 to 2,6%, is higher in women and increases steadily with age. Interventions performed by General Practitioners may help patients to discontinue long-term benzodiazepine use. We have designed a trial to evaluate the effectiveness and safety of two brief general practitioner-provided interventions, based on gradual dose reduction, and will compare the effectiveness of these interventions with that of routine clinical practice.</p> <p>Methods/Design</p> <p>In a three-arm cluster randomized controlled trial, general practitioners will be randomly allocated to: a) a group in which the first patient visit will feature a structured interview, followed by visits every 2-3 weeks to the end of dose reduction; b) a group in which the first patient visit will feature a structured interview plus delivery of written instructions to self-reduce benzodiazepine dose, or c) routine care. Using a computerized pharmaceutical prescription database, 495 patients, aged 18-80 years, taking benzodiazepine for at least 6 months, will be recruited in primary care health districts of three regions of Spain (the Balearic Islands, Catalonia, and Valencia). The primary outcome will be benzodiazepine use at 12 months. The secondary outcomes will include measurements of anxiety and depression symptoms, benzodiazepine dependence, quality of sleep, and alcohol consumption.</p> <p>Discussion</p> <p>Although some interventions have been shown to be effective in reducing benzodiazepine consumption by long-term users, the clinical relevance of such interventions is limited by their complexity. This randomized trial will compare the effectiveness and safety of two complex stepped care interventions with that of routine care in a study with sufficient statistical power to detect clinically relevant differences.</p> <p>Trial Registration</p> <p>Current Controlled Trials: <a href="http://www.controlled-trials.com/ISRCTN13024375">ISRCTN13024375</a></p

Brucella abortus Uses a Stealthy Strategy to Avoid Activation of the Innate Immune System during the Onset of Infection

To unravel the strategy by which Brucella abortus establishes chronic infections, we explored its early interaction with innate immunity. Methodology/Principal Findings Brucella did not induce proinflammatory responses as demonstrated by the absence of leukocyte recruitment, humoral or cellular blood changes in mice. Brucella hampered neutrophil (PMN) function and PMN depletion did not influence the course of infection. Brucella barely induced proinflammatory cytokines and consumed complement, and was strongly resistant to bactericidal peptides, PMN extracts and serum. Brucella LPS (BrLPS), NH-polysaccharides, cyclic glucans, outer membrane fragments or disrupted bacterial cells displayed low biological activity in mice and cells. The lack of proinflammatory responses was not due to conspicuous inhibitory mechanisms mediated by the invading Brucella or its products. When activated 24 h post-infection macrophages did not kill Brucella, indicating that the replication niche was not fusiogenic with lysosomes. Brucella intracellular replication did not interrupt the cell cycle or caused cytotoxicity in WT, TLR4 and TLR2 knockout cells. TNF-α-induction was TLR4- and TLR2-dependent for live but not for killed B. abortus. However, intracellular replication in TLR4, TLR2 and TLR4/2 knockout cells was not altered and the infection course and anti-Brucella immunity development upon BrLPS injection was unaffected in TLR4 mutant mice. Conclusion/Significance We propose that Brucella has developed a stealth strategy through PAMPs reduction, modification and hiding, ensuring by this manner low stimulatory activity and toxicity for cells. This strategy allows Brucella to reach its replication niche before activation of antimicrobial mechanisms by adaptive immunity. This model is consistent with clinical profiles observed in humans and natural hosts at the onset of infection and could be valid for those intracellular pathogens phylogenetically related to Brucella that also cause long lasting infections

Insights into the innate immunity of the Mediterranean mussel Mytilus galloprovincialis

<p>Abstract</p> <p>Background</p> <p>Sessile bivalves of the genus <it>Mytilus </it>are suspension feeders relatively tolerant to a wide range of environmental changes, used as sentinels in ecotoxicological investigations and marketed worldwide as seafood. Mortality events caused by infective agents and parasites apparently occur less in mussels than in other bivalves but the molecular basis of such evidence is unknown. The arrangement of Mytibase, interactive catalogue of 7,112 transcripts of <it>M. galloprovincialis</it>, offered us the opportunity to look for gene sequences relevant to the host defences, in particular the innate immunity related genes.</p> <p>Results</p> <p>We have explored and described the Mytibase sequence clusters and singletons having a putative role in recognition, intracellular signalling, and neutralization of potential pathogens in <it>M. galloprovincialis</it>. Automatically assisted searches of protein signatures and manually cured sequence analysis confirmed the molecular diversity of recognition/effector molecules such as the antimicrobial peptides and many carbohydrate binding proteins. Molecular motifs identifying complement C1q, C-type lectins and fibrinogen-like transcripts emerged as the most abundant in the Mytibase collection whereas, conversely, sequence motifs denoting the regulatory cytokine MIF and cytokine-related transcripts represent singular and unexpected findings. Using a cross-search strategy, 1,820 putatively immune-related sequences were selected to design oligonucleotide probes and define a species-specific Immunochip (DNA microarray). The Immunochip performance was tested with hemolymph RNAs from mussels injected with <it>Vibrio splendidus </it>at 3 and 48 hours post-treatment. A total of 143 and 262 differentially expressed genes exemplify the early and late hemocyte response of the <it>Vibrio</it>-challenged mussels, respectively, with AMP trends confirmed by qPCR and clear modulation of interrelated signalling pathways.</p> <p>Conclusions</p> <p>The Mytibase collection is rich in gene transcripts modulated in response to antigenic stimuli and represents an interesting window for looking at the mussel immunome (transcriptomes mediating the mussel response to non-self or abnormal antigens). On this basis, we have defined a new microarray platform, a mussel Immunochip, as a flexible tool for the experimental validation of immune-candidate sequences, and tested its performance on <it>Vibrio</it>-activated mussel hemocytes. The microarray platform and related expression data can be regarded as a step forward in the study of the adaptive response of the <it>Mytilus </it>species to an evolving microbial world.</p