360 research outputs found
Experience based efficient approach for DNA-led identification of highly carbonized human remains
No full textIn case of severely burned bodies, victim identification by visual or fingerprints recognition is often prevented by altered body conditions. To overcome these circumstances, different techniques are available. Among these, the most reliable is molecular identification, especially in cases of detached body parts. However, DNA analysis of highly burned remains is a very challenging task. The high temperatures reached at the time of burning can lead to the complete destruction of the genetic material, making DNA typing arduous.
This work presented a successful identification through molecular analysis of 11 heavily carbonized victims assigned to the Institute of Legal Medicine of Modena (Italy) between June 2022 and June 2023: a helicopter crash, a femicide and two car accidents.
Post-mortem (PM) and ante-mortem (AM) data were compared, allowing victims’ identification and their quick return to relatives. Complete autosomal and Y chromosome STRs profiles were obtained for all the corpses. For the helicopter crash case, the utility of the DVI module implemented in the Familias software is shown as this aid the fast association of the seven victims involved with the familiar references available for identification.
The importance of the sampling strategy and the need of a systematic approach to select the most promising biological material for a more successful downstream DNA-based identification is also highlighted
Nrf2 deficiency influences susceptibility to steroid resistance via HDAC2 reduction
No full textAbnormal lung inflammation and oxidant burden are associated with a significant reduction in histone deacetylase 2 (HDAC2) abundance and steroid resistance. We hypothesized that Nrf2 regulates steroid sensitivity via HDAC2 in response to inflammation in mouse lung. Furthermore, HDAC2 deficiency leads to steroid resistance in attenuating lung inflammatory response, which may be due to oxidant/antioxidant imbalance. Loss of antioxidant transcription factor Nrf2 resulted in decreased HDAC2 level in lung, and increased inflammatory lung response which was not reversed by steroid. Thus, steroid resistance or inability of steroids to control lung inflammatory response is dependent on Nrf2-HDAC2 axis. These findings have implications in steroid resistance, particularly during the conditions of oxidative stress when the lungs are more susceptible to inflammatory response, which is seen in patients with chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, and inflammatory bowel disease
Reversible bilateral blepharoptosis following oxaliplatin infusion: a case report and literature review
No full textOxaliplatin, a platinum analogue employed in the treatment of colorectal cancer and various other neoplasms, is characterized by a broad range of adverse events. Peripheral neuropathy is probably the most peculiar and clinically relevant toxicity associated with its use and can be distinguished into two types: acute and chronic neurotoxicity.We report a case of acute reversible bilateral palpebral ptosis and dyspnea without bronchospasm or laryngospasm which occurred at the end of the third administration of adjuvant oxaliplatin by infusion for stage III colon cancer in a 54-year-old woman. Chlorphenamine and hydrocortisone were administered with fast resolution of dyspnea and slight improvement of ptosis. Complete resolution with no sequelae occurred in one hour. No further recurrence of blepharoptosis was described during the following days. The subsequent cycles were prescribed at reduced dosage without acute complications
Serum Amphiregulin expression in severe asthma patients treated with anti-IL-5 therapy
No full textRationale: The purpose of the study is to investigate the hypothesis that anti-IL-5 humanized monoclonal antibody Mepolizumab (MEP) could have a role in both eosinophils and pro-fibrotic mechanisms.
Methods: The study involved 19 severe asthmatic patients (age range 43-68, 10 females), who received MEP for at least 1 year. Clinical and functional parameters (FEV1%, FVC%, FeNO levels, blood eosinophils, Asthma Control Test (ACT), Oral Corticosteroid (OCS) administration, exacerbations) and serum the levels of Amphiregulin were evaluated at baseline and after treatment.
Results: After treatment, the blood eosinophil count decreased from 750 ± 470,2 eos/μL to 98,53 ± 53,21 eos/μL (p < 0.05). ACT score improved from 18,1±5,0 to 22,8±3,4 (p<0.05). Exacerbation rate decreased from 3.3± 2.5 per year to 0.8± 1,9/year (p < 0.05). The daily dose of 12.4 ± 7,8 mg prednisone decreased to 2.1 ± 6.3 mg/day (p < 0.5). FeNO level decreased from 75,3± 57,7 ppb to 53,8± 41,5 ppb after 12 months. The FEV1% predicted increased significantly (73,1± 24 vs 81,3±18,2), whereas the FVC% predicted showed no significant change. Serum Amphiregulin levels decreased significantly from 15,11± 5,78 pg/mL at baseline to 11,49±3,69 pg/mL after treatment (<0.05).
Conclusions: Our findings support the hypothesis that MEP is able to reduce tissue inflammation and remodelling by acting on both eosinophils and Th2 pathway, as well as on amphiregulin production. In particular, the down-regulation of amphiregulin may result in a weakening of the pro-fibrotic process and in a reduced triggering on eosinophils
Anàlisi genètica i funcional de la migranya hemiplègica i la migranya comuna
No full text[cat] Aquesta tesi es centra en la genètica de la migranya. La migranya comuna és un trastorn neurològic caracteritzat per episodis recurrents de mal de cap. Els criteris de la IHS (International Headache Society) subclasifiquen la malaltia en migranya amb aura (MA) i migranya sense aura (MO). L'aura són símptomes neurològics transitoris que poden acompanyar el mal de cap. Les aures més freqüents són les aures visuals, tot i que també existeixen les aures sensorials essent l'aura hemiplègica la seva forma severa. La nostra investigació es va dividir en dues areas d'acord amb la base genètica dels trastorns, d'una banda, s'ha estudiat la genètica complexa de la migranya comuna, d'altra banda s'ha estudiat una forma rara de la migranya que presenta una herència mendeliana anomenada migranya hemiplègica familiar (FHM).
Per entendre més la base genètica de la migranya comuna es va utilitzar un estudi d'associació tipus cas-control amb gens candidats. Amb aquesta finalitat es van seleccionar al voltant de 550 pacients amb migranya (MA i MO) i el seu corresponent grup de control. Per tal d'analitzar la seva implicació en la susceptibilitat genètica a la migranya, es van triar gens que codifiquen per als canals de la superfamília heterogeni de potencial receptor transitori (Transient Receptor Potential- TRP) que se sap que estan implicats en les vies nociceptives. Aquesta feina ha donat lloc a una publicació (Carreño et al. SNP variants within the vanilloid TRPV1 and TRPV3 receptor genes are associated with migraine in the Spanish population. Am J Med Genet B Neuropsychiatr Genet. 2012).
En el cas particular de les formes monogèniques de FHM es coneixen tres gens involucrats en la malatia (CACNA1A, ATP1A2 i SCN1A), les proteïnes codificades per aquests gens tenen un paper rellevant en la neurotransmissió del glutamat. L'anàlisi funcional de les mutacions que causen FHM han mostrat en última instància un augment de l'alliberament de la neurotransmissió. En el cas de mutacions al CACNA1A s'ha vist un efecte de guany de funció, a diferència de les mutacions al ATP1A2 que presenten un efecte de pèrdua de funció. En aquest treball s'ha fet un screening mutacional per identificar mutacions en pacients per seqüenciació directa. Quan les mutacions eren suficientment interessants s'han generat construccions en vectors d'expressió per subseqüents estudis funcionals en cèl·lules eucariotes. Aquesta feina ha donat lloc a tres publicacions. A la primera (Serra et al. A mutation in the first intracellular loop of CACNA1A prevents P/Q channel modulation by SNARE proteins and lowers exocytosis. Proc Natl Acad Sci. 2010) es va identificar un canvi que modula la funció del canal de CACNA1A. Aquest estudi ajuda a explicar la contribució genètica en la heterogeneïtat clínica d'una família i a entendre millor el mecanisme molecular dels canals de calci tipus P/Q. El segon (Carreño et al. Acute striatal necrosis in hemiplegic migraine with the novo CACNA1A mutation. Headache. 2011) és un informe d'un pacient que presenta una necrosi aguda stratial. Té una rellevància clínica a causa de l'aparició primerenca dels símptomes neurològics previs als atacs hemiplègics. El tercer i últim treball (Carreño et al. Screening of the ATP1A2 and CACNA1A genes in patients with hemiplegic migraine: clinical, genetic and functional studies. [work in progress]) recull l'screening mutacional al gens ATP1A2 i CACNA1A en 19 pacients amb FHM. Es van identificar 5 mutacions prèviament descrites i dues mutacions noves.[eng] This Thesis is focused in migraine genetics, migraine is a prevalent neurological disorder characterized by recurrent episodes of headache. This research was divided in two areas according to the genetic basis of the disorders; on the one hand we studied the common migraine with a complex genetics, on the other hand we studied the rare mendelian forms of familial hemiplegic migraine (FHM).
To understand more the genetic basis of the common migraine a case-control association study approach was used with candidate genes. For that purpose, around 550 patients with migraine and their corresponding control group were selected. In order to analyze their involvement in the genetic susceptibility to migraine, we chose genes encoding for channels of the heterogeneous superfamily of Transient Receptor Potential (TRP) which are known to be involved in the nociceptive pathway.
In the particular case of FHM, a monogenic form of the disorder, there are three genes known to be involved in the FHM (CACNA1A, ATP1A2 and SCN1A), whose encoded proteins are playing a relevant role in the neurotransmission of the glutamate. Functional analysis of the mutations causing FHM have shown ultimately an increased neurotransmission release. CACNA1A previous studies reveled a gain-of-function effect from FHM mutations, unlike mutations on ATP1A2 that present a loss-of-function effect. Our work consisted on identifying mutations in patients by direct sequencing. If the mutations were interesting enough vector constructions were generated for functional studies in eukaryotic cells. This work gave rise to three publications: First; the identification of a change that modulates the function of the CACNA1A channel. This study contributes to explain the genetic contribution in the clinical heterogeneity of one family and to know more about the molecular mechanism of the P/Q calcium channel. Second; a report of a patient that presents an acute stratial necrosis that had clinical relevance because of the early onset of the neurological symptoms previous to the hemiplegic attacks. Third; a mutational screening of ATP1A2 and CACNA1A genes in 19 patients with FHM. 5 previously described mutations and two new mutations were found. Functional studies were carried out for the newly mutations
IOF position statement: Vitamin D recommendations for older adults
No full textThis position paper of the International Osteoporosis Foundation makes recommendations for vitamin D nutrition in elderly men and women from an evidence-based perspective. © International Osteoporosis Foundation and National Osteoporosis Foundation 2010.Bischoff-Ferrari HA, 2009, BRIT MED J, V339, DOI 10.1136-bmj.b3692; Bischoff-Ferrari HA, 2005, JAMA-J AM MED ASSOC, V293, P2257, DOI 10.1001-jama.293.18.2257; Blum M, 2008, J AM COLL NUTR, V27, P274; Boonen S, 2007, J CLIN ENDOCR METAB, V92, P1415, DOI 10.1210-jc.2006-1404; DURAZOARVIZU RA, 2010, J NUTR, DOI DOI 10.3945-JM.109.116681; Flicker L, 2005, J AM GERIATR SOC, V53, P1881, DOI 10.1111-j.1532-5415.2005.00468.x; Fuleihan GEH, 2009, CLIN REV BONE MINER, V7, P77; Goussous R, 2005, J CLIN ENDOCR METAB, V90, P707, DOI 10.1210-jc.2004-1380; Harris SS, 2002, J AM COLL NUTR, V21, P357; Harris SS, 1998, J AM COLL NUTR, V17, P282; Heaney RP, 2003, AM J CLIN NUTR, V77, P204; Holick MF, 2008, J CLIN ENDOCR METAB, V93, P677, DOI 10.1210-jc.2007-2308; Mithal A, 2009, OSTEOPOROSIS INT, V20, P1807, DOI 10.1007-s00198-009-0954-6; OOMS ME, 1995, J CLIN ENDOCR METAB, V80, P1052, DOI 10.1210-jc.80.4.1052; Trang HM, 1998, AM J CLIN NUTR, V68, P854; Visser M, 2003, J CLIN ENDOCR METAB, V88, P5766, DOI 10.1210-jc.2003-030604; Wortsman J, 2000, AM J CLIN NUTR, V72, P690; Wortsman J, 2003, AM J CLIN NUTR, V77, P134217018816
Holistic computational design within additive manufacturing through topology optimization combined with multiphysics multi-scale materials and process modelling
No full textAdditive manufacturing (AM) processes have proven to be a perfect match for topology optimization (TO), as they are able to realize sophisticated geometries in a unique layer-by-layer manner. From a manufacturing viewpoint, however, there is a significant likelihood of process-related defects within complex geometrical features designed by TO. This is because TO seldomly accounts for process constraints and conditions and is typically perceived as a purely geometrical design tool. On the other hand, advanced AM process simulations have shown their potential as reliable tools capable of predicting various process-related conditions and defects. Thus far, geometry design by topology optimization and multiphysics manufacturing simulations have been viewed as two mostly separate paradigms, whereas one should really conceive them as one holistic computational design tool. More specifically, AM process models provide input to physics-based TO, where consequently, not only the designed component will function optimally, but also will have near-to-minimum manufacturing defects. In this regard, we aim at giving a thorough overview of holistic computational design tool concepts applied within AM. First, literature on TO for performance optimization is reviewed and then the most recent developments within physics-based TO techniques related to AM are covered. Process simulations play a pivotal role in the latter type of TO and serve as additional constraints on top of the primary end-user optimization objectives. As a natural consequence of this, a comprehensive and detailed review of non-metallic and metallic additive manufacturing simulations is performed, where the latter is divided into micro-scale and deposition-scale simulations. Material multi-scaling techniques, which are central to the process-structure-property relationships, are reviewed next, followed by a subsection on process multi-scaling techniques, which are reduced-order versions of advanced process models and are incorporable into physics-based TO due to their lower computational requirements. Finally the paper is concluded and suggestions for further research paths discussed.Computational Design and Mechanic
A common HLA-DPA1 variant is associated with hepatitis B virus infection but fails to distinguish active from inactive Caucasian carriers
No full textBackground and Aims: Chronic infection with the hepatitis B virus (HBV) is a major health issue worldwide. Recently, single nucleotide polymorphisms (SNPs) within the human leukocyte antigen (HLA)-DP locus were identified to be associated with HBV infection in Asian populations. Most significant associations were observed for the A alleles of HLA-DPA1 rs3077 and HLA-DPB1 rs9277535, which conferred a decreased risk for HBV infection. We assessed the implications of these variants for HBV infection in Caucasians.
Methods: Two HLA-DP gene variants (rs3077 and rs9277535) were analyzed for associations with persistent HBV infection and with different clinical outcomes, i.e., inactive HBsAg carrier status versus progressive chronic HBV (CHB) infection in Caucasian patients (n = 201) and HBsAg negative controls (n = 235).
Results: The HLA-DPA1 rs3077 C allele was significantly associated with HBV infection (odds ratio, OR = 5.1, 95% confidence interval, CI: 1.9–13.7; p = 0.00093). However, no significant association was seen for rs3077 with progressive CHB infection versus inactive HBsAg carrier status (OR = 2.7, 95% CI: 0.6–11.1; p = 0.31). In contrast, HLA-DPB1 rs9277535 was not associated with HBV infection in Caucasians (OR = 0.8, 95% CI: 0.4–1.9; p = 1).
Conclusions: A highly significant association of HLA-DPA1 rs3077 with HBV infection was observed in Caucasians. However, as a differentiation between different clinical courses of HBV infection was not possible, knowledge of the HLA-DPA1 genotype cannot be translated into personalized anti-HBV therapy approaches
A newly developed whole genome sequencing protocol enables early tracking of Enterovirus D68 molecular evolution
No full textHuman enterovirus D68 (EV-D68) has been associated with an increase in mild-to-severe pediatric respiratory diseases worldwide. The rate of circulation of this virus is largely underestimated in the population and genetic evolutionary data are usually available only for partial sequences. To achieve a timely genomic surveillance, a reliable, high-throughput EV-68 sequencing assay is required. Here we report an improved high-throughput EV-D68 whole-genome sequencing assay performed directly on clinical samples that is suitable for short-read sequencing platforms. Between June and December 2022, a total 37 (1.9%) respiratory samples were EV-D68 positive and together with 52 additional samples with a median cycle of quantification (Cq) of 28.3, ranging from 18 to 36.8 Cq were included in the validation analyses. Overall, all the primers had good performance and no mismatches were detected in more than 85% of sequences (932 whole-genome dataset). Using a cut-off of Cq <32 in at least 85.5% of samples a whole-genome or partial genome was obtained, confirming an acceptable positive sequencing rate for the designed method. A total of 65 whole-genome sequences were obtained and have a mean coverage of 98.4% across the genome, with a median depth of 6158x (range 2815x-7560x). Based on the obtained data, this method is cost effective resulting in an easy-to-perform protocol helpful for tracing the evolution of EV-D68 in protein different from VP1. EV-D68 could become a significant pathogen for public health in the next future, and thus this protocol for whole genome sequencing could help clinical and molecular virologists to be ready for molecular epidemiology surveillance
Can Medical Devices Help Mitigate Global Environmental Change Effects on Human and Animal Health? A Pilot Study
No full textGlobalization and urbanization are new challenges for the ability to protect public health. Indeed, the anthropogenic impact is changing the environment on a global scale. These changes can have direct and indirect health effects on both human and animal populations, introducing new diseases. Heat waves and floods are an example of these changes. Global Environmental Change (GEC) consequences on human health and well-being are stronger in urban areas, which are inhabited by 70% of the European population. In this context, the use of appropriate medical devices can also help mitigate the effects of climate change. Studies into lifestyle, environment quality and potential fields of application can be useful tools to identify possible types of medical device that could help to support the therapeutic needs and the prevention of health both in everyday life, and in the case of environmental alerts. A study was carried out on the potential role of medical devices (MDs) in mitigating the effects of GEC on human and animal health, by issuing two different questionnaires to specific professional clusters: the first to doctors, pharmacists, and veterinarians, the second to MD manufacturers. The data obtained from this study confirm the strong connection between GEC and the increase in the use of some MDs. Results obtained from questionnaires circulated to MD manufacturers confirmed this trend. MD manufacturers also declared that there are no longer any seasonal trends in market demand for some medical devices. This is a pilot study to consider MDs as a mitigation tool for CEGs
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