Fibulin-2 has previously been considered as a marker to distinguish rat liver myofibroblasts from hepatic stellate cells. The function of other fibulins in acute or chronic liver damage has not yet ...been investigated. The aim of this study has been to evaluate the expression of fibulin-1 and -2 in models of rat liver injury and in human liver cirrhosis. Their cellular sources have also been investigated. In normal rat liver, fibulin-1 and -2 were both mainly present in the portal field. Fibulin-1-coding transcripts were detected in total RNA of normal rat liver, whereas fibulin-2 mRNA was only detected by sensitive, real-time quantitative polymerase chain reaction. In acute liver injury, the expression of fibulin-1 was significantly increased (17.23-fold after 48 h), whereas that of fibulin-2 was not modified. The expression of both fibulin-1 and -2 was increased in experimental rat liver cirrhosis (19.16- and 26.47-fold, respectively). At the cellular level, fibulin-1 was detectable in hepatocytes, “activated” hepatic stellate cells, and liver myofibroblasts (2.71-, 122.65-, and 469.48-fold over the expression in normal rat liver), whereas fibulin-2 was restricted to liver myofibroblasts and was regulated by transforming growth factor beta-1 (TGF-β1) in 2-day-old hepatocyte cultures and in liver myofibroblasts. Thus, fibulin-1 and -2 respond differentially to single and repeated damaging noxae, and their expression is differently present in liver cells. Expression of the fibulin-2 gene is regulated by TGF-β1 in liver myofibroblasts.
The aim of this study was to evaluate the impact on the national health system of COVID-19 infection in vaccinated patients undergoing haemodialysis.BACKGROUNDThe aim of this study was to evaluate ...the impact on the national health system of COVID-19 infection in vaccinated patients undergoing haemodialysis.From the cohort of vaccinated dialysis patients enrolled in 118 dialysis centres, we calculated hospitalisation incidence in COVID-19-infected subjects. COVID-19-related hospitalisations and ICU admissions were analysed over two time periods (prior to administration of the third dose and following administration of the third dose of vaccine) and adjusted for several co-variates. Using the general population as the reference, we then calculated the Standardized Incidence Ratio (SIR) of hospitalisation.METHODSFrom the cohort of vaccinated dialysis patients enrolled in 118 dialysis centres, we calculated hospitalisation incidence in COVID-19-infected subjects. COVID-19-related hospitalisations and ICU admissions were analysed over two time periods (prior to administration of the third dose and following administration of the third dose of vaccine) and adjusted for several co-variates. Using the general population as the reference, we then calculated the Standardized Incidence Ratio (SIR) of hospitalisation.Eighty-two subjects out of 1096 infected patients were hospitalised (7.5%) and sixty-four hospitalisations occurred among the 824 infected persons after the third dose. Age ≥ 60 years (Adj RR 2.91; 95% CI 1.34-6.30) and lung disease (Adj RR = 2.45; 95% CI 1.32-4.54) were the only risk factors associated with hospitalisation. The risk of ICU admission in the second time period (Time 2) was reduced by 86% (RR = 0.14; 95% CI 0.03-0.71) compared to the first time period (Time 1). The SIR of hospitalisation (SIR 14.51; 95% CI 11.37-17.65) and ICU admission (SIR 14.58; 95% CI 2.91-26.24) showed an increase in the number of events in dialysis patients compared to the general population.RESULTSEighty-two subjects out of 1096 infected patients were hospitalised (7.5%) and sixty-four hospitalisations occurred among the 824 infected persons after the third dose. Age ≥ 60 years (Adj RR 2.91; 95% CI 1.34-6.30) and lung disease (Adj RR = 2.45; 95% CI 1.32-4.54) were the only risk factors associated with hospitalisation. The risk of ICU admission in the second time period (Time 2) was reduced by 86% (RR = 0.14; 95% CI 0.03-0.71) compared to the first time period (Time 1). The SIR of hospitalisation (SIR 14.51; 95% CI 11.37-17.65) and ICU admission (SIR 14.58; 95% CI 2.91-26.24) showed an increase in the number of events in dialysis patients compared to the general population.Our analysis revealed that while the second variant of the virus increased infection rates, it was concurrently associated with mitigated severity of infections. Dialysis patients exhibited a higher susceptibility to both COVID-19 hospitalisation and ICU admission than the general population throughout the pandemic.CONCLUSIONSOur analysis revealed that while the second variant of the virus increased infection rates, it was concurrently associated with mitigated severity of infections. Dialysis patients exhibited a higher susceptibility to both COVID-19 hospitalisation and ICU admission than the general population throughout the pandemic.
Hypoparathyroidism is a rare disease characterized by low serum calcium levels and absent or deficient parathyroid hormone level. Regarding the epidemiology of chronic hypoparathyroidism, there are ...limited data in Italy and worldwide. Therefore, the purpose of this study was to build a unique database of patients with chronic hypoparathyroidism, derived from the databases of 16 referral centers for endocrinological diseases, affiliated with the Italian Society of Endocrinology, and four centers for endocrine surgery with expertise in hypoparathyroidism, to conduct an epidemiological analysis of chronic hypoparathyroidism in Italy. The study was approved by the Institutional Review Board. A total of 537 patients with chronic hypoparathyroidism were identified. The leading etiology was represented by postsurgical hypoparathyroidism (67.6%), followed by idiopathic hypoparathyroidism (14.6%), syndromic forms of genetic hypoparathyroidism (11%), forms of defective PTH action (5.2%), non-syndromic forms of genetic hypoparathyroidism (0.9%), and, finally, other forms of acquired hypoparathyroidism, due to infiltrative diseases, copper or iron overload, or ionizing radiation exposure (0.7%). This study represents one of the first large-scale epidemiological assessments of chronic hypoparathyroidism based on data collected at medical and/or surgical centers with expertise in hypoparathyroidism in Italy. Although the study presents some limitations, it introduces the possibility of a large-scale national survey, with the final aim of defining not only the prevalence of chronic hypoparathyroidism in Italy, but also standards for clinical and therapeutic approaches.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase (TP). Allogeneic hematopoietic stem ...cell transplantation (HSCT) has been proposed as a treatment for patients with MNGIE and a standardized approach to HSCT in this condition has recently been developed. We report on the transplant course, management and short-term follow-up in two MNGIE patients who underwent HSCT. The source of stem cells was bone marrow taken from an HLA 9/10 allele-matched unrelated donor in the first patient and from an HLA 10/10 allele-matched sibling donor in the second. Both patients achieved full donor chimerism, and we observed restoration of buffy coat TP activity and lowered urine nucleoside concentrations in both of them. The post-transplant clinical follow-up showed improvement in gastrointestinal dysmotility, abdominal cramps and diarrhea. Neurological assessment remained unchanged. However, the first patient died 15 months after HSCT due to gastrointestinal obstruction and shock; the second patient died 8 months after the procedure due to respiratory distress following septic shock. Although HSCT corrects biochemical abnormalities and improves gastrointestinal symptoms, the procedure can be risky in subjects already in poor medical condition as are many MNGIE patients. Since transplant-related morbidity and mortality increases with progression of the disease and number of comorbidities, MNGIE patients should be submitted to HSCT when they are still relatively healthy, in order to minimize the complications of the procedure. Anyway, there is still incomplete knowledge on the natural history of the disease in many affected patients and it is not yet clear when the best time to do a transplant is. Further clues to the therapeutic potential of HSCT could result from a prolonged observation in a greater number of non-transplanted and transplanted patients, which would allow us to answer the questions of if, how and when MNGIE patients require HSCT treatment.
In August 2016, a magnitude 6.0 earthquake struck Central Italy, starting a devastating seismic sequence, aggravated by other two events of magnitude 5.9 and 6.5, respectively. After the first ...mainshock, four Italian institutions installed a dense temporary network of 50 seismic stations in an area of 260 km
. The network was registered in the International Federation of Digital Seismograph Networks with the code 3A and quoted with a Digital Object Identifier ( https://doi.org/10.13127/SD/ku7Xm12Yy9 ). Raw data were converted into the standard binary miniSEED format, and organized in a structured archive. Then, data quality and completeness were checked, and all the relevant information was used for creating the metadata volumes. Finally, the 99 Gb of continuous seismic data and metadata were uploaded into the INGV node of the European Integrated Data Archive repository. Their use was regulated by a Memorandum of Understanding between the institutions. After an embargo period, the data are now available for many different seismological studies.
Carotenoid cleavage dioxygenase 2 and candidate aldehyde dehydrogenase, and UDP-glycosyltransferase enzymes involved in saffron crocin biosynthesis are localized in the chromoplast, the endoplasmic ...reticulum, and the cytoplasm.
Saffron is the dried stigmas of
Crocus sativus
and is the most expensive spice in the world. Its red color is due to crocins, which are apocarotenoid glycosides that accumulate in the vacuole to a level up to 10% of the stigma dry weight. Previously, we characterized the first dedicated enzyme in the crocin biosynthetic pathway, carotenoid cleavage dioxygenase2 (CsCCD2), which cleaves zeaxanthin to yield crocetin dialdehyde. In this work, we identified six putative
aldehyde dehydrogenase
(
ALDH
) genes expressed in
C. sativus
stigmas. Heterologous expression in
Escherichia coli
showed that only one of corresponding proteins (CsALDH3I1) was able to convert crocetin dialdehyde into the crocin precursor crocetin. CsALDH3I1 carries a carboxyl-terminal hydrophobic domain, similar to that of the
Neurospora crassa
membrane-associated apocarotenoid dehydrogenase YLO-1. We also characterized the UDP-glycosyltransferase CsUGT74AD1, which converts crocetin to crocins 1 and 2′. In vitro assays revealed high specificity of CsALDH3I1 for crocetin dialdehyde and long-chain apocarotenals and of CsUGT74AD1 for crocetin. Following extract fractionation, CsCCD2, CsALDH3I1, and CsUGT74AD1 were found in the insoluble fraction, suggesting their association with membranes or large insoluble complexes. Analysis of protein localization in both
C. sativus
stigmas and following transgene expression in
Nicotiana benthamiana
leaves revealed that CsCCD2, CsALDH3I, and CsUGT74AD1 were localized to the plastids, the endoplasmic reticulum, and the cytoplasm, respectively, in association with cytoskeleton-like structures. Based on these findings and current literature, we propose that the endoplasmic reticulum and cytoplasm function as transit centers for metabolites whose biosynthesis starts in the plastid and are accumulated in the vacuole.
Abstract
Null
mutations in progranulin gene (
GRN
) reduce the progranulin production resulting in haploinsufficiency and are tightly associated with tau‐negative frontotemporal lobar degeneration ...with TAR DNA‐binding protein 43‐positive inclusions (FTLD‐TDP). Missense mutations of
GRN
were also identified, but their effects are not completely clear, in particular unanswered is the question of what neuropathology they elicit, also considering that their occurrence has been reported in patients with typical clinical features of Alzheimer disease. They describe two fraternal twins carrying the missense
GRN
Cys139Arg mutation affected by late‐onset dementia and we report the neuropathological study of one of them. Both patients were examined by neuroimaging, neuropsychological assessment and genetic analysis of
GRN
and other genes associated with dementia. The brain of one was obtained at autopsy and examined neuropathologically. One sister presented clinical and MRI features leading to the diagnosis of Alzheimer disease. The other underwent autopsy and the brain showed neuropathological hallmarks of Alzheimer disease with abundant Aβ‐amyloid deposition and Braak stage V of neurofibrillary pathology, in the absence of the hallmark lesions of FTLD‐TDP. Their findings may contribute to better clarify the role of progranulin in neurodegenerative diseases indicating that some
GRN
mutations, in particular missense ones, may act as strong risk factor for Alzheimer disease rather than induce FTLD‐TDP.
Background
Nodal metastasis is considered a major prognostic factor in patients with ampulla of Vater carcinoma (AVC). No study has investigated the significance of the ratio between metastatic and ...resected/examined lymph nodes (LNR) in patients with AVC.
Methods
Demographic, operative, and pathology data, including number of resected/evaluated nodes and LNR, were collected from patients who underwent pancreaticoduodenectomy with radical intent for invasive AVC from 1990 to 2005. Survival rates and recurrence patterns were evaluated and predictors were identified.
Results
In 90 evaluable patients (51 males, 39 females, median age 62.5 years), 5-year disease-specific survival (DSS) was 61%. The median number of resected/evaluated nodes was 16 (range: 5–47); 50% of the patients had nodal metastases. The 5-year DSS according to LNR was 75%, 49%, 38%, and 0% for LNR = 0, LNR >0 and ≤0.2, LNR >0.2, and ≤0.4, and LNR >0.4 (
P
= 0.002), respectively. The 5-year DSS was 81% in patients with >16 resected/evaluated nodes compared with 45% in those with ≤16 resected/evaluated nodes (
P
= 0.001). On multivariate analysis LNR and a number of resected/evaluated nodes >16 were significant predictors of survival; a number of resected/evaluated nodes >16 was also the only independent predictor of recurrence.
Conclusions
After curative resection for AVC, LNR and a cutoff of 16 resected/evaluated nodes are powerful prognostic factors. LNR might represent a major parameter for patient stratification in adjuvant treatment trials.
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