Labile plasma iron and echocardiographic parameters are associated with cardiac events in ß-thalassemic patients.

BACKGROUND AND AIM: Notwithstanding the improvement in therapies, patients affected by thalassemia major (TM) and intermedia (TI) are still at high risk of cardiac complications. This study aimed at evaluating the incidence and predictive factors for developing cardiac events in adult ß-TM and TI patients. POPULATION AND METHODS: Data on diagnosis and clinical history were collected retrospectively; prospective data on new-onset cardiac failure and arrhythmias, echocardiographic parameters, biochemical variables including non-transferrin-bound iron (NTBI) and labile plasma iron (LPI), magnetic resonance imaging (MRI) T2* measurement of hepatic and cardiac iron deposits, and iron chelation therapy were recorded during a 6-year follow-up. RESULTS: Thirty-seven patients, 29 TM and 8 TI, were included. At baseline, 8 TM patients and 1 TI patient had previously experienced a cardiac event (mainly heart failure). All patients were on chelation therapy and only 3 TM patients had mild-to-severe cardiac siderosis. During follow-up, 11 patients (29.7%) experienced a new cardiac event. The occurrence of cardiac events was correlated to high LPI levels (OR 12.0, 95% CI 1.56-92.3, p .017), low mean pre-transfusion haemoglobin (OR 0.21, 95% C.I. 0.051-0.761, p .21) and echocardiographic parameters suggestive of myocardial hypertrophy. Multivariate analysis disclosed high LPI and left ventricle mass index (LVMI) as independent variables significantly associated with cardiac events. Cardiac iron deposits measured by MRI T2* failed to predict cardiac events. CONCLUSION: LPI, Hb levels and echocardiographic parameters assessing cardiac remodelling are associated with cardiac events in adult TM and TI patients. LPI might represent both a prognostic marker and a potential target for novel treatment strategies. Further studies are warranted to confirm our findings on larger populations.

Infections in liver and lung transplant recipients: a national prospective cohort.

Infections are a major complication of solid organ transplants (SOTs). This study aimed to describe recipients' characteristics, and the frequency and etiology of infections and transplant outcome in liver and lung SOTs, and to investigate exposures associated to infection and death in liver transplant recipients. The study population included recipients of SOTs performed in Italy during a 1-year period in ten Italian lung transplant units and eight liver transplant units. Data on comorbidities, infections, retransplantation, and death were prospectively collected using a web-based system, with a 6-month follow-up. The cumulative incidence of infection was 31.7% and 47.8% in liver and lung transplants, respectively, with most infections occurring within the first month after transplantation. Gram-negatives, which were primarily multidrug-resistant, were the most frequent cause of infection. Death rates were 0.42 per 1000 recipient-days in liver transplants and 1.41 per 1000 recipient-days in lung transplants. Infection after SOT in adult liver recipients is associated to an increased risk of death (OR = 13.25; p-value < 0.001). Given the frequency of infection caused by multidrug-resistant microorganisms in SOT recipients in Italy and the heavy impact of infections on the transplant outcome, the reinforcement of surveillance and control activities to prevent the transmission of multidrug-resistant microorganisms in SOT recipients represents a priority. The implementation of the study protocol in liver and lung transplant units and the sharing of results have increased the awareness about the threat due to antimicrobial resistance in the country.

Organ transplantation from "increased infectious risk donors": the experience of the Nord Italia Transplant program - A retrospective study.

The purpose of this study was to assess the safety and the clinical outcome associated with organ transplantation from increased infectious risk donors (IRD). We retrospectively identified all adult deceased IRD referred to the Nord Italia Transplant program coordinating center from November 2006 to November 2011. All potential donors were screened for social risk factors that may increase the risk of donor-derived infection with human immunodeficiency (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). All recipients were followed monthly for the first 6 months post-transplant. A total of 86 potential IRD were identified during the study period. Three hundred and seventy-nine organs from IRD were offered to the transplant centers, but only 185 (48.8%) were used for transplantation. Organs from IRD were transplanted into 174 recipients. The complete follow-up data were available for 152 of 174 (87.3%) recipients. During a mean follow-up of 11.7 months (median 12; range 2.4-12), no transmission of HIV, HBV, or syphilis was documented by serology and nucleic acid testing (NAT) testing. Two patients transplanted with organs from HCV-RNA-positive donors, as expected, developed post-transplant HCV infection. In conclusion, the use of organs from IRD was associated with a safe increase in the transplant procedures in our country.

Renal transplantation in sensitized children and young adults: a nationwide approach.

Background: High levels of preformed anti-HLA antibodies dramatically diminish renal transplant outcomes. Most desensitization programmes guarantee good intermediate outcomes but quite disappointing long-term prognosis. The search for a fully compatible kidney increases time on the waiting list. Methods: In February 2011, a nationwide hyperimmune programme (NHP) was begun in Italy: all available kidneys are primarily proposed to highly sensitized patients with a panel reactive antibody above 80%. In this manuscript, we evaluate the outcome of paediatric patients transplanted with this approach. Results: Twenty-one patients were transplanted. Complete data are available for 20 patients. Mean age at transplantation was 14.5 years [standard deviation (SD) ± 5.5)]. Mean time on the waiting list was 29.3 months (SD ± 27.5). Median follow-up was 29.2 months (range: 11.2-59.3). The average number of HLA mismatches in these patients was 2.3 versus 3.7 in 48 standard patients transplanted in the same period (P < 0.001). Only one graft was lost. Two cases of humoral rejection occurred and were successfully treated. No cellular rejection was reported. Median creatinine clearance was 84, 88, 77 and 77 mL/min/1.73 m 2 respectively 1, 6, 12 and 24 months after transplant. Conclusions: Transplantation of sensitized patients avoiding prohibited antigens is feasible, at least in a selected cohort of patients. In order to be able to further improve this approach, which in our opinion is very successful, it would be necessary to expand the donor pool, possibly increasing the number of countries participating in the programme. In this series, time on the waiting list did not increase significantly. This allocation policy should ideally lead to an outcome comparable to that expected in standard patients, which is particularly desirable in young patients who have the longest life expectancy. Since long-term results of desensitization programmes are not (yet) convincing, we suggest that these programmes should be reserved for selected cases where compatible organs cannot be found within a reasonable time span.

Liver transplant recipients and prioritization of anti-HCV therapy: an Italian cohort analysis.

BACKGROUND AND AIMS: In patients with hepatitis C virus (HCV), recurrence of infection after liver transplant (LT) is universal and associated with worst survival. We present the results of an Italian cohort to compare the 3-year outcome of HCV-Ab-positive and HCV-Ab-negative LT recipients and to assess the potential interaction between HCV-Ab sero-status and other risk factors for LT failure. METHODS: The study is a multicentre cohort including a sample of liver transplant centres. Participant's information was collected at the local level. The best functional form of variables was decided according to the objective methods based on information theory. Association between transplant failure and potential risk factors was assessed in univariate and multivariate Poisson regression model with random intercept. RESULTS: Between June 2007 and May 2009, 1164 LT recipients were enrolled in 16 Italian transplant centres, of them 275 (23.63%) experienced LT failure. Incidence rates of LT failure was 0.32 and 0.23 per 1000 person-days in HCV-Ab-positive and HCV-Ab-negative recipients respectively (P = 0.003). Inferential models according to Akaike information criterion indicated that donor-recipient age difference and donor-recipient sex matching were more informative to predict LT failure than the age and the sex as separate variables. Multivariate analysis provided evidence that HCV-Ab sero-status, time after LT, donor-recipient age difference, donor-recipient sex matching and recipient's MELD score were significantly associated with LT failure. Moreover, the effect of HCV-Ab sero-status on LT failure was modified by the simultaneous action of time after LT and donor-recipient age difference. No interaction was found between recipient's HCV-Ab sero-status and either recipient's MELD or donor-recipient sex matching. CONCLUSION: In view of the imminent introduction of new anti-HCV therapies, our study provides information to assess which LT recipients should be prioritized for receiving these highly effective, but expensive, new treatments. This is particularly relevant for those clinical settings where healthcare prioritization is endorsed by national authorities.

A high-density, SNP-based consensus map of tetraploid wheat as a bridge to integrate durum and bread wheat genomics and breeding.

Consensus linkage maps are important tools in crop genomics. We have assembled a high-density tetraploid wheat consensus map by integrating 13 data sets from independent biparental populations involving durum wheat cultivars (Triticum turgidum ssp. durum), cultivated emmer (T. turgidum ssp. dicoccum) and their ancestor (wild emmer, T. turgidum ssp. dicoccoides). The consensus map harboured 30 144 markers (including 26 626 SNPs and 791 SSRs) half of which were present in at least two component maps. The final map spanned 2631 cM of all 14 durum wheat chromosomes and, differently from the individual component maps, all markers fell within the 14 linkage groups. Marker density per genetic distance unit peaked at centromeric regions, likely due to a combination of low recombination rate in the centromeric regions and even gene distribution along the chromosomes. Comparisons with bread wheat indicated fewer regions with recombination suppression, making this consensus map valuable for mapping in the A and B genomes of both durum and bread wheat. Sequence similarity analysis allowed us to relate mapped gene-derived SNPs to chromosome-specific transcripts. Dense patterns of homeologous relationships have been established between the A- and B-genome maps and between nonsyntenic homeologous chromosome regions as well, the latter tracing to ancient translocation events. The gene-based homeologous relationships are valuable to infer the map location of homeologs of target loci/QTLs. Because most SNP and SSR markers were previously mapped in bread wheat, this consensus map will facilitate a more effective integration and exploitation of genes and QTL for wheat breeding purposes.

A controlled study of a lecithinized delivery system of curcumin (Meriva®) to alleviate the adverse effects of cancer treatment.

A proprietary lecithin delivery system of curcumin (Meriva) was evaluated in a controlled study to assess its efficacy in alleviating the side effects of cancer chemo- and radiotherapy in 160 patients undergoing these treatments. In both cases, a semi-quantitative evaluation of the side effects was carried out using a visual analogue scale, assessing also the plasma free radical status in all patients. Results showed that lecithinized curcumin might alleviate the burden of side effects associated to chemo- and radiotherapy, suggesting that the anecdotal use of various preparations of curcumin as a supportive agent for cancer treatment is well worth a systematic investigation in larger scale clinical trials. The capacity of curcumin to upregulate anti-oxidative responses and downregulate inflammatory pathways could explain its beneficial effect in tempering the prolonged and systemic oxidative and inflammatory effects of cancer treatment, and the beneficial effects observed in the plasma oxidative status in all patients of the treatment group support this view.

Searching for novel sources of field resistance to Ug99 and Ethiopian stem rust races in durum wheat via association mapping.

Puccinia graminis f. sp. tritici, the causative agent of stem rust in wheat, is a devastating disease of durum wheat. While more than 50 stem rust resistance (Sr) loci have been identified in wheat, only a few of them have remained effective against Ug99 (TTKSK race) and other durum-specific Ethiopian races. An association mapping (AM) approach based on 183 diverse durum wheat accessions was utilized to identify resistance loci for stem rust response in Ethiopia over four field-evaluation seasons and artificial inoculation with Ug99 and a mixture of durum-specific races. The panel was profiled with simple sequence repeat, Diversity Arrays Technology and sequence-tagged site markers (1,253 in total). The resistance turned out to be oligogenic, with twelve QTL-tagging markers that were significant (P < 0.05) across three or four seasons. R (2) values ranged from 1.1 to 11.3 %.Twenty-four additional single-marker/QTL regions were found to be significant over two seasons. The AM results confirmed the role of Sr13, previously described in bi-parental mapping studies, and the role of chromosome regions putatively harbouring Sr9, Sr14, Sr17 and Sr28. Three minor QTLs were coincident with those reported in hexaploid wheat and five overlapped with those recently reported in the Sebatel × Kristal durum mapping population. Thirteen single-marker/QTL regions were located in chromosome regions where no Sr genes/QTLs have been previously reported. The allelic variation identified in this study is readily available and can be exploited for marker-assisted selection, thus providing additional opportunities for a more durable stem rust resistance under field conditions.

Exploring the Protective Effect of Food Drugs against Viral Diseases: Interaction of Functional Food Ingredients and SARS-CoV-2, Influenza Virus, and HSV.

A complex network of processes inside the human immune system provides resistance against a wide range of pathologies. These defenses form an innate and adaptive immunity, in which certain immune components work together to counteract infections. In addition to inherited variables, the susceptibility to diseases may be influenced by factors such as lifestyle choices and aging, as well as environmental determinants. It has been shown that certain dietary chemical components regulate signal transduction and cell morphologies which, in turn, have consequences on pathophysiology. The consumption of some functional foods may increase immune cell activity, defending us against a number of diseases, including those caused by viruses. Here, we investigate a range of functional foods, often marketed as immune system boosters, in an attempt to find indications of their potential protective role against diseases caused by viruses, such as the influenza viruses (A and B), herpes simplex virus (HSV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in some cases mediated by gut microbiota. We also discuss the molecular mechanisms that govern the protective effects of some functional foods and their molecular constituents. The main message of this review is that discovering foods that are able to strengthen the immune system can be a winning weapon against viral diseases. In addition, understanding how the dietary components function can aid in the development of novel strategies for maintaining human bodily health and keeping our immune systems strong.

CREB-H is a stress-regulator of hepcidin gene expression during early postnatal development.

Hepcidin, the hepatic iron hormone, is the central regulator of iron homeostasis. Cyclic AMP-Responsive Element-Binding protein 3-like 3 (CREB3L3/CREB-H) is a liver homeostatic regulator of essential nutrients (i.e. glucose and lipids) and has been previously involved in hepcidin response to pathologic stress signals. Here, we asked whether CREB-H has also a physiologic role in iron homeostasis through hepcidin. To this end, we analyzed hepcidin gene expression and regulation in the liver of wild type and Creb3l3 knockout mice during early postnatal development, as a model of "physiologic" stressful condition. The effect of iron challenge in vivo and BMP6 stimulation in vitro have been also addressed. In addition, we investigated the BMP signaling pathway and hepcidin promoter activity following CREB3L3 silencing and hepcidin promoter mutation in HepG2 cells. Creb3l3 knockout suckling and young-adult mice showed a prominent serum and hepatic iron accumulation, respectively, due to impaired hepcidin mRNA expression which progressively returned to normal level in adult mice. Interestingly, upon iron challenge, while the upstream BMP/SMAD signaling pathway controlling hepcidin was equally responsive in both strains, hepcidin gene expression was impaired in knockout mice and more iron accumulated in the liver. Accordingly, hepcidin gene response to BMP6 was blunted in primary CREB-H knockout hepatocytes and in HepG2 cells transfected with CREB-H siRNA or carrying a hepcidin promoter mutated in the CREB-H binding site. In conclusion, CREB-H has a role in maintaining the homeostatic balance of iron traffic through hepcidin during the critical postnatal period and in response to iron challenge. KEY MESSAGES: CREB-H KO mice develop liver iron overload shortly after weaning that normalizes in adulthood. CHEB-H is involved in hepcidin gene response to oral iron in vivo. CREB-H loss hampers hepcidin promoter response to BMP6. CREB-H is a key stress-sensor controlling hepcidin gene transcription in physiologic and pathophysiologic states.

Tailoring FPOX enzymes for enhanced stability and expanded substrate recognition.

Fructosyl peptide oxidases (FPOX) are deglycating enzymes that find application as key enzymatic components in diabetes monitoring devices. Indeed, their use with blood samples can provide a measurement of the concentration of glycated hemoglobin and glycated albumin, two well-known diabetes markers. However, the FPOX currently employed in enzymatic assays cannot directly detect whole glycated proteins, making it necessary to perform a preliminary proteolytic treatment of the target protein to generate small glycated peptides that can act as viable substrates for the enzyme. This is a costly and time consuming step. In this work, we used an in silico protein engineering approach to enhance the overall thermal stability of the enzyme and to improve its catalytic activity toward large substrates. The final design shows a marked improvement in thermal stability relative to the wild type enzyme, a distinct widening of its access tunnel and significant enzymatic activity towards a range of glycated substrates.

Givosiran for the treatment of acute hepatic porphyria.

INTRODUCTION: Acute hepatic porphyrias (AHPs) are a family of rare inherited disorders characterized by enzyme dysfunctions in the hepatic pathway of heme biosynthesis. In AHPs, accumulation of the neurotoxic porphyrin precursors delta-aminolevulinic acid and porphobilinogen, caused by enhanced activity of hepatic aminolevulinate synthase 1 (ALAS1), is associated with acute, potentially life-threatening neurovisceral attacks. Symptoms during and between attacks dramatically reduce patients' quality of life (QoL). Givosiran is the first mRNA-targeted treatment for AHPs, silencing ALAS1 expression. AREAS COVERED: For givosiran, this review summarizes its chemistry, mechanism of action, pharmacokinetics, pharmacodynamics, safety, preclinical and clinical data in AHP, postmarketing surveillance, and regulatory status. A literature search of public and internal databases was performed, bibliographies of retrieved articles were manually searched to identify additional studies of relevance, and information was also provided by Alnylam Pharmaceuticals. EXPERT OPINION: Givosiran is a small interfering RNA (siRNA) therapeutic that reduces hepatic activity of ALAS1 and decreases accumulation of neurotoxic porphyrin precursors in patients with AHPs, ultimately reducing the number of acute attacks and improving symptoms and QoL between attacks. As AHPs are lifelong diseases, long-term safety data are needed for givosiran as an siRNA-based therapy.

Challenges in diagnosis and management of acute hepatic porphyrias: from an uncommon pediatric onset to innovative treatments and perspectives.

Acute hepatic porphyrias (AHPs) are a family of four rare genetic diseases resulting from a deficiency in one of the enzymes involved in heme biosynthesis. AHP patients can experience potentially life-threatening acute attacks, characterized by severe abdominal pain, along with other signs and symptoms including nausea, mental confusion, hyponatraemia, hypertension, tachycardia and muscle weakness. Some patients also experience chronic manifestations and long-term complications, such as chronic pain syndrome, neuropathy and porphyria-associated kidney disease. Most symptomatic patients have only a few attacks in their lifetime; nevertheless, some experience frequent attacks that result in ongoing symptoms and a significant negative impact on their quality of life (QoL). Initial diagnosis of AHP can be made with a test for urinary porphobilinogen, [Formula: see text]-aminolaevulinic acid and porphyrins using a single random (spot) sample. However, diagnosis is frequently missed or delayed, often for years, because the clinical symptoms of AHP are non-specific and mimic other more common disorders. Delayed diagnosis is of concern as some commonly used medications can trigger or exacerbate acute attacks, and untreated attacks can become severe, potentially leading to permanent neurological damage or fatality. Other attack triggers include hormonal fluctuations in women, stress, alcohol and low-calorie diets, which should be avoided in patients where possible. For the management of attacks, intravenous hemin is approved, whereas new therapeutic approaches are currently being investigated as a baseline therapy for prevention of attacks and improvement of QoL. Among these, a novel siRNA-based agent, givosiran, has shown very promising results in a recently concluded Phase III trial and has been approved for the management of AHPs. Here, we propose a challenging case study-with a very unusual pediatric onset of variegate porphyria-as a starting point to summarize the main clinical aspects (namely, clinical manifestations, diagnostic challenges, and therapeutic management) of AHPs, with a focus on the latest therapeutic innovations.

Iron Metabolism in the Disorders of Heme Biosynthesis.

Given its remarkable property to easily switch between different oxidative states, iron is essential in countless cellular functions which involve redox reactions. At the same time, uncontrolled interactions between iron and its surrounding milieu may be damaging to cells and tissues. Heme-the iron-chelated form of protoporphyrin IX-is a macrocyclic tetrapyrrole and a coordination complex for diatomic gases, accurately engineered by evolution to exploit the catalytic, oxygen-binding, and oxidoreductive properties of iron while minimizing its damaging effects on tissues. The majority of the body production of heme is ultimately incorporated into hemoglobin within mature erythrocytes; thus, regulation of heme biosynthesis by iron is central in erythropoiesis. Additionally, heme is a cofactor in several metabolic pathways, which can be modulated by iron-dependent signals as well. Impairment in some steps of the pathway of heme biosynthesis is the main pathogenetic mechanism of two groups of diseases collectively known as porphyrias and congenital sideroblastic anemias. In porphyrias, according to the specific enzyme involved, heme precursors accumulate up to the enzyme stop in disease-specific patterns and organs. Therefore, different porphyrias manifest themselves under strikingly different clinical pictures. In congenital sideroblastic anemias, instead, an altered utilization of mitochondrial iron by erythroid precursors leads to mitochondrial iron overload and an accumulation of ring sideroblasts in the bone marrow. In line with the complexity of the processes involved, the role of iron in these conditions is then multifarious. This review aims to summarise the most important lines of evidence concerning the interplay between iron and heme metabolism, as well as the clinical and experimental aspects of the role of iron in inherited conditions of altered heme biosynthesis.

Endothelial Dysfunction in Acute Hepatic Porphyrias.

Background Acute hepatic porphyrias (AHPs) are a group of rare diseases caused by dysfunctions in the pathway of heme biosynthesis. Although acute neurovisceral attacks are the most dramatic manifestations, patients are at risk of developing long-term complications, several of which are of a vascular nature. The accumulation of non-porphyrin heme precursors is deemed to cause most clinical symptoms. Aim We measured the serum levels of endothelin-1 (ET-1) and nitric oxide (NO) to assess the presence of endothelial dysfunction (ED) in patients with AHPs. Forty-six patients were classified, according to their clinical phenotype, as symptomatic (AP-SP), asymptomatic with biochemical alterations (AP-BA), and asymptomatic without biochemical alterations (AP-AC). Results Even excluding those under hemin treatment, AP-SP patients had the lowest NO and highest ET-1 levels, whereas no significant differences were found between AP-BA and AP-AC patients. AP-SP patients had significantly more often abnormal levels of ED markers. Patients with the highest heme precursor urinary levels had the greatest alterations in ED markers, although no significant correlation was detected. Conclusions ED is more closely related to the clinical phenotype of AHPs than to their classical biochemical alterations. Some still undefined disease modifiers may possibly determine the clinical picture of AHPs through an effect on endothelial functions.

Acute kidney injury after liver transplantation, perioperative risk factors, and outcome: prospective observational study of 1681 patients (OLTx Study).

BACKGROUND: Acute kidney injury (AKI) represents a frequent complication after orthotopic liver transplantation (OLT). This study aimed to evaluate early postoperative AKI incidence during the first 72 h after OLT, perioperative risk factors, and AKI impact on survival. METHODS: From January 2011 to December 2013, 1681 patients underwent OLT in 19 centers and were enrolled in this prospective cohort study. RESULTS: According to RIFLE criteria, AKI occurred in 367 patients, 21.8% (R: 5.8%, I: 6.4%, F: 4.8%, L: 4.8%). Based on multivariate analysis, intraoperative risk factors for AKI were: administration of 5-10 RBCs (OR 1.8, 95% CI 1.3-2.7), dopamine use (OR 1.6, 95% CI 1.2-2.3), post-reperfusion syndrome (OR 1.5, 95% CI 1.0-2.3), surgical complications (OR 2.0, 95% CI 1.3-3.0), and cardiological complications (OR 2.2, 95% CI 1.2-4.0). Postoperative risk factors were: norepinephrine (OR 1.4, 95% CI 1.0-2.0), furosemide (OR 4.2, 95% CI 3.0-5.9), more than 10 RBCs transfusion, (OR 3.7, 95% CI 1.4-10.5), platelets administration (OR 1.6, 95% CI 1.1-2.4), fibrinogen administration (OR 3.0, 95% CI, 1.5-6.2), hepatic complications (OR 4.6, 95% CI 2.9-7.5), neurological complications (OR 2.4, 95% CI 1.5-3.7), and infectious complications (OR 2.7, 95% CI 1.8-4.3). NO-AKI patients' 5-year survival rate was higher than AKI patients (68.06, 95% CI 62.7-72.7 and 81.2, 95% CI 78.9-83.3, P<0.001). CONCLUSIONS: AKI still remains an important risk factor for morbidity and mortality after OLT. Further research to develop new strategies aimed at preventing or minimizing post-OLT AKI is needed.

Recognized and Emerging Features of Erythropoietic and X-Linked Protoporphyria.

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inherited disorders resulting from defects in two different enzymes of the heme biosynthetic pathway, i.e., ferrochelatase (FECH) and delta-aminolevulinic acid synthase-2 (ALAS2), respectively. The ubiquitous FECH catalyzes the insertion of iron into the protoporphyrin ring to generate the final product, heme. After hemoglobinization, FECH can utilize other metals like zinc to bind the remainder of the protoporphyrin molecules, leading to the formation of zinc protoporphyrin. Therefore, FECH deficiency in EPP limits the formation of both heme and zinc protoporphyrin molecules. The erythroid-specific ALAS2 catalyses the synthesis of delta-aminolevulinic acid (ALA), from the union of glycine and succinyl-coenzyme A, in the first step of the pathway in the erythron. In XLP, ALAS2 activity increases, resulting in the amplified formation of ALA, and iron becomes the rate-limiting factor for heme synthesis in the erythroid tissue. Both EPP and XLP lead to the systemic accumulation of protoporphyrin IX (PPIX) in blood, erythrocytes, and tissues causing the major symptom of cutaneous photosensitivity and several other less recognized signs that need to be considered. Although significant advances have been made in our understanding of EPP and XLP in recent years, a complete understanding of the factors governing the variability in clinical expression and the severity (progression) of the disease remains elusive. The present review provides an overview of both well-established facts and the latest findings regarding these rare diseases.

An Italian multicentre distributed data research network to study the use, effectiveness, and safety of immunosuppressive drugs in transplant patients: Framework and perspectives of the CESIT project.

The goal of post-transplant immunosuppressive drug therapy is to prevent organ rejection while minimizing drug toxicities. In clinical practice, a multidrug approach is commonly used and involves drugs with different mechanisms of action, including calcineurin inhibitors (CNI) (tacrolimus or cyclosporine), antimetabolite (antimet) (mycophenolate or azathioprine), inhibitors of mechanistic target of rapamycin (mTOR) (sirolimus or everolimus), and/or steroids. Although evidence based on several randomized clinical trials is available, the optimal immunosuppressive therapy has not been established and may vary among organ transplant settings. To improve the knowledge on this topic, a multiregional research network to Compare the Effectiveness and Safety of Immunosuppressive drugs in Transplant patients (CESIT) has been created with the financial support of the Italian Medicines Agency. In this article, we describe the development of this network, the framework that was designed to perform observational studies, and we also give an overview of the preliminary results that we have obtained. A multi-database transplant cohort was enrolled using a common data model based on healthcare claims data of four Italian regions (Lombardy, Veneto, Lazio, and Sardinia). Analytical datasets were created using an open-source tool for distributed analysis. To link the National Transplant Information System to the regional transplant cohorts, a semi-deterministic record linkage procedure was performed. Overall, 6,914 transplant patients from 2009-19 were identified: 4,029 (58.3%) for kidney, 2,219 (32.1%) for liver, 434 (6.3%) for heart, and 215 (3.1%) for lung. As expected, demographic and clinical characteristics showed considerable variability among organ settings. Although the triple therapy in terms of CNI + antimet/mTOR + steroids was widely dispensed for all settings (63.7% for kidney, 33.5% for liver, 53.3% for heart, and 63.7% for lung), differences in the active agents involved were detected. The CESIT network represents a great opportunity to study several aspects related to the use, safety, and effectiveness of post-transplant maintenance immunosuppressive therapy in real practice.

Temporal trends of waitlistings for liver transplantation in Italy: The ECALITA (Evolution of IndiCAtion in LIver transplantation in ITAly) registry study.

BACKGROUND: Over the last decades relevant epidemiological changes of liver diseases have occurred, together with greatly improved treatment opportunities. AIM: To investigate how the indications for elective adult liver transplantation and the underlying disease etiologies have evolved in Italy. METHODS: We recruited from the National Transplant Registry a cohort comprising 17,317 adults patients waitlisted for primary liver transplantation from January-2004 to December-2020. Patients were divided into three Eras:1(2004-2011),2(2012-2014) and 3(2015-2020). RESULTS: Waitlistings for cirrhosis decreased from 65.9% in Era 1 to 46.1% in Era 3, while those for HCC increased from 28.7% to 48.7%. Comparing Eras 1 and 3, waitlistings for HCV-related cirrhosis decreased from 35.9% to 12.1%, yet those for HCV-related HCC increased from 8.5% to 26.7%. Waitlistings for HBV-related cirrhosis remained almost unchanged (13.2% and 12.4%), while those for HBV-related HCC increased from 4.0% to 11.6%. ALD-related cirrhosis decreased from 16.9% to 12.9% while ALD-related HCC increased from 1.9% to 3.9%. CONCLUSIONS: A sharp increase in liver transplant waitlisting for HCC and a concomitant decrease of waitlisting for cirrhosis have occurred In Italy. Despite HCV infection has noticeably decreased, still remains the primary etiology of waitlisting for HCC, while ALD and HBV represent the main causes for cirrhosis.

Mitochondrial genomes and Doubly Uniparental Inheritance: new insights from Musculista senhousia sex-linked mitochondrial DNAs (Bivalvia Mytilidae).

BACKGROUND: Doubly Uniparental Inheritance (DUI) is a fascinating exception to matrilinear inheritance of mitochondrial DNA (mtDNA). Species with DUI are characterized by two distinct mtDNAs that are inherited either through females (F-mtDNA) or through males (M-mtDNA). DUI sex-linked mitochondrial genomes share several unusual features, such as additional protein coding genes and unusual gene duplications/structures, which have been related to the functionality of DUI. Recently, new evidence for DUI was found in the mytilid bivalve Musculista senhousia. This paper describes the complete sex-linked mitochondrial genomes of this species. RESULTS: Our analysis highlights that both M and F mtDNAs share roughly the same gene content and order, but with some remarkable differences. The Musculista sex-linked mtDNAs have differently organized putative control regions (CR), which include repeats and palindromic motifs, thought to provide sites for DNA-binding proteins involved in the transcriptional machinery. Moreover, in male mtDNA, two cox2 genes were found, one (M-cox2b) 123bp longer. CONCLUSIONS: The complete mtDNA genome characterization of DUI bivalves is the first step to unravel the complex genetic signals allowing Doubly Uniparental Inheritance, and the evolutionary implications of such an unusual transmission route in mitochondrial genome evolution in Bivalvia. The observed redundancy of the palindromic motifs in Musculista M-mtDNA may have a role on the process by which sperm mtDNA becomes dominant or exclusive of the male germline of DUI species. Moreover, the duplicated M-COX2b gene may have a different, still unknown, function related to DUI, in accordance to what has been already proposed for other DUI species in which a similar cox2 extension has been hypothesized to be a tag for male mitochondria.