Erythropoietic protoporphyrias: Pathogenesis, diagnosis and management.

The erythropoietic protoporphyrias consist of three ultra-rare genetic disorders of the erythroid heme biosynthesis, including erythropoietic protoporphyria (EPP1), X-linked protoporphyria (XLEPP) and CLPX-protoporphyria (EPP2), which all lead to the accumulation of protoporphyrin IX (PPIX) in erythrocytes. Affected patients usually present from early childhood with episodes of severe phototoxic pain in the skin exposed to visible light. The quantification of PPIX in erythrocytes with a metal-free PPIX ≥3 times the upper limit of normal confirms the diagnosis. Protoporphyria-related complications include liver failure, gallstones, mild anaemia and vitamin D deficiency with reduced bone mineral density. The management is focused on preventing phototoxic reactions and treating the complications. Vitamin D should be supplemented, and DEXA scans in adults should be considered. In EPP1, even in cases of biochemically determined iron deficiency, supplementation of iron may stimulate PPIX production, resulting in an increase in photosensitivity and the risk of cholestatic liver disease. However, for patients with XLEPP, iron supplementation can reduce PPIX levels, phototoxicity and liver damage. Because of its rarity, there is little data on the management of EPP-related liver disease. As a first measure, any hepatotoxins should be eliminated. Depending on the severity of the liver disease, phlebotomies, exchange transfusions and ultimately liver transplantation with subsequent haematopoietic stem cell transplantation (HSCT) are therapeutic options, whereby multidisciplinary management including porphyria experts is mandatory. Afamelanotide, an alpha-melanocyte-stimulating hormone analogue, is currently the only approved specific treatment that increases pain-free sunlight exposure and quality of life.

Evidence-based consensus guidelines for the diagnosis and management of erythropoietic protoporphyria and X-linked protoporphyria.

Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses. Limited expertise with these disorders among physicians leads to diagnostic delays. Here, we present evidence-based consensus guidelines for the diagnosis, monitoring, and management of erythropoietic protoporphyria and X-linked protoporphyria. A systematic literature review was conducted, and reviewed among subcommittees of experts, divided by topic. Consensus on guidelines was reached within each subcommittee and then among all members of the committee. The appropriate biochemical and genetic testing to establish the diagnosis is reviewed in addition to the interpretation of results. Prevention of symptoms, management of acute phototoxicity, and pharmacologic and nonpharmacologic treatment options are discussed. The importance of ongoing monitoring for liver disease, iron deficiency, and vitamin D deficiency is discussed with management guidance. Finally, management of pregnancy and surgery and the safety of other therapies are summarized. We emphasize that these are multisystemic disorders that require longitudinal monitoring. These guidelines provide a structure for evidence-based diagnosis and management for practicing physicians. Early diagnosis and management of these disorders are essential, particularly given the availability of new and emerging therapies.

Linear Antenna Array Sectorized Beam Scanning Approaches Using Element Position Perturbation in the Azimuth Plane.

In this paper, two sector beam scanning approaches (BSAs) based on element position perturbations (EPPs) in the azimuth plane are introduced. In EPP-BSA, the elements' excitations are kept constant and the elements' positions in the direction normal to the array line are changed according to a predetermined EPP pattern. The magnitude and repetition rate of the selected EPP pattern determines the steering angle of the main beam. However, EPP-BSA results in a wide scanning range with a significant increase in the side lobe level (SLL). To mitigate this drawback, a reduction in the SLL of the array pattern is firstly performed using the single convolution/genetic algorithm (SC/GA) technique and then perturbing the elements' positions in the azimuth plane. This combination between SLL reduction and EPP-BSA (SLL/EPP-BSA) results in a smaller scanning range with a relatively constant half power beamwidth (HPBW) and a much lower SLL. In addition, keeping the synthesized excitation coefficients constant without adding progressive phase shifters facilitates the manufacturing process and reduces the cost of the feeding network. Furthermore, a planar antenna array thinning approach is proposed to realize the EPP-BSA. The results are realized using the computer simulation technology (CST) microwave studio software package, which provides users with an optimized modeling environment and results in realizable and realistic designs.

Gold-nanoparticle-enriched breast tissue in breast cancer treatment using the INTRABEAM® system: a Monte Carlo study.

Using a 50-kV INTRABEAM® system after breast-conserving surgery, breast skin injury and long treatment time remain the challenging problems when large-size spherical applicators are used. This study has aimed to address these problems using gold (Au) nanoparticles (NPs). For this, surface and isotropic doses were measured using a Gafchromic EBT3 film and a water phantom. The particle propagation code EGSnrc/Epp was used to score the corresponding doses using a geometry similar to that used in the measurements. The simulation was validated using a gamma index of 2%/2 mm acceptance criterion in the gamma analysis. After validation Au-NP-enriched breast tissue was simulated to quantify any breast skin dose reduction and shortening of treatment time. It turned out that the gamma value deduced for validation of the simulation was in an acceptable range (i.e., less than one). For 20 mg-Au/g-breast tissue, the calculated Dose Enhancement Ratio (DER) of the breast skin was 0.412 and 0.414 using applicators with diameters of 1.5 cm and 5 cm, respectively. The corresponding treatment times were shortened by 72.22% and 72.30% at 20 mg-Au/g-breast tissue concentration, respectively. It is concluded that Au-NP-enriched breast tissue shows significant advantages, such as reducing the radiation dose received by the breast skin as well as shortening the treatment time. Additionally, the DERs were not significantly dependent on the size of the applicators.

Evidence in the UK Biobank for the underdiagnosis of erythropoietic protoporphyria.

PURPOSE: Erythropoietic protoporphyria (EPP), characterized by painful cutaneous photosensitivity, results from pathogenic variants in ferrochelatase (FECH). For 96% of patients, EPP results from coinheriting a rare pathogenic variant in trans of a common hypomorphic variant c.315-48T>C (minor allele frequency 0.05). The estimated prevalence of EPP derived from the number of diagnosed individuals in Europe is 0.00092%, but this may be conservative due to underdiagnosis. No study has estimated EPP prevalence using large genetic data sets. METHODS: Disease-associated FECH variants were identified in the UK Biobank, a data set of 500,953 individuals including 49,960 exome sequences. EPP prevalence was then estimated. The association of FECH variants with EPP-related traits was assessed. RESULTS: Analysis of pathogenic FECH variants in the UK Biobank provides evidence that EPP prevalence is 0.0059% (95% confidence interval [CI]: 0.0042-0.0076%), 1.7-3.0 times more common than previously thought in the UK. In homozygotes for the common c.315-48T>C FECH variant, there was a novel decrement in both erythrocyte mean corpuscular volume (MCV) and hemoglobin. CONCLUSION: The prevalence of EPP has been underestimated secondary to underdiagnosis. The common c.315-48T>C allele is associated with both MCV and hemoglobin, an association that could be important both for those with and without EPP.

Sequential paternal haploidentical donor liver and HSCT in EPP allow discontinuation of immunosuppression post-organ transplant.

BACKGROUND: EPP is characterized by photosensitivity and by liver disease. When LT is performed in EPP, recurrence often occurs in the allograft due to ongoing protoporphyrin production in bone marrow. Therefore, curative treatment requires allogeneic HSCT after LT. Long-term immunosuppression could be spared by using the same donor for both transplants. METHODS: A 2-year-old girl with EPP in liver failure underwent liver transplant from her father. Transfusion and apheresis therapy were used to lower protoporphyrin levels before and after liver transplant. Ten weeks after liver transplant, she underwent HSCT, using the same donor. Conditioning was with treosulfan, fludarabine, cyclophosphamide, and ATG. GVHD prophylaxis was with abatacept, methotrexate, MMF, and tacrolimus. We followed the patient's erythrocyte protoporphyrin and liver and skin health for 2 years after transplant. RESULTS: After hematopoietic stem cell engraftment, a decline in protoporphyrin levels was observed, with clinical resolution of photosensitivity. Liver biopsies showed no evidence of EPP. Mild ACR occurred and responded to steroid pulse. Two years post-HSCT, the patient has been weaned off all immunosuppression and remains GVHD and liver rejection free. CONCLUSIONS: Sequential liver and HSCT from the same haploidentical donor are feasible in EPP. This strategy can allow for discontinuation of immune suppression.

Hematopoietic cell transplant for reversal of liver fibrosis in a pediatric patient with erythropoietic protoporphyria.

BACKGROUND: EPP is a rare disorder of heme biosynthesis in which patients present with disabling photosensitivity. A subset of patients develop severe liver disease with progressive liver failure necessitating an OLT. A HCT can potentially cure EPP by replacing the native bone marrow, which is the primary site of heme synthesis. However, due to concerns for inherent risks of treatment-related toxicities, the use of HCT has been reserved for patients undergoing an OLT to avoid disease recurrence in the hepatic graft. Data for HCT in EPP are lacking, particularly in the pediatric population. CASE (METHODS/RESULTS): We present the case of a 12-year-old patient with EPP photosensitivity and cirrhosis, whom we successfully treated with pre-emptive allogeneic HCT, significantly improving the patient's quality of life. We used a matched-unrelated donor bone marrow-derived graft. Our patient achieved full donor peripheral blood chimerism and has not had any evidence of GVHD. In addition to resolution of photosensitivity, our patient had reversal of liver fibrosis which we feel was largely due to intervention at an early stage of compensated cirrhosis. CONCLUSION: Our case highlights the successful application of a known RIC regimen to this rare disorder that was well tolerated with sustained donor engraftment. It also emphasizes the importance of timing for HCT in patients with EPP and liver fibrosis. HCT should be considered early in pediatric patients with EPP-hepatopathy to prevent progression to liver failure and need for OLT with lifelong immunosuppression.

Inherited genetic late-onset erythropoietic protoporphyria: A systematic review of the literature.

BACKGROUND: Inherited genetic erythropoietic protoporphyria (EPP) is characterized by a photosensitive rash that emerges during infancy or early childhood. Acquired EPP can erupt at any age, even during adulthood, and is associated with hematological disorders. A third, less-studied type of EPP is also inherited but appears later in life (during adulthood). PURPOSE: To evaluate the characteristics of inherited genetic late-onset (IGLO) EPP. METHODS: A systematic comprehensive search of the literature was conducted using PubMed, Google Scholar, ScienceDirect, and clinicaltrials.gov databases. Studies describing patients with IGLO EPP were included. Additionally, we present an index case of a patient, treated at our clinic in whom inherited genetic EPP was diagnosed at age 21 years. RESULTS: The search yielded 1514 citations. Five publications were eligible for review. Along with our case, 7 patients (4 males) were included in the analysis. Mean age at disease onset was 34.2 years (range 18-69, median 30). Most patients presented with mild pruritus and rash in a photosensitive distribution. Mean level of free erythrocyte protoporphyrin IX (FEP) was 8.6 µmol/L. A mutant ferrochelatase gene (FECH) in trans to a hypomorphic FECH allele was found in 3 of the 4 patients who underwent genetic testing. CONCLUSION: We describe the distinct features of IGLO EPP. This work emphasizes that a diagnosis of inherited genetic EPP should not be ruled out in adults with new-onset photosensitive manifestations.

Identification of early and extra-early maturing tropical maize inbred lines resistant to Exserohilum turcicum in sub-Saharan Africa.

Northern corn leaf blight (NCLB) incited by the fungus Exserohilum turcicum is a foliar disease that significantly limits maize production and productivity in West and Central Africa (WCA), particularly in the mid-altitudes but during the last decade it has become a menace in lowland agro-ecologies. The most economical and environmentally friendly disease management strategy is the cultivation of maize varieties resistant or tolerant to NCLB. However, no early maturing (EM) and extra-early maturing (EEM) NCLB resistant varieties are commercially available in WCA. One hundred inbred lines each of EM and EEM derived from tropical maize germplasm were inoculated with a virulent isolate of E. turcicum at five locations in Nigeria during the 2017 and 2018 growing seasons. The objective of the study was to identify promising NCLB resistant lines and to investigate inter-relationships among the traits. Analysis of variance revealed highly significant genotype and genotype by environment (G × E) interactions for disease severity, grain yield (GYLD), and other agronomic traits. The average disease severity (TURC) values ranged from 1.9 to 5.8 and 2.9 to 5.7 for the EM and EEM inbred lines, respectively. The levels of reaction of the inbred lines to NCLB ranged from highly resistant to highly susceptible. Stepwise regression analysis showed that ears per plant, ear and plant aspects were significantly influenced by the disease scores. Ears per plant, ear and plant aspects, TURC and GYLD traits were employed to develop a base index (BI) for selecting NCLB resistant inbred lines for hybrid development. TZEI 135 and TZEEI 1 were outstanding in GYLD and also had the highest positive BI values in the EM and EEM inbred lines, respectively. The identification of NCLB resistant lines in this study has set the premise for development of NCLB resistant hybrids for WCA as well as the improvement of tropical maize breeding populations for NCLB resistance.

Evaluación de la eficacia de las lengüetas en las tiras de la mascarilla autofiltrante para mejorar las técnicas de retirada adecuadas al mismo tiempo que se reduce la transmisión por contacto de los patógenos.

RESUMENLas mascarillas respiratorias autofiltrantes (filtering facepiece respirators, FFR) N95 certificadas por el Instituto Nacional de Seguridad y Salud Laborales (National Institute for Occupational Safety and Health, NIOSH) se utilizan en los centros de atención sanatoria como medida de control para mitigar las exposiciones a partículas atmosféricas infecciosas. Cuando la superficie externa de una FFR se contamina, supone un riesgo de transmisión para el usuario. La guía de los Centros para el Control y Prevención de Enfermedades (Centers for Disease Control and Prevention, CDC) recomienda que el personal sanitario retire las FFR agarrando las tiras en la parte posterior de la cabeza para evitar el contacto con la superficie posiblemente contaminada. Al parecer, la adherencia a la técnica de retirada adecuada es baja, debido a numerosos factores que incluyen la dificultad para ubicar y agarrar las tiras. En este estudio se compara el impacto de lengüetas ubicadas en las tiras de la FFR con el de mascarillas comparativas (sin lengüetas) sobre la retirada adecuada, la facilidad de uso, la comodidad y la reducción de la transmisión de la contaminación al usuario. El uso de un agente fluorescente como rastreador de contactos para explorar la contaminación de las FFR en manos y áreas de la cabeza de 20 sujetos humanos demostró que no hubo diferencia entre las tiras de la FFR con lengüetas y las mascarillas comparativas en el sentido de estimular la retirada adecuada de las mismas (p = 0.48), pero la hizo más fácil (p = 0.04), según indican siete de ocho sujetos que usaron las lengüetas. Siete de 20 sujetos opinaron que las FFR con lengüetas son más fáciles de retirar, mientras que solo dos de 20 sujetos indicaron que las FFR sin lengüetas son más fáciles de retirar. La incomodidad no fue un factor relevante para ninguno de los tipos de tiras de las FFR. Al retirar una FFR con las manos contaminadas, el uso de lengüetas redujo de forma importante la cantidad del rastreador de contactos transferida en comparación con las tiras sin lengüetas (p = 0.012). Las FFR con lengüetas en las tiras están asociadas con la facilidad de la retirada y una transferencia notablemente menor del rastreador de contactos fluorescente.

Psychosocial issues in erythropoietic protoporphyria - the perspective of parents, children, and young adults: A qualitative study.

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare photodermatoses, generally presenting in childhood with severe and painful phototoxicity. EPP has been reported to negatively affect quality of life (QoL), but there is limited information on the psychosocial issues faced by patients and families. To address this, an online focus group study was conducted to explore the perspective of parents of children with EPP, and young adults and children with EPP. Five focus groups were conducted in a semi-structured format, with moderator-led discussions exploring the impact on QoL. Three focus groups included parents of children with EPP, one with children aged 10-11 years, and another with young adults aged 24-25 years, for a total of 24 participants. Thematic data analysis showed that parents experience guilt for being unable to protect their children and frustration with the current state of knowledge of EPP. Parents also admitted that the disease can lead to stress within family members which is difficult to manage. Young adults expressed embarrassment over having to explain the disease to others. They reported that the teenage years were the most difficult to navigate; however, they learned to adapt to their disease as they grew older. Children expressed that they had limited understanding of their disease and wished they were told what symptoms to expect by physicians earlier in life. Our findings emphasize the significant impact on QoL for these families and a lack of age appropriate information for children with EPP. These findings can help improve counseling and support resources for patients and caregivers.

Digital PCR (dPCR) analysis reveals that the homozygous c.315-48T>C variant in the FECH gene might cause erythropoietic protoporphyria (EPP).

Alterations in the ferrochelatase gene (FECH) are the basis of the phenotypic expressions in erythropoietic protoporphyria. The phenotype is due to the presence of a mutation in the FECH gene associated in trans to the c.315-48 T > C variant in the intron 3. The latter is able to increase the physiological quota of alternative splicing events in the intron 3. Other two variants in the FECH gene (c.1-252A > G and c.68-23C > T) have been found to be associated to the intron 3 variant in some populations and together, they constitute a haplotype (ACT/GTC), but eventually, their role in the alternative splicing event has never been elucidated. The absolute number of the aberrantly spliced FECH mRNA molecules and the absolute expression of the FECH gene were evaluated by digital PCR technique in a comprehensive cohort. The number of splicing events that rose in the presence of the c.315-48 T > C variant, both in the heterozygous and homozygous condition was reported for the first time. Also, the percentage of the inserted FECH mRNA increased, even doubled in the T/C cases, compared to T/T cases. The constant presence of variants in the promoter and intron 2 did not influence or modulate the aberrant splicing. The results of FECH gene expression suggested that the homozygosity for the c.315-48 T > C variant could be considered pathological. Thus, this study identified the homozygotes for the c.315-48 T > C variant as pathological. By extension, when the samples were categorised according to the haplotypes, the GTC haplotype in homozygosis was pathological.

A nutrition intervention is effective in improving dietary components linked to cardiometabolic risk in youth with first-episode psychosis.

Severe mental illness is characterised by a 20-year mortality gap due to cardiometabolic disease. Poor diet in those with severe mental illness is an important and modifiable risk factor. The present study aimed to (i) examine baseline nutritional intake in youth with first-episode psychosis (FEP), (ii) evaluate the feasibility and acceptability of nutritional intervention early in FEP and (iii) to evaluate the effectiveness of early dietary intervention on key nutritional end points. Participants were recruited over a 12-month period from a community-based programme specifically targeting young people aged 15-25 years with newly diagnosed FEP. Individual dietetic consultations and practical group sessions were offered as part of a broader lifestyle programme. Dietary assessments were conducted before and at the end of the 12-week intervention. Participants exceeded recommended energy and Na intakes at baseline. Retention within the nutrition intervention was 67 %, consistent with other interventions offered to FEP clients. There was a 47 % reduction in discretionary food intake (-94 g/d, P<0·001) and reductions in daily energy (-24 %, P<0·001) and Na (-26 %, P<0·001) intakes. Diet quality significantly improved, and the mean change was 3·6 (95 % CI 0·2, 6·9, P<0·05), although this finding was not significant after Bonferroni's correction. Increased vegetable intake was the main factor contributing to improved diet quality. Nutrition intervention delivered shortly after initiation of antipsychotic medication is feasible, acceptable and effective in youth with FEP. Strategies to prevent weight gain and metabolic decline will contribute to prevent premature cardiometabolic disease in this vulnerable population.

Perigenual anterior cingulate event-related potential precedes stop signal errors.

Momentary lapses in attention disrupt goal-directed behavior. Attentional lapse has been associated with increased "default-mode" network (DMN) activity. In our previous fMRI study of a stop signal task (SST), greater activation of the perigenual anterior cingulate cortex (pgACC) - an important node of the DMN - predicts stop signal errors. In event-related potential (ERP) studies, the amplitude of an error-preceding positivity (EPP) also predicts response error. However, it is not clear whether the EPP originates from DMN regions. Here, we combined high-density array EEG and an SST to examine response-locked ERPs of error preceding trials in twenty young adult participants. The results showed an EPP in go trials that preceded stop error than stop success trials. Importantly, source modeling identified the origin of the EPP in the pgACC. By employing a bootstrapping procedure, we further confirmed that pgACC rather than the dorsal ACC as the source provides a better fit to the EPP. Together, these results suggest that attentional lapse in association with EPP in the pgACC anticipates failure in response inhibition.

Programmed cell death in kiwifruit stigmatic arms and its relationship to the effective pollination period and the progamic phase.

BACKGROUND AND AIMS: Kiwifruit is a crop with a highly successful reproductive performance, which is impaired by the short effective pollination period of female flowers. This study investigates whether the degenerative processes observed in both pollinated and non-pollinated flowers after anthesis may be considered to be programmed cell death (PCD). METHODS: Features of PCD in kiwifruit, Actinidia chinensis var. deliciosa, were studied in both non-pollinated and pollinated stigmatic arms using transmission electron microscopy, DAPI (4',6-diamidino-2-phenylindole) staining, TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling) assays, DNA gel electrophoresis and caspase-like activity assays. KEY RESULTS: In the secretory tissues of the stigmatic arms, cell organelles disintegrated sequentially while progressive vacuolization was detected. At the same time, chromatin condensation, nuclear deformation, and DNA fragmentation and degradation were observed. These features were detected in both non-pollinated and pollinated stigmatic arms; they were evident in the stigmas of pollinated flowers by the second day after anthesis but only by 4 d after anthesis in non-pollinated flowers. In addition, in pollinated stigmatic arms, these features were first initiated in the stigma and gradually progressed through the style, consistent with pollen tube growth. This timing of events was also observed in both non-pollinated and pollinated stigmatic arms for caspase-3-like activity. CONCLUSIONS: The data provide evidence to support the hypothesis that PCD processes occurring in the secretory tissue of non-pollinated kiwifruit stigmatic arms could be the origin for the observed short effective pollination period. The results obtained in the secretory tissue of pollinated kiwifruit stigmatic arms upon pollination support the idea that PCD might be accelerated by pollination, pointing to the involvement of PCD during the progamic phase.

Prophylactic use of standardized extract of propolis of Apis mellifera (EPP-AF®) reduces lung inflammation and improves survival in experimental lethal sepsis.

ETHNOPHARMACOLOGICAL RELEVANCE: Sepsis poses one of the biggest public health problems, necessitating the search for new therapeutic alternatives. For centuries, propolis has been widely used in folk medicine to treat various inflammatory and infectious diseases. Given its extensive use, it has excellent potential as an adjuvant treatment for patients with sepsis. OBJECTIVE: This study evaluated prophylactic treatment with standardized propolis extract (EPP-AF®) and followed the prognosis of sepsis induced by ligation and cecal ligation and puncture (CLP). METHODS: Initially, for survival assessment, Swiss mice were separated into five groups: Sham (false operated), control (PBS), ATB (received antibiotic, 8 mg/kg), P10 (received EPP-AF®, 10 mg/kg), and P100 (received EPP-AF®, 100 mg/kg). The animals received PBS, antibiotic, or EPP-AF® by the subcutaneous route 6 h before the CLP procedure. Animal survival was assessed every 12 h for five days when all of them were euthanized. RESULTS: We show that the treatment with EPP-AF® significantly increased the life expectancy of animals with sepsis compared to the control group. Interestingly, prophylactic treatment with EPP-AF® showed no effect on the number of colony-forming units in the peritoneum, blood, or lung. However, there was a decrease in cellular influx in the peritoneum. This alteration was unrelated to the number of bone marrow cells or the differential counting of peripheral blood cells. The coagulogram remained unchanged, including the number of platelets and prothrombin time-activated partial thromboplastin time. However, the inflammatory infiltrate and bleeding in the lung tissue were lower in the animals that received EPP-AF®. CONCLUSION: Thus, it was possible to conclude that prophylactic treatment with EPP-AF® preserved the lung parenchyma, resulting in an increased lifespan of mice with sepsis. It can be a helpful adjuvant in prophylactic treatment with antibiotics in presurgical conditions.

Dietary NMN supplementation enhances motor and NMJ function in ALS.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease that causes the degeneration of motor neurons in the motor cortex and spinal cord. Patients with ALS experience muscle weakness and atrophy in the limbs which eventually leads to paralysis and death. NAD+ is critical for energy metabolism, such as glycolysis and oxidative phosphorylation, but is also involved in non-metabolic cellular reactions. In the current study, we determined whether the supplementation of nicotinamide mononucleotide (NMN), an NAD+ precursor, in the diet had beneficial impacts on disease progression using a SOD1G93A mouse model of ALS. We found that the ALS mice fed with an NMN-supplemented diet (ALS+NMN mice) had modestly extended lifespan and exhibited delayed motor dysfunction. Using electrophysiology, we studied the effect of NMN on synaptic transmission at neuromuscular junctions (NMJs) in symptomatic of ALS mice (18 weeks old). ALS+NMN mice had larger end-plate potential (EPP) amplitudes and maintained better responses than ALS mice, and also had restored EPP facilitation. While quantal content was not affected by NMN, miniature EPP (mEPP) amplitude and frequency were elevated in ALS+NMN mice. NMN supplementation in diet also improved NMJ morphology, innervation, mitochondrial structure, and reduced reactive astrogliosis in the ventral horn of the lumbar spinal cord. Overall, our results indicate that dietary consumption of NMN can slow motor impairment, enhance NMJ function and improve healthspan of ALS mice.

The Incidence of Distant Metastases in Patients with Pleural Mesothelioma Screened for a Multimodal Approach: How Much Staging Do We Really Need?

Pleural mesothelioma (PM) is a very aggressive malignancy with a poor prognosis. Most patients receive systemic treatment only; however, some patients may benefit from multimodality treatment. A precise staging of patients undergoing multimodal treatment is mandatory. We investigated the pattern of metastasis in a cohort of patients screened for multimodal treatment to define the extent of staging examinations. Additionally, we investigated the occurrence of metastasis during follow-up. We investigated a single-center experience of 545 patients newly diagnosed and/or treated with PM between the years 2010 and 2022. Patients who were treated naïvely and had a whole set of imaging of the brain were included and further analyzed. A total of 54% of all patients with cerebral imaging had an available 18FDG-PET CT scan. We also recorded metastasis during treatment follow-up. There were 110 patients who had a whole set of imaging (CT = 89% and MRI = 11%) of the brain, and 54% of all patients with cerebral imaging had an available 18FDG-PET CT scan. We identified four patients with cerebral metastasis at the time of first diagnosis, which means that 5.4% of the cohort had cerebral metastasis and 13.3% of all patients in the subgroup with complete data of 18FDG-PET CT had distant non-cerebral metastasis. During the longitudinal follow-up, we found 11 patients with newly diagnosed metastases after a median time of 1.6 years (range: 2 months to 3.3 years) after first diagnosis without metastases. Distant metastases are more frequent in mesothelioma patients than previously thought. This implies that extensive staging is needed for patients selected for multimodal treatment, including brain imaging and 18FDG-PET CT.