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Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14–20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57–1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=−0·604; serum, r=−0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. European Union's Seventh Framework Programme; European Research Council.

Background Hereditary hemorrhagic telangiectasia (HHT) is a multisystemic inherited vascular dysplasia that leads to nosebleeds and visceral arteriovenous malformations (AVMs). Anti-angiogenic drugs thalidomide and bevacizumab have been increasingly used off-label with variable results. The HHT working group within the ERN for Rare Multisystemic Vascular Diseases (VASCERN), developed a questionnaire-based retrospective capture of adverse events (AEs) classified using the Common Terminology Criteria for Adverse Events. Results Sixty-nine HHT patients received bevacizumab, 37 (50.6%) for high output cardiac failure/hepatic AVMs, and 32 (49.4%) for bleeding; the 69 patients received bevacizumab for a mean of 11 months for a total of 63.8 person/years treatment. 67 received thalidomide, all for epistaxis and/or gastrointestinal bleeding; they received thalidomide for a mean of 13.4 months/patient for a total of 75 person/years treatment. AEs were reported in 58 patients, 33 with bevacizumab, 37 with thalidomide. 32 grade 1–3 AEs related to bevacizumab were reported with an average incidence rate of 50 per 100 person-years. 34 grade 1–3 AEs related to thalidomide were reported with an average incidence rate of 45.3 per 100 person-years. Bevacizumab AEs were more common in females (27 AEs in 46 women) than males (6 in 23, p  < 0.001). Thalidomide AEs occurred at more similar rates in males (25 AEs in 41 men, 60.9%) and females (12 in 26 (46.2%), but were more common in ENG patients (17 in 17) than in ACVRL1 (14 in 34, p  < 0.0001). For bevacizumab, the most common reports were of joint pains (7/69, 10%), headache (3/69, 4.4%) and proteinuria (2/69, 3%), and for thalidomide, peripheral neuropathy (12/67, 18%); drowsiness (8/67, 12%); and dizziness (6/67, 9%). Fatal adverse events were more common in males ( p  = 0.009), and in patients with ENG pathogenic variants ( p  = 0.012). One fatal AE was possibly related to bevacizumab (average incidence rate: 1.5 per 100 person-years); 3 fatal AEs were possibly related to thalidomide (average incidence rate: 4 per 100 person-years). Conclusions With potential increase in use of Bevacizumab and Thalidomide in HHT patients, data presented support appropriate weighing of the toxicities which can arise in HHT settings and the practice recommendations for their prevention and management.

The excavations undertaken at the Campo de Hockey site in 2008 led to the identification of a major Neolithic necropolis in the former Island of San Fernando (Bay of Cadiz). This work presents the results of the latest studies, which indicate that the site stands as one of the oldest megalithic necropolises in the Iberian Peninsula. The main aim of this work is to present with precision the chronology of this necropolis through a Bayesian statistical model that confirms that the necropolis was in use from c. 4300 to 3800 cal BC. The presence of prestige grave goods in the earliest and most monumental graves suggest that the Megalithism phenomenon emerged in relation to maritime routes linked to the distribution of exotic products. We also aim to examine funerary practices in these early megalithic communities, and especially their way of life and the social reproduction system. As such, in addition to the chronological information and the Bayesian statistics, we provide the results of a comprehensive interdisciplinary study, including anthropological, archaeometric and genetic data.

Background/objective: The objective of this research was to evaluate how different antibiotic prophylaxis protocols influence the development of postoperative complications after the extraction of impacted mandibular third molars. Methods: This investigation was designed as a double-blind, randomized controlled trial. A total of eighty patients who fulfilled the inclusion criteria were randomly allocated to one of three treatment groups. Group 1 (n = 27) was administered 2 g of oral amoxicillin one hour prior to the procedure; Group 2 (n = 27) received 500 mg of oral amoxicillin every eight hours for five days following the surgery; and Group 3 (n = 26) was given 750 mg of oral amoxicillin every eight hours for the same postoperative period. The outcome variables measured were infectious complications, postoperative pain, postoperative inflammation, and others such as the rescue medication taken by the patient. Results: Two patients in each group showed signs of infection after the extraction of the impacted third molar (p = 0.412). No significant differences were observed in pain intensity between the different study groups, nor in the intensity of inflammation. No statistically significant differences were observed in the consumption or non-consumption of rescue analgesics. Conclusions: The results of the present study suggest that the preoperative administration of 2 g of amoxicillin in the extraction of impacted third molars in healthy patients could be sufficient to prevent infectious complications. The administration of postoperative doses of 500 mg every 8 h or 750 mg every 8 h does not generate benefits in patients in terms of postoperative pain or inflammation.

Pheochromocytomas and Paragangliomas (PPGL) are rare neuroendocrine tumors with favorable prognosis, although a significant subset (20–25%) progress to metastasis, worsening patient prognosis. For metastatic cases, pharmacological interventions become essential, yet most tumors show poor response to treatment. While clinical trials are ongoing, there is no established treatment for metastatic PPGL. Like other neuroendocrine tumors, PPGL exhibit high membrane expression of somatostatin receptors, and despite Peptide Receptor Radionuclide Therapy, PRRT, strategies have successfully been implemented, trials with cold somatostatin analogs were abandoned prematurely due to inconsistent results. To investigate this issue and identify potential therapeutic tools, we widely profiled somatostatin receptors expression in PPGL and conducted a comprehensive functional screening on wild-type and SDHB knockdown PPGL cell lines of native and synthetic somatostatin analogs. Results revealed that pheochromocytomas and paragangliomas similarly display a predominant SSTR2 and SSTR1 expression regardless of molecular cluster. Treatment with somatostatin, cortistatin, octreotide or pasireotide did not exert clear antitumoral effects on model cell lines. Notably, the selective SST 2 agonist BIM-23120 significantly reduced cell proliferation and induced apoptosis in an SST 2 -dependent manner, but only in SDHB knocked-down PPGL cells. Indeed, only SDHB KD cells showed stronger membrane-enriched SST 2 and clear receptor internalization upon BIM-23120 treatment. Molecular analysis revealed a generalized dephosphorylation affecting key proliferation, growth and cell survival pathways in response to BIM-23120 (unlike when treating with octreotide). Altogether, our results provide novel information on the status of the somatostatin system in PPGL and identify new potential therapeutic tools selectively targeting somatostatin receptors on this refractory tumor.

Von Hippel-Lindau syndrome (VHL) is a rare disease of dominant inheritance that increases susceptibility to tumor development, with a complete penetrance at the age of 60. In this report, we present the unprecedented case of a VHL carrier who remains healthy at 72. Under the course of this study, it was discovered that this patient carries a mutation for a second rare disease, Neuronal Ceroid Lipofuscinosis (NCL or CNL). We hypothesize that the CLN mutation she carries offers a protective effect, preventing tumor development in the cells potentially suffering a VHL second hit mutation. To test this hypothesis, we ran a series of molecular experiments and confirmed that cell viability of primary endothelial cells decreases upon CLN5 silencing. Our results further elucidate the cell biology implications of two rare diseases interacting.

Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase γ (POLγ), a heterotrimeric complex consisting of a catalytic POLγA subunit and two accessory POLγB subunits 1 . More than 300 mutations in POLG , the gene encoding the catalytic subunit, have been linked to severe, progressive conditions with high rates of morbidity and mortality, for which no treatment exists 2 . Here we report on the discovery and characterization of PZL-A, a first-in-class small-molecule activator of mtDNA synthesis that is capable of restoring function to the most common mutant variants of POLγ. PZL-A binds to an allosteric site at the interface between the catalytic POLγA subunit and the proximal POLγB subunit, a region that is unaffected by nearly all disease-causing mutations. The compound restores wild-type-like activity to mutant forms of POLγ in vitro and activates mtDNA synthesis in cells from paediatric patients with lethal POLG disease, thereby enhancing biogenesis of the oxidative phosphorylation machinery and cellular respiration. Our work demonstrates that a small molecule can restore function to mutant DNA polymerases, offering a promising avenue for treating POLG disorders and other severe conditions linked to depletion of mtDNA. An activator of DNA polymerase γ restores function to disease-causing mutant variants and demonstrates a potential route to treatments for inherited mitochondrial disorders involving POLG mutations.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by arteriovenous malformations and hemorrhages. This vascular disease results mainly from mutations in 2 genes involved in the TGF-β pathway (ENG and ALK1) that are exclusively expressed by endothelial cells. The present study identified miR-27a and miR-205 as two circulating miRNAs differentially expressed in HHT patients. The plasma levels of miR-27a are elevated while those of miR-205 are reduced in both HHT1 and HHT2 patients compared to healthy controls. The role of miR-205 in endothelial cells was further investigated. Our data indicates that miR-205 expression displaces the TGF-β balance towards the anti-angiogenic side by targeting Smad1 and Smad4. In line, overexpression of miR-205 in endothelial cells reduces proliferation, migration and tube formation while its inhibition shows opposite effects. This study not only suggests that detection of circulating miRNA (miR-27a and miR-205) could help for the screening of HHT patients but also provides a functional link between the deregulated expression of miR-205 and the HHT phenotype.

Inflammatory bowel disease (IBD) and celiac disease (CeD) are immune-mediated digestive disorders with shared genetic, immunological, and environmental risk factors. This study aimed to assess whether the coexistence of CeD and IBD is associated with a differential IBD disease course. Multicenter case-control study. This study included patients with both CeD and IBD, and controls with IBD alone in a 1:2 ratio, matched by sex, IBD type, and year of diagnosis. CeD was diagnosed based on a Marsh score >1. Data on IBD phenotype and treatment, mortality and neoplasm development were collected from medical records. The study included 66 celiac-IBD patients (30 ulcerative colitis, 6 indeterminate colitis, 30 Crohn's disease; mean age 30 ± 14 years) and 132 non-celiac-IBD patients (68 ulcerative colitis, 4 indeterminate colitis, 60 Crohn's disease; mean age 32 ± 14 years). Among patients with CeD, Marsh type 3 was the most frequently observed lesion. No significant differences were observed between celiac and non-celiac-IBD patients in terms of IBD extension, extraintestinal manifestations, or coexisting autoimmune diseases. Similarly, no differences were found in outcomes including perianal disease, use of mesalamine, immunomodulators, biologics, need for surgery, or development of neoplasms. No deaths occurred in either group. In this large multicenter cohort, the concurrent diagnosis of CeD and patients with IBD was not associated with a different IBD phenotype or worse outcomes compared to non-celiac-IBD patients. The coexistence of CeD does not appear to alter the natural history of IBD.

Does celiac disease influence the course of inflammatory bowel disease? What was already known? Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, and celiac disease, are digestive disorders caused by an abnormal immune response. Both conditions share some genetic and environmental risk factors and can sometimes occur in the same person. However, it was unclear whether having celiac disease in addition to IBD could make IBD more severe or change its course. What did we want to study? We aimed to compare the course of IBD in patients who also had celiac disease with that of patients with IBD alone, to determine whether the coexistence of both conditions influenced the type of IBD, its severity, or the treatments required. How was the study performed? We conducted a multicenter study including 66 patients with both IBD and celiac disease and compared them with 132 similar patients with IBD without celiac disease. The groups were matched by sex, type of IBD, and year of diagnosis. Medical records were reviewed to collect information on disease extent, symptoms outside the intestine, treatments received, need for surgery, development of cancer, and survival. What did we find? No important differences were observed between patients with and without celiac disease. Both groups showed similar IBD characteristics, including disease extent and behavior. There were also no differences in complications such as perianal disease, use of immunosuppressive or biologic drugs, need for surgery, development of tumors, or mortality. What do these results mean? Having celiac disease in addition to IBD does not appear to worsen the course of IBD or modify its natural history. This information can help reassure patients and clinicians that the coexistence of celiac disease is unlikely to negatively affect IBD outcomes.