Torcular pseudomass is frequently detected on fetal magnetic resonance imaging and reduces with gestational age.

BACKGROUND: The torcular pseudomass is an incidental extra-axial midline mass located between the venous sinuses and the occipital squama in the pediatric population. Although this structure is presumed to be a developmental feature, it has not been characterized on fetal MRI. OBJECTIVE: To determine the frequency, imaging features and longitudinal in utero evolution of torcular pseudomass using fetal MRI. MATERIALS AND METHODS: We present a single-center retrospective study of fetal MRI performed at a tertiary hospital. Two independent reviewers first ordinally scored torcular pseudomass as absent, focal, crescentic or bulky based on morphology. We reviewed available follow-up fetal and postnatal MRI and further classified torcular pseudomass as stable, involuted or progressive. We also collected clinical and demographic data from electronic charts and compared them among categories, corrected for multiple comparisons. RESULTS: This study included a total of 219 fetuses with median gestational age of 28 weeks (interquartile range [IQR]: 23-32 weeks). Torcular pseudomass was absent in 8% (n=17) and present as a focal mass in 15% (n=33), crescentic in 45% (n=98) and bulky in 32% (n=71) of the cases. Median gestational age was statistically different among torcular pseudomass categories and inversely associated with size. Follow-up fetal MRI was available in 9.6% (n=21) of cases (median interval 4 weeks; IQR: 2-9 weeks) and torcular pseudomass in these cases was classified as stable in 67% (n=14), involuted in 29% (n=6) and progressive in 5% (n=1). Postnatal MRI was available in 5% (n=12) of fetuses (median interval 11.5 months, IQR: 3-17 months), and among these cases torcular pseudomass was classified as stable in 33% (n=4) and involuted in 67% (n=8). CONCLUSION: Torcular pseudomass is highly prevalent in the fetal population and shows a natural tendency to involute, even in utero, although it sometimes persists during early infanthood.

BRCA Mutations and Fertility Preservation.

Hereditary cancers mostly affect the adolescent and young adult population (AYA) at reproductive age. Mutations in BReast CAncer (BRCA) genes are responsible for the majority of cases of hereditary breast and ovarian cancer. BRCA1 and BRCA2 act as tumor suppressor genes as they are key regulators of DNA repair through homologous recombination. Evidence of the accumulation of DNA double-strand break has been reported in aging oocytes, while BRCA expression decreases, leading to the hypothesis that BRCA mutation may impact fertility. Moreover, patients exposed to anticancer treatments are at higher risk of fertility-related issues, and BRCA mutations could exacerbate the treatment-induced depletion of the ovarian reserve. In this review, we summarized the functions of both genes and reported the current knowledge on the impact of BRCA mutations on ovarian ageing, premature ovarian insufficiency, female fertility preservation strategies and insights about male infertility. Altogether, this review provides relevant up-to-date information on the impact of BRCA1/2 mutations on fertility. Notably, BRCA-mutated patients should be adequately counselled for fertility preservation strategies, considering their higher sensitivity to chemotherapy gonadotoxic effects.

Adult polyglucosan body disease-an atypical compound heterozygous with a novel GBE1 mutation.

INTRODUCTION: Adult polyglucosan body disease (APBD) is an autosomal recessive leukodystrophy characterized by neurogenic bladder starting after 40 years old, spastic paraparesis and peripheral neuropathy. It is mainly resultant from the GBE1 homozygous p.Tyr329Ser (c.986A>C) mutation, especially in Ashkenazi-Jewish patients, although some cases of compound heterozygous have been reported. A genotype-phenotype correlation is not established, but atypical phenotypes have been described mainly in non-p.Tyr329Ser pathogenic variants. CASE REPORT: We describe an atypical case in a 62-year-old Portuguese woman, presenting the typical clinical triad of APBD plus prominent autonomic dysfunction, suggested by orthostatic hypotension and thermoregulatory dysfunction; she has compound heterozygous GBE1 mutations, namely, p.Asn541Asp (c.1621A>G) and p.Arg515Gly (c.1543C>G), the last one not yet reported in literature and whose pathogenicity was suggested by bioinformatics analysis and confirmed by sural nerve biopsy that showed intra-axonal polyglucosan bodies. DISCUSSION: Besides the report of a novel GBE1 mutation, this case also expands the phenotypic spectrum of this disorder, reinforcing autonomic dysfunction as a possible and prominent manifestation of APBD, mimicking autosomal dominant leukodystrophy with autonomic disease in some way. Therefore, we questioned a possible relationship between this genotype and the phenotype marked by dysautonomia. Additionally, we review previously reported cases of APBD in non-homozygous p.Tyr329Ser patients with atypical phenotypes.

Should patients with symptomatic cholelithiasis before 30 years of age be tested for ABCB4 gene mutations?

BACKGROUND AND AIMS: Low phospholipid-associated cholelithiasis syndrome (LPAC) is characterized by recurrent symptomatic cholelithiasis in young adults associated with ABCB4 gene mutations. Current diagnosing criteria are complex and heterogeneous, making this a largely underdiagnosed entity. Also, although recommended, genetic testing is not necessary for the diagnosis and its real advantages are not clear. The aim of our study was to explore the prevalence of ABCB4 mutations in symptomatic patients with cholelithiasis before the age of 30. METHODS: We conducted a multicentric prospective cohort study including patients with symptomatic cholelithiasis presenting before 30 years of age in 4 Portuguese centres between January 2017 and December 2019. ABCB4 gene was analyzed by next generation sequencing (NGS) including all exons and flanking regions. In 17/32 patients ABCB11 and ATP8B1 variants were also analyzed by NGS. RESULTS: Thirty-two patients were included (75% females, median age of symptom onset was 23 ± 5 years). We found that 8/32 (25%) patients had mutations in ABCB4 gene, 3/17 (18%) in ATP8B1 gene and 1/17 (6%) in ABCB11 gene. 44% (8/18) of patients with LPAC syndrome criteria had identified variants, while the prevalence of mutations in patients with symptoms onset before 30 as sole criteria was 29%. CONCLUSION: Our results suggest that LPAC should be systematically suspected and investigated in patients with symptomatic cholelithiasis before age of thirty, but genetic testing should only be attempted in patients complying with the more stringent LPAC criteria.

OXPHOS dysfunction regulates integrin-ß1 modifications and enhances cell motility and migration.

Mitochondria are central organelles for cellular metabolism. In cancer cells, mitochondrial oxidative phosphorylation (OXPHOS) dysfunction has been shown to promote migration, invasion, metastization and apoptosis resistance. With the purpose of analysing the effects of OXPHOS dysfunction in cancer cells and the molecular players involved, we generated cybrid cell lines harbouring either wild-type (WT) or mutant mitochondrial DNA (mtDNA) [tRNAmut cybrids, which harbour the pathogenic A3243T mutation in the leucine transfer RNA gene (tRNAleu)]. tRNAmut cybrids exhibited lower oxygen consumption and higher glucose consumption and lactate production than WT cybrids. tRNAmut cybrids displayed increased motility and migration capacities, which were associated with altered integrin-ß1 N-glycosylation, in particular with higher levels of ß-1,6-N-acetylglucosamine (GlcNAc) branched N-glycans. This integrin-ß1 N-glycosylation pattern was correlated with higher levels of membrane-bound integrin-ß1 and also with increased binding to fibronectin. When cultured in vitro, tRNAmut cybrids presented lower growth rate than WT cybrids, however, when injected in nude mice, tRNAmut cybrids produced larger tumours and showed higher metastatic potential than WT cybrids. We conclude that mtDNA-driven OXPHOS dysfunction correlates with increased motility and migration capacities, through a mechanism that may involve the cross talk between cancer cell mitochondria and the extracellular matrix.

Mechanical Thrombectomy in Acute Ischemic Stroke: Initial Single-Center Experience and Comparison with Randomized Controlled Trials.

BACKGROUND: Until recently, intravenous thrombolysis was the only reperfusion therapy with proven efficacy in patients with acute ischemic stroke. However, this treatment option has low recanalization rates in large-vessel occlusions. The search for additional treatments continued until 5 randomized trials (MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, and REVASCAT) revealed the superiority of mechanical thrombectomy for anterior circulation large-vessel occlusion. After 1 year of performing thrombectomy with stent retrievers in our tertiary hospital, we intended to answer the question: is it possible to achieve similar results in a "real-world" setting? METHODS: We analyzed data from our prospective observational registry, compared it with the trials aforementioned, and concluded that the answer is affirmative. RESULTS: Our study population of 77 patients, with a mean age of 68,2 years and 48,1% men, is comparable with these trials in much of selection criteria, baseline characteristics, and rate of previous intravenous thrombolysis (72,7%). Recovery of functional independence at 90 days was achieved in almost two thirds of patients, similarly to the referred trials. We devoted special emphasis on fast recanalization, keeping a simple image selection protocol (based on non-enhanced and computed tomography angiography) and not waiting for clinical response to thrombolysis in patients eligible for mechanical thrombectomy. We emphasize a successful recanalization rate of 87% and only 2,6% symptomatic intracranial hemorrhage. CONCLUSION: In summary, mechanical thrombectomy seems to be a safe and effective treatment option in a "real-world" scenario, with results similar to those of the recent randomized controlled trials.

Unveiling the Pathogenic Molecular Mechanisms of the Most Common Variant (p.K329E) in Medium-Chain Acyl-CoA Dehydrogenase Deficiency by in Vitro and in Silico Approaches.

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common genetic disorder affecting the mitochondrial fatty acid ß-oxidation pathway. The mature and functional form of human MCAD (hMCAD) is a homotetramer assembled as a dimer of dimers (monomers A/B and C/D). Each monomer binds a FAD cofactor, necessary for the enzyme's activity. The most frequent mutation in MCADD results from the substitution of a lysine with a glutamate in position 304 of mature hMCAD (p.K329E in the precursor protein). Here, we combined in vitro and in silico approaches to assess the impact of the p.K329E mutation on the protein's structure and function. Our in silico results demonstrated for the first time that the p.K329E mutation, despite lying at the dimer-dimer interface and being deeply buried inside the tetrameric core, seems to affect the tetramer surface, especially the ß-domain that forms part of the catalytic pocket wall. Additionally, the molecular dynamics data indicate a stronger impact of the mutation on the protein's motions in dimer A/B, while dimer C/D remains similar to the wild type. For dimer A/B, severe disruptions in the architecture of the pockets and in the FAD and octanoyl-CoA binding affinities were also observed. The presence of unaffected pockets (C/D) in the in silico studies may explain the decreased enzymatic activity determined for the variant protein (46% residual activity). Moreover, the in silico structural changes observed for the p.K329E variant protein provide an explanation for the structural instability observed experimentally, namely, the disturbed oligomeric profile, thermal stability, and conformational flexibility, with respect to the wild-type.

Non-anesthesiologist administration of propofol sedation for colonoscopy is safe in low risk patients: results of a noninferiority randomized controlled trial.

BACKGROUND AND STUDY AIMS: Propofol provides the best sedation in colonoscopy. The safety of non-anesthesiologist administration of propofol (NAAP) is still a matter of debate. The aim of the current study was to evaluate sedation safety, colonoscopy quality, and patient satisfaction with NAAP. PATIENTS AND METHODS: The study was a single-blinded, noninferiority, randomized controlled trial comparing NAAP (Group A) with anesthesiologist-administered sedation (Group B) performed at a single academic institution. Patients (18 - 80 years) who underwent colonoscopy and were at low anesthetic risk (American Society of Anesthesiologists class I - II) were included. The primary end point was the incidence of adverse events. Secondary end points were propofol dose, patient satisfaction and pain, colonoscopy quality indicators, and procedure and recovery times. RESULTS: A total of 277 patients were included in the analysis. The incidence of adverse events was 39.3 % in Group A and 39.0 % in Group B (absolute difference - 0.3 %, 95 % confidence interval [CI] - 12.0 % to 11.4 %; P = 0.959). There were no sentinel adverse events. The following interventions (Group A vs. Group B) were necessary: atropine administration (0 % vs. 5.5 %; P = 0.004); airway repositioning (8.7 % vs. 4.7 %; P = 0.196); increased oxygen administration (6.7 % vs. 3.9 %; P = 0.317), and increased fluid rate (2.7 % vs. 0.8 %; P = 0.379). There were no differences in cecal intubation and adenoma detection rates. Recovery times were longer in Group B (58 ±â€Š33 vs. 67 ±â€Š29 minutes; P = 0.032). There were no differences in mean propofol dose, withdrawal time, painless colonoscopy, satisfaction, and amnesia. All but two patients (Group B) were willing to repeat the colonoscopy. CONCLUSIONS: NAAP is equivalent to anesthesiologist-administered sedation in the rate of adverse events in a low risk population. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02067065).

Scaling up experimental ocean acidification and warming research: from individuals to the ecosystem.

Understanding long-term, ecosystem-level impacts of climate change is challenging because experimental research frequently focuses on short-term, individual-level impacts in isolation. We address this shortcoming first through an interdisciplinary ensemble of novel experimental techniques to investigate the impacts of 14-month exposure to ocean acidification and warming (OAW) on the physiology, activity, predatory behaviour and susceptibility to predation of an important marine gastropod (Nucella lapillus). We simultaneously estimated the potential impacts of these global drivers on N. lapillus population dynamics and dispersal parameters. We then used these data to parameterize a dynamic bioclimatic envelope model, to investigate the consequences of OAW on the distribution of the species in the wider NE Atlantic region by 2100. The model accounts also for changes in the distribution of resources, suitable habitat and environment simulated by finely resolved biogeochemical models, under three IPCC global emissions scenarios. The experiments showed that temperature had the greatest impact on individual-level responses, while acidification had a similarly important role in the mediation of predatory behaviour and susceptibility to predators. Changes in Nucella predatory behaviour appeared to serve as a strategy to mitigate individual-level impacts of acidification, but the development of this response may be limited in the presence of predators. The model projected significant large-scale changes in the distribution of Nucella by the year 2100 that were exacerbated by rising greenhouse gas emissions. These changes were spatially heterogeneous, as the degree of impact of OAW on the combination of responses considered by the model varied depending on local-environmental conditions and resource availability. Such changes in macro-scale distributions cannot be predicted by investigating individual-level impacts in isolation, or by considering climate stressors separately. Scaling up the results of experimental climate change research requires approaches that account for long-term, multiscale responses to multiple stressors, in an ecosystem context.

The burden of alcoholism in fifteen years of cirrhosis hospital admissions in Portugal.

BACKGROUND & AIMS: Deploying a longitudinal perspective, we observe how cirrhosis caused mortality rates in Portugal are converging with the levels reported in the European Union (15 countries). However, we still lack analysis of the burden of alcoholic cirrhosis in terms of hospital admissions and associated mortality. As Portugal may be considered a paradigmatic case in Europe, our aim was to characterize the evolution of hospital admissions for alcoholic cirrhosis between 1993 and 2008 and draw conclusions for other countries. METHODS: Retrospective analysis of the hepatic cirrhosis admissions in 97 Portuguese state hospitals was carried out based on the National Registry. RESULTS: We report a convergence in terms of mortality rates resulting from cirrhosis between Portugal and European Union (a differential of 6.7 deaths per 100 000 habitants in 1994 to 0.4 in 2008). We accounted for 81 543 hospital admissions for cirrhosis: 84% for alcoholic cirrhosis and 16% for non-alcoholic cirrhosis. Hospital admissions have increased 29% in men and with no increase in women. In the male, alcoholic cirrhosis patient group aged between 40 and 54, the rise in hospital admissions was more pronounced with an increase of around 45%. These patients underwent longer lengths of stay and reported higher mortality rates and passing away 20 years earlier than the average national expectancy of life. CONCLUSIONS: These data draw attention to the burden of alcohol consumption not only in Portugal but also in other countries and its impacts on hospital systems and on policy making.

Candida glabrata drug:H+ antiporter CgTpo3 (ORF CAGL0I10384g): role in azole drug resistance and polyamine homeostasis.

OBJECTIVES: The ability of opportunistic pathogenic Candida species to persist and invade specific niches in the human host depends on their resistance to natural growth inhibitors and antifungal therapy. This work describes the role of the Candida glabrata drug:H(+) antiporter CgTpo3 (ORF CAGL0I10384g) in this context. METHODS: Deletion and cloning of CgTPO3 was achieved using molecular biology tools. C. glabrata strain susceptibility was assayed based on growth in liquid and solid media and through MIC determination. Radiolabelled compound accumulation or HPLC were used for the assessment of the role of CgTpo3 as a drug or polyamine transporter. Quantitative RT-PCR was used for expression analysis. RESULTS: CgTpo3 was found to confer resistance to azole drugs in C. glabrata. This protein was found to be localized to the plasma membrane and to decrease the intracellular accumulation of [(3)H]clotrimazole, playing a direct role in its extrusion from pre-loaded C. glabrata cells. CgTPO3 was further found to confer resistance to spermine, complementing the susceptibility phenotypes exhibited by the deletion of its Saccharomyces cerevisiae homologue, TPO3. In spermine-stressed C. glabrata cells, CgTPO3 is transcriptionally activated in a CgPdr1-dependent manner, contributing to a decrease in the intracellular concentration of this polyamine. Clotrimazole exposure was found to lead to the intracellular accumulation of spermine, and pre-exposure to this polyamine was found consistently to lead to increased clotrimazole resistance. CONCLUSIONS: Altogether, these results point to a significant role for CgTpo3 in azole drug resistance and in the tolerance to high polyamine concentrations, such as those found in the urogenital tract.

Cerebral venous thrombosis: an unexpected complication from spinal surgery.

PURPOSE: To provide new insights into the pathophysiology, prevention and diagnosis of cerebral venous thrombosis (CVT) associated with iatrogenic cerebrospinal fluid (CSF) leaks and/or external CSF drainage. METHODS: Case report and literature review. RESULTS: We describe the case of a 30-year-old woman who developed a CSF fistula after lumbar spinal surgery. The treatment included rest, hydration, caffeine, and continuous lumbar CSF drainage. After closure of the fistula, the patient complained of severe orthostatic headache. Thrombosis involving the superior sagittal sinus, the right transverse sinus, the right sigmoid sinus, and the right jugular vein was diagnosed after neurological deterioration. CONCLUSION: A few reports have associated CVT with various forms of spinal meningeal injury. However, it has been rarely documented following spinal surgery complicated by accidental durotomy and/or external lumbar CSF drainage. CSF hypovolemia may precipitate CVT in patients having prothrombotic risk factors. Patients who have or had CSF leaks and/or lumbar CSF drains who present with symptoms of intracranial CSF hypotension should remain in the horizontal position to prevent CVT. In that context, the diagnosis of CVT depends on a high degree of suspicion.

Single-centre case series report of regional anaesthesia for pain management in vaso-occlusive crisis.

Sickle cell disease is characterised by episodes of vaso-occlusive crisis, a painful complication. Regional anaesthesia has shown promising results in reducing opioid consumption and pain scores. Patients with vaso-occlusive crises who underwent regional anaesthesia in the paediatric intensive care unit were studied. Data regarding pain location, regional analgesia technique, the local anaesthetic used and dose, daily opioid consumption, daily pain scores, use of adjuvants and complications were recorded. The primary outcome was to evaluate the effect of regional anaesthesia on opioid consumption. In this study, we describe 10 cases, referring to six paediatric patients with the vaso-occlusive crisis who underwent regional anaesthesia for severe pain and were unresponsive to increasing doses of opioids. Six cases received epidural analgesia, three continuous peripheral nerve blocks and one received both techniques. Opioid consumption was reduced (58%), and pain scores decreased (72%), both statistically significant reductions.

Application of the new PRINTO classification criteria for juvenile idiopathic arthritis in a sample of Portuguese patients.

BACKGROUND: The International League of Associations for Rheumatology (ILAR) classification system for juvenile idiopathic arthritis (JIA) does not depict homogenous subgroups of disease. As to unify our language with the adult rheumatic diseases, the Pediatric Rheumatology International Trials Organization (PRINTO) is attempting to revise these criteria. OBJECTIVE: To reclassify a JIA sample according to the new provisional PRINTO subsets: systemic JIA (sJIA), RF-positive JIA (RF-JIA), early-onset ANA-positive JIA (eoANA-JIA), enthesitis/spondylitis-related JIA (ESR-JIA), "other JIA" and "unclassified JIA". METHODS: Retrospective study including JIA patients followed in a Pediatric Rheumatology Unit at a university hospital. Medical records were reviewed, and patients were reclassified as per the provisional PRINTO criteria. RESULTS: Of a total of 104 patients, 41 (39.4%) were reclassified as "other JIA", 36 (34.6%) as eoANA-JIA, 15 (14.4%) as ESR-JIA, 8 (7.7%) as sJIA and 4 (3.8%) as RF-JIA. More than 90% of the oligoarticular JIA were reclassified into either eoANA-JIA or "other JIA". Only one negative RF polyarticular JIA converted to RF-JIA due to the presence of a positive anti-citrulinated peptide antibody (ACPA). The psoriatic arthritis (PsA) subgroup disappeared into eoANA-JIA (25%), ESR-JIA (25%) or "other JIA" (50%). There were significant differences in age of onset, but not on the gender ratio or uveitis presence. Antinuclear antibody was more frequent in females (p=0.035) and younger patients (p<0.001). CONCLUSION: The number of affected joints and PsA features elapsed in favour of laboratory RF, ACPA and ANA traits. PsA and oligoarticular JIA were abolished. The "other JIA" entity is heterogenous and prevalent, claiming reformulation.