Dissociable Structural and Functional Hippocampal Outputs via Distinct Subiculum Cell Classes.

The mammalian hippocampus, comprised of serially connected subfields, participates in diverse behavioral and cognitive functions. It has been postulated that parallel circuitry embedded within hippocampal subfields may underlie such functional diversity. We sought to identify, delineate, and manipulate this putatively parallel architecture in the dorsal subiculum, the primary output subfield of the dorsal hippocampus. Population and single-cell RNA-seq revealed that the subiculum can be divided into two spatially adjacent subregions associated with prominent differences in pyramidal cell gene expression. Pyramidal cells occupying these two regions differed in their long-range inputs, local wiring, projection targets, and electrophysiological properties. Leveraging gene-expression differences across these regions, we use genetically restricted neuronal silencing to show that these regions differentially contribute to spatial working memory. This work provides a coherent molecular-, cellular-, circuit-, and behavioral-level demonstration that the hippocampus embeds structurally and functionally dissociable streams within its serial architecture.

Unscrambling Quantum Information with Clifford Decoders.

Quantum information scrambling is a unitary process that destroys local correlations and spreads information throughout the system, effectively hiding it in nonlocal degrees of freedom. In principle, unscrambling this information is possible with perfect knowledge of the unitary dynamics [B. Yoshida and A. Kitaev, arXiv:1710.03363.]. However, this Letter demonstrates that even without previous knowledge of the internal dynamics, information can be efficiently decoded from an unknown scrambler by monitoring the outgoing information of a local subsystem. We show that rapidly mixing but not fully chaotic scramblers can be decoded using Clifford decoders. The essential properties of a scrambling unitary can be efficiently recovered, even if the process is exponentially complex. Specifically, we establish that a unitary operator composed of t non-Clifford gates admits a Clifford decoder up to t≤n.

Stabilizer Rényi Entropy.

We introduce a novel measure for the quantum property of "nonstabilizerness"-commonly known as "magic"-by considering the Rényi entropy of the probability distribution associated to a pure quantum state given by the square of the expectation value of Pauli strings in that state. We show that this is a good measure of nonstabilizerness from the point of view of resource theory and show bounds with other known measures. The stabilizer Rényi entropy has the advantage of being easily computable because it does not need a minimization procedure. We present a protocol for an experimental measurement by randomized measurements. We show that the nonstabilizerness is intimately connected to out-of-time-order correlation functions and that maximal levels of nonstabilizerness are necessary for quantum chaos.

Is Ustekinumab Effective in Refractory Crohn's Disease of the Pouch and Chronic Pouchitis? A Systematic Review.

Crohn's disease (CD) of the pouch and chronic pouchitis represent the most common long-term complications of total proctocolectomy and ileal pouch anal anastomosis (IPAA) for refractory ulcerative colitis (UC). These conditions are treated with multiple agents, including antibiotics, immunomodulators, and biologics. Among the latter, ustekinumab is approved for both CD and UC. We performed a systematic review to evaluate the efficacy of this anti-IL12/23 in CD of the pouch and chronic refractory pouchitis. Pubmed, Embase, Ovid, and the Cochrane Controlled Trials Register were searched to identify studies published until August 2020 investigating the use of ustekinumab for these conditions. Eighty-six eligible patients with IPAA-51 with CD of the pouch, 35 with chronic pouchitis-were identified from 2 retrospective studies and 5 case reports. Reported clinical response to ustekinumab was 63 and 85% in chronic pouchitis and CD of the pouch after 4-12 and 4-16 weeks, respectively. Clinical remission was reported in 10% of patients with chronic pouchitis and 27% of patients with CD of the pouch after 8-52 and 4-52 weeks of treatment, respectively. Endoscopic response was reported in 60% and 67% of patients with chronic pouchitis and CD of the pouch after 24-32 and 8-24 weeks of treatment respectively. Small sample sizes and large heterogeneity of therapy protocols/outcome definitions were significant studies limitations. In conclusion, there is a limited and inconclusive body of evidence suggesting that ustekinumab may be a therapeutic option for patients with chronic pouchitis and CD of the pouch refractory to other therapies.

Isospectral Twirling and Quantum Chaos.

We show that the most important measures of quantum chaos, such as frame potentials, scrambling, Loschmidt echo and out-of-time-order correlators (OTOCs), can be described by the unified framework of the isospectral twirling, namely the Haar average of a k-fold unitary channel. We show that such measures can then always be cast in the form of an expectation value of the isospectral twirling. In literature, quantum chaos is investigated sometimes through the spectrum and some other times through the eigenvectors of the Hamiltonian generating the dynamics. We show that thanks to this technique, we can interpolate smoothly between integrable Hamiltonians and quantum chaotic Hamiltonians. The isospectral twirling of Hamiltonians with eigenvector stabilizer states does not possess chaotic features, unlike those Hamiltonians whose eigenvectors are taken from the Haar measure. As an example, OTOCs obtained with Clifford resources decay to higher values compared with universal resources. By doping Hamiltonians with non-Clifford resources, we show a crossover in the OTOC behavior between a class of integrable models and quantum chaos. Moreover, exploiting random matrix theory, we show that these measures of quantum chaos clearly distinguish the finite time behavior of probes to quantum chaos corresponding to chaotic spectra given by the Gaussian Unitary Ensemble (GUE) from the integrable spectra given by Poisson distribution and the Gaussian Diagonal Ensemble (GDE).

Unloading the Left Ventricle Before Reperfusion in Patients With Anterior ST-Segment-Elevation Myocardial Infarction.

BACKGROUND: In ST-segment-elevation myocardial infarction (STEMI), infarct size correlates directly with heart failure and mortality. Preclinical testing has shown that, in comparison with reperfusion alone, mechanically unloading the left ventricle (LV) before reperfusion reduces infarct size and that 30 minutes of unloading activates a cardioprotective program that limits reperfusion injury. The DTU-STEMI pilot trial (Door-To-Unload in STEMI Pilot Trial) represents the first exploratory study testing whether LV unloading and delayed reperfusion in patients with STEMI without cardiogenic shock is safe and feasible. METHODS: In a multicenter, prospective, randomized exploratory safety and feasibility trial, we assigned 50 patients with anterior STEMI to LV unloading by using the Impella CP followed by immediate reperfusion (U-IR) versus delayed reperfusion after 30 minutes of unloading (U-DR). The primary safety outcome was a composite of major adverse cardiovascular and cerebrovascular events at 30 days. Efficacy parameters included the assessment of infarct size by using cardiac magnetic resonance imaging. RESULTS: All patients completed the U-IR (n=25) or U-DR (n=25) protocols with respective mean door-to-balloon times of 72 versus 97 minutes. Major adverse cardiovascular and cerebrovascular event rates were not statistically different between the U-IR versus U-DR groups (8% versus 12%, respectively, P=0.99). In comparison with the U-IR group, delaying reperfusion in the U-DR group did not affect 30-day mean infarct size measured as a percentage of LV mass (15±12% versus 13±11%, U-IR versus U-DR, P=0.53). CONCLUSIONS: We report that LV unloading using the Impella CP device with a 30-minute delay before reperfusion is feasible within a relatively short time period in anterior STEMI. The DTU-STEMI pilot trial did not identify prohibitive safety signals that would preclude proceeding to a larger pivotal study of LV unloading before reperfusion. An appropriately powered pivotal trial comparing LV unloading before reperfusion to the current standard of care is required. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03000270.

Long-term follow-up after multiple plastic stenting for refractory pancreatic duct strictures in chronic pancreatitis.

BACKGROUND: Dominant pancreatic duct strictures in chronic pancreatitis are often managed by endoscopic placement of a single plastic stent. Insertion of multiple plastic stents (MPS) has been proven to be effective in managing refractory strictures, but data are still limited. The aim of this study was to investigate the efficacy and long-term results of MPS to dilate pancreatic duct strictures in chronic pancreatitis. METHODS: 48 patients (34 men; mean age 44 years) with chronic pancreatitis and a single pancreatic stent through a refractory stricture in the pancreatic head underwent the following protocol: 1) removal of the single pancreatic stent; 2) balloon dilation of the stricture; 3) insertion of the maximum number of stents; 4) stent removal after 6 - 12 months. RESULTS: The median number of pancreatic plastic stents placed was 3 (diameter 7 - 11.5 Fr, length 3 - 7 cm). Five patients (10.4 %) had persistent strictures after MPS removal. During a mean follow-up of 9.5 years (0.3 - 15.5 years) after stent removal, 74.4 % (32/43) of the patients were asymptomatic, and 25.6 % (11/43) experienced pancreatitis recurrence or pancreatic type pain after a mean time of 26.4 months (8/43, 18.6 % underwent plug extraction without evidence of stricture recurrence; 3/43, 7.0 % had stricture recurrence). No major complications were recorded. CONCLUSION: Endoscopic multiple plastic stenting of chronic pancreatitis-related pancreatic duct strictures showed satisfactory long-term results, with the option of re-treatment. This procedure can be considered an important therapeutic alternative for painful pancreatic duct strictures located in the head of the pancreas in the setting of chronic pancreatitis.

Predicting the pressure of the total cavopulmonary connection: clinical testing of a mathematical equation.

INTRODUCTION: Some authors advocate the use of a dedicated formula to predict the Fontan pressure starting from pre-Fontan catheterisation data. This paper aims at testing the predictive value of the mentioned formula through a retrospective clinical study. METHODS AND RESULTS: Pre-Fontan catheterisation data and Fontan pressure measured at the completion were retrospectively collected. Pre-Fontan data were used to calculate the predicted pressure in the Fontan system. The predicted values were compared to the Fontan pressure measured at the Fontan completion and with the needs for fenestration. One hundred twenty-four Fontan patients were retrospectively enrolled (At Fontan: median age 30.73 [24.70-37.20] months, median weight 12.00 [10.98-14.15] kg). Fontan conduit was fenestrated in 78 patients. A poor correlation (r2 = 0.05128) between the measured and predicted data for non-fenestrated patients was observed. In the case of Fontan-predicted pressure <17.59 mmHg, the formula identified a good short-term clinical outcome with a sensitivity of 92%. CONCLUSION: The proposed formula showed a poor capability in estimating the actual pressure into the Fontan system and in identifying patients needing fenestration. As the pressure into the Fontan system is determined by multiple factors, the tested formula could be an additional data in a multi-parametric approach.

An expanded immunohistochemical profile of osteoclast-rich undifferentiated carcinoma of the urinary tract.

Osteoclast-rich undifferentiated carcinoma of the urinary tract (ORUCUT) is a rare tumor composed of ovoid to spindle-shaped mononuclear cells with intermixed or focally clustered osteoclast-like giant cells. Previous studies have demonstrated that the mononuclear cells are neoplastic cells, while the giant cells are reactive cells of histiocytic lineage. The association between these tumors and classic urothelial carcinomas suggest that the mononuclear cells are derived from urothelial cells; however, no studies have been conducted to assess the immunohistochemical profile of ORUCUT with more specific urothelial markers. This study identified 21 cases of ORUCUT and performed immunohistochemistry for GATA3, uroplakin II, and thrombomodulin along with pancytokeratin (AE1/3) on all cases. Mononuclear cells stained positive in 20 cases (95%) for GATA3 and 19 cases (90%) for thrombomodulin. None of the mononuclear cells were positive for uroplakin II and only three cases showed focal positivity for AE1/3. The osteoclast-like giant cells were negative for GATA3, uroplakin II, thrombomodulin, and AE1/3, providing additional support to a reactive origin for these cells. Additionally, 15 cases (71%) were associated with either in situ or invasive urothelial carcinoma. This study provides an expanded immunohistochemical profile for ORUCUT and more definitively supports a urothelial origin for this tumor.

Altered miR-193a-5p expression in children with cow's milk allergy.

BACKGROUND: Cow's milk allergy (CMA) is one of the most common food allergies in children. Epigenetic mechanisms have been suggested to play a role in CMA pathogenesis. We have shown that DNA methylation of Th1/Th2 cytokine genes and FoxP3 affects CMA disease course. Preliminary evidence suggests that also the miRNome could be implicated in the pathogenesis of allergy. Main study outcome was to comparatively evaluate miRNome in children with CMA and in healthy controls. METHODS: Peripheral blood mononuclear cells were obtained from children aged 4-18 months: 10 CMA patients, 9 CMA patients who outgrew CMA, and 11 healthy controls. Small RNA libraries were sequenced using a next-generation sequencing-based approach. Functional assessment of IL-4 expression was also performed. RESULTS: Among the miRNAs differently expressed, 2 were upregulated and 14 were downregulated in children with active CMA compared to healthy controls. miR-193a-5p resulted the most downregulated miRNA in children with active CMA compared to healthy controls. The predicted targets of miR-193a-5p resulted upregulated in CMA patients compared to healthy controls. Peripheral blood CD4+ T cells transfected with a miR193a-5 inhibitor showed a significant upregulation of IL-4 mRNA and its protein expression. Children who outgrew CMA showed miRNA-193a-5p level, and its related targets expression, similar to that observed in healthy controls. CONCLUSIONS: Our results suggest that miR-193a-5p is a post-transcriptional regulator of IL-4 expression and could have a role in IgE-mediated CMA. This miRNA could be a novel diagnostic and therapeutic target for this common form of food allergy in childhood.

Effect of lifelong football training on the expression of muscle molecular markers involved in healthy longevity.

PURPOSE: We investigated whether lifelong football training affects the expression of healthy longevity-related muscle molecular markers. METHODS: Biopsies were collected from the vastus lateralis muscle of 10 lifelong football-trained men (68.2 ± 3.0 years) and of 10 active untrained healthy men (66.7 ± 1.3 years). Gene and protein expression was measured by RTqPCR on RNA and by western blotting on protein extracts from muscle biopsies, respectively. RESULTS: The expression of AMPKα1/α2, NAMPT, TFAM and PGC1α, which are markers of oxidative metabolism, and MyHC ß isoform expression was higher in the muscle of football-trained men vs untrained men. Also citrate synthase activity was higher in trained than in untrained men (109.3 ± 9.2 vs 75.1 ± 9.2 mU/mg). These findings were associated with a healthier body composition in trained than in untrained men [body weight: 78.2 ± 6.5 vs 91.2 ± 11.2 kg; body mass index BMI: 24.4 ± 1.6 vs 28.8 ± 4.0 kg m-2; fat%: 22.6 ± 8.0 vs 31.4 ± 5.0%)] and with a higher maximal oxygen uptake (VO2max: 34.7 ± 3.8 vs 27.3 ± 4.0 ml/min/kg). Also the expression of proteins involved in DNA repair and in senescence suppression (Erk1/2, Akt and FoxM1) was higher in trained than in untrained men. At BMI- and age-adjusted multiple linear regression analysis, fat percentage was independently associated with Akt protein expression, and VO2max was independently associated with TFAM mRNA and with Erk1/2 protein expression. CONCLUSIONS: Lifelong football training increases the expression of key markers involved in muscle oxidative metabolism, and in the DNA repair and senescence suppression pathways, thus providing the molecular basis for healthy longevity.

The Influenza A PB1-F2 and N40 Start Codons Are Contained within an RNA Pseudoknot.

Influenza A is a negative-sense RNA virus with an eight-segment genome. Some segments encode more than one polypeptide product, but how the virus accesses alternate internal open reading frames (ORFs) is not completely understood. In segment 2, ribosomal scanning produces two internal ORFs, PB1-F2 and N40. Here, chemical mapping reveals a Mg(2+)-dependent pseudoknot structure that includes the PB1-F2 and N40 start codons. The results suggest that interactions of the ribosome with the pseudoknot may affect the level of translation for PB1-F2 and N40.

Functional foods and cardiometabolic diseases* International Task Force for Prevention of Cardiometabolic Diseases.

Mounting evidence supports the hypothesis that functional foods containing physiologically-active components may be healthful. Longitudinal cohort studies have shown that some food classes and dietary patterns are beneficial in primary prevention, and this has led to the identification of putative functional foods. This field, however, is at its very beginning, and additional research is necessary to substantiate the potential health benefit of foods for which the diet-health relationships are not yet scientifically validated. It appears essential, however, that before health claims are made for particular foods, in vivo randomized, double-blind, placebo controlled trials of clinical end-points are necessary to establish clinical efficacy. Since there is need for research work aimed at devising personalized diet based on genetic make-up, it seems more than reasonable the latter be modeled, at present, on the Mediterranean diet, given the large body of evidence of its healthful effects. The Mediterranean diet is a nutritional model whose origins go back to the traditional dietadopted in European countries bordering the Mediterranean sea, namely central and southern Italy, Greece and Spain; these populations have a lower incidence of cardiovascular diseases than the North American ones, whose diet is characterized by high intake of animal fat. The meeting in Naples and this document both aim to focus on the changes in time in these two different models of dietary habits and their fall out on public health.

Establishing novel diagnostic criteria for the glucose tolerance test for the diagnosis of gestational diabetes and gestational hyperglycemia.

OBJECTIVE: To establish diagnostic criteria for the 75-g 2-h glucose tolerance test (GTT) to diagnose gestational diabetes and define the clinical entity of gestational hyperglycemia. METHODS: A retrospective analysis was performed of the results from 500 patients who had a 75-g 1-h glucose challenge test (GCT) in early pregnancy as part of a two-step approach to screening and testing for gestational diabetes. The selected cohort was considered to have normal islet ß-cell function, and upper glycemic levels of normal glucose tolerance in the third trimester were statistically calculated, taking the cutoff threshold values to be the diagnostic criteria for the 75-g 2-h GTT. Gestational hyperglycemia was diagnosed from the false-positive GCT result when ≥8.0 mmol/L (144 mg/dL). RESULTS: The diagnostic criteria for the 75-g 2-h GTT were calculated as follows: fasting plasma glucose ≥5.4 mmol/L (97 mg/dL); 1-h plasma glucose ≥10.5 mmol/L (189 mg/dL); and 2-h plasma glucose ≥8.4 mmol/L (151 mg/dL). The new criteria confirmed a prevalence of gestational diabetes of 11.1% and gestational hyperglycemia of 13.6% in the study population. CONCLUSION: Novel diagnostic criteria for the 75-g 2-h GTT were established by statistical analysis. This resulted in a more acceptable prevalence of gestational diabetes in our community and the false-positive GCT allowed the detection of gestational hyperglycemia.

PEGylated helper-dependent adenoviral vector expressing human Apo A-I for gene therapy in LDLR-deficient mice.

Helper-dependent adenoviral (HD-Ad) vectors have great potential for gene therapy applications; however, their administration induces acute toxicity that impairs safe clinical applications. We previously observed that PEGylation of HD-Ad vectors strongly reduces the acute response in murine and primate models. To evaluate whether PEGylated HD-Ad vectors combine reduced toxicity with the correction of pathological phenotypes, we administered an HD-Ad vector expressing the human apolipoprotein A-I (hApoA-I) to low-density lipoprotein (LDL)-receptor-deficient mice (a model for familial hypercholesterolemia) fed a high-cholesterol diet. Mice were treated with high doses of HD-Ad-expressing apo A-I or its PEGylated version. Twelve weeks later, LDL levels were lower and high-density lipoprotein (HDL) levels higher in mice treated with either of the vectors than in untreated mice. After terminal killing, the areas of atherosclerotic plaques were much smaller in the vector-treated mice than in the control animals. Moreover, the increase in pro-inflammatory cytokines was lower and consequently the toxicity profile better in mice treated with PEGylated vector than in mice treated with the unmodified vector. This finding indicates that the reduction in toxicity resulting from PEGylation of HD-Ad vectors does not impair the correction of pathological phenotypes. It also supports the clinical potential of these vectors for the correction of genetic diseases.

Identification of potential conserved RNA secondary structure throughout influenza A coding regions.

Influenza A is a negative sense RNA virus of significant public health concern. While much is understood about the life cycle of the virus, knowledge of RNA secondary structure in influenza A virus is sparse. Predictions of RNA secondary structure can focus experimental efforts. The present study analyzes coding regions of the eight viral genome segments in both the (+) and (-) sense RNA for conserved secondary structure. The predictions are based on identifying regions of unusual thermodynamic stabilities and are correlated with studies of suppression of synonymous codon usage (SSCU). The results indicate that secondary structure is favored in the (+) sense influenza RNA. Twenty regions with putative conserved RNA structure have been identified, including two previously described structured regions. Of these predictions, eight have high thermodynamic stability and SSCU, with five of these corresponding to current annotations (e.g., splice sites), while the remaining 12 are predicted by the thermodynamics alone. Secondary structures with high conservation of base-pairing are proposed within the five regions having known function. A combination of thermodynamics, amino acid and nucleotide sequence comparisons along with SSCU was essential for revealing potential secondary structures.

S100B induces the release of pro-inflammatory cytokines in alveolar type I-like cells.

S100B, a 21kDa cytosolic calcium-binding protein of the EF-hand type, present in high abundance in the brain, stimulates inflammatory responses in different cellular types inside and outside the central nervous system. Most of extracellular S100B effects are mediated by Receptor for Advanced Glycation End-products (RAGE). RAGE is highly expressed in lung by Alveolar Type-I (AT-I) cells and its activation contributes to ALI/ARDS pathogenesis. In this in-vitro study, we tested the hypothesis that S100B stimulates an ATI-derived cell line (R3/1) to secrete inflammatory mediators involved in lung inflammation. Our main result is that S100B stimulates R3/1 cells to secrete TNF-alpha and IL-6 (well-known pro-inflammatory cytokines in lung inflammation and neurogenic pulmonary edema), but not sICAM-1, CINC-1 or CINC-3. Soluble RAGE (sRAGE) reduced S100B-dependent secretion of TNF-alpha but did not decrease S100B-dependent secretion of IL-6. Moreover, in absence of S100B, sRAGE enhanced IL-6 release. This study demonstrates that in vitro S100B dose-dependently stimulated R3/1 cells, to enhance the secretion of TNF-alpha and IL-6; S100B pro-inflammatory activity might be mediated at least in part by RAGE. Besides acting as decoy receptor, sRAGE could have pro-inflammatory properties.

Congenital coronary artery anomalies in sports medicine. Why to know them.

The anomalous origin of a coronary artery (AOCA) is a challenging topic, due to its rarity, the complexity of the pathophysiological aspects, the clinical presentation (often silent), the difficulty of diagnosis, and the potential risk of causing acute cardiovascular events up to sudden cardiac death, particularly when triggered by heavy physical exercise or sport practice. Increasing interest in sport medical literature is being given to this topic. This paper reviews current knowledge of AOCAs in the specific context of the athletic setting addressing epidemiological and pathophysiological aspects, diagnostic work-up, sports participation, individual risk assessment, therapeutic options, and return to play decision after surgery.