Optimization Strategies in Complex Systems

We consider a class of combinatorial optimization problems that emerge in a variety of domains among which: condensed matter physics, theory of financial risks, error correcting codes in information transmissions, molecular and protein conformation, image restoration. We show the performances of two algorithms, the``greedy'' (quick decrease along the gradient) and the``reluctant'' (slow decrease close to the level curves) as well as those of a``stochastic convex interpolation''of the two. Concepts like the average relaxation time and the wideness of the attraction basin are analyzed and their system size dependence illustrated.Comment: 8 pages, 3 figure

Low Vitamin K and Vitamin D Dietary Intake in Patients with Inflammatory Bowel Diseases

The inadequate dietary intake of Vitamin D and Vitamin K is an easily reversible factor favoring IBD-associated bone loss, but data on Vitamin K are lacking. A 28-item quantitative food frequency questionnaire was administered to 193 IBD patients (89 Crohn’s disease and 104 ulcerative colitis), and 199 controls. Patients’ demographics, clinical and laboratory findings were analyzed in relation to recommended daily allowances. VitD intake was inadequate both in the IBD and control patients (8.3 ± 4.5 µg/day in IBD, 53.1% RDA, and 9.7 ± 5.9 µg/day, 63.2% RDA, respectively). Conversely, the mean ViK intake was less than adequate in IBD, at 116.7 ± 116.3 µg/day (78.7% RDA), and high in controls, at 203.1 ± 166.9 µg/day (138.8% RDA). Nonetheless, due to marked interindividual differences, diets were severely lacking VitK in 40% of UC and 49% of CD patients, more so in females and those with active disease. The intake of Vit D was non-significantly lower in colitis than that in Crohn’s disease (7.9 vs. 8.7 µg/day). The opposite was observed for VitK (123.5 vs. 107.0 µg/day). Thus, the diet lacks the micronutrients involved in bone wellbeing in a large proportion of IBD patients. While VitD supplementation is the rule, VitK shortages need proactive nutritional intervention. Keywords: IBD; vitamin K; vitamin D; diet in IB

Combined Effects of Age and Comorbidities on Electrocardiographic Parameters in a Large Non-Selected Population

Background: Previous studies have evaluated average electrocardiographic (ECG) values in healthy subjects or specific subpopulations. However, none have evaluated ECG average values in not selected populations, so we examined ECG changes with respect to age and sex in a large primary population. Methods: From digitized ECG stored from 2008 to 2021 in the Modena province, 130,471 patients were enrolled. Heart rate, P, QRS and T wave axis, P, QRS and T wave duration, PR interval, QTc, and frontal QRS-T angle were evaluated. Results: All ECG parameters showed a dependence on age, but only some of them with a straight-line correlation: QRS axis (p < 0.001, R2 = 0.991, r = 0.996), PR interval (p < 0.001, R2 = 0.978, r = 0.989), QTc (p < 0.001, R2 = 0.935, r = 0.967), and, in over 51.5 years old, QRS-T angle (p < 0.001, R2 = 0.979, r = 0.956). Differences between females and males and in different clinical settings were observed. Conclusions: ECG changes with ageing are explainable by intrinsic modifications of the heart and thorax and with the appearance of cardiovascular diseases and comorbidities. Age-related reference values were computed and applicable in clinical practice. Significant deviations from mean values and from Z-scores should be investigated

Long-term outcomes of acute severe ulcerative colitis in the rescue therapy era: A multicentre cohort study

BACKGROUND: The long‐term course of ulcerative colitis after a severe attack is poorly understood. Second‐line rescue therapy with cyclosporine or infliximab is effective for reducing short‐term colectomy but the impact in the long‐term is controversial. OBJECTIVE: The purpose of this study was to evaluate the long‐term course of acute severe ulcerative colitis patients who avoid early colectomy either because of response to steroids or rescue therapy. METHODS: This was a multicentre retrospective cohort study of adult patients with acute severe ulcerative colitis admitted to Italian inflammatory bowel disease referral centres from 2005 to 2017. All patients received intravenous steroids, and those who did not respond received either rescue therapy or colectomy. For patients who avoided early colectomy (within 3 months from the index attack), we recorded the date of colectomy, last follow‐up visit or death. The primary end‐point was long‐term colectomy rate in patients avoiding early colectomy. RESULTS: From the included 372 patients with acute severe ulcerative colitis, 337 (90.6%) avoided early colectomy. From those, 60.5% were responsive to steroids and 39.5% to the rescue therapy. Median follow‐up was 44 months (interquartile range, 21–85). Colectomy‐free survival probability was 93.5%, 81.5% and 79.4% at 1, 3 and 5 years, respectively. Colectomy risk was higher among rescue therapy users than in steroid‐responders (log‐rank test, p = 0.02). At multivariate analysis response to steroids was independently associated with a lower risk of long‐term colectomy (adjusted odds ratio = 0.5; 95% confidence interval, 0.2–0.8), while previous exposure to antitumour necrosis factor‐α agents was associated with an increased risk (adjusted odds ratio = 3.0; 95% confidence interval, 1.5–5.7). Approximately 50% of patients required additional therapy or new hospitalisation within 5 years due to a recurrent flare. Death occurred in three patients (0.9%). CONCLUSIONS: Patients with acute severe ulcerative colitis avoiding early colectomy are at risk of long‐term colectomy, especially if previously exposed to antitumour necrosis factor‐α agents or if rescue therapy during the acute attack was required because of steroid refractoriness

Safety of treatments for inflammatory bowel disease: Clinical practice guidelines of the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD)

Inflammatory bowel diseases are chronic conditions of unknown etiology, showing a growing incidence and prevalence in several countries, including Italy. Although the etiology of Crohn's disease and ulcerative colitis is unknown, due to the current knowledge regarding their pathogenesis, effective treatment strategies have been developed. Several guidelines are available regarding the efficacy and safety of available drug treatments for inflammatory bowel diseases. Nevertheless, national guidelines provide additional information adapted to local feasibility, costs and legal issues related to the use of the same drugs. These observations prompted the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) to establish Italian guidelines on the safety of currently available treatments for Crohn's disease and ulcerative colitis. These guidelines discuss the use of aminosalicylates, systemic and low bioavailability corticosteroids, antibiotics (metronidazole, ciprofloxacin, rifaximin), thiopurines, methotrexate, cyclosporine A, TNFα antagonists, vedolizumab, and combination therapies. These guidelines are based on current knowledge derived from evidence-based medicine coupled with clinical experience of a national working group

A comparison of diagnostic tests for lactose malabsorption - which one is the best?

<p>Abstract</p> <p>Background</p> <p>Perceived milk intolerance is a common complaint, and tests for lactose malabsorption (LM) are unreliable. This study assesses the agreement between diagnostic tests for LM and describes the diagnostic properties of the tests.</p> <p>Methods</p> <p>Patients above 18 years of age with suspected LM were included. After oral intake of 25 g lactose, a combined test with measurement of serum glucose (s-glucose) and hydrogen (H2) and methane (CH4) in expired air was performed and symptoms were recorded. In patients with discrepancies between the results, the combined test was repeated and a gene test for lactose non-persistence was added. The diagnosis of LM was based on an evaluation of all tests. The following tests were compared: Increase in H2, CH4, H2+CH4 and H2+CH4x2 in expired air, increase in s-glucose, and symptoms. The agreement was calculated and the diagnostic properties described.</p> <p>Results</p> <p>Sixty patients were included, seven (12%) had LM. The agreement (kappa-values) between the methods varied from 0.25 to 0.91. The best test was the lactose breath test with measurement of the increase in H2 + CH4x2 in expired air. With a cut-off level < 18 ppm, the area under the ROC-curve was 0.967 and sensitivity was 100%. This shows that measurement of CH4 in addition to H2 improves the diagnostic properties of the breath test.</p> <p>Conclusion</p> <p>The agreement between commonly used methods for the diagnosis of LM was unsatisfactory. A lactose breath test with measurement of H2 + CH4x2 in expired air had the best diagnostic properties.</p

Lafora disease E3-ubiquitin ligase malin is related to TRIM32 at both the phylogenetic and functional level

<p>Abstract</p> <p>Background</p> <p>Malin is an E3-ubiquitin ligase that is mutated in Lafora disease, a fatal form of progressive myoclonus epilepsy. In order to perform its function, malin forms a functional complex with laforin, a glucan phosphatase that facilitates targeting of malin to its corresponding substrates. While laforin phylogeny has been studied, there are no data on the evolutionary lineage of malin.</p> <p>Results</p> <p>After an extensive search for malin orthologs, we found that malin is present in all vertebrate species and a cephalochordate, in contrast with the broader species distribution previously reported for laforin. These data suggest that in addition to forming a functional complex, laforin and perhaps malin may also have independent functions. In addition, we found that malin shares significant identity with the E3-ubiquitin ligase TRIM32, which belongs to the tripartite-motif containing family of proteins. We present experimental evidence that both malin and TRIM32 share some substrates for ubiquitination, although they produce ubiquitin chains with different topologies. However, TRIM32-specific substrates were not reciprocally ubiquitinated by the laforin-malin complex.</p> <p>Conclusions</p> <p>We found that malin and laforin are not conserved in the same genomes. In addition, we found that malin shares significant identity with the E3-ubiquitin ligase TRIM32. The latter result suggests a common origin for malin and TRIM32 and provides insights into possible functional relationships between both proteins.</p

Dysregulated RNA polyadenylation contributes to metabolic impairment in non-alcoholic fatty liver disease

Pre-mRNA processing is an essential mechanism for the generation of mature mRNA and the regulation of gene expression in eukaryotic cells. While defects in pre-mRNA processing have been implicated in a number of diseases their involvement in metabolic pathologies is still unclear. Here, we show that both alternative splicing and alternative polyadenylation, two major steps in pre-mRNA processing, are significantly altered in non-alcoholic fatty liver disease (NAFLD). Moreover, we find that Serine and Arginine Rich Splicing Factor 10 (SRSF10) binding is enriched adjacent to consensus polyadenylation motifs and its expression is significantly decreased in NAFLD, suggesting a role mediating pre-mRNA dysregulation in this condition. Consistently, inactivation of SRSF10 in mouse and human hepatocytes in vitro, and in mouse liver in vivo, was found to dysregulate polyadenylation of key metabolic genes such as peroxisome proliferator-activated receptor alpha (PPARA) and exacerbate diet-induced metabolic dysfunction. Collectively our work implicates dysregulated pre-mRNA polyadenylation in obesity-induced liver disease and uncovers a novel role for SRSF10 in this process

Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice

RNA alternative splicing (AS) expands the regulatory potential of eukaryotic genomes. The mechanisms regulating liver-specific AS profiles and their contribution to liver function are poorly understood. Here, we identify a key role for the splicing factor RNA-binding Fox protein 2 (RBFOX2) in maintaining cholesterol homeostasis in a lipogenic environment in the liver. Using enhanced individual-nucleotide-resolution ultra-violet cross-linking and immunoprecipitation, we identify physiologically relevant targets of RBFOX2 in mouse liver, including the scavenger receptor class B type I (Scarb1). RBFOX2 function is decreased in the liver in diet-induced obesity, causing a Scarb1 isoform switch and alteration of hepatocyte lipid homeostasis. Our findings demonstrate that specific AS programmes actively maintain liver physiology, and underlie the lipotoxic effects of obesogenic diets when dysregulated. Splice-switching oligonucleotides targeting this network alleviate obesity-induced inflammation in the liver and promote an anti-atherogenic lipoprotein profile in the blood, underscoring the potential of isoform-specific RNA therapeutics for treating metabolism-associated diseases