Search Results (12)

In addition to their role in lipid absorption, bile acids (BAs) are also known for several relevant (endocrine) activities including contributing to the regulation of energy homeostasis and some non-communicable diseases (NCDs). Furthermore, moderately elevated unconjugated bilirubin levels, as observed in Gilbert’s syndrome (GS), may protect against NCDs. We therefore hypothesized that the BA profile in GS subjects differs from that of normo-bilirubinemic individuals. To test this, we performed a human case-control study, in which GS (n = 60) and controls (n = 60) were matched for age and gender, and serum BA concentrations were measured by liquid-chromatography mass spectrometry (LC–MS). Despite analyzing a comprehensive panel of BAs, no significant differences between the two groups were observed. These data suggest that bile acid concentrations are similar between groups, indicating that altered bilirubin metabolism unlikely influences their transport into the blood. Full article

Background: Hexokinase (HK) deficiency is a rare autosomal recessively inherited disease manifested by chronic nonspherocytic hemolytic anemia. Most patients present with a mild to severe course of the disease (fetal hydrocephalus, neonatal hyperbilirubinemia, severe anemia). We reviewed 37 cases of patients with hexokinase deficiency described so far, focusing on the severity of the disease, clinical presentation, treatment applied, and genetic test results. Methods: We present a 10-year-old girl who initially presented with symptoms of weakness, excessive fatigue, and yellowing of the skin and sclerae. Genetic testing detected the (TA)7 variant in both alleles of the UGT1A1 gene and diagnosed Gilbert’s disease. In the follow-up, red cell hemolysis was observed. The diagnosis was extended, and tests for red cell enzymopathy were performed and a reduced level of hexokinase—0.65 IU/gHb (normal 0.78–1.57) was found. Next-generation sequencing revealed a new sense-change variant in exon 7 in the hexokinase gene not previously reported in databases. Results: Up to this date, only around 37 cases of hexokinase deficiency associated with hereditary nonspherocytic hemolytic anemia have been documented around the world. Diagnosing hexokinase deficiency involves clinical evaluation, laboratory testing, and genetic analysis. Management focuses on treating symptoms and preventing complications; there is no cure for the underlying enzyme deficiency. In patients with severe anemia, the treatment is multiple blood transfusions followed by iron chelation therapy. Conclusions: Understanding and diagnosing hexokinase deficiency is critical for providing appropriate care and improving the quality of life for affected individuals. Full article

Gilbert syndrome is the most common hyperbilirubinemia, associated with a mutation in the UGT1A1 bilirubin gene, which produces an enzyme that conjugates bilirubin with glucuronic acid. Episodes of jaundice occurring in GS negatively affect patients’ quality of life. This systematic review aimed to analyze clinical studies regarding nutrition in people with GS. The study followed the PRISMA guidelines and utilized the Ebsco, Embase, Cochrane, PubMed, Scopus, and Web of Science databases to search clinical trials focused on diet/nutrition in GS (1963–2023 years). The methodological quality of selected studies was assessed using the Jadad scale. As a result, 19 studies met the inclusion criteria. The research mainly focused on the impact of caloric restriction, consumption of various diet variants, and vegetables and fruits on hyperbilirubinemia and metabolic health. A nutritional intervention consisting of not applying excessive calorie restrictions and consuming fats and biologically active compounds in vegetables and fruits (Cruciferae, Apiaceous, Rutaceae) may prevent the occurrence of jaundice episodes. It is justified to conduct further research on detecting such compounds in food, which, by influencing the expression of the UGT liver enzyme gene, could contribute to regulating bilirubin concentration in the blood of people with GS. Full article

During the first year of the COVID-19 pandemic, heritage sites, which protect natural and cultural resources, experienced the dauting task of sustaining business operations during the pandemic while serving the public by preserving and conserving resources. These businesses undertook risk reduction measures, conceptualized as adjustments, to mitigate the spread of disease while maintaining business operations. By engaging with Gilbert White’s (1942) Adjustment Theory, this study examines the adjustments made by Texas heritage sites in response to emerging risks associated with the COVID-19 pandemic. Specifically, we analyze adjustments made to reduce risk to visitors, financial stability, and programmatic offerings; explore the extent to which these adjustments facilitated sustainability, business expansion, and innovation; and identify what factors contributed to or hindered their recovery. This mixed-methods study employed an online survey and a follow-up semi-structured phone interview with heritage site managers. Our findings indicate Texas heritage sites implemented a range of fiscal and health related adjustments in response to the pandemic. Specific to fiscal adjustments, we found changes in visitors led to adjustments in business operations which also facilitated revenue generation for these entities. We also observed how new opportunities arose from the health adjustments in the form of remote offerings and new markets. Our findings emphasize the importance of adjustments made by heritage sites to continue their operations during the pandemic while also offering strategies to mitigate future risks. Full article

Background: The angiotensin-converting enzyme (ACE) metabolizes a number of important peptides participating in blood pressure regulation and vascular remodeling. Elevated blood ACE is a marker for granulomatous diseases and elevated ACE expression in tissues is associated with increased risk of cardiovascular diseases. Objective and Methodology: We applied a novel approach —ACE phenotyping—to find a reason for conformationally impaired ACE in the blood of one particular donor. Similar conformationally altered ACEs were detected previously in 2–4% of the healthy population and in up to 20% of patients with uremia, and were characterized by significant increase in the rate of angiotensin I hydrolysis. Principal findings: This donor has (1) significantly increased level of endogenous ACE inhibitor in plasma with MW less than 1000; (2) increased activity toward angiotensin I; (3) M71V mutation in ABCG2 (membrane transporter for more than 200 compounds, including bilirubin). We hypothesize that this patient may also have the decreased level of free bilirubin in plasma, which normally binds to the N domain of ACE. Analysis of the local conformation of ACE in plasma of patients with Gilbert and Crigler-Najjar syndromes allowed us to speculate that binding of mAbs 1G12 and 6A12 to plasma ACE could be a natural sensor for estimation of free bilirubin level in plasma. Totally, 235 human plasma/sera samples were screened for conformational changes in soluble ACE. Conclusions/Significance: ACE phenotyping of plasma samples allows us to identify individuals with conformationally altered ACE. This type of screening has clinical significance because this conformationally altered ACE could not only result in the enhancement of the level of angiotensin II but could also serve as an indicator of free bilirubin levels. Full article

Heme oxygenase (HO) has both beneficial and detrimental effects via its metabolites, including carbon monoxide (CO), biliverdin or bilirubin, and ferrous iron. HO-1 is an inducible form of HO that is upregulated by oxidative stress, nitric oxide, CO, and hypoxia, whereas HO-2 is a constitutive form that regulates vascular tone and homeostasis. In brains injured by trauma, ischemia-reperfusion, or Alzheimer’s disease (AD), the long-term expression of HO-1 can be detected, which can lead to cytotoxic ferroptosis via iron accumulation. In contrast, the transient induction of HO-1 in the peri-injured region may have regenerative potential (e.g., angiogenesis, neurogenesis, and mitochondrial biogenesis) and neurovascular protective effects through the CO-mediated signaling pathway, the antioxidant properties of bilirubin, and the iron-mediated ferritin synthesis. In this review, we discuss the dual roles of HO-1 and its metabolites in various neurovascular diseases, including age-related macular degeneration, ischemia-reperfusion injury, traumatic brain injury, Gilbert’s syndrome, and AD. Full article

Trypanosomiasis and leishmaniasis are among the major neglected diseases that affect poor people, mainly in developing countries. In Ethiopia, the latex of Aloe rugosifolia Gilbert & Sebsebe is traditionally used for the treatment of protozoal diseases, among others. In this study, the in vitro antitrypanosomal activity of the leaf latex of A. rugosifolia was evaluated against Trypanosoma congolense field isolate using in vitro motility and in vivo infectivity tests. The latex was also tested against the promastigotes of Leishmania aethiopica and L. donovani clinical isolates using alamar blue assay. Preparative thin-layer chromatography of the latex afforded a naphthalene derivative identified as plicataloside (2,8-O,O-di-(β-D-glucopyranosyl)-1,2,8-trihydroxy-3-methyl-naphthalene) by means of spectroscopic techniques (HRESI-MS, ¹H, ¹³C-NMR). Results of the study demonstrated that at 4.0 mg/mL concentration plicataloside arrested mobility of trypanosomes within 30 min of incubation period. Furthermore, plicataloside completely eliminated subsequent infectivity in mice for 30 days at concentrations of 4.0 and 2.0 mg/mL. Plicataloside also displayed antileishmanial activity against the promastigotes of L. aethopica and L. donovani with IC₅₀ values 14.22 ± 0.41 µg/mL (27.66 ± 0.80 µM) and 18.86 ± 0.03 µg/mL (36.69 ± 0.06 µM), respectively. Thus, plicataloside may be used as a scaffold for the development of novel drugs effective against trypanosomiasis and leishmaniasis. Full article

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder worldwide. The aim of our study was to assess the role of bilirubin, and the heme oxygenase 1 (HMOX1) and bilirubin UDP-glucuronosyl transferase (UGT1A1) promoter gene variants, which are involved in bilirubin homeostasis, in the NAFLD development in adult patients. The study was performed on 84 patients with NAFLD and 103 age/sex-matched controls. Routine biochemistry, inflammatory markers, adipokines, and the fibrosis/steatohepatitis stage were determined in the NAFLD patients. The (GT)n/(TA)n dinucleotide variations in HMOX1/UGT1A1 gene promoters, respectively, were analyzed by fragment analysis. Compared to controls, serum bilirubin concentrations in NAFLD patients tended to be decreased, while the prevalence of phenotypic Gilbert syndrome was significantly low. Genetic variations in HMOX1 and UGT1A1 gene promoters did not differ between NAFLD patients and controls, and no relationship was found in the NAFLD patients between these gene variants and any of the laboratory or histological parameters. In conclusion, metabolism of bilirubin is dysregulated in NAFLD patients, most likely due to increased oxidative stress, since frequencies of the major functional variants in the HMOX1 or UGT1A1 gene promoters did not have any effect on development of NAFLD in adult patients. Full article

Laboratory medicine, along with genetic investigations in sports medicine, is taking on an increasingly important role in monitoring athletes’ health conditions. Acute or intense exercise can result in metabolic imbalances, muscle injuries or reveal cardiovascular disorders. This study aimed to monitor the health status of a basketball player with an integrated approach, including biochemical and genetic investigations and advanced imaging techniques, to shed light on the causes of recurrent syncope he experienced during exercise. Biochemical analyses showed that the athlete had abnormal iron, ferritin and bilirubin levels. Coronary Computed Tomographic Angiography highlighted the presence of an intramyocardial bridge, suggesting this may be the cause of the observed syncopes. The athlete was excluded from competitive activity. In order to understand if this cardiac malformation could be caused by an inherited genetic condition, both array-CGH and whole exome sequencing were performed. Array-CGH showed two intronic deletions involving MACROD2 and COMMD10 genes, which could be related to a congenital heart defect; whole exome sequencing highlighted the genotype compatible with Gilbert syndrome. However, no clear pathogenic mutations related to the patient’s cardiological phenotype were detected, even after applying machine learning methods. This case report highlights the importance and the need to provide exhaustive personalized diagnostic work up for the athletes in order to cover the cause of their malaise and for safeguarding their health. This multidisciplinary approach can be useful to create ad personam training and treatments, thus avoiding the appearance of diseases and injuries which, if underestimated, can become irreversible disorders and sometimes can result in the death of the athlete. Full article

Bilirubin is an important antioxidant and a modulator of biological functions. However, most of the protection against oxidative stress was shown in vitro or ex vivo. The aim of this case-control study was to investigate whether subjects with Gilbert’s syndrome (GS) experience different levels of lipid and protein oxidation (as well as differences in oxidative stress related markers) compared to healthy controls. GS subjects (n = 119) demonstrated higher serum levels of unconjugated bilirubin (p < 0.001), a lower BMI (p < 0.001), 37% higher antioxidant potential assessed as ferric reducing ability potential (p < 0.001), higher advanced oxidation protein products (p < 0.01) andlower apolipoprotein B (p < 0.05), hs-C-reactive protein (p < 0.05), interleukin 6 (p < 0.001) and interleukin 1 beta (p < 0.05) values compared to healthy controls (n = 119). Furthermore, the resting heart rate was significantly lower in the GS group (p < 0.05). Stronger protective effects for GS subjects were demonstrated in the older subgroup (n = 104, average age 50 years) compared to those of the younger group (n = 134, average age 27 years). Although not all markers related to oxidative stress were different between the groups (e.g., malondialdehyde, homocysteine, oxLDL, and myeloperoxidase; p > 0.05), the observed differences contribute to the explanation of why GS serves as an important protector in the pathogenesis of metabolic, oxidative stress related diseases. Full article

Malaria is one of the three major global public health threats due to a wide spread resistance of the parasites to the standard antimalarial drugs. Considering this growing problem, the ethnomedicinal approach in the search for new antimalarial drugs from plant sources has proven to be more effective and inexpensive. The leaves of Aloe pulcherrima Gilbert and Sebsebe, an endemic Ethiopian plant, are locally used for the treatment of malaria and other infectious diseases. Application of the leaf latex of A. pulcherrima on preparative silica gel TLC led to the isolation of two C-glycosylated anthrones, identified as nataloin (1) and 7-hydroxyaloin (2) by spectroscopic techniques (UV, IR, ¹H- and ¹³C-NMR, HR-ESIMS). Both the latex and isolated compounds displayed antimalarial activity in a dose-independent manner using a four-day suppressive test, with the highest percent suppression of 56.2% achieved at 200 mg/kg/day for 2. The results indicate that both the leaf latex of A. pulcherrima and its two major constituents are endowed with antiplasmodial activities, which support the traditional use of the leaves of the plant for the treatment of malaria. Full article

Question: What are the benefits associated with the use of anti–epidermal growth factor receptor (anti-EGFR) therapies in squamous cell carcinoma of the head and neck (HNSCC)? Anti-EGFR therapies of interest included cetuximab, gefitinib, lapatinib, zalutumumab, erlotinib, and panitumumab. Perspectives: Head-and-neck cancer includes malignant tumours arising from a variety of sites in the upper aerodigestive tract. The most common histologic type is squamous cell carcinoma, and most common sites are the oral cavity, the oropharynx, the hypopharynx, and the larynx. Worldwide, HNSCC is the sixth most common neoplasm, and despite advances in therapy, long-term survival in HNSCC patients is poor. Primary surgery followed by chemoradiation, or primary chemoradiation, are the standard treatment options for patients with locally advanced (stages III–IVB) HNSCC; however, meta-analytic data indicate that the benefit of concurrent platinum-based chemotherapy disappears in patients over the age of 70 years. Cancer Care Ontario’s Program in Evidence-Based Care is sponsored by Cancer Care Ontario and the Ministry of Health and Long-Term Care. Cetuximab is a monoclonal antibody approved for use in combination with radiation in the treatment of patients with untreated locally advanced HNSCC and as monotherapy for patients with recurrent or metastatic (stage IVC) HNSCC who have progressed on platinum-based therapy. Given the interest in anti-EGFR agents in advanced HNSCC, the Head and Neck Cancer Disease Site Group (DSG) of Cancer Care Ontario’s Program in Evidence-Based Care (PEBC) chose to systematically review the literature pertaining to this topic so as to develop evidence-based recommendations for treatment. Outcomes: Outcomes of interest included overall and progression-free survival, quality of life, tumour response rate and duration, and the toxicity associated with the use of anti-EGFR therapies. Methodology: The medline, embase, and Cochrane Library databases, the American Society of Clinical Oncology online conference proceedings, the Canadian Medical Association InfoBase, and the National Guidelines Clearinghouse were systematically searched to locate primary articles and practice guidelines. The reference lists from relevant review articles were searched for additional trials. All evidence was reviewed, and that evidence informed the development of the clinical practice guideline. The resulting recommendations were approved by the Report Approval Panel of the pebc, and by the Head and Neck Cancer dsg. An external review by Ontario practitioners completed the final phase of the review process. Feedback from all parties was incorporated to create the final practice guideline. Results: The electronic search identified seventy-four references that were reviewed for inclusion. Only four phase iii trials met the inclusion criteria for the present guideline. No practice guidelines, systematic reviews, or meta-analyses were found during the course of the literature search. The randomized controlled trials (rcts) involved three distinct patient populations: those with locally advanced hnscc being treated for cure, those with incurable advanced recurrent or metastatic hnscc being treated with first-line platinum-based chemotherapy, and those with incurable advanced recurrent or metastatic hnscc who had disease progression despite, or who were unsuitable for, first-line platinum-based chemotherapy. Practice Guideline: These recommendations apply to adult patients with locally advanced (nonmetastatic stages iii–ivb) or recurrent or metastatic (stage ivc) hnscc. 1. Platinum-based chemoradiation remains the current standard of care for treatment of locally advanced hnscc. 2. In patients with locally advanced hnscc who are medically unsuitable for concurrent platinumbased chemotherapy or who are over the age of 70 years (because concurrent chemotherapy does not appear to improve overall survival in this patient population), the addition of cetuximab to radical radiotherapy should be considered to improve overall survival, progression-free survival, and time to local recurrence. 3. Cetuximab in combination with platinum-based combination chemotherapy is superior to chemotherapy alone in patients with recurrent or metastatic hnscc, and is recommended to improve overall survival, progression-free survival, and response rate. 4. The role of anti-egfr therapies in the treatment of locally advanced hnscc is currently under study in large randomized trials, and patients with hnscc should continue to be offered clinical trials of novel agents aimed at improving outcomes. Qualifying Statements: Chemoradiation is the current standard of care for patients with locally advanced hnscc, and to date, there is no evidence that compares cetuximab plus radiotherapy with chemoradiation, or that examines whether the addition of cetuximab to chemoradiation is of benefit in these patients. However, five ongoing trials are investigating the effect of the addition of egfr inhibitors concurrently with, before, or after chemoradiotherapy; those trials should provide direction about the best integration of cetuximab into standard treatment. In patients with recurrent or metastatic hnscc who experience progressive disease despite, or who are unsuitable for, first-line platinum-based chemotherapy, gefitinib at doses of 250 mg or 500 mg daily, compared with weekly methotrexate, did not increase median overall survival [hazard ratio (hr): 1.22; 96% confidence interval (ci): 0.95 to 1.57; p = 0.12 (for 250 mg daily vs. weekly methotrexate); hr: 1.12; 95% ci: 0.87 to 1.43; p = 0.39 (for 500 mg daily vs. weekly methotrexate)] or objective response rate (2.7% for 250 mg and 7.6% for 500 mg daily vs. 3.9% for weekly methotrexate, p > 0.05). As compared with methotrexate, gefitinib was associated with an increased incidence of tumour hemorrhage (8.9% for 250 mg and 11.4% for 500 mg daily vs. 1.9% for weekly methotrexate). Full article