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Orphanet Journal of Rare Diseases Mar 2015Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle. HHH has a panethnic distribution, with a... (Review)
Review
BACKGROUND
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle. HHH has a panethnic distribution, with a major prevalence in Canada, Italy and Japan. Acute clinical signs include intermittent episodes of vomiting, confusion or coma and hepatitis-like attacks. Alternatively, patients show a chronic course with aversion for protein rich foods, developmental delay/intellectual disability, myoclonic seizures, ataxia and pyramidal dysfunction. HHH syndrome is caused by impaired ornithine transport across the inner mitochondrial membrane due to mutations in SLC25A15 gene, which encodes for the mitochondrial ornithine carrier ORC1. The diagnosis relies on clinical signs and the peculiar metabolic triad of hyperammonemia, hyperornithinemia, and urinary excretion of homocitrulline. HHH syndrome enters in the differential diagnosis with other inherited or acquired conditions presenting with hyperammonemia.
METHODS
A systematic review of publications reporting patients with HHH syndrome was performed.
RESULTS
We retrospectively evaluated the clinical, biochemical and genetic profile of 111 HHH syndrome patients, 109 reported in 61 published articles, and two unpublished cases. Lethargy and coma are frequent at disease onset, whereas pyramidal dysfunction and cognitive/behavioural abnormalities represent the most common clinical features in late-onset cases or during the disease course. Two common mutations, F188del and R179* account respectively for about 30% and 15% of patients with the HHH syndrome. Interestingly, the majority of mutations are located in residues that have side chains protruding into the internal pore of ORC1, suggesting their possible interference with substrate translocation. Acute and chronic management consists in the control of hyperammonemia with protein-restricted diet supplemented with citrulline/arginine and ammonia scavengers. Prognosis of HHH syndrome is variable, ranging from a severe course with disabling manifestations to milder variants compatible with an almost normal life.
CONCLUSIONS
This paper provides detailed information on the clinical, metabolic and genetic profiles of all HHH syndrome patients published to date. The clinical phenotype is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels. Early intervention allows almost normal life span but the prognosis is variable, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
Topics: Aging; Humans; Hyperammonemia; Mutation; Origin Recognition Complex; Ornithine; Protein Conformation; Urea Cycle Disorders, Inborn
PubMed: 25874378
DOI: 10.1186/s13023-015-0242-9 -
Ageing Research Reviews Dec 2023Alterations in nitric oxide (NO) synthesis have been reported in Alzheimer's disease and vascular dementia. However, as the measurement of NO in biological samples is... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Alterations in nitric oxide (NO) synthesis have been reported in Alzheimer's disease and vascular dementia. However, as the measurement of NO in biological samples is analytically challenging, alternative, stable circulatory biomarkers of NO synthesis may be useful to unravel new pathophysiological mechanisms and treatment targets in dementia.
METHODS
We conducted a systematic review and meta-analysis of the circulating concentrations of arginine metabolites linked to NO synthesis, arginine, citrulline, asymmetric (ADMA) and symmetric (SDMA) dimethylarginine, and ornithine, in Alzheimer's disease and vascular dementia. We searched for relevant studies in PubMed, Scopus, and Web of Science from inception to the 31st of May 2023. The JBI checklist and GRADE were used to assess the risk of bias and the certainty of evidence, respectively.
RESULTS
In 14 selected studies, there were no significant between-group differences in arginine and ornithine concentrations. By contrast, compared to controls, patients with dementia had significantly higher ADMA (standard mean difference, SMD=0.62, 95% CI 0.06-1.19, p = 0.029), SDMA (SMD=0.70, 95% CI 0.34-1.35, p<0.001), and citrulline concentrations (SMD=0.50, 95% CI 0.08-0.91, p = 0.018). In subgroup analysis, the effect size was significantly associated with treatment with cholinesterase inhibitors and/or antipsychotics for ADMA, and underlying disorder (Alzheimer's disease), study continent, and analytical method for citrulline.
CONCLUSION
Alterations in ADMA, SDMA, and citrulline, biomarkers of NO synthesis, may be useful to investigate the pathophysiology of different forms of dementia and identify novel therapeutic strategies. (PROSPERO registration number: CRD42023439528).
Topics: Humans; Alzheimer Disease; Dementia, Vascular; Citrulline; Arginine; Biomarkers; Ornithine
PubMed: 38007048
DOI: 10.1016/j.arr.2023.102139 -
Frontiers in Molecular Biosciences 2023Systemic sclerosis (SSc) is a chronic autoimmune disease, marked by an unpredictable course, high morbidity, and increased mortality risk that occurs especially in the... (Review)
Review
Systemic sclerosis (SSc) is a chronic autoimmune disease, marked by an unpredictable course, high morbidity, and increased mortality risk that occurs especially in the diffuse and rapidly progressive forms of the disease, characterized by fibrosis of the skin and internal organs and endothelial dysfunction. Recent studies suggest that the identification of altered metabolic pathways may play a key role in understanding the pathophysiology of the disease. Therefore, metabolomics might be pivotal in a better understanding of these pathogenic mechanisms. Through a systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA), searches were done in the PubMed, EMBASE, Web of Science, and Scopus databases from 2000 to September 2022. Three researchers independently reviewed the literature and extracted the data based on predefined inclusion and exclusion criteria. Of the screened studies, 26 fulfilled the inclusion criteria. A total of 151 metabolites were differentially distributed between SSc patients and healthy controls (HC). The main deregulated metabolites were those derived from amino acids, specifically homocysteine (Hcy), proline, alpha-N-phenylacetyl-L-glutamine, glutamine, asymmetric dimethylarginine (ADMA), citrulline and ornithine, kynurenine (Kyn), and tryptophan (Trp), as well as acylcarnitines associated with long-chain fatty acids and tricarboxylic acids such as citrate and succinate. Additionally, differences in metabolic profiling between SSc subtypes were identified. The diffuse cutaneous systemic sclerosis (dcSSc) subtype showed upregulated amino acid-related pathways involved in fibrosis, endothelial dysfunction, and gut dysbiosis. Lastly, potential biomarkers were evaluated for the diagnosis of SSc, the identification of the dcSSc subtype, pulmonary arterial hypertension, and interstitial lung disease. These potential biomarkers are within amino acids, nucleotides, carboxylic acids, and carbohydrate metabolism. The altered metabolite mechanisms identified in this study mostly point to perturbations in amino acid-related pathways, fatty acid beta-oxidation, and in the tricarboxylic acid cycle, possibly associated with inflammation, vascular damage, fibrosis, and gut dysbiosis. Further studies in targeted metabolomics are required to evaluate potential biomarkers for diagnosis, prognosis, and treatment response.
PubMed: 37614441
DOI: 10.3389/fmolb.2023.1215039 -
Cells Aug 2023There is an increasing interest in biomarkers of nitric oxide dysregulation and oxidative stress to guide management and identify new therapeutic targets in patients... (Meta-Analysis)
Meta-Analysis Review
There is an increasing interest in biomarkers of nitric oxide dysregulation and oxidative stress to guide management and identify new therapeutic targets in patients with chronic obstructive pulmonary disease (COPD). We conducted a systematic review and meta-analysis of the association between circulating metabolites within the arginine (arginine, citrulline, ornithine, asymmetric, ADMA, and symmetric, SDMA dimethylarginine), transsulfuration (methionine, homocysteine, and cysteine) and folic acid (folic acid, vitamin B, and vitamin B) metabolic pathways and COPD. We searched electronic databases from inception to 30 June 2023 and assessed the risk of bias and the certainty of evidence. In 21 eligible studies, compared to healthy controls, patients with stable COPD had significantly lower methionine (standardized mean difference, SMD = -0.50, 95% CI -0.95 to -0.05, = 0.029) and folic acid (SMD = -0.37, 95% CI -0.65 to -0.09, = 0.009), and higher homocysteine (SMD = 0.78, 95% CI 0.48 to 1.07, < 0.001) and cysteine concentrations (SMD = 0.34, 95% CI 0.02 to 0.66, = 0.038). Additionally, COPD was associated with significantly higher ADMA (SMD = 1.27, 95% CI 0.08 to 2.46, = 0.037), SDMA (SMD = 3.94, 95% CI 0.79 to 7.08, = 0.014), and ornithine concentrations (SMD = 0.67, 95% CI 0.13 to 1.22, = 0.015). In subgroup analysis, the SMD of homocysteine was significantly associated with the biological matrix assessed and the forced expiratory volume in the first second to forced vital capacity ratio, but not with age, study location, or analytical method used. Our study suggests that the presence of significant alterations in metabolites within the arginine, transsulfuration, and folic acid pathways can be useful for assessing nitric oxide dysregulation and oxidative stress and identifying novel treatment targets in COPD. (PROSPERO registration number: CRD42023448036.).
Topics: Humans; Cysteine; Nitric Oxide; Metabolomics; Arginine; Methionine; Racemethionine; Folic Acid; Homocysteine; Vitamins
PubMed: 37681911
DOI: 10.3390/cells12172180 -
Medicine Sep 2023Transjugular intrahepatic portosystemic shunt (TIPS) can be an effective treatment for cirrhotic patients who develop variceal bleeding and ascites. However, TIPS... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Transjugular intrahepatic portosystemic shunt (TIPS) can be an effective treatment for cirrhotic patients who develop variceal bleeding and ascites. However, TIPS placement is associated with an increased risk of developing hepatic encephalopathy (HE). Recently, there have been efforts to use the typical medical therapies prophylactically in patients undergoing TIPS placement to prevent post-TIPS HE.
METHODS
We conducted literature searches in MEDLINE, Embase, CINAHL, Scopus, and Cochrane to examine studies that use prophylactic medical therapy for preventing post-TIPS HE. A narrative synthesis and grading of recommendations assessment assessment were done for all studies. Meta-analysis was performed for eligible studies using the Mantel-Haenszel method random-effects model. Nine hundred twenty-one articles were screened and 5 studies were included in the study after 2 levels of screening. The medications studied were rifaximin, lactulose, lactitol, L-Ornithine-L-aspartate (LOLA), albumin, and combination therapies.
RESULTS
Narrative results showed that lactulose, lactitol, LOLA and albumin prophylaxis were not associated with reduction in HE occurrence or mortality. A combination of rifaximin and lactulose was found to be associated with lower occurrence of HE, and the results were not different when LOLA was added. Meta-analysis (n = 3) showed that rifaximin treatment was not associated with changes in HE occurrences.
CONCLUSION
In conclusion, a vast majority of medications were not found to be effective post-TIPS HE prophylaxis when used alone. A rifaximin and lactulose combination therapy may be beneficial. Overall, there is significant limitation in the current data and more studies are needed to yield more robust meta-analysis results in the future.
Topics: Humans; Hepatic Encephalopathy; Lactulose; Rifaximin; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Albumins; Primary Prevention
PubMed: 37746955
DOI: 10.1097/MD.0000000000035266 -
The Cochrane Database of Systematic... Jun 2013Human African trypanosomiasis, or sleeping sickness, is a painful and protracted disease affecting people in the poorest parts of Africa and is fatal without treatment.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Human African trypanosomiasis, or sleeping sickness, is a painful and protracted disease affecting people in the poorest parts of Africa and is fatal without treatment. Few drugs are currently available for second-stage sleeping sickness, with considerable adverse events and variable efficacy.
OBJECTIVES
To evaluate the effectiveness and safety of drugs for treating second-stage human African trypanosomiasis.
SEARCH METHODS
We searched the Cochrane Infectious Diseases Group Specialized Register (January 2013), CENTRAL (The Cochrane Library Issue 12 2012) , MEDLINE (1966 to January 2013), EMBASE (1974 to January 2013), LILACS (1982 to January 2013 ), BIOSIS (1926-January 2013), mRCT (January 2013) and reference lists. We contacted researchers working in the field and organizations.
SELECTION CRITERIA
Randomized and quasi-randomized controlled trials including adults and children with second-stage HAT, treated with anti-trypanosomal drugs.
DATA COLLECTION AND ANALYSIS
Two authors (VL and AK) extracted data and assessed methodological quality; a third author (JS) acted as an arbitrator. Included trials only reported dichotomous outcomes, and we present these as risk ratio (RR) with 95% confidence intervals (CI).
MAIN RESULTS
Nine trials with 2577 participants, all with Trypansoma brucei gambiense HAT, were included. Seven trials tested currently available drugs: melarsoprol, eflornithine, nifurtimox, alone or in combination; one trial tested pentamidine, and one trial assessed the addition of prednisolone to melarsoprol. The frequency of death and number of adverse events were similar between patients treated with fixed 10-day regimens of melarsoprol or 26-days regimens. Melarsoprol monotherapy gave fewer relapses than pentamidine or nifurtimox, but resulted in more adverse events.Later trials evaluate nifurtimox combined with eflornithine (NECT), showing this gives few relapses and is well tolerated. It also has practical advantages in reducing the frequency and number of eflornithine slow infusions to twice a day, thus easing the burden on health personnel and patients.
AUTHORS' CONCLUSIONS
Choice of therapy for second stage Gambiense HAT will continue to be determined by what is locally available, but eflornithine and NECT are likely to replace melarsoprol, with careful parasite resistance monitoring. We need research on reducing adverse effects of currently used drugs, testing different regimens, and experimental and clinical studies of new compounds, effective for both stages of the disease.
Topics: Animals; Antiprotozoal Agents; Drug Therapy, Combination; Eflornithine; Humans; Melarsoprol; Nifurtimox; Pentamidine; Prednisolone; Randomized Controlled Trials as Topic; Recurrence; Trypanosoma brucei gambiense; Trypanosomiasis, African
PubMed: 23807762
DOI: 10.1002/14651858.CD006201.pub3 -
Cancers May 2020Several immunotherapy agents are the standard of care of many solid malignancies. Nevertheless, the majority of patients do not benefit from the currently available... (Review)
Review
Several immunotherapy agents are the standard of care of many solid malignancies. Nevertheless, the majority of patients do not benefit from the currently available immunotherapies. It is therefore of paramount importance to identify the prognostic and predictive factors of tumor response/resistance and to design effective therapeutic strategies to overcome primary resistance and improve the efficacy of immunotherapy. The aim of this review is to underline the influence of the tumor and host metabolism on the antitumor immune response and to discuss possible strategies to improve the efficacy of available treatments by targeting the specific metabolic pathways in tumors or immune cells and by modifying patients' nutritional statuses. A systematic search of the Medline and EMBASE databases was carried out to identify scientific papers published until February 2020, which reported original research articles on the influence of tumor or host metabolism on antitumor immune response. The literature data showed the key role of glycolysis and mitochondrial oxidative phosphorylation, arginine, tryptophan, glutamine, lipid metabolism and microbiome on immune cell function. Moreover, specific nutritional behaviors, such as a low dietary intake of vitamin C, low glycemic index and alpha-linolenic acid, eicosapentenoic acid, docosahexaenoic acid, ornithine ketoglutarate, tryptophan and probiotic supplementation were associated with the potential clinical benefits from the currently available immunotherapies.
PubMed: 32375310
DOI: 10.3390/cancers12051153 -
International Journal of Medical... 2021Neutrophil extracellular traps (NETs) have been implicated in host immune responses. Attempts have been made to examine how NETs affect the pathogenesis of...
Neutrophil extracellular traps (NETs) have been implicated in host immune responses. Attempts have been made to examine how NETs affect the pathogenesis of complications such as autoimmune and vascular disorders. This study aimed to explore the relationship between NETs and vasculitis. The current study entailed the searching of PsycINFO, PubMed, Web of Science, and CINAHL for articles related to the research topic. The search terms and phrases included "vasculitis," "NETs," "neutrophil extracellular traps," "NETosis," and "pathogenesis." The search was limited to articles published between 2009 and 2019. Researchers have shown that NETs contribute to the pathogenesis of vasculitis through different mechanisms and processes, including renal failure and vascular damage. The protective effects of NETs have also been highlighted. Overall, some scholars have shown the effectiveness of using DNase I and the PAD4 inhibitor Cl-amidine to treat vasculitis by restricting NET formation. However, observations have been noted in only animal experimental models. Neutrophil hyperactivity and its role in vasculitis are not yet fully understood. More studies aiming to determine the accurate function of NETs in vasculitis pathogenesis, particularly in humans, should be undertaken. Intensive research on NETs and vasculitis can increase the knowledge of medical practitioners and contribute to the development of new treatment methods to enhance patient outcomes in the future.
Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Apoptosis; Deoxyribonuclease I; Disease Models, Animal; Extracellular Traps; Giant Cell Arteritis; Humans; Neutrophils; Ornithine; Protein-Arginine Deiminase Type 4; Regulated Cell Death; Takayasu Arteritis
PubMed: 33746569
DOI: 10.7150/ijms.53728 -
Alimentary Pharmacology & Therapeutics Apr 2015Interventional treatment for overt hepatic encephalopathy (OHE), includes non-absorbable disaccharides, neomycin, rifaximin, L-ornithine-L-aspartate and branched chain... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Interventional treatment for overt hepatic encephalopathy (OHE), includes non-absorbable disaccharides, neomycin, rifaximin, L-ornithine-L-aspartate and branched chain amino acids (BCAA). However, the optimum regimen remains inconclusive.
AIM
To compare interventions in terms of patients' adverse events and major clinical outcomes.
METHODS
Literature search of PubMed, Embase, Scopus, and Cochrane Library studies published up to July 31 2014. RCTs of above interventions in OHE patients were included. Network meta-analysis combined direct and indirect evidence to estimate odds ratios (ORs) and mean difference (MD) between treatments and the probabilities of ranking for treatment based on clinical outcomes.
RESULTS
Twenty eligible RCTs were included. When compared with observation, only L-ornithine-L-aspartate (OR 3.71, P < 0.001) and BCAA (OR 3.37, P < 0.001) improved clinical efficacy significantly. However, when L-ornithine-L-aspartate was compared with BCAA, non-absorbable disaccharides and neomycin, there was a trend suggesting that L-ornithine-L-aspartate may be the most effective intervention with respect to clinical improvement (OR 1.10), rifaximin (OR 1.31), non-absorbable disaccharides (OR 2.75), neomycin (OR 2.22). In addition, L-ornithine-L-aspartate (MD -20.18, 95% CI -40.12 to -0.27) provided a significant reduction in blood ammonia concentration compared with observation. Neomycin appeared to be associated with more adverse events in comparison with non-absorbable disaccharides (OR 10.15), rifaximin (OR 17.31), L-ornithine-L-aspartate (OR 3.16) or BCAA (OR 7.69).
CONCLUSIONS
L-ornithine-L-aspartate treatment may show a trend in superiority for clinical efficacy among standard interventions for OHE. Rifaximin shows the greatest reduction in blood ammonia concentration, and treatment with neomycin demonstrates a higher probability in causing adverse effects among the five compared interventions.
Topics: Amino Acids, Branched-Chain; Ammonia; Dipeptides; Disaccharides; Gastrointestinal Agents; Hepatic Encephalopathy; Humans; Mental Health; Neomycin; Randomized Controlled Trials as Topic; Rifamycins; Rifaximin
PubMed: 25684317
DOI: 10.1111/apt.13122 -
Cureus Jan 2024There are no guidelines for the most effective medication to reduce hepatic encephalopathy (HE) or the associated mortality. The purpose of this study is to determine... (Review)
Review
There are no guidelines for the most effective medication to reduce hepatic encephalopathy (HE) or the associated mortality. The purpose of this study is to determine the most effective possible treatment among the single treatment options or the combined treatment options for decreasing the morbidity and mortality of HE. We evaluated the outcomes by various parameters such as the quality of life, reduction in ammonia, all causes of mortality, adverse events, reversal of minimal HE, and development of overt HE. We systematically searched PubMed, Cochrane, Web of Science, and Scopus till the 19th of January 2023 for studies that assess various treatment options for HE. Data were extracted from eligible studies and pooled in a frequentist network meta-analysis as standardized mean difference (SMD) and their 95% confidence interval (CI) using the MetaInsight web-based tool. The Cochrane Tool was used to assess the randomized controlled trials' quality (RCT), while the NIH tool was used to assess the quality of the included cohort studies. Utilizing the R software, the network meta-analysis was conducted. In addition to a significant variation in cases of (Lactulose and Rifaximin) compared with Rifaximin (RR= 0.39, 95% CI [0.17; 0.89]), the results demonstrated a significantly lower incidence of overt HE in (Lactulose and Rifaximin) compared with placebo (RR=0.19, 95% CI [0.09; 0.40]). Most arms demonstrated a statistically significant reduction in the incidence of overt HE compared to albumin and placebo. The results also demonstrated a significant reduction in ammonia between L-ornithine-L-aspartate (LOLA) and probiotics (MD= -19.17, 95% CI [-38.01; -0.32]), as well as a significant difference in the incidence of LOLA compared to placebo (MD= -22.62, 95% CI [-39.16; -6.07]). This network meta-analysis has significant data for managing subclinical HE in people without a history of overt HE. Our analysis showed that (Lactulose and Rifaximin), followed by (Rifaximin and L-carnitine), followed by (Lactulose and Rifaximin with zinc) were the best combinations regarding overt HE. LOLA reduced ammonia best, followed by Nitazoxanide and finally Lactulose. (Lactulose and Nitazoxanide) have the least adverse effects, followed by (Rifaximin and L-carnitine), then Probiotics. Yet, all mortality outcomes and quality of life changes yielded no useful findings. Future studies like RCTs must be done to compare our therapies directly.
PubMed: 38435950
DOI: 10.7759/cureus.53341