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Photodiagnosis and Photodynamic Therapy Jun 2024Protoporphyrin IX (PPIX) is the final precursor of heme, forming heme when iron is inserted. Individuals with erythropoietic protoporphyrias (EPP) have accumulation of... (Review)
Review
BACKGROUND
Protoporphyrin IX (PPIX) is the final precursor of heme, forming heme when iron is inserted. Individuals with erythropoietic protoporphyrias (EPP) have accumulation of PPIX, causing photosensitivity and increased liver disease risk. Many also have iron deficiency and anemia. We investigated outcomes of oral iron supplements in individuals with EPP.
METHODS
A systematic review identified literature on oral iron supplements in EPP patients. Subsequently, we administered iron supplements to EPP patients with iron deficiency. The primary outcome was impact on PPIX level. Secondary outcomes were adverse events and relative differences in hemoglobin and iron parameters.
RESULTS
The systematic review found 13 case reports and one uncontrolled clinical trial with uncertain results. From our department 10 patients with EPP and iron deficiency took daily dosages of 330 mg of ferrous fumarate for two months. Five of our patients had anemia at baseline. After 2 months of supplementation seven patients had increased PPIX level compared to baseline, two had decrease, one remained unchanged. The administration of iron led to a rise in ferritin, and in four of the anemic patients also to an improvement in blood hemoglobin. A small transiently elevation in plasma alanine transaminase concentration was observed during supplementation.
CONCLUSIONS
Overall, iron supplementation in EPP patients replenished iron stores and elevated erythrocyte PPIX and plasma alanine transaminase. For anemic patients, there was some degree of normalization of the hemoglobin level. If iron therapy is needed for EPP patients, monitoring of photosensitivity, PPIX, hemoglobin, and plasma liver enzymes is advisable.
Topics: Humans; Protoporphyria, Erythropoietic; Protoporphyrins; Dietary Supplements; Male; Female; Adult; Iron; Anemia, Iron-Deficiency; Middle Aged; Treatment Outcome
PubMed: 38734198
DOI: 10.1016/j.pdpdt.2024.104211 -
Brain Communications 2024New treatments are needed to improve the prognosis of pneumococcal meningitis. We performed a systematic review on adjunctive treatments in animal models of pneumococcal... (Review)
Review
New treatments are needed to improve the prognosis of pneumococcal meningitis. We performed a systematic review on adjunctive treatments in animal models of pneumococcal meningitis in order to identify treatments with the most potential to progress to clinical trials. Studies testing therapy adjunctive to antibiotics in animal models of pneumococcal meningitis were included. A literature search was performed using Medline, Embase and Scopus for studies published from 1990 up to 17 February 2023. Two investigators screened studies for inclusion and independently extracted data. Treatment effect was assessed on the clinical parameters disease severity, hearing loss and cognitive impairment and the biological parameters inflammation, brain injury and bacterial load. Adjunctive treatments were evaluated by their effect on these outcomes and the quality, number and size of studies that investigated the treatments. Risk of bias was assessed with the SYRCLE risk of bias tool. A total of 58 of 2462 identified studies were included, which used 2703 experimental animals. Disease modelling was performed in rats (29 studies), rabbits (13 studies), mice (12 studies), gerbils (3 studies) or both rats and mice (1 study). Meningitis was induced by injection of into the subarachnoid space. Randomization of experimental groups was performed in 37 of 58 studies (64%) and 12 studies (12%) were investigator-blinded. Overall, 54 treatment regimens using 46 adjunctive drugs were evaluated: most commonly dexamethasone (16 studies), daptomycin (5 studies), complement component 5 (C5; 3 studies) antibody and Mn(III)tetrakis(4-benzoicacid)porphyrin chloride (MnTBAP; 3 studies). The most frequently evaluated outcome parameters were inflammation [32 studies (55%)] and brain injury [32 studies (55%)], followed by disease severity [30 studies (52%)], hearing loss [24 studies (41%)], bacterial load [18 studies (31%)] and cognitive impairment [9 studies (16%)]. Adjunctive therapy that improved clinical outcomes in multiple studies was dexamethasone (6 studies), C5 antibodies (3 studies) and daptomycin (3 studies). HMGB1 inhibitors, matrix metalloproteinase inhibitors, neurotrophins, antioxidants and paquinimod also improved clinical parameters but only in single or small studies. Evaluating the treatment effect of adjunctive therapy was complicated by study heterogeneity regarding the animal models used and outcomes reported. In conclusion, 24 of 54 treatment regimens (44%) tested improved clinically relevant outcomes in experimental pneumococcal meningitis but few were tested in multiple well-designed studies. The most promising new adjunctive treatments are with C5 antibodies or daptomycin, suggesting that these drugs could be tested in clinical trials.
PubMed: 38707710
DOI: 10.1093/braincomms/fcae131 -
American Journal of Obstetrics and... May 2023Green-stained amniotic fluid, often referred to as meconium-stained amniotic fluid, is present in 5% to 20% of patients in labor and is considered an obstetric hazard.... (Review)
Review
Green-stained amniotic fluid, often referred to as meconium-stained amniotic fluid, is present in 5% to 20% of patients in labor and is considered an obstetric hazard. The condition has been attributed to the passage of fetal colonic content (meconium), intraamniotic bleeding with the presence of heme catabolic products, or both. The frequency of green-stained amniotic fluid increases as a function of gestational age, reaching approximately 27% in post-term gestation. Green-stained amniotic fluid during labor has been associated with fetal acidemia (umbilical artery pH <7.00), neonatal respiratory distress, and seizures as well as cerebral palsy. Hypoxia is widely considered a mechanism responsible for fetal defecation and meconium-stained amniotic fluid; however, most fetuses with meconium-stained amniotic fluid do not have fetal acidemia. Intraamniotic infection/inflammation has emerged as an important factor in meconium-stained amniotic fluid in term and preterm gestations, as patients with these conditions have a higher rate of clinical chorioamnionitis and neonatal sepsis. The precise mechanisms linking intraamniotic inflammation to green-stained amniotic fluid have not been determined, but the effects of oxidative stress in heme catabolism have been implicated. Two randomized clinical trials suggest that antibiotic administration decreases the rate of clinical chorioamnionitis in patients with meconium-stained amniotic fluid. A serious complication of meconium-stained amniotic fluid is meconium aspiration syndrome. This condition develops in 5% of cases presenting with meconium-stained amniotic fluid and is a severe complication typical of term newborns. Meconium aspiration syndrome is attributed to the mechanical and chemical effects of aspirated meconium coupled with local and systemic fetal inflammation. Routine naso/oropharyngeal suctioning and tracheal intubation in cases of meconium-stained amniotic fluid have not been shown to be beneficial and are no longer recommended in obstetrical practice. A systematic review of randomized controlled trials suggested that amnioinfusion may decrease the rate of meconium aspiration syndrome. Histologic examination of the fetal membranes for meconium has been invoked in medical legal litigation to time the occurrence of fetal injury. However, inferences have been largely based on the results of in vitro experiments, and extrapolation of such findings to the clinical setting warrants caution. Fetal defecation throughout gestation appears to be a physiologic phenomenon based on ultrasound as well as in observations in animals.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Meconium Aspiration Syndrome; Meconium; Amniotic Fluid; Chorioamnionitis; Pregnancy Complications; Inflammation; Heme
PubMed: 37012128
DOI: 10.1016/j.ajog.2022.11.1283 -
Biomedicine & Pharmacotherapy =... Feb 2023Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by skin photosensitivity caused by accumulation of protoporphyrin IX. We aimed to... (Review)
Review
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by skin photosensitivity caused by accumulation of protoporphyrin IX. We aimed to review the clinical evidence of efficacy and safety of skin photosensitivity treatments in individuals with EPP or XLP. We systematically searched MEDLINE, Embase, the Cochrane Library, and ClinicalTrials.gov. A total of 40 studies with data on 18 treatment modalities were included. Comprehensive treatment safety data were obtained from the European Medicines Agency and the United States Food and Drug Administration. The studies used different outcome measures to evaluate the sensitivity without a generally accepted method to assess treatment effect on skin photosensitivity. Of the included studies, 13 were controlled trials. Gathered, the trials showed moderate positive effect of inorganic sunscreen application and subcutaneous implant of afamelanotide and no effect of organic sunscreen application, or oral treatment with beta-carotene, cysteine, N-acetylcysteine, vitamin C, or warfarin. Studies without control groups suggested treatment effect of foundation cream, dihydroxyacetone/lawsone cream, narrow-band ultraviolet B phototherapy, erythrocyte transfusion, extracorporeal erythrocyte photodynamic therapy, or oral treatment with zinc sulphate, terfenadine, cimetidine, or canthaxanthin, but the real effect is uncertain. Assessment of treatment effect on photosensitivity in patients with EPP or XLP carries a high risk of bias since experienced photosensitivity varies with both weather conditions, exposure pattern, and pigmentation. Controlled trials of promising treatment options are important although challenging in this small patient population.
Topics: United States; Humans; Protoporphyria, Erythropoietic; Sunscreening Agents; Photosensitivity Disorders; Genetic Diseases, X-Linked; Protoporphyrins
PubMed: 36525819
DOI: 10.1016/j.biopha.2022.114132 -
Acta Ophthalmologica Mar 2023Treatment of chronic central serous chorioretinopathy (cCSC) remains a topic of controversy. As cCSC is a disease that can wax and wane, treatment efficacy is difficult... (Meta-Analysis)
Meta-Analysis Review
Treatment of chronic central serous chorioretinopathy (cCSC) remains a topic of controversy. As cCSC is a disease that can wax and wane, treatment efficacy is difficult to assess especially when trials compare active treatments without any placebo/control group. In this study, we systematically reviewed short-term efficacies of any cCSC treatment tested in randomized controlled trials (RCT) and employed network meta-analyses to compare to non-treatment controls. We searched 11 literature databases on 20 March 2022 for RCTs of treatment of cCSC. We identified 17 RCTs including a total of 1172 eyes. Treatments included conventional laser (44 eyes), half-dose or half-fluence photodynamic therapy (PDT) (298 eyes), ranibizumab (16 eyes), antioxidants (50 eyes), mineralocorticoid receptor antagonists (187 eyes), rifampicin (91 eyes), selective retina therapy (SRT) (67 eyes) and subthreshold micropulse laser (192 eyes). Compared with controls, significant benefit on complete subretinal fluid resolution was only obtained from half-dose or half-fluence PDT (OR: 20.6; 95% CI: 6.3-66.7; p < 0.0001) and conventional laser (OR: 36.4; 95% CI: 2.0-655.7; p = 0.015), and at an order of magnitude lower degree from SRT (OR: 3.4; 95% CI: 1.7-6.8; p = 0.00075). Compared with controls and after sensitivity analyses, significant benefit in the change in best-corrected visual acuity was only obtained by half-dose/-fluence PDT (-0.13 logMAR; 95% CI: -0.20 to -0.06 logMAR; p = 0.00021). In conclusion, three treatment options provide significant improvement over no treatment: half-dose/-fluence PDT, conventional laser and to a much lesser degree SRT. Considering that conventional laser can only be applied for extrafoveal leaks, and the long-term data available for PDT-based treatments finding persisting treatment results, half-dose or half-fluence PDT is the only viable treatment option for patients with cCSC. Shortage issues with verteporfin should not lead to employment of ineffective treatment modalities, as they put patients at unnecessary risk of adverse events.
Topics: Humans; Photosensitizing Agents; Central Serous Chorioretinopathy; Photochemotherapy; Network Meta-Analysis; Porphyrins; Visual Acuity; Fluorescein Angiography; Treatment Outcome; Tomography, Optical Coherence; Chronic Disease; Randomized Controlled Trials as Topic
PubMed: 36178171
DOI: 10.1111/aos.15263 -
PloS One 2022Actovegin is a hemodialysate of calf's blood and has been used for several decades in the countries of Central Asia, East Asia, Russia and some European countries. It...
BACKGROUND
Actovegin is a hemodialysate of calf's blood and has been used for several decades in the countries of Central Asia, East Asia, Russia and some European countries. It has been used to treat patients with various neurological conditions, vascular disorders, and ischemic stroke.
OBJECTIVES
To perform a systematic review to evaluate the effect of Actovegin in patients who have suffered an ischemic stroke.
METHODS
A search of MEDLINE, PubMed, Cochrane and Embase was carried out from inception to October 10, 2021 for clinical trials and observational studies with a control group, published in English or Russian.
RESULTS
Of 220 identified unique records, 84 full-text articles were screened, and 5 studies were selected that met the inclusion criteria. This included 4 observational studies with control groups and one randomized, placebo-controlled clinical trial. These studies enrolled a total of 3879 patients of which 720 patients received Actovegin administered intravenously and/or orally for a duration ranging from 10 to 180 days. Because of study heterogeneity, meta-analysis was not performed. No consistent evidence on improved survival, quality of life, neurologic symptoms, activities of daily living or disability was identified. One study showed statistically significant improvements in the Alzheimer's Disease Assessment Scale, cognitive subscale, extended version (ADAS-cog+) for Actovegin compared with placebo at 6 months but the clinical relevance of this change is uncertain. One study reported a higher incidence of recurrent ischemic stroke, transient ischemic attack or intracerebral hemorrhage in patients taking Actovegin compared to placebo.
CONCLUSIONS
The benefits of Actovegin are uncertain and that there is potential risk of harm in patients with stroke. More evidence is needed from rigorously designed clinical trials to justify the role of Actovegin in patients with ischemic stroke.
Topics: Activities of Daily Living; Heme; Humans; Ischemic Attack, Transient; Ischemic Stroke; Observational Studies as Topic; Quality of Life; Randomized Controlled Trials as Topic; Stroke
PubMed: 35771887
DOI: 10.1371/journal.pone.0270497 -
Cancers Jun 2022Acute porphyrias are a group of metabolic disorders resulting in defective porphyrin synthesis and reduced heme production, which carries a risk of malignancy.... (Review)
Review
Acute porphyrias are a group of metabolic disorders resulting in defective porphyrin synthesis and reduced heme production, which carries a risk of malignancy. Porphyrias are inborn defects in the heme biosynthesis pathway resulting in neurovisceral manifestations and cutaneous photosensitivity attacks with multi-systemic involvement. Its estimated prevalence nears 5 per 100,000 patients worldwide. Subclinical liver disease is common, which can progress into transaminitis, fibrosis, cirrhosis, and malignancy. However, data on the incidence of primary liver cancer are lacking. We aim to determine the risk of hepatocellular carcinoma (HCC) in patients with porphyria. A systematic review and pooled analysis were conducted through 2021 on studies assessing blood tests, imaging, cancer development, liver transplant, surgical resection, and outcomes in porphyria. In total, 19 studies, which included 7381 patients with porphyria (3476 females), were considered for the final review. In eight studies, alpha-fetoprotein levels were elevated between 200 and 1000 IU/mL. Of the total cohort of patients with porphyria, primary liver cancer was diagnosed in 351 patients (4.8%), of whom 243 (3.3% of the total) were found to have HCC. A subset of patients was found to have cholangiocarcinoma ( = 18; 0.3% of the total). Interestingly, advanced liver disease or cirrhosis was not a prerequisite for the formation of HCC in a small group of patients. Of the total cohort, 30 patients underwent liver resection, 48 patients underwent liver transplantation, and 327 patients died. Patients with porphyria are at risk of developing primary liver malignancy. Further studies should aim to develop diagnostic and prognostic models aimed at the early detection of HCC in porphyria.
PubMed: 35740611
DOI: 10.3390/cancers14122947 -
PloS One 2022Heme-oxygenase 1 (HMOX1) is a critical stress response gene that catalyzes the multistep oxidation of heme. A GT(n) repeat of variable length in the promoter in has been...
INTRODUCTION
Heme-oxygenase 1 (HMOX1) is a critical stress response gene that catalyzes the multistep oxidation of heme. A GT(n) repeat of variable length in the promoter in has been associated with a wide range of human diseases, including infections. This paper aims to summarise and systematically review associations between the length of the HMOX1 GT(n) promoter and infectious disease in humans.
METHODS
A search using relevant terms was performed in PubMED and EMBASE through to 15/01/21 identifying all research that studied an association between the HMOX1 GT(n) repeat polymorphism and the incidence and/or outcome of any human infectious disease. Citations were screened for additional studies. Potential studies were screened for inclusion by two authors. Data was extracted on allele frequency, genotype, strength of association, mechanism of genotyping, and potential biases. A narrative review was performed across each type of infection.
RESULTS
1,533 studies were identified in the search, and one via citation screening. Sixteen studies were ultimately included, seven in malaria, three in HIV, three in sepsis, and one each in pneumonia, hepatitis C, and acute respiratory distress syndrome (ARDS). Sample sizes for nearly all studies were small (biggest study, n = 1,646). Allelic definition was different across all included studies. All studies were at some risk of bias. In malaria, three studies suggested that longer alleles were associated with reduced risk of severe malaria, particularly malaria-induced renal dysfunction, with four studies identifying a null association. In sepsis, two studies suggested an association with longer alleles and better outcomes.
CONCLUSIONS
Despite the importance of HMOX1 in survival from infection, and the association between repeat length and gene expression, the clinical data supporting an association between repeat length and incidence and/or outcome of infection remain inconclusive.
Topics: Communicable Diseases; Genetic Predisposition to Disease; Heme; Heme Oxygenase-1; Humans; Polymorphism, Genetic; Sepsis
PubMed: 35551540
DOI: 10.1371/journal.pone.0267399 -
The Cochrane Database of Systematic... Aug 2021Traditionally, amalgam has been used for filling cavities in posterior teeth, and it continues to be the restorative material of choice in some low- and middle-income... (Review)
Review
BACKGROUND
Traditionally, amalgam has been used for filling cavities in posterior teeth, and it continues to be the restorative material of choice in some low- and middle-income countries due to its effectiveness and relatively low cost. However, there are concerns over the use of amalgam restorations (fillings) with regard to mercury release in the body and the environmental impact of mercury disposal. Dental composite resin materials are an aesthetic alternative to amalgam, and their mechanical properties have developed sufficiently to make them suitable for restoring posterior teeth. Nevertheless, composite resin materials may have potential for toxicity to human health and the environment. The United Nations Environment Programme has established the Minamata Convention on Mercury, which is an international treaty that aims "to protect the [sic] human health and the environment from anthropogenic emissions and releases of mercury and mercury compounds". It entered into force in August 2017, and as of February 2021 had been ratified by 127 governments. Ratification involves committing to the adoption of at least two of nine proposed measures to phase down the use of mercury, including amalgam in dentistry. In light of this, we have updated a review originally published in 2014, expanding the scope of the review by undertaking an additional search for harms outcomes. Our review synthesises the results of studies that evaluate the long-term effectiveness and safety of amalgam versus composite resin restorations, and evaluates the level of certainty we can have in that evidence.
OBJECTIVES
To examine the effects (i.e. efficacy and safety) of direct composite resin fillings versus amalgam fillings.
SEARCH METHODS
An information specialist searched five bibliographic databases up to 16 February 2021 and used additional search methods to identify published, unpublished and ongoing studies SELECTION CRITERIA: To assess efficacy, we included randomised controlled trials (RCTs) comparing dental composite resin with amalgam restorations in permanent posterior teeth that assessed restoration failure or survival at follow-up of at least three years. To assess safety, we sought non-randomised studies in addition to RCTs that directly compared composite resin and amalgam restorative materials and measured toxicity, sensitivity, allergy, or injury.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included a total of eight studies in this updated review, all of which were RCTs. Two studies used a parallel-group design, and six used a split-mouth design. We judged all of the included studies to be at high risk of bias due to lack of blinding and issues related to unit of analysis. We identified one new trial since the previous version of this review (2014), as well as eight additional papers that assessed safety, all of which related to the two parallel-group studies that were already included in the review. For our primary meta-analyses, we combined data from the two parallel-group trials, which involved 1645 composite restorations and 1365 amalgam restorations in 921 children. We found low-certainty evidence that composite resin restorations had almost double the risk of failure compared to amalgam restorations (risk ratio (RR) 1.89, 95% confidence interval (CI) 1.52 to 2.35; P < 0.001), and were at much higher risk of secondary caries (RR 2.14, 95% CI 1.67 to 2.74; P < 0.001). We found low-certainty evidence that composite resin restorations were not more likely to result in restoration fracture (RR 0.87, 95% CI 0.46 to 1.64; P = 0.66). Six trials used a split-mouth design. We considered these studies separately, as their reliability was compromised due to poor reporting, unit of analysis errors, and variability in methods and findings. Subgroup analysis showed that the findings were consistent with the results of the parallel-group studies. Three trials investigated possible harms of dental restorations. Higher urinary mercury levels were reported amongst children with amalgam restorations in two trials, but the levels were lower than what is known to be toxic. Some differences between amalgam and composite resin groups were observed on certain measures of renal, neuropsychological, and psychosocial function, physical development, and postoperative sensitivity; however, no consistent or clinically important harms were found. We considered that the vast number of comparisons made false-positive results likely. There was no evidence of differences between the amalgam and composite resin groups in neurological symptoms, immune function, and urinary porphyrin excretion. The evidence is of very low certainty, with most harms outcomes reported in only one trial.
AUTHORS' CONCLUSIONS
Low-certainty evidence suggests that composite resin restorations may have almost double the failure rate of amalgam restorations. The risk of restoration fracture does not seem to be higher with composite resin restorations, but there is a much higher risk of developing secondary caries. Very low-certainty evidence suggests that there may be no clinically important differences in the safety profile of amalgam compared with composite resin dental restorations. This review supports the utility of amalgam restorations, and the results may be particularly useful in parts of the world where amalgam is still the material of choice to restore posterior teeth with proximal caries. Of note, however, is that composite resin materials have undergone important improvements in the years since the trials informing the primary analyses for this review were conducted. The global phase-down of dental amalgam via the Minamata Convention on Mercury is an important consideration when deciding between amalgam and composite resin dental materials. The choice of which dental material to use will depend on shared decision-making between dental providers and patients in the clinic setting, and local directives and protocols.
Topics: Bias; Child; Composite Resins; Dental Amalgam; Dental Caries; Dentition, Permanent; Humans; Randomized Controlled Trials as Topic
PubMed: 34387873
DOI: 10.1002/14651858.CD005620.pub3 -
International Journal of Molecular... Apr 2020Stroke is one of the largest problems and clinical-social challenges within neurology and, in general, pathology. Here, we briefly reviewed the main pathophysiological...
BACKGROUND
Stroke is one of the largest problems and clinical-social challenges within neurology and, in general, pathology. Here, we briefly reviewed the main pathophysiological mechanisms of ischemic stroke, which represent targets for medical interventions, including for a calf blood deproteinized hemodialysate/ultrafiltrate.
METHODS
We conducted a systematic review of current related literature concerning the effects of Actovegin, of mainly the pleiotropic type, applied to the injury pathways of ischemic stroke.
RESULTS
The bibliographic resources regarding the use of Actovegin in ischemic stroke are scarce. The main Actovegin actions refer to the ischemic stroke lesion items' ensemble, targeting tissue oxidation, energy metabolism, and glucose availability through their augmentation, combating ischemic processes and oxidative stress, and decreasing inflammation (including with modulatory connotations, by the nuclear factor-κB pathway) and apoptosis-like processes, counteracting them by mitigating the caspase-3 activation induced by amyloid β-peptides.
CONCLUSION
Since no available therapeutic agents are capable of curing the central nervous system's lesions, any contribution, such as that of Actovegin (with consideration of a positive balance between benefits and risks), is worthy of further study and periodic reappraisal, including investigation into further connected aspects.
Topics: Amyloid beta-Peptides; Animals; Antioxidants; Brain Ischemia; Heme; Humans; Stroke
PubMed: 32365943
DOI: 10.3390/ijms21093181