CoFeSe2 @DMSA@FA Nanocatalyst for Amplification of Oxidative Stress to Achieve Multimodal Tumor Therapy.

Nanomedicine has significantly advanced precise tumor therapy, providing essential technical blessing for active drug accumulation, targeted consignment, and mitigation of noxious side effects. To enhance anti-tumor efficacy, the integration of multiple therapeutic modalities has garnered significant attention. Here, we designed an innovative CoFeSe2 @DMSA@FA nanocatalyst with Se vacancies (abbreviated as CFSDF), which exhibits synergistic chemodynamic therapy (CDT) and photothermal therapy (PTT), leading to amplified tumor oxidative stress and enhanced photothermal effects. The multifunctional CFSDF nanocatalyst exhibits the remarkable ability to catalyze the Fenton reaction within the acidic tumor microenvironment, efficiently converting hydrogen peroxide (H2 O2 ) into highly harmful hydroxyl radicals (⋅OH). Moreover, the nanocatalyst effectively diminishes GSH levels and ameliorates intracellular oxidative stress. The incorporation of FA modification enables CFSDF to evade immune detection and selectively target tumor tissues. Numerous in vitro and in vivo investigations have consistently demonstrated that CFSDF optimizes its individual advantages and significantly enhances therapeutic efficiency through synergistic effects of multiple therapeutic modalities, offering a valuable and effective approach to cancer treatment.

Outbreak of lead poisoning from a civilian indoor firing range in the UK.

INTRODUCTION: Lead exposure from discharged lead dust is a recognised risk at firing ranges. We report a lead poisoning outbreak among staff and their close contacts at a UK civilian indoor 24 m firing range. METHODS: A retrospective review was undertaken of data collected on all patients at risk of lead poisoning identified either by direct referral to the Clinical Toxicology clinicians at the West Midlands Poisons Unit, or via the Trace Elements Supra-Regional Assay Service Laboratory at Sandwell hospital. RESULTS: Eighty-seven patients were identified as having possible lead exposure, either at the firing range or via close contacts. Of these, 63 patients aged between 6 months and 78 years attended for blood lead concentration (BLC) testing. The highest BLC at presentation was 11.7 µmol/L (242 µg/dL). Only nine patients reported any symptoms at presentation. Fifteen patients received lead chelation therapy with oral dimercaptosuccinic acid (or succimer) 30 mg/kg/day or intravenous sodium calcium edetate (EDTA) 75 mg/kg/day, dependent on stock availability. DISCUSSION: This report highlights the need for vigilance of lead poisoning as an occupational hazard in the UK, including at recreational facilities such as indoor firing ranges. It emphasises the importance of regulation of lead exposure in the workplace, particularly given the vague symptoms of lead poisoning, and proposes re-appraisal of UK legislation. This report also highlights potential issues surrounding stock availability of rarely used antidotes for uncommon presentations in the event of an outbreak of poisoning.

Evidence-based clinical practice guideline for management of urinary tract infection and primary vesicoureteric reflux.

We present updated, evidence-based clinical practice guidelines from the Indian Society of Pediatric Nephrology (ISPN) for the management of urinary tract infection (UTI) and primary vesicoureteric reflux (VUR) in children. These guidelines conform to international standards; Institute of Medicine and AGREE checklists were used to ensure transparency, rigor, and thoroughness in the guideline development. In view of the robust methodology, these guidelines are applicable globally for the management of UTI and VUR. Seventeen recommendations and 18 clinical practice points have been formulated. Some of the key recommendations and practice points are as follows. Urine culture with > 104 colony forming units/mL is considered significant for the diagnosis of UTI in an infant if the clinical suspicion is strong. Urine leukocyte esterase and nitrite can be used as an alternative screening test to urine microscopy in a child with suspected UTI. Acute pyelonephritis can be treated with oral antibiotics in a non-toxic infant for 7-10 days. An acute-phase DMSA scan is not recommended in the evaluation of UTI. Micturating cystourethrography (MCU) is indicated in children with recurrent UTI, abnormal kidney ultrasound, and in patients below 2 years of age with non-E. coli UTI. Dimercaptosuccinic acid scan (DMSA scan) is indicated only in children with recurrent UTI and high-grade (3-5) VUR. Antibiotic prophylaxis is not indicated in children with a normal urinary tract after UTI. Prophylaxis is recommended to prevent UTI in children with bladder bowel dysfunction (BBD) and those with high-grade VUR. In children with VUR, prophylaxis should be stopped if the child is toilet trained, free of BBD, and has not had a UTI in the last 1 year. Surgical intervention in high-grade VUR can be considered for parental preference over antibiotic prophylaxis or in children developing recurrent breakthrough febrile UTIs on antibiotic prophylaxis.

Exstrophy-epispadias complex: are the kidneys and kidney function spared?

BACKGROUND: Exstrophy-epispadias complex (EEC) is a complex malformation of the lower abdominal wall, bladder, and pelvic floor, which necessitates multiple successive reconstruction procedures. Surgical and infectious complications are frequent. Our aim was to evaluate kidney function in these patients. METHODS: This cross-sectional study included patients with EEC, followed since birth in a pediatric urology clinic, who underwent nephrological evaluation (blood pressure (BP) measurement and blood and urine chemistries) and imaging studies (urinary tract ultrasound and DMSA kidney scan) during 2017-2020. RESULTS: Forty-three patients (29 males), median age 9 years (interquartile range 6-19), were included. Eleven (26%) used clean intermittent catheterization (CIC) for bladder drainage. At least one sign of kidney injury was identified in 32 (74%) patients; elevated BP, decreased kidney function (estimated glomerular filtration rate (eGFR) < 90 ml/min/1.73 m2), and proteinuria/albuminuria were detected in 29%, 12%, and 36% of patients, respectively. Urinary tract dilatation (UTD) was found in 13 (37%) ultrasound examinations. Parenchymal kidney defects were suspected in 46% and 61% of ultrasound and DMSA scintigraphy, respectively. UTD was significantly associated with DMSA-proven kidney defects (p = 0.043) and with elevated BP, 39% vs. 20% in those without UTD. Decreased eGFR and elevated BP were less frequent among patients on CIC than among patients who voided spontaneously: 10% vs. 14% and 18% vs. 36%, respectively. Recurrent UTIs/bacteriuria and nephro/cystolithiasis were reported by 44% and 29% patients, respectively. CONCLUSION: The high rate of signs of kidney injury in pediatric patients with EEC dictates early-onset long-term kidney function monitoring by joint pediatric urological and nephrological teams. A higher resolution version of the Graphical abstract is available as Supplementary information.

Membranous nephropathy caused by dimercaptosuccinic acid in a patient with Wilson's disease: a case report and literature review.

BACKGROUND: Dimercaptosuccinic acid (DMSA) therapy is a kind of chelation therapy for patients with Wilson 's disease (WD). While there have been reports of side effects associated with DMSA, the development of membranous nephropathy as a result of this therapy is uncommon. CASE PRESENTATION: We present a case of a 19-year-old male patient with Wilson's disease who experienced proteinuria while receiving long-term DMSA treatment. Further evaluation revealed abnormally low levels of serum ceruloplasmin and serum albumin, as well as a 24-hour urinary protein excretion of 4599.98 mg/24 h. A renal biopsy confirmed the presence of membranous nephropathy. After ruling out other potential causes, we determined that the patient's membranous nephropathy was likely caused by DMSA. Following treatment with glucocorticoids, there was a significant reduction in proteinuria. CONCLUSION: This case highlights the possibility of DMSA-induced membranous nephropathy and the importance of considering this diagnosis in patients receiving DMSA treatment. Given the widespread use of DMSA in the treatment of Wilson's disease, further research is needed to fully understand the potential role of this drug in the development of membranous nephropathy.

Detecting visual texture patterns in binary sequences through pattern features.

We measured human ability to detect texture patterns in a signal detection task. Observers viewed sequences of 20 blue or yellow tokens placed horizontally in a row. They attempted to discriminate sequences generated by a random generator ("a fair coin") from sequences produced by a disrupted Markov sequence (DMS) generator. The DMSs were generated in two stages: first a sequence was generated using a Markov chain with probability, pr = 0.9, that a token would be the same color as the token to its left. The Markov sequence was then disrupted by flipping each token from blue to yellow or vice versa with probability, pd-the probability of disruption. Disruption played the role of noise in signal detection terms. We can frame what observers are asked to do as detecting Markov texture patterns disrupted by noise. The experiment included three conditions differing in pd (0.1, 0.2, 0.3). Ninety-two observers participated, each in only one condition. Overall, human observers' sensitivities to texture patterns (d' values) were markedly less than those of an optimal Bayesian observer. We considered the possibility that observers based their judgments not on the entire texture sequence but on specific features of the sequences such as the length of the longest repeating subsequence. We compared human performance with that of multiple optimal Bayesian classifiers based on such features. We identify the single- and multiple-feature models that best match the performance of observers across conditions and develop a pattern feature pool model for the signal detection task considered.

The Induction of Long-Term Potentiation by Medial Septum Activation under Urethane Anesthesia Can Alter Gene Expression in the Hippocampus.

We studied changes in the expression of early genes in hippocampal cells in response to stimulation of the dorsal medial septal area (dMSA), leading to long-term potentiation in the hippocampus. Rats under urethane anesthesia were implanted with stimulating electrodes in the ventral hippocampal commissure and dMSA and a recording electrode in the CA1 area of the hippocampus. We found that high-frequency stimulation (HFS) of the dMSA led to the induction of long-term potentiation in the synapses formed by the ventral hippocampal commissure on the hippocampal CA1 neurons. One hour after dMSA HFS, we collected the dorsal and ventral hippocampi on both the ipsilateral (damaged by the implanted electrode) and contralateral (intact) sides and analyzed the expression of genes by qPCR. The dMSA HFS led to an increase in the expression of bdnf and cyr61 in the ipsilateral hippocampi and egr1 in the ventral contralateral hippocampus. Thus, dMSA HFS under the conditions of degeneration of the cholinergic neurons in the medial septal area prevented the described increase in gene expression. The changes in cyr61 expression appeared to be dependent on the muscarinic M1 receptors. Our data suggest that the induction of long-term potentiation by dMSA activation enhances the expression of select early genes in the hippocampus.

Clinical Spectrum of Mercury Poisoning in India: Case-series from a Poison Control Center.

BACKGROUND: Mercury is a naturally occurring heavy metal that finds wide application in industrial and household settings. It exists in three chemical forms which include elemental (Hg0 ), inorganic mercurous (Hg+) or mercuric (Hg++) salts, and organic compounds. All forms are highly toxic, particularly to the nervous, gastrointestinal, and renal systems. Common circumstances of exposure include recreational substance use, suicide or homicide attempts, occupational hazards, traditional medicines, and endemic food ingestions as witnessed in the public health disasters in Minamata Bay, Japan and in Iraq. Poisoning can result in death or long-term disabilities. Clinical manifestations vary with chemical form, dose, rate, and route of exposure. AIMS AND OBJECTIVES: To summarize the incidence of mercury poisoning encountered at an Indian Poison Center and use three cases to highlight the marked variations observed in clinical manifestations and long-term outcomes among poisoned patients based on differences in chemical forms and routes of exposure to mercury. MATERIALS AND METHODS: A structured retrospective review of the enquiry-database of the Poison Information Center and medical records of patients admitted between August 2019 and August 2021 in a tertiary care referral center was performed. All patients with reported exposure to mercury were identified. We analyzed clinical data and laboratory investigations which included heavy metal (arsenic, mercury, and lead) estimation in whole blood and urine samples. Additionally, selected patients were screened for serum voltage-gated potassium ion channels (VGKC)- contactin-associated protein-like 2 (CASPR2) antibodies. Three cases with a classical presentation were selected for detailed case description. RESULTS: Twenty-two cases were identified between August 2019 and August 2021. Twenty (91%) were acute exposures while two (9%) were chronic. Of these, three representative cases have been discussed in detail. Case 1 is a 3.5-year-old girl who was ought to the emergency department with suspected elemental-mercury ingestion after biting a thermometer. Clinical examination was unremarkable. Chest and abdominal radiography revealed radiodense material in the stomach. Subsequent serial radiographs documented distal intestinal transit of the radiodense material. The child remained asymptomatic. This case exemplifies the largely nontoxic nature of elemental mercury ingestion as it is usually not absorbed from the gastrointestinal tract. Case 2 is a 27-year-old lady who presented with multiple linear nodules over both upper limbs after receiving a red intravenous injection for anemia. Imaging revealed metallic-density deposits in viscera and bones. Nodular biopsy was suggestive of mercury granulomas. A 24-hour urine mercury levels were elevated. She was advised chelation therapy with oral dimercaptosuccinic acid (DMSA). Case 3 is a 22-year-old lady who presented with acrodynia, neuromyotonia, tremulousness, postural giddiness, tachycardia, and hypertension for 2 months, associated with intractable, diffuse burning pain over the buttocks and both lower limbs, 1 month after completing a 3-week course of traditional medications for polycystic ovarian syndrome. A 24-hour urine normetanephrine levels and mercury levels were markedly elevated. Serum anti-VGKC antibodies were present. She was treated with glucocorticoids and oral DMSA with a favorable clinical response. CONCLUSIONS: The clinical manifestations of mercury toxicity are highly variable depending on the source, form, and route of mercury exposure and are related to its toxicokinetics.

Update on dermatomyositis.

PURPOSE OF REVIEW: This review summarizes and comments on current knowledge in dermatomyositis. RECENT FINDINGS: The 2018 European Neuromuscular Centre classification of dermatomyositis has been challenging by the discovery of clinicopathological features associated with dermatomyositis-specific antibody (DMSA) that were not incorporated in the original criteria. These features include but may not be limited to the presence of perifascicular necrosis in anti-Mi-2 dermatomyositis; presence of diffuse nonperifascicular sarcoplasmic myxovirus resistance protein A expression in anti-MDA5 dermatomyositis; and dermatomyositis sine dermatitis in anti-NXP-2 dermatomyositis. Variations and subclassifications within the same DMSA subtypes are observed: anti-MDA5 dermatomyositis is clinically subcategorized into good, intermediate, and poor prognostic subgroups; concurrent anti-CCAR1 and anti-TIF1-γ positivity identify anti-TIF1-γ-positive patient with a lower risk for cancer-associated myositis. Owing to distinct IFN1-signaling pathway activation in dermatomyositis, JAK-STAT inhibitor - the pathway-targeted therapy, have been studied with promising results in refractory dermatomyositis and some new-onset dermatomyositis. In addition, the potential serum biomarkers for IFN1 pathway activation are being investigated for their performance in monitoring the disease activity and the efficacy of the treatment. SUMMARY: DMSA, evidence of prominent IFN1 pathway activation, and risk/severity-associated biomarkers would likely play major roles in future dermatomyositis classification, disease monitoring, and treatment decision.

Chemistry, Pharmacology, and Toxicology of Monoisoamyl Dimercaptosuccinic Acid: A Chelating Agent for Chronic Metal Poisoning.

Arsenic, a metalloid, is known to cause deleterious effects in various body organs, particularly the liver, urinary bladder, and brain, and these effects are primarily mediated through oxidative stress. Chelation therapy has been considered one of the promising medical treatments for arsenic poisoning. Meso 2,3- dimercaptosuccinic acid (DMSA) has been recognized as one of the most effective chelating drugs to treat arsenic poisoning. However, the drug is compromised with a number of shortcomings, including the inability to treat chronic arsenic poisoning due to its extracellular distribution. Monoisoamyl 2,3-dimercaptosuccinic acid, one of the analogues of meso 2,3-dimeraptosuccinic acid (DMSA), is a lipophilic chelator and has shown promise to be considered as a potential future chelating agent/antidote not only for arsenic but also for a few other heavy metals like lead, mercury, cadmium, and gallium arsenide. The results from numerous studies carried out in the recent past, mainly from our group, strongly support the clinical application of MiADMSA. This review paper summarizes most of the scientific details including the chemistry, pharmacology, and safety profile of MiADMSA. The efficacy of MiADMSA mainly against arsenic toxicity but also a few other heavy metals was also discussed. We also reviewed a few other strategies in order to achieve the optimum effects of MiADMSA, like combination therapy using two chelating agents or coadministration of a natural and synthetic antioxidant (including phytomedicine) along with MiADMSA for treatment of metal/metalloid poisoning. We also briefly discussed the use of nanotechnology (nano form of MiADMSA i.e. nano-MiADMSA) and compared it with bulk MiADMSA. All these strategies have been shown to be beneficial in getting more pronounced therapeutic efficacy of MiADMSA, as an adjuvant or as a complementary agent, by significantly increasing the chelating efficacy of MiADMSA.

Comparison of renal parenchymal trauma after standard, mini and ultra-mini percutaneous tract dilation in porcine models.

OBJECTIVE: To evaluate whether reducing tract dilation diameter in PCNL (percutaneous nephrolithotomy) procedures results in minimizing of renal trauma of the percutaneous tract. METHODS: A percutaneous renal access tract was established bilaterally to 11 pigs. Two pigs were euthanized immediately after the experiment, while nine pigs were sacrificed 1 month later. The percutaneous accesses were dilated up to 30Fr, 22Fr or 12Fr. The animals underwent a contrast-enhanced computer tomography immediately after the procedure and 30 days later. DMSA-scintigraphy with SPECT-CT was also performed. The kidneys of all animals were harvested for histological evaluation. The volume of scar tissue and the percentage of renal volume replaced by scar tissue were calculated. RESULTS: Immediate post-procedural CT-scans revealed a significant difference in defect diameter among the three modalities. However, the scar volume calculated on CT-images and histopathology showed a significant difference only when 30Fr dilation was compared to 12Fr dilation. The percentage of scar volume was negligible in all cases, but there was still a statistical difference between 30 and 12Fr dilation. Dilation up to 22Fr revealed no statistical differences compared to the other two modalities. DMSA-scintigraphy showed no scar tissue in any case. CONCLUSION: Dilation up to 30Fr may cause a significantly larger scar tissue on renal parenchyma compared to 12Fr dilation as it was shown on CT-images and microscopic evaluation, but based on the DMSA/SPECT-CT this difference seems to be insignificant to the renal function. The scar tissue caused by 22Fr dilation seemed to have no significant difference from the other modalities.

Different coatings on magnetic nanoparticles dictate their degradation kinetics in vivo for 15 months after intravenous administration in mice.

BACKGROUND: The surface coating of iron oxide magnetic nanoparticle (MNPs) drives their intracellular trafficking and degradation in endolysosomes, as well as dictating other cellular outcomes. As such, we assessed whether MNP coatings might influence their biodistribution, their accumulation in certain organs and their turnover therein, processes that must be understood in vivo to optimize the design of nanoformulations for specific therapeutic/diagnostic needs. RESULTS: In this study, three different MNP coatings were analyzed, each conferring the identical 12 nm iron oxide cores with different physicochemical characteristics: 3-aminopropyl-triethoxysilane (APS), dextran (DEX), and dimercaptosuccinic acid (DMSA). When the biodistribution of these MNPs was analyzed in C57BL/6 mice, they all mainly accumulated in the spleen and liver one week after administration. The coating influenced the proportion of the MNPs in each organ, with more APS-MNPs accumulating in the spleen and more DMSA-MNPs accumulating in the liver, remaining there until they were fully degraded. The changes in the physicochemical properties of the MNPs (core size and magnetic properties) was also assessed during their intracellular degradation when internalized by two murine macrophage cell lines. The decrease in the size of the MNPs iron core was influenced by their coating and the organ in which they accumulated. Finally, MNP degradation was analyzed in the liver and spleen of C57BL/6 mice from 7 days to 15 months after the last intravenous MNP administration. CONCLUSIONS: The MNPs degraded at different rates depending on the organ and their coating, the former representing the feature that was fundamental in determining the time they persisted. In the liver, the rate of degradation was similar for all three coatings, and it was faster than in the spleen. This information regarding the influence of coatings on the in vivo degradation of MNPs will help to choose the best coating for each biomedical application depending on the specific clinical requirements.

MiADMSA abrogates sodium tungstate-induced oxidative stress in rats.

Tungsten (W) and its compounds have emerged as a relatively new area of environmental health concern in the last decade. Tungsten is environmentally benign due to its increasing use in armour-piercing munitions and as a replacement for lead in other ammunition. It has also been identified in various hazardous waste sites and therefore been proposed for inclusion in the Environmental Protection Agency National Priorities List. The major objective of this study was to evaluate the therapeutic efficacy of orally administered monoisoamyl 2, 3-dimercaptosuccinic acid (MiADMSA) against tungstate induced oxidative injury in blood, liver and kidneys of male Wistar rats. MiADMSA, a thiol chelator has gained wide recognition recently as a future chelating drug of choice specifically for arsenic and was chosen for this study as tungstate ions too have an affinity toward the -SH group thus, being less bioavailable in the body. We determined the effects of MiADMSA (50 mg/kg, p.o.) against sodium tungstate (500 ppm in drinking water, daily for 28 days) induced biochemical changes indicative of oxidative stress in blood, and other soft tissues of of male Wistar rats. Tungsten exposure led to an increased levels of Reactive Oxygen Species (ROS) in liver, kidney, spleen and blood accompanied also by an increase in TBARS levels. The GSH: GSSG ratio also showed a decrease on sodium tungstate intoxication. Treatment with MiADMSA restored most of the sodium tungstate-induced alterations in the biomarkers suggestive of oxidative stress. These preliminary results led us to conclude that sub-acute exposure to tungstate-induced oxidative stress could be effectively reduced by the administration of MiADMSA and thus might be a promising antidote for studying in detail its efficacy in reducing body tungstate burden and its excretion post tungstate exposure.

Metal oxide-based macroporous ordered double affinity molecularly imprinted polymer for specific separation and enrichment of glycoprotein from food samples: a co-modification of DMSA and boronate affinity.

Metal oxide-based macroporous ordered double affinity molecularly imprinted polymers (D-MIPs) were developed as solid phase extraction (SPE) adsorbents for the specific identification of ovalbumin (OVA) under physiological pH conditions prior to ultraviolet visible (UV-vis) spectrophotometric detection. Herein, macroporous alumina (MA) was used as a matrix; dimercaptosuccinic acid (DMSA) and 3-aminophenylboric acid (APBA) were employed as dual-functional monomers; APBA is a self-polymerizing monomer. The effects of synthesis conditions, SPE conditions as well as selectivity, reproducibility, and reusability were studied. The co-modification of DMSA and boronate affinity renders the adsorbent exhibiting a high adsorption capacity (114.4 mg g-1) and short equilibrium time (30 min). The surface imprinting technology causes the adsorbent to have high selectivity towards OVA. The OVA recovery range is 91.1-99.6%. This study provides a promising method for the enrichment of OVA and other cis-diol-containing analytes in complex biological samples. A novel metal oxide-based macroporous ordered nanoparticle with a combination of DMSA and boronate affinity was successfully prepared for specific separation and enrichment of glycoprotein from complex biological samples.

A new recommendation for febrile urinary tract infection in children aged 2-24 months: Tepecik UTI Guideline-2.

AIM: Urinary tract infections (UTIs) represent a common febrile illness in infancy. The study compared two UTI guidelines in terms of number of imaging studies, presence of parenchymal damage and radiation exposure in patients with the first febrile UTI between 2 and 24 months of age. METHOD: The results of Tepecik UTI Guideline-1 used until 2012 (Group 1, n = 105) were retrospectively compared with Tepecik UTI Guideline-2 (Group 2) used after 2013. In Group 1, urinary tract ultrasonography (US), dimercaptosuccinic acid (DMSA) and voiding cystourethrography (VCUG) were made in all patients. In Group 2, if the US result was abnormal, patients were evaluated with VCUG and DMSA. If the US was normal, only DMSA was performed. If the DMSA was abnormal, the VCUG was undergone (n: 43, 40.9%). RESULTS: The abnormal VCUG detection rate was 69.2% in Group 1 and 30.8% in Group 2 (p = 0.09). Sensitivity and specificity of US in the diagnosis of vesicoureteral reflux (VUR) was 15.9% and 96.7% in Group 1 and 61.5% and 70.5% in Group 2, respectively. Abnormal DMSA findings were observed among 33.3% (Groups 1) and 66.7% (Groups 2) subjects, respectively (p > 0.05). The median radiation exposure (500 mrem) of patients in Group 1 was statistically significantly higher than those in Group 2 (200 mrem) (p < 0.001). CONCLUSION: The VCUG should not be the first examination to be considered in such patients. We think that Tepecik UTI Guideline-2 reduces unnecessary invasive procedure and radiation exposure and not missed VUR in the management of children with UTI at 2-24 months. Needs prospective follow-up studies before considering this recommendation.

Characteristics, Treatment, and Prognosis of Elemental Mercury Intoxication in Children: A Single-Center Retrospective Study.

OBJECTIVES: Mercury exposure is common and can be toxic, especially in children. Children are often drawn to elemental mercury because of its density, color, and proclivity to form beads. METHODS: We present data on 49 children with mercury intoxication (MI) and 60 children with mercury exposure from Turkey. RESULTS: The most common source of mercury was broken thermometer in schools. Inhaling mercury vapor was the most common route of exposure. The median exposure time was 6 (6-16) hours in the MI group, and the time to 1st symptoms was 10 (0-24) hours. In the MI group, the median blood mercury level was 21 µg/L (13-32.3), the median spot urine mercury level was 40 µg/L (7.66-78), and the median 24-hour urine mercury level was 25.8 µg/L (11-64). The most common symptoms in patients with MI were malaise, muscle pain, muscle cramps, abdominal pain, nausea, headache, and decreased appetite. The patients were treated with n-acetyl cysteine, 2,3-dimercaptopropane sulfonic acid, D-penicillamine, and meso 2,3-dimercaptosuccinic acid. A positive correlation was found between exposure time and urinary mercury level in the MI group (r = 0.793, P < 0.001). A positive moderate correlation was found between exposure time and blood level in the mercury exposure group (r = 0.535, P < 0.00). The neurological and systemic examinations of patients were all normal at the 1st follow-up visit 1 month after discharge. CONCLUSIONS: Diagnosis, removal of the exposure source, and use of chelation therapy can result in complete resolution of the signs and symptoms of MI.

Biomimetic Antidote Nanoparticles: a Novel Strategy for Chronic Heavy Metal Poisoning.

Chronic lead poisoning has become a major factor in global public health. Chelation therapy is usually used to manage lead poisoning. Dimercaptosuccinic acid (DMSA) is a widely used heavy metal chelation agent. However, DMSA has the characteristics of poor water solubility, low oral bioavailability, and short half-life, which limit its clinical application. Herein, a long-cycle slow-release nanodrug delivery system was constructed. We successfully coated the red blood cell membrane (RBCM) onto the surface of dimercaptosuccinic acid polylactic acid glycolic acid copolymer (PLGA) nanoparticles (RBCM-DMSA-NPs), which have a long cycle and detoxification capabilities. The NPs were characterized and observed by particle size meters and transmission electron microscopy. The results showed that the particle size of RBCM-DMSA-NPs was approximately 146.66 ± 2.41 nm, and the zeta potential was - 15.34 ± 1.60 mV. The homogeneous spherical shape and clear core-shell structure of the bionic nanoparticles were observed by transmission electron microscopy. In the animal tests, the area under the administration time curve of RBCM-DMSA-NPs was 156.52 ± 2.63 (mg/L·h), which was 5.21-fold and 2.36-fold that of free DMSA and DMSA-NPs, respectively. Furthermore, the median survival of the RBCM-DMSA-NP treatment group (47 days) was 3.61-fold, 1.32-fold, and 1.16-fold for the lead poisoning group, free DMSA, and DMSA-NP groups, respectively. The RBCM-DMSA-NP treatment significantly extended the cycle time of the drug in the body and improved the survival rate of mice with chronic lead poisoning. Histological analyses showed that RBCM-DMSA-NPs did not cause significant systemic toxicity. These results indicated that RBCM-DMSA-NPs could be a potential candidate for long-term chronic lead exposure treatment.

Apigenin-Loaded PLGA-DMSA Nanoparticles: A Novel Strategy to Treat Melanoma Lung Metastasis.

The flavone apigenin (APG), alone as well as in combination with other chemotherapeutic agents, is known to exhibit potential anticancer effects in various tumors and inhibit growth and metastasis of melanoma. However, the potential of apigenin nanoparticles (APG-NPs) to prevent lung colonization of malignant melanoma has not been well investigated. APG-loaded PLGA-NPs were surface-functionalized with meso-2,3-dimercaptosuccinic acid (DMSA) for the treatment of melanoma lung metastasis. DMSA-conjugated APG-loaded NPs (DMSA-APG-NPs) administered by an oral route exhibited sustained APG release and showed considerable enhancement of plasma half-life, Cmax value, and bioavailability compared to APG-NPs both in plasma and the lungs. DMSA-conjugated APG-NPs showed comparably higher cellular internalization in B16F10 and A549 cell lines compared to that of plain NPs. Increased cytotoxicity was observed for DMSA-APG-NPs compared to APG-NPs in A549 cells. This difference between the two formulations was lower in B16F10 cells. Significant depolarization of mitochondrial transmembrane potential and an enhanced level of caspase activity were observed in B16F10 cells treated with DMSA-APG-NPs compared to APG-NPs as well. Western blot analysis of various proteins was performed to understand the mechanism of apoptosis as well as prevention of melanoma cell migration and invasion. DMSA conjugation substantially increased accumulation of DMSA-APG-NPs given by an intravenous route in the lungs compared to APG-NPs at 6 and 8 h. This was also corroborated by scintigraphic imaging studies with radiolabeled formulations administered by an intravenous route. Conjugation also allowed comparatively higher penetration as evident from an in vitro three-dimensional tumor spheroid model study. Finally, the potential therapeutic efficacy of the formulation was established in experimental B16F10 lung metastases, which suggested an improved bioavailability with enhanced antitumor and antimetastasis efficacy of DMSA-conjugated APG-NPs following oral administration.

N,N'bis-(2-mercaptoethyl) isophthalamide (NBMI) exerts neuroprotection against lead-induced toxicity in U-87 MG cells.

N,N'-bis(2-mercaptoethyl)isophthalamide (NBMI) is a novel lipophilic heavy metal chelator and thiol redox antioxidant. This study was designed to investigate the neuroprotective activity of NBMI in U-87 MG cells exposed to lead acetate (PbAc). Cells were pretreated with NBMI for 24 h prior to a 48 h exposure to PbAc. Cell death (55%, p < 0.0001) and reduction of intracellular GSH levels (0.70-fold, p < 0.005) induced by 250 µM Pb were successfully attenuated by NBMI pretreatment at concentrations as low as 10 µM. A similar pretreatment with the FDA-approved Pb chelator dimercaptosuccinic acid (DMSA) proved ineffective, indicating a superior PKPD profile for NBMI. Pretreatment with NBMI successfully counteracted Pb-induced neuroinflammation by reducing IL-1ß (0.59-fold, p < 0.05) and GFAP expression levels. NBMI alone was also found to significantly increase ferroportin expression (1.97-fold, p < 0.05) thereby enhancing cellular ability to efflux heavy metals. While no response was observed on the apoptotic pathway, this study demonstrated for the first time that necrotic cell death induced by Pb in U-87 MG cells is successfully attenuated by NBMI. Collectively these data demonstrate NBMI to be a promising neuroprotective compound in the realm of Pb poisoning.

Retrospective evaluation of the pediatric multicystic dysplastic kidney patients: experience of two centers from southeastern Turkey

Background/aim: The objective of this study is to determine the clinical features of unilateral multicystic dysplastic kidney (MCDK) patients. Materials and methods: The demographic, clinical, laboratory, and radiologic features of MCDK patients at Diyarbakir Children's Hospital and Diyarbakir Gazi Yasargil Training and Research Hospital between January 2008-June 2019 were retrospectively evaluated. Results: A total of 111 [59 (53.2%) male and 52(46.8%) female] patients with MCDK were followed for a mean period of 41.89 ± 32.03 months. MCDK was located on the left and right sides in 46 (41.4%) and 65 (58.6%) of the children, respectively (p > 0.05). A total of 87 (78.4%) patients had antenatal diagnosis. The mean age at diagnosis was 13.7 ± 34.2 months. Of the 49 voiding cystourethrogram (VCUG)-performed patients, vesicoureteral reflux was detected in 11 patients (22.4%). Other associated urological anomalies in the patients were detected in 12 (10.8%) patients. On Tc-99m dimercaptosuccinic acid (DMSA) scintigraphy which was performed in all patients showed scarring in four children. Eight patients had history of UTI (7.2%). Renal failure, hypertension, and proteinuria were diagnosed in three children (2.7%). Sixty-nine (62%) patients developed compensatory hypertrophy. Conclusion: All cases should be followed up closely and VCUG should be reserved for patients with recurrent UTI and other urological problems indicated by ultrasonography and abnormal DMSA scan results.