Serum and tissue metallome of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) patients have late presentation at the time of diagnosis and a poor prognosis. Metal dyshomeostasis is known to play a role in cancer progression. However, the blood and tissue metallome of PDAC patients has not been assessed. This study aimed to determine the levels of essential and toxic metals in the serum and pancreatic tissue from PDAC patients. Serum samples were obtained from PDAC patients before surgical resection. Tissue (tumor and adjacent normal pancreas) were obtained from the surgically resected specimen. Inductively coupled plasma-mass spectrometry (ICP-MS) analysis was performed to quantify the levels of 10 essential and 3 toxic metals in these samples. Statistical analysis was performed to identify dysregulated metals in PDAC and their role as potential diagnostic and prognostic biomarkers. Significantly decreased serum levels of magnesium, potassium, calcium, iron, zinc, selenium, arsenic, and mercury and increased levels of molybdenum were shown to be associated with PDAC. There were significantly decreased levels of zinc, manganese and molybdenum, and increased levels of calcium and selenium in the pancreatic tumor tissue compared with the adjacent normal pancreas. Notably, lower serum levels of calcium, iron, and selenium, and higher levels of manganese, were significantly associated with a poor prognosis (i.e., overall survival) in PDAC patients. In conclusion, this is the first study to comprehensively assess the serum and tissue metallome of PDAC patients. It identified the association of metals with PDAC diagnosis and prognosis.

Strategies for inducing and validating zinc deficiency and zinc repletion.

Given the growing interest in the role of zinc in the onset and progression of diseases, there is a crucial demand for reliable methods to modulate zinc homeostasis. Using a dietary approach, we provide validated strategies to alter whole-body zinc in mice, applicable across species. For confirmation of zinc status, animal growth rates as well as plasma and urine zinc levels were evaluated. The accessible and cost-effective methodology outlined will increase scientific rigor, ensuring reproducibility in studies exploring the impact of zinc deficiency and repletion on the onset and progression of diseases.NEW & NOTEWORTHY This methods paper details dietary approaches to alter zinc homeostasis in rodents and qualitative and quantitative methods to ensure the zinc status of experimental animals. The outlined accessible and cost-effective protocol will elevate scientific rigor, ensuring reproducibility in studies exploring the impact of zinc deficiency and repletion on the onset and progression of a multitude of health conditions and diseases.

Zinc Supplementation Initiated Prior to or During Pregnancy Modestly Impacted Maternal Status and High Prevalence of Hypozincemia in Pregnancy and Lactation: The Women First Preconception Maternal Nutrition Trial.

BACKGROUND: Data regarding effects of small-quantity-lipid-based nutrient supplements (SQ-LNS) on maternal serum zinc concentrations (SZC) in pregnancy and lactation are limited. OBJECTIVES: The objectives of this study were to evaluate the effect of preconception compared with prenatal zinc supplementation (compared with control) on maternal SZC and hypozincemia during pregnancy and early lactation in women in low-resource settings, and assess associations with birth anthropometry. METHODS: From ∼100 women/arm at each of 3 sites (Guatemala, India, and Pakistan) of the Women First Preconception Maternal Nutrition trial, we compared SZC at 12- and 34-wk gestation (n = 651 and 838, respectively) and 3-mo postpartum (n = 742) in women randomly assigned to daily SQ-LNS containing 15 mg zinc from ≥3 mo before conception (preconception, arm 1), from ∼12 wk gestation through delivery (early pregnancy, arm 2) or not at all (control, arm 3). Birth anthropometry was examined for newborns with ultrasound-determined gestational age. Statistical analyses were performed separately for each time point. RESULTS: At 12-wk gestation and 3-mo postpartum, no statistical differences in mean SZC were observed among arms. At 34-wk, mean SZC for arms 1 and 2 were significantly higher than for arm 3 (50.3, 50.8, 47.8 µg/dL, respectively; P = 0.005). Results were not impacted by correction for inflammation or albumin concentrations. Prevalence of hypozincemia at 12-wk (<56 µg/dL) was 23% in Guatemala, 26% in India, and 65% in Pakistan; at 34 wk (<50 µg/dL), 36% in Guatemala, 48% in India, and 74% in Pakistan; and at 3-mo postpartum (<66 µg/dL) 79% in Guatemala, 91% in India, and 92% in Pakistan. Maternal hypozincemia at 34-wk was associated with lower birth length-for-age Z-scores (all sites P = 0.013, Pakistan P = 0.008) and weight-for-age Z-scores (all sites P = 0.017, Pakistan P = 0.022). CONCLUSIONS: Despite daily zinc supplementation for ≥7 mo, high rates of maternal hypozincemia were observed. The association of hypozincemia with impaired fetal growth suggests widespread zinc deficiency in these settings. This trial is registered at clinicaltrials.gov as #NCT01883193.

Ratiometric Fluorescence Detection of Levofloxacin Based on a Cube-like Zn(II)-Eu(III) Nanocluster: Functionalized Sodium Alginate Film for the Detection in Serum and Medicine.

A cube-like Zn(II)-Eu(III) nanocluster 1 (molecular sizes: 1.8 × 2.0 × 2.0 nm) was constructed by the use of a new long-chain Schiff base ligand. It shows a ratiometric fluorescence response to levofloxacin (LFX) with high sensitivity and selectivity, which can be expressed as I615 nm/I550 nm = A*[LFX]2 + B*[LFX] + C. It is used to quantitatively detect the LFX concentrations in fetal calf serum (FCS) and tablets sold in pharmacy. Filter paper strips bearing 1 can be used to qualitatively detect LFX by a color change to red under a UV lamp. 1 and its hybrid with sodium alginate (SA), 1@SA, display potential applications in the qualitative detection of LFX in FCS and the medicine. The limit of detection of 1 to LFX is as low as 2.1 × 10-2 nM.

Serum zinc concentration and dietary zinc intake in relation to cognitive function: an analysis of the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort.

PURPOSE: There are several pathways by which zinc may be a modifiable factor to slow age-related cognitive decline. We investigated the associations between serum and dietary zinc and cognitive impairment in a longitudinal cohort. METHODS: We used data from the REasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort (n = 30,239) and the REGARDS Trace Element Study (n = 2666). Baseline serum zinc concentrations (2003-2007) were measured using inductively coupled plasma mass spectrometry. Baseline dietary zinc intake was measured via the Block food frequency questionnaire. Serum zinc concentrations and dietary zinc intake were categorized into quartiles. The outcome of interest was impairment on the Six-Item Screener (SIS), a measure of global cognitive functioning administered annually. The Enhanced Cognitive Battery (ECB), a more comprehensive series of tests assessing memory and fluency, was administered every two years and considered a secondary outcome. Associations between zinc and incident impairment were assessed using multivariable logistic regression. RESULTS: Among 2065 participants with serum zinc data, 184 individuals developed impairment over 10 years of follow-up. In adjusted models, there was no significant association between serum zinc and impairment as assessed by the SIS or the ECB. Among 18,103 participants who had dietary data, 1424 experienced incident impairment on the SIS. Dietary zinc intake was not significantly associated with impairment as assessed by the SIS or the ECB in adjusted models. CONCLUSION: Findings from this U.S. cohort did not support the hypothesis that serum zinc concentration or dietary zinc intake is associated with the risk of cognitive impairment.

The interaction effects of zinc and polygenic risk score with benzo[a]pyrene exposure on lung cancer risk: A prospective case-cohort study among Chinese populations.

The relationship of exposure to benzo[a]pyrene (BaP) with lung cancer risk has been firmly established, but whether this association could be modified by other environmental or genetic factors remains to be explored. To investigate whether and how zinc (Zn) and genetic predisposition modify the association between BaP and lung cancer, we performed a case-cohort study with a 5.4-year median follow-up duration, comprising a representative subcohort of 1399 participants and 359 incident lung cancer cases. The baseline concentrations of benzo[a]pyrene diol epoxide-albumin adduct (BPDE-Alb) and Zn were quantified. We also genotyped the participants and computed the polygenic risk score (PRS) for lung cancer. Our findings indicated that elevated BPDE-Alb and PRS were linked to increased lung cancer risk, with the HR (95%CI) of 1.54 (1.36, 1.74) per SD increment in ln-transformed BPDE-Alb and 1.27 (1.14, 1.41) per SD increment in PRS, but high plasma Zn level was linked to a lower lung cancer risk [HR (95%CI)=0.77 (0.66, 0.91) per SD increment in ln-transformed Zn]. There was evidence of effect modification by Zn on BaP-lung cancer association (P for multiplicative interaction = 0.008). As Zn concentrations increased from the lowest to the highest tertile, the lung cancer risk per SD increment in ln-transformed BPDE-Alb decreased from 2.07 (1.48, 2.89) to 1.33 (0.90, 1.95). Additionally, we observed a significant synergistic interaction of BPDE-Alb and PRS [RERI (95%CI) = 0.85 (0.03, 1.67)], with 42% of the incident lung cancer cases among individuals with high BPDE-Alb and high PRS attributable to their additive effect [AP (95%CI) = 0.42 (0.14, 0.69)]. This study provided the first prospective epidemiological evidence that Zn has protective effect against BaP-induced lung tumorigenesis, whereas high genetic risk can enhance the harmful effect of BaP. These findings may provide novel insight into the environment-environment and environment-gene interaction underlying lung cancer development, which may help to develop prevention and intervention strategies to manage BaP-induced lung cancer.

Preoperative zinc status predicts the occurrence and healing time of pancreatic fistula after distal pancreatectomy.

BACKGROUND: There are few studies that examined the relationship between preoperative zinc (Zn) concentrations and postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP). METHODS: Data from 98 patients who underwent DP between January 2016 and April 2022 were retrospectively reviewed. Patients' clinicopathological and surgical outcomes were analyzed, and we examined the relationship between Zn and clinically relevant POPF (CR-POPF) after DP. RESULTS: In this series, 41 (41.8%) patients had POPF and 31 (31.8%) patients had CR-POPF. The cut-off value for the preoperative Zn concentration was 74 µg/dL for POPF and CR-POPF. Patients with low Zn concentrations were significantly related with high age, low albumin concentrations, higher CRP concentrations, higher NLR, lower PNI, higher rates of POPF and CR-POPF, longer POPF healing time, longer hospital stay, and postoperative complications than patients with high Zn concentrations. The healing time of POPF after DP was significantly negatively correlated with serum Zn concentrations. A multivariate logistic regression analysis showed that preoperative lower Zn concentrations and a prolonged operation time were independent predictors of CR-POPF and the healing time of POPF after DP. The POPF healing time in patients with high Zn was significantly shorter than that in patients with low Zn concentrations. CONCLUSIONS: This retrospective study showed the association between the preoperative Zn concentrations and the occurrence of POPF and the healing time after DP. Zn is a simple biomarker for malnutrition, which may lead to POPF after DP.

Analysis of similarities and differences between transient symptomatic zinc deficiency and acrodermatitis enteropathica in children: a case report of a Chinese Yi-ethnic infant.

BACKGROUND: Transient symptomatic zinc deficiency (TSZD), an acquired type of zinc deficiency, is a rare, but probably underrecognized disease, extremely in breastfed premature with low birthweight infants. Its clinical manefestations are similar to Acrodermatitis enteropathica (AE), which is a genetic zinc absorption disorder caused by SLC39A4 gene mutations. This gene encodes a member of the zinc/iron-regulated transporter-like protein (ZIP) family. The encoded protein localizes to cell membranes and is required for zinc uptake in the intestine. TSZD is often misdiagnosed as AE because of their extremely similar manefestations, characterized by a typical rash. Therefore, the differention between them is still a clinical challenging. CASE PRESENTATION: Here, we present a case of TSZD in a 4 month and 23 days female Chinese Yi-ethnic premature with AE-like skin lesions, mainly presenting periorificial, perianal and perineal crusted, eroded, erythemato-squamous eruption. Laboratory examination showed the patient's blood zinc level was significantly decreased. Further sequencing of the SLC39A4 gene showed no mutation in the infant and her parents. Skin lesions significantly improved after 6 days of initial zinc supplementation (3 mg/kg/d), and maintenance treatment with 1 mg/kg/day of zinc was discontinued after 8 months without recurrence. CONCLUSIONS: The clinical manifestations of TSZD and AE are extremely similar, leading to a high rate of clinical misdiagnosis. While genetic analysis of the SLC39A4 gene is a reliable method for differentiating TSZD from AE. It is recommended that SLC39A4 gene test should be performed as far as possible in children with AE-like rash.

Sialoglycan recognition is a common connection linking acidosis, zinc, and HMGB1 in sepsis.

Blood pH is tightly maintained between 7.35 and 7.45, and acidosis (pH <7.3) indicates poor prognosis in sepsis, wherein lactic acid from anoxic tissues overwhelms the buffering capacity of blood. Poor sepsis prognosis is also associated with low zinc levels and the release of High mobility group box 1 (HMGB1) from activated and/or necrotic cells. HMGB1 added to whole blood at physiological pH did not bind leukocyte receptors, but lowering pH with lactic acid to mimic sepsis conditions allowed binding, implying the presence of natural inhibitor(s) preventing binding at normal pH. Testing micromolar concentrations of divalent cations showed that zinc supported the robust binding of sialylated glycoproteins with HMGB1. Further characterizing HMGB1 as a sialic acid-binding lectin, we found that optimal binding takes place at normal blood pH and is markedly reduced when pH is adjusted with lactic acid to levels found in sepsis. Glycan array studies confirmed the binding of HMGB1 to sialylated glycan sequences typically found on plasma glycoproteins, with binding again being dependent on zinc and normal blood pH. Thus, HMGB1-mediated hyperactivation of innate immunity in sepsis requires acidosis, and micromolar zinc concentrations are protective. We suggest that the potent inflammatory effects of HMGB1 are kept in check via sequestration by plasma sialoglycoproteins at physiological pH and triggered when pH and zinc levels fall in late stages of sepsis. Current clinical trials independently studying zinc supplementation, HMGB1 inhibition, or pH normalization may be more successful if these approaches are combined and perhaps supplemented by infusions of heavily sialylated molecules.

Efficacy of Normalising Serum Zinc Level for Patients with Olfactory Dysfunction and Zinc Deficiency.

INTRODUCTION: Zinc deficiency may worsen the severity of olfactory dysfunction; however, the relationship between serum zinc levels and therapeutic effects on olfactory dysfunction remains uncertain. This study investigated the relationship between normalising serum zinc levels and the therapeutic effects on olfactory dysfunction. METHODS: Forty-two patients diagnosed with post-infectious, post-traumatic, and idiopathic olfactory dysfunction, with serum zinc levels <70 µg/dL, were included in the study. All patients were treated with mecobalamin, tokishakuyakusan, and polaprezinc. The patients were divided into 2 groups: the zinc-normalised (≥70 µg/dL) and zinc-deficient (<70 µg/dL) groups, based on their post-treatment serum zinc levels. Olfactory test results were compared in each of the 2 groups. RESULTS: The patients were treated for a median of 133 days. The zinc-normalised group had significantly better results in all olfactory tests (detection/recognition thresholds of the T&T olfactometer, odour identification test (Open Essence), Visual Analogue Scale for olfactory dysfunction, and self-administered odour questionnaire). In contrast, only the self-administered odour questionnaire showed a significant improvement in the zinc-deficient group, with no significant differences observed in the other olfactory tests. When comparing the changes in the olfactory test scores between the 2 groups, significant differences were observed in the detection/recognition thresholds of the T&T olfactometer test and Open Essence results. CONCLUSION: These findings suggest that patients with olfactory dysfunction may have difficulty improving their olfactory function if they also have zinc deficiency. Furthermore, normalisation of zinc deficiency may contribute to the improvement of olfactory dysfunction with general treatment.

Association of Diabetic Peripheral Neuropathy with Micronutrients.

INTRODUCTION: Diabetes mellitus (DM) is a common metabolic disorder that has been defined by hyperglycemia. Diabetic patients usually have high levels of oxidative stress. Mitochondrial dysfunction and inflammation of blood vessels are associated with a greater need for micronutrients in diabetic patients. These micronutrients may have an association with the complications in diabetics. The purpose of this study was to show the association of diabetic peripheral neuropathy (DPN) with levels of micronutrients such as copper (Cu), zinc (Zn), magnesium (Mg), and vitamin B12 (Vit B12). MATERIALS AND METHODS: This cross-sectional study was conducted in the Department of Medicine, Lala Lajpat Rai Memorial Medical College, Meerut. A total of 130 randomly selected cases of confirmed type-2 diabetic patients were included in this study. DPN cases were identified using the Michigan neuropathy screening instrument. Out of 130 diabetic patients, 28 patients were found to have diabetic neuropathy. The level of various micronutrients was assessed and correlated with the development of DPN. RESULTS: The association of DPN with Zn (p-value of 0.02) and Vit B12 (p-value of 0.008) was found to be significant, whereas Cu (p-value of 0.57) and Mg (p-value of 0.24) were found to be insignificant.

Serum concentrations of selenium, copper, and zinc in neonatal foals: Influence of failure of passive transfer and age-related changes.

Background: An adequate supply of trace elements is very important for equine neonates, as deficiencies can lead to health problems and even death. Objective: This study investigated serum concentrations of selenium (Se), copper (Cu), and zinc (Zn) in neonatal foals up to the 8th day of life. The influences of disease, age, and failure of passive transfer (FPT) on these concentrations were analyzed. Animals and procedure: Serum concentrations of Se, Cu, and Zn were determined from blood samples of 93 foals by means of inductively coupled plasma mass spectrometry. The foals were divided into 2 groups based on health status: clinically sick (n = 51) and clinically healthy (n = 42). The latter group was further divided into foals with FPT (n = 20) and those without (n = 22). Results: Mean serum concentrations for Se, Cu, and Zn were 60 ± 40 µg/L, 0.25 ± 0.22 mg/L, and 605 ± 285 µg/L, respectively. A significant influence of age on serum Cu concentration was observed (P < 0.0001). No differences were observed between any of the serum concentrations in clinically sick and clinically healthy foals on the 1st day of life. The FPT status was not associated with reduced serum concentrations of Se, Cu, or Zn. Conclusion and clinical relevance: It is not necessary to supplement trace elements in all foals with FPT.

Concentrations sériques de sélénium, de cuivre et de zinc chez les poulains nouveau-nés : influence de l'échec du transfert passif et des changements liés à l'âge. Contexte: Un apport suffisant en oligo-éléments est très important pour les nouveau-nés équins, car des carences peuvent entraîner des problèmes de santé, voire la mort. Objectif: Cette étude a examiné les concentrations sériques de sélénium (Se), de cuivre (Cu) et de zinc (Zn) chez les poulains nouveau-nés jusqu'au 8ème jour de vie. Les influences de maladies, de l'âge et de l'échec du transfert passif (FPT) sur ces concentrations ont été analysées. Animaux et procédure: Les concentrations sériques de Se, Cu et Zn ont été déterminées à partir d'échantillons de sang de 93 poulains au moyen d'une spectrométrie de masse à plasma à couplage inductif. Les poulains ont été divisés en 2 groupes en fonction de leur état de santé: cliniquement malades (n = 51) et cliniquement sains (n = 42). Ce dernier groupe a été divisé en poulains avec FPT (n = 20) et ceux sans (n = 22). Résultats: Les concentrations sériques moyennes de Se, Cu et Zn étaient respectivement de 60 ± 40 µg/L, 0,25 ± 0,22 mg/L et 605 ± 285 µg/L. Une influence significative de l'âge sur la concentration sérique de Cu a été observée (P < 0,0001). Aucune différence n'a été observée entre les concentrations sériques chez les poulains cliniquement malades et cliniquement sains au premier jour de leur vie. Le statut FPT n'était pas associé à une réduction des concentrations sériques de Se, Cu ou Zn. Conclusion et pertinence clinique: Il n'est pas nécessaire de supplémenter tous les poulains en oligo-éléments avec FPT.(Traduit par Dr Serge Messier).

Are the elements zinc, copper, magnesium, and rubidium related to nutrition and iodine deficiency in pregnant Bulgarian women from iodine deficient region?

OBJECTIVE: Trace elements are essential for the biochemistry of the cell. Their reference values have been found to differ considerably in pregnant women stratified by age, place of residence, anthropometric status, and length of pregnancy. In optimal amounts, these elements reduce the risk of pregnancy complications. Subclinical hypothyroidism in pregnancy is associated with adverse maternal and neonatal outcomes. The aim of the study was to determine the effects of zinc (Zn), copper (Cu), magnesium (Mg), and rubidium (Rb) on pregnant women in an iodine deficiency region and find the relationship with the thyroid status and nutrition. METHODS: We evaluated the iodine status of 61 healthy pregnant women from an iodine deficient region in Bulgaria. Thyroid stimulating hormone (TSH) and thyroxin free (FT4) levels were measured using ELISA. RESULTS: We found elevated levels of copper that differed the most between the first and second trimesters; Cu and TSH were found to be positively correlated (р < 0.05). Lower Cu levels were found in pregnant women consuming pulses more than 2-3 times a week (р = 0.033). The women consuming fish more than 2-3 times a week had higher levels of Rb. We found a pronounced iodine deficiency in more than half of the examined women in the first to third trimesters, without any effect of pregnancy on the ioduria (р=0.834). All second and third trimester cases were associated with severe ioduria (< 150 µg/L). CONCLUSION: The high Cu levels were associated with subclinical hypothyroidism (SCH) and less pulse consumption during pregnancy in an iodine deficiency endemic area. SCH was found in 24% of the pregnant women in such an area while in 13% of them SCH had progressed to overt hypothyroidism.

Factors Influencing Wound Healing in Diabetic Foot Patients.

Background and objectives: Diabetic foot stands out as one of the most consequential and devastating complications of diabetes. Many factors, including VIPS (Vascular management, Infection management, Pressure relief, and Source of healing), influence the prognosis and treatment of diabetic foot patients. There are many studies on VIPS, but relatively few studies on "sources of healing". Nutrients that affect wound healing are known, but objective data in diabetic foot patients are insufficient. We hypothesized that "sources of healing" would have many effects on wound healing. The purpose of this study is to know the affecting factors related to the source of healing for diabetic foot patients. Materials and Methods: A retrospective review identified 46 consecutive patients who were admitted for diabetic foot management from July 2019 to April 2021 at our department. Several laboratory tests were performed for influencing factor evaluation. We checked serum levels of total protein, albumin, vitamin B, iron, zinc, magnesium, copper, Hb, HbA1c, HDL cholesterol, and LDL cholesterol. These values of diabetic foot patients were compared with normal values. Patients were divided into two groups based on wound healing rate, age, length of hospital stay, and sex, and the test values between the groups were compared. Results: Levels of albumin (37%) and Hb (89%) were low in the diabetic foot patients. As for trace elements, levels of iron (97%) and zinc (95%) were low in the patients, but levels of magnesium and copper were usually normal or high. There were no differences in demographic characteristics based on wound healing rate. However, when compared to normal adult values, diabetic foot patients in our data exhibited significantly lower levels of hemoglobin, total protein, albumin, iron, zinc, copper, and HDL cholesterol. When compared based on age and length of hospital stay, hemoglobin levels were significantly lower in both the older age group and the group with longer hospital stays. Conclusions: Serum levels of albumin, Hb, iron, and zinc were very low in most diabetic foot patients. These low values may have a negative relationship with wound healing. Nutrient replacements are necessary for wound healing in diabetic foot patients.

Genetic Causal Associations between Various Serum Minerals and Risk of Depression: A Mendelian Randomization Study.

BACKGROUND: Previous observational studies have discovered a connection between depression and mineral status. Confirming this potential connection is challenging due to confounding factors and potential reverse causality which is inherent in observational studies. MATERIALS AND METHODS: We performed a Mendelian randomization (MR) analysis to estimate the causal association of serum minerals with depression. Leveraging summary-level data on depression, a genome-wide association study (GWAS) was applied. The data on serum minerals were collected from the FinnGen Biobank database. MR assessments representing causality were produced by inverse-variance weighted approaches with multiplicative random and fixed effects. RESULT: Sensitivity analyses were performed to validate the reliability of the results. A noteworthy correlation emerged between serum zinc levels and reduced risk of depression. An odds ratio (OR) of 0.917 for depression associated with a one standard deviation increase in serum zinc levels (OR = 0.968; 95% CI = 0.953-0.984, p = 1.19 × 10-4, random effects model inverse variance weighted (IVW)); (OR = 0.928; 95% CI = 0.634-1.358, p = 0.766, MR Egger). Sensitivity assessments supported this causation. However, the risk of depression did not exhibit an association with other minerals. CONCLUSIONS: In summary, a higher zinc concentration is causally associated with a reduced depression risk. This MR outcome may assist clinicians in the regulation of specific mineral intake, particularly for high-risk patients with serum zinc deficiencies.

Metal Exposure and Risk of Parkinson Disease: A Systematic Review and Meta-Analysis.

Metal exposure has been suggested as a possible environmental risk factor for Parkinson disease (PD). We searched the PubMed, EMBASE, and Cochrane databases to systematically review the literature on the relationship between metal exposure and PD risk and to examine the overall quality of each study and the exposure assessment method. A total of 83 case-control studies and 5 cohort studies published during the period 1963-July 2021 were included, of which 73 were graded as being of low or moderate overall quality. Investigators in 69 studies adopted self-reported exposure and biomonitoring after disease diagnosis for exposure assessment approaches. The meta-analyses showed that concentrations of copper and iron in serum and concentrations of zinc in either serum or plasma were lower, while concentrations of magnesium in CSF and zinc in hair were higher, among PD cases as compared with controls. Cumulative lead levels in bone were found to be associated with increased risk of PD. We did not find associations between other metals and PD. The current level of evidence for associations between metals and PD risk is limited, as biases from methodological limitations cannot be ruled out. High-quality studies assessing metal levels before disease onset are needed to improve our understanding of the role of metals in the etiology of PD.

Lower-Dose Zinc for Childhood Diarrhea - A Randomized, Multicenter Trial.

BACKGROUND: The World Health Organization recommends 20 mg of zinc per day for 10 to 14 days for children with acute diarrhea; in previous trials, this dosage decreased diarrhea but increased vomiting. METHODS: We randomly assigned 4500 children in India and Tanzania who were 6 to 59 months of age and had acute diarrhea to receive 5 mg, 10 mg, or 20 mg of zinc sulfate for 14 days. The three primary outcomes were a diarrhea duration of more than 5 days and the number of stools (assessed in a noninferiority analysis) and the occurrence of vomiting (assessed in a superiority analysis) within 30 minutes after zinc administration. RESULTS: The percentage of children with diarrhea for more than 5 days was 6.5% in the 20-mg group, 7.7% in the 10-mg group, and 7.2% in the 5-mg group. The difference between the 20-mg and 10-mg groups was 1.2 percentage points (upper boundary of the 98.75% confidence interval [CI], 3.3), and that between the 20-mg and 5-mg groups was 0.7 percentage points (upper boundary of the 98.75% CI, 2.8), both of which were below the noninferiority margin of 4 percentage points. The mean number of diarrheal stools was 10.7 in the 20-mg group, 10.9 in the 10-mg group, and 10.8 in 5-mg group. The difference between the 20-mg and 10-mg groups was 0.3 stools (upper boundary of the 98.75% CI, 1.0), and that between the 20-mg and 5-mg groups was 0.1 stools (upper boundary of the 98.75% CI, 0.8), both of which were below the noninferiority margin (2 stools). Vomiting within 30 minutes after administration occurred in 19.3%, 15.6%, and 13.7% of the patients in the 20-mg, 10-mg, and 5-mg groups, respectively; the risk was significantly lower in the 10-mg group than in the 20-mg group (relative risk, 0.81; 97.5% CI, 0.67 to 0.96) and in the 5-mg group than in the 20-mg group (relative risk, 0.71; 97.5% CI, 0.59 to 0.86). Lower doses were also associated with less vomiting beyond 30 minutes after administration. CONCLUSIONS: Lower doses of zinc had noninferior efficacy for the treatment of diarrhea in children and were associated with less vomiting than the standard 20-mg dose. (Funded by the Bill and Melinda Gates Foundation; ZTDT ClinicalTrials.gov number, NCT03078842.).

Correlation of metal ions with specific brain region volumes in neurodegenerative diseases.

Background/aim: There are reports stating that deteriorations in metal homeostasis in neurodegenerative diseases promote abnormal protein accumulation. In this study, the serum metal levels in Alzheimer's disease (AD) and Parkinson's disease (PD) and its relationship with the cortical regions of the brain were investigated. Materials and methods: The patients were divided into 3 groups consisting of the AD group, PD group, and healthy control group (n = 15 for each). The volumes of specific brain regions were measured over the participants' 3-dimensional magnetic resonance images, and they were compared across the groups. Copper, zinc, iron, and ferritin levels in the serums were determined, and their correlations with the brain region volumes were examined. Results: The volumes of left hippocampus and right substantia nigra were lower in the AD and PD groups, while the volume of the left nucleus caudatus (CdN) and bilateral insula were lower in the AD group compared to the control group. Serum zinc levels were lower in the AD and PD groups, while the iron level was lower in the PD group in comparison to the control group. In addition, the serum ferritin level was higher in the AD group than in the control group. Serum zinc and copper levels in the AD group were positively correlated with the volumes of the right entorhinal cortex, thalamus, CdN, and insula. Serum zinc and copper levels in the PD group showed a negative correlation with the left nucleus accumbens (NAc), right putamen, and right insula volumes. While the serum ferritin level in the PD group displayed a positive correlation with the bilateral CdN, putamen, and NAc, as well as the right hippocampus and insula volumes, no area was detected that showed a correlation with the serum ferritin level in the AD group. Conclusion: A relationship was determined between the serum metal levels in the AD and PD groups and certain brain cortical regions that showed volumetric changes, which can be important for the early diagnosis of neurodegenerative diseases.

Zinc Status Alters Alzheimer's Disease Progression through NLRP3-Dependent Inflammation.

Alzheimer's disease is a devastating neurodegenerative disease with a dramatically increasing prevalence and no disease-modifying treatment. Inflammatory lifestyle factors increase the risk of developing Alzheimer's disease. Zinc deficiency is the most prevalent malnutrition in the world and may be a risk factor for Alzheimer's disease potentially through enhanced inflammation, although evidence for this is limited. Here we provide epidemiological evidence suggesting that zinc supplementation was associated with reduced risk and slower cognitive decline, in people with Alzheimer's disease and mild cognitive impairment. Using the APP/PS1 mouse model of Alzheimer's disease fed a control (35 mg/kg zinc) or diet deficient in zinc (3 mg/kg zinc), we determined that zinc deficiency accelerated Alzheimer's-like memory deficits without modifying amyloid ß plaque burden in the brains of male mice. The NLRP3-inflammasome complex is one of the most important regulators of inflammation, and we show here that zinc deficiency in immune cells, including microglia, potentiated NLRP3 responses to inflammatory stimuli in vitro, including amyloid oligomers, while zinc supplementation inhibited NLRP3 activation. APP/PS1 mice deficient in NLRP3 were protected against the accelerated cognitive decline with zinc deficiency. Collectively, this research suggests that zinc status is linked to inflammatory reactivity and may be modified in people to reduce the risk and slow the progression of Alzheimer's disease.SIGNIFICANCE STATEMENT Alzheimer's disease is a common condition mostly affecting the elderly. Zinc deficiency is also a global problem, especially in the elderly and also in people with Alzheimer's disease. Zinc deficiency contributes to many clinical disorders, including immune dysfunction. Inflammation is known to contribute to the risk and progression of Alzheimer's disease; thus, we hypothesized that zinc status would affect Alzheimer's disease progression. Here we show that zinc supplementation reduced the prevalence and symptomatic decline in people with Alzheimer's disease. In an animal model of Alzheimer's disease, zinc deficiency worsened cognitive decline because of an enhancement in NLRP3-driven inflammation. Overall, our data suggest that zinc status affects Alzheimer's disease progression, and that zinc supplementation could slow the rate of cognitive decline.

The Role of Copper and Zinc in Irritable Bowel Syndrome: A Mendelian Randomization Study.

Irritable bowel syndrome (IBS) has been associated with copper and zinc imbalance and a zinc-deficient diet. Mendelian randomization was used in this study to evaluate if genetically determined copper and zinc levels play a causal role in the development of IBS. Three single-nucleotide polymorphisms (SNPs; rs1175550, rs2769264, and rs2769270) associated with erythrocyte copper levels, and 3 SNPs associated with erythrocyte zinc levels (rs11638477, rs1532423, and rs2120019) in the Australian Twin Study (1993-1996 and 2001-2005) were used as instrumental variables for levels of these metals. The association of these SNPs with IBS was tested using summary statistics computed from data on 340,331 individuals from the UK Biobank, 5,548 of whom had IBS (2006-2010). Genetically predicted high serum copper levels were associated with a lower risk of IBS (odds ratio = 0.89; 95% confidence interval: 0.80, 0.98). Genetically predicted, high serum zinc levels were nonsignificantly associated with a higher risk of IBS (odds ratio = 1.06; 95% confidence interval: 0.95, 1.18). Sensitivity analysis did not suggest the presence of pleiotropy. These results suggest that high erythrocyte copper levels may be protective against IBS development. Targeting higher levels, therefore, may provide an avenue to reduce the likelihood of IBS development in high-risk individuals.