The Immune Response of OAS1, IRF9, and IFI6 Genes in the Pathogenesis of COVID-19.

COVID-19 is characterized by a wide range of clinical manifestations, where aging, underlying diseases, and genetic background are related to worse outcomes. In the present study, the differential expression of seven genes related to immunity, IRF9, CCL5, IFI6, TGFB1, IL1B, OAS1, and TFRC, was analyzed in individuals with COVID-19 diagnoses of different disease severities. Two-step RT-qPCR was performed to determine the relative gene expression in whole-blood samples from 160 individuals. The expression of OAS1 (p < 0.05) and IFI6 (p < 0.05) was higher in moderate hospitalized cases than in severe ones. Increased gene expression of OAS1 (OR = 0.64, CI = 0.52-0.79; p = 0.001), IRF9 (OR = 0.581, CI = 0.43-0.79; p = 0.001), and IFI6 (OR = 0.544, CI = 0.39-0.69; p < 0.001) was associated with a lower risk of requiring IMV. Moreover, TGFB1 (OR = 0.646, CI = 0.50-0.83; p = 0.001), CCL5 (OR = 0.57, CI = 0.39-0.83; p = 0.003), IRF9 (OR = 0.80, CI = 0.653-0.979; p = 0.03), and IFI6 (OR = 0.827, CI = 0.69-0.991; p = 0.039) expression was associated with patient survival. In conclusion, the relevance of OAS1, IRF9, and IFI6 in controlling the viral infection was confirmed.

Genetic variants in ATP2B2 as risk factors for mortality in patients unrelated but not associated with families with severe COVID-19.

Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus Disease 2019 (COVID-19). The disease has a wide range of clinical manifestations, from asymptomatic to severe. Ancestral contribution, sex, immune response, and genetic factors influence the presentation of the disease. The objective of the present study was to validate these genetic variants in patients with severe COVID-19 who died and in survivor patients. Methods: Single nucleotide variants (SNVs) in six genes: ATPase plasma membrane Ca2+ transporting 2 (ATP2B2), transmembrane serine protease 2 (TMPRSS2), dedicator of cytokinesis 2 (DOCK2), (interferon alpha and beta receptor subunit 2) IFNAR2, tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A), and tumor necrosis factor receptor superfamily, member 1B (TNFRSF1B), were explored in two groups: the first consisted of severe COVID-19-related patients (familial cases from 58 families, n = 130), and the second group of unrelated severe COVID-19 patients (n = 1045). In each study group, death was evaluated as the outcome. Results: In non-related patients with severe COVID-19, carriers of GG genotype (rs2289274) in the ATP2B2 gene showed a high-risk probability of non-surviving (OR = 1.43). Survival analysis to 75 days indicates that carriers of GG have a higher risk than GA or AA genotypes (p = 0.0059). The haplotype GG (rs2289273-rs2289274) in ATP2B2 was found to be associated with a high risk of death in severe non-related COVID-19 patients. No significant associations were found between severe COVID-19-related patients and SNVs in ATP2B2, TMPRSS2, DOCK2, IFNAR2, TNFRSF1A, or TNFRSF1B. Conclusions: Unrelated patients with severe COVID-19 that carry the GG genotype (rs2289274) in ATP2B2 showed a high death risk. Survival analysis to 75 days indicates that carriers of GG have a higher risk of non-survival compared to GA or AA genotypes.

Oxidative Damage and Telomere Length as Markers of Lung Cancer Development among Chronic Obstructive Pulmonary Disease (COPD) Smokers.

Lung cancer (LC) constitutes an important cause of death among patients with Chronic Obstructive Pulmonary Disease (COPD). Both diseases may share pathobiological mechanisms related to oxidative damage and cellular senescence. In this study, the potential value of leucocyte telomere length, a hallmark of aging, and 8-OHdG concentrations, indicative of oxidative DNA damage, as risk biomarkers of LC was evaluated in COPD patients three years prior to LC diagnosis. Relative telomere length measured using qPCR and serum levels of 8-OHdG were determined at the baseline in 99 COPD smokers (33 with LC and 66 age-matched COPD without LC as controls). Of these, 21 COPD with LC and 42 controls had the biomarkers measured 3 years before. Single nucleotide variants (SNVs) in TERT, RTEL, and NAF1 genes were also determined. COPD cases were evaluated, which showed greater telomere length (p < 0.001) and increased serum 8-OHdG levels (p = 0.004) three years prior to LC diagnosis compared to the controls. This relationship was confirmed at the time of LC diagnosis. No significant association was found between the studied SNVs in cases vs. controls. In conclusion, this preliminary study shows that longer leucocyte telomere length and increased 8-OHdG serum levels can be useful as early biomarkers of the risk for future lung cancer development among COPD patients.

Circulating miR-206 and miR-1246 as Markers in the Early Diagnosis of Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease.

Lung cancer (LC) is the most common cause of cancer death, with 75% of cases being diagnosed in late stages. This study aimed to determine potential miRNAs as biomarkers for the early detection of LC in chronic obstructive pulmonary disease (COPD) cases. Ninety-nine patients were included, with registered clinical and lung function parameters followed for 6 years. miRNAs were determined in 16 serum samples from COPD patients (four with LC and four controls) by next generation sequencing (NGS) at LC diagnosis and 3 years before. The validation by qPCR was performed in 33 COPD-LC patients and 66 controls at the two time points. Over 170 miRNAs (≥10 TPM) were identified; among these, miR-224-5p, miR-206, miR-194-5p, and miR-1246 were significantly dysregulated (p < 0.001) in COPD-LC 3 years before LC diagnosis when compared to the controls. The validation showed that miR-1246 and miR-206 were differentially expressed in COPD patients who developed LC three years before (p = 0.035 and p = 0.028, respectively). The in silico enrichment analysis showed miR-1246 and miR-206 to be linked to gene mediators in various signaling pathways related to cancer. Our study demonstrated that miR-1246 and miR-206 have potential value as non-invasive biomarkers of early LC detection in COPD patients who could benefit from screening programs.

Expression of angiogenic and lymphangiogenic genes in primary cutaneous melanoma: relationship with angiolymphatic invasion and disease-free survival.

Melanoma is one of the most common cancers in the world. The main routes of tumor progression are related to angiogenesis and lymphangiogenesis. These routes can occur by local invasion, which is called angiolymphatic invasion (ALI). In this study, we assess gene expression of relevant biomarkers of angiogenesis and lymphangiogenesis in 80 FFPE melanoma samples to determine a molecular profile that correlates with ALI, tumor progression, and disease-free survival. The results were enhanced by a posttranscriptional analysis by an immunofluorescence assay. Three SNPs in the VEGFR-2 gene were genotyped in 237 malignant melanoma (MM) blood DNA samples by qPCR. A significant correlation was found for LYVE -1 and ALI, qualitative ( P  = 0.017) and quantitative ( P  = 0.005). An increased expression of protein LIVE-1 in ALI samples supported these results ( P  = 0.032). VEGFR2 was lower in patients who showed disease progression ( P  = 0.005) and protein VEGFR2 posttranscriptional expression decreased ( P  = 0.016). DFS curves showed differences ( P  = 0.023) for VEGFR2 expression detected versus the absence of VEGFR2 expression. No significant influence on DFS was detected for the remaining analyzed genes. Cox regression analysis suggested that VEGFR2 expression has a protective role (HR = 0.728; 95% CI = 0.552-0.962; P  = 0.025) on disease progression. No significant association was found between any of the studied SNPs of VEGFR2 and DFS or progression rate. Our main results suggest that LYVE-1 gene expression is closely related to ALI; the relationship with the development of metastases in MM deserves further studies. Low expression of VEGFR2 was associated with disease progression and the expression of VEGFR2 correlates with an increased DFS.

Differential expression of antiviral and immune-related genes in individuals with COVID-19 asymptomatic or with mild symptoms.

COVID-19 is characterized by a wide range of symptoms where the genetic background plays a key role in SARS-CoV-2 infection. In this study, the relative expression of IRF9, CCL5, IFI6, TGFB1, IL1B, OAS1, and TFRC genes (related to immunity and antiviral activity) was analyzed in upper airway samples from 127 individuals (97 COVID-19 positive and 30 controls) by using a two-step RT-PCR. All genes excepting IL1B (p=0.878) showed a significantly higher expression (p<0.005) in COVID-19 cases than in the samples from the control group suggesting that in asymptomatic-mild cases antiviral and immune system cells recruitment gene expression is being promoted. Moreover, IFI6 (p=0.002) and OAS1 (p=0.044) were upregulated in cases with high viral loads, which could be related to protection against severe forms of this viral infection. In addition, a higher frequency (68.7%) of individuals infected with the Omicron variant presented higher viral load values of infection when compared to individuals infected with other variants (p<0.001). Furthermore, an increased expression of IRF9 (p<0.001), IFI6 (p<0.001), OAS1 (p=0.011), CCL5, (p=0.003) and TGFB1 (p<0.001) genes was observed in individuals infected with SARS-CoV-2 wildtype virus, which might be due to immune response evasion of the viral variants and/or vaccination. The obtained results indicate a protective role of IFI6, OAS1 and IRF9 in asymptomatic -mild cases of SARS-CoV-2 infection while the role of TGFB1 and CCL5 in the pathogenesis of the disease is still unclear. The importance of studying the dysregulation of immune genes in relation to the infective variant is stand out in this study.

Pathogenic Variants of SLC22A12 (URAT1) and SLC2A9 (GLUT9) in Spanish Patients with Renal Hypouricemia: Founder Effect of SLC2A9 Variant c.374C>T; p.(T125M).

Renal hypouricemia (RHUC) is a rare inherited disorder characterized by impaired urate reabsorption in the proximal tubule resulting in low urate serum levels and increased urate excretion. Some patients may present severe complications such as exercise-induced acute renal failure and nephrolithiasis. RHUC is caused by inactivating mutations in the SLC22A12 (RHUC type 1) or SLC2A9 (RHUC type 2) genes, which encode urate transporters URAT1 and GLUT9, respectively. In this study, our goal was to identify mutations associated with twenty-one new cases with RHUC through direct sequencing of SLC22A12 and SLC2A9 coding exons. Additionally, we carried out an SNPs-haplotype analysis to determine whether the rare SLC2A9 variant c.374C>T; p.(T125M), which is recurrent in Spanish families with RHUC type 2, had a common-linked haplotype. Six intragenic informative SNPs were analyzed using PCR amplification from genomic DNA and direct sequencing. Our results showed that ten patients carried the SLC22A12 mutation c.1400C>T; p.(T467M), ten presented the SLC2A9 mutation c.374C>T, and one carried a new SLC2A9 heterozygous mutation, c.593G>A; p.(R198H). Patients carrying the SLC2A9 mutation c.374C>T share a common-linked haplotype, confirming that it emerged due to a founder effect.

An approach to the effects of longevity, sexual maturity, and reproduction on telomere length and oxidative stress in different Psittacidae species.

Introduction: Aging is a multifactorial process that includes molecular changes such as telomere shortening. Telomeres shorten progressively with age in vertebrates, and their shortening rate has a significant role in determining the lifespan of a species. However, DNA loss can be enhanced by oxidative stress. The need for novel animal models has recently emerged as a tool to gather more information about the human aging process. Birds live longer than other mammals of the same size, and Psittacidae species are the most persevering of them, due to special key traits. Methods: We aimed to determine telomere length by qPCR, and oxidative stress status using colorimetric and fluorescence methods in different species of the order Psittaciformes with different lifespans. Results: We found that telomeres shorten with age for both long- and short-lived birds (p < 0.001 and p = 0.004, respectively), with long-lived birds presenting longer telomeres than short-lived ones (p = 0.001). In addition, short-lived birds accumulated more oxidative stress products than long-lived birds (p = 0.013), who showed a better antioxidant capacity (p < 0.001). Breeding was found related to telomere shortening in all species (p < 0.001 and p = 0.003 for long- and short-lived birds). Short-lived birds, especially breeding females, increased their oxidative stress products when breeding (p = 0.021), whereas long-lived birds showed greater resistance and even increased their antioxidant capacity (p = 0.002). Conclusion: In conclusion, the relationship between age and telomere length in Psittacidae was verified. The influence of breeding increased cumulative oxidative damage in short-lived species, while long-lived species may counteract this damage.

VEGFC Gene Expression Is Associated with Tumor Progression and Disease-Free Survival in Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (CSCC) is one of the most common cancers in the skin. CSCC belongs to the non-melanoma skin cancers, and its incidence is increasing every year around the world. The principal routes of tumor progression are related to angiogenesis and lymphangiogenesis. In this study, we assess the gene expression of the relevant biomarkers of both routes in 49 formalin-fixed paraffin-embedded (FFPE) CSCC samples in an attempt to determine a molecular profile that correlates with the tumor progression and disease-free survival (DFS). The results were enhanced by a posttranscriptional analysis using an immunofluorescence assay. Overexpression of the vascular endothelial growth factor C (VEGFC) gene was found in patients with tumor progression (p = 0.022) and in patients with perineural invasion (p = 0.030). An increased expression of protein VEGFC in samples with tumor progression supported these results (p = 0.050). In addition, DFS curves showed differences (p = 0.027) for tumors with absent-low VEGFC expression versus those with high levels of VEGFC expression. No significant influence on DFS was detected for the remaining analyzed genes. VEGFC expression was found to be a risk factor in the disease progression (HR = 2.675; 95% CI: 1.089-6.570; p = 0.032). Our main results suggest that VEGFC gene expression is closely related to tumor progression, DFS, and the presence of perineural invasion.

Gout associated with reduced renal excretion of uric acid. Renal tubular disorder that nephrologists do not treat.

Gout is recurrent inflammatory arthritis caused by the deposition of monosodium urate crystals in the joints. The risk factors that predispose to suffering from gout include non-modifiable factors such as gender, age, ethnicity and genetics, and modifiable factors such as diet and lifestyle. It has been shown that the heritability of uric acid levels in the blood is greater than 30%, which indicates that genetics play a key role in these levels. Hyperuricaemia is often a consequence of reduced renal urate excretion since more than 70% is excreted by the kidneys, mainly through the proximal tubule. The mechanisms that explain that hyperuricaemia associated with reduced renal urate excretion is, to a large extent, a proximal renal tubular disorder, have begun to be understood following the identification of two genes that encode the URAT1 and GLUT9 transporters. When they are carriers of loss-of-function mutations, they explain the two known variants of renal tubular hypouricaemia. Some polymorphisms in these genes may have an opposite gain-of-function effect, with a consequent increase in urate reabsorption. Conversely, loss-of-function polymorphisms in other genes that encode transporters involved in urate excretion (ABCG2, ABCC4) can lead to hyperuricaemia. Genome-wide association study (GWAS) methods have made it possible to locate new gout-related loci associated with reduced renal urate excretion (NIPAL1, FAM35A).

Ozone Eliminates SARS-CoV-2 from Difficult-to-Clean Office Supplies and Clinical Equipment.

(1) Background: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) continues to cause profound health, economic, and social problems worldwide. The management and disinfection of materials used daily in health centers and common working environments have prompted concerns about the control of coronavirus disease 2019 (COVID-19) infection risk. Ozone is a powerful oxidizing agent that has been widely used in disinfection processes for decades. The aim of this study was to assess the optimal conditions of ozone treatment for the elimination of heat-inactivated SARS-CoV-2 from office supplies (personal computer monitors, keyboards, and computer mice) and clinical equipment (continuous positive airway pressure tubes and personal protective equipment) that are difficult to clean. (2) Methods: The office supplies and clinical equipment were contaminated in an area of 1 cm2 with 1 × 104 viral units of a heat-inactivated SARS-CoV-2 strain, then treated with ozone using two different ozone devices: a specifically designed ozonation chamber (for low-medium ozone concentrations over large volumes) and a clinical ozone generator (for high ozone concentrations over small volumes). SARS-CoV-2 gene detection was carried out using quantitative real-time polymerase chain reaction (RT-qPCR). (3) Results: At high ozone concentrations over small surfaces, the ozone eliminated SARS-CoV-2 RNA in short time periods-i.e., 10 min (at 4000 ppm) or less. The optimum ozone concentration over large volumes was 90 ppm for 120 min in ambient conditions (24 °C and 60-75% relative humidity). (4) Conclusions: This study showed that the appropriate ozone concentration and exposure time eliminated heat-inactivated SARS-CoV-2 RNA from the surfaces of different widely used clinical and office supplies, decreasing their risk of transmission, and improving their reutilization. Ozone may provide an additional tool to control the spread of the COVID-19 pandemic.

Ozone treatment effectively eliminates SARS-CoV-2 from infected face masks.

The current COVID-19 pandemic is causing profound health, economic, and social problems worldwide. The global shortage of medical and personal protective equipment (PPE) in specialized centers during the outbreak demonstrated the need for efficient methods to disinfect and recycle them in times of emergency. We have previously described that high ozone concentrations destroyed viral RNA in an inactivated SARS-CoV-2 strain within a few minutes. However, the efficient ozone dosages for active SARS-CoV-2 are still unknown. The present study aimed to evaluate the systematic effects of ozone exposure on face masks from hospitalized patients infected with SARS-CoV-2. Face masks from COVID-19 patients were collected and treated with a clinical ozone generator at high ozone concentrations in small volumes for short periods. The study focused on SARS-CoV-2 gene detection (assessed by real-time quantitative polymerase chain reaction (RT-qPCR)) and on the virus inactivation by in vitro studies. We assessed the effects of different high ozone concentrations and exposure times on decontamination efficiency. We showed that high ozone concentrations (10,000, 2,000, and 4,000 ppm) and short exposure times (10, 10, and 2 minutes, respectively), inactivated both the original strain and the B.1.1.7 strain of SARS-CoV-2 from 24 contaminated face masks from COVID-19 patients. The validation results showed that the best condition for SARS-CoV-2 inactivation was a treatment of 4,000 ppm of ozone for 2 minutes. Further studies are in progress to advance the potential applications of these findings.

La gota asociada a reducción de la excreción renal de ácido úrico. Esa tubulopatía que no tratamos los nefrólogos / Gout associated with reduced renal excretion of uric acid. Renal tubular disorder that nephrologists do not treat

La gota es una artritis inflamatoria recurrente provocada por el depósito de cristales de urato monosódico en las articulaciones. Entre los factores de riesgo que predisponen a padecer gota se encuentran aquellos no modificables como sexo, edad, raza y genética y los modificables como dieta y estilo de vida. Se ha indicado que la heredabilidad de los niveles de ácido úrico en sangre es superior al 30%, lo que indica que la genética tiene un papel clave en dichos niveles.La hiperuricemia es a menudo una consecuencia de la reducción de la excreción renal de urato, ya que más del 70% se excreta por el riñón, principalmente, por el túbulo proximal.Los mecanismos que explican que la hiperuricemia asociada a la reducción de la excreción renal de urato es, en gran medida, una tubulopatía proximal, se han empezado a conocer al saberse la existencia de dos genes que codifican los transportadores URAT1 y GLUT9 que, cuando son portadores de mutaciones de pérdida de función, explican las dos variantes conocidas de hipouricemia tubular renal.Algunos polimorfismos presentes en esos genes pueden tener un efecto contrario de ganancia de función, con la consecuencia de un incremento en la reabsorción de urato. A la inversa, polimorfismos de pérdida de función en otros genes que codifican trasportadores implicados en la excreción de urato (ABCG2, ABCC4) favorecen la hiperuricemia.Los métodos de asociación genómica amplia (GWAS) han permitido localizar nuevos locus relacionados con gota asociada a reducción de la excreción renal de urato (NIPAL1, FAM35A). (AU)

Gout is recurrent inflammatory arthritis caused by the deposition of monosodium urate crystals in the joints. The risk factors that predispose to suffering from gout include non-modifiable factors such as gender, age, ethnicity and genetics, and modifiable factors such as diet and lifestyle. It has been shown that the heritability of uric acid levels in the blood is greater than 30%, which indicates that genetics play a key role in these levels.Hyperuricaemia is often a consequence of reduced renal urate excretion since more than 70% is excreted by the kidneys, mainly through the proximal tubule.The mechanisms that explain that hyperuricaemia associated with reduced renal urate excretion is, to a large extent, a proximal renal tubular disorder, have begun to be understood following the identification of two genes that encode the URAT1 and GLUT9 transporters. When they are carriers of loss-of-function mutations, they explain the two known variants of renal tubular hypouricaemia.Some polymorphisms in these genes may have an opposite gain-of-function effect, with a consequent increase in urate reabsorption. Conversely, loss-of-function polymorphisms in other genes that encode transporters involved in urate excretion (ABCG2, ABCC4) can lead to hyperuricaemia.Genome-wide association study (GWAS) methods have made it possible to locate new gout-related loci associated with reduced renal urate excretion (NIPAL1, FAM35A). (AU)

Gene Expression Studies in Formalin-Fixed Paraffin-Embedded Samples of Cutaneous Cancer: The Need for Reference Genes.

Formalin-fixed paraffin-embedded (FFPE) tumour samples may provide crucial data regarding biomarkers for neoplasm progression. Analysis of gene expression is frequently used for this purpose. Therefore, mRNA expression needs to be normalized through comparison to reference genes. In this study, we establish which of the usually reported reference genes is the most reliable one in cutaneous malignant melanoma (MM) and cutaneous squamous cell carcinoma (CSCC). ACTB, TFRC, HPRT1 and TBP expression was quantified in 123 FFPE samples (74 MM and 49 CSCC biopsies) using qPCR. Expression stability was analysed by NormFinder and Bestkeeper softwares, and the direct comparison method between means and SD. The in-silico analysis with BestKeeper indicated that HPRT1 was more stable than ACTB and TFRC in MM (1.85 vs. 2.15) and CSCC tissues (2.09 vs. 2.33). The best option to NormFinder was ACTB gene (0.56) in MM and TFRC (0.26) in CSCC. The direct comparison method showed lower SD means of ACTB expression in MM (1.17) and TFRC expression in CSCC samples (1.00). When analysing the combination of two reference genes for improving stability, NormFinder indicated HPRT1 and ACTB to be the best for MM samples, and HPRT1 and TFRC genes for CSCC. In conclusion, HPRT1 and ACTB genes in combination are the most appropriate choice for normalization in gene expression studies in MM FFPE tissue, while the combination of HPRT1 and TFRC genes are the best option in analysing CSCC FFPE samples. These may be used consistently in forthcoming studies on gene expression in both tumours.

Persistence of SARS-CoV-2 infection on personal protective equipment (PPE).

BACKGROUND: SARS-CoV-2 stability and infection persistence has been studied on different surfaces, but scarce data exist related to personal protective equipment (PPE), moreover using realist viral loads for infection. Due to the importance for adequate PPE management to avoid risk of virus infection, RNA stability was evaluated on PPE. METHODS: Persistence of SARS-CoV-2 infection and detection of genomic RNA in PPE (gowns and face masks) were determined by in-vitro assays and RT-qPCR, respectively. Samples were infected with a clinical sample positive for SARS-CoV-2 (Clin-Inf), and with a heat-inactivated SARS-CoV-2 strain sample (Str-Inf) as a control. RESULTS: PPE samples infected with Clin-Inf were positive for the 3 viral genes on gowns up to 5 days post-infection, whereas these overall genes were detected up to 30 days in the case of face masks. However, gowns and FFP2 masks samples contaminated with Clin-Inf showed a cytopathic effect over VERO cells up to 5-7 days post-infection. CONCLUSIONS: SARS-CoV-2 RNA was detected on different PPE materials for 5 to 30 days, but PPE contaminated with the virus was infectious up to 5-7 days. These findings demonstrate the need to improve PPE management and to formulate strategies to introduce viricidal compounds in PPE fabrics.

Gout associated with reduced renal excretion of uric acid. Renal tubular disorder that nephrologists do not treat. / La gota asociada a reducción de la excreción renal de ácido úrico. Esa tubulopatía que no tratamos los nefrólogos.

Gout is recurrent inflammatory arthritis caused by the deposition of monosodium urate crystals in the joints. The risk factors that predispose to suffering from gout include non-modifiable factors such as gender, age, ethnicity and genetics, and modifiable factors such as diet and lifestyle. It has been shown that the heritability of uric acid levels in the blood is greater than 30%, which indicates that genetics play a key role in these levels. Hyperuricaemia is often a consequence of reduced renal urate excretion since more than 70% is excreted by the kidneys, mainly through the proximal tubule. The mechanisms that explain that hyperuricaemia associated with reduced renal urate excretion is, to a large extent, a proximal renal tubular disorder, have begun to be understood following the identification of two genes that encode the URAT1 and GLUT9 transporters. When they are carriers of loss-of-function mutations, they explain the two known variants of renal tubular hypouricaemia. Some polymorphisms in these genes may have an opposite gain-of-function effect, with a consequent increase in urate reabsorption. Conversely, loss-of-function polymorphisms in other genes that encode transporters involved in urate excretion (ABCG2, ABCC4) can lead to hyperuricaemia. Genome-wide association study (GWAS) methods have made it possible to locate new gout-related loci associated with reduced renal urate excretion (NIPAL1, FAM35A).

Metformin: Experimental and Clinical Evidence for a Potential Role in Emphysema Treatment.

Rationale: Cigarette smoke (CS) inhalation triggers oxidative stress and inflammation, leading to accelerated lung aging, apoptosis, and emphysema, as well as systemic pathologies. Metformin is beneficial for protecting against aging-related diseases. Objectives: We sought to investigate whether metformin may ameliorate CS-induced pathologies of emphysematous chronic obstructive pulmonary disease (COPD). Methods: Mice were exposed chronically to CS and fed metformin-enriched chow for the second half of exposure. Lung, kidney, and muscle pathologies, lung proteostasis, endoplasmic reticulum (ER) stress, mitochondrial function, and mediators of metformin effects in vivo and/or in vitro were studied. We evaluated the association of metformin use with indices of emphysema progression over 5 years of follow-up among the COPDGene (Genetic Epidemiology of COPD) study participants. The association of metformin use with the percentage of emphysema and adjusted lung density was estimated by using a linear mixed model. Measurements and Main Results: Metformin protected against CS-induced pulmonary inflammation and airspace enlargement; small airway remodeling, glomerular shrinkage, oxidative stress, apoptosis, telomere damage, aging, dysmetabolism in vivo and in vitro; and ER stress. The AMPK (AMP-activated protein kinase) pathway was central to metformin's protective action. Within COPDGene, participants receiving metformin compared with those not receiving it had a slower progression of emphysema (-0.92%; 95% confidence interval [CI], -1.7% to -0.14%; P = 0.02) and a slower adjusted lung density decrease (2.2 g/L; 95% CI, 0.43 to 4.0 g/L; P = 0.01). Conclusions: Metformin protected against CS-induced lung, renal, and muscle injury; mitochondrial dysfunction; and unfolded protein responses and ER stress in mice. In humans, metformin use was associated with lesser emphysema progression over time. Our results provide a rationale for clinical trials testing the efficacy of metformin in limiting emphysema progression and its systemic consequences.

Effects of Ozone Treatment on Personal Protective Equipment Contaminated with SARS-CoV-2.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing profound health, economic, and social problems worldwide. Management of personal protective equipment (PPE) and its potential limited availability have created concerns about the increased risks for healthcare professionals at hospitals and nursing homes. Ozone is a powerful oxidant agent. The objectives of this study were to examine the effects of ozone treatment on PPE contaminated with SARS-CoV-2, and to explore whether relative humidity could modify those effects. METHODS: PPE contaminated by heat-inactivated SARS-CoV-2 were treated with different ozone concentrations, exposure times, and relative humidity conditions. SARS-CoV-2 gene amplification was assessed by real-time polymerase chain reaction. RESULTS: There was no amplification of SARS-CoV-2 in PPE after the following ozone exposures: 30 s at 10,000 ppm (20 g/m3), 5 min at 4000 ppm, and 10 min at 2000 ppm. At lower ozone concentrations, 4-12 ppm (0.008-0.024 g/m3), the effects were highly dependent on the relative humidity conditions. CONCLUSIONS: Oxidative stress induced by ozone exposure eliminated heat-inactivated SARS-CoV-2 in different PPE components under appropriate exposure times, ozone concentrations, and relative humidity conditions. These findings could have implications in decreasing the risk of contamination associated with personal protective equipment management and in increasing its availability. Further research in the original SARS-CoV-2 strain is guaranteed.