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Jorge Barrera-Alcocer,1 Leonel García-Benavides,2 José F Muñoz-Valle,3 Ulises de la Cruz-Mosso,3 Ramón A González,4 Sonia Luquín,5 Luz del C Alarcón-Romero,1 Linda A Marino-Ortega,1 Ines Matia-Garcia,1 Isela Parra-Rojas1 1Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero, México; 2Instituto de Terapéutica Experimental y Clínica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, México; 3Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, México; 4Centro de Investigación en Dinámica Celular, Instituto de Investigación en Ciencias Básicas y Aplicadas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, México; 5Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, MéxicoCorrespondence: Isela Parra-RojasLaboratorio de Investigación en Obesidady Diabetes, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Avenida Lázaro Cárdenas S/N, Ciudad Universitaria, Chilpancingo, Guerrero, 39090, MéxicoTel/Fax +52 7474719310Email iprojas@yahoo.comBackground: Human adenovirus 36 (HAd36) infection has been associated with obesity. Experiments using 3T3-L1 adipocyte cultured cells and human adipose stem cells (hASCc) have shown that HAd36 stimulates the expression of genes implicated in cell differentiation and increased lipid accumulation. The presence of HAd36 in adipose tissue of overweight and obese women has also been confirmed. This study aims to analyze the presence of HAd36 DNA in the adipose tissue of women undergoing surgery for weight reduction and its relationship with obesity through changes in adipocyte morphology as well as the expression of C/EBPβ and HIF-1α.Methods: Fifty-two subcutaneous adipose tissue biopsies were collected. The anthropometric parameters measured were weight, height, skin folds, body circumferences, and body fat percentage. Biochemical measures were performed for glucose, cholesterol, triglycerides, cholesterol HDL-c, and LDL-c. The presence of HAd36 DNA was performed by conventional PCR. Adipocyte morphology was analyzed in H&E-stained sections using ImageJ/Fiji software. The expression of genes C/EBPβ, HIF-1α and β-actin was determined using TaqMan probes.Results: HAd36 DNA was detected in 31% of adipose tissue samples. The presence of viral DNA was not significantly associated with anthropometric, clinical, or metabolic measurements, or with changes in adipose tissue morphology. The levels of mRNA expression for C/EBPβ and HIF-1α did not show significant differences between positive and negative samples for HAd36 (p> 0.05).Conclusion: The presence of HAd36 DNA in adipose tissue was identified, but it was not related to morphological changes of adipocytes, or the expression of C/EBPβ and HIF-1α. Further studies are needed to confirm these findings.Keywords: human adenovirus 36, obesity, gene expression, adipose tissue

The circadian rhythms generated by the master biological clock located in the brain's hypothalamus influence central physiological processes. At the molecular level, a core set of clock genes interact to form transcription-translation feedback loops that provide the molecular basis of the circadian rhythm. In animal models of disease, a desynchronization of clock genes in peripheral tissues with the central master clock has been detected. Interestingly, patients with vascular dementia have sleep disorders and irregular sleep patterns. These alterations in circadian rhythms impact hormonal levels, cardiovascular health (including blood pressure regulation and blood vessel function), and the pattern of expression and activity of antioxidant enzymes. Additionally, oxidative stress in vascular dementia can arise from ischemia-reperfusion injury, amyloid-beta production, the abnormal phosphorylation of tau protein, and alterations in neurotransmitters, among others. Several signaling pathways are involved in the pathogenesis of vascular dementia. While the precise mechanisms linking circadian rhythms and vascular dementia are still being studied, there is evidence to suggest that maintaining healthy sleep patterns and supporting proper circadian rhythm function may be important for reducing the risk of vascular dementia. Here, we reviewed the main mechanisms of action of molecular targets related to the circadian cycle and oxidative stress in vascular dementia.

Background and Objectives : Central aortic pressure (CAP) can be measured through noninvasive methods, and CAP wave analysis can provide information about arterial stiffness. The objective of this study was to compare CAP in women with preeclampsia and normotensive postpartum women from an urban region in western Mexico. Materials and Methods: We recruited 78 women in immediate puerperium, including 39 with preeclampsia and 39 with normotension, who received delivery care in our hospital between September 2017 and January 2018. Pulse wave analysis was used to assess central hemodynamics as well as arterial stiffness with an oscillometric device. For this purpose, the measurement of the wave of the left radial artery was obtained with a wrist applanation tonometer and the ascending aortic pressure wave was generated using the accompanying software (V 1.1, Omron, Japan). Additionally, the systolic CAP, diastolic pressure, pulse pressure, heart rate, and rise rate adjusted for a heart rate of 75 bpm were determined. The radial pulse wave was calibrated using the diastolic and mean arterial pressures obtained from the left brachial artery. For all the statistical analyses, we considered p < 0.05 to be significant. Results: The results were as follows: a systolic CAP of 125.40 (SD 15.46) vs. 112.10 (SD 10.12) with p < 0.0001 for women with and without preeclampsia, respectively. Systolic CAP was significantly elevated in women with preeclampsia and could indicate an elevated risk of cardiovascular disease. Conclusion: CAP is an important parameter that can be measured in this group of patients and is significantly elevated in women with postpartum preeclampsia, even when the brachial blood pressure is normal.

Ischemia-reperfusion (I-R) injury is damage caused by restoring blood flow into ischemic tissues or organs. This complex and characteristic lesion accelerates cell death induced by signaling pathways such as apoptosis, necrosis, and even ferroptosis. In addition to the direct association between I-R and the release of reactive oxygen species and reactive nitrogen species, it is involved in developing mitochondrial oxidative damage. Thus, its mechanism plays a critical role via reactive species scavenging, calcium overload modulation, electron transport chain blocking, mitochondrial permeability transition pore activation, or noncoding RNA transcription. Other receptors and molecules reduce tissue and organ damage caused by this pathology and other related diseases. These molecular targets have been gradually discovered and have essential roles in I-R resolution. Therefore, the current study is aimed at highlighting the importance of these discoveries. In this review, we inquire about the oxidative damage receptors that are relevant to reducing the damage induced by oxidative stress associated with I-R. Several complications on surgical techniques and pathology interventions do not mitigate the damage caused by I-R. Nevertheless, these therapies developed using alternative targets could work as coadjuvants in tissue transplants or I-R-related pathologies., Competing Interests: The authors declare that they have no conflict of interest during the performance of this review, and it was conducted for academic purposes., (Copyright © 2022 Walter Ángel Trujillo-Rangel et al.)

Aim: Intestinal dysfunction in cirrhosis patients is linked to death by bacterial infections. Currently, there is no effective therapy for this complication. This study aims to evaluate butyrate, a novel postbiotic, on the intestinal inflammatory response, tight junction proteins and the microbiota in the cholestasis model., Methods and Results: Wistar rats underwent 15 days of bile duct ligation (BDL). We administered butyrate at a concentration of 1%. The BDL group did not receive treatment. The results showed that butyrate could significantly reduce pro-inflammatory cytokines (IL-17A, IFN-γ, TNF-α) in the ileum and colon while promoting IL-10 expression in the colon. Moreover, it significantly promotes tight junction protein (cld-1, occludin and ZO-1) expression in the ileum. A similar effect was observed in the colon except for ZO-1. Additionally, butyrate limited taxa diversity loss and promoted probiotic genera expansion such as Lachnospira, Prevotella and Lactobacillus. The increase in Turicibacter and Clostridiaceae distinguished the BDL group., Conclusions: Butyrate is effective in regulating the inflammatory response, tight junction proteins and limits bacterial diversity loss., Significance and Impact of the Study: This research reveals that butyrate could represent an interesting postbiotic metabolomic intervention for intestinal epithelium dysfunction in liver disease., (© 2021 The Society for Applied Microbiology.)

The use of herbarium mixture has been empirical, and the properties are not yet known. The aim of this study was to evaluate the effect of oral administration of herbarium mixture ( Guazuma ulmifolia [G. ulmifolia]/Tecoma stans [T. stans] ) on metabolic profile in patients with type 2 diabetes mellitus (T2DM). A randomized, double-blind, placebo-controlled, clinical trial was carried out in 40 patients with T2DM. They were between 40 and 65 years of age, with body mass index (BMI) between 25.0 and 34.9 kg/m 2 and HbA1c >7.0%. BMI, waist circumference, fasting glucose, HbA1c, lipids, kidney, and liver function were measured. The patients were randomly assigned to receive the herbarium mixture ( G. ulmifolia/T. stans ) 400 mg before each meal, or placebo for 90 days. Herbarium mixture group showed decreased waist circumference (99 ± 14 vs. 98 ± 15 cm; P  = .019), fasting glucose (12.0 ± 5.7 vs. 10.3 ± 5.1 mM; P  = .019), and HbA1c (9.9% ± 2.7% vs. 8.9% ± 2.5%, P  = .002). In conclusion, the administration of herbarium mixture ( G. ulmifolia/T. stans ) improved the glycemic profile in patients with T2DM. ClinicalTrial registration: NCT03313856 ClinicalTrials.gov.

Background: There is no treatment for septic acute kidney injury (sAKI). The anti-inflammatory activity of prolonged-release pirfenidone (PR-PFD) could be beneficial in this clinical setting., Methods: This study was a double-blind randomized clinical trial in sAKI patients with nephrology consultation at the Civil Hospital of Guadalajara, in addition to the usual treatment of AKI associated with sepsis; patients were randomized to receive either PR-PFD at 1,200 mg/day (group A) or 600 mg/day (group B) or a matched placebo for 7 consecutive days. The primary objective was the decrease in serum creatinine (sCr) and increase in urinary volume (UV); the secondary objectives were changes in serum electrolytes, acid-base status, and mortality., Results: Between August 2016 and August 2017, 88 patients were randomized. The mean age was 54 (17 ± SD) years, and 47% were male. The main site of infection was the lung (39.8%), septic shock was present in 39.1% of the cases, and the mean SOFA score was 8.8 points. 28 patients received PFD 1,200 mg, 30 patients received PFD 600 mg, and 30 patients received placebo. During the study, sCr did not differ among the groups. The reversion rate of sCr, UV, and mortality was not different among the groups ( p =0.70, p =0.47, and p =0.38, respectively). Mild adverse events were not different among the groups., Conclusion: PR-PFD did not improve the clinical course of sAKI and seemed to be safe in terms of adverse events. This trial is registered with NCT02530359., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Jonathan S. Chávez-Iñiguez et al.)

Adenoviral vector AdhMMP8 (human Metalloproteinase-8 cDNA) administration has been proven beneficial in various experimental models of liver injury improving liver function and decreasing fibrosis. In this study, we evaluated the potential therapeutic AdhMMP8 effect in a chronic kidney damage experimental model. Chronic injury was induced by orogastric adenine administration (100mg/kg/day) to Wistar rats for 4 weeks. AdhMMP8 (3x1011vp/kg) was administrated in renal vein during an induced-ligation-ischemic period to facilitate kidney transduction causing no-additional kidney injury as determined by histology and serum creatinine. Animals were sacrificed at 7- and 14-days post-Ad injection. Fibrosis, histopathological features, serum creatinine (sCr), BUN, and renal mRNA expression of αSMA, Col-1α, TGF-β1, CTGF, BMP7, IL-1, TNFα, VEGF and PAX2 were analyzed. Interestingly, AdhMMP8 administration resulted in cognate human MMP8 protein detection in both kidneys, whereas hMMP8 mRNA was detected only in the left kidney. AdhMMP8 significantly reduced kidney tubule-interstitial fibrosis and glomerulosclerosis. Also, tubular atrophy and interstitial inflammation were clearly decreased rendering improved histopathology, and down regulation of profibrogenic genes expression. Functionally, sCr and BUN were positively modified. The results showed that AdhMMP8 decreased renal fibrosis, suggesting that MMP8 could be a possible therapeutic candidate for kidney fibrosis treatment., Competing Interests: The authors have declared that no competing interests exist.

Background: There is a correlation between the endocannabinoid system and hepatic fibrosis based on the activation of CB1 and CB2 receptors; where CB1 has profibrogenic effects. Gene therapy with a plasmid carrying a shRNA for CB1 delivered by hydrodynamic injection has the advantage of hepatic tropism, avoiding possible undesirable effects of CB1 pharmacological inhibition., Objective: To evaluate hydrodynamics-based liver transfection in an experimental model of liver cirrhosis of a plasmid with the sequence of a shRNA for CB1 and its antifibrogenic effects., Methods: Three shRNA (21pb) were designed for blocking CB1 mRNA at positions 877, 1232 and 1501 (pshCB1-A, B, C). Sequences were cloned in the pENTR™/U6. Safety was evaluated monitoring CB1 expression in brain tissue. The silencing effect was determined in rat HSC primary culture and CCl4 cirrhosis model. Hydrodynamic injection in cirrhotic liver was through iliac vein and with a dose of 3mg/kg plasmid. Serum levels of liver enzymes, mRNA levels of TGF-β1, Col IA1 and α-SMA and the percentage of fibrotic tissue were analyzed., Results: Hydrodynamic injection allows efficient CB1 silencing in cirrhotic livers and pshCB1-B (position 1232) demonstrated the main CB1-silencing. Using this plasmid, mRNA level of fibrogenic molecules and fibrotic tissue considerably decrease in cirrhotic animals. Brain expression of CB1 remained unaltered., Conclusion: Hydrodynamics allows a hepatotropic and secure transfection in cirrhotic animals. The sequence of the shCB1-B carried in a plasmid or any other vector has the potential to be used as therapeutic strategy for liver fibrosis., Competing Interests: The authors have declared that no competing interests exist.

Type 2 diabetes mellitus (T2DM) is associated with premature atherosclerosis and arterial stiffening due to the accumulation of advanced glycation end-products in vessel walls. Green tea polyphenols are considered cardio-protective substances. In this randomised double-blind placebo-controlled trial (NCT02627898), we evaluated the effect of Green tea extract on arterial stiffness parameters, lipids, body composition and sRAGE levels. Twenty normotensive patients with T2DM treated with the standard therapy and statins, mean age 53.2 ± 9.4 years and mean BMI 30.1 ± 4.5 kg/m 2 , were randomised to receive a daily dose of 400 mg of green tea extract (polyphenols ≥90%, EGCG ≥45%) or placebo for 12 weeks. Compared to placebo, administration of green tea extract decreased central augmentation index (-3.05 ± 10.8% vs. 6.7 ± 0.1%, p  = .04). These findings suggest that green tea extract could be used as an adjunct to the standard therapy to improve arterial stiffness in T2DM.

The therapeutic effects of telmisartan, an angiotensin II receptor antagonist and a peroxisome proliferator-activated receptor- γ (PPAR- γ ) agonist, have been demonstrated in several disorders. It has antioxidant and immune response modulator properties and has shown promising results in the treatment of an ischemia/reperfusion (I/R) lesion. In this study, a skeletal muscle (right gastrocnemius muscle) I/R lesion was induced in rats and different reperfusion times (1 h, 24 h, 72 h, 7-day, and 14-day subgroups) were assessed. Furthermore, levels of oxidative markers such as enzymatic scavengers (catalase (CAT) and superoxide dismutase (SOD)) and metabolites (nitrates and 8-oxo-deoxyguanosine) were determined. The degree of tissue injury (total lesioned fibers and inflammatory cell count) was also evaluated. We observed an increase in CAT and SOD expression levels under telmisartan treatment, with a decrease in injury and oxidative biomarker levels in the 72 h, 7-day, and 14-day subgroups. Telmisartan reduced oxidative stress and decreased the damage of the I/R lesion.

Introduction: Liposuction is a popular surgical procedure. As in any surgery, there are risks and complications, especially when combined with fat injection. Case reports of fat embolism have described a possible explanation as the puncture and tear of gluteal vessels during the procedure, especially when a deep injection is planned., Methods: A total of 10 dissections were performed in five fresh cadavers. Each buttocks was divided into four quadrants. We focused on the location where the gluteal vessels enter the muscle and the diameter of the vessels. Colorant at two different angles was injected (30° and 45°). We evaluated the relation of the colorant with the main vessels., Results: We found two perforators per quadrant. The thickness of the gluteal muscle was 2.84 ± 1.54 cm. The area under the muscle where the superior gluteal vessels traverse the muscle was located 6.4 ± 1.54 cm from the intergluteal crease and 5.8 ± 1.13 cm from the superior border of the muscle. The inferior gluteal vessels were located 8.3 ± 1.39 cm from the intergluteal crease and 10 ± 2.24 cm from the superior border of the muscle. When we compared the fat injected at a 30° angle, the colorant stayed in the muscle. Using a 45° angle, the colorant was in contact with the superior gluteal artery and the sciatic nerve. No puncture or tear was observed in the vessels or the nerve., Conclusions: The location where the vessels come in contact with the muscle, which can be considered for fat injection, were located in quadrants 1 and 3. A 30° angle allows for an injection into the muscle without passing into deeper structures, unlike a 45° injection angle.

Aim: To evaluate whether a combination of isosorbide dinitrate spray and chitosan gel (10%) topically applied can have additive benefits for management of diabetic foot ulcers., Methods: In a randomized, placebo-controlled, double-blinded clinical trial, 68 patients were divided into four groups: Group 1: treated with chitosan gel; Group 2: isosorbide dinitrate spray; Group 3: combination of isosorbide dinitrate spray and chitosan gel; Group 4: placebo., Results: Histological analyses showed a significant regeneration in all groups ( p < 0.001). On the final assessment of the ulcer, using the combination was found a wound closure percentage of 71 ± 30, 70 ± 27 using isosorbide dinitrate, 58 ± 30 with chitosan and 50 ± 16 with placebo. The number of patients who achieved complete ulcer closure was six using the combination, four with isosorbide dinitrate, three with chitosan and one with placebo. The progression in the healing process of the ulcer showed marked inmunohistochemical differences of Von Willebrand Factor, desmin, vascular endothelial growth factor-A and α-smooth muscle actin in all groups ( p < 0.001), but without notable differences between them., Conclusion: The combination was better than placebo to reduce the dimensions of the ulcer, accelerate healing and increase the number of patients who achieved complete closure of the ulcer, but the combination was not better than chitosan or isosorbide dinitrate used separately.

The objective of our study was to examine the effect of alpha-lipoic acid (ALA) on clinical and neurophysiologic outcomes after surgery for idiopathic carpal tunnel syndrome (CTS). We conducted a randomized, double-blind, placebo-controlled clinical trial in 20 adults diagnosed with idiopathic CTS after clinical and neurophysiologic assessment. Eligible participants took 600 mg ALA or placebo per day for 1 month before surgery, and for 2 months afterward. Further clinical and neurophysiologic assessments were undertaken immediately before surgical decompression, and at 12 weeks postoperatively with additional clinical assessments at the 4th and 8th week after surgery. Clinical outcome measures were taken by Boston Questionnaire score, the presence or absence of Tinel's sign, and Phalen's test findings. Median nerve conduction studies were also undertaken and interpreted according to Dumitru's reference values. Nineteen patients completed the study; one member of the placebo group was lost during follow-up. There were significant improvements in clinical and neurophysiologic variables in the ALA treatment group, present even before surgery. Boston Questionnaire scores had improved significantly in both groups. In the ALA group, none of the participants had positive Phalen's or Tinel's signs at 12 weeks, and motor and sensory fiber latency and amplitude had significantly improved; in the placebo group, only the sensory distal latency had improved significantly. In conclusion, ALA administered 1 month before open decompression and for 2 months afterward improves the clinical and neurophysiologic outcomes after surgery.

[This corrects the article DOI: 10.1371/journal.pone.0187907.].

Ischemia-reperfusion (I/R) injury is a well-known phenomenon that involves different pathophysiological processes. Connection in diverse systems of survival brings about cellular dysfunction or even apoptosis. One of the survival systems of the cells, to the assault caused by ischemia, is the activation of the renin-angiotensin-aldosterone system (also known as an axis), which is focused on activating diverse signaling pathways to favor adaptation to the decrease in metabolic supports caused by the hypoxia. In trying to adapt to the I/R event, great changes occur that unchain cellular dysfunction with the capacity to lead to cell death, which translates into a poor prognosis due to the progression of dysfunction of the cellular activity. The search for the understanding of the diverse therapeutic alternatives in molecular coupling could favor the prognosis and evolution of patients who are subject to the I/R process.

Background and rationale for the study. Bacterial translocation is an important triggering factor of infection and mortality in cirrhosis. In a rat model using bile duct ligation (BDL), bacterial translocation appears within 24 h after ligation. The dynamic between TH1/TH2/TH17 cytokines and the integrity of the colonic mucosa in the context of cirrhosis is little known. This study aims to determine the link between bacterial translocation and intestinal inflammation in a cholestasis model. Additionally, alterations of the colonic mucus layer and the bacterial load were also addressed., Results: Bacterial translocation detected by microbiological cultures and MALDI-TOF showed that Escherichia coli predominates in mesenteric lymph nodes of BDL rats. Intestinal bacterial load analyzed by qPCR indicates a dramatic Escherichia/Shigella overgrowth at 8 and 30 days post-BDL. IFN-γ, IL-4, and IL-17 evaluated by Western blotting were increased at 8 and 30 days in the small intestine. In the colon, in contrast, only IFN-γ was significantly increased. The colonic mucus layer and mucin-2 expression determined by Alcian blue staining and immunohistochemistry surprisingly showed an increase in the mucus layer thickness related to increased mucin-2 expression during the entire process of liver damage. Hepatic enzymes, as well as collagen I, collagen III, TNF-α, and IL-6 liver gene expression were increased. In conclusion, bacterial overgrowth associated with bacterial translocation is linked to the over-expression of IFN-γ, IL-4, IL-17 and mucin-2. These molecules might facilitate the intestinal permeability through exacerbating the inflammatory process and disturbing tight junctions, leading to the perpetuation of the liver damage.

Background and Aims: ADSCs transplantation had been shown in some experimental models of kidney damage that it improves kidney function and reduces fibrosis. In this study we evaluated the effect of human adipose tissue-derived stem cell (hADSC) therapy in a chronic kidney damage experimental model., Methods: A chronic kidney injury was induced by daily orogastric administration of adenine (100mg/kg) to male Wistar rats for 28 days. hADSCs were isolated, expanded and characterized before transplantation. hADSC administration was performed in a tail vein at a dose of 2 x106 cells/animal. Animals were sacrificed at 7 days post-treatment. The percentage of fibrotic tissue, serum and urine levels of urea, creatinine, total protein and renal mRNA of COL1A1, TGFB1, CTGF, ACTA2, IL6, IL10, TNF were analyzed., Results: hADSCs treatment significantly reduces kidney fibrosis, improves urea and creatinine serum and urine levels, and diminishes COL1A1, TGFB1, CTGF, ACTA2 mRNA kidney levels., Conclusions: These results showed that cell therapy using hADSCs improves renal function and reduces fibrosis.

Background and Aims: hADSCs transplantation in cirrhosis models improves liver function and reduces fibrosis. In addition, Ad-huPA gene therapy diminished fibrosis and increased hepatocyte regeneration. In this study, we evaluate the combination of these therapies in an advanced liver fibrosis experimental model., Methods: hADSCs were expanded and characterized before transplantation. Ad-huPA was simultaneously administrated via the ileac vein. Animals were immunosuppressed by CsA 24 h before treatment and until sacrifice at 10 days post-treatment. huPA liver expression and hADSCs biodistribution were evaluated, as well as the percentage of fibrotic tissue, hepatic mRNA levels of Col-αI, TGF-β1, CTGF, α-SMA, PAI-I, MMP2 and serum levels of ALT, AST and albumin., Results: hADSCs homed mainly in liver, whereas huPA expression was similar in Ad-huPA and hADSCs/Ad-huPA groups. hADSCs, Ad-huPA and hADSCs/Ad-huPA treatment improves albumin levels, reduces liver fibrosis and diminishes Collagen α1, CTGF and α-SMA mRNA liver levels. ALT and AST serum levels showed a significant decrease exclusively in the hADSCs group., Conclusions: These results showed that combinatorial effect of cell and gene-therapy does not improve the antifibrogenic effects of individual treatments, whereas hADSCs transplantation seems to reduce liver fibrosis in a greater proportion., Competing Interests: The authors declare that the funder Innovare provided support in the form of salaries for author JAB, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Besides, author JAB has the USA patent applications numbers 7807457, 7858368 and 8043955 related to application of human uPA wild type/or its truncated version.

Background: Keloids and hypertrophic scars are dermal fibro-proliferative disorders unique to humans. Their treatment is a true challenge with multiple options, but not all the time with good results. Unfortunately this problem is not uncommon in patients with history of burn injury. The aim of this article is to evaluate the use of verapamil and pressure garments in patients with hypertrophic or keloid scar caused by burn injury., Methods: We included patients with a hypertrophic or keloid scar caused by burn injury candidate to treatment with pressure garment. The pathologic scars were evaluated by serial photographic records, Vancouver and Posas scales. The scales of Vancouver and Posas were compared with t Student., Results: We included 13 scars in 11 patients. Four scars were located in the legs, 4 in the arms, 4 in the face-neck and 1 in the abdomen. The dose of verapamil was calculated .03mg per kg. Injections were scheduled every 7 to 10 days until complete 6 sessions. Taking in count Posas scale, patients referred improvement in pigmentation (.01), thickness (.005), pliability (.01) and surface area (.004). In the Vancouver scale the observers mentioned improvement in elevation (.008), pigmentation (.014), vascularity (.022), flexibility (.014) and pruritus (.003). No adverse effects were found in verapamil injection., Conclusions: Verapamil was useful in conjunction with pressure garment to improve the condition of the keloid and hypertrophic scar caused by burn.

Unlabelled: BACKGROUND AND RATIONALE FOR THE STUDY: IL-17, TGF-β1/2 are cytokines involved in the development of kidney, pulmonary and liver fibrosis. However, their expression kinetics in the pathogenesis of cholestatic liver fibrosis have not yet been fully explored. The aim of the study was to analyze the expression of IL-17, RORγt, NKp46, TGF-β1, and TGF-β2 in the liver of rats with bile duct ligation (BDL)., Results: Hepatic IL-17A gene expression analyzed by qRT-PCR showed a dramatic increase of 350 and 10 fold, at 8 and 30 days post BDL, respectively. TGFβ1 and TGFβ2 gene expression significantly increased throughout the whole fibrotic process. At the protein level in liver homogenates, IL-17, TGF-β1, and RORγt significantly increased at 8 and 30 days after BDL. Interestingly, a significant increase in the protein levels of TGF-β2 and decrease of NKp46 was observed only 30 days after BDL. Unexpectedly, TGF-β2 exhibited stronger signals than TGF-β1 at the gene expression and protein levels. Histological analysis showed bile duct proliferation and collagen deposition., Conclusions: Our results suggest that pro-fibrogenic cytokines IL-17, TGF-β1 and, strikingly, TGF-β2 might be important players of liver damage in the pathogenesis of early and advanced experimental cholestatic fibrosis. Th17 cells might represent an important source of IL-17, while NK cell depletion may account for the perpetuation of liver damage in the BDL model.

Ischemia/reperfusion (I/R) lesions are a phenomenon that occurs in multiple pathological states and results in a series of events that end in irreparable damage that severely affects the recovery and health of patients. The principal therapeutic approaches include preconditioning, postconditioning, and remote ischemic preconditioning, which when used separately do not have a great impact on patient mortality or prognosis. Oxidative stress is known to contribute to the damage caused by I/R; however, there are no pharmacological approaches to limit or prevent this. Here, we explain the relationship between I/R and the oxidative stress process and describe some pharmacological options that may target oxidative stress-states., Competing Interests: The authors declare that they have no competing interests.

Introduction: Botulinum toxin is widely used in glabellar musculature. The authors express the need to individualize the approach by means of muscular identification to improve effectiveness. Despite these guidelines, the fixed-point technique is still used., Objective: Comparison of effectiveness of botulinum toxin administration in the glabellar zone by using fixed-site application versus objective-muscle-identification., Materials and Methods: Prolective dynamic cohort study. Patients (after previous informed consent) were assessed on their facial expressions, level of satisfaction, re-interventions, adverse effects, dosage, dilution, and number of injections. All patients who experienced either of both techniques of botulinum toxin administration (fixed-site or objective-muscle-identification) were subjected to followup by the following parameters: statistical analysis: student's t Test (inter-group mean comparisons), paired student's t test (intra-group mean comparisons), χ (2) with Fisher exact text., Results: Sixty-two patients were evaluated (31 fixed-site approach, 31 objective-muscle-identification). No patient abandoned the trial during followup. Fixed-site injections required larger doses (16 vs 12 U, p = 0.001), greater volume (0.48 vs. 0.37 ml, p = 0.001), and more application sites (4 vs 2, p = 0.001), compared to the objective-muscle-identification approach. Under the objective-muscle-identification technique, facial expressions were better attenuated (52 vs 65%, p = 0.001), with a higher initial satisfaction level (6 vs 9, p = 0.001) and final satisfaction level (9 vs 9.9, p = 0.001)., Conclusions: Botulinum toxin application is more effective when administered through the objective-muscle-identification approach (less frowning, lower doses, less fixed sites injected, and patients more satisfied at the end)., Level of Evidence Iii: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Background: Patients who have suffered multiple traumatic injuries, have a serious risk for death. Hypothermia, acidosis and coagulopathy are three complications in these patients, whose presence is known as lethal triad and indicates bad prognosis., Aim: To determine if the lethal triad in multiple trauma patients is associated with higher mortality and Injury Score Severity (ISS)., Material and Methods: One hundred multiple trauma patients aged 26 to 56 years (90 males), admitted to an emergency room, were studied. Body temperature, prothrombin time, partial thromboplastin time, platelet count and blood gases were determined on admission., Results: Twenty six patients had the lethal triad and 15% died in the emergency room within the first 6 hours. No death was recorded among the 74 patients without the lethal triad. The mean ISS among patients with and without the lethal triad was 31.7 and 25.6, respectively (p < 0.05)., Conclusions: The presence of the lethal triad among patients with multiple trauma is associated with a higher mortality and ISS.