IND Group Research Articles

Efficacy of intranasal administration of dexmedetomidine in combination with midazolam for sedation in infant with cleft lip and palate undergoing CT scan: a randomized controlled trial

BackgroundThere is a great challenge to sedation for infants with cleft lip and palate undergoing CT scan, because there is the younger age and no consensus on the type, dosage, and route of drug administration.ObjectiveThis study aimed to evaluate the efficacy of intranasal administration of dexmedetomidine combined with midazolam as a sedative option for infants with cleft lip and palate under imaging procedures.MethodsInfants scheduled for cleft lip and palate repair surgery were randomly assigned to the IND group (intranasal dexmedetomidine 2 µg/kg alone) and the INDM group (intranasal dexmedetomidine 2 µg/kg combined with midazolam 0.05 mg/kg). The primary outcome was the proportion of infants underwent successful computed tomography (CT) scans under intranasal sedation. The secondary outcomes included onset time and duration of sedation, recovery time, Ramsay sedation scale, hemodynamic parameters during sedation, and adverse events. Data analyses involved the unpaired t-test, the repeated-measures analysis of variance test, and the continuity correction χ2 test.ResultsOne hundred five infants were included in the analysis. The proportion of infants underwent successful CT scans under sedation was significantly greater in the INDM group than in the IND group (47 [95.9%] vs. 45 [80.4%], p = 0.016). Additionally, the INDM group had a shorter onset time and a longer duration of sedation statistically (12 [8.5, 17] min vs. 16 [12, 20] min, p = 0.001; 80 [63.6, 92.5] min vs. 68.5 [38, 89] min, p = 0.014, respectively), and their recovery time was significantly longer (43 [30, 59.5] min vs. 31.5 [20.5, 53.5] min, p = 0.006). The difference in Ramsay sedation scale values 20 min after administration was statistically significant between the groups. No statistically significant difference was found between the groups in changes in heart rate and respiratory rate.ConclusionIntranasal administration of dexmedetomidine in combination with midazolam resulted in higher sedation success in comparison with sole dexmedetomidine. However, it has a relatively prolonged duration of sedation and recovery time.Trial registrationChiCTR2100049122, Clinical trial first registration date: 21/07/2021.

Induction Immunotherapy vs. Consolidation Immunotherapy for Unresectable Stage III NSCLC

Consolidation immunotherapy after chemoradiotherapy (CRT) is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). However, whether upfront immunotherapy before CRT has similar benefits has not been addressed. This study aimed at exploring the efficacy and safety of induction immunotherapy for unresectable stage III NSCLC through real-world data. Patients diagnosed with stage III NSCLC who received immunotherapy in combination with sequential (sCRT) or concurrent CRT (cCRT) between November 2018 and December 2021 were retrospectively identified. Patients were divided into induction (Ind), consolidation (Con) and induction plus consolidation (Ind+Con) immunotherapy groups. Progression-free survival (PFS) and overall survival (OS) were assessed from the initiation of treatment and estimated by Kaplan‒Meier method. The potential factors affecting PFS and OS were analyzed by univariate and multivariate Cox regression models. One hundred and two patients were included, with 52 (51.0%) patients in the Ind group, 35 (34.3%) in the Con group and 15 (14.7%) in the Ind+Con group. Median PFS was 24.0 months vs. 36.0 months vs. 19.0 months in the three groups, and 2-year PFS were 43.0% vs 51.1% vs 44.4% (p = 0.940). Median OS was not reached (NR) vs. 44.0 months vs. NR, with a 2-year OS rate of 80.5% vs. 84.4% vs. 86.2% (p = 0.861). In the cCRT setting, 2-year PFS rates were 56.7% vs. 71.6% vs. 100.0% (p = 0.439), 2-year OS rates were 92.3% vs. 89.3% vs. 100.0% in the three groups (p = 0.827). In multivariate analysis, elder (HR = 0.487, p = 0.037) and cCRT (HR = 0.282, p = 0.001) were the independent factors favoring PFS, while only elder (HR = 0.088, p = 0.021) was the independent factors favoring OS. Adverse events were similar in the three arms. Further analysis found the objective response rate (ORR) and disease control rate (DCR) in the Ind and Ind+Con group after induction immunotherapy were 59.7% and 98.5%, respectively. Only 1 (1.5%) patient developed progression. Subgroup analysis showed no significant difference in PFS (p = 0.520) and OS (p = 0.116) between patients who responded to induction immunotherapy (PR+CR) and those who did not (SD+PD). Patients with <4 cycles of induction immunotherapy exhibited numerically better PFS than those with ≥4 cycles of induction immunotherapy (p = 0.113) and improved OS (p = 0.021). Induction immunotherapy may achieve similar survival benefits to consolidation immunotherapy, and the combination of induction and consolidation immunotherapy with cCRT appears to achieve better outcomes. It seems feasible and safe to upfront immunotherapy before CRT, and further investigations on the combination of induction immunotherapy and CRT are warranted.

The role of natural compounds in rat mammary cancer: the beneficial effects of Santolina chamaecyparissus L. aqueous extract

Breast cancer is the most diagnosed cancer among women, and a leading cause of death worldwide. Santolina chamaecyparissus L. is a plant with multiple health benefits, including anticancer and anti-diabetic properties. This study aimed to assess the chemopreventive effects of S. chamaecyparissus aqueous extract (SCE) in an animal model of mammary cancer. A total of 28 four-week-old female Wistar rats were divided into four groups: control, MNU-induced (IND), SCE-supplemented (SCE), and SCE+IND. SCE was added to drinking water (12.72 mg/kg body weight) ad libitum. MNU was administered via the intraperitoneal route at 50 days of age. Weekly monitoring of body weight, food/drink intake, humane endpoints, and number of mammary tumours were recorded. Twenty weeks after MNU administration, animals were sacrificed by anaesthetic overdose and a necropsy was performed. Blood samples were used to determine blood count and serum biochemistry analysis, while kidney and liver samples were analysed for oxidative stress. Tumour samples were collected for gene expression and histology studies. SCE chemical composition was analysed by LC-MS and contained 19 phenolic compounds, with the most abundant being myricetin-O-glucuronide and 1,3-O-dicaffeoylquinic acid. Two animals in the IND group were sacrificed due to exceeding the humane endpoint limits. SCE supplementation delayed mammary tumour development, reducing its volume and weight. SCE had a positive impact on haematological parameters, particularly the neutrophil-lymphocyte ratio (P=0.026). No significant differences were observed in serum biochemistry, except for creatinine kinase MB, or in oxidative stress markers. Gene expression analysis showed significantly reduced VEGF expression levels (P=0.0158) in tumours from SCE+IND. These findings suggest that SCE is deserving of further study to identify the individual compounds and to understand its influence on animal models during cancer development.

Multimodality therapy for lung cancer invading the chest wall: A study of the French EPITHOR database

ObjectivesAccording to a nation-based study, we intend to report the data of the patients operated on for lung cancer invading the chest wall, taking into consideration the completion of induction chemotherapy (Ind_CT), induction radiochemotherapy (Ind_RCT) or no induction therapy (0_Ind). Materials and methodsAll patients with a primary lung cancer invading the chest wall who underwent radical resection from 2004 to 2019 were included. Superior sulcus tumors were excluded. ResultsOverall, 688 patients were included: 522 operated without induction therapy, 101 with Ind_CT and 65 with Ind_RCT. Postoperative 90-day mortality was 10.7% in the 0_Ind group, 5.0% in the Ind_CT group, 7.7% in the Ind_RCT group (p = 0.17). Incomplete resection rate was 14.0% in the 0_Ind group, 6.9% in the Ind_CT group, 6.2% in the Ind_RCT group (p = 0.04). In the 0_Ind group, 70% of the patients received adjuvant therapies. Overall survival (OS) analysis disclosed the best long-term outcomes in the Ind_RCT group (5-year OS probability: 56.5% versus 40.0% and 40.5% for 0_Ind and Ind_CT groups, respectively; p = 0.035). At multivariable analysis, Ind_RCT (HR = 0.571; p = 0.008), age > 60 years old (HR = 1,373; p = 0.005), male sex (HR = 1.710; p < 0.001), pneumonectomy (HR = 1.368; p = 0.025), pN2 status (HR = 1.981; p < 0.001), ≥3 resected ribs (HR = 1.329; p = 0.019), incomplete resection (HR = 2.284; p < 0.001) and lack of adjuvant therapy (HR = 1.959; p < 0.001) were associated with OS. Ind_CT was not associated with survival (HR = 0.848; p = 0.257). ConclusionInduction chemoradiation therapy seems to improve survival. Therefore, the present results should be confirmed by a prospective randomized trial testing the benefit of induction radiochemotherapy for NSCLC invading the chest wall.

Proteomic profiling of cerebrospinal fluid in pediatric myelin oligodendrocyte glycoprotein antibody-associated disease

BackgroundMyelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an autoimmune demyelinating disorder of the central nervous system.MethodsExtracted proteins from 34 cerebrospinal fluid (CSF) samples [patients with MOGAD (MOG group, n = 12); healthy controls (HC group, n = 12); patients with MOG seronegative and metagenomics next-generation sequencing-negative inflammatory neurological diseases (IND group, n = 10)] were processed and subjected to label-free quantitative proteomics. Supervised partial least squares-discriminant analysis (PLS-DA) and orthogonal PLS-DA (O-PLS-DA) models were also performed based on proteomics data. Functional analysis of differentially expressed proteins (DEPs) was performed using Gene Ontology, InterPro, and Kyoto Encyclopedia Genes and Genomes. An enzyme-linked immunosorbent assay was used to determine the complement levels in serum from patients with MOGAD.ResultsFour hundred and twenty-nine DEPs (149 upregulated and 280 downregulated proteins) were identified in the MOG group compared to the HC group according to the P value and fold change (FC). Using the O-PLS-DA model, 872 differentially abundant proteins were identified with variable importance projection (VIP) scores > 1. Five proteins (gamma-glutamyl hydrolase, cathepsin F, interalpha-trypsin inhibitor heavy chain 5, latent transforming growth factor beta-binding protein 4 and leukocyte-associated immunoglobulin-like receptor 1) overlapping between the top 30 DEPs with top-ranked P value and FC and top 30 proteins in PLS-DA VIP lists were acquired. Functional analysis revealed that the dysregulated proteins in the MOG group were primarily involved in complement and coagulation cascades, cell adhesion, axon guidance, and glycosphingolipid biosynthesis compared to the HC group.ConclusionThe proteomic alterations in CSF samples from children with MOGAD identified in the current study might provide opportunities for developing novel biomarker candidates.

Hypoxia-Activated Prodrugs with Dual COX-2/CA Inhibitory Effects on Attenuating Cardiac Inflammation under Hypoxia.

Cardiac inflammation is generally accompanied by hypoxia, while myocardial injury and an abnormal microenvironment caused by hypoxia tend to suppress the efficacy of common anti-inflammatory drugs. To improve the anti-inflammatory effect under hypoxia, a hypoxia-activated prodrug HAP1 consisting of a cyclooxygenase-2 (COX-2) inhibitor Ind and a carbonic anhydrase (CA) inhibitor Ace was synthesized. HAP1 was found to be activated by nitroreductase (NTR) under hypoxia to release two pharmacophores and achieve the combinatory medication intensively at the hypoxic site, better than Ind or Ace alone. When NTR activity was inhibited by Na2WO4 under hypoxia, no pharmacophores were found to release from HAP1 without exhibiting its activity. However, the efficacy of the Ind and Ace combination group (I&A) was not affected. Furthermore, HAP1 showed advantages over I&A in vivo not only in improving bioavailability but also in reducing side effects. The HAP approach turns out to inhibit cardiac inflammation efficiently and safely under hypoxia.

Clinical Efficacy of Combined Use of Azilsartan with Indapamide and Azilsartan with Nitrendipine in Patients with Arterial Hypertension

The aim of our study was a comparative evaluation of the effectiveness of the combined use of azilsartan with indapamide, and azilsartan with nitrendipine in achieving antihypertensive and organ-protective effects in patients with arterial hypertension (AH). Methods and Results: The study included 101 patients aged 30-75 years (mean age of 53,1±11,2 years) with AH Grades 1-2 (ESC/ESH, 2018), who were on outpatient treatment at the Republican Specialized Scientific and Practical Medical Center for Cardiology. After the screening stage, all patients were discontinued from previous therapy and assigned to the 2 regimes of dual therapy. Group 1 included 50 AH patients treated with azilsartan (Az) and indapamide (Ind); Group 2 included 51 patients treated with Az and nitrendipine (Nit). The average daily dose of Az was 49.3±6.0 mg, Nit - 10.88±4.3 mg, and Ind - 1.69±0.5 mg. The effectiveness of the prescribed therapy was evaluated after 6 months of treatment. The 6-month dual therapy with Az+Ind and Az+Net is characterized by high antihypertensive efficacy with a significant positive effect on the parameters of diurnal blood pressure (BP) profile in AH patients. Achieving the target level of BP in both groups provided high organ-protective efficacy, expressed in a significant regression of LV hypertrophy and LV dimensions, a decrease in the carotid intima-media thickness (CMIT) and arterial rigidity. However, the best cardio- and vaso-protective efficacy was noted in Group 1, which was expressed in a more pronounced improvement in the left ventricular diastolic function, a decrease in the CIMT on both sides, and a significant improvement in the parameters of central hemodynamics and arterial stiffness. Dual therapy with Az+Ind and Az+Nit in AH patients was accompanied by a positive effect on the metabolic profile and excellent nephroprotection, with an advantage in the Az+Ind group. A significant decrease in the blood level of LDL-C, TC, and uric acid is characteristic in both groups of patients. A significant decrease in the levels of FBG and TG occurs only in the Az+Ind therapy.

The influence of different proton pump inhibitors and potassium-competitive acid blockers on indomethacin-induced small intestinal injury.

The influence of gastric acid inhibitors (GAIs) on nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy is controversial. Herein, the influences of different GAIs on NSAID-induced intestinal injury and the underlying mechanisms are clarified. Indomethacin (IND; 10mg/kg/day) was administered to mice to induce small intestinal injury. Disease activity was examined macroscopically and histologically. The permeability of small intestine was evaluated by measuring plasma lipopolysaccharide levels. 16S rDNA sequencing was performed to determine the composition of intestinal flora. Among the four GAIs, ilaprazole (IPZ) significantly attenuated IND-induced small intestinal injury and maintained the integrity of the mucosal barrier. Omeprazole (OPZ) and vonoprazan (VPZ) ameliorated ulceration without significant differences, while rabeprazole (RPZ) failed to protect against the injury. To explore the potential mechanism, we investigated changes in the gut microbiota mediated by GAIs. After 5-day administration, GAIs significantly altered the composition of the gut microbiota. The IND group had a significant decrease in alpha diversity compared with the control group, and this decrease was reversed by OPZ and IPZ treatment, respectively. After IPZ treatment, the community membership was more assembled in the control group than the IND group. Further, we found that Lactobacillus was significantly increased in the groups of OPZ, IPZ, and VPZ, while Bacteroides was significantly increased in the RPZ group. Our results indicated that GAIs have different influences on the mucosal barrier, possibly by altering the composition of intestinal microbiota, and the impacts mediated by various GAIs in the IND-induced intestinal damage model seem different.

Conservative treatment of congenital clubfoot in children

In outpatient department of CITO 207 children with clubfoot were treated by Vilenskiy's functional technique. After application of plaster bandage from the middle third of the femur to the toes the influence was directed on the certain muscle groups. Then step-by-step application of fixative tutors from polymeric materials (polivik) was used. There were 3 groups of patients: 1st group 126 patients were treated starting from the first month of life; I Ind group 57 patients, aged 25 years,, after failed treatment at other hospitals; Illrd group 24 patients with recurrence of the deformity after conservative treatment. Follow up ranged from 1 to 25 years. Good results were achieved in 94 cases (74.6%) (I group), 31 (54.4%) (II group) and in 9 patients (37.5%)) (IIIgroup). Satisfactory results were noted in 15 (11.9%)), 8 (14%)), 5 (20.8%)) patients, respectively, and unsatisfactory results in 17 (13.4%)), 18 (31.6%)) and 10 (41.6%), respectively.

A proportion of CD4+ T cells from patients with chronic Chagas disease undergo a dysfunctional process, which is partially reversed by benznidazole treatment

Signs of senescence and the late stages of differentiation associated with the more severe forms of Chagas disease have been described in the Trypanosoma cruzi antigen-specific CD4+ T-cell population. However, the mechanisms involved in these functions are not fully known. To date, little is known about the possible impact of benznidazole treatment on the T. cruzi-specific functional response of CD4+ T cells. The functional capacity of CD4+ T cells was analyzed by cytometric assays in chronic Chagas disease patients, with indeterminate form (IND) and cardiac alterations (CCC) (25 and 15, respectively) before and after benznidazole treatment. An increase in the multifunctional capacity (expression of IFN-γ, IL-2, TNF-α, perforin and/or granzyme B) of the antigen-specific CD4+ T cells was observed in indeterminate versus cardiac patients, which was associated with the reduced coexpression of inhibitory receptors (2B4, CD160, CTLA-4, PD-1 and/or TIM-3). The functional profile of these cells shows statistically significant differences between IND and CCC (p<0.001), with a higher proportion of CD4+ T cells coexpressing 2 and 3 molecules in IND (54.4% versus 23.1% and 4.1% versus 2.4%, respectively). A significant decrease in the frequencies of CD4+ T cells that coexpress 2, 3 and 4 inhibitory receptors was observed in IND after 24-48 months of treatment (p<0.05, p<0.01 and p<0.05, respectively), which was associated with an increase in antigen-specific multifunctional activity. The IND group showed, at 9-12 months after treatment, an increase in the CD4+ T cell subset coproducing three molecules, which were mainly granzyme B+, perforin+ and IFN-γ+ (1.4% versus 4.5%). A CD4+ T cell dysfunctional process was detected in chronic Chagas disease patients, being more exacerbated in those patients with cardiac symptoms. After short-term benznidazole treatment (9-12 months), indeterminate patients showed a significant increase in the frequency of multifunctional antigen-specific CD4+ T cells.

Neutrophils from patients with the cardiac clinical form of Chagas disease release less NETs than neutrophils from healthy individuals

Chagas disease (CD) is a global health concern with approximately 12000 deaths per year worldwide. In the chronic phase, about 30% of patients develop the cardiac clinical form, which presents symptoms associated with the presence of inflammatory cells in the cardiac tissue. Neutrophils are inflammatory cells able to modulate the chronic immune response against pathogens. These cells are capable of interacting with Trypanosoma cruzi, the aetiological agent of CD, and perform several effector functions, such as NET release. However, few studies have been carried out to investigate the role of these cells in the disease. To investigate the release of NETs by neutrophils from CD patients by measuring the amount of DNA and elastase released. Measurement of DNA release by neutrophils from chronic CD patients presenting the indeterminate (IND group; n=18) and cardiac (CARD group; n=15) clinical forms and nonchagasic subjects (n=18) stimulated with soluble antigen of T.cruzi was quantified using the Quant-iT™ PicoGreen® dsDNA assay kit. Patients from CARD group release less DNA (117.3±21.85ng/mL; *P=.0131) than neutrophils from control (177.7±58.41ng/mL). Elastase enzyme degranulation was measured using the substrate N-methoxysuccinyl-Ala-Ala-Pro-Val p-nitroanilide (SAAVNA). Absorbance values of elastase degranulation activity showed that only cells from healthy individuals presented a high release profile of elastase. Also, we found a negative correlation between DNA released concentration and risk of death (r=-.6574; *P=.0173); the lower the neutrophil DNA release from chagasic patients with cardiac event, the higher the risk of death. These preliminary data show that patients with the cardiac form of CD release less NETs than nonchagasic individuals, raising the possibility that lower release of NETs enhances risk of death in CD patients with cardiac events.

Inefficacy of chromogranin a assays as neuroendocrine tumor diagnostic tools compared to the NETest.

4612 Background: Chromogranin A (CgA) remains a commonly used diagnostic and monitoring tool for neuroendocrine tumor disease despite NCCN guidelines identifying it as a category 3 (major concerns about utility) biomarker. Several commercial assays have been developed to measure this protein (or its fragments) and are available both at CLIA-certified laboratories (USA) as well as in NET Centres of Excellence (CoEs - Europe). CgA is typically reimbursed by insurance companies and appears in several guidelines (e.g., ENETS). We sought to directly evaluate the accuracy of detecting NET disease using two different CgA assays, one in the USA (NEOLISA, EuroDiagnostica, IBL-America, CLIA-certified laboratory) and one in an ENETS CoE (CgA ELISA, Demeditec Diagnostics, Germany). We compared the results to the NETest, a circulating mRNA assay, recently validated as an IVD for NETs. Methods: Patients: NETs ( n=258) including lung: n=43; duodenum n=9; gastric: n=44; pancreas: n=67; small bowel: n=40; appendix: n=10; rectum: n=45. No image-evidence of disease ( n=122) (IND) and image-positive disease (IPD) ( n=136). CgA assays (plasma): NEOLISA, ULN &gt;108ng/ml, DD: ULN&gt;99ng/ml. Data mean±SEM. NETest (whole blood): qRT-PCR - multianalyte algorithmic analyses, CLIA-laboratory. All samples de-identified and assessed blinded. Statistics: Mann-Whitney U-test, Pearson correlation &amp; McNemar-test. Results: In the entire group ( n=258), NEOLISA assay CgA levels were significantly ( p&lt;0.0001) higher (216±91ng/ml) vs. the DD-assay (76±8ng/ml). The assays exhibited a high concordance in output (Pearson r=0.81, p&lt;0.0001), but there were 10.9% ( n=31) discordant results. This reflected the NEOLISA assay detecting more CgA-positive samples. IPD group: CgA-positives were detected in 48/136 (35%, NEOLISA) vs. 28 (21%, DD-assay). McNemar’s Chi2=15.04, p&lt;0.001 OR: 11.0, indicating the NEOLISA was significantly better than the DD-assay. The NETest, in contrast, was positive in 135/136 (99%; OR: 87-106, p&lt;0.0001). IND group: CgA-positives were detected in 12/122 (10%, NEOLISA) vs. 9 (7%, DD-assay; p=NS). The majority (75%) of positives were associated with gastric NETs. The NETest was positive in 7 (6%); 4 were gastric NETs and 3 exhibited elevated CgA. Conclusions: Two standard CgA assays used for NET management (one accepted by Medicare in the USA, the second used at a CoE in Europe) only detect NET disease in 21-35% of cases. In contrast, a circulating mRNA fingerprint, the NETest, is ~99% accurate for detecting NET disease.

Effects of vaccination on acute-phase protein response in broiler chicken.

Broiler chickens experience an acute-phase response (APR) through vaccination, which reflects the innate immunity and stress related to immunization. It is also considered that APR can modulate adaptive immunity and response to infection. As biomarkers for APR, assessing the acute-phase proteins (APPs) function and their levels in response to immunization is of great value for vaccine design, development and administration. In this study, the heterophils/lymphocyte (H/L) ratio and the level of APPs was evaluated in broilers with three different Newcastle disease (ND) vaccination regimens. Inactivated ND vaccine (IND) was administered by the intramuscular route. Live attenuated strains, Lasota and Vitapest, was administered by ocular routes. H/L ratio, serum amyloid A (SAA) and alpha-1 acid glycoprotein (AGP) were measured before and after two rounds of vaccination on days 10 and 21. In a comparison between the three vaccines, H/L ratio in IND group significantly increased to 3 fold (1.48 ± 0.41) after the first vaccination while the Lasota and Vitapest showed a milder response. The concentration of SAA increased after 24h by 1.8-fold in IND group (0.116 ± 0.015 mg/L) and 2-fold in Lasota group (0.14 ± 0.002 mg/L). Significant changes were found in Vitapest group after 48h post vaccination (0.113 ± 0.016 mg/L). Elevation pattern of AGP, 24 hours after first vaccination in IND (3.5-fold) and Vitapest (2.5-fold) was different from Lasota in which the peak was reached after 48 hours (2.9-fold). Except for IND group, no significant changes in SAA and AGP concentrations were detected after the second vaccination. A significant positive correlation between SAA values at day 22 and HI titers at day 28 (r = 0.998, P≤0. 0.005) was found. According to these results, different types of ND vaccines can cause different patterns of acute phase responses. Assessment of stress and level of acute-phase proteins can be used for prediction of immune response outcomes in vaccine design and development.

Early insulin resistance is associated with alterations in gut permeability and microbial activity in rats fed a moderately westernized diet

AbstractIn Western societies, unbalanced diets may lead to intestinal allostatic stress, with microbial dysbiosis and alteration of the gut barrier function. These local modifications may induce a low-grade inflammation via endotoxemic process, which contribute to systemic alterations clustering into the metabolic syndrome (MetS) and increasing the risk of cardiovascular diseases and type 2 diabetes. We investigated the sequence of events initiating the MetS in rats challenged with a diet that differed moderately from the dietary guidelines, regarding the proportions and nature of energy, carbohydrates, lipids and fibre.Male Wistar rats (265 g upon arrival) were with either a standard diet (Con, n = 10, 3730 kcalkg, 4.0% lipids, 6.3% sucrose, 58.0% starch, 5.0% fibre) or a westernized induction diet (Ind, n = 10, moderately enriched in energy (4120 kcal/kg), lipid (24.0%), and sugars (15%, half sucrose-half fructose), and low in starch (25.5%) and fibre (1.25%). An oral glucose tolerance test (OGTT) was performed after 3 weeks. Rats were euthanized after a further week for body composition and collection of caecum content and tissue samples. LPS-binding protein (LPS-BP) was assayed in plasma; ileum and colon samples were used for measurement of wall barrier function (using Ussing chambers) and microbial activity was assessed in caecum (enzymes and metabolites).Body weight did not differ between Con and Ind groups at any time, as well as the absolute masses and proportions of visceral adipose tissue and liver. Fasting triglyceride, glucose, insulin and LPS-BP concentrations, HOMA index and glucose AUC during the OGTT were similar in both groups. When compared to the Con group, Ind rats showed significantly higher risk markers, i.e.: (1) Insulin AUC (x2); (2) Hepatic triglyceride content (x2.8); (3) Wall permeability at both the para- and transcellular levels (x2.6 and 4.3, respectively) in the ileum (but not in the colon). In the caecum, H2S absolute and relative amounts were twice higher in the Ind group, in relation with 2–3-fold increases in specific and total activities of microbial cysteine desulfhydrase and proteases.Multiple dietary changes mimicking a moderately westernized diet induced an increased ileal permeability and changes in the caecal microbial activity, without evidence of endotoxemia. These perturbations were associated with detrimental rupture of homeostasis at both the splanchnic (hepatic steatosis) and systemic (insulin resistance) levels. In this realistic model, these alterations preceded the occurrence of clinical markers of the MetS (obesity and elevated plasma concentrations of glucose and triglyceride).

The Protective Effect of Lercanidipine on Indomethacin-Induced Gastric Ulcers in Rats

Abstract Nonsteroidal anti-inflammatory drugs (NSAID) are among the aggressive factors causing gastric ulcer. They cause oxidative damage in the gastric tissue and lead to intracellular calcium deposition. Lercanidipine is a calcium channel blocker derived from the third generation dihydropyridine. The aim of this study is to analyse the effect of lercanidipine on indomethacin-induced gastric ulcers. A total of 24 albino Wistar male rats were divided into four groups; those who received indomethacin 25 mg/kg (IND), 5 mg mg/kg lercanidipine +25 mg/kg indomethacin (LC-5), 10 mg/kg lercanidipine+25mg/kg indomethacin (LC-10) and healthy rats who received 0.5 mL distilled water. Six hours after the application of indomethacin, the animals were sacrificed by high dose thiopental sodium. The stomachs of the animals were excised to perform a macroscopic analysis and the ulcerous region was measured on millimeter paper. All the stomachs were subjected to a biochemical analysis. Macroscopic analysis revealed hyperaemia on the gastric surface of the indomethacin group. Ulcerous tissues formed by oval, circular or irregular mucosal defects in varying diameters and depths were observed on the whole surface of the stomach. Hyperaemia was lower and ulcerous region was smaller in groups LC-5 and LC-10 compared to IND group. Malondialdehyde and myeloperoxidase levels were significantly lower and total glutathione and cyclooxygenase-1 activity were higher in groups LC-5 and LC-10. Lercanidipine did not change the cyclooxygenase-2 activity. Lercanidipine in doses 10 mg/kg is more effective compared to 5 mg/kg. Lercanidipinine can be useful in the treatment of NSAID-induced gastric damage.

Influence of Preoperative Oropharyngeal Microflora on the Occurrence of Postoperative Pneumonia and Survival in Patients Undergoing Esophagectomy for Esophageal Cancer.

The aim of this study was to clarify the correlation between oropharyngeal microflora and postoperative complications as well as long-term survival after esophagectomy. Although the oral cavity is known to be a potential reservoir for pathogens, the influence of abnormal oropharyngeal microflora on the outcomes of patients undergoing esophagectomy remains unknown. This study included 675 patients who underwent esophagectomy between 2007 and 2014. Saliva samples from the oropharynx were collected 2 days before the operation. There were 442 patients with indigenous flora (Ind group) and 233 with allopatric flora. Among the patients with allopatric flora, 140 had antibiotic-sensitive microbes only (Allo-S group) while 93 had different types of antibiotic-resistant microbes (Allo-R group). We investigated the correlation between the types of oropharyngeal microflora and the incidence of postoperative complications as well as long-term outcomes. Sixteen microbes could be cultivated from the saliva samples. The incidence of postoperative pneumonia in the Allo-S and Allo-R groups was significantly higher than in the Ind group (P < 0.001). In addition, acute respiratory distress syndrome was more often observed in the Allo-R group than in the other groups (P = 0.002). A significantly higher rate of antibiotic use and longer hospital stays were observed in the Allo-R group compared with the Ind group. Multivariate logistic regression analysis revealed that the presence of allopatric antibiotic-resistant microbes in the oropharynx was an independent risk factor for postoperative pneumonia (odds ratio, 3.93; 95% confidence interval, 2.41-6.42). The overall survival was significantly poorer in the Allo-R group than in the other groups. Preoperative oropharyngeal culture is a simple and low-cost method that can predict both the occurrence of postoperative pneumonia and poor prognosis after esophagectomy.

PD1 and PDL1 molecules control suppressor activity of regulatory T cells in chronic Chagas cardiomyopathy patients

IntroductionChagas disease, caused by the protozoan Trypanosoma cruzi (T. cruzi), is the fourth most important tropical disease, which affects approximately 7 million people worldwide. The mechanisms involved in the development of this disease are not completely well understood. An important protective role of regulatory T cells (Treg) in Chagas disease has been observed; however, the specific mechanisms remain unclear. We evaluated apoptosis as a possible mechanism mediated by Treg cells (CD4+CD25HighFOXP3+) to orchestrate the immune response in chronic Chagas disease. Methods and resultsPatients with Chagas disease were grouped as the indeterminate (IND; asymptomatic patients with Chagas disease; n = 10) and dilated cardiomyopathy (CARD; n = 10). Healthy T. cruzi-negative individuals (NI; n = 10) were included as a control group. In order to evaluate the apoptotic cell profile, the expression of PD1, PD1L, CD39, CD95, CD95L molecules were investigated. We also evaluated the proportion of CD14+ cells expressing caspase 3. The IND group presented a substantially higher expression of CD39 by Treg cells as compared to the CARD group. On the other hand, the CARD group showed higher expression of PD-1 by Treg cells than both NI and IND groups. Significant positive correlations were observed between Treg CD95L+ cells and CD14 cells expressing caspase 3 as well as between Treg CD39 cells and CD14+ Caspase3+ cells in the IND group. ConclusionOur data indicate that the expressions of different molecules that induce apoptosis are associated with suppressive mechanisms mediated by Treg cells and suggest a possible role for PD1 and PDL1 molecules in the morbidity of chronic Chagas disease.

Impact of long-term potassium supplementation on thiazide diuretic-induced abnormalities of glucose and uric acid metabolisms.

Treatment of hypertension with thiazide diuretics may trigger hypokalemia, hyperglycemia, and hyperuricemia. Some studies suggest simultaneous potassium supplementation in hypertensive patients using thiazide diuretics. However, few clinical studies have reported the impact of long-term potassium supplementation on thiazide diuretic-induced abnormalities in blood glucose and uric acid (UA) metabolisms. One hundred hypertensive patients meeting the inclusion criteria were equally randomized to two groups: IND group receiving indapamide (1.25-2.5 mg daily) alone, and IND/KCI group receiving IND (1.25-2.5 mg daily) plus potassium chloride (40 mmol daily), both for 24 weeks. At the end of 24-week follow-up, serum K+ level in IND group decreased from 4.27 ± 0.28 to 3.98 ± 0.46 mmol/L (P < 0.001), and fasting plasma glucose (FPG) and UA increased from 5.11 ± 0.52 to 5.31 ± 0.57 mmol/L (P < 0.05), and from 0.404 ± 0.078 to 0.433 ± 0.072 mmol/L (P < 0.05), respectively. Serum K+ level in IND/KCl group decreased from 4.27 ± 0.36 to 3.89 ± 0.28 mmol/L (P < 0.001), and FPB and UA increased from 5.10 ± 0.41 to 5.35 ± 0.55 mmol/L (P < 0.01), and from 0.391 ± 0.073 to 0.457 ± 0.128 mmol/L (P < 0.001), respectively. The difference value between the serum K+ level and FPG before and after treatment was not statistically significant between the two groups. However, the difference value in UA in IND/KCl group was significantly higher than that in IND group (0.066 (95% confidence interval (CI): 0.041-0.090) mmol/L vs. 0.029 (95% CI: 0.006-0.058) mmol/L, P < 0.05). The results showed that long-term routine potassium supplementation could not prevent or attenuate thiazide diuretic-induced abnormalities of glucose metabolism in hypertensive patients; rather, it may aggravate the UA metabolic abnormality.

Patterns of Oxytocin Use in Those Undergoing Trial of Labor After Cesarean (TOLAC) [19N

INTRODUCTION: Oxytocin use in the management of TOLAC is controversial. Data assessing the relationship between oxytocin use and adverse outcomes is scant. METHODS: Chart review of 159 patients with one prior cesarean undergoing TOLAC divided into those who were: (1) induced with oxytocin (IND, n=44), (2) augmented with oxytocin (AUG, n=37) and (3) managed expectantly after presenting in labor (SPON, n=78). Following obtained: maternal baseline characteristics, amount administered and duration of oxytocin use if used, incidence of adverse outcomes. Chi-square and ANOVA were used for statistical analysis. RESULTS: Baseline characteristics between groups were similar. Two cases of uterine ruptures and one of hemorrhage occurred in the IND group. All three cases had an initial Bishop score less than 5. Average total amount of oxytocin administered and duration of oxytocin use in this subgroup were 4412 milliunits and 12.7 hours. Five patients underwent cervical ripening balloon placement followed by oxytocin for induction. In this subgroup, none experienced adverse outcomes and three of the five had a successful TOLAC. Average total amount of oxytocin administered and duration of oxytocin use were 1988 milliunits and 7.3 hours. One case of uterine dehiscence necessitating surgical intervention occurred in the SPON group. There were no complications in the AUG group. No significant differences were noted among the groups regarding other outcomes including cesarean delivery rate. CONCLUSION: Induction of labor in the presence of an unfavorable cervix and prior cesarean is associated with adverse outcomes. Cervical ripening balloon has a role in achieving a successful TOLAC.

NSAID use in intervertebral disc degeneration: what are the effects on matrix homeostasis in vivo?

Background ContextNon-steroidal anti-inflammatory drugs (NSAIDs) are a widely used treatment for low back pain (LBP). Literature on NSAID use in articular cartilage has shown detrimental effects; however, minimal data exist to detail the effects of NSAIDs in intervertebral disc degeneration (IDD). As IDD is a major cause of LBP, we explored the effects of indomethacin, a commonly used NSAID, on disc matrix homeostasis in an animal model of IDD. PurposeThis study aimed to determine the effects of oral indomethacin administration on IDD in an in vivo rabbit model. This study hypothesized that indomethacin use would accelerate the progression of IDD based upon serial imaging and tissue outcomes. Study Design/SettingThis was a laboratory-based, controlled, in vivo evaluation of the effects of oral indomethacin administration on rabbit intervertebral discs. MethodsSix skeletally mature New Zealand white rabbits were divided into two groups: disc puncture alone to induce IDD (Puncture group) and disc puncture plus indomethacin (Punc+Ind group). The Punc+Ind group received daily administration of 6mg/kg oral indomethacin. Serial magnetic resonance imaging (MRI) was obtained at 0, 4, 8, and 12 weeks. The MRI index and the nucleus pulposus (NP) area were calculated. Discs were harvested at 12 weeks for determination of disc glycosaminoglycan (GAG) content, relative gene expression measured by real-time polymerase chain reaction, and histologic analyses. ResultsThe MRI index and the NP area of punctured discs in the Punc+Ind group demonstrated no worsening of degeneration compared with the Puncture group. Histologic analysis was consistent with less severe disc degeneration in the Punc+Ind group. Minimal differences in gene expression of matrix genes were observed between Puncture and Punc+Ind groups. The GAG content was higher in animals receiving indomethacin in both annulus fibrosus and NP at adjacent uninjured discs. ConclusionsOral indomethacin administration did not result in acceleration of IDD in an in vivo rabbit model. Future research is needed to ascertain long-term effects of indomethacin and other NSAIDs on disc matrix homeostasis.