Probiotic Supplementation Attenuates Chemotherapy-Induced Intestinal Mucositis in an Experimental Colorectal Cancer Liver Metastasis Rat Model.

The use of chemotherapeutic agents is of paramount importance when treating colorectal cancer (CRC). Unfortunately, one of the most frequent chemotherapy (CTx) side effects is intestinal mucositis (IM), which may present with several clinical symptoms such as nausea, bloating, vomiting, pain, and diarrhea and even can result in life-threatening complications. There is a focused scientific effort towards developing new therapies to prevent and treat IM. The aim of this study was to assess the outcomes of probiotic supplementation on CTx-induced IM in a CRC liver metastasis rat model. Six-week-old male Wistar rats received either a multispecies probiotic or placebo mixture. On the 28th experiment day, rats received FOLFOX CTx, and afterwards, the severity of diarrhea was evaluated twice daily. Stool samples were collected for further microbiome analysis. Additionally, immunohistochemical stainings of ileum and colon samples with were performed with MPO, Ki67, and Caspase-3 antibodies. Probiotic supplementation alleviates the severity and length of CTx-induced diarrhea. Additionally, probiotics significantly reduced FOLFOX-induced weight and blood albumin loss. Furthermore, probiotic supplementation mitigated CTx-induced histological changes in the gut and promoted intestinal cell regeneration. This study shows that multispecies probiotic supplementation attenuates FOLFOX-induced IM symptoms by inhibiting apoptosis and promoting intestinal cell proliferation.

Experimental Static Cold Storage of the Rat Uterus: Protective Effects of Relaxin- or Erythropoietin-Supplemented HTK-N Solutions.

Uterus transplantation (UTx) is the only treatment method for women with absolute uterine infertility. Currently, the number of grafts retrieved from deceased donors is increasing; hence, prolonged cold ischemia time is inevitable. Thus, this study was designed to assess the effect of the novel relaxin (RLN)- or erythropoietin (EPO)-supplemented Custodiol-N (HTK-N) solutions in an experimental uterus static cold storage (SCS) model. A total of 15 Sprague Dawley rats were used. Uterus horns were randomly assigned into three groups (n = 10/group). SCS was performed by keeping samples at 4 °C in HTK-N solution without or with different additives: 10 IU/mL EPO or 20 nM RLN. Tissue samples were taken after 8 and 24 h of preservation. Uterine tissue histology, and biochemical and immunohistochemical markers were analyzed. No significant differences in SCS-induced tissue damage were observed between groups after 8 h of preservation. Uterine tissue histology, MDA, SOD levels and the TUNEL-positive cell number showed severe damage in HTK-N without additives after 24 h of preservation. This damage was significantly attenuated by adding RLN to the preservation solution. EPO showed no favorable effect. Our study shows that RLN as an additive to an HTK-N solution can serve as an effective uterine tissue preservative in the uterus SCS setting.

Machine Perfusion in Liver Transplantation: A Systematic Review and Meta-Analysis.

Background: Liver transplantation (LTx) is the only treatment option for patients with end-stage liver disease. Novel organ preservation techniques such as hypothermic machine perfusion (HMP) or normothermic machine perfusion (NMP) are under investigation in order to improve organ quality from extended criteria donors and donors after circulatory death. The aim of this study was to systematically review the literature reporting LTx outcomes using NMP or HMP compared to static cold storage (SCS). Methods: The following data were retrieved: graft primary nonfunction rate, early allograft dysfunction (EAD) rate, biliary complication rate, and 12-month graft and patient survival. A total of 15 studies were included (6 NMP and 9 HMP studies), and meta-analysis was performed only for HMP studies because NMP had considerable differences. Results: The systematic review showed the potential of NMP to reduce graft injury and lower the liver graft discard rate. The performed quantitative analyses showed that the use of HMP reduces the rate of EAD (odds ratio [OR] 0.51; 95% confidence interval [CI] 0.34-0.76; p = 0.001; I 2 = 0%) and non-anastomotic biliary strictures (OR 0.34; 95% CI 0.17-0.67; p = 0.002; I 2 = 0%) compared to SCS. Conclusion: Our systematic review and meta-analysis revealed that the use of HMP reduces the rate of EAD and non-anastomotic biliary strictures compared to SCS.

Relaxin and Erythropoietin Significantly Reduce Uterine Tissue Damage during Experimental Ischemia-Reperfusion Injury.

Successful uterus transplantation, a potential treatment method for women suffering from absolute uterine infertility, is negatively affected by ischemia-reperfusion injury (IRI). The aim of this study is to investigate the protective effect of relaxin (RLX) or/and erythropoietin (EPO) on experimental uterus IRI. Eighty rats, randomly assigned into eight groups (n = 10/group), were pretreated with either saline, 5 µg/kg human relaxin-2, 4000 IU/kg recombinant human erythropoietin or their combination. Ischemia was achieved by clamping the aorta and ovarian arteries for 60 min, following 120 min of reperfusion and tissue sampling. For sham animals, clamping was omitted during surgery. There were no differences in tissue histological score, malondialdehyde (MDA) and superoxide dismutase (SOD) levels, myeloperoxidase (MPO) and TUNEL-positive cell count between all sham-operated rats. Pretreatment with RLX preserved normal tissue morphology, reduced MDA levels, MPO and TUNEL-positive cell count, preserved SOD activity and upregulated NICD and HES1 gene expression when compared to the control group. Pretreatment with EPO reduced MDA levels. In conclusion, pretreatment with RLX, EPO or a combination of both EPO and RLX significantly alleviates uterine tissue damage caused by IRI.

Probiotic Supplementation Suppresses Tumor Growth in an Experimental Colorectal Cancer Liver Metastasis Model.

Colorectal cancer (CRC) ranks third in incidence and second in mortality of all cancers worldwide. At the time of primary diagnosis, around 20% of patients already have metastatic CRC and only around 20% are candidates for radical resection. Thus, most of the patients have to undergo chemotherapy (CTx). Due to chemoresistance and side effects, novel treatment additives are crucial for controlling the disease and prolonging patient survival. The aim of this study was to evaluate probiotic supplementation and its antitumorigenic effects in an experimental CRC liver metastasis model. Six-week-old male Wistar rats received either a multispecies probiotic (1.2 × 109 CFU/daily) or placebo mixture. On day 14 of the experiment, rat CRC cells (CC531) were implanted under the liver capsule later treated by FOLFOX CTx. Change in tumor volume was measured by performing micro computed tomography (micro-CT) scanning on experimental days 28 and 34. Additionally, immunohistochemical staining with anti-MPO, anti-Ki67, and anti-CD31 were performed. Tumor apoptosis was evaluated using TUNEL staining. Micro-CT image analysis indicates that probiotic supplementation significantly inhibits tumor growth. No synergistic effects between probiotic supplementation and FOLFOX CTx was observed. Reduced tumor volume was achieved by inhibiting angiogenesis, as tumor microvascular density was significantly lower in rats receiving probiotic supplementation. This study shows that a multispecies probiotic mixture significantly reduces angiogenesis and inhibits CRC liver metastasis growth in an experimental rat model.

Preventing hemorrhoids during pregnancy: a multicenter, randomized clinical trial.

BACKGROUND: To compare specific dietary and behavioral recommendations for hemorrhoids prevention during pregnancy. METHODS: This was a randomized, single-blind, multicenter trial conducted in three different clinical centers. Patients were randomly allocated into two groups in a ratio of 1:1. Intervention consisted of specific dietary and behavioral counseling. The primary outcome of this study was the rate of hemorrhoids at the time of discharge from the obstetrics unit. Categorical variables were compared by the Chi-Squared or Fisher exact tests, as appropriate. Continuous variables were compared using either the Student's t-test or the Mann-Whitney U test. Binary logistic regression model was used to identify independent predictors of hemorrhoids after delivery. This analysis was performed on factors with a p-value < 0.10 in univariate analysis. Statistical analysis was performed using IBM SPSS 23.0 and GraphPad Prism 9 software. A P-value of less than 0.05 was considered significant for all tests. RESULTS: We observed a significantly lower hemorrhoids rate in the intervention group at the time of discharge from the obstetrics unit after delivery (intention-to-treat (ITT) (the relative risk (RR) 0.38; 95% the confidence interval (CI) 0.24-0.59; p < 0.001) per-protocol (PP) (RR 0.42; 95% CI 0.27-0.64; p < 0.001). There was no significant difference in spontaneous miscarriage rate between the groups for both ITT and PP analysis. Additional binary logistic regression analysis revealed that the intervention applied in this study was the only protective factor. Both, the history of hemorrhoids before pregnancy and the increase of newborn height was associated with a higher risk of hemorrhoids. CONCLUSIONS: Our suggested intervention, aimed to modify dietary and behavioral habits, significantly reduces the rate of hemorrhoids after pregnancy and can be safely recommended to pregnant women. TRIAL REGISTRATION: Date of registration: 2016-05-09; Date of initial patient enrollment: 2016-06-02; Trial registration number: 158200-16-843-357; Trial registration site URL: https://www.mf.vu.lt/mokslas/vilniaus-regioninis-biomedicininiu-39tyrimu-etikos-komitetas#isduoti40vrbtek-leidimai .

Ischemic Preconditioning for Liver Transplantation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: In recent decades, liver transplantation (LTx) has increased the survival and quality of life of patients with end-stage organ failure. Unfortunately, LTx is limited due to the shortage of donors. A lot of effort is put into finding new ways to reduce ischemia-reperfusion injury (IRI) in liver grafts to increase the number of suitable organs procured from expanded-criteria donors (ECD). The aim of this study was to systematically review the literature reporting LTx outcomes when using ischemic preconditioning (IPC) or remote ischemic preconditioning (RIPC) to reduce IRI in liver grafts. METHODS: A literature search was performed in the MEDLINE, Web of Science, and EMBASE databases. The following combination was used: "Liver" OR "Liver Transplantation" AND "Ischemic preconditioning" OR "occlusion" OR "clamping" OR "Pringle." The following outcome data were retrieved: the rates of graft primary nonfunction (PNF), retransplantation, graft loss, and mortality; stay in hospital and the intensive care unit; and postoperative serum liver damage parameters. RESULTS: The initial search retrieved 4,522 potentially relevant studies. After evaluating 17 full-text articles, a total of 9 randomized controlled trials (RCTs) were included (7 IPC and 2 RIPC studies) in the qualitative synthesis; the meta-analysis was only performed on the data from the IPC studies. RIPC studies had considerable methodological differences. The meta-analysis revealed the beneficial effect of IPC when comparing postoperative aspartate aminotransferase (AST) corresponding to a statistically lower mortality rate in the IPC group (odds ratio [OR] 0.51; 95% confidence interval [CI] 0.27-0.98; p = 0.04). CONCLUSION: IPC lowers postoperative AST levels and reduces the mortality rate; however, data on the benefits of RIPC are lacking.

Local Perianal Anesthetic Infiltration Is Safe and Effective for Anorectal Surgery.

Background: General or regional anesthesia is predominantly used for anorectal surgery, however in the recent years more attention was drawn in the use of local anesthesia for anorectal surgery. In this study we present the technique and results of the use of local perianal anesthetic infiltration for minor anorectal operations. Methods: In this cohort study patients undergoing surgery for hemorrhoids, anal fissures and low anal fistulas were included. Posterior perineal block was induced with a mixture containing 0.125% bupivacaine and 0.5% lidocaine. All patients were followed up at 30 days either by a post-operative visit or a telephone call and all post-operative complications over the post-operative 30-day period were registered. Results: One thousand and twenty-six consecutive patients were included in our study. For all patients' intraoperative analgesia was achieved after performing perianal anesthetic infiltration and no additional support from the anesthesia team was necessary in any of case. Complications were observed in 14 (1.4%). Urinary retention occurred in 5 (0.5%) cases. Six cases of bleeding occurred after hemorrhoidectomy (0.6%) and 1 (0.1%) after lateral internal sphincterotomy. Perianal abscess developed for two patients (0.2%). Conclusions: Local anesthesia using posterior perineal block technique is safe and effective for intraoperative analgesia in anorectal surgery, saving a substantial operation cost by avoiding the involvement of an anesthesia team and resulting in minimal incidence of urinary retention and other complications.

Relaxin Positively Influences Ischemia-Reperfusion Injury in Solid Organ Transplantation: A Comprehensive Review.

In recent decades, solid organ transplantation (SOT) has increased the survival and quality of life for patients with end-stage organ failure by providing a potentially long-term treatment option. Although the availability of organs for transplantation has increased throughout the years, the demand greatly outweighs the supply. One possible solution for this problem is to extend the potential donor pool by using extended criteria donors. However, organs from such donors are more prone to ischemia reperfusion injury (IRI) resulting in higher rates of delayed graft function, acute and chronic graft rejection and worse overall SOT outcomes. This can be overcome by further investigating donor preconditioning strategies, graft perfusion and storage and by finding novel therapeutic agents that could reduce IRI. relaxin (RLX) is a peptide hormone with antifibrotic, antioxidant, anti-inflammatory and cytoprotective properties. The main research until now focused on heart failure; however, several preclinical studies showed its potentials for reducing IRI in SOT. The aim of this comprehensive review is to overview currently available literature on the possible role of RLX in reducing IRI and its positive impact on SOT.

Factors Influencing Quality of Life during the First Trimester of Pregnancy: A Prospective Cohort Study.

Introduction: Pregnancy, delivery and postpartum periods are associated with fast changesleading to decreased self-confidence, anxiety, stress or even maternal depression impairing theirquality of life (QOL). Although considered important, QOL of women during pregnancy is poorlyunderstood. The aim of our study was to assess factors influencing QOL during first trimester ofpregnancy. The secondary goal of our study was to evaluate whether QOL during first trimester ofpregnancy is associated with newborn weight. Materials and methods: A prospective cohort studywas performed including pregnant women during the first trimester visit. Our questionnaireconsisted of the SF-36 QOL questionnaire, Wexner fecal incontinence scale, and other additionalinformation. The SF-36 questionnaire mental (MCS) and physical (PCS) health scores were used inorder to evaluate QOL of women during first trimester of pregnancy. Two multiple logisticregression models were created in order to determine independent variables that influence the QOL.Results: 440 pregnant women were included in the study. The two main domains that were used inthe study were MCS and PCS, their medians were 50.0 (25.0; 50.0) and 50.1 (39.4; 59.0) pointsrespectively. From the two logistic regression models we determined several independent factorsthat influence QOL of women during the first trimester of pregnancy. Additionally, we determinedthat women who reported worse QOL tended to give birth to newborns large for their gestationalage. Conclusions: We found several significant variables that influence QOL of women during thefirst trimester of pregnancy. We also found that that lower MCS and PCS scores during the firsttrimester are associated with newborns large for gestational age.

The Significance of Endometrial Scratching for Clinical Pregnancy Rate in Long Agonist and Antagonist Protocols.

Background and Objectives: Assisted reproductive techniques today have helped many infertile couples achieve their desired pregnancy. However, unsuccessful implantation is usually the key failure in in vitro fertilization cycles. Many factors are now being studied to improve the implantation rate, one being endometrial artificial injury (endometrial scratching). The purpose of this study was to assess whether local endometrial artificial injury improved pregnancy rate, in long agonist and antagonist protocols. Materials and Methods: A retrospective analysis was carried out at the JSC Baltic American Clinic from January 1, 2016 to December 31, 2018. Women who were undergoing in vitro fertilization treatment were enrolled in the study. Medical data including demographic factors, menstrual history, and anamnesis of infertility were collected from medical records. Subjects were divided into intervention and control groups. The outcome of this study was clinical pregnancy rate (CPR). Results: A total of 137 women presenting with primary or secondary infertility were enrolled in the study. Clinical pregnancy was observed in 44/71 (61.9%) patients in the intervention group and 33/66 (50%) in the group without endometrial scratching (p value = 0.16). CPR in the intervention group was significantly higher in the patient group that had undergone ovarian stimulation with a long agonist protocol rather than the antagonist protocol (73.8% vs. 41.4%; p value = 0.006). In the multivariable logistic regression model, previously failed in vitro fertilization (IVF) (odds ratio (OR) = 0.07, 95% confidence interval (CI) 0.01-0.47), stimulation with the long agonist protocol (OR = 19.89, 95% CI 3.57-18.63), antagonist protocol (OR = 0.05, 95% CI 0.01-0.34), number of embryos (OR = 1.37, 95% CI 1.05-1.38), and number of blastocysts (OR = 2.96, 95% CI 1.43-8.36) remained important independent prognostic factors for clinical pregnancy. Conclusions: Our study findings indicate that randomized controlled studies are required to define patients for this procedure and to prove the effect and safety of local endometrial injury, before it is introduced to routine clinical practice.