Helminth-induced regulation of T-cell transfer colitis requires intact and regulated T cell Stat6 signaling in mice.

Infection with parasitic worms (helminths) alters host immune responses and can inhibit pathogenic inflammation. Helminth infection promotes a strong Th2 and T regulatory response while suppressing Th1 and Th17 function. Th2 responses are largely dependent on transcriptional programs directed by Stat6-signaling. We examined the importance of intact T cell Stat6 signaling on helminth-induced suppression of murine colitis that results from T cell transfer into immune-deficient mice. Colonization with the intestinal nematode Heligmosomoides polygyrus bakeri resolves WT T cell transfer colitis. However, if the transferred T cells lack intact Stat6 then helminth exposure failed to attenuate colitis or suppress MLN T cell IFN-γ or IL17 production. Loss of Stat6 signaling resulted in decreased IL10 and increased IFN-γ co-expression by IL-17+ T cells. We also transferred T cells from mice with constitutive T cell expression of activated Stat6 (Stat6VT). These mice developed a severe eosinophilic colitis that also was not attenuated by helminth infection. These results show that T cell expression of intact but regulated Stat6 signaling is required for helminth infection-associated regulation of pathogenic intestinal inflammation.

Shoulder tip pain after cesarean section: General versus spinal anesthesia.

Background and Aim: Shoulder tip pain is a common but overlooked complication during the postoperative cesarean section. In this study, we aimed to investigate the relationship between the anesthesia method and the incidence of shoulder tip pain. Patients and Methods: In this randomized clinical study, 117 patients who underwent cesarean section were divided into two groups as spinal anesthesia and general anesthesia. The demographic characteristics, the presence, the severity of shoulder tip pain, and also analgesic consumption in the first 24 hours were compared. Results: The incidence of shoulder tip pain was significantly higher in the spinal anesthesia group than in the general anesthesia group (p = 0.032). While there was no statistically significant difference in terms of the number of patients who needed opioid treatment within the first 24 hours between patients with and without STP, a statistically significant difference was observed in terms of the use of nonsteroidal anti-inflammatory drugs (P < 0.001). Conclusions: This study shows that the frequency and severity of shoulder pain are higher in women who have had cesarean section under spinal anesthesia, compared to those who had received general anesthesia.

Helminth-Induced Production of TGF-ß and Suppression of Graft-versus-Host Disease Is Dependent on IL-4 Production by Host Cells.

Helminths stimulate the secretion of Th2 cytokines, like IL-4, and suppress lethal graft-versus-host disease (GVHD) after bone marrow transplantation. This suppression depends on the production of immune-modulatory TGF-ß and is associated with TGF-ß-dependent in vivo expansion of Foxp3+ regulatory T cells (Treg). In vivo expansion of Tregs is under investigation for its potential as a therapy for GVHD. Nonetheless, the mechanism of induced and TGF-ß-dependent in vivo expansion of Tregs, in a Th2 polarized environment after helminth infection, is unknown. In this study, we show that helminth-induced IL-4 production by host cells is critical to the induction and maintenance of TGF-ß secretion, TGF-ß-dependent expansion of Foxp3+ Tregs, and the suppression of GVHD. In mice with GVHD, the expanding donor Tregs express the Th2-driving transcription factor, GATA3, which is required for helminth-induced production of IL-4 and TGF-ß. In contrast, TGF-ß is not necessary for GATA3 expression by Foxp3+ Tregs or by Foxp3- CD4 T cells. Various cell types of innate or adaptive immune compartments produce high quantities of IL-4 after helminth infection. As a result, IL-4-mediated suppression of GVHD does not require invariant NKT cells of the host, a cell type known to produce IL-4 and suppress GVHD in other models. Thus, TGF-ß generation, in a manner dependent on IL-4 secretion by host cells and GATA3 expression, constitutes a critical effector arm of helminthic immune modulation that promotes the in vivo expansion of Tregs and suppresses GVHD.

STAT6 and Furin Are Successive Triggers for the Production of TGF-ß by T Cells.

Production of TGF-ß by T cells is key to various aspects of immune homeostasis, with defects in this process causing or aggravating immune-mediated disorders. The molecular mechanisms that lead to TGF-ß generation by T cells remain largely unknown. To address this issue, we take advantage of the fact that intestinal helminths stimulate Th2 cells besides triggering TGF-ß generation by T lymphocytes and regulate immune-mediated disorders. We show that the Th2 cell-inducing transcription factor STAT6 is necessary and sufficient for the expression of TGF-ß propeptide in T cells. STAT6 is also necessary for several helminth-triggered events in mice, such as TGF-ß-dependent suppression of alloreactive inflammation in graft-versus-host disease. Besides STAT6, helminth-induced secretion of active TGF-ß requires cleavage of propeptide by the endopeptidase furin. Thus, for the immune regulatory pathway necessary for TGF-ß production by T cells, our results support a two-step model, composed of STAT6 and furin.

IL-6 mediated JAK/STAT3 signaling pathway in cancer patients with cachexia.

OBJECTIVES: We investigated the changes in the IL-6 and STAT3 expression levels in cachectic and non-cachectic patients with gastric, lung and breast cancer and evaluated the association between IL-6 and STAT3 levels and cancer types in terms of cachexia condition. BACKGROUND: Cancer-associated cachexia, observed in nearly 50‒80 % of cancer patients, has drawn attention in advanced patients. IL-6/JAK/STAT pathway plays an essential role in the progression of cancer cachexia through the regulation of the inflammatory response. METHODS: This study consisted of 48 gastric, breast and lung cancer patients (18 cachectic and 30 non-cachectic) and healthy individuals. Total RNA isolation and cDNA synthesis was performed after the collection of blood samples. IL-6 and STAT3 expression levels were analyzed by RT- PCR analysis. RESULTS: Our findings demonstrated that IL-6 mRNA levels considerably increased 19.89±8.25, 5.18±2.81 and 15.33±9.54-fold in gastric, lung and breast cancer patients with cachexia, respectively. Additionally, a 16.67±7.13, 14.21±11.72 and 8.85±3.89-fold increase in the STAT3 expression level was detected in cachectic gastric, lung and breast cancer patients, respectively (p<0.01). CONCLUSION: STAT3 may be considered as a therapeutic target for cachectic patients with gastric, lung and breast cancer. Furthermore, IL-6 mediates STAT3 activation in cachectic gastric and breast cancer patients (Tab. 5, Fig. 2, Ref. 62).

Recirculating Immunocompetent Cells in Colitic Mice Intensify Their Lung Response to Bacterial Endotoxin.

BACKGROUND: Patients with inflammatory bowel disease have higher incidence of airway hyperresponsiveness compared to the general population. Lung inflammation leading to airway hyperresponsiveness causes illnesses for more than ten percent of the population in USA. AIMS: We investigated the lung response to bacterial endotoxin in colitic mice. METHODS: Rag-1 mice were transplanted with negatively selected splenic T cells. Some mice groups were treated with NSAID to develop colitis. All mice were treated with bacterial endotoxin and necropsied 3 weeks later. RESULTS: Colitic mice developed intensified lung inflammation on day 21 of treatment with bacterial endotoxin. Pulmonary lymphocytes from colitic mice displayed a proinflammatory cytokine profile, expressed high ICAM1 and low FoxP3. CD11c+, CD8+ cells bound and responded to non-systemic antigens from gut-localized microbiota and had higher expression of TLR4. CONCLUSIONS: Colitic mice developed exacerbated lung inflammation in response to bacterial endotoxin compared to non-colitic mice. Proinflammatory cytokines from pulmonary lymphocytes induced high expression of ICAM1 and suppressed FoxP3 on CD4+ cells. CD11c+, CD8+ cells binding and responding to gut-localized antigens as well as high expression of TLR4 indicate innate and adaptive lung response to bacterial endotoxin. Inflammatory cells from colons of colitic mice homed in the lungs as well as the intestine suggesting recirculation of sensitized immunocompetent cells. These data support our hypothesis that colitis intensifies lung inflammation.

Intestinal helminths regulate lethal acute graft-versus-host disease and preserve the graft-versus-tumor effect in mice.

Donor T lymphocyte transfer with hematopoietic stem cells suppresses residual tumor growth (graft-versus-tumor [GVT]) in cancer patients undergoing bone marrow transplantation (BMT). However, donor T cell reactivity to host organs causes severe and potentially lethal inflammation called graft-versus-host disease (GVHD). High-dose steroids or other immunosuppressive drugs are used to treat GVHD that have limited ability to control the inflammation while incurring long-term toxicity. Novel strategies are needed to modulate GVHD, preserve GVT, and improve the outcome of BMT. Regulatory T cells (Tregs) control alloantigen-sensitized inflammation of GVHD, sustain GVT, and prevent mortality in BMT. Helminths colonizing the alimentary tract dramatically increase the Treg activity, thereby modulating intestinal or systemic inflammatory responses. These observations led us to hypothesize that helminths can regulate GVHD and maintain GVT in mice. Acute GVHD was induced in helminth (Heligmosomoides polygyrus)-infected or uninfected BALB/c recipients of C57BL/6 donor grafts. Helminth infection suppressed donor T cell inflammatory cytokine generation and reduced GVHD-related mortality, but maintained GVT. H. polygyrus colonization promoted the survival of TGF-ß-generating recipient Tregs after a conditioning regimen with total body irradiation and led to a TGF-ß-dependent in vivo expansion/maturation of donor Tregs after BMT. Helminths did not control GVHD when T cells unresponsive to TGF-ß-mediated immune regulation were used as donor T lymphocytes. These results suggest that helminths suppress acute GVHD using Tregs and TGF-ß-dependent pathways in mice. Helminthic regulation of GVHD and GVT through intestinal immune conditioning may improve the outcome of BMT.

Evaluation of antioxidant properties, elemental and phenolic contents composition of wild nettle (Urtica dioica L.) from Tunceli in Turkey.

Wild nettle (Urtica dioica L.) types were sampled from different geographical regions in Tunceli (Turkey) to determine their mineral, vitamin, phenolic contents and their antioxidant properties. The total phenol varied from 37.419 ± 0.380 to 19.182 ± 1.00 mg of GAEs g(-1) of dry nettle. The highest radical scavenging effect was observed in Mazgirt parting of the ways 7.5 km with 33.70 ± 0.849 mg mL(-1). The highest reducing power was observed in the nettles from Mazgirt parting of the ways 7.5 km. Among the various macronutrients estimated in the plant samples, potassium was present in the highest quantity followed by calcium and phosphate. Kaempferol and resveratrol were not determined in some nettle samples but rutin levels were determined in all samples. Vitamin A concentrations were ranged between 13.64 ± 1.90 and 5.74 ± 1.00 (mg kg(-1) dry weight). These results show that Urtica dioica L. collected from Tunceli in Turkey could be considered as a natural alternative source for food, pharmacology and medicine sectors.

The effects of glycyrrhizin on experimental acute pancreatitis in rats.

INTRODUCTION: Although physiopathology of acute pancreatitis (AP) is not fully understood, the roles of reactive oxygen species (ROS) and changes of cytokines have been determined. AIM: To investigate anti-inflammatory and anti-oxidant effects of glycyrrhizin (GL) on taurocholate-induced AP in rats. MATERIALS AND METHODS: Thirty six rats were randomly divided into three groups as sham, AP and AP+GL (n=12 per group). AP was induced by 1 ml/kg body weight using 5% taurocholate injection into the biliopancreatic duct in groups II and III after clamping the hepatic duct. In groups III, GL (20 mg/kg) was given by oral gavage twice daily for 4 days. Group I and II did not receive any treatment. After the rats were killed; blood samples were taken to measure amylase, lipase, calcium, albumin, urea, glucose, AST and LDH assays before killing. Pancreatic tissue samples were also taken for biochemical analyses and histopathology. RESULTS: Amylase, lipase, AST and urea levels were significantly lower in the AP+GL group than in the AP group. Cytokines including IL-6, TNF-α and MPO levels were significantly lower in the AP+GL group than in the AP group. Even so there is no statistically difference between in the AP+GL group and the AP group in terms of pancreatic tissue IL-1ß, IL-6 and TNF-α levels. DISCUSSION: GL treatment significantly decreased pancreatic tissue MPO activities and MDA levels in the AP+GL group compared with the other groups (p = 0.001 and p = 0.05, respectively). Acinar cell necrosis, hemorrhage, and edema determined that were significantly lower in the AP+GL group than in the AP group (p < 0.001). CONCLUSIONS: GL treatment for acute necrotizing pancreatitis in rats suppressed the levels of pro-inflammatory cytokines, and caused a clear recovery of histological changes.

After Bone Marrow Transplantation, the Cell-Intrinsic Th2 Pathway Promotes Recipient T Lymphocyte Survival and Regulates Graft-versus-Host Disease.

Recipient T cells can aggravate or regulate lethal and devastating graft-versus-host disease (GVHD) after bone marrow transplantation (BMT). In this context, we have shown before that intestinal immune conditioning with helminths is associated with survival of recipient T cells and Th2 pathway-dependent regulation of GVHD. We investigated the mechanism of survival of recipient T cells and their contribution to GVHD pathogenesis in this helminth infection and BMT model after myeloablative preparation with total body irradiation in mice. Our results indicate that the helminth-induced Th2 pathway directly promotes the survival of recipient T cells after total body irradiation. Th2 cells also directly stimulate recipient T cells to produce TGF-ß, which is required to regulate donor T cell-mediated immune attack of GVHD and can thereby contribute to recipient T cell survival after BMT. Moreover, we show that recipient T cells, conditioned to produce Th2 cytokines and TGF-ß after helminth infection, are fundamentally necessary for GVHD regulation. Taken together, reprogrammed or immune-conditioned recipient T cells after helminth infection are crucial elements of Th2- and TGF-ß-dependent regulation of GVHD after BMT, and their survival is dependent on cell-intrinsic Th2 signaling.

Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans: report of an expert meeting.

The present report summarizes the United States Department of Veterans Affairs (VA) field-based meeting titled "Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans." Our Veteran patient population experiences a high incidence of service-related chronic physical and mental health problems, such as infection, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), various forms of hematological and non-hematological malignancies, neurologic conditions, end-stage organ failure, requiring transplantation, and posttraumatic stress disorder (PTSD). We report the views of a group of scientists who focus on the current state of scientific knowledge elucidating the mechanisms underlying the aforementioned disorders, novel therapeutic targets, and development of new approaches for clinical intervention. In conclusion, we dovetailed on four research areas of interest: 1) microbiome interaction with immune cells after hematopoietic cell and/or solid organ transplantation, graft-versus-host disease (GVHD) and graft rejection, 2) intestinal inflammation and its modification in IBD and cancer, 3) microbiome-neuron-immunity interplay in mental and physical health, and 4) microbiome-micronutrient-immune interactions during homeostasis and infectious diseases. At this VA field-based meeting, we proposed to explore a multi-disciplinary, multi-institutional, collaborative strategy to initiate a roadmap, specifically focusing on host microbiome-immune interactions among those with service-related chronic diseases to potentially identify novel and translatable therapeutic targets.

Morbidity and mortality of the Hartmann procedure for diverticular disease over 18 years in a single institution.

AIM: Hartmann's procedure for perforated diverticulitis is associated with substantial morbidity and mortality. This study analyses factors associated with morbidity/mortality and possible changes over time. METHOD: Patients treated by urgent Hartmann's procedure for perforated diverticulitis between 1992 and 2010 were studied, and information was collected on age, sex, perioperative details, 30-day morbidity and mortality recorded in an institutional review board approved database supplemented by chart review. Patients were divided into four groups based on the year of surgery. Univariate and multivariate logistic regression analysis was performed to identify risk factors associated with morbidity and mortality. RESULTS: In all, 199 patients (51% female, mean age 65 years, mean body mass index 28 kg/m(2)) were identified. The American Society of Anesthesiologists (ASA) score was 4 in 30% of patients and Hinchey Stage IV in 16%. The mean length of stay was 12.5 ± 10 days. Mortality was 15% and did not change significantly over time. Overall morbidity was 52% and significantly increased over time on univariate analysis (P = 0.007) but not on multivariate analysis (P = 0.11). Independent predictors of morbidity on multivariate analysis were Hinchey IV (P < 0.001) and hypoproteinaemia (P = 0.001). Independent predictors for mortality were ASA > 3 (P = 0.01), abnormal creatinine (P = 0.007), steroid use (P = 0.007), Hinchey IV (P = 0.032), low albumin (P < 0.001) and low body mass index (P = 0.001). CONCLUSION: Mortality after Hartmann's procedure for perforated diverticulitis has not decreased during the last 18 years. Morbidity has actually increased over time although this is related to increased disease severity and comorbidity. Future efforts should focus on the identification of patient subgroups benefiting from earlier elective surgery and alternative surgical approaches when perforated diverticulitis does occur.

Physical activity and perceptions of neighborhood walkability among Turkish women in low and high socio-economic environments: an exploratory study.

The purpose of this study was to compare the levels of physical activity, exercise stages of change, and perceptions of neighborhood walkability among Turkish women who were living in low and high socio-economic (SES) environments. The participants included 188 women in low SES and 206 in high SES environments, between the ages of 18 and 65 years. The Low SES group had a higher rate of inactivity, and relative to the High SES group, was less likely to rate the neighborhood environment as promoting and supportive of physical activity. Intervention programs for women living in low SES areas should be developed and administered while taking the level of physical activity, exercise stages of change, and perceptions of neighborhood walkability into consideration.

Peripartum management of tuberous sclerosis complex complicated by massive angiomyolipomas.

Tuberous sclerosis complex is a genetic disease that can affect multiple organs, commonly the renal, central nervous, cardiac and respiratory systems. Here, we present the peripartum management of a woman with a new diagnosis of tuberous sclerosis complex associated with massive renal angiomyolipomas. There was significant risk of catastrophic haemorrhage from the angiomyolipomas during pregnancy. This created a challenging scenario for the anaesthetists, obstetricians, urologists and interventional radiologists involved in their care, necessitating collaborative working, numerous investigations and honest patient-centred discussions. Evidence for the management of tuberous sclerosis and angiomyolipomas in pregnancy does not appear to have been previously reported. After much consideration, arterial embolisation of the most vascular area of the angiomyolipoma was completed at 28 weeks gestation under remifentanil sedation. An elective caesarean section under combined spinal epidural anaesthesia was completed at 37 + 3 weeks gestation. Central nervous system involvement must always be considered; benign tumours within the brain and spinal cord may contraindicate neuraxial techniques. Early multidisciplinary involvement is essential due to the diverse and complex nature of tuberous sclerosis. Individuals differ in their presentation and disease severity; therefore, they must be assessed on an individual basis with management tailored accordingly.

The negative effects of surgery persist beyond the early postoperative period after laparoscopic colorectal resection.

PURPOSE: The recovery benefits of laparoscopy are traditionally believed to minimize the initial negative impact of surgery on early postoperative quality of life (QOL). We evaluate whether laparoscopic colectomy leads to recovery of QOL early after surgery and evaluate factors associated with the change in QOL. METHODS: Preoperative and early postoperative QOL data (SF-36) were prospectively accrued for patients undergoing laparoscopic colorectal resection (LCR) (2002-2009). Changes in postoperative QOL from preoperative values and effects of patient, disease, operation and postoperative outcomes on these changes were evaluated. RESULTS: One hundred and sixty-six patients (female = 86) underwent LCR for cancer (n = 79), Crohn's disease (n = 24), diverticulitis (n = 38), and ulcerative colitis (n = 25) with complete SF-36 scores. Median age was 56.9 (range: 15-91) years, mean body mass index 27.4 ± 6.2 kg/m(2) with American Society of Anesthesiologists (ASA) class being II in 94 patients. Median operative time was 152.5 (range: 50-358) min; mean length of stay (LOS) 4.5 ± 3.3 days. At 4 weeks, the postoperative SF-36 physical component scale (PCS) continued to be lower than the preoperative PCS (41.8 ± 8.8 vs. 47.1 ± 9.4, P < 0.001), while the postoperative SF-36 mental component scale (MCS) was similar to the preoperative MCS (45.6 ± 10.2 vs. 46.1 ± 11.9, P = 0.17). Gender, age, operation, LOS, surgeon, ASA, BMI, complications, and readmission were not associated with a change in QOL from preoperative values. Cancer as an indication for surgery was associated with less improvement of MCS and PCS (P = 0.024 and 0.004, respectively). CONCLUSIONS: Although patients who undergo LCR may have clinical evidence of healing at 4 weeks after surgery, QOL does not return to the preoperative level. This finding may help develop evidence-based recommendations pertaining to timing of return to full activity.

Parasitic Infections of the Gastrointestinal Track and Liver.

Parasites have coevolved with humans. Several of them colonize the human body and establish a symbiotic relationship. Other parasites cause severe and lethal diseases. Prevalence of parasitic infections is decreased in highly industrialized countries, largely due to enforced hygienic practices. In contrast, parasites cause significant morbidity and mortality in parts of the world with barriers to effective public hygiene. Some parasites have emerged as potent pathogens in specific patient populations, such as immune suppressed individuals, regardless of sanitation. This article reviews common parasites encountered in clinical practice and, in the setting of host-parasite symbiosis, discusses their immune regulatory role.

First direct human-to-cat transmission of the SARS-CoV-2 B.1.1.7 variant.

A highly transmissible severe acute respiratory coronavirus 2 (SARS-CoV-2) caused the coronavirus diseases 2019 (COVID-19) pandemic, which resulted the highest morbidity and mortality rates among SARS-CoV and MERS-CoV. SARS-CoV-2 B.1.1.7 variant indicated the higher transmission among human-to-human and increasing hospitalisation. SARS-CoV-2 infection was observed in domestic animals showing human-to-pet transmission. In the current study, we report the first direct known human-to-cat transmission of the SARS-CoV-2 B.1.1.7 variant within the same family. Previous findings showed that companion animals can get infected by COVID-19 patients after 3-6 weeks; however, according to our molecular findings, the cat was infected by the viral variant at the same period. Moreover, B.1.1.7 infection caused and developed several clinical symptoms including cardiac and ocular abnormalities. Overall, our findings determined the first direct and high transmission ability of the B.1.1.7 variant from COVID-19 affected family members to cat. This result showed that the SARS-CoV-2 B.1.1.7 variant could have the highest transition capacity from human to domestic cat as shown for human-to-human. The governmental or worldwide policies should consider more detailed against the war with COVID-19 pandemic.

Risk factors for diabetic foot ulcers in metreleptin naïve patients with lipodystrophy.

AIM: Patients with lipodystrophy are at high risk for chronic complications of diabetes. Recently, we have reported 18 diabetic foot ulcer episodes in 9 subjects with lipodystrophy. This current study aims to determine risk factors associated with foot ulcer development in this rare disease population. METHODS: Ninety metreleptin naïve patients with diabetes registered in our national lipodystrophy database were included in this observational retrospective cohort study (9 with and 81 without foot ulcers). RESULTS: Patients with lipodystrophy developing foot ulcers had longer diabetes duration (p = 0.007), longer time since lipodystrophy diagnosis (p = 0.008), and higher HbA1c levels (p = 0.041). Insulin use was more prevalent (p = 0.003). The time from diagnosis of diabetes to first foot ulcer was shorter for patients with generalized lipodystrophy compared to partial lipodystrophy (p = 0.036). Retinopathy (p < 0.001), neuropathy (p < 0.001), peripheral artery disease (p = 0.001), and kidney failure (p = 0.003) were more commonly detected in patients with foot ulcers. Patients with foot ulcers tended to have lower leptin levels (p = 0.052). Multiple logistic regression estimated significant associations between foot ulcers and generalized lipodystrophy (OR: 40.81, 95% CI: 3.31-503.93, p = 0.004), long-term diabetes (≥ 15 years; OR: 27.07, 95% CI: 2.97-246.39, p = 0.003), and decreased eGFR (OR: 13.35, 95% CI: 1.96-90.67, p = 0.008). CONCLUSIONS: Our study identified several clinical factors associated with foot ulceration among patients with lipodystrophy and diabetes. Preventive measures and effective treatment of metabolic consequences of lipodystrophy are essential to prevent the occurrence of foot ulcers in these high-risk individuals.