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White matter injury (WMI) is thought to be a major contributor to long-term cognitive dysfunctions after traumatic brain injury (TBI). This damage occurs partly due to apoptotic death of oligodendrocyte lineage cells (OLCs) after the injury, triggered directly by the trauma or in response to degenerating axons. Recent research suggests that the gut microbiota modulates the inflammatory response through the regulation of peripheral immune cell infiltration after TBI. Additionally, T-cells directly impact OLCs differentiation and proliferation. Therefore, we hypothesized that the gut microbiota plays a critical role in regulating the OLC response to WMI influencing T-cells differentiation and activation. Gut microbial depletion early after TBI chronically reduced re-myelination, acutely decreased OLCs proliferation, and was associated with increased myelin debris accumulation. Surprisingly, the absence of T-cells in gut microbiota depleted mice restored OLC proliferation and remyelination after TBI. OLCs co-cultured with T-cells derived from gut microbiota depleted mice resulted in impaired proliferation and increased expression of MHC-II compared with T cells from control-injured mice. Furthermore, MHC-II expression in OLCs appears to be linked to impaired proliferation under gut microbiota depletion and TBI conditions. Collectively our data indicates that depletion of the gut microbiota after TBI impaired remyelination, reduced OLCs proliferation with concomitantly increased OLC MHCII expression, and required the presence of T cells. This data suggests that T cells are an important mechanistic link by which the gut microbiota modulate the oligodendrocyte response and white matter recovery after TBI.

The influence of the gut microbiota on traumatic brain injury (TBI) is presently unknown. This knowledge gap is of paramount clinical significance as TBI patients are highly susceptible to alterations in the gut microbiota by antibiotic exposure. Antibiotic-induced gut microbial dysbiosis established prior to TBI significantly worsened neuronal loss and reduced microglia activation in the injured hippocampus with concomitant changes in fear memory response. Importantly, antibiotic exposure for 1 week after TBI reduced cortical infiltration of Ly6C high monocytes, increased microglial pro-inflammatory markers, and decreased T lymphocyte infiltration, which persisted through 1 month post-injury. Moreover, microbial dysbiosis was associated with reduced neurogenesis in the dentate gyrus 1 week after TBI. By 3 months after injury (11 weeks after discontinuation of the antibiotics), we observed increased microglial proliferation, increased hippocampal neuronal loss, and modulation of fear memory response. These data demonstrate that antibiotic-induced gut microbial dysbiosis after TBI impacts neuroinflammation, neurogenesis, and fear memory and implicate gut microbial modulation as a potential therapeutic intervention for TBI.

Clinical trials of therapeutics for traumatic brain injury (TBI) demonstrating preclinical efficacy for TBI have failed to replicate these results in humans, in part due to the absence of clinically feasible therapeutic windows for administration. Minocycline, an inhibitor of microglial activation, has been shown to be neuroprotective when administered early after experimental TBI but detrimental when administered chronically to human TBI survivors. Rather than focusing on the rescue of primary injury with early administration of therapeutics which may not be clinically feasible, we hypothesized that minocycline administered at a clinically feasible time point (24 h after injury) would be neuroprotective in a model of TBI plus delayed hypoxemia. We first explored several different regimens of minocycline dosing with the initial dose 24 h after injury and 2 h prior to hypoxemia, utilizing short-term neuropathology to select the most promising candidate. We found that a short course of minocycline reduced acute microglial activation, monocyte infiltration and hippocampal neuronal loss at 1 week post injury. We then conducted a preclinical trial to assess the long-term efficacy of a short course of minocycline finding reductions in hippocampal neurodegeneration and synapse loss, preservation of white matter myelination, and improvements in fear memory performance at 6 months after injury. Timing in relation to injury and duration of minocycline treatment and its impact on neuroinflammatory response may be responsible for extensive neuroprotection observed in our studies.

Background Despite our growing knowledge about the pathomechanisms of cancer cachexia, a whole clinical picture of the cachectic patient is still missing. Our objective was to evaluate the clinical characteristics in cancer patients with and without cachexia to get the whole picture of a cachectic patient. Methods Cancer patients of the University Clinic “Klinikum rechts der Isar” with gastrointestinal, gynecological, hematopoietic, lung and some other tumors were offered the possibility to take part in the treatment concept including a nutrition intervention and an individual training program according to their capability. We now report on the first 503 patients at the time of inclusion in the program between March 2011 and October 2015. We described clinical characteristics such as physical activity, quality of life, clinical dates and food intake. Results Of 503 patients with cancer, 131 patients (26.0%) were identified as cachectic, 369 (73.4%) as non-cachectic. The change in cachexia were 23% reduced capacity performance (108 Watt for non-cachectic-patients and 83 Watt for cachectic patients) and 12% reduced relative performance (1.53 Watt/kg for non-cachectic and 1.34 Watt/kg for cachectic patients) in ergometry test. 75.6% of non-cachectic and 54.3% of cachectic patients still received curative treatment. Conclusion Cancer cachectic patients have multiple symptoms such as anemia, impaired kidney function and impaired liver function with elements of mild cholestasis, lower performance and a poorer quality of life in the EORTC questionnaire. Our study reveals biochemical and clinical specific features of cancer cachectic patients.

This randomized trial of adjuvant therapy after resection of pancreatic cancer found a significant survival benefit for chemotherapy with fluorouracil. Chemoradiotherapy alone or followed by chemotherapy was not beneficial and even appeared to shorten survival. Chemoradiotherapy was not beneficial and even appeared to shorten survival. Pancreatic cancer, with an overall five-year survival rate ranging from 0.4 percent 1 to 4 percent, 2 has a poor prognosis and is one of the top 10 causes of death from cancer in the Western world. 3 , 4 Surgical resection improves the outlook, although only about 10 percent of patients with pancreatic cancer are eligible for the procedure. 5 – 9 Most treatment failures are due to local recurrence, hepatic metastases, or both and occur within one to two years after surgery. 10 – 12 Adjuvant (postoperative) therapy may improve long-term survival, 7 – 9 , 13 _ 16 but its routine use is not universal 8 because the results of . . .

Introduction Though early hypotension after pediatric in-hospital cardiac arrest (IHCA) is associated with inferior outcomes, ideal post-arrest blood pressure (BP) targets have not been established. We aimed to leverage prospectively collected BP data to explore the association of post-arrest BP thresholds with outcomes. We hypothesized that post-arrest systolic and diastolic BP thresholds would be higher than the currently recommended post-cardiopulmonary resuscitation BP targets and would be associated with higher rates of survival to hospital discharge. Methods We performed a secondary analysis of prospectively collected BP data from the first 24 h following return of circulation from index IHCA events enrolled in the ICU-RESUScitation trial (NCT02837497). The lowest documented systolic BP (SBP) and diastolic BP (DBP) were percentile-adjusted for age, height and sex. Receiver operator characteristic curves and cubic spline analyses controlling for illness category and presence of pre-arrest hypotension were generated exploring the association of lowest post-arrest SBP and DBP with survival to hospital discharge and survival to hospital discharge with favorable neurologic outcome (Pediatric Cerebral Performance Category of 1–3 or no change from baseline). Optimal cutoffs for post-arrest BP thresholds were based on analysis of receiver operator characteristic curves and spline curves. Logistic regression models accounting for illness category and pre-arrest hypotension examined the associations of these thresholds with outcomes. Results Among 693 index events with 0–6 h post-arrest BP data, identified thresholds were: SBP > 10th percentile and DBP > 50th percentile for age, sex and height. Fifty-one percent ( n  = 352) of subjects had lowest SBP above threshold and 50% ( n  = 346) had lowest DBP above threshold. SBP and DBP above thresholds were each associated with survival to hospital discharge (SBP: aRR 1.21 [95% CI 1.10, 1.33]; DBP: aRR 1.23 [1.12, 1.34]) and survival to hospital discharge with favorable neurologic outcome (SBP: aRR 1.22 [1.10, 1.35]; DBP: aRR 1.27 [1.15, 1.40]) (all p  < 0.001). Conclusions Following pediatric IHCA, subjects had higher rates of survival to hospital discharge and survival to hospital discharge with favorable neurologic outcome when BP targets above a threshold of SBP > 10th percentile for age and DBP > 50th percentile for age during the first 6 h post-arrest.

Purpose: Malnutrition is a major risk factor of immune dysfunction and poor outcome in cancer patients. The prognostic nutritional index (PNI), which is established by serum albumin level and peripheral lymphocyte count, was shown to correlate with prognosis of hepatocellular carcinoma (HCC) patients following liver resection and non-surgical interventions. The aim of this study was to analyze the predictive value of preoperative PNI in liver transplantation (LT) patients with HCC. Patients and Methods: A total of 123 HCC patients that underwent LT were included in the analysis. The prognostic impact of preoperatively assessed clinical factors including the PNI on post-LT outcome was analyzed by uni- and multivariate analysis. Results: Post-transplant tumor recurrence rates were 5.1% in high-PNI (> 42) and 55.6% in low-PNI (≤ 42) patients (p < 0.001). Preoperative high-PNI could be identified as a significant and independent promoter of both recurrence-free survival (hazard ratio [HR] = 10.12, 95% CI: 3.40– 30.10; p < 0.001) and overall survival (HR = 1.69, 95% CI: 1.02– 2.79; p = 0.004) following LT. Apart from that low-PNI proved to be a significant and independent predictor of microvascular tumor invasion (OR = 7.71, 95% CI: 3.17– 18.76; p < 0.001). In contrast, no tumor morphology features including the Milan criteria revealed an independent prognostic value. Conclusion: Our data indicate that preoperative PNI correlates with biological tumor aggressiveness and outcome following LT in HCC patients and may therefore be useful for refining oncologic risk stratification.

Little is known about the factors that enable the mobilisation of human mesenchymal stem cells (MSC) from the bone marrow into the blood stream and their recruitment to and retention in the tumour. We found specific migration of MSC towards growth factors present in pancreatic tumours, such as PDGF, EGF, VEGF and specific inhibitors Glivec, Erbitux and Avastin interfered with migration. Within a few hours, MSC migrated into spheroids consisting of pancreatic cancer cells, fibroblasts and endothelial cells as measured by time-lapse microscopy. Supernatant from subconfluent MSC increased sprouting of HUVEC due to VEGF production by MSC itself as demonstrated by RT-PCR and ELISA. Only few MSCs were differentiated into endothelial cells in vitro , whereas in vivo differentiation was not observed. Lentiviral GFP-marked MSCs, injected in nude mice xenografted with orthotopic pancreatic tumours, preferentially migrated into the tumours as observed by FACS analysis of green fluorescent cells. By immunofluorescence and intravital microscopic studies, we found the interaction of MSC with the endothelium of blood vessels. Mesenchymal stem cells supported tumour angiogenesis in vivo , that is CD31 + vessel density was increased after the transfer of MSC compared with siVEGF-MSC. Our data demonstrate the migration of MSC toward tumour vessels and suggest a supportive role in angiogenesis.

Background Pancreatic fistula (PF) is a common complication after pancreatic surgery. It is unclear how microbes in PF fluid affect outcomes and which microbes are present after pancreatoduodenectomy (PD) and distal pancreatectomy (DP). The aim of this study was to compare the microbiological spectrum of PF fluid after PD versus DP, and its association with postoperative complications. Methods Bacterial strains and antibiotic resistance rates of bacterial swabs obtained from the PF fluid of patients who underwent DP or PD were analysed. Cultured bacteria were classified as Enterobacterales and as ‘other intestinal and non‐intestinal microorganisms’ based on whether they are typically part of the normal human intestinal flora. Results A total of 847 patients had a pancreatic resection (PD 600; DP 247) between July 2007 and December 2016. Clinically relevant PF was detected in 131 patients (15·5 per cent). Bacterial swabs were obtained from 108 patients (DP 47; PD 61), of which 19 (17·6 per cent) were sterile. Enterobacterales were detected in 74 per cent of PF fluid swabs after PD, and in 34 per cent after DP. Infected, polymicrobial or multidrug‐resistant PF fluid was more common after PD (rates of 95, 50 and 48 per cent respectively) than after DP (66, 26 and 6 per cent respectively). Patients with higher grade complications (Clavien–Dindo grade IV–V) or grade C PF had more Enterobacterales and multidrug‐resistant Enterobacterales in the PF fluid after DP. Conclusion Enterobacterales and multidrug‐resistant bacteria are detected frequently after PD and DP, and are associated with more severe complications and PF in patients undergoing DP. Antecedentes La fístula pancreática (pancreatic fistula, PF) es una complicación frecuente de la cirugía pancreática. No está claro cómo los microorganismos que se encuentran en el líquido de la PF (pancreatic fistula fluid, PFF) afectan los resultados y qué microbios están presentes después de la duodenopancreatectomía (pancreaticoduodenectomy, PD) y de la pancreatectomía distal (distal pancreatectomy, DP). El objetivo de este estudio fue comparar el espectro microbiológico del PFF después de PD versus DP y su asociación con las complicaciones postoperatorias. Métodos Se analizaron las cepas bacterianas y las tasas de resistencia a los antibióticos de las muestras bacterianas obtenidas del PFF de pacientes de nuestra institución que se sometieron a DP o PD. Las bacterias identificadas en los cultivos se clasificaron en \"enterobacterias\" y \"otros microorganismos intestinales y no intestinales\" en función de si típicamente forman parte de la flora intestinal humana normal o no. Resultados Un total de 847 pacientes se sometieron a resección pancreática (PD: 600, DP: 247) entre julio de 2007 y diciembre de 2016, y se detectó FP clínicamente relevante en 131 pacientes (15,5%). Se obtuvieron muestras bacterianas de 108 pacientes (DP n = 47, PD N = 61), de los cuales 19 (18%) eran estériles. Se detectaron enterobacterias en el 74% del PFF después de PD y en el 34% después de DP. El PFF infectado, con flora polimicrobiana o flora multirresistente fue más frecuente después de la PD (95,1%, 50%, 47,5%, respectivamente) que después de la DP (66,0%, 25,8%, 6,4%, respectivamente). Los pacientes con complicaciones de grado superior (Clavien‐Dindo 4/5) o PF grado C presentaron más enterobacterias y enterobacterias multirresistentes en el PFF después de DP. Conclusión Las enterobacterias y las bacterias multirresistentes se detectaron con frecuencia después de la PD y la DP, y se asociaron a complicaciones más graves y PF en pacientes sometidos a DP. This study showed that, despite the absence of intestinal lumen opening, pancreatic fistulas after distal pancreatectomy frequently contain intestinal bacteria, which markedly worsen the clinical outcome. Understanding the pathogenetic mechanism behind this high prevalence of intestinal bacteria within distal pancreatectomy‐associated pancreatic fistulas may help to generate effective therapeutic regimens. Enterobacteria associated with complications after distal pancreatectomy

The role of adjuvant treatment in pancreatic cancer remains uncertain. The European Study Group for Pancreatic Cancer (ESPAC) assessed the roles of chemoradiotherapy and chemotherapy in a randomised study. After resection, patients were randomly assigned to adjuvant chemoradiotherapy (20 Gy in ten daily fractions over 2 weeks with 500 mg/m2 fluorouracil intravenously on days 1–3, repeated after 2 weeks) or chemotherapy (intravenous fluorouracil 425 mg/m2 and folinic acid 20 mg/m2 daily for 5 days, monthly for 6 months). Clinicians could randomise patients into a two-by-two factorial design (observation, chemoradiotherapy alone, chemotherapy alone, or both) or into one of the main treatment comparisons (chemoradiotherapy versus no chemoradiotherapy or chemotherapy versus no chemotherapy). The primary endpoint was death, and all analyses were by intention to treat. 541 eligible patients with pancreatic ductal adenocarcinoma were randomised: 285 in the two-by-two factorial design (70 chemoradiotherapy, 74 chemotherapy, 72 both, 69 observation); a further 68 patients were randomly assigned chemoradiotherapy or no chemoradiotherapy and 188 chemotherapy or no chemotherapy. Median follow-up of the 227 (42%) patients still alive was 10 months (range 0–62). Overall results showed no benefit for adjuvant chemoradiotherapy (median survival 15·5 months in 175 patients with chemoradiotherapy vs 16·1 months in 178 patients without; hazard ratio 1·18 [95% Cl 0·90–1·55], p=0·24). There was evidence of a survival benefit for adjuvant chemotherapy (median survival 19·7 months in 238 patients with chemotherapy vs 14·0 months in 235 patients without; hazard ratio 0·66 [0·52–0·83], p=0·0005). This study showed no survival benefit for adjuvant chemoradiotherapy but revealed a potential benefit for adjuvant chemotherapy, justifying further randomised controlled trials of adjuvant chemotherapy in pancreatic cancer.