Prospective qualitative and quantitative non-invasive evaluation of intestinal acute GVHD by contrast-enhanced ultrasound sonography.

Intestinal acute GVHD (I-aGVHD) is a life-threatening complication after allografting. Non-invasive bed-side procedures to evaluate extension and treatment response are still lacking. We hypothesized that, during I-aGVHD, contrast-enhanced ultrasound sonography (CEUS) could detect microcirculation changes (MVC) of the bowel wall (BW) and help to monitor treatment response. We prospectively employed CEUS in 83 consecutive patients. Of these, 14 patients with biopsy-proven intestinal GVHD (I-GVHD) were defined as the study group, whereas 16 patients with biopsy-proven stomach GVHD (U-GVHD) without intestinal symptoms, 6 normal volunteers and 4 patients with neutropenic enterocolitis were defined as the control group. All patients were evaluated with both standard ultrasonography (US) and CEUS at the onset of intestinal symptoms, during clinical follow-up and at flare of symptoms. Standard US revealed BW thickening of multiple intestinal segments, useful to determine the extension of GVHD. CEUS showed MVC, which correlated with GVHD activity, treatment response, and predicted flare of intestinal symptoms. US and CEUS findings were superimposable at diagnosis and in remission. CEUS was, however, more sensitive and specific to identify subclinical activity in patients with clinical relevant improvement. These findings were not observed in the control groups. CEUS is a non-invasive, easily reproducible bed-side tool useful to monitor I-aGVHD

Endoscopic diagnosis of acute intestinal GVHD following allogeneic hematopoietic SCT: a retrospective analysis in 175 patients

Diagnosis of acute intestinal GVHD (aGVHD) following allogeneic hematopoietic cell transplantation is based on clinical symptoms and histological lesions. This retrospective analysis aimed to validate the ‘Freiburg Criteria' for the endoscopic grading of intestinal aGVHD. Grade 1: no clear-cut criteria; grade 2: spotted erythema; grade 3: aphthous lesions; and grade 4: confluent defects, ulcers, denudation of the mucosa. Having excluded patients with infectious diarrhea, we evaluated 175 consecutive patients between January 2001 and June 2009. Setting a cutoff between grade 1 (no change in therapy) and grade 2 (intensification of immunosuppression), macroscopy had a sensitivity of 89.2% (95% confidence interval (CI): 80.4–94.9%), a specificity of 79.4% (95% CI: 69.6–87.1%), a positive-predictive value of 79.6% (95% CI: 70.0–87.2%) and a negative-predictive value of 89.0% (95% CI: 80.2–94.9%). In all, 20% of patients with aGVHD in the lower gastrointestinal tract (GIT) had lesions only in the terminal ileum. In all patients with aGVHD ⩾2 of the upper GIT, typical lesions were also found in the lower GIT. Ileo-colonoscopy showed the highest diagnostic yield for aGVHD. In conclusion, the ‘Freiburg Criteria' for macroscopic diagnosis of intestinal aGVHD provide high accuracy for identifying aGVHD ⩾2

Colon biopsies for evaluation of acute graft-versus-host disease (A-GVHD) in allogeneic bone marrow transplant patients

BACKGROUND: Proper histomorphological interpretation of intestinal acute graft versus host disease (A-GVHD) associated with allogeneic bone marrow transplantation (BMT) is critical for clinical managaement. However, studies methodically evaluating different histomorphological features of A-GVHD are rare. METHODS: Colonic biopsies from 44 allogeneic BMT patients having biopsy-proven cutaneous A-GVHD were compared with colon biopsies from 48 negative controls. RESULTS: A-GVHD showed intra-cryptal apoptosis in 91% and pericryptal apoptosis in adjacent lamina propria in 70% (p < 0.002). Nonspecific apoptosis along the surface epithelium was observed in all groups with comparable frequency. The number of apoptotic cells in mucosa were approximately four times (5.3 per 10 HPF) the negative controls (p < 0.002) in A-GVHD group. 48% of cases with A-GVHD showed decreased number of lymphocytes in lamina propria. Some features, including intraepithelial lymphocytes in surface or crypt epithelium; and neutrophils, eosinophils, and edema in lamina propria, did not demonstrate significant difference in A-GVHD and negative controls. Pericryptal apoptosis, dilated crypts, irregular distribution of crypts, decreased lymphocytes, increased microvessel network, focal fibrosis, presence of muciphages, reactive changes in surface epithelium with mucin depletion, mucosal ulceration, and/or reduced mucosal thickness showed higher association with A-GVHD group. CONCLUSIONS: Intracyptal apoptosis is a reliable indicator of A-GVHD. Its diagnostic significance was improved if intracyptal apoptosis was associated with features which were observed more frequently in A-GVHD group as mentioned above

Sliding charge density wave in manganites

The so-called stripe phase of the manganites is an important example of the complex behaviour of metal oxides, and has long been interpreted as the localisation of charge at atomic sites. Here, we demonstrate via resistance measurements on La_{0.50}Ca_{0.50}MnO_3 that this state is in fact a prototypical charge density wave (CDW) which undergoes collective transport. Dramatic resistance hysteresis effects and broadband noise properties are observed, both of which are typical of sliding CDW systems. Moreover, the high levels of disorder typical of manganites result in behaviour similar to that of well-known disordered CDW materials. Our discovery that the manganite superstructure is a CDW shows that unusual transport and structural properties do not require exotic physics, but can emerge when a well-understood phase (the CDW) coexists with disorder.Comment: 13 pages; 4 figure

Sickle cell trait and priapism: a case report and review of the literature

Background A 32 year-old African-American man presented to our institution after attempting suicide via ingestion with quetiapine. He had reported a history of several days of substance abuse with alcohol, cocaine and marijuana related to a partying binge. Following this, his partner removed him from his residence resulting in a suicide attempt. During hospitalization the patient developed priapism, a condition he had not experienced before. Case presentation Given this was his first time with priapism, an extensive work-up revealed the patient had previously undiagnosed sickle cell trait, which we postulate to have been a significant factor in his development of acute priapism. Sickle cell trait is considered to be a generally benign condition except for a few rare complications under more demanding physical conditions. However, upon reviewing the literature on the association of sickle cell trait with priapism, we believe this may not be the case. Case reports and small series that appeared in the 1960s and 1970s indicated an association between priapism and sickle trait. Little has been reported recently, and the general teaching regarding sickle cell trait does not include this information. However, one case was reported with the use of phosphodiesterase-5 (PDE-5) inhibitors and the development of priapism in a patient with sickle cell trait. These medications are now first line treatment in erectile dysfunction. They act by enhancing nitric oxide (NO) production leading to relaxation of smooth muscle in the corpora cavernosa and penile arteries. Conclusion Priapism was not reported in the initial studies of these medications. Further review of the literature indicates this may be a complex relationship. Interestingly, PDE5 inhibitors also have been postulated to be protective in sickle cell disease and perhaps also sickle cell trait because priapism might be caused by reduced NO availability. In this article, we examine the evidence linking sickle cell trait to priapism, explore the implications of PDE5 use, particularly in the setting of sickle cell trait, and propose that teaching about sickle cell trait include a discussion of priapism risk

Administration of defined microbiota is protective in a murine Salmonella infection model.

Salmonella typhimurium is a major cause of diarrhea and causes significant morbidity and mortality worldwide, and perturbations of the gut microbiota are known to increase susceptibility to enteric infections. The purpose of this study was to investigate whether a Microbial Ecosystem Therapeutic (MET-1) consisting of 33 bacterial strains, isolated from human stool and previously used to cure patients with recurrent Clostridium difficile infection, could also protect against S. typhimurium disease. C57BL/6 mice were pretreated with streptomycin prior to receiving MET-1 or control, then gavaged with S. typhimurium. Weight loss, serum cytokine levels, and S. typhimurium splenic translocation were measured. NF-κB nuclear staining, neutrophil accumulation, and localization of tight junction proteins (claudin-1, ZO-1) were visualized by immunofluorescence. Infected mice receiving MET-1 lost less weight, had reduced serum cytokines, reduced NF-κB nuclear staining, and decreased neutrophil infiltration in the cecum. MET-1 also preserved cecum tight junction protein expression, and reduced S. typhimurium translocation to the spleen. Notably, MET-1 did not decrease CFUs of Salmonella in the intestine. MET-1 may attenuate systemic infection by preserving tight junctions, thereby inhibiting S. typhimurium from gaining access to the systemic circulation. We conclude that MET-1 may be protective against enteric infections besides C. difficile infection

Pharmacokinetic targeting of intravenous busulfan reduces conditioning regimen related toxicity following allogeneic hematopoietic cell transplantation for acute myelogenous leukemia

Optimal conditioning therapy for hematopoietic cell transplantation (HCT) in acute myelogenous leukemia (AML) remains undefined. We retrospectively compared outcomes of a consecutive series of 51 AML patients treated with oral busulfan (1 mg/kg every 6 hours for 4 days) and cyclophosphamide (60 mg/kg IV × 2 days) - (Bu/Cy) with 100 consecutive AML patients treated with pharmacokinetic targeted IV busulfan (AUC < 6000 μM/L*min per day × 4 days) and fludarabine (40 mg/m2 × 4 days) - (t-IV Bu/Flu). The Bu/Cy and t-IV Bu/Flu groups significantly differed according to donor relation, stem cell source, aGVHD prophylaxis, remission status, primary vs. secondary disease, median age, and % blasts prior to HCT (p < 0.01 for each). Conditioning with t-IV Bu/Flu reduced early toxicity including idiopathic pneumonia syndrome (IPS) and hepatic veno-occlusive disease (VOD). Additionally, the trajectory of early NRM (100 day: 16% vs. 3%, and1 year: 25% vs. 15% for Bu/Cy and t-IV Bu/Flu, respectively) favored t-IV Bu/Flu. Grade II-IV aGVHD (48% vs. 82%, p < 0.0001), as well as moderate/severe cGVHD (7% vs. 40%, p < 0.0001) differed between the Bu/Cy and t-IV Bu/Flu groups, due to the predominance of peripheral blood stem cells in the t-IV Bu/Flu group. Pharmacokinetic targeting of intravenous busulfan in combination with fludarabine is associated with reduced conditioning regimen related toxicity compared to oral busulfan and cyclophosphamide. However, multivariable analysis did not demonstrate significant differences in overall survival (p = 0.78) or non-relapse mortality (p = 0.6) according to conditioning regimen delivered

High exposures to bioactivated cyclophosphamide are related to the occurrence of veno-occlusive disease of the liver following high-dose chemotherapy

We investigated whether the occurrence of veno-occlusive disease of the liver (VOD) may be associated with individual variations in the pharmacokinetics of high-dose cyclophosphamide. Patients received single or multiple courses of cyclophosphamide (1000 or 1500 mg m−2 day−1), thiotepa (80 or 120 mg m−2 day−1) and carboplatin (265–400 mg m−2 day−1) (CTC) for 4 consecutive days. The area under the plasma concentration–time curves (AUCs) were calculated for cyclophosphamide and its activated metabolites 4-hydroxycyclophosphamide and phosphoramide mustard based on multiple blood samples. Possible relationships between the AUCs and the occurrence of VOD were studied. A total of 59 patients (115 courses) were included. Four patients experienced VOD after a second CTC course. The first-course AUC of 4-hydroxycyclophosphamide (P=0.003) but not of phosphoramide mustard (P=0.101) appeared to be predictive of the occurrence of VOD after multiple courses. High exposures to bioactivated cyclophosphamide may lead to increased organ toxicity

Follow the foreign leader? Why following foreign incumbents is an effective electoral strategy

Previous research suggests that political parties respond to left–right policy positions of successful foreign political parties (“foreign leaders”). We evaluate whether this is an effective electoral strategy: specifically, do political parties gain votes in elections when they respond to successful foreign parties? We argue that parties that follow foreign leaders will arrive at policy positions closer to their own (domestic) median voter, which increases their electoral support. The analysis is based on a two-stage model specification of parties’ vote shares and suggests that following foreign leaders is a beneficial election strategy in national election because it allows them to better identify the position of their own median voter. These findings have important implications for our understanding of political representation, parties’ election strategies, and for policy diffusion

KeV Warm Dark Matter and Composite Neutrinos

Elementary keV sterile Dirac neutrinos can be a natural ingredient of the composite neutrino scenario. For a certain class of composite neutrino theories, these sterile neutrinos naturally have the appropriate mixing angles to be resonantly produced warm dark matter (WDM). Alternatively, we show these sterile neutrinos can be WDM produced by an entropy-diluted thermal freeze-out, with the necessary entropy production arising not from an out-of-equilibrium decay, but rather from the confinement of the composite neutrino sector, provided there is sufficient supercooling.Comment: 12 pages, 2 figures, published versio