Pre-transplant platelet-to- lymphocyte ratio predicts outcome after allogeneic hematopoietic stem cell transplantation.

For many patients with hematological malignancies such as acute leukemia or myelodysplastic syndrome allogeneic hematopoietic stem cell transplantation (allogeneic HSCT) is the only curative treatment option. Despite the curative potential of this treatment many patients experience relapse of their underlying disease or die due to multiple complications e.g. infections. Risk scores could help to assess the individual prognosis and guide patients and treating physicians to choose between different treatment options. Parameters reflecting the inflammatory status, such as neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR), have been demonstrated to be associated with prognosis and treatment complications in patients with various cancers. In this study, we evaluate pre-HSCT NLR, MLR and PLR as predictive markers in patients undergoing allogeneic HSCT. We demonstrate that a high (> 133) PLR level is associated with better clinical outcome. Patients with high pre-HSCT PLR show a significant better overall survival (p = 0.001), less relapses (p = 0.016), lower non-relapse-mortality (p = 0.022), less transfusions of red blood cells, platelets and fresh frozen plasma (p = 0.000), fewer episodes of fever (p = 0.002), considerably less different antibiotics (p = 0.005), fewer intensive care unit treatment (p = 0.017) and a lower in-hospital mortality (p = 0.024). Pre-HSCT PLR is easy to calculate by daily routine and could help to predict patient outcome after allogeneic HSCT.

Current practice in nutrition after allogeneic hematopoietic stem cell transplantation - Results from a survey among hematopoietic stem cell transplant centers.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is frequently associated with impaired oral intake and malnutrition, which potentially increases morbidity and mortality. Therefore, nutrition is one of the major challenges in the post-transplant period. METHODS: To document the current clinical approach in nutritional treatment, we designed a questionnaire concerning the current practice in nutrition after alloHSCT and distributed it to German speaking centers performing alloHSCT in Germany, Austria and Switzerland between November 2018 and March 2020. Twenty-eight (39%) of 72 contacted centers completed the survey, 23 from Germany, two from Austria and three from Switzerland, representing 50% of alloHSCT activity within the participating countries in 2018. RESULTS: All centers reported having nutritional guidelines for patients undergoing alloHSCT, whereby 86% (n = 24) provided a low-microbial diet during the neutropenic phase. The criteria to start parenteral nutrition (PN) directly after alloHSCT seemed to be consistent, 75% (n = 21) of the corresponding centers started PN if the oral nutritional intake or the bodyweight dropped below a certain limit. In the setting of intestinal graft-versus-host disease (GvHD) the current practice appeared to be more heterogenous. About 64% (n = 18) of the centers followed a special diet, added food stepwise modulated by GvHD symptoms, while only four centers regularly stopped oral intake completely (intestinal GvHD grade >1). Half of the centers (54%, n = 15) applied a lactose-free diet, followed by 43% (n = 12) which provided fat- and 18% (n = 5) gluten-free food in patients with intestinal GvHD. Supplementation of micronutrients in acute intestinal GvHD patients was performed by 54% (n = 15) of the centers, whereas vitamin D (89%, n = 25) and vitamin B12 (68%, n = 19) was added regularly independently of the presence of GvHD. Only 5 (18%) participating centers ever observed a food-associated infection during hospitalization, whereas food-associated infections were reported to occur more often in the outpatient setting (64%, n = 18). CONCLUSION: The survey documented a general consensus about the need for nutritional guidelines for patients undergoing alloHSCT. However, the nutritional treatment in clinical practice (i.e. lactose-, gluten- or fat-free in intestinal GvHD) as well as the use of food supplements was very heterogeneous. In line with current general recommendations the centers seemed to focus on safe food handling practice rather than providing a strict neutropenic diet. More high-quality data are required to provide evidence-based nutrition to patients during and after alloHSCT.

Decrease of blood anti-α1,3 Galactose Abs levels in multiple sclerosis (MS) and clinically isolated syndrome (CIS) patients.

The etiology of multiple sclerosis (MS) remains elusive. Among the possible causes, the increase of anti-Neu5Gc antibodies during EBV primo-infection of Infectious mononucleosis (IMN) may damage the integrity of the blood-brain barrier facilitating the transfer of EBV-infected B cells and anti-EBV T cell clones in the brain. We investigated the change in titers of anti-Neu5Gc and anti-α1,3 Galactose antibodies in 49 IMN, in 76 MS, and 73 clinically isolated syndrome (CIS) patients, as well as age/gender-matched healthy individuals. Anti-Gal and anti-Neu5Gc are significantly increased during IMN (p=0.02 and p<1.10-4 respectively), but not in acute CMV primo-infection. We show that, whereas there was no change in anti-Neu5Gc in MS/CIS, the two populations exhibit a significant decrease in anti-Gal (combined p=2.7.10-3), in contrast with patients with non-MS/CIS central nervous system pathologies. Since anti-Gal result from an immunization against α1,3 Gal, lacking in humans but produced in the gut, our data suggest that CIS and MS patients have an altered microbiota or an altered response to this microbiotic epitope.

Silicate glass alteration enhanced by iron: origin and long-term implications.

Silicate glasses are used as containment matrices for deep geological disposal of nuclear waste arising from spent fuel reprocessing. Understanding the dissolution mechanisms of glasses in contact with iron, an element present in large amounts in the immediate environment (overpack, claystone, etc.) would be a major breakthrough toward predicting radionuclide release in the geosphere after disposal. Two different reacted glass-iron interfaces-a short-term nuclear system and a long-term archeological system-were examined using a multiscale and multianalytical approach including, for the first time on samples of this type, STXM under synchrotron radiation. Comparisons revealed remarkable similarities between the two systems and shed light on Fe-Si interactions, including migration of iron within a porous gel layer and precipitation of Fe-silicates that locally increase short-term glass alteration and are sustainable over the long-term.

Effect of paraoxonase-1 polymorphism on clinical outcomes in patients treated with clopidogrel after an acute myocardial infarction.

Paraoxonase-1 (PON1) Q192R polymorphism was recently suggested to determine per se clopidogrel response on major cardiovascular events (MACEs). We assessed the impact of PON1, CYP2C19, and ABCB1 polymorphisms on MACE in clopidogrel-treated acute myocardial infarction (AMI) patients (N = 2,210), including those undergoing percutaneous coronary intervention (PCI) (n = 1,538). PON1 polymorphism was not associated with increased risk of in-hospital death and MACEs at 1 year (adjusted hazard ratio (HR) 1.03, 95% confidence interval (CI) 0.66-1.61 and adjusted HR 0.77, 95% CI 0.42-1.41 for QQ versus RR in all and PCI patients, respectively). The presence of two CYP2C19 loss-of-function (LOF) alleles was associated with the risk of in-hospital death and MACEs at 1 year in the overall population (adjusted odds ratio (OR) 3.67, 95% CI 1.05-12.80 and adjusted HR 1.96, 95% CI 1.08-3.54) and in PCI patients (adjusted OR 6.87, 95% CI 2.52-18.72 and adjusted HR 3.06, 95% CI 1.47-6.41). Unlike CYP2C19 polymorphism, PON1 (Q192R) polymorphism is not a major pharmacogenetic contributor of clinical response to clopidogrel in AMI patients.

Low prevalence of colonoscopic surveillance of inflammatory bowel disease patients with longstanding extensive colitis: a clinical practice survey nested in the CESAME cohort.

BACKGROUND: Surveillance colonoscopy is recommended for inflammatory bowel disease (IBD) patients with longstanding extensive colitis (LEC). AIMS: To assess modalities and results of colonoscopic surveillance in a subset of CESAME cohort patients at high risk of colorectal cancer (CRC) and followed in university French hospitals. METHODS: Among 910 eligible patients with more than a 7-year history of extensive colitis at CESAME enrolment, 685 patients completed a questionnaire on surveillance colonoscopy and 102 were excluded because of prior proctocolectomy. Finally, 583 patients provided information spanning a median period of 41months (IQR 38-43) between cohort enrolment and the end of follow-up. Details of the colonoscopic procedures and histological findings were obtained for 440 colonoscopies in 270 patients. RESULTS: Only 54% (n=312) of the patients with LEC had at least one surveillance colonoscopy during the study period, with marked variations across the nine participating centres (27% to 70%, P≤0.0001). Surveillance rate was significantly lower in Crohn's colitis than in ulcerative colitis (UC) (48% vs. 69%, P≤0.0001). Independent predictors of colonoscopic surveillance were male gender, UC IBD subtype, longer disease duration, previous history of CRC and disease management in a centre with large IBD population. Random biopsies, targeted biopsies and chromoendoscopy were performed during respectively 71%, 27 and 30% of surveillance colonoscopies. Two cases of high-grade dysplasia were detected in patients undergoing colonoscopic surveillance. Two advanced-stage CRC were diagnosed in patients who did not have colonosocopic surveillance. CONCLUSIONS: Colonoscopic surveillance rate is low in IBD patients with longstanding extensive colitis.

Adenovirus dodecahedron allows large multimeric protein transduction in human cells.

Adenovirus dodecahedron is a virus-like particle composed of only two viral proteins of human adenovirus serotype 3 that are responsible for virus attachment and internalization. We show here that this dodecameric particle, devoid of genetic information, efficiently penetrates human cells and can deliver large multimeric proteins such as immunoglobulins.

Flow cytometry analysis of gamma-radiation-induced Epstein-Barr virus reactivation in lymphocytes.

Epstein-Barr virus (EBV), a member of the gamma-herpesvirus family, is involved in the development of several diseases, and the infection is believed to persist for life in latent form. Ionizing radiation at clinically relevant doses may increase the amount of virus reactivation in B cells, and the combination of radiation with stress could amplify EBV reactivation. In vitro experiments were performed on several cell lines, including EBV-positive Burkitt lymphoma cells. The presence of the immediate-early protein ZEBRA, which is a hallmark of EBV reactivation, was evaluated using flow cytometry, which enabled us to measure the percentage of ZEBRA-positive cells. The process was studied previously in the EBV-positive Burkitt lymphoma cell line B95-8. Forty-eight hours after irradiation alone, 13.6 and 19.9% ZEBRA-positive cells were observed at 2 and 4 Gy, respectively, compared to the basal level of 1.85%. Thus irradiation induces EBV reactivation. The addition of a glucocorticoid (the final effector of the stress response) had no effect on EBV reactivation in our model. However, the combination of radiation and treatment with a glucocorticoid (dexamethasone) increased the expression of ZEBRA in B95-8 cells (15.8 and 28.75% of the cells was positive at 24 and 48 h after gamma irradiation, respectively). Thus the combination of gamma radiation and a glucocorticoid may play an important role in EBV reactivation.

Gulf war syndrome: could it be triggered by biological warfare-vaccines using pertussis as an adjuvant?

Several recent epidemiological studies have shown that vaccinations against biological warfare using pertussis as an adjuvant were associated with the Gulf war syndrome. If such epidemiological findings are confirmed, we propose that the use of pertussis as an adjuvant could trigger neurodegeneration through induction of interleukin-1beta secretion in the brain. In turn, neuronal lesions may be sustained by stress or neurotoxic chemical combinations. Particular susceptibility for IL-1beta secretion and potential distant neuronal damage could provide an explanation for the diversity of the symptoms observed on veterans.

[The Gulf war syndrome]. / Le syndrome de la guerre du Golfe.

SPARSE DATA: The Gulf war syndrome remains a little know entity since its first appearance 10 years ago. The objective of our work was to synthesize the data published on the subject in the scientific literature. We analysed the results of American and English epidemiological surveys, from which it was difficult to distinguish the existence of a univocal syndrome. IMPRECISE DEFINITION: It is difficult to give a clear clinical definition of the syndrome, the signs of which fluctuate depending on the studies. Chronic fatigue is frequently associated with the Gulf war syndrome, although some studies have described electrophysiological neurological lesions. NUMEROUS HYPOTHESES: The role of stress, vaccinations and their adjuvants, exposition to neurotoxic substances and weak uranium have been incriminated. We propose that multiple factors be integrated in the research for the genesis of this atypic syndrome.

Influence of three successive antiviral treatments on viral heterogeneity in nonresponder chronic hepatitis C patients.

The purpose of the present study was to assess the viral diversity of hepatitis C virus (HCV) in six nonresponder patients during three unsuccessful treatments. These patients were treated successively with IFN-alpha2a (IFN-alpha) at a posology of 3.10(6) units (MIU) three times a week, 10 MIU three times a week, and a combination of IFN-alpha (3 MIU) plus ribavirin (1,000 mg/day). However, only two chronically infected patients could be included in the study due to the persistence of HCV RNA during the three successive treatments. The viral diversity was analysed by cloning and sequencing the HVR-1 region. The treatment of the two nonresponder patients was associated with the persistence of a wide diversity in the viral population and with the emergence of new or minor variants. Under the influence of standard doses of IFN-alpha, a rearrangement of the quasispecies present was observed at this time point. No significant change in viral load or in the complexity of the quasispecies was observed. A second treatment with a high dose of IFN-alpha induced a significant decrease in the associated viral load and, in one case, resulted in a radical change of the viral diversity. Administration of a combination of IFN-alpha and ribavirin did not affect the evolution of the variants but was followed by the emergence of various multiple variants. These results reinforce the hypothesis of the presence of preexisting quasispecies best adapted to the host environment, and therefore resistant to any current therapy.

Structure of the fiber head of Ad3, a non-CAR-binding serotype of adenovirus.

Adenoviruses of serotype Ad3 (subgenus B) use a still-unknown host cell receptor for viral attachment, whereas viruses from all other known subgenera use the coxsackie and adenovirus receptor (CAR). The receptor binding domain (head) of the Ad3 fiber protein has been expressed in Escherichia coli inclusion bodies. After denaturation and renaturation using a rapid dilution method, crystals of trimeric head were obtained. The 1.6 A resolution X-ray structure shows a strict conservation of the beta-sheet scaffold of the protein very similar to the head structures of the CAR-binding serotypes Ad2, Ad5, and Ad12. The conformation of the loops is different, with the exception of the AB loop, which forms the center of the interface in the Ad12-CAR complex structure. The structure explains why a mutation in Ad5 of one residue in the AB loop to glutamic acid, as in Ad3, abrogates binding to CAR. It is possible that the Ad3 receptor binding site is nevertheless situated similar to the CAR binding site, although it cannot be excluded that other regions of the relatively hydrophobic head surface may be used.

[Hepatitis C virus culture systems]. / Les systèmes de culture du virus de l'hépatite C.

Hepatitis C virus pathogenesis and cycle are difficult to study because of the lack of culture system able to replicate efficiently the virus. Furthermore such a system will permit screen new antiviral drugs. Studies were realized to select cell culture system able to allow hepatitis C virus replication. Primary cell cultures and cell lines were used to performed HCV culture. Most of these works used lymphocyte and hepatocyte primary cultures or cell lines because of HCV tropism in these cells in vivo. Animals and arthropods cell lines were used as well for their capacity to bind and replicate HCV. The aim of this review is to present the different cell systems used to replicate HCV in culture and the results obtained.

Mutations in the rpoB gene of rifampicin-resistant Mycobacterium tuberculosis strains isolated in Brazil and France.

We evaluated the mutations in a 193bp of the rpoB gene by automated sequencing of rifampicin (RMP)-resistant and susceptible Mycobacterium tuberculosis strains isolated from Brazil (25 strains) and France (37 strains). In RMP-resistant strains, mutations were identified in 100% (16/16) from France and 89% (16/18) from Brazil. No mutation was detected in the 28 RMP-susceptible strains. Among RMP-resistant or RMP-susceptible strains deletion was observed. A double point mutation which had not been reported before was detected in one strain from France. Among French resistant strains mutations were found in codons 531 (31.2%), 526, 513 and 533 (18.7% each). In Brazilian strains the most common mutations were in codons 531 (72.2%), 526 (11.1%) and 513 (5.5%). The heterogeneity found in French strains may be related to the fact that most of those strains were from African or Asian patients.

Mosquito cells bind and replicate hepatitis C virus.

Several studies have demonstrated some hepatitis C virus (HCV) replication in lymphocyte and hepatocyte cell lines such as in African green monkey Vero cells. The aim of the present study was to select other cell lines able to bind and replicate HCV. Human hepatoma PLC/PRF/5 cells, human lymphoma Namalwa cells, Vero and mosquito AP61 cells were inoculated with HCV-positive plasma, washed six times and examined for the presence of the viral genome at different times post infection, using an RT-PCR method. Binding of HCV to cells was estimated by HCV RNA detection in cells 2 hr after inoculation and in the last wash of these cells. Successive virus passages in cells were carried out. All the cells studied were able to bind HCV but only AP61 and Vero cells provided evidence of replication and production of infectious virus: virus RNA was detected during 28 days post-infection in four successive virus passages. CD81 molecules, a putative HCV receptor, were detected by cytofluorometric analysis. Vero cells express CD81 molecules whereas these molecules were not detected on AP61 cells. It is suggested that other receptors are involved in HCV binding to Vero and AP61 cells.

Chronic restraint stress induces severe disruption of the T-cell specific response to tetanus toxin vaccine.

Chronic stress is known to induce immunological disorders. In the present study we examined the consequences of chronic restraint stress on the immune response to tetanus toxin in mice. We investigated the repartition of subsets of lymphoid cells in blood and spleen, the functional ability of lymphocytes to proliferate and to produce cytokines, and antibody titres against tetanus toxin following stress. We report discordance of the stimulation index of lymphocytes in the restraint group: the proliferating rate severely decreased following stimulation with a relevant antigen, whereas it increased with mitogen. Thus, we report a decrease in cytokine production with relevant antigen (interferon-gamma and interleukin-10), without a T helper type 1 and 2 secretion imbalance. Moreover, we observed an alteration in the humoral response, including a delay in isotype maturation and an immunoglobulin G1/G2a imbalance.

Mutations in the rpoB gene of rifampicin-resistant Mycobacterium tuberculosis strains isolated in Brazil and France

We evaluated the mutations in a 193bp of the rpoB gene by automated sequencing of rifampicin (RMP)-resistant and susceptible Mycobacterium tuberculosis strains isolated from Brazil (25 strains) and France (37 strains). In RMP-resistant strains, mutations were identified in 100 percent (16/16) from France and 89 percent (16/18) from Brazil. No mutation was detected in the 28 RMP-susceptible strains. Among RMP-resistant or RMP-susceptible strains deletion was observed. A double point mutation which had not been reported before was detected in one strain from France. Among French resistant strains mutations were found in codons 531 (31.2 percent), 526, 513 and 533 (18.7 percent each). In Brazilian strains the most common mutations were in codons 531 (72.2 percent), 526 (11.1 percent) and 513 (5.5 percent). The heterogeneity found in French strains may be related to the fact that most of those strains were from African or Asian patients

Study on TEMPO-mediated selective oxidation of hyaluronan and the effects of salt on the reaction kinetics.

2,2,6,6-Tetramethyl-1-piperidinyloxy radical (TEMPO)-mediated oxidation of hyaluronan was studied at pH 10.2 and temperature of 0 degrees C with NaOCl as the primary oxidant. As with other polysaccharides, a high selectivity of oxidation was observed. The degradation of the polymer was essentially caused by the oxidation process. The primary oxidant and the pH of the reaction mixture did not alter the molecular weight of hyaluronan during oxidation. The kinetics of the oxidation process was investigated at different concentrations of reactants and the inorganic salts, NaBr, NaCl, and Na2SO4. An increase in the salt concentration in the mixture causes a major decrease in the rate of the oxidation, and this decrease is independent of the nature of the salt.