Psoralen and ultraviolet A light treatment directly affects phosphatidylinositol 3-kinase signal transduction by altering plasma membrane packing

Psoralen and ultraviolet A light (PUNTA) are used to kill pathogens in blood products and as a treatment of aberrant cell proliferation in dermatitis, cutaneous T-cell lymphoma, and graft versus-host disease. DNA damage is well described, but the direct effects of PUVA on cell signal transduction are poorly understood. Because platelets are anucleate and contain archetypal signal transduction machinery, they are ideally suited to address this. Lipidomics on platelet membrane extracts showed that psoralen forms adducts with unsaturated carbon bonds of fatty acyls in all major phospholipid classes after PUVA. Such adducts increased lipid packing as measured by a blue shift of an environment-sensitive fluorescent probe in model liposomes. Furthermore, the interaction of these liposomes with lipid order-sensitive proteins like amphipathic lipid-packing sensor and a-synuclein was inhibited by PUVA. In platelets, PUVA caused poor membrane binding of Akt and Bruton's tyrosine kinase effectors following activation of the collagen glycoprotein VI and thrombin protease-activated receptor (PAR) 1. This resulted in defective Akt phosphorylation despite unaltered phosphatidylinositol 3,4,5-trisphosphate levels. Downstream integrin activation was furthermore affected similarly by PUVA following PAR1 (effective half-maximal concentration (EC), 8.4 +/- 1.1 versus 4.3 +/- 1.1 mu M) and glycoprotein VI (EC50, 1.61 +/- 0.85 versus 0.26 +/- 0.21 mu g/ml) but not PAR4 (EC50, 50 +/- 1 versus 58 +/- 1 mu m) signal transduction. Our findings were confirmed in T-cells ftom graft-versus-host disease patients treated with extracorporeal photopheresis, a form of systemic PUVA. In conclusion, PUVA increases the order of lipid phases by covalent modification of phospholipids, thereby inhibiting membrane recruitment of effector kinases

Recommendations on the use of ruxolitinib for the treatment of myelofibrosis

Objectives: Myelofibrosis (MF) is a severe disease, with decreased life expectancy and heavy symptom burden. Ruxolitinib is the only approved pharmacotherapy for the treatment of MF patients. In Belgium, ruxolitinib is only reimbursed for MF patients with splenomegaly for whom the disease is categorized as intermediate-2 or high risk. The improvement of symptoms without spleen volume reduction is not considered sufficient to continue treatment. The aim of this manuscript is to provide guidance for the safe and effective administration of ruxolitinib, considering the particularities of the Belgian reimbursement criteria. Methods: Our recommendations are based on a consensus reached during two meetings, where available data and observations derived from clinical experience were discussed. Results and discussion: We recommend changing the current Belgian reimbursement conditions to include the evaluation of disease-related symptoms along with splenomegaly to decide whether ruxolitinib treatment should be continued or not. Indeed, the decrease in disease-related symptoms seems to be an equally important parameter as the decrease in splenic volume in the evaluation of the response to ruxolitinib. We also advocate for the treatment with ruxolitinib of MF patients in lower-risk categories with severe disease-related symptoms, as this drug could greatly improve their quality of life. Optimization of the ruxolitinib dose is recommended to avoid an unnecessary decrease in platelet count or hemoglobin that may jeopardize treatment continuation. Conclusion: With the aim to optimize the treatment of MF patients, the Belgian regulation for ruxolitinib should be revised in terms of reimbursement criteria, dose titration, stopping rules, and patient follow-up.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Response of cassava (Manihot esculenta Crantz) genotypes to natural infestation by scale insect pest Stictococcus vayssierei Richard (Hemiptera: Stictococcidae)

Cassava is mostly grown for its starchy roots, which ensure food security. However, it is heavily attacked by the African root and tuber scale (ARTS) Stictococcus vayssierei in Central Africa. This pest is a severe constraint to the production of cassava, food and income security for smallholder farmers. Crop resistance development through the selection of varieties with resistant traits against targeted pests is a promising approach to pest control. This study investigated cassava genotypes' response to natural infestation and determined their resistance levels against S. vayssierei. Six cassava genotypes (two local and four improved) were planted in a completely randomized block design with four replicates. Agronomic parameters and ARTS density were evaluated at 3, 6, 9 and 12 months after planting (MAP). Biochemical content was determined on the pith and cortex of 12 MAP aged tuberous roots. As a result, the improved Excel variety recorded the highest scale density per plant with 102.83 ± 4.14 ARTS/P at 9 MAP. At 12 MAP, high activity of total cyanide (69.18 ± 0.88 and 69.16 ± 1.44 mg/kg) and phenylalanine ammonia-lyase (0.142 ± 0.020 and 0.145 ± 0.010 ΔA/min/mg) were observed in the cortex of the tuberous roots of the improved varieties TMS 96/0023 and TMS 92/0057 which were colonized by the lowest ARTS density. The local variety (Douma) had a high content of total phenols (44.87 ± 1.15 µg/g) in the pith. It also produced the highest yield (23.8 ± 2.9 t ha-1). Varieties TMS 96/0023, TMS 92/0057 and Douma may be the most suitable varieties for the control of ARTS stress

Safety and Effectiveness of Vedolizumab in Patients with Steroid-Refractory GI Acute GvHD : A Retrospective Record Review

Allogeneic hematopoietic cell transplantation can be curative in patients with hematological malignancies but carries a significant risk of graft-versus-host disease (GvHD). There are no standard treatments for steroid-refractory (SR) gastrointestinal (GI) acute GvHD (aGvHD). This multicenter, international, retrospective medical record review aimed to evaluate the off-label use of vedolizumab, a gut-selective immunomodulator, for treatment of SR GI aGvHD. Data from medical records of patients were collected, and criteria for extraction included: no more than 1 allogeneic hematopoietic cell transplantation and at least 1 dose of vedolizumab as treatment for SR GI aGvHD (stage I-IV GI aGvHD following ≥1 previous treatment regimen containing ≥1 mg/kg methylprednisolone or equivalent). Descriptive analyses of response rate, overall survival (OS), and serious adverse effects (SAEs) were performed. Twenty-nine patients were identified from 7 sites and had received 1-10 doses of IV vedolizumab 300 mg (median 3 doses) as treatment for SR GI aGvHD. The overall response rate at 6-10 weeks after vedolizumab initiation was 64% and OS at 6 months was 54%. There were 29 SAEs including 12 infections; 3 SAEs were considered possibly related to vedolizumab (2 of which were infections). Thirteen SAEs were fatal, 1 of which was possibly vedolizumab-related. There were 8 non-serious infections with confirmed GI origin and 1 serious (in 8 patients); there was no apparent pattern in the timing of these infections relative to the initiation of vedolizumab treatment. Further data on the efficacy and safety of vedolizumab in this setting are required from prospective trials

Disease and treatment characteristics of polycythemia vera patients in Belgium: Results from a scientific survey

Objective: The current survey aimed to gather predefined disease parameters and treatment strategies to characterize the polycythemia vera (PV) patient population in Belgium. Methods: Cross-sectional data from PV patients, seen at least once between May 2014 and May 2015 at 10 sites in Belgium, were collected in aggregated form and analyzed descriptively and quantitatively. Results: Data from 343 PV patients were collected. Of these, 174 (50.7%) were male and 256 (74.6%) were ≥60 years of age. Ninety-two (26.8%) had a prior history of thrombotic events. Considerable proportions of patients had increased hematological parameters (hematocrit > 45% [31.2%], leukocytes > 10 × 109/L [33.3%], and platelet > 400 × 109/L [38.2%]). Most patients had non-palpable spleen (284, 87.7%) and no phlebotomies during the past 6 months (197, 57.4%). Low-dose aspirin was given as thrombosis prophylaxis in 249 (72.6%) patients, while 232 (67.6%) received hydroxyurea (HU) as cytoreductive treatment. Forty-one patients (12.0%) were reported as resistant and/or intolerant to HU. Seventeen patients (5.0%) received ruxolitinib in the context of clinical trials. Conclusion: This survey provides better insight into the characteristics of Belgian PV patients and currently used treatment strategies. It shows that 232 (67.6%) PV patients continue to receive HU despite being potentially HU-resistant.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

La Convention nationale décrète que les divers représentants du peuple détenus dans diverses maisons d’arrêt à Paris, et qui sont malades, pourront se faire transférer dans leur domicile pour y rétablir leur santé, lors de la séance du 4 brumaire an III (25 octobre 1794)

Blaux Nicolas françois, Richou Louis, Joseph, Dubusc Charles, François, Saladin Jean-baptiste-michel, Faure Pierre-Joseph-Denis-Guillaume, Chastellain Jean-Claude, Varlet Charles, Zachée, Joseph, Corbel Vincent-Claude, Le Breton Pierre-Jean, Le Breton Roch-Pierre-Francois. La Convention nationale décrète que les divers représentants du peuple détenus dans diverses maisons d’arrêt à Paris, et qui sont malades, pourront se faire transférer dans leur domicile pour y rétablir leur santé, lors de la séance du 4 brumaire an III (25 octobre 1794). In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome C - Du 3 au 18 brumaire an III (24 octobre au 8 novembre 1794) Paris : CNRS éditions, 2000. pp. 68-69

Intraconzole versus amphotericin B plus nystatin in the prophylaxis of fungal infections in neutropenic cancer patients

The efficacy and safety of itraconazole oral solution and a combination of amphotericin B capsules plus nystatin oral suspension were compared in the prophylaxis of fungal infections in neutropenic patients. In an open, randomized, multicentre trial, 144 patients received itraconazole oral solution 100 mg bd, and 133 patients received amphotericin B 500 mg tds plus nystatin 2 MU qds. Overall, 65% of itraconazole-treated patients were considered to have had successful prophylaxis, compared with 53% in the polyene group. Proven deep fungal infections occurred in 5% of patients in each group. Fewer patients receiving itraconazole than amphotericin plus nystatin had superficial infections (3 versus 8%; P = 0.066). This trend in favour of itraconazole was seen in patients with profound neutropenia (neutrophil count <0.1 × 109 cells/L at least once) or prolonged neutropenia (neutrophil count <1.0 × 109 cells/L for > 14 days). The median time to prophylactic failure was longer in the itraconazole group (37 days) than in the polyene group (34 days). The number of patients with fungal colonization (nose, sputum, stool) changed more favourably from baseline to endpoint in the itraconazole group than in the polyene group. Both treatments were safe and well tolerated; however, patients receiving amphotericin plus nystatin had a higher incidence of nausea and rash. In conclusion, itraconazole oral solution at doses of 100 mg bd and oral amphotericin B plus nystatin have similar prophylactic efficacy against fungal infections in neutropenic patients. On the basis of reduced incidence of superficial fungal infections, fungal colonization and specific adverse events, itraconazole may be the preferred treatment

La Convention nationale décrète que les divers représentants du peuple détenus dans diverses maisons d’arrêt à Paris, et qui sont malades, pourront se faire transférer dans leur domicile pour y rétablir leur santé, lors de la séance du 4 brumaire an III (25 octobre 1794)

Blaux Nicolas françois, Richou Louis, Joseph, Dubusc Charles, François, Saladin Jean-baptiste-michel, Faure Pierre-Joseph-Denis-Guillaume, Chastellain Jean-Claude, Varlet Charles, Zachée, Joseph, Corbel Vincent-Claude, Le Breton Pierre-Jean, Le Breton Roch-Pierre-Francois. La Convention nationale décrète que les divers représentants du peuple détenus dans diverses maisons d’arrêt à Paris, et qui sont malades, pourront se faire transférer dans leur domicile pour y rétablir leur santé, lors de la séance du 4 brumaire an III (25 octobre 1794). In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome C - Du 3 au 18 brumaire an III (24 octobre au 8 novembre 1794) Paris : CNRS éditions, 2000. pp. 68-69