Case report: Cyclophosphamide pulse therapy for chronic recalcitrant erythema nodosum leprosum

Chronic recalcitrant erythema nodosum leprosum (ENL) or type 2 reaction (T2R) is a severe condition found in approximately 50% of multibacillary leprosy subjects. T2R is associated with important morbidities and may lead to several disabilities, not only due to nerve damage but also due to the prolonged use of corticosteroids, thalidomide, or immunosuppressors. We describe here four leprosy patients with chronic recalcitrant ENL treated with cyclophosphamide pulse therapy. All subjects had been on prednisone and thalidomide therapy for at least 30 months but showed inflammatory activity when doses were reduced. Pulse therapy with 1.0 g of cyclophosphamide was used every 4–6 weeks for a minimum of three applications. After pulse therapy, all cases presented total or partial regression of symptoms, and we were able to taper thalidomide and prednisone doses, with better control of ENL, avoiding further hospital admissions and disabilities. No side effects were observed during or after infusion therapy. Cyclophosphamide pulse therapy may be useful and safe to control chronic recalcitrant ENL

Development of Cutaneous Leishmaniasis after Leishmania Skin Test

Thirty-year-old female with a previous history of a cutaneous ulcer suspicious of leishmaniasis 20 years ago presented with a new complaint of a depressed papular lesion 8 × 7 mm in the right lower extremity. The lesion was of 10-day duration. Because early cutaneous leishmaniasis (CL) lesions may have a non-ulcerated appearance, a Leishmania skin test (LST) was performed on the forearm with a strong positive result (38 × 32 mm). After 8 days, the lesion in the leg, which was diagnosed as folliculitis, completely healed. However, a typical CL ulcer (26 × 24 mm) developed at the LST site. Histopathology of the new lesion did not identifiy parasites, but the findings were consistent with a diagnosis of CL. Further analysis identified amastigotes by immunohistochemical stain. Mononuclear cells harvested from the patient were stimulated with Leishmania antigen and showed high levels of production of both tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ): 2,943 pg/mL and 2,313 pg/mL, respectively. After 40 days of treatment with antimony and pentoxifylline, the ulcer resolved. The development of CL at the LST site suggests a strong Th1 immune response, and it is an in vivo documentation of the role of the host immune response in the pathology of CL. It teaches us that LST should be cautiously, if at all, used in patients with self-healing CL ulcers

THE EFFECT OF DEPTH ON THE DRAG FORCE DURING UNDERWATER GLIDING: A CFD APPROACH

Swimming events are the sum of a gliding part and a swimming part. The gliding is used after the start and turns, and this phase typically corresponds to 10-25% of the total event time (Chatard et al., 1990). Taking this into account, one can notice that gliding is very important in swimming events and, therefore, its biomechanical study in order to make it more efficient is also very relevant. The gliding can be studied experimentally, by using voluntary subjects gliding in a controlled manner in a swimming pool (using video or velocimetry, for instance), or by using Computational Fluid Dynamics (CFD). Although the experimental method gives “real” values it also presents some drawbacks, like usually imposing a heavy setup and also the fact that it is difficult to control all variables, like depth, attitude or intersegment positions of the swimmer. The CFD method does not have these limitations and its results are comparable to those obtained by the experimental method (Bixler & Riewald, 2002; Silva et al., 2005; Bixler et al., 2007; Vilas Boas et al., 2010). This work aims to study the effects of the depth and velocity on the drag force experienced by a swimmer during gliding using the CFD method

Leishmania braziliensis Infection Enhances Toll-Like Receptors 2 and 4 Expression and Triggers TNF-α and IL-10 Production in Human Cutaneous Leishmaniasis

Cutaneous leishmaniasis (CL) caused by infection with Leishmania braziliensis is characterized by an exaggerated inflammatory response that controls the parasite burden, but also contributes to pathology. While myeloid cells are required to eliminate the parasite, recent studies indicate that they may also participate in the inflammatory response driving disease progression. The innate immune response to leishmania is driven in part by the Toll-like receptors (TLRs) TLR2, TLR4, and TLR9. In this study, we used flow cytometric analysis to compare TLR2 and TLR4 expression in monocyte subsets (classical, intermediate, and non-classical) from CL patients and healthy subjects (HS). We also determined if there was an association of either the pro-inflammatory cytokine TNF or the anti-inflammatory cytokine IL-10 with TLR2 or TLR4 expression levels after L. braziliensis infection. In vitro infection with L. braziliensis caused CL monocytes to up-regulate TLR2 and TLR4 expression. We also found that intermediate monocytes expressed the highest levels of TLR2 and TLR4 and that infected monocytes produced more TNF and IL-10 than uninfected monocytes. Finally, while classical and intermediate monocytes were mainly responsible for TNF production, classical monocytes were the main source of IL-10. Collectively, our studies revealed that up-regulated TLR2/4 expression and TNF production by intermediate/inflammatory subsets of monocytes from patients correlates with detrimental outcome of cutaneous leishmaniasis

Computational fluid dynamics vs. inverse dynamics methods to determine passive drag in two breaststroke glide positions

Computational fluid dynamics (CFD) plays an important role to quantify, understand and "observe" the water movements around the human body and its effects on drag (D). We aimed to investigate the flow effects around the swimmer and to compare the drag and drag coefficient (CD) values obtained from experiments (using cable velocimetry in a swimming pool) with those of CFD simulations for the two ventral gliding positions assumed during the breaststroke underwater cycle (with shoulders flexed and upper limbs extended above the head-GP1; with shoulders in neutral position and upper limbs extended along the trunk-GP2). Six well-trained breaststroke male swimmers (with reasonable homogeneity of body characteristics) participated in the experimental tests; afterwards a 3D swimmer model was created to fit within the limits of the sample body size profile. The standard k-ε turbulent model was used to simulate the fluid flow around the swimmer model. Velocity ranged from 1.30 to 1.70 m/s for GP1 and 1.10 to 1.50 m/s for GP2. Values found for GP1 and GP2 were lower for CFD than experimental ones. Nevertheless, both CFD and experimental drag/drag coefficient values displayed a tendency to jointly increase/decrease with velocity, except for GP2 CD where CFD and experimental values display opposite tendencies. Results suggest that CFD values obtained by single model approaches should be considered with caution due to small body shape and dimension differences to real swimmers. For better accuracy of CFD studies, realistic individual 3D models of swimmers are required, and specific kinematics respected.info:eu-repo/semantics/publishedVersio

A synthetic biology approach to engineer "therapeutic" bacteria

The high incidence and mortality of solid tumors like breast cancer makes the development of novel therapeutic agents a high priority. Curcumin, a natural substance from the rhizome of Curcuma longa, has captured the attention of the scientific community. Pre-clinical trials and extensive research has demonstrated its ability to prevent cancer. Indeed, curcumin has been shown to target critical genes involved in angiogenesis, apoptosis, cell cycle and metastasis, and consequently to inhibit cell growth. Currently, the clinical use of curcumin is mainly limited by its poor bioavailability which implies repetitive oral doses in order to achieve the therapeutic concentrations inside the cell. The idea of the present work is to design a strategy that could link the common technique used to treat solid tumors (ultrasound) with the therapeutic effects of curcumin. The plan is to use the temperature increase (consequence of ultrasound treatment) to trigger the in situ expression of curcumin by engineered bacteria. Escherichia coli was chosen as the model organism in which the genes involved in the curcumin pathway will be cloned. Those genes (4-coumarate: CoA ligase, diketide-CoA synthase and curcumin synthase) were successfully cloned under the control of a temperature sensitive promoter (dnaK). The proof-of-concept that the dnaK promoter can be induced by a temperature increase, leading to the expression of the 3 necessary genes, is currently being tested, using several biochemical assays. Moreover, several knockouts (KO) of specific genes from the E. coli K-12 MG1655 genome were performed in order to maximize the production of curcumin. The deletion strategy, as well as the definition of the non-essential genes to be KO, was determined in silico. This strategy included one single KO (gnd gene) and the multiple KO of five non-essential genes for aerobic growth (fumA, fumB, fumC, ccmA and argO) and serA gene for anaerobic growth. After optimizing the genes expression under the control of the temperature inducible promoter, the several KO will be transformed with this construction to confirm the improvement of curcumin production

HOW TO START IN BACKSTROKE CONSIDERING THE NEW RULES?

FINA recently changed the rule that governs the starting position for the backstroke starting technique. With this change, swimmers may now decide to start with the feet emerged, which was previously strictly forbidden. This new liberalization naturally determines the rise of a new technical question for swimmers and coaches: do a starting position with the feet emerged allow a better performance, or better performance conditions for the following actions? To our knowledge no previous scientific results are available concerning this question, allowing to support any technical decision. During this presentation we will try to deliver arguments to support a technical option in this particular topic, based on the research developed by our group, comparing the traditional starting technique with the feet immerged (BSFI), with the one allowed nowadays, with both feet totally, or partially, emerged (BSFE). To fulfil this purpose, we studied six experienced male swimmers that maximally performed 4 repetitions of each technique over a distance of 15 meters. All performances were dual-media videotaped (50 Hz) in the sagittal plane, synchronized with kinetic and EMG data simultaneously registered. Kinetic data were assessed using an underwater force plate mounted on a special support on the wall of the pool, allowing the registration of the horizontal component of the forces exerted by the swimmers’ feet. The handgrip system was adapted to reproduce its legal position and configuration, but instrumented with a load cell (Globus, Italy) to allow the assessment of the horizontal component of the forces exerted by swimmers’ upper limbs. Findings pointed out that BSFI was significantly faster till the 5m reference, with less muscular activity, and with a tendency to produce higher forces against the starting wall. No argument was obtained to support the use of the BSFE in swimming competitions

Development of Inhalable Superparamagnetic Iron Oxide Nanoparticles (SPIONs) in microparticulate system for antituberculosis drug delivery

Tuberculosis (TB) is an infectious disease which affects millions of people worldwide. Inhalable polymeric dry powders are promising alternatives as anti-TB drug carriers to the alveoli milieu and infected macrophages, with potential to significantly improve the therapeutics efficiency. Here, the development of a magnetically responsive microparticulate system for pulmonary delivery of an anti-TB drug candidate (P3) is reported. Microparticles (MPs) are developed based on a cast method using calcium carbonate sacrificial templates and incorporate superparamagnetic iron oxide nanoparticles to concentrate MPs in alveoli and enable drug on demand release upon actuation of an external alternate magnetic field (AMF). The MPs are shown to be suitable for P3 delivery to the lower airways and for alveolar macrophage phagocytosis. The developed MPs reveal unique and promising features to be used as an inhalable dry powder allowing the AMF control over dosage and frequency of drug delivery anticipating improved TB treatments.The authors wish to acknowledge the financial support from the Portuguese Foundation for Science and Technology (FCT) for the postdoctoral grant of M.S.M. (SFRH/BPD/110868/2015) and R.M.A.D (SFRH/BPD/112459/2015), FCT grant of E.T. (IF/01390/2014) and Recognize project (UTAP-ICDT/CTM-BIO/0023/2014). This article is also a result of the project “Accelerating tissue engineering and personalized medicine discoveries by the integration of key enabling nanotechnologies, marine-derived biomaterials and stem cells,” supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). The authors acknowledge the financial support from the European Union Framework Programme for Research and Innovation HORIZON 2020, under the TEAMING Grant Agreement No. 739572 – The Discoveries CTR.info:eu-repo/semantics/publishedVersio