Insight into the molecular pathophysiology of myelodysplastic syndromes: targets for novel therapy

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by abnormal cellular differentiation and maturation with variable progression to acute leukemia. Over the last decade, scientific discoveries have unraveled specific pathways involved in the complex pathophysiology of MDS. Prominent examples include aberrations in cytokines and their signaling pathways (such as tumor necrosis factor-alpha, interferon-gamma, SMAD proteins), mutations in genes encoding the RNA splicing machinery (SF3B1, SRSF2, ZRSR2, and U2AF1 genes), mutations in genes disrupting the epigenetic machinery (TET2, DNMT3A, DNMT3B, EZH2, ASXL1). In addition, abnormalities in regulatory T-cell dynamics and atypical interactions between the bone marrow microenvironment, stroma and progenitor cells, and abnormal maintenance of telomeres are also notable contributors to the complex pathogenesis of MDS. These pathways represent potential targets for novel therapies. Specific therapies include drugs targeting aberrant DNA methylation and chromatin remodeling, modulating/activating the immune system to enhance tumor-specific cellular immune responses and reduce anomalous cytokine signaling, and blocking abnormal interaction between hematopoietic progenitors and stromal cells

Solubility of CO2 in Aqueous Solutions of 2-Amino-2-Methyl-1-Propanol at High Pressure

Carbon dioxide is one of the major green house gases. It is removed from different streams using amine absorption process. Sterically hindered amines are suggested as good CO2 absorbers. Solubility of carbon dioxide (CO2) was measured in aqueous solutions of 2-Amino-2-methyl-1-propanol (AMP) at temperatures 30 oC, 40 oC and 60 oC. The effect of pressure and temperature was studied over various concentrations of AMP. It has been found that pressure has positive effect on CO2 solubility where as solubility decreased with increasing temperature. Absorption performance of AMP increased with increasing pressure. Solubility of aqueous AMP was compared with mo-ethanolamine (MEA) and the absorption capacity of aqueous solutions of AMP was found to be better

Limited effectiveness of home drinking water purification efforts in Karachi, Pakistan

Objective: In many developing-country urban areas, municipally supplied water is not microbiologically safe. This study evaluated drinking water quality and effect of home water purification efforts in Karachi, Pakistan.Methods: Members of 300 households, including 100 households who used the Aga Khan University Hospital Laboratory and 200 of their neighbors were interviewed. In 293 consenting households, structured observations were performed and drinking water was analyzed for the presence of coliforms, using the multiple tube fermentation technique.Results: Although 193 of the 293 households (66%) reported using some method to purify their drinking water, including 169 (58%) who boiled their water, only 48 (16%) of the drinking water samples were free of coliforms. Although a combination of boiling and filtering was the most effective method of purification, only 38% of samples that had been boiled and filtered were free of coliforms.CONCLUSIONS: Further refinements and evaluations of home-based efforts to purify and store water are needed

Do design variations in the artificial disc influence cervical spine biomechanics? A finite element investigation

Various ball and socket-type designs of cervical artificial discs are in use or under investigation. Many artificial disc designs claim to restore the normal kinematics of the cervical spine. What differentiates one type of design from another design is currently not well understood. In this study, authors examined various clinically relevant parameters using a finite element model of C3–C7 cervical spine to study the effects of variations of ball and socket disc designs. Four variations of ball and socket-type artificial disc were placed at the C5–C6 level in an experimentally validated finite element model. Biomechanical effects of the shape (oval vs. spherical ball) and location (inferior vs. superior ball) were studied in detail. Range of motion, facet loading, implant stresses and capsule ligament strains were computed to investigate the influence of disc designs on resulting biomechanics. Motions at the implant level tended to increase following disc replacement. No major kinematic differences were observed among the disc designs tested. However, implant stresses were substantially higher in the spherical designs when compared to the oval designs. For both spherical and oval designs, the facet loads were lower for the designs with an inferior ball component. The capsule ligament strains were lower for the oval design with an inferior ball component. Overall, the oval design with an inferior ball component, produced motion, facet loads, implant stresses and capsule ligament strains closest to the intact spine, which may be key to long-term implant survival

Venous thromboembolism following hematopoietic stem cell transplantation-a systematic review and meta-analysis

Venous thromboembolism (VTE) is a common complication of hematopoietic stem cell transplantation (HSCT). Graft-versus-host disease (GVHD) is another complication of HSCT that may modify the risk of VTE. Our objective was to explore the incidence of VTE (deep venous thrombosis and pulmonary embolism) following HSCT and to evaluate its association with GVHD. A comprehensive search of Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus was conducted to search for both retrospective and prospective HSCT studies which had reported VTE. Random-effects meta-analysis was used to pool incidence rates. We included 17 studies reporting on allogeneic- and 10 on autologous-HSCT; enrolling 6693 patients; of which 5 were randomized. The overall incidence of VTE after HSCT was 5%(4-7%). Incidence in allogeneic-HSCT was 4%(2-6%) and in autologous-HSCT was 4%(1-15%). Eleven and nine studies reported data on acute and chronic GVHD, respectively. The incidence of VTE in chronic GVHD was 35%(20-54%), whereas in acute GVHD it was 47%(32-62%). Based on the results of this meta-analysis, VTE is a fairly common complication after HSCT, emphasizing the importance of assimilating guidelines for both treatment and prophylaxis in this patient population

Functional Role of Glutamine 28 and Arginine 39 in Double Stranded RNA Cleavage by Human Pancreatic Ribonuclease

Human pancreatic ribonuclease (HPR), a member of RNase A superfamily, has a high activity on double stranded (ds) RNA. By virtue of this activity HPR appears to be involved in the host-defense against pathogenic viruses. To delineate the mechanism of dsRNA cleavage by HPR, we have investigated the role of glutamine 28 and arginine 39 of HPR in its activity on dsRNA. A non-basic residue glycine 38, earlier shown to be important for dsRNA cleavage by HPR was also included in the study in the context of glutamine 28 and arginine 39. Nine variants of HPR respectively containing Q28A, Q28L, R39A, G38D, Q28A/R39A, Q28L/R39A, Q28A/G38D, R39A/G38D and Q28A/G38D/R39A mutations were generated and functionally characterized. The far-UV CD-spectral analysis revealed all variants, except R39A, to have structures similar to that of HPR. The catalytic activity of all HPR variants on single stranded RNA substrate was similar to that of HPR, whereas on dsRNA, the catalytic efficiency of all single residue variants, except for the Q28L, was significantly reduced. The dsRNA cleavage activity of R39A/G38D and Q28A/G38D/R39A variants was most drastically reduced to 4% of that of HPR. The variants having reduced dsRNA cleavage activity also had reduction in their dsDNA melting activity and thermal stability. Our results indicate that in HPR both glutamine 28 and arginine 39 are important for the cleavage of dsRNA. Although these residues are not directly involved in catalysis, both arginine 39 and glutamine 28 appear to be facilitating a productive substrate-enzyme interaction during the dsRNA cleavage by HPR

Finite Element Analysis of Bone and Experimental Validation

This chapter describes the application of the finite element (FE) method to bone tissues. The aspects that differ the most between bone and other materials’ FE analysis are the type of elements used, constitutive models, and experimental validation. These aspects are looked at from a historical evolution stand point. Several types of elements can be used to simulate similar bone structures and within the same analysis many types of elements may be needed to realistically simulate an anatomical part. Special attention is made to constitutive models, including the use of density-elasticity relationships made possible through CT-scanned images. Other more complex models are also described that include viscoelasticity and anisotropy. The importance of experimental validation is discussed, describing several methods used by different authors in this challenging field. The use of cadaveric human bones is not always possible or desirable and other options are described, as the use of animal or artificial bones. Strain and strain rate measuring methods are also discussed, such as rosette strain gauges and optical devices.publishe

A multi-centric, single-blinded, randomized, parallel-group study to evaluate the effectiveness of nasoalveolar moulding treatment in non-syndromic patients with complete unilateral cleft lip, alveolus and palate (NAMUC study): a study protocol for a randomized controlled trial.

BACKGROUND Cleft lip and palate (CLP) are among the most common congenital anomaly that affects up to 33,000 newborns in India every year. Nasoalveolar moulding (NAM) is a non-surgical treatment performed between 0 and 6 months of age to reduce the cleft and improve nasal aesthetics prior to lip surgery. The NAM treatment has been a controversial treatment option with 51% of the cleft teams in Europe, 37% of teams in the USA and 25 of cleft teams in India adopting this methodology. This treatment adds to the already existing high burden of care for these patients. Furthermore, the supporting evidence for this technique is limited with no high-quality long-term clinical trials available on the effectiveness of this treatment. METHOD The NAMUC study is an investigator-initiated, multi-centre, single-blinded randomized controlled trial with a parallel group design. The study will compare the effectiveness of NAM treatment provided prior to lip surgery against the no-treatment control group in 274 patients with non-syndromic unilateral complete cleft lip and palate. The primary endpoint of the trial is the nasolabial aesthetics measured using the Asher McDade index at 5 years of age. The secondary outcomes include dentofacial development, speech, hearing, cost-effectiveness, quality of life, patient perception, feeding and intangible benefits. Randomization will be carried out via central online system and stratified based on cleft width, birth weight and clinical trial site. DISCUSSION We expect the results from this study on the effectiveness of treatment with NAM appliance in the long term along with the cost-effectiveness evaluation can eliminate the dilemma and differences in clinical care across the globe. TRIAL REGISTRATION ClinicalTrials.gov CTRI/2022/11/047426 (Clinical Trials Registry India). Registered on 18 November 2022. The first patient was recruited on 11 December 2022. CTR India does not pick up on Google search with just the trial number. The following steps have to be carried out to pick up. How to search: ( https://ctri.nic.in/Clinicaltrials/advsearch.php -use the search boxes by entering the following details: Interventional trial > November 2022 > NAMUC)

Impacts of biomedical hashtag-based Twitter campaign: #DHPSP utilization for promotion of open innovation in digital health, patient safety, and personalized medicine

The open innovation hub Digital Health and Patient Safety Platform (DHPSP) was recently established with the purpose to invigorate collaborative scientific research and the development of new digital products and personalized solutions aiming to improve human health and patient safety. In this study, we evaluated the effectiveness of a Twitter-based campaign centered on using the hashtag #DHPSP to promote the visibility of the DHPSP initiative. Thus, tweets containing #DHPSP were monitored for five weeks for the period 20.10.2020–24.11.2020 and were analyzed with Symplur Signals (social media analytics tool). In the study period, a total of 11,005 tweets containing #DHPSP were posted by 3020 Twitter users, generating 151,984,378 impressions. Analysis of the healthcare stakeholder-identity of the Twitter users who used #DHPSP revealed that the most of participating user accounts belonged to individuals or doctors, with the top three user locations being the United States (501 users), the United Kingdom (155 users), and India (121 users). Analysis of co-occurring hashtags and the full text of the posted tweets further revealed that the major themes of attention in the #DHPSP Twitter-community were related to the coronavirus disease 2019 (COVID-19), medicine and health, digital health technologies, and science communication in general. Overall, these results indicate that the #DHPSP initiative achieved high visibility and engaged a large body of Twitter users interested in the DHPSP focus area. Moreover, the conducted campaign resulted in an increase of DHPSP member enrollments and website visitors, and new scientific collaborations were formed. Thus, Twitter campaigns centered on a dedicated hashtag prove to be a highly efficient tool for visibility-promotion, which could be successfully utilized by healthcare-related open innovation platforms or initiatives