Myeloablative Versus Reduced Intensity Conditioning Regimens for Allogeneic Hematopoietic Stem Cell Transplant for Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Retrospective Analysis

The conditioning regimens used for the allo-HSCT include either myeloablative conditioning (MAC) or reduced intensity conditioning (RIC) regimens based on the age, performance status and co-morbidities. Studies comparing the survival outcomes of RIC and MAC allo-HSCT in AML and MDS patients have reported contradictory results. We therefore retrospectively analyzed our data of AML and MDS patients who received MAC and RIC allo-HSCT at our center and compared the long term outcome of the two conditioning regimens. One hundred twenty six consecutive patients were evaluated, 32 (25.4%) underwent MAC allo-HSCT and 94 (74.6%) underwent RIC allo-HSCT. The most common MAC regimen used was busulfan plus cyclophosphamide and the most common RIC regimen used was fludarabine plus melphalan. The median age was higher in RIC group (44 years, range 4–75 years) compared to MAC group (31 yrs, range 6–51 yrs, p = 0.001). There was no significant difference in terms of overall survival (p = 0.498), relapse-free survival (p = 0.791) and non-relapse mortality (p = 0.366) between the two groups. In multivariate analysis, only chronic graft-versus-host disease resulted in decreased risk of relapse and improved overall survival irrespective of the conditioning regimens used.     

Heritability of quantitative traits associated with type 2 diabetes mellitus in large multiplex families from South India

India is a major contributor to the global public health burden of diabetes. We have undertaken a family study of large multiplex families from Chennai, South India, and report on the familial aggregation of quantitative traits associated with type 2 diabetes mellitus in these pedigrees. Five hundred twenty-four individuals older than 19 years from 26 large multiplex pedigrees were ascertained. Detailed questionnaires and phenotype data were obtained on all participating individuals including fasting blood glucose, fasting insulin, lipid profiles, height, weight, and other anthropometric and clinical measures. Heritability estimates were calculated for all quantitative traits at the univariate level, and bivariate analyses were done to determine the correlation in genetic and environmental control across these quantitative traits. Heritability estimates ranged from 0.21 to 0.72. The heritability estimates for traits most directly related to type 2 diabetes mellitus were 0.24 ± 0.08 for fasting blood glucose and 0.41 ± 0.09 for fasting insulin. In addition, there was evidence for common genetic control for many pairs of these traits. These bivariate analyses suggested common genes for fasting insulin and central obesity measures (body mass index, waist, and hip), with complete genetic correlation between fasting insulin and waist. Quantitative traits associated with type 2 diabetes mellitus have heritabilities suggestive of some familial or genetic effect. The evidence for pleiotropic control of insulin and central obesity-related traits supports the presence of an insulin resistance syndrome in South Asians with a tendency for central obesity.     

Genetic variants of the T-cell immunoglobulin mucin 1 but not the T-cell immunoglobulin mucin 3 gene are associated with asthma in an African American population

BACKGROUND: The T-cell immunoglobulin mucin ( TIM ) proteins and their genetic variants have been suggested to play a role in regulating allergic diseases. OBJECTIVE: Genetic association of the sequence variants for TIM-1 and TIM-3 genes with asthma in an African American population was investigated. METHODS: Both case-control and family-based association analyses were performed for a total of 7 polymorphisms, including 3 single nucleotide polymorphism (SNPs) and 1 insertion/deletion polymorphism in the TIM-1 and 3 SNPs in the TIM-3 genes. The exposure to hepatitis A virus as judged by seropositivity was also examined. RESULTS: In the case-control design, the frequencies of the TT genotype for SNP rs2277025 and the homozygous deletion variant (157delMTTTVP) in the fourth exon of the TIM-1 gene were higher among patients with patients with asthma compared with the controls (odds ratio [OR], 2.779, P = .016; and OR, 3.09, P = .022, respectively). This association was substantiated by haplotype analysis of these and 2 additional SNPs (OR, 2.48; P = .004), and also by family-based tests for the allele and haplotype carrying 157delMTTTVP (P = .009 and P = .048, respectively). Furthermore, this association seems to exist even in the hepatitis A virus-seronegative subjects in our data. None of the 3 variants in TIM-3 genes yielded significant association with either asthma or asthma-related phenotypes. CONCLUSION: Our findings suggest that the genetic variants of the TIM-1 but not the TIM-3 gene contribute to asthma susceptibility in this African-American population.     

HLA alleles and sustained peanut consumption promote IgG4 responses in subjects protected from peanut allergy

We investigated the interplay between genetics and oral peanut protein exposure in the determination of the immunological response to peanut using the targeted intervention in the LEAP clinical trial. We identified an association between peanut-specific IgG4 and HLA-DQA1*01:02 that was only observed in the presence of sustained oral peanut protein exposure. The association between IgG4 and HLA-DQA1*01:02 was driven by IgG4 specific for the Ara h 2 component. Once peanut consumption ceased, the association between IgG4-specific Ara h 2 and HLA-DQA1*01:02 was attenuated. The association was validated by observing expanded IgG4-specific epitopes in people who carried HLA-DQA1*01:02. Notably, we confirmed the previously reported associations with HLA-DQA1*01:02 and peanut allergy risk in the absence of oral peanut protein exposure. Interaction between HLA and presence or absence of exposure to peanut in an allergen- and epitope-specific manner implicates a mechanism of antigen recognition that is fundamental to driving immune responses related to allergy risk or protection.     

Epigenetics/epigenomics and prevention by curcumin of early stages of inflammatory-driven colon cancer

Colorectal cancer (CRC) is associated with significant morbidity and mortality in the US and worldwide. CRC is the second most common cancer-related death in both men and women globally. Chronic inflammation has been identified as one of the major risk factors of CRC. It may drive genetic and epigenetic/epigenomic alterations, such as DNA methylation, histone modification, and non-coding RNA regulation. Current prevention modalities for CRC are limited and some treatment regimens such as use the nonsteroidal anti-inflammatory drug aspirin may have severe side effects, namely gastrointestinal ulceration and bleeding. Therefore, there is an urgent need of developing alternative strategies. Recently, increasing evidence suggests that several dietary cancer chemopreventive phytochemicals possess anti-inflammation and antioxidative stress activities, and may prevent cancers including CRC. Curcumin (CUR) is the yellow pigment that is found in the rhizomes of turmeric (Curcuma longa). Many studies have demonstrated that CUR exhibit strong anticancer, antioxidative stress, and anti-inflammatory activities by regulating signaling pathways, such as nuclear factor erythroid-2-related factor 2, nuclear factor-κB, and epigenetics/epigenomics pathways of histones modifications, and DNA methylation. In this review, we will discuss the latest evidence in epigenetics/epigenomics alterations by CUR in CRC and their potential contribution in the prevention of CRC.     

First Nations Health: Antibiotic prescribing for respiratory tract infection across a national primary care network in 2019

BackgroundRespiratory tract infection (RTI) is the leading reason for avoidable antimicrobial use in primary care, yet provider-level feedback on its use is only available in some provinces. The aim of this study was to validate case definitions for RTI across the Canadian Primary Care Sentinel Surveillance Network (CPCSSN) and determine baseline provider-level variability in antimicrobial prescribing in 2019.MethodsThe RTI case definitions were developed using demographic, diagnostic coding and keywords in electronic medical record. Manual chart abstraction was performed to identify cases of acute otitis media. Remaining RTI definitions were validated using a random sample of 5,164 patients with encounters in 2019. The proportion of patients with an RTI treated with antibiotics was determined by provider, per patient, per episode and per patient encounter.ResultsNegative predictive value, positive predictive value and prevalence were as follows: 1.00 (0.99–1.00), 0.99 (0.96–0.99) and 4.14% (4.10–4.19) for common cold; 1.00 (0.99–1.00), 0.94 (0.88–0.98) and 1.09% (1.07–1.12) for acute otitis media; 0.98 (0.96–1.00), 0.93 (0.87–0.97) and 1.2% (1.18–1.22) for acute pharyngitis; 0.99 (0.99–1.00), 0.88 (0.81–0.93) and 1.99% (1.96–2.02) for sinusitis; 0.99 (0.97–0.99), 0.95 (0.89–0.98) and 4.01% (3.97–4.05) for acute bronchitis/asthma. By provider, median (interquartile range [IQR]) proportion treated with antibiotics (per patient) was 6.72 (14.92) for common cold, 64.29 (40.00) for acute otitis media, 20.00 (38.89) for pharyngitis, 54.17 (38.09) for sinusitis, 8.33 (20.00) for acute bronchitis/asthma and 21.10 (20.56) for overall RTI.ConclusionThe CPCSSN can provide national surveillance of antimicrobial prescribing practices for RTI across primary care. Baseline variability underscores the need for provider feedback and quality improvement.     

Development and characterization of emulsomes for sustained and targeted delivery of an antiviral agent to liver

In this study we developed emulsomes, a novel lipoidal vesicular system with an internal solid fat core surrounded by a phospholipid bilayer. Plain emulsomal formulations composed of solid lipid (trilaurin or tristearin), cholesterol and soya phosphatidylcholine and stearylamine containing cationic emulsomes loaded with an antiviral drug (zidovudine) were prepared by a simple cast film method followed by sonication to produce emulsomes of nanometric size range. All different types of formulations were optimized for lipid ratios and characterized in-vitro for shape, morphology, size and in-vitro drug release profile. Emulsomal formulations displayed a sufficiently slow drug release profile (12-15% after 24 h). In-vivo organ distribution studies in rats demonstrated better uptake of emulsomal formulations by the liver cells. Further, a significantly higher (P < 0.05) liver concentration of drug was estimated over a period of 24 h for cationic emulsomes than for plain neutral emulsomes. We concluded that cationic emulsomes could fuse with the endosomal membrane due to charge-charge interaction and were released in the cytoplasm before lysosomal degradation and could sustain drug release over a prolonged period. The proposed cationic emulsome-based system showed excellent potential for intracellular hepatic targeting and the strategy could play a vital role in the effective treatment of life-threatening viral infections, such as hepatitis, HIV and Epstein-Barr virus infection.     

Critical appraisal of commercially available suspending vehicles for extemporaneous compounding of cardiovascular medicines: physical and chemical stability mini review

Oral liquid formulations are compounded by pharmacists to meet the needs of patients when a suitable commercially available product is not available. To minimize the errors associated with measuring multiple excipients and to enhance the shelf-life of the medicines, commercially available suspending bases are commonly used. This review aims to compare the stability and shelf life of commercially available extemporaneous formulation to traditional formulation methods. Five (5) databases were searched (Pubmed, SCOPUS, Science direct, Embase, and EBSCOhost). Twelve articles, comprising of seven cardiovascular medications (amiodarone, captopril, carvedilol, furosemide, nifedipine, sotalol, and valsartan), met the study inclusion criteria and were reviewed. Chemical stability of the drugs was comparable between the two formulation methods except for furosemide, captopril, and valsartan. The traditional compounding method provided superior stability for furosemide (90?vs. 14?days) and captopril (50?vs. 14?days), while the commercial vehicles provided superior stability for valsartan (90?vs. 14?days). Physical stability tests indicated that sedimentation does occur with both formulation methods. Microbial studies within the data were lacking and further research can be undertaken in this area. This review highlights the importance of assessing the suitability of compounding ingredients prior to preparation of the formulation.