Arginine-engrafted biodegradable polymer for the systemic delivery of therapeutic siRNA

Small interfering RNA (siRNA) represent an interesting class of developmental nucleic acid-based therapeutics. Cationic carriers for deoxyribonucleic acids (DNA) are potential vehicles for siRNA delivery. However, in contrast to supercoiled plasmid DNA, the physical properties of siRNA molecules induces the formation of larger, loosely-packed complexes with most polycationic carriers, and consequently, poor target silencing. Here, we investigate a gene delivery agent, arginine-grafted bioreducible poly (disulfide amine) polymer (ABP) for siRNA delivery as it contains arginine residues with siRNA binding properties. ABP combines the attributes of polycations and poly disulfide-amines namely- excellent cell-penetrability and rapid release after disulphide bond reduction in the intracellular compartment. ABP bound siRNA, assembled into stable 150 nm sized nanoparticles and efficiently released complexed siRNA upon cellular entry. We investigated the utility of ABP in a combinatorial RNAi strategy for solid cancer therapy. Systemic administration of ABP-siRNA resulted in a preferential and enhanced accumulation of carrier-siRNA complexes in the tumor tissue. Two administrations of the formulation with a siRNA cocktail targeting Bcl-2, VEGF and Myc at 0.3 mg total siRNA/kg body weight could effectively regress advanced stage tumors. Our results establish the promise of ABP as a common systemic delivery platform for both siRNA and DNA therapeutics.     

Myeloablative transplantation using either cord blood or bone marrow leads to immune recovery, high long-term donor chimerism and excellent survival in chronic granulomatous disease

The curative potential of hematopoietic stem cell transplantation in patients with chronic granulomatous disease depends on availability of a suitable donor, successful donor engraftment, and maintenance of long-term donor chimerism. Twelve consecutive children (median age, 59.5 months; range, 8-140 months) with severe chronic granulomatous disease (serious bacterial/fungal infections pretransplantation; median, 3; range, 2-9) received myeloablative hematopoietic stem cell transplantation using sibling bone marrow ([SibBM]; n = 5), unrelated cord blood (UCB; n = 6), and sibling cord blood (n = 1) at our center between 1997 and 2010. SibBM and sibling cord blood were HLA matched at 6/6, whereas UCB were 5/6 (n = 5) or 6/6 (n = 1). Recipients of SibBM were conditioned with busulfan and cyclophosphamide ± anti-thymocyte globulin (ATG), whereas 6 of 7 cord blood recipients received fludarabine/busulfan/cyclophosphamide/ATG. Seven patients received granulocyte-colony stimulating factor-mobilized granulocyte transfusions from directed donors. The first 2 UCB recipients had primary graft failure but successfully underwent retransplantation with UCB. Highest acute graft-versus-host disease was grade III (n = 1). Extensive chronic graft-vs-host disease developed in 3 patients. All patients are alive with median follow-up of 70.5 months (range, 12-167 months) with high donor chimerism (>98%, n = 10; 94%, n?= 1; and 92%, n = 1). Myeloablative hematopoietic stem cell transplantation led to correction of neutrophil dysfunction, durable donor chimerism, excellent survival, good quality of life, and low incidence of graft-vs-host disease regardless of graft source.     

Major Primary Congenital Coronary Artery Anomalies: An Angiographic Study

Congenital Coronary artery anomalies are found in about 1 % population (0.6% to 1.5% in different geographic studies). Angiographic recognition of these anomalies is important because of their clinical significance (sudden death) and importance in patients undergoing coronary interventions or cardiac surgery. Our study included 3215 patients who underwent diagnostic coronary angiography during the 2 years period from 2008 to 2010. Twenty nine (0.90%) patients (22 male and 7 female) had major congenital coronary anomalies of which twenty seven (93.10%) patients had anomalies of origin and distribution while two (6.89%) had coronary artery fistulae. Right coronary artery was the commonest anomalous vessel, involved in 14 (48.27%) patients. It was originating from the left sinus of Valsalva in 10, from the non-facing aortic sinus in 2 and from left anterior descending artery in 2 patients. Anomalous origin of left circumflex artery was the second commonest anomaly, seen in 10 (34.48%) patients. Anomalous left anterior descending artery was found to be originating from right coronary artery in 2 (6.89%) and anomalous left coronary artery from right coronary artery was seen in one (3.4%) patient. Among patients with coronary fistulae, one (3.4%) had fistulae between the left anterior descending artery and the main pulmonary artery, one (3.4%) between the conal artery and the right atrium. The fistulae in our series were small & without significant shunt circulation. Atherosclerotic plaques in anomalous arteries were seen in only 8 (27.58%) patients, significantly less than the incidence (51.5%) of overall coronary artery disease in 3215 patients studied in this series. In two (6.89%) patients only the anomalous vessels were involved in coronary artery disease. Congenital coronary artery anornalies do not appear to be associated with an increased risk for development of coronary atherosclerosis. Recognition of coronary anomalies is important in patients undergoing coronary angiography, coronary interventions and cardiac surgery. Variations in the frequency of major congenital coronary anomalies may have a genetic background.     

Determining economic feasibility of fluticasone propionate-salmeterol vs montelukast in the treatment of persistent asthma using a net benefit approach and cost-effectiveness acceptability curves.

BACKGROUND: The choice of treatment can have a major impact on the total costs associated with asthma care. OBJECTIVE: To determine the relative cost-effectiveness of twice-daily treatment with inhaled fluticasone propionate-salmeterol via Diskus, 100/50 microg, with that of once-daily treatment with oral montelukast as initial maintenance therapy in patients with persistent asthma uncontrolled with a short-acting beta2-agonist alone. METHODS: Data from a randomized, double-blind, double-dummy, 12-week clinical trial were analyzed. Efficacy end points included (1) symptom-free days (SFDs) during the 12-week period and (2) a 12% or greater increase in forced expiratory volume in 1 second (FEV1) from baseline. The economic analysis was performed from a payer's perspective, and hence only direct costs were included in the analysis. The incremental cost-effectiveness ratio (ICER), which is the mean difference in average costs divided by the mean difference in average effectiveness, was calculated for both effectiveness outcomes (SFDs and FEV1). RESULTS: For the SFDs end point, the ICER for fluticasone propionate-salmeterol vs montelukast was $2.87 (95% confidence interval, -$1.08 to $6.65), indicating that it costs, on average, an extra $2.87 per day for an additional SFD with fluticasone propionate-salmeterol than with montelukast. With regard to FEV1, the ICER was $1.79 (95% confidence interval, -$0.72 to $3.86), indicating that it costs, on average, an extra $1.79 per day to achieve a lung function improvement of 12% or greater from baseline with fluticasone propionate-salmeterol than with montelukast. At a widely acceptable ceiling ratio of $9.95 per day, the probability of fluticasone propionate-salmeterol being more cost-effective than montelukast was 99.8% for SFDs and was almost 100% for an FEV1 improvement of 12% of greater. CONCLUSIONS: Treating 2 main components of asthma, inflammation and smooth muscle dysfunction, using fluticasone propionate-salmeterol is more cost-effective than using a single mediator antagonist alone, such as montelukast, as initial maintenance therapy for persistent asthma in patients treated with a short-acting beta2-agonist only.     

Recurrent Hydatid Cyst of Liver with Asymptomatic Concomitant Hydatid Cyst of Lung: An Unusual Presentation-Case Report

A 40-year-old male patient presented to us with complaints of pain in abdomen for the past 2 weeks and fever for 3 days. The patient gave history of being previously operated for hydatid cyst of liver 15 years back. His chest radiograph and computed tomography scan revealed a cystic lesion in the right lobe of liver and a cyst in left lung. The patient was managed surgically. Aspirate from the cyst fluid showed plenty of hooklets and scolices of Echinococcus granulosus. An intact brood capsule was also seen. Diagnosis of hydatidosis was further confirmed by histopathological examination. Post-operative the patient had a good recovery.     

Cancer statistics for the US Hispanic/Latino population, 2021

The Hispanic/Latino population is the second largest racial/ethnic group in the continental United States and Hawaii, accounting for 18% (60.6 million) of the total population. An additional 3 million Hispanic Americans live in Puerto Rico. Every 3 years, the American Cancer Society reports on cancer occurrence, risk factors, and screening for Hispanic individuals in the United States using the most recent population-based data. An estimated 176,600 new cancer cases and 46,500 cancer deaths will occur among Hispanic individuals in the continental United States and Hawaii in 2021. Compared to non-Hispanic Whites (NHWs), Hispanic men and women had 25%-30% lower incidence (2014-2018) and mortality (2015-2019) rates for all cancers combined and lower rates for the most common cancers, although this gap is diminishing. For example, the colorectal cancer (CRC) incidence rate ratio for Hispanic compared with NHW individuals narrowed from 0.75 (95% CI, 0.73-0.78) in 1995 to 0.91 (95% CI, 0.89-0.93) in 2018, reflecting delayed declines in CRC rates among Hispanic individuals in part because of slower uptake of screening. In contrast, Hispanic individuals have higher rates of infection-related cancers, including approximately two-fold higher incidence of liver and stomach cancer. Cervical cancer incidence is 32% higher among Hispanic women in the continental US and Hawaii and 78% higher among women in Puerto Rico compared to NHW women, yet is largely preventable through screening. Less access to care may be similarly reflected in the low prevalence of localized-stage breast cancer among Hispanic women, 59% versus 67% among NHW women. Evidence-based strategies for decreasing the cancer burden among the Hispanic population include the use of culturally appropriate lay health advisors and patient navigators and targeted, community-based intervention programs to facilitate access to screening and promote healthy behaviors. In addition, the impact of the COVID-19 pandemic on cancer trends and disparities in the Hispanic population should be closely monitored.     

Effect of antispermatogenic agents on cell marker enzymes of rat Sertoli cells in vitro

OBJECTIVE: To examine the role of Sertoli cells in the antispermatogenic action of two nonsteroidal male contraceptive compounds (CDRI-84/35 and gossypol) by evaluating their effect on some key parameters of Sertoli cell function in vitro. METHODS: Primary cultures of Sertoli cell were established from 18-day-old rat testis and treated on day 5 with different concentrations (1.0, 0.1, 0.01, and 0.001 mM) of either CDRI-84/35 or gossypol in vitro. Lactate (secretion), along with beta-glucuronidase, gamma-glutamyl transpeptidase, lactate dehydrogenase (LDH) and aromatase activities, was measured in these cells to examine the functions targeted by antispermatogenic agents in Sertoli cells. RESULTS: CDRI-84/35 significantly affected Sertoli cell parameters (stimulation in most of the cases) that are important for germ cell development like lactate secretion, LDH activity, aromatase activity (estradiol secretion) and so on. Gossypol in comparison to CDRI-84/35 had a more severe effect on Sertoli cells with complete inhibition of enzyme activities at higher concentrations. CONCLUSION: It is probable that the antispermatogenic action of CDRI-84/35 and gossypol is routed through Sertoli cells by disruption of important cell functions that support spermatogenesis in vivo. However, the two compounds appear to have different course of action in Sertoli cells, ultimately leading to spermatogenic failure.     

Breast cancer statistics, 2011

In this article, the American Cancer Society provides an overview of female breast cancer statistics in the United States, including trends in incidence, mortality, survival, and screening. Approximately 230,480 new cases of invasive breast cancer and 39,520 breast cancer deaths are expected to occur among US women in 2011. Breast cancer incidence rates were stable among all racial/ethnic groups from 2004 to 2008. Breast cancer death rates have been declining since the early 1990s for all women except American Indians/Alaska Natives, among whom rates have remained stable. Disparities in breast cancer death rates are evident by state, socioeconomic status, and race/ethnicity. While significant declines in mortality rates were observed for 36 states and the District of Columbia over the past 10 years, rates for 14 states remained level. Analyses by county-level poverty rates showed that the decrease in mortality rates began later and was slower among women residing in poor areas. As a result, the highest breast cancer death rates shifted from the affluent areas to the poor areas in the early 1990s. Screening rates continue to be lower in poor women compared with non-poor women, despite much progress in increasing mammography utilization. In 2008, 51.4% of poor women had undergone a screening mammogram in the past 2 years compared with 72.8% of non-poor women. Encouraging patients aged 40 years and older to have annual mammography and a clinical breast examination is the single most important step that clinicians can take to reduce suffering and death from breast cancer. Clinicians should also ensure that patients at high risk of breast cancer are identified and offered appropriate screening and follow-up. Continued progress in the control of breast cancer will require sustained and increased efforts to provide high-quality screening, diagnosis, and treatment to all segments of the population.     

Antihyperglycaemic activity of Ceriops tagal in normoglycaemic and streptozotocin-induced diabetic rats

Antihyperglycaemic effect of the crude extract (1) and four fractions (2, 3, 4, and 5) of Ceriops tagal (Perr.) C.B. Rob. (Rhizophoraceae) were evaluated in normal healthy sucrose-loaded and STZ-induced diabetic rats. The crude extract improved the glucose tolerance of the sucrose-loaded rats significantly (p < 0.05) with 33.2% activity, while in STZ-induced diabetic rats the extract caused a fall of 10.9% in hyperglycaemia. All of the four isolated fractions improved the glucose tolerance of normal rats post sucrose load, albeit to varying degree. Fraction 4 exerted the strongest effect of 37.2% (p < 0.05) in sucrose-loaded rats while in STZ-induced diabetic rats it caused a fall of 17% (p < 0.05) in hyperglycaemia. The fasting blood glucose levels of STZ-induced diabetic rats were normalized and the glucose tolerance of these animals was significantly improved after 20 days of daily oral administration of fraction 4 at a 100 mg/kg dose.