IL-4 contributes to failure, and colludes with IL-10 to exacerbate Leishmania donovani infection following administration of a subcutaneous leishmanial antigen vaccine

Visceral leishmaniasis caused by the protozoan parasite Leishmania donovani complex is a potentially fatal disease if left untreated. Few treatment options exist and are toxic, costly and ineffective against resistant strains. Thus a safe and efficacious vaccine to combat this disease is needed. Previously, we reported that intraperitoneal administration of leishmanial antigens (LAg) entrapped in liposomes conferred protection to BALB/c mice against L. donovani challenge infection. However, this vaccine failed to protect mice when administered subcutaneously. We therefore evaluated whether formulation of LAg in combination with two commonly used human-compatible adjuvants, alum and saponin, could improve the protective efficacy of subcutaneously administered LAg, to a level comparable to that of the intraperitoneal liposomal vaccinatio

Comparison of BCG, MPL and cationic liposome adjuvant systems in leishmanial antigen vaccine formulations against murine visceral leishmaniasis

<p>Abstract</p> <p>Background</p> <p>The development of an effective vaccine against visceral leishmaniasis (VL) caused by <it>Leishmania donovani </it>is an essential aim for controlling the disease. Use of the right adjuvant is of fundamental importance in vaccine formulations for generation of effective cell-mediated immune response. Earlier we reported the protective efficacy of cationic liposome-associated <it>L. donovani </it>promastigote antigens (LAg) against experimental VL. The aim of the present study was to compare the effectiveness of two very promising adjuvants, Bacille Calmette-Guerin (BCG) and Monophosphoryl lipid A (MPL) plus trehalose dicorynomycolate (TDM) with cationic liposomes, in combination with LAg, to confer protection against murine VL.</p> <p>Results</p> <p>All the three formulations afforded significant protection against <it>L. donovani </it>in both the visceral organs, liver and spleen. Although comparable level of protection was observed in BCG+LAg and MPL-TDM+LAg immunized mice, highest level of protection was exhibited by the liposomal LAg immunized group. Significant increase in anti-LAg IgG levels were detected in both MPL-TDM+LAg and liposomal LAg immunized animals with higher levels of IgG2a than IgG1. But BCG+LAg failed to induce any antibody response. As an index of cell-mediated immunity DTH responses were measured and significant response was observed in mice vaccinated with all the three different formulations. However, highest responses were observed with liposomal vaccine immunization. Comparative evaluation of IFN-γ and IL-4 responses in immunized mice revealed that MPL-TDM+LAg group produced the highest level of IFN-γ but lowest IL-4 level, while BCG+LAg demonstrated generation of suboptimum levels of both IFN-γ and IL-4 response. Elicitation of moderate levels of prechallenge IFN-γ along with optimum IL-4 corresponds with successful vaccination with liposomal LAg.</p> <p>Conclusion</p> <p>This comparative study reveals greater effectiveness of the liposomal vaccine for protection against progressive VL in BALB/c. Again, evaluation of the immune responses by vaccination emphasizes the need of stimulation of potent cellular immunity based on both Th1 and Th2 cell responses to confer protection against VL.</p

Changing trends of blood transfusion requirement in obstetrics and gynaecology

Background: With the advent of the new pharmacological drugs and surgical advances compared to yesteryears, that the requirement of blood transfusion in obstetrics and gynaecology has decreased. Earlier obstetrical haemorrhage had been the commonest reason for blood transfusion. This trend seems to be changing. To evaluate this an observational study was done at a peripheral hospital to assess various indications for blood transfusion in maternity ward over a period of one year.  Methods: A total of 129 transfusions were studied in a period of one year and requirement of transfusion was assessed by the same team of doctors as per AABB guidelines for blood transfusion.  Results: A total of 87 obstetric patients required transfusion out of which 51.2% patients were transfused for anaemia near term. Postpartum haemorrhage constituted only 1.15% and ante partum haemorrhage only 4.6%. 17.24% of patients were transfused for incomplete abortion after taking medical abortion. 42 patients were transfused blood for various gynaecological reasons of which puberty menorrhagia constituted 19.01% and patients with perimenopausal bleeding were 28.57%.Conclusions: This study highlights the changing trends in requirement of blood transfusion and the need to emphasise on antenatal nutrition, supplements and contraception

Characterization of a distinct lethal arteriopathy syndrome in twenty-two infants associated with an identical, novel mutation in FBLN4 gene, confirms fibulin-4 as a critical determinant of human vascular elastogenesis

Background: Vascular elasticity is crucial for maintaining hemodynamics. Molecular mechanisms involved in human elastogenesis are incompletely understood. We describe a syndrome of lethal arteriopathy associated with a novel, identical mutation in the fibulin 4 gene (FBLN4) in a unique cohort of infants from South India. Methods: Clinical characteristics, cardiovascular findings, outcomes and molecular genetics of twenty-two infants from a distinct population subgroup, presenting with characteristic arterial dilatation and tortuosity during the period August 2004 to June 2011 were studied. Results: Patients (11 males, 11 females) presented at median age of 1.5 months, belonging to unrelated families from identical ethno-geographical background; eight had a history of consanguinity. Cardiovascular features included aneurysmal dilatation, elongation, tortuosity and narrowing of the aorta, pulmonary artery and their branches. The phenotype included a variable combination of cutis laxa (52%), long philtrum-thin vermillion (90%), micrognathia (43%), hypertelorism (57%), prominent eyes (43%), sagging cheeks (43%), long slender digits (48%), and visible arterial pulsations (38%). Genetic studies revealed an identical c.608A > C (p. Asp203Ala) mutation in exon 7 of the FBLN4 gene in all 22 patients, homozygous in 21, and compound heterozygous in one patient with a p. Arg227Cys mutation in the same conserved cbEGF sequence. Homozygosity was lethal (17/21 died, median age 4 months). Isthmic hypoplasia (n = 9) correlated with early death (<= 4 months). Conclusions: A lethal, genetic disorder characterized by severe deformation of elastic arteries, was linked to novel mutations in the FBLN4 gene. While describing a hitherto unreported syndrome in this population subgroup, this study emphasizes the critical role of fibulin-4 in human elastogenesis

Concurrent tolerance allocation and scheduling for complex assemblies

Traditionally, tolerance allocation and scheduling have been dealt with separately in the literature. The aim of tolerance allocation is to minimize the tolerance cost. When scheduling the sequence of product operations, the goal is to minimize the makespan, mean flow time, machine idle time, and machine idle time cost. Calculations of manufacturing costs derived separately using tolerance allocation and scheduling separately will not be accurate. Hence, in this work, component tolerance was allocated by minimizing both the manufacturing cost (sum of the tolerance and quality loss cost) and the machine idle time cost, considering the product sequence. A genetic algorithm (GA) was developed for allocating the tolerance of the components and determining the best product sequence of the scheduling. To illustrate the effectiveness of the proposed method, the results are compared with those obtained with existing wheel mounting assembly discussed in the literature

Multi-objective optimization for optimum tolerance synthesis with process and machine selection using a genetic algorithm

This paper presents a new approach to the tolerance synthesis of the component parts of assemblies by simultaneously optimizing three manufacturing parameters: manufacturing cost, including tolerance cost and quality loss cost; machining time; and machine overhead/idle time cost. A methodology has been developed using the Genetic Algorithm (GA) technique to solve this multi-objective optimization problem. The effectiveness of the proposed methodology has been demonstrated by solving a wheel mounting assembly problem consisting of five components, two subassemblies, two critical dimensions, two functional tolerances, and eight operations. Significant cost saving can be achieved by employing this methodology

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research