Sickle Cell Disease- A Case Report in a theoretical approach

Sickle cell disease (SCD) is a major healthcare and societal problem affecting millions of people worldwide. In United States of America (USA), it is the most common genetic disorder affecting more than 80,000 people per year; majority of which are the African Americans Arabian and Indian (6,10). It is a genetic blood disorder affecting the red blood cells. Sickle cell pain is the hallmark of sickle cell disease and is associated with a very high mortality and morbidity rates (12). Being a genetic abnormality, the complete eradication of the disease from the affected seems to be difficult. Genetic counselling during pregnancy being the prime preventive step, Hematopoietic stem cell transplantation becomes the mainstay of treatment for complete eradication of the disease. But it is not done very often because of the significant risks involved.

Reversible bacteriophage resistance by shedding the bacterial cell wall

Phages are highly abundant in the environment and a major threat for bacteria. Therefore, bacteria have evolved sophisticated defense systems to withstand phage attacks. Here, we describe a previously unknown mechanism by which mono- and diderm bacteria survive infection with diverse lytic phages. Phage exposure leads to a rapid and near complete conversion of walled cells to a cell wall-deficient state, which remain viable in osmoprotective conditions and can revert to the walled state. While shedding the cell wall dramatically reduces the number of progeny phages produced by the host, it does not always preclude phage infection. Altogether, these results show that the formation of cell wall-deficient cells prevents complete eradication of the bacterial population and suggest that cell wall-deficiency may limit the efficacy of phage therapy, especially in highly osmotic environments or when used together with antibiotics that target the cell wall.

Bma-LAD-2, an intestinal cell adhesion protein, as a potential therapeutic target for lymphatic filariasis

Lymphatic filariasis (LF) is a debilitating disease that afflicts over 70 million people worldwide. It is caused by the parasitic nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori. While efforts to eliminate LF have seen substantial success, complete eradication will likely require more time and resources than predicted. Identifying new drug and vaccine targets in adult filariae could help elimination efforts.This study’s aim was to evaluate intestinal proteins in adult Brugia malayi worms as possible therapeutic targets. Using siRNA, we successfully inhibited transcripts of four candidate genes: Bma-Serpin, Bma-ShTK, Bma-Reprolysin, and Bma-LAD-2. Of those, Bma-LAD-2, an immunoglobulin superfamily cell adhesion molecule (IgSF CAM), was determined to be essential for adult worm survival. We observed a 70.42% knockdown in Bma-LAD-2 transcript levels 1 day post-siRNA incubation and an 87.02% reduction in protein expression 2 days post-siRNA incubation. This inhibition of Bma-LAD-2 expression resulted in an 80% decrease in worm motility over 6 days, a 93.43% reduction in microfilaria release (Mf) by day 6 post-siRNA incubation, and a significant decrease in MTT reduction. Transmission electron microscopy revealed the loss of microvilli and unraveling of mitochondrial cristae in the intestinal epithelium of Bma-LAD-2 siRNA-treated worms. Strikingly, Bma-LAD-2 siRNA-treated worms exhibited an almost complete loss of pseudocoelomic fluid, suggesting that loss of these tight junctions led to the leakage and subsequent loss of the worm’s structural integrity. Luciferase immunoprecipitation system assay demonstrated that serum from 30 patients with LF did not have detectable IgE antibodies against Bma-LAD-2, indicating that LF exposure does not result in IgE sensitization to this antigen.These results indicate that Bma-LAD-2 is an essential protein for adult Brugia malayi and may be an effective drug or vaccine target. In addition, these findings further validate the strategy of targeting the worm intestine to prevent and treat helminthic infections.Author SummaryBrugia malayi is a parasitic nematode that can cause lymphatic filariasis, a debilitating disease prevalent in tropical and subtropical countries. Significant progress has been made towards eliminating the disease. However, complete eradication may require new therapeutics such as drugs or a vaccine that kill adult filariae. In this study, we identified an immunoglobulin superfamily cell adhesion molecule (Bma-LAD-2) as a potential drug and vaccine candidate. When we knocked down Bma-LAD-2 expression, we observed a decrease in worm motility, fecundity, and metabolism. We also visualized the loss of microvilli, destruction of the mitochondria in the intestinal epithelium, and loss of pseudocoelomic fluid contents after Bma-LAD-2 siRNA treatment. Finally, we demonstrated that serum from filaria-infected patients does not contain preexisting IgE to Bma-LAD-2, which indicates that this antigen would likely be safe to administer as a vaccine in endemic populations.

Efficacy of a Topical Wound Agent Methanesulfonic Acid and Dimethylsulfoxide on In Vitro Biofilms

A topical desiccating wound agent containing methanesulfonic acid, dimethylsulfoxide and amorphous silica was evaluated in three in vitro models for its efficacy against biofilms produced by Pseudomonas aeruginosa (ATCC-15442) and Staphylococcus aureus (ATCC-6538). The in vitro biofilm models used were; the MBEC Assay®, Centre for Disease Control (CDC) Biofilm Reactor® and a Semi-solid biofilm model. A 30-s exposure of a topical wound desiccating agent was used in each model. A complete eradication of viable cells was demonstrated in all models for both strains (p < 0.0001). Imaging with scanning electron microscopy (SEM) was performed where possible. All three models demonstrated complete eradication of viable cells with a 30 s application of a topical wound desiccating agent.

Targeting emerging Mycobacterium avium infections: perspectives into pathways and antimicrobials for future interventions

Mycobacterium avium is an emerging opportunistic pathogen, globally. Infections caused by M. avium are laborious to treat and could result in drug resistance. This review discusses the importance of many factors including the cell wall in M. avium pathogenesis, since this unique structure modulates the pathogen’s ability to thrive in various hosts and environmental niches including conferring resistance to killing by antimicrobials. More research efforts in future are solicited to develop novel therapeutics targeting M. avium. The complete eradication of M. avium infection in immunocompromised individuals would need a deeper understanding of the source of infection, unique underlying mechanisms and its uncharacterized pathways. This could, perhaps in future, hold the key to target and treat M. avium more effectively.

Chemical Disinfection of Potato Cutting Machinery to Avoid Dissemination of Clavibacter sepedonicus

A potential cause of the dissemination of the potato ring rot bacterium Clavibacter sepedonicus (Cs) is the use of automated seed potato cutters. The present study focuses on the question of whether disinfection practices are sufficient to prevent the transmission of Cs from contaminated machine parts to a new tuber lot. The disinfection efficacy was determined by establishing the culturability of Cs that remained after spray application of sodium-p-toluenesulfochloramide solution on clean and fouled specimens of machinery material that had been provided with an imprint of Cs biofilm. Although conventional spraying, with the authorized concentration of sodium-p-toluenesulfochloramide, of inoculated rubber, PVC and lacquered steel led to a substantial decrease of colony forming units, the treatment was insufficient for complete eradication of Cs. The presence of dirt negatively affected the efficacy of the disinfectant.

Persistent or recurrent Barrett’s neoplasia after an endoscopic therapy session is associated with DNA content abnormality and can be detected by DNA flow cytometric analysis of paraffin-embedded tissue

Endoscopic therapy is currently the standard of care for the treatment of high-grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) in patients with Barrett’s esophagus (BE). Visible lesions are treated with endoscopic mucosal resection (EMR), which is often coupled with radiofrequency ablation (RFA). However, endoscopic therapy may require multiple sessions (one session every 2-3 months) and does not always assure complete eradication of neoplasia. Furthermore, despite complete eradication, recurrences are not uncommon. This study assesses which potential risk factors can predict a poor response after endoscopic sessions. Forty-five BE patients who underwent at least one endoscopic session (EMR alone or ablation with or without preceding EMR) for the treatment of HGD/IMC, low-grade dysplasia (LGD), or indefinite for dysplasia (IND) were analyzed. DNA flow cytometry was performed on 82 formalin-fixed paraffin-embedded samples from the 45 patients, including 78 HGD/IMC, 2 LGD, and 2 IND. Eight non-dysplastic BE samples were used as controls. Three to four 60-micron thick sections were cut from each tissue block, and the area of HGD/IMC, LGD, or IND was manually dissected. Potential associations between clinicopathologic risk factors and persistent/recurrent HGD/IMC following each endoscopic session were examined using univariate and multivariate Cox models with frailty terms. Sixty (73%) of the 82 specimens showed abnormal DNA content (aneuploidy or elevated 4N fraction). These were all specimens with HGD/IMC (representing 77% of that group). Of these 60 HGD/IMC samples with abnormal DNA content, 42 (70%) were associated with subsequent development of persistent/recurrent HGD/IMC (n = 41) or esophageal adenocarcinoma (EAC; n = 1) within a mean follow-up time of 16 months (range: 1 month to 9.4 years). In contrast, only 6 (27%, all HGD/IMC) of the 22 remaining samples (all with normal DNA content) were associated with persistent/recurrent HGD/IMC. For outcome analysis per patient, 11 (24%) of the 45 patients developed persistent/recurrent HGD/IMC or EAC, despite multiple endoscopic sessions (mean: 3.6, range: 1–11). In a univariate Cox model, the presence of abnormal DNA content (hazard ratio [HR] = 3.8, p = 0.007), long BE segment ≥ 3 cm (HR = 3.4, p = 0.002), endoscopic nodularity (HR = 2.5, p = 0.042), and treatment with EMR alone (HR = 2.9, p = 0.006) were significantly associated with an increased risk for persistent/recurrent HGD/IMC or EAC. However, only abnormal DNA content (HR = 6.0, p = 0.003) and treatment with EMR alone (HR = 2.7, p = 0.047) remained as significant risk factors in a multivariate analysis. Age ≥ 60 years, gender, ethnicity, body mass index (BMI) ≥ 30 kg/m2, presence of hiatal hernia, and positive EMR lateral margin for neoplasia were not significant risk factors for persistent/recurrent HGD/IMC or EAC (p > 0.05). Three-month, 6-month, 1-year, 3-year, and 6-year adjusted probabilities of persistent/recurrent HGD/IMC or EAC in the setting of abnormal DNA content were 31%, 56%, 67%, 79%, and 83%, respectively. The corresponding probabilities in the setting of normal DNA content were 10%, 21%, 28%, 38%, and 43%, respectively. In conclusion, in BE patients with baseline HGD/IMC, both DNA content abnormality and treatment with EMR alone were significantly associated with persistent/recurrent HGD/IMC or EAC following each endoscopic session. DNA content abnormality as detected by DNA flow cytometry identifies HGD/IMC patients at highest risk for persistent/recurrent HGD/IMC or EAC, and it also serves as a diagnostic marker of HGD/IMC with an estimated sensitivity of 77%. The diagnosis of HGD/IMC in the setting of abnormal DNA content may warrant alternative treatment strategies as well as long-term follow-up with shorter surveillance intervals.

The Comprehensive Nuclear Test-Ban Treaty, a legal anomaly?

It is well-recorded that nuclear attacks happened twice in history, in Hiroshima and Nagasaki, but it is often overlooked that nuclear explosions were more frequent, with over 2,000 tests taking place in more than 60 locations worldwide. These special circumstances prompted the General Assembly to adopt a comprehensive ban treaty (CTBT) in 1996, which has yet to enter into force. Borrowing from Kelman’s social conformity theory, this article explains how and why states chose to conform to a non-binding agreement. It argues that, as interested parties developed an anti-testing narrative that seemed simultaneously hopeful and realistic, they stabilized actor’s reaction and catalyzed a shift in attitudes towards nuclear testing from forbearance to an authoritative global moratorium, which accounts for the complete eradication of the atmospheric experiments. C’est un fait bien établi que l’histoire a connu deux attaques nucléaires, à Hiroshima et Nagasaki. Ce que l’on sait moins, c’est que les explosions nucléaires étaient bien plus fréquentes, avec plus de 2 000 tests effectués sur une soixantaine de sites de par le monde. Ces circonstances particulières ont poussé l’Assemblée générale des Nations unies à adopter, en 1996, un traité d’interdiction complète des essais nucléaires (TICE), qui n’est pas encore entré en vigueur. S’inspirant de la théorie du conformisme social de Kelman, cet article explique comment et pourquoi des États ont choisi de respecter un accord non contraignant. Il avance que, à mesure que les parties intéressées développaient un discours anti-essais nucléaires qui paraissait à la fois réaliste et porteur d’espoir, elles ont stabilisé les réactions des acteurs et déclenché un changement des mentalités à l’égard des essais nucléaires, passant de l’indulgence à un moratoire général faisant autorité, ce qui explique la disparition complète des essais atmosphériques. Het is algemeen bekend dat er in de geschiedenis twee kernaanvallen zijn geweest, in Hiroshima en Nagasaki, maar vaak wordt over het hoofd gezien dat er nog andere kernexplosies hebben plaatsgevonden, met ruim 2000 proeven op meer dan 60 locaties over de hele wereld. Deze bijzondere omstandigheden hebben de Algemene Vergadering ertoe aangezet om in 1996 een alomvattend verbodsverdrag (CTBT) goed te keuren, dat nog steeds niet in werking is getreden. Aan de hand van de sociale-conformiteitstheorie van Kelman wordt in dit artikel uitgelegd hoe en waarom staten ervoor kiezen zich te conformeren aan een niet-bindende overeenkomst. Het betoogt dat, naarmate de betrokken partijen een narratief tegen kernproeven ontwikkelden dat tegelijk hoopvol en realistisch leek, zij de reactie van de actoren stabiliseerden en als katalysator werkten voor de verschuiving in de houding ten opzichte van kernproeven van gedoging naar een wereldwijd officieel moratorium, wat de volledige uitroeiing van de atmosferische experimenten verklaart. Está bien documentado que los ataques nucleares han sucedido dos veces en la historia, en Hiroshima y Nagasaki, pero en ocasiones pasa desapercibido que las explosiones nucleares han sido más frecuentes, con más de 2.000 ensayos llevándose a cabo en más de 60 emplazamientos a escala mundial. Estas circunstancias especiales llevaron a la Asamblea General a adoptar el tratado de prohibición completa (TPCEN) en 1996, el cual aun no ha entrado en vigor. Basándose en la teoría de la conformidad social de Kelman, este artículo explica cómo y porqué los Estados eligieron conformarse con un acuerdo no vinculante. Se argumenta que a medida que las partes interesadas desarrollaron una narrativa anti-ensayo que parecía esperanzadora y realista a la vez, ello mismo llevó a apaciguar la posible reacción de los actores y a catalizar un cambio en relación a los ensayos nucleares que fuera de la tolerancia a una moratoria global fidedigna, lo cual equivale a una completa erradicación de los experimentos atmosféricos. É ben noto che nella storia siano avvenuti due attacchi nucleari, a Hiroshima e Nagasaki, ma è spesso trascurato che le esplosioni nucleari siano state molto più frequenti, con oltre 2000 test che hanno avuto luogo in più di 60 sedi nel mondo. Queste circostanze speciali hanno indotto l'Assemblea generale nel 1996, ad adottare un trattato di messa al bando globale (CTBT), che deve ancora entrare in vigore. Prendendo spunto dalla teoria della conformità sociale di Kelman, questo articolo spiega come e perché gli Stati hanno scelto di conformarsi a un accordo non vincolante. Sostiene che, dato che le parti interessate hanno sviluppato una narrativa anti-test che sembrava allo stesso tempo speranzosa e realistica, esse hanno stabilizzato la reazione degli attori e catalizzato un cambiamento negli atteggiamenti nei confronti dei test nucleari dalla tolleranza a un'autorevole moratoria globale, che spiega la completa eliminazione degli esperimenti atmosferici. Es ist bekannt, dass es in der Geschichte zweimal zu nuklearen Angriffen kam, in Hiroshima und Nagasaki. Es wird aber oft übersehen, dass es häufiger nukleare Explosionen gegeben hat, mit über 2.000 Tests an mehr als 60 Orten weltweit. Diese besonderen Umstände veranlassten die Generalversammlung 1996 zur Verabschiedung eines umfassenden Verbotsvertrags (CTBT), der noch nicht in Kraft getreten ist. In Anlehnung an die soziale Konformitätstheorie von Kelman erklärt dieser Artikel, wie und warum Staaten sich dafür entschieden haben, sich einem unverbindlichen Abkommen zu fügen. Er argumentiert, dass je nachdem die beteiligten Parteien ein Anti-Test-Narrativ entwickelten, das gleichzeitig hoffnungsvoll und realistisch erschien, diese die Reaktion der Akteure stabilisierten und eine Verschiebung in der Haltung gegenüber Atomtests von der Duldung zu einem autoritativen globalen Moratorium herbeiführten, was die vollständige Abschaffung der atmosphärischen Experimente erklärt.