Diseases

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369 KiB

Open AccessFeature PaperCommunication

Facilitating a More Efficient Commercial Review Process for Pediatric Drugs and Biologics

by Ryan D. Rykhus, Zachary V. Shepard, Alix Young, Hadley Frisby, Kailee A. Calder, Collin M. Coon, Justin A. Falk, Sydney R. McAndrews, Aspen Turner, Christina Chang, Johanna Michelsohn, Raegan Petch, Sarah M. Dieker, Benjamin H. Markworth, Kevin Alamo-Perez, Aaron J. Hosack, Jacob M. Berg, Christian Schmidt, Joachim Storsberg and Mark A. Brown

Diseases 2018, 6(1), 2; https://doi.org/10.3390/diseases6010002 - 22 Dec 2017

Viewed by 3430

Abstract

Over the past two decades, the biopharmaceutical industry has seen unprecedented expansion and innovation in concert with significant technological advancements. While the industry has experienced marked growth, the regulatory system in the United States still operates at a capacity much lower than the [...] Read more.

Over the past two decades, the biopharmaceutical industry has seen unprecedented expansion and innovation in concert with significant technological advancements. While the industry has experienced marked growth, the regulatory system in the United States still operates at a capacity much lower than the influx of new drug and biologic candidates. As a result, it has become standard for months or even years of waiting for commercial approval by the U.S. Food and Drug Administration. These regulatory delays have generated a system that stifles growth and innovation due to the exorbitant costs associated with awaiting approval from the nation’s sole regulatory agency. The recent re-emergence of diseases that impact pediatric demographics represents one particularly acute reason for developing a regulatory system that facilitates a more efficient commercial review process. Herein, we present a range of initiatives that could represent early steps toward alleviating the delays in approving life-saving therapeutics. Full article

(This article belongs to the Special Issue Pediatric Diseases)

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206 KiB

Open AccessFeature PaperArticle

Having a Child Diagnosed with Cancer: Raising the Challenges Encountered by the Caregivers at the Pediatric Oncology Ward in Egypt

by Hanan El Malla

Diseases 2017, 5(4), 36; https://doi.org/10.3390/diseases5040036 - 19 Dec 2017

Cited by 3 | Viewed by 3354

Abstract

Having a child diagnosed with a life-threatening illness, and undergoing a severe treatment regimen, is a massive challenge for many caregivers, not the least of who are those with low socioeconomic status and living in a society where deeply rooted cultural and societal [...] Read more.

Having a child diagnosed with a life-threatening illness, and undergoing a severe treatment regimen, is a massive challenge for many caregivers, not the least of who are those with low socioeconomic status and living in a society where deeply rooted cultural and societal misconceptions are immensely noticeable. The aim of the study is to raise the great concerns experienced by the caregivers at the pediatric oncology ward in Egypt. The study is comprised of 24 caregivers of children with cancer undergoing treatment at the inpatient ward. Semi-structured interviews and participant observations were used as a means of data collection. Numerous concerns are addressed in this study which are all related to fear of the illness and guilty feelings of having caused the child this illness. The fears and concerns addressed in this paper seem to obstruct the caregivers’ overall psychosocial wellbeing, which is known to have multiple effects on the child’s overall wellbeing. Thus, it is very important to take into consideration caregivers in the child’s cancer treatment. Full article

(This article belongs to the Special Issue Pediatric Diseases)

1766 KiB

Open AccessArticle

Competitive Promoter-Associated Matrix Attachment Region Binding of the Arid3a and Cux1 Transcription Factors

by Dongkyoon Kim, Christian Schmidt, Mark A. Brown and Haley Tucker

Diseases 2017, 5(4), 34; https://doi.org/10.3390/diseases5040034 - 10 Dec 2017

Cited by 2 | Viewed by 4187

Abstract

Arid3a/Bright/Dril1 is a B cell-specific transactivator that regulates immunoglobulin heavy chain (IgH) gene transcription by binding promoter and enhancer-associated matrix attachment regions (MARs) within the IgH gene locus. Promoter MAR-mediated Arid3a transactivation is antagonized by direct competition of MAR binding by Cux1/CDP—a ubiquitously [...] Read more.

Arid3a/Bright/Dril1 is a B cell-specific transactivator that regulates immunoglobulin heavy chain (IgH) gene transcription by binding promoter and enhancer-associated matrix attachment regions (MARs) within the IgH gene locus. Promoter MAR-mediated Arid3a transactivation is antagonized by direct competition of MAR binding by Cux1/CDP—a ubiquitously expressed repressor originally termed NF-μNR. We report that the NF-μNR complex includes Arid3a in B cells but not in non-B cells through mobility shift assays. The binding activity of NF-μNR and Arid3a in B cells is reciprocally altered during the cell division cycle and by the B cell mitogen lipopolysaccharide LPS. LPS treatment had no effect on Arid3a localization but increased its total abundance within the nucleus and cytoplasm. We show that this increased level of Arid3a is capable of displacing Cux from the MARs to facilitate IgH gene transcription. Finally, we showed that the MARs (termed Bf150 and Tx125) associated with the V_H1 rearranged variable region expressed in the S107 murine plasmacytoma, can repress reporter gene transcription in non-B cells and that they can relieve the repression mediated by Eμ enhancer in B cells. These results have significant implications for early human development and demonstrate that MARs in IgH locus, NF-µNR and Arid3a regulate IgH gene expression in a concerted fashion. This paves the way for future studies examining the misregulation of this pathway in pediatric disease. Full article

(This article belongs to the Special Issue Pediatric Diseases)

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Review

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11 pages, 216 KiB

Open AccessReview

Congenital Nasolacrimal Duct Obstruction (CNLDO): A Review

by Aldo Vagge, Lorenzo Ferro Desideri, Paolo Nucci, Massimiliano Serafino, Giuseppe Giannaccare, Andrea Lembo and Carlo Enrico Traverso

Diseases 2018, 6(4), 96; https://doi.org/10.3390/diseases6040096 - 22 Oct 2018

Cited by 44 | Viewed by 7600

Abstract

Congenital nasolacrimal duct obstruction (CNLDO) is a common condition causing excessive tearing or mucoid discharge from the eyes, due to blockage of the nasolacrimal duct system. Nasolacrimal duct obstruction affects as many as 20% children aged <1 year worldwide and is often resolved [...] Read more.

Congenital nasolacrimal duct obstruction (CNLDO) is a common condition causing excessive tearing or mucoid discharge from the eyes, due to blockage of the nasolacrimal duct system. Nasolacrimal duct obstruction affects as many as 20% children aged <1 year worldwide and is often resolved without surgery. Available treatment options are conservative therapy, including observation, lacrimal sac massage and antibiotics, and invasive therapy. Observation, combined with conservative options, seems to be the best option in infants aged <1 year. Meanwhile, in children aged >1 year, nasolacrimal probing successfully addresses most obstructions. However, the most favorable timing for probing remains controversial. To alleviate persistent epiphora and mucous drainage that is refractory to probing, repeat probing, silicone tube intubation, balloon catheter dilation or dacryocystorhinostomy can be considered as available treatment options. Our review aims to provide an update to CNDO management protocols. Full article

(This article belongs to the Special Issue Pediatric Diseases)

25 pages, 310 KiB

Open AccessReview

Prevention of Progression in Myopia: A Systematic Review

by Aldo Vagge, Lorenzo Ferro Desideri, Paolo Nucci, Massimiliano Serafino, Giuseppe Giannaccare and Carlo E. Traverso

Diseases 2018, 6(4), 92; https://doi.org/10.3390/diseases6040092 - 30 Sep 2018

Cited by 28 | Viewed by 13594

Abstract

The prevalence of myopia has increased worldwide in recent decades and now is endemic over the entire industrial world. This increase is mainly caused by changes in lifestyle and behavior. In particular, the amount of outdoor activities and near work would display an [...] Read more.

The prevalence of myopia has increased worldwide in recent decades and now is endemic over the entire industrial world. This increase is mainly caused by changes in lifestyle and behavior. In particular, the amount of outdoor activities and near work would display an important role in the pathogenesis of the disease. Several strategies have been reported as effective. Spectacles and contact lenses have shown only slight results in the prevention of myopia and similarly ortokerathology should not be considered as a first-line strategy, given the high risk of infectious keratitis and the relatively low compliance for the patients. Thus, to date, atropine ophthalmic drops seem to be the most effective treatment for slowing the progression of myopia, although the exact mechanism of the effect of treatment is still uncertain. In particular, low-dose atropine (0.01%) was proven to be an effective and safe treatment in the long term due to the lowest rebound effect with negligible side effects. Full article

(This article belongs to the Special Issue Pediatric Diseases)

10 pages, 246 KiB

Open AccessReview

Treatment of Major Depressive Disorder in Pediatric Populations

by Drew R. Neavin, Jeremiah Joyce and Cosima Swintak

Diseases 2018, 6(2), 48; https://doi.org/10.3390/diseases6020048 - 4 Jun 2018

Cited by 12 | Viewed by 6502

Abstract

Major depressive disorder (MDD) is a severe illness that afflicts about 16.6% of people over their lifetime. MDD is highly correlated with suicidality, and often first presents in adolescence. Unfortunately, many pediatric patients suffering from MDD go undiagnosed, and current evidence-based treatment options [...] Read more.

Major depressive disorder (MDD) is a severe illness that afflicts about 16.6% of people over their lifetime. MDD is highly correlated with suicidality, and often first presents in adolescence. Unfortunately, many pediatric patients suffering from MDD go undiagnosed, and current evidence-based treatment options in the U.S. are limited to psychotherapy and two selective serotonin reuptake inhibitors approved by the United States Food and Drug Administration. Molecular mechanisms have been shown to play a role in MDD pathogenesis, progression, and response to medication, yet few studies have explored the role of these pathways in pediatric MDD. In this review, we outline the gravity and importance of MDD in pediatric patients, some challenges in diagnosis and treatment, current treatments available for pediatric patients, and research to investigate differences between pediatric and adult MDD. We hope that this review will provide an outline of the current understanding and treatment of MDD in pediatric patients, and provide thoughtful insights for future work that could advance our understanding of MDD in pediatric populations, and also identify new therapeutic strategies. Full article

(This article belongs to the Special Issue Pediatric Diseases)

16 pages, 1178 KiB

Open AccessReview

Zebrafish Models of Rare Hereditary Pediatric Diseases

by Máté Varga, Dorottya Ralbovszki, Eszter Balogh, Renáta Hamar, Magdolna Keszthelyi and Kálmán Tory

Diseases 2018, 6(2), 43; https://doi.org/10.3390/diseases6020043 - 22 May 2018

Cited by 12 | Viewed by 7746

Abstract

Recent advances in sequencing technologies have made it significantly easier to find the genetic roots of rare hereditary pediatric diseases. These novel methods are not panaceas, however, and they often give ambiguous results, highlighting multiple possible causative mutations in affected patients. Furthermore, even [...] Read more.

Recent advances in sequencing technologies have made it significantly easier to find the genetic roots of rare hereditary pediatric diseases. These novel methods are not panaceas, however, and they often give ambiguous results, highlighting multiple possible causative mutations in affected patients. Furthermore, even when the mapping results are unambiguous, the affected gene might be of unknown function. In these cases, understanding how a particular genotype can result in a phenotype also needs carefully designed experimental work. Model organism genetics can offer a straightforward experimental setup for hypothesis testing. Containing orthologs for over 80% of the genes involved in human diseases, zebrafish (Danio rerio) has emerged as one of the top disease models over the past decade. A plethora of genetic tools makes it easy to create mutations in almost any gene of the zebrafish genome and these mutant strains can be used in high-throughput preclinical screens for active molecules. As this small vertebrate species offers several other advantages as well, its popularity in biomedical research is bound to increase, with “aquarium to bedside” drug development pipelines taking a more prevalent role in the near future. Full article

(This article belongs to the Special Issue Pediatric Diseases)

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5 pages, 174 KiB

Open AccessReview

Revisiting CD28 Superagonist TGN1412 as Potential Therapeutic for Pediatric B Cell Leukemia: A Review

by Katelyn E. Brown

Diseases 2018, 6(2), 41; https://doi.org/10.3390/diseases6020041 - 19 May 2018

Cited by 6 | Viewed by 6185

Abstract

Pediatric acute lymphoblastic leukemia (ALL) represents the most common pediatric cancer diagnosis, with numbers rising gradually every year. This paper proposes a novel therapeutic agent for pediatric ALL on the basis of a failed clinical drug trial in 2006. TGN1412 was a promising [...] Read more.

Pediatric acute lymphoblastic leukemia (ALL) represents the most common pediatric cancer diagnosis, with numbers rising gradually every year. This paper proposes a novel therapeutic agent for pediatric ALL on the basis of a failed clinical drug trial in 2006. TGN1412 was a promising therapeutic agent that yielded outstanding results in both in vitro studies and animal trials. It is a CD28 superagonist monoclonal antibody that activates T regulatory (T_Reg) cells in the absence of costimulation of the T cell receptor (TCR) by an antigen-presenting cell. This drug was intended as a solution to T cell deficient diseases such as B cell leukemia and autoimmune diseases such as rheumatoid arthritis. When phase I clinical trials were conducted, all volunteers that received the drug experienced severe cytokine release syndrome (CRS) and faced multiple-organ failure within hours. TGN1412 was reassessed and re-entered clinical trials as a therapeutic for rheumatoid arthritis. A new assay was developed to better quantify T cell response, and volunteers in this trial experienced no pro-inflammatory cytokine release. This essay analyzes how misinformation contributed to the failure of TGN1412 in clinical trials and how revisiting this therapeutic could yield a novel treatment for pediatric B cell leukemia. Full article

(This article belongs to the Special Issue Pediatric Diseases)

209 KiB

Open AccessFeature PaperReview

Familial Screening for Left-Sided Congenital Heart Disease: What Is the Evidence? What Is the Cost?

by Daniel J. Perry, Connor R. Mullen, Horacio G. Carvajal, Anoop K. Brar and Pirooz Eghtesady

Diseases 2017, 5(4), 29; https://doi.org/10.3390/diseases5040029 - 8 Dec 2017

Cited by 2 | Viewed by 3681

Abstract

Since the American Heart Association’s recommendation for familial screening of adults with congenital heart disease for bicuspid aortic valve, similar recommendations for other left-sided heart defects, such as hypoplastic left heart syndrome (HLHS), have been proposed. However, defining at-risk populations for these heart [...] Read more.

Since the American Heart Association’s recommendation for familial screening of adults with congenital heart disease for bicuspid aortic valve, similar recommendations for other left-sided heart defects, such as hypoplastic left heart syndrome (HLHS), have been proposed. However, defining at-risk populations for these heart defects based on genetics is less straightforward due to the wide variability of inheritance patterns and non-genetic influences such as environmental and lifestyle factors. We discuss whether there is sufficient evidence to standardize echocardiographic screening for first-degree relatives of children diagnosed with HLHS. Due to variations in the inclusion of cardiac anomalies linked to HLHS and the identification of asymptomatic individuals with cardiac malformations, published studies are open to interpretation. We conclude that familial aggregation of obstructive left-sided congenital heart lesions in families with history of HLHS is not supported and recommend that additional screening should adopt a more conservative definition of what truly constitutes this heart defect. More thorough consideration is needed before embracing familial screening recommendations of families of patients with HLHS, since this could inflict serious costs on healthcare infrastructure and further burden affected families both emotionally and financially. Full article

(This article belongs to the Special Issue Pediatric Diseases)

Other

Jump to: Research, Review

149 KiB

Open AccessFeature PaperComment

Risk Evaluation Requires an Independent Mind

by Christian Schmidt and Joachim Storsberg

Diseases 2017, 5(4), 28; https://doi.org/10.3390/diseases5040028 - 24 Nov 2017

Cited by 1 | Viewed by 2733

Abstract

Biomedical research pertaining to pathologies observed in adolescents can involve areas where patients can expect no immediate benefits. Here, Congress stipulates that local review boards are restricted to approving procedures posing no greater than minimal risk (45 CFR 46.404). An evaluation of risk [...] Read more.

Biomedical research pertaining to pathologies observed in adolescents can involve areas where patients can expect no immediate benefits. Here, Congress stipulates that local review boards are restricted to approving procedures posing no greater than minimal risk (45 CFR 46.404). An evaluation of risk embraces the current state of the art with regard to the safety and efficacy of procedures. A tendency of biomedical scholars to cite highly cited documents can introduce a bias in an argumentation in favor or against a given recommendation in the context that bias in citations can be correlated with an imprudent use of funds for research. We use choice examples to highlight the necessity of approaching any scholarly task with an independent mind. Full article

(This article belongs to the Special Issue Pediatric Diseases)

745 KiB

Open AccessCommentary

The Evolution of Pediatric Disease—A Moving Target in Public Health

by Mark A. Brown

Diseases 2017, 5(3), 18; https://doi.org/10.3390/diseases5030018 - 31 Aug 2017

Cited by 1 | Viewed by 3457

Abstract

There is a growing threat in the re-emergence of diseases that impact pediatric demographics. While major strides have been made in the field of childhood cancers, there are still more questions than answers. In addition, public resistance to recommended practices related to childhood [...] Read more.

There is a growing threat in the re-emergence of diseases that impact pediatric demographics. While major strides have been made in the field of childhood cancers, there are still more questions than answers. In addition, public resistance to recommended practices related to childhood vaccinations fueled by misinformation has allowed infectious diseases to resurface in developed nations. Meanwhile, climate change and other destabilizing factors are shifting vector populations and driving the emergence of new diseases. Herein we call upon the community of human health researchers to confront the evolving specter of pediatric disease. Full article

(This article belongs to the Special Issue Pediatric Diseases)

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