Int J Mol Sci. 2022 Jun 21;23(13):6899. doi: 10.3390/ijms23136899.

ABSTRACT

Specific antibody responses to subfornical organs, including Nax antibody, have been reported in patients with adipsic hypernatremia of unknown etiology who do not have structural lesions in the hypothalamic-pituitary gland. The subfornical organ, also referred to as the window of the brain, is a sensing site that monitors sodium and osmotic pressure levels. On the other hand, ROHHAD syndrome is a rare disease for which the etiology of the hypothalamic disorder is unknown, and there have been some reports in recent years describing its association with autoimmune mechanisms. In addition, abnormal Na levels, including hypernatremia, are likely to occur in this syndrome. When comparing the clinical features of adipsic hypernatremia due to autoimmune mechanisms and ROHHAD syndrome, there are similar hypothalamic-pituitary dysfunction symptoms in addition to abnormal Na levels. Since clinical diagnoses of autoimmunological adipsic hypernatremia and ROHAD syndrome might overlap, we need to understand the essential etiology and carry out precise assessments to accurately diagnose patients and provide effective treatment. In this review, I review the literature on the autoimmune mechanism reported in recent years and describe the findings obtained so far and future directions.

PMID:35805903 | PMC:PMC9266522 | DOI:10.3390/ijms23136899

Int J Environ Res Public Health. 2022 Jul 5;19(13):8208. doi: 10.3390/ijerph19138208.

ABSTRACT

Most of rare disease (RD) patients are assisted in their homes by their family as informal caregivers, causing a substantial burden among family members devoted to care. The role of informal caregivers has been associated with increased levels of stress, poor physical/mental health and impaired HRQOL. The present study assessed the impact on HRQOL and perceived burden of long-term informal caregiving, as well as the inter-relationships of individuals affected by different RD in six European countries, taking advantage of the data provided by the BURQOL-RD project (France, Germany, Italy, Spain, Sweden and UK). Correlation analysis was used to explore the relation between caregiver HRQOL and caregiver burden (Zarit Burden Interview). Multinomial logistic regression models were used to explore the role of explanatory variables on each domain of caregivers HRQOL measured by EQ-5D. Caregivers' HRQOL is inversely correlated with burden of caring. Mobility dimension of EQ-5D was significantly associated with patients age, time devoted to care by secondary caregivers, patient gender and patient utility index. Patients' age, burden scores and patient utility index significantly predict the capacity of caregivers to perform activities of daily living. Employed caregivers are less likely of reporting 'slight problems' in pain/discomfort dimensions than unemployed caregivers. The EQ-5D instrument is sensitive to measure differences in HRQOL between caregivers with different levels of burden of care.

PMID:35805867 | PMC:PMC9266302 | DOI:10.3390/ijerph19138208

Int J Environ Res Public Health. 2022 Jun 21;19(13):7553. doi: 10.3390/ijerph19137553.

ABSTRACT

Patients with rare diseases (RDs) need tailored, continuous, and multidisciplinary hospital care. This retrospective cohort study aimed to analyse the healthcare burden of RD patients using a multi-database approach, by linking the data of the Rare Diseases Registry of Tuscany with the regional hospital discharge database. The study population included 21,354 patients diagnosed with a RD between 1 January 2000 and 31 December 2017. The healthcare burden was evaluated for all the RDs during 2009-2018 period. The hospitalisation rate (per 1000) decreased over the years, ranging from 606.9 in 2009 (95% CI: 589.2-625.0) to 443.0 in 2018 (95% CI: 433.2-453.0). A decrease in the average length of stay (LOS) was observed in the earlier years, followed by an increase up to a steady trend (8.3 days in 2018). The patients with RDs of metabolism and the genitourinary system showed the highest hospitalisation rate (903.3 and 644.0 per 1000, respectively). The patients with rare immune system disorders and diseases of the skin and subcutaneous tissue showed the highest LOS (9.7 and 9.5 days, respectively). The methodological approach presented in this population-based study makes it possible to estimate the healthcare burden of RDs, which is crucial in the decision-making and planning aimed at improving patient care.

PMID:35805212 | PMC:PMC9265803 | DOI:10.3390/ijerph19137553

Cells. 2022 Jul 5;11(13):2114. doi: 10.3390/cells11132114.

ABSTRACT

Natural naphthoquinones and their derivatives exhibit a broad spectrum of pharmacological activities and have thus attracted much attention in modern drug discovery. However, it remains unclear whether naphthoquinones are potential drug candidates for anti-angiogenic agents. The aim of this study was to evaluate the anti-angiogenic properties of a novel naphthoquinone derivative, PPE8, and explore its underlying mechanisms. Determined by various assays including BrdU, migration, invasion, and tube formation analyses, PPE8 treatment resulted in the reduction of VEGF-A-induced proliferation, migration, and invasion, as well as tube formation in human umbilical vein endothelial cells (HUVECs). We also used an aorta ring sprouting assay, Matrigel plug assay, and immunoblotting analysis to examine PPE8's ex vivo and in vivo anti-angiogenic activities and its actions on VEGF-A signaling. It has been revealed that PPE8 inhibited VEGF-A-induced micro vessel sprouting and was capable of suppressing angiogenesis in in vivo models. In addition, PPE8 inhibited VEGF receptor (VEGFR)-2, Src, FAK, ERK1/2, or AKT phosphorylation in HUVECs exposed to VEGF-A, and it also showed significant decline in xenograft tumor growth in vivo. Taken together, these observations indicated that PPE8 may target VEGF-A-VEGFR-2 signaling to reduce angiogenesis. It also supports the role of PPE8 as a potential drug candidate for the development of therapeutic agents in the treatment of angiogenesis-related diseases including cancer.

PMID:35805198 | DOI:10.3390/cells11132114

Orphanet J Rare Dis. 2022 Jul 8;17(1):258. doi: 10.1186/s13023-022-02397-4.

ABSTRACT

INTRODUCTION: Drugs for rare diseases (DRDs) offer important health benefits, but challenge traditional health technology assessment, reimbursement, and pricing processes due to limited effectiveness evidence. Recently, modified processes to address these challenges while improving patient access have been proposed in Canada. This review examined processes in 12 jurisdictions to develop recommendations for consideration during formal government-led multi-sectoral discussions currently taking place in Canada.

METHODS: (i) A scoping review of DRD reimbursement processes, (ii) key informant interviews, (iii) a case study of evaluations for and the reimbursement status of a set of 7 DRDs, and (iv) a virtual, multi-stakeholder consultation retreat were conducted.

RESULTS: Only NHS England has a process specifically for DRDs, while Italy, Scotland, and Australia have modified processes for eligible DRDs. Almost all consider economic evaluations, budget impact analyses, and patient-reported outcomes; but less than half accept surrogate measures. Disease severity, lack of alternatives, therapeutic value, quality of evidence, and value for money are factors used in all decision-making process; only NICE England uses a cost-effectiveness threshold. Budget impact is considered in all jurisdictions except Sweden. In Italy, France, Germany, Spain, and the United Kingdom, specific factors are considered for DRDs. However, in all jurisdictions opportunities for clinician/patient input are the same as those for other drugs. Of the 7 DRDs included in the case study, the number that received a positive reimbursement recommendation was highest in Germany and France, followed by Spain and Italy. No relationship between recommendation type and specific elements of the pricing and reimbursement process was found.

CONCLUSIONS: Based on the collective findings from all components of the project, seven recommendations for possible action in Canada are proposed. These focus on defining "appropriate access", determining when a "full" HTA may not be needed, improving coordination among stakeholder groups, developing a Canadian framework for Managed Access Plans, creating a pan-Canadian DRD/rare disease data infrastructure, genuine and continued engagement of patient groups and clinicians, and further research on different decision and financing options, including MAPs.

PMID:35804398 | PMC:PMC9264608 | DOI:10.1186/s13023-022-02397-4

PLoS One. 2022 Jul 8;17(7):e0271246. doi: 10.1371/journal.pone.0271246. eCollection 2022.

ABSTRACT

Nucleotide Excision Repair is one of the five DNA repair systems. More than 30 proteins are involved in this process, including the seven XP proteins. When mutated, the genes coding for these proteins are provoking the rare disease Xeroderma Pigmentosum, which causes cutaneous defects and a high prevalence of skin cancers in patients. The CSA and CSB proteins are also involved in Nucleotide Excision Repair, and their mutation leads to Cockayne Syndrome, another rare disease, causing dwarfism, neurodegeneration, and ultimately early death, but without high skin cancer incidence. Some mutations of ERCC5, the gene coding for XPG, may give rise to a combined Xeroderma Pigmentosum and Cockayne Syndrome. A defect in Nucleotide Excision Repair alone cannot explain all these phenotypes. XPG has been located in the nucleolus, where ribosome biogenesis happens. This energy-consuming process starts with the transcription of the ribosomal DNA in a long ribosomal RNA, the pre-rRNA 47S, by RNA Polymerase 1. 47S pre-rRNA undergoes several cleavages and modifications to form three mature products: the ribosomal RNAs 18S, 5.8S and 28S. In the cytoplasm, these three products will enter the ribosomes' composition, the producers of protein in our cells. Our work aimed to observe ribosome biogenesis in presence of an unstable XPG protein. By working on Xeroderma Pigmentosum/Cockayne Syndrome cell lines, meaning in the absence of XPG, we uncovered that the binding of UBF, as well as the number of unresolved R-loops, is increased along the ribosomal DNA gene body and flanking regions. Furthermore, ribosomal RNA maturation is impaired, with increased use of alternative pathways of maturation as well as an increase of immature precursors. These defective processes may explain the neurodegeneration observed when the XPG protein is heavily truncated, as ribosomal homeostasis and R-loops resolution are critical for proper neuronal development.

PMID:35802638 | PMC:PMC9269744 | DOI:10.1371/journal.pone.0271246

Front Oncol. 2022 Jun 20;12:862326. doi: 10.3389/fonc.2022.862326. eCollection 2022.

ABSTRACT

BACKGROUND AND PURPOSE: Benzimidazoles have attracted much attention over the last few decades due to their broad-spectrum pharmacological properties. Increasing evidence is showing the potential use of benzimidazoles as anti-angiogenic agents, although the mechanisms that impact angiogenesis remain to be fully defined. In this study, we aim to investigate the anti-angiogenic mechanisms of MFB, a novel 2-aminobenzimidazole derivative, to develop a novel angiogenesis inhibitor.

EXPERIMENTAL APPROACH: MTT, BrdU, migration and invasion assays, and immunoblotting were employed to examine MFB's effects on vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation, migration, invasion, as well as signaling molecules activation. The anti-angiogenic effects of MFB were analyzed by tube formation, aorta ring sprouting, and matrigel plug assays. We also used a mouse model of lung metastasis to determine the MFB's anti-metastatic effects.

KEY RESULTS: MFB suppressed cell proliferation, migration, invasion, and endothelial tube formation of VEGF-A-stimulated human umbilical vascular endothelial cells (HUVECs) or VEGF-C-stimulated lymphatic endothelial cells (LECs). MFB suppressed VEGF-A and VEGF-C signaling in HUVECs or LECs. In addition, MFB reduced VEGF-A- or tumor cells-induced neovascularization in vivo. MFB also diminished B16F10 melanoma lung metastasis. The molecular docking results further showed that MFB may bind to VEGFR-2 rather than VEGF-A with high affinity.

CONCLUSIONS AND IMPLICATIONS: These observations indicated that MFB may target VEGF/VEGFR signaling to suppress angiogenesis and lymphangiogenesis. It also supports the role of MFB as a potential lead in developing novel agents for the treatment of angiogenesis- or lymphangiogenesis-associated diseases and cancer.

PMID:35795066 | PMC:PMC9251317 | DOI:10.3389/fonc.2022.862326

BMC Bioinformatics. 2022 Jul 6;23(1):263. doi: 10.1186/s12859-022-04810-y.

ABSTRACT

BACKGROUND AND OBJECTIVE: Although rare diseases are characterized by low prevalence, approximately 400 million people are affected by a rare disease. The early and accurate diagnosis of these conditions is a major challenge for general practitioners, who do not have enough knowledge to identify them. In addition to this, rare diseases usually show a wide variety of manifestations, which might make the diagnosis even more difficult. A delayed diagnosis can negatively affect the patient's life. Therefore, there is an urgent need to increase the scientific and medical knowledge about rare diseases. Natural Language Processing (NLP) and Deep Learning can help to extract relevant information about rare diseases to facilitate their diagnosis and treatments.

METHODS: The paper explores several deep learning techniques such as Bidirectional Long Short Term Memory (BiLSTM) networks or deep contextualized word representations based on Bidirectional Encoder Representations from Transformers (BERT) to recognize rare diseases and their clinical manifestations (signs and symptoms).

RESULTS: BioBERT, a domain-specific language representation based on BERT and trained on biomedical corpora, obtains the best results with an F1 of 85.2% for rare diseases. Since many signs are usually described by complex noun phrases that involve the use of use of overlapped, nested and discontinuous entities, the model provides lower results with an F1 of 57.2%.

CONCLUSIONS: While our results are promising, there is still much room for improvement, especially with respect to the identification of clinical manifestations (signs and symptoms).

PMID:35794528 | DOI:10.1186/s12859-022-04810-y

Indian J Ophthalmol. 2022 Jul;70(7):2675-2677. doi: 10.4103/ijo.IJO_2817_21.

NO ABSTRACT

PMID:35791200 | DOI:10.4103/ijo.IJO_2817_21

Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2022 Jun;44(3):484-490. doi: 10.3881/j.issn.1000.503X.13465.

ABSTRACT

Rare diseases refer to the diseases with low prevalence,among which more than 150 kinds involve the kidney.Most of the rare renal diseases have genetic background.Due to complex etiology and diverse clinical phenotypes,most patients have progressed to the final stage of the disease before a clear diagnosis.Gene testing is a powerful tool for the diagnosis of rare renal diseases.The emergence of the next-generation sequencing (NGS) significantly improves the diagnostic efficiency and quality and provides an unprecedented opportunity to understand the molecular genetic basis of rare renal diseases and further select or develop targeted therapies.This article reviews the application progress,challenges,and prospects of NGS in rare kidney diseases.

PMID:35791948 | DOI:10.3881/j.issn.1000.503X.13465

Indian J Ophthalmol. 2022 Jul;70(7):2613-2615. doi: 10.4103/ijo.IJO_2816_21.

NO ABSTRACT

PMID:35791171 | DOI:10.4103/ijo.IJO_2816_21

Indian J Ophthalmol. 2022 Jul;70(7):2605-2609. doi: 10.4103/ijo.IJO_3002_21.

ABSTRACT

This case series describes the ocular and retinal manifestations of rare eye diseases in systemic syndromes. This observational case series consists of five patients with varied ophthalmic manifestations and documentation of imaging in rare pediatric and adult retinopathies. Two patients had Kearns Sayre syndrome (KSS) based on the classical triad of external ophthalmoplegia, pigmentary retinopathy, and onset before 20 years of age. In one patient of KSS, the mitochondrial retinopathy was seen in an asymmetric pattern, and the second patient presented with KSS after being mis-diagnosed as myasthenia gravis elsewhere. A case of Senior Loken syndrome in pediatric age is described in this series with varied ophthalmic manifestations ranging from retinitis pigmentosa to orbital abscess. This series also enlightens features of Hallervorden Spatz syndrome presenting with bull's eye maculopathy and a case of spino-cerebellar ataxia type 7 presenting with pigmentary retinopathy.

PMID:35791168 | DOI:10.4103/ijo.IJO_3002_21

Indian J Ophthalmol. 2022 Jul;70(7):2584. doi: 10.4103/ijo.IJO_905_22.

NO ABSTRACT

PMID:35791161 | DOI:10.4103/ijo.IJO_905_22

Indian J Ophthalmol. 2022 Jul;70(7):2559-2563. doi: 10.4103/ijo.IJO_2627_21.

ABSTRACT

PURPOSE: Fraser syndrome is a rare congenital disorder comprising cryptophthalmos, syndactyly, and many times, urogenital anomalies. Herein, the authors aimed to study and report the clinical features and orbital anomalies in cases diagnosed with Fraser syndrome.

METHODS: The authors retrospectively evaluated the records of patients with Fraser syndrome who had presented to a tertiary eye care hospital in northern India in the last 2 years (from January 2019 to December 2020). The clinical features were studied, entered in MS Excel, and the data was evaluated.

RESULTS: Data of 15 patients with Fraser syndrome were found. Majority of the patients were males and presented in the pediatric age group. Bilateral involvement was more common, and the most common variant of cryptophthalmos was abortive. Complete and medial madarosis of the eyebrows was the most common periocular finding. Complete cryptophthalmos was associated with cystic globes, whereas abortive forms had superior symblepharon. Common systemic features included syndactyly, bifid nose, and urogenital anomaly.

CONCLUSION: Fraser syndrome is an extremely rare developmental disorder; it encompasses a wide range of ocular, periocular, and orbital anomalies, along with multiple pre-existing systemic anomalies. The treating ophthalmologist should always be careful in examining these patients.

PMID:35791156 | DOI:10.4103/ijo.IJO_2627_21

Indian J Ophthalmol. 2022 Jul;70(7):2386-2396. doi: 10.4103/ijo.IJO_252_22.

ABSTRACT

Advent of new sequencing technologies and modern diagnostic procedures has opened the door for a deeper understanding of disorders about which little was known previously. Discovery of novel genes, new genetic variants in previously known genes and better techniques of functional validation has immensely contributed to unraveling the molecular basis of genetic disorders. Availability of knockout animal models like the zebrafish and gene editing tools like CRISPR-Cas9 has elucidated the function of many new genes and helped us to better understand the functional consequences of various gene defects. This has also led to better diagnosis and therapeutic interventions. In this context, a good body of research work has been done on X-linked recessive disorders with ocular findings. This review will focus on ocular and genetic findings of these rare disorders. To our knowledge, this is the first comprehensive review encompassing ocular and genomic spectrum of X-linked recessive disorders.

PMID:35791118 | DOI:10.4103/ijo.IJO_252_22

Indian J Ophthalmol. 2022 Jul;70(7):2232-2238. doi: 10.4103/ijo.IJO_322_22.

ABSTRACT

Rare eye diseases (REDs) are mostly progressive and are the leading cause of irreversible blindness. The disease onset can vary from early childhood to late adulthood. A high rate of consanguinity contributes to India's predisposition to RED. Most gene variations causing REDs are monogenic and, in some cases, digenic. All three types of Mendelian inheritance have been reported in REDs. Some of the REDs are related to systemic illness with variable phenotypes in affected family members. Approximately, 50% of the children affected by REDs show associated phenotypes at the early stages of the disease. A precise clinical diagnosis becomes challenging due to high clinical and genetic heterogeneity. Technological advances, such as next-generation sequencing (NGS), have improved genetic and genomic testing for REDs, thereby aiding in determining the underlying causative gene variants. It is noteworthy that genetic testing together with genetic counseling facilitates a more personalized approach in the accurate diagnosis and management of the disease. In this review, we discuss REDs identified in the Indian population and their underlying genetic etiology.

PMID:35791102 | DOI:10.4103/ijo.IJO_322_22

Indian J Ophthalmol. 2022 Jul;70(7):2230-2231. doi: 10.4103/ijo.IJO_871_22.

NO ABSTRACT

PMID:35791101 | DOI:10.4103/ijo.IJO_871_22

Indian J Ophthalmol. 2022 Jul;70(7):2225-2230. doi: 10.4103/ijo.IJO_302_22.

ABSTRACT

The prevalence of rare diseases has been estimated to be around 6%-8%, most of which are genetic in origin. Rare eye diseases constitute a critical public health concern. The major concerns for people suffering from these conditions are diagnosis, treatment, rehabilitation, limited resources, and health infrastructure. Also, as the number of people suffering from these disorders is less, it becomes difficult to study the epidemiological distribution and natural course of the disease. Thus, there is a need to establish registries for such rare disorders. This will help in creating a database of those suffering from rare eye diseases and will prove advantageous for both the patients and the researchers. For patients, it will be helpful as it will provide them will access to families suffering from similar problems, provide rehabilitation services, and provide access to clinical trials working on the development of new treatments for these rare disorders. From the researchers' point of view, it will be beneficial for them as they will then have access to a pool of data that can be used as a starting point of research on these rare disorders. At present, very few registries exist around the world and none in India. A systematic review of registries for rare eye diseases on Google and PubMed was done for existing registries, their methodology, services provided, applications, and advantages.

PMID:35791100 | DOI:10.4103/ijo.IJO_302_22

Indian J Ophthalmol. 2022 Jul;70(7):2216-2217. doi: 10.4103/ijo.IJO_782_22.

NO ABSTRACT

PMID:35791096 | DOI:10.4103/ijo.IJO_782_22

Indian J Ophthalmol. 2022 Jul;70(7):2214-2215. doi: 10.4103/ijo.IJO_1083_22.

NO ABSTRACT

PMID:35791095 | DOI:10.4103/ijo.IJO_1083_22