scholarly journals RPE65-related retinal dystrophy: mutational and phenotypic spectrum in 45 affected patients

2021 ◽  
Author(s):  
R Lopez-Rodriguez ◽  
E Lantero ◽  
F Blanco-Kelly ◽  
A Avila-Fernandez ◽  
I Martin Merida ◽  
...  
Keyword(s):  
Age At Onset ◽  
Disease Onset ◽  
Retinal Dystrophy ◽  
Rank Test ◽  
Ophthalmological Examination ◽  
Symptomatic Disease ◽  
Inherited Retinal Dystrophies ◽  
Kaplan Meier ◽  
Almost All ◽  
First Year Of Life

ABSTRACTBackgroundBiallelic pathogenic RPE65 variants are related to a spectrum of clinically overlapping inherited retinal dystrophies (IRD). Most affected individuals show a severe progression, with 50% of patients legally blind by 20 years of age. A better knowledge of the mutational spectrum and the phenotype-genotype correlation in RPE65-related IRD is needed.MethodsForty-five affected subjects from 27 unrelated families with a clinical diagnosis of RPE65-related IRD were included. Clinical evaluation consisted on self-reported ophthalmological history and objective ophthalmological examination. Patients’ genotype was classified accordingly to variant class (truncating or missense) or to variant location at different protein domains. Main phenotypic outcome was age at onset (AAO) of the symptomatic disease and a Kaplan–Meier analysis of disease symptom event-free survival was performed.ResultsTwenty-nine different RPE65 variants were identified in our cohort, 7 of them novel. Most frequent variants were p.(Ile98Hisfs*26), p.(Pro111Ser) and p.(Gly187Glu) accounting for the 24% of the detected alleles. Patients carrying two missense alleles showed a later disease onset than those with 1 or 2 truncating variants (Log Rank test p<0.05). While the 60% of patients carrying a missense/missense genotype presented symptoms before or at the first year of life, almost all patients with at least 1 truncating allele (91%) had an AAO ≤1 year (p<0.05).ConclusionOur findings suggest an association between the type of the RPE65 carried variant and the AAO. Thus, our results provide useful data on RPE65-associated IRD phenotypes which may help to improve clinical and therapeutic management of these patients.

scholarly journals The natural history of Canavan disease: 23 new cases and comparison with patients from literature

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Annette Bley ◽  
Jonas Denecke ◽  
Alfried Kohlschütter ◽  
Gerhard Schön ◽  
Sandra Hischke ◽  
...  
Keyword(s):  
Severity Score ◽  
Canavan Disease ◽  
Psychomotor Development ◽  
Rank Test ◽  
First Year ◽  
Study Cohort ◽  
Pooled Data ◽  
Kaplan Meier ◽  
History Of ◽  
First Year Of Life

Abstract Background Canavan disease (CD, MIM # 271900) is a rare and devastating leukodystrophy of early childhood. To identify clinical features that could serve as endpoints for treatment trials, the clinical course of CD was studied retrospectively and prospectively in 23 CD patients. Results were compared with data of CD patients reported in three prior large series. Kaplan Meier survival analysis including log rank test was performed for pooled data of 82 CD patients (study cohort and literature patients). Results Onset of symptoms was between 0 and 6 months. Psychomotor development of patients was limited to abilities that are usually gained within the first year of life. Macrocephaly became apparent between 4 and 18 months of age. Seizure frequency was highest towards the end of the first decade. Ethnic background was more diverse than in studies previously reported. A CD severity score with assessment of 11 symptoms and abilities was developed. Conclusions Early hallmarks of CD are severe psychomotor disability and macrocephaly that develop within the first 18 months of life. While rare in the first year of life, seizures increase in frequency over time in most patients. CD occurs more frequently outside Ashkenazi Jewish communities than previously reported. Concordance of phenotypes between siblings but not patients with identical ASPA mutations suggest the influence of yet unknown modifiers. A CD severity score may allow for assessment of CD disease severity both retrospectively and prospectively.

scholarly journals Rare Co-Occurrence of Visual Snow in a Female Carrier With RPGRORF15-Associated Retinal Disorder

2021 ◽  
Vol 12 ◽  
Author(s):  
Aekkachai Tuekprakhon ◽  
Aulia Rahmi Pawestri ◽  
Ragkit Suvannaboon ◽  
Ketwarin Thongyou ◽  
Adisak Trinavarat ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Disease Onset ◽  
Retinal Dystrophy ◽  
Female Carrier ◽  
Ophthalmological Examination ◽  
Early Disease ◽  
Rare Form ◽  
Inactivation Pattern ◽  
Retinal Disorder ◽  
Female Carriers

X-linked retinitis pigmentosa (XLRP), a rare form of retinitis pigmentosa (RP), is predominantly caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. Affected males often present with severe phenotypes and early disease onset. In contrast, female carriers are usually asymptomatic or show stationary phenotypes. Herein, we reported an 8-year-old female carrier, a daughter of a confirmed RP father with RPGR mutation, with an early onset of progressive cone-rod pattern retinal dystrophy. Additionally, the carrier experienced visual snow-like symptom as long as she recalled. Ophthalmological examination showed the reduction of visual acuity and attenuation of photoreceptor functions since the age of 5 years. Further analysis revealed a heterozygous pathogenic variant of the RPGR gene and a random X-inactivation pattern. Although she harboured an identical RPGR variant as the father, there were phenotypic intrafamilial variations. The information on the variety of genotypic and phenotypic presentations in XLRP carriers is essential for further diagnosis, management, and monitoring of these cases, including the design of future gene therapy trials.

Associations between regorafenib-induced adverse events (AEs) and efficacy in metastatic colorectal cancer (mCRC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 556-556 ◽  
Author(s):  
Takeru Wakatsuki ◽  
Eiji Shinozaki ◽  
Mitsukuni Suenaga ◽  
Izuma Nakayama ◽  
Tomohiro Matsushima ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Adverse Events ◽  
Univariate Analysis ◽  
Rank Test ◽  
Multikinase Inhibitor ◽  
Log Rank Test ◽  
Kaplan Meier ◽  
Almost All ◽  
Therapy Target

556 Background: It is occasionally recognized that, in molecular targeted therapy, target-specific AEs can surrogate its efficacy, such as skin toxicities and anti-EGFR antibodies. Because of multikinase inhibitor, regorafenib is involved in various kinds of adverse events; however, the clinical associations between AEs and efficacy remain unclear. The aim of this study is to reveal what AEs could surrogate efficacy of regorafenib. Methods: AEs were graded according to CTCAE ver. 4.0. We defined as “CRP increased”, if CRP increased more than 5 mg/dl during treatment compared with the baseline level. Time to treatment failure (TTF) and overall survival (OS) were estimated using Kaplan-Meier methods and compared by the log-rank test. Covariates which were significant in univariate analysis were included in multivariate analysis. Results: One-hundred and two patients were enrolled in this study. Almost all patients were PS 0-1 and received 160mg of regorafenib as an initial dose. The median TTF and the median OS were 2.0 and 8.0 months, respectively. Major AEs were Hand-foot skin reaction (HFSR) in 82.4% (≥Gr3:38.2%), Hypertension (HT) in 39.2% (16.7%), Rash in 23.5% (8.8%), Blood bilirubin increased (BBI) in 58.8% (2.9%), Thrombocytopenia in 48.0% (3.9%), Neutropenia in 20.5% (0%), and CRP increased in 46.1%. Regarding TTF, in univariate analysis, BBI, AST increased Gr0-1, neutropenia, absence of CRP increased, Diarrhea, HFSR, and Rash Gr0-2 were associated with longer TTF. In multivariate analysis, HFSR (HR 0.34 95%CI 0.19-0.63, p = 0.001) and Rash ≥Gr3 (HR 2.43 95%CI 1.13-5.21, p = 0.023) retained to be significant. With respect to OS, in univariate analysis, AST increased Gr0-1, ALT increased Gr0-1, neutropenia, absence of CRP increased, HFSR, and Rash Gr0-2 were associated with longer OS. In multivariate analysis, HFSR (HR 0.47 95%CI 0.24-0.91, p = 0.026), neutropenia (HR 0.54 95%CI 0.30-0.95, p = 0.032) and AST ≥Gr2 (HR 5.72 95%CI 2.11-15.63, p = 0.023) retained to be significant. Conclusions: HFSR and neutropenia might surrogate regorafenib efficacy in mCRC. Elucidation of the mechanisms of these AEs may help to understand which the pathway is the key role of regorafenib treatment in mCRC.

Variable course of Unverricht-Lundborg disease

Neurology ◽  
2017 ◽  
Vol 89 (16) ◽  
pp. 1691-1697 ◽  
Author(s):  
Laura Canafoglia ◽  
Edoardo Ferlazzo ◽  
Roberto Michelucci ◽  
Pasquale Striano ◽  
Adriana Magaudda ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Time Course ◽  
Proportional Hazards ◽  
Cell Damage ◽  
Age At Onset ◽  
Disease Onset ◽  
Rank Test ◽  
Genetically Determined

Objective:To explore the course of Unverricht-Lundborg disease (EPM1) and identify the risk factors for severity, we investigated the time course of symptoms and prognostic factors already detectable near to disease onset.Methods:We retrospectively evaluated the features of 59 Italian patients carrying the CSTB expansion mutation, and coded the information every 5 years after the disease onset in order to describe the cumulative time-dependent probability of reaching disabling myoclonus, relevant cognitive impairment, and inability to work, and evaluated the influence of early factors using the log-rank test. The risk factors were included in a Cox multivariate proportional hazards regression model.Results:Disabling myoclonus occurred an average of 32 years after disease onset, whereas cognitive impairment occurred a little later. An age at onset of less than 12 years, the severity of myoclonus at the time of first assessment, and seizure persistence more than 10 years after onset affected the timing of disabling myoclonus and cognitive decline. Most patients became unable to work years before the appearance of disabling myoclonus or cognitive decline.Conclusions:A younger age at onset, early severe myoclonus, and seizure persistence are predictors of a more severe outcome. All of these factors may be genetically determined, but the greater hyperexcitability underlying more severe seizures and myoclonus at onset may also play a role by increasing cell damage due to reduced cystatin B activity.

Progression in familial and nonfamilial MS

2008 ◽  
Vol 14 (3) ◽  
pp. 300-306 ◽  
Author(s):  
Marcus Koch ◽  
Maarten Uyttenboogaart ◽  
Marco Heerings ◽  
Dorothea Heersema ◽  
Jop Mostert ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cox Regression ◽  
Age At Onset ◽  
Disease Onset ◽  
Genetic Research ◽  
Primary Progressive ◽  
Kaplan Meier ◽  
Younger Age ◽  
Relapsing Remitting ◽  
History Of

Objective To investigate whether the timing of secondary or primary progression is different between patients with familial and nonfamilial multiple sclerosis (MS). Methods Information on the family history of 313 patients with MS was taken from our prospective hospital-based database. We used Kaplan—Meier analyses and Cox regression models to evaluate differences between familial and nonfamilial MS in several endpoint measures. We investigated the risk of developing secondary progression in all patients with a relapsing—remitting disease onset, the length of the relapsing—remitting phase and age at onset of progression in patients with secondary progressive MS and the age at disease onset in patients with primary progressive MS (PPMS). Results Among the primary progressive patients, those with familial MS had a significantly younger age at disease onset than patients with nonfamilial MS (mean 33.04 years versus mean 37.73 years in nonfamilial MS, P = 0.02). There were no significant differences between familial and nonfamilial MS patients in any other investigated measure. Conclusions Familial MS appears related to the time of disease onset in PPMS. Patients with familial PPMS may be an important patient group for future genetic research in MS. Multiple Sclerosis 2008; 14: 300—306. http://msj.sagepub.com

Colorectal Liver Metastases - Does the Number of Lesions Determine the Sensibility of Resection?

Swiss Surgery ◽  
2000 ◽  
Vol 6 (1) ◽  
pp. 6-10
Author(s):  
Knoefel ◽  
Brunken ◽  
Neumann ◽  
Gundlach ◽  
Rogiers ◽  
...  
Keyword(s):  
Liver Metastases ◽  
Colorectal Liver Metastases ◽  
Rank Test ◽  
Log Rank Test ◽  
Kaplan Meier ◽  
Chirurgische Entfernung

Die komplette chirurgische Entfernung von Lebermetastasen bietet Patienten nach kolorektalem Karzinom die einzige kurative Chance. Es gibt jedoch eine, anscheinend unbegrenzte, Anzahl an Parametern, die die Prognose dieser Patienten bestimmen und damit den Sinn dieser Therapie vorhersagen können. Zu den am häufigsten diskutierten und am einfachsten zu bestimmenden Parametern gehört die Anzahl der Metastasen. Ziel dieser Studie war es daher die Wertigkeit dieses Parameters in der Literatur zu reflektieren und unsere eigenen Patientendaten zu evaluieren. Insgesamt konnte von 302 Patienten ein komplettes Follow-up erhoben werden. Die gebildeten Patientengruppen wurden mit Hilfe einer Kaplan Meier Analyse und konsekutivem log rank Test untersucht. Die Literatur wurde bis Dezember 1998 revidiert. Die Anzahl der Metastasen bestätigte sich als ein prognostisches Kriterium. Lagen drei oder mehr Metastasen vor, so war nicht nur die Wahrscheinlichkeit einer R0 Resektion deutlich geringer (17.8% versus 67.2%) sondern auch das Überleben der Patienten nach einer R0 Resektion tendenziell unwahrscheinlicher. Das 5-Jahres Überleben betrug bei > 2 Metastasen 9% bei > 2 Metastasen 36%. Das 10-Jahres Überleben beträgt bislang bei > 2 Metastasen 0% bei > 2 Metastasen 18% (p < 0.07). Die Anzahl der Metastasen spielt in der Prognose der Patienten mit kolorektalen Lebermetastasen eine Rolle. Selbst bei mehr als vier Metastasen ist jedoch gelegentlich eine R0 Resektion möglich. In diesen Fällen kann der Patient auch langfristig von einer Operation profitieren. Das wichtigere Kriterium einer onkologisch sinnvollen Resektabilität ist die Frage ob technisch und funktionell eine R0 Resektion durchführbar ist. Ist das der Fall, so sollte auch einem Patienten mit mehreren Metastasen die einzige kurative Chance einer Resektion nicht vorenthalten bleiben.

scholarly journals Exploring polypharmacy phenomenon in newly diagnosed relapsing–remitting multiple sclerosis: a cohort ambispective single-centre study

2021 ◽  
Vol 12 ◽  
pp. 204062232098312
Author(s):  
Aurora Zanghì ◽  
Emanuele D’Amico ◽  
Salvatore Lo Fermo ◽  
Francesco Patti
Keyword(s):  
Multiple Sclerosis ◽  
Age At Onset ◽  
Rank Test ◽  
Multinomial Regression ◽  
Single Centre ◽  
Centre Study ◽  
Relapsing Remitting ◽  
Single Centre Study ◽  
Remitting Multiple Sclerosis ◽  
Relapsing Remitting Multiple Sclerosis

Aims: We aimed to examine the frequency of polypharmacy in a large cohort of patients at the time of diagnosis of relapsing–remitting multiple sclerosis (RRMS) and to explore its effects on discontinuation of first disease-modifying treatment (DMT) using survival analysis. Methods: This was a cohort ambispective single-centre study. We enrolled RRMS patients starting their first DMT between 1st January 2013 and 31st December 2015. According to the number of medicines prescribed (except DMTs), we divided the patients into three groups: no-poly RRMS, minor-poly RRMS (from one to three medications), and major-poly RRMS (more than three medications). Results: A total of 392 RRMS patients were enrolled (mean age 41.1). The minor-poly RRMS group included 61 patients (15.6%) and the major-poly RRMS group included 112 (28.6%). Individuals in these groups were older and had higher median body mass index (BMI) than patients in the no-poly RRMS group ( p < 0.05). Upon multinomial regression analysis, older age at onset was associated with minor and major polypharmacy (OR 1.050, CI 1.010–1.093, p = 0.015 and OR 1.063, CI 1.026–1.101, p = 0.001, respectively) and higher BMI was associated with major polypharmacy (OR 1.186, CI 1.18–1.29, p = 0.001). The rates of discontinuation of first DMT were similar among the three groups (50.7% for no-Poly RRMS, 50.8% for minor-Poly RRMS, and 53.3% for major-Poly RRMS, p = 0.264). At log-Rank test, there were no differences among the three groups ( p = 0.834). Conclusion: Polypharmacy was more common in older RRMS patients with high BMI.

Adult systemic lupus erythematosus in Egypt: The nation-wide spectrum of 3661 patients and world-wide standpoint

Lupus ◽  
2021 ◽  
pp. 096120332110142
Author(s):  
Tamer A Gheita ◽  
Rasha Abdel Noor ◽  
Esam Abualfadl ◽  
Osama S Abousehly ◽  
Iman I El-Gazzar ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Age Of Onset ◽  
Wide Spectrum ◽  
Age At Onset ◽  
Disease Onset ◽  
Clinical Manifestations ◽  
Population Based ◽  
Systemic Lupus ◽  
Cross Sectional

Objective The aim of this study was to present the epidemiology, clinical manifestations and treatment pattern of systemic lupus erythematosus (SLE) in Egyptian patients over the country and compare the findings to large cohorts worldwide. Objectives were extended to focus on the age at onset and gender driven influence on the disease characteristics. Patients and method This population-based, multicenter, cross-sectional study included 3661 adult SLE patients from Egyptian rheumatology departments across the nation. Demographic, clinical, and therapeutic data were assessed for all patients. Results The study included 3661 patients; 3296 females and 365 males (9.03:1) and the median age was 30 years (17–79 years), disease duration 4 years (0–75 years) while the median age at disease onset was 25 years (4–75 years). The overall estimated prevalence of adult SLE in Egypt was 6.1/100,000 population (1.2/100,000 males and 11.3/100,000 females).There were 316 (8.6%) juvenile-onset (Jo-SLE) and 3345 adult-onset (Ao-SLE). Age at onset was highest in South and lowest in Cairo (p < 0.0001). Conclusion SLE in Egypt had a wide variety of clinical and immunological manifestations, with some similarities with that in other nations and differences within the same country. The clinical characteristics, autoantibodies and comorbidities are comparable between Ao-SLE and Jo-SLE. The frequency of various clinical and immunological manifestations varied between gender. Additional studies are needed to determine the underlying factors contributing to gender and age of onset differences.

scholarly journals Cohort study of the overall survival of patients with pancreatic cancer in a hospital of specialties of Quito-Ecuador in the period 2007–2017

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Andrés Moreno Roca ◽  
Luciana Armijos Acurio ◽  
Ruth Jimbo Sotomayor ◽  
Carlos Céspedes Rivadeneira ◽  
Carlos Rosero Reyes ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cohort Study ◽  
Survival Time ◽  
Univariate Analysis ◽  
Rank Test ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Icd 10 ◽  
The Difference ◽  
Clinical Records

Abstract Objectives Pancreatic cancers in most patients in Ecuador are diagnosed at an advanced stage of the disease, which is associated with lower survival. To determine the characteristics and global survival of pancreatic cancer patients in a social security hospital in Ecuador between 2007 and 2017. Methods A retrospective cohort study and a survival analysis were performed using all the available data in the electronic clinical records of patients with a diagnosis of pancreatic cancer in a Hospital of Specialties of Quito-Ecuador between 2007 and 2017. The included patients were those coded according to the ICD 10 between C25.0 and C25.9. Our univariate analysis calculated frequencies, measures of central tendency and dispersion. Through the Kaplan-Meier method we estimated the median time of survival and analyzed the difference in survival time among the different categories of our included variables. These differences were shown through the log rank test. Results A total of 357 patients diagnosed with pancreatic cancer between 2007 and 2017 were included in the study. More than two-thirds (69.9%) of the patients were diagnosed in late stages of the disease. The median survival time for all patients was of 4 months (P25: 2, P75: 8). Conclusions The statistically significant difference of survival time between types of treatment is the most relevant finding in this study, when comparing to all other types of treatments.

scholarly journals Carbon Dot Nanoparticles: Exploring the Potential Use for Gene Delivery in Ophthalmic Diseases

Nanomaterials ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 935
Author(s):  
Manas R. Biswal ◽  
Sofia Bhatia
Keyword(s):  
Gene Delivery ◽  
Therapeutic Option ◽  
Retinal Dystrophy ◽  
Retinal Cells ◽  
Adeno Associated Virus ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Efficient Gene ◽  
New Type ◽  
Viral Nanoparticles

Ocular gene therapy offers significant potential for preventing retinal dystrophy in patients with inherited retinal dystrophies (IRD). Adeno-associated virus (AAV) based gene transfer is the most common and successful gene delivery approach to the eye. These days, many studies are using non-viral nanoparticles (NPs) as an alternative therapeutic option because of their unique properties and biocompatibility. Here, we discuss the potential of carbon dots (CDs), a new type of nanocarrier for gene delivery to the retinal cells. The unique physicochemical properties of CDs (such as optical, electronic, and catalytic) make them suitable for biosensing, imaging, drug, and gene delivery applications. Efficient gene delivery to the retinal cells using CDs depends on various factors, such as photoluminescence, quantum yield, biocompatibility, size, and shape. In this review, we focused on different approaches used to synthesize CDs, classify CDs, various pathways for the intake of gene-loaded carbon nanoparticles inside the cell, and multiple studies that worked on transferring nucleic acid in the eye using CDs.

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