Exon-Trapping Assay Improves Clinical Interpretation of COL11A1 and COL11A2 Intronic Variants in Stickler Syndrome Type 2 and Otospondylomegaepiphyseal Dysplasia

Stickler syndrome (SS) is a hereditary connective tissue disorder affecting bones, eyes, and hearing. Type 2 SS and the SS variant otospondylomegaepiphyseal dysplasia (OSMED) are caused by deleterious variants in COL11A1 and COL11A2, respectively. In both genes, available database information indicates a high rate of potentially deleterious intronic variants, but published evidence of their biological effect is usually insufficient for a definite clinical interpretation. We report four previously unpublished intronic variants in COL11A1 (c.2241 + 5G>T, c.2809 − 2A>G, c.3168 + 5G>C) and COL11A2 (c.4392 + 1G>A) identified in type 2 SS/OSMED individuals. The pathogenic effect of these variants was first predicted in silico and then investigated by an exon-trapping assay. We demonstrated that all variants can induce exon in-frame deletions, which lead to the synthesis of shorter collagen XI α1 or 2 chains. Lacking residues are located in the α-triple helical region, which has a crucial role in regulating collagen fibrillogenesis. In conclusion, this study suggests that these alternative COL11A1 and COL11A2 transcripts might result in aberrant triple helix collagen. Our approach may help to improve the diagnostic molecular pathway of COL11-related disorders.

Download Full-text

Type 2 Diabetes Mellitus and Vertebral Fracture Risk

Current Osteoporosis Reports ◽

10.1007/s11914-020-00646-8 ◽

2021 ◽

Author(s):

Fjorda Koromani ◽

Samuel Ghatan ◽

Mandy van Hoek ◽

M. Carola Zillikens ◽

Edwin H. G. Oei ◽

...

Keyword(s):

Diabetes Mellitus ◽

Vertebral Fracture ◽

Fracture Risk ◽

Vertebral Fractures ◽

Bone Fragility ◽

Marrow Fat ◽

Systematic Screening ◽

Published Evidence ◽

Vertebral Fracture Risk

Abstract Purpose of Review The purpose of this review is to summarize the recently published evidence concerning vertebral fracture risk in individuals with diabetes mellitus. Recent Findings Vertebral fracture risk is increased in individuals with T2DM. The presence of vertebral fractures in T2DM is associated with increased non-vertebral fracture risk and mortality. TBS could be helpful to estimate vertebral fracture risk in individuals with T2DM. An increased amount of bone marrow fat has been implicated in bone fragility in T2DM. Results from two recent studies show that both teriparatide and denosumab are effective in reducing vertebral fracture risk also in individuals with T2DM. Summary Individuals with T2DM could benefit from systematic screening in the clinic for presence of vertebral fractures.

Download Full-text

Hybrid Mamdani Fuzzy Rules and Convolutional Neural Networks for Analysis and Identification of Animal Images

Computation ◽

10.3390/computation9030035 ◽

2021 ◽

Vol 9 (3) ◽

pp. 35

Author(s):

Hind R. Mohammed ◽

Zahir M. Hussain

Keyword(s):

Neural Networks ◽

Convolutional Neural Networks ◽

High Speed ◽

Moving Objects ◽

Real Life ◽

Fuzzy Rules ◽

High Rate ◽

Moving Images ◽

Animal Images

Accurate, fast, and automatic detection and classification of animal images is challenging, but it is much needed for many real-life applications. This paper presents a hybrid model of Mamdani Type-2 fuzzy rules and convolutional neural networks (CNNs) applied to identify and distinguish various animals using different datasets consisting of about 27,307 images. The proposed system utilizes fuzzy rules to detect the image and then apply the CNN model for the object’s predicate category. The CNN model was trained and tested based on more than 21,846 pictures of animals. The experiments’ results of the proposed method offered high speed and efficiency, which could be a prominent aspect in designing image-processing systems based on Type 2 fuzzy rules characterization for identifying fixed and moving images. The proposed fuzzy method obtained an accuracy rate for identifying and recognizing moving objects of 98% and a mean square error of 0.1183464 less than other studies. It also achieved a very high rate of correctly predicting malicious objects equal to recall = 0.98121 and a precision rate of 1. The test’s accuracy was evaluated using the F1 Score, which obtained a high percentage of 0.99052.

Download Full-text

Number of cases of type 1 and 2 diabetes diagnosed in Amapá between 2007 and 2012

Panorama brasileiro de tungstênio (w) entre os anos de 2008 e 2014 ◽

10.32749/nucleodoconhecimento.com.br/health/diabetes-cases ◽

2020 ◽

pp. 18-26

Author(s):

Kauê de Melo Souza ◽

Lucas Facco ◽

Amanda Alves Fecury ◽

Maria Helena Mendonça de Araújo ◽

Euzébio de Oliveira ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Genetic Factors ◽

Sedentary Lifestyle ◽

High Rate ◽

Main Risk Factor ◽

Food Education ◽

Different Types

Diabetes mellitus is a succession of different types of disorders in metabolism that are characterized by causing a high rate of blood sugar. Because it is a disease with genetic factors type 1 diabetes has as main risk factor heredity, while type 2 diabetes besides these factors, includes obesity, high blood pressure, poor food education and advancing age. This study aims to show the number of cases of type 1 and 2 diabetes diagnosed in Amapá with the variables gender, age group, sedentary lifestyle, overweight, smoking, between 2007 and 2012. The data for the research were taken from the computer department of SUS, DATASUS (http://datasus.saude.gov.br). Type 1 and 2 diabetes mellitus (DM1 and DM2) are diseases that are tied to disturbances in production or in the efficient use of insulin. Smoking, as well as sedentary lifestyle and overweight are important risk factors for the development of DM2. Type 2 diabetes mellitus provides the development of various organic nerve lesions. In addition, DM2, through its chronicity, enables the development of retinopathies, nephropathies and other conditions negative to the individual’s health.

Download Full-text

1α,25-dihydroxyvitamin D3 promotes osseointegration of titanium implant via downregulating AGEs/RAGE pathway in T2DM

Endocrine Connections ◽

10.1530/ec-18-0241 ◽

2018 ◽

Vol 7 (11) ◽

pp. 1186-1195 ◽

Cited By ~ 1

Author(s):

Tingting Jia ◽

Ya-nan Wang ◽

Dongjiao Zhang ◽

Xin Xu

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Bone Microarchitecture ◽

Titanium Implant ◽

Underlying Mechanism ◽

High Rate ◽

Alizarin Red

Diabetes-induced advanced glycation end products (AGEs) overproduction would result in compromised osseointegration of titanium implant and high rate of implantation failure. 1α,25-dihydroxyvitamin D3 (1,25VD3) plays a vital role in osteogenesis, whereas its effects on the osseointegration and the underlying mechanism are unclear. The purpose of this study was to investigate that 1,25VD3 might promote the defensive ability of osseointegration through suppressing AGEs/RAGE in type 2 diabetes mellitus. In animal study, streptozotocin-induced diabetic rats accepted implant surgery, with or without 1,25VD3 intervention for 12 weeks. After killing, the serum AGEs level, bone microarchitecture and biomechanical index of rats were measured systematically. In vitro study, osteoblasts differentiation capacity was analyzed by alizarin red staining, alkaline phosphatase assay and Western blotting, after treatment with BSA, AGEs, AGEs with RAGE inhibitor and AGEs with 1,25VD3. And the expression of RAGE protein was detected to explore the mechanism. Results showed that 1,25VD3 could reverse the impaired osseointegration and mechanical strength, which possibly resulted from the increased AGEs. Moreover, 1,25VD3 could ameliorate AGEs-induced damage of cell osteogenic differentiation, as well as downregulating the RAGE expression. These data may provide a theoretical basis that 1,25VD3 could work as an adjuvant treatment against poor osseointegration in patients with type 2 diabetes mellitus.

Download Full-text

Systematic evaluation of nine monogenic autoinflammatory diseases reveals common and disease-specific correlations with allergy-associated features

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-219137 ◽

2021 ◽

pp. annrheumdis-2020-219137

Author(s):

Daniella Muallem Schwartz ◽

Moses M Kitakule ◽

Brian LP Dizon ◽

Cristhian Gutierrez-Huerta ◽

Sarah A Blackstone ◽

...

Keyword(s):

High Rate ◽

Autoinflammatory Diseases ◽

Th2 Cells ◽

Systematic Evaluation ◽

Neutrophilic Dermatosis ◽

Tumour Necrosis Factor Receptor ◽

Periodic Syndrome ◽

Clinical Phenotypes ◽

Type 2 Immunity

BackgroundMonogenic autoinflammatory diseases (AID) are caused by mutations in innate immune genes. The effects of these mutations on allergic inflammation are unknown.ObjectivesWe investigated allergic, immunological and clinical phenotypes in FMF (familial Mediterranean fever), CAPS (cryopyrin-associated periodic syndrome), TRAPS (tumour necrosis factor receptor-associated periodic syndrome), HIDS (hyper-IgD syndrome), PAPA (pyogenic arthritis, pyoderma gangrenosum and acne), DADA2 (deficiency of adenosine deaminase 2), HA20 (haploinsufficiency of A20), CANDLE (chronic atypical neutrophilic dermatosis, lipodystrophy, elevated temperature) and SAVI (STING-associated vasculopathy of infancy).MethodsIn this cross-sectional study, clinical data were assessed in 425 patients with AID using questionnaires and chart reviews. Comparator data were obtained from public databases. Peripheral blood mononuclear cells obtained from 55 patients were stimulated and CD4+ cytokine production assessed.ResultsClinical laboratory features of Type 2 immunity were elevated in CAPS but reduced in most AID, particularly DADA2. Physician-diagnosed allergic diseases were prevalent in multiple AID, including CAPS and DADA2. T helper 2 (Th2) cells were expanded in CAPS, TRAPS and HIDS; Th9 cells were expanded in HA20.ConclusionsCAPS is characterised by an enhanced Type 2 signature, whereas FMF and CANDLE are associated with reduced Type 2 responses. DADA2 is associated with reduced Type 2 responses but a high rate of physician-diagnosed allergy. Therefore, NLRP3-driven autoinflammation may promote Type 2 immunity, whereas AID like DADA2 may manifest clinical phenotypes that masquerade as allergic disorders. Further investigations are needed to determine the contribution of autoinflammation to allergic clinical and immunological phenotypes, to improve the treatment of patients with AID.

Download Full-text

Stickler Syndrome: A Review of Clinical Manifestations and the Genetics Evaluation

Journal of Personalized Medicine ◽

10.3390/jpm10030105 ◽

2020 ◽

Vol 10 (3) ◽

pp. 105

Author(s):

Megan Boothe ◽

Robert Morris ◽

Nathaniel Robin

Keyword(s):

Molecular Genetic ◽

Clinical Manifestations ◽

High Rate ◽

Stickler Syndrome ◽

Molecular Genetic Testing ◽

Ocular Complications ◽

Increased Risk ◽

Auditory Systems ◽

Detection And Diagnosis ◽

Early Detection And Diagnosis

Stickler Syndrome (SS) is a multisystem collagenopathy frequently encountered by ophthalmologists due to the high rate of ocular complications. Affected individuals are at significantly increased risk for retinal detachment and blindness, and early detection and diagnosis are critical in improving visual outcomes for these patients. Systemic findings are also common, with craniofacial, skeletal, and auditory systems often involved. SS is genotypically and phenotypically heterogenous, which can make recognizing and correctly diagnosing individuals difficult. Molecular genetic testing should be considered in all individuals with suspected SS, as diagnosis not only assists in treatment and management of the patient but may also help identify other at-risk family members. Here we review common clinical manifestation of SS and genetic tests frequently ordered as part of the SS evaluation.

Download Full-text

Mediterranean Diet Effects on Type 2 Diabetes Prevention, Disease Progression, and Related Mechanisms. A Review

Nutrients ◽

10.3390/nu12082236 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2236 ◽

Cited By ~ 1

Author(s):

Sandra Martín-Peláez ◽

Montse Fito ◽

Olga Castaner

Keyword(s):

Type 2 Diabetes ◽

Mediterranean Diet ◽

Healthy Lifestyle ◽

Diabetes Type 2 ◽

Antioxidant Compounds ◽

Published Evidence ◽

Quality Diet ◽

The Mediterranean ◽

Traditional Mediterranean Diet

The search for a quality diet has grown over the past decade. Diet is considered one of the pillars for the prevention and progression of several diseases, among them: diabetes. Type 2 diabetes (T2D) is an epidemic of western countries that increases the vulnerability of other diseases, such as cardiovascular and cancer. T2D is associated with lifestyle and diet. The traditional Mediterranean diet has proven its benefits over several cardiovascular risk factors, and specifically on diabetes. This review compiles recent published evidence on the effects of the Mediterranean diet on the incidence and progression of type 2 diabetes (T2D) and its relation with several other cardiovascular healthy diets. We will also focus on how the Mediterranean diet could play a role in T2D-related mechanisms, such as anti-inflammatory or antioxidant compounds, glucagon-like peptide agonist compounds, and changes in gut microbiota. Each component of the Mediterranean diet could be involved in processes related to diabetes homeostasis, many of them sharing common physio-pathological pathways. The importance of this diet within the set of habits of a healthy lifestyle must be emphasized.

Download Full-text

The Magnificent VWF SNPs and Where to Find Them: A Journey in Exon 28 of the Hispanic Population

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqz112.032 ◽

2019 ◽

Vol 152 (Supplement_1) ◽

pp. S16-S17

Author(s):

Mohammad Barouqa ◽

Jui Choudhuri ◽

Roger Fecher ◽

Jack Jacob ◽

Saed Sadeghi ◽

...

Keyword(s):

African American ◽

African Americans ◽

Wide Spectrum ◽

Von Willebrand Disease ◽

High Rate ◽

Coagulation Disorder ◽

Hispanic Population ◽

Protein Ratio ◽

A1 Domain

Abstract von Willebrand disease (VWD) is a common coagulation disorder with a prevalence of 0.1% to 1.0% manifesting as a wide spectrum of bleeding symptoms. Type 1 is diagnosed by confirming a quantitative decrease in VWF level, while type 3 has undetectable levels of VWF. Type 2 VWD variants are characterized by functional and binding defects. Initial diagnosis and follow-up depend mainly on measuring VWF protein and VWF activity and calculating the activity to protein ratio. Ristocetin cofactor activity (VWF:RCo) is the most widely used and gold standard activity assay. In our institute, we use a cutoff of VWF:RCo/VWF:Ag <0.7 to screen for possible type 2 VWD. However, the use of this ratio is flawed by the presence of specific SNPs (I1380V, N1435S, and D1472H) in the A1 domain, especially in African Americans. These SNPs lead to a decrease in ristocetin binding to VWF and hence decreased VWF:RCo/VWF:Ag ratio. In this retrospective study, we analyzed the levels of VWF:AG and VWF:RCo based on patients’ ethnicity using an in-house data mining software from 2011 to 2016. Then, we validated several exon 28 primers, kindly provided by Dr. Montgomery (Blood Center of Wisconsin), used to detect type 2 mutations and SNPs in African Americans. We excluded cases diagnosed as positive for VWD and included only cases rendered nondiagnostic of VWD following a comprehensive panel including multimers, collagen binding, and molecular studies when indicated. In our Hispanic population (n = 936), VWF:Ag was 138.9% and 117% (average and median) and VWF:RCo was 110.5% and 93.0% (average and median); 43.2% of Hispanics had VWF:RCo/VWF:Ag <0.7. In our African American population (n = 664), VWF:Ag was 163.0% and 138.5% (average and median) and VWF:RCo was 108.5% and 92.0% (average and median); 50.6% of the African American patients had VWF:RCo/VWF:Ag <0.7. Patients from Caucasian origins (n = 242) had VWF:Ag of 149.6% and 113.0% (average and median) and VWF:RCo of 137.6% and 116.0% (average and median), respectively; 30.9% of Caucasian patients had VWF:RCo/VWF:Ag of less than 0.7. We then selected four random Hispanic cases with VWF:RCo/VWF:Ag <0.5 as part of the validation study of exon 28 sequencing. Using a Sanger sequence assay, we found multiple benign/likely benign single-nucleotide polymorphisms (SNPs) at exon 28 that code for VWF antigen A1 domain. All four cases showed P.Thr1381Ala and P.Thr1547 = [OC1] polymorphism, three showed p.Val1565Leu polymorphism, and two showed p.Ala1555 = polymorphism. The statistical analysis of VWF:Ag/VWF:RCo levels from Hispanics shows a similar trend to African Americans with a high rate of cases with VWF:RCo/VWF:Ag <0.7 in comparison to Caucasians. However, the finding of SNPs and absence of known African American polymorphisms suggest that these SNPs may be the cause of decreased ristocetin binding in Hispanics. This study calls for ethnic-based considerations in VWD workflows.

Download Full-text

Revisiting comorbidities in gout: a cluster analysis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2013-203779 ◽

2013 ◽

Vol 74 (1) ◽

pp. 142-147 ◽

Cited By ~ 76

Author(s):

Pascal Richette ◽

Pierre Clerson ◽

Laure Périssin ◽

René-Marc Flipo ◽

Thomas Bardin

Keyword(s):

Cluster Analysis ◽

Renal Failure ◽

Large Cohort ◽

High Rate ◽

Cross Sectional ◽

High Prevalence ◽

History Of ◽

Obesity Hypertension ◽

Almost All

ObjectivesThe reciprocal links between comorbidities and gout are complex. We used cluster analysis to attempt to identify different phenotypes on the basis of comorbidities in a large cohort of patients with gout.MethodsThis was a cross-sectional multicentre study of 2763 gout patients conducted from November 2010 to May 2011. Cluster analysis was conducted separately for variables and for observations in patients, measuring proximity between variables and identifying homogeneous subgroups of patients. Variables used in both analyses were hypertension, obesity, diabetes, dyslipidaemia, heart failure, coronary heart disease, renal failure, liver disorders and cancer.ResultsComorbidities were common in this large cohort of patients with gout. Abdominal obesity, hypertension, metabolic syndrome and dyslipidaemia increased with gout duration, even after adjustment for age and sex. Five clusters (C1–C5) were found. Cluster C1 (n=332, 12%) consisted of patients with isolated gout and few comorbidities. In C2 (n=483, 17%), all patients were obese, with a high prevalence of hypertension. C3 (n=664, 24%) had the greatest proportion of patients with type 2 diabetes (75%). In C4 (n=782, 28%), almost all patients presented with dyslipidaemia (98%). Finally, C5 (n=502, 18%) consisted of almost all patients with a history of cardiovascular disease and renal failure, with a high rate of patients receiving diuretics.ConclusionsCluster analysis of comorbidities in gout allowed us to identify five different clinical phenotypes, which may reflect different pathophysiological processes in gout.

Download Full-text

Influence of Environmental Humidity on Wear Behavior of Aluminum Alloy Impregnated Graphite Composite Under Insufficient Lubrication

ASME/STLE 2007 International Joint Tribology Conference, Parts A and B ◽

10.1115/ijtc2007-44394 ◽

2007 ◽

Author(s):

Hozumi Goto ◽

Yusaku Shibuya

Keyword(s):

Wear Behavior ◽

High Rate ◽

Lubricating Oil ◽

Dry Sliding ◽

Graphite Composite ◽

Wear Mode ◽

Type 3 ◽

Rate Type

Wear characteristics of an Al-Si alloy impregnated graphite composite containing 56 vol% graphite and its matrices in contact with bearing steel were investigated under insufficient lubrication. Pin-on-disk type wear tests in air were conducted at various levels of relative humidity (RH) under dry sliding and drip feed lubrication (0.005 to 0.02 cm3) before each test by using base oil for engines. Changes in friction and wear were continuously monitored during the tests. Four types of wear mode for the composite were obtained: steady wear with a low rate (Type 1), high wear after a lubricating oil shortage (Type 2), no wear after pin lifting (Type 3) and steady wear with a high rate (Type 4). Type 1 appears over the whole range of RH (5 to 80%). Type 2 is found at low RH levels of 5 and 10%. Type 3 occurs at a frequency of 30 percents between 10 and 35% RH. Type 4 is seen over the whole RH range under dry sliding. The appearance of each wear mode at a specified RH depends on wear behavior of the matrices associated with RH under drip feed lubrication.

Download Full-text