scholarly journals Linkage analysis identifies an isolated strabismus locus at 14q12 overlapping with FOXG1 syndrome region

2020 ◽  
Author(s):  
Xin (Cynthia) Ye ◽  
Nicole M. Roslin ◽  
Andrew D. Paterson ◽  
Christopher Lyons ◽  
Victor Pegado ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Linkage Analysis ◽  
Future Study ◽  
Early Recognition ◽  
Treatment Options ◽  
Large Family ◽  
Mendelian Inheritance ◽  
Single Linkage ◽  
Multiple Loci ◽  
Foxg1 Syndrome

AbstractStrabismus is a common condition, affecting 1-4% of individuals. Isolated strabismus has been studied in families with Mendelian inheritance patterns. Despite the identification of multiple loci via linkage analyses, no specific genes have been identified from these studies. The current study is based on a seven-generation family with isolated strabismus inherited in an autosomal dominant manner. A total of 13 individuals from a common ancestor have been included for linkage analysis, and a single linkage signal has been identified at chromosome 14q12 with a multipoint LOD score of 4.69. Disruption of this locus is known to cause FOXG1 syndrome (or congenital Rett syndrome; OMIM #613454 and *164874), in which 84% of affected individuals present with strabismus. With the incorporation of next generation sequencing and in-depth bioinformatic analyses, a 4bp non-coding deletion was prioritized as the top candidate for the observed strabismus phenotype. The deletion is predicted to disrupt regulation of FOXG1, which encodes a transcription factor of the Forkhead family. Suggestive of an auto-regulation effect, the disrupted sequence matches the consensus FOXG1 and Forkhead family transcription factor binding site and has been observed in previous ChIP-seq studies to be bound by Foxg1 in early mouse brain development. The findings of this study indicate that the strabismus phenotype commonly observed within FOXG1 syndrome is separable from the more severe syndromic characteristics. Future study of this specific deletion may shed light on the regulation of FOXG1 expression and may enhance our understanding of the mechanisms contributing to strabismus and FOXG1 syndrome.Author summaryEye misalignment, or strabismus, can affect up to 4% of individuals. When strabismus is detected early, intervention in young children based on eye patching and/or corrective lenses can be beneficial. In some cases, corrective surgeries are used to align the eyes, with many individuals requiring multiple surgeries over a lifetime. A better understanding of the causes of strabismus may lead to earlier detection as well as improved treatment options. Hippocrates observed that strabismus runs in families over 2,400 years ago, an early recognition of what we now recognize as a portion of cases arising from genetic causes. We describe a large family affected by strabismus and identify a single region on chromosome 14 that may be responsible. The region contains FOXG1, in which mutations are known to cause a severe syndrome, with 84% of affected individuals also having strabismus. We identify a 4bp deletion in the region that appears to auto-regulate when FOXG1 is active. Future study of this genetic alteration may enhance our understanding of the mechanisms of strabismus.

scholarly journals Linkage analysis identifies an isolated strabismus locus at 14q12 overlapping with FOXG1 syndrome region

2020 ◽  
pp. jmedgenet-2020-107226
Author(s):  
Xin (Cynthia) Ye ◽  
Nicole M Roslin ◽  
Andrew D Paterson ◽  
Christopher J Lyons ◽  
Victor Pegado ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Linkage Analysis ◽  
Mendelian Inheritance ◽  
Single Linkage ◽  
Multiple Loci ◽  
Early Mouse ◽  
Foxg1 Syndrome ◽  
Generation Sequencing ◽  
Shed Light ◽  
Specific Deletion

Strabismus is a common condition, affecting 1%–4% of individuals. Isolated strabismus has been studied in families with Mendelian inheritance patterns. Despite the identification of multiple loci via linkage analyses, no specific genes have been identified from these studies. The current study is based on a seven-generation family with isolated strabismus inherited in an autosomal dominant manner. A total of 13 individuals from a common ancestor have been included for linkage analysis. Among these, nine are affected and four are unaffected. A single linkage signal has been identified at an 8.5 Mb region of chromosome 14q12 with a multipoint LOD (logarithm of the odds) score of 4.69. Disruption of this locus is known to cause FOXG1 syndrome (or congenital Rett syndrome; OMIM #613454 and *164874), in which 84% of affected individuals present with strabismus. With the incorporation of next-generation sequencing and in-depth bioinformatic analyses, a 4 bp non-coding deletion was prioritised as the top candidate for the observed strabismus phenotype. The deletion is predicted to disrupt regulation of FOXG1, which encodes a transcription factor of the Forkhead family. Suggestive of an autoregulation effect, the disrupted sequence matches the consensus FOXG1 and Forkhead family transcription factor binding site and has been observed in previous ChIP-seq studies to be bound by Foxg1 in early mouse brain development. Future study of this specific deletion may shed light on the regulation of FOXG1 expression and may enhance our understanding of the mechanisms contributing to strabismus and FOXG1 syndrome.

scholarly journals Nonvascular Complications of Injectable Fillers—Prevention and Management

2020 ◽  
Vol 53 (03) ◽  
pp. 335-343
Author(s):  
Kuldeep Singh ◽  
Shahin Nooreyezdan
Keyword(s):  
Early Recognition ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Vascular Complications ◽  
Physical Characteristics ◽  
Clear Understanding ◽  
Type Iv ◽  
Acute Infections ◽  
Tyndall Effect ◽  
Delayed Complications

AbstractInjectable filler treatments have increased in popularity because of enhanced safety profile and improved physical characteristics. ISAPS (International Society of Plastic Surgery) put out global data showing 3.7 million hyaluronic acid (HA) filler procedures in 2018, making it the second most often performed procedure in the world, after botulinum toxin. And these are only ‘those’ performed by qualified plastic surgeons. There was a concomitant increase in both the nonvascular and vascular complications, which coincided with the number and type of filler procedures performed. Filler complications were reviewed from existing literature, and an attempt was made to understand etiology, elucidate clinical features, and clarify optimum treatment strategies for each. Complications can be early or delayed in presentation, early consisting of injection site complications like bruising, edema, and hypersensitivity, Tyndall effect, and intravascular injection. Delayed complications included hypersensitivity type IV, acute infections like cellulitis, abscesses, and herpes and delayed ones like granulomas, biofilms, and atypical mycobacterial infections. These were analyzed and treatment options, protocols, and consensus guidelines were suggested. A clear understanding of facial anatomy, physical characteristics of all fillers used, early recognition, and treatment options of complications will ensure optimum outcomes.

scholarly journals The CMT2D Locus: Refined Genetic Position and Construction of a Bacterial Clone-Based Physical Map

1999 ◽  
Vol 9 (6) ◽  
pp. 568-574 ◽  
Author(s):  
Rachel E. Ellsworth ◽  
Victor Ionasescu ◽  
Charles Searby ◽  
Val C. Sheffield ◽  
Valerie V. Braden ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Yeast Artificial Chromosome ◽  
Sequence Data ◽  
Physical Map ◽  
Muscular Atrophy ◽  
Large Family ◽  
Artificial Chromosome ◽  
Single Chromosome ◽  
Mixed Features ◽  
Bacterial Clone

Charcot-Marie-Tooth (CMT) disease is a progressive neuropathy of the peripheral nervous system, typically characterized by muscle weakness of the distal limbs. CMT is noted for its genetic heterogeneity, with four distinct loci already identified for the axonal form of the disease (CMT2). In 1996, linkage analysis of a single large family revealed the presence of a CMT2 locus on chromosome 7p14 (designatedCMT2D). Additional families have been linked subsequently to the same genomic region, including one with distal spinal muscular atrophy (dSMA) and one with mixed features of dSMA and CMT2; symptoms in both of these latter families closely resemble those seen in the original CMT2D family. There is thus a distinct possibility that CMT2 and dSMA encountered in these families reflect allelic heterogeneity at a single chromosome 7 locus. In the study reported here, we have performed more detailed linkage analysis of the original CMT2D family based on new knowledge of the physical locations of various genetic markers. The region containing the CMT2D gene, as defined by the original family, overlaps with those defined by at least two other families with CMT2 and/or dSMA symptoms. Both yeast artificial chromosome (YAC) and bacterial clone-based [bacterial artificial chromosome (BAC) and P1-derived artificial chromosome (PAC)] contig maps spanning ∼3.4 Mb have been assembled across the combinedCMT2D critical region, with the latter providing suitable clones for systematic sequencing of the interval. Preliminary analyses have already revealed at least 28 candidate genes and expressed-sequence tags (ESTs). The mapping information reported here in conjunction with the evolving sequence data should expedite the identification of the CMT2D/dSMA gene or genes.

Junctional Ectopic Tachycardia: Recognition and Modern Management Strategies

2020 ◽  
Vol 40 (1) ◽  
pp. 46-55
Author(s):  
Kirsti G. Catton ◽  
Jennifer K. Peterson
Keyword(s):  
Risk Factors ◽  
Congenital Heart ◽  
Heart Surgery ◽  
Early Recognition ◽  
Treatment Options ◽  
Age Groups ◽  
Atrioventricular Node ◽  
Congenital Heart Surgery ◽  
Junctional Ectopic Tachycardia ◽  
Perioperative Morbidity

Junctional ectopic tachycardia is a common dysrhythmia after congenital heart surgery that is associated with increased perioperative morbidity and mortality. Risk factors for development of junctional ectopic tachycardia include young age (neonatal and infant age groups); hypomagnesemia; higher-complexity surgical procedure, especially near the atrioventricular node or His bundle; and use of exogenous catecholamines such as dopamine and epinephrine. Critical care nurses play a vital role in early recognition of dysrhythmias after congenital heart surgery, assessment of hemodynamics affecting cardiac output, and monitoring the effects of antiarrhythmic therapy. This article reviews the underlying mechanisms of junctional ectopic tachycardia, incidence and risk factors, and treatment options. Currently, amiodarone is the pharmacological treatment of choice, with dexmedetomidine increasingly used because of its anti-arrhythmic properties and sedative effect.

scholarly journals Hyperthyroidism with Biventricular Heart Failure and Cirrhotic Transformation of the Liver

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
Rashmi Dhital ◽  
Shivani Vyas ◽  
Priyadarshani Sharma ◽  
Theresa Lynn ◽  
Oreoluwa Oladiran ◽  
...  
Keyword(s):  
Early Recognition ◽  
Treatment Options ◽  
Young Female ◽  
Good Prognosis ◽  
Thyroid Peroxidase ◽  
Free T4 ◽  
Gradual Improvement ◽  
Fluid Analysis ◽  
Cardiac Cirrhosis ◽  
Congestive Liver

Cardiovascular symptoms remain the most common presenting features and leading causes of death in hyperthyroidism. We report a young female with reported thyroid disease and medication noncompliance presenting with atrial fibrillation, severe atrioventricular regurgitation, severely dilated right heart with reduced function, and moderate pulmonary hypertension (PH), which was further complicated by congestive liver injury with ascites and pancytopenia. Thyroid work-up revealed suppressed TSH, elevated free T4 and T3 along with elevated anti-thyroglobulin antibodies, thyroid peroxidase antibodies, and thyroid-stimulating immunoglobulin, suggesting Graves’ thyrotoxicosis. Ultrasound of the abdomen was suggestive of liver cirrhosis and ascites, which was thought to be cardiac cirrhosis, after multiple negative work-ups for alternate causes of cirrhosis. Ascitic fluid analysis revealed portal hypertension as the cause. The patient was restarted on antithyroid medication with gradual improvement of thyroid function and in clinical and echocardiogram findings. In contrast to primary PH that carries a poor prognosis and has limited treatment options, PH due to Graves’ disease carries a good prognosis with prior reports of resolution after appropriate treatment, emphasizing the importance of early recognition. Also, unlike cirrhosis caused by alcohol or viral hepatitis, the effect of cardiac cirrhosis on overall prognosis has not been clearly established.

scholarly journals Ovarian Cancer Metastasis to the Breast: A Case Report and Review of the Literature

2020 ◽  
Vol 13 (3) ◽  
pp. 1317-1324 ◽  
Author(s):  
Giuseppe Caruso ◽  
Lucia Musacchio ◽  
Giusi Santangelo ◽  
Innocenza Palaia ◽  
Federica Tomao ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Lymph Nodes ◽  
Cancer Metastasis ◽  
Early Recognition ◽  
Treatment Options ◽  
Rare Event ◽  
Axillary Lymph Nodes ◽  
Axillary Lymph ◽  
Breast Cancers ◽  
Platinum Based Chemotherapy

Although ovarian cancer often presents as a widespread disease, metastases to the breast and/or axillary lymph nodes are a very rare event, accounting for only 0.03–0.6% of all breast cancers. Its early recognition and accurate distinction from primary breast cancer are of crucial importance to choose an adequate systemic therapy over unnecessary surgeries. We presented the case of a 53-year-old woman who was diagnosed with breast metastases 2 years after the diagnosis of advanced primary serous ovarian cancer. The patient underwent primary cytoreductive surgery and platinum-based chemotherapy in combination with bevacizumab, followed by bevacizumab maintenance for 18 months. After 2 years of negative follow-ups, the disease unexpectedly spread to the left breast and axillary lymph nodes. No axillary lymph node dissection or breast surgery was performed. The patient received axillary radiotherapy and multiple chemotherapy lines: gemcitabine/cisplatin, liposomal doxorubicin, topotecan, olaparib/cediranib, paclitaxel, and cisplatin. Unfortunately, none of these treatments improved her prognosis and she died 3 years after the disease recurrence. Ovarian cancer metastasis to the breast reveals a disseminated disease with a poor prognosis. Currently, no valid treatment options are available as the disease shows multidrug chemoresistance. In the era of precision medicine, the characterization of genetic and molecular markers may play a role in offering new promising targeted therapies.

Splenic Rupture: An Unusual Complication of Colonoscopy

2007 ◽  
Vol 73 (4) ◽  
pp. 393-396 ◽  
Author(s):  
Stefan Holubar ◽  
Amit Dwivedi ◽  
J. Eisendorfer ◽  
R. Levine ◽  
R. Strauss
Keyword(s):  
Hemorrhagic Shock ◽  
Splenic Injury ◽  
Early Recognition ◽  
Rare Complication ◽  
Treatment Options ◽  
Unusual Complication ◽  
Angiographic Embolization ◽  
Diagnostic Colonoscopy ◽  
Life Threatening ◽  
Therapeutic Colonoscopy

Splenic injury is a known, albeit rare, complication of diagnostic and therapeutic colonoscopy. Within a 6-month period, we observed two colonoscopic splenic injuries. We report these two cases of splenic injury who presented differently after colonoscopy: one presented as frank hemorrhagic shock, and the other as a subacute splenic hemorrhage with symptomatic anemia. The first patient presented with hemorrhagic shock several hours after a diagnostic colonoscopy and required an emergency splenectomy. The second patient presented with symptomatic anemia several days after a diagnostic colonoscopy and was treated by angiographic embolization. Clinical presentation and discussion of the mechanisms of injury, available treatment options, and strategies for preventing colonoscopic splenic injuries are presented. Awareness of this complication is paramount in early recognition and management of this potentially life-threatening injury.

scholarly journals Approach to the Patient: Management of the Post–Bariatric Surgery Patient With Weight Regain

2020 ◽  
Vol 106 (1) ◽  
pp. 251-263
Author(s):  
Nawfal W Istfan ◽  
Marine Lipartia ◽  
Wendy A Anderson ◽  
Donald T Hess ◽  
Caroline M Apovian
Keyword(s):  
Bariatric Surgery ◽  
Weight Regain ◽  
Early Recognition ◽  
Treatment Options ◽  
Clinical Problem ◽  
Dietary Counseling ◽  
Surgery Patient ◽  
Rate Of Increase ◽  
Bariatric Surgery Patient

Abstract Context Weight regain (WR) after bariatric surgery is emerging as a common clinical problem due to the increase in the number of procedures performed. Early interventions are necessary to curtail the potential recurrence of comorbid conditions. However, it is often difficult to recognize WR early enough to introduce mitigating measures because there are no current guidelines for timely diagnosis and assessment of the severity of this condition. Objective We present a practical approach for the early recognition of WR, based on 11-year follow-up data from our multiethnic bariatric surgery patient population. Methods We classify WR according to the rate of increase in weight relative to nadir weight, normalized per 30-day interval. We also review pertinent literature about the etiologic factors contributing to WR after bariatric surgery. Results According to our algorithm, mild, moderate, and rapid WR are defined as weight increases of 0.2% to <0.5%, 0.5% to 1.0%, and more than 1.0% of nadir weight per 30 days, respectively. Treatment options, including dietary counseling, use of antiobesity medication, and consideration of surgical revision, are described. A case is presented to illustrate the utility of timely identification of WR and the importance of collaboration between bariatric surgeons, obesity medicine specialists, and dietitians. Conclusion Our approach emphasizes the importance of regular long-term follow-up for all bariatric surgery patients.

scholarly journals 4296 Targeting ERG Through Toll-Like Receptor 4 in Prostate Cancer

2020 ◽  
Vol 4 (s1) ◽  
pp. 17-17
Author(s):  
Ben Greulich ◽  
Josh Plotnik ◽  
Peter Hollenhorst
Keyword(s):  
Prostate Cancer ◽  
Transcription Factor ◽  
Protein Interactions ◽  
Treatment Options ◽  
Clonogenic Survival ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Functional Assays ◽  
Prostate Cells ◽  
Tlr4 Activation

OBJECTIVES/GOALS: The objective of this research was to learn how the oncogenic transcription factor, ERG, is regulated in prostate cancer. If we could learn how ERG is regulated and which genes are important for its oncogenic phenotype in prostate cells, we could design new therapeutic strategies against ERG, which has proven to be difficult to target. METHODS/STUDY POPULATION: We conducted an shRNA screen in prostate cells to determine candidate genes and pathways that are important for ERG function. To validate the findings of the screen, we performed a variety of cell-based functional assays, including trans-well migration, wound healing, and clonogenic survival assays. To further investigate the mechanism between ERG and the genes revealed by the screen, we performed biochemical and molecular biology experiments such as Western blotting and qRT-PCR for protein and mRNA expression, co-immunoprecipitation assays to determine protein-protein interactions, and chromatin immunoprecipitation (ChIP-qPCR) to determine transcription factor binding to DNA sites. RESULTS/ANTICIPATED RESULTS: The screen revealed that genes involved in the toll-like receptor 4 (TLR4) pathway are important for ERG-mediated migration. We tested the effect of a TLR4 inhibitor on ERG function and observed decreased migration and clonogenic survival exclusively in ERG-positive cells. Expression of pMEK and pERG was reduced when TLR4 was inhibited, which suggests a mechanism in which TLR4 upregulates pMEK, leading to the phosphorylation and activation of ERG. This is supported by functional assays in which cells expressing a phosphomimetic ERG are resistant to the TLR4 inhibitor. We demonstrated that ERG drives the transcription of TLR4 and its endogenous ligands HSPA8 and BGN. Therefore, ERG can sensitize the cell to TLR4 activation by increasing the number of receptors as well as providing the ligands needed for stimulation. DISCUSSION/SIGNIFICANCE OF IMPACT: This research provides a new therapeutic pathway for treating ERG-positive patients through TLR4 inhibition. This can be beneficial because many patients become resistant to the standard therapy, leaving very few treatment options. TLR4-based therapies could provide an alternative for patients who have developed resistance.

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