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1.
J Endocrinol Invest ; 47(8): 1911-1921, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38310625

ABSTRACT

PURPOSE: Asymptomatic patients with clinically non-functional pituitary neuroendocrine tumors (CNF-PitNETs) are usually followed up. However, the natural course of CNF-PitNETs according to sex and age remains unclear. Therefore, this study assessed growth patterns of CNF-PitNETs according to sex and age. METHODS: In this longitudinal study, we enrolled 431 consecutive patients with CNF-PitNETs who were treated at Seoul National University Hospital from 1997 to 2021. The patients underwent hormone function testing and visual field testing, and were subsequently followed up with imaging over a median duration of 66 months. RESULTS: The median age of the patients was 53.0 years, and 37.1% (n = 160) were men. Men were older and harbored more macroadenomas than women. The annual tumor volume change was higher in men than in women (0.21 vs. 0.04 cm3/year, P < 0.001). The estimated cutoff value of age for significant tumor growth was 51 years. In men, the annual tumor volume change was similar across all age groups. In women, those aged ≤ 50 years showed significantly lower annual tumor volume change than those aged > 50 years (0.01, 0.11, and 0.17 cm3/year, P = 0.001). When comparing sexes within the same age group, the annual tumor volume changes was significantly lower for women than for men, only in patients aged ≤ 50 years (0.01 vs. 0.15 cm3/year, P < 0.001). CONCLUSIONS: Among patients with CNF-PitNET, tumor growth was slower in women aged ≤ 50 years than in men and women aged > 50. These findings may guide the customization of surveillance strategies for CNF-PitNETs according to sex and age.


Subject(s)
Neuroendocrine Tumors , Pituitary Neoplasms , Humans , Male , Female , Pituitary Neoplasms/pathology , Pituitary Neoplasms/epidemiology , Pituitary Neoplasms/diagnosis , Middle Aged , Longitudinal Studies , Neuroendocrine Tumors/pathology , Neuroendocrine Tumors/epidemiology , Neuroendocrine Tumors/diagnosis , Sex Factors , Age Factors , Aged , Adult , Tumor Burden , Follow-Up Studies , Prognosis
2.
Eur J Neurol ; 27(2): 343-351, 2020 02.
Article in English | MEDLINE | ID: mdl-31535427

ABSTRACT

BACKGROUND AND PURPOSE: The rate at which the chance of a good outcome of endovascular stroke therapy (EVT) decays with time when eligible patients are selected by baseline diffusion-weighted magnetic resonance imaging (DWI-MRI) and whether ischaemic core size affects this rate remain to be investigated. METHODS: This study analyses a prospective multicentre registry of stroke patients treated with EVT based on pretreatment DWI-MRI that was categorized into three groups: small [Diffusion-Weighted Imaging Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS)] (8-10), moderate (5-7) and large (<5) cores. The main outcome was a good outcome at 90 days (modified Rankin Scale 0-2). The interaction between onset-to-groin puncture time (OTP) and DWI-ASPECTS categories regarding functional outcomes was investigated. RESULTS: Ultimately, 985 patients (age 69 ± 11 years; male 55%) were analysed. Potential interaction effects between the DWI-ASPECTS categories and OTP on a good outcome at 90 days were observed (Pinteraction  = 0.06). Every 60-min delay in OTP was associated with a 16% reduced likelihood of a good outcome at 90 days amongst patients with large cores, although no associations were observed amongst patients with small to moderate cores. Interestingly, the adjusted rates of a good outcome at 90 days steeply declined between 65 and 213 min of OTP and then remained smooth throughout 24 h of OTP (Pnonlinearity  = 0.15). CONCLUSIONS: Our study showed that the probability of a good outcome after EVT nonlinearly decreased, with a steeper decline at earlier OTP than at later OTP. Discrepant effects of OTP on functional outcomes by baseline DWI-ASPECTS categories were observed. Thus, different strategies for EVT based on time and ischaemic core size are warranted.


Subject(s)
Stroke , Aged , Aged, 80 and over , Alberta , Brain Ischemia/diagnostic imaging , Brain Ischemia/therapy , Diffusion Magnetic Resonance Imaging , Female , Humans , Male , Middle Aged , Prospective Studies , Stroke/diagnostic imaging , Stroke/therapy , Time-to-Treatment , Treatment Outcome
3.
Indoor Air ; 27(2): 320-328, 2017 03.
Article in English | MEDLINE | ID: mdl-27007057

ABSTRACT

Whether indoor painting aggravates preexisting allergic diseases remains unclear. We aimed to evaluate the impact of new classroom painting on aggravation of asthma, allergic rhinitis (AR), and atopic dermatitis (AD) in children. Studied school was previously painted with conventional water-based paint 20 years ago and had natural ventilation system. We identified a total of 172 children aged 10-12 years with allergic diseases in 17 classrooms, which were allocated to newly painted rooms with low-volatile organic compounds (VOC), water-based paint, or existing rooms. After painting, there was no intervention or internal airflow to influence indoor air environment in both classrooms. We prospectively assessed the symptom severity and serious events of allergic diseases between both classrooms at baseline and after one and eight weeks after painting. At one and eight weeks, there were no significant changes in the Childhood Asthma Control Test scores, the fractional nitric oxide levels, lung function in asthmatic children in either classroom. There were also no significant changes in the severity score of AR or AD, or serious events in all allergic diseases. These findings suggest classroom painting with this new paint at the levels encountered in this study might not be a major aggravating factor for school-aged children with allergic diseases.


Subject(s)
Air Pollution, Indoor/adverse effects , Hypersensitivity/etiology , Paint/toxicity , Symptom Flare Up , Volatile Organic Compounds/toxicity , Air Pollution, Indoor/analysis , Asthma/chemically induced , Child , Dermatitis, Atopic/chemically induced , Female , Humans , Male , Paint/analysis , Prospective Studies , Rhinitis, Allergic/chemically induced , Volatile Organic Compounds/analysis
4.
Ann Oncol ; 27(10): 1953-8, 2016 10.
Article in English | MEDLINE | ID: mdl-27502709

ABSTRACT

BACKGROUND: The dynamics of PD-L1 expression may limit its use as a tissue-based predictive biomarker. We sought to expand our understanding of the dynamics of PD-L1 expression and tumor-infiltrating lymphocytes (TILs) in patients with lung cancer-related brain metastases. EXPERIMENTAL DESIGN: Paired primary lung cancers and brain metastases were identified and assessed for PD-L1 and CD3 expression by immunohistochemistry. Lesions with 5% or greater PD-L1 expression were considered positive. Agreement statistics and the χ(2) or Fisher's exact test were used for analysis. RESULTS: We analyzed 146 paired lesions from 73 cases. There was disagreement of tumor cell PD-L1 expression in 10 cases (14%, κ = 0.71), and disagreement of TIL PD-L1 expression in 19 cases (26%, κ = 0.38). Most paired lesions with discordant tumor cell expression of PD-L1 were obtained 6 or more months apart. When specimens were categorized using a proposed tumor microenvironment categorization scheme based on PD-L1 expression and TILs, there were significant changes in the classifications because many of the brain metastases lacked either PD-L1 expression, tumor lymphocyte infiltration or both even when they were present in the primary lung cancer specimens (P = 0.009). CONCLUSIONS: We identified that there are significant differences between the tumor microenvironment of paired primary lung cancers and brain metastases. When physicians decide to treat patients with lung cancer with a PD-1 or PD-L1 inhibitor, they must do so in the context of the spatial and temporal heterogeneity of the tumor microenvironment.


Subject(s)
B7-H1 Antigen/genetics , Biomarkers, Tumor/genetics , Brain Neoplasms/genetics , Lung Neoplasms/genetics , Programmed Cell Death 1 Receptor/genetics , Adult , Aged , Brain Neoplasms/pathology , Brain Neoplasms/secondary , CD3 Complex/genetics , Clinical Decision-Making , Female , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/pathology , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphocytes, Tumor-Infiltrating/pathology , Male , Middle Aged , Tumor Microenvironment/genetics
5.
Clin Genet ; 89(4): 484-488, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26060040

ABSTRACT

Muscular dystrophy (MD) is a genetically and clinically heterogeneous group of disorders. Here, we performed targeted sequencing of 18 limb-girdle MD (LGMD)-related genes in 35 patients who were highly suspected of having MD. We identified one or more pathogenic variants in 23 of 35 patients (65.7%), and a genetic diagnosis was performed in 20 patients (57.1%). LGMD2B was the most common LGMD type, followed by LGMD1B, LGMD2A, and LGMD2G. Among the three major LGMD types in this group, LGMD1B was correlated with the lowest creatine kinase (CK) levels and the earliest onset, whereas LGMD2B was correlated with the highest CK levels and the latest onset. Thus, next-generation sequencing-based gene panels can be a helpful tool for the diagnosis of MDs, particularly in young children and those displaying atypical symptoms.

6.
Clin Genet ; 88(1): 80-4, 2015 Jul.
Article in English | MEDLINE | ID: mdl-24917129

ABSTRACT

Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is an autosomal recessive disorder caused by mutations in the VPS33B and VIPAS39. Here, we report novel mutations identified in four patients with ARC syndrome. We analyzed the entire coding regions of the VPS33B and VIPAS39 genes by direct sequencing. To detect novel splice site mutations, mRNA transcripts were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and sequencing. All four patients had compound heterozygous variants in the VPS33B gene. One patient had a previously reported splice site variant with unknown significance, c.239+5G>A, and a novel nonsense mutation, c.621G>A. The other three patients had the c.403+2T>A mutation, and each of them carried one of the splice site variants, c.239+5G>A or c.499-11G>A. c.239+5G>A and c.499-11G>A created novel splice sites which resulted in abnormal transcripts. No significant VIPAS39 mutation was detected in all patients. In patients suspected with ARC syndrome, mutation analysis of the VPS33B gene should be employed as a primary diagnostic test before performing invasive testing procedures such as organ biopsies. Performing mRNA analysis can be useful in predicting the pathogenic phenotype when the mutation seems to affect a normal splicing mechanism.


Subject(s)
Arthrogryposis/genetics , Cholestasis/genetics , Mutation , RNA Splice Sites/genetics , Renal Insufficiency/genetics , Vesicular Transport Proteins/genetics , Arthrogryposis/diagnosis , Cholestasis/diagnosis , DNA Mutational Analysis , Female , Heterozygote , Humans , Infant , Infant, Newborn , Male , Phenotype , Renal Insufficiency/diagnosis , Republic of Korea
7.
Transpl Infect Dis ; 17(6): 890-6, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26538076

ABSTRACT

We report the case of a renal transplant recipient with pulmonary and splenic mucormycosis whose demise was accelerated by a myocardial abscess. Once pulmonary and splenic mucormycosis was diagnosed, liposomal amphotericin B was started and immunosuppressant treatments were discontinued. The pulmonary cavities regressed during treatment, but new myocardial and peri-allograft abscesses developed. The myocardial abscess diffusely infiltrated the left ventricular wall and was associated with akinesia, which led to sudden cardiac arrest. This case demonstrates a rare manifestation of mucormycosis and highlights the fatality and invasiveness of this infection.


Subject(s)
Heart Diseases/microbiology , Kidney Transplantation/adverse effects , Mucormycosis/pathology , Adult , Amphotericin B/administration & dosage , Amphotericin B/therapeutic use , Antifungal Agents/administration & dosage , Antifungal Agents/therapeutic use , Fatal Outcome , Female , Heart Diseases/pathology , Humans , Immunocompromised Host , Mucormycosis/drug therapy , Myocardium
8.
J Wound Care ; 24(1): 23-33, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25543820

ABSTRACT

OBJECTIVE: Wound healing is enhanced in the presence of an external electrical field. The purpose of this study was first to investigate whether microelectric potentials (EPs) can be generated when the innovative design of a silver (Ag)- and zinc (Zn)-printed wound care device was exposed to saline solution which is commonly used to clean wound sites; and second to measure the generated EPs while the device was exposed to bacterial culture suspensions to mimic infection. METHOD: An Ag/Zn-printed test specimen as a wound care device was designed to accommodate Ag and Zn half-cell potentials by alternatively printing them on a woven polyester material in a well-characterised dot matrix pattern. A well-calibrated high impedance EPs measuring system was used to measure any EPs generated. Ultrasensitive inductively coupled plasma analysis was performed to determine whether the device induced any increase in trace metals in rabbit blood following implantation for 2-4 weeks. RESULTS: EPs were consistently generated under various conductive solutions at the levels of 120.4±26.3mV (average±standard deviation) on Ag dots and -506.5±76.3mV over Zn dots to form microcircuits with EPs of 626.7±86.3mV between the Ag and Zn metallic elements of the dressing. Interestingly, the patterns of EPs generated with stable polarities were consistent when the device was exposed to bacterial suspensions for mimicking wound infection. Implantation of the device did not cause any increase in Ag or Zn in rabbit blood. CONCLUSION: The Ag/Zn-printed wound device generated sustained EPs successfully in the presence of various conductive fluids without changing EPs including polarities. Consistently generated EPs at each battery couple with Ag/Zn-based wound device would restore disrupted physiologic bioelectric signals on wound sites, which could lead to improved wound healing. DECLARATION OF INTEREST: The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US Department of the Army, the US Department of Defense, the Department of Veterans Affairs, or the Henry M. Jackson Foundation for Advancement of Military Medicine. The research was supported by the US Air Force medical support agency (AFMSA), office of the Air Force Surgeon General, USA.


Subject(s)
Bacterial Physiological Phenomena , Electric Stimulation Therapy/instrumentation , Wound Healing/physiology , Wound Infection/microbiology , Wound Infection/therapy , Animals , Electric Stimulation Therapy/methods , Rabbits , Silver , Zinc
9.
Clin Genet ; 86(5): 482-6, 2014 Nov.
Article in English | MEDLINE | ID: mdl-24134185

ABSTRACT

The aim of our study was to assess the frequency of germline mutations and develop the genetic testing strategy in patients with apparently sporadic pheochromocytoma/paraganglioma (PPGL) in Korea. We included 53 patients diagnosed with non-syndromic PPGL without a family history of PPGLs in three referral centers from 2004 to 2011. Succinate dehydrogenase complex B (SDHB), SDHD, Von Hippel-Lindau (VHL), and rearranged during transfection (RET) genes were examined by direct sequencing and multiple ligation-dependent probe amplification. The study patients were composed of 26 men and 27 women, and mean age was 50.1 ± 13.5 years. The frequency of germline mutations was 13.2% (7/53): RET (n = 2), VHL (n = 1), SDHB (n = 2), and SDHD (n = 2). Six of seven mutation carriers were diagnosed before the age of 50. One of two patients harboring an SDHB mutation had malignant PPGLs. One patient with multifocal head and neck paraganglioma (PGL) and pheochromocytoma (PHEO) carried a SDHD mutation. The carriers of germline mutations in patients with apparently sporadic PPGL were 13.2% in our study. We recommend genetic testing in patients below 50 years and SDHD genetic testing in patients with multifocal PPGLs. In malignant PPGLs, SDHB genetic testing may be performed.


Subject(s)
Adrenal Gland Neoplasms/genetics , Adrenal Gland Neoplasms/pathology , Genetic Association Studies , Germ-Line Mutation/genetics , Paraganglioma/genetics , Pheochromocytoma/genetics , Pheochromocytoma/pathology , Adolescent , Adult , Aged , Female , Genetic Predisposition to Disease , Heterozygote , Humans , Male , Middle Aged , Paraganglioma/pathology , Proto-Oncogene Proteins c-ret/genetics , Republic of Korea , Succinate Dehydrogenase/genetics , Von Hippel-Lindau Tumor Suppressor Protein/genetics
10.
J Wound Care ; 23(6): 314, 316-9, 321-2 passim, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24920202

ABSTRACT

The link between inflammation and tumourisation has long been considered as a key event in clinical cancer development. Inflammation and inflammatory diseases can be caused by many factors including infectious agents, altered genetics and various degrees of injuries from simple cuts to traumatic wounds, such as those suffered in battlefield. Improved management of all wound types is critical in protecting affected individuals against the development of tumourisation cues, which may potentially lead to cancer development. There have been numerous studies on the mechanism of inflammation-induced tumourisation. Thus, in this mini review, we summarised evidence demonstrating the potential link between infectious agents and their moonlight proteins, wounding, trauma, overactive repair mechanisms, and carcinogenesis.


Subject(s)
Carcinogenesis , Infections/complications , Wound Healing , Wounds and Injuries/complications , Humans , Infections/physiopathology , Inflammasomes/physiology , Wounds and Injuries/physiopathology
11.
Perfusion ; 29(1): 89-93, 2014 Jan.
Article in English | MEDLINE | ID: mdl-23842614

ABSTRACT

The Fontan procedure represents the final stage of the transition to single ventricle physiology. Conversion of very complex congenital heart anatomy, such as hypoplastic left heart syndrome, double-outlet right ventricle or double-inlet left ventricle, to a single ventricle has grown in popularity as morbidity and mortality have improved. As these patients grow, survivors are at risk for impaired ventricular dysfunction, plastic bronchitis, protein-losing enteropathy and late failure. Late failing Fontan patients represent a particularly vexing scenario for clinicians, as the only durable treatment option is cardiac transplantation. However, in the short-term, some of these patients require support beyond medical management, with mechanical circulatory support via extracorporeal life support or a ventricular assist device. We report the successful bridge of an adolescent female post-Fontan conversion with late severe cardiac failure. The patient was initially resuscitated with extracorporeal life support, transitioned to a single Berlin Heart EXCOR® ventricular assist device and, subsequently, underwent successful cardiac transplantation.


Subject(s)
Cardiopulmonary Resuscitation/methods , Heart Failure/therapy , Heart Transplantation , Adolescent , Cardiopulmonary Resuscitation/standards , Extracorporeal Membrane Oxygenation/standards , Female , Heart-Assist Devices/standards , Humans , Treatment Outcome
12.
Perfusion ; 29(1): 82-8, 2014 Jan.
Article in English | MEDLINE | ID: mdl-23868320

ABSTRACT

Mechanical circulatory support emerged for the pediatric population in the late 1980s as a bridge to cardiac transplantation. The Total Artificial Heart (TAH-t) (SynCardia Systems Inc., Tuscon, AZ) has been approved for compassionate use by the Food and Drug Administration for patients with end-stage biventricular heart failure as a bridge to heart transplantation since 1985 and has had FDA approval since 2004. However, of the 1,061 patients placed on the TAH-t, only 21 (2%) were under the age 18. SynCardia Systems, Inc. recommends a minimum patient body surface area (BSA) of 1.7 m(2), thus, limiting pediatric application of this device. This unique case report shares this pediatric institution's first experience with the TAH-t. A 14-year-old male was admitted with dilated cardiomyopathy and severe biventricular heart failure. The patient rapidly decompensated, requiring extracorporeal life support. An echocardiogram revealed severe biventricular dysfunction and diffuse clot formation in the left ventricle and outflow tract. The decision was made to transition to biventricular assist device. The biventricular failure and clot formation helped guide the team to the TAH-t, in spite of a BSA (1.5 m(2)) below the recommendation of 1.7 m(2). A computed tomography (CT) scan of the thorax, in conjunction with a novel three-dimensional (3D) modeling system and team, assisted in determining appropriate fit. Chest CT and 3D modeling following implantation were utilized to determine all major vascular structures were unobstructed and the bronchi were open. The virtual 3D model confirmed appropriate device fit with no evidence of compression to the left pulmonary veins. The postoperative course was complicated by a left lung opacification. The left lung anomalies proved to be atelectasis and improved with aggressive recruitment maneuvers. The patient was supported for 11 days prior to transplantation. Chest CT and 3D modeling were crucial in assessing whether the device would fit, as well as postoperative complications in this smaller pediatric patient.


Subject(s)
Cardiomyopathy, Dilated/surgery , Heart Failure/surgery , Heart Transplantation/methods , Heart, Artificial , Adolescent , Cardiomyopathy, Dilated/therapy , Heart Failure/therapy , Humans , Male
13.
Asian-Australas J Anim Sci ; 27(7): 960-4, 2014 Jul.
Article in English | MEDLINE | ID: mdl-25050037

ABSTRACT

An experiment was conducted to determine the effects of diets containing coarse-texture rice straw and small particle size alfalfa pellets as a part of total mixed ration (TMR) on milk productivity and chewing activity in lactating dairy cows. Sixteen multiparous Holstein dairy cows (670±21 kg body weight) in mid-lactation (194.1±13.6 days in milk) were randomly assigned to TMR containing 50% of timothy hay (TH) or TMR containing 20% of rice straw and 30% of alfalfa pellet mixture (RSAP). Geometric mean lengths of TH and RSAP were found to be 5.8 and 3.6, respectively. Dry matter intake, milk yield and milk composition were measured. Moreover, eating and ruminating times were recorded continuously using infrared digital camcorders. Milk yield and milk composition were not detected to have significant differences between TH and RSAP. Dry matter intake (DMI) did not significantly differ for cows fed with TH or RSAP. Although particle size of TH was larger than RSAP, eating, ruminating and total chewing time (min/d or min/kg of DMI) on TH and RSAP were similar. Taken together, our results suggest that using a proper amount of coarse-texture rice straw with high value nutritive alfalfa pellets may stimulate chewing activity in dairy cows without decreasing milk yield and composition even though the quantity of rice straw was 40% of TH.

14.
Br J Surg ; 100(12): 1566-78, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24264778

ABSTRACT

BACKGROUND: Robot-assisted gastrectomy (RAG) has been developed in the hope of improving surgical quality and overcoming the limitations of conventional laparoscopically assisted gastrectomy (LAG) and open gastrectomy (OG) for gastric cancer. The aim of this study was to determine the extent of evidence in support of these ideals. METHODS: A systematic review of the three operation types (RAG, LAG and OG) was carried out to evaluate short-term outcomes including duration of operation, retrieved lymph nodes, estimated blood loss, resection margin status, technical postoperative complications and hospital stay. RESULTS: Nine non-randomized observational clinical studies involving 7200 patients satisfied the eligibility criteria. RAG was associated with longer operating times than LAG and OG (weighted mean difference 61.99 and 65.73 min respectively; P ≤ 0.001). The number of retrieved lymph nodes and the resection margin length in RAG were comparable with those of LAG and OG. Estimated blood loss as significantly less in RAG than in OG (P = 0.002), but not LAG. Mean hospital stay for RAG was similar to that for LAG (P = 0.14). In contrast, hospital stay was significantly shorter, by a mean of 2.18 days, for RAG compared with OG (P < 0.001). Postoperative complications were similar for all three operative approaches. CONCLUSION: Short-term oncological outcomes of RAG were comparable with those of the other approaches. LAG was a shorter procedure and less expensive than RAG. Future studies involving RAG should focus on minimizing duration of operation and reducing cost.


Subject(s)
Gastrectomy/methods , Laparoscopy/methods , Robotics/methods , Stomach Neoplasms/surgery , Aged , Blood Loss, Surgical , Female , Humans , Laparoscopy/statistics & numerical data , Length of Stay/statistics & numerical data , Lymph Node Excision/methods , Lymph Node Excision/statistics & numerical data , Male , Middle Aged , Operative Time , Postoperative Complications/etiology , Publication Bias , Robotics/statistics & numerical data , Treatment Outcome
15.
J Nanosci Nanotechnol ; 13(10): 7194-7, 2013 Oct.
Article in English | MEDLINE | ID: mdl-24245227

ABSTRACT

White organic light emitting diodes (WOLEDs) were fabricated utilizing blue emitting organic light emitting diodes and color conversion layers containing CdSe/ZnS quantum dots (QDs). The best color purity of the WOLEDs was achieved by using the red and green QDs ratio of 1:9.5. Commission Internationale de l'Eclairage coordinates of the WOLEDs slightly shifted from (0.35, 0.33) to (0.35, 0.32) with increasing applied voltage from 9 to 14 V, indicative of a deep stabilized white color. Color tunable mechanisms of WOLEDs with a color conversion layer containing CdSe/ZnS QDs are described on the basis of the experimental results.

16.
Nat Genet ; 24(1): 84-7, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10615134

ABSTRACT

Recombination between repeated sequences at various loci of the human genome are known to give rise to DNA rearrangements associated with many genetic disorders. Perhaps the most extensively characterized genomic region prone to rearrangement is 17p12, which is associated with the peripheral neuropathies, hereditary neuropathy with liability to pressure palsies (HNPP) and Charcot-Marie-Tooth disease type 1A (CMT1A;ref. 2). Homologous recombination between 24-kb flanking repeats, termed CMT1A-REPs, results in a 1.5-Mb deletion that is associated with HNPP, and the reciprocal duplication product is associated with CMT1A (ref. 2). Smith-Magenis syndrome (SMS) is a multiple congenital anomalies, mental retardation syndrome associated with a chromosome 17 microdeletion, del(17)(p11.2p11.2) (ref. 3,4). Most patients (>90%) carry deletions of the same genetic markers and define a common deletion. We report seven unrelated patients with de novo duplications of the same region deleted in SMS. A unique junction fragment, of the same apparent size, was identified in each patient by pulsed field gel electrophoresis (PFGE). Further molecular analyses suggest that the de novo17p11.2 duplication is preferentially paternal in origin, arises from unequal crossing over due to homologous recombination between flanking repeat gene clusters and probably represents the reciprocal recombination product of the SMS deletion. The clinical phenotype resulting from duplication [dup(17)(p11.2p11.2)] is milder than that associated with deficiency of this genomic region. This mechanism of reciprocal deletion and duplication via homologous recombination may not only pertain to the 17p11.2 region, but may also be common to other regions of the genome where interstitial microdeletion syndromes have been defined.


Subject(s)
Abnormalities, Multiple/genetics , Chromosome Aberrations , Chromosomes, Human, Pair 17 , Intellectual Disability/genetics , Recombination, Genetic , Female , Genotype , Humans , In Situ Hybridization, Fluorescence , Male , Pedigree , Syndrome
17.
HNO ; 66(2): 120-121, 2018 02.
Article in English | MEDLINE | ID: mdl-29230509
18.
Physiol Genomics ; 44(23): 1154-63, 2012 Dec 01.
Article in English | MEDLINE | ID: mdl-23073384

ABSTRACT

The discovery of causal mechanisms associated with nonsyndromic craniosynostosis has proven to be a difficult task due to the complex nature of the disease. In this study, differential transcriptome correlation analysis was used to identify two molecularly distinct subtypes of nonsyndromic craniosynostosis, termed subtype A and subtype B. In addition to unique correlation structure, subtype A was also associated with high IGF pathway expression, whereas subtype B was associated with high integrin expression. To identify a pathologic link between altered gene correlation/expression and the disease state, phosphorylation assays were performed on primary osteoblast cell lines derived from cases within subtype A or subtype B, as well as on primary osteoblast cell lines with novel IGF1R variants previously reported by our lab (Cunningham ML, Horst JA, Rieder MJ, Hing AV, Stanaway IB, Park SS, Samudrala R, Speltz ML. Am J Med Genet A 155A: 91-97, 2011). Elevated IRS1 (pan-tyr) and GSK3ß (ser-9) phosphorylation were observed in two novel IGF1R variants with receptor L domain mutations. In subtype A, a hypomineralization phenotype coupled with decreased phosphorylation of IRS1 (ser-312), p38 (thr-180/tyr-182), and p70S6K (thr-412) was observed. In subtype B, decreased phosphorylation of IRS1 (ser-312) as well as increased phosphorylation of Akt (ser-473), GSK3ß (ser-9), IGF1R (tyr-1135/tyr-1136), JNK (thr-183/tyr-187), p70S6K (thr-412), and pRPS6 (ser-235/ser-236) was observed, thus implicating the activation of IRS1-mediated Akt signaling in potentiating craniosynostosis in this subtype. Taken together, these results suggest that despite the stimulation of different pathways, activating phosphorylation patterns for IRS1 were consistent in cell lines from both subtypes and the IGF1R variants, thus implicating a key role for IRS1 in the pathogenesis of nonsyndromic craniosynostosis.


Subject(s)
Craniosynostoses/genetics , Insulin Receptor Substrate Proteins/genetics , Transcriptional Activation , Transcriptome/genetics , Cell Line , Cells, Cultured , Child , Child, Preschool , Cluster Analysis , Craniosynostoses/classification , Craniosynostoses/pathology , Glycogen Synthase Kinase 3/genetics , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Infant , Insulin Receptor Substrate Proteins/metabolism , JNK Mitogen-Activated Protein Kinases/genetics , JNK Mitogen-Activated Protein Kinases/metabolism , Mutation , Oligonucleotide Array Sequence Analysis , Osteoblasts/cytology , Osteoblasts/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Receptor, IGF Type 1/genetics , Receptor, IGF Type 1/metabolism , Ribosomal Protein S6/genetics , Ribosomal Protein S6/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/genetics , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Signal Transduction/genetics , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolism
19.
Clin Genet ; 82(1): 77-82, 2012 Jul.
Article in English | MEDLINE | ID: mdl-21534944

ABSTRACT

Exon rearrangements and point mutations are common in PARK2, the most important causative gene of autosomal recessive early-onset Parkinson disease (EOPD). However, gene dosage analysis alone cannot conclusively determine the phase of exon rearrangements and the incidence of molecularly confirmed parkin-type EOPD may be underestimated. To fully characterize the mutation spectrum, we performed sequencing and gene dosage analyses of SNCA, PARK2, PINK1, and PARK7 in 114 unrelated EOPD patients with onset age ≤40 years. Mutational phase of exon rearrangements was determined by reverse-transcriptase PCR (RT-PCR) and sequence analysis using a patient's own RNA. Fourteen different PARK2 mutations (3 point mutations plus 11 exon rearrangements) were identified in 18 patients, comprising 1 homozygote (0.9%), 13 compound heterozygotes (11.4%), 3 single heterozygotes (2.6%), and 1 with unknown phase (0.9%). By phase determination, more than 80% (5 of 6) of patients with apparently contiguous multi-exon deletions and 30% (5 of 18) of all PARK2 mutation carriers were additionally diagnosed as compound heterozygotes, respectively. This study shows that compound heterozygous mutations constituted a significant portion of patients with apparently contiguous multi-exon deletions. Phase determination is a prerequisite to molecular diagnosis for autosomal recessive EOPD, especially in subjects with PARK2 exon rearrangements.


Subject(s)
Parkinson Disease/genetics , Sequence Deletion , Ubiquitin-Protein Ligases/genetics , Adolescent , Adult , Age of Onset , Asian People , Base Sequence , Child , Exons , Female , Gene Dosage , Heterozygote , Humans , Male , Molecular Sequence Data , Parkinsonian Disorders , Point Mutation , Reverse Transcriptase Polymerase Chain Reaction
20.
Eur J Neurol ; 18(7): 962-71, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21159068

ABSTRACT

BACKGROUND: Silent brain infarctions (SBIs), leukoaraiosis (LA), and microbleeds (MBs) are ischaemic silent radiologic abnormalities that act as predictors of subsequent strokes. This study investigated the independent effect of silent radiologic abnormalities on initial stroke severity and short-term outcome. METHODS: A consecutive series of patients who had their first ischaemic stroke within 72 h of symptom onset were included. Demographic and clinical characteristics were collected on admission, and magnetic resonance imaging was performed to evaluate the ischaemic lesion, SBI, LA, and MB. Factors potentially associated with lower initial stroke severity (admission NIH Stroke Scale 0-5) and good short-term outcome (discharge NIH Stroke Scale 0-5, modified Rankin Scale 0-1) were validated by multivariate analysis. RESULTS: Silent brain infarctions were noted in 82 (45%) of the 182 patients. Although there were no statistically significant differences in stroke subtypes and lesion location, univariate analysis revealed that patients with SBI had reduced stroke severity (P = 0.005) and infarction volume (P = 0.001). After adjusting for covariates, the presence of SBI was independently associated with lower stroke severity and good short-term outcome when the NIH Stroke Scale was used as dependent variable (OR 3.368, 95% CI 1.361-8.332, P = 0.009; OR 3.459, 95% CI 1.227-9.755, P = 0.019, respectively). However, the presence of SBI lost significance when the discharge-modified Rankin Scale was used as dependent variable (P = 0.058). CONCLUSION: Amongst silent radiologic abnormalities, SBI was the only predictor of reduced stroke severity and infarct volume. Silent brain infarction deserves more attention in evaluating stroke severity.


Subject(s)
Brain Infarction/pathology , Stroke/pathology , Age Factors , Aged , Brain Infarction/complications , Brain Infarction/epidemiology , Female , Humans , Hypertension/epidemiology , Image Interpretation, Computer-Assisted , Leukoaraiosis/complications , Leukoaraiosis/pathology , Magnetic Resonance Imaging , Male , Middle Aged , Prevalence , Recovery of Function , Risk Factors , Stroke/complications
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