Early Onset Of Symptoms Research Articles

Clinical and radiological characteristics of diffuse idiopathic skeletal hyperostosis in two medical centers in Cali, Colombia: Report of 24 cases

IntroductionDiffuse idiopathic skeletal hyperostosis (DISH) is a condition characterized by calcification and progressive ossification of ligaments and entheses. Most patients remain asymptomatic until advanced stages of the disease, where limitation and pain are characteristic. ObjectiveTo describe the demographic, clinical, and radiological characteristics of patients with DISH evaluated in the Centro Médico Imbanaco and Clínica de Artritis Temprana, in Cali, Colombia. Materials and methodsA descriptive, cross-sectional study was conducted by reviewing the records of patients diagnosed with DISH between January 2000 and October 2018. The diagnosis was confirmed according to the Resnick-Niwayama criteria. A total of 24 patients were found, and all were included for the final analysis. Results and discussionThe series included 20 men and 4 women, with a median age at diagnosis of 70.5 years (IQR 61.3–73.8 years), being lower in women (71.5 versus 60 years; p=0.04). The median time of onset of the symptoms was 5 years (IQR 3–10 years), and the duration was shorter in women (5 versus 4 years; p=0.20). It was observed that 54% were overweight and 20% were diabetic. The main symptom was cervical limitation. The most affected vertebral segments due to the ossification of the anterior longitudinal ligament (ALL) were C5-C6, T8-T10 and L1-L3 (cervical C; thoracic T; lumbar L). The peripheral involvement was mainly in the iliac crests. All patients received physiotherapy, and three of them underwent cervical surgery. The degree of functional limitation was assessed in 19 patients using the mHAQ (Modified Health Assessment Questionnaire) and BASFI (Functional Ankylosing Spondylitis Functional (BASFI) questionnaires. The median score of both questionnaires was 2 times higher in women. ConclusionDiffuse idiopathic skeletal hyperostosis was more frequent in men over 65 years of age, and was associated with metabolic conditions such as obesity and diabetes. Although the differences were not significant, the results suggest that women have a more severe phenotype of the disease, explained by the early onset and progressive course of symptoms, as well as greater functional limitation measured by mHAQ and BASFI.

Correlation between ETFDH mutations and dysregulation of serum myomiRs in MADD patients.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare fatty acids oxidation disorder which is often associated with deficiency of electron transfer flavoprotein dehydrogenase (ETFDH). In this study we reported clinical features and evaluation of expression profile of circulating muscle-specific miRNAs (myomiRs) in two MADD patients carrying different ETFDH gene mutations. Patient 1 was a compound heterozygote for two missense mutations. She showed a late onset MADD clinical phenotype and a significant increase of serum myomiRs. Patient 2, carrying a missense and a frameshift mutation, displayed early onset symptoms and a slight increase of some serum myomiRs.

Two novel mutations in ADAMTS13 in a Chinese boy with congenital thrombocytopenic purpura: a case report

BackgroundMutations in the ADAMTS13 gene family have been reported to cause congenital thrombotic thrombocytopenic purpura (cTTP), a rare disease characterized by thrombocytopenia and hemolytic anemia. Nearly 150 causative mutations in ADAMTS13 have been identified; however, only a few of them were detected in Chinese patients.Case presentationA 5-year-old Chinese boy presented with history of thrombocytopenic purpura, hemolytic anemia, and renal injury since the neonatal period. Gene analysis revealed two novel mutations in ADAMTS13: a missense mutation 332G > A (p:Gly111Glu) in exon4 and a nonsense mutation 3121C > T (p:Gln1041stop) in exon 24. Genetic analysis of his parents confirmed the heterozygous nature of the mutations.ConclusionWe report two novel mutations in ADAMTS13 (332G > A, 3121C > T) in a Chinese boy. These two mutations may lead to early onset of cTTP and severe symptoms.

Características clínico-radiológicas de la hiperostosis esquelética idiopática difusa en 2 centros médicos de Cali, Colombia: reporte de 24 casos

IntroductionDiffuse idiopathic skeletal hyperostosis (DISH) is a condition characterised by calcification and progressive ossification of ligaments and entheses. Most patients remain asymptomatic until advanced stages of the disease, where limitation and pain are characteristic. ObjectiveTo describe the demographic, clinical, and radiological characteristics of patients with DISH evaluated in the Centro Médico Imbanaco and Clínica de Artritis Temprana, in Cali, Colombia. Materials and methodsA descriptive, cross-sectional study was conducted by reviewing the records of patients diagnosed with DISH between January 2000 and October 2018. The diagnosis was confirmed according to the Resnick-Niwayama criteria. A total of 24 patients were found, and all were included for the final analysis. Results and discussionThe series included 20 men and 4 women, with a median age at diagnosis of 70.5 years (IQR 61.3-73.8 years), being lower in women (71.5 versus 60 years; P=.04). The median time of onset of the symptoms was 5 years (IQR 3-10 years), and the duration was shorter in women (5 versus 4 years; P=.20). It was observed that 54% were overweight and 20% were diabetic. The main symptom was cervical limitation. The most affected vertebral segments due to the ossification of the anterior longitudinal ligament (ALL) were C5-C6, T8-T10 and L1-L3 (cervical C; thoracic T; lumbar L). The peripheral involvement was mainly in the iliac crests. All patients received physiotherapy, and three of them underwent cervical surgery. The degree of functional limitation was assessed in 19 patients using the mHAQ (Modified Health Assessment Questionnaire) and BASFI (Functional Ankylosing Spondylitis Functional (BASFI) questionnaires. The median score of both questionnaires was 2 times higher in women ConclusionDiffuse idiopathic skeletal hyperostosis was more frequent in men over 65 years of age, and was associated with metabolic conditions such as obesity and diabetes. Although the differences were not significant, the results suggest that women have a more severe phenotype of the disease, explained by the early onset and progressive course of symptoms, as well as greater functional limitation measured by mHAQ and BASFI.

Abstract IA10: Immune checkpoint inhibitor-associated cardiotoxicities: Learning from mice and humans

Abstract Immune checkpoint inhibitors (ICI) have transformed cancer therapy, with regulatory approval now in 16 distinct cancer types. These agents include monoclonal antibodies blocking cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 receptor (PD-1), and its ligand (PD-L1), and work by activating the immune system (1). ICI can also lead to immune-related adverse events (irAE) including colitis, dermatitis, pneumonitis, endocrinopathies, and other irAE (2). Cardiovascular toxicities including myocarditis have emerged as uncommon but often fatal toxicities associated with ICI (3). Our group initially described cases of fulminant and fatal myocarditis after treatment with ICI (4). These patients presented with refractory electrophysiologic disturbances and concomitant myositis, with pathology confirming T-cell and macrophage infiltration into the myocardium (4). Since then other case series of myocarditis have described an estimated incidence of 0.3% to greater than 1% when ICI are used in combination (5-8). We published the largest such case series including 122 patients with ICI-associated myocarditis; these patients had early onset of symptoms (median 30 days after initial exposure to ICI), frequent deaths (50% mortality), and dramatically increased reporting of cases in 2017, the latter perhaps consistent with growing recognition of this new clinical syndrome as well as more widespread use of ICI (8). More recently, we have demonstrated association of ICI with other cardiovascular complications including myocarditis, pericarditis, vasculitis, and arrhythmias (8). Existing clinical practice extrapolates from general myocarditis literature for diagnosis of ICI-associated myocarditis, with diagnosis being made using a combination of biomarkers (specifically troponin), cardiac imaging, and biopsy (9). We have recently developed case definitions for drug-induced myocarditis, especially in oncology clinical trials (10). To better define mechanisms of ICI-associated myocarditis, our group has developed several mouse models. These include pharmacologic models (where mice in various genetic backgrounds are treated with antibodies) and genetic mouse models (where one or more immune checkpoints are genetically deleted) and recapitulate the syndrome of myocarditis observed in humans treated with ICI. The mice have sudden cardiac death, electrocardiographic perturbations, and macrophage and T-cell infiltrations in the heart, all consistent with human disease (Moslehi et al., unpublished). Importantly, the early data suggest a critical role for CTLA-4 in the development of myocarditis. Treatment with abatacept attenuates the myocarditis in mice. We have extended these observations to humans where in at least one case, severe ICI-associated myocarditis was successfully treated with abatacept (11). Citation Format: Javid J. Moslehi. Immune checkpoint inhibitor-associated cardiotoxicities: Learning from mice and humans [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA10.

The unique contribution of blushing to the development of social anxiety disorder symptoms: results from a longitudinal study.

BackgroundSelf‐conscious emotional reactivity and its physiological marker – blushing has been proposed to be an etiological mechanism of social anxiety disorder (SAD), but so far, untested in longitudinal designs. This study tested, for the first time, whether self‐conscious emotional reactivity (indexed as physiological blushing) contributes to the development of SAD symptoms over and above social behavioral inhibition (BI), which has been identified as the strongest predictor of SAD development in early childhood.MethodsOne hundred fifteen children (45% boys) and their mothers and fathers participated at ages 2.5, 4.5, and 7.5 years. Social BI was observed at all time points in a stranger approach task, and physiological blushing (blood volume, blood pulse amplitude, and temperature increases) was measured during a public performance (singing) and watching back the performance at ages 4.5 and 7.5. Child early social anxiety was reported by both parents at 4.5 years, and SAD symptoms were diagnosed by clinicians and reported by both parents at 7.5 years.ResultsHigher social BI at 2.5 and 4.5 years predicted greater social anxiety at 4.5 years, which, in turn, predicted SAD symptoms at 7.5 years. Blushing (temperature increase) at 4.5 years predicted SAD symptoms at 7.5 years over and above the influence of social BI and early social anxiety.ConclusionsThat blushing uniquely contributes to the development of SAD symptoms over and above social BI suggests two pathways to childhood SAD: one that entails early high social BI and an early onset of social anxiety symptoms, and the other that consists of heightened self‐conscious emotional reactivity (i.e. blushing) in early childhood.

Prediction of VLCAD deficiency phenotype by a metabolic fingerprint in newborn screening bloodspots

PurposeNewborns who test positive for very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) in newborn screening may have a severe phenotype with early onset of life-threatening symptoms but may also have an attenuated phenotype and never become symptomatic. The objective of this study is to investigate whether metabolomic profiles in dried bloodspots (DBS) of newborns allow early phenotypic prediction, permitting tailored treatment and follow-up. MethodsA metabolic fingerprint was generated by direct infusion high resolution mass spectrometry in DBS of VLCADD patients (n = 15) and matched controls. Multivariate analysis of the metabolomic profiles was applied to differentiate subgroups. ResultsConcentration of six acylcarnitine species differed significantly between patients and controls. The concentration of C18:2- and C20:0-carnitine, 13,14-dihydroretinol and deoxycytidine monophosphate allowed separation between mild and severe patients. Two patients who could not be prognosticated on early clinical symptoms, were correctly fitted for severity in the score plot based on the untargeted metabolomics. ConclusionDistinctive metabolomic profiles in DBS of newborns with VLCADD may allow phenotypic prognostication. The full potential of this approach as well as the underlying biochemical mechanisms need further investigation.

Abstract 50: RNA Expression for Diagnosis of Stroke Etiology Differentiating Large Artery and Cardioembolic Stroke: Analytical Validation of Testing From the BASE Clinical Trial

Background: An accurate test to differentiate large artery stroke (LAS) patients from those with cardioembolic stroke (CES) would be of significant clinical utility. Using the Biomarkers of Acute Stroke Etiology (BASE) trial (NCT02014896) dataset, our purpose was to utilize blood gene expression signatures for accurately differentiating LAS from CES acute stroke etiologies. Methods: The BASE trial enrolled suspected stroke patients presenting to 20 hospitals within 24 hrs of symptom onset. Final gold standard diagnosis and stroke etiology were determined by an adjudication committee using all hospital data but blinded to RNA test results. Whole blood, obtained in PAX tubes, was frozen at -20C within 72 hrs and analyzed at a core lab (Ischemia Care, Dayton, OH) using Affymetrix HTA microarrays. Genes on the HTA microarray were filtered to eliminate genes with low expression or high CV (> 10%) when run on replicate samples leaving 9,513 potential signature genes. A two-way random forest classifier was built through cross validation of the training data resulting in a 45 gene diagnostic signature. Results: This is a planned interim cohort study of the 1700 patients enrolled in the BASE trial that does not include lacunar strokes, TIA, or stroke mimics. Overall, 222 patients were enrolled with NIHSS>5, 70 (32%) with LAS and 152 (68%) with CES; 59% were male, and median (IQR) age was 70.7 yrs (62.0, 80.2). Median (IQR) time from symptom onset to blood collection was 1200 (448, 1568) minutes. Coexistent pathology at presentation included atrial fibrillation 90 (48%), hypertension 153 (82%), hyperlipidemia 87 (47%), diabetes 60 (32%), and coronary artery disease 70 (37%). Patients were randomly divided into training (148), early symptom onset (<18hrs) validation (39) and a late symptom onset (>18 hrs) validation (35). The diagnostic gene signature results in the early validation cohort distinguished LAS from CES; C-statistic 0.78 (0.50-1.0, 95% CI), sensitivity 0.90 (0.55-1.0, 95% CI) and specificity of 0.70 (0.43-1.0, 95% CI). Conclusion: Early RNA expression differentiates large artery stroke patients from those with cardioembolic stroke, and may have therapeutic and secondary prevention implications.

Development of transomental hernia shortly after laparoscopic colonic surgery: a case report

BackgroundA transomental hernia is defined as bowel invagination into an abnormal hiatus of the omentum. It is a rare type of internal hernia that is sometimes lethal. We herein report a case of a transomental hernia developing shortly after laparoscopic sigmoidectomy.Case presentationA 71-year-old man underwent laparoscopic sigmoidectomy. He was admitted to our hospital because of abdominal pain and nausea on postoperative day 12. Laboratory investigation showed increased levels of inflammatory markers. Abdominal computed tomography showed a closed loop and mesenteric edema of the small intestine with ascites. We performed an emergency operation under the diagnosis of strangulated bowel obstruction. Operative findings showed internal herniation of strangulated ileal loops through a defect of the omentum with hemorrhagic ascites. The incarcerated small bowel was resected and reconstructed because the ischemic change was irreversible after the reduction. We partially resected the omentum that had formed the defect. The patient’s postoperative progress was good, and he was discharged on postoperative day 8.ConclusionsAlmost all internal hernias after intestinal surgery are mesenteric hernias; however, we should bear in mind that the more lethal transomental hernia is also possible. Therefore, immediate surgical exploration should be performed in a timely manner for internal hernias, especially for patients with early-onset symptoms after laparoscopic intestinal surgery.

Novel mutation of the FHL1 gene associated with congenital myopathy and early respiratory muscles involvement: a case report

Background: Congenital myopathies are a diverse group of diseases that share features from the early onset of symptoms in the first year of life, such as hypotonia, muscle weakness, and developmental delays, and are often associated with respiratory insufficiency and feeding difficulties. Case presentation: Here, we report an 8-year-old boy having hypotonia and signs of respiratory insufficiency that ended with tracheostomy and ventilator-dependent status. Muscle biopsy showed histological findings of congenital fiber-type disproportion myopathy. The whole exome sequencing revealed a novel hemizygous missense variant (c.530A > C p.Gln177Pro) that confirms the diagnosis of FHL1-associated congenital myopathy. Conclusion: The findings in this study help to expand the genetic and mutational spectrum of the FHL1 gene associated with respiratory insufficiency and help in formulating a precise strategy for prognosis and future management of patients.

P98 Distal myopathy induced the onset of arrhythmogenic right ventricular cardiomyopathy in a pedigree carrying novel DSG2 null variant

Abstract Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare cardiac disease predominantly caused by variants in desmosome genes. Variants in human Desmoglein-2 (DSG2) gene can cause ARVC with incomplete penetrance. However, it remains unknown whether ARVC would penetrate by distal myopathy. Methods We performed targeted next-generation sequencing using a cardiomyopathy/ion channelopathy panel in a Chinese ARVC pedigree. Plasmids of DSG2 were constructed, and pathogenicity of the DSG2 variant was investigated by real-time PCR, western blots, Immunofluorescence, and electron microscope. Results We identified a novel nonsense variant in DSG2 (c.710T > A, p.Leu237Ter) and a reported pathogenic missense variant of distal myopathy in MYH7 (c. 1322C > T, p.Thr441Met) in the proband of an ARVC pedigree. The functional analyses suggested that the nonsense variant could affect the expression and cell location of DSG2, and the number and shape of desmosomes were affected as well, indicating that the variant was implicated in the pathogenesis of ARVC. We found only patients carrying the distal myopathy pathogenic variant would manifested early-onset severe ARVC phenotype, which suggested that MYH7-p.Thr441Met variant could induced the onset of ARVC in the DSG2-p.Leu237Ter variant carriers. Conclusions Our study identified a novel null variant in DSG2 gene (c.710T > A, p.Leu237Ter) in an ARVC pedigree with incomplete penetrance. Only patients who carried a distal myopathy associated variant in MYH7 (c. 1322C > T, p.Thr441Met) would induce the onset of ARVC with early-onset and severe symptoms.

Commentary on: Comparative Analysis of Cytokines of Tumor Cell Lines, Malignant and Benign Effusions Around Breast Implants.

As recently as 2011 we considered the risk of breast implant associated-anaplastic large cell lymphoma (BIA-ALCL) to be 1 in 1 million; only 27 cases had been reported in the literature, and only 1 case-control study suggested an association, without evidence of causation, between this cancer and breast implants.1 We now recognize BIA-ALCL is a rare non-Hodgkin’s T-cell lymphoma that is associated with textured breast implants; around 800 recognized cases have been reported worldwide and the incidence appears to be increasing. As many as 87% of patients present as stage I disease due to the early onset of visible symptoms, predominantly delayed-onset peri-implant seroma.2 At this early stage the disease is indolent and curable with appropriate surgery alone with no recurrence and this has been recognized since 2011.3

Central Nervous System Involvement in Peripheral T-Cell Lymphoma

Background: Central nervous system (CNS) involvement by peripheral T cell lymphoma (PTCL) is a rare condition. Among primary CNS lymphomas, only 2% are secondary to PTCL, while the risk of CNS relapse in all cases of PTCL is estimated at 2% to 6%. Little is known about the presentation and outcomes of PTCL patients with CNS involvement given the rarity of this entity. In this study, we describe patient characteristics, histology, and clinical course of patients with CNS involvement by PTCL. Methods: The Mayo Clinic Lymphoma Database was used to identify PTCL patients with primary or secondary CNS involvement seen at our institution between 2000 and 2018. A total of 12 patients were identified and their medical records were reviewed for patient and disease characteristics, CNS-directed treatment modality, and outcomes. The Kaplan-Meier method was used for time-to-event analysis. Results: The median age at CNS diagnosis was 63 years (range 41 to 76) and 11 (93%) patients were male. The histological diagnoses were PTCL, NOS in 9 (75%) patients, enteropathy-associated T-cell lymphoma in 2 (17%) patients, and angioimmunoblastic T-cell lymphoma in 1 (8%) patient. Five patients presented with primary T-cell CNS lymphoma (all with a PTCL, NOS histology), while the remaining 7 (58%) patients also had systemic involvement. All patients presented with neurologic symptoms at the time of CNS involvement diagnosis including: focal motor deficits in 6 patients (unilateral upper extremity weakness, gait impairments, and hemiparesis), cognitive decline in 5 patients (memory impairments, reduced attention, and confusion), headache in 4 patients, and seizure in 3 patients. The CNS disease location included the brain parenchyma in 9 (75%) patients, leptomeninges in 1 (8%) patient, and lumbar plexus in 1 (8%) patient. One patient (8%) had positive CSF finding only without radiologic evidence of involvement. CSF analysis was performed in 11 patients. Elevated protein levels were noted in 3 (27%) patients, malignant cells in 2 (18%), and no clear abnormalities in the remaining 6 (55%) patients. Concomitant bone marrow involvement was seen in only 1 patient. Elevated LDH was seen in 2 patients. The a median LDH was 195 U/L (range 139 to 4,360) The most common CNS-directed therapies were: high-dose methotrexate (MTX)-based regimens in 8 (67%) patients, including high-dose MTX in combination with temozolomide (n=2), or cytarabine and thiotepa (n=2). Intrathecal MTX, temozolomide and dexamethasone, lenalidomide, high-dose steroids, and surgical resection were the treatment modality used for one patient each. At a median follow up of 18 months, eight (75%) out of 12 patients were not alive at the time of last follow up. The median overall survival (OS) from diagnosis was 16 months (95% CI: 2.8-173). The median progression free survival (PFS) from initiation of CNS-directed therapy was 9 months (95% CI: 1.6-33) (figure). Four patients had a PFS longer than 12 months. These 4 patients were treated with: temozolomide/dexamethasone, high-dose MTX, lenalidomide, and high-dose MTX followed by cytarabine/thiothepa. Conclusion: CNS involvement by T-cell lymphoma is a rare complication that carries a poor prognosis. Early onset of neurologic symptoms should trigger prompt investigation of CNS involvement. Despite the short OS and PFS, some patients may achieve a relatively longer disease free interval. Disclosures Bennani: Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board. Cerhan:Celgene: Research Funding; NanoString: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Nowakowski:Celgene: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Curis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding; NanoString: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees. Ansell:Mayo Clinic Rochester: Employment; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding. Paludo:Celgene: Research Funding; Verily Life Sciences: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding.

Evaluation of renal markers of T1D in Sprague-Dawley exposed to 2-aminoanthracene.

The incidence of type 1 diabetes (T1D) and its associated risks of chronic kidney disease or end-stage renal disease development are on the rise. T1D is an autoimmune disease in which insulin-producing beta cells are destroyed. Increased incidence of T1D has been suggested to be a result of environmental factors such as exposure to polycyclic aromatic hydrocarbons (PAHs). 2-aminoanthracene (2AA) is a PAH that has been associated with the onset of early diabetic symptoms. This study was conducted to assess if 2AA dietary ingestion would induce T1D renal injuries. To accomplish study goals, Sprague-Dawley rats were assigned into three 2AA dietary (0, 50, and 100 mg/kg-2AA) ingestion groups for 12 weeks. Animals were evaluated for various morphometric indices, clinical markers, and gene expression. The rats in the 100 mg/kg group lost 5% less weight than the other treatment groups and converted roughly 3% more of their food intake into body mass. Renal histopathology indicated no significant difference between groups. The kidney weight per bodyweight of the 100 mg/kg treatment group was 30.1% greater than the control group. Creatinine concentration of the 100 mg/kg group was 46.2% greater than the control group. Serum glucose levels were significantly elevated in rats exposed to 2AA. On the contrary, serum albumin concentration was significantly reduced in 2AA-treated rats. T1D and genetic markers of renal injury such as FABP1, SPP1, IL-1B, and IL-7 were elevated in treated groups. These results suggest that 2AA may induce the early diabetic renal injuries.

THE RELATIONSHIP OF APOE ε4 TO THE RELATIVE TIMES AND HAZARDS OF DEMENTIA

Although APOE ε4 is an established risk factor for dementia, it is unclear whether it is associated with elevated risk or earlier symptom onset. Longitudinal study of 10,400 white-race individuals in the ARIC cohort followed from age 60 to incident dementia diagnosis, death, or censoring. All-cause dementia was defined using standardized algorithms incorporating longitudinal cognitive change, proxy report, and hospital or death certificate dementia codes. Death was ascertained via the National Death Index and death certificates. We used a parametric mixture of generalized gamma distributions to simultaneously estimate the distribution of event times and the proportion of individuals who experience each outcome (i.e., dementia and its competing risk, dementia-free death) by APOE ε4 status (≥ 1 allele vs. no alleles). Age-adjustment was through use of age as the time scale. APOE ε4 carrier status was associated with a doubling of the overall frequency of dementia incidence to 25% compared to 13% (p < 0.001) in non- ε4 carriers. The distributions of time to dementia was modified by APOE ε4 status (p=0.007): median time to dementia onset among APOE ε4 carriers was 81.9 years compared to 83.3 years in non-APOE ε4 carriers (p = 0.005). No differences in results were found by sex. APOE ε4 carrier status is associated with both elevated risk and earlier time to dementia onset. These findings clarify the causal role of APOE in dementia etiology, could help better identify at-risk subgroups, and may help facilitate better research recruitment.

Therapeutic Prospects in Preeclampsia - A Mini-Review.

Preeclapmsia (PE) is characterized by early onset symptoms such as elevated blood pressure, proteinuria and edema in the pregnant woman, and may result in seizures in the affected female. Currently, there are no therapeutic drugs available to treat this condition, but there are interventions to regulate the symptoms based on the gestational period of the fetus, although the largely favored option is delivery of the fetus and placenta. A search for biomolecules associated with PE was conducted so as to identify diagnostic markers and therapeutic leads. The literature search resulted in the identification of biomolecules such as Corin and Placental Protein 13 (PP13), among others that are associated with PE. Thereby, giving an insight into the various mechanistic pathways involved in the causation of PE. However, it is also evident that PE cannot be solely attributed to any single mechanism but is due to an interplay of different factors that have led to the development of this disease condition. The identified biomarkers would ultimately help in understanding this complex disease and perhaps lead to the discovery of potential effective molecular targets for clinical trials, thereby providing a valuable therapeutic option for affected pregnant women.

Phenotype and genotype of polycystic ovary syndrome in Asia: Ethnic differences.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-aged women, and ethnic diversity has been reported in its manifestation. This review addressed phenotype and genetic studies in Asian women with PCOS. Generally, East Asians are less hirsute, and the hirsutism score cutoff is lower than the Caucasian counterpart. It is not clear whether there are any significant differences in the prevalence or severity of irregular menstruation (IM) or characteristics of polycystic ovary (PCO) across ethnicities. Interestingly, the IM/PCO subgroup is a relatively common phenotype in East Asian patients but not in Caucasian patients. The prevalence of insulin resistance in PCOS patients varies depending on the index used and the cutoff, but women with PCOS showed a higher degree of insulin resistance than those of controls across ethnicities. Lower body mass index (BMI) and lower prevalence of metabolic syndrome were reported in East Asian patients, but despite lower BMI, a comparative study reported that Asian women with PCOS were more likely to have diabetes compared with Caucasian patients, suggesting they also have metabolic complications. Unlike East Asian patients, South Asian patients showed an increased degree of hirsutism, early onset of symptoms, and severe insulin resistance and metabolic risks compared with Caucasians. Genetic components play important roles in the pathogenesis of PCOS, and genome-wide association studies of PCOS suggest that similar genetic risk factors exist between Asian and Caucasian patients. Continuous comparative studies are needed to standardize the diagnosis and management of PCOS across different ethnicities.

1794 Esophageal Adenocarcinoma in a Patient With Inclusion Body Myositis

INTRODUCTION: Inflammatory myopathies are rare autoimmune diseases characterized by chronic muscle inflammation and weakness. Dysphagia is often an early onset symptom in inflammatory myopathies. Here we present a case of esophageal adenocarcinoma diagnosed in a patient with inclusion body myositis (IBM) and chronic progressive dysphagia. CASE DESCRIPTION/METHODS: A 59 year old woman with an 8 year history of gradually progressive IBM presented to the ER with worsening dysphagia; she has had progressive dysphagia over the preceding 10 days to the point she is unable to tolerate solids. Despite longstanding, progressive symptoms, referral to a gastroenterologist was never made as it was assumed her symptoms were from her underlying IBM. On exam, she is a functional quadriplegic from her underlying IBM and is largely bedbound as a result. Her labs were notable for a macrocytic anemia with negative inflammatory myopathy antibody panel. Barium esophagram revealed a large filling defect in the mid to distal esophagus measuring approximately 3.6 × 2.4 cm and subsequent upper endoscopy revealed an 8cm nearly obstructive distal esophageal mass which appeared to arise in the setting of suspected Barrett’s esophagus. Biopsies demonstrated esophageal adenocarcinoma with signet cell features. Subsequent staging was consistent with cT3N0 disease though she was deemed not to be a surgical candidate due to her quadriplegia and severe deconditioning. An endoscopic esophageal bare metal stent was placed for symptom palliation and she was referred to hospice. DISCUSSION: The inflammatory myopathies are a group of autoimmune diseases characterized by chronic muscle inflammation accompanied by weakness. IBM, in contrast to polymyositis and dermatomyositis, has normal or minimally elevated creatine kinase, insidious progression, and is poorly responsive to immunosuppressive therapy. While IBM is generally not thought to be a paraneoplastic syndrome, there are case reports of them being paraneoplastic with a negative antibody panel (as seen in this case). Bulbar symptoms are common in IBM, and &gt;50% of patients will develop oropharyngeal dysphagia usually due to cricoarytenoid weakness. In this case, the patient’s dysphagia was prematurely attributed to IBM, precluding a timely diagnosis of esophageal adenocarcinoma. In patients with inflammatory myopathy and dysphagia, endoscopy is still of utmost importance and symptoms should not be solely attributed to underlying IBM.

P.37Onset and course of core symptoms in myotonic dystrophies

Myotonic dystrophies (DM) are the most frequent autosomal dominant neuromuscular disorders in adults. The overall clinical spectrum is well known and varies from asymptomatic to severely affected patients, notably muscular weakness, myotonia, pain and extra muscular manifestations. The aim of this study was to assess the first and onset of early symptoms. We performed an online survey for DM1 and DM2 patients. Besides demographic data and common questionnaires (Checklist individual strength, RespiCheck, INQoL) we focused on age of onset, first symptom, time of diagnosis, inheritance, and current symptoms at the time of the survey. Data sets of 394 patients were evaluated, 207 DM1 and 187 DM2 patients. The mean age was 46.51 yrs. for DM1 (56% female), 53.33 yrs. for DM2 (71% female). In both DM1 and DM2, the by far most common early symptoms were myotonia and muscle weakness. With an onset before age 35, myotonia was mentioned most frequently as first symptom (DM1 47.4%, DM2 48.8%; muscle weakness: DM1 38.3%, DM2 22.5%). Later at an onset between age 35 to 66, muscle weakness was the most frequent reported first symptom (DM1 57.1%, DM2 45.0%; myotonia: DM1 27.0%, DM2 33.0%). Some patients (DM1 22.5%, DM2 9.7%) with myotonia as first symptom did no longer report on myotonia at the time of completing the questionnaire. Neuropsychological symptoms like daytime sleepiness or decline in concentration were rather rarely as first symptoms. Myotonia and muscle weakness are by far the most mentioned early symptoms related to the age of onset. With progression of the disease, the frequency of myotonia decreases and the frequency of muscle weakness increases, indicating an age-depending change of the first noticed symptom. As consequence, clinical evaluations should be performed on a frequent basis to detect changes of symptoms and facilitate early symptomatic treatment. In addition, the indication of therapeutic measures must be reviewed over time, as the manifestation of symptoms is variable during the course of the disease.

Prenatal and childhood adverse life events, inflammation and depressive symptoms across adolescence

BackgroundNo study has investigated the role of inflammation in explaining the association between early exposures to adverse life events and depressive symptoms in adolescence. MethodUsing data from the Avon Longitudinal Study of Parents and Children, we tested if inflammatory markers [serum C-reactive protein (CRP) and interleukin 6 (IL-6)] at age 9 years mediate the association between adverse life events, measured separately for the prenatal (since the beginning of pregnancy) and the childhood (ages 0–9 years) periods, and the development of depressive symptoms at ages 10–17 years. Data (n = 4,263) were analyzed using mediation analysis in a latent growth curve modeling framework. ResultsDepressive symptoms at the beginning of adolescence (age 10) were associated with the number of prenatal events, the number of events around birth and the increase in events over time in childhood (ages 0–9), even after adjustment for confounders. IL-6 partially mediated the association between increasing exposure to events over time in childhood and depressive symptoms at the beginning of adolescence. IL-6 did not mediate any other association between events and symptoms. There was no evidence for mediation by CRP, which was generally unrelated to exposure to events. LimitationsThe small size of the mediation effect and the robust direct effects of events prenatally and around birth suggest there are multiple routes from early stressors to adolescent depression. ConclusionsIn the general adolescent population, increasing exposure to psychosocial stressors over time during childhood is associated with the early onset of depressive symptoms, partly via increasing levels of plasma IL-6.