Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Activated immune cells : 1H-NMR spectroscopy and flow cytometry studies

Proton nuclear magnetic resonance (lH-NMR) spectroscopy has been used to study immune cell activation. One-dimensional and two—dimensional 1H-NMR spectra of activated immune cells are dominated by signals arising from elevated levels of isotropically tumbling (ie., NMR-visible) mobile lipid. An increase in the level of mobile lipid compared with that seen in resting cells has been observed in a variety of activated immune cells. The appearance of the mobile lipid is associated with activation and can be induced by a variety of stimuli. However, the origin and function of the neutral lipid resonances in 1H-NMR spectra of activated immune and other cell types has been unresolved. I propose that the mobile lipids arise from phosphatidylcholine (PC) cycling

Harnessing clinical psychiatric data with an electronic assessment tool (OPCRIT+):the utility of symptom dimensions

Progress in personalised psychiatry is dependent on researchers having access to systematic and accurately acquired symptom data across clinical diagnoses. We have developed a structured psychiatric assessment tool, OPCRIT+, that is being introduced into the electronic medical records system of the South London and Maudsley NHS Foundation Trust which can help to achieve this. In this report we examine the utility of the symptom data being collected with the tool. Cross-sectional mental state data from a mixed-diagnostic cohort of 876 inpatients was subjected to a principal components analysis (PCA). Six components, explaining 46% of the variance in recorded symptoms, were extracted. The components represented dimensions of mania, depression, positive symptoms, anxiety, negative symptoms and disorganization. As indicated by component scores, different clinical diagnoses demonstrated distinct symptom profiles characterized by wide-ranging levels of severity. When comparing the predictive value of symptoms against diagnosis for a variety of clinical outcome measures (e.g. 'Overactive, aggressive behaviour'), symptoms proved superior in five instances (R(2) range: 0.06-0.28) whereas diagnosis was best just once (R(2):0.25). This report demonstrates that symptom data being routinely gathered in an NHS trust, when documented on the appropriate tool, have considerable potential for onward use in a variety of clinical and research applications via representation as dimensions of psychopathology

Median and interquartile range Anderson-Rubin component scores and proportion of individuals with high scores (above the upper tertile) as a function of clinical ICD diagnostic category.

<p>Diagnoses listed are the largest two-digit subgroups within each broad ICD range (e.g. F06/F00–09). Figures are in the format of Median/Interquartile range/Proportion of individuals with high scores.</p

Diagnosis only (D), symptoms only (S) and models containing both sets of predictors (D+S) and their associations with various clinical outcome measures.

<p>Columns 2–4 report Nagelkerke’s Pseudo R² (^aadjusted R² where linear regression is used) for each model and overall model significance (*significant at the <0.05 level, **significant at the <0.01 level, ***significant at the <0.001 level). Column 5 details the best fitting model based on the likelihood ratio test (p<0.05) or the non-significance of other models in the comparison^b. Column 6 details, in descending order of significance, predictors in the best model with a p-value of <0.1. M = Mania, D = Depression, P = Positive symptoms, A = Anxiety, N = Negative symptoms, Di = Disorganization, FXX = ICD10 diagnostic category.</p

Distribution of ICD-10 clinical diagnoses and demographic information.

<p>Rows provide details for all cases within 8 broad ICD ranges (in bold) and underneath each of these the accompanying largest two-digit subgroup within that range.</p

Component loadings, after direct oblimin rotation, of the 39 symptoms extracted from the OPCRIT+ checklist.

<p>Loadings greater than 0.3 are printed in bold. A six-component solution, with their interpretations, is presented. Item communalities and the percent of variance explained by each component are also presented.</p

Flow chart detailing the four steps of the analysis and the number of subjects included at each step.

<p>Flow chart detailing the four steps of the analysis and the number of subjects included at each step.</p