Ahmed M. Gharib

Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation–polyendocrinopathy–enteropathy–X-linked–like syndrome

BACKGROUND Mutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers. OBJECTIVE We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC. METHODS We initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wild-type forkhead box protein 3 and an immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX)-like phenotype for STAT1 mutations. RESULTS We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M [2 patients]). STAT1 phosphorylation in response to IFN-γ, IL-6, and IL-21 was increased and prolonged. CD4(+) IL-17-producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4(+) T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2-induced STAT5 phosphorylation. CONCLUSIONS Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.

Necrotic core thickness and positive arterial remodeling index: Emergent biomechanical factors for evaluating the risk of plaque rupture

Fibrous cap thickness is often considered as diagnostic of the degree of plaque instability. Necrotic core area (Core(area)) and the arterial remodeling index (Remod(index)), on the other hand, are difficult to use as clinical morphological indexes: literature data show a wide dispersion of Core(area) thresholds above which plaque becomes unstable. Although histopathology shows a strong correlation between Core(area) and Remod(index), it remains unclear how these interact and affect peak cap stress (Cap(stress)), a known predictor of rupture. The aim of this study was to investigate the change in plaque vulnerability as a function of necrotic core size and plaque morphology. Cap(stress) value was calculated on 5,500 idealized atherosclerotic vessel models that had the original feature of mimicking the positive arterial remodeling process described by Glagov. Twenty-four nonruptured plaques acquired by intravascular ultrasound on patients were used to test the performance of the associated idealized morphological models. Taking advantage of the extensive simulations, we investigated the effects of anatomical plaque features on Cap(stress). It was found that: 1) at the early stages of positive remodeling, lesions were more prone to rupture, which could explain the progression and growth of clinically silent plaques and 2) in addition to cap thickness, necrotic core thickness, rather than area, was critical in determining plaque stability. This study demonstrates that plaque instability is to be viewed not as a consequence of fibrous cap thickness alone but rather as a combination of cap thickness, necrotic core thickness, and the arterial remodeling index.

Immune deficiencies, infection, and systemic immune disordersDominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation–polyendocrinopathy–enteropathy–X-linked–like syndrome

BACKGROUND Mutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers. OBJECTIVE We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC. METHODS We initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wild-type forkhead box protein 3 and an immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX)-like phenotype for STAT1 mutations. RESULTS We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M [2 patients]). STAT1 phosphorylation in response to IFN-γ, IL-6, and IL-21 was increased and prolonged. CD4(+) IL-17-producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4(+) T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2-induced STAT5 phosphorylation. CONCLUSIONS Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.

B1-insensitive T2 preparation for improved coronary magnetic resonance angiography at 3 T

At 3 T, the effective wavelength of the RF field is comparable to the dimension of the human body, resulting in B1 standing wave effects and extra variations in phase. This effect is accompanied by an increase in B0 field inhomogeneity compared to 1.5 T. This combination results in nonuniform magnetization preparation by the composite MLEV weighted T2 preparation (T2 Prep) sequence used for coronary magnetic resonance angiography (MRA). A new adiabatic refocusing T2 Prep sequence is presented in which the magnetization is tipped into the transverse plane with a hard RF pulse and refocused using a pair of adiabatic fast‐passage RF pulses. The isochromats are subsequently returned to the longitudinal axis using a hard RF pulse. Numerical simulations predict an excellent suppression of artifacts originating from B1 inhomogeneity while achieving good contrast enhancement between coronary arteries and surrounding tissue. This was confirmed by an in vivo study, in which coronary MR angiograms were obtained without a T2 Prep, with an MLEV weighted T2 Prep and the proposed adiabatic T2 Prep. Improved quantitative and qualitative coronary MRA image measurement was achieved using the adiabatic T2 Prep at 3 T. Magn Reson Med, 2006. Published 2006 Wiley‐Liss, Inc.

Outcomes of spontaneous and assisted pregnancies in Turner syndrome: the U.S. National Institutes of Health experience.

OBJECTIVE To assess fetal and maternal outcomes of pregnancies in women with Turner syndrome (TS). DESIGN Retrospective case series. SETTING Clinical research center. PATIENT(S) 276 adults with cytogenetically proven TS participating in an intramural natural history protocol. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Menstrual and obstetric histories, 50-cell karyotypes, and cardiovascular evaluation including aortic diameter measurements. RESULT(S) Our cohort included five women with spontaneous pregnancies and five with pregnancies using assisted reproduction (ART). All five women with spontaneous pregnancies had spontaneous puberty, despite 45,X in ≥90% of their 50-cell karyotype. Participants had a total of 13 pregnancies and 14 live births. One child had cerebral palsy; the others were chromosomally and developmentally normal. Delivery was by cesarean section in four out of seven spontaneous and six out of six ART-related pregnancies. One mother experienced preeclampsia in an ART-related twin pregnancy that required a preterm delivery; she has marked but stable aortic dilation years later. CONCLUSION(S) Approximately 2% of our study cohort experienced spontaneous pregnancies despite high-grade X monosomy, and a similar number achieved pregnancy via oocyte donation and ART. The potential for life-threatening cardiovascular complications warrants comprehensive screening before conception or single-embryo transfer, and caution regarding unintentional pregnancies for TS women.

Utility of Various Functional and Anatomic Imaging Modalities for Detection of Ectopic Adrenocorticotropin-Secreting Tumors

CONTEXT Because ectopic ACTH-secreting (EAS) tumors are often occult, improved imaging is needed. OBJECTIVE Our objective was to evaluate the utility of [(111)In-DTPA-d-Phe]pentetreotide scintigraphy [octreotide (OCT)] imaging at 6 mCi [low OCT (LOCT)] and 18 mCi [high OCT (HOCT)], [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) and [(18)F]l-3,4-dihydroxyphenylalanine (F-DOPA)-PET scans, computed tomography (CT), and magnetic resonance imaging (MRI). DESIGN AND SETTING The study was a prospective evaluation at a clinical research center. PATIENTS Forty-one subjects participated, 30 (17 female) with resected EAS tumors and 11 (three female) with occult EAS, based on inferior petrosal sinus sampling results and imaging studies. INTERVENTION INTERVENTION included CT and MRI of neck, chest, abdomen, LOCT (with or without HOCT) and FDG- or F-DOPA-PET without CT every 6-12 months. MAIN OUTCOME MEASURE Tumor identification was the main outcome measure. RESULTS Most recent results were analyzed. Eighteen patients had tumor resected on the first visit; otherwise, surgery occurred 33 +/- 25 (9-99) months later. Tumor size was 1.9 +/- 1.7 (0.8-8.0) cm; 83% were intrathoracic. CT, MRI, LOCT, HOCT, FDG-PET, and F-DOPA-PET had sensitivities per patient of 93% [95% confidence interval (CI) = 79-98%], 90% (95% CI = 74-96%), 57% (95% CI = 39-73%), 50% (95% CI = 25-75%), 64% (95% CI = 35-85%), and 55% (95% CI = 28-79%) and positive predictive values (PPV) per lesion of 66, 74, 79, 89, 53, and 100%, respectively. LOCT and PET detected only lesions seen by CT/MRI; abnormal LOCT or F-DOPA-PET improved PPV of CT/MRI. By modality, the fraction of patients with one or more false-positive findings was 50% by CT, 31% by MRI, 18% by L/HOCT, and 18% by FDG-PET. Eight occult EAS patients had 64 +/- 58 (9-198) months follow-up; others had none. CONCLUSIONS High sensitivity and PPV suggest thoracic CT/MRI plus LOCT scans for initial imaging, with lesion confirmation by two modalities.

Coronary artery anomalies and variants: technical feasibility of assessment with coronary MR angiography at 3 T.

The purpose of this study was to prospectively use a whole-heart three-dimensional (3D) coronary magnetic resonance (MR) angiography technique specifically adapted for use at 3 T and a parallel imaging technique (sensitivity encoding) to evaluate coronary arterial anomalies and variants (CAAV). This HIPAA-compliant study was approved by the local institutional review board, and informed consent was obtained from all participants. Twenty-two participants (11 men, 11 women; age range, 18-62 years) were included. Ten participants were healthy volunteers, whereas 12 participants were patients suspected of having CAAV. Coronary MR angiography was performed with a 3-T MR imager. A 3D free-breathing navigator-gated and vector electrocardiographically-gated segmented k-space gradient-echo sequence with adiabatic T2 preparation pulse and parallel imaging (sensitivity encoding) was used. Whole-heart acquisitions (repetition time msec/echo time msec, 4/1.35; 20 degrees flip angle; 1 x 1 x 2-mm acquired voxel size) lasted 10-12 minutes. Mean examination time was 41 minutes +/- 14 (standard deviation). Findings included aneurysms, ectasia, arteriovenous fistulas, and anomalous origins. The 3D whole-heart acquisitions developed for use with 3 T are feasible for use in the assessment of CAAV.

Cardiovascular magnetic resonance at 3.0T: Current state of the art

There are advantages to conducting cardiovascular magnetic resonance (CMR) studies at a field strength of 3.0 Telsa, including the increase in bulk magnetization, the increase in frequency separation of off-resonance spins, and the increase in T1 of many tissues. However, there are significant challenges to routinely performing CMR at 3.0T, including the reduction in main magnetic field homogeneity, the increase in RF power deposition, and the increase in susceptibility-based artifacts.In this review, we outline the underlying physical effects that occur when imaging at higher fields, examine the practical results these effects have on the CMR applications, and examine methods used to compensate for these effects. Specifically, we will review cine imaging, MR coronary angiography, myocardial perfusion imaging, late gadolinium enhancement, and vascular wall imaging.

Nonalcoholic Steatohepatitis and Hepatic Fibrosis in HIV-1–Monoinfected Adults With Elevated Aminotransferase Levels on Antiretroviral Therapy

BACKGROUND Persistent aminotransferase elevations are common in human immunodeficiency virus (HIV)-infected patients on antiretroviral therapy (ART), including those without hepatitis B or C coinfection, but their clinical significance is unknown. METHODS HIV-infected adults with aminotransferase levels elevated above the upper limit of normal for ≥6 months while receiving ART, and without chronic viral hepatitis or other known causes of chronic liver disease, underwent a detailed metabolic assessment and liver biopsy. RESULTS Sixty-two HIV-infected subjects completed the study. Forty (65%) had clinically significant liver pathology, including 34 (55%) with nonalcoholic steatohepatitis (NASH) and 11 (18%) with bridging fibrosis, 10 of whom also had NASH. Nonspecific abnormalities alone were seen in 22 (35%) subjects, including mild steatosis, mild to moderate inflammation, and evidence of drug adaptation. Insulin resistance, obesity, and the presence of either of 2 minor alleles in the PNPLA3 gene were significantly associated with increased risk of NASH and fibrosis. NASH and/or fibrosis were not associated with duration of HIV infection or ART, specific antiretroviral drugs, history of opportunistic infection, immune status, or duration of aminotransferase elevation. CONCLUSIONS HIV-infected adults with chronic aminotransferase elevations while receiving ART have a high rate of liver disease. Noninvasive testing can help identify liver disease in such patients, but liver biopsy is necessary to definitively identify those at risk for liver disease progression and complications. Longitudinal follow-up of this cohort will better characterize the natural history of aminotransferase elevations in this population and identify noninvasive biomarkers of liver disease progression.

Coronary MR angiography at 3T during diastole and systole

To investigate the impact of end‐systolic imaging on quality of right coronary magnetic resonance angiography (MRA) in comparison to diastolic and to study the effect of RR interval variability on image quality.