Septal Ablation Versus Surgical Myomectomy for Hypertrophic Obstructive Cardiomyopathy.

PURPOSE OF REVIEW: Patients with hypertrophic cardiomyopathy (HCM) who have left ventricular outflow tract obstruction (LVOTO) often experience severe symptoms and functional limitation. Relief of LVOTO can be achieved by two invasive interventions, i.e., surgery myectomy and alcohol septal ablation (ASA), leading in experienced hands to a dramatic improvement in clinical status. Despite extensive research, however, the choice of the best option in individual patients remains challenging and poses numerous clinical dilemmas. RECENT FINDINGS: Invasive strategies have been recently incorporated in recommendations for the diagnosis and treatment of HCM on both sides of the Atlantic. These guidelines are based on a bulk of well-designed but retrospective studies as well as on expert opinions. Evidence now exists that adequate evaluation and management of HCM requires a multidisciplinary team capable of choosing the best available options. Management of LVOTO still varies largely based on local expertise and patient preference. Following the trend that has emerged for other cardiac diseases amenable to invasive interventions, the concept of a "HCM heart team" is coming of age.

SLCO1B1 Gene Polymorphisms (rs2306283 and rs4149056) and Statin-Induced Myopathy in Jordanian Diabetics.

BACKGROUND: The use of statins to lower high serum cholesterol levels may be associated with a number of adverse reactions, including severe myopathy. The solute carrier organic anion transporter 1B1 (SLCO1B1) gene, which encodes the organic anion-transporting polypeptide OATP1B1, is related to the intracellular transport of statins. The aim of this research was to study the association of rs2306283 and rs4149056 genetic polymorphism of the SLCO1B1 gene with the development of statin-induced myopathy in Jordanian diabetics receiving statins. METHODS: We included 413 patients attending the Diabetes Clinics of the National Center for Diabetes, Endocrinology and Genetics, Amman, Jordan. The study was approved by the Institutional Review Board of NCDEG. Myopathy was defined as the elevation of creatine kinase more than 3 times the upper limit of normal. Every subject signed an informed consent form and donated 3-5 mL of venous blood. Genome DNA was extracted from lymphocytes of peripheral blood. Genotypes were identified using the Tetra Amplification Refractory Mutation System of SLCO1B1. RESULTS: The minor allele frequencies of rs2306283 [G] and rs4149056 [C] were 0.38 and 0.23, respectively. The two SNPs followed the Hardy-Weinberg equilibrium. The development of SIM was significantly associated with the homozygous and heterozygous minor allele genotype of rs4149056 (CC and CT), and the homozygous wild type allele genotype of rs2306283 (AA). There was no linkage disequilibrium between the two SNPs in the studied subgroups. CONCLUSION: Genetic polymorphism in the SLCO1B1 Gene is a risk factor for the development of SIM in Jordanian patients.

Testotoxicosis without Testicular Mass: Revealed by Peripheral Precocious Puberty and Confirmed by Somatic LHCGR Gene Mutation.

Purpose: Testotoxicosis is an autosomal dominant form of limited gonadotropin-independent precocious puberty in boys. It is caused by a heterozygous constitutively activating mutation of the LHCGR gene encoding the luteinizing/hormone receptor (LHR). Some twenty mutations of the LHCGR gene have been reported. Most of them are constitutive mutations isolated from blood leukocyte DNA, although others are somatic, found only in testicular tumoural tissue. In all the previously reported cases of these somatic mutations, the tumour, whether a nodular Leydig cell adenoma or hyperplasia, was easily visible on testicular ultrasonography. The aim of this study was to describe an unusual presentation of a patient with the clinical and hormonal characteristics of testotoxicosis but no well-circumscribed lesion at testicular ultrasonography.Materials and Methods: Molecular analysis of the LHCGR gene was performed by direct sequencing of DNA extracted from peripheral leucocytes and testicular biopsy.Results: Molecular analysis didn't find any LHR mutation in blood, whereas it revealed for the first time a somatic D578H mutation in testicular tissue despite no evidence of a nodular aspect at testis ultrasonography.Conclusions: This observation underlines the need to look for a somatic LHCGR gene mutation from the testicular biopsies of all boys with testotoxicosis with no constitutive LHCGR gene mutation identified from blood DNA, even in the absence of circumscribed testicular lesion at ultrasonography. In addition, based on the known link between LHR mutations and testicular tumourigenesis, yearly ultrasound monitoring of the testes should be considered for these patients.

The Cape Town Declaration on Access to Cardiac Surgery in the Developing World.

Twelve years after cardiologists and cardiac surgeons from all over the world issued the 'Drakensberg Declaration on the Control of Rheumatic Fever and Rheumatic Heart Disease in Africa', calling on the world community to address the prevention and treatment of rheumatic heart disease (RHD) through improving living conditions, to develop pilot programmes at selected sites for control of rheumatic fever and RHD, and to periodically review progress made and challenges that remain, RHD still accounts for a major proportion of cardiovascular diseases in children and young adults in low- and middle-income countries, where more than 80% of the world population live. Globally equal in prevalence to human immunodeficiency virus infection, RHD affects 33 million people worldwide. Prevention efforts have been important but have failed to eradicate the disease. At the present time, the only effective treatment for symptomatic RHD is open heart surgery, yet that life-saving cardiac surgery is woefully absent in many endemic regions. In this declaration, we propose a framework structure to create a co-ordinated and transparent international alliance to address this inequality.

In vivo percutaneous microwave ablation in kidneys: Correlation with ex vivo data and ablation work.

PURPOSE: To compare diameters of in vivo microwave ablation (MWA) performed in swine kidneys with ex vivo diameters, and to correlate with ablation work (AW), a new metric reflecting total energy delivered. MATERIAL AND METHODS: Eighteen in vivo MWA were performed in 6 swine kidneys successively using one or two antennas (MicroThermX®). Ablation consisted in delivering power (45-120W) for 5-15minutes. Ex vivo diameters were provided by the vendors and obtained on bovine liver tissue. AW was defined as the sum of (power)*(time)*(number of antennas) for all phases of an ablation (in kJoules). Kidneys were removed laparoscopically immediately after ablation. After sacrifice, ablations zones were evaluated macroscopically, and maximum diameters of the zones were recorded. Wilcoxon sum rank test and Pearson's correlation were used for comparisons. RESULTS: For a single antenna (n=12), the in vivo diameters ranged from 12 to 35mm, and 15-49mm for 2 antennas (n=6). The in vivo diameters remained shorter than ex vivo diameters by 8.6%±30.1 on 1 antenna and 11.7%±26.5 on 2 antennas (P=0.31 and 0.44, respectively). AW ranged from 13.5 to 108kJ. Diameters increased linearly with AW both with 1 and 2 antennas, but only moderate correlations were observed (r=0.43 [95% confidence interval: -0.19; 0.81], P=0.16; and 0.57 [-0.44; 0.95], P=0.24, respectively). CONCLUSION: Although diameters after in vivo renal MWA increased linearly with AW, the moderate correlation and wide standard deviations observed may justify a careful imaging monitoring during treatment delivery and settings adaptation, if needed, for optimal ablation.

CT and MR imaging features of mucinous tubular and spindle cell carcinoma of the kidneys. A multi-institutional review.

Mucinous tubular and spindle cell carcinoma (MTSCC) of the kidney is a recently identified renal malignancy. Diagnosis of this rare subtype of renal tumour can be challenging for pathologists, and as such, any additional data would be helpful to improve diagnostic reliability. As imaging features of this new and rare sub-type have not yet been clearly described, the purpose of this study was to describe the main radiologic features on computed tomography (CT) and magnetic resonance imaging (MRI), based jointly on the literature and findings from a multi-institutional retrospective review of pathology and imaging databases. Using a combination of CT/MRI features, diagnosis of MTSCC could be suggested in many cases. A combination of slow enhancement with plateau on dynamic contrast-enhanced CT/MRI, intermediate to high T2 signal intensity contrasting with low apparent diffusion coefficient values on MRI appeared evocative of this diagnosis. KEY POINTS: • A slow enhancement with plateau is observed either on CT or MRI. • High T2 signal components but low apparent coefficient diffusion are evocative. • T2-weighted imaging features depend on the mucin components of the tumour.

Tubulocystic renal cell carcinoma: a new radiological entity.

UNLABELLED: Tubulocystic renal cell carcinoma (TC-RCC) is a recently identified renal malignancy. While approximately 100 cases of TC-RCC have been reported in the pathology literature, imaging features have not yet been clearly described. The purpose of this review is to describe the main radiologic features of this rare sub-type of RCC on ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), based jointly on the literature and findings from a multi-institutional retrospective HIPAA-compliant review of pathology and imaging databases. Using a combination of sonographic and CT/MRI features, diagnosis of TC-RCC appeared to be strongly suggested in many cases. KEY POINTS: • Tubulocystic renal cell carcinoma is a new entity with typical imaging features • Diagnosis of tubulocystic renal cell carcinoma can be suggested preoperatively by imaging • Cystic renal lesions with high echogenicity may correspond to tubulocystic carcinoma.

Multiparametric magnetic resonance imaging for the differentiation of low and high grade clear cell renal carcinoma.

PURPOSE: To retrospectively evaluate the ability of magnetic resonance (MR) imaging to differentiate low from high Fuhrman grade renal cell carcinoma (RCC). MATERIALS AND METHODS: MR images from 80 consecutive pathologically proven RCC (57 clear cell, 16 papillary and 7 chromophobe) were evaluated. Double-echo chemical shift, dynamic contrast-enhanced T1- and T2-weighted images and apparent diffusion coefficient (ADC) maps were reviewed independently. Signal intensity index (SII), tumour-to-spleen SI ratio (TSR), ADC ratio, wash-in (WiI) and wash-out indices (WoI) between different phases were calculated and compared to pathological grade and size. The Fuhrman scoring system was used. Low grade (score ≤ 2) and high grade (score ≥ 3) tumours were compared using univariate and multivariate analyses. RESULTS: No associations between grade and imaging factors were found for papillary and chromophobe RCCs. For clear cell RCCs, there was a significant association between the grade and parenchymal WiI (WiI2) (P = 0.02) or ADCr (P = 0.03). A significant association between tumour grade and size (P = 0.01), WiI2 (P = 0.02) and ADCr (P = 0.05) remained in multivariate analysis. CONCLUSIONS: Multiparametric MRI can be used to accurately differentiate low Fuhrman grade clear cell RCC from high grade. High Fuhrman grade (≥ 3) RCCs were larger, had lower parenchymal wash-in indices and lower ADC ratios than low grade. KEY POINTS: • Fuhrman grade of clear cell RCC can be differentiated with multiparametric MR imaging. • Fuhrman grade significantly differed for size, parenchymal wash-in index and ADC ratio. • No significant associations were found for papillary and chromophobe renal cell carcinoma.

Routinely performed multiparametric magnetic resonance imaging helps to differentiate common subtypes of renal tumours.

OBJECTIVES: To retrospectively evaluate the ability of multiparametric magnetic resonance (MR) imaging to differentiate renal tumours. METHODS: MR images from 100 consecutive pathologically proven solid renal tumours without macroscopic fat [57 clear cell, 16 papillary and 7 chromophobe renal cell carcinomas (RCCs), 16 oncocytomas and 4 minimal fat angiomyolipomas (AMLs)] between 2009 and 2012 were evaluated. Two radiologists blinded to pathology results independently reviewed double-echo chemical shift, dynamic contrast-enhanced T1- and T2-weighted images and apparent diffusion coefficient (ADC) maps. Signal intensity index (SII), tumour-to-spleen SI ratio (TSR), ADC ratio, wash-in (WiI) and wash-out indices (WoI) between different phases were calculated. RESULTS: There were significant differences between papillary RCCs and other renal tumours for arterial WiI (P < 0.001), initial WoI (P = 0.006) and ADC ratio (P < 0.001); between chromophobe RCCs and oncocytomas for TSR (P = 0.02), parenchymal WiI (P = 0.03), late WiI (P = 0.02), initial WoI (P = 0.03) and late WoI (P = 0.04); and between clear cell RCCs and oncocytomas for SII (P = 0.01) and parenchymal WiI (P = 0.01). Papillary RCCs were distinguished from other tumours (sensitivity 37.5 %, specificity 100 %) and oncocytomas from chromophobe RCCs (sensitivity 25 %, specificity 100 %) and clear cell RCCs (sensitivity 100 %, specificity 94.2 %). CONCLUSION: MR imaging provides criteria able to accurately distinguish papillary RCCs from other tumours and oncocytomas from chromophobe and clear cell RCCs. KEY POINTS: • Multiparametric MR parameters accurately distinguish papillary RCCs with high specificity (100 %). • Oncocytomas can be distinguished from chromophobe RCCs with high specificity (100 %). • Oncocytomas can be distinguished from clear cell RCCs with high specificity (94.2 %). • In oncocytomatosis, imaging follow-up with such parameters analysis could be promoted.

Thiopurine S-methytransferase gene polymorphism in rheumatoid arthritis.

BACKGROUND AND AIMS: Thiopurine S-methyltransferase (TPMT) is responsible for inactivation of thiopurine drugs which are commonly used in leukemia, organ transplantation and autoimmune diseases. The gene encoding TPMT is polymorphic, and both phenotyping and genotyping studies have shown ethnic variations in gene sequence and enzyme activity worldwide. The aim of this study is to identify the most common genetic polymorphisms of TPMT in healthy Jordanian volunteers and patients with rheumatoid arthritis (RA). METHODS: A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to identify the frequency of TPMT (*2, *3A, *3B, and *3C) polymorphisms in 250 healthy Jordanian volunteers and 110 RA patients. RESULTS: Only four healthy subjects (1.6%) and one RA patient (0.9%) with variant alleles were identified in this study. Two healthy subjects had the TPMT*3A allele and the other two had the TPMT*3B allele, whereas the one RA patient had the TPMT*3A allele. No homozygous polymorphisms were detected and all genotypes detected were heterozygous (*1/*3A) (*1/*3B). None of the subjects had TPMT*2 or TPMT*3C variant alleles. CONCLUSIONS: Mutant alleles identified in this study have a low frequency. TPMT (*3A and *3B) were the only detected heterozygous alleles. No homozygous variant allele was detected. Further studies are necessary to identify other variant alleles that might uniquely occur in Jordanians.

Effect of mint drink on metabolism of nicotine as measured by nicotine to cotinine ratio in urine of Jordanian smoking volunteers.

INTRODUCTION: Variation in nicotine metabolism may be due to genetic alterations in CYP 2A6, environmental factors, and diet. The purpose of this research was to evaluate mint drink effect on nicotine metabolism as judged by nicotine/cotinine ratio in urine of Jordanian smokers. METHODS: Twenty-four Jordanian smoker volunteers were allocated randomly into two groups. They either received mint drink 3 times a day for 1 week during the mint drink period or avoided menthol-containing products and mint drink for 1 week during the off-menthol period. One group treatment sequence was mint drink, off-menthol, while the other group treatment was off-menthol, mint drink. Early morning urine samples were collected at baseline and at the end of each period. Samples were analyzed by liquid chromatography-mass spectrometry for the nicotine and cotinine concentrations. Nicotine/cotinine ratio was calculated and compared among the different periods for each participant using the paired t test. RESULTS: All participants showed a consistent pattern of higher nicotine/cotinine ratios during mint drink compared with off-menthol periods, although to a variable extent. Mean nicotine/cotinine ratio during mint drink for all participants (1.327 ± 0.707) was higher than that during off-menthol (0.993 ± 0.547). Paired t test statistical analysis revealed a p < .0001. The mean difference in nicotine/cotinine ratio between the two periods was (-0.335), and the 95% confidence interval of the mean difference was (-0.451) - (-0.219). CONCLUSION: Mint drink increased nicotine/cotinine ratio in urine, suggesting a reduction in conversion of nicotine to cotinine.

Echocardiography accurately assesses the pathological abnormalities of chronic endomyocardial fibrosis.

Endomyocardial fibrosis (EMF) is a cardiomyopathy with high prevalence in Sub-Saharan Africa with unclear etiology, pathogenesis and natural history. Most pathological abnormalities can potentially be diagnosed by echocardiography allowing surgery in some cases. With increasing availability of echocardiography in endemic areas for EMF we designed a study aiming at assessing its accuracy in defining EMF structural abnormalities pre-operatively, and describe pathological findings through detailed intraoperative examination and evaluation of histopathological changes in tissue obtained from excisional biopsies. Transthoracic echocardiography was performed pre-operatively to 29 patients with chronic severe EMF. All patients were submitted to excisional endomyocardial biopsies during surgery and careful standardized intra-operative evaluation was also done. Surgical and histopathological findings were compared to those obtained by echocardiography. Of the 29 patients studied, 16 had moderate lesions while 13 had severe disease. Their mean age was 12 (±4.6) years and 17 were males. All but one patient were in NYHA functional class III or IV at time of surgery. All patients had severe atrioventricular valve regurgitation with valves considered suitable for repair. We evaluated tissue from 25 left ventricles and 12 right ventricles. Endocardial thickening was the most prominent abnormality due to deposition of hyaline and cellular collagen underneath a layer of apparently normal endocardial endothelial cells. The mean endocardial thickness was 2,541 ± 1,707 µm. There was high agreement between echocardiographic and intraoperative findings, with the findings coinciding completely in 24 patients. Severe EMF assessed by echocardiography was associated with intense endocardial fibrosis on histology. In contrast, the presence of inflammation in peripheral blood was not associated with tissue inflammation. Structural abnormalities of chronic severe EMF are accurately diagnosed by transthoracic echocardiography, allowing this non-invasive technique to be used as the gold standard for diagnosis and surgical management of chronic EMF in endemic areas.

A rare case of mantle cell lymphoma as lymphomatous polyposis with widespread involvement of the digestive tract.

Lymphomatous polyposis of the gastrointestinal tract is rare. It refers to a heterogeneous group of small B-cell lymphomas including mantle cell lymphoma, follicular lymphoma and MALT lymphoma. It is characterized by the presence of multiple lymphomatous polyps along one or more segments of the digestive tract. Clinical symptoms are non-specific. We herein report the case of a 74-year old man initially admitted for an upper and lower gastrointestinal endoscopy to explore a positive Hemoccult test. The endoscopy revealed multiple polyps all along the gastrointestinal tract. Histopathological study showed a diffuse lymphomatous proliferation of small B-cells whose immunohistochemical features were compatible with a mantle cell lymphoma. Tumoral B-cells showed a positivity of cyclin D1 markers but negativity for CD5. Immunochemotherapy with R-CHOP (rituximab, cyclophosphamide, adriamycine, vincristine and prednisone) was initiated. Based on this case study, the pitfalls of gastrointestinal tract lymphomatous polyposis diagnosis, prognosis and treatment options are discussed.

Expression of the familial cardiac valvular dystrophy gene, filamin-A, during heart morphogenesis.

Myxoid degeneration of the cardiac valves is a common feature in a heterogeneous group of disorders that includes Marfan syndrome and isolated valvular diseases. Mitral valve prolapse is the most common outcome of these and remains one of the most common indications for valvular surgery. While the etiology of the disease is unknown, recent genetic studies have demonstrated that an X-linked form of familial cardiac valvular dystrophy can be attributed to mutations in the Filamin-A gene. Since these inheritable mutations are present from conception, we hypothesize that filamin-A mutations present at the time of valve morphogenesis lead to dysfunction that progresses postnatally to clinically relevant disease. Therefore, by carefully evaluating genetic factors (such as filamin-A) that play a substantial role in MVP, we can elucidate relevant developmental pathways that contribute to its pathogenesis. In order to understand how developmental expression of a mutant protein can lead to valve disease, the spatio-temporal distribution of filamin-A during cardiac morphogenesis must first be characterized. Although previously thought of as a ubiquitously expressed gene, we demonstrate that filamin-A is robustly expressed in non-myocyte cells throughout cardiac morphogenesis including epicardial and endocardial cells, and mesenchymal cells derived by EMT from these two epithelia, as well as mesenchyme of neural crest origin. In postnatal hearts, expression of filamin-A is significantly decreased in the atrioventricular and outflow tract valve leaflets and their suspensory apparatus. Characterization of the temporal and spatial expression pattern of filamin-A during cardiac morphogenesis is a crucial first step in our understanding of how mutations in filamin-A result in clinically relevant valve disease.

Late donor cardiectomy after paediatric heterotopic cardiac transplantation.

BACKGROUND: Cardiac transplantation is a life-saving procedure in infants and children with advanced cardiomyopathy. However, it is greatly limited by shortage of paediatric donors and the complications of long-term immunosuppression, including post-transplant lymphoproliferative disorder (PTLD). We report the management of an infant who had heterotopic cardiac transplantation for advanced cardiomyopathy with secondary pulmonary hypertension who developed seemingly incurable PTLD. METHODS: An 8-month-old girl presented in 1994 with signs of severe heart failure, secondary to dilated cardiomyopathy. At age 11 months, the patient underwent a heterotopic cardiac transplantation. FINDINGS: The patient developed many episodes of PTLD associated with Epstein-Barr virus infection that were resistant to several therapies, including reduction of immunosuppression. Native heart recovery enabled removal of the donor heart 10.5 years after the original operation to allow complete cessation of immunosuppression. Her postoperative course was uncomplicated and the outcome was excellent. 3.5 years after surgery, the patient remains well, in complete remission from her PTLD, and has normal cardiac function. INTERPRETATION: This case shows several issues relating to the use of heterotopic cardiac transplantation in infants and the capacity of the heart to recover. It also provides new insights into the interaction between the immune system with several aspects of modern management of post-transplantation PTLD. FUNDING: None.

Effects of clenbuterol on contractility and Ca2+ homeostasis of isolated rat ventricular myocytes.

Clenbuterol, a compound classified as a beta2-adrenoceptor (AR) agonist, has been employed in combination with left ventricular assist devices (LVADs) to treat patients with severe heart failure. Previous studies have shown that chronic administration of clenbuterol affects cardiac excitation-contraction coupling. However, the acute effects of clenbuterol and the signaling pathway involved remain undefined. We investigated the acute effects of clenbuterol on isolated ventricular myocyte sarcomere shortening, Ca2+ transients, and L-type Ca2+ current and compared these effects to two other clinically used beta2-AR agonists: fenoterol and salbutamol. Clenbuterol (30 microM) produced a negative inotropic response, whereas fenoterol showed a positive inotropic response. Salbutamol had no significant effects. Clenbuterol reduced Ca2+ transient amplitude and L-type Ca2+ current. Selective beta1-AR blockade did not affect the action of clenbuterol on sarcomere shortening but significantly reduced contractility in the presence of fenoterol and salbutamol (P < 0.05). Incubation with 2 microg/ml pertussis toxin significantly reduced the negative inotropic effects of 30 microM clenbuterol. In addition, overexpression of inhibitory G protein (Gi) by adenoviral transfection induced a stronger clenbuterol-mediated negative inotropic effect, suggesting the involvement of the Gi protein. We conclude that clenbuterol does not increase and, at high concentrations, significantly depresses contractility of isolated ventricular myocytes, an effect not seen with fenoterol or salbutamol. In its negative inotropism, clenbuterol predominantly acts through Gi, and the consequent downstream signaling pathways activation may explain the beneficial effects observed during chronic administration of clenbuterol in patients treated with LVADs.

Pharmacological inhibition of AMP-deaminase in rat cardiac myocytes.

Because mutation of AMP deaminase 1 gene leading to reduced AMP deaminase activity may result in protection of cardiac function in patients with heart disease, inhibitors of AMP deaminase (AMPD) may have therapeutic applications. This study evaluated the effect of a specific inhibitor of AMP deaminase 3-[2-(3-carboxy-4-bromo-5,6,7,8-tetrahydronaphthyl)ethyl]-3,6,7,8-tetrahydroimidazo [4,5-d][1,3]diazepin-8-ol (AMPDI) on the isolated human enzyme and on nucleotide catabolism in rat cardiomyocytes. AMPDI effectively inhibited isolated human AMPD with an IC(50) = 0.5 micro M. AMPDI was much less effective with isolated cardiomyocytes (IC(50) = 0.5 mM). AMPDI is a very effective inhibitor of AMPD that despite lower efficiency in the cell system examined could be useful for in vivo studies.

[Nasofrontal fistula and epidermoid cyst: a case study]. / Fistule et kyste épidermoïde naso-frontaux: à propos d'une observation.

Nasofrontal fistulas, also called nasofrontal dermal sinuses, are very rare and found for the most part in children. This congenital malformation may be revealed by local infection or neuromeningitis, making this a serious disorder. We report one case of nasofrontal dermal sinus diagnosed in an 11-month-old girl, which was complicated by left fronto-orbital infection. Through this case, the authors stress the role of imaging methods in confirming the diagnosis and looking for associated cysts (dermoid and epidermoid).