Systematic review of atraumatic splenic rupture

BACKGROUND: Atraumatic splenic rupture (ASR) is an ill defined clinicopathological entity. METHODS: The aim was to characterize aetiological and risk factors for ASR-related mortality in order to aid disease classification and treatment. A systematic literature review (1980-2008) was undertaken and logistic regression analysis employed. RESULTS: Some 632 publications reporting 845 patients were identified. The spleen was normal in 7.0 per cent (atraumatic-idiopathic rupture). One, two or three aetiological factors were found in 84.1, 8.2 and 0.7 per cent respectively (atraumatic-pathological rupture). Six major aetiological groups were defined: neoplastic (30.3 per cent), infectious (27.3 per cent), inflammatory, non-infectious (20.0 per cent), drug- and treatment-related (9.2 per cent) and mechanical (6.8 per cent) disorders, and normal spleen (6.4 per cent). Treatment comprised total splenectomy (84.1 per cent), organ-preserving surgery (1.2 per cent) or conservative measures (14.7 per cent). The ASR-related mortality rate was 12.2 per cent. Splenomegaly (P = 0.040), age above 40 years (P = 0.007) and neoplastic disorders (P = 0.008) were associated with increased ASR-related mortality on multivariable analysis. CONCLUSION: The condition can be classified simply into atraumatic-idiopathic (7.0 per cent) and atraumatic-pathological (93.0 per cent) splenic rupture. Splenomegaly, advanced age and neoplastic disorders are associated with increased ASR-related mortality.

The role of common single-nucleotide polymorphisms on exon 9 and exon 12 skipping in nonmutated CFTR alleles

Classic cystic fibrosis (CF) is caused by two loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, whereas patients with nonclassic CF have at least one copy of a mutant gene that retains partial function of the CFTR protein. In addition, there are several other phenotypes associated with CFTR gene mutations, such as idiopathic chronic pancreatitis. In CFTR-associated disorders and in nonclassic CF, often only one CFTR mutation or no CFTR mutations can be detected. In this study, we screened 23 patients with CFTR-associated disorders for CFTR mutations by complete gene testing and quantitative transcript analysis. Mutations were found in 10 patients. In cells from respiratory epithelium, we detected aberrant splicing of CFTR mRNA in all investigated individuals. We observed a highly significant association between the presence of coding single-nucleotide polymorphisms (coding SNPs, or cSNPs) and increased skipping of exon 9 and 12. This association was found both in patients and in normal individuals carrying the same cSNPs. The cSNPs c.1540A>G, c.2694T>G, and c.4521G>A may have affected pre-mRNA splicing by changing regulatory sequence motifs of exonic splice enhancers, leading to lower amounts of normal transcripts. The analysis of CFTR exons indicated that less frequent and weak exonic splicing enhancer (ESE) motifs make exon 12 vulnerable to skipping. The number of splice variants in individuals with cSNPs was similar to previously reported values for the T5 allele, suggesting that cSNPs may enhance susceptibility to CFTR related diseases. In addition, cSNPs may be responsible for variation in the phenotypic expression of CFTR mutations. Quantitative approaches rather than conventional genomic analysis are required to interpret the role of cSNPs.

Hyperaldosteronism in pregnancy

Aldosterone is a key regulator of electrolyte and water homeostasis and plays a central role in blood pressure regulation. Hormonal changes during pregnancy, among them increased progesterone and aldosterone production, lead to the required plasma volume expansion of the maternal body as an accommodation mechanism for fetus growth. This review discusses the regulation of aldosterone production by aldosterone synthase (CYP11B2); the impact on aldosterone secretion due to the presence of a chimeric gene originating from a crossover between CYP11B1 and CYP11B2 in glucocorticoid remediable aldosteronism (GRA) - the inherited form of hypertension; enhanced aldosterone production in aldosterone-producing adenoma (APA); and idiopathic hyperaldosteronism (IHA). Features of hyperaldosteronism are also found in patients with apparent mineralocorticoid excess (AME), in which glucocorticoids exacerbate activation of the mineralocorticoid receptor (MR) because of a defect in the 11beta-hydroxysteroid dehydrogenase type 2 enzyme. Regulation of aldosterone production and tissue-specific activation of the mineralocorticoid receptor are prerequisites for optimal control of body fluids and blood pressure during pregnancy and contribute largely to the wellbeing of the mother-to-be.

Suprasellar germinomas in childhood and adolescence: diagnostic pitfalls

The clinical and neuro-endocrine data of seven young male patients with suprasellar germinomas seen between 1984 and 1992 are reported. The most common initial symptom was 'idiopathic' central diabetes insipidus (DI), which occurred in all seven patients. The time interval between the appearance of this first clinical sign and the definitive diagnosis of a suprasellar germinoma ranged from 3 to 66 months. Raised prolactin levels and growth hormone deficiency were indicators of a process located in the hypothalamic-pituitary region. An increased beta-HCG level in the serum or the CSF confirmed the diagnostic suspicion of a germinoma and was helpful as a tumor marker in follow-up. Neuro-radiologic studies (CT or MRI) were also disappointing in the early stage when patients presented only with DI. Later on, as patients developed additional symptoms or signs related to the tumor, imaging studies were positive. Given the variable rate of tumor progression, the nonspecific early signs of hypothalamic-pituitary dysfunction (DI) as well as the often negative early imaging studies, the diagnosis of suprasellar germinoma is difficult but should always be considered in the presence of so-called 'idiopathic' central DI. Repeated brain MRIs are mandatory in young patients with idiopathic DI in order not to miss an underlying suprasellar germinoma.

Small intestinal intussusception in five dogs with acute renal failure and suspected leptospirosis (L. australis)

OBJECTIVES This case series describes 5 dogs with small intestinal intussusception and acute kidney injury due to infection with Leptospira interrogans serovar Australis. CASE SERIES SUMMARY Small intestinal intussusception was observed in 4 dogs diagnosed with acute kidney injury due to leptospirosis presented between 1997 and 2005. Intussusception was diagnosed at initial presentation or later during hospitalization. An additional dog fulfilling our inclusion criteria was presented to a small animal specialty clinic nearby and was included. Upon admission, all dogs were severely azotemic and thrombocytopenic. All 5 dogs showed the strongest microscopic agglutination test serology reaction to L. interrogans serovar Australis. Two dogs survived with no apparent residual renal damage, 1 survived with subsequent mild chronic kidney disease, and 2 dogs were euthanized at the owners' request due to a guarded prognosis. NEW OR UNIQUE INFORMATION PROVIDED Intussusception can occur or may be seen in dogs with leptospirosis due to L. interrogans serovar Australis and patients should be monitored closely for this potential complication. As all 5 dogs described in this case series showed the highest titer for L. interrogans serovar Australis, these precautions may be especially applied in geographic areas where this particular serovar is seen.

Valgus Hip With High Antetorsion Causes Pain Through Posterior Extraarticular FAI

BACKGROUND: Valgus hips with increased antetorsion present with lack of external rotation and posterior hip pain that is aggravated with hip extension and external rotation. This may be the result of posterior femoroacetabular impingement (FAI). QUESTIONS/PURPOSES: We asked whether (1) the range of motion (ROM); (2) the location of anterior and posterior bony collision zones; and (3) the prevalence of extraarticular impingement differ between valgus hips with increased antetorsion compared with normal hips and hips with idiopathic FAI. METHODS: Surface models based on CT scan reconstructions of 13 valgus hips with increased antetorsion, 22 hips with FAI, and 27 normal hips were included. Validated three-dimensional collision detection software was used to quantify the simulated hip ROM and the location of impingement on the acetabular and the femoral sides. RESULTS: Hips with coxa valga and antetorsion showed decreased extension, external rotation, and adduction, whereas internal rotation in 90° of flexion was increased. Impingement zones were more anteroinferior on the femur and posteroinferior on the acetabular (pelvic) side; and the zones were more frequently extraarticular, posterior, or to a lesser degree anterior against the inferior iliac spine. We found a higher prevalence of extraarticular impingement for valgus hips with increased antetorsion. CONCLUSIONS: Valgus hips with increased antetorsion predispose to posterior extraarticular FAI and to a lesser degree anteroinferior spine impingement. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

Integration of merged delayed-enhanced magnetic resonance imaging and multidetector computed tomography for the guidance of ventricular tachycardia ablation: a pilot study

BACKGROUND Delayed enhancement (DE) MRI can assess the fibrotic substrate of scar-related VT. MDCT has the advantage of inframillimetric spatial resolution and better 3D reconstructions. We sought to evaluate the feasibility and usefulness of integrating merged MDCT/MRI data in 3D-mapping systems for structure-function assessment and multimodal guidance of VT mapping and ablation. METHODS Nine patients, including 3 ischemic cardiomyopathy (ICM), 3 nonischemic cardiomyopathy (NICM), 2 myocarditis, and 1 redo procedure for idiopathic VT, underwent MRI and MDCT before VT ablation. Merged MRI/MDCT data were integrated in 3D-mapping systems and registered to high-density endocardial and epicardial maps. Low-voltage areas (<1.5 mV) and local abnormal ventricular activities (LAVA) during sinus rhythm were correlated to DE at MRI, and wall-thinning (WT) at MDCT. RESULTS Endocardium and epicardium were mapped with 391 ± 388 and 1098 ± 734 points per map, respectively. Registration of MDCT allowed visualization of coronary arteries during epicardial mapping/ablation. In the idiopathic patient, integration of MRI data identified previously ablated regions. In ICM patients, both DE at MRI and WT at MDCT matched areas of low voltage (overlap 94 ± 6% and 79 ± 5%, respectively). In NICM patients, wall-thinning areas matched areas of low voltage (overlap 63 ± 21%). In patients with myocarditis, subepicardial DE matched areas of epicardial low voltage (overlap 92 ± 12%). A total number of 266 LAVA sites were found in 7/9 patients. All LAVA sites were associated to structural substrate at imaging (90% inside, 100% within 18 mm). CONCLUSION The integration of merged MDCT and DEMRI data is feasible and allows combining substrate assessment with high-spatial resolution to better define structure-function relationship in scar-related VT.

Outflow tract tachycardia with R/S transition in lead V3: six different anatomic approaches for successful ablation.

OBJECTIVES The aim of this study was to analyze different anatomic mapping approaches for successful ablation of outflow tract tachycardia with R/S transition in lead V(3). BACKGROUND Idiopathic ventricular tachycardia can originate from different areas in the outflow tract, including the right and left ventricular endocardium, the epicardium, the pulmonary artery, and the aortic sinus of Valsalva. Although electrocardiographic criteria may be helpful in predicting the area of origin, sometimes the focus is complex to determine, especially when QRS transition in precordial leads is in V(3). METHODS We analyzed surface electrocardiograms of 33 successfully ablated patients with outflow tract tachycardia: 20 from the right ventricular outflow tract (RVOT) and 13 from different sites. The R/S transition was determined, and the different anatomic approaches needed for successful catheter ablation were studied. RESULTS Overall, R/S transition in lead V(3) was present in 19 (58%) of all patients. In these patients, mapping was started and successfully completed in the RVOT in 11 of 19 (58%) patients. The remaining eight patients with R/S transition in lead V(3) needed five additional anatomic accesses for successful ablation: from the left ventricular outflow tract (n = 3), aortic sinus of Valsalva (n = 2), coronary sinus (n = 1), the epicardium via pericardial puncture (n = 1), and the trunk of the pulmonary artery (n = 1), respectively. CONCLUSIONS A R/S transition in lead V(3) is common. In patients with outflow tract tachycardia with R/S transition in lead V(3), a stepwise endocardial and epicardial mapping through up to six anatomic approaches can lead to successful radiofrequency catheter ablation.

The cam-type deformity - what is it: SCFE, osteophyte, or a new disease?

Cam-type deformity of the proximal femur is a risk factor for the development of cam-type femoroacetabular impingement and a prearthrotic condition of the hip. The etiology of cam-type deformity remains unclear. There are a number of causes of cam-type deformity including sequellae of slipped capital femoral epiphysis, Legg-Calvé-Perthes disease or Perthes-like deformities, postinfectious, and traumatic. However, the majority of cam-type deformities arise without any apparent preexisting hip disease. These "idiopathic" cam-type deformities likely represent a majority of cases, and show clear racial and sex differences, as well as developmental and genetic influences. Idiopathic cam-type deformity also seems to be a distinct entity from residual or silent slipped capital femoral epiphysis, as well as osteoarthritis-induced osteophytes. In this paper we examine the different pathogenetic aspects of the proximal femur that contribute to cam-type deformity and/or symptomatic cam-type femoroacetabular impingement.

Microbial communities in the respiratory tract of patients with interstitial lung disease

Background Molecular methods based on phylogenetic differences in the 16S rRNA gene are able to characterise the microbiota of the respiratory tract in health and disease. Objectives Our goals were (1) to characterise bacterial communities in lower and upper airways of patients with interstitial lung disease (ILD) and (2) to compare the results with the microbiota of patients with Pneumocystis pneumonia (PCP) and normal controls. Methods We examined the upper and lower respiratory tract of 18 patients with ILD of whom 5, 6, and 7 had idiopathic interstitial pneumonia (IIP), non-IIP and sarcoidosis, respectively. In addition, six immune-compromised patients with PCP and nine healthy subjects were included as controls. Exclusion criteria were recent bacterial/viral respiratory tract infection, HIV-positivity and subjects receiving antibiotic therapy. Bronchoalveolar lavage fluid and oropharyngeal swabs were simultaneously collected, and microbiota was characterised by ultra-deep 16S rRNA gene sequencing. Results The microbiota in lower airways of the majority of patients (30; 90%) primarily consisted of Prevotellaceae, Streptococcaceae and Acidaminococcaceae. α and β diversity measurements revealed no significant differences in airway microbiota composition between the five different groups of patients. Comparison of bacterial populations in upper and lower respiratory tract showed significant topographical discontinuities for 7 (23%) individuals. Conclusions IIP, non-IIP and sarcoidosis are not associated with disordered airway microbiota and a pathogenic role of commensals in the disease process is therefore unlikely. Nevertheless, molecular analysis of the topographical microbiota continuity along the respiratory tract may provide additional information to assist management of individual patients.

THE ROLE OF A2B ADENOSINE RECEPTOR SIGNALING IN ADENOSINE DEPENDENT LUNG DISEASE

Chronic lung diseases and acute lung injuries are two distinctive pulmonary disorders that result in significant morbidity and mortality. Adenosine is a signaling nucleoside generated in response to injury and can serve both protective and destructive functions in tissues and cells through interaction with four G-protein coupled adenosine receptors: A1R, A2AR, A2BR, and A3R. However, the relationship between these factors is poorly understood. Recent findings suggest the A2BR has been implicated in the regulation of both chronic lung disease and acute lung injury. The work presented in this dissertation utilized the adenosine deaminase-deficient mouse model and the bleomycin-induced pulmonary injury model to determine the distinctive roles of the A2BR at different stages of the disease. Results demonstrate that the A2BR plays a protective role in attenuating vascular leakage in acute lung injuries and a detrimental role at chronic stages of the disease. In addition, tissues from patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis were utilized to examine adenosine metabolism and signaling in chronic lung diseases. Results demonstrate that components of adenosine metabolism and signaling are altered in a manner that promotes adenosine production and signaling in the lungs of these patients. Furthermore, this study provides the first evidence that A2BR signaling can promote the production of inflammatory and fibrotic mediators in patients with these disorders. Taken together, these findings suggest that the A2BR may have a bi-phasic effect at different stages of lung disease. It is protective in acute injury, whereas pro-inflammatory and pro-fibrotic at the chronic stage. Patients with acute lung injury or chronic lung disease may both benefit from adenosine and A2BR-based therapeutics.

Xenobiotic Metabolism Genes and Clubfoot

Idiopathic or isolated clubfoot is a common orthopedic birth defect that affects approximately 135,000 children worldwide. It is characterized by equinus, varus and adductus deformities of the ankle and foot. Correction of clubfoot involves months of serial manipulations, castings and bracing, with surgical correction needed in forty percent of cases. Multifactorial etiology has been suggested in numerous studies with both environmental and genetic factors playing an etiologic role. Maternal smoking during pregnancy is the only common environmental factor that has consistently been shown to increase the risk for clubfoot. Moreover, a positive family history of clubfoot and maternal smoking increases the risk of clubfoot twenty fold. These findings suggest that genetic variation in smoking metabolism genes may increase susceptibility to clubfoot. Based on this reasoning, we interrogated eight candidate genes, chosen based on their involvement in phase 1 and 2 cigarette smoke metabolism. Twenty-two SNPs and two null alleles in eight genes (CYP1A1, CYP1A2, CYP1B1, CYP2A6, EPHX1, NAT2, GSTM1 and GSTT1) were genotyped in a dataset composed of nonHispanic white and Hispanic multiplex and simplex families. Only one SNP in CYP1A1, rs1048943, had significantly altered transmission in the aggregate and multiplex NHW datasets (p=0.003 and p=0.009). Perturbation of CYP1A1 by rs1048943 polymorphism causes an increase in the amount of harmful, adduct forming metabolic intermediates. A significant gene interaction between EPHX1 and NAT2 was also found (p=0.007). This interaction may affect the metabolism of harmful metabolic intermediates. Additionally, marginal interactions were found for other xenobiotic genes and these interactions may play a contributory role in clubfoot. Importantly, for CYP1A2, significant maternal (p=0.03; RR=1.24; 95% CI: 1.04-1.44) and fetal (p=0.01; RR=1.33; 95% CI: 1.13-1.54) genotypic effects were identified suggesting that both maternal and fetal genotypes impact normal limb development. No association was found for maternal smoking status and tobacco metabolism genes. Together, these results suggest that xenobiotic metabolism genes may play a contributory role in the etiology of clubfoot regardless of maternal smoking status and may impact foot development through perturbation of tobacco metabolic pathways.

T-786C polymorphism of the endothelial nitric oxide synthase gene and neuralgia-inducing cavitational osteonecrosis of the jaws.

OBJECTIVE: We hypothesized that, similar to idiopathic hip osteonecrosis, the T-786C mutation of the endothelial nitric oxide synthase (eNOS) gene affecting nitric oxide (NO) production was associated with neuralgia-inducing cavitational osteonecrosis of the jaws (NICO). DESIGN: In 22 NICO patients, not having taken bisphosphonates, mutations affecting NO production (eNOS T-786C, stromelysin 5A6A) were measured by polymerase chain reaction. Two healthy normal control subjects were matched per case by race and gender. RESULTS: Homozygosity for the mutant eNOS allele (TT) was present in 6 out of 22 patients (27%) with NICO compared with 0 out of 44 (0%) race and gender-matched control subjects; heterozygosity (TC) was present in 8 patients (36%) versus 15 control subjects (34%); and the wild-type normal genotype (CC) was present in 9 patients (36%) versus 29 controls (66%) (P = .0008). The mutant eNOS T-786C allele was more common in cases (20 out of 44 [45%]) than in control subjects (15 out of 88 [17%]) (P = .0005). The distribution of the stromelysin 5A6A genotype in cases did not differ from control subjects (P = .13). CONCLUSIONS: The eNOS T-786C polymorphism affecting NO production is associated with NICO, may contribute to the pathogenesis of NICO, and may open therapeutic medical approaches to treatment of NICO through provision of L-arginine, the amino-acid precursor of NO.

Neuroimaging of epilepsy: lesions, networks, oscillations

While analysis and interpretation of structural epileptogenic lesion is an essential task for the neuroradiologist in clinical practice, a substantial body of epilepsy research has shown that focal lesions influence brain areas beyond the epileptogenic lesion, across ensembles of functionally and anatomically connected brain areas. In this review article, we aim to provide an overview about altered network compositions in epilepsy, as measured with current advanced neuroimaging techniques to characterize the initiation and spread of epileptic activity in the brain with multimodal noninvasive imaging techniques. We focus on resting-state functional magnetic resonance imaging (MRI) and simultaneous electroencephalography/fMRI, and oppose the findings in idiopathic generalized versus focal epilepsies. These data indicate that circumscribed epileptogenic lesions can have extended effects on many brain systems. Although epileptic seizures may involve various brain areas, seizure activity does not spread diffusely throughout the brain but propagates along specific anatomic pathways that characterize the underlying epilepsy syndrome. Such a functionally oriented approach may help to better understand a range of clinical phenomena such as the type of cognitive impairment, the development of pharmacoresistance, the propagation pathways of seizures, or the success of epilepsy surgery.

ANKRD1, the gene encoding cardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene.

OBJECTIVES: We evaluated ankyrin repeat domain 1 (ANKRD1), the gene encoding cardiac ankyrin repeat protein (CARP), as a novel candidate gene for dilated cardiomyopathy (DCM) through mutation analysis of a cohort of familial or idiopathic DCM patients, based on the hypothesis that inherited dysfunction of mechanical stretch-based signaling is present in a subset of DCM patients. BACKGROUND: CARP, a transcription coinhibitor, is a member of the titin-N2A mechanosensory complex and translocates to the nucleus in response to stretch. It is up-regulated in cardiac failure and hypertrophy and represses expression of sarcomeric proteins. Its overexpression results in contractile dysfunction. METHODS: In all, 208 DCM patients were screened for mutations/variants in the coding region of ANKRD1 using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct deoxyribonucleic acid sequencing. In vitro functional analyses of the mutation were performed using yeast 2-hybrid assays and investigating the effect on stretch-mediated gene expression in myoblastoid cell lines using quantitative real-time reverse transcription-polymerase chain reaction. RESULTS: Three missense heterozygous ANKRD1 mutations (P105S, V107L, and M184I) were identified in 4 DCM patients. The M184I mutation results in loss of CARP binding with Talin 1 and FHL2, and the P105S mutation in loss of Talin 1 binding. Intracellular localization of mutant CARP proteins is not altered. The mutations result in differential stretch-induced gene expression compared with wild-type CARP. CONCLUSIONS: ANKRD1 is a novel DCM gene, with mutations present in 1.9% of DCM patients. The ANKRD1 mutations may cause DCM as a result of disruption of the normal cardiac stretch-based signaling.