Percutaneous transendocardial VEGF gene therapy: MRI guided delivery and characterization of 3D myocardial strain

BackgroundPatients with myocardial infarcts have unfavorable left ventricular (LV) remodeling and devastating outcomes. This study was performed to determine whether VEGF-gene delivered transendocardially under MR-guidance improves LV three-dimensional (3D) strain (circumferential, longitudinal and radial), reduces infarct transmurality and increases vascular density in a canine model of permanent LAD coronary artery occlusion.MethodsImaging was performed using a 1.5-T MR scanner. Three days after occlusion, a percutaneous catheter was advanced under MR-guidance into the LV chamber for transendocardial delivery of VEGF-gene therapy (n = 6) or LacZ-gene as control (n = 6) into infarcted and peri-infarcted myocardium. MRI was performed before (3 days) and after (50 days) the delivery of therapy using cine, tagged and delayed contrast enhancement. Histochemical and pathological stains were used to assess myocardial viability and vascular density, respectively.ResultsTransendocardial delivery of VEGF-gene therapy and LacZ-gene under MRI guidance was successful in all animals. Significant improvement in 3D strain was observed within 50 days in treated animals. On the other hand, control animals demonstrated deterioration in regional strain over time. Significant reductions in infarct transmurality and increases in capillary and arteriole densities were also observed in VEGF-treated as compared to control animals.ConclusionMR-guided transendocardial delivery of VEGF-gene improved myocardial strain and enhanced transmural infarct resorption. This minimally invasive technique may be useful for delivery of local therapies, designed to promote angiogenesis or myogenesis.     

Urethral Venous Malformation: An Unusual Cause of Recurrent Post-Coital Gross Haematuria in Association with Haematospermia

Three cases of recurrent post-coital haematuria are described. Extensive protracted investigations pinpointed urethral varicosities as the likely cause. All patients were successfully treated with diathermy fulguration.     

Public perceptions of quarantine: community-based telephone survey following an infectious disease outbreak

Background  

The use of restrictive measures such as quarantine draws into sharp relief the dynamic interplay between the individual rights of the citizen on the one hand and the collective rights of the community on the other. Concerns regarding infectious disease outbreaks (SARS, pandemic influenza) have intensified the need to understand public perceptions of quarantine and other social distancing measures.     

Characterization of bacteriocin HV219, produced by Lactococcus lactis subsp. lactis HV219 isolated from human vaginal secretions

Bacteriocin HV219, produced by Lactococcus lactis subsp. lactis HV219, is active against Gram-positive and Gram-negative bacteria. Activity was lost when treated with proteolytic enzymes, SDS, Triton X-114 and Triton X-100, but not at pH 2.0 to 10.0 or after 20 min at 121 degrees C. Growth in the presence of yeast extract as sole nitrogen source yielded 3200 AU/ml. No bacHV219 activity was recorded in MRS broth with maltose, mannose, lactose or sucrose as sole carbohydrate, but fructose yielded 1600 AU/ml. K(2)HPO(4) at 10.0 g/l yielded 3200 AU/ml. Addition of 1.0 mg/l cyanocobalamin, l-ascorbic acid and thiamine to MRS broth yielded 3200 AU/ml, 1600 AU/ml and 1600 AU/ml, respectively. The mode of activity is bacteriolytic, as confirmed by atomic force microscopy.     

PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2

Background:

Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!.

Methods:

The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes.

Results:

All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS.

Conclusion:

Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.     

Unified criteria for ultrasonographic diagnosis of ADPKD

Individuals who are at risk for autosomal dominant polycystic kidney disease are often screened by ultrasound using diagnostic criteria derived from individuals with mutations in PKD1. Families with mutations in PKD2 typically have less severe disease, suggesting a potential need for different diagnostic criteria. In this study, 577 and 371 at-risk individuals from 58 PKD1 and 39 PKD2 families, respectively, were assessed by renal ultrasound and molecular genotyping. Using sensitivity data derived from genetically affected individuals and specificity data derived from genetically unaffected individuals, various diagnostic criteria were compared. In addition, data sets were created to simulate the PKD1 and PKD2 case mix expected in practice to evaluate the performance of diagnostic criteria for families of unknown genotype. The diagnostic criteria currently in use performed suboptimally for individuals with mutations in PKD2 as a result of reduced test sensitivity. In families of unknown genotype, the presence of three or more (unilateral or bilateral) renal cysts is sufficient for establishing the diagnosis in individuals aged 15 to 39 y, two or more cysts in each kidney is sufficient for individuals aged 40 to 59 y, and four or more cysts in each kidney is required for individuals > or = 60 yr. Conversely, fewer than two renal cysts in at-risk individuals aged > or = 40 yr is sufficient to exclude the disease. These unified diagnostic criteria will be useful for testing individuals who are at risk for autosomal dominant polycystic kidney disease in the usual clinical setting in which molecular genotyping is seldom performed.     

Family History of Renal Disease Severity Predicts the Mutated Gene in ADPKD

Mutations of PKD1 and PKD2 account for 85 and 15% of cases of autosomal dominant polycystic kidney disease (ADPKD), respectively. Clinically, PKD1 is more severe than PKD2, with a median age at ESRD of 53.4 versus 72.7 yr. In this study, we explored whether a family history of renal disease severity predicts the mutated gene in ADPKD. We examined the renal function (estimated GFR and age at ESRD) of 484 affected members from 90 families who had ADPKD and whose underlying genotype was known. We found that the presence of at least one affected family member who developed ESRD at age ≤55 was highly predictive of a PKD1 mutation (positive predictive value 100%; sensitivity 72%). In contrast, the presence of at least one affected family member who continued to have sufficient renal function or developed ESRD at age >70 was highly predictive of a PKD2 mutation (positive predictive value 100%; sensitivity 74%). These data suggest that close attention to the family history of renal disease severity in ADPKD may provide a simple means of predicting the mutated gene, which has prognostic implications.Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disorder, with a prevalence of one in 500 to 1000 in the general population. It is the third most common single cause of ESRD in the United States, accounting for 5% of people with ESRD.^1–5 ADPKD is genetically heterogeneous, with two disease genes (PKD1 on chromosome 16 and PKD2 on chromosome 4) accounting for most of the cases. Mutations of PKD1 and PKD2 are thought to account for 85 and 15% of cases, respectively, in linkage-characterized European populations.^6,7 Although the clinical manifestations overlap completely between two gene types, there is a strong locus effect on renal disease severity. Patients with PKD1 have significantly more severe renal disease than patients with PKD2, with larger kidneys and earlier onset at ESRD (median age 53.4 versus 72.7 yr, respectively).^8,9 By contrast, a weak allelic effect (based on the 5′ versus 3′ location of the germline mutations) on renal disease severity may exist for type 1¹⁰ but not type 2 ADPKD.¹¹ In addition, significant intrafamilial renal disease variability is evident, which is thought to be due to genetic and environmental modifiers.^11,12PKD1 is a large, complex gene containing 46 exons spanning 50 kb, with 33 of these exons at the 5′ end being duplicated elsewhere on chromosome 16. PKD2 is a single-copy gene, consisting of 15 exons spanning a 68-kb genomic region. There is marked allelic heterogeneity for both gene types, with 314 truncating mutations having been described in PKD1 and 91 truncating mutations in PKD2.^1,2 PKD1 encodes polycystin 1 (PC1), a large receptor-like protein, and PKD2 encodes polycystin 2 (PC2), a nonselective cation channel that transports calcium. Both PC1 and PC2 physically interact to form a complex that regulates intracellular levels of calcium and are located in the primary cilia of renal tubular cells. Recent studies suggested that the polycystin complex in the primary cilia of renal tubular cells serves as a mechanosensor for urine flow and that dysfunction of this mechanosensor may lead to cellular proliferation and cystogenesis.^1,2Recent advances in our understanding of the molecular pathobiology of ADPKD have led to the discovery of a number of drugs (e.g., tolvaptan, somatostatin, mammalian target of rapamycin inhibitors) that may target cyst growth and delay renal disease progression.^1,2 Several of these promising drugs are being or will be tested in clinical trials, and disease-modifying treatment may become a reality in the not-too-distant future.¹ In this context, the knowledge of ADPKD gene type may allow for the optimization of the design of such clinical trials, and identification of those affected individuals who are most likely to benefit from these novel therapies should they become available; however, the gene type is seldom known for most families in the clinical setting. Although molecular genetic testing, either by linkage or direct mutation analysis, can elucidate the gene type, such testing has its limitations.¹³ Linkage studies require DNA samples from several affected family members and are of limited utility in small families or de novo cases. Mutation-based screening for ADPKD is expensive and yields a definitive pathogenic mutation in only 42 to 63% of cases because the large and complex structure of PKD1 results in many unclassified missense variants whose pathogenicity often cannot be predicted with complete certainty.^14,15In this study, we explored whether renal disease severity can be used as clinical predictors of underlying gene type in families with ADPKD. To predict PKD1, we explored various cutoffs of early age at ESRD as indicative of severe renal disease. To predict PKD2, we explored various cutoffs of late age with renal sufficiency or at ESRD as indicative of milder renal disease. We then evaluated the performance characteristics of these cutoffs to define the optimal criteria for clinical prediction of ADPKD gene type.     

The impact of implantable cardioverter-defibrillator therapy on survival in autosomal-dominant arrhythmogenic right ventricular cardiomyopathy (ARVD5)

OBJECTIVES: We sought to determine the impact of implantable cardioverter-defibrillator (ICD) therapy in patients with familial arrhythmogenic right ventricular cardiomyopathy (ARVC). BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy is a cause of sudden cardiac death, which may be prevented by ICD. METHODS: We studied 11 families in which a 3p25 deoxyribonucleic acid (DNA) haplotype at locus ARVD5 segregated with disease and compared mortality in subjects who received an ICD with that in control subjects who were matched for age, gender, ARVC status, and family. Subjects (n = 367) at 50% a priori risk of inheriting ARVC were classified as high risk (HR) (n = 197), low risk (n = 92), or unknown (n = 78) on the basis of clinical events, DNA haplotyping, and/or pedigree position. Forty-eight HR subjects (30 males, [median age 32 years] and 18 females [median age 41 years]) were followed after ICD (secondary to ventricular tachycardia [VT] in 27%). Survival was compared with 58 HR control subjects who were alive at the same age to-the-day at which the ICD subject received the device. RESULTS: In the HR group, 50% of males were dead by 39 years and females by 71 years: relative risk of death was 5.1 (95% confidence interval 3 to 8.5) for males. The five-year mortality rate after ICD in males was zero compared with 28% in control subjects (p = 0.009). Within five years, the ICD fired for VT in 70% and for VT >240 beats/min in 30%, with no difference in discharge rate when analyzed by ICD indication. CONCLUSIONS: The unknown mutation at the ARVD5 locus causing ARVC results in high mortality. Risk stratification using genetic haplotyping and ICD therapy produced improved survival for males.     

Familial risk of preeclampsia in Newfoundland: a population-based study

This study sought to quantify the familial risk of preeclampsia (proteinuric hypertension) in Newfoundland and to identify characteristics in probands that predict increased familial risk. Reviewed were 5173 obstetric charts from 10 hospitals, representing 99% of deliveries on the island of Newfoundland for a 1-yr period from April 1996 to March 1997; pregnancy-induced hypertension was diagnosed according to strict criteria. Family obstetric histories were obtained from identified probands with preeclampsia, and sisters and mothers of probands were interviewed. In addition, the obstetric charts from sisters and mothers were reviewed to identify preeclampsia. The incidence of preeclampsia in the population was 5.6% (n = 292), and in primiparous women it was 7.9%. Factors independently associated with increased risk of preeclampsia included primiparous delivery, multiple gestation, pregestational and gestational diabetes, maternal age of more than 35 yr, and region of the province. Of 330 sisters identified, 217 had 445 pregnancies, with 331 charts located for review. The incidence of preeclampsia (based on chart review) in 163 primiparous sisters was 20.2%. The relative risk of preeclampsia in primiparous sisters of probands with preeclampsia compared with primiparous women in the population was 2.6 (95% confidence interval, 1.8 to 3.6). Factors in probands independently associated with a higher risk of preeclampsia in sisters included at least 2+ proteinuria and region of the province. This population-based study, which used unbiased ascertainment and strict diagnostic criteria, demonstrated a significantly higher risk of preeclampsia in sisters of probands with preeclampsia, particularly when probands were defined by severity of preeclampsia and by geographic region.