Mechanism of improvement in mitral regurgitation after cardiac resynchronization therapy.

AIMS: The aim of the current study was to evaluate the relationship between the presence of left ventricular (LV) dyssynchrony at baseline and acute vs. late improvement in mitral regurgitation (MR) after cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Sixty eight patients consecutive (LV ejection fraction 23 +/- 8%) with at least moderate MR (>or=grade 2+) were included. Echocardiography was performed at baseline, 1 day after CRT initiation and at 6 months follow-up. Speckle tracking radial strain was used to assess LV dyssynchrony at baseline. The majority of patients improved in MR after CRT, with 43% improving immediately after CRT, and 20% improving late (after 6 months) after CRT. Early and late responders had similar extent of LV dyssynchrony (209 +/- 115 ms vs. 190 +/- 118 ms, P = NS); however, the site of latest activation in early responders was mostly inferior or posterior (adjacent to the posterior papillary muscle), whereas the lateral wall was the latest activated segment in late responders. CONCLUSION: Current data suggest that the presence of baseline LV dyssynchrony is related to improvement in MR after CRT. LV dyssynchrony involving the posterior papillary muscle may lead to an immediate reduction in MR, whereas LV dyssynchrony in the lateral wall resulted in late response to CRT.     

Differential gene expression analysis of tubule forming and non-tubule forming endothelial cells: CDC42GAP as a counter-regulator in tubule formation

The formation of new tubular structures from a quiescent endothelial lining is one of the hallmarks of sprouting angiogenesis. This process can be mimicked in vitro by inducing capillary-like tubular structures in a three-dimensional (3D) fibrin matrix. We aimed to analyze the differential mRNA expression in two phenotypically distinct cell populations from the same culture, namely in tubule-forming endothelial cells and monolayer endothelial cells not participating in tubule formation. A fibrin-rich 3D matrix derived from human plasma was used to facilitate tubule formation by human foreskin microvascular endothelial cells (hMVEC). After 7 days of stimulation with VEGF, bFGF, and TNF-alpha, the culture consisted of a monolayer and capillary-like sprouts that had grown into the fibrinous matrix. A method was developed to separate the monolayer and tubule-forming populations of hMVEC, keeping their cellular integrity intact to ensure mRNA extraction and cDNA production. Subsequent array analysis resulted in an inventory of differentially expressed genes that were associated with either tube-forming (angiogenic) or non-angiogenic capacity. Differential gene expression was verified by real-time PCR on the original RNA samples as well as on RNA obtained from laser-capture microdissected cross sections of monolayers and capillary structures in the 3D fibrinous matrix. The expression of CDC42GAP, an inhibitor of active-state small Rho GTPases, was reduced in tubular hMVEC. Overexpression of CDC42GAP in hMVEC attenuated endothelial tubule formation, while its suppression by siRNA slightly enhanced this process. Thus, CDC42GAP was identified as a counter-regulatory mediator for tubule formation.     

Effect of pulmonary vein anatomy and left atrial dimensions on outcome of circumferential radiofrequency catheter ablation for atrial fibrillation

Multislice computed tomography (MSCT) is commonly acquired before radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) to plan and guide the procedure. MSCT allows accurate measurement of the left atrial (LA) and pulmonary vein (PV) dimensions and classification of the PV anatomy. The aim of the present study was to investigate the effect of LA dimensions, PV dimensions, and PV anatomy on the outcome of circumferential RFCA for AF. A total of 100 consecutive patients undergoing RFCA for AF (paroxysmal 72%, persistent 28%) were studied. The LA dimensions, PV dimensions, and PV anatomy were evaluated three dimensionally using MSCT. The PV anatomy was classified as normal or atypical according to the absence/presence of a common trunk or additional veins. After a mean follow-up of 11.6 ± 2.8 months, 65 patients (65%) maintained sinus rhythm. The enlargement of the left atrium in the anteroposterior direction on MSCT was related to a greater risk of AF recurrence. No relation was found between the PV dimensions and the outcome of RFCA. In addition, normal right-sided PV anatomy was related to a greater risk of AF recurrence compared to atypical right-sided PV anatomy. Multivariate analysis showed that an anteroposterior LA diameter on MSCT (odds ratio 1.083, p = 0.027) and normal right-sided PV anatomy (odds ratio 6.711, p = 0.006) were independent predictors of AF recurrence after RFCA. In conclusion, enlargement of the anteroposterior LA diameter and the presence of normal anatomy of the right PVs are independent risk factors for AF recurrence. No relation was found between the PV dimensions and outcome of RFCA.     

Altered Chloroplast Ribosomal Proteins Associated with Erythromycin-Resistant Mutants in Two Genetic Systems of Chlamydomonas reinhardi

The phenotype of several erythromycin-resistant mutants of Chlamydomonas reinhardi was further characterized in terms of the electrophoretic properties of their chloroplast ribosomal proteins. In mutant ery-M2d a single protein of the large (52 S) subunit has altered properties, which probably result from a change in its primary sequence. This mutation is inherited in a Meudelian manner. In mutant ery-U1a, which is inherited in a uniparental manner, a different single protein of the 52 S subunit is altered. This change might result from a change in either the primary sequence of the protein or in some form of secondary modification. These results indicate that these two distinct genetic systems must cooperate in the production of chloroplast ribosomes.     

Some cases demonstrating the clinical usefulness of therapeutic drug monitoring in thiopurine-treated inflammatory bowel disease patients

The thiopurines azathioprine and 6-mercaptopurine (6-MP) are effective drugs in steroid-dependent and refractory inflammatory bowel disease patients. Therapeutic drug monitoring (TDM) is a new concept to improve drug efficacy and prevent toxic adverse events. As thiopurine metabolism is influenced by genetic polymorphisms of methylating enzymes, metabolite levels may vary considerably, enabling significant adverse effects. In the present paper five patients are described to demonstrate the clinical usefulness of TDM when applying thiopurines for inflammatory bowel disease. Emphasized are patients with liver function test abnormalities and myelosuppression due to inappropriate 6-MP metabolite levels, and subsequently the treatment of these events. In addition, sophisticated 6-MP metabolite level-guided therapy, including non-compliance, is demonstrated. These cases demonstrate that TDM may improve effectivity and safety of thiopurine treatment.     

The Psychosocial Distress Questionnaire-Breast Cancer (PDQ-BC) is a useful instrument to screen psychosocial problems

Purpose

Recently, the Psychosocial Distress Questionnaire-Breast Cancer (PDQ-BC), a screening instrument specific for patients with early-stage breast cancer, was developed. The aim of this study was to further examine the psychometric properties of the PDQ-BC, in particular the subscales social support, sexual problems and financial problems.

Methods

Before patients received treatment (N?=?123), they completed the PDQ-BC, the World Health Organization Quality of Life (WHOQOL-100) and the Center for Epidemiologic Studies Depression Scale (CES-D).

Results

Floor effects were present in 44% of the subscales, whereas ceiling effects were only found in the social support subscale (11%). The PDQ-BC subscales social support, sexual problems and financial problems were highly correlated with the corresponding WHOQOL-100 facets social support, sexual activity and financial resources. Furthermore, the subscale depressive symptoms (PDQ-BC) was highly significantly correlated with the CES-D. Low correlations were found between the PDQ-BC subscales and questionnaires that were expected to be unrelated. Exceptions are the subscales trait anxiety and state anxiety, which had a high correlation with the CES-D. The Cronbach’s alpha coefficients of the subscales trait anxiety, state anxiety, depressive symptoms, body image and physical problems ranged from 0.70 to 0.87. Social problems had a low consistency (0.39). Corrected item–total correlations confirmed the PDQ-BC structure.

Conclusions

The PDQ-BC has expected floor effects, few ceiling effects and sufficient internal consistency. Furthermore, the construct validity on the PDQ-BC subscales social support, sexual problems and financial problems was good. Thus, the PDQ-BC can be used to screen psychosocial problems in patients with early-stage breast cancer as part of routine care.     

Prevalence and Implications of Cerebrospinal Fluid Leukocytosis in Papua New Guinean Children Hospitalized with Severe Malaria

Cerebrospinal fluid (CSF) leukocytosis in severe malaria was assessed in 87 children in Papua New Guinea participating in a detailed longitudinal observational study who had undergone lumbar puncture for further investigation of altered consciousness and/or convulsions. After rigorous exclusion of non-malarial infection, 16 (20.5%) of 78 children with Plasmodium falciparum monoinfection but 0 of 9 with P. vivax/mixed-species malaria had a detectable CSF leukocytosis, which was unrelated to prior, including complex, seizures. There were eight children with a CSF leukocyte density > 10 cells/μL (9.2% of the total sample), half of whom had cerebral malaria (4 of 22, 18.1%). Cerebrospinal fluid leukocytosis is infrequent in severe pediatric malaria, especially in children with P. vivax infections, and it is generally mild. Its presence in a blood slide–positive child should prompt consideration of alternative diagnoses and empiric antibiotic therapy.Studies reporting cerebrospinal fluid (CSF) leukocytosis in cases of pediatric cerebral malaria have been conducted mainly in sub-Saharan Africa where Plasmodium falciparum monoinfections predominate. Approximately 10% of children with cerebral malaria and no bacteriologic evidence of acute bacterial meningitis have CSF pleocytosis of > 10 cells/μL in this setting.¹ Plasmodium vivax is increasingly recognized as a cause of severe malarial illness in Oceania and parts of Asia and South America.There is limited evidence that CSF leukocytosis can also be found in patients with P. vivax malaria and altered consciousness,^2,3 but these studies did not rigorously exclude co-infections with bacterial and, as in studies in Africa of cerebral malaria caused by P. falciparum,¹ viral, or fungal pathogens. Febrile seizures caused by non-malarial infections may also cause CSF leukocytosis in some children⁴ and are a common feature of pediatric severe malaria, thus further exacerbating diagnostic uncertainties when a severely ill child seeks treatment in a malaria-endemic setting. Therefore, there is a need for a prospective study that determines whether severe pediatric malaria caused by P. falciparum or P. vivax can cause CSF leukocytosis after other infective causes of encephalopathy have been excluded and after taking prior febrile seizures into account.We studied hospitalized children in Papua New Guinea who were enrolled in a detailed observational study of severe pediatric infections conducted in coastal Madang Province where there is transmission of multiple Plasmodium species. The study was approved by the Papua New Guinea Institute of Medical Research Institutional Review Board and the Medical Research Advisory Committee of Papua New Guinea (MRAC 10.08), and parental written consent was obtained before recruitment in all cases. To rule out acute bacterial meningitis in children in Papua New Guinea, routine lumbar puncture is usually performed if a child has impaired consciousness or after febrile seizures but has no clinical evidence of increased intracranial pressure.⁵ Cerebrospinal fluid leukocytes at presentation were quantified by microscopic examination using the Neubauer improved chamber (BoeCo, Hamburg, Germany). When erythrocytes were present, an adjusted leukocyte count calculated as leukocytes – [erythrocytes/100] was used⁵ (

Myocardial strain to detect subtle left ventricular systolic dysfunction

In daily clinical practice, LV systolic function is routinely assessed with the use of two‐dimensional echocardiography. Using biplane LV end‐diastolic and end‐systolic volumes, LVEF is calculated. The introduction of real‐time three‐dimensional echocardiography has improved the accuracy of echocardiographic assessment of LVEF. However, calculated LVEF may not truly represent LV systolic function in specific cardiac diseases or when subtle LV dysfunction is present. Two‐dimensional speckle tracking echocardiography enables assessment of myocardial strain, thereby providing detailed information on global and regional LV deformation. This is of particular interest when subtle LV systolic dysfunction is present despite preserved LVEF. In this review, the potential use of LV global longitudinal strain to detect subtle LV systolic dysfunction is illustrated in various clinical scenarios.     

Clinical features and outcome of patients with cutaneous melioidosis during a nosocomial outbreak in a temperate region of Australia

Six cases of cutaneous melioidosis from southwestern Australia, a non‐endemic region occurred as a result of Burkholderia pseudomallei contamination of normal saline that was used for irrigating superficial wounds. Treatment with parenteral meropenem, given by continuous infusion for 2 weeks, followed by oral antibiotics was successful in all cases.