A novel C-terminal truncation SCN5A mutation from a patient with sick sinus syndrome, conduction disorder and ventricular tachycardia

OBJECTIVES: Individual mutations in the SCN5A-encoding cardiac sodium channel alpha-subunit cause single cardiac arrhythmia disorders, but a few cause multiple distinct disorders. Here we report a family harboring an SCN5A mutation (L1821fs/10) causing a truncation of the C-terminus with a marked and complex biophysical phenotype and a corresponding variable and complex clinical phenotype with variable penetrance. METHODS AND RESULTS: A 12-year-old male with congenital sick sinus syndrome (SSS), cardiac conduction disorder (CCD), and recurrent monomorphic ventricular tachycardia (VT) had mutational analysis that identified a 4 base pair deletion (TCTG) at position 5464-5467 in exon 28 of SCN5A. The mutation was also present in six asymptomatic family members only two of which showed mild ECG phenotypes. The deletion caused a frame-shift mutation (L1821fs/10) with truncation of the C-terminus after 10 missense amino acid substitutions. When expressed in HEK-293 cells for patch-clamp study, the current density of L1821fs/10 was reduced by 90% compared with WT. In addition, gating kinetic analysis showed a 5-mV positive shift in activation, a 12-mV negative shift of inactivation and enhanced intermediate inactivation, all of which would tend to reduce peak and early sodium current. Late sodium current, however, was increased in the mutated channels. CONCLUSIONS: The L1821fs/10 mutation causes the most severe disruption of SCN5A structure for a naturally occurring mutation that still produces current. It has a marked loss-of-function and unique phenotype of SSS, CCD and VT with incomplete penetrance.     

Tracheostomy and related host-pathogen interaction are associated with airway inflammation as characterized by tracheal aspirate analysis

In the last years an increasing number of subjects experienced respiratory failure and underwent tracheostomy. The aim of the present study was to analyze tracheal aspirates from the inflammatory point of view. Samples were collected from 38 consecutive tracheostomized patients: 13 COPD, 6 with neurologic disorders and 19 with other different causes of respiratory failure. We analyzed cells and soluble mediators related to inflammation and/or infection. We also compared results obtained in the tracheal aspirate of COPD patients with the same determination in the sputum of another group of non-tracheostomized COPD patients (n=41). Regardless of the underlying diagnosis, most of the samples were Pseudomonas aeruginosa positive and cells and soluble mediator did not differ. Treatment with steroids was associated with lower amount of total cells, neutrophils and lymphocytes, whereas treatment with antibiotics was not. Tracheal aspirate neutrophils correlated with PaCO(2) values; neutrophils and eosinophils correlated with their percentages in blood. As compared with sputa obtained from another group of culture-positive non-tracheostomized COPDs, tracheal aspirates showed similar cell count, proportions of inflammatory cells, and infection/inflammatory mediators. In conclusion tracheal aspirates presented high amounts of viable cells and soluble mediators independently to the cause of respiratory failure leading to tracheotomy and they represent suitable specimens to study infection/inflammation interactions.     

Time of non-invasive ventilation

Non-invasive ventilation (NIV) is a safe, versatile and effective technique that can avert side effects and complications associated with endotracheal intubation. The success of NIV relies on several factors, including the type and severity of acute respiratory failure, the underlying disease, the location of treatment, and the experience of the team. The time factor is also important. NIV is primarily used to avert the need for endotracheal intubation in patients with early-stage acute respiratory failure and post-extubation respiratory failure. It can also be used as an alternative to invasive ventilation at a more advanced stage of acute respiratory failure or to facilitate the process of weaning from mechanical ventilation. NIV has been used to prevent development of acute respiratory failure or post-extubation respiratory failure. The number of days of NIV and hours of daily use differ, depending on the severity and course of the acute respiratory failure and the timing of application. In this review article, we analyse, compare and discuss the results of studies in which NIV was applied at various times during the evolution of acute respiratory failure.     

Obesity,dyslipidaemia and candidate gene polymorphisms: a cross-sectional study among the Liangmai and Mizo tribes of Manipur,India

BackgroundThe prevalence of obesity and dyslipidaemia was observed to be increased among the tribal populations, due to globalization.Materials and methodsIn the present study, data on demographic, somatometric and blood samples were collected from 613 participants of both sex, age 18–60 years, further lipid profiling and genotyping was executed. Multifactor dimensionality reduction (MDR) software was used for gene–gene interactions analysis.ResultsSignificantly differences were observed with respect to the general characteristic and selected gene polymorphisms in both the tribes. Among the Liangmai tribe, MC4R gene was found to pose significant decreased risk for waist–height ratio (WHtR) (OR = 0.56; 95% confidence interval (CI)= 0.32–0.99; p value = .04) and HDL (OR = 0.58; 95% CI = 0.36–0.92; p value = .02). Similar trends of significant decreased risk (OR = 0.39; 95% CI = 0.20–0.76; p value=.006) for BMI were observed among the Mizo tribe. The gene–gene interaction revealed the combined model of FTO+MC4R genes shows an increased risk for BMI in both the tribes. The independent significant increased risk posed by FTO gene was moderated by interaction with MC4R gene.ConclusionsThe observed differences can possibly attribute to both their respective ancestries resulting in different gene pools and the physical environment. The results of the study highlight the importance of gene–gene and gene–environment interactions in adverse phenotype groups.

KEY MESSAGE

• Among the tribal population, the prevalence of obesity and dyslipidaemia has been increased.
• Differential distribution and associations of selected markers hint towards differential genetic architecture in these populations.
• MC4R rs17782313 polymorphism was found to show a significantly decreased risk for WHtR and low HDL among the Liangmai tribe and BMI among the Mizo tribe.
• Significant increased risk posed by FTO rs9939609 gene polymorphism was moderated by the interaction with MC4R rs17782313.

     

Genomic Analysis of Three Metastatic Prostate Cancer Patients with Exceptional Responses to Carboplatin Indicating Different Types of DNA Repair Deficiency

Platinum-based regimens have not been proved to increase survival from advanced prostate cancer (PCa). Incontrovertible evidence that a proportion of prostate cancers have homologous recombination DNA (HRD) repair defects, and that such genomic aberrations are synthetically lethal with both poly(ADP)-ribose polymerase inhibition and platinum, has increased interest in the utilisation of these drugs against a subset of these diseases. Here in we report three patients with advanced castration-resistant PCa with HRD defects having exceptional responses to carboplatin.     

Risk factors for extubation failure in patients following a successful spontaneous breathing trial

BACKGROUND: To assess the factors associated with reintubation in patients who had successfully passed a spontaneous breathing trial. METHODS: We used logistic regression and recursive partitioning analyses of prospectively collected clinical data from adults admitted to ICUs of 37 hospitals in eight countries, who had undergone invasive mechanical ventilation for > 48 h and were deemed ready for extubation. RESULTS: Extubation failure occurred in 121 of the 900 patients (13.4%). The logistic regression analysis identified the following associations with reintubation: rapid shallow breathing index (RSBI) [odds ratio (OR), 1.009 per unit; 95% confidence interval (CI), 1.003 to 1.015]; positive fluid balance (OR, 1.70; 95% CI, 1.15 to 2.53); and pneumonia as the reason for initiating mechanical ventilation (OR, 1.77; 95% CI, 1.10 to 2.84). The recursive partitioning analysis allowed the separation of patients into different risk groups for extubation failure: (1) RSBI of > 57 breaths/L/min and positive fluid balance (OR, 3.0; 95% CI, 1.8 to 4.8); (2) RSBI of < 57 breaths/L/min and pneumonia as reason for mechanical ventilation (OR, 2.0; 95% CI, 1.1 to 3.6); (3) RSBI of > 57 breaths/L/min and negative fluid balance (OR, 1.4; 95% CI, 0.8 to 2.5); and (4) RSBI of < 57 breaths/L/min (OR, 1 [reference value]). CONCLUSIONS: Among routinely measured clinical variables, RSBI, positive fluid balance 24 h prior to extubation, and pneumonia at the initiation of ventilation were the best predictors of extubation failure. However, the combined predictive ability of these variables was weak.     

Systems biology of tumor dormancy: linking biology and mathematics on multiple scales to improve cancer therapy

For many decades, it has been appreciated that tumor progression is not monotonic, and development of a cancer cell does not equate to inevitable cancer presentation in the clinic. Tumor progression is challenged by numerous intrinsic and extrinsic bottlenecks that can hold the tumor in dormant stages for prolonged periods. Given the complex, multiscale nature of these bottlenecks, the Center of Cancer Systems Biology organized a workshop on critical issues of systems biology of tumor dormancy. The program for the meeting this past July, chaired by N. Almog and H. Enderling, included discussions and interactive breakout sessions on regulation of tumor dormancy by angiogenesis, tumor-immune system interactions, cancer stem cell kinetics, and cell signaling pathways. Three important conclusions emerged from the meeting. The first was the urgent need to differentiate between tumor cell and tumor population dormancy of the primary tumor and metastatic deposits, the second was the continued need for interdisciplinary dialogs, and the third was the need to bring cross-scale mechanistic thinking to the field to achieve a more robust understanding of tumor dormancy and its clinical implications.