Cured by tonsillectomy: was it really a PFAPA syndrome?

We show how an ultrafast pump-pump excitation induces strong fluorescence depletion in biological samples, such as bacteria-containing droplets, in contrast with fluorescent interferents, such as polycyclic aromatic compounds, despite similar spectroscopic properties. Application to the optical remote discrimination of biotic versus non-biotic particles is proposed. Further improvement is required to allow the discrimination of one pathogenic among other non-pathogenic micro-organisms. This improved selectivity may be reached with optimal coherent control experiments, as discussed in the paper.

The human CFTR protein expressed in CHO cells activates aquaporin-3 in a cAMP-dependent pathway: study by digital holographic microscopy.

The transmembrane water movements during cellular processes and their relationship to ionic channel activity remain largely unknown. As an example, in epithelial cells it was proposed that the movement of water could be directly linked to cystic fibrosis transmembrane conductance regulator (CFTR) protein activity through a cAMP-stimulated aqueous pore, or be dependent on aquaporin. Here, we used digital holographic microscopy (DHM) an interferometric technique to quantify in situ the transmembrane water fluxes during the activity of the epithelial chloride channel, CFTR, measured by patch-clamp and iodide efflux techniques. We showed that the water transport measured by DHM is fully inhibited by the selective CFTR blocker CFTRinh172 and is absent in cells lacking CFTR. Of note, in cells expressing the mutated version of CFTR (F508del-CFTR), which mimics the most common genetic alteration encountered in cystic fibrosis, we also show that the water movement is profoundly altered but restored by pharmacological manipulation of F508del-CFTR-defective trafficking. Importantly, whereas activation of this endogenous water channel required a cAMP-dependent stimulation of CFTR, activation of CFTR or F508del-CFTR by two cAMP-independent CFTR activators, genistein and MPB91, failed to trigger water movements. Finally, using a specific small-interfering RNA against the endogenous aquaporin AQP3, the water transport accompanying CFTR activity decreased. We conclude that water fluxes accompanying CFTR activity are linked to AQP3 but not to a cAMP-stimulated aqueous pore in the CFTR protein.

Polyanalgesic Consensus Conference--2012: recommendations on trialing for intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel.

INTRODUCTION: Trialing for intrathecal pump placement is an essential part of the decision-making process in placing a permanent device. In both the United States and the international community, the proper method for trialing is ill defined. METHODS: The Polyanalgesic Consensus Conference (PACC) is a group of well-published experienced practitioners who meet to update the state of care for intrathecal therapies on the basis of current knowledge in the literature and clinical experience. Anexhaustive search is performed to create a base of information that the panel considers when making recommendations for best clinical practices. This literature, coupled with clinical experience, is the basis for recommendations and for identification of gaps in the base of knowledge regarding trialing for intrathecal pump placement. RESULTS: The panel has made recommendations for the proper methods of trialing for long-term intrathecal drug delivery. CONCLUSION: The use of intrathecal drug delivery is an important part of the treatment algorithm for moderate to severe chronic pain. It has become common practice to perform a temporary neuroaxial infusion before permanent device implantation. On the basis of current knowledge, the PACC has developed recommendations to improve care. The need to update these recommendations will be very important as new literature is published.

The fourth transmembrane segment of the Na,K-ATPase alpha subunit: a systematic mutagenesis study.

The Na,K-ATPase is a major ion-motive ATPase of the P-type family responsible for many aspects of cellular homeostasis. To determine the structure of the pathway for cations across the transmembrane portion of the Na,K-ATPase, we mutated 24 residues of the fourth transmembrane segment into cysteine and studied their function and accessibility by exposure to the sulfhydryl reagent 2-aminoethyl-methanethiosulfonate. Accessibility was also examined after treatment with palytoxin, which transforms the Na,K-pump into a cation channel. Of the 24 tested cysteine mutants, seven had no or a much reduced transport function. In particular cysteine mutants of the highly conserved "PEG" motif had a strongly reduced activity. However, most of the non-functional mutants could still be transformed by palytoxin as well as all of the functional mutants. Accessibility, determined as a 2-aminoethyl-methanethiosulfonate-induced reduction of the transport activity or as inhibition of the membrane conductance after palytoxin treatment, was observed for the following positions: Phe(323), Ile(322), Gly(326), Ala(330), Pro(333), Glu(334), and Gly(335). In accordance with a structural model of the Na,K-ATPase obtained by homology modeling with the two published structures of sarcoplasmic and endoplasmic reticulum calcium ATPase (Protein Data Bank codes 1EUL and 1IWO), the results suggest the presence of a cation pathway along the side of the fourth transmembrane segment that faces the space between transmembrane segments 5 and 6. The phenylalanine residue in position 323 has a critical position at the outer mouth of the cation pathway. The residues thought to form the cation binding site II ((333)PEGL) are also part of the accessible wall of the cation pathway opened by palytoxin through the Na,K-pump.

Eosinophilic esophagitis: Updated consensus recommendations for children and adults.

Eosinophilic esophagitis (EoE) is a clinicopathologic condition of increasing recognition and prevalence. In 2007, a consensus recommendation provided clinical and histopathologic guidance for the diagnosis and treatment of EoE; however, only a minority of physicians use the 2007 guidelines, which require fulfillment of both histologic and clinical features. Since 2007, the number of EoE publications has doubled, providing new disease insight. Accordingly, a panel of 33 physicians with expertise in pediatric and adult allergy/immunology, gastroenterology, and pathology conducted a systematic review of the EoE literature (since September 2006) using electronic databases. Based on the literature review and expertise of the panel, information and recommendations were provided in each of the following areas of EoE: diagnostics, genetics, allergy testing, therapeutics, and disease complications. Because accumulating animal and human data have provided evidence that EoE appears to be an antigen-driven immunologic process that involves multiple pathogenic pathways, a new conceptual definition is proposed highlighting that EoE represents a chronic, immune/antigen-mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. The diagnostic guidelines continue to define EoE as an isolated chronic disorder of the esophagus diagnosed by the need of both clinical and pathologic features. Patients commonly have high rates of concurrent allergic diatheses, especially food sensitization, compared with the general population. Proved therapeutic options include chronic dietary elimination, topical corticosteroids, and esophageal dilation. Important additions since 2007 include genetic underpinnings that implicate EoE susceptibility caused by polymorphisms in the thymic stromal lymphopoietin protein gene and the description of a new potential disease phenotype, proton pump inhibitor-responsive esophageal eosinophila. Further advances and controversies regarding diagnostic methods, surrogate disease markers, allergy testing, and treatment approaches are discussed.

Nouveautés en médecine ambutatoire: dépistage, traitement et iatrogénicité [Innovations in ambulatory care: screening, treatment and iatrogenicity]

Cette année, six études utiles pour la pratique ont été retenues. L'indication à la mammographie entre 40 et 49 ans devrait être évaluée individuellement et en tenant compte des risques/bénéfices de cet examen. Au-delà de 65 ans, un dépistage systématique de la fibrillation auriculaire avec prise de pouls puis ECG (si pouls irrégulier) pourrait être réalisé de manière systématique. Les risques de complications postcolonoscopie existent, particulièrement suite à des biopsies/polypectomies, et ce risque devrait être discuté. Les inhibiteurs de la pompe à protons au long court sont un facteur de risque de fracture de hanche. S'il est important de prendre en charge des pressions artérielles élevées au-delà de 80 ans, il faut être prudent (orthostatisme). Une corticothérapie précoce suite à une paralysie faciale périphérique est efficace. This year we have selected six studies useful for the day to day practice. A mammography in women 40 to 49 years of age should be evaluated taking into account the patient's profile and the possible risks and benefits of this exam. In patients over 65 years of age, a systematic atrial fibrillation screening, with pulse rate measuring then ECG (if irregular beat) should be realised on a regular basis. The risks for complications following colonoscopies do exist, especially after biopsies/polypectomies and this risk should be discussed. Long term proton pump inhibitor treatment is a risk factor for hip fracture. It is important to treat high blood pressure problems in the elderly, but the orthostatic risks should be adressed. A corticoid treatment started quickly for Bell's palsy is efficient

Functional effects of Na+,K+-ATPase gene mutations linked to familial hemiplegic migraine.

Familial hemiplegic migraine type 2, an autosomal dominant form of migraine with aura, has been associated with four distinct mutations in the alpha2-subunit of the Na+,K+-ATPase. We have introduced these mutations in the alpha2-subunit of the human Na+,K+-ATPase and the corresponding mutations in the Bufo marinus alpha1-subunit and studied these mutants by expression in Xenopus oocyte. Metabolic labeling studies showed that the mutants were synthesized and associated with the beta-subunit, except for the alpha2HW887R mutant, which was poorly synthesized, and the alpha1BW890R, which was partially retained in the endoplasmic reticulum. [3H]ouabain binding showed the presence of the alpha2HR689Q and alpha2HM731T at the membrane, whereas the alpha2HL764P and alpha2HW887R could not be detected. Functional studies with the mutants of the B. marinus Na+,K+-ATPase showed a reduced or abolished electrogenic activity and a low K+ affinity for the alpha1BW890R mutant. Through different mechanisms, all these mutations result in a strong decrease of the functional expression of the Na+,K+-pump. The decreased activity in alpha2 isoform of the Na+,K+-pump expressed in astrocytes seems an essential component of hemiplegic migraine pathogenesis and may be responsible for the cortical spreading depression, which is one of the first events in migraine attacks.

Physiology and transcriptome of the polycyclic aromatic hydrocarbon-degrading Sphingomonas sp. LH128 after long-term starvation.

The survival, physiology and gene expression profile of the phenanthrene-degrading Sphingomonas sp. LH128 was examined after an extended period of complete nutrient starvation and compared with a non-starved population that had been harvested in exponential phase. After 6 months of starvation in an isotonic solution, only 5 % of the initial population formed culturable cells. Microscopic observation of GFP fluorescent cells, however, suggested that a larger fraction of cells (up to 80 %) were still alive and apparently had entered a viable but non-culturable (VBNC) state. The strain displayed several cellular and genetic adaptive strategies to survive long-term starvation. Flow cytometry, microscopic observation and fatty acid methyl ester (FAME) analysis showed a reduction in cell size, a change in cell shape and an increase in the degree of membrane fatty acid saturation. Transcriptome analysis showed decreased expression of genes involved in ribosomal protein biosynthesis, chromosomal replication, cell division and aromatic catabolism, increased expression of genes involved in regulation of gene expression and efflux systems, genetic translocations, and degradation of rRNA and fatty acids. Those phenotypic and transcriptomic changes were not observed after 4 h of starvation. Despite the starvation situation, the polycyclic aromatic hydrocarbon (PAH) catabolic activity was immediate upon exposure to phenanthrene. We conclude that a large fraction of cells maintain viability after an extended period of starvation apparently due to tuning the expression of a wide variety of cellular processes. Due to these survival attributes, bacteria of the genus Sphingomonas, like strain LH128, could be considered as suitable targets for use in remediation of nutrient-poor PAH-contaminated environments.

Cross-talk between glutamate and potassium regulation at the astrocyte membrane

Astrocytes play a central role in the brain by regulating glutamate and extracellular potassium concentrations ([K+]0), both released by neurons into the extracellular space during neuronal activity. Glutamate uptake is driven by the inwardly directed sodium gradient across the astrocyte membrane and involves the influx of three sodium ions and one proton and the efflux of one K+ ion per glutamate molecule. The glutamate transport induced rise in intracellular sodium stimulates the Na+/K+-ATPase which leads to significant energetic costs in astrocytes. To evaluate how these two fundamental functions of astrocytes, namely glutamate transport and K+ buffering, which are directly associated with neuronal activity, coexist and if they influence each other, in this thesis work we examined different cellular parameters of astrocytes. We therefore investigated the impact of altered [K+]0 on glutamate transporter activity. To assess this question we measured intracellular sodium fluctuations in mouse primary cultured astrocytes using dynamic fluorescence imaging. We found that glutamate uptake was tightly modulated both in amplitude and kinetics by [K+]0. Elevated [K+]0 strongly decreased glutamate transporter activity, with significant consequences on the cells energy metabolism. To ultimately evaluate potential effects of [K+]0 and glutamate on the astrocyte mitochondrial energy production we extended these studies by investigating their impact on the cytosolic and mitochondrial pH. We found that both [K+],, and glutamate strongly influenced cytosolic and mitochondrial pH, but in opposite directions. The effect of a simultaneous application of K+ and glutamate, however, did not fit with the arithmetical sum of each individual effects, suggesting that an additional non¬linear process is involved. We also investigated the impact of [K+]0 and glutamate transport, respectively, on intracellular potassium concentrations ([K+]0 in cultured astrocytes by characterizing and applying a newly developed Insensitive fluorescent dye. We observed that [K+]i followed [K+]0 changes in a nearly proportional way and that glutamate superfusion caused a reversible, glutamate-concentration dependent drop of [K+],, Our study shows the powerful influence of [K+]u on glutamate capture. These findings have strong implications for our understanding of the tightly regulated interplay between astrocytes and neurons in situations where [K+]0 undergoes large activity-dependent fluctuations. However, depending on the extent of K+ versus glutamate extracellular rise, energy metabolism in astrocytes will be differently regulated. Moreover, the novel insights obtained during this thesis work help understanding some of the underlying processes that prevail in certain pathologies of central nervous system, such as epilepsy and stroke. These results will possibly provide a basis for the development of novel therapeutic strategies. -- Les astrocytes jouent un rôle central dans le cerveau en régulant les concentrations de potassium (K+) et de glutamate, qui sont relâchés par les neurones dans l'espace extracellulaire lorsque ceux- ci sont actifs. La capture par les astrocytes du glutamate est un processus secondairement actif qui implique l'influx d'ions sodium (Na+) et d'un proton, ainsi que l'efflux d'ions K+, ce processus entraîne un coût métabolique important. Nous avons évalué comment ces fonctions fondamentales des astrocytes, la régulation du glutamate et du K+ extracellulaire, qui sont directement associés à l'activité neuronale, coexistent et si elles interagissent, en examinant différents paramètres cellulaires. Dans ce projet de thèse nous avons évalué l'impact des modifications de la concentration de potassium extracellulaire ([K+],,) sur le transport du glutamate. Nous avons mesuré le transport du glutamate par le biais des fluctuations internes de Na+ grâce à un colorant fluorescent en utilisant de l'imagerie à fluorescence dynamique sur des cultures primaires d'astrocytes. Nous avons trouvé que la capture du glutamate était étroitement régulée par [K+]0 aussi bien dans son amplitude que dans sa cinétique. Par la suite, nous avons porté notre attention sur l'impact de [K+]0 et du glutamate sur le pH cytosolique et mitochondrial de l'astrocyte dans le but, in fine, d'évaluer les effets potentiels sur la production d'énergie par la mitochondrie. Nous avons trouvé qu'autant le K+ que le glutamate, de manière individuelle, influençaient fortement le pH, cependant dans des directions opposées. Leurs effets individuels, ne peuvent toutefois pas être additionnés ce qui suggère qu'un processus additionnel non-linéaire est impliqué. En appliquant une nouvelle approche pour suivre et quantifier la concentration intracellulaire de potassium ([K+]0 par imagerie à fluorescence, nous avons observé que [K+]i suivait les changements de [K+]0 de manière quasiment proportionnelle et que la superfusion de glutamate induisait un décroissement rapide et réversible de [K+]i, qui dépend de la concentration de glutamate. Notre étude démontre l'influence de [K+]0 sur la capture du glutamate. Ces résultats permettent d'améliorer notre compréhension de l'interaction entre astrocytes et neurones dans des situations où [K+]0 fluctue en fonction de l'activité neuronale. Cependant, en fonction de l'importance de l'augmentation extracellulaire du K+ versus le glutamate, le métabolisme énergétique des astrocytes va être régulé de manière différente. De plus, les informations nouvelles que nous avons obtenues durant ce travail de thèse nous aident à comprendre quelques- uns des processus sous-jacents qui prévalent dans certaines pathologies du système nerveux central, comme par exemple l'épilepsie ou l'accident vasculaire cérébral. Ces informations pourront être importantes à intégrer dans la cadre du développement de nouvelles stratégies thérapeutiques.

Enteral nutrition in critically ill patients with severe hemodynamic failure after cardiopulmonary bypass.

BACKGROUND & AIMS: The study was designed to investigate and quantify nutritional support, and particularly enteral nutrition (EN), in critically ill patients with severe hemodynamic failure. METHODS: Prospective, descriptive study in a surgical intensive care unit (ICU) in a university teaching hospital: patients aged 67+/-13 yrs (mean+/-SD) admitted after cardiac surgery with extracorporeal circulation, staying 5 days in the ICU with acute cardiovascular failure. Severity of disease was assessed with SAPS II, and SOFA scores. Variables were energy delivery and balance, nutrition route, vasopressor doses, and infectious complications. Artificial feeding delivered according to ICU protocol. EN was considered from day 2-3. Energy target was set 25 kcal/kg/day to be reached stepwise over 5 days. RESULTS: Seventy out of 1114 consecutive patients were studied, aged 67+/-17 years, and staying 10+/-7 days in the ICU. Median SAPS II was 43. Nine patients died (13%). All patients had circulatory failure: 18 patients required intra-aortic balloon-pump support (IABP). Norepinephrine was required in 58 patients (83%). Forty patients required artificial nutrition. Energy delivery was very variable. There was no abdominal complication related to EN. As a mean, 1360+/-620 kcal/kg/day could be delivered enterally during the first 2 weeks, corresponding to 70+/-35% of energy target. Enteral nutrient delivery was negatively influenced by increasing dopamine and norepinephrine doses, but not by the use of IABP. CONCLUSION: EN is possible in the majority of patients with severe hemodynamic failure, but usually results in hypocaloric feeding. EN should be considered in patients with careful abdominal and energy monitoring.

Extracorporeal membrane oxygenation support in acardia.

In extreme situations, such as hyperacute rejection of heart transplant or major heart trauma, heart preservation may not be possible. Our experimental team works on a project of peripheral extracorporeal membrane oxygenation (ECMO) support in acardia as a bridge to heart transplantation or artificial heart implantation. An ECMO support was established in five calves (58.6 ± 6.9 kg) by the transjugular insertion to the caval axis of a self-expanded cannula, with carotid artery return. After baseline measurements, ventricular fibrillation was induced, great arteries were clamped, heart was excised, and right and left atria remnants, containing pulmonary veins, were sutured together leaving an atrial septal defect over the caval axis cannula. Measurements of pump flow and arterial pressure were taken with the pulmonary artery clamped and anastomosed with the caval axis for a total of 6 hours. Pulmonary artery anastomosis to the caval axis provided an acceptable 6 hour hemodynamic stability, permitting a peripheral access ECMO support in extreme scenarios indicating a heart explantation.

Y-688, a new quinolone active against quinolone-resistant Staphylococcus aureus: lack of in vivo efficacy in experimental endocarditis.

Y-688 is a new fluoroquinolone with increased activity against ciprofloxacin-resistant staphylococci. The MICs of Y-688 and other quinolones were determined for 58 isolates of ciprofloxacin-resistant and methicillin-resistant Staphylococcus aureus (MRSA). The MICs at which 50% and 90% of bacteria were inhibited were >/=128 and >/=128 mg/liter, respectively, for ciprofloxacin, 16 and 32 mg/liter, respectively, for sparfloxacin, and 0.25 and 1 mg/liter, respectively, for Y-688. This new quinolone was further tested in rats with experimental endocarditis due to either of two isolates of ciprofloxacin-resistant MRSA (namely, P8/128 and CR1). Infected animals were treated for 3 days with ciprofloxacin, vancomycin, or Y-688. Antibiotics were administered through a computerized pump to simulate human-like pharmacokinetics in the serum of rats. The anticipated peak and trough levels of Y-688 were 4 and 1 mg/liter at 0.5 and 12 h, respectively. Treatment with ciprofloxacin was ineffective. Vancomycin significantly decreased vegetation bacterial counts for both organisms (P less, similar 0.05). In contrast, Y-688 only marginally decreased vegetation bacterial counts (P greater, similar 0.05). Moreover, several vegetation that failed Y-688 treatment grew staphylococci for which the MICs of the test antibiotic were increased two to eight times. Y-688 also selected for resistance in vitro, and isolates for which the MICs were increased eight times emerged at a frequency of ca. 10(-8). Thus, in spite of its low MIC for ciprofloxacin-resistant MRSA, Y-688 failed in vivo and its use carried the risk of resistance selection. The fact that ciprofloxacin-resistant staphylococci became rapidly resistant to this potent new drug suggests that the treatment of ciprofloxacin-resistant MRSA with new quinolones might be more problematic than expected.

CYP3A5 and ABCB1 genes influence blood pressure and response to treatment, and their effect is modified by salt.

The permeability-glycoprotein efflux-transporter encoded by the multidrug resistance 1 (ABCB1) gene and the cytochromes P450 3A4/5 encoded by the CYP3A4/5 genes are known to interact in the transport and metabolism of many drugs. Recent data have shown that the CYP3A5 genotypes influence blood pressure and that permeability-glycoprotein activity might influence the activity of the renin-angiotensin system. Hence, these 2 genes may contribute to blood pressure regulation in humans. We analyzed the association of variants of the ABCB1 and CYP3A5 genes with ambulatory blood pressure, plasma renin activity, plasma aldosterone, endogenous lithium clearance, and blood pressure response to treatment in 72 families (373 individuals; 55% women; mean age: 46 years) of East African descent. The ABCB1 and CYP3A5 genes interact with urinary sodium excretion in their effect on ambulatory blood pressure (daytime systolic: P=0.05; nighttime systolic and diastolic: P<0.01), suggesting a gene-gene-environment interaction. The combined action of these genes is also associated with postproximal tubular sodium reabsorption, plasma renin activity, plasma aldosterone, and with an altered blood pressure response to the angiotensin-converting enzyme inhibitor lisinopril (P<0.05). This is the first reported association of the ABCB1 gene with blood pressure in humans and demonstration that genes encoding for proteins metabolizing and transporting drugs and endogenous substrates contribute to blood pressure regulation.

The inflammasome: an integrated view.

An inflammasome is a multiprotein complex that serves as a platform for caspase-1 activation and caspase-1-dependent proteolytic maturation and secretion of interleukin-1β (IL-1β). Though a number of inflammasomes have been described, the NLRP3 inflammasome is the most extensively studied but also the most elusive. It is unique in that it responds to numerous physically and chemically diverse stimuli. The potent proinflammatory and pyrogenic activities of IL-1β necessitate that inflammasome activity is tightly controlled. To this end, a priming step is first required to induce the expression of both NLRP3 and proIL-1β. This event renders the cell competent for NLRP3 inflammasome activation and IL-1β secretion, and it is highly regulated by negative feedback loops. Despite the wide array of NLRP3 activators, the actual triggering of NLRP3 is controlled by integration a comparatively small number of signals that are common to nearly all activators. Minimally, these include potassium efflux, elevated levels of reactive oxygen species (ROS), and, for certain activators, lysosomal destabilization. Further investigation of how these and potentially other as yet uncharacterized signals are integrated by the NLRP3 inflammasome and the relevance of these biochemical events in vivo should provide new insight into the mechanisms of host defense and autoinflammatory conditions.

Biometal muscle to restore atrial transport function in a permanent atrial fibrillation animal model: a potential tool in the treatment of end-stage heart failure.

BACKGROUND: Half of the patients with end-stage heart failure suffer from persistent atrial fibrillation (AF). Atrial kick (AK) accounts for 10-15% of the ejection fraction. A device restoring AK should significantly improve cardiac output (CO) and possibly delay ventricular assist device (VAD) implantation. This study has been designed to assess the mechanical effects of a motorless pump on the right chambers of the heart in an animal model. METHODS: Atripump is a dome-shaped biometal actuator electrically driven by a pacemaker-like control unit. In eight sheep, the device was sutured onto the right atrium (RA). AF was simulated with rapid atrial pacing. RA ejection fraction (EF) was assessed with intracardiac ultrasound (ICUS) in baseline, AF and assisted-AF status. In two animals, the pump was left in place for 4 weeks and then explanted. Histology examination was carried out. The mean values for single measurement per animal with +/-SD were analysed. RESULTS: The contraction rate of the device was 60 per min. RA EF was 41% in baseline, 7% in AF and 21% in assisted-AF conditions. CO was 7+/-0.5 l min(-1) in baseline, 6.2+/-0.5 l min(-1) in AF and 6.7+/-0.5 l min(-1) in assisted-AF status (p<0.01). Histology of the atrium in the chronic group showed chronic tissue inflammation and no sign of tissue necrosis. CONCLUSIONS: The artificial muscle restores the AK and improves CO. In patients with end-stage cardiac failure and permanent AF, if implanted on both sides, it would improve CO and possibly delay or even avoid complex surgical treatment such as VAD implantation.