Hepatitis C virus proteins promote mitochondrial bioenergetic dysfunction and nitro-oxidative stress: insights into pathogenesis

HCV-infection induces a state of oxidative stress more pronounced than in many other inflammatory diseases. Here we propose a temporal sequence of events in the HCV-infected cell whereby the primary alteration consists in release of Ca2+ from the ER followed by uptake into mitochondria. This triggers successive mitochondrial dysfunctions leading to generation of ROS and to a progressive metabolic adaptive response. Pathogenetic implications of the model and new opportunities for therapeutic intervention are discussed.

Mécanismes physiopathologiques impliqués dans la dysfonction d'organes au cours du sepsis [Pathophysiological mechanisms of organ dysfunction in sepsis].

Sepsis is defined as the systemic inflammatory response to an infection. The occurrence of organ dysfunction increases the severity of sepsis. Complex interactions between multiple immunomodulating mediators and various cell populations, activated secondarily to the initial infectious insult, promote the development of organ dysfunction in sepsis. Although septic organ dysfunction has long been considered as the end result of chaotic, uncontrolled and deregulated inflammatory cascades, it might instead represent an adaptive response to avoid the occurrence of irreversible tissue damage and end-organ injury. In this article, we review the major mechanisms involved in organ dysfunction during sepsis, and also present the concept of organ dysfunction as an adaptive response to the septic process.

Dysfonction métabolique et stress chronique: un nouveau regard sur la pandémie de "diabésité" [Metabolic dysfunction and chronic stress: a new sight at "diabesity" pandemic]

Chronic stress in Western society can activate the autonomus, neuroendocrine and inflammatory/immunlogic systems. Chronic exposure to stressors can indeed stimulate the hypothalamic-pituitary-adrenal axis and induce a disbalance between anabolic and catabolic hormones, responsible of an increased in visceral fat and of insulin resistance. These metabolic consequences can lead to pre-diabetes. Exposure to chronic stress results in allostatic load and its pathophysiologic consequences. The knowledge of this mecanisms and the cardiovascular and metabolic risk related, should influence our way of thinking about patient care. To decrease allostatic load, practitioners can rely on therapeutic relation. Therapeutic education is one of the skill that can be use to create therapeutic relation.

Bacterial flagellin triggers cardiac innate immune responses and acute contractile dysfunction.

BACKGROUND: Myocardial contractile failure in septic shock may develop following direct interactions, within the heart itself, between molecular motifs released by pathogens and their specific receptors, notably those belonging to the toll-like receptor (TLR) family. Here, we determined the ability of bacterial flagellin, the ligand of mammalian TLR5, to trigger myocardial inflammation and contractile dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: TLR5 expression was determined in H9c2 cardiac myoblasts, in primary rat cardiomyocytes, and in whole heart extracts from rodents and humans. The ability of flagellin to activate pro-inflammatory signaling pathways (NF-kappaB and MAP kinases) and the expression of inflammatory cytokines was investigated in H9c2 cells, and, in part, in primary cardiomyocytes, as well as in the mouse myocardium in vivo. The influence of flagellin on left ventricular function was evaluated in mice by a conductance pressure-volume catheter. Cardiomyocytes and intact myocardium disclosed significant TLR5 expression. In vitro, flagellin activated NF-kappaB, MAP kinases, and the transcription of inflammatory genes. In vivo, flagellin induced cardiac activation of NF-kappaB, expression of inflammatory cytokines (TNF alpha, IL-1 beta, IL-6, MIP-2 and MCP-1), and provoked a state of reversible myocardial dysfunction, characterized by cardiac dilation, reduced ejection fraction, and decreased end-systolic elastance. CONCLUSION/SIGNIFICANCE: These results are the first to indicate that flagellin has the ability to trigger cardiac innate immune responses and to acutely depress myocardial contractility.

Serum anticholinergic activity and postoperative cognitive dysfunction in elderly patients.

BACKGROUND: Cerebral cholinergic transmission plays a key role in cognitive function, and anticholinergic drugs administered during the perioperative phase are a hypothetical cause of postoperative cognitive dysfunction (POCD). We hypothesized that a perioperative increase in serum anticholinergic activity (SAA) is associated with POCD in elderly patients. METHODS: Seventy-nine patients aged >65 years undergoing elective major surgery under standardized general anesthesia (thiopental, sevoflurane, fentanyl, and atracurium) were investigated. Cognitive functions were assessed preoperatively and 7 days postoperatively using the extended version of the CERAD-Neuropsychological Assessment Battery. POCD was defined as a postoperative decline >1 z-score in at least 2 test variables. SAA was measured preoperatively and 7 days postoperatively at the time of cognitive testing. Hodges-Lehmann median differences and their 95% confidence intervals were calculated for between-group comparisons. RESULTS: Of the patients who completed the study, 46% developed POCD. Patients with POCD were slightly older and less educated than patients without POCD. There were no relevant differences between patients with and without POCD regarding gender, demographically corrected baseline cognitive functions, and duration of anesthesia. There were no large differences between patients with and without POCD regarding SAA preoperatively (pmol/mL, median [interquartile range]/median difference [95% CI], P; 1.14 [0.72, 2.37] vs 1.13 [0.68, 1.68]/0.12 [-0.31, 0.57], P = 0.56), SAA 7 days postoperatively (1.32 [0.68, 2.59] vs 0.97 [0.65, 1.83]/0.25 [-0.26, 0.81], P = 0.37), or changes in SAA (0.08 [-0.50, 0.70] vs -0.02 [-0.53, 0.41]/0.1 [-0.31, 0.52], P = 0.62). There was no significant relationship between changes in SAA and changes in cognitive function (Spearman rank correlation coefficient preoperatively of 0.03 [95% CI, -0.21, 0.26] and postoperatively of -0.002 [95% CI, -0.24, 0.23]). CONCLUSIONS: In this panel of patients with low baseline SAA and clinically insignificant perioperative anticholinergic burden, although a relationship cannot be excluded in some patients, our analysis suggests that POCD is probably not a substantial consequence of anticholinergic medications administered perioperatively but rather due to other mechanisms.

Le syndrome hépatorénal chez le patient cirrhotique [Hepatorenal syndrome in patients with liver cirrhosis].

Hepatorenal syndrome is a particular form of functional renal failure which may develop in patients with liver cirrhosis. On a clinical standpoint, precise diagnostic criteria have been established to clearly define this entity, whereas recent advances in the understanding of the biology of vasoactive mediators and the physiology of microcirculation have allowed to better anticipate its pathophysiological mechanisms. During the course of cirrhosis, sinusoidal portal hypertension leads to splanchnic and systemic vasodilation, responsible for a reduction of effective arterial blood volume. As a result, a state of intense renal vasoconstriction develops, leading to renal failure in the absence of any organic renal disease. At this stage, liver transplantation is the only definitive therapy able to reverse renal dysfunction. In recent years, innovative therapies have shown promise to prolong survival in patients with hepatorenal syndrome, including the administration of analogs of vasopressin (mainly terlipressin), the insertion of transjugular intrahepatic portosystemic shunts and the use of novel techniques of dialysis. On a preventive viewpoint, several simple measures have been shown to reduce the risk of hepatorenal syndrome in cirrhotic patients, including the appropriate use of diuretics, the avoidance of nephrotoxic drugs, the prophylaxis of spontaneous bacterial peritonitis and optimal fluid management in patients undergoing large volume paracentesis.

Postoperative cognitive dysfunction POCD, serum anticholinergic activity and intraoperative cerebral perfusion in geriatric patients

Background: Inadequate intraoperative cerebral perfusion and increased serum anticholinergic activity (SAA) have been suggested as possible causes of postoperative cognitive dysfunction (POCD). Methods: 53 patients aged >65 yrs undergoing elective major surgical procedures under standardized general anaesthesia. Cerebral perfusion was monitored with transcranial Doppler and near-infrared spectroscopy. Mx, an index of cerebral autoregulation was calculated based on the correlation of spontaneous changes inmean arterial blood pressure (MAP) and cerebral blood flow velocity. Cognitive function was measured preoperatively and 7 days postoperatively using the CERAD-Neuropsychological Battery. A postoperative decline >1 z-score in at least 2 cognitive variables was defined as POCD. SAA was measured preoperatively and 7 days postoperatively (data available for 38 patients). CRP was measured at the same time points and 2 days postoperatively. Results: Age was 75_7 yrs (mean_SD). 23 patients (43%) developed POCD. There were no statistical significant differences between patients with POCD and without POCD in age (77_7 vs 73_6 yrs), MAP (74_12 vs 78_11 mmHg), cerebral tissue oxygenation indices (67_6 vs 69_4 %) SAA preoperatively (1.74_1.52 vs 1.74_1.21) and 7 days postoperatively (1.90_1.63 vs 1.84_1.39) and CRP preoperatively (32_72 vs 7_9), 2 days postoperatively (176_129 vs 111_69) and 7days postoperatively (53_43 vs 48_25). Patients with POCD had less efficient autoregulation than patients without POCD (Mx 0.55_0.15 vs 0.45_0.20, p = 0.046). However, the percentage of patients with clearly impaired autoregulation (ie, Mx>0.5) was statistically not different between groups (with POCD: 65%; without POCD: 38%; p = 0.06) but there seems to be a trend. Conclusions: Our data on the association between cerebral perfusion and POCD in elderly patients are inconclusive and more patients need to be investigated. In this small group of patients SAA seems not to be associated with POCD.

Troubles sexuels masculins et obésité [Male sexual dysfunction and obesity].

Obesity concerns more than 200 million people in the world, with an increasing prevalence in western countries. It is closely related to multiple medical conditions, such as diabetes and hypertension. It was recently shown that testosterone deficiency syndrome and erectile dysfunction (ED) are also linked to male obesity. In this group of patients, ED may be due to defects in corpus cavernosum relaxation, endocrine modifications and nerve signal alterations. Weight loss and increased physical activities can improve erectile function in 30% of obese patients. Additional medical treatments of ED enhance erectile function in more than 80% of patients. Self image improvement associated with appropriate erectile dysfunction medical treatment allow better sexual life and potentially increased motivation for weight loss.

Bacterial flagellin elicits innate immune defenses and cardiac dysfunction in vivo

Résumé Les agents pathogènes responsables d'infection entraînent chez l'hôte deux types de réponses immunes, la première, non spécifique, dite immunité innée, la seconde, spécifique à l'agent concerné, dite immunité adaptative. L'immunité innée, qui représente la première ligne de défense contre les pathogènes, est liée à la reconnaissance par les cellules de l'hôte de structures moléculaires propres aux micro-organismes (« Pathogen-Associated Molecular Patterns », PAMPs), grâce à des récepteurs membranaires et cytoplasmiques (« Pattern Recognition Receptors », PRRs) identifiant de manière spécifique ces motifs moléculaires. Les récepteurs membranaires impliqués dans ce processus sont dénommés toll-like récepteurs, ou TLRS. Lorsqu'ils sont activés par leur ligand spécifique, ces récepteurs activent des voies de signalisation intracellulaires initiant la réponse inflammatoire non spécifique et visant à éradiquer l'agent pathogène. Les deux voies de signalisation impliquées dans ce processus sont la voie des « Mitogen-Activated Protein Kinases » (MAPKs) et celle du « Nuclear Factor kappaB » (NF-κB), dont l'activation entraîne in fine l'expression de protéines de l'inflammation dénommées cytokines, ainsi que certaines enzymes produisant divers autres médiateurs inflammatoires. Dans certaines situations, cette réponse immune peut être amplifiée de manière inadéquate, entraînant chez l'hôte une réaction inflammatoire systémique exagérée, appelée sepsis. Le sepsis peut se compliquer de dysfonctions d'organes multiples (sepsis sévère), et dans sa forme la plus grave, d'un collapsus cardiovasculaire, définissant le choc septique. La défaillance circulatoire du choc septique touche les vaisseaux sanguins d'une part, le coeur d'autre part, réalisant un tableau de «dysfonction cardiaque septique », dont on connaît mal les mécanismes pathogéniques. Les bactéries à Gram négatif peuvent déclencher de tels phénomènes, notamment en libérant de l'endotoxine, qui active les voies de l'immunité innée par son interaction avec un toll récepteur, le TLR4. Outre l'endotoxine, la plupart des bactéries à Gram négatif relâchent également dans leur environnement une protéine, la flagelline, qui est le constituant majeur du flagelle bactérien, organelle assurant la mobilité de ces micro-organismes. Des données récentes ont indiqué que la flagelline active, dans certaines cellules, les voies de l'immunité innée en se liant au récepteur TLRS. On ne connaît toutefois pas les conséquences de l'interaction flagelline-TLRS sur le développement de l'inflammation et des dysfonctions d'organes au cours du sepsis. Nous avons par conséquent élaboré le présent travail en formulant l'hypothèse que la flagelline pourrait déclencher une telle inflammation et représenter ainsi un médiateur potentiel de la dysfonction d'organes au cours du sepsis à Gram négatif, en nous intéressant plus particulièrement àl'inflammation et à la dysfonction cardiaque. Dans la première partie de ce travail, nous avons étudié les effets de la flagelline sur l'activation du NF-κB et des MAPKs, et sur l'expression de cytokines inflammatoires au niveau du myocarde in vitro (cardiomyocytes en culture) et in vivo (injection de flagelline recombinante à des souris). Nous avons observé tout d'abord que le récepteur TLRS est fortement exprimé au niveau du myocarde. Nous avons ensuite démontré que la flagelline active la voie du NF-κB et des MAP kinases (p38 et JNK), stimule la production de cytokines et de chemokines inflammatoires in vitro et in vivo, et entraîne l'activation de polynucléaires neutrophiles dans le tissu cardiaque in vivo. Finalement, au plan fonctionnel, nous avons pu montrer que la flagelline entraîne une dilatation et une réduction aiguë de la contractilité du ventricule gauche chez la souris, reproduisant les caractéristiques de la dysfonction cardiaque septique. Dans la deuxième partie, nous avons déterminé la distribution du récepteur TLRS dans les autres organes majeurs de la souris (poumon, foie, intestin et rein}, et avons caractérisé dans ces organes l'effet de la flagelline sur l'activation du NF-κB et des MAPKs, l'expression de cytokines, et l'induction de l'apoptose. Nous avons démontré que le TLRS est exprimé de façon constitutive dans ces organes, et que l'injection de flagelline y déclenche les cascades de l'immunité innée et de processus apoptotiques. Finalement, nous avons également déterminé que la flagelline entraîne une augmentation significative de multiples cytokines dans le plasma une à six heures après son injection. En résumé, nos données démontrent que la flagelline bactérienne (a) entraîne une inflammation et une dysfonction importantes du myocarde et (b) active de manière très significative les mécanismes d'immunité innée dans les principaux organes et entraîne une réponse inflammatoire systémique. Par conséquent, la flagelline peut représenter un médiateur puissant de l'inflammation et de la dysfonction d'organes, notamment du coeur, au cours du choc septique déclenché par les bactéries à Gram négatif. Summary Pathogenic microorganisms trigger two kinds of immune responses in the host. The first one is immediate and non-specific and is termed innate immunity, whereas the second one, specifically targeted at the invading agent, is termed adaptative immunity. Innate immunity, which represents the first line of defense against invading pathogens, confers the host the ability to recognize molecular structures common to many microbial pathogens, ("Pathogen-Associated Molecular Patterns", PAMPs), through cytosolic or membrane-associated receptors ("Pattern Recognition Receptors", PRRs), the latter being represented by a family of receptors termed "toll-like receptors or TLRs". Once activated by the binding of their specific ligand, these receptors activate intracellular signaling pathways, which initiate the non-specific inflammatory response aimed at eradicating the pathogens. The two pathways implicated in this process are the mitogen-activated protein kinases (MAPK) and the nuclear factor kappa B (NF-κB) signaling pathways, whose activation elicit in fine the expression of inflammatory proteins termed cytokines, as well as various enzymes producing a wealth of additional inflammatory mediators. In some circumstances, the innate immune response can become amplified and dysregulated, triggering an overwhelming systemic inflammatory response in the host, identified as sepsis. Sepsis can be associated with multiple organ dysfunction (severe sepsis), and in its most severe form, with cardiovascular collapse, defming septic shock. The cardiovascular failure associated with septic shock affects blood vessels as well as the heart, resulting in a particular form of acute heart failure termed "septic cardiac dysfunction ", whose pathogenic mechanisms remain partly undefined. Gram-negative bacteria can initiate such phenomena, notably by releasing lipopolysaccharide (LPS), which activates innate immune signaling by interacting with its specific toll receptor, the TLR4. Besides LPS, most Gram-negative bacteria also release flagellin into their environment, which is the main structural protein of the bacterial flagellum, an appendage extending from the outer bacterial membrane, responsible for the motility of the microorganism. Recent data indicated that flagellin activate immune responses upon binding to its receptor, TLRS, in various cell types. However, the role of flagellin/TLRS interaction in the development of inflammation and organ dysfunction during sepsis is not known. Therefore, we designed the present work to address the hypothesis that flagellin might trigger such inflammatory responses and thus represent a potential mediator of organ dysfunction during Gram-negative sepsis, with a particular emphasis on cardiac inflammation and contractile dysfunction. In the first part of this work, we investigated the effects of flagellin on NF-κB and MAPK activation and the generation of pro-inflammatory mediators within the heart in vitro (cultured cardiomyocytes) and in vivo (injection of recombinant flagellin into mice). We first observed that TLRS protein is strongly expressed by the myocardium. We then demonstrated that flagellin activates NF-κB and MAP kinases (p38 and JNK), upregulates the transcription of pro-inflammatory cytokines and chemokines in vitro and in vivo, and stimulates the activation of polymorphonuclear neutrophils within the heart in vivo. Finally, we demonstrated that flagellin triggers acute cardiac dilation, and a significant reduction of left ventricular contractility, mimicking characteristics of clinical septic cardiac dysfunction. In the second part, we determined the TLRS distribution in other mice major organs (lung, liver, gut and kidney) and we characterized in these organs the effects of flagellin on NF-κB and MAPK activation, on the expression of pro-inflammatory çytokines, and on the induction of apoptosis. We demonstrated that TLRS protein is constitutively expressed and that flagellin activates prototypical innate immune responses and pro-apoptotic pathways in all these organs. Finally, we also observed that flagellin induces a significant increase of multiple cytokines in the plasma from 1 to 6 hours after its intravenous administration. Altogether, these data provide evidence that bacterial flagellin (a) triggers an important inflammatory response and an acute dysfunction of the myocardium, and (b) significantly activates the mechanisms of innate immunity in most major organs and elicits a systemic inflammatory response. In consequence, flagellin may represent a potent mediator of inflammation and multiple organ failure, notably cardiac dysfunction, during Gram-negative septic shock.

The prevalence of erectile dysfunction and its association with antiretroviral therapy in HIV-infected men: the Swiss HIV Cohort Study.

BACKGROUND: Here, we aimed to determine the prevalence of erectile dysfunction (ED) among HIV-infected men and its association with components of antiretroviral therapy. METHODS: Cross-sectional data on sexual dysfunction were collected in the Swiss HIV Cohort Study (SHCS) between December 2009 and November 2010. Multilevel logistic regression models were used to estimate the association between ED and exposure to 24 different antiretroviral drugs from four drug classes. RESULTS: During the study period, 5,194 of 5,539 eligible men in the SHCS had a follow-up visit; 4,064 men answered a question on ED for the first time. Among these men, ED was experienced often by 459 (11%), sometimes by 543 (13%), rarely by 389 (10%), never by 2,526 (62%) and 147 (4%) did not know. ED was associated with older age, an earlier HIV diagnosis and depression. No association was found with any drug class; however, ED was associated with cumulative exposure to either zalcitabine (OR 1.29 per year of use; 95% CI 1.07, 1.55) or enfuvirtide (OR 1.28; 95% CI 1.08, 1.52). CONCLUSIONS: Around 1 in 10 men in the SHCS reported often experiencing ED. We found no association between ED and any drug class, but those exposed to zalcitabine or enfurvitide (drugs no longer or rarely used) were more likely to report ED; this second association was probably not causal.

Retinal dysfunction in combined methylmalonic aciduria and homocystinuria (Cblc) disease: a spectrum of disorders.

BACKGROUND: Cobalamin C methylmalonic aciduria with homocystinuria (cblC disease) is a rare hereditary inborn error of cobalamin metabolism, characterised by neurological, haematological and ophthalmological abnormalities. PATIENTS AND METHODS: Three consecutive patients with Cblc disease were examined. Investigations included slit lamp and fundus examination and full-field ERG. RESULTS: A maculopathy associated with both photopic and scotopic abnormal ERG was present in two cases and a salt and pepper retinopathy with abnormal photopic ERG was detected in the third patient. CONCLUSIONS: Despite early treatment and regular metabolic controls, all our patients exhibited both retinal and ERG abnormalities. There was no correlation between funduscopic appearance and the type of photoreceptor dysfunction. A literature review disclosed a retinopathy in 29 / 70 cases with cblC disease, with an abnormal ERG in 8 of the 12 tested cases, most with retinopathy. Retinal dysfunction in cblC disease may be more frequent than previously thought, and can involve cones only or both rods and cones. We recommend a formal ocular examination with full-field ERG in patients with Cblc disease.

Brain dysfunction in sepsis: what can we learn from cerebral perfusion studies?

Investigations on the relationship between sepsis, brain dysfunction, and cerebral perfusion are methodologically very difficult to perform. It is important to interpret the results of such studies in view of our limited ability to diagnose and quantify brain dysfunction and to consider our limited understanding of the mechanisms that lead to or are associated with brain dysfunction in sepsis.

"I'll look it up on the Web first": barriers and overcoming barriers to consult for sexual dysfunction among young men.

QUESTIONS UNDER STUDY: Our aim was to identify the barriers young men face to consult a health professional when they encounter sexual dysfunctions and where they turn to, if so, for answers. METHODS: We conducted an exploratory qualitative research including 12 young men aged 16-20 years old seen in two focus groups. Discussions were triggered through vignettes about sexual dysfunction. RESULTS: Young men preferred not to talk about sexual dysfunction problems with anyone and to solve them alone as it is considered an intimate and embarrassing subject which can negatively impact their masculinity. Confidentiality appeared to be the most important criterion in disclosing an intimate subject to a health professional. Participants raised the problem of males' accessibility to services and lack of reason to consult. Two criteria to address the problem were if it was long-lasting or considered as physical. The Internet was unanimously considered as an initial solution to solve a problem, which could guide them to a face-to-face consultation if necessary. CONCLUSIONS: Results suggest that Internet-based tools should be developed to become an easy access door to sexual health services for young men. Wherever they consult and for whatever problem, sexual health must be on the agenda.

Aortic valve dysfunction and aortic dilatation in adults with coarctation of the aorta

Objectif: Déterminer la prévalence de la dysfonction de la valve aortique, de la dilatation de l'aorte proximale et des interventions au niveau de la valve aortique et de l'aorte ascendante chez les adultes avec une coarctation de l'aorte. Contexte: La dysfonction de la valve aortique et la dilatation de l'aorte proximale sont rares chez les enfants et les adolescents avec une coarctation de l'aorte. A long terme, les adultes pourraient être plus à risque de développer ce type de pathologie. Méthode: Nous avons rétrospectivement passé en revue tous les adultes avec une coarctation de l'aorte corrigée ou pas suivis au « Boston Children's Hospital » entre 2004 et 2010. Résultats: 216 adultes (56 % d'hommes) avec une coarctation ont été identifiés. L'âge médian à la dernière évaluation était de 28 (de 18 à 75) ans. Une bicuspidie aortique était présente dans 66% des cas. Au dernier contrôle, 3% avaient une sténose aortique modérée ou sévère et 4% avaient une insuffisance aortique modérée à sévère. Une dilatation de la racine de l'aorte ou de l'aorte ascendante était présente dans 28%, respectivement 42% des patients. Une dilatation au moins modérée de la racine de l'aorte ou de l'aorte ascendante (score Z > 4) était présente dans 8%, respectivement 14%. Les patients avec une bicuspidie aortique étaient plus sujets à avoir une dilatation au moins modérée de la racine de l'aorte ou de l'aorte ascendante comparés à ceux sans bicuspidie (20% contre 0%; p<0.001). L'âge était associé à une dilatation de l'aorte ascendante (p=0.04). Au dernier suivi, 6% avait nécessité une intervention au niveau de la valve aortique et 3% un remplacement de la racine de l'aorte ou de l'aorte ascendante.

Hypertension artérielle: macrocirculation et microcirculation [Arterial hypertension: macrocirculation and microcirculation]

The aim of the present report is to outline, in concise from, the changes in vascular structure which accompany hypertension. Consideration will be given to their potential contribution to hypertensive end organ damage. In so doing, it is important to consider both the macrovascular and microvascular levels, because interactions between them are presently believed to be critically important. The links between hypertension and the pathogenesis of arteriosclerosis fall outside the scope of this short review.