Lower limb lymphedema and neurological complications after lymphadenectomy for gynecological cancer.

OBJECTIVE: Lymphadenectomy is a frequent procedure for surgical staging of gynecological malignancies. Nevertheless, minor complications, such as lower limb lymphedema (LLL) and neurological complications (NCs), after pelvic and aorto-caval lymphadenectomy still remain underinvestigated. The present study considers short-term and long-term incidence and risk factors for LLL and NC in patients with gynecological cancer who underwent lymphadenectomy. MATERIALS AND METHODS: In 2 different institutions, University of Turin and University of Lausanne, a total of 152 patients who received lymphadenectomy for endometrial, cervical, or ovarian cancer were retrospectively identified. During the follow-up, data about LLL and NC were collected by means of a questionnaire. Short-term and long-term incidence of LLL and NC was evaluated, and risk factors, such as age, body mass index, type of cancer, surgical approach, number and extension of the removed lymph nodes, presence of lymph node metastasis, and adjuvant treatments, were analyzed. RESULTS: Short-term incidence of LLL and NC after lymphadenectomy was high (36%) and predictive of long-term persistence. Between the analyzed risk factors, number of removed lymph nodes and adjuvant radiotherapy were significantly associated with an increased incidence of minor complications (P < 0.05). CONCLUSIONS: Lower limb lymphedema and NC are more frequent than expected. They are related to the radicality of lymphadenectomy and adjuvant radiotherapy. They affect the quality of life of the patients treated for gynecological cancer and their perceptions of healing. Minor complications are commonly persistent and need a prompt diagnosis and a specialized management to improve their prognosis.

The monocarboxylate transporter MCT4 : mechanism of regulation in astrocytes and its putative role in cerebral ischemia

Despite its small fraction of the total body weight (2%), the brain contributes for 20% and 25% respectively of the total oxygen and glucose consumption of the whole body. Indeed, glucose has been considered the energy substrate par excellence for the brain. However, evidence accumulated over the last half century revealed an important role for the monocarboxylate lactate in fulfilling the energy needs of neurons. This is particularly true during physiological neuronal activation and in pathological conditions. Lactate transport into and out of the cell is mediated by a family of proton-linked transporters called monocarboxylate transporters (MCTs). In the central nervous system, only three of them have been well characterized: MCT2 is the predominant neuronal isoform, while the other non¬neuronal cell types of the brain express the ubiquitous isoform MCT1. Quite recently, the MCT4 isoform has been described in astrocytes. Due to its high transport capacity compared to the other two isoforms, MCT4 is particularly adapted for glycolytic cells. Because of its recent discovery in the brain, nothing was known about its regulation in the central nervous system. Here we show that MCT4 is regulated by oxygen levels in primary cultures of astrocytes in a time- and concentration-dependent manner via the hypoxia inducible factor-la (HIF-la). Moreover, we showed that MCT4 expression is essential for astrocyte survival under low oxygen conditions. In parallel, we investigated the possible implication of the pyruvate kinase isoform Pkm2, a strong enhancer of glycolysis, in its regulation. Then we showed that MCT4 expression, as well as the expression of the other two MCT isoforms, is altered in a murine model of stroke. Surprisingly, neurons started to express MCT4, as well as MCT1, under such conditions. Altogether, these data suggest that MCT4, due to its high transport capacity for lactate, may be the isoform that enables cells to operate a major metabolic adaptation in response to pathological situations that alter metabolic homeostasis of the brain. -- Le cerveau représente 2% du poids corporel total, mais il contribue pour 20% de la consommation totale d'oxygène et 25% de celle de glucose au repos. Le glucose est considéré comme le substrat énergétique par excellence pour le cerveau. Néanmoins, depuis un demi- siècle maintenant, de plus en plus de travaux ont démontré que le lactate joue un rôle majeur dans le métabolisme cérébral et est capable du subvenir aux besoins énergétiques des neurones. Le lactate est tout particulièrement nécessaire pendant l'activation neuronale ainsi qu'en situation pathologique. Le transport du lactate à travers la barrière hématoencéphalique ainsi qu'à travers les membranes cellulaires est assuré par la famille des transporteurs aux monocarboxylates (MCTs). Dans le système nerveux central, uniquement trois d'entre eux ont été décrits: MCT2 est considéré comme le transporteur neuronal, alors que les autres types cellulaires qui constituent le cerveau expriment l'isoforme ubiquitaire MCT1. Récemment, l'isoforme MCT4 a été rapportée sur les astrocytes. Dû à sa grande capacité de transport pour le lactate, MCT4 est tout particulièrement adapté pour soutenir le métabolisme des cellules hautement glycolytiques, comme les astrocytes. En raison de sa toute récente découverte, les aspects comprenant sa régulation et son rôle dans le cerveau sont pour l'instant méconnus. Les résultats exposés dans ce travail démontrent dans un premier temps que l'expression de MCT4 est régulée par les niveaux d'oxygène dans les cultures d'astrocytes corticaux par le biais du facteur de transcription HIF-la. De plus, nous avons démontré que l'expression de MCT4 est essentielle à la survie des astrocytes quand le niveau d'oxygénation baisse. En parallèle, des résultats préliminaires suggèrent que l'isoforme 2 de la pyruvate kinase, un puissant régulateur de la glycolyse, pourrait jouer un rôle dans la régulation de MCT4. Dans la deuxième partie du travail nous avons démontré que l'expression de MCT4, ainsi que celle de MCT1 et MCT2, est altérée dans un modèle murin d'ischémie cérébrale. De façon surprenante, les neurones expriment MCT4 dans cette condition, alors que ce n'est pas le cas en condition physiologique. En tenant compte de ces résultats, nous suggérons que MCT4, dû à sa particulièrement grande capacité de transport pour le lactate, représente le MCT qui permet aux cellules du système nerveux central, notamment les astrocytes et les neurones, de s'adapter à de très fortes perturbations de l'homéostasie métabolique du cerveau qui surviennent en condition pathologique.

On regeneration and collateral sprouting to hind limb digits after sciatic nerve injury in the rat

This study examines the proportions of regenerative and collateral sprouting to the skin after peripheral nerve injury. Methods: In the first experimental paradigm, primary afferent neurones were pre-labelled with Diamidino Yellow (DY), injected in digit 3, followed by sciatic nerve section and repair. After three months of regeneration, digit 3 was re-injected with Fast Blue (FB) to label regernating cells. Fluoro-Gold (FG) was applied to the femoral (FEM) and musculocutaneous (MC) nervers four days later to quantify their contribution to the innveration. In the second experimental paradigm, sciatic nerve was first sectioned and repaired. Three months later, the sciatic was resected, and digit 3 injected with FB. After four more days, FEM and MC were resected and FG injected in all digits. Results: Neurones in dorsal root ganglion (DRG) L5 had a higher rate of correct reinnervation of digit 3 (44-72%) than neurones in DRG L4 (14-44%). Like in control cases, only occasional axons were traced from the FEM and MC. In the second experiment, only occasional labelled neurones appeared. Conclusions: The results indicate differences in the capacity for correct peripheral sensory reinnvervation between segmental levels and that in this model collateral sprouting was practically non-existent compared to regenerative sprouting.

JNK Inhibition Reduced Retinal Ganglion Cell Death after Ischemia/Reperfusion In Vivo and after Hypoxia In Vitro.

Mitogen-activated protein kinases (MAPKs) are key regulators that have been linked to cell survival and death. Among the main classes of MAPKs, c-jun N-terminal kinase (JNK) has been shown to mediate cell stress responses associated with apoptosis. In Vitro, hypoxia induced a significant increase in 661W cell death that paralleled increased activity of JNK and c-jun. 661W cells cultured in presence of the inhibitor of JNK (D-JNKi) were less sensitive to hypoxia-induced cell death. In vivo, elevation in intraocular pressure (IOP) in the rat promoted cell death that correlated with modulation of JNK activation. In vivo inhibition of JNK activation with D-JNKi resulted in a significant and sustained decrease in apoptosis in the ganglion cell layer, the inner nuclear layer and the photoreceptor layer. These results highlight the protective effect of D-JNKi in ischemia/reperfusion induced cell death of the retina.

A probable dual mode of action for both L- and D-lactate neuroprotection in cerebral ischemia.

Lactate has been shown to offer neuroprotection in several pathologic conditions. This beneficial effect has been attributed to its use as an alternative energy substrate. However, recent description of the expression of the HCA1 receptor for lactate in the central nervous system calls for reassessment of the mechanism by which lactate exerts its neuroprotective effects. Here, we show that HCA1 receptor expression is enhanced 24 hours after reperfusion in an middle cerebral artery occlusion stroke model, in the ischemic cortex. Interestingly, intravenous injection of L-lactate at reperfusion led to further enhancement of HCA1 receptor expression in the cortex and striatum. Using an in vitro oxygen-glucose deprivation model, we show that the HCA1 receptor agonist 3,5-dihydroxybenzoic acid reduces cell death. We also observed that D-lactate, a reputedly non-metabolizable substrate but partial HCA1 receptor agonist, also provided neuroprotection in both in vitro and in vivo ischemia models. Quite unexpectedly, we show D-lactate to be partly extracted and oxidized by the rodent brain. Finally, pyruvate offered neuroprotection in vitro whereas acetate was ineffective. Our data suggest that L- and D-lactate offer neuroprotection in ischemia most likely by acting as both an HCA1 receptor agonist for non-astrocytic (most likely neuronal) cells as well as an energy substrate.

Neuronal death after perinatal cerebral hypoxia-ischemia: Focus on autophagy-mediated cell death.

Neonatal hypoxic-ischemic encephalopathy is a critical cerebral event occurring around birth with high mortality and neurological morbidity associated with long-term invalidating sequelae. In view of the great clinical importance of this condition and the lack of very efficacious neuroprotective strategies, it is urgent to better understand the different cell death mechanisms involved with the ultimate aim of developing new therapeutic approaches. The morphological features of three different cell death types can be observed in models of perinatal cerebral hypoxia-ischemia: necrotic, apoptotic and autophagic cell death. They may be combined in the same dying neuron. In the present review, we discuss the different cell death mechanisms involved in neonatal cerebral hypoxia-ischemia with a special focus on how autophagy may be involved in neuronal death, based: (1) on experimental models of perinatal hypoxia-ischemia and stroke, and (2) on the brains of human neonates who suffered from neonatal hypoxia-ischemia.

Right heart ischemia in cases of sepsis.

Data from the literature suggest that cases of sepsis complicated by right ventricular (RV) dysfunction have poorer prognosis. In these cases progressive hypoperfusion associated to increasing, injury-related, pulmonary vascular resistance account for RV ischemia. In the present analysis, we wanted to evaluate whether prevalent RV cardiac ischemic damage could be detected in a series of fatal sepsis cases. We retrospectively investigated 20 cases of sepsis that underwent forensic autopsy (study group-11♀, 9♂, mean age 57 years) and compared them to a group of 20 cases of hanging (hanging group-4 ♀, 16 ♂, mean age 44 years) as well as to a group of 20 cases of myocardial infarction (MI group-9 ♀, 11 ♂, mean age 65 years), as examples of cardiac damage due to global hypoxia during agony and ischemic damage, respectively. We performed immunohistochemistry with the antibodies anti-fibronectin and C5b-9. The reactions were semiquantitively classified and the groups were compared. In 30% of the cases of sepsis prevalent RV ischemic damage could be detected with the antibody anti-fibronectin. This expression was significantly different from that observed in cases of MI (p=0.028) and hanging (p<0.001). Our study showed that, in cases of fatal sepsis, prevalent RV ischemic damage occurred in a substantial minority of cases.

Acid-sensing ion channel 1a drives AMPA receptor plasticity following ischemia and acidosis in hippocampal CA1 neurons

The CA1 region of the hippocampus is particularly vulnerable to ischemic damage. While NMDA receptors play a major role in excitotoxicity, it is thought to be exacerbated in this region by two forms of post-ischemic AMPA receptor (AMPAR) plasticity - namely, anoxic long-term potentiation (a-LTP), and a delayed increase in the prevalence of Ca2+ -permeable GluA2-lacking AMPARs (CP-AMPARs). The acid-sensing ion channel 1a (ASIC1a) which is expressed in CA1 pyramidal neurons, is also known to contribute to post-ischemic neuronal death and to physiologically induced LTP. This raises the question - does ASIC1a activation drive the post-ischemic forms of AMPAR plasticity in CA1 pyramidal neurons? We have tested this by examining organotypic hippocampal slice cultures (OHSCs) exposed to oxygen glucose deprivation (OGD), and dissociated cultures of hippocampal pyramidal neurons (HPN) exposed to low pH (acidosis). We find that both a-LTP and the delayed increase in the prevalence of CP-AMPARs are dependent on ASIC1a activation during ischemia. Indeed, acidosis alone is sufficient to induce the increase in CP-AMPARs. We also find that inhibition of ASIC1a channels circumvents any potential neuroprotective benefit arising from block of CP-AMPARs. By demonstrating that ASIC1a activation contributes to post-ischemic AMPAR plasticity, our results identify a functional interaction between acidotoxicity and excitotoxicity in hippocampal CA1 cells, and provide insight into the role of ASIC1a and CP-AMPARs as potential drug targets for neuroprotection. We thus propose that ASIC1a activation can drive certain forms of CP-AMPAR plasticity, and that inhibiting ASIC1a affords neuroprotection.

Quelle prise en charge pour une suspicion de thrombose veineuse profonde des membres inférieurs [Suspicion of lower limb deep vein thrombosis: update on diagnosis and treatment].

Si l'examen clinique revêt une importance essentielle en lymphologie et exige des praticiens expérimentés, la lymphoscintigraphie et plus récemment la lympho-fluoroscopie au vert d'indocyanine constituent des moyens d'investigation précieux dans la prévention, le diagnostic et le traitement des pathologies vasculaires lymphatiques. L'intérêt de la lymphoscintigraphie réside dans l'analyse qualitative et quantitative de la migration des macromolécules par les vaisseaux lymphatiques et l'évaluation du secteur lymphatique profond. La lympho-fluoroscopie se distingue de la lymphoscintigraphie par l'obtention d'une cartographie détaillée des vaisseaux lymphatiques superficiels et d'images dynamiques en temps réel. Elle apporte à l'angiologue et au physiothérapeute des informations irremplaçables sur leur contractilité et la présence de dérivations compensatoires à privilégier lors du drainage lymphatique manuel. Venous thromboembolism is a frequent disease with an annual incidence of 0.75-2.69/1000 reaching 2-7/1000 > 70 years. Deep vein thrombosis (DVT) and pulmonary embolism are two manifestations of the same underlying disease. Most frequent localization of DVT is at lower limbs. The diagnostic workup begins with an estimation of DVT risk, a judicious use of D-Dimers, and compression venous ultrasound depending on DVT probability. The development of direct oral anticoagulants and recent data on interventional DVT treatment, in selected cases, have widened the therapeutic spectrum of DVT. The present article aims at informing the primary care physician of the optimized workup of patients with lower limb suspicion of DVT.

A probable dual mode of action for both L- and D-lactate neuroprotection in cerebral ischemia.

Lactate has been shown to offer neuroprotection in several pathologic conditions. This beneficial effect has been attributed to its use as an alternative energy substrate. However, recent description of the expression of the HCA1 receptor for lactate in the central nervous system calls for reassessment of the mechanism by which lactate exerts its neuroprotective effects. Here, we show that HCA1 receptor expression is enhanced 24 hours after reperfusion in an middle cerebral artery occlusion stroke model, in the ischemic cortex. Interestingly, intravenous injection of L-lactate at reperfusion led to further enhancement of HCA1 receptor expression in the cortex and striatum. Using an in vitro oxygen-glucose deprivation model, we show that the HCA1 receptor agonist 3,5-dihydroxybenzoic acid reduces cell death. We also observed that D-lactate, a reputedly non-metabolizable substrate but partial HCA1 receptor agonist, also provided neuroprotection in both in vitro and in vivo ischemia models. Quite unexpectedly, we show D-lactate to be partly extracted and oxidized by the rodent brain. Finally, pyruvate offered neuroprotection in vitro whereas acetate was ineffective. Our data suggest that L- and D-lactate offer neuroprotection in ischemia most likely by acting as both an HCA1 receptor agonist for non-astrocytic (most likely neuronal) cells as well as an energy substrate.

Myocardial perfusion scintigraphy in the detection of silent ischemia in asymptomatic diabetic patients

OBJECTIVE: This study was aimed to evaluate myocardial perfusion in asymptomatic patients with type 1 (DM1) and type 2 diabetes mellitus (DM2) without previous diagnoses of coronary artery disease (CAD) or cerebral infarction. MATERIALS AND METHODS: Fifty-nine consecutive asymptomatic patients (16 DM1, 43 DM2) underwent myocardial perfusion scintigraphy with 99mTc-sestamibi (MPS). They were evaluated for body mass index, metabolic control of DM, type of therapy, systemic arterial hypertension, dyslipidemia, nephropathy, retinopathy, peripheral neuropathy, smoking, and familial history of CAD. RESULTS: MPS was abnormal in 15 patients (25.4%): 12 (20.3%) with perfusion abnormalities, and 3 with isolated left ventricular dysfunction. The strongest predictors for abnormal myocardial perfusion were: age 60 years and above (p = 0.017; odds ratio [OR] = 6.0), peripheral neuropathy (p = 0.028; OR = 6.1), nephropathy (p = 0.031; OR = 5.6), and stress ECG positive for ischemia (p = 0.049; OR = 4.08). CONCLUSION: Silent myocardial ischemia occurs in more than one in five asymptomatic diabetic patients. The strongest predictors of ischemia in this study were: patient age, peripheral neuropathy, nephropathy, retinopathy and a stress ECG positive for ischemia.

Prevalence and determinants of periodic limb movements in the general population.

OBJECTIVE: Periodic limb movements during sleep (PLMS) are sleep phenomena characterized by periodic episodes of repetitive stereotyped limb movements. The aim of this study was to describe the prevalence and determinants of PLMS in a middle to older aged general population. METHODS: Data from 2,162 subjects (51.2% women, mean age = 58.4 ± 11.1 years) participating in a population-based study (HypnoLaus, Lausanne, Switzerland) were collected. Assessments included laboratory tests, sociodemographic data, personal and treatment history, and full polysomnography at home. PLMS index (PLMSI) was determined, and PLMSI > 15/h was considered as significant. RESULTS: Prevalence of PLMSI > 15/h was 28.6% (31.3% in men, 26% in women). Compared to subjects with PLMSI ≤ 15/h, subjects with PLMSI > 15/h were older (p < 0.001), were predominantly males (p = 0.007), had a higher proportion of restless legs syndrome (RLS; p < 0.001), had a higher body mass index (p = 0.001), and had a lower mean glomerular filtration rate (p < 0.001). Subjects with PLMSI > 15/h also had a higher prevalence of diabetes, hypertension, and beta-blocker or hypnotic treatments. The prevalence of antidepressant use was higher, but not statistically significant (p = 0.07). Single nucleotide polymorphisms (SNPs) within BTBD9 (rs3923809), TOX3 (rs3104788), and MEIS1 (rs2300478) genes were significantly associated with PLSMI > 15/h. Conversely, mean hemoglobin and ferritin levels were similar in both groups. In the multivariate analysis, age, male gender, antidepressant intake, RLS, and rs3923809, rs3104788, and rs2300478 SNPs were independently associated with PLMSI > 15/h. INTERPRETATION: PLMS are highly prevalent in our middle-aged European population. Age, male gender, RLS, antidepressant treatment, and specific BTBD9, TOX3, and MEIS1 SNP distribution are independent predictors of PLMSI > 15/h. ANN NEUROL 2016;79:464-474.