Evaluation of Memantine in AAV-AD Rat: A Model of Late-Onset Alzheimer's Disease Predementia.

BACKGROUND: Though our understanding of Alzheimer's disease (AD) remains elusive, it is well known that the disease starts long before the first signs of dementia. This is supported by the large number of symptomatic drug failures in clinical trials and the increased trend to enroll patients at predementia stages with either mild or no cognitive symptoms. However, the design of pre-clinical studies does not follow this attitude, in particular regarding the choice of animal models, often irrelevant to mimic predementia Late Onset Alzheimer's Disease (LOAD). OBJECTIVES: We aimed to pharmacologically validate the AAV-AD rat model to evaluate preventive treatment of AD. METHODS: We evaluated an N-methyl-D-aspartate receptor antagonist, named memantine, in AAV-AD rats, an age-dependent amyloid rat model which closely mimics Alzheimer's pathology including asymptomatic and prodromal stages. Memantine was used at a clinically relevant dose (20 mg daily oral administration) from 4 (asymptomatic phase) to 10 (mild cognitive impairment phase) months of age. RESULTS: A 6-month treatment with memantine promoted a non-amyloidogenic cleavage of APP followed by a decrease in soluble Aß42. Consequently, both long-term potentiation and cognitive impairments were prevented. By contrast, the levels of hyperphosphorylated endogenous tau remained unchanged, indicating that a long-term memantine treatment is ineffective to restrain the APP processing-induced tauopathy. CONCLUSIONS: Together, our data confirm that relevant models to LOAD, such as the AAV-AD rat, can provide a framework for a better understanding of the disease and accurate assessment of preventive treatments.

Rapid onset of squamous cell carcinoma in a thin skin graft donor site.

BACKGROUND: Squamous cell carcinomas are malignant tumours of epithelial origin that can appear on sites subjected to chronic inflammation after a period of several years. The rapid development of squamous cell carcinoma at the donor site for a thin skin graft is a rare and poorly understood situation. PATIENTS AND METHODS: We report the case of a patient undergoing thin skin grafting to cover the area of removal of a vertex squamous cell carcinoma and in whom squamous cell carcinoma appeared at the donor site within 9 weeks. DISCUSSION: In our case, we ruled out intraoperative contamination because two sets of surgical instruments were used. Given the number of cases reported in the literature, a chance event seems unlikely. The hypothesis of an acute inflammatory process caused by scarring of the thin skin graft site appears to us the most convincing. Development of cancer at the graft donor site may thus be added to the list of complications of thin skin grafting.

[External canthus reconstruction with tarso-conjunctival transposition flap and Hübner's graft]. / Reconstruction du canthus externe par lambeaux de transposition tarso-conjonctivaux et greffons de Hübner.

The external canthus defects with resection of the superior and inferior eyelids external portion remains difficult to treat. The reconstruction has to focus on both the reconstruction of the tarso-conjunctival plan and the musculo-cutaneous plan but has also to treat the disappearance of the external canthus. Usually the tarso-conjunctival plan is reconstructed by a septal transplant, conqual or of palatine mucous membrane. The technique presented here suggests to use two tarso-conjunctival transposition flaps to reconstruct the external canthus and the canthal external ligament. The palpebral defect is then pulled medialy, and is easily reconstructed by a Hübner's graft. The coverage of these tarso-conjunctival flaps and grafts is realized with local cutaneous or musculo-cutaneous flaps. The aim of this reconstruction is to allow a functional and aesthetic reconstruction with respected lid margins with eyelashes. Thanks to this technique, it is possible to reconstruct external canthus defects up to half of the superior and inferior eyelids.

[Cheek reconstruction]. / Reconstruction jugale.

We describe the different cheek reconstruction techniques with primary emphasis on the superficial layers. In addition to the clinical context, location and size of the lesion will be taken into account to choose the best method that will optimize the functional and aesthetic results while minimizing potential sequelae. Main evaluation criteria include absence of natural orifice deformation, scar location, skin cover quality and respect of volumes.

Omega-3 fatty acids and brain resistance to ageing and stress: body of evidence and possible mechanisms.

The increasing life expectancy in the populations of rich countries raises the pressing question of how the elderly can maintain their cognitive function. Cognitive decline is characterised by the loss of short-term memory due to a progressive impairment of the underlying brain cell processes. Age-related brain damage has many causes, some of which may be influenced by diet. An optimal diet may therefore be a practical way of delaying the onset of age-related cognitive decline. Nutritional investigations indicate that the ω-3 poyunsaturated fatty acid (PUFA) content of western diets is too low to provide the brain with an optimal supply of docosahexaenoic acid (DHA), the main ω-3 PUFA in cell membranes. Insufficient brain DHA has been associated with memory impairment, emotional disturbances and altered brain processes in rodents. Human studies suggest that an adequate dietary intake of ω-3 PUFA can slow the age-related cognitive decline and may also protect against the risk of senile dementia. However, despite the many studies in this domain, the beneficial impact of ω-3 PUFA on brain function has only recently been linked to specific mechanisms. This review examines the hypothesis that an optimal brain DHA status, conferred by an adequate ω-3 PUFA intake, limits age-related brain damage by optimizing endogenous brain repair mechanisms. Our analysis of the abundant literature indicates that an adequate amount of DHA in the brain may limit the impact of stress, an important age-aggravating factor, and influences the neuronal and astroglial functions that govern and protect synaptic transmission. This transmission, particularly glutamatergic neurotransmission in the hippocampus, underlies memory formation. The brain DHA status also influences neurogenesis, nested in the hippocampus, which helps maintain cognitive function throughout life. Although there are still gaps in our knowledge of the way ω-3 PUFA act, the mechanistic studies reviewed here indicate that ω-3 PUFA may be a promising tool for preventing age-related brain deterioration.

[Schmid-Meyer fronto-temporal flap for nasal reconstruction]. / Le lambeau fronto-temporal de Schmid-Meyer dans les reconstructions nasales.

INTRODUCTION: Many surgical techniques have already been described to repair full thickness defects of the inferior part of the nose. The Schmid-Meyer fronto-temporal flap procedure, a little known technique, is based on the old principle of autonomization of a cutaneous flap and uses a tailor-made composite cartilaginous graft placed in the temporal region. This graft is progressively detached and allows mucosal/cartilaginous/and cutaneous nasal repair. Can this technique still be used for nasal full-thickness reconstruction? PATIENTS AND METHOD: Nine cases of nasal reconstruction using this procedure were performed. The 4-steps of the operative technique were described and the results were analyzed retrospectively. RESULTS: This procedure allows, for some specific indications, excellent reconstruction of the ala, the columella or the nasal tip. In eight cases out of nine, the result was judged good or very good by both patients and physicians. In 78%, the reconstruction was performed under local anesthesia. DISCUSSION: The Schmid-Meyer flap procedure may still be used for full-thickness reconstruction of the lower third of the nose because it allows a high quality of nasal reconstruction and few scar sequels.

[Moldable titanium mesh for chest wall reconstruction, an elegant solution about a case report]. / Reconstruction d'une pariétectomie thoracique transfixiante par grille de titane malléable, une solution élégante à propos d'un cas.

INTRODUCTION: Several surgical techniques are available for full thickness chest wall reconstruction. The choice has to be adapted to the size of the loss of tissue, its location, and must finally be accepted by the patient's. We propose a new and unpublished solution. CASE REPORT: We have in our care a 54 years-old patient suffering from a previous loss of chest wall tissue measuring 7 cm(2) due to surgical treatment of mediastinal Hodgkin's disease with sternal and costal invasion. Because of the sequelae, the goal focused on aesthetic reconstruction. Heartbeat was visible under the skin due to a loss of secondary left breast tissue from an initial treatment with absorbable Vicryl(©) mesh followed by a local skin, and glandular flap. Our choice of reconstruction consisted of inserting a moldable titanium mesh followed by 200 g implants in each breast during the same operation. We did not experience any complications and the patient is satisfied with the results. DISCUSSION: No example of reconstruction using only a moldable titanium mesh was found in the literature on chest wall reconstruction. Our elegant choice is innovative in our discipline. However, this reconstruction materiel is already part of therapy procedures in other specialized surgeries. CONCLUSION: This case report illustrates the various facets of our speciality: bring a solution at once repair, aesthetic and unique according to the request of the patient. The use of a moldable titanium mesh allows the reconstruction of stable chest wall. The small size does not present any functional difficulties, but rather unsightly sequel.

[The complete dorsum nasal island flap based on the superior alar artery]. / Lambeau total du dos du nez basé sur l'artère alaire supérieure.

The complete dorsal nasal aesthetic unit can be raised in a vascular island flap based on the superior alar artery, at the level of the nasalis muscle. This flap uses the vertical glabellar cutaneous laxity. It hides scars between the nasal aesthetics units and its distal rotation point allows a pure translation of the nasal skin without distortions encountered when using medial canthal rotation flaps. This local flap is reliable and had been successfully used for four patients without complications or secondary procedures. It allows large reconstructions for up to 25 mm defects leaving minimal scars. It represents an interesting alternative for the reconstruction of defects of the nasal tip or supra tip of the nose, and has also been used for alar reconstructions.

[Primitive neuroendocrine cancer of the breast. Post-traumatic discovery of a man]. / Tumeur neuroendocrine primitive du sein. Découverte post-traumatique chez un homme.

We report a primitive neuroendocrine breast tumor (NET) in a male. This situation is uncommon by its mode of discovery. We have treated a 74-year-old man with a lesion in the left areola initially considered as an organized hematoma due to a severe trauma. The ablation was performed by direct access under local anesthesia. The analysis of the piece has showed a NET of the breast due to the positivity of the neuroendocrine, cytokeratin and hormone markers. No other NET lesion was found, excluding the secondary origin of the breast tumor. Complementary therapies associated mastectomy, lymphadenectomy, hormonotherapy. Male breast cancer is rare. NET are exceptional, only a dozen of male NET is reported. These tumors affect a specific population and have a better prognosis than infiltrating ductal carcinoma. In our case, no causal link can be demonstrated between trauma and tumor microenvironment necessary for the growth of quiescent cancer cells.

[Conchal flap with a superior pedicle to reconstruct the middle or upper third of the auricle]. / Le lambeau de conque à pédicule supérieur pour les reconstructions hélicéennes supérieures ou moyennes.

The middle or upper third of the auricle can be reconstructed with a composite chondro-cutaneous peninsular flap of the conchal part of the auricle. This peninsular flap is based on the anastomotic network between the posterior auricular and the superficial temporal artery. The authors report their experience about 24 clinical cases. Most of the cases were partial auricular amputations for squamous cell carcinoma. The surgical procedure allows a hidden cartilaginous donor site, the concha, allowing in a single operation a color- and texture-matched reconstruction. This flap represents an alternative to more complex surgical procedures, and can easily be realised under local anaesthesia.

Reduced serine racemase expression contributes to age-related deficits in hippocampal cognitive function.

To gain insight into the contribution of d-serine to impaired cognitive aging, we compared the metabolic pathway and content of the amino acid as well as d-serine-dependent synaptic transmission and plasticity in the hippocampus of young and old rats of the Wistar and Lou/C/Jall strains. Wistar rats display cognitive impairments with aging that are not found in the latter strain, which is therefore considered a model of healthy aging. Both mRNA and protein levels of serine racemase, the d-serine synthesizing enzyme, were decreased in the hippocampus but not in the cerebral cortex or cerebellum of aged Wistar rats, whereas the expression of d-amino acid oxidase, which degrades the amino acid, was not affected. Consequently, hippocampal levels of endogenous d-serine were significantly lower. In contrast, serine racemase expression and d-serine levels were not altered in the hippocampus of aged Lou/C/Jall rats. Ex vivo electrophysiological recordings in hippocampal slices showed a marked reduction in N-methyl-d-aspartate-receptor (NMDA-R)-mediated synaptic potentials and theta-burst-induced long-term potentiation (LTP) in the CA1 area of aged Wistar rats, which were restored by exogenous d-serine. In contrast, NMDA-R activation, LTP induction and responses to d-serine were not altered in aged Lou/C/Jall rats. These results further strengthen the notion that the serine racemase-dependent pathway is a prime target of hippocampus-dependent cognitive deficits with aging. Understanding the processes that specifically affect serine racemase during aging could thus provide key insights into the treatment of memory deficits in the elderly.

Contribution of the d-Serine-Dependent Pathway to the Cellular Mechanisms Underlying Cognitive Aging.

An association between age-related memory impairments and changes in functional plasticity in the aging brain has been under intense study within the last decade. In this article, we show that an impaired activation of the strychnine-insensitive glycine site of N-methyl-d-aspartate receptors (NMDA-R) by its agonist d-serine contributes to deficits of synaptic plasticity in the hippocampus of memory-impaired aged rats. Supplementation with exogenous d-serine prevents the age-related deficits of isolated NMDA-R-dependent synaptic potentials as well as those of theta-burst-induced long-term potentiation and synaptic depotentiation. Endogenous levels of d-serine are reduced in the hippocampus with aging, that correlates with a weaker expression of serine racemase synthesizing the amino acid. On the contrary, the affinity of d-serine binding to NMDA-R is not affected by aging. These results point to a critical role for the d-serine-dependent pathway in the functional alterations of the brain underlying memory impairment and provide key information in the search for new therapeutic strategies for the treatment of memory deficits in the elderly.

[Optimized negative pressure therapy. Case report]. / Thérapie par pression négative optimisée. A propos d'un cas.

Our patient showed major abdominal cutaneous necrosis. Detersion removed the entire thickness of half of the right-hand wall of the abdomen. We are going to explain how, by combining well known procedures, we conducted this closure. This deals with a patient aged 53, with a long case history of dermatomyositis and highly debilitating sub-cutaneous calcinosis. This patient has been treated with Imurel and high doses of corticoids since 1997. In the face of the much debilitated terrain of the patient, it was not certain that a local flap or even a pediculated flap could be made to cover this loss of substance with a minimum of risk. A cutaneous extension was then envisaged using a system of Wisebands fillets. To protect the parietal plate, accelerate its growth and reduce the skin tension, we used in combination a system of foam dressing with negative pressure therapy (NPT). The optimized NPT was used for 2 weeks. The Wisebands were installed for 1 month. The treatment lasted for 50 days and required five short sessions of general anaesthesia. The histopathological interpretation revealed an EBV lymphoma. The assessment of the extension and the therapeutic treatment of the lymphoma contributed to the duration of hospitalisation and the number of general anaesthesia sessions. The synergy effect of these two associated procedures have allowed a faster skin closure; 18 months later, no complications have occurred. The wound has closed totally and the abdominal wall is solid in spite of not having resorted to a flap or separation.

Age-related alterations of GABAergic input to CA1 pyramidal neurons and its control by nicotinic acetylcholine receptors in rat hippocampus.

The aim of this study was to determine whether age-associated alterations in the GABAergic input to pyramidal neurons in the hippocampus are due to a dysfunction of GABAergic interneurons, and/or a decrease in their cholinergic control via nicotinic receptors (nAChRs). Electrophysiological recordings were obtained from pyramidal cells in the CA1 area of hippocampal slices from young (3-4 months old) and aged (25-30 months old) Sprague-Dawley rats. Synaptic GABA(A) receptor-mediated inhibitory postsynaptic currents and inhibitory postsynaptic potentials induced by stimulation of the stratum oriens were significantly smaller in aged rats. The frequency (but not amplitude) of spontaneous and miniature GABA inhibitory postsynaptic currents (IPSCs) was reduced in aged rats, suggesting a presynaptic alteration. Tetanic stimulation of cholinergic afferents to release endogenous acetylcholine, or an exogenous application of the nAChR agonist cytisine, increased the frequency of spontaneous IPSCs in young rats; however these effects were not evident in aged rats, indicating that the nicotinic control of GABA release is lowered during aging. None of these age-related alterations were reversed by a chronic treatment with donepezil, a cholinesterase inhibitor. Immunofluorescent labeling of GABA interneurons with somatostatin (SOM), parvalbumin (PV) or calbindin (CB), together with the vesicular acetylcholine transporter VAChT, revealed a selective loss of subpopulations of SOM and CB positive interneurons. This loss was associated with a general decrease in density of the cholinergic network in aged rats. Thus, the lower GABAergic inhibition observed in the aged rat hippocampus is due to a selective loss/dysfunction of subpopulations of GABAergic interneurons, associated with a widespread cholinergic deficit.

A critical role for the glial-derived neuromodulator D-serine in the age-related deficits of cellular mechanisms of learning and memory.

Age-associated deficits in learning and memory are closely correlated with impairments of synaptic plasticity. Analysis of N-methyl-D-aspartate receptor (NMDAr)-dependent long-term potentiation (LTP) in CA1 hippocampal slices indicates that the glial-derived neuromodulator D-serine is required for the induction of synaptic plasticity. During aging, the content of D-serine and the expression of its synthesizing enzyme serine racemase are significantly decreased in the hippocampus. Impaired LTP and NMDAr-mediated synaptic potentials in old rats are rescued by exogenous D-serine. These results highlight the critical role of glial cells and presumably astrocytes, through the availability of D-serine, in the deficits of synaptic mechanisms of learning and memory that occur in the course of aging.

Spatial learning and synaptic hippocampal plasticity in type 2 somatostatin receptor knock-out mice.

Somatostatin is implicated in a number of physiological functions in the CNS. These effects are elicited through the activation of at least five receptor subtypes. Among them, sst2 receptors appear the most widely expressed in the cortex and hippocampal region. However, the specific role of this somatostatin receptor subtype in these regions is largely undetermined. In this study, we investigated the role of the sst2 receptor in the hippocampus using mice invalidated for the sst2 gene (sst2 KO mice). Complementary experimental approaches were used. First, mice were tested in behavioral tests to explore the consequences of the gene deletion on learning and memory. Spatial discrimination learning in the radial maze was facilitated in sst2 KO mice, while operant learning of a bar-pressing task was slightly altered. Mice were then processed for electrophysiological study using the ex vivo hippocampal slice preparation. Extracellular recordings in the CA1 area showed an enhancement in glutamatergic (AMPA and NMDA) responses in sst2 KO mice which displayed an increase in the magnitude of the short-term potentiation and long-term depression. In contrast, long-term potentiation was not significantly altered. Taken together, these data demonstrate that somatostatin, acting via sst2 hippocampal receptors, may contribute to a global decrease in glutamate efficiency and consequently alter glutamate-dependent plasticity and spatial learning.

Decrease in calbindin content significantly alters LTP but not NMDA receptor and calcium channel properties.

The contribution of the cytosolic calcium binding protein calbindin D(28K) (CaBP) to the synaptic plasticity was investigated in hippocampal CA1 area of wild-type and antisense transgenic CaBP-deficient mice. We showed that long-term potentiation (LTP) induced by tetanic stimulation in CaBP-deficient mice was impaired. The fundamental biophysical properties of NMDA receptors and their number were not modified in CaBP-deficient mice. We also demonstrated that the physiological properties of calcium channels were identical between genotypes. An insufficient Ca(2+) entry through NMDA receptors or calcium channels, or a decrease in NMDA receptor density are unlikely to explain this impairment of LTP. Interestingly, we showed that the loss of LTP was not prevented by glycine but was restored in the presence of a low concentration of the NMDA receptor antagonist D-APV (5 microM) and of the calcium chelator BAPTA-AM (5 microM). Moreover, we observed a loss of LTP in the wild-type mice when the postsynaptic tetanic-induced [Ca(2+)](i) rise is excessively increased. Conversely, a weaker tetanus stimulation allowed LTP induction and maintenance in CaBP-deficient mice. These results suggest that a higher cytosol [Ca(2+)](i), due to the decrease of CaBP expression may impair LTP induction and maintenance mechanisms without affecting the mechanisms of calcium entry. Thus, CaBP plays a critical role in long term synaptic plasticity by limiting the elevation of calcium rise in the cytosol to some appropriate spatio-temporal pattern.

[Programmed left ventricular stimulation in non-sustained ventricular arrhythmias]. / La stimulation ventriculaire programmée dans les arythmies ventricularies non soutenues.

The presence of nonsustained ventricular arrhythmia (NSVA) is an independent factor of sudden rhythmic death. The primary objective of our study was to evaluate the correlation between inducibility during programmed ventricular stimulation (PVS) and the presence of ventricular late potentials, the ejection fraction, the grade of arrhythmia, and the underlying cardiopathy. The secondary objective was to evaluate the interest of PVS in patients with NSVA. Ninety eight patients with NSVA have been tested by PVS and 14 were inducible. During the mean follow up of 24 months, 8 patients died, 3 of them suddenly. A significative statistical correlation was found between ventricular late potentials and inducibility (negative predictive value = 91%; p = 0.03). No correlation was found between the ejection fraction, the grade of arrhythmia, the cardiopathy and inducibility. In patients with ischaemic cardiopathy, PVS has allowed to identify a subgroup of patients with high risk of sudden death. In this subgroup, serial PVS for drug testing has contributed to choose the therapeutic regimen supposed to be more effective for prevention of fatal arrhythmia. Multiple factors explain sudden death, even though the initial treatment has been chosen by electrophysiologic studies. For non inducible patients, empiric treatment is not proven to be reliable, and the best therapeutic regimen is still unidentified, especially in the subgroup of patients with low ejection fraction. In this subgroup, the implantable cardioverter defibrillator vives better protection against sudden rhythmic death.

NMDA receptor activation in the aged rat hippocampus.

Age-related alterations of N-methyl-D-aspartate receptor (NMDAr) activation were investigated in the CA1 field of hippocampal slices from young (3-6 months old) and aged (25-33 months old) Sprague-Dawley rats by using ex vivo extracellular electrophysiological recording techniques. NMDAr-mediated field excitatory postsynaptic potentials (fEPSPs) were induced by electrical stimulation of glutamatergic fibers in a magnesium (Mg(2+))-free medium supplemented with the non-NMDAr antagonist CNQX. The fEPSPs were significantly smaller in aged rats, whereas the response of presynaptic afferent fibers remained unaffected. No significant age-related differences were found in the ability of Mg(2+) to depress the magnitude of NMDAr-mediated fEPSPs. The responsiveness of postsynaptic NMDAr to the agonist was assessed in both groups of animals. No age-related differences were recorded either in the depolarizing effect of bath-applied NMDA or in the magnitude of the depolarization after altering extracellular Mg(2+) concentration. Finally, short-term potentiation (STP) of excitatory transmission was studied in young and aged rats considering the pivotal role of NMDAr in synaptic plasticity. No age-related alterations of the magnitude and the time course of STP in response to 10 or 30Hz conditioning stimulation were found. Because of the decrease in the magnitude of NMDAr-mediated synaptic transmission in aged animals, the absence of obvious modifications of synaptic plasticity suggests the occurrence of compensatory mechanisms that are discussed.

Involvement of sst2 somatostatin receptor in locomotor, exploratory activity and emotional reactivity in mice.

Somatostatin (SRIF) controls many physiological and pathological processes in the central nervous system but the respective roles of the five receptor isotypes (sst1-5) that mediate its effects are yet to be defined. In the present study, we attempted to identify functions of the sst2 receptor using mice with no functional copy of this gene (sst2 KO mice). In contrast with control 129Sv/C57Bl6 mice, sst2 mRNA was no longer detectable in the brain of sst2 KO mice; 125I-labeled Tyr0DTrp8-SRIF14 binding was also greatly reduced in almost all brain structures except for the hippocampal CA1 area, demonstrating that sst2 accounts for most SRIF binding in mouse brain. Invalidation of this subtype generated an increased anxiety-related behaviour in a number of behavioural paradigms, while locomotor and exploratory activity was decreased in stress-inducing situations. No major motor defects could be detected. sst2 KO mice also displayed increased release of pituitary ACTH, a main regulator of the stress response. Thus, somatostatin, via sst2 receptor isotype pathways, appears involved in the modulation of locomotor, exploratory and emotional reactivity in mice.