The reduction in glutamate release is predictive of cognitive and emotional alterations that are corrected by the positive modulator of AMPA receptors S 47445 in perinatal stressed rats.

S 47445 is a positive modulator of glutamate AMPA-type receptors, possessing neurotrophic and enhancing synaptic plasticity effects as well as pro-cognitive and anti-stress properties. Here, the drug was assessed in the perinatal stress (PRS) rat model, known to have a high predictive validity with monoaminergic antidepressants. The effects of a chronic treatment (i.p.) with S 47445 were investigated on risk-taking, motivational and cognitive behavior. S 47445 (1 and 10 mg/kg) increased the exploration of the elevated-plus maze and light/dark box as well as the time spent grooming in the splash test, and improved social memory in PRS rats. Also, the effects of S 47445 were examined on the synaptic neurotransmission. The reduced depolarization-evoked glutamate release induced by PRS was corrected with S 47445 (10 mg/kg). Remarkably, the reduction in glutamate release induced by PRS and corrected by S 47445 chronic treatment was correlated with all the behavioral changes. S 47445 at 10 mg/kg also normalized the lower levels of synaptic vesicle-associated proteins in ventral hippocampus in PRS rats. Finally, S 47445 reversed the decrease of mGlu5 receptors, GR and OXTR induced by PRS. Collectively, in an animal model of stress-related disorders, S 47445 corrected the imbalance between excitatory and inhibitory neurotransmission by regulating glutamate-evoked release that is predictive of PRS behavioral alterations, and also normalized the reduction of trafficking of synaptic vesicles induced by PRS. These results support the interest of glutamatergic-based therapeutic strategies to alleviate stress-related disorders.

Proteomic characterization in the hippocampus of prenatally stressed rats.

Rats exposed to early life stress are considered as a valuable model for the study of epigenetic programming leading to mood disorders and anxiety in the adult life. Rats submitted to prenatal restraint stress (PRS) are characterized by an anxious/depressive phenotype associated with neuroadaptive changes in the hippocampus. We used the model of PRS to identify proteins that are specifically affected by early life stress. We therefore performed a proteomic analysis in the hippocampus of adult male PRS rats. We found that PRS induced changes in the expression profile of a number of proteins, involved in the regulation of signal transduction, synaptic vesicles, protein synthesis, cytoskeleton dynamics, and energetic metabolism. Immunoblot analysis showed significant changes in the expression of proteins, such as LASP-1, fascin, and prohibitin, which may lie at the core of the developmental programming triggered by early life stress.

Impact of early life stress on alcohol consumption and on the short- and long-term responses to alcohol in adolescent female rats.

We examined the interaction between early life stress and vulnerability to alcohol in female rats exposed to prenatal restraint stress (PRS rats). First we studied the impact of PRS on ethanol preference during adolescence. PRS slightly increased ethanol preference per se, but abolished the effect of social isolation on ethanol preference. We then studied the impact of PRS on short- and long-term responses to ethanol focusing on behavioral and neurochemical parameters related to depression/anxiety. PRS or unstressed adolescent female rats received 10% ethanol in the drinking water for 4 weeks from PND30 to PND60. At PND60, the immobility time in the forced-swim test did not differ between PRS and unstressed rats receiving water alone. Ethanol consumption had no effect in unstressed rats, but significantly reduced the immobility time in PRS rats. In contrast, a marked increase in the immobility time was seen after 5 weeks of ethanol withdrawal only in unstressed rats. Hippocampal levels of neuropeptide Y (NPY) and mGlu1a metabotropic glutamate receptors were increased at the end of ethanol treatment only in unstressed rats. Ethanol treatment had no effect on levels of corticotropin-releasing hormone (CRH) in the hippocampus, striatum, and prefrontal cortex of both groups of rats. After ethanol withdrawal, hippocampal levels of mGlu1 receptors were higher in unstressed rats, but lower in PRS rats, whereas NPY and CRH levels were similar in the two groups of rats. These data indicate that early life stress has a strong impact on the vulnerability and responsiveness to ethanol consumption during adolescence.

Perinatal undernutrition modifies cell proliferation and brain-derived neurotrophic factor levels during critical time-windows for hypothalamic and hippocampal development in the male rat.

Maternal perinatal undernutrition (MPU) modifies the activity of the hypothalamic-pituitary-adrenal axis and sensitises to the development of metabolic and cognitive adult diseases. Because the hypothalamus and hippocampus are involved in the regulation of neuroendocrine activity, energy metabolism and cognition, we hypothesised that a maternal 50% food restriction (FR50) from day 14 of pregnancy (E14) until postnatal day 21 (P21) would affect the development of these structures in male rat offspring. Protein and mRNA levels of brain-derived neurotrophic factor (BDNF) and cell proliferation [analysed by 5-bromodeoxyuridine (BrdU) incorporation] were compared in both control and FR50 rats from E21 to P22. Although the pattern of the evolution of BDNF concentration and cell proliferation throughout development was not strikingly different between groups, several disturbances at specific developmental stages were observed. FR50 rats exhibited a delayed increase of hippocampal BDNF content whereas, in the hypothalamus, BDNF level was augmented from E21 to P14 and associated, at this latter stage, with an increased mRNA expression of TRkB-T2. In both groups, a correlation between BDNF content and the number of BrdU positive cells was noted in the dentate gyrus, whereas opposite variations were observed in CA1, CA2 and CA3 layers, and in the arcuate and ventromedial nuclei. In the hippocampus, P15-FR50 rats showed an increased number of BrdU positive cells in all regions, whereas, at P22, a decrease was observed in the CA2. In the hypothalamus, between E21 and P8, MPU increases the number of BrdU positive cells in all regions analysed and, until P15, marked differences were noticed in the median eminence, the paraventricular nucleus and the arcuate nucleus. Taken together, the results obtained in the present study show that MPU changes the time course of production of BDNF and cell proliferation in specific hippocampal and hypothalamic areas during sensitive developmental windows, suggesting that these early perinatal modifications may have long-lasting consequences.

Maternal perinatal undernutrition impairs chromaffin cells proliferation in the postnatal rat.

Numerous data show that malnutrition during early life programs chronic diseases in adulthood. Many of these disorders may result from alterations in the development of neuroendocrine systems, such as the hypothalamo-pituitary-adrenal axis and the sympathoadrenal system. We have previously reported that maternal 50% food restriction during late pregnancy and lactation reduces adrenal weight and impairs chromaffin cell differentiation in male rats at weaning. In addition, maternal undernutrition modifies the expression of several genes involved in proliferation and apoptosis. This study therefore investigated the impact of maternal food restriction on adrenal cell growth in the late postnatal rat. Histological analysis showed that the number of proliferating chromaffin cells assessed by nuclear labelling with BrdU was reduced by 45%, whereas the level of apoptosis visualised by caspase-3 immunoreactivity was increased by 340% in adrenal medulla of offspring from undernourished mothers. In contrast, maternal food restriction did not affect proliferation and apoptosis in cortical cells of rats. These developmental changes were associated with overexpression of TGFbeta2. These data show that perinatal undernutrition impairs the balance between chromaffin cell proliferation and apoptosis. These modifications may lead to "malprogramming" of adrenal medulla development, which could contribute to the pathogenesis of chronic diseases in adulthood.

[Followup of pregnant women in the context of malaria: two case reports]. / Suivi de la grossesse dans le cadre du Paludisme: à propos de deux observations.

Whether or not a pregnant women should travel to regions where malaria is highly endemic will always be open to question as no prophlaxis can guarantee complete protection in every case. No chemoprophylaxis is 100% effective or entirely without side-effects, particularly for pregnant women whose immune status provides a favourable environment for the emergence of this parasitosis. The advice given will depend on the country and the region, a possible resistance of the parasite to treatment, the season, the length and circumstances of the stay and individual factors. The choice of treatment is very limited as many therapies are contra-indicated in pregnancy; in addition it is extremely important to give a sufficiently clear explanation concerning precautions and prophylaxis as well as of how a possible bout of malaria should be treated, particularly in case of extended stay.

Gastric ulcers and Helicobacter heilmannii.

OBJECTIVE: To compare 14 patients with gastric ulcer and Helicobacter heilmannii with other patients with gastric ulcer: age and sex matched patients, patients colonized by Helicobacter pylori and patients on nonsteroidal anti-inflammatory drugs (NSAIDs). SETTING: The endoscopy unit of a university-affiliated hospital. PATIENTS AND METHODS: All patients underwent endoscopy with two antral biopsies and smears from biopsies (touch cytology) in addition to biopsies of ulcers. Most patients had fundic biopsies (n = 10), antral biopsies for culture (n = 7) and/or a urease test (n = 9). Serologic determination of antibodies against H. pylori was obtained in nine patients. RESULTS: Patients with H. heilmannii diagnosed on smears from biopsies (touch cytology) had multiple and antral ulcers in 11 samples, and nodular or irregular lesions in five samples. No patient had a history of peptic ulcer disease. Biopsy revealed mild chronic gastritis in all patients, with features of reactive gastritis in nine. No patient had coexistent infection with H. pylori. Only two of ten patients with follow-up endoscopies had persistent H. heilmannii infection on smear or biopsy. No patient had symptomatic recurrence. Patients with H. pylori infection were older and often had recurrent ulceration. The majority of ulcers associated with NSAIDs occurred in elderly women. CONCLUSIONS: Newly diagnosed gastric ulcers are associated with H. heilmannii infection. Healing is associated with the disappearance of H. heilmannii and the regression of reactive gastritis. Ulcers differ from those associated with H. pylori infection or with the use of NSAIDs, suggesting that H. heilmannii is a possible cause of gastric ulcers.

Are perforated gastroduodenal ulcers related to Helicobacter pylori infection?

The prevalence of Helicobacter pylori gastritis in 36 patients with a perforated ulcer undergoing endoscopy prior to or at least 2 months after perforation was 56%, intermediate between that of age and sex matched healthy blood donors (36%) who had measurement of circulating antibodies to Helicobacter pylori and of ulcer patients without perforation matched for age, sex and ulcer location (86%). In the 20 patients with Helicobacter pylori gastritis, 8 had a history of peptic ulcer and 7 of 9 patients with a follow-up of at least 12 months and no preventive treatment had a symptomatic relapse. The group of patients without infection included 6 young patients (< 40) who did not use non steroidal anti-inflammatory drugs and 10 older patients (> 60): 9 used non steroidal anti-inflammatory drugs and seven had a normal gastric mucosa on biopsy. One patient without Helicobacter pylori had a second perforation, the only relapse in this group. We conclude that patients with perforated ulcers are a heterogeneous group with a recurrent ulcer disease mainly in patients with Helicobacter pylori.

Gastrospirillum hominis ("Helicobacter heilmanii"): a cause of gastritis, sometimes transient, better diagnosed by touch cytology?

OBJECTIVE: Besides Helicobacter pylori, another spirillar microorganism, provisionally called Gastrospirillum hominis, has been described in the human stomach in association with gastritis. The aim of this study was to assess the role of cytology in the diagnosis, to assess the gastritis associated with this infection, and to approach its natural history. METHODS: Charts and endoscopic biopsies and smears (touch cytology) from 28 patients with G. hominis seen between 1986 and 1992 were reviewed and compared with biopsies and smears from 28 patients with H. pylori gastritis. RESULTS: G. hominis was seen on smears from all 28 patients but diagnosed in only 15 of the corresponding sets of biopsies. No patient had evidence of H. pylori colonization. All patients had chronic antral gastritis with lymphoplasmocytes, and neutrophils were present in 13 patients. In addition, reactive changes were frequent: foveolar hyperplasia (n = 25), vasodilation (n = 23), lamina propria edema (n = 23), and increased intracytoplasmic mucin (n = 19). In contrast, intestinal metaplasia (n = 3) and glandular atrophy (n = 2) were infrequent, and lymphoid nodules were not seen. In patients with H. pylori, reactive changes were mild, and the lymphoplasmocytic infiltration was more intense (p < 0.005). Eleven patients had at least two endoscopic examinations with biopsies, with persistent colonization in only four. Seven patients cleared the infection with a concomitant regression of gastritis. CONCLUSIONS: G. hominis is more often detected in smears than biopsies. It is seen in association with a peculiar form of gastritis-associating chronic and reactive changes. Colonization may be a transient phenomenon and is never associated with H. pylori.

Helicobacter pylori: 200 patients with a follow-up of 5 years. An observation endoscopic study.

OBJECTIVES: As data on the long-term effects of Helicobacter pylori infection are limited, our aim was to review patients seen repeatedly at endoscopy with biopsies for a minimal period of 5 years. METHODS: The records of 200 patients who had at least two endoscopic examinations with antral biopsies and touch cytology (imprints from biopsies) with an interval of at least 60 months between the first and the last endoscopy. Helicobacter pylori diagnosis was based on the smear. RESULTS: At the first endoscopy, 57% had Helicobacter pylori on the smear, 70% had chronic gastritis on biopsy. During a mean follow-up of 70 months, a colonization rate of 3% per year and an eradication rate of 1% per year were observed. Helicobacter pylori status remained unchanged in 89%. During follow-up, duodenal ulcer was diagnosed at endoscopy in 21 patients, with a significantly (p < 0.05) higher frequency in Helicobacter pylori positive patients, in the presence of gastritis and in men. In two patients, the sequence of colonization and later duodenal ulcer was observed. CONCLUSION: Our retrospective observation study based on endoscopy confirms the chronicity of Helicobacter pylori infection and the low incidence of colonization and eradication. Duodenal ulcer occurred more frequently in Helicobacter pylori positive patients.

Touch cytology. A quick, simple, sensitive screening test in the diagnosis of infections of the gastrointestinal mucosa.

To assess the role of touch cytology (imprint from endoscopic biopsy specimens) in the diagnosis of mucosal infections of the gastrointestinal tract, we reviewed all records and specimens of patients seen during a 30-month period. Touch cytology was performed by rolling biopsy specimens on glass slides. After air fixation, a rapid staining method similar to May-Grünwald-Giemsa was used. The following infections and pathogens were diagnosed (in decreasing order of frequency): Helicobacter pylori gastritis (n = 53), Candida albicans esophagitis (n = 40), Giardia lamblia (n = 13), Gastrospirillum hominis (n = 11), and Blastocystis hominis (n = 8). The smear was positive in 45 patients with H pylori, in 35 patients with C albicans, in nine patients with G lamblia, in 11 patients with G hominis, and in eight patients with B hominis. Cytology was the only positive test in eight, nine, four, seven, and eight patients, respectively, and increased thus the diagnostic yield obtained by histologic examination.

Vascular anatomy of the pisiformis bone.

The authors examined 41 dried pisiform specimens; it was found that the vascular apertures were situated on the lateral aspect, in the proximal half of the ridge occupied by the ulnar artery, on the medial aspect and at the distal tip of the bone. An average number of 6.9 foramina were encountered, their mean diameter attained 40/100 mm. In 34 injected specimens the nutrient vessels of the pisiforme were traced from the ulnar artery and its carpal dorsal and deep volar branches; all the tiny bony twigs anastomosed with one another and contributed to an arterial circle running around the pisiforme. The carpal dorsal artery which provides at least 2 descending branches toward the proximal tip of the bone, can be called the main pedicle; when its superficial branches are ligated, the pedicle is long enough (3 cm) to make the replacement of the lunate by the pisiform attached to the flexor carpi ulnaris quite safe in Kienböck's disease, without any risk of osteonecrosis.

[Arterial vascularization of the triceps sural muscle]. / Contribution à l'étude de la vascularisation artérielle du muscle triceps sural.

The triceps surae muscle, the dorsal and medial leg skin constitute a very important reserve of muscular and myocutaneous flaps. The material on which the study was carried out consisted of 20 legs from standard cadavers. The superficialis femoral artery was injected with terebenthene and minimum mixture. The medial head of gastrocnemius is 23.3 em long, 6.9 cm wide, 1.25 mm thick at distal third. Its dominant blood supply is carried by the medialis gastrocnemius artery. It rises from popliteal artery 1.2 cm above the femoral tibial articulation with 1.9 mm diameter. It runs 3 cm down before entering muscle where it provides 2 or 3 mean branches. These branches give musculocutaneous arteries to the skin of the dorsal leg. The same study was performed for the lateral head of gastrocnemius and soleus. We studied also arteries of dorsomedial leg skin. The characteristics of long saphenous and short saphenous arteries were described. These muscles and dorsomedial leg skin can be used as muscular or myocutaneous flap for covering defects between the lower leg and the lower thigh.

Anatomical basis for the use of muscle flaps in the leg.

The aim of this study is to define the anatomical features of each of the anterior crural muscles and to determine their respective usefulness as flaps for surgical repair.

[The arterial blood supply of the skin flap of the dorsal foot]. / Contribution à l'étude de la vascularisation artérielle du lambeau du dos du pied.

The dorsal foot skin supplied by the arteria dorsalis pedis the dorsal venous arch, the peroneal sensory nerves and the musculus extensor digitorum brevis is a very good myocutaneous flap. The material on which the study was carried out, consisted of 20 feet from standard cadavers, injected with a mixture of terebenthene and minium through the arteria tibialis anterior. The m. extensor digitorum brevis is 6.1 cm long, 1.7 cm wide, 3.9 mm thick. It is mainly supplied by the a. dorsalis pedis and its branches: the a. tarsea dorsalis (constant) and the a. metatarsea dorsalis (12 of 20 specimens). The average diameter of the a. dorsalis pedis at the upper limit of the m. extensor retinaculum was 2.14 mm and this was chosen as the most proximal limit of the dorsalis pedis flap. The a. tarsea dorsalis was present in all the specimens, with a diameter of 0.95 mm at its origin and a length of 35 mm. On average, this artery divided into four branches to the m. dorsalis pedis. The a. metatarsea dorsalis was present in 12 of 20 specimens, with an average diameter of 0.53 mm and a length of 22 mm. On average, this artery divided into three branches to the m. dorsalis pedis. We drew three lines in the proximal, middle and distal third of each flap design and calculated the sum of arterial branch sections with our lines. We think this provides a reasonable indication of the comparative richness of the cutaneous blood supply in the flap. The mean number of cutaneous branches was 10 in the proximal third, 6.7 in the middle third (13 if branches supplying the m. extensor pedis brevis are included) and 5 in the distal third. The myocutaneous dorsalis pedis arterialized flap can be safely used as an island flap to cover the ankle or heel and as a free flap for palm defects.

[Contribution to the study of the vascularization of the fascia lata tensor muscle]. / Contribution à l'étude de la vascularisation du muscle tenseur du fascia lata.

The tensor fascia lata is a short flat muscle arising from the anterior superior iliac spine and inserting into the fascia lata at mid thigh. It is supplied by three arterial pedicles of unequal importance, branching from the external iliac, gluteal and deep femoral arteries. The 'dominant' blood supply is carried by the lateral circumflex femoral artery which comes from the deep femoral and enters the muscle, approximately 8.8 cm beneath the anterior superior iliac spine. This vessel varies in size from 2 to 3.5 mm; it is 8 cm long but can be lengthened by ligating the branch for the vastus lateralis. On the deep sheath of the iliotibial tract it gives off three branches which supply each third of the fleshy body. The upper branch runs vertically to the iliac insertion of the muscle but not so far as the iliac crest and provides no cutaneous twig. On the contrary, the mid branch runs transversally through the muscle and sends perforating vessels to the skin overlying the fascia lata 6--7 cm below the anterior superior iliac spine. The descending branch runs parallel to the muscular fibers of the muscle and supplies the skin of the lateral lower thigh down to 8 cm above the knee. So the pedicle supports an area of the skin which is double the length (22 cm) and triple the width (9.5 cm) of the fleshy body. The tensor fascia lata including the two layers of the iliotibial tract but excluding its upper insertion, together with the skin of the lateral aspect of the thigh can be safely used as a myocutaneous flap for covering defects of the trochanteric, ischial and sacral areas.