Genetic deletion of melanin‐concentrating hormone neurons impairs hippocampal short‐term synaptic plasticity and hippocampal‐dependent forms of short‐term memory

The cognitive role of melanin‐concentrating hormone (MCH) neurons, a neuronal population located in the mammalian postero‐lateral hypothalamus sending projections to all cortical areas, remains poorly understood. Mainly activated during paradoxical sleep (PS), MCH neurons have been implicated in sleep regulation. The genetic deletion of the only known MCH receptor in rodent leads to an impairment of hippocampal dependent forms of memory and to an alteration of hippocampal long‐term synaptic plasticity. By using MCH/ataxin3 mice, a genetic model characterized by a selective deletion of MCH neurons in the adult, we investigated the role of MCH neurons in hippocampal synaptic plasticity and hippocampal‐dependent forms of memory. MCH/ataxin3 mice exhibited a deficit in the early part of both long‐term potentiation and depression in the CA1 area of the hippocampus. Post‐tetanic potentiation (PTP) was diminished while synaptic depression induced by repetitive stimulation was enhanced suggesting an alteration of pre‐synaptic forms of short‐term plasticity in these mice. Behaviorally, MCH/ataxin3 mice spent more time and showed a higher level of hesitation as compared to their controls in performing a short‐term memory T‐maze task, displayed retardation in acquiring a reference memory task in a Morris water maze, and showed a habituation deficit in an open field task. Deletion of MCH neurons could thus alter spatial short‐term memory by impairing short‐term plasticity in the hippocampus. Altogether, these findings could provide a cellular mechanism by which PS may facilitate memory encoding. Via MCH neuron activation, PS could prepare the day's learning by increasing and modulating short‐term synaptic plasticity in the hippocampus. © 2015 Wiley Periodicals, Inc.     

The Erythrocyte Membrane Disturbances in Protein-Energy Malnutrition: Nature and Mechanisms

In protein-energy malnutrition (PEM), as observed in Kivu, the RBC have an increased ratio of surface area to volume which is demonstrated by the presence of target cells on light microscopy and cup cells with scanning electron microscopy. The osmotic fragility is decreased. These abnormalities can be attributed to the accumulation of cholesterol and phosphatidylcholine (PC) in the RBC membrane. The molar ratio of cholesterol to phospholipids is moderately increased. Several findings suggest that the cholesterol and PC build-up results from disturbed exchanges in these lipids between the RBC and the plasma lipoproteins. Firstly, the osmotic fragility of a patient's RBC gradually becomes normal when the cells are transfused into a healthy recipient. Secondly, the cholesterol flux between the RBC and the plasma LDL seems to be low. Thirdly, the increase in RBC PC cannot be explained by a diminished fatty acids transport between the deep RBC PC pool and the RBC phosphatidylethanolamine (PE) pool. Finally complex disturbances of the plasma lipoproteins are obvious. It is improbable that the cholesterol and PC build-up accounts for the premature RBC destruction which has been described in Kivu PEM. However, the observation of an increased fatty acid turnover in RBC PC and PE, as well as other data previously obtained in Kivu PEM, lead to the conclusion that membrane peroxidation may be a major cause of the shortened erythrocyte life-span in this syndrome.     

The Italian translation of the Celiac Disease-specific Quality of Life Scale in celiac patients on gluten free diet

BackgroundA recently devised tool, the Celiac Disease-specific Quality of Life Scale has been proposed to assess specifically quality of life in celiac patients.AimTo assess the validity and reliability of the Italian translation of the Celiac Disease-specific Quality of Life Scale.MethodsThe Celiac Disease-specific Quality of Life Scale underwent forward/backward translation. Adults patients on gluten free diet by at least one year, consecutively recruited, completed SF36 questionnaire, the Italian version of Celiac Disease-specific Quality of Life Scale, the Health Related Quality of Life question and an abdominal pain scale. The study fulfilled criteria for acceptable psychometric assessment according to the International Quality of Life Assessment project.ResultsTwo-hundred-thirty celiac patients were recruited after about nine years from diagnosis. Factor analysis indicates that there are some similarities and discrepancies between the English and the Italian questionnaires. Despite this, the Italian Celiac Disease-specific Quality of Life Scale was able to identify the same four factors characterizing the patients’ answers (dysphoria, limitations, health concerns, inadequate treatment).ConclusionThe Celiac Disease-specific Quality of Life Scale is useful for assessing Celiac Disease-related Quality of Life. A wide use of the Italian Celiac Disease-specific Quality of Life Scale may be of help in obtaining comparable data on QOL in different setting and countries.     

Suppression of the humoral response to anti-CD3 monoclonal antibody

Anti-CD3 monoclonal antibodies are used clinically to treat organ allograft rejection. Their administration can result in reversal of rejection even in episodes resistant to other modes of therapy. A major limitation to their use has been the humoral response of the patients against the mAbs, resulting in loss of therapeutic efficacy. We have established an animal model for anti-CD3 treatment using the antimurine CD3 mAb, 145-2C11. Exposure of mice to this mAb, like exposure of humans to its antihuman analog OKT3, results in suppression of graft rejection but also stimulates a strong humoral response that abrogates the efficacy of further treatments. Administration of an additional dose of anti-CD3 mAb did not prolong skin graft survival--and, in some instances, resulted in a lethal anaphylactic reaction. In an attempt to suppress the humoral response against the anti-CD3 mAb, anti-CD4 mAb was administered prior to the anti-CD3 mAb treatment. Pretreatment of mice with anti-CD4 mAb (GK1.5) almost completely suppressed the humoral response to anti-CD3 mAb, and permitted readministration of the anti-CD3 mAB without loss of efficacy as assessed by prolongation of skin graft survival. The data suggest that the use of anti-CD4 mAb to suppress the humoral response against anti-CD3 mAb should be attempted clinically, as it might permit repeated courses of anti-CD3 administration, thus significantly improving the efficacy of these agents in the therapy of organ allograft rejection.     

Description of an indolaminergic cell component in the cat locus coeruleus: A fluorescence histochemical and radioautographic study

Using Falck-Hillarp fluorescence histochemical and radioautographic techniques, it has been found that, in addition to the well-known catecholaminergic cells, the locus coeruleus (LC) of the cat contains a sizeable component of indolaminergic neurons. Indolaminergic cell bodies occur in all subdivisions of the LC complex. They are most numerous in the LC proper and subcoeruleus area, but are also present in the medial and lateral parabrachial, and K?lliker-Fuse nuclei. In all, the indolaminergic cells are estimated to make up 7-10% of the monoaminergic neuronal population of the LC complex. With the exception of the K?lliker-Fuse nucleus, where somewhat larger cells occur, the indolaminergic cell bodies in different parts of the LC complex share a common fluorescence histochemical appearance. They display round to fusiform shapes and measure 30 x 18 micron on the average, which makes them cytoarchitectonically similar to the small type of noradrenergic cells in the LC. The formaldehyde-induced fluorescence of the indolaminergic cells in the LC complex was analyzed microspectrofluorometrically and the recorded excitation and emission spectra (maxima at 370 and 530 nm, respectively) were found to be identical with those recorded from midline raphe neurons. No evidence of noradrenaline content was found in the indolaminergic cells of the LC. Radioautographic experiments after intratissular injections of tritiated serotonin showed that the indolaminergic cells of the LC complex possess uptake mechanisms for serotonin. Taken together these results provide strong evidence for serotonin being the transmitter of the indolaminergic neurons discovered in the LC of the cat.     

Evidence that antihuman tumor necrosis factor monoclonal antibody prevents OKT3-induced acute syndrome.

We have used an antihuman tumor necrosis factor monoclonal antibody, CB006 (murine IgG1), to prevent the OKT3-induced acute clinical syndrome. This syndrome is due to the massive, although transient release in the circulation of various cytokines (TNF, interferon gamma, interleukin 2, interleukin 6) and represents one important side effect linked to in vivo use of OKT3. Fourteen kidney allograft recipients undergoing prophylactic OKT3 therapy were treated with CB006 in a single i.v. injection of either 0.4 mg/kg (group I, 7 patients) or 2 mg/kg (group II, 7 patients), 1 hr before the first OKT3 administration. Nineteen consecutive patients formed a historical control group. None of the CB006-pretreated patients showed any of the common, severe OKT3-associated symptoms (hypotension, respiratory distress, or neurotoxicity), which were observed in 10% of the historical controls. In addition, CB006-treated patients showed a lower frequency of pyrexia (> or = 39 degrees C) and gastrointestinal symptoms. None of the CB006-treated patients presented severe vomiting or diarrhea, defined as repeated episodes inducing significant fluid and electrolyte loss. Two out of the 7 patients in group I and group II had mild transitory diarrhea. Mild single vomiting episodes occurred in 2 group I patients and 3 group II patients. At variance in all controls, gastrointestinal symptoms were long lasting and associated with major prostration due to electrolyte and fluid loss. Importantly, CB006-treated patients who presented mild symptoms had detectable bioactive circulating TNF, showing incomplete inactivation of OKT3-induced TNF by CB006. CB006 was perfectly well tolerated, did not induce xenosensitization, and did not affect the biological or clinical effectiveness of OKT3.     

Nonsteroid antiinflammatory agents as a substitute treatment for steroids in ATGAM-treated cadaver kidney recipients

A nonsteroid antiinflammatory agent (Ibuprofen) was used in a controlled randomized study to determine its ability to replace steroids in the prophylaxis of cadaveric kidney rejection. Thirty-three cadaver kidney recipients were randomly assigned either to a control group (16 patients) receiving azathioprine, high doses of prednisolone, and antithymocyte globulin (ATGAM) for three months, or to an experimental group (17 patients) receiving azathioprine and ATGAM according to the same protocol, ibuprofen instead of steroids. The frequency of rejection was higher in the experimental group (2.18 episodes per patient) than in the control group (1.44 episodes per patient). Nevertheless, in the experimental group 5 patients had no early rejection episode, 60% of early rejections were totally reversible without steroids, and 3 patients never received steroids at all during the first year and had normal renal function and biopsies. Steroids had to be introduced in the treatment of 14 patients, but after an average period of 32.5 days after surgery OKT3+ cell level was higher in the experimental group than in the control group, but similar to the OKT3+ cell level of patients receiving conventional therapy without ATGAM. Whatever the type of treatment, an increase in the OKT4+/OKT8+ ratio was associated in most cases with increased serum creatinine values. Conversely, a decreased OKT4+/OKT8+ ratio associated with renal failure was found in cases showing biological evidence of cytomegalovirus infection.     

Coffee drinking and risk of preterm birth

OBJECTIVES: We analysed the association between coffee drinking before and during the three trimesters of pregnancy and the risk of preterm birth of babies normal for gestational age (NGA) or small for gestational age (SGA). METHODS: Case-control study conducted in University clinics of North Italy. Cases were 502 women who delivered at <37 weeks of gestation. The controls included 1966 women who gave birth at term (>or=37 weeks of gestation) to healthy infants on randomly selected days at the hospitals where cases had been identified. RESULTS: There was inverse association for coffee consumption in the third trimester of pregnancy in SGA cases compared to NGA (heterogeneity test between OR: chi1(2)=5.6811 P<0.05). In comparison with not drinkers, all the ORs of overall intake of caffeine were closed near the unity for both SGA and NGA preterm birth. CONCLUSION: Compared with no consumption, a low consumption of coffee during pregnancy may not have significant effects on preterm birth.     

A Fas agonist induces high levels of apoptosis in haematological malignancies

We developed and tested a potent hexameric Fas agonist, termed MegaFasL, for its cytotoxic effects on a panel of human haematopoietic malignant cells and healthy human haematopoietic progenitor cells (CD34+CD38low). Results demonstrated that MegaFasL induced apoptosis in cell lines and primary cells representing multiple myeloma (MM), acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) and Burkitt's lymphoma. Cells from a chronic myeloid leukaemia (CML) line and from patients with chronic lymphocytic leukaemia (CLL) were resistant. Furthermore, CD34+CD38low progenitor cells were also resistant to MegaFasL. The data indicate that MegaFasL could be a highly efficient therapeutic agent ex vivo or potentially in vivo.