Diffuse Large B-Cell Epstein-Barr Virus-Positive Primary CNS Lymphoma in Non-AIDS Patients: High Diagnostic Accuracy of DSC Perfusion Metrics.

BACKGROUND AND PURPOSE: Immunodeficiency-associated CNS lymphoma may occur in different clinical scenarios beyond AIDS. This subtype of CNS lymphoma is diffuse large B-cell and Epstein-Barr virus-positive. Its accurate presurgical diagnosis is often unfeasible because it appears as ring-enhancing lesions mimicking glioblastoma or metastasis. In this article, we describe clinicoradiologic features and test the performance of DSC-PWI metrics for presurgical identification. MATERIALS AND METHODS: Patients without AIDS with histologically confirmed diffuse large B-cell Epstein-Barr virus-positive primary CNS lymphoma (December 2010 to January 2022) and diagnostic MR imaging without onco-specific treatment were retrospectively studied. Clinical, demographic, and conventional imaging data were reviewed. Previously published DSC-PWI time-intensity curve analysis methodology, to presurgically identify primary CNS lymphoma, was used in this particular lymphoma subtype and compared with a prior cohort of 33 patients with Epstein-Barr virus-negative CNS lymphoma, 35 with glioblastoma, and 36 with metastasis data. Normalized curves were analyzed and compared on a point-by-point basis, and previously published classifiers were tested. The standard percentage of signal recovery and CBV values were also evaluated. RESULTS: Seven patients with Epstein-Barr virus-positive primary CNS lymphoma were included in the study. DSC-PWI normalized time-intensity curve analysis performed the best for presurgical identification of Epstein-Barr virus-positive CNS lymphoma (area under the receiver operating characteristic curve of 0.984 for glioblastoma and 0.898 for metastasis), followed by the percentage of signal recovery (0.833 and 0.873) and CBV (0.855 and 0.687). CONCLUSIONS: When a necrotic tumor is found in a potentially immunocompromised host, neuroradiologists should consider Epstein-Barr virus-positive CNS lymphoma. DSC-PWI could be very useful for presurgical characterization, with especially strong performance of normalized time-intensity curves.

The Postnatal Leptin Surge Supports Immune Cell Function in Rats.

BACKGROUND: Leptin plays an important role in the regulation of the immune response. There is a physiological surge of leptin in rodents during the neonatal period, which has mainly been studied in the context of brain development. However, little is known about the effects of this neonatal leptin surge on immunity. Therefore, we investigated whether blocking this leptin surge could affect several immune functions. METHODS: Male and female rats were injected subcutaneously with 5 mg/Kg/day of rat pegylated super leptin antagonist during the neonatal period (PND5-9). On the peripubertal period, relevant functions as well as cytokine release by spleen leukocytes were studied in these animals. RESULTS: The results showed that the animals significantly display an impaired anti-tumor NK activity and chemotactic and proliferation capacity of lymphocytes in response to mitogens. In addition, several cytokine concentrations, released under mitogen-stimulated conditions, were also altered. CONCLUSION: In conclusion, the neonatal leptin surge seems to be involved in the establishment of an adequate immune response and cytokine profile, which are crucial for the maintenance of a healthy life.

Anterior chamber associated immune deviation to cytosolic neural antigens avoids self-reactivity after optic nerve injury and polarizes the retinal environment to an anti-inflammatory profile.

It has been hypothesized that anterior chamber-associated immune deviation (ACAID) to neural antigens induced prior to central nervous system injury can inhibit self-reactivity and lessen secondary degeneration. This work evaluated the effect of ACAID induced to three neural tissue-derived extracts (whole extract, cytosolic extract, CE; or organelle-membrane extract) prior to optic nerve injury on retinal ganglion cell (RGC) survival. The results show that only ACAID to the CE increased RGC survival at 7 and14 days post-injury (dpi). This effect was achieved by retinal polarization towards an anti-inflammatory profile, driven by regulatory T cells and M2-type macrophages at 7 dpi.

Long term sex-dependent psychoneuroendocrine effects of maternal deprivation and juvenile unpredictable stress in rats.

We have analysed the long-term psychoneuroendocrine effects of maternal deprivation (MD) [24 h at postnatal day (PND) 9] and/or exposure to chronic unpredictable stress (CUS) during the periadolescent period (PND 28 to PND 43) in male and female Wistar rats. Animals were tested in the elevated plus maze (EPM, anxiety) at PND 44 and in two memory tests, spontaneous alternation and novel object recognition (NOT) in adulthood. The expression of hippocampal glucocorticoid (GR) and mineralocorticoid (MR) receptors, as well as of synaptophysin, neural cell adhesion molecule and brain-derived neurotrophic factor, was analysed by in situ hybridisation in selected hippocampal regions. Endocrine determinations of leptin, testosterone and oestradiol plasma levels were carried out by radioimmunoassay. Young CUS animals showed decreased anxiety behaviour in the EPM (increased percentage of time and entries in the open arms) irrespective of neonatal treatment. Memory impairments were induced by the two stressful treatments as was revealed by the NOT, with males being most clearly affected. Although each stressful procedure, when considered separately, induced different (always decrements) effects on the three synaptic molecules analysed and affected males and females differently, the combination of MD and CUS induced an unique disruptive effect on the three synaptic plasticity players. MD induced a long-term significant decrease in hippocampal GR only in males, whereas CUS tended to increase MR in males and decrease MR in females. Both neonatal MD and periadolescent CUS induced marked reductions in testosterone and oestradiol in males, whereas MD male animals also showed significantly decreased leptin levels. By contrast, in females, none of the hormones analysed was altered by any of the stressful procedures. Taking our data together in support of the 'two-hit' hypothesis, MD during neonatal life and/or exposure to CUS during the periadolescent period induced a permanent deficit in memory, which was accompanied by a decrement in markers for hippocampal plasticity. The long-term effects on body weight and hormone levels, particularly among males, might reflect sex-dependent lasting metabolic alterations as well as an impaired reproductive function.

Adolescent exposure to nicotine and/or the cannabinoid agonist CP 55,940 induces gender-dependent long-lasting memory impairments and changes in brain nicotinic and CB(1) cannabinoid receptors.

We have analysed the long-term effects of adolescent (postnatal day 28-43) exposure of male and female rats to nicotine (NIC, 1.4 mg/kg/day) and/or the cannabinoid agonist CP 55,940 (CP, 0.4 mg/kg/day) on the following parameters measured in the adulthood: (1) the memory ability evaluated in the object location task (OL) and in the novel object test (NOT); (2) the anxiety-like behaviour in the elevated plus maze; and (3) nicotinic and CB(1) cannabinoid receptors in cingulated cortex and hippocampus. In the OL, all pharmacological treatments induced significant decreases in the DI of females, whereas no significant effects were found among males. In the NOT, NIC-treated females showed a significantly reduced DI, whereas the effect of the cannabinoid agonist (a decrease in the DI) was only significant in males. The anxiety-related behaviour was not changed by any drug. Both, nicotine and cannabinoid treatments induced a long-lasting increase in CB(1) receptor activity (CP-stimulated GTPγS binding) in male rats, and the nicotine treatment also induced a decrease in nicotinic receptor density in the prefrontal cortex of females. The results show gender-dependent harmful effects of both drugs and long-lasting changes in CB(1) and nicotinic receptors.

The endocannabinoid system, eating behavior and energy homeostasis: the end or a new beginning?

The endocannabinoid system (ECS) consists of two receptors (CB(1) and CB(2)), several endogenous ligands (primarily anandamide and 2-AG), and over a dozen ligand-metabolizing enzymes. The ECS regulates many aspects of embryological development and homeostasis, including neuroprotection and neural plasticity, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and the focus of this review: hunger, feeding, and metabolism. This mini-review summarizes the main findings that supported the clinical use of CB1 antagonists/inverse agonists, the clinical concerns that have emerged, and the possible future of cannabinoid-based therapy of obesity and related diseases. The ECS controls energy balance and lipid metabolism centrally (in the hypothalamus and mesolimbic pathways) and peripherally (in adipocytes, liver, skeletal muscle and pancreatic islet cells), acting through numerous anorexigenic and orexigenic pathways. Obese people seem to display an increased endocannabinoid tone, driving CB(1) receptor in a feed-forward dysfunction. Several CB(1) antagonists/inverse agonists have been developed for the treatment of obesity. Although these drugs were found to be efficacious at reducing food intake as well as abdominal adiposity and cardiometabolic risk factors, they resulted in adverse psychiatric effects that limited their use and finally led to the end of the clinical use of systemic CB(1) ligands with significant inverse agonist activity for complicated obesity. However, the existence of alternatives such as CB(1) partial agonists, neutral antagonists, antagonists restricted to the periphery, allosteric modulators and other potential targets within the ECS indicate that a cannabinoid-based therapy for the management of obesity and its associated cardiometabolic sequelae should remain open for consideration.

Critical role of the endocannabinoid system in the regulation of food intake and energy metabolism, with phylogenetic, developmental, and pathophysiological implications.

The endocannabinoid system (ECS) consists of two receptors (CB(1) and CB(2)), several endogenous ligands (primarily anandamide and 2-AG), and over a dozen ligand-metabolizing enzymes. The ECS has deep phylogenetic roots and regulates many aspects of embryological development and homeostasis, including neuroprotection and neural plasticity, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and the focus of this review: hunger, feeding, and metabolism. The ECS controls energy balance and lipid metabolism centrally (in the hypothalamus and mesolimbic pathways) and peripherally (in adipocytes and pancreatic islet cells), acting through numerous anorexigenic and orexigenic pathways (e.g., ghrelin, leptin, orexin, adiponectin, endogenous opioids, and corticotropin-releasing hormone). Obesity leads to excessive endocannabinoid production by adipocytes, which drives CB(1) in a feed-forward dysfunction. Phylogenetic research suggests the genes for endocannabinoid enzymes, especially DAGLalpha and NAPE-PLD, may harbor mildly deleterious alleles that express disease-related phenotypes. Several CB(1) inverse agonists have been developed for the treatment of obesity, including rimonabant, taranabant, and surinabant. These drugs are efficacious at reducing food intake as well as abdominal adiposity and cardiometabolic risk factors. However, given the myriad beneficial roles of the ECS, it should be no surprise that systemic CB(1) blockade induces various adverse effects. Alternatives to systemic blockade include CB(1) partial agonists, pleiotropic drugs, peripherally restricted antagonists, allosteric antagonists, and endocannabinoid ligand modulation. The ECS offers several discrete targets for the management of obesity and its associated cardiometabolic sequelae.

Adolescent exposure to nicotine modifies acute functional responses to cannabinoid agonists in rats.

We have studied functional interactions between nicotine and the cannabinoid receptor agonist CP 55,940 (CP) in the modulation of behavioural and corticosterone responses of male and female adolescent Wistar rats. The animals underwent a subchronic nicotine treatment (0.4 mg/kg i.p., once daily) during the periadolescent period (postnatal days 34-43). Twenty-four hours after the last injection of nicotine an acute dose of CP (1 or 100 microg/kg i.p.) was administered. Thirty minutes after the cannabinoid injection, the animals were tested individually in the holeboard immediately followed by the elevated plus-maze. We also measured corticosterone levels by radioimmunoassay. In males, neither CP (1 microg/kg) nor nicotine induced any modification in anxiety when administered alone. However, the combination of the two drugs resulted in a significant anxiogenic-like effect. In females, the lower dose of CP was anxiogenic and nicotine, which did not induce any effect per se, prevented this response. In the holeboard, subchronic nicotine and the acute cannabinoid treatment interacted in the modulation of horizontal activity and the nature of this interaction also showed a clear sexual dimorphism. Both, the cannabinoid agonist and nicotine increased corticosterone concentrations and the animals receiving the two drugs showed higher levels than the animals receiving the cannabinoid alone. The data provide evidence for the existence of functional interactions between nicotine and cannabinoids in the modulation of behavioural responses and adrenocortical activity in adolescent rats.

Neuroprotection by the cannabinoid agonist WIN-55212 in an in vivo newborn rat model of acute severe asphyxia.

This study was designed to evaluate the neuroprotective effect of the cannabinoid agonist WIN-55212 after inducing acute severe asphyxia in newborn rats. The left common carotid artery was ligated in anaesthetised 7-day-old Wistar rats, which were then asphyxiated by inhaling 100% nitrogen for 10 min. Pups recovering from asphyxia were s.c. administered vehicle (n=23), WIN-55212 (0.1 mg/kg, n=18), or WIN-55212 plus the CB1 receptor antagonist SR141716 (3 mg/kg, n=10). Pups undergoing a sham operation served as controls (n=12). Coronal sections of the brain were obtained on the 14th day after surgery and observed under light microscope after Nissl or Fluoro-Jade B (FJB) staining, to respectively quantify surviving or degenerating neurones in the CA1 area of the hippocampus and parietal cortex. Acute asphyxia led to early neurone loss amounting to 19% in the hippocampus and 29% in the cortex (both ANOVA P<0.05 vs. control). Delayed neurone loss occurred in the proportions 13% in the hippocampus and 20% in the cortex (both ANOVA P<0.05 vs. control). Neuronal loss was fully prevented by WIN-55212 administration. Co-administration of SR141716 failed to modify the protective effect of WIN-55212 on early neuronal death, but abolished the WIN-55212-induced prevention of delayed neuronal death. We conclude that when administered after acute severe asphyxia in newborn rats, WIN-55212 shows a neuroprotective effect, reducing both early and delayed neurone loss. This effect is achieved through two parallel CB1-dependent and -independent mechanisms.

Behavioral characterization of a mouse model of premature immunosenescence.

In previous studies we have shown that differences in life span among members of Swiss mouse populations appear to be related to their performance in a T-maze, with a slow performance ("slow" mice) being linked to an impaired immune function and a shorter life span when compared to "fast" mice, which led us to propose the slow mice as a model of immunosenescence. In the present study we demonstrate that in a tightrope test of neuromuscular vigor and coordination the slow mice show a worse performance, needing more time to complete the task. Moreover, these animals show a decreased locomotor activity and an increased level of emotionality/anxiety in three standard behavioral tests (the holeboard, the open field and the plus-maze) when compared to fast mice. All these behavioral features were most marked in the slow females. The results also indicate that slow animals show a decreased chemotaxis of macrophages and lymphocytes, as well as a reduced lymphoproliferative response to mitogens. The data supports our claim that slow or hyperemotional mice, in which immune and neurobehavioural functions appear to be impaired, may be a useful model of premature aging.

Effect of perezone, aminoperezone and their corresponding isomers isoperezone and isoaminoperezone upon in vitro platelet aggregation.

The effect on platelet aggregation of perezone, isoperezone, aminoperezone and isoaminoperezone has been determined in human platelets, using adenosinediphosphate (ADP), epinephrine and collagen as inducers. Perezone inhibited ADP- epinephrine- and collagen-induced platelet aggregation; isoperezone, aminoperezone and isoaminoperezone did not. The difference in biological responses could be the result of their structures. While isoperezone, aminoperezone and isoaminoperezone have carbonyl groups in the vicinity of other functional groups, this is not the case for perezone, in which one of the carbonyl groups has an adjacent free position.

Characterization of a novel human immunodeficiency virus type 1 neutralizable epitope within the immunodominant region of gp41.

Previously, we generated human monoclonal antibodies using peripheral blood mononuclear cells from an asymptomatic human immunodeficiency virus type 1 (HIV-1)-seropositive donor. One of these monoclonal antibodies (designated clone 3, CL3) recognized 10 amino acids (GCSGKLICTT) within the immunodominant region (cluster I) of the transmembrane envelope glycoprotein gp41 and neutralized infection of target cells with different laboratory isolates. Because the epitope recognized by CL3 has two cysteine residues that could potentially produce a disulfide loop in gp41, we analyzed binding of our monoclonal antibody to the cyclic and linear motif of the peptide sequence IWGCSGKLICTTAVP (residues 600-614). The CL3 antibody did not bind to the synthetic cyclic peptide but did recognize the linear form. Two polyclonal rabbit sera against both the linear and cyclic peptides were then generated. Both antisera bound to viral glycoproteins gp41 and gp160, but neither sera neutralized HIV-1 laboratory isolates. Using a set of alanine-substituted IWGCSGKLICTTAV peptides, we analyzed binding of polyclonal antisera and CL3. The profile of binding of polyclonal antisera to these peptides was different from that of CL3 to the same peptides. This suggests that CL3 recognized a unique neutralizable core epitope, which was not immunogenic in either the cyclic or the linear IWGCSGKLICTTAVP peptides used as immunogens in the rabbits.

Antigenic homology of HIV-1 GP41 and human platelet glycoprotein GPIIIa (integrin beta3).

Fifty-eight of 89 serum samples (65.17%) from HIV-1-infected individuals at various disease stages contain antibodies that react with a platelet peptide located in the cytoplasmic domain of integrin beta3, glycoprotein GPIIIa (aa749-761; sequence DRKEFAKFEEERA). Rabbit polyclonal antibodies raised against the synthetic platelet peptide also react with the structurally homologous HIV-1 gp41-derived peptide (EKNEQELLELDKW(A)) and bind to a Western blot band with molecular weight corresponding to HIV-1 gp41. These findings point to molecular mimicry between HIV-1 and a human membrane protein found in platelets and other cells that could be of pathologic consequence.

Immunodominant synthetic peptides of Taenia crassiceps in murine and human cysticercosis.

The screening of a cDNA library of Taenia crassiceps revealed a clone designated KETc7 that induced high levels of protection against murine cysticercosis in previous experiments. The molecular structure of the deduced 100-amino acid sequence of the corresponding proline-rich polypeptide was studied to detect potentially immunologically active epitopes. Several candidate epitopes were identified, three of which were synthesized by solid-phase peptide synthesis and used as antigens in enzyme-linked immunosorbent assay (ELISA) for detection of specific antibodies in a selected panel of sera from mice infected with Taenia crassiceps and pigs infected with Taenia solium, as well as in the serum and cerebrospinal fluid of human patients with neurocysticercosis. The three peptides detected antibodies in serum from all infected mice. Seven of nine sera from patients with neurocysticercosis reacted strongly with peptide GK-3, and four of them with peptides GK-1 and GK-2. A lower reactivity was observed in sera from experimentally infected pigs. Peptide GK-3 reacted also with 45 out of 77 cerebrospinal fluids (CSF) from patients with confirmed neurocysticercosis and with 14 out of 68 CSF from control patients with other neurological disorders. This is the first report on synthetic peptides that are prominent in the humoral response of murine, porcine and human cysticercosis. Their identification implies finer molecular tools in the exploration of this form of host-parasite relationship, as well as hints to their application in immunodiagnosis and in vaccine design.

Síndrome de Poems: caso clínico / Poems' syndrome: a clinical case

A 48 years old male is reported. He presented with lower limb progressive and severe polyneuropathy, hypertrichosis, endocrinological alterations (hypothyroidism and hypogonadism) and organomegaly (hepatosplenomegaly and lymphadenopathies). This syndrome was associated with an osteosclerosis myeloma. The patient died two months after admission