Modeling realistic synaptic inputs of CA1 hippocampal pyramidal neurons and interneurons via Adaptive Generalized Leaky Integrate-and-Fire models.

Computational models of brain regions are crucial for understanding neuronal network dynamics and the emergence of cognitive functions. However, current supercomputing limitations hinder the implementation of large networks with millions of morphological and biophysical accurate neurons. Consequently, research has focused on simplified spiking neuron models, ranging from the computationally fast Leaky Integrate and Fire (LIF) linear models to more sophisticated non-linear implementations like Adaptive Exponential (AdEX) and Izhikevic models, through Generalized Leaky Integrate and Fire (GLIF) approaches. However, in almost all cases, these models are tuned (and can be validated) only under constant current injections and they may not, in general, also reproduce experimental findings under variable currents. This study introduces an Adaptive GLIF (A-GLIF) approach that addresses this limitation by incorporating a new set of update rules. The extended A-GLIF model successfully reproduces both constant and variable current inputs, and it was validated against the results obtained using a biophysical accurate model neuron. This enhancement provides researchers with a tool to optimize spiking neuron models using classic experimental traces under constant current injections, reliably predicting responses to synaptic inputs, which can be confidently used for large-scale network implementations.

Mathematical generation of data-driven hippocampal CA1 pyramidal neurons and interneurons copies via A-GLIF models for large-scale networks covering the experimental variability range.

Efficient and accurate large-scale networks are a fundamental tool in modeling brain areas, to advance our understanding of neuronal dynamics. However, their implementation faces two key issues: computational efficiency and heterogeneity. Computational efficiency is achieved using simplified neurons, whereas there are no practical solutions available to solve the problem of reproducing in a large-scale network the experimentally observed heterogeneity of the intrinsic properties of neurons. This is important, because the use of identical nodes in a network can generate artifacts which can hinder an adequate representation of the properties of a real network. To this aim, we introduce a mathematical procedure to generate an arbitrary large number of copies of simplified hippocampal CA1 pyramidal neurons and interneurons models, which exhibit the full range of firing dynamics observed in these cells - including adapting, non-adapting and bursting. For this purpose, we rely on a recently published adaptive generalized leaky integrate-and-fire (A-GLIF) modeling approach, leveraging on its ability to reproduce the rich set of electrophysiological behaviors of these types of neurons under a variety of different stimulation currents. The generation procedure is based on a perturbation of model's parameters related to the initial data, firing block, and internal dynamics, and suitably validated against experimental data to ensure that the firing dynamics of any given cell copy remains within the experimental range. A classification procedure confirmed that the firing behavior of most of the pyramidal/interneuron copies was consistent with the experimental data. This approach allows to obtain heterogeneous copies with mathematically controlled firing properties. A full set of heterogeneous neurons composing the CA1 region of a rat hippocampus (approximately 1.2 million neurons), are provided in a database freely available in the live paper section of the EBRAINS platform. By adapting the underlying A-GLIF framework, it will be possible to extend the numerical approach presented here to create, in a mathematically controlled manner, an arbitrarily large number of non-identical copies of cell populations with firing properties related to other brain areas.

Determining firms׳ utility functions and competitive roles from data on market shares using Lotka-Volterra models.

In this article, we include data on historical and estimated market shares of two markets. In particular, we include annual data on the market shares of the Japanese beer market (1963-2000) and biannual data on the market shares of the mobile phones market in Greece (1998-2007). In addition, we estimate monthly data on market shares for both markets. We show how this data can be used to derive firms' utility functions and their competitive roles.

Association of CTLA-4 polymorphisms with improved overall survival in melanoma patients treated with CTLA-4 blockade: a pilot study.

CTLA-4 blockade with monoclonal antibodies can lead to cancer regression in patients with metastatic melanoma (MM). CTLA-4 gene polymorphisms may influence the response to anti-CTLA-4 antibodies although few data are available regarding this issue. We analyzed six CTLA-4 single nucleotide polymorphisms (-1661A > G, -1577G > A, -658C > T, -319C > T, +49A > G, and CT60G > A) in 14 Italian MM patients and 45 healthy subjects. We found a significant association between the -1577G/A and CT60G/A genotypes and improved overall survival (Pc < 0.006, Bonferroni corrected), further confirmed by the diplotype analysis (-1577 & CT60 GG-AA diplotype, p < 0.001). A positive trend toward an association between these genotypes and response to therapy was also observed.

Clinical and biological features of an intranodal palisaded myofibroblastoma.

Intranodal palisaded myofibroblastoma (IPM) is a rare benign tumor of the lymph nodes probably arising from smooth muscle-like cells. The tumor is characterized by intranodal proliferation of spindle cells. Neoplastic spindle-cell proliferation is most often of metastatic repetition which is very important in the recognition of IPM, because it may be mistaken for metastasis or other tumors such as Kaposi's sarcoma. We report a novel case of IPM that confirms the myofibroblastic differentiation of the tumor. The onset of IPM has been associated with Epstein-Barr virus (EBV). In addition, recently reported cases of IPM have been seen with cyclin 1 overexpression and also with human herpes virus (HHV)-8 and EBV DNA sequences. In our case, there was no evidence of HHV-8 and EBV DNA sequences and we were not able to find cyclin 1 overexpression.

Predictive factors of outcome after liver transplantation in patients with cirrhosis and hepatocellular carcinoma.

Studies to define the optimal upper limits of tumor size and number as predictors of outcome after orthotopic liver transplantation (OLT) have yielded conflicting results. We analyzed 72 patients with cirrhosis and hepatocellular carcinoma (HCC) who underwent OLT over a 12-year period in a single center. Predictive factors for survival and tumor recurrence, according to the Milan criteria, were also examined. Our cohort included 60 men and 12 women of mean age 54 +/- 8 years and mean follow-up of 40 +/- 39 months. Origin of cirrhosis was postviral in 70% and Child class B or C in two thirds of patients. HCC was multifocal in 61%; about one fifth of patients had micro- or macrovascular involvement or positive nodes upon histologic examination. The cumulative size of the lesions was <3 cm in 17 patients; >3 to < or =5 cm in 28 patients; >5 to < or =8 cm in 14 patients; and >8 cm in 13 patients. According to the number and size of tumor nodules, 49 patients met the Milan criteria. During follow-up 25 patients died, 13 due to tumor recurrence. The 1- and 2-year survivals were 90% and 85% for patients who met the Milan criteria versus 57% and 51% for patients exceeding those limits (P = .006). A cumulative tumor size >8 cm was predictive of survival and tumor recurrence upon multivariate analysis. The adoption of Milan criteria for selection of cirrhotic patients has improved survival and reduced the rate of tumor recurrence. The evaluation of cumulative tumor size might further improve patient selection.

Detection and molecular characterisation of thyroid cancer precursor lesions in a specific subset of Hashimoto's thyroiditis.

Hashimoto's thyroiditis (HT) represents the most common cause of hypothyroidism and nonendemic goiter, but its clinical and pathological heterogeneity opens the question if this disease should be more properly considered as a spectrum of different thyroid conditions rather than as a single nosological entity. In this study, we analysed 133 cases of HT for the expression of galectin-3, a lectin molecule involved in malignant transformation, apoptosis and cell cycle control. An unexpected expression of galectin-3 was demonstrated in a subset of HT together with the presence of HBME-1, c-met and cyclin-D1 that are also involved in malignant transformation and deregulated cell growth. Furthermore, a loss of allelic heterozygosity in a specific cancer-related chromosomal region was demonstrated in some HT harbouring galectin-3-positive follicular cells, by using laser capture microdissection. On the basis of the morphological and molecular findings we identified four subsets of HT: (a) HT with classic features of chronic autoimmune thyroiditis; (b) HT associated to hyperplastic/adenomatous lesions; (c) HT harbouring thyroid cancer precursors; (d) HT associated to unequivocal thyroid microcarcinomas. Our findings provide a well-substantiated morphological and molecular demonstration that HT may include a spectrum of different thyroid conditions ranging from chronic autoimmune thyroiditis to thyroiditis triggered by specific immune-response to cancer-related antigens.

Evaluation of a commercial serological kit for detection of salivary immunoglobulin G to Helicobacter pylori: a multicentre study.

OBJECTIVE: To evaluate the usefulness of a commercial serological enzyme immunoassay (EIA) for detecting salivary immunoglobulin (Ig) G to Helicobacter pylori. DESIGN: Prospective, multicentre study. SETTING: The study was conducted at 11 gastroenterology hospital centres throughout Italy. PARTICIPANTS AND INTERVENTIONS: Two hundred and thirteen dyspeptic patients underwent gastroscopy with antral biopsies. At each centre, two of the following three tests for H. pylori diagnosis were performed: urease quick test, histology, and 13C-urea breath test. Samples of unstimulated saliva and venous blood were collected from each patient. Salivary and serum H. pylori IgG were determined with the EIA Helori-test IgG (Eurospital, Trieste, Italy). MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative predictive values, and accuracy of the salivary and serum EIAs. RESULTS: By using a receiver operating characteristic curve, salivary EIA yielded 81% (95% confidence interval 73-87%) sensitivity, 73% (62-83%) specificity, 84% (76-90%) positive predictive value, 69% (58-79%) negative predictive value, and 78% (72-84%) accuracy. At the cut-off suggested by the manufacturer, serum EIA had 90% (84-95%) sensitivity, 78% (67-86%) specificity, 88% (81-93%) positive predictive value, 82% (71-90%) negative predictive value, and 86% (81-91%) accuracy. CONCLUSION: In this large multicentre study, detection of salivary H. pylori IgG with a commercial serological EIA was a fairly accurate diagnostic method. Data confirm that saliva testing does not compare favourably with serology in the assessment of H. pylori status.

Orbital osteoclastoma of apparent extraskeletal origin in a pagetic patient: a case report.

A large mass in the right orbit, causing proptosis, ptosis of the right upper eyelid, and limitation to eye movements, was surgically removed from a 51-year-old woman suffering from Paget's bone disease (PBD). Histologically, a giant cell tumor of the bone (osteoclastoma) was diagnosed. No bony involvement was apparent either operatively, microscopically, or on preoperative computed tomographic scans. The neoplasm has not recurred in a 3-year follow-up. In addition to the fact that osteoclastoma complicating PBD is rare, the extraskeletal origin of the tumor is a matter of interest and can be tentatively explained by an unusually powerful systemic stimulus acting on circulating osteoclast precursors. HUM PATHOL 31:1527-1531.

Long-term follow-up of achalasic patients treated with botulinum toxin.

Botulinum toxin A (BoTx), a potent inhibitor of acetylcholine release from nerve endings both within the myenteric plexus and at the nerve-muscle junction, has been shown to decrease the lower esophageal sphincter (LES) pressure in patients with achalasia. Because of this property, the esophageal injection of BoTx has been suggested as an alternative treatment in achalasia. The objective of this study was to determine the long-term efficacy and safety of intrasphincteric injection of BoTx in a group of achalasic patients. Nineteen patients (mean age 56.1 +/- 19.2 years) were enrolled in the study. All of them were injected endoscopically with 100 U of BoTx by sclerotherapy needle at different sites of the LES. Symptom score (dysphagia, regurgitation and chest pain, each on a 0-3 scale), esophageal manometer and esophageal radionuclide emptying were assessed before the treatment and at 4 weeks, 3 months and 1 year after BoTx injection. In case of failure or relapse (symptom score > 2), the treatment was repeated. All but five patients (74%) were in clinical remission at 1 month. Mean symptom score after 1 month of BoTx decreased from 7.1 +/- 0.9 to 2.2 +/- 2.5 (p < 0.05). LES pressure decreased from 38.4 +/- 13.7 to 27.4 +/- 13.5 mmHg (p < 0.05) and 10-min radionuclide retention decreased from 70.9 +/- 20.7% to 33.8 +/- 27.0% (p < 0.05). Side-effects (transient chest pain) were mild and infrequent. At 12 months, the clinical score was 0.9 +/- 0.5 (p < 0.05 vs. basal); mean LES pressure was 22.0 +/- 7.1 (p < 0.05 vs. basal) and 10-min radionuclide retention was 15.8 +/- 6.0% (p < 0.05 vs. basal). The efficacy of the first injection of BoTx lasted for a mean period of 9 months (range 2-14 months). At the time of writing (follow-up period mean 17.6 months, range 2-31), 14 patients (10 with one injection) were still in remission (74%). Our results showed that one or two intrasphincteric injections of BoTx resulted in clinical and objective improvement in about 74% of achalasic patients and are not associated with serious adverse effects; the efficacy of BoTx treatment was long lasting; this procedure could be considered an attractive treatment, especially in elderly patients who are poor candidates for more invasive procedures.

A scanning transmission microscopy and energy-dispersive X-ray microanalysis of idiopathic ocular calcification and oxalosis in AIDS patients.

In a series of 98 consecutive eyeballs enucleated at postmortem from 86 patients dying with AIDS, the incidence of calcium deposits was 14 and 18.6%, respectively, for oxalates and calcium hydroxyapatite. The calcific eyes were examined by scanning electron microscopy (SEM) coupled with energy-dispersive X-ray microanalysis to confirm the elemental nature of the precipitates. Transmission electron microscopy was used in 2 of the cases with oxalosis. Oxalates with a free end exhibited a plate-like shape at SEM and appeared acicular at TEM, due to the reduced thickness of ultrathin sections. Crystals that were embedded in tissues such as the sclera or degenerate detached retinal tissue formed either spherules or plates at SEM. No clear relationship with intracellular structures could be found at TEM, possibly due to postmortem autolysis phenomena. Calcium hydroxyapatite deposits appeared at SEM as fine granules distributed over the collagen fibers of the corneal and conjunctival stroma and the scleral lamellae, but were also present intracellularly, both in the nucleus and cytoplasm of epithelial cells.

Ocular, cerebral and systemic interrelationships of cytomegalovirus infection in a post-mortem study of AIDS patients.

PURPOSE: Eighty-six post-mortems of AIDS patients were reviewed microscopically and the presence of cytomegalovirus (CMV) infection in the viscera, brain and eye was recorded. METHODS: Immunohistochemical stains and in situ hybridisation with a CMV probe were performed. RESULTS AND CONCLUSION: CMV infection was observed in 63% of the cases. Visceral, cerebral and ocular involvement were overall 49%, 33% and 29%, respectively. The visceral form with no concomitant ocular and/or cerebral infection was the main cause of death (31%) in the 54 CMV-infected patients. Although CMV retinitis occurred mostly (20%) as a component of systemic disease, in 13% of the CMV-infected patients the eyes only were involved, while there were no cases with CMV limited to the brain. In the absence of systemic involvement, 9% of the cases showed concomitant ocular and cerebral infection, but because we failed to observe CMV optic neuritis without ocular involvement, retrograde viral spread from the brain through the optic nerve appears to be an infrequent mechanism of CMV retinitis.

Double-blind study of a multivitamin complex supplemented with ginseng extract.

To remedy the deterioration in quality of life in large cities, the addition of ginseng root extract to a multivitamin base appears to produce a promising dietary supplement. The aim of the present study was to compare the quality-of-life parameters in subjects receiving multivitamins plus ginseng with those found in subjects receiving multivitamins alone. The study was comparative, randomized and double-blind, and it involved 625 patients of both sexes divided into two groups taking one capsule per day for 12 weeks. Group A received vitamins, minerals, trace elements and ginseng extract G115 (Pharmaton Capsules) while group B received vitamins, minerals and trace elements (multivitamin capsules) only. The resulting quality-of-life was assessed by a standardized 11-item questionnaire, validated by the Medical School of the National Autonomous University of Mexico (UNAM). Of the 625 patients recruited, 124 were excluded from the study due to lack of compliance with the treatment, so that 338 patients in group A and 163 patients in group B completed the study. By the end of the study, the 4th of the monthly assessments showed that both the group-A and the group-B treatments had induced a significant increase in the quality-of-life index, the change being 11.9 points for Pharmaton Capsules in group A which was significantly superior to the 6.4 average increase with the group-B capsules containing multivitamins alone. Group A showed significant improvement in every one of the 11 questionnaire items, whereas group B did not show significant improvement in any of these items. Significant increases in body weight and in diastolic blood pressure were recorded in the group B treated with the multivitamin alone. Adverse effects of the capsules were minimal in both groups. This study has demonstrated that Pharmaton Capsules were more effective than the multivitamin capsules alone in improving the quality-of-life in a population subjected to the stress of high physical and mental activity.

[Simvastatin in the treatment of hypercholesterolemia]. / La simvastatina nel trattamento delle ipercolesterolemie.

We have treated twelve patients with simvastatin: six had type IIA hypercholesterolaemia and the other six had type IIB. These patients have been examined before and after therapy, by an ophthalmologist. After therapy, the levels of the total cholesterol and triglycerides were decreased while HDL cholesterol was increased. Untoward side effects of ophthalmologic alterations were not observed.

Sexual lifestyle / behavioral changes in a cohort of intravenous drug users.

PIP: This article reports on a study of HIV seroprevalence and sexual lifestyles among Italian intravenous drug users (IVDUs). Unlike the situation in the US and most of Europe, where HIV infection is found primarily among homosexual and bisexual men, intravenous drug users account for 66% of the hiv cases in Italy. This study, which ran from January through March of 1990, involved interviews with 124 IV heroin users having methadone treatment in a Public Assistance Center in Rome. The goals of the study included conducting a demographic survey and investigation of the serological condition of IVDUs, investigating the sexual behavior of both HIV positive and negative subjects, and investigating any changes in the sexual habits of the subjects following awareness of their serological condition. 34 of those interviewed were women and 90 were men. Ages ranged from 18-41 years. Of the 124 subjects, 120 were heterosexual, 2 homosexual, and 2 bisexual. 39 heterosexuals, as well as the 2 homosexuals and the 2 bisexuals, tested HIV positive. 96% of the IVDUs interviewed reported being sexually active, and 67% indicated having at least 1 sexual intercourse a week (28% reported 10 or less sexual intercourses in a year). Although all those interviewed acknowledged being aware of the risk of sexually transmitted AIDS, 60% of the HIV positive and 88% of the HIV negative subjects did not use condoms regularly (56% of the HIV negative subjects never used condoms). The article lists some of the reasons given for irregular use of condoms. Concerning changes in sexual habits, 46% of the HIV negative and 63% of the HIV positive subjects indicated reducing the number of sexual partners and/or using condoms.^ieng

[Hyperlipidemia: physiopathology and our experience in the ambulatory care of 3 groups of patients undergoing blood lipid normalization treatment]. / Le iperlipidemie. Fisiopatologia e nostre esperienze ambulatoriali su tre gruppi di pazienti sottoposti a trattamento normolipemizzante.

The authors tested the efficacy of three different lipid-lowering drugs in subjects with more or less severe alterations of the lipoprotein pattern. All subjects were submitted to blood tests prior to and at the end of treatment with special attention to the trend of the lipid pattern, assaying cholesterol, HDL, LDL, triglyceride, total lipid blood levels and lipid electrophoresis. The drugs employed were: pantothenic acid, sulodexide, and DEAE-dextran.

[Cryptogenetic ulcerative colitis. Our clinical experience with new therapeutic approaches]. / Colite ulcerosa criptogenetica. Nostra esperienza clinica sulle nuove vedute terapeutiche.

Sixteen patients with flare-ups of ulcerative colitis were studied. Before and after treatment, patients were submitted to the customary laboratory tests and to x-ray (contrast enema) and endoscopic examination, biopsy material being harvested during the latter. Treatment consisted in the oral administration of 2-4 g 5-ASA daily for 30 days. Only one patient did not tolerate 5-ASA which was withdrawn. All other patients had good or very good results with remission of symptoms.

[Duhring and Brocq dermatitis herpetiformis. Recent immunologic findings. Personal observations in a patient]. / Dermatite erpetiforme di Duhring e Brocq. Recenti acquisizioni immunologiche. Osservazioni personali su un paziente.

The clinical, anatomopathological and therapeutic aspects of herpetiform dermatitis are nowadays almost completely clarified; for this reason in this study we limit ourselves to evaluating only its essential characteristics. The above study is mainly intended to present an exhaustive documentation of the immunological pattern of Duhring-Brocq dermatitis.