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Traumatic brain injury (TBI) has reached epidemic proportions around the world and is a major public health concern in the United States. Approximately 2.8 million individuals sustain a traumatic brain injury and are treated in an Emergency Department yearly in the U.S., and about 50,000 of them die. Persistent symptoms develop in 10-15% of the cases including neuropsychiatric disorders. Anxiety is the second most common neuropsychiatric disorder that develops in those with persistent neuropsychiatric symptoms after TBI. Abnormalities or atrophy in the temporal lobe has been shown in the overwhelming number of TBI cases. The basolateral amygdala (BLA), a temporal lobe structure that consolidates, stores and generates fear and anxiety-based behavioral outputs, is a critical brain region in the anxiety circuitry. In this review, we sought to capture studies that characterized the relationship between human post-traumatic anxiety and structural/functional alterations in the amygdala. We compared the human findings with results obtained with a reproducible mild TBI animal model that demonstrated a direct relationship between the alterations in the BLA and an anxiety-like phenotype. From this analysis, both preliminary insights, and gaps in knowledge, have emerged which may open new directions for the development of rational and more efficacious treatments.

Objective: Sensory deficits are important risk factors for delirium but have been investigated in single-center studies and single clinical settings. This multicenter study aims to evaluate the association between hearing and visual impairment or bi-sensory impairment (visual and hearing impairment) and delirium. Design: Cross-sectional study nested in the 2017 "Delirium Day" project. Setting and participants: Patients 65 years and older admitted to acute hospital medical wards, emergency departments, rehabilitation wards, nursing homes, and hospices in Italy. Methods: Delirium was assessed with the 4AT (a short tool for delirium assessment) and sensory deficits with a clinical evaluation. We assessed the association between delirium, hearing and visual impairment in multivariable logistic regression models, adjusting for: Model 1, we included predisposing factors for delirium (ie, dementia, weight loss and autonomy in the activities of daily living); Model 2, we added to Model 1 variables, which could be considered precipitating factors for delirium (ie, psychoactive drugs and urinary catheters). Results: A total of 3038 patients were included; delirium prevalence was 25%. Patients with delirium had a higher prevalence of hearing impairment (30.5% vs 18%; P < .001), visual impairment (24.2% vs 15.7%; P < .01) and bi-sensory impairment (16.2% vs 7.5%) compared with those without delirium. In the multivariable logistic regression analysis, the presence of bi-sensory impairment was associated with delirium in Model 1 [odds ratio (OR) 1.5, confidence interval (CI) 1.2-2.1; P = .00] and in Model 2 (OR 1.4; CI 1.1-1.9; P = .02), whereas the presence of visual and hearing impairment alone was not associated with delirium either in Model 1 (OR 0.8; CI 0.6-1.2, P = .36; OR 1.1; CI 0.8-1.4; P = .42) or in Model 2 (OR 0.8, CI 0.6-1.2, P = .27; OR 1.1, CI 0.8-1.4, P = .63). Conclusions and implications: Our findings support the importance of routine screening and specific interventions by a multidisciplinary team to implement optimal management of sensory impairments and hence prevention and the management of the patients with delirium.

Significance In this manuscript, we report a rare case of a patient with localized seizures originating from the right anterior and dorsal posteromedial cortex (PMC). We mapped the electrophysiological and neuroimaging connectivity of the ictal onset site and replicated seizure auras by stimulating the homotopical PMC site in the left hemisphere. Our findings provide a causal link between PMC and the sense of self and provide unique clues about the pathophysiology of self-dissociation in neuropsychiatric conditions., The posteromedial cortex (PMC) is known to be a core node of the default mode network. Given its anatomical location and blood supply pattern, the effects of targeted disruption of this part of the brain are largely unknown. Here, we report a rare case of a patient (S19_137) with confirmed seizures originating within the PMC. Intracranial recordings confirmed the onset of seizures in the right dorsal posterior cingulate cortex, adjacent to the marginal sulcus, likely corresponding to Brodmann area 31. Upon the onset of seizures, the patient reported a reproducible sense of self-dissociation—a condition he described as a distorted awareness of the position of his body in space and feeling as if he had temporarily become an outside observer to his own thoughts, his “me” having become a separate entity that was listening to different parts of his brain speak to each other. Importantly, 50-Hz electrical stimulation of the seizure zone and a homotopical region within the contralateral PMC induced a subjectively similar state, reproducibly. We supplement our clinical findings with the definition of the patient’s network anatomy at sites of interest using cortico-cortical–evoked potentials, experimental and resting-state electrophysiological connectivity, and individual-level functional imaging. This rare case of patient S19_137 highlights the potential causal importance of the PMC for integrating self-referential information and provides clues for future mechanistic studies of self-dissociation in neuropsychiatric populations.

Retinal ganglion cell (RGC) loss underlies several conditions which give rise to significant visual compromise, including glaucoma and ischaemic optic neuropathies. Neuroprotection of RGCs is a clinical well-defined unmet need in these diseases, and adenosine A

Distinct regions of the cerebellum connect to separate regions of the cerebral cortex forming a complex topography. Although cerebellar organization has been examined in group-averaged data, study of individuals provides an opportunity to discover features that emerge at a higher spatial resolution. Here, functional connectivity MRI was used to examine the cerebellum of two intensively sampled individuals (each scanned 31 times). Connectivity to somatomotor cortex showed the expected crossed laterality and topography of the body maps. A surprising discovery was connectivity to the primary visual cortex along the vermis with evidence for representation of the central field. Within the hemispheres, each individual displayed a hierarchical progression from the inverted anterior lobe somatomotor map through to higher-order association zones. The hierarchy ended at Crus I/II and then progressed in reverse order through to the upright somatomotor map in the posterior lobe. Evidence for a third set of networks was found in the most posterior extent of the cerebellum. Detailed analysis of the higher-order association networks revealed robust representations of two distinct networks linked to the default network, multiple networks linked to cognitive control, as well as a separate representation of a language network. Although idiosyncratic spatial details emerged between subjects, each network could be detected in both individuals, and seed regions placed within the cerebellum recapitulated the full extent of the spatially specific cerebral networks. The observation of multiple networks in juxtaposed regions at the Crus I/II apex confirms the importance of this zone to higher-order cognitive function and reveals new organizational details. NEW & NOTEWORTHY Stable, within-individual maps of cerebellar organization reveal orderly macroscale representations of the cerebral cortex with local juxtaposed zones representing distinct networks. In addition, individuals reveal idiosyncratic organizational features.

Objectives To explore the impact of sex and age on relationship between prodromal constipation and disease phenotype in Parkinson’s disease at early stages. Methods A total of 385 Parkinson’s disease patients from the PRIAMO study were classified according to the presence of prodromal constipation and followed for 24 months. Multivariable mixed-effect models were applied. All analyses were performed separately for sex (64.1% men) and median age (different by sex: 67 years-old in men and 68 years-old in women). Results As for sex, prodromal constipation was associated with greater odds of attention/memory complaints and apathy symptoms in women only. As for age, prodromal constipation was associated with lower cognitive and higher apathy scores in older patients only. Conclusions Prodromal constipation anticipates lower cognitive performances and more severe apathy since the earliest stages in women and older patients. Sex- and age-related heterogeneity of prodromal markers of Parkinson’s disease may impact disease phenotype.

Using procedures optimized to explore network organization within the individual, the topography of a candidate language network was characterized and situated within the broader context of adjacent networks. The candidate network was first identified using functional connectivity and replicated across individuals, acquisition tasks, and analytical methods. In addition to classical language regions near the perisylvian cortex and temporal pole, regions were also observed in dorsal posterior cingulate, midcingulate, and anterior superior frontal and inferior temporal cortex. The candidate network was selectively activated when processing meaningful (as contrasted with nonword) sentences, whereas spatially adjacent networks showed minimal or even decreased activity. Results were replicated and triplicated across two prospectively acquired cohorts. Examined in relation to adjacent networks, the topography of the language network was found to parallel the motif of other association networks, including the transmodal association networks linked to theory of mind and episodic remembering (often collectively called the default network). The several networks contained juxtaposed regions in multiple association zones. Outside of these juxtaposed higher-order networks, we further noted a distinct frontotemporal network situated between language regions and a frontal orofacial motor region and a temporal auditory region. A possibility is that these functionally related sensorimotor regions might anchor specialization of neighboring association regions that develop into a language network. What is most striking is that the canonical language network appears to be just one of multiple similarly organized, differentially specialized distributed networks that populate the evolutionarily expanded zones of human association cortex. NEW & NOTEWORTHY This research shows that a language network can be identified within individuals using functional connectivity. Organizational details reveal that the language network shares a common spatial motif with other association networks, including default and frontoparietal control networks. The language network is activated by language task demands, whereas closely juxtaposed networks are not, suggesting that similarly organized but differentially specialized distributed networks populate association cortex.

The incidence of inguinal hernia is higher in elderly because of aging-related diseases like prostatism, bronchitis, collagen laxity. A conservative management is common in elderly to reduce surgery-related risks, however watchful waiting can expose to obstruction and strangulation. The aim of the present study was to assess the impact of emergency surgery in a large series of elderly with complicated groin hernia and to identify the independent risk factors for postoperative morbidity and mortality. The predictive performance of prognostic risk scores has been also assessed.This is a prospective observational study carried out between January 2017 and June 2018 in elderly patients who underwent emergency surgery for complicated hernia in 38 Italian hospitals. Pre-operative, surgical and postoperative data were recorded for each patient. ASA score, Charlson's comorbidity index, P-POSSUM and CR-POSSUM were assessed.259 patients were recruited, mean age was 80 years. A direct repair without mesh was performed in 62 (23.9%) patients. Explorative laparotomy was performed in 56 (21.6%) patients and bowel resection was necessary in 44 (17%). Mortality occurred in seven (2.8%) patients. Fifty-five (21.2%) patients developed complications, 12 of whom had a major one. At univariate and multivariate analyses, Charlson's comorbidity index ≥ 6, altered mental status, and need for laparotomy were associated with major complications and mortality CONCLUSION: Emergency surgery for complicated hernia is burdened by high morbidity and mortality in elderly patients. Preoperative comorbidity played a pivotal role in predicting complications and mortality and therefore Charlson's comorbidity index could be adopted to select patients for elective operation.

To evaluate the performance of visual inspection alone and associated to radiographic and laser fluorescence (LF) methods in detecting non-evident caries lesions at adolescents' proximal surfaces.Adolescents (12 to 17 years old) were assessed for the presence of caries lesions through visual inspection, radiographic examination, and LF method (DIAGNOdent pen), at non-cavitated (NC) and cavitated lesion (CAV) thresholds. Temporary separation with orthodontic rubbers followed by direct visual inspection was the reference standard method. Two examiners conducted the examinations, and the first examiner reassessed around 20% of the sample, to evaluate inter- and intra-examiner reproducibility, respectively. Sensitivity, specificity, accuracy, and utility values were calculated for the methods alone and combined with visual inspection using two different strategies: simultaneous and sequential combination.A total of 834 proximal surfaces (51 adolescents) were included. Visual inspection presented higher reproducibility values (higher than 0.98). Moreover, visual inspection presented higher sensitivity (around 0.51) than those obtained with other diagnostic strategies (varying from 0.09 to 0.20) at the NC threshold. For CAV, visual inspection presented higher specificity (0.996) than the sequential association with adjunct methods (around 0.97), but with lower sensitivity. Accuracy and utility values for combined strategies were similar or lower than those achieved with the visual inspection performed alone.Visual inspection alone performs better for detecting caries lesions in premolars and molars of adolescents than other diagnostic strategies.The best diagnostic strategy for caries detection of proximal caries lesions in adolescents is the visual inspection alone.

Nerve agents are organophosphorus acetylcholinesterase inhibitors. Acute exposure to nerve agents can cause rapid death. In this review, we summarize the history of nerve agent development and use in warfare, the mechanisms by which these agents cause death or long-term brain damage, and the treatments for preventing death or long-term morbidity. The G-series nerve agents, tabun, sarin, soman, ethyl sarin, and cyclosarin, were developed by the Nazis. VX, the best-known of the V-series agents, was synthesized in the 1950's by a British scientist. Little is known about the development of the novichoks (the "A-series") by the former Soviet Union. Nerve agents were used for the first time in the battlefield by the Iraqi government in the Iran-Iraq War, in the 1980s. The Chemical Weapons Convention, in 1993, banned all chemical weapons production and use, yet, sarin was subsequently used in terrorist attacks in Japan and, recently, in the war in Syria. Pyridostigmine has been used as a prophylactic treatment, and bioscavengers are presently investigated as a better alternative. Atropine, along with an oxime, can prevent rapid death from the nerve agent-induced peripheral cholinergic crisis. Treatment with diazepam or midazolam for the cessation of nerve agent-induced status epilepticus cannot protect against brain damage, and, therefore, these benzodiazepines should be replaced by novel anticonvulsants and neuroprotectants. The AMPA/GluK1 receptor antagonist LY293558 (tezampanel) has shown superior antiseizure and neuroprotective efficacy against soman, particularly when administered in combination with caramiphen, an antagonist of muscarinic and NMDA receptors. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.

Association cortex is organized into large-scale distributed networks. One such network, the default network (DN), is linked to diverse forms of internal mentation, opening debate about whether shared or distinct anatomy supports multiple forms of cognition. Using within-individual analysis procedures that preserve idiosyncratic anatomical details, we probed whether multiple tasks from two domains, episodic projection and theory of mind (ToM), rely on the same or distinct networks. In an initial experiment (6 subjects, each scanned 4 times), we found evidence that episodic projection and ToM tasks activate separate regions distributed throughout the cortex, with adjacent regions in parietal, temporal, prefrontal, and midline zones. These distinctions were predicted by the hypothesis that the DN comprises two parallel, interdigitated networks. One network, linked to parahippocampal cortex (PHC), is preferentially recruited during episodic projection, including both remembering and imagining the future. A second juxtaposed network, which includes the temporoparietal junction (TPJ), is differentially engaged during multiple forms of ToM. In two prospectively acquired independent experiments, we replicated and triplicated the dissociation (each with 6 subjects scanned 4 times). Furthermore, the dissociation was found in all zones when analyzed independently, including robustly in midline regions previously described as hubs. The TPJ-linked network is interwoven with the PHC-linked network across the cortex, making clear why it is difficult to fully resolve the two networks in group-averaged or lower-resolution data. These results refine our understanding of the functional-anatomical organization of association cortex and raise fundamental questions about how specialization might arise in parallel, juxtaposed association networks. NEW & NOTEWORTHY Two distributed, interdigitated networks exist within the bounds of the canonical default network. Here we used repeated scanning of individuals, across three independent samples, to provide evidence that tasks requiring episodic projection or theory of mind differentially recruit the two networks across multiple cortical zones. The two distributed networks thus appear to preferentially subserve distinct functions.

Visual inspection (VIS) with radiographic examination (RAD) is the recommended diagnostic strategy for detecting caries in children; however, this recommendation is based on accuracy studies. The authors conducted a clinical trial to compare the detection and subsequent treatment of carious lesions in primary molars performed with VIS alone and with RAD.Children (3-6 years old) were randomly assigned to 2 groups according to the diagnostic strategy used for caries detection on primary molars: VIS or RAD. Participants were diagnosed and treated according to the management plan related to the allocated group. The primary outcome was the number of new operative interventions during the 2-year follow-up period. Other secondary outcomes were also compared. Comparisons were performed with Mann-Whitney test using an intention-to-treat approach.Of the 252 children included and randomized, 216 were followed-up after 2 years (14.3% attrition rate). There was no difference between the groups for the primary outcome (P = .476). For the secondary outcomes, the RAD group had more restoration replacements (P = .038) and more restorations performed since the beginning of the study (P = .038) compared with the VIS group. In addition, the RAD group had a higher number of false-positive results than the VIS group (P.001).Simultaneous use of VIS and RAD for caries diagnosis in primary molars of children who seek dental treatment does not provide additional benefits compared with VIS alone.Dentists should perform VIS only, not RAD, for detecting carious lesions in preschool-aged children. ClinicalTrials.gov: NCT02078453.

Nerve agents are organophosphate (OP) compounds and among the most powerful poisons known to man. A terrorist attack on civilian or military populations causing mass casualties is a real threat. The OP nerve agents include soman, sarin, cyclosarin, tabun, and VX. The major mechanism of acute toxicity is the irreversible inhibition of acetylcholinesterase. Acetylcholinesterase inhibition results in the accumulation of excessive acetylcholine levels in synapses, leading to progression of toxic signs including hypersecretions, tremors, status epilepticus, respiratory distress, and death. Miosis and rhinorrhea are the most common clinical findings in those individuals acutely exposed to OP nerve agents. Prolonged seizures are responsible for the neuropathology. The brain region that shows the most severe damage is the amygdala, followed by the piriform cortex, hippocampus, cortex, thalamus, and caudate/putamen. Current medical countermeasures are only modestly effective in attenuating the seizures and neuropathology. Anticonvulsants such as benzodiazepines decrease seizure activity and improve outcome, but their efficacy depends upon the administration time after exposure to the nerve agent. Administration of benzodiazepines may increase the risk for seizure recurrence. Recent studies document long-term neurologic and behavior deficits, and technological advances demonstrate structural brain changes on magnetic resonance imaging.

The currently Food and Drug Administration–approved anticonvulsant for the treatment of status epilepticus (SE) induced by nerve agents is the benzodiazepine diazepam; however, diazepam does not appear to offer neuroprotective benefits. This is of particular concern with respect to the protection of children because, in the developing brain, synaptic transmission mediated via GABAA receptors, the target of diazepam, is weak. In the present study, we exposed 21-day-old male rats to 1.2 × LD50 soman and compared the antiseizure, antilethality, and neuroprotective efficacy of diazepam (10 mg/kg), LY293558 (an AMPA/GluK1 receptor antagonist; 15 mg/kg), caramiphen (CRM, an antimuscarinic with NMDA receptor-antagonistic properties; 50 mg/kg), and LY293558 (15 mg/kg) + CRM (50 mg/kg), administered 1 hour after exposure. Diazepam, LY293558, and LY293558 + CRM, but not CRM alone, terminated SE; LY293558 + CRM treatment acted significantly faster and produced a survival rate greater than 85%. Thirty days after soman exposure, neurodegeneration in limbic regions was most severe in the CRM-treated group, minimal to severe—depending on the region—in the diazepam group, absent to moderate in the LY293558-treated group, and totally absent in the LY293558 + CRM group. Amygdala and hippocampal atrophy, a severe reduction in spontaneous inhibitory activity in the basolateral amygdala, and increased anxiety-like behavior in the open-field and acoustic startle response tests were present in the diazepam and CRM groups, whereas the LY293558 and LY293558 + CRM groups did not differ from controls. The combined administration of LY293558 and CRM, by blocking mainly AMPA, GluK1, and NMDA receptors, is a very effective anticonvulsant and neuroprotective therapy against soman in young rats.

ObjectivesTo evaluate the sensitivity and specificity of the modified Evans blue dye test compared to the fibre-optic endoscopic evaluation of swallowing to detect aspiration in tracheostomised patients.MethodsThis observational accuracy study included 17 patients hospitalised for respiratory complications, subjected to prolonged intubation, and for this reason, tracheostomised.ResultsMean patient age was 60.2 ± 21.0 years. Aspiration was identified in 10 patients when assessed by fibre-optic endoscopic evaluation of swallowing; of these, 1 had aspiration when evaluated by modified Evans blue dye test. The dye test had a sensitivity of 10.0 per cent and specificity of 100.0 per cent for detecting aspiration. Fibre-optic endoscopic evaluation of swallowing revealed no statistically significant associations between aspiration presence and: speech and language therapy duration, intubation time, or tracheostomy plus mechanical ventilation duration.ConclusionThe modified Evans blue dye test is simple and inexpensive, and does not require prior knowledge in endoscopy; it may be used as an initial screening test in all tracheostomised patients for evaluating aspiration. However, fibre-optic endoscopic evaluation of swallowing should be used for a more comprehensive diagnosis of tracheostomy patients, especially for those at high risk for aspiration.

Examination of large-scale distributed networks within the individual reveals details of cortical network organization that are absent in group-averaged studies. One recent discovery is that a distributed transmodal network, often referred to as the “default network,” comprises two closely interdigitated networks, only one of which is coupled to posterior parahippocampal cortex. Not all studies of individuals have identified the same networks, and questions remain about the degree to which the two networks are separate, particularly within regions hypothesized to be interconnected hubs. In this study we replicate the observation of network separation across analytical (seed-based connectivity and parcellation) and data projection (volume and surface) methods in two individuals each scanned 31 times. Additionally, three individuals were examined with high-resolution (7T; 1.35 mm) functional magnetic resonance imaging to gain further insight into the anatomical details. The two networks were identified with separate regions localized to adjacent portions of the cortical ribbon, sometimes inside the same sulcus. Midline regions previously implicated as hubs revealed near complete spatial separation of the two networks, displaying a complex spatial topography in the posterior cingulate and precuneus. The network coupled to parahippocampal cortex also revealed a separate region directly within the hippocampus, at or near the subiculum. These collective results support that the default network is composed of at least two spatially juxtaposed networks. Fine spatial details and juxtapositions of the two networks can be identified within individuals at high resolution, providing insight into the network organization of association cortex and placing further constraints on interpretation of group-averaged neuroimaging data. NEW & NOTEWORTHY Recent evidence has emerged that canonical large-scale networks such as the “default network” fractionate into parallel distributed networks when defined within individuals. This research uses high-resolution imaging to show that the networks possess juxtapositions sometimes evident inside the same sulcus and within regions that have been previously hypothesized to be network hubs. Distinct circumscribed regions of one network were also resolved in the hippocampal formation, at or near the parahippocampal cortex and subiculum.

Background Excessive foot pronation during running in individuals with foot varus alignment may be reduced by medially wedged insoles. Research question This study investigated the effects of a medially wedged insole at the forefoot and at the rearfoot on the lower limbs angles and internal moments of runners with excessive foot pronation and foot varus alignment. Methods Kinematic and kinetic data of 19 runners (11 females and 8 males) were collected while they ran wearing flat (control condition) and medially wedged insoles (insole condition). Both insoles had arch support. We used principal component analysis for data reduction and dependent t-test to compare differences between conditions. Results The insole condition reduced ankle eversion (p = 0.003; effect size = 0.63); reduced knee range of motion in the transverse plane (p = 0.012; effect size = 0.55); increased knee range of motion in the frontal plane in early stance and had earlier knee adduction peak (p = 0.018; effect size = 0.52); reduced hip range of motion in the transverse plane (p = 0.031; effect size = 0.48); reduced hip adduction (p = 0.024; effect size = 0.50); reduced ankle inversion moment (p = 0.012; effect size = 0.55); and increased the difference between the knee internal rotation moment in early stance and midstance (p = 0.012; effect size = 0.55). Significance Insoles with 7˚ medial wedges at the forefoot and rearfoot are able to modify motion and moments patterns that are related to lower limb injuries in runners with increased foot pronation and foot varus alignment with some non-desired effects on the knee motion in the frontal plane.

Two novel and exciting avenues of neuroscientific research involve the study of task-driven dynamic reconfigurations of functional connectivity networks and the study of functional connectivity in real-time. While the former is a well-established field within neuroscience and has received considerable attention in recent years, the latter remains in its infancy. To date, the vast majority of real-time fMRI studies have focused on a single brain region at a time. This is due in part to the many challenges faced when estimating dynamic functional connectivity networks in real-time. In this work, we propose a novel methodology with which to accurately track changes in time-varying functional connectivity networks in real-time. The proposed method is shown to perform competitively when compared to state-of-the-art offline algorithms using both synthetic as well as real-time fMRI data. The proposed method is applied to motor task data from the Human Connectome Project as well as to data obtained from a visuospatial attention task. We demonstrate that the algorithm is able to accurately estimate task-related changes in network structure in real-time. Hum Brain Mapp 38:202-220, 2017. © 2016 Wiley Periodicals, Inc.

One of the devastating effects of acute exposure to organophosphates, like nerve agents, is the induction of severe and prolonged status epilepticus (SE), which can cause death, or brain damage if death is prevented. Seizures after exposure are initiated by muscarinic receptor hyperstimulation—after inhibition of acetylcholinesterase by the organophosphorus agent and subsequent elevation of acetylcholine—but they are reinforced and sustained by glutamatergic hyperexcitation, which is the primary cause of brain damage. Diazepam is the FDA-approved anticonvulsant for the treatment of nerve agent-induced SE, and its replacement by midazolam is currently under consideration. However, clinical data derived from the treatment of SE of any etiology, as well as studies on the control of nerve agent-induced SE in animal models, have indicated that diazepam and midazolam control seizures only temporarily, their antiseizure efficacy is reduced as the latency of treatment from the onset of SE increases, and their neuroprotective efficacy is limited or absent. Here, we review data on the discovery of a novel anticonvulsant and neuroprotectant, LY293558, an AMPA/GluK1 receptor antagonist. Treatment of soman-exposed immature, young-adult, and aged rats with LY293558, terminates SE with limited recurrence of seizures, significantly protects from brain damage, and prevents long-term behavioral deficits, even when LY293558 is administered 1 h post-exposure. More beneficial effects and complete neuroprotection is obtained when LY293558 administration is combined with caramiphen, which antagonizes NMDA receptors. Further efficacy studies may bring the LY293558 + caramiphen combination therapy on the pathway to approval for human use.

CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Aim To evaluate the mRNA expression levels of the cytokines interferon-γ, tumour necrosis factor-α, interleukin (IL)-1β, IL-10, IL-6, VEGF, and AGT and the chemokine CCL2/MCP-1 in periapical interstitial fluid associated with root canal infections before and after the reduction of the bacterial load using a cleaning procedure. Methodology The case group included 11 patients with chronic liver disease, and the control group included 11 healthy patients. Clinical samples were taken from teeth with pulp necrosis. After cleaning and drying the canal, three paper points were introduced into the root canal and passed through the root apex (2 mm) into the periapical tissues for 1 min. The samples were collected immediately after root canal cleaning and 7 days later to characterize those gene expression levels using real-time PCR. The data were subjected to the Shapiro–Wilk and the Wilcoxon tests. Results In the control group, significantly increased expression of the pro-inflammatory cytokines IFN-γ and TNF-α was observed in teeth with restrained bacterial loads (day 7) (P < 0.05). Similarly, increased TNF-α expression was found on day 7 in the liver group (P < 0.05). No differences were observed in the expression levels of the IL-1β, IL-10 and, IL-6, MCP-1/CCL-2 and VEGF between the first collection (day 0) and second collection (day 7), over time in either group. Conclusion Chronic liver disease patients exhibited sufficient immunologic ability showing relatively similar expression levels of cytokines, chemokines and angiogenic factors in periapical samples compared with the responses from no-chronic liver disease patients. The outcomes of this study suggest that liver impairment did not compromise the periapical immune response

Alzheimer’s disease (AD) is a progressive and neurodegenerative pathology that can affect people over 65 years of age. It causes several complications, such as behavioral changes, language deficits, depression, and memory impairments. One of the methods used to treat AD is the increase of acetylcholine (ACh) in the brain by using acetylcholinesterase inhibitors (AChEIs). In this study, we used the ZINC databank and the Lipinski’s rule of five to perform a virtual screening and a molecular docking (using Auto Dock Vina 1.1.1) aiming to select possible compounds that have quaternary ammonium atom able to inhibit acetylcholinesterase (AChE) activity. The molecules were obtained by screening and furtherin vitroassays were performed to analyze the most potent inhibitors through the IC50value and also to describe the interaction models between inhibitors and enzyme by molecular docking. The results showed that compound D inhibited AChE activity from different vertebrate sources and butyrylcholinesterase (BChE) fromEquus ferus(EfBChE), with IC50ranging from 1.69 ± 0.46 to 5.64 ± 2.47 µM. Compound D interacted with the peripheral anionic subsite in both enzymes, blocking substrate entrance to the active site. In contrast, compound C had higher specificity as inhibitor ofEfBChE. In conclusion, the screening was effective in finding inhibitors of AChE and BuChE from different organisms.

Background: This is the first randomized, double-blind, placebo-controlled trial (EUDRACT No. 2009-013923-43) evaluating nickel oral hyposensitizing treatment (NiOHT) in patients with “systemic nickel allergy syndrome” (SNAS), characterized by Ni-allergic contact dermatitis and systemic reactions after eating Ni-rich food. Methods: Adults with positive Ni-patch test, who reported symptoms suggesting SNAS, which improved after Ni-poor diet, and were positive to Ni-oral challenge were eligible. Patients were randomly assigned to three treatments (1.5 μg, 0.3 μg, or 30 ng Ni/week) or placebo for a year, with progressive reintroduction of Ni-rich foods form the 5th month. Out of 141 patients randomized, 113 completed the trial. Endpoints were efficacy and tolerability of treatment. Results: During Ni-rich food re-introduction, the 1.5 μg Ni/week group had a mean VAS score significantly higher than placebo (p = 0.044), with significant improvement of gastrointestinal symptoms (p = 0.016;) and significantly fewer rescue medications. Cutaneous manifestations also improved but without reaching statistical significance. After the treatment, oral challenge with higher Ni doses than at baseline were needed to cause symptoms to flare-up in significantly more patients given 1.5 μg Ni/week than placebo (p = 0.05). Patients reported no side-effects. Conclusions: NiOHT is effective in SNAS, in particular on gastrointestinal manifestations, with trend toward improvement of cutaneous symptoms.

A central question for cognitive neuroscience is whether there is a single neural system controlling the allocation of attention. A dorsal frontoparietal network of brain regions is often proposed as a mediator of top-down attention to all sensory inputs. We used functional magnetic resonance imaging in humans to show that the cortical networks supporting top-down attention are in fact modality-specific, with distinct superior fronto-parietal and fronto-temporal networks for visuospatial and non-spatial auditory attention respectively. In contrast, parts of the right middle and inferior frontal gyri showed a common response to attentional control regardless of modality, providing evidence that the amodal component of attention is restricted to the anterior cortex., Highlights ► Fronto-temporal systems involved in auditory non-spatial top-down attention ► Dorsal attention network involved in visuospatial top-down attention ► Only middle and inferior frontal gyri significantly activated for both modalities ► There are modality specific neural mechanisms modulating top-down attention

Moebius syndrome (MS) is a rare congenital facial diplegia characterized by partial or complete sixth and seventh cranial nerve palsy. Orofacial manifestations include micrognathia, increased overbite, high arched palate, morphological changes in the tongue, and dental crowding. Case reports and small case series have shown a high prevalence of caries in MS patients. The purpose of this study was to compare the prevalence of caries between individuals with Moebius syndrome and controls using the International Caries Detection and Assessment System (ICDAS).A total of 90 participants were divided into two groups: (1) the study group, comprising 34 individuals with MS; and (2) the control group, comprising 56 age- and gender-matched healthy subjects without MS. All individuals were evaluated for the presence of caries using the ICDAS. For statistical analysis, different ICDAS scores were used as cutoff points.The number of carious lesions in the MS group was higher only for early-stage caries (i.e., ICDAS scores of 1 and 2; 27.0±23.0 versus 16.0±14.1 and 26.3±23.2 versus 15.2±13.6, respectively).Moebius syndrome patients have more early carious lesions than controls without the syndrome.

Sublingual immunotherapy with monomelic carbamylated allergoid (LAIS) is an effective and well tolerated treatment of respiratory allergy. The aim of the present study was to correlate the efficacy of two maintenance doses (1000 AU vs 3000 AU) of LAIS with the immunological modulation of allergen-driven Th1, Th2 and T regulatory cytokines produced in vitro by PBMCs, in patients suffering from mite allergic rhinitis. Forty-eight consecutive patients with mite allergic rhinitis were recruited. Patients were randomly assigned to group A (n=24) or group B (n=24), respectively receiving 1000 AU or 3000 AU weekly during one-year maintenance phase. Each patient was evaluated for rhinitis severity (ARIA protocol), and for drug consumption at the time of the inclusion and after 6 and 12 months of treatment. Patients were also asked to report the perceived severity of the disease and the tolerability of the treatment in a visual analogical scale (VAS). Before and at the end of the treatment allergen-driven release of cytokines by PBMCs in vitro was measured. After 1-year treatment, a statistically significant reduction of all clinical parameters was observed in all patients, associated with reduction of IL-4 and increase of INF-γ secreted in vitro by mite-challenged PBMCs. Notably, the group treated with the higher dose showed significantly better clinical and immunological results. The efficacy of LAIS is correlated to the immune modulation in a clear dose-dependent effect.

The central role of T regulatory cells in the responses against harmless environmental antigens has been confirmed by many studies. Impaired T regulatory cell function is implicated in many pathological conditions, particularly allergic diseases. The "hygiene hypothesis" suggests that infections and infestations may play a protective role for allergy, whereas environmental pollutants favor the development of allergic diseases. Developing countries suffer from a variety of infections and are also facing an increasing diffusion of environmental pollutants. In these countries allergies increase in relation to the spreading use of xenobiotics (pesticides, herbicides, pollution, etc.) with a rate similar to those of developed countries, overcoming the protective effects of infections. We review here the main mechanisms of non-self tolerance, with particular regard to relations between T regulatory cell activity, infections and infestations such as helminthiasis, and exposure to environmental xenobiotics with relevant diffusion in developing countries.

This review deals with the bactericidal, anti-fungal and even anti-parasitary properties of ruthenium complexes, both inorganic and organometallic, establishing comparisons between these and the available commercial drugs. The description is mostly composed of results found in the literature of the past two decades, complemented with relevant results from our groups research on antimicrobial ruthenium complexes. The complexes are divided into five groups according to the kind of ligands, geometry and chemical nature. The first group comprises ruthenium octahedral complexes with Schiff bases, the most well explored kind of ruthenium antimicrobials. The second group comprises complexes with planar ligands and an overall more flattened geometry, designed for DNA intercalation. In the following two groups, ruthenium complexes feature a particular functionality, which is, in one case, the presence of the PTA ligand for higher solubility in water, and, in the second, the mimicry of an active organic drug. Finally, a small section presents the most recent results on supramolecular antimicrobials comprising ruthenium, in particular a polymer and a cyclodextrin adduct.

In spite of extensive recent progress, a comprehensive understanding of how actin cytoskeleton remodelling supports stable junctions remains to be established. Here we design a platform that integrates actin functions with optimized phenotypic clustering and identify new cytoskeletal proteins, their functional hierarchy and pathways that modulate E-cadherin adhesion. Depletion of EEF1A, an actin bundling protein, increases E-cadherin levels at junctions without a corresponding reinforcement of cell-cell contacts. This unexpected result reflects a more dynamic and mobile junctional actin in EEF1A-depleted cells. A partner for EEF1A in cadherin contact maintenance is the formin DIAPH2, which interacts with EEF1A. In contrast, depletion of either the endocytic regulator TRIP10 or the Rho GTPase activator VAV2 reduces E-cadherin levels at junctions. TRIP10 binds to and requires VAV2 function for its junctional localization. Overall, we present new conceptual insights on junction stabilization, which integrate known and novel pathways with impact for epithelial morphogenesis, homeostasis and diseases.

In asthmatics, a rapid decline in pulmonary function is observed, likely as a consequence of airways remodeling. Persistence of allergen exposure in patients with occupational asthma (OA) maintains chronic bronchial inflammation, resulting in a more severe lung function decline. Few studies were performed on the effects of allergen exposure cessation.This study aims at evaluating the influence of allergen exposure cessation on respiratory decline in allergic asthmatic workers.Two groups of workers with allergic OA were selected. The first group (30 workers) changed job after the diagnosis and was no more exposed to sensitizing allergens, and the second group (28 subjects) did not and, as a consequence of preventive measures in the work place, was exposed to a lower level of allergens. All were treated with conventional therapy, according to GINA protocols. FEV1 changes during a 12-year period were evaluated.Despite pharmacological therapy, the pulmonary function decay slope was steeper in workers continuously exposed to the sensitizing agent (even at reduced level) than in those with a complete cessation of exposure: final FEV1 loss was 512.5 ± 180 ml versus 332.5 ± 108 ml, respectively. The difference became significant after 4 years from the cessation of the exposure.The study shows that the cessation of the exposure to allergen in the work place appears the most effective measure in limiting pulmonary function decline in asthmatic workers and underlines the importance of allergic risk assessment and control in the management of occupational asthma.

Certain pathogens recruit host complement inhibitors such as factor H (fH) to evade the immune system. Microbial complement inhibitor-binding molecules can be promising vaccine targets by eliciting Abs that neutralize this microbial defense mechanism. One such Ag, meningococcal factor H-binding protein (fHbp), was used in clinical trials before the protein was discovered to bind fH. The potential effect of fH binding on vaccine immunogenicity had not been assessed in experimental animals because fHbp binds human fH specifically. In this study, we developed a human fH transgenic mouse model. Transgenic mice immunized with fHbp vaccine had 4- to 8-fold lower serum bactericidal Ab responses than those of control mice whose native fH did not bind the vaccine. In contrast, Ab responses were unimpaired in transgenic mice immunized with a control meningococcal group C polysaccharide–protein conjugate vaccine. In transgenic mice, immunization with an fH nonbinding mutant of fHbp elicited Abs with higher bactericidal activity than that of fHbp vaccination itself. Abs elicited by the mutant fHbp more effectively blocked fH binding to wild-type fHbp than Abs elicited by fHbp that bound fH. Thus, a mutant fHbp vaccine that does not bind fH but that retains immunogenicity is predicted to be superior in humans to an fHbp vaccine that binds human fH. In the case of mutant fHbp vaccination, the resultant Ab responses may be directed more at epitopes in or near the fH binding site, which result in greater complement-mediated serum bactericidal activity; these epitopes may be obscured when human fH is bound to the wild-type fHbp vaccine.

Some patients with nickel (Ni) allergic contact dermatitis suffer from systemic (intestinal or cutaneous) symptoms after ingestion of Ni-rich foods and experience symptoms reduction with low-Ni diet, a condition termed “systemic Ni allergy syndrome” (SNAS). We aimed at evaluating whether oral administration of low nickel doses improved clinical conditions and modulated immunological aspects of SNAS, without significant side effects. Thirty-six SNAS patients were enrolled. Treatment started after 1-month of low-Ni diet and consisted in an incremental oral NiOH dose phase (0.3ng to 1.5 μg/week) followed by a 12-months maintenance phase (1.5 μg/week). Randomly, twenty-four patients added Ni therapy to low-Ni diet and 12 remained with diet alone. All patients were allowed rescue medications (antihistamines and topical steroids). After 4 months, Ni-rich foods were gradually reintroduced. In vitro allergen-driven IL13, IL5 and IFNγ release by peripheral blood mononuclear cells was evaluated before and after treatment. Twenty-three patients receiving NiOH and the 12 control patients completed the study. Evaluation of SNAS clinical severity (by VAS and drug consumption) showed a significant difference in favor of NiOH-treated patients compared to controls. Twenty of 23 patients in the NiOH group and none in the control group tolerated Ni-rich food reintroduction. Release of all studied cytokines in culture supernatants was significantly lower after NiOH treatment. In conclusion NiOH is effective in reducing symptoms and drug consumption in SNAS and is able to modulate inflammatory parameters.

The influence of different treatment schedules of sublingual immunotherapy (SLIT) in activating IL-10-producing T-cells, crucial in inducing allergen-specific tolerance, is not completely understood. The present work was designed to evaluate allergen driven interleukin release by mononuclear cells in the early phase of SLIT, after application of different induction schemes. Twenty mite-allergic patients were enrolled, 10 (group A) treated with a traditional 98 day induction scheme and 10 (group B) with a 16 day scheme with monomeric allergoid vaccine. At the end of the induction phase, the cumulative doses taken by group A and group B patients were equivalent to 50.5 and 50.3 μg of mite group 1 allergens, respectively. The release of Th1-, Th2- and Treg-related interleukins was assessed in culture supernatants of 5 μg/ml Der-p1-stimulated mononuclear cells, isolated before and after the induction phases. No relevant treatment-related side effects were observed. Interleukin release was similar in the two groups at the enrolment. Non-stimulated and Der p 1 stimulated release of studied cytokines was similar in the two groups at enrolment. Der p 1 stimulation significantly increased IL-10 release (p

OBJETIVO: Avaliar os efeitos da evaporação e da pasteurização do leite humano na sua composição bioquímica e imunológica e em sua osmolaridade. MÉTODOS: As amostras de leite humano maduro foram divididas em quatro grupos de estudo: leite humano in natura, leite humano pasteurizado, leite humano evaporado a 70% do volume inicial e leite humano pasteurizado e evaporado a 70%, com 12 diferentes amostras de leite em cada grupo. Das amostras dos grupos, foram dosadas as concentrações de sódio, potássio, cálcio, fósforo, magnésio, proteína, gordura, lactose, imunoglobulina A e osmolaridade. RESULTADOS: A pasteurização do leite humano não mostrou alterações estatisticamente significantes na concentração dos elementos sódio, potássio, cálcio, fósforo, magnésio, proteína, gordura, lactose, nem na osmolaridade; no entanto, mostrou redução significante na concentração média de imunoglobulina A. A evaporação mostrou aumento estatisticamente significativo de 38% em média na concentração dos elementos sódio, potássio, cálcio, fósforo, magnésio, proteína, gordura e lactose e redução média de 45% na concentração da imunoglobulina A, sem alteração significativa da osmolaridade em relação ao leite sem processamento. CONCLUSÃO: Através da evaporação a 70% do volume inicial do leite humano, pode ser obtido leite humano com condições de satisfazer as necessidades nutricionais preconizadas para o recém-nascido pré-termo, com exceção do cálcio e do fósforo. OBJECTIVE: To assess the effects of evaporation and pasteurization of human milk on its biochemical and immunological composition and on its osmolarity. METHODS: The samples of mature human milk were categorized into four study groups: in natura human milk, pasteurized human milk, human milk evaporated at 70% of the baseline volume and human milk pasteurized and evaporated at 70%, with 12 different samples of milk in each group. The samples were used to determine the concentrations of sodium, potassium, calcium, phosphorus, magnesium, protein, fat, lactose, immunoglobulin A and osmolarity. RESULTS: The pasteurization of human milk did not show statistically significant changes in the concentration of sodium, potassium, calcium, phosphorus, magnesium, protein, fat, lactose, or in osmolarity; however, it showed remarkable reduction in the mean concentration of immunoglobulin A. Evaporation had a mean increase of 38% in the concentration of sodium, potassium, calcium, phosphorus, magnesium, protein, fat and lactose and mean reduction of 45% in the concentration of immunoglobulin A, without significant change in osmolarity in unprocessed milk. CONCLUSION: By evaporation at 70% of the baseline value of human milk, it is possible to obtain human milk that meets the nutritional requirements recommended for preterm infants, except for calcium and phosphorus.

The brain comprises an excitatory/inhibitory neuronal network that maintains a finely tuned balance of activity critical for normal functioning. Excitatory activity in the basolateral amygdala (BLA), a brain region that plays a central role in emotion and motivational processing, is tightly regulated by a relatively small population of gamma-aminobutyric acid (GABA) inhibitory neurons. Disruption in GABAergic inhibition in the BLA can occur when there is a loss of local GABAergic interneurons, alterations in GABAA receptor activation, or dysregulation of mechanisms that modulate BLA GABAergic inhibition. Disruptions in GABAergic control of the BLA emerge during development, in aging populations, or after a trauma, ultimately resulting in hyperexcitability. BLA hyperexcitability manifests behaviorally as an increase in anxiety, emotional dysregulation, or the development of seizure activity. This article reviews the anatomy, development, and physiology of the GABAergic system in the BLA, and circuits that modulate GABAergic inhibition, including the dopaminergic, serotonergic, noradrenergic, and cholinergic systems. We highlight how alterations in various neurotransmitter receptors, including the acid sensing ion channel 1a (ASIC1a), cannabinoid receptor 1 (CB1), and glutamate receptor subtypes, expressed on BLA interneurons, modulate GABAergic transmission and how defects of these systems affects inhibitory tonus within the BLA. Finally, we discuss alterations in the BLA GABAergic system in neurodevelopmental (autism/Fragile X syndrome) and neurodegenerative (Alzheimer’s disease) diseases, and after the development of epilepsy, anxiety, and traumatic brain injury. A more complete understanding of the intrinsic excitatory/inhibitory circuit balance of the amygdala and how imbalances in inhibitory control contribute to excessive BLA excitability will guide the development of novel therapeutic approaches in neuropsychiatric diseases.

Objectives To evaluate the effect of patient satisfaction on health-related quality of life among dermatological outpatients, independently of patients’ sociodemographic, and clinical characteristics. Design Prospective cohort study. Satisfaction was evaluated with a standardized questionnaire three days after the visit by telephone interview. Quality of life and psychiatric disorders were measured with validated instruments (Skindex-29 and Ghq-12) before the dermatological visit and after four weeks. At the four week interview also self-reported medication adherence was assessed. Setting Outpatient clinics of a large dermatological hospital in Rome, Italy. Patients A consecutive sample of 1389 outpatients was approached, and 52% agreed to participate. Inclusion criteria were met by 424 patients, and 396 (93%) of them completed the study. Main outcome measures Improvement in health related quality of life. Results At multivariate analysis satisfied patients have approximately twice the odds for an improved quality of life on the emotions scale (OR = 1.99; 95%CI 1.1 to 3.7; P = 0.03) and on the functioning scale (OR = 2.2; 95%CI 1.1 to 4.7; P = 0.03). Patients with psychiatric disorders at baseline were less likely to have an improved quality of life on the functioning scale (OR = 0.3; 95%CI 0.2 to 0.8; P = 0.01). Conclusions This is the first prospective study showing that patient satisfaction and psychiatric disorders have a significant effect on quality of life improvement among dermatological patients, independently of patient characteristics. Particular attention should be devoted to improving physicians’ interpersonal skills, the major component of patient satisfaction.

Purpose: Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair activity that confers resistance to radiation- and alkylator-induced cytotoxic abasic sites in human cells. We assayed apurinic/apyrimidinic endonuclease activity in medulloblastomas and primitive neuroectodermal tumors (PNET) to establish correlates with tumor and patient characteristics and with response to adjuvant radiation plus multiagent chemotherapy. Experimental Design: Ap endo activity was assayed in 52 medulloblastomas and 10 PNETs from patients 0.4 to 21 years old. Ape1/Ref-1, the predominant human Ap endo activity, was measured in 42 medulloblastomas by immunostaining. Cox proportional hazards regression models were used to analyze the association of activity with time to tumor progression (TTP). Results: Tumor Ap endo activity varied 180-fold and was significantly associated with age and gender. Tumor Ape1/Ref-1 was detected almost exclusively in nuclei. In a multivariate model, with Ap endo activity entered as a continuous variable, the hazard ratio for progression after adjuvant treatment in 46 medulloblastomas and four PNETs increased by a factor of 1.073 for every 0.01 unit increase in activity (P ≤ 0.001) and was independent of age and gender. Suppressing Ap endo activity in a human medulloblastoma cell line significantly increased sensitivity to 1,3-bis(2-chlororethyl)-1-nitrosourea and temozolomide, suggesting that the association of tumor activity with TTP reflected, at least in part, abasic site repair. Conclusions: Our data (a) suggest that Ap endo activity promotes resistance to radiation plus chemotherapy in medulloblastomas/PNETs, (b) provide a potential marker of treatment outcome, and (c) suggest clinical use of Ap endo inhibitors to overcome resistance.

Subarachnoid block is a widely used technique for Caesarean section. Its quality can be improved by adding opioids to the local anaesthetics. We studied the quality of the block and its maternal-fetal repercussions when different doses of sufentanil were combined with hyperbaric bupivacaine using the intrathecal route in pregnant women undergoing Caesarean section.This was a prospective, randomized, double-blind, controlled trial with 80 pregnant women, ASA I-II, who were scheduled for elective Caesarean section under subarachnoid block. Patients were distributed into four groups according to the dose of sufentanil used: no sufentanil (Group 1, control) or 2.5, or 5.0 or 7.5 microg sufentanil (Groups 2-4, respectively). In every group, the local anaesthetic used was hyperbaric bupivacaine 0.5% (12.5 mg) and the total volume of the solution 4 mL. The onset time of the block, maximum level of sensory block, motor block level, duration of analgesia, maternal side-effects and maternal-fetal cardiovascular repercussions were evaluated.Onset of the block was significantly shorter in the groups receiving opioids compared with the control group. Analgesia was significantly prolonged in Groups 3 and 4. The occurrence of pruritus and somnolence was significantly higher in the group receiving sufentanil 7.5 microg than in other groups. With the exception of pruritus, no differences were observed between groups with respect to cardiovascular or other maternal effects.The addition of sufentanil 5.0 and 7.5 microg to hyperbaric bupivacaine provided adequate anaesthesia for Caesarean section and good postoperative analgesia. Pruritus was the most common side-effect and had a significantly higher incidence when a dose of sufentanil 7.5 microg was used.

Objective Epidemiological studies have shown that the prevalence of psychiatric disorders among dermatological patients is high. We aimed at estimating the short-term incidence of psychiatric disorders among patients with skin disease. Methods The 12-item General Health Questionnaire (GHQ-12) was used to identify subjects free from psychiatric morbidity at their first dermatological visit. The GHQ-12 was administered again after 1 month during a computer-assisted telephone interview. Results A total of 277 subjects was included in the study. At the follow-up interview, 21 (7.6%) were found to have significant psychiatric morbidity. Only lack of improvement was associated with increased incidence of psychiatric morbidity (13.6%), with an odds ratio of 3.1 (95% confidence interval 1.2–7.8), after adjustment for gender, age, educational level and clinical severity. Conclusions Physicians should devote special attention to the risk of psychiatric complications in patients who have not improved with treatment.

IntroductionMucositis induced by anti-neoplastic drugs is an important, dose-limiting and costly side-effect of cancer therapy.AimTo evaluate the effect of the topical application of S-nitrosoglutathione (GSNO), a nitric oxide donor, on 5-fluorouracil (5-FU)-induced oral mucositis in hamsters.Materials and methodsOral mucositis was induced in male hamsters by two intraperitoneal administrations of 5-FU on the first and second days of the experiment (60 and 40 mg/kg, respectively) followed by mechanical trauma on the fourth day. Animals received saline, HPMC or HPMC/GSNO (0.1, 0.5 or 2.0 mM) 1 h prior to the 5-FU injection and twice a day for 10 or 14 days. Samples of cheek pouches were harvested for: histopathological analysis, TNF-α and IL-1β levels, immunohistochemical staining for iNOS, TNF-α, IL-1β, Ki67 and TGF-β RII and a TUNEL assay. The presence and levels of 39 bacterial taxa were analyzed using the Checkerboard DNA-DNA hybridization method. The profiles of NO released from the HPMC/GSNO formulations were characterized using chemiluminescence.ResultsThe HPMC/GSNO formulations were found to provide sustained release of NO for more than 4 h at concentration-dependent rates of 14 to 80 nmol/mL/h. Treatment with HPMC/GSNO (0.5 mM) significantly reduced mucosal damage, inflammatory alterations and cell death associated with 5-FU-induced oral mucositis on day 14 but not on day 10. HPMC/GSNO administration also reversed the inhibitory effect of 5-FU on cell proliferation on day 14. In addition, we observed that the chemotherapy significantly increased the levels and/or prevalence of several bacterial species.ConclusionTopical HPMC/GSNO accelerates mucosal recovery, reduces inflammatory parameters, speeds up re-epithelization and decreases levels of periodontopathic species in mucosal ulcers.

Psychiatric disorders are frequent among patients with skin diseases. We aimed at identifying factors associated with psychiatric morbidity in dermatological outpatients. All adults attending the outpatient clinics of a dermatological hospital on predetermined days were given the 12-item General Health Questionnaire. The dermatologists indicated the diagnosis and location of skin lesions and rated the disease severity. A total of 1389 patients were asked to take part in the study. Of the 722 who accepted, 389 had a complete set of data and were included in the analysis. To verify the representativeness of our sample, we used the administrative registries to compare participants with the total population of patients who attended the clinics during the same period, and we examined the distribution of missing data. There was a tendency towards a younger age in the sample studied, but no evidence of substantial selection bias. The prevalence of psychiatric morbidity was 20.6%. We found higher probability of psychiatric disorders in women, controlling for age, clinical severity and localization of lesions. In women, but not in men, the prevalence of psychiatric morbidity was higher in patients with lesions on the face or hands. Given that the identification and appropriate management of psychiatric morbidity are important, it seems that the dermatologist should be particularly alert to the possibility of a concurrent psychiatric disorder in women with lesions on the face or hands.

Summary Background and objective Situations may occur in anaesthetic practice where the use of neuromuscular blocking drugs is unsuitable or contraindicated. We investigated the use of propofol given 5 min after fentanyl to permit endotracheal intubation in children. Methods We studied the intubating conditions and cardiovascular parameters in 60 ASA I and II children. Intravenous midazolam (0.1 mg kg−1) was given as premedication 5 min before the induction of anaesthesia. The children received different doses of propofol (group I, 2.5 mg kg−1; group II, 3.0 mg kg−1; group III, 3.5 mg kg−1) preceded by fentanyl (3.0 µg kg−1) given 5 min earlier. No neuromuscular blocking agents were administered. The intubating conditions were assessed using a four-point scoring system based on the degree of difficulty of laryngoscopy, the position of vocal cords and the intensity of coughing. Results Tracheal intubating conditions were adequate in 20% of the patients in group I, in 75% of the patients in group II and in 80% of the patients in group III (P

In all industrial countries, the number of elderly patients who need dialysis has increased in recent years. In the present study, we retrospectively analyzed two different age groups of nondiabetic peritoneal dialysis patients treated at the same unit by the same team of physicians and nurses with the same protocols. However, our purpose was to study possible differences in technique and survival rates, causes of dropout, complications, hospitalization rate, and everyday needs between the two groups. The results of 63 consecutive nondiabetic patients older than 70 years treated with continuous ambulatory peritoneal dialysis (CAPD) were compared with those of 86 nondiabetic patients aged 40 to 60 years treated during the same period. Patient survival was significantly worse in the elderly patients, but the observed to expected survival ratio with respect to age was similar. Technique survival was comparable in the two groups. Total hospitalization was 5,501 days (32 d/yr) in the elderly patients and 4,511 days (18 d/yr; P < 0.05) in the younger group. The peritonitis rate was 0.52 episodes/patient-year in the elderly patients and 0.37 episodes/patient-year in the younger patients (P < 0.002). The exit site infection rate was similar in the two groups (0.30 episodes/yr v0.29 episodes/yr). Other complications related to CAPD did not differ between the elderly and younger patients. Rehabilitation and biochemical data after 1 year of CAPD were similar in the two groups of patients. After 1 year of treatment, 12% of the younger patients and 43% of the elderly patients (P < 0.005) needed a partner for dialysis. Twenty-nine of 39 (74%) of the elderly patients and 30 of 53 (57%) of the younger patients considered their lifestyle acceptable after 1 year of dialysis. Thirty-four of 39 (87%) of the elderly patients and 32 of 53 (60%) of the younger patients (P < 0.02) rated their physical and social state after rehabilitation as better or comparable to that they had before terminal uremia.

Application of evidence-based perioperative care protocols reduces complication rates, accelerates recovery and shortens hospital stay. Presently, there are no comprehensive guidelines for perioperative care for gastrectomy.An international working group within the Enhanced Recovery After Surgery (ERAS®) Society assembled an evidence-based comprehensive framework for optimal perioperative care for patients undergoing gastrectomy. Data were retrieved from standard databases and personal archives. Evidence and recommendations were classified according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system and were discussed until consensus was reached within the group. The quality of evidence was rated 'high', 'moderate', 'low' or 'very low'. Recommendations were graded as 'strong' or 'weak'.The available evidence has been summarized and recommendations are given for 25 items, eight of which contain procedure-specific evidence. The quality of evidence varies substantially and further research is needed for many issues to improve the strength of evidence and grade of recommendations.The present evidence-based framework provides comprehensive advice on optimal perioperative care for the patient undergoing gastrectomy and facilitates multi-institutional prospective cohort registries and adequately powered randomized trials for further research.

Systemic (gastrointestinal and skin) reactions to ingestion of nickel rich foods in patients with nickel allergic contact dermatitis characterize Systemic Nickel Allergy Syndrome (SNAS). The objective of the study was to describe the nosologic framework of the syndrome and to compare sensibility and specificity for SNAS diagnosis between two different low nickel diets - BraMa-Ni and the usually prescribed list of forbidden foods - along with patient adherence to diet. One hundred forty-five patients with suspected SNAS (by history and benefit from nickel dietary restrictions) were selected and orally challenged with nickel for a definite diagnosis. Specificity and sensibility of the diets were calculated in relation to the results of nickel challenges. The nosologic framework of SNAS was deduced from the clinical pictures of 98 patients with positive nickel challenge and characterized essentially by skin and gastrointestinal symptoms, whereas all other symptoms (dizziness, headache etc.) were never elicited by the oral nickel challenge. The specificity and sensibility of BraMa-Ni in detecting SNAS were significantly higher than the forbidden food list diet, with an excellent patient adherence. Therefore, BraMa-Ni diet can be prescribed for the treatment of the syndrome other than for the diagnosis, the gold standard of which remains the oral nickel challenge.

Aims and Background Screening by mammography has been shown to be effective in reducing breast cancer mortality. We present the results of a mammographic and clinical screening program carried out in an Italian health district. Methods The first screening round started in June 1987 and ended in July 1990, and 25,100 women between the age of 50 and 60 years were invited. The second screening round invited 34,332 women between the age of 50 and 64 years and was carried out from September 1990 to September 1993. Women with positive or equivocal results at palpation or mammography were referred for immediate diagnostic assessment followed by surgery, when required. Results The attendance rate was 67.3% at the first and 62.1% at the repeat screening. At the first screening, 206 biopsies were advised and 197 were performed; 129 of the 197 were found to be malignant. At repeat screening, 248 biopsies were recommended, 208 were performed, and 125 were found to be malignant. The cancer detection rate was 7.7 per thousand at the first and 5.9 per thousand at repeat screening. Of 129 cancers, 107 (83.0%) were T1 at first screening; 6.2% were in situ carcinomas. Axillary lymph nodes were histologically positive in 24% of cases. At repeat screening, 77.6% (97/125) of cancers were T1; 11.2% were in situ carcinomas. Positive axillary lymph nodes were found in 16.8% of cases. Conclusions The attendance to screening was satisfactory. A higher frequency of small tumors (83.0%) was found at first screening than before the introduction of screening (56.6%). A marked difference in lymph node positivity (24.0% vs 40.6% in the pre-screening era) was also observed. Such a difference was even more evident at repeat screening. Quality standards of the screening in our study proved to be higher than those currently recommended. The reported results are encouraging, also considering the greater chance for conservative treatment.

This experimental study was conducted on 14 volunteer female clerks to measure viewing distance variation and related ophthalmological changes in office activities with (session 1) and without (session 2) VDU. A video camera connected to an electronic elaborator was used to determine eye-screen distance of the VDU operators during the task. Before and after each of the two work sessions far refraction, far phorias, near point of accommodation (APP), and fusional convergence were measured. Blinking rate of each subject was measured by a transducer only during the "VDU session'. The objective measurements of the eye-screen distance, whose range was between 48.42 and 65.33 cm, allowed a precise quantification of the occupational visual load during session 1. The accommodation was about 1.5-2D on average and the fusional convergence 10-13 delta on average. The symptomatology shows a number of disturbances in session 1 (71.4%) clearly higher than in session 2 (35.7%). The study of refraction before and after the task has shown a slight excess of accommodation compared to the theoretical value in both sessions, more marked in session 1. The APP shows no statistical significative variation. A tendency to exophoria was registered at the beginning and at the end of the trial and the fusional convergence clearly decreased, especially in the first session.

A multicentre prospective study was performed to estimate the incidence of hospital infections and to identify the most relevant risk factors for sepsis in a large and unselected population of high-risk newborns. The study involved 49 neonatal intensive care units and 17 neonatal intermediate care units in Italy. Newborns were followed up from admittance to the units until discharge. Data on demographics and clinical characteristics, exposure to the principal invasive procedures, and onset of infectious complications were prospectively collected. Only infections developing after 48 h from admittance to the unit were recorded. A multiple logistic regression was performed to identify which factors were independently associated with sepsis. Among the 8263 newborns included in the analysis, the incidence of infected newborns was 14.4 per 100 newborns and 0.9/100 days of stay. The incidence of infections was 19.1/100 newborns and 1.2/100 days of stay. Sepsis represented 15.4% of all infections (incidence 2.9/100 newborns and 0.2/100 days of stay). The following factors were independently associated with sepsis: umbilical catheterization, both through the vein and the artery for more than 5 days; mechanical ventilation for more than 5 days; necrotizing enterocolitis; birth weight equal to or less than 2500 g; nasogastric tube; total parenteral nutrition; and transfer from other hospitals. Umbilical catheters accounted for the highest proportion of sepsis (62%), followed by arterial catheters (31%), nasopharyngeal cannulae (26%), tracheal cannulae (20%), and nasal cannulae (20%). The population attributable risk for the other procedures was less than 10%. This study demonstrates that in a large and unselected newborn population, several host factors and invasive procedures are independently associated with an increased risk of sepsis. After adjustment for clinical severity, intravascular catheterization and assisted ventilation were found to be responsible for a considerable proportion of observed sepsis. They shoudl therefore be considered as priorities for interventions, aimed both at reducing unnecessary use and promoting more strict compliance with aseptic practices.

Environmental dust from animal breeding facilities was never screened for the presence of enterococci, nor of vancomycin-resistant enterococci (VRE), despite the possibility of being a vehicle of transmission of strains and antibiotic resistance genes between food-producing animals and man. Bio-security measures in pig facilities include disinfection with biocides to avoid the dissemination of opportunistic pathogenic bacteria, namely enterococci and in particular VRE. We thus undertook collection of enterococci and VRE in a representative number of breeding pig facilities in Portugal (n=171) and analyzed their susceptibility to benzalkonium chloride (BC) and chlorhexidine (CHX). A prevalence of 15% of VRE was found, with 6% high-level resistance found, and MIC values for CHX and BC were similar to those commonly found among enterococcal isolates from related environments, 8 μg/ml and 4 μg/ml, respectively. Among the isolated high-level vancomycin resistant Enterococcus faecium carrying the vanA genotype, we found multilocus sequence types closely related to pig and human isolates from European countries and Brazil. These results strongly advise constant surveillance of this environment and its inclusion in future epidemiologic studies on VRE.

Our aims were to (1) assess the corticospinal tracts (CSTs) in infants with focal injury and healthy term controls using probabilistic tractography and (2) to correlate the conventional magnetic resonance imaging (MRI) and tractography findings in infants with focal injury with their later motor function.We studied 20 infants with focal lesions and 23 controls using MRI and diffusion tensor imaging. Tract volume, fractional anisotropy (FA), apparent diffusion coefficient (ADC) values, axial diffusivity and radial diffusivity (RD) of the CSTs were determined. Asymmetry indices (AIs) were calculated by comparing ipsilateral to contralateral CSTs. Motor outcome was assessed using a standardized neurological examination.Conventional MRI was able to predict normal motor development (n = 9) or hemiplegia (n = 6). In children who developed a mild motor asymmetry (n = 5), conventional MRI predicted a hemiplegia in two and normal motor development in three infants. The AIs for tract volume, FA, ADC and RD showed a significant difference between controls and infants who developed a hemiplegia, and RD also showed a significant difference in AI between controls and infants who developed a mild asymmetry.Conventional MRI was able to predict subsequent normal motor development or hemiplegia following focal injury in newborn infants. Measures of RD obtained from diffusion tractography may offer additional information for predicting a subsequent asymmetry in motor function.

Individual calibration (IC) for caries detection methods based on fluorescence is time-consuming, especially for paediatric dentists, if the calibration has to be performed tooth-by-tooth. However, it is not clear how this calibration actually interfere in laser fluorescence (LF) readings.This in vivo study was to verify the influence of different modes of IC on laser fluorescence (LF) readings.Ninety six occlusal and 95 buccal surfaces of 1st permanent molars were examined using LF device after IC performed on control (no IC), the examined teeth, a permanent incisor, a 1st primary molar or a 2nd primary molar. All modes of IC were performed in the same child. Wilcoxon test and Bland-Altman analysis were used to compare the readings. Intraclass correlation coefficients (ICC) were calculated.Laser fluorescence readings without prior calibration were higher than readings performed after any mode of IC and resulted in different values of ICC. After other IC modes, the LF readings were statistically similar.The absence of IC influences LF readings and LF reproducibility, but different IC methods can be considered in clinical practice.