Midazolam vs diazepam in prolonged seizures in children: A pharmacoeconomic approach.

OBJECTIVE: A previous European cost-utility study reported that use of buccal midazolam in the community setting for the treatment of prolonged seizures (ie, seizures lasting ≥5 minutes) in children was associated with an overall €12 507 399 reduction in annual costs charged to the Italian national health service compared with rectal diazepam. We re-evaluated these findings by applying a more conservative approach. METHODS: The Italian Delphi panel reconvened to apply a more conservative assessment of available reports. A decision-tree model was used, allowing for different treatment pathways depending on whether or not a caregiver administers treatment, an ambulance is required for transport of the child to hospital, and an inpatient stay is required. Direct medical costs were derived from Italian healthcare system data. Estimates of the annual number of prolonged tonic-clonic seizures expected in the country were based on studies which assessed seizure duration using video-EEG recordings and medical records. RESULTS: Although drug acquisition costs were greater for buccal midazolam than for rectal diazepam, the acquisition cost difference was outweighed by larger cost savings resulting mostly from a reduction in hospital admissions. Assuming that 1.2% of tonic and/or clonic seizures occurring in children and adolescents over a 12-month period are prolonged, the annual nationwide reduction in costs from preferring buccal midazolam to rectal diazepam was estimated at €3 577 587.9. CONCLUSIONS: In this more conservative revised analysis, the high cost of buccal midazolam is still counteracted by greater cost savings compared with rectal diazepam, but cost reduction was less than previously estimated.

Bacille Calmette-Guérin/DNAhsp65 prime-boost is protective against diabetes in non-obese diabetic mice but not in the streptozotocin model of type 1 diabetes.

Type I diabetes is a disease caused by autoimmune destruction of the beta cells in the pancreas that leads to a deficiency in insulin production. The aim of this study was to evaluate the prophylactic potential of a prime-boost strategy involving bacille Calmette-Guérin (BCG) and the pVAXhsp65 vaccine (BCG/DNAhsp65) in diabetes induced by streptozotocin (STZ) in C57BL/6 mice and also in spontaneous type 1 diabetes in non-obese diabetic (NOD) mice. BCG/DNAhsp65 vaccination in NOD mice determined weight gain, protection against hyperglycaemia, decreased islet inflammation, higher levels of cytokine production by the spleen and a reduced number of regulatory T cells in the spleen compared with non-immunized NOD mice. In the STZ model, however, there was no significant difference in the clinical parameters. Although this vaccination strategy did not protect mice in the STZ model, it was very effective in NOD mice. This is the first report demonstrating that a prime-boost strategy could be explored as an immunomodulatory procedure in autoimmune diseases.

Experimental autoimmune encephalomyelitis evolution was not modified by multiple infections with Strongyloides venezuelensis.

According to the hygiene hypothesis, the increased incidence of allergic and autoimmune diseases in developed countries is mainly explained by the decreased contact between the human population and certain environmental agents as lactobacillus, mycobacteria and helminths. In this study, we evaluated the effect of multiple infections with Strongyloides venezuelensis on the development of experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Multiple infections before EAE induction were not able to change the evolution of the disease. No alterations were observed in weight loss, clinical score and inflammation intensity at the central nervous system. The presence of significant levels of parasite-specific IgG1 but not IgG2b suggested a Th2 polarization. However, the percentage and absolute number of CD4+CD25+Foxp3+ T cells were not changed, being their levels in the spleen and lymph nodes of infected rats comparable to the ones found in normal animals. These results suggest that a Th2-polarized response without concomitant expansion of Foxp3+ regulatory T cells was not able to modify EAE progression. Even though these results do not threaten the hygiene hypothesis, they suggest that this paradigm might be an oversimplification. They also emphasize the need of a study to compare the immunoregulatory ability associated with different helminth spp.

Recovery from Strongyloides venezuelensis infection in Lewis rats is associated with a strong Th2 response.

In this study, we investigated the characteristics of the infection and subsequent immunity induced by Strongyloides venezuelensis in Lewis rats. Animals were infected with 4000 L3 of S. venezuelensis and number of eggs per gram of faeces indicated an acute phase around day 8 and a recovery phase around day 32 after infection. A strong Th2 polarization during recovery phase was ascertained by a significant increase in IgG1 and IgE compared with that in the acute period. A shift in the cytokine profile confirmed these findings. A predominant production of IFN-gamma during the acute phase was followed by IL-10 production during recovery. Together these findings show that experimental infection of Lewis rats with S. venezuelensis presents a kinetics of parasite establishment and immunity similar to that described in other models of helminthic infection.

Treatment of Wernicke's encephalopathy with high dose of thiamine in a patient with pyloric sub-stenosis: description of a case.

Wernicke's encephalopathy (WE) is an acute or subacute syndrome that results from a deficiency in vitamin B1 (thiamine). The syndrome is characterised by a classical triad of symptoms: nystagmus and ophthalmoplegia,mental-status changes, and unsteadiness of stance and gait. When patients with WE are inappropriately treated with low doses of thiamine, mortality rates average out at 20% and Korsakoff's Psychosis develops in about 85% of survivors(Sechi and Serra in Lancet Neurol 6(5):442­455,2007). We report the case of a patient with a pyloric substenosis that developed a WE, and was treated with high doses of thiamine showing after few days of treatment a great improvement of neurological and neuroradiological assessment, even though cognitive impairment was still severe at discharge and at 6 months follow-up.

Association of myelin peptide with vitamin D prevents autoimmune encephalomyelitis development.

Multiple sclerosis is a chronic, inflammatory and demyelinating disease of the central nervous system (CNS). As there is no cure for this disease, new therapeutic strategies and prophylactic measures are necessary. We recently described the therapeutic activity of the association between myelin oligodendrocyte glycoprotein peptide (MOG) and active vitamin D3 (VitD) against experimental autoimmune encephalomyelitis (EAE). The objective of this work was to evaluate the prophylactic potential of this association in EAE. C57BL/6 mice were vaccinated with MOG in the presence of VitD and then subjected to EAE induction. Animals were euthanized 7 and 19days after disease induction and the following parameters were evaluated: body weight, clinical score, inflammatory process in the CNS, amount of dendritic cells (DCs) and regulatory T cells in the spleen and cytokine production by spleen and CNS cell cultures. Vaccination with MOG associated with VitD determined a drastic reduction in clinical score, body weight loss, CNS inflammation, DCs maturation and also in the production of cytokines by CNS and spleen cell cultures. Collectively, our data indicate that this association prevents EAE development. A similar effect from specific self-antigens associated with VitD is expected in other autoimmune conditions and deserves to be experimentally appraised.

Acute Strongyloides venezuelensis infection did not prevent EAE development: implications for hygiene hypothesis.

Prevalence of allergic and autoimmune pathologies is clearly increasing in developed countries. This has been attributed to a decreased exposure to certain microorganisms and been referred as hygiene hypothesis. In this study we evaluated if a previous infection with Strongyloides venezuelensis would alter the progression of experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Animals were initially infected with 4000 L3 infective larvae of S. venezuelensis by subcutaneous route. Encephalomyelitis was then induced during the acute phase of the infection by immunization with myelin basic protein emulsified with Complete Freund's Adjuvant plus Mycobacterium butyricum. Previous infection downmodulated cytokine production but did not change clinical and histopathological EAE manifestations. Cytometric analysis with antibodies specific for CD4+CD25+Foxp3+ regulatory T cells indicated that infection also did not alter the frequency of these cells in spleen and regional lymph nodes. This finding could partly explain the failure of this worm to avoid EAE progression. Altogether these results demonstrated that infection with S. venezuelensis was not able to modify EAE progression in Lewis rats. In the context of the hygiene hypothesis, these results reinforce the necessity of a comparative study among different helminth species to identify the ones with immunoregulatory competence.

Effects of kidney-pancreas transplantation on atherosclerotic risk factors and endothelial function in patients with uremia and type 1 diabetes.

Cardiovascular disease and the development of coronary artery disease play a pivotal role in increasing mortality in patients with type 1 diabetes. The aim of our study was to evaluate the effects of pancreas transplantation on atherosclerotic risk factors, endothelial-dependent dilation (EDD), and progression of intima media thickness (IMT) in patients with uremia and type 1 diabetes after kidney-alone (KA) or kidney-pancreas (KP) transplantation. A cross-sectional study comparing two groups of patients with type 1 diabetes was performed. Sixty patients underwent KP transplantation and 30 patients underwent KA transplantation. Age and cardiovascular risk profile were comparable in patients before transplantation. In all patients, atherosclerotic risks factors (lipid profile, fasting and post-methionine load plasma homocysteine, von Willebrand factor levels, D-dimer fragments, and fibrinogen) were assessed and Doppler echographic evaluation of IMT and endothelial function with flow-mediated and nitrate dilation of the brachial artery was performed. Twenty healthy subjects were chosen as controls (C) for EDD. Compared with patients undergoing KA transplantation, patients undergoing KP transplantation showed lower values for HbA1c (KP = 6.2 +/- 0.1% vs. KA = 8.4 +/- 0.5%; P < 0.01), fasting homocysteine (KP = 14.0 +/- 0.7 mcromol/l vs. KA = 19.0 +/- 2.0 micromol/l; P = 0.02), von Willebrand factor levels (KP = 157.9 +/- 8.6% vs. KA = 212.5 +/- 16.2%; P < 0.01), D-dimer fragments (KP = 0.29 +/- 0.02 microg/ml vs. KA = 0.73 +/- 0.11 microg/ml;P < 0.01), fibrinogen (KP = 363.0 +/- 11.1 mg/dl vs. KA = 397.6 +/- 19.4 mg/dl; NS), triglycerides (KP = 122.7 +/- 8.6 mg/dl vs. KA = 187.0 +/- 30.1 mg/dl; P = 0.01), and urinary albumin excretion rate (KP = 13.5 +/- 1.9 mg/24 h vs. KA = 57.3 +/- 26.3 mg/24 h; P < 0.01). Patients undergoing KP transplantation showed a normal EDD (KP = 6.21 +/- 2.42%, KA = 0.65 +/- 2.74%, C = 8.1 +/- 2.1%; P < 0.01), whereas no differences were observed in nitrate-dependent dilation. Moreover, IMT was lower in patients undergoing KP transplantation than in patients undergoing KA transplantation (KP = 0.74 +/- 0.03 mm vs. KA = 0.86 +/- 0.09 mm; P = 0.04). Our study showed that patients with type 1 diabetes have a lower atherosclerotic risk profile after KP transplantation than after KA transplantation. These differences are tightly correlated with metabolic control, fasting homocysteine levels, lower D-dimer fragments, and lower von Willebrand factor levels. Normal endothelial function and reduction of IMT was observed only in patients undergoing KP transplantation.

Electroencephalographic background desynchronization during cerebral blood flow reduction.

OBJECTIVE: The aim of this study is to evaluate the usefulness of a spectral function detecting cerebral hypoperfusion. METHODS: Continuous electroencephalographic monitoring was employed during 47 consecutive carotid endarterectomies. Patients were assigned to 3 different groups according to the entity of electroencephalographic changes during carotid clamping (major changes: group A; moderate changes: group B; no change: group C). The desynchronization function, indicating the reduction of the 8-15 Hz band power, and the desynchronization index were calculated. RESULTS: Group A function decreased within 20s from clamping, with a constant slope (7.14). Desynchronization indexes were: 76.85% (group A), 40.23% (group B) and 15.29% (group C). Difference among groups was statistically significant (P < 0.0001). A case of syncope due to asystole is also reported, showing the same pattern in the descending phase of the function. CONCLUSIONS: The stereotyped time course of the desynchronization function describes the cerebral reaction to significant blood flow reduction. Values of desynchronization index exceeding 65% seem to correctly detect patients with cerebral hypoxic risk. SIGNIFICANCE: The analysis of the 8-15 Hz band desynchronization is helpful in the evaluation of cerebral hypoperfusion during carotid endarterectomy. This method could be employed in monitoring different clinical situations of ischemia.

Cognitive processes in insulin-dependent diabetes.

Cognitive processes in a group of neurologically asymptomatic patients with relatively severe but uncomplicated insulin-dependent diabetes mellitus (IDDM) were studied. In comparison with a homogeneous group of normoglycemic controls, the diabetic group performed significantly worse in global memory, abstract reasoning, and eye-hand coordination tests. The two groups scored similarly in intelligence, concentration and attention, spatial, visual, and psychomotor tests. The neuropsychological deficits did not correlate with the duration or the severity of the disease. Whether these mild neuropsychological deficits are transient or stable or whether they are caused by central nervous system vascular or metabolic dysfunctions or by the emotional influence of the chronic illness on the intellectual and educational development of patients remains unclear. Our findings need to be cautiously interpreted and perhaps could not be extended to diabetic patients with better metabolic control.

Computer-assisted EEG monitoring during carotid endarterectomy.

The purpose of this study was to develop a reliable method of EEG analysis during carotid endarterectomy. EEGs of 104 patients under general anesthesia were processed by three different methods: a) "on-line" visual analysis during surgery, b) "off-line" visual analysis in laboratory, and c) computer analysis. To identify pathological EEGs, variability and asymmetry indexes of the 0.5-3.5 Hz and 8-15 Hz bands, absolute power and variability indexes of spectral edge frequency (SEF), and main dominant frequency were evaluated. On-line visual analysis showed clamp-related modifications in 29 EEGs (27.9%). Off-line visual analysis detected 24 pathological EEGs (23.1%): 18 with major changes and 6 with moderate changes. Computer analysis showed 21 EEGs (20.19%) with at least one altered index and 7 (6.7%) with altered variability for both SEF and 8-15 Hz power. The statistical analysis was significant for SEF variability and for 8-15 Hz power variability and asymmetry (P < 0.0001, analysis of variance test). While SEF and 8-15 Hz power variability did not appear influenced by anesthesia and single electrode artifacts, 8-15 Hz power asymmetry index was confounded by the presence of contralateral internal carotid occlusion. The data show that the use of these spectral indexes adds objective information to visual analysis, supporting and making easier intraoperative strategies. Their routine clinical use does not involve additional costs remaining technical requirements unchanged compared to traditional recording.

Prevention of left ventricular hypertrophy by ACE-inhibitor, ramipril in comparison with calcium-channel antagonist, felodipine.

This perspective study was performed to demonstrate the prevention of left ventricular hypertrophy by ACE-inhibitor, ramipril, in hypertensives of recent onset. Thirty-four hypertensive patients, treated with ramipril (group I), and 32 controls who received another frequently employed drug (the calcium channel-antagonist, felodipine (group II), were evaluated. Neither of two groups received any anti-hypertensive drug and did not suffer from left ventricular hypertrophy. All selected patients underwent M-mode echocardiography for measuring the following parameters: diastolic diameter of left ventricle, (DDLV); systolic diameter of left ventricle (SDLV); inter-ventricular septum (IVS); thickness of the posterior wall (PW); and left ventricular mass index (LVMI). Two anti-hypertensive drugs reduce systemic hypertension the same way. But, in hypertensives receiving ramipril (group I), the echocardiographic parameters of the left ventricle increased non-significantly. On the other hand, in those treated with felodipine (II group), these parameters significantly changed. The mechanisms of non-increase in cardiac and non-cardiac proteins, due to the ACE-inhibitors, are illustrated.

Analysis of temporal non-stationarities in EEG signals by means of parametric modelling.

A method for the analysis of variability of EEG signals is described. We examined simulated signals and real EEGs obtained from a normal subject and two epileptic patients. The first step of the method is based on autoregressive (AR) modelling of short EEG epochs. Prediction coefficients of the AR model were computed as a function of time from partially-overlapping moving windows of 2 s duration. The temporal behaviour of these coefficients was analysed to detect variability: quasi-stationary activity causes only smooth changes in the coefficients while variations in the amplitude and/or the frequency content of the signal are shown to produce sharp changes in the coefficients. A segmentation algorithm was developed to detect and quantify with a numerical value (Difference Measure, DM) the AR coefficients variations.

Status epilepticus.

Status epilepticus (SE) is a medical emergency. It requires prompt and adequate diagnosis and treatment, as it may induce CNS injury. It is mainly distinguished into generalised and partial SE on the basis of its major clinical features. There are very few data about SE physiopathology, but it is generally characterised by increasing unresponsiveness to treatment. SE diagnosis is based on EEG recording, associated with neuroimaging techniques and laboratory assays to detect underlying pathologies. During SE we distinguish three different conditions: initial, defined and refractory. Benzodiazepines represent first-line treatment, followed by phenytoin. Refractory SE requires ICU treatment to perform general anaesthesia.

The role of transcranial Doppler in carotid artery surgery.

In order to evaluate the usefulness of transcranial Doppler (TCD) in carotid artery surgery, 90 patients who underwent carotid endarterectomy were studied. Transcranial Doppler was performed preoperatively with digital compression of the carotid artery and intraoperatively at the time of cross-clamping, together with routine EEG monitoring. The percentage residual middle cerebral artery velocity (%MCAV) during carotid artery compression or cross-clamping was considered. The intraoperative %MCAV at cross-clamping was compared with the values obtained in the preoperative examination during the compression test and with the EEG data; the EEG records were blindly reviewed by a neurologist and divided into three groups: group A, normal; group B, moderate anomalies and group C, major anomalies. There were no significant differences between preoperative %MCAV (compression test) and intraoperative %MCAV (cross-clamping) by separate analysis of the data related to systolic, diastolic and mean velocity. The systolic, diastolic, mean %MCAV and the Gosling index after cross-clamping were then compared with the EEG data: no significant differences were seen between groups A and B; on the other hand, in all patients with major EEG anomalies (group C) the %MCAV at TCD was reduced to 0. In conclusion, preoperative TCD associated with carotid artery compression appears a safe and useful way of identifying patients at risk of cerebral ischaemia during carotid artery cross-clamping. Patients with no residual flow at intraoperative TCD need to be considered as presenting a very high risk of ischaemia and in this group the use of a shunt is mandatory.

FFT approximation in Alzheimer's disease.

The electroencephalographic modifications that occur during the course of Alzheimer's disease are characterised by an increase in the potential of low frequency bands, a diminution in the potential of alpha activity, and a change in the topographical distribution of the potential of all band frequencies. In this study, the fast Fourier transform (FFT) approximation was used to characterise modifications in the electroencephalogram location or orientation of the source of the dipole equivalent of the delta, theta, alpha1, alpha2, beta1 and beta2 frequencies in 20 with patients with Alzheimer's disease and in a control group of 20 age-matched subjects. A statistical (t-test) comparison of the two groups revealed a significant change in the location of the dipolar source along the vertical axis in 18 (90%) of the patients; this change involved all the frequency bands. There was also a significant movement of the dipolar source of the alpha1 band towards the anterior regions. In addition, the control group showed that there was a significant correlation between age and a more surface expression of the source of the delta, theta, alpha1 and beta1 bands.

Signs of cardiac autonomic dysfunction during sleep in patients with Alzheimer's disease.

Autonomic nervous system (ANS) failure may be an important complication in some neurological diseases. Conventional tests for the assessment of ANS functions during wakefulness cannot be used for many patients with dementia of the Alzheimer's type (DA) because of their poor cooperation. In 6 of 16 patients with presenile DAT we found signs of sympathetic cardiac dysfunction during sleep, measured as the decrease in body movement-related heart rate variation (Rbm). The study of Rbm during sleep seems to be a useful tool for ascertaining ANS function in DAT. The presence or absence of ANS dysfunction could be a more reliable criterion than age of onset for identifying subgroups of this disease.

Increased interictal cerebral glucose metabolism in a cortical-subcortical network in drug naive patients with cryptogenic temporal lobe epilepsy.

Positron emission tomography with [18F]-2-fluoro-2-deoxy-D-glucose ([18F]FDG) has been used to assess the pattern of cerebral metabolism in different types of epilepsies. However, PET with [18F]FDG has never been used to evaluate drug naive patients with cryptogenic temporal lobe epilepsy, in whom the mechanism of origin and diffusion of the epileptic discharge may differ from that underlying other epilepsies. In a group of patients with cryptogenic temporal lobe epilepsy, never treated with antiepileptic drugs, evidence has been found of significant interictal glucose hypermetabolism in a bilateral neural network including the temporal lobes, thalami, basal ganglia, and cingular cortices. The metabolism in these areas and frontal lateral cortex enables the correct classification of all patients with temporal lobe epilepsy and controls by discriminant function analysis. Other cortical areas--namely, frontal basal and lateral, temporal mesial, and cerebellar cortices--had bilateral increases of glucose metabolism ranging from 10 to 15% of normal controls, although lacking stringent statistical significance. This metabolic pattern could represent a pathophysiological state of hyperactivity predisposing to epileptic discharge generation or diffusion, or else a network of inhibitory circuits activated to prevent the diffusion of the epileptic discharge.