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Objective. In this contribution we present a special Fano test for charged particles in presence of magnetic fields in the MC code TOol for PArticle Simulation (TOPAS), as well as the determination of magnetic field correction factorskBfor Farmer-type ionization chambers using proton beams.Approach. Customized C++ extensions for TOPAS were implemented to model the special Fano tests in presence of magnetic fields for electrons and protons. The Geant4-specific transport parameters,DRoverRandfinalRange,were investigated to optimize passing rate and computation time. ThekBwas determined for the Farmer-type PTW 30013 ionization chamber, and 5 custom built ionization chambers with same geometry but varying inner radius, testing magnetic flux density ranging from 0 to 1.0 T and two proton beam energies of 157.43 and 221.05 MeV.Main results. Using the investigated parameters, TOPAS passed the Fano test within 0.39 ± 0.15% and 0.82 ± 0.42%, respectively for electrons and protons. The chamber response (kB,M,Q) gives a maximum at different magnetic flux densities depending of the chamber size, 1.0043 at 1.0 T for the smallest chamber and 1.0051 at 0.2 T for the largest chamber. The local dose differencecBremained ≤ 0.1% for both tested energies. The magnetic field correction factorkB, for the chamber PTW 30013, varied from 0.9946 to 1.0036 for both tested energies.Significance. The developed extension for the special Fano test in TOPAS MC code with the adjusted transport parameters, can accurately transport electron and proton particles in magnetic field. This makes TOPAS a valuable tool for the determination ofkB. The ionization chambers we tested showed thatkBremains small (≤0.72%). To the best of our knowledge, this is the first calculations ofkBfor proton beams. This work represents a significant step forward in the development of MRgPT and protocols for proton dosimetry in presence of magnetic field.

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Alterations of the visual evoked potential (VEP) component P1 at the occipital region represent the most extended functional references of early visual dysfunctions in schizophrenia (SZ). However, P1 deficits are not reliable enough to be accepted as standard susceptibility markers for use in clinical psychiatry. We have previously reported a novel approach combining a standard checkerboard pattern-reversal stimulus, spectral resolution VEP, source detection techniques and statistical procedures which allowed the correct classification of all patients as SZ compared to controls. Here, we applied the same statistical approach but to a single surface VEP - in contrast to the complex EEG source analyses in our previous report. P1 and N1 amplitude differences among spectral resolution VEPs from a POz-F3 bipolar montage were computed for each component. The resulting F-values were then Z-transformed. Individual comparisons of each component of P1 and N1 showed that in 72% of patients, their individual Z-score deviated from the normal distribution of controls for at least one of the two components. Crossvalidation against the distribution in the SZ-group improved the detection rate to 93%. In all, six patients were misclassified. Clinical validation yielded striking positive (78.13%) and negative (92.69%) predictive values. The here presented procedure offers a potential clinical screening method for increased susceptibility to SZ which should then be followed by high density electrode array and source detection analyses. The most important aspect of this work is represented by the fact that this diagnostic technique is low-cost and involves equipment that is feasible to use in typical community clinics.

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Basic visual dysfunctions are commonly reported in schizophrenia; however their value as diagnostic tools remains uncertain. This study reports a novel electrophysiological approach using checkerboard visual evoked potentials (VEP). Sources of spectral resolution VEP-components C1, P1 and N1 were estimated by LORETA, and the band-effects (BSE) on these estimated sources were explored in each subject. BSEs were Z-transformed for each component and relationships with clinical variables were assessed. Clinical effects were evaluated by ROC-curves and predictive values. Forty-eight patients with schizophrenia (SZ) and 55 healthy controls participated in the study. For each of the 48 patients, the three VEP components were localized to both dorsal and ventral brain areas and also deviated from a normal distribution. P1 and N1 deviations were independent of treatment, illness chronicity or gender. Results from LORETA also suggest that deficits in thalamus, posterior cingulum, precuneus, superior parietal and medial occipitotemporal areas were associated with symptom severity. While positive symptoms were more strongly related to sensory processing deficits (P1), negative symptoms were more strongly related to perceptual processing dysfunction (N1). Clinical validation revealed positive and negative predictive values for correctly classifying SZ of 100% and 77%, respectively. Classification in an additional independent sample of 30 SZ corroborated these results. In summary, this novel approach revealed basic visual dysfunctions in all patients with schizophrenia, suggesting these visual dysfunctions represent a promising candidate as a biomarker for schizophrenia.

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A neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), occurs in some older men carrying a small CGG repeat expansion (pre-mutation) in the FMR1 gene. We surveyed a sample of older pre-mutation males to estimate the prevalence and spectrum of neurological involvement. Twelve pre-mutation males aged 50-82 years and 11 age-matched normal controls ascertained in an unbiased manner were included in a neurological assessment that also used standard scales for tremor (Clinical Rating Scale for Tremor), ataxia (International Cooperative Ataxia Rating Scale, ICARS) and parkinsonian signs (Unified Parkinson's Disease Rating Scale). Axial FLAIR images of the brain, and neuropsychological and molecular tests were also conducted in pre-mutation carriers. The neurological disorder meeting all the criteria for diagnosis of 'definite' to 'possible' FXTAS occurred in five of 12 pre-mutation carriers (41.7%), and this prevalence was significantly higher compared with normal controls (0%). The ataxia (ICARS) score and the sum of all three tremor/ataxia scores were significantly higher in pre-mutation carriers than in controls, and mRNA was elevated in all but one carrier, but did not correlate with the degree of neurological involvement. In conclusion, the findings provide further evidence that the pre-mutation allele of FMR1 is a significant cause of late-onset neurodegeneration, presenting with a broad spectrum of clinical manifestations.

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Múltiples investigaciones han demostrado que los pacientes esquizofrénicos presentan déficits cognoscitivos, entre ellos trastornos de la atención. Interesados en este aspecto se hizo una revisión de la literatura que ha utilizado el componente P300 de los potenciales relacionados a eventos para evaluar las funciones cognoscitivas en pacientes esquizofrénicos. Se comparan con los resultados obtenidos en el estudio realizado en el Hospital Clínico-quirúrgico Hermanos Amejeiras de la República de Cuba en 20 pacientes esquizofrénicos paranoides (DSM IV) comparados con 20 sujetos normales, encontrándose diferencias estadísticamente significativas en la latencia y amplitud del P300, p:<0.0001(AU)

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Múltiples investigaciones han demostrado que los pacientes esquizofrénicos presentan déficits cognoscitivos, entre ellos trastornos de la atención. Interesados en este aspecto se hizo una revisión de la literatura que ha utilizado el componente P300 de los potenciales relacionados a eventos para evaluar las funciones cognoscitivas en pacientes esquizofrénicos. Se comparan con los resultados obtenidos en el estudio realizado en el Hospital Clínico-quirúrgico ®Hermanos Amejeiras¼ de la República de Cuba en 20 pacientes esquizofrénicos paranoides (DSM IV) comparados con 20 sujetos normales, encontrándose diferencias estadísticamente significativas en la latencia y amplitud del P300, p:<0.0001

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OBJECTIVE: To quantify serum protein levels and protein-binding of methadone in vitro in heroin-addicted patients showing objective signs of heroin abstinence. SUBJECTS AND METHODS: Serum samples were obtained from patients (n = 27) hospitalized to participate in a methadone detoxification program and from healthy volunteers (n = 21). The severity of the abstinence syndrome was assessed before blood sampling using a standardized scale. Concentrations of both albumin and alpha1-acid glycoprotein (AAG) were measured in all serum samples. The protein-binding of alpha1-methadone was determined by the ultrafiltration technique and the unbound concentration was measured by liquid scintillation counting. RESULTS: The mean of the AAG concentrations was significantly increased in patients showing signs of withdrawal while the albumin concentrations did not change. Also, the unbound methadone was significantly decreased in this group when compared to the control. A positive correlation (Pearson r = 0.48; p < 0.005) indicates that AAG levels rise during abstinence as the score of withdrawal symptoms increases. Additionally, pooled data from all individuals show the binding of methadone to be related to AAG (r = 0.46; p < 0.05) levels and not to albumin. CONCLUSIONS: The observed changes in protein-binding in abstinence individuals suggest the need for increased dosages of methadone when such patients are treated. Levels of AAG or protein-binding appear to be components of the interindividual variance observed in the response to methadone treatment, hence these variables could be included in future kinetic and dynamic studies.

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Based on a retrospective study, we report the clinical and electrophysiological characteristics of 62 cases of effort-induced atrio-ventricular block (AVB). The diagnosis of effort-induced AVB was established by stress test and/or Holter ECG. This series consisted of 18 women and 44 men with a mean age of 64 +/- 13 years. AVB presented in the form of poor adaptation to effort in 41 patients (66%), fainting and/or presyncope suggestive of Stokes-Adams attacks in 20 patients (32%), associated with poor adaptation to effort, except in 5 patients. 48 patients (77%) did not have any underlying heart disease. The ECG was normal in 25 patients (40%) or abnormal, demonstrating a 1st degree AVB and/or an intraventricular conduction disorder. On electrophysiological investigation, the AVB was type II (Mobitz II) in 48 patients (77%), generally 2/1. The block was infranodal, either in or below the His bundle, in 56 patients (90%). When it was situated above the His bundle, it was organic and degenerative, situated at the AV node, at the node-His junction, or even proximally in the His bundle. Effort-induced AVB implies DDD atrioventricular stimulation. The presence of this anomaly should be investigated in patients with poor adaptation to effort, but also when the clinical picture is dominated by Stokes-Adam attacks.

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In order to study the corrective effects of thyroxine (T4) on functional abnormalities induced by congenital hypothyroidism, small doses of T4 were injected to propylthiouracil-treated (PTU-treated) rat pups for 2 consecutive days on selected periods of development (days 3 and 4, 6 and 7, 9 and 10, 12 and 13, 18 and 19). Some animals also received thyroid replacement therapy from days 12 to 17. The animals were tested electrophysiologically on day 30, by recording the compound action potential and the cochlear microphonic from the round window after click and tone burst stimulation. PTU-treated animals given T4 for 2 consecutive days demonstrated both AP and CM threshold shifts. On the contrary, PTU-treated animals given T4 from days 12 to 17 demonstrated a normal CM output of the cochlea, but still showed elevated AP thresholds. These results are discussed with previous data concerning the corrective effects of T4 on cochlear structures in PTU-treated rats previously described.

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In order to study the long-term effects of neonatal hypothyroidism on the organ of Corti, rats were given propylthiouracil (PTU) during the first 30 days after birth. Cochlear changes occurring after the cessation of antithyroid treatment were studied by both physiological (brainstem auditory evoked responses: BAERs, electrocochleography) and morphological techniques (transmission and scanning electron microscopy). The first appearance of BAERs was noted between days 37 and 45. Maturation of auditory potentials was achieved within 10-15 days but was incomplete since the animals definitely demonstrated elevated thresholds around 60-70 dB SPL. Morphological results indicated that some structures, like the inner sulcus epithelium, were able to restart maturational processes that had been interrupted during the period of hypothyroidism. However, these maturational changes were considerably limited and rapidLy accompanied by severe degenerative changes involving almost all cochlear structures. Degenerative changes included the deposition of an amorphous substance within the organ of Corti, severe alterations in pillar cells (absence of formation of the tunnel of Corti, distortion of microtubules), severe outer hair cell losses with abnormalities in their innervation (absence of development of efferents and loss of afferent dendrites).

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The Gunn rat which develops neonatal hyperbilirubinemia has been used as an experimental model to evaluate the effect of bilirubin on the auditory system. Electrocochleographic and morphological studies (including light microscopy, surface preparations and transmission electron microscopy) did not reveal any cochlear abnormality in homozygous Gunn rats. Brainstem auditory evoked potentials showed morphological and amplitude changes suggesting a functional damage in the brainstem auditory pathways. These results suggest that hearing loss, when observed in kernicterus, is primarily due to neuronal damage at the level of brainstem auditory nuclei.

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The comparative ototoxicity of four aminoglycosides (amikacin, dibekacin, gentamicin and tobramycin) was evaluated in the rat during the critical period of cochlear development. Newborn rats received a daily subcutaneous injection of one of the four antibiotics for 8 consecutive days, starting on day 8 after birth (amikacin: 225 mg/kg, dibekacin: 60 mg/kg, gentamicin and tobramycin: 45 mg/kg). Evaluation of ototoxicity was assessed one month after the end of the treatment using cochlear recordings (action potential and cochlear microphonic), surface preparations and scanning electron microscopy. No functional or structural evidence of ototoxicity was found in animals treated with dibekacin. Tobramycin had a weak ototoxic effect characterized by a slight increase in N1 latency and moderate damage to OHC stereocilia (fusion and formation of giant cilia). Gentamicin-treated animals demonstrated more severe evidence of ototoxicity including increased thresholds for CM, and a higher incidence of missing hair cells and damage to OHC stereocilia. The maximal cochlear damage was observed in amikacin-treated animals: both AP and CM thresholds were severely impaired, cell counts and SEM showed extensive loss of hair cells.

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Previous works have demonstrated that mammals are more susceptible to aminoside ototoxicity during the period of auditory development. In order to test the intrauterine ototoxicity of dibekacin, an experiment was designated in pregnant guinea pigs intoxicated during the last three weeks of gestation (100, 60 and 30 mg/kg for 8 days). Newborn guinea pigs were tested electrophysiologically by recording cochlear potentials from the round window in response to filtered clicks of various frequency. No fetal ototoxicity due to dibekacin could be detected in the 36 animals tested. This study indicates that dibekacin has a very low ototoxic effect, even during the period of increased sensitivity to antibiotics. Comparatively, kanamycin has a major ototoxic effect when it is administrated at the same dosage during the same period of time.

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The development of cochlear function was studied in 81 rat pups by recording the cochlear microphonic (CM) and the compound action potential (AP) from the round window in response to tone bursts and filtered clicks of various frequencies. The first electrophysiological response was the CM which could be obtained from 8- to 9-day-old animals. The AP first appeared at 11-12 days. As development progressed, cochlear potentials showed systematic changes in response parameters: the amplitude and threshold sensitivity of both CM and AP increased progressively with age as N1 latency decreased. All the parameters were within the adult range by the 15th day for the CM and by the 4th week for the AP. The results are discussed in relation to the developmental changes in the middle ear and to the morphological maturation of the organ of Corti.

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Auditory brainstem potentials were recorded in 54 old adult subjects ranging in age from 61 to 89 years. Attention was paid to interwave latencies in order to assess the effects of aging on central conduction time. The data were compared to those obtained in 41 young adult subjects. Advancing age resulted in a slight-prolongation of I-III, III-V and I-V interpeak latencies when compared to young adult subjects (about 0.2 ms); nevertheless there were no statistical differences between the mean values of old and young subjects. Abnormalities of brainstem potentials were found in 30% of the old patients; i.e. interpeak latency prolongation and desynchronisation. Brainstem abnormalities were more likely to be found in patients with delta E.E.G. activity and criteria of deterioration at the psychometric tests. Lesser degrees of abnormalities (7%) were seen in old patients without any vascular or neurologic disorder, than in patients with one of those pathological processes (77%). The results suggest that brainstem potentials abnormalities observed in old subjects are not related to age as such, but to associated vascular or degenerative disorders, the frequency of which increases with age.

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In order to test the relationship between the ototoxicity of kanamycin and the onset of the auditory function, two groups of developing rats were intoxicated with kanamycin before and after the period of onset of cochlear potentials (8th postnatal day). Kanamycin was shown to have a weak ototoxic effect before the 8th postnatal day and a strong ototoxic effect after this period. These results indicate a critical period of sensitivity to ototoxic antibiotics during auditory development.

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