4Din vivodosimetry for a FLASH electron beam using radiation-induced acoustic imaging.

OBJECTIVE: The primary goal of this research is to demonstrate the feasibility of radiation-induced acoustic imaging (RAI) as a volumetric dosimetry tool for ultra-high dose rate FLASH electron radiotherapy (FLASH-RT) in real time. This technology aims to improve patient outcomes by accurate measurements of in vivo dose delivery to target tumor volumes. Approach: The study utilized the FLASH-capable eRT6 LINAC to deliver electron beams under various doses (1.2 Gy/pulse to 4.95 Gy/ pulse) and instantaneous dose rates (1.55×105 Gy/s to 2.75×106 Gy/s), for imaging the beam in water and in a rabbit cadaver with RAI. A custom 256-element matrix ultrasound array was employed for real-time, volumetric (4D) imaging of individual pulses. This allowed for the exploration of dose linearity by varying the dose per pulse and analyzing the results through signal processing and image reconstruction in RAI. Main Results: By varying the dose per pulse through changes in source-to-surface distance (SSD), a direct correlation was established between the peak-to-peak amplitudes of pressure waves captured by the RAI system and the radiochromic film dose measurements. This correlation demonstrated dose rate linearity, including in the FLASH regime, without any saturation even at an instantaneous dose rate up to 2.75×106 Gy/s. Further, the use of the 2D matrix array enabled 4D tracking of FLASH electron beam dose distributions on animal tissue for the first time. Significance: This research successfully shows that 4D in vivo dosimetry is feasible during FLASH-RT using a RAI system. It allows for precise spatial (~mm) and temporal (25 frames/s) monitoring of individual FLASH beamlets during delivery. This advancement is crucial for the clinical translation of FLASH-RT as enhancing the accuracy of dose delivery to the target volume the safety and efficacy of radiotherapeutic procedures will be improved. .

Uncovering the Protective Neurologic Mechanisms of Hypofractionated FLASH Radiotherapy.

Implementation of ultra-high dose-rate FLASH radiotherapy (FLASH-RT) is rapidly gaining traction as a unique cancer treatment modality able to dramatically minimize normal tissue toxicity while maintaining antitumor efficacy compared with standard-of-care radiotherapy at conventional dose rate (CONV-RT). The resultant improvements in the therapeutic index have sparked intense investigations in pursuit of the underlying mechanisms. As a preamble to clinical translation, we exposed non-tumor-bearing male and female mice to hypofractionated (3 × 10 Gy) whole brain FLASH- and CONV-RT to evaluate differential neurologic responses using a comprehensive panel of functional and molecular outcomes over a 6-month follow-up. In each instance, extensive and rigorous behavioral testing showed FLASH-RT to preserve cognitive indices of learning and memory that corresponded to a similar protection of synaptic plasticity as measured by long-term potentiation (LTP). These beneficial functional outcomes were not found after CONV-RT and were linked to a preservation of synaptic integrity at the molecular (synaptophysin) level and to reductions in neuroinflammation (CD68+ microglia) throughout specific brain regions known to be engaged by our selected cognitive tasks (hippocampus, medial prefrontal cortex). Ultrastructural changes in presynaptic/postsynaptic bouton (Bassoon/Homer-1 puncta) within these same regions of the brain were not found to differ in response to dose rate. With this clinically relevant dosing regimen, we provide a mechanistic blueprint from synapse to cognition detailing how FLASH-RT reduces normal tissue complications in the irradiated brain. Significance: Functional preservation of cognition and LTP after hypofractionated FLASH-RT are linked to a protection of synaptic integrity and a reduction in neuroinflammation over protracted after irradiation times.

The sparing effect of FLASH-RT on synaptic plasticity is maintained in mice with standard fractionation.

Long-term potentiation (LTP) was used to gauge the impact of conventional and FLASH dose rates on synaptic transmission. Data collected from the hippocampus and medial prefrontal cortex confirmed significant inhibition of LTP after 10 fractions of 3 Gy (30 Gy total) conventional radiotherapy. Remarkably, 10x3Gy FLASH radiotherapy and unirradiated controls were identical and exhibited normal LTP.

Irreversible hippocampal changes induced by high fructose diet in rats.

Some reports have described that a high fructose diet is associated with a deficit of hippocampus-dependent cognitive functions. In this study, we have evaluated the effects of fructose on spatial memory and molecular markers in the hippocampus and prefrontal cortex and analyzed whether those alterations are reversible. Male Wistar rats (n = 60) began their treatment during adolescence. A group was forced to drink a solution of 10% fructose for twelve weeks. Another group was subjected to the same fructose intake schedule, but later fructose was removed, and tap water was provided for four weeks. After treatments, spatial memory was evaluated with Barnes maze. Different neurogenesis, inflammation, astrocyte, and energy homeostasis markers were evaluated with immunofluorescence, ELISA, and Western blot. Changes were analyzed using two-way repeated-measures ANOVA, one-way ANOVA, and Tukeýs posthoc test (p < 0.05). Results showed that after long-term consumption of fructose, there was an impairment of spatial memory. This deficit was concomitant with the abolition of hippocampal neurogenesis and significant increases of IL-1b in the hippocampus and prefrontal cortex. Levels of COX-2 were decreased in the hippocampus. Besides, fructose induced a significant increase in GFAP and a decrease of glutamine synthetase. Likewise, energy homeostasis-associated neuropeptide orexin-A and their receptors (ORX R1 and ORX R2) were significantly increased. The spatial memory deficit, neuroinflammation, and changes in some proteins expression were permanent one month after the fructose elimination from the diet. These results suggest that fructose induces substantial hippocampal and cortical changes, and those are irreversible after a shift in the diet.

Whole-brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefrontal cortex.

BACKGROUND: Whole-brain radiotherapy is a primary treatment for brain tumors and brain metastasis, but it also induces long-term undesired effects. Since cognitive impairment can occur, research on the etiology of secondary effects has focused on the hippocampus. Often overlooked, the hypothalamus controls critical homeostatic functions, some of which are also susceptible after whole-brain radiotherapy. Therefore, using whole-brain irradiation (WBI) in a rat model, we measured neurotransmitters and receptors in the hypothalamus. The prefrontal cortex and brainstem were also analyzed since they are highly connected to the hypothalamus and its regulatory processes. METHODS: Male Wistar rats were exposed to WBI with 11 Gy (Biologically Effective Dose = 72 Gy). After 1 month, we evaluated changes in gamma-aminobutyric acid (GABA), glycine, taurine, aspartate, glutamate, and glutamine in the hypothalamus, prefrontal cortex, and brainstem according to an HPLC method. Ratios of Glutamate/GABA and Glutamine/Glutamate were calculated. Through Western Blott analysis, we measured the expression of GABAa and GABAb receptors, and NR1 and NR2A subunits of NMDA receptors. Changes were analyzed comparing results with sham controls using the non-parametric Mann-Whitney U test (p < 0.05). RESULTS: WBI with 11 Gy induced significantly lower levels of GABA, glycine, taurine, aspartate, and GABAa receptor in the hypothalamus. Also, in the hypothalamus, a higher Glutamate/GABA ratio was found after irradiation. In the prefrontal cortex, WBI induced significant increases of glutamine and glutamate, Glutamine/Glutamate ratio, and increased expression of both GABAa receptor and NMDA receptor NR1 subunit. The brainstem showed no statistically significant changes after irradiation. CONCLUSION: Our findings confirm that WBI can affect rat brain regions differently and opens new avenues for study. After 1 month, WBI decreases inhibitory neurotransmitters and receptors in the hypothalamus and, conversely, increases excitatory neurotransmitters and receptors in the prefrontal cortex. Increments in Glutamate/GABA in the hypothalamus and Glutamine/Glutamate in the frontal cortex indicate a neurochemical imbalance. Found changes could be related to several reported radiotherapy secondary effects, suggesting new prospects for therapeutic targets.

Hippocampal neurogenesis regulates recovery of defensive responses by recruiting threat- and extinction-signalling brain networks.

Safe exposure to a context that was previously associated with threat leads to extinction of defensive responses. Such contextual fear extinction involves the formation of a new memory that inhibits a previously acquired contextual fear memory. However, fear-related responses often return with the simple passage of time (spontaneous fear recovery). Given that contextual fear and extinction memories are hippocampus-dependent and hippocampal neurogenesis has been reported to modify preexisting memories, we hypothesized that neurogenesis-mediated modification of preexisting extinction memory would modify spontaneous fear recovery. To test this, rats underwent contextual fear conditioning followed by extinction. Subsequently, we exposed rats to an enriched environment or focal X-irradiation to enhance or ablate hippocampal neurogenesis, respectively. Over a month later, rats were tested to evaluate spontaneous fear recovery. We found that enhancing neurogenesis after, but not before, extinction prevented fear recovery. In contrast, neurogenesis ablation after, but not before, extinction promoted fear recovery. Using the neuronal activity marker c-Fos, we identified brain regions recruited in these opposing neurogenesis-mediated changes during fear recovery. Together, our findings indicate that neurogenesis manipulation after extinction learning modifies fear recovery by recruiting brain network activity that mediates the expression of preexisting contextual fear and extinction memories.

Chronic Consumption of Fructose Induces Behavioral Alterations by Increasing Orexin and Dopamine Levels in the Rat Brain.

It has been widely described that chronic intake of fructose causes metabolic alterations which can be associated with brain function impairment. In this study, we evaluated the effects of fructose intake on the sleep⁻wake cycle, locomotion, and neurochemical parameters in Wistar rats. The experimental group was fed with 10% fructose in drinking water for five weeks. After treatment, metabolic indicators were quantified in blood. Electroencephalographic recordings were used to evaluate the sleep architecture and the spectral power of frequency bands. Likewise, the locomotor activity and the concentrations of orexin A and monoamines were estimated. Our results show that fructose diet significantly increased the blood levels of glucose, cholesterol, and triglycerides. Fructose modified the sleep⁻wake cycle of rats, increasing the waking duration and conversely decreasing the non-rapid eye movement sleep. Furthermore, these effects were accompanied by increases of the spectral power at different frequency bands. Chronic consumption of fructose caused a slight increase in the locomotor activity as well as an increase of orexin A and dopamine levels in the hypothalamus and brainstem. Specifically, immunoreactivity for orexin A was increased in the ventral tegmental area after the intake of fructose. Our study suggests that fructose induces metabolic changes and stimulates the activity of orexinergic and dopaminergic neurons, which may be responsible for alterations of the sleep⁻wake cycle.

Quinine and carbenoxolone enhance the anticonvulsant activity of some classical antiepileptic drugs.

Objective Quinine (QUIN) and carbenoxolone (CNX) elicit anticonvulsant effects typically characterized by the reduction of the epileptiform activity as well as changes in behavioral parameters related to seizures. Therefore, the aim of this study was to analyze the effects of these molecules on the anticonvulsant activity of some classical antiepileptic drugs. Methods Male Wistar rats were used. Valproate (VPA), phenytoin (PHT), or carbamazepine (CBZ) was administered at sub-therapeutic doses for intraperitoneal via. Subsequently, animals were administered with a single dose of QUIN or CNX. The anticonvulsant activity was evaluated with the maximal electroshock (MES) test and pentylenetetrazole (PTZ) administration. Additionally, the plasma levels of CBZ were determined using an HPLC method. Results All the control rats presented generalized tonic-clonic seizures after the MES test or the administration of PTZ. For the MES test, all of the antiepileptic drugs increased their anticonvulsant activity when were co-administered with QUIN. For the PTZ test, only the combination CBZ plus QUIN significantly increased the percentage of protection against the generalized tonic-clonic seizures. The co-administration of CBZ plus QUIN resulted in an augmented concentration of CBZ in plasma. Discussion The present study shows that QUIN and CNX enhance the anticonvulsant activity of some classical antiepileptic drugs. However, only the combination CBZ/QUIN had significant effects on both MES and PTZ models. Such anticonvulsant activity could be attributed to increased levels of CBZ in plasma. We propose that these molecules could improve the pharmacological actions of antiepileptic drugs administered at sub-therapeutic doses.

Unilateral microinjection of carbenoxolone into the pontis caudalis nucleus inhibits the pentylenetetrazole-induced epileptiform activity in rats.

Pontine reticular formation (PRF) is involved in the generation and maintenance of generalized epileptic seizures. Carbenoxolone (CBX) is a gap junction blocker with anticonvulsant properties. Therefore, the present study was designed to explore the effects of CBX microinjected into the pontis caudalis nucleus (PnC) on generalized tonic-clonic seizures (GTCS) and epileptiform activity induced by pentylenetetrazole (PTZ). All control rats presented GTCS after a single dose of PTZ. The microinjection of CBX into the PnC reduced the GTCS incidence induced by PTZ. Moreover, the CBX significantly increased the latency to the first myoclonic jerk. Additionally, CBX significantly decreased the spectral power and the amplitude of the epileptiform activity induced by PTZ. By contrast, the microinjection of a gap junction opener (trimethylamine) did not cause anticonvulsant effects and even increased the duration of the GTCS. These findings suggest that the PnC is a particular nucleus where the CBX could exert its action mechanisms and elicit anticonvulsant effects.

Prediction of Mechanical Properties and Subjective Consistency of Meningiomas Using T1-T2 Assessment Versus Fractional Anisotropy.

OBJECTIVE: This study aims to evaluate quantitatively the mechanical properties of meningiomas and their correlation with the qualitative surgeon's assessment of consistency, as well as comparing the capability to predict tumor consistency of fractional anisotropy values calculated from the diffusion tensor imaging and T1/T2 signal intensities. METHODS: Sixteen patients with the diagnosis of intracranial meningioma were included. Fractional anisotropy values were calculated and T1/T2 assessment was performed. The qualitative assessment of the tumor consistency intraoperatively was determined by a neurosurgeon and quantitative assessment was obtained with the Warner-Bratzler mechanical test. RESULTS: Surgeon's qualitative assessment was concordant with the cutting force obtained from the mechanical tests (P = 0.046). There was a high correlation between tumor consistency reported by the surgeon and T1/T2 assessment (0.622/P = 0.01) and a moderate correlation with cutting force (0.532/P = 0.034) and elasticity (0.49/P = 0.05). Fractional anisotropy values for hard tumors were not significantly higher than for soft tumors (P = 0.115). There was no significant correlation between the fractional anisotropy and mechanical measurements (0.192/P = 0.3). Predictions of hard consistency in meningiomas were obtained with a sensitivity of 25% and a specificity of 100% when using the T1/T2 assessment and a sensitivity of 87.5% and a specificity of 50% when using the fractional anisotropy value. CONCLUSIONS: Qualitative surgeon's assessment was in accordance with measured mechanical properties. Fractional anisotropy value was not an independent predictor for tumor consistency and was not correlated with the mechanical tests results. T1/T2 assessment was correlated with mechanical properties and it can be used to discriminate very hard or soft tumors.

Anticonvulsant effects of mefloquine on generalized tonic-clonic seizures induced by two acute models in rats.

BACKGROUND: Mefloquine can cross the blood-brain barrier and block the gap junction intercellular communication in the brain. Enhanced electrical coupling mediated by gap junctions is an underlying mechanism involved in the generation and maintenance of seizures. For this reason, the aim of this study was to analyze the effects of the systemic administration of mefloquine on tonic-clonic seizures induced by two acute models such as pentylenetetrazole and maximal electroshock. RESULTS: All the control rats presented generalized tonic-clonic seizures after the administration of pentylenetetrazole. However, the incidence of seizures induced by pentylenetetrazole significantly decreased in the groups administered systematically with 40 and 80 mg/kg of mefloquine. In the control group, none of the rats survived after the generalized tonic-clonic seizures induced by pentylenetetrazole, but survival was improved by mefloquine. Besides, mefloquine significantly modified the total spectral power as well as the duration, amplitude and frequency of the epileptiform activity induced by pentylenetetrazole. For the maximal electroshock model, mefloquine did not change the occurrence of tonic hindlimb extension. However, this gap junction blocker significantly decreased the duration of the tonic hindlimb extension induced by the acute electroshock. CONCLUSIONS: These data suggest that mefloquine at low doses might be eliciting some anticonvulsant effects when is systemically administered to rats.

Properties of a commercial PTW-60019 synthetic diamond detector for the dosimetry of small radiotherapy beams.

A CVD based radiation detector has recently become commercially available from the manufacturer PTW-Freiburg (Germany). This detector has a sensitive volume of 0.004 mm(3), a nominal sensitivity of 1 nC Gy(-1) and operates at 0 V. Unlike natural diamond based detectors, the CVD diamond detector reports a low dose rate dependence. The dosimetric properties investigated in this work were dose rate, angular dependence and detector sensitivity and linearity. Also, percentage depth dose, off-axis dose profiles and total scatter ratios were measured and compared against equivalent measurements performed with a stereotactic diode. A Monte Carlo simulation was carried out to estimate the CVD small beam correction factors for a 6 MV photon beam. The small beam correction factors were compared with those obtained from stereotactic diode and ionization chambers in the same irradiation conditions The experimental measurements were performed in 6 and 15 MV photon beams with the following square field sizes: 10 × 10, 5 × 5, 4 × 4, 3 × 3, 2 × 2, 1.5 × 1.5, 1 × 1 and 0.5 × 0.5 cm. The CVD detector showed an excellent signal stability (<0.2%) and linearity, negligible dose rate dependence (<0.2%) and lower response angular dependence. The percentage depth dose and off-axis dose profiles measurements were comparable (within 1%) to the measurements performed with ionization chamber and diode in both conventional and small radiotherapy beams. For the 0.5 × 0.5 cm, the measurements performed with the CVD detector showed a partial volume effect for all the dosimetric quantities measured. The Monte Carlo simulation showed that the small beam correction factors were close to unity (within 1.0%) for field sizes ≥1 cm. The synthetic diamond detector had high linearity, low angular and negligible dose rate dependence, and its response was energy independent within 1% for field sizes from 1.0 to 5.0 cm. This work provides new data showing the performance of the CVD detector compared against a high spatial resolution diode. It also presents a comparison of the CVD small beam correction factors with those of diode and ionization chamber for a 6 MV photon beam.

Whole-brain irradiation increases NREM sleep and hypothalamic expression of IL-1ß in rats.

PURPOSE: Although it has mainly been described qualitatively, whole brain irradiation induces somnolence in patients with malignant diseases. Therefore, we used a rat model to quantify the effects of irradiation of healthy brain tissue on both sleep-wake patterns and the expression of the pro-inflammatory cytokine interleukin-1ß (IL-1ß), which is known to induce sleep. MATERIALS AND METHODS: Different groups were examined at three time points after irradiation (1 day, 30 days and 60 days). Polysomnographic recordings were performed on each rat before and after total cranial irradiation (12 Gy). IL-1ß protein levels in several brain regions were assessed by enzyme-linked immunosorbent assays, and site-specific immunoreactivity was observed by immunofluorescence. RESULTS: We found that both non-rapid eye movement sleep and IL-1ß protein expression in the hypothalamus increased 30 days after irradiation. CONCLUSIONS: Whole brain irradiation increases sleep in our rat model, and this finding is similar to qualitative reports from patients. Because IL-1ß has been proposed as a sleep-promoting molecule, we propose that the polysomnographic results may be attributable, at least in part, to the delayed overexpression of IL-1ß in the hypothalamus.

Comparison of trigeminal neuralgia radiosurgery plans using two film detectors for the commissioning of small photon beams.

Trigeminal neuralgia (TN) is a chronic, episodic facial pain syndrome that can be extremely intense, and it occurs within the regions of the face that are innervated by the three branches of the trigeminal nerve. Stereotactic radiosurgery (SRS) is the least invasive procedure to treat TN. SRS uses narrow photon beams that require high spatial resolution techniques for their measurement. The use of radiographic or radiochromic films for small-field dosimetry is advantageous because high spatial resolution and two-dimensional dose measurements can be performed. Because these films have different properties, it is expected that the calculated dose distributions for TN patients will behave differently, depending on the detector used for the commissioning of the small photon beams. This work is based on two sets of commissioned data: one commissioned with X-OMAT V2 film and one commissioned with EBT2 film. The calculated dose distributions for 23 TN patients were compared between the commissioning datasets. The variables observed were the differences in the half widths of the 35 and 40 Gy isodose lines (related to the entrance distance to the brainstem) and the volume of the brainstem that received a dose of 12 Gy or more (V12). The results of this comparison showed that there were statistically significant differences between the two calculated dose distributions. The magnitudes of these differences were up to 0.33 mm and 0.38 mm for the 35 and 40 Gy isodose lines. The corresponding difference for the V12 was up to 2.1cc. It is clear that these differences may impact the treatment of TN patients, and then it must be important to perform this type of analysis when observing complication rates. Clinical reports on irradiation techniques for trigeminal neuralgia should consider that different detectors used for commissioning treatment planning systems might result in small but significant differences in dose distributions.

Chronic paroxetine treatment: effects on other non-serotonergic neurotransmitter systems.

Due to its efficacy and acceptability, paroxetine is situated in the top ten of drugs prescribed for the treatment of major depression and essentially all anxiety disorders. Adults under paroxetine treatment report relief after 4-6 weeks of administration; furthermore, this drug can be prescribed for periods lasting longer than one year. Therefore, paroxetine treatment has a pattern of ingestion that is mainly chronic rather than acute. There is a considerable number of reviews in the literature concerning the effects of paroxetine on the serotonergic system; however, the alterations caused by chronic ingestion of this drug in other neurotransmitter systems have received little attention. For this reason, we consider very important to review the experimental studies concerning the effects of chronic paroxetine intake on neurotransmitter levels, neuronal firing rate and the expression of receptors and transporters in different neurotransmitter systems in the brain. According to the experimental data analyzed in this work, we can establish that long-term paroxetine intake has the ability to increase GABA, glutamate, dopamine and noradrenaline levels in the brain. Furthermore, high levels of AMPA, orexine-1,2 and histamine-1 receptors have been reported in different brain regions after treatment with paroxetine over several weeks. In addition, paroxetine has differential effects on neuropeptide systems, such as galanine, opioid receptors and substance P. Available data lead us to establish that chronic ingestion of paroxetine induces changes in several neurotransmitters and neuropeptides, thus illuminating how each one may contribute to the antidepressant and anxiolytic response elicited by this drug. We consider that all reported changes in the neurotransmitter systems should be further considered to individualize clinical treatment and, in the case of patients taking a drug "cocktail", to gain better control over drug interactions and adverse effects.

Differences in HIV-1 viral loads between male and female antiretroviral-untreated Mexican patients.

BACKGROUND AND AIMS: HIV-1 viral load is used to monitor AIDS progression and effect of antiretroviral therapy (ART). Several reports have indicated that the HIV-1 viral load of infected individuals is lower in females than in males. There are no reports exploring this issue in the Mexican population. We analyzed the relationship between sex and viral load in Mexican patients differing in CD4 T-cell count, age and treatment status. METHODS: A retrospective study was performed in 3949 male and 696 female HIV-1-infected individuals. Statistical distributions were compared using the Mann-Whitney U nonparametric test. RESULTS: Among the antiretroviral-untreated group, females had a significantly lower viral load than males (0.52 female/male median viral load ratio, p = 0.008). When classified according to different ranges of CD4⁺ T cell counts, females had consistently lower viral loads than males, although statistical significance was achieved only for the group in the range of 201-350 (p = 0.014). Patients with the lowest CD4⁺ T-cell counts showed similar viral loads for both sexes. No differences were observed in the ART group. CONCLUSIONS: This study demonstrates a baseline difference in viral load between male and female ART-untreated Mexican patients. The overall tendency indicating a lower viral load in females in the same ranges of CD4⁺ T-cell counts than males, suggests that the lower viral load in females is not indicative of a lower risk of developing AIDS. These observations suggest a significant influence of sex on viral dynamics and immune response despite variations in demographic factors.

Evaluation of the Gafchromic(®) EBT2 film for the dosimetry of radiosurgical beams.

PURPOSE: Radiosurgery uses small fields and high-radiation doses to treat intra- and extracranial lesions in a single session. The lack of a lateral electronic equilibrium and the presence of high-dose gradients in these fields are challenges for adequate measurements. The availability of radiation detectors with the high spatial resolution required is restricted to only a few. Stereotactic diodes and EBT radiochromic films have been demonstrated to be good detectors for small-beam dosimetry. Because the stereotactic diode is the standard measurement for the dosimetry of radiosurgical beams, the goal of this work was to perform measurements with the radiochromic film Gafchromic(®) EBT2 and compare its results with a stereotactic diode. METHODS: Total scatter factors, tissue maximum, and off-axis ratios from a 6 MV small photon beams were measured using EBT2 radiochromic film in a water phantom. The film-measured data were evaluated by comparing it with the data measured with a stereotactic field diode (IBA-Dosimetry). RESULTS: The film and diode measurements had excellent agreement. The differences between the detectors were less than or equal to 2.0% for the tissue maximum and the off-axis ratios. However, for the total scatter factors, there were significant differences, up to 4.9% (relative to the reference field), for field sizes less than 1.0 cm. CONCLUSIONS: This work found that the Gafchromic(®) EBT2 film is adequate for small photon beam measurements, particularly for tissue maximum and off-axis ratios. However, careful attention must be taken when measuring output factors of small beams below 1.0 cm due to the film's energy dependence. The measurement differences may be attributable to the film's active layer composition because EBT2 incorporates higher Z elements (i.e., bromide and potassium), hence revealing a potential energy dependence for the dosimetry of small photon beams.

[Major neurotransmitters involved in the regulation of sleep-wake cycle]. / Principales neurotransmisores involucrados en la regulación del ciclo sueño-vigilia.

Neuronal activity in the central nervous system undergoes a variety of electrophysiological changes along the sleep-wake cycle. These changes are modulated by a complex interaction between different neurochemical systems located throughout the brain. Within brainstem and hypothalamus there are a number of neuronal populations that promote wakefulness through the action of different neurotransmitters like noradrenaline, serotonin, histamine and orexin. These systems act together in the generation and maintenance of wakefulness, however although each one contributes in a unique way no neurotransmitter seems to be absolutely necessary because wakefulness is not completely inhibited in the absence of any of them. On the other hand, neurons located in the hypothalamus and brainstem are involved in initiating and maintaining sleep. These neurons contain neurotransmitters such as acetylcholine and GABA and have projections to nuclei involved in wakefulness regulation. Recently, models have been proposed suggesting that sleep is modulated by flip-flop switches which are characterized by neuronal circuits with different neurotransmitters and that interacting to regulate the initiation and maintenance of the different stages of sleep wake cycle. This review is based on pharmacological, electrophysiological and neurochemical studies with the aim of analyze the major neurotransmitters and the cerebral regions involved in the regulation of wakefulness and different states of sleep.

Radiation-induced neuroinflammation and radiation somnolence syndrome.

Cranial irradiation remains a standard treatment for malignant and benign brain diseases. Although this procedure helps to lengthen the life expectancy of the patient, the appearance of adverse effects related to radiation-induced injury is inevitable. Radiation somnolence syndrome (RSS) has been described as a delayed effect observed mainly after whole-brain radiotherapy in children. The RSS was first linked to demyelination, but more recently it has been proposed that the inflammatory response plays a primary role in the aforementioned syndrome. To evaluate the feasibility of this hypothesis, we explored previous work about RSS and reviewed published research that included measurements of the inflammatory response in models of brain exposure to ionizing radiation. Pro-inflammatory cytokines such as interleukin-1ß, tumor necrosis factor-α, interleukin-6 and interleukin-18 as well as other inflammatory markers such as cyclooxygenase-2, prostaglandin E2, glial fibrillary acid protein, intercellular adhesion molecule-1 and nuclear factor-κB appear to be involved in the brain's response to radiation. However, certain publications have described the somnogenic effects of these cytokines and inflammatory markers. Although the radiation response is a complex phenomenon that involves several molecular and cellular processes, we propose that inflammation may be closely related to the adverse effects of brain irradiation and therefore to the etiology of RSS.

Sleep deprivation and sleep recovery modifies connexin36 and connexin43 protein levels in rat brain.

Gap junctional communication is mainly mediated by connexin36 and connexin43 in neurons and astrocytes, respectively. It has been suggested that connexin36 allows electrical coupling between neurons whereas connexin43 participates in several process including release of ATP. It was recently reported that blockage of gap junctional communication mediated by connexin36 can disrupt the sleep architecture of the rat. However, there is no experimental approach about effects of sleep deprivation on connexins expression. Therefore, we examined in adult male Wistar rats whether protein levels of connexin36 and connexin43 change in pons, hypothalamus, and frontal cortex after 24 h of total sleep deprivation and 4 h of sleep recovery. Western blot revealed that total sleep deprivation significantly decreases the levels of connexin36 in the hypothalamus and this decrease maintains after sleep recovery. Meanwhile, connexin43 is not altered by total sleep deprivation but interestingly the sleep recovery period induces an increase of this connexin. These results suggest that electrical coupling between hypothalamic neurons could be altered by sleep deprivation and that sleep recovery drives changes in connexin43 expression probably as a mechanism related to ATP release and energy regulation during sleep.