Pituitary adenylate cyclase activating polypeptide concentrations in the sheep mammary gland, milk, and in the lamb blood plasma after suckling.

Pituitary adenylate cyclase activating polypeptide (PACAP) is involved in development and reproduction. We previously described elevated PACAP levels in the milk compared to the plasma, and the presence of its specific PAC1 receptor in the mammary gland. This study aimed to determine PACAP and vasoactive intestinal peptide (VIP) levels in female suckling lambs compared to ewe plasma and mammary gland, as well as their age-dependent alterations. mRNA expressions of PACAP, VIP, PAC1 receptor and brain-derived neurotrophic factor (BDNF) were quantified in the milk whey and mammary gland. PACAP38-like immunoreactivity (PACAP38-LI) was measured in plasma, milk whey and mammary gland by radioimmunoassay, VIP-LI by enzyme-linked immunoassay. PACAP38-LI was 5, 6 times higher in the milk compared to the plasma of lactating sheep. It significantly increased in the lamb plasma 1 h, but returned to basal level 2 h after suckling. However, VIP mRNA was not present in the mammary gland, we detected the VIP protein in the milk whey. BDNF mRNA significantly decreased with age to approximately 60% and 25% in the 3- and 10-year-old sheep respectively, compared to the 3-month-old lambs. No differences were found between mammary and jugular vein plasma PACAP and VIP concentrations, or during the daily cycle. We propose a rapid absorption of PACAP38 from the milk and/or its release in suckling lambs. PACAP accumulated in the milk might be synthesized in the mammary gland or secreted from the plasma of the mothers. PACAP is suggested to have differentiation/proliferation promoting and immunomodulatory effects in the newborns and/or a local function in the mammary gland.

Genetic deletion of TRPA1 receptor attenuates amyloid beta- 1-42 (Aß1-42)-induced neurotoxicity in the mouse basal forebrain in vivo.

Amyloid ß 1-42 peptide (Aß1-42) accumulates in Alzheimer's disease (AD) that is toxic to the basal forebrain cholinergic (BFC) neurons in substantia innominata-nucleus basalis magnocellularis complex (SI-NBM). Transient Receptor Potential Ankyrin1 (TRPA1) receptor is present in murine brain, however its role in neurotoxic processes is unclear. We investigated the Aß1-42-induced neurotoxicity in TRPA1 wild-type (TRPA1+/+) and knockout (TRPA1-/-) mice. Expression and neuroanatomical localization of TRPA1 receptor were examined using RT qPCR. Cholinergic fibre loss was determined on acetylcholinesterase (AChE) stained brain slices, and choline acetyltransferase (ChAT) immunohistochemistry was used to assess the cholinergic cell loss. Novel object recognition (NOR), radial arm maze (RAM) and Y-maze tests were used to investigate memory loss. Aß1-42-injected WT mice showed marked loss of cholinergic fibres and cell bodies, which was significantly attenuated in TRPA1-/- animals. According to the NOR and RAM tests, pronounced memory loss was detected in Aß1-42-injected TRPA1+/+ mice, but not in TRPA1-/- group. Our findings demonstrate that TRPA1 KO animals show substantially reduced morphological damage and memory loss after Aß1-42 injection in the SI-NBM. We conclude that TRPA1 receptors may play an important deteriorating role in the Aß1-42-induced cholinergic neurotoxicity and the consequent memory loss in the murine brain.

Investigation of Lake Hévíz Mineral Water Balneotherapy and Hévíz Mud Treatment in Murine Osteoarthritis and Rheumatoid Arthritis Models.

Arthritic diseases are the most frequent causes of chronic pain and disability. Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and progressive structural joint damage. Osteoarthritis is a degenerative process of the articular cartilage associated with hypertrophic changes in the bone. The aim of the present study was to investigate the anti-inflammatory and analgesic effects of Hévíz thermal water and mud in monosodium iodoacetate- (MIA-) (25 mg/ml, 20 µl i.a.) induced osteoarthritis and Complete Freund's adjuvant- (CFA-) (1 mg/ml, 50-50 µl s.c) induced rheumatoid arthritis murine models. The mechanonociceptive threshold of female NMRI mice (n=6- 8 mice/ group) was measured by aesthesiometry, and paw volume was monitored with plethysmometry, knee joint diameter with digital micrometer, and dynamic weight bearing on the hind limbs with a Bioseb instrument. Periarticular bone destruction was assessed by SkyScan 1176 in vivo micro-CT. Inflammatory cytokines were detected by ELISA in plasma samples. Treatments (30 min, every working day) with tap water, sand, and a combined therapy of tap water and sand served as controls. Hévíz medicinal water and combined treatment with water and mud significantly decreased the mechanical hyperalgesia and knee oedema in MIA-induced osteoarthritis model. However, balneotherapy did not influence mechanical hyperalgesia, weight bearing, or oedema formation induced by CFA. Neither medicinal water nor mud treatment ameliorated deep structural damage of the bones or the joints in the animal models. On the basis of the present findings, we conclude that balneotherapy is an effective complementary treatment to reduce the pain sensation and swelling in degenerative joint diseases such as osteoarthritis. Our experimental data are in agreement with the previous human studies that also confirmed antinociceptive and anti-inflammatory effects of thermal water and Hévíz mud treatments.

Upregulation of extraneuronal TRPV1 expression in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Chronic rhinosinusitis (CRS) is a multifactorial upper airway disease with unclear etiology. Neuronal Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) channels have been implicated in the pathogenesis of CRS. We aimed to detect the expression of extraneuronal TRPV1 and TRPA1 receptors in nasal polyp (NP) tissue samples. METHODOLOGY: Samples were obtained from fourty-two CRS pateints with nasal polyp and sixteen healthy controls to measure receptor gene expression by quantitative PCR, protein localization by immunohistochemistry and cytokine profile by multiplex bead immunoassay. RESULTS: Non-neuronal TRPV1, TRPA1 receptors were expressed in biopsy samples of NP. A population of mast cells and macrophages were immunopositive for TRPV1 and TRPA1. A fraction of plasma cells expressed TRPV1 but not TRPA1 and neither receptor was present on eosinophils. The local gene expression of extraneuronal TRPV1, TRPA1 receptors was also proven. TRPV1 mRNA levels were significantly increased in CRSwNP patients with asthma and allergic rhinitis compared to their NP counterparts. CONCLUSIONS: Elevated TRPV1 levels in comorbid asthma and allergy may have a function in CRSwNP. Subpopulation-specific TRPV1 presence on plasma and mast cells can indicate delicate roles in regulating activation and release of inflammatory mediators.

Marijuana smoke induces severe pulmonary hyperresponsiveness, inflammation, and emphysema in a predictive mouse model not via CB1 receptor activation.

Sporadic clinical reports suggested that marijuana smoking induces spontaneous pneumothorax, but no animal models were available to validate these observations and to study the underlying mechanisms. Therefore, we performed a systematic study in CD1 mice as a predictive animal model and assessed the pathophysiological alterations in response to 4-mo-long whole body marijuana smoke with integrative methodologies in comparison with tobacco smoke. Bronchial responsiveness was measured with unrestrained whole body plethysmography, cell profile in the bronchoalveolar lavage fluid with flow cytometry, myeloperoxidase activity with spectrophotometry, inflammatory cytokines with ELISA, and histopathological alterations with light microscopy. Daily marijuana inhalation evoked severe bronchial hyperreactivity after a week. Characteristic perivascular/peribronchial edema, atelectasis, apical emphysema, and neutrophil and macrophage infiltration developed after 1 mo of marijuana smoking; lymphocyte accumulation after 2 mo; macrophage-like giant cells, irregular or destroyed bronchial mucosa, goblet cell hyperplasia after 3 mo; and severe atelectasis, emphysema, obstructed or damaged bronchioles, and endothelial proliferation at 4 mo. Myeloperoxidase activity, inflammatory cell, and cytokine profile correlated with these changes. Airway hyperresponsiveness and inflammation were not altered in mice lacking the CB1 cannabinoid receptor. In comparison, tobacco smoke induced hyperresponsiveness after 2 mo and significantly later caused inflammatory cell infiltration/activation with only mild emphysema. We provide the first systematic and comparative experimental evidence that marijuana causes severe airway hyperresponsiveness, inflammation, tissue destruction, and emphysema, which are not mediated by the CB1 receptor.

[RADIOSURGERY OF INTRACEREBRAL CAVERNOMAS--CURRENT INTERNATIONAL TRENDS]. / AZ INTRACEREBRALIS CAVERNOMÁK SUGÁRSEBÉSZETE--HOL TART MA A VILÁG?

Although still a controversial management option, radio-surgery of intracranial cavernomas has become increasingly popular world-wide during the last decade. Microsurgery is a safe and effective treatment for symptomatic hemispheric cavernomas. However, the indication for microsurgical resection of deep eloquent cavernomas is relatively limited even in experienced hands. The importance of radiosurgery has recently been appreciated in parallel with increasing positive experiences both in terms of effectiveness and safety, especially for cases high risk for surgical resection, in the brainstem, thalamus and basal ganglia. While radiosurgery was earlier indicated mainly for surgically inaccessible lesions that had bled multiple times, a more proactive policy has recently become more accepted. In our opinion preventive treatment with the low morbidity radiosurgery serves the patients' interest especially for deep eloquent lesions that had bled not more than once, due to the cumulative morbidity of repeated hemorrhages. Despite our increasing knowledge on natural history, there is currently no available treatment algorithm for cavernomas. Arguments for all three treatment modalities (observation, microsurgery and radiosurgery) are established, but their indication criteria are yet to be defined. It is time to organize a prospective population based data collection in Hungary, which appears to be the most realistic way to clarify indication criteria.

Radiosurgery for cerebral cavernomas.

The role of stereotactic radiosurgery (SRS) in the management of cerebral cavernomas (CCMs) remains controversial. However, during the last decade the increasing knowledge on natural history and numerous publications from SRS centers using modern treatment protocols has been changing the initial resistance of the neurosurgical community. Unfortunately, the quality of publications on CCM SRS remains heterogeneous. Controversies arise from the lack of control groups, the different definition of hemorrhage, heterogeneous patient populations, and poor definition of treatment protocols. The key for proper interpretation of results is the understanding of the natural history of CCMs, which is varied both according to anatomical location and the presence or absence of previous hemorrhage. Hemispheric lesions appear to be more benign with lower annual bleed rate and risk of persisting disability, whereas those found in the thalamus, basal ganglia and brainstem typically have higher rebleed risk resulting in higher cumulative morbidity following subsequent hemorrhages. However, we are still unable at presentation to predict the future behavior of an individual lesion. In the present paper we critically review and analyze the modern SRS literature on CCMs. The expanding number of available data with current treatment protocols strongly supports the initial intuition that SRS is an effective treatment alternative for deep-seated CCMs with multiple hemorrhages reducing pretreatment annual rebleed rates from 32% pre-treatment to 1.5% within 2 years after treatment (N.=197). Moreover, it appears to stabilize lesions with no more than one bleed, and it is also effective for CCMs causing therapy resistant epilepsy especially if applied within 3 years after presentation. In modern SRS series the rate of persisting adverse radiation effects is low, resulting only in mild morbidity even in deep-seated lesions (4.16%, N.=376), and morbidity caused by post-treatment hemorrhages is also low (5.3%, N.=132). Admittedly, there is no high quality evidence to define the relative roles of microsurgery, SRS and wait-and-see policy in the management of detected CCMs at present. However, based on increasing positive experience, we recommend early SRS soon after presentation in neurologically intact or minimally disabled patients harboring deep-seated CCMs, because waiting for the cumulative morbidity of the natural history to justify an otherwise low-risk intervention does not serve the patient well.

The selective PAC1 receptor agonist maxadilan inhibits neurogenic vasodilation and edema formation in the mouse skin.

We have earlier shown that PACAP-38 decreases neurogenic inflammation. However, there were no data on its receptorial mechanism and the involvement of its PAC1 and VPAC1/2 receptors (PAC1R, VPAC1/2R) in this inhibitory effect. Neurogenic inflammation in the mouse ear was induced by topical application of the Transient Receptor Potential Ankyrin 1 (TRPA1) receptor activator mustard oil (MO). Consequent neurogenic edema, vasodilation and plasma leakage were assessed by measuring ear thickness with engineer's micrometer, detecting tissue perfusion by laser Doppler scanning and Evans blue or indocyanine green extravasation by intravital videomicroscopy or fluorescence imaging, respectively. Myeloperoxidase activity, an indicator of neutrophil infiltration, was measured from the ear homogenates with spectrophotometry. The selective PAC1R agonist maxadilan, the VPAC1/2R agonist vasoactive intestinal polypeptide (VIP) or the vehicle were administered i.p. 15 min before MO. Substance P (SP) concentration of the ear was assessed by radioimmunoassay. Maxadilan significantly diminished MO-induced neurogenic edema, increase of vascular permeability and vasodilation. These inhibitory effects of maxadilan may be partially due to the decreased substance P (SP) levels. In contrast, inhibitory effect of VIP on ear swelling was moderate, without any effect on MO-induced plasma leakage or SP release, however, activation of VPAC1/2R inhibited the increased microcirculation caused by the early arteriolar vasodilation. Neither the PAC1R, nor the VPAC1/2R agonist influenced the MO-evoked increase in tissue myeloperoxidase activity. These results clearly show that PAC1R activation inhibits acute neurogenic arterial vasodilation and plasma protein leakage from the venules, while VPAC1/2R stimulation is only involved in the attenuation of vasodilation.

The role of motion platform on postural instability and head vibration exposure at driving simulators.

This paper explains the effect of a motion platform for driving simulators on postural instability and head vibration exposure. The sensed head level-vehicle (visual cues) level longitudinal and lateral accelerations (ax,sensed=ax_head and ay,sensed=ay_head, ayv=ay_veh and ayv=ay_veh) were saved by using a motion tracking sensor and a simulation software respectively. Then, associated vibration dose values (VDVs) were computed at head level during the driving sessions. Furthermore, the postural instabilities of the participants were measured as longitudinal and lateral subject body centre of pressure (XCP and YCP, respectively) displacements just after each driving session via a balance platform. The results revealed that the optic-head inertial level longitudinal accelerations indicated a negative non-significant correlation (r=-.203, p=.154>.05) for the static case, whereas the optic-head inertial longitudinal accelerations depicted a so small negative non-significant correlation (r=-.066, p=.643>.05) that can be negligible for the dynamic condition. The XCP for the dynamic case indicated a significant higher value than the static situation (t(47), p<.0001). The VDVx for the dynamic case yielded a significant higher value than the static situation (U(47), p<.0001). The optic-head inertial lateral accelerations resulted a negative significant correlation (r=-.376, p=.007<.05) for the static platform, whereas the optic-head inertial lateral accelerations showed a positive significant correlation (r=.418, p=.002<.05) at dynamic platform condition. The VDVy for the static case indicated a significant higher value rather than the dynamic situation (U(47), p<.0001). The YCP for the static case yielded significantly higher than the dynamic situation (t(47), p=.001<0.05).

Effect of PACAP treatment on kidney morphology and cytokine expression in rat diabetic nephropathy.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide, exerting diverse effects. One of its frequently examined functions is cell protection, which is achieved mainly via inhibiting apoptotic, inflammatory and oxidative processes. All its three receptors (PAC1, VPAC1, VPAC2) are expressed in the kidney and PACAP has been shown to have protective effects against different renal pathologies. Diabetic nephropathy is the leading cause of end stage renal disease. The aim of the present study was to investigate the possible ameliorative effect of PACAP in streptozotocin-induced diabetic nephropathy and to evaluate its anti-inflammatory effect in this model. Diabetes was induced by a single intravenous injection of streptozotocin (65 mg/kg) in male Wistar rats. PACAP-treated animals were administered ip. 20 µg PACAP every second day, while untreated animals were given vehicle. Kidneys were removed after 8-weeks survival. Besides the complex histological analysis (glomerular PAS positive area/glomerulus area, tubular damage, arteriolar hyalinosis), expression of several cytokines was evaluated by cytokine array and Luminex assay. Histological analysis revealed severe diabetic changes in kidneys of control diabetic animals (glomerular PAS-positive area expansion, tubular damage, Armanni-Ebstein phenomenon). PACAP treatment significantly diminished the damage. Diabetic kidneys showed significant cytokine activation compared to their healthy controls. PACAP was effective in downregulation of several cytokines including CINC-1, TIMP-1, LIX, MIG, s-ICAM. To conclude, PACAP is effective in ameliorating diabetic nephropathy at least partly through its well-known anti-inflammatory effect. These results raise the opportunity for the use of PACAP as a possible therapeutic or preventive method in treating the complications of diabetes.

CPR degradation diagram.

During untreated ventricular fibrillation (VF), before CPR is applied, different bodily systems deteriorate at different rates. This paper describes the times when the EEG disappears, when respiratory arrest occurs, and when PD-PEA occurs. It also describes the frequency of VF waves over a 7-min period and how the frequency increases with good CPR.

Vagus nerve stimulation in children with intractable epilepsy: indications, complications and outcome.

PURPOSE: To analyze the indication, complications and outcome of vagus nerve stimulation in intractable childhood epilepsy. MATERIALS AND METHODS: We retrospectively reviewed the data of 69 children who had insertion of vagal nerve stimulator (VNS) between June 1995 and August 2006 for medically intractable epilepsy. Outcome was based on the Engel's classification. Statistical analysis of the data was also done to see if any of the parameters significantly influenced the outcome. RESULT: Thirty-eight patients (55.08 %) had a satisfactory outcome (Engel class I, II or III), and in 31 patients (44.92 %), there was no worthwhile improvement of seizures (Engel class IV). There was no statistical significance between the type of seizure and outcome (Fisher's exact test, p = 0.351). Statistical analysis also showed that the following parameters did not significantly influence the outcome (p > 0.05): age at insertion of VNS, age of first fit, duration between first fit and insertion of VNS and the length of follow-up. Complications included infection, lead fracture, fluid collection around the stimulator, neck pain and difficulty swallowing. CONCLUSION: Vagus nerve stimulation is a relatively safe and potentially effective treatment for children with medically intractable epilepsy.

Embolization of residual fistula following stereotactic radiosurgery in cerebral arteriovenous malformations.

Treatment of brain arteriovenous malformations (BAVMs) often requires a multitechnique approach. We present 2 cases of BAVM, in which initial stereotactic radiosurgery (SRS) was successful in obliterating a significant volume of the nidus. At follow-up angiography, residual fistulas were identified and selectively embolized; this procedure cured the lesions. Many series describe initial embolization to reduce the nidal volume followed by SRS to the remnant. The described cases highlight the value of primary radiosurgery followed by selective fistula embolization.

Nonpulsatile and noninvasive transmittance and reflectance tissue-bed oximetry.

A new optical device was developed that measures blood pressure noninvasively, in small human subjects (neonates and premature infants) and small animals (Roeder RAR. Transducer for indirect measurement of blood pressure in small human subjects and animals, Purdue University, BME; 2003.: xi, 50 p.). The ability of this device to measure oxygen saturation enhances its value. The objective of this research was to add the ability to obtain SaO(2) from the same device and to obtain the calibration curve. Another objective was to determine which measurement method (transmittance or reflectance) is preferable. This new oximeter is unlike the conventional pulse oximeter in that it does not require a pulse, making it ideal for measuring oxygen saturation noninvasively in small human subjects with small amplitude pulses or without a pulse. A study was performed in 11 pigs, ranging in weight 20-27 kg. The pig tail was used as the measuring site for %SaO(2) measurements. Arterial blood samples were obtained from the femoral artery and oxygen saturation was measured with a blood-gas analyzer. A small blood-pressure cuff was used to render the optical path bloodless. A comparison of the transmittance and reflectance methods for measuring oxygen saturation was made. %SaO(2) measurements ranged from 4% to 100%. It was found that both the transmittance and reflectance methods can be used to measure %SaO(2) reliably in situations with or without a pulse.

Stereotactic radiosurgery for brain arteriovenous malformations: quantitative MR assessment of nidal response at 1 year and angiographic factors predicting early obliteration.

INTRODUCTION: We investigated the role of magnetic resonance angiography (MRA) in the early follow-up of patients after stereotactic radiosurgery (STRS) for cerebral arteriovenous malformations (AVMs) and determined the influence of individual morphological factors of AVMs in early response to treatment. METHODS: A group of 40 patients (41 AVMs) consented to a dedicated 1.5-T MR protocol 12 months after receiving STRS for a brain AVM. In addition to standard spin echo sequences, 3-D contrast-enhanced sliding interleaved Ky MRA (CE-SLINKY) and dynamic time-resolved subtraction angiography (MR-DSA) were performed. Nidal volumes were calculated using CE-SLINKY data in patients with a persisting arteriovenous shunt. Planning angiographic data was investigated in all 40 patients. The following AVM factors were used in the statistical analysis to determine their role in nidus obliteration: (1) maximum linear dimension, (2) nidal volume, (3) AVM location (4) nidal morphology, (5) venous drainage, (6) "high-flow angiographic change", (7) prior embolization, and (8) dose reduction. RESULTS: Complete nidal obliteration was found in 9 patients, 26 showed greater than 50% nidal reduction and 6 had less than 50%. Two AVM factors, venous drainage and AVM location, were found to significantly correlate with rate of obliteration. CONCLUSION: We successfully demonstrated the use of MRA to quantitatively assess the response of AVMs to STRS. Two AVM factors, venous drainage and AVM location were found to correlate with rate of obliteration prior to the application of the Bonferroni correction, but if this more rigorous statistical test was applied then none of the factors was found to be significant.

The use of stereotactic radiosurgery in the management of meningiomas.

This is a systematic review of a consecutive series of 309 meningiomas treated with gamma knife stereotactic radiosurgery between 1994 and 2000. There was an extreme selection bias towards lesions unfavourable for surgery, determined by the patients referred for treatment: 70% of tumours involved the skull base, 47% specifically the cavernous sinus: 15% of patients had multiple meningiomatosis or type 2 neurofibromatosis. Tumour histology was the main determinant of growth control (p < 0.001), the 5-year actuarial control rates being 87% for typical meningiomas, 49% for atypical tumours and 0% for malignant lesions. Complications from radiosurgery were rare, occurring in 3% of tumours, and were most frequently trigeminal and eye movement disturbances treating cavernous sinus meningiomas. Given the problems inherent in managing these tumours, radiosurgery is a valuable strategy and adjuvant treatment for these meningiomas.

Ventricular fibrillation frequency.

BACKGROUND: Ventricular-fibrillation (VF) wave frequency is known to decrease with prolonged, untreated VF. VF wave frequency is used as an algorithm to identify VF in AEDs and ICDs; yet the nature of the frequency change is not appreciated. METHODS: In this study, anesthetized pigs were used and VF was induced electrically. VF wave frequency was measured each second during VF for periods up to 200 sec. Defibrillation was achieved with transchest electrodes. VF wave frequency was plotted for each second during VF. In 2 animals, CPR was applied and VF wave frequency was measured. RESULTS: In all cases VF wave frequency decreased with increasing duration of VF. At the onset of VF, the VF wave frequency ranged from 5 to 12/sec. A plot of the normalized ratio of VF wave frequency during fibrillation to the VF frequency at induction decreased to between 0.1 and 0.8 of the initial frequency. In one of the animals, VF was initiated, CPR was provided and the VF wave frequency was measured over a 200-second period. Then, the procedure was repeated without CPR. Beyond 130 seconds, the VF frequency with CPR was higher than that without CPR, indicating myocardial oxygenation. CONCLUSION: Those who use VF wave frequency to identify the presence of VF should be aware of the nature of the VF wave frequency decrease with the passage of time.

Brain arteriovenous malformations: measurement of nidal volume using a combination of static and dynamic magnetic resonance angiography techniques.

Arteriovenous malformations of the brain are complex vascular lesions that are an important cause of death and long-term disability. Currently, catheter angiography (CA) is the reference standard procedure for the diagnosis and follow-up of treated arteriovenous malformations (AVMs). This is an invasive procedure with potential risks. Magnetic resonance angiography (MRA) is commonly used in neurovascular imaging as a non-invasive alternative. Various MRA techniques have been used in the diagnosis and follow-up of AVMs but these have suffered from lack of temporal or spatial resolution. In this 60-patient study we describe the combination of two techniques: dynamic magnetic resonance digital subtraction angiography with a high temporal resolution, and a non-dynamic contrast-enhanced time-of-flight sequence with a high spatial resolution technique, in the assessment of AVM. The results showed an excellent correlation between MRA and CA measurement of both maximum linear dimension and AVM nidus volume.