Publications by authors named "Davide Martelli"

31 Publications

Reversible Tau Phosphorylation Induced by Synthetic Torpor in the Spinal Cord of the Rat.

Front Neuroanat 2021 2;15:592288. Epub 2021 Feb 2.

Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.

Tau is a key protein in neurons, where it affects the dynamics of the microtubule system. The hyperphosphorylation of Tau (PP-Tau) commonly leads to the formation of neurofibrillary tangles, as it occurs in tauopathies, a group of neurodegenerative diseases, including Alzheimer's. Hypothermia-related accumulation of PP-Tau has been described in hibernators and during synthetic torpor (ST), a torpor-like condition that has been induced in rats, a non-hibernating species. Remarkably, in ST PP-Tau is reversible and Tau de-phosphorylates within a few hours following the torpor bout, apparently not evolving into pathology. These observations have been limited to the brain, but in animal models of tauopathies, PP-Tau accumulation also appears to occur in the spinal cord (SpCo). The aim of the present work was to assess whether ST leads to PP-Tau accumulation in the SpCo and whether this process is reversible. Immunofluorescence (IF) for AT8 (to assess PP-Tau) and Tau-1 (non-phosphorylated Tau) was carried out on SpCo coronal sections. AT8-IF was clearly expressed in the dorsal horns (DH) during ST, while in the ventral horns (VH) no staining was observed. The AT8-IF completely disappeared after 6 h from the return to euthermia. Tau-1-IF disappeared in both DH and VH during ST, returning to normal levels during recovery. To shed light on the cellular process underlying the PP-Tau pattern observed, the inhibited form of the glycogen-synthase kinase 3β (the main kinase acting on Tau) was assessed using IF: VH (i.e., in motor neurons) were highly stained mainly during ST, while in DH there was no staining. Since tauopathies are also related to neuroinflammation, microglia activation was also assessed through morphometric analyses, but no ST-induced microglia activation was found in the SpCo. Taken together, the present results show that, in the DH of SpCo, ST induces a reversible accumulation of PP-Tau. Since during ST there is no motor activity, the lack of AT8-IF in VH may result from an activity-related process at a cellular level. Thus, ST demonstrates a newly-described physiological mechanism that is able to resolve the accumulation of PP-Tau and apparently avoid the neurodegenerative outcome.
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http://dx.doi.org/10.3389/fnana.2021.592288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884466PMC
February 2021

Sympathetic nerves control bacterial clearance.

Sci Rep 2020 09 14;10(1):15009. Epub 2020 Sep 14.

Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia.

A neural reflex mediated by the splanchnic sympathetic nerves regulates systemic inflammation in negative feedback fashion, but its consequences for host responses to live infection are unknown. To test this, conscious instrumented sheep were infected intravenously with live E. coli bacteria and followed for 48 h. A month previously, animals had undergone either bilateral splanchnic nerve section or a sham operation. As established for rodents, sheep with cut splanchnic nerves mounted a stronger systemic inflammatory response: higher blood levels of tumor necrosis factor alpha and interleukin-6 but lower levels of the anti-inflammatory cytokine interleukin-10, compared with sham-operated animals. Sequential blood cultures revealed that most sham-operated sheep maintained high circulating levels of live E. coli throughout the 48-h study period, while all sheep without splanchnic nerves rapidly cleared their bacteraemia and recovered clinically. The sympathetic inflammatory reflex evidently has a profound influence on the clearance of systemic bacterial infection.
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http://dx.doi.org/10.1038/s41598-020-72008-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490383PMC
September 2020

Author Correction: Neural control of fasting-induced torpor in mice.

Sci Rep 2020 Mar 3;10(1):4263. Epub 2020 Mar 3.

Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-61223-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051994PMC
March 2020

Neural control of fasting-induced torpor in mice.

Sci Rep 2019 10 29;9(1):15462. Epub 2019 Oct 29.

Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy.

Torpor is a peculiar mammalian behaviour, characterized by the active reduction of metabolic rate, followed by a drop in body temperature. To enter torpor, the activation of all thermogenic organs that could potentially defend body temperature must be prevented. Most of these organs, such as the brown adipose tissue, are controlled by the key thermoregulatory region of the Raphe Pallidus (RPa). Currently, it is not known which brain areas mediate the entrance into torpor. To identify these areas, the expression of the early gene c-Fos at torpor onset was assessed in different brain regions in mice injected with a retrograde tracer (Cholera Toxin subunit b, CTb) into the RPa region. The results show a network of hypothalamic neurons that are specifically activated at torpor onset and a direct torpor-specific projection from the Dorsomedial Hypothalamus to the RPa that could putatively mediate the suppression of thermogenesis during torpor.
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http://dx.doi.org/10.1038/s41598-019-51841-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820542PMC
October 2019

[The accuracy of hospital discharge records and their use in identifying and staging chronic kidney disease].

G Ital Nefrol 2019 Sep 24;36(5). Epub 2019 Sep 24.

UO Nefrologia, Dialisi e Ipertensione, Ospedale S.Orsola-Malpighi, Bologna.

Administrative databases contain precious information that can support the identification of specific pathologies. Specifically, chronic kidney disease (CKD) patients could be identified using hospital discharge records (HDR); these should contain information on the CKD stage using subcategories of the ICD9-CM classification's 585 code (subcategories can be expressed just by adding a fourth digit to this code). To verify the accuracy of HDR data regarding the coding of CKD collected in the Italian region Emilia-Romagna, we analyzed the HDR records of patients enrolled in the PIRP project, which could easily be matched with eGFR data obtained through laboratory examinations. The PIRP database was used as the gold standard because it contains data on CKD patients followed up since 2004 in thirteen regional nephrology units and includes data obtained from reliable and homogeneous laboratory measurement. All HDR of PIRP patients enrolled between 2009 and 2017 were retrieved and matched with available laboratory data on eGFR, collected within 15 days before or after discharge. We analyzed 4.168 HDR, which were classified as: a) unreported CKD (n=1.848, 44.3%); b) unspecified CKD, when code 585.9 (CKD, not specified) or 586 was used (n=446, 10.7%); c) wrong CKD (n=833, 20.0%); d) correct CKD (n=1041, 25.0%). We noticed the proportion of unreported CKD growing from 32.9% in 2009 to 56.6% in 2017, and the correspondent proportion of correct CKDs decreasing from 25.4% to 22.3%. Across disciplines, Nephrology showed the highest concordance (69.1%) between the CKD stage specified in the HDRs and the stage reported in the matched laboratory exam, while none of the other disciplines, except for Geriatrics, reached 20% concordance. When the CKD stage was incorrectly coded, it was generally underestimated; among HDRs with unreported or unspecified CKD at least half of the discharges were matched with lab exams reporting CKD in stage 4 or 5. We found that the quality of CKD stage coding in the HDR record database was very poor, and insufficient to identify CKD patients unknown to nephrologists. Moreover, the growing proportion of unreported CKD could have an adverse effect on patients' timely referral to a nephrologist, since general practitioners might remain unaware of their patients' illness. Actions aimed at improving the training of the operators in charge of HDRs compilation and, most of all, at allowing the exploitation of the informative potential of HDRs for epidemiological research are thus needed.
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September 2019

[Minimal change disease during lithium therapy: case report].

G Ital Nefrol 2019 Jul 24;36(4). Epub 2019 Jul 24.

UO Nefrologia e Dialisi, Ospedale Santa Maria delle Croci, Ravenna, Ausl Romagna.

Lithium is a largely used and effective therapy in the treatment of bipolar disorder. Its toxic effects on kidneys are mostly diabetes insipidus, hyperchloremic metabolic acidosis and tubulointerstitial nephritis. Also, a correlation between lithium and minimal change disease has sometimes been described. We report here the case of a patient with severe bipolar disorder on lithium therapy who, without any pre-existing nephropathy, developed nephrotic syndrome and AKI with histopathologic findings pointing to minimal change disease. The patient was treated with symptomatic therapy; the discontinuation of lithium therapy resulted in the remission of AKI and of the nephrotic syndrome, thus suggesting a close relationship between lithium and minimal change disease.
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July 2019

Stretchable Low Impedance Electrodes for Bioelectronic Recording from Small Peripheral Nerves.

Sci Rep 2019 07 22;9(1):10598. Epub 2019 Jul 22.

Department of Physics and Astronomy, University of Bologna, Bologna, Italy.

Monitoring of bioelectric signals in peripheral sympathetic nerves of small animal models is crucial to gain understanding of how the autonomic nervous system controls specific body functions related to disease states. Advances in minimally-invasive electrodes for such recordings in chronic conditions rely on electrode materials that show low-impedance ionic/electronic interfaces and elastic mechanical properties compliant with the soft and fragile nerve strands. Here we report a highly stretchable low-impedance electrode realized by microcracked gold films as metallic conductors covered with stretchable conducting polymer composite to facilitate ion-to-electron exchange. The conducting polymer composite based on poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) obtains its adhesive, low-impedance properties by controlling thickness, plasticizer content and deposition conditions. Atomic Force Microscopy measurements under strain show that the optimized conducting polymer coating is compliant with the micro-crack mechanics of the underlying Au-layer, necessary to absorb the tensile deformation when the electrodes are stretched. We demonstrate functionality of the stretchable electrodes by performing high quality recordings of renal sympathetic nerve activity under chronic conditions in rats.
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http://dx.doi.org/10.1038/s41598-019-46967-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646361PMC
July 2019

Temporal validation of the CT-PIRP prognostic model for mortality and renal replacement therapy initiation in chronic kidney disease patients.

BMC Nephrol 2019 05 17;20(1):177. Epub 2019 May 17.

Nephrology, Dialysis and Hypertension Unit, Policlinico S.Orsola-Malpighi, Bologna, Italy.

Background: A classification tree model (CT-PIRP) was developed in 2013 to predict the annual renal function decline of patients with chronic kidney disease (CKD) participating in the PIRP (Progetto Insufficienza Renale Progressiva) project, which involves thirteen Nephrology Hospital Units in Emilia-Romagna (Italy). This model identified seven subgroups with specific combinations of baseline characteristics that were associated with a differential estimated glomerular filtration rate (eGFR) annual decline, but the model's ability to predict mortality and renal replacement therapy (RRT) has not been established yet.

Methods: Survival analysis was used to determine whether CT-PIRP subgroups identified in the derivation cohort (n = 2265) had different mortality and RRT risks. Temporal validation was performed in a matched cohort (n = 2051) of subsequently enrolled PIRP patients, in which discrimination and calibration were assessed using Kaplan-Meier survival curves, Cox regression and Fine & Gray competing risk modeling.

Results: In both cohorts mortality risk was higher for subgroups 3 (proteinuric, low eGFR, high serum phosphate) and lower for subgroups 1 (proteinuric, high eGFR), 4 (non-proteinuric, younger, non-diabetic) and 5 (non-proteinuric, younger, diabetic). Risk of RRT was higher for subgroups 3 and 2 (proteinuric, low eGFR, low serum phosphate), while subgroups 1, 6 (non-proteinuric, old females) and 7 (non-proteinuric, old males) showed lower risk. Calibration was excellent for mortality in all subgroups while for RRT it was overall good except in subgroups 4 and 5.

Conclusions: The CT-PIRP model is a temporally validated prediction tool for mortality and RRT, based on variables routinely collected, that could assist decision-making regarding the treatment of incident CKD patients. External validation in other CKD populations is needed to determine its generalizability.
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http://dx.doi.org/10.1186/s12882-019-1345-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524315PMC
May 2019

Validation of 'Somnivore', a Machine Learning Algorithm for Automated Scoring and Analysis of Polysomnography Data.

Front Neurosci 2019 18;13:207. Epub 2019 Mar 18.

The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia.

Manual scoring of polysomnography data is labor-intensive and time-consuming, and most existing software does not account for subjective differences and user variability. Therefore, we evaluated a supervised machine learning algorithm, Somnivore, for automated wake-sleep stage classification. We designed an algorithm that extracts features from various input channels, following a brief session of manual scoring, and provides automated wake-sleep stage classification for each recording. For algorithm validation, polysomnography data was obtained from independent laboratories, and include normal, cognitively-impaired, and alcohol-treated human subjects (total = 52), narcoleptic mice and drug-treated rats (total = 56), and pigeons ( = 5). Training and testing sets for validation were previously scored manually by 1-2 trained sleep technologists from each laboratory. -measure was used to assess precision and sensitivity for statistical analysis of classifier output and human scorer agreement. The algorithm gave high concordance with manual visual scoring across all human data (wake 0.91 ± 0.01; N1 0.57 ± 0.01; N2 0.81 ± 0.01; N3 0.86 ± 0.01; REM 0.87 ± 0.01), which was comparable to manual inter-scorer agreement on all stages. Similarly, high concordance was observed across all rodent (wake 0.95 ± 0.01; NREM 0.94 ± 0.01; REM 0.91 ± 0.01) and pigeon (wake 0.96 ± 0.006; NREM 0.97 ± 0.01; REM 0.86 ± 0.02) data. Effects of classifier learning from single signal inputs, simple stage reclassification, automated removal of transition epochs, and training set size were also examined. In summary, we have developed a polysomnography analysis program for automated sleep-stage classification of data from diverse species. Somnivore enables flexible, accurate, and high-throughput analysis of experimental and clinical sleep studies.
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http://dx.doi.org/10.3389/fnins.2019.00207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431640PMC
March 2019

c-Fos expression in the limbic thalamus following thermoregulatory and wake-sleep changes in the rat.

Exp Brain Res 2019 Jun 18;237(6):1397-1407. Epub 2019 Mar 18.

Department of Biomedical and NeuroMotor Sciences, University of Bologna, Piazza di Porta San Donato, 2, 40126, Bologna, Italy.

A cellular degeneration of two thalamic nuclei belonging to the "limbic thalamus", i.e., the anteroventral (AV) and mediodorsal (MD) nuclei, has been shown in patients suffering from Fatal Familial Insomnia (FFI), a lethal prion disease characterized by autonomic activation and severe insomnia. To better assess the physiological role of these nuclei in autonomic and sleep regulation, c-Fos expression was measured in rats during a prolonged exposure to low ambient temperature (T, - 10 °C) and in the first hours of the subsequent recovery period at normal laboratory T (25 °C). Under this protocol, the thermoregulatory and autonomic activation led to a tonic increase in waking and to a reciprocal depression in sleep occurrence, which was more evident for REM sleep. These effects were followed by a clear REM sleep rebound and by a rebound of Delta power during non-REM sleep in the following recovery period. In the anterior thalamic nuclei, c-Fos expression was (1) larger during the activity rather than the rest period in the baseline; (2) clamped at a level in-between the normal daily variation during cold exposure; (3) not significantly affected during the recovery period in comparison to the time-matched baseline. No significant changes were observed in either the MD or the paraventricular thalamic nucleus, which is also part of the limbic thalamus. The observed changes in the activity of the anterior thalamic nuclei appear, therefore, to be more specifically related to behavioral activation than to autonomic or sleep regulation.
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http://dx.doi.org/10.1007/s00221-019-05521-2DOI Listing
June 2019

Anti-inflammatory reflex action of splanchnic sympathetic nerves is distributed across abdominal organs.

Am J Physiol Regul Integr Comp Physiol 2019 03 21;316(3):R235-R242. Epub 2018 Dec 21.

Florey Institute of Neuroscience and Mental Health , Parkville, Victoria , Australia.

The splanchnic anti-inflammatory pathway has been proposed as the efferent arm of the inflammatory reflex. Although much evidence points to the spleen as the principal target organ where sympathetic nerves inhibit immune function, a systematic study to locate the target organ(s) of the splanchnic anti-inflammatory pathway has not yet been made. In anesthetized rats made endotoxemic with lipopolysaccharide (LPS, 60 µg/kg iv), plasma levels of tumor necrosis factor-α (TNF-α) were measured in animals with cut (SplancX) or sham-cut (Sham) splanchnic nerves. We confirm here that disengagement of the splanchnic anti-inflammatory pathway in SplancX rats (17.01 ± 0.95 ng/ml, mean ± SE) strongly enhances LPS-induced plasma TNF-α levels compared with Sham rats (3.76 ± 0.95 ng/ml). In paired experiments, the responses of SplancX and Sham animals were compared after the single or combined removal of organs innervated by the splanchnic nerves. Removal of target organ(s) where the splanchnic nerves inhibit systemic inflammation should abolish any difference in LPS-induced plasma TNF-α levels between Sham and SplancX rats. Any secondary effects of extirpating organs should apply to both groups. Surprisingly, removal of the spleen and/or the adrenal glands did not prevent the reflex splanchnic anti-inflammatory action nor did the following removals: spleen + adrenals + intestine; spleen + intestine + stomach and pancreas; or spleen + intestine + stomach and pancreas + liver. Only when spleen, adrenals, intestine, stomach, pancreas, and liver were all removed did the difference between SplancX and Sham animals disappear. We conclude that the reflex anti-inflammatory action of the splanchnic nerves is distributed widely across abdominal organs.
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http://dx.doi.org/10.1152/ajpregu.00298.2018DOI Listing
March 2019

Circulating epinephrine is not required for chronic stress to enhance metastasis.

Psychoneuroendocrinology 2019 01 15;99:191-195. Epub 2018 Sep 15.

Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia; Division of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, Victoria, 3002, Australia; Cousins Center for PNI, UCLA Semel Institute, Jonsson Comprehensive Cancer Center, and UCLA AIDS Institute, University of California Los Angeles, Los Angeles, CA, 90095, USA. Electronic address:

Signaling through β-adrenergic receptors drives cancer progression and β-blockers are being evaluated as a novel therapeutic strategy to prevent metastasis. Orthotopic mouse models of breast cancer show that β-adrenergic signaling induced by chronic stress accelerates metastasis, and that β-adrenergic receptors on tumor cells are critical for this. Endogenous catecholamines are released during chronic stress: norepinephrine from the adrenal medulla and sympathetic nerves, and epinephrine from the adrenal medulla. β-adrenergic receptors are much more sensitive to epinephrine than to norepinephrine. To determine if epinephrine is necessary in the effects of stress on cancer progression, we used a denervation strategy to eliminate circulating epinephrine, and quantified the effect on metastasis. Using both human xenograft and immune-intact murine models of breast cancer, we show that circulating epinephrine is dispensable for the effects of chronic stress on cancer progression. Measured levels of circulating norepinephrine were sufficiently low that they were unlikely to influence β-adrenergic signaling, suggesting a possible role for norepinephrine release from sympathetic nerve terminals.
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http://dx.doi.org/10.1016/j.psyneuen.2018.09.012DOI Listing
January 2019

[Minimal Change Relapse During Pregnancy].

G Ital Nefrol 2018 Jul;35(4)

AUSL della Romagna - U.O. Nefrologia e Dialisi, Ospedale Santa Maria delle Croci, Ravenna, Italia.

The appearance of nephrotic syndrome during pregnancy is considered an exceptional event, whose incidence is around 0.012-0.025% of all pregnancies, and it is even more rare when the cause is represented by minimal lesions glomerulonephritis. In this article we will describe the case of a patient with a histological diagnosis of glomerulonephritis with minimal lesions, tending to frequent relapses. She was in complete remission since 2013 after treatment with cyclosporine. suspended in May 2017. After few weeks she become pregnant, and the pregnancy was regular until the 23rd week. when a recurrence of nephrotic syndrome appears. She was treated with steroids bolus followed by oral steroid, and afterwards gave birth to a live fetus with spontaneous delivery at 37 weeks The few data in the literature confirm that recurrence of glomerulonephritis due to minimal lesions in pregnancy should be treated rapidly with steroids, that can induce rapid remission and protect both the pregnant than the fetus from even serious damage.
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July 2018

Vagal afferent activation suppresses systemic inflammation via the splanchnic anti-inflammatory pathway.

Brain Behav Immun 2018 10 5;73:441-449. Epub 2018 Jun 5.

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3010, Australia; Department of Biomedical and Neuromotor Science (DIBINEM), University of Bologna, Bologna, Italy. Electronic address:

Electrical stimulation of the vagus nerve (VNS) is a novel strategy used to treat inflammatory conditions. Therapeutic VNS activates both efferent and afferent fibers; however, the effects attributable to vagal afferent stimulation are unclear. Here, we tested if selective activation of afferent fibers in the abdominal vagus suppresses systemic inflammation. In urethane-anesthetized rats challenged with lipopolysaccharide (LPS, 60 µg/kg, i.v.), abdominal afferent VNS (2 Hz for 20 min) reduced plasma tumor necrosis factor alpha (TNF) levels 90 min later by 88% compared with unmanipulated animals. Pre-cutting the cervical vagi blocked this anti-inflammatory action. Interestingly, the surgical procedure to expose and prepare the abdominal vagus for afferent stimulation ('vagal manipulation') also had an anti-inflammatory action. Levels of the anti-inflammatory cytokine IL-10 were inversely related to those of TNF. Prior bilateral section of the splanchnic sympathetic nerves reversed the anti-inflammatory actions of afferent VNS and vagal manipulation. Sympathetic efferent activity in the splanchnic nerve was shown to respond reflexly to abdominal vagal afferent stimulation. These data demonstrate that experimentally activating abdominal vagal afferent fibers suppresses systemic inflammation, and that the efferent neural pathway for this action is in the splanchnic sympathetic nerves.
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http://dx.doi.org/10.1016/j.bbi.2018.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319822PMC
October 2018

Integrating Competing Demands of Osmoregulatory and Thermoregulatory Homeostasis.

Physiology (Bethesda) 2018 05;33(3):170-181

Florey Institute of Neuroscience and Mental Health, University of Melbourne , Parkville , Australia.

Mammals are characterized by a stable core body temperature. When maintenance of core temperature is challenged by ambient or internal heat loads, mammals increase blood flow to the skin, sweat and/or pant, or salivate. These thermoregulatory responses enable evaporative cooling at moist surfaces to dissipate body heat. If water losses incurred during evaporative cooling are not replaced, body fluid homeostasis is challenged. This article reviews the way mammals balance thermoregulation and osmoregulation.
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http://dx.doi.org/10.1152/physiol.00037.2017DOI Listing
May 2018

[Atypical hemolytic uremic syndrome related to Oxalyplatin Cancer Chemotherapy responsive to Eculizumab].

G Ital Nefrol 2017 Jan-Feb;34(1)

We describe the case of a patient with adenocarcinoma of the colon treated with FOLFOX-4 (5-Fluorouracil, Folinic acid, Oxalyplatin), with subsequent appearance of atypical hemolytic uremic syndrome (aHUS). From 1999 to 2009, 13 cases of atypical HUS receiving chemotherapy with oxaliplatin have been described, as well as some sporadic cases. None of these cases has been treated with eculizumab. This is the first report of a patient with aHUS secondary to Oxalyplatin treated with Eculizumab. This treatment induced a complete remission of the syndrome and, later on, it has been discontinued with clinical and laboratory permanent remission. We identified some genetic mutations in this patient that might have a pathogenic role in the determining aHUS when associated with exposure to Oxalyplatin. Oxalyplatin withdrawal and its replacement to Irinotecan allowed the patient to receive first line chemotherapy continuation (FOLFIRI) with the same life expectancy and the same symptoms free period.
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November 2017

Wake-sleep and cardiovascular regulatory changes in rats made obese by a high-fat diet.

Behav Brain Res 2017 03 21;320:347-355. Epub 2016 Dec 21.

Department of Biomedical and Neuromotor Sciences-Physiology, Alma Mater Studiorum - University of Bologna, Piazza di Porta San Donato, 2, 40126, Bologna, Italy. Electronic address:

Obesity is known to be associated with alterations in wake-sleep (WS) architecture and cardiovascular parameters. This study was aimed at assessing the possible influence of diet-induced obesity (DIO) on sleep homeostasis and on the WS state-dependent levels of arterial pressure (AP) and heart rate in the rat. Two groups of age-matched Sprague-Dawley rats were fed either a high-fat hypercaloric diet, leading to DIO, or a normocaloric standard diet (lean controls) for 8 weeks. While under general anesthesia, animals were implanted with instrumentation for the recording of electroencephalogram, electromyogram, arterial pressure, and deep brain temperature. The experimental protocol consisted of 48h of baseline, 12h of gentle handling, enhancing wake and depressing sleep, and 36-h post-handling recovery. Compared to lean controls, DIO rats showed: i) the same amount of rapid-eye movement (REM) and non-REM (NREM) sleep in the rest period, although the latter was characterized by more fragmented episodes; ii) an increase in both REM sleep and NREM sleep in the activity period; iii) a comparable post-handling sleep homeostatic response, in terms of either the degree of Delta power increase during NREM sleep or the quantitative compensation of the REM sleep loss at the end of the 36-h recovery period; iv) significantly higher levels of AP, irrespectively of the different WS states and of the changes in their intensity throughout the experimental protocol. Overall, these changes may be the reflection of a modification in the activity of the hypothalamic areas where WS, autonomic, and metabolic regulations are known to interact.
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http://dx.doi.org/10.1016/j.bbr.2016.12.024DOI Listing
March 2017

Letter to the editor: Parasympathetic innervation of the rodent spleen?

Am J Physiol Heart Circ Physiol 2015 Dec;309(12):H2158

Department of Anatomy and Neuroscience, University of Melbourne, Australia; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia; and

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http://dx.doi.org/10.1152/ajpheart.00766.2015DOI Listing
December 2015

The interface between cholinergic pathways and the immune system and its relevance to arthritis.

Arthritis Res Ther 2015 Mar 31;17:87. Epub 2015 Mar 31.

Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, 3010, Australia.

The nervous and immune systems are likely to be interacting in arthritis, with the possible involvement of both neural and non-neural cholinergic transmission. Centrally acting muscarinic agonists, electrical stimulation of the vagus and treatment with nicotinic receptor agonists can all act systemically to reduce inflammation, although the responsible pathways are incompletely understood. While this 'cholinergic anti-inflammatory pathway' is widely viewed as a significant pathophysiological mechanism controlling inflammation, the evidence supporting this view is critically reviewed and considered inconclusive; an alternative pathway via sympathetic nerves is implicated. This review also discusses how cholinergic pathways, both neural and non-neural, may impact on inflammation and specifically arthritis. Nicotinic agonists have been reported to reduce the incidence and severity of murine arthritis, albeit an observation we could not confirm, and clinical studies in rheumatoid arthritis have been proposed and/or are underway. While the therapeutic potential of nicotinic agonists and vagal stimulation is clear, we suggest that the 'cholinergic anti-inflammatory pathway' should not be uncritically embraced as a significant factor in the pathogenesis of rheumatoid arthritis.
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http://dx.doi.org/10.1186/s13075-015-0597-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378008PMC
March 2015

Reply to "Letter to the editor: Does low-frequency power of heart rate variability correlate with cardiac sympathetic tone in normal sheep?".

Am J Physiol Heart Circ Physiol 2015 Jan;308(2):H148-9

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia; Department of Physiology, University of Auckland, Auckland, New Zealand

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http://dx.doi.org/10.1152/ajpheart.00848.2014DOI Listing
January 2015

Enhanced slow-wave EEG activity and thermoregulatory impairment following the inhibition of the lateral hypothalamus in the rat.

PLoS One 2014 14;9(11):e112849. Epub 2014 Nov 14.

Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy.

Neurons within the lateral hypothalamus (LH) are thought to be able to evoke behavioural responses that are coordinated with an adequate level of autonomic activity. Recently, the acute pharmacological inhibition of LH has been shown to depress wakefulness and promote NREM sleep, while suppressing REM sleep. These effects have been suggested to be the consequence of the inhibition of specific neuronal populations within the LH, i.e. the orexin and the MCH neurons, respectively. However, the interpretation of these results is limited by the lack of quantitative analysis of the electroencephalographic (EEG) activity that is critical for the assessment of NREM sleep quality and the presence of aborted NREM-to-REM sleep transitions. Furthermore, the lack of evaluation of the autonomic and thermoregulatory effects of the treatment does not exclude the possibility that the wake-sleep changes are merely the consequence of the autonomic, in particular thermoregulatory, changes that may follow the inhibition of LH neurons. In the present study, the EEG and autonomic/thermoregulatory effects of a prolonged LH inhibition provoked by the repeated local delivery of the GABAA agonist muscimol were studied in rats kept at thermoneutral (24°C) and at a low (10°C) ambient temperature (Ta), a condition which is known to depress sleep occurrence. Here we show that: 1) at both Tas, LH inhibition promoted a peculiar and sustained bout of NREM sleep characterized by an enhancement of slow-wave activity with no NREM-to-REM sleep transitions; 2) LH inhibition caused a marked transitory decrease in brain temperature at Ta 10°C, but not at Ta 24°C, suggesting that sleep changes induced by LH inhibition at thermoneutrality are not caused by a thermoregulatory impairment. These changes are far different from those observed after the short-term selective inhibition of either orexin or MCH neurons, suggesting that other LH neurons are involved in sleep-wake modulation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0112849PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232523PMC
December 2015

Reflex control of inflammation by the splanchnic anti-inflammatory pathway is sustained and independent of anesthesia.

Am J Physiol Regul Integr Comp Physiol 2014 Nov 27;307(9):R1085-91. Epub 2014 Aug 27.

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia; Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia

Following an immune challenge, there is two-way communication between the nervous and immune systems. It is proposed that a neural reflex--the inflammatory reflex--regulates the plasma levels of the key proinflammatory cytokine TNF-α, and that its efferent pathway is in the splanchnic sympathetic nerves. The evidence for this reflex is based on experiments on anesthetized animals, but anesthesia itself suppresses inflammation, confounding interpretation. Here, we show that previous section of the splanchnic nerves strongly enhances the levels of plasma TNF-α in conscious rats 90 min after they received intravenous LPS (60 μg/kg). The same reflex mechanism, therefore, applies in conscious as in anesthetized animals. In anesthetized rats, we then determined the longer-term effects of splanchnic nerve section on responses to LPS (60 μg/kg iv). We confirmed that prior splanchnic nerve section enhanced the early (90 min) peak in plasma TNF-α and found that it reduced the 90-min peak of the anti-inflammatory cytokine IL-10; both subsequently fell to low levels in all animals. Splanchnic nerve section also enhanced the delayed rise in two key proinflammatory cytokines IL-6 and interferon γ. That enhancement was undiminished after 6 h, when other measured cytokines had subsided. Finally, LPS treatment caused hypotensive shock in rats with cut splanchnic nerves but not in sham-operated animals. These findings demonstrate that reflex activation of the splanchnic anti-inflammatory pathway has a powerful and sustained restraining influence on inflammatory processes.
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http://dx.doi.org/10.1152/ajpregu.00259.2014DOI Listing
November 2014

The low frequency power of heart rate variability is neither a measure of cardiac sympathetic tone nor of baroreflex sensitivity.

Am J Physiol Heart Circ Physiol 2014 Oct 25;307(7):H1005-12. Epub 2014 Jul 25.

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia; Department of Physiology, University of Auckland, Auckland, New Zealand

The lack of noninvasive approaches to measure cardiac sympathetic nerve activity (CSNA) has driven the development of indirect estimates such as the low-frequency (LF) power of heart rate variability (HRV). Recently, it has been suggested that LF HRV can be used to estimate the baroreflex modulation of heart period (HP) rather than cardiac sympathetic tone. To test this hypothesis, we measured CSNA, HP, blood pressure (BP), and baroreflex sensitivity (BRS) of HP, estimated with the modified Oxford technique, in conscious sheep with pacing-induced heart failure and in healthy control sheep. We found that CSNA was higher and systolic BP and HP were lower in sheep with heart failure than in control sheep. Cross-correlation analysis showed that in each group, the beat-to-beat changes in HP correlated with those in CSNA and in BP, but LF HRV did not correlate significantly with either CSNA or BRS. However, when control sheep and sheep with heart failure were considered together, CSNA correlated negatively with HP and BRS. There was also a negative correlation between CSNA and BRS in control sheep when considered alone. In conclusion, we demonstrate that in conscious sheep, LF HRV is neither a robust index of CSNA nor of BRS and is outperformed by HP and BRS in tracking CSNA. These results do not support the use of LF HRV as a noninvasive estimate of either CSNA or baroreflex function, but they highlight a link between CSNA and BRS.
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http://dx.doi.org/10.1152/ajpheart.00361.2014DOI Listing
October 2014

Neural control of inflammation by the greater splanchnic nerves.

Temperature (Austin) 2014 Apr-Jun;1(1):14-5. Epub 2014 May 7.

Florey Institute of Neuroscience and Mental Health; University of Melbourne; Parkville, Australia; Department of Anatomy and Neuroscience; University of Melbourne; Parkville, Australia.

The brain influences immune function through a powerful neural reflex that suppresses the release of a key pro-inflammatory cytokine, tumor necrosis factor α, after immune challenge. The efferent motor pathway of this reflex is in the splanchnic nerves, not the vagi. This reflex regulates inflammation but does not suppress fever.
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http://dx.doi.org/10.4161/temp.29135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972513PMC
September 2016

The direct cooling of the preoptic-hypothalamic area elicits the release of thyroid stimulating hormone during wakefulness but not during REM sleep.

PLoS One 2014 3;9(2):e87793. Epub 2014 Feb 3.

Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy.

Thermoregulatory responses to temperature changes are not operant during REM sleep (REMS), but fully operant in non-REM sleep and wakefulness. The specificity of the relationship between REMS and the impairment of thermoregulation was tested by eliciting the reflex release of Thyrotropin Releasing Hormone (TRH), which is integrated at hypothalamic level. By inducing the sequential secretion of Thyroid Stimulating Hormone (TSH) and Thyroid Hormone, TRH intervenes in the regulation of obligatory and non-shivering thermogenesis. Experiments were performed on male albino rats implanted with epidural electrodes for EEG recording and 2 silver-copper wire thermodes, bilaterally placed in the preoptic-hypothalamic area (POA) and connected to small thermoelectric heat pumps driven by a low-voltage high current DC power supply. In preliminary experiments, a thermistor was added in order to measure hypothalamic temperature. The activation of TRH hypophysiotropic neurons by the thermode cooling of POA was indirectly assessed, in conditions in which thermoregulation was either fully operant (wakefulness) or not operant (REMS), by a radioimmunoassay determination of plasmatic levels of TSH. Different POA cooling were performed for 120 s or 40 s at current intensities of 80 mA and 125 mA, respectively. At both current intensities, POA cooling elicited, with respect to control values (no cooling current), a significant increase in plasmatic TSH levels in wakefulness, but not during REMS. These results confirm the inactivation of POA thermal sensitivity during REMS and show, for the first time, that this inactivation concerns also the fundamental endocrine control of non-shivering thermogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087793PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3911997PMC
October 2014

Waking and sleeping in the rat made obese through a high-fat hypercaloric diet.

Behav Brain Res 2014 Jan 19;258:145-52. Epub 2013 Oct 19.

Department of Biomedical and NeuroMotor Sciences - Physiology, Alma Mater Studiorum - University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy. Electronic address:

Sleep restriction leads to metabolism dysregulation and to weight gain, which is apparently the consequence of an excessive caloric intake. On the other hand, obesity is associated with excessive daytime sleepiness in humans and promotes sleep in different rodent models of obesity. Since no consistent data on the wake-sleep (WS) pattern in diet-induced obesity rats are available, in the present study the effects on the WS cycle of the prolonged delivery of a high-fat hypercaloric (HC) diet leading to obesity were studied in Sprague-Dawley rats. The main findings are that animals kept under a HC diet for either four or eight weeks showed an overall decrease of time spent in wakefulness (Wake) and a clear Wake fragmentation when compared to animals kept under a normocaloric diet. The development of obesity was also accompanied with the occurrence of a larger daily amount of REM sleep (REMS). However, the capacity of HC animals to respond to a "Continuous darkness" exposure condition (obtained by extending the Dark period of the Light-Dark cycle to the following Light period) with an increase of Sequential REMS was dampened. The results of the present study indicate that if, on one hand, sleep curtailment promotes an excess of energy accumulation; on the other hand an over-exceeding energy accumulation depresses Wake. Thus, processes underlying energy homeostasis possibly interact with those underlying WS behavior, in order to optimize energy storage.
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http://dx.doi.org/10.1016/j.bbr.2013.10.014DOI Listing
January 2014

The emerging role of the parabrachial complex in the generation of wakefulness drive and its implication for respiratory control.

Respir Physiol Neurobiol 2013 Sep 28;188(3):318-23. Epub 2013 Jun 28.

Florey Institute of Neuroscience and Mental Health, Gate 11, Royal Parade, University of Melbourne, Victoria 3052, Australia.

The parabrachial complex is classically seen as a major neural knot that transmits viscero- and somatosensory information toward the limbic and thalamic forebrain. In the present review we summarize recent findings that imply an emerging role of the parabrachial complex as an integral part of the ascending reticular arousal system, which promotes wakefulness and cortical activation. The ascending parabrachial projections that target wake-promoting hypothalamic areas and the basal forebrain are largely glutamatergic. Such fast synaptic transmission could be even more significant in promoting wakefulness and its characteristic pattern of cortical activation than the cholinergic or mono-aminergic ascending pathways that have been emphasized extensively in the past. A similar role of the parabrachial complex could also apply for its more established function in control of breathing. Here the parabrachial respiratory neurons may modulate and adapt breathing via the control of respiratory phase transition and upper airway patency, particularly during respiratory and non-respiratory behavior associated with wakefulness.
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http://dx.doi.org/10.1016/j.resp.2013.06.019DOI Listing
September 2013

The inhibition of neurons in the central nervous pathways for thermoregulatory cold defense induces a suspended animation state in the rat.

J Neurosci 2013 Feb;33(7):2984-93

Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum-University of Bologna, 40126 Bologna Italy.

The possibility of inducing a suspended animation state similar to natural torpor would be greatly beneficial in medical science, since it would avoid the adverse consequence of the powerful autonomic activation evoked by external cooling. Previous attempts to systemically inhibit metabolism were successful in mice, but practically ineffective in nonhibernators. Here we show that the selective pharmacological inhibition of key neurons in the central pathways for thermoregulatory cold defense is sufficient to induce a suspended animation state, resembling natural torpor, in a nonhibernator. In rats kept at an ambient temperature of 15°C and under continuous darkness, the prolonged inhibition (6 h) of the rostral ventromedial medulla, a key area of the central nervous pathways for thermoregulatory cold defense, by means of repeated microinjections (100 nl) of the GABA(A) agonist muscimol (1 mm), induced the following: (1) a massive cutaneous vasodilation; (2) drastic drops in deep brain temperature (reaching a nadir of 22.44 ± 0.74°C), heart rate (from 440 ± 13 to 207 ± 12 bpm), and electroencephalography (EEG) power; (3) a modest decrease in mean arterial pressure; and (4) a progressive shift of the EEG power spectrum toward slow frequencies. After the hypothermic bout, all animals showed a massive increase in NREM sleep Delta power, similarly to that occurring in natural torpor. No behavioral abnormalities were observed in the days following the treatment. Our results strengthen the potential role of the CNS in the induction of hibernation/torpor, since CNS-driven changes in organ physiology have been shown to be sufficient to induce and maintain a suspended animation state.
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http://dx.doi.org/10.1523/JNEUROSCI.3596-12.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619194PMC
February 2013

Waking and sleeping following water deprivation in the rat.

PLoS One 2012 24;7(9):e46116. Epub 2012 Sep 24.

Department of Human and General Physiology, Alma Mater Studiorum-University of Bologna, Italy.

Wake-sleep (W-S) states are affected by thermoregulation. In particular, REM sleep (REMS) is reduced in homeotherms under a thermal load, due to an impairment of hypothalamic regulation of body temperature. The aim of this work was to assess whether osmoregulation, which is regulated at a hypothalamic level, but, unlike thermoregulation, is maintained across the different W-S states, could influence W-S occurrence. Sprague-Dawley rats, kept at an ambient temperature of 24°C and under a 12 h∶12 h light-dark cycle, were exposed to a prolonged osmotic challenge of three days of water deprivation (WD) and two days of recovery in which free access to water was restored. Two sets of parameters were determined in order to assess: i) the maintenance of osmotic homeostasis (water and food consumption; changes in body weight and fluid composition); ii) the effects of the osmotic challenge on behavioral states (hypothalamic temperature (Thy), motor activity, and W-S states). The first set of parameters changed in WD as expected and control levels were restored on the second day of recovery, with the exception of urinary Ca(++) that almost disappeared in WD, and increased to a high level in recovery. As far as the second set is concerned, WD was characterized by the maintenance of the daily oscillation of Thy and by a decrease in activity during the dark periods. Changes in W-S states were small and mainly confined to the dark period: i) REMS slightly decreased at the end of WD and increased in recovery; ii) non-REM sleep (NREMS) increased in both WD and recovery, but EEG delta power, a sign of NREMS intensity, decreased in WD and increased in recovery. Our data suggest that osmoregulation interferes with the regulation of W-S states to a much lesser extent than thermoregulation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0046116PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3454381PMC
March 2013

Hypothalamic osmoregulation is maintained across the wake-sleep cycle in the rat.

J Sleep Res 2010 Sep 31;19(3):394-9. Epub 2010 Mar 31.

Department of Human and General Physiology, Alma Mater Studiorum-University of Bologna, Bologna, Italy.

In different species, rapid eye movement sleep (REMS) is characterized by a thermoregulatory impairment. It has been postulated that this impairment depends on a general insufficiency in the hypothalamic integration of autonomic function. This study aims to test this hypothesis by assessing the hypothalamic regulation of body fluid osmolality during the different wake-sleep states in the rat. Arginine-vasopressin (AVP) plasma levels were determined following intracerebroventricular (ICV) infusions of artificial cerebrospinal fluid (aCSF), either isotonic or made hypertonic by the addition of NaCl at three different concentrations (125, 250 and 500 mM). Animals were implanted with a cannula within a lateral cerebral ventricle for ICV infusions and with electrodes for the recording of the electroencephalogram. ICV infusions were made in different animals during Wake, REMS or non-REM sleep (NREMS). The results show that ICV infusion of hypertonic aCSF during REMS induced an increase in AVP plasma levels that was not different from that observed during either Wake or NREMS. These results suggest that the thermoregulatory impairment that characterizes REMS does not depend on a general impairment in the hypothalamic control of body homeostasis.
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http://dx.doi.org/10.1111/j.1365-2869.2009.00810.xDOI Listing
September 2010