Carey, Hannah V., Matthew T. Andrews, and Sandra L. Martin. Mammalian Hibernation: Cellular and Molecular Responses to Depressed Metabolism and Low Temperature. Physiol Rev 83: 1153-1181, 2003; 10....

https://www.physiology.org/doi/pdf/10.1152/physrev.00008.2003

Mammalian Hibernation: Cellular and Molecular Responses to Depressed Metabolism and Low Temperature

The active migration of tumor cells, a crucial requirement for metastasis development and cancer progression, is regulated by signal substances including neurotransmitters. We investigated the migration of tumor cells within a three-dimensional collagen matrix using time-lapse videomicroscopy and computer-assisted analysis of the migration path. Tumor cell migration is induced by norepinephrine, dopamine and substance P. We show that this induced migration, using MDA-MB-468 breast and PC-3 prostate carcinoma cells, can be inhibited by using specific, clinically established receptor antagonists to the beta2-adrenoceptor, the D2 receptor, or the neurokinin-1 receptor, respectively. All of the investigated neurotransmitters significantly activated the cyclic adenosine-monophosphate response element binding protein (CREB). Furthermore, microarray analysis revealed changes of gene expression toward a highly motile tumor cell type, including an upregulation of the alpha2 integrin, which is an essential adhesion receptor for collagen in migration. The gene for the tumor suppressor gelsolin was downregulated. These 2 critical alterations were confirmed on the protein level by flow-cytometry and immunoblotting, respectively. Neurotransmitters thus induce a metastatogenic tumor cell type by directly regulating gene expression and increased migratory activity, which can be prevented by established neurotransmitter antagonists.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.20410

Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs.

Torpor during hibernation defines the nadir of mammalian metabolism where whole animal rates of metabolism are decreased to as low as 2% of basal metabolic rate This capacity to decrease profoundly the metabolic demand of organs and tissues has the potential to translate into novel therapies for the treatment of ischemia associated with stroke, cardiac arrest or trauma where delivery of oxygen and nutrients fails to meet demand If metabolic demand could be arrested in a regulated way, cell and tissue injury could be attenuated Metabolic suppression achieved during hibernation is regulated, in part, by the central nervous system through indirect and possibly direct means In this study, we review recent evidence for mechanisms of central nervous system control of torpor in hibernating rodents including evidence of a permissive, hibernation protein complex, a role for A1 adenosine receptors, mu opiate receptors, glutamate and thyrotropin-releasing hormone Central sites for regulation of torpor include the hippocampus, hypothalamus and nuclei of the autonomic nervous system In addition, we discuss evidence that hibernation phenotypes can be translated to non-hibernating species by H2S and 3-iodothyronamine with the caveat that the hypothermia, bradycardia, and metabolic suppression induced by these compounds may or may not be identical to mechanisms employed in true hibernation

Central nervous system regulation of mammalian hibernation: implications for metabolic suppression and ischemia tolerance

What Is Evidence-Based About Myofascial Chains: A Systematic Review

Metastin, the gene product of metastasis suppressor gene KiSS-1, is the endogenous ligand for the G-protein-coupled receptor GPR54 (or AXOR12, or OT7T175). The expression of KiSS-1 gene and peptide and the distribution of metastin were studied in the rat central nervous system by reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemical methods. KiSS-1 gene and peptide expression was higher in the hypothalamus than in the brainstem and spinal cord. In the brain, metastin-like immunoreactivity (irMT) was found mainly in three groups of cells: dorsomedial hypothalamic nucleus, nucleus of the solitary tract, and caudal ventrolateral medulla. Immunoreactive fibers of varying density were noted in bed nucleus of stria terminalis, septal nuclei, nucleus accumbens, caudate putamen, diagonal band, amygdala, hypothalamus, zona incerta, thalamus, periaqueductal gray, raphe nuclei, lateral parabrachial nucleus, locus coeruleus, spinal trigeminal tract, rostral ventrolateral medulla, and medullary reticular nucleus. Preabsorption of the antiserum with metastin peptide fragment (45-54)-NH2 (1 microg/ml) resulted in no staining in any of the sections. The biological activity of metastin was assessed by monitoring intracellular calcium [Ca2+]i in cultured hippocampal neurons, which are known to express GPR54. Metastin increased [Ca2+]i in a population of cultured hippocampal neurons. The results show that metastin is biologically active in rat central neurons, and its anatomical distribution suggests a possible role in nociception and autonomic and neuroendocrine functions.

KiSS-1 expression and metastin-like immunoreactivity in the rat brain.

Although systematic reviews are conducted in the field of anatomical research, no instruments exist for the assessment of study quality. Thus, our objective was to develop a valid tool that reliably assesses the methodological quality of observational cadaveric studies. The QUACS scale (QUality Appraisal for Cadaveric Studies) was developed using an expert consensus process. It consists of a 13-item checklist addressing the design, conduct and report of cadaveric dissection studies. To evaluate inter-rater reliability, a blinded investigator obtained an initial pool of 120 observational cadaveric studies. Sixty-eight of them were selected randomly according to sample size calculations. Three independent researchers rated each publication by means of the QUACS scale. The reliability of the total score was estimated using the intraclass correlation coefficient (ICC). To assess agreement among individual items, margin-free kappa values were calculated. For construct validity, two experts (an anatomist and an experienced physician) categorized the quality of 15 randomly selected studies as ‘excellent’ (4 points), ‘moderate to good’ (3 points), poor to moderate’ (2 points) or ‘poor’ (1 point). Kendall's tau rank correlation was used to compare the expert ratings with the scores on the QUACS scale. An evaluation of feasibility was carried out during the reliability analysis. All three raters recorded the duration of quality appraisal for each article. Means were used to describe average time exposure. The ICC for the total score was 0.87 (95% confidence interval: 0.82–0.92; P < 0.0001). For individual items, margin-free kappa values ranged between 0.56 and 0.96 with an agreement of 69–97% among the three raters. Kendall's tau B coefficient of the association between expert ratings and the results obtained with the QUACS scale was 0.69 (P < 0.01). Required rating time per article was 5.4 ± 1.6 min. The QUACS scale is highly reliable and exhibits strong construct validity. Thus, it can confidently be applied in assessing the methodological quality of observational dissection studies.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/joa.12292

Appraising the methodological quality of cadaveric studies: validation of the QUACS scale

CONTEXT Medical students are at risk of occupational exposure to blood-borne viruses following needlestick injuries (NSIs) during medical school. The reporting of NSIs is an important step in the prevention of further injuries and in the initiation of early prophylaxis or treatment. The objective of this study was to describe the mechanisms whereby medical students experience occupational percutaneous blood exposure through NSIs and to discuss rational strategies for prevention. METHODS Incidents of exposure to blood-borne pathogens among medical students at a large German university were analysed. Year 6 medical students completed a written survey immediately before the clinical part of their training began, describing incidents that had occurred during the previous 5 years. RESULTS In our study, 58.8% (183/311) of participating medical students recalled at least one NSI that had occurred during their studies. Overall, 284 NSIs were reported via an anonymous questionnaire. DISCUSSION Occupational exposure to blood is a common problem among medical students. Efforts are required to ensure greater awareness of the risks associated with blood-borne pathogens among German medical students. Proper training in percutaneous procedures and how to act in the event of injury should be given in order to reduce the number of injuries.

Needlestick injuries among German medical students: time to take a different approach?

The present review describes the distribution and the function-dependent reactivity pattern of those peptidergic and aminergic components of the neuroendocrine system of hibernating mammals that have been studied by histological, pharmacological and physiological techniques. Particular attention has been paid to the intrinsic connectivity of the peptidergic apparatus and its input systems. Since the reactivity patterns of the neuroendocrine system show remarkable fluctuations in relation to the various stages of hibernation and euthermia, these fluctuations have been analyzed with respect to (1) their causative role in the regulation of hibernation and (2) their secondary response to physiological changes during hibernation. The author's investigations described in this review have mainly been performed in European hedgehogs (Erinaceus europaeus), European and golden hamsters (Cricetus cricetus, Mesocricetus auratus), dormice (Glis glis), and in Richardson's and Columbian ground squirrels (Spermophilus richardsonii, Spermophilus columbianus), by the use of light- and electron-microscopic immunocytochemistry and histochemistry, in situ hybridization, radioimmunoassays and stereotaxically guided application techniques. These experiments were also performed in hypothermic animals. The (partially published) results obtained by the author and his associates are reviewed with reference to the body of evidence found in the recent literature. With respect to their reactivity patterns, several neuropeptide and transmitter systems can be regarded as candidates for control systems of hibernation. Neuronal complexes immunoreactive for endogenous opiates, in particular enkephalin, and also for vasopressin, somatostatin, substance P, corticotropin-releasing factor and serotonin are probably involved in the neuroendocrine control of hibernation.

The neuroendocrine system in hibernating mammals: present knowledge and open questions.

The dispersed cell culture as model for functional studies of the subcommissural organ: preparation and characterization of the culture system.

The subcommissural organ (SCO) of mammals is innervated by several neuropeptide and neurotransmitter systems. So far, substance P (SP), oxytocin (OXT), vasopressin (VP), somatostatin (SOM), thyrotropin-releasing factor (TRF), and angiotensin II (ANGII) were identified in neuropeptidergic input systems, and serotonin (5HT), gamma-amino butyric acid (GABA), noradrenaline (NA), dopamine (DA), and acetylcholine (Ach) were neurotransmitters observed in systems afferent to the SCO. In the present report, based on literature data and our own investigations, we describe the occurrence of peptide and transmitter receptors in the SCO by means of autoradiographic and biochemical studies. Further, we summarize aspects of the signal transduction cascades possibly linked to different receptor types of the SCO; these studies included the use of calcium imaging (FURA-2 technique), ELISA technique, and immunocytochemistry. Receptors were identified for adenosine, angiotensin II, imidazoline, glucocorticoids, mineralocorticoids, NA, and embryonic brain kinase. The studies on intracellular signal-transduction indicated receptors for tachykinins and for ATP. In SCO cells, Ca(++) and c-AMP were identified to act as second messengers. As important transcription factor, cAMP-/Ca(++)-response element binding protein (CREB) was observed. Ach and NA did not show a significant effect on the subcommissural signal transduction.

Frank Nürnberger

Papers

Appraising the methodological quality of cadaveric studies: validation of the QUACS scale

Needlestick injuries among German medical students: time to take a different approach?

The neuroendocrine system in hibernating mammals: present knowledge and open questions.

The dispersed cell culture as model for functional studies of the subcommissural organ: preparation and characterization of the culture system.

Presence and functional significance of neuropeptide and neurotransmitter receptors in subcommissural organ cells.