Involvement of hyaluronidases in colorectal cancer

Background  

Hyaluronidases belong to a class of enzymes that degrade, predominantly, hyaluronan. These enzymes are known to be involved in physiological and pathological processes, such as tumor growth, infiltration and angiogenesis, but their exact role in tumor promotion or suppression is not clear yet. Advanced colorectal cancer is associated with elevated amounts of hyaluronan of varying size. The aim of the present study was therefore to illuminate the importance of hyaluronidases in colon carcinoma progression.     

1H NMR-based metabonomics approach in a rat model of acute liver injury and regeneration induced by CCl4 administration

The administration of carbon tetrachloride (CCl₄) has been established as a model of toxin-induced acute and chronic liver injury. In the present study, we investigate the progression of the biochemical response to acute CCl₄-induced liver injury, capturing metabolic variations during both toxic insult and regeneration using NMR-based metabonomic analysis of liver tissue and plasma.A single dose of CCl₄ (1 mL/kg BW) was intraperitoneally administered to male Wister rats sacrificed every 12 h up to 72 h post treatment, while healthy animals served as controls. Acquired ¹H NMR spectra of liver tissue extracts and plasma samples were explored with multivariate analysis and the resulted models were correlated with conventional biochemical and histopathological indices of toxicity for monitoring the progression of experimental injury.The metabonomic analysis resulted in discrimination between the subjects under toxic insult (up to 36 h) and those at the regenerative phase (peaked at 48 h). At 72 h normalization of liver's pathology similar to the controls group was apparent. Principal component analysis (PCA) trajectories highlighted the time points of the greater degree of toxic insult and the regenerative state.A number of metabolites such as glucose, lactate, choline, formate exhibited variations suggesting CCl₄ induced impairment in essential biochemical pathways as energy metabolism, lipid biosynthesis and transmethylation reactions. The latter provides new evidence of B12 and folate pathways deficiency, indicative of new mechanistic implications possibly by direct inhibition of B12 dependent enzymes by the chlorinated radicals of CCl₄ metabolism.     

Ablating the Imperceptible: A Novel Application of Para‐Hisian Pacing

In some elderly patients with atrial fibrillation, especially in combination with heart failure, a rate control strategy may be preferred. When pharmacological therapy is ineffective or not tolerated, it is reasonable to perform atrioventricular (AV) node ablation with ventricular pacing. We describe a case in which this approach was necessary for management. However, the presence of periprocedural, drug‐induced AV block just before ablation provided a unique and challenging circumstance. We discuss the steps taken to ensure a successful procedure.     

Evaluation of a direct test for seasonal influenza in outpatients

ObjectiveTo present our experience regarding the use of a rapid diagnostic test for seasonal influenza A and B.MethodsWe systematically collected and analyzed our data regarding the use of a rapid diagnostic test for seasonal influenza A and B in patients with specific respiratory symptoms that sought medical services, during the time period from 01/01/2009 to 30/05/2009, from a network of physicians (SOS Doctors) who perform house-call visits in the area of Attica, Greece.ResultsFrom the total of 16,335 house-call visits performed during the evaluated period, 3412 (20.8%) were due to respiratory/influenza symptoms; 197 (5.8%) patients were tested for influenza. From the 184 patients with available data regarding the test result, 97 (52.7%) were positive for influenza. Significantly more oseltamivir and less antibiotic treatment were prescribed to patients with positive test result compared with those with a negative test result. Additionally, the impact of the test in the participating physicians' decision making was obvious, as doctors who used the test systematically prescribed significantly more oseltamivir and less antibiotic treatment compared to the doctors who didn't use the test.ConclusionThe use of a rapid test for seasonal influenza enabled the targeted treatment with oseltamivir, as well as a reduction in antibiotic treatment, in patients found positive for influenza in our clinical setting.     

Insight into pain‐inducing and ‐related gene expression: a challenge for development of novel targeted therapeutic approaches

The multidimensional issue of pain in relation to the need for efficient treatment has been the focus of extensive research. Gaining insight into the molecular mechanisms of pain and identifying specific genes and proteins as possible drug targets is strongly required considering that not all patients can be adequately treated with the currently available drugs. This up‐to‐date review aimed to summarize the findings of recent proteomic and genomic approaches in different types of pain to comment on their potential role in pain signaling pathways and to evaluate their possible contribution to the development of novel and possibly more targeted pain therapeutic strategies. Although pain treatment strategies have been greatly improved during the past century, no ideal targeted pain treatment has been developed. The development of modern and accurate platforms of technology for the study of genetics and physiology of pain has led to the identification of an increased number of altered genes and proteins that are involved in pain‐related pathways. Through genomics and proteomics, pain‐related genes and proteins, respectively, may be identified as diagnostic markers or drug targets improving therapeutic strategies. Furthermore, such molecular mediators of pain may reveal novel strategies for individualized pain management. The utilization of unique experimental approaches (through specific animal models) as well as powered genetic association studies conducted on appropriate populations is more than essential.     

The role of endocannabinoids in pain modulation

The endocannabinoid system (ES) is comprised of cannabinoid (CB) receptors, their endogenous ligands (endocannabinoids), and proteins responsible for their metabolism. Endocannabinoids serve as retrograde signaling messengers in GABAergic and glutamatergic synapses, as well as modulators of postsynaptic transmission, that interact with other neurotransmitters. Physiological stimuli and pathological conditions lead to differential increases in brain endocannabinoids that regulate distinct biological functions. Furthermore, endocannabinoids modulate neuronal, glial, and endothelial cell function and exert neuromodulatory, anti‐excitotoxic, anti‐inflammatory, and vasodilatory effects. Analgesia is one of the principal therapeutic targets of cannabinoids. Cannabinoid analgesia is based on the suppression of spinal and thalamic nociceptive neurons, but peripheral sites of action have also been identified. The chronic pain that occasionally follows peripheral nerve injury differs fundamentally from inflammatory pain and is an area of considerable unmet therapeutic need. Over the last years, considerable progress has been made in understanding the role of the ES in the modulation of pain. Endocannabinoids have been shown to behave as analgesics in models of both acute nociception and clinical pain such as inflammation and painful neuropathy. The framework for such analgesic effects exists in the CB receptors, which are found in areas of the nervous system important for pain processing and in immune cells that regulate the neuro‐immune interactions that mediate the inflammatory hyperalgesia. The purpose of this review is to present the available research and clinical data, up to date, regarding the ES and its role in pain modulation, as well as its possible therapeutic perspectives.