Christian Zammit

Oligodendrocyte pathophysiology and treatment strategies in cerebral ischemia.

Oligodendrocytes (OLs), the myelin‐forming cells of the central nervous system, form a functional unit with axons and play a crucial role in axonal integrity. An episode of hypoxia–ischemia causes rapid and severe damage to these particularly vulnerable cells via multiple pathways such as overactivation of glutamate and ATP receptors, oxidative stress, and disruption of mitochondrial function. The cardinal effect of OL pathology is demyelination and dysmyelination, and this has profound effects on axonal function, transport, structure, metabolism, and survival. The OL is a primary target of ischemia in adult‐onset stroke and especially in periventricular leukomalacia and should be considered as a primary therapeutic target in these conditions. More emphasis is needed on therapeutic strategies that target OLs, myelin, and their receptors, as these have the potential to significantly attenuate white matter injury and to establish functional recovery of white matter after stroke. In this review, we will summarize recent progress on the role of OLs in white matter ischemic injury and the current and emerging principles that form the basis for protective strategies against OL death.

The central role of aquaporins in the pathophysiology of ischemic stroke

Stroke is a complex and devastating neurological condition with limited treatment options. Brain edema is a serious complication of stroke. Early edema formation can significantly contribute to infarct formation and thus represents a promising target. Aquaporin (AQP) water channels contribute to water homeostasis by regulating water transport and are implicated in several disease pathways. At least 7 AQP subtypes have been identified in the rodent brain and the use of transgenic mice has greatly aided our understanding of their functions. AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome. In models of vasogenic edema, brain swelling is more pronounced in AQP4-null mice than wild-type providing strong evidence of the dual role of AQP4 in the formation and resolution of both vasogenic and cytotoxic edema. AQP4 is co-localized with inwardly rectifying K+-channels (Kir4.1) and glial K+ uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction. AQP4-null mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events. Associations with the gap junction protein Cx43 possibly recapitulate its role in edema dissipation within the astroglial syncytium. Other roles ascribed to AQP4 include facilitation of astrocyte migration, glial scar formation, modulation of inflammation and signaling functions. Treatment of ischemic cerebral edema is based on the various mechanisms in which fluid content in different brain compartments can be modified. The identification of modulators and inhibitors of AQP4 offer new therapeutic avenues in the hope of reducing the extent of morbidity and mortality in stroke.

Central axons preparing to myelinate are highly sensitivity to ischemic injury

Developing central white matter is subject to ischemic‐type injury during the period that precedes myelination. At this stage in maturation, central axons initiate a program of radial expansion and ion channel redistribution. Here we test the hypothesis that during radial expansion axons display heightened ischemic sensitivity, when clusters of Ca2+ channels decorate future node of Ranvier sites.

Kv1.1 knock-in ataxic mice exhibit spontaneous myokymic activity exacerbated by fatigue, ischemia and low temperature.

Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder characterized by myokymia and attacks of ataxic gait often precipitated by stress. Several genetic mutations have been identified in the Shaker-like K+ channel Kv1.1 (KCNA1) of EA1 individuals, including V408A, which result in remarkable channel dysfunction. By inserting the heterozygous V408A, mutation in one Kv1.1 allele, a mouse model of EA1 has been generated (Kv1.1V408A/+). Here, we investigated the neuromuscular transmission of Kv1.1V408A/+ ataxic mice and their susceptibility to physiologically relevant stressors. By using in vivo preparations of lateral gastrocnemius (LG) nerve–muscle from Kv1.1+/+ and Kv1.1V408A/+ mice, we show that the mutant animals exhibit spontaneous myokymic discharges consisting of repeated singlets, duplets or multiplets, despite motor nerve axotomy. Two-photon laser scanning microscopy from the motor nerve, ex vivo, revealed spontaneous Ca2 + signals that occurred abnormally only in preparations dissected from Kv1.1V408A/+ mice. Spontaneous bursting activity, as well as that evoked by sciatic nerve stimulation, was exacerbated by muscle fatigue, ischemia and low temperatures. These stressors also increased the amplitude of compound muscle action potential. Such abnormal neuromuscular transmission did not alter fiber type composition, neuromuscular junction and vascularization of LG muscle, analyzed by light and electron microscopy. Taken together these findings provide direct evidence that identifies the motor nerve as an important generator of myokymic activity, that dysfunction of Kv1.1 channels alters Ca2 + homeostasis in motor axons, and also strongly suggest that muscle fatigue contributes more than PNS fatigue to exacerbate the myokymia/neuromyotonia phenotype. More broadly, this study points out that juxtaparanodal K+ channels composed of Kv1.1 subunits exert an important role in dampening the excitability of motor nerve axons during fatigue or ischemic insult.

Non‑infective occupational risk factors for hepatocellular carcinoma: A review (Review)

Liver cancer is the second leading worldwide cause of cancer-associated mortalities. Hepatocellular carcinoma, which accounts for the majority of liver tumors, ranks fifth among types of human cancer. Well-established risk factors for liver cancer include the hepatitis B and C viruses, aflatoxins, alcohol consumption, and oral contraceptives. Tobacco smoking, androgenic steroids, and diabetes mellitus are suspected risk factors. Current knowledge regarding non-infective occupational risk factors for liver cancer is inconclusive. The relevance of liver disorders to occupational medicine lies in the fact that the majority of chemicals are metabolized in the liver, and toxic metabolites generated via metabolism are the predominant cause of liver damage. However, their non-specific clinical manifestations that are similar in a number of liver diseases make diagnosis difficult. Furthermore, concomitant conditions, such as viral hepatitis and alcohol or drug abuse, may mask liver disorders that result from occupational hepatotoxic agents and block the demonstration of an occupational cause. The identification of environmental agents that result in human cancer is a long and often difficult process. The purpose of the present review is to summarize current knowledge regarding the association of non-infective occupational risk exposure and HCC, to encourage further research and draw attention to this global occupational public health problem.

Influence of football on physiological cardiac indexes in professional and young athletes

Background: After long-term intensive training, considerable morphological and functional heart changes occur in professional athletes. Such changes arise progressively and regress upon interruption of the physical activity. Morphological and functional alterations on heart are known as “Athletes heart” condition. Objective: This study aims to compare echocardiographic parameters in two different groups of professional athletes. Furthermore, a prospective study is performed analyzing the echocardiographic changes occurring in 12 professional players in 3 years of follow-up. Materials and Methods: 78 football players were examined from July 2011 to May 2016 (40 enrolled in Group A and 38 in Group B). Twelve players of GROUP A were followed for 3 consecutive seasons. The general clinical examination, the cardiopulmonary evaluation, the ECG, the ergometer stress test, the spirometric examination and the standard cardiac eco color doppler test were recorded. Results: Left ventricle dimensions, left atrium dimensions, and interventricular septum dimensions were higher in A players than in B players. Moreover, following up 12 players for 3 years, a statistically significant increase of such values was observed. Discussion: In A players, higher dimensions of the left chambers and the interventricular septum were observed, compared to B players. No statistically significant difference was found regarding the ejection fraction. The 3 years follow-up showed a statistically significant increase of both left chambers and interventricular septum dimensions, particularly in the second and third year. Conclusions: These findings demonstrated that A players have higher echocardiographic parameters respect to B players. The results of this study support the scientific theory that long-term intensive training influences heart function, inducing “athletes heart” with morphological adaptations. No significant echocardiographic variation within the examined sample was observed for different roles (goalkeeper, defender, midfielder, or attacker) or skills of individual players.

Vesicular glutamate release from central axons contributes to myelin damage

The axon myelin sheath is prone to injury associated with N-methyl-d-aspartate (NMDA)-type glutamate receptor activation but the source of glutamate in this context is unknown. Myelin damage results in permanent action potential loss and severe functional deficit in the white matter of the CNS, for example in ischemic stroke. Here, we show that in rats and mice, ischemic conditions trigger activation of myelinic NMDA receptors incorporating GluN2C/D subunits following release of axonal vesicular glutamate into the peri-axonal space under the myelin sheath. Glial sources of glutamate such as reverse transport did not contribute significantly to this phenomenon. We demonstrate selective myelin uptake and retention of a GluN2C/D NMDA receptor negative allosteric modulator that shields myelin from ischemic injury. The findings potentially support a rational approach toward a low-impact prophylactic therapy to protect patients at risk of stroke and other forms of excitotoxic injury.Neuronal activity can lead to vesicular release of glutamate. Here the authors demonstrate that vesicular release of glutamate occurs in axons during ischemic conditions, and that an allosteric modulator of GluN2C/D is protective in models of ischemic injury.

Functional Changes of Orexinergic Reaction to Psychoactive Substances

It is becoming increasingly apparent the importance of the central nervous system (CNS) as the major contributor to the regulation of systemic metabolism. Antipsychotic drugs are used often to treat several psychiatric disorders, including schizophrenia and bipolar disorder However, antipsychotic drugs prescription, particularly the second-generation ones (SGAs), such as clozapine and olanzapine, is related to a considerable weight gain which usually leads to obesity. The aim of this paper is to assess the influence of orexin A on sympathetic and hyperthermic reactions to several neuroleptic drugs. Orexin A is a neuropeptide which effects both body temperature and food intake by increasing sympathetic activity. Orexin A-mediated hyperthermia is reduced by haloperidol and is blocked by clozapine and olanzapine. Orexin A-mediated body temperature elevation is increased by risperidone. These hyperthermic effects are delayed by quietapine. In this paper, it is discussed the orexinergic pathway activation by neuroleptic drugs and its influence on human therapeutic strategies. With the aim to determine that neuroleptic drugs mediate body temperature control through to the orexinergic system, we summarized our previously published data. Psychiatric disorders increase the risk of developing metabolic disorders (e.g., weight gain, increased blood pressure, and glucose or lipid levels). Therefore, the choice of antipsychotic drug to be prescribed, based on the relevant risks and benefits of each individual drug, has an essential role in human health prevention.

Role of Sex Hormones in the Control of Vegetative and Metabolic Functions of Middle-Aged Women

Aims: In womens life, menopause is characterized by significant physiological changes often associated with an increase in body mass and obesity-associated sicknesses. Numerous researches described interdependencies of estrogen deficiency, aging, and resting energy expenditure (REE) downfall in the obesity correlated with the menopause. The aim of this study was to determining whether healthy, obese menopausal women underwent HRT treatment, showed changes in their REE, autonomic asset, and assessment of oxidative stress in comparison with obese pre- and post-menopausal women. Methodology: In this study, we measured the body composition, the REE, the oxidative stress, the diet assimilation, and the autonomic nervous system activity in three groups: pre-menopause women (n = 50), post-menopause women following hormone-replacement therapy (HRT; n = 50), and post-menopause women not following HRT (n = 50). Results: In the group with HRT a significant increase of the sympathetic activity and REE was described. Finally this group showed a notable increment of oxidative stress compared with the others, and utilizing BIA instrument, the free fat mass was increased respect to the fat mass of obese women. Conclusion: The study highlights the importance of the HRT-related physiological changes that influence body weight in menopause women. This results are important because have a practical implications for prevention and/or treatment of the obesity.

Cerebral White Matter Injuries Following a Hypoxic/Ischemic Insult During the Perinatal Period: Pathophysiology, Prognostic Factors, and Future Strategy of Treatment Approach. A Minireview

Recent advances in medical care have significantly improved the survival rate of neonates who suffer a hypoxic/ ischemic event, before, during, or after birth. These infants are extremely vulnerable to brain injury and are at high risk of developing motor and cognitive abnormalities later on in life. The regional distribution of perinatal brain injury varies, and depends primarily on; the severity, pattern and type of insult, the metabolic status, and on the gestational age. The principal neuropathological substrate that is affected in the premature infant is cerebral white matter. The aim of this article is to re-examine the current knowledge on the ischemic pathophysiology of all cellular components that comprise the white matter, pred ict the consequences of the long-term neurological outcome, and analyze possible therapeutic strategies. Although oligodendrocytes have long been regarded as the hallmark of perinatal white matter injury, axons, astrocytes and microglia, all contribute to the complex pattern of brain injury that occurs in this cohort of individuals. It is hoped that a better understanding of the pathophysiology of white matter injury and its underlying prognostic factors, may lead to the development of new therapeutic strategies for such a complex and debilitating condition.