Challenges and Opportunities in Pathophysiology

Challenges and Opportunities in Pathophysiology

Helin Gosalia
NIHR SLaM Clinical Research Facility @ King’s, SLaM Biomedical Research Centre, King’s College London, London, UK

Diana Y. Wei
NIHR SLaM Clinical Research Facility @ King’s, SLaM Biomedical Research Centre, King’s College London, London, UK; Department of Neurology, King’s College Hospital, London, UK

Peter J. Goadsby
NIHR SLaM Clinical Research Facility @ King’s, SLaM Biomedical Research Centre, King’s College London, London, UK; Department of Neurology, King’s College Hospital, London, UK; Department of Neurology, University of California, Los Angeles, CA, USA


Cluster headache is a primary headache disorder and is the most prevalent of the trigeminal autonomic cephalalgias. Cluster headache significantly impacts those affected, necessitating early diagnosis and management. Despite unique clinical features, such as patients experiencing attacks in a circannual pattern and often with a circadian rhythm within bouts, cluster headache patients often are misdiagnosed, mismanaged and have a delay in diagnosis. Preclinical, neuroimaging and clinical studies have advanced our understanding of cluster headache pathophysiology. The trigeminovascular system, the trigeminal autonomic reflex, and the hypothalamus are all involved in the pathophysiology of cluster headache. As our understanding of the pathophysiology of cluster headaches has evolved, new therapeutic options, such as calcitonin gene-related peptide monoclonal antibodies, non-invasive vagal nerve stimulation and sphenopalatine ganglion stimulation, have proved to have efficacy in the treatment of cluster headache. Herein, we aim to review developments to aid readers in their understanding of this debilitating disorder. 

Corrado Moretti
Department of Pediatrics, Policlinico Umberto I, Sapienza University of Rome, Italy

Camilla Gizzi
Department of Neonatology and NICU, Sant’Eugenio Hospital – ASL RM 2, Rome, Italy

Caterina Silvia Barbara
Pediatric Intensive Care Unit, Department of Maternal Science, Policlinico Umberto I, Sapienza University of Rome, Italy

Nicola Pozzi
Neonatal Intensive Care Unit, Department of Maternal and Child Health, San Pio Hospital, Benevento, Italy

Fabio Midulla
Department of Maternal Science, Policlinico Umberto I, Sapienza University of Rome, Italy

Paola Cogo
Department of Medicine, University Hospital S.Maria della Misericordia, University of Udine, Italy


Bronchiolitis is one of the most frequent acute diseases of the lower respiratory tract in infants worldwide, and Respiratory Syncytial Virus remains the most common and aggressive viral disease. The course of the disease is usually benign, but its severity may change by evolving into parenchymal disease. In the more severe cases, its clinical and radiological characteristics may be consistent with acute respiratory distress syndrome. Management of these cases includes admission to paediatric intensive care and invasive mechanical ventilation. This paper reviews the definition of paediatric and neonatal acute respiratory distress syndrome, which was primarily designed and validated for adults. The article investigates the pathophysiology of paediatric acute respiratory distress syndrome further, describing how damage to the alveolar-capillary units, surfactant inactivation and inflammation occurs. Mechanisms that contribute to acute lung injury, such as volutrauma, barotrauma, stress and strain, are illustrated in detail, and an overview of the strategies that may help minimize neonatal lung injury and optimize ventilatory support is provided. These strategies include lung-protective mechanical ventilation, surfactant treatment, inhaled nitric oxide, high frequency oscillatory ventilation, recruiting manoeuvres, prone position and neuromuscular blocking agents. The objective is to help clinicians understand the peculiar pathophysiology of severe bronchiolitis and so guide them in preventing or attenuating lung injury during treatment. As such, this paper aims to contribute to defining optimal treatment of severe cases of bronchiolitis.

Dimitrios Panagopoulos, Georgios Strantzalis, Maro Gavra, Boviatsis Efstathios, Stefanos Korfias & Ploutarchos Karydakis


Chiari malformations comprise a group of disorders, which share in common inherent anatomical abnormalities that involve the region of the brain stem and cerebellum, eventually coexisting with entities such as hydrocephalus, spina bifida, syringomyelia and tethered cord syndrome.In the mean-time, from the original description of this syndrome, several researchers have focused on an effort to elucidate the pathogenesis of Chiari malformation from a point of view that it is a primary neural anomaly.

The aim of the current review is to investigate the time course of our knowledge regarding Chiari malformation, which has expanded significant in the past decades. As new insight has occurred regarding the pathophysiology and natural history of Chiari I malformation (CIM), in association with the widespread availability of MRI,the treatment modalities and algorithm for this patient population has been substantially evolved.Our purpose is to present a review of CIM and its most significant associated comorbidities,comment on techniques for surgical intervention and their expected outcomes.

There is a bulk of literature reviews centered on Chiari malformations· in this context, we attempted a literature review, including a discussion centered onthe historical background, anatomical forms, pathophysiology, clinical presentation, relationships with other diseases and diagnostic procedures for these abnormalities. Moreover, a bibliographic search was performed, using Thomson Reuters web of Science and Pubmed databases, in order to identify the most noteworthy papers about Chiari Syndrome. The following parameters were recorded: article titles, number of total citations and citations per year, authors’ names, authors’ h-index, institution and country where the research took place, year of publication, the journal of publication and journal’s impact factor. In addition, we reviewed the journals’ Impact Factor and SCImago Journal Rank (SJR). To obtain all those parameters, besides Web of sciences, we utilized Scopus, SCimago Journal and Country rankings, and In Cites Journal Citation Reports.

Our search resulted in 9.972 articles, published from 1855 until now (March2022). All articles are in English. The 50 most cited papers are presented in Table S1. All of them combined have been cited 8.999 times, in 3.262 different articles, with an average citation per item of 179.98.

We have attempted to present a thorough overview of this group of disorders, as well as to trace the evolution of our knowledge regarding the anatomical abnormalities associated with this condition, imaging and treatment gold standards and future perspectives.

The real pathophysiology, embryological background and natural history of CM have still not been entirely elucidated. This is in concordance with the fact that new suggestions have been submitted for the management of this malformation and more sophisticated imaging techniques have been introduced, in order to investigate in more details, the diagnosis. However, a lot of controversies remain, mainly centered on the optimum strategy which should be selected for selection of the appropriate surgical candidates and most efficacious treatment protocols, in order to obtain efficient decompression of the cranio-cervical junction.

Max Oliver Mackay Walker, Katie Peppercorn & Warren Perry Tate
Department of Biochemistry, School of Biomedical Science, University of Otago, Dunedin, New Zealand

Katherine H Hall
Department of General Practice and Rural Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand


Long COVID is now well accepted as an ongoing post-viral syndrome resulting from infection of a single virus, the pandemic SARS-CoV-2. It mirrors the post-viral fatigue syndrome, Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, a global debilitating illness arising mainly from sporadic geographically-specific viral outbreaks, and from community endemic infections, but also from other stressors. Core symptoms of both syndromes are post-exertional malaise (a worsening of symptoms following mental or physical activity), pervasive fatigue, cognitive dysfunction (brain fog), and sleep disturbance. Long COVID patients frequently also suffer from shortness of breath, relating to the lung involvement of the SARS-CoV-2 virus. There is no universally accepted pathophysiology, or recognized biomarkers yet for Long COVID or indeed for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Clinical case definitions with very similar characteristics for each have been defined. Chronic inflammation, immune dysfunction, and disrupted energy production in the peripheral system has been confirmed in Long COVID and has been well documented in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.     Neuroinflammation occurs in the brain in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome as shown from a small number of positron emission tomography and magnetic resonance spectroscopy studies, and has now been demonstrated for Long COVID. Oxidative stress, an increase in reactive oxygen and reactive nitrogen species, and free radicals, has long been suggested as a potential cause for many of the symptoms seen in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, resulting from both activation of the brain’s immune system and dysregulation of mitochondrial function throughout the body. The brain as a high producer of energy may be particularly susceptible to oxidative stress. It has been shown in peripheral immune cells that the balanced production of proteins involved in regulation of the reactive oxygen species in mitochondria is disturbed in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Fluctuations in the chronic low level neuroinflammation during the ongoing course of Long COVID as well as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome have been proposed to cause the characteristic severe relapses in patients. This review explores oxidative stress as a likely significant contributor to the pathophysiology of Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, and the mechanisms by which oxidative stress could cause the symptoms seen in both syndromes. Treatments that could mitigate oxidative stress and thereby lessen the debilitating symptoms to improve the life of patients are discussed.

A Robert Spitzer
Mackinac Neurology


The treatment of sleep disorders is problematic because the diagnoses consist of an array of unrelated terms, there is little knowledge or link to disease processes, and progression from the patient presentation to effective therapy is not systematic. The purpose of this paper is to provide a coherent framework for understanding sleep disorders, based on anatomy and pathophysiology.

A classification of sleep disorders based on classical neurological diagnosis is presented. First, the diagnostic process in classical, clinical neurology is reviewed. In this traditional approach, diagnoses are not inferred directly from symptoms. Rather, symptoms are used to identify putative anatomic localizations, and pathophysiological mechanisms. Diagnoses are inferred as a second step from the localizations and mechanisms of disease. Subsequently, testing may be applied as necessary, using a probabilistic interpretation to guide treatment. Treatment for diseases classified in this manner is more likely to be successful. In addition, be generating alternative hypotheses during this process, if initial treatments are not successful, alternative approaches may be considered.

The anatomy and physiology of sleep disorders is briefly reviewed. The process of diagnosis is then presented, starting with specific symptoms, including insomnia, hypersomnia, limb movement disorders, fatigue and pain syndromes. Groups of symptoms, as syndromes, are considered. By relating the symptoms to the localizations and pathophysiology, a more ordered approach to management is presented. The distinction of etiology from diagnosis is discussed. Etiologies that have resolved are typically not treatable.

Prior research on fibromyalgia is summarized, including possible anatomic and pathophysiological substrates, and underlying sleep disorders. Other forms of fatigue are contrasted, with implications for different treatments.

Fatima Khwaja
Department of Preventive Medicine, Stony Brook University, Stony Brook, New York

Robert A. Honkanen
Department of Ophthalmology, Stony Brook University, Stony Brook, New York

Basil Rigas
Department of Preventive Medicine, Stony Brook University, Stony Brook, New York; Department of Ophthalmology, Stony Brook University, Stony Brook, New York


Dry eye disease (DED), a multifactorial disorder of the ocular surface and tear film, affects 5-50% of the global population. Currently, no satisfactory treatments of DED exist. Ongoing efforts to identify novel therapeutic agents are handicapped by the limitations of its preclinical animal models, which to some extent reflect the pathophysiological complexities of DED..  A plethora of DED models employing multiple animal species (mice, rats, cats, rabbits, dogs, and non-human primates) has been reported, each aiming to capture components of DED that appear to determine its pathophysiology and response to novel treatments. Here, we review the main animal models of DED and attempt to place each in the context of drug discovery. We also discuss a nascent method for ex vivo culture of human conjunctival cells that may abbreviate early screening of candidate therapeutics. Despite the remaining challenges, there is justified optimism that with the contribution of these preclinical models, the development of an efficacious and safe treatment of DED will be forthcoming.

Nicholas Caffes, Dr.
University of Maryland School of Medicine

Jesse A. Stokum, Dr.
University of Maryland School of Medicine

Richard Zhao, PhD
Departments of Pathology, University of Maryland ,School of Medicine, Baltimore, Maryland 21201, USA

Ruchira M. Jha, Dr. J. Marc Simard
University of Maryland School of Medicine


The development of cerebral edema following traumatic brain injury is one of the most significant predictors of outcome and is associated with high rates of morbidity and mortality. A prominent focus of neurosurgical and neurocritical care is the evaluation and aggressive management of cerebral edema and subsequent intracranial hypertension. Despite numerous advances and capabilities in neurocritical care, treatments remain primarily reactive and are instituted only after secondary pathophysiological pathways have culminated in an intracranial pressure crisis. Recent reviews have focused on several key molecular contributors to post-traumatic cerebral edema and on several potential anti-edema therapeutic targets. The present article provides a contemporary overview of post-traumatic cerebral edema by reviewing important historical concepts, fundamental pathophysiological mechanisms, various causes and key contributors specific to traumatic brain injury, and established treatments of downstream intracranial hypertension.

Oishi Sikdar
Department of Women and Children’s Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King’s College London

Anne Greenough
Neonatal Intensive Care Centre, King’s College Hospital NHS Foundation Trust, 4th Floor Golden Jubilee Wing, Denmark Hill, London, SE5 9RS


Sickle Cell Disease is a life-threatening hereditary blood disorder which affects millions of people worldwide. Pulmonary complications are important causes of morbidity and mortality in patients with sickle cell disease. Asthma is a recognised comorbidity of sickle cell disease and may occur in between 15 and 28% of children with sickle cell disease. It has been associated with increased episodes of acute chest syndrome and all cause mortality. Obstructive lung disease, however, is common in children with sickle cell disease, independent of an asthma diagnosis. This review explores the pathophysiology, diagnosis and therapeutic opportunities for asthma in sickle cell disease patients. The diagnostic challenges and inconsistencies in current clinical approaches are highlighted. Convergence of inflammatory pathways in sickle cell disease and asthma occurs, but there is also a heightened level of inflammation unique to sickle cell disease. Thus, wheezing may not be due to asthma but be a manifestation of sickle cell disease per se and the result of the increased pulmonary vascular volume.  As a consequence, anti-asthma therapy may not be appropriate for all wheezy children with sickle cell disease and commencing treatment on the basis of a physician’s diagnosis alone is inappropriate. Data from paediatric cohorts suggest use of spirometry, aeroallergen sensitisation tests, impulse oscillometry and dedicated interdisciplinary pulmonary clinics could improve diagnosis accuracy. Corticosteroids and bronchodilators are well-established treatments for asthma; observational studies suggest they may provide benefit for some children with sickle cell disease, but therapies such as hydroxyurea may improve respiratory outcomes in others. It is, therefore, essential children are thoroughly investigated and followed-up and a personalised approach taken to their care. Prospective randomised studies are required to establish the effectiveness of asthma therapies in children with sickle cell disease. 

Toshimi Chiba
Division of Internal Medicine, Department of Oral Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan

Maiko Mori
Ajinomoto Co., Inc., 15-1, Kyobashi 1-chome, Chuo-ku, Tokyo 104-8315, Japan

Yuka Ikenoue
Research Institute, EA Pharma Co., Ltd., 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa, 210-8681, Japan

Kazuyuki Suzuki
Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan


Background: Some foods can exacerbate the symptoms of irritable bowel syndrome (IBS), although the associations between the pathophysiology of IBS and IgG food antibodies levels are not well known. We examined IgG antibodies elicited in response to food and celiac disease in diarrhea-predominant IBS (IBS-D).

Methods: Twenty patients with IBS-D and 20 healthy controls (HC), were enrolled. Serum immunoglobulin (Ig) G antibodies to 88 dietary items were measured and scored in accordance with the rate of antibody positivity. Serum tissue transglutaminase-IgA (tTG-IgA) and IgA endomysial antibody (EMA) were measured as markers of celiac disease. Serum IgE antibodies were also measured.

Results: For the 88-item food-related IgG scores there was no significant difference in the number of dietary items with a ≥ 0.5 IgG score between the IBS and HC groups. Total IgG scores between groups were not significantly different. Scores for wheat, rye, and oats were not significantly different for the IBS versus the HC group. IgG scores for apples were significantly higher in the IBS versus the HC group. Serum tTG-IgA and EMA titers were negative in both groups and not significantly different between groups. Serum IgE was also not significantly different between groups. One patient with high titers for wheat, rye, and oats had duodenal mucosa histology classified as Marsh 1 and was negative for human leukocyte antigen DQ haplotypes HLA-DQ2/HLA-DQ8.

Conclusions: We investigated IgG antibodies to food, tTG-IgA, and EMA in patients with IBS-D in whom IgG levels are likely influenced by dietary habits.

Dhanasekhar Kesavelu


Functional gastrointestinal disorders (FGIDs) are common among infants, yet precise diagnosis and optimal management strategies remain a challenge. Understanding the prevalence and impact of these conditions is essential for improving infant health. We present a comprehensive review of the evolution of treatment strategies for FGIDs tracing the identification of the first case to the recent advancements in disease management. The article explores the journey of the Rome criteria, which is the most widely used diagnostic parameter for FGIDs, as it transformed from consensus-based recommendations culminating in the present-day evidence-based guidelines, setting the stage for the upcoming Rome V criteria. FGIDs were initially hypothesized solely as a GI entity; however, thorough etio-pathologic research has elucidated the complex bio-psychosocial basis of FGIDs. In infants, these conditions can be particularly challenging to identify and manage due to their limited ability to communicate discomfort and distress. The article briefly refers to pathophysiology and diagnostic challenges as an exploratory background for effective management. An overview of existing research can shed light on the various treatment approaches for FGIDs in infants. We examined pharmacotherapy in FGID management in terms of its indications and limitations, which would allow its judicious use in clinical practice.  The article underscores the efficacy and safety of a dietary approach in FGID management in infants, especially in the absence of red flags. We highlight key research details that led to newer advancements in nutritional interventions such as probiotics. L reuteri DSM 17938 is the most extensively studied probiotic with proven benefits and manifold indications. We highly recommend large prospective studies to identify the ideal therapeutic agent that can provide a potential opportunity to prevent FGIDs.

Dr. Urmila Anandh


COVID 19 pandemic had a major impact on solid transplantation worldwide. This impact was felt more severely in resource constrained countries like India. In the initial phase of the pandemic, transplantation activities were halted. This was because of increased strain on the healthcare facilities by the pandemic and all non-urgent surgeries were disrupted. Also, there was concern among physicians about the risk of immunosuppression during the ongoing pandemic. After receiving guidance from national health authorities, transplantation activities were cautiously restarted. With increasing understanding about the pathophysiology of the viral infection transplantation activity increased over the months and both COVID- 19 infected individuals were accepted as donor and recipients. This was done after a thorough clinical, microbiological and radiological evaluation. Vaccination was made available early in India and guidelines for vaccination were adopted for all kidney transplant recipients. Like everywhere else, it was noted that vaccine efficacy was suboptimal in transplant recipients and breakthrough infections were common. COVID-19 associated mucormycosis was a unique feature during the second wave of the pandemic in India. It almost manifested as an epidemic and had devastating consequences in our country. This review aims to look at the response of Indian transplant physicians combating the COVID-19 pandemic in the last two years. Mention is also made about the mucormycosis infections (an epidemic within the pandemic) which was an important issue during the second wave of the pandemic.

M. Sawkat Anwer, PhD, DMVH
Distinguished Professor Emeritus Department of Comparative Pathophysiology Cummings School of Veterinary Medicine at Tufts University 200 Westboro Road North Grafton, MA 01536


Artificial Intelligent (AI)-powered technology is expected to significantly alter the way healthcare is delivered. Artificial Intelligence tools, such as machine learning and deep learning, have shown promise in supporting diagnostic assessments, recommending treatments, guiding surgical care, monitoring patients, supporting population health management, and enhancing drug development research. These tools at varying stages of maturity can also reduce provider burden and increase efficiency by recording digital notes, optimizing operational processes, and automating laborious tasks. Challenges surrounding AI tools include high-quality data access, potentially biased data, inadequate transparency, and uncertainty over liability. Fundamental changes in governmental oversight of health care, industry-hospital communication, the patient-provider relationship, and human-AI cooperation will be necessary to take advantage of the opportunities and overcome the challenges. We need to be critical and at the same time receptive as we embrace AI tools to deliver healthcare. It would be important to maintain human oversight and control to avoid unintended consequences of runaway machines making life and death decisions.

Leslie M. Klevay, MD, SD in Hyg., FAAAS, FASN
Emeritus professor of internal medicine, University of North Dakota School of Medicine and Health Sciences, Grand Forks North Dakota USA


The idea that dietary fat is poisonous arose nearly ¾ of a century ago. Criteria for associating disease incidence with environmental change were published a couple decades later. Intakes of dietary fat did not increase while ischemic heart disease risk was increasing; in contrast, dietary copper decreased. Intakes of copper calculated from food tables are falsely high by an average of 77%. Approximately half of adults consume less than 0.9 mg of copper per day when chemical analyses are done. This amount is less than nutritional guidelines. When hypercholesterolemia was discovered in copper deficient rats, a search was begun for anatomical, chemical and physiological similarities between animals deficient in copper and people with ischemic heart disease; more than 80 of these similarities have been identified. The copper deficiency theory on the etiology and pathophysiology of ischemic heart disease is the simplest and most general theory that has been proposed because it incorporates other theories on fetal programming, homocysteine and iron overload. It satisfies classical criteria of nutritional deficiency and association of an environmental characteristic with disease prevalence.

Alessia Bogni
European Commission, Joint Research Centre (JRC), Ispra, Italy

Jessica Ponti
European Commission, Joint Research Centre (JRC), Ispra, Italy

Uwe Holzwart
European Commission, Joint Research Centre (JRC), Ispra, Italy

Agapios Sachinidis
University of Cologne, Center of Physiology and Pathophysiology, Institute of Neurophysiology, Cologne, Germany

Susanne Bremer-Hoffmann
European Commission, Joint Research Centre (JRC), Ispra, Italy


The physicochemical properties of titanium dioxide (TiO2) in nanoforms is often exploited as colorant in food, pharmaceuticals and other consumer products. However, the current evidence of potential hazards associated with titanium dioxide (TiO2) in nanoforms led to a ban of TiO2 as food additive in Europe. This regulatory decision has also an impact on thousands of pharmaceuticals.

In the present study, we tested the internalisation, accumulation and resulting biological effects of different types of TiO2 nanomaterial in short and long-term vitro cultures. Even if we could demonstrate that all tested cell lines were able to take up and accumulate nanomaterial for a period of up to 30 days, the cellular responses using conventional in vitro tests were limited in all tested cell lines. Nevertheless, a transcriptomics study revealed that that the response to the accumulated material differed between two selected cell types. A keratinocyte like cell line reacted with a modified rate of keratinogenesis whereas the enterocyte like cell demonstrated mainly interactions with cell homeostasis. To further clarify possible harmful effects of TiO2, the study suggests analyzing cell/tissue type specific effects of TiO2.

Ramirez-Yanez German O., DDS, MDSc, MSc, PhD


Mouth breathing is a sign associated with Sleep and Breathing related Disorders and Obstructive Sleep Apnea in children. The aim of this paper is to provide a comprehensive overview of the changes in the human physiology when mouth breathing and, how it may affect the oral and general health in humans. The potential reactions produced at the cellular level and, how those reactions may lead to a negative impact in the human health are presented. Mouth breathing affects the O2/CO2 exchange at the lungs, which may lead to the production of the Hypoxia Inducible Factor (HIF) in all the cells in the human body, as well as stimulates the production of Erythropoietin in the kidney.  Mouth breathing also causes a major loose of CO2, which increases the production of bicarbonates in the kidney and release of essential minerals through the urine. All those reactions may facilitate the development and progression of chronic diseases in humans. It is recommended to consider mouth breathing as an oral habit that may associate with a cascade of events in the human physiology leading to chronic health problems. The health professionals should consider mouth breathing as a health risk factor and treat it as early as possible.

Victor Hugo Cruz-Rivas
Doctorado en Investigaciones Cerebrales, Universidad Veracruzana, Xalapa, Veracruz, México

Jorge Manzo-Denes, Fausto Rojas-Durán, Emiliano Gonzalo Aranda-Abreu, Deissy Herrera-Covarrubias, Jorge Suárez-Medellin, Isauro Luis García-Hernández, María Elena Hernández-Aguilar
Instituto de Investigaciones Cerebrales, Universidad Veracruzana, Xalapa, Veracruz, México


The prostate is an accessory sex gland responsible for producing and excreting prostate fluid. In the male rat, hormones such as testosterone (T) and prolactin (PRL) and the pelvic and hypogastric nerves regulate the gland, providing afferent information and adrenergic and cholinergic innervation to the prostate. Damages in the innervation or alterations in the hormonal levels of T and PRL changes the prostate’s cytoarchitecture and function that can promote the presence of cancer. However, sexual activity delays effects induced by hormonal alterations or dysfunction of the autonomic nervous system, but it does not mean that they do not appear since the cases of death from prostate cancer is still increasing. That is why this review has the fundamental purpose of showing the relationship between the hormones, autonomic nervous system, and sexual behavior in the pathophysiology of the prostate, with the ultimate aim of trying to understand the role that each one plays in diseases of the prostate. To date, results show that morphological changes in the prostate correlate with an increase in prolactin serum levels, a decrease in androgen and long prolactin receptors, and an increase in short prolactin receptors. Also, damage in the innervation induces an increase in androgen and muscarinic receptors in the major pelvic ganglia that supply the nerves that control the prostate in animal with sexual experience.

Natalia Zubieta-DeUrioste

Christian Arias-Reyes

Lida Sanchez

Nestor Freddy Armijo-Subieta

Alfredo Merino-Luna

Ivan Solarte

Raffo Escalante-Kanashiro

Jose Antonio Carmona-Suazo

Enrique Maravi Poma

Rosalinda Jimenez-Aguilar

Jose M. Calle-Aracena

Alberto Lopez-Bascope

Roberto Vera

Rafaela Zubieta-DeUrioste

Ninoska Rossel

Yeshua Peña-Y-Lilio

Gary Chambi-Quilla

Luis Herrera-Leon

Santiago Garrido-Salazar

Francisco Ney Villacorta Cordova

Fausto Vinicio Maldonado Coronel

Elisabeth Deindl

Ricki Sheldon

Roberto Alfonso Accinelli

Edith M Schneider-Gasser

Jorge Soliz

Gustavo Zubieta-Calleja


The COVID-19 pandemic, caused by the SARS-COV-2 virus, has had devastating consequences worldwide. Remarkably, the incidence, virus transmission capacity, and severity of COVID-19 have been reported to be significantly decreased in high-altitude human populations. The clinical significance of these findings is enormous, as they suggest that permanent inhabitants of high altitudes have developed adaptive protective changes against certain pathologies. However, these observations have been overshadowed by contradictory reports on the COVID-19 mortality rate at high altitude, ascribed to low population densities. These interpretations, however, fail to consider that the environmental conditions of high-altitude regions of the temperate and tropical geographical zones are radically different from each other. Contrary to common thought, the conditions of high-altitude areas of countries within the tropical zone are so benign that they have favored the growth and development of densely populated cities. In this work, we use data from a COVID-19 database covering five Latin American countries in the tropical and subtropical geographic zone that corresponded to the period between the start of the pandemic and the end of 2020, when no vaccine was yet available. Our results reveal that residing above 1,000 m in tropical countries was a protective factor against COVID-19 mortality. Interestingly, this protective effect was independent of population size. The findings presented here, and those from other similar studies, substantiate the need for more research to reveal the secrets of the physiology of permanent high-altitude residents. In conclusion, our findings clearly demonstrate that the high-altitude environment in tropical and subtropical geographic zones significantly contributes to the decreased mortality impact of the SARS-COV-2 virus in high-altitude-exposed populations.

Paba Dotes Ana Belen
Physical Medicine and Rehabilitation Department, Hospital Regional Universitario de Málaga, Spain.

De Torres-Garcia Irene
Physical Medicine and Rehabilitation Department, Hospital Regional Universitario de Málaga, Spain. Civil Hospital, Plaza del Hospital Civil, s/n, 29009, Malaga, Spain


Case: Acquired brain damage is one of the most complex pathologies that affect the central nervous system, there is great variability in its pathophysiology, from traumatic focal injuries to diffuse axonal injuries, including spasticity. It supposes a great comorbidity and functional repercussion in patients, hindering their subsequent recovery. We report a case of a young patient with a history of quadriplegia due to acquired brain damage secondary to thrombosis of the dural sinus. The patient presented sensorimotor deficit, restricted function, and a great situation of dependency. He required three cycles of high doses of incobotulinumtoxinA (IncoBoNT) according to his specific need, the first infiltration was 800 U, the second 800 U, and the last 500 U over a period of 14 weeks. Thanks to the previous objectives agreement with the patient the results were satisfactory and relevant for him, presenting a great functional improvement of spasticity and associated pain, as assessed by the visual analog scale score.
Conclusion: IncoBoNT at high doses and short intervals has been shown to be an effective and valuable tool for personalized treatment adapted to the needs of severely affected neurological patients.

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