Physiology of Midkine and Its Potential Pathophysiological Role in COVID-19

SARS-CoV2 infection not only causes abnormal severe pneumonia but also induces other relevant pathophysiological effects on several tissues and organs. In this regard, the clinical complications observed in COVID-19 include acute coronary syndrome, pulmonary thromboembolism, myocarditis and, in the severe cases, the occurrence of disseminated intravascular coagulation. Literature on COVID-19 highlighted the central role of the Renin Angiotensin Aldosterone System in the determinism of SARS-CoV2 cellular internalization in the target tissues. Lung degeneration and respiratory distress appear to be dependent on the perturbance of physiological mechanisms, such as the uncontrolled release of pro-inflammatory cytokines, a dysregulation of the fibrinolytic coagulative cascade and the hyperactivation of immune effector cells. In this mini review, we address the physiology of Midkine, a growth factor able to bind heparin, and its pathophysiological potential role in COVID-19 determinism. Midkine increases in many inflammatory and autoimmune conditions and correlates with several dysfunctional immune-inflammatory responses that appear to show similarities with the pathophysiological elicited by SARS-CoV2. Midkine, together with its receptor, could facilitate the virus entry, fostering its accumulation and increasing its affinity with Ace2 receptor. We also focus on Netosis, a particular mechanism of pathogen clearance exerted by neutrophils, which under certain pathological condition becomes dysfunctional and can cause tissue damage. Moreover, we highlight the mechanism of autophagy that the new coronavirus could try to escape in order to replicate itself, as well as on pulmonary fibrosis induced by hypoxia and on the release of cytokines and mediators of inflammation, correlating the interplay between Midkine and SARS-CoV2

A preliminary note on population structure in eastern South Pacific common bottlenose dolphins, <i>Tursiops truncatus</i>

Previous studies of eastern South Pacific common bottlenose dolphins, Tursiops truncatus, defined offshore and inshore ecotypes in Peru based on cranial and tooth morphology, documented the presence of a single resident inshore community (‘pod-R’) in central-north Chile, and confirmed the presence of offshore bottlenose dolphins off Chile. Here, mtDNA control region (331bp) was examined to evaluate genetic relationships between four geographic areas: inshore pod-R (n=8), Chilean offshore population (n=8), Peruvian inshore (n=3) and offshore (n=12)ecotypes. This is the first genetic analysis of T. truncatus in this ocean basin. Phylogenetic analysis grouped the three Peruvian specimens morphologically identified as inshore ecotype in an independent cluster, supported by 100% bootstrap value. The net genetic distance between Peruvian inshore and Peruvian offshore ecotypes was estimated at 2.9%, and even higher when compared with Chilean bottlenose dolphins. Morphological and mtDNA evidence combined argues for considering inshore and offshore ecotypes as evolutionary significant units, to be managed accordingly. Despite its inshore behavioural ecology, pod-R presented a high divergence from the Peruvian inshore ecotype and a relatively closer affinity with the Chilean offshore stock (3.41% and 0.87% net interpopulational distance, respectively). However, homogeneity tests showed significant genetic differences of pod-R with all other groups, including Chilean offshore. This, combined with a low nucleotide diversity (0.0069) and behavioural observations, suggest that pod-R may be reproductively isolated and active protection measures are recommended. Only one haplotype from a total of 21 was shared by Peruvian and Chilean offshore animals. Their net genetic distance was estimated at 0.024 and no significant differences were found in haplotype frequencies, suggesting a single, wide-ranging ‘Peru-Chile offshore stock’

Live-captures of common bottlenose dolphins <i>Tursiops truncatus</i> and unassessed bycatch in Cuban waters: evidence of sustainability found wanting

In the period 1986-2004, 238 common bottlenose dolphins Tursiops truncatus were exported from Cuba, as shown by UNEP/WCMC data, more than 60% of these to facilities in Latin America and the Caribbean, some 32% to Europe and the rest to Canada and Israel. There is a very significant increase in exported numbers, reaching 28 individuals per annum in 2002. It is unclear how many T. truncatus have been used in domestic dolphinaria. A review of available information did not identify evidence to corroborate hypotheses that: (i) T. truncatus off Sabana-Camagüey Archipelago (where removals occur) does not show population structure; and (ii) virtually no bycatches occur in Cuban waters. Here it is argued that, considering Cuba's fully developed marine fisheries, some level of mortality from bycatch is inevitable. Other potential threats are also identified. Global phylogenetics research of T. truncatus is revealing unexpected and more complex, stock structures, in inshore (coastal) forms within relatively small areas. In Cuba, low mean group sizes (less than 10) suggest that one or more coastal stock(s) are exploited. Sex distribution of measured specimens suggest a significant bias towards extraction of females. It is concluded that sustainability of harvest levels of Cuban T. truncatus cannot be evaluated until abundance estimates become available and population structure is verified by molecular genetic methods. Pérez-Cao (2004) indicated that available density estimates should not be used to determine [safe] catch quotas. The authors strongly recommend that international trade of T. truncatus from Cuba ceases until no-detriment can be authenticated and that more research be developed. Similar arguments may be applicable to other unassessed but exploited populations in the Wider Caribbean

Common bottlenose dolphins <i>Tursiops truncatus</i> of Pacific South America, asynoptic review of population identification data. Report of the IWC Scientific Committee Meeting SC/67A/SM/10, Bled, Slovenia, May 2017

We succinctly summarize population ID information for common bottlenose dolphins Tursiops truncatus of the Pacific coast of South America, covering four coastal range states. Phylogenetic uncertainties relate primarily to offshore vs. coastal (inshore) ecotypes and biogeographic borders between the five proposed populations (2 offshore, 3 coastal): Colombia-Ecuador Offshore stock (probably = ETP Offshore), Peru-Chile Offshore, Ecuador Coastal, Peru Coastal and an unique community (Pod-R) on the north-central coast of Chile. Main questions concern the extent of gene flow between the offshore stocks at one hand, and with -and between- the three coastal populations at the other hand. Seven cranial characters, four non-metric (separation of occipital condyles, pterygoid bone development, exostosis of periotic) and three metric (tooth width, antorbital process length, maximum width palatines), dorsal fin shape, body stockiness, mt-DNA (control region), habitat, prey composition, parasite load, behaviour and prevalence of some infectious diseases differentiate coastal from offshore forms. 'Pod-R' is the southernmost (29°15'S) and only confirmed coastal form community in Chilean waters, albeit with an offshore (falcate) dorsal fin. Bottlenose dolphins which regularly transit nearshore in the Lagos and Aysén regions (Chilean Patagonia) and occasionally enter deep fjords, present an offshore morphotype. We suggest that two other coastal areas in Chile where bottlenose dolphins have been documented over decades, one a ca. 60 km stretch of coastline centered at Valparaiso/Laguna Verde (33°10'S) in central Chile, and a 190 km coastline around the Mejillones Peninsula (23°10'S) in northern Chile, may not host coastal but offshore form animals. The continental border of the Atacama Trench off northern and northcentral Chile leaves an extremely narrow, steep shelf with nearshore deep water, locally with strong coastal upwelling and increased productivity. This habitat seems to attract oceanic cetaceans, including offshore T. truncatus, sperm whales, large balaenopterids, and other species. The southern distribution range of true coastal morphotype bottlenose dolphins in Pacific South America remains unknown but off Chile distance-to-shore may not be the reliable indicator of ecotype as it is further north in the study region

Review of lobomycosis and lobomycosis-like disease (LLD) in Cetacea from South America. Scientific Committee document SC/60/DW13, International Whaling Commission, June 2008, Santiago, Chile

Caused by a yeast-like organism known as Lacazia loboi, Lobomycosis (or lacaziosis) naturally affects humans, common bottlenose dolphins (Tursiops truncates) inhabiting coastal waters from southern Brazil to Gulf of Mexico and Atlantic coast of Florida, as well as botos-cinza (Sotalia guianensis). These species are usually found in coastal waters, subject to runoff provided by large rivers and a considerable burden of associated contaminants. Histological and morphological studies demonstrated that the etiological agent of L. loboi infecting humans is different from the one found to infected dolphins. Moreover, it likely that dolphin-human infections do not occur although infected bottlenose dolphins were from populations engaged in cooperative fishing that involve a relative small number of dolphins and humans. The records of Lobomycosis and Lobomycosis-like disease (LLD) in Tramandaí estuary (29o58´S), Rio Grande do Sul, Brazil, represent the southernmost distribution of L. loboi. On the other hand, the northernmost distribution of this disease is reported in the southern portion of Indian River Lagoon (27°25´N), Florida, USA. LLD seems to be more widespread, infecting both toothed small cetaceans and baleen whales, from the tropical Atlantic to the Pacific. Future studies should evaluate the association with impaired immune function in affected dolphins and the emergency of Lobomycosis. It may be associated with an immunosuppressive factor of environmental origin, such as exposure to pesticides or other agricultural or industrial contaminants, introduced through runoff or point sources of pollution, altering conditions to favour disease emergence. Lobomycosis should be assigned as neglected tropical disease, as should be the case of LLD, if future investigations indicate their connection as an emerging pathogen, its pathogenicity and environment requirements

Skin diseases in cetaceans. Scientific Committee document SC/60/DW8, International Whaling Commission, June 2008, Santiago, Chile

Micro-organisms that are known or suspected to cause skin diseases in cetaceans are briefly reviewed. Viruses belonging to four families i.e. Caliciviridae, Herpesviridae, Papillomaviridae and Poxviridae were detected by electron microscopy, histology and molecular techniques in vesicular skin lesions, black dots perceptible by the touch, warts and tattoos in several species of odontocetes and mysticetes. Herpesviruses, poxviruses and likely a cutaneous papillomavirus are cetacean specific. Among bacteria, Dermatophilus spp., Erysipelothrix rhusiopathiae, Mycobacterium marinum, Pseudomonas spp., Streptococcus iniae and Vibrio spp. were isolated from ulcerative dermatitis, pyogranulomatous dermatitis and panniculitis, diamond skin disease and slow-healing ulcers and abscesses. Aeremonas spp., Mycobacterium marinum, Pseudomonas spp. and Vibrio spp. are normally present in the marine environment while Erysipelothrix rhusiopathiae and Streptococcus iniae are fish pathogens that may also infect captive dolphins. Most seem to be opportunistic pathogens, exploiting some break-down in the host’s defenses to initiate an infection. Selection of antibiotic-resistant bacteria through the prophylactic use of antibiotics in aquaculture is suggested to be a growing problem in South America and may account for the emergence of unusual cutaneous conditions. At least four groups of fungi i.e. Candida albicans, Fusarium spp., Trichophyton spp. and Lacazia loboi cause skin diseases. Candidiasis occurs predominantly in captive odontocetes. The lesions are often localized around the body orifices and may become extensive, granulating and ulcerated. Fusariosis is characterized by firm, erythematous, cutaneous nodules. Trichophyton spp. was isolated from widespread superficial nodules in an Atlantic T. truncates kept in captivity in Japan. Lobomycosis or lacaziosis is distinguished by grayish, whitish to slightly pink, verrucuous lesions, often in pronounced relief that may ulcerate. While initially described only in Tursiops truncates and Sotalia guianensis from the Americas, lobomycosis seems to be expanding to other continents. The role of ballast water in transporting fungi worldwide should be investigated. Finally, ciliated protozoans, likely Kyaroikeus cetarius, caused invasive dermatitis in small cetaceans from the USA and Korea. The aquatic environment of cetaceans is naturally home to bacteria and fungi but cetacean skin has several mechanisms to impede invasion. Chemical contaminants may affect natural skin barriers and depress the immune system. Wounds and specific viral infection (poxvirus, herpesvirus) may provide routes of entry

A preliminary overview of skin and skeletal diseases and traumata in small cetaceans from South American waters

We succinctly review and document new cases of diseases of the skin and the skeletal system and external traumata in cetaceans from Ecuador, Colombia, Peru, Chile, Argentina, Uruguay, Brazil, and Venezuela. The survey revealed 590 cases diagnosed with a significant pathology, injury or malformation on a total of 7635 specimens of 12 odontocete species examined or observed in 1984-2007. Tattoo skin disease (TSD), lobomycosis-like disease (LLD) and cutaneous diseases of unknown aetiology seem to be emerging in several populations. TSD was confirmed in eight species from the SE Pacific and SW Atlantic. LLD affected only inshore Tursiops truncatus but was found in four tropical countries, namely Colombia, Ecuador, Peru and Brazil. Lobomycosis was confirmed by histology in one male from the Tramandaí estuary, southern Brazil. All LLD-affected specimens were encountered in the vicinity of major ports and cities and a possible association with chemical or organic water pollution is suspected. Whitish velvety cutaneous marks associated with scars occurred in inshore T. truncatus, Sotalia guianensis and Pseudorca crassidens. Large, rounded lesions were seen in a Cephalorhynchus eutropia calf and a C. commersonii. Cutaneous wounds and scars as well as body traumata possibly related to net entanglements and boat collisions were observed in 73 delphinids and Phocoena spinipinnis. Traumatic injuries resulted in the partial or complete amputation and other disfiguring scars of appendages in 17 cases. Fractures of the skull, ribs and vertebrae thought to be caused by fisheries-related interactions or boat collisions were seen in single individuals of Delphinus capensis, Lagenorhynchus obscurus, T. truncatus, S. guianensis and Ziphius cavirostris. Prevalence of osteopathology in small cetaceans from Peru, Brazil and Venezuela ranged widely, from 5.4% to 69.1%. In four species from Peru, lytic cranial lesions were the most frequently observed disease (5.4%-42.9%), followed by hyperostosis and ankylosing spondylitis in offshore (31%, n=42) and inshore (15.4%, n=26) T. truncatus. Fractures and other bone traumata were present in 47.2% of 53 axial skeletons of S. guianensis from the northern Rio de Janeiro state (Brazil) in 1987-1998. A high prevalence (48.4%, n=31) of, apparently congenital, malformations of cervical vertebrae, observed in a 2001-2006 sample, may be explained by a hypothetical genetic bottleneck in this population. Malformations with deficient ossification would clearly increase susceptibility for fractures. This study demonstrates the utility of a continent-wide analysis to discern epizootiological trends more readily than any local study could provide. Secondly, it underscores the need for focussed research on the effects of human activities on the spread of diseases in cetaceans, particularly in near-shore populations that utilize highly degraded coastal habitats

Pain and Frailty in Hospitalized Older Adults

Introduction: Pain and frailty are prevalent conditions in the older population. Many chronic diseases are likely involved in their origin, and both have a negative impact on quality of life. However, few studies have analysed their association. Methods: In light of this knowledge gap, 3577 acutely hospitalized patients 65&nbsp;years or older enrolled in the REPOSI register, an Italian network of internal medicine and geriatric hospital wards, were assessed to calculate the frailty index (FI). The impact of pain and some of its characteristics on the degree of frailty was evaluated using an ordinal logistic regression model after adjusting for age and gender. Results: The prevalence of pain was 24.7%, and among patients with pain, 42.9% was regarded as chronic pain. Chronic pain was associated with severe frailty (OR = 1.69, 95% CI 1.38–2.07). Somatic pain (OR = 1.59, 95% CI 1.23–2.07) and widespread pain (OR = 1.60, 95% CI 0.93–2.78) were associated with frailty. Osteoarthritis was the most common cause of chronic pain, diagnosed in 157 patients (33.5%). Polymyalgia, rheumatoid arthritis and other musculoskeletal diseases causing chronic pain were associated with a lower degree of frailty than osteoarthritis (OR = 0.49, 95%CI 0.28–0.85). Conclusions: Chronic and somatic pain negatively affect the degree of frailty. The duration and type of pain, as well as the underlying diseases associated with chronic pain, should be evaluated to improve the hospital management of frail older people