https://doi.org/10.1111/anae.15049 Extreme
measures have already been undertaken, including: closure of hospital
wards; restricting visitor access to hospital; identification of
external triage areas; dedicated patient transport and isolation
pathways; and cessation of elective surgery, with only emergency, trauma
and selected oncological surgery proceeding. Notably, operating rooms
are allocated as emergency critical care beds and anaesthetists have
been re‐allocated to critical care management and rapid response
emergency care, including dedicated COVID‐19 emergency teams to assist
patients in non‐critical care settings. In terms of public health,
several measures have been implemented, including: the use of
telemedicine consultations; domestic isolation of COVID‐19 patients who
are not severely unwell; production and distribution of educational
videos and television segments; and firm restrictions against public
gatherings. Most recently, much of northern Italy had a quarantine
imposed, affecting up to 16 million residents 19,
and on 11 March 2020, all Italian territories were identified as ‘red
zones’ by the Government, with firm restrictions on any public activity 20.
The acuity of the epidemic burden on healthcare
infrastructure has also led to the identification of certain hospitals
as ‘COVID‐19 sanatoriums,’ and we forecast a possible future of
‘COVID‐19 positive’ and ‘COVID‐19 negative’ hospitals. Finally, there
has been activation of military forces to construct field hospitals with
bio‐containment level resources. The role of anaesthetists and
intensivists has been critical, complex and dynamic. They have been
directly responsible for the early clinical management of critically ill
patients, and have faced the hardest task of undertaking critical,
ethically and psychologically disrupting triage, unavoidable though it
may be. To support clinicians with these ethical decisions, The Società
Italiana di Anestesia Analgesia Rianimazione e Terapia Intensiva
(SIAARTI) produced guidance on clinical management and triage during the
crisis 21.
Clinical management
Specific aspects of COVID‐19 patient care distinguish it from routine clinical practice (Table 2).
In these settings, there are factors that must be considered for:
oxygen administration and non‐invasive ventilation of the spontaneously
ventilating patient; airway management of the patient requiring tracheal
intubation; clinical management with PPE; and human factors
Table 2.
Clinical aspects of COVID‐19 patients during the
Italian outbreak. Preliminary observations based on data from Gruppo
Italiano per la Valutazione degli Interventi in Terapia Intensiva; http://giviti.marionegri.it)
Typical patient characteristics
Age
60–70 years
Sex
Male
Most common comorbidity
Obesity
Typical investigation findings
Procalcitonin
< 0.15 ng.ml−1 (normal)
Brain natriuretic peptide
< 100 pg.ml−1 (normal)
Creatine phosphokinase
Elevated, particularly in younger patients
Albumin
Reduced
Lymphocytes
Reduced
Chest X‐ray features
Bilateral interstitial pneumonitis
CT chest features
Parenchymal and interstitial involvement
Lung ultrasound
Diffuse B‐lines may indicate those who respond to high PEEP.
Anterior lung regions aerated or posterior atelectasis may indicate those who respond to prone positioning
Possible treatments and therapies
Antiretrovirals
Lopinavir or ritonavir
Other agents
Choroquine or hydroxychloroquine
Antibiotic prophylaxis
Piperacillin/tazobactam or ceftriazone or trimethoprim/sulfamethoxazole
Secretion management
N‐acetylecysteine
Other pharmacological agents
Corticosteroids or immune suppression, for example, tocilizumab
Sedation
Deep
Ventilation
Lung‐protective ventilation with high PEEP. Compliance is usually good.
Neuromuscular blockade
Deep, particularly during prone positioning
Fluid balance
Negative
Positioning
Consider up to seven cycles of prone positioning
Extracorporeal membrane oxygenation
Rarely used, but might be considered for those unresponsive to conventional ventilation
Renal replacement therapy
Challenging
COVID‐19, coronavirus disease 2019.
Oxygen administration
Given the aggressive pulmonary involvement associated
with COVID‐19, the requirement for non‐invasive or invasive oxygen
therapy is likely. All oxygen administration strategies in the
spontaneously ventilating patient carry risks of aerosolisation and
disease transmission. Hudson and Venturi masks, nasal cannulae and
helmets, carry a lower‐risk of transmission when compared with high‐flow
nasal oxygen and non‐invasive ventilation (NIV) with facemasks or hoods 22. Data from the SARS 23 and MERS 24
outbreaks cautioned against the use of high‐flow nasal oxygen or
non‐invasive ventilation, although this has recently been countered by
data demonstrating no increased dissemination of bacteria with high‐flow
nasal oxygen, yet viral spread remains unexplored 25.
As well as the potential risk of viral aerosolisation and the need for
careful isolation precautions, non‐invasive ventilation may also be
insufficient to manage COVID‐19‐induced respiratory failure, and
preliminary observations from the current Italian outbreak suggest there
may be a poor response to non‐invasive ventilation 3, 23, 25-27.
Delaying avoidable tracheal intubation may be beneficial 28, but delaying unavoidable tracheal intubation is a significant concern 27.
Invasive ventilation is associated with reduced aerosolisation and is
thus safer for staff and other patients. That said, it might also be
associated with hypoxia, haemodynamic failure and cardiac arrest 29, 30
during tracheal intubation, and a risk of staff exposure to high viral
load secretions, given that the very act of tracheal intubation is
associated with the greatest risk of exposure to healthcare
professionals 31.
Patient triage based on expected prognostic outcomes has become
increasingly important. Thus, early tracheal intubation is encouraged,
as late or emergency tracheal intubation in rapidly deteriorating
patients may be associated with greater risks, both to patients and
healthcare professionals.
Ethical burden and moral distress have been emerging
factors in the Italian outbreak, like that already seen in Wuhan.
Invasive ventilation must account for available personnel and critical
care beds, which have become rapidly saturated as our daily experience
is showing, with 650 COVID‐19 patients in critical care settings in
Italy on 8 March 2020 32.
Alternatives to tracheal intubation might reduce the demand on critical
care beds. Multidisciplinary evaluation, co‐operation and
decision‐making are strongly advised during this evolving and highly
dynamic crisis.
Airway management
Protocols and experiences in airway management for this and other coronavirus outbreaks 3, 23, 33-35,
as confirmed by our ongoing experience in Italy, is a necessity to
rigorously prepare for airway management. This includes utilisation of
cognitive aids such as checklists, cross‐checking and pre‐planned and
explicitly defined airway management strategies 36.
Any airway management procedure should be managed electively rather
than as an emergency, and any means to maximise first‐pass success
should be adopted. Procedures should be performed in a negative pressure
chamber (if available) or isolation area that is equipped with a
replenished, complete and checked emergency airway trolley. Entry and
departure of staff from the immediate clinical area must be strictly
monitored and restricted to those who are required. Thorough airway
assessment should guide clinicians to determine the safety of asleep
tracheal intubation, rather than awake tracheal intubation (ATI) 37, 38.
Clinicians must note that ATI is potentially a highly
aerosol‐generating procedure, thus the decision to undertake ATI must be
carefully considered.
Tracheal intubation
Patients with COVID‐19 are at risk of rapid arterial
oxygen desaturation, and therefore effective pre‐oxygenation is
mandatory. After pre‐emptive optimisation and correction of haemodynamic
disturbances, pre‐oxygenation with a fraction of inspired oxygen of 1.0
for at least 3 min at tidalvolume breathing or eight vital capacity
breaths should be carried out 39.
Rapid sequence intubation is indicated for all cases to minimise the
apnoea time during which significant aerosolisation can occur with
facemask ventilation. Therefore, facemask ventilation should only be
performed gently in the event of critical arterial oxygen desaturation 40.
In order to maximise first‐pass success and not compromise optimal
ventilation (if needed), cricoid force should not be performed, unless
there are other indications 41, 42. Apnoeic oxygenation is recommended to prevent desaturation 43, ideally with low‐flow nasal oxygenation during tracheal intubation attempts. Despite the benefits of high‐flow nasal oxygen 44,
it is an aerosol‐generating technique, particularly when the airway
operator is in close proximity to the patient, and should be avoided.
Cautious administration of general anaesthetic agents is
recommended to minimise haemodynamic instability, and rocuronium
1.2 mg.kg−1 or suxamethonium 1 mg.kg−1 should be given to ensure rapid onset of neuromuscular blockade, maximise first‐pass success 45
and prevent coughing and associated aerosolisation. Neuromuscular
monitoring is advisable. The most skilled and experienced airway
operator should perform airway instrumentation, and all conditions
should be optimised to ensure the highest chance of first‐pass tracheal
intubation success. We strongly recommend the use of a
videolaryngoscope, which would ideally be disposable but with a separate
screen to minimise patient contact. Pre‐loading an appropriately‐sized
tracheal tube on an introducer is also advised, as this may also improve
the first‐pass success rate 46.
In the event of a failed tracheal intubation, gentle
manual ventilation may be used, followed by a maximum of two attempts at
tracheal intubation (with consideration of change in position, device
and technique between attempts). After two failures, or any time if a
rescue airway is needed, a second generation supraglottic device is
strongly advised. Supraglottic airway devices that allow flexible
bronchoscopic intubation are preferable 47.
An early emergency front‐of‐neck airway (surgical or percutaneous
cricothyroidotomy) should be considered before a ‘cannot intubate,
cannot oxygenate’ scenario independently of critical arterial oxygen
desaturation 36.
If ATI is indicated, 37, 38, an experienced operator should perform it 48, 49 and administration of intravenous sedation may minimise coughing 50.
Aerosol or vaporised delivery of local anaesthesia should be minimised,
and consideration given to the use of mucosal atomisers, swabs and
tampons, and if clinical expertise permits, nerve blocks.
Ultrasound‐guided techniques could be adopted, though they might be
time‐consuming and carry challenges in terms of decontamination.
Single‐use flexible bronchoscopes should be used as they are associated
with a reduced risk of cross‐contamination 51,
and a separate screen is strongly advised. The diameter of the tracheal
tube should be the smallest appropriate to reduce the risk of tube
impingement on the arytenoids with consequent coughing. Awake tracheal
intubation with videolaryngoscopy is faster than with flexible
bronchoscopy and could be considered 52.
In the event of failed ATI, tracheostomy with local anaesthesia is a
viable alternative and must be considered, despite the potential for
aerosolisation 31.
Should a ‘cannot intubate, cannot oxygenate’ scenario occur, an
emergency front‐of‐neck airway should be performed with the
aforementioned principles.
Emergency tracheal intubation may be required for
COVID‐19 patients. This setting increases risks to patients and
healthcare workers and is often performed outside of the operating
theatre or intensive care environment. However, the acuity of airway
management should not compromise the safety of clinicians, and thus team
members must have PPE donned before commencing airway management. This
could require the delivery of gentle facemask ventilation in a hypoxic
patient to buy time for the patient and treating clinicians. Principles
of airway management in emergencies are like those in more controlled
settings.
After successful tracheal intubation, careful management
of the tracheal tube is crucial. Auscultation is not advisable due to
the challenges with PPE and the risk of cross‐contamination 23,
but confirmation of tracheal tube placement should ideally rely on
viewing the tracheal tube pass through the vocal cords, with an
appropriate and repeated capnographic trace and chest wall movement. All
of the aforementioned considerations need to be adopted for tracheal
tube exchange manoeuvres, and strategies for protected extubation should
be addressed, especially after prolonged tracheal intubation or
documented difficult airway management 53.
High‐efficiency particulate air filters should be placed between the
primary airway device and the breathing circuit, including the
expiratory limb of the circuit once the patient is connected to the
ventilator 54.
To prevent viral dispersion, unnecessary respiratory circuit
disconnections are discouraged. If disconnection is required, patient
sedation should be optimised to prevent coughing, the ventilator should
be turned to stand‐by mode and the tracheal tube clamped (Fig. 1).
Società Italiana di Anestesia Analgesia
Rianimazione e Terapia Intensiva guidance on airway management of the
patient with coronavirus disease 2019.
Non‐technical skills
The management of patients with COVID‐19 places
additional physical and psychological burdens on healthcare workers.
Physical burdens include repeated donning and doffing of PPE and
physical restrictions to routine practice due to PPE. Psychological
burdens include: management in unfamiliar environments; communication
challenges with PPE; and changes to standard practice. Identification of
suitable environments for airway management, team briefing and
co‐ordination, task assignment and briefings, team training and the use
of checklists and cognitive aids are all crucial to reduce physical and
cognitive work‐loads (Fig. 1).
To reduce physical risks, consideration of predefined
roles and ergonomics is imperative. There should be an independent
practitioner observing the donning and doffing of PPE 23, 55.
Only the most experienced healthcare workers with full PPE should be
present inside the isolation chamber. Suggested team assignments,
utilised in our clinical practice during this current crisis, include an
inner isolated chamber and an outer chamber (Fig. 2).
In the isolated chamber, all staff should have full PPE donned. Outside
of the chamber, additional PPE and other members of staff are
available.
Suggested team roles and ergonomics for elective tracheal intubation.
Personal protective equipment
Coronaviruses are typically found in the lower respiratory
tract linked with angiotensin converting enzyme receptors, with the
primary mechanism of transmission through contact and droplet spread of
respiratory secretions, which travel up to 2 m 10. The importance of PPE cannot be overstated, but clinicians must also be aware that effectiveness is rarely 100% 3.
Moreover, experiences in Italy have demonstrated that supplies of PPE
are unlikely to meet demand, thus the use of centralised storage and
distribution of PPE is recommended as well as considering the
preparation of dedicated PPE kits in keeping with WHO recommendations 17.
One of the key supply restrictions is that of appropriate
filtering face piece (FFP) masks. These are different to conventional
masks such as surgical masks as they create a facial seal, filtering the
air with different filter capacities (Table 3).
Although 2019‐nCoV has a size of 0.06–0.14 μm, the virus is carried
with droplets that are larger than 0.3 μm, and therefore facial
respirator masks with a filter against particles sized > 0.3 μm are
appropriate.
Table 3.
Filtering face piece (FFP) protection levels. FFP2, N95 and FFP3 masks are recommended for the management of COVID‐19 patients
Filter standard
Filter capacity (removal percentage of all particles ≥ 0.3 µm
FFP1
80%
FFP2
94%
N95
95%
FFP3
99%
N100
99.97%
COVID‐19, coronavirus disease 2019.
The levels of protection for airway management in COVID‐19
patients adopted in most of hospitals in Italy are either second‐ or
third‐level PPE, preferring the use of airborne‐level PPEs for critical
care aeorsol‐generating procedures, including tracheal intubation,
bronchoscopy and ATI. So far, the outbreak‐related global PPE shortage
has forced the use of lower‐protection PPEs for aeorsol‐generating
procedures. Airborne‐level protection should include: helmets, covers or
hoods; FFP3 or FFP2/N95 masks, goggles or face shields (if no helmets);
hazmat suits or long sleeved fluid‐resistant gowns; double gloves
(possibly different colours); and overshoes. Whenever possible, the
maximum available protection level should be used, especially for
aeorsol‐generating procedures.
Donning and doffing of PPE should be practiced and when
performed clinically, an external observer should supervise its
meticulous performance in accordance with checklists 23.
In our experience, PPE donning and doffing presents the greatest
challenge to daily working. In particular, doffing of PPE, especially
when clinicians are tired and cognitively overloaded, is associated with
the greatest risk of contamination. Team members should doff PPE
individually and one at a time. Cycles of thorough hand disinfection
must be undertaken and supervised, and meticulous waste disposal must be
completed.
Transport
Local protocols should be designed for post‐procedural
transport of patients with PPE and biocontainment procedures strictly
adhered to 55. This must factor staff and public safety during transport.
Briefing, debriefing and training
Pre‐procedural briefing and post‐procedural debriefing are
mandatory to review errors and determine improvements for future
practice. Team‐based simulation and training remains critical throughout
the evolution of this pandemic, involving any level of healthcare
professionals 56. The development of local protocols and checklists, development and adoption of dedicated early warning scores 57,
and accounting for regional variation in practice, is strongly
recommended given the number of clinicians involved, as well as the
risks to healthcare professionals.
Conclusion
We have faced many challenges with the onset of the COVID‐19
outbreak throughout Italy and it is likely that other countries will
face similar challenges in the coming weeks and months. We have shared
systemic and clinical knowledge and experiences gained during the course
of the Italian outbreak, with the aims of educating and supporting
clinicians elsewhere in the global healthcare community who may face
similar scenarios. Only with appropriate informed planning, training and
team working will healthcare systems be best placed to face this new
pandemic.
https://en.wikipedia.org/wiki/Caspase_1
pelkkä kaspaasi-1 näyttää riittävän Gasdermiinin pilkkoamiseen.
intgerleukiinit IL-1b ja IL-18 eivät ilmeisesti vaikuta siihen GasdermiiniD- aukon tekemiseen vaan niiden ilmeneminen tapahtuu sen aukon avulla. Jos aukkoa ei mudoostu, ne jäävät solun sisään. erään tiedon mukaan. Siis olennaista on kaspaasi-1.n aktivoituminen gasdermiini D kanavan muodostumiseen pikkuhiljaa. Miten hanakasti se tukee pelkkää kanavaa ilman ilman monomeerin löytämää kohdetta, esim bakteeria tai parasiitti? Siis pelkän solustressin takia viruksen ollessa sille näkymätön. Kanava sinänsä on edullinen virukselle, koska sen omat kanavat ovat pieniä ja ehkä niisä lie vielä jotain joniselektiivisyytäkin. tässä kun ei ole joniselektiivisyyttä vaan se hävittää membraanipotentiaalin tarvitsemat jonitasapainot nopeasti ja päästää vettä soluun.
Se on tosiaan huomionarvoinen kohde tällä kertaa. Siitä tuleva tieto on aika tuoretta, viime joulukuulta ja muutenkin vain parilta viime vuodelta on enemmän tietoa.
Huom kuvan pyörylät ovat gasdermiiniaukkoja eikä viruksia!
Abstract
Gasdermin‐D (GSDMD), a member of the gasdermin protein
family, mediates pyroptosis in human and murine cells. Cleaved by
inflammatory caspases, GSDMD inserts its N‐terminal domain (GSDMDNterm) into cellular membranes and assembles large oligomeric complexes permeabilizing the membrane. So far, the mechanisms of GSDMDNterm
insertion, oligomerization, and pore formation are poorly understood.
Here, we apply high‐resolution (≤ 2 nm) atomic force microscopy (AFM) to
describe how GSDMDNterm inserts and assembles in membranes. We observe GSDMDNterm
inserting into a variety of lipid compositions, among which
phosphatidylinositide (PI(4,5)P2) increases and cholesterol reduces
insertion. Once inserted, GSDMDNterm assembles arc‐, slit‐,
and ring‐shaped oligomers, each of which being able to form
transmembrane pores. This assembly and pore formation process is
independent on whether GSDMD has been cleaved by caspase‐1, caspase‐4,
or caspase‐5. Using time‐lapse AFM, we monitor how GSDMDNterm
assembles into arc‐shaped oligomers that can transform into larger
slit‐shaped and finally into stable ring‐shaped oligomers. Our
observations translate into a mechanistic model of GSDMDNterm transmembrane pore assembly, which is likely shared within the gasdermin protein family.'
Viroporiinista mainitaan että se aktivoi inflammasomin ja aiheuttaa mainitut interleukiinit ... siis aika varhain. Viroporiinin aiheuttama solustressi ja kalsiumin ja muiden jonien epätasapaino tunnistuu, vaikka virusgenomia ei havaittaisikaan ja tässä käsittääkseni GSDMD pääsee vähitellen myös raekntamaan sen lisäaukon kun gasdermin D myös pilkkoutuu . Riittääkö sen pilkkoamiseen pelkkä kaspaasi -1? Ilmeisesti riittää, mutta varmastikin nopeammin tapahtuu sen muodostuminen jos on myös TLR- tietä tapahtunutta kaspaasien muodostusta lisäksi. Viroporiinin aukko ei voi olla kovin suuri, muta kun viroporiini on aktivoinut inflammasomin ja saanut aikaan gasdermiiniaukkojen muodostuksen, Nesteaukot 10-14 nm toimivat ilman jonisensitiivisyyttä ja vettä tulvii soluun ja solu paisuu, samalla solusta virtaa tekijöitä ulos. Ilmeiseti virus kaapaa tämän solun puolustusfunktion stressireaktiovälitteisesti. Tuo iso kanava on tarkoitettu isompien mikrobien esim EHEC ym , bakteereiden ja parasiittien pois saamiseksi solusta ja tappamiseksi niin solun sisällä kuin solun ulkopuolella. Sen takia GasderminD omaa pätevän pääsyn kaikkiin solukalvoihin, sen kohdemolekyylit ovat fosfoinositolilipidit , fosfatidyyliseriini ( plasmamembraanin sisäkalvossa, , fosfatidyylietanolamini kalvon sisä-keskiosissa, fosfotidihappo (sytoplasmassa) ja jopa kardiolipiini, jota on vain mitokondrian sisäkalvoissa. Lisäksi se tekee interaktion niihin fosfatidyyliinositolimuotoihin joita tuman sisäpuolella ensisijaisesti valitaan ( muotoja joissa on 4 tai 5 aseman fosfaatti). Gasdermin D molekyylin N-terminaaliset osat puhkaisevat reikiä soluun solutilojen sisäpuolelta noudattaen lipidikerrosten lipidien hierarkiaa. Aluksi varmaan vain pieni reikä, josta vesi pääsee soluun, kaliumit ulos, kalsiumia sisään ja niin turvottamaan solun pyöreäksi mikä jo mekaanisesti levittää kanavaa.
Viroporins
are virus encoded proteins that alter membrane permeability and can
trigger subsequent cellular signals. Oligomerization of viroporin
subunits results in formation of a hydrophilic pore which facilitates
ion transport across host cell membranes. These viral channel proteins
may be involved in different stages of the virus infection cycle.
Inflammasomes are large multimolecular complexes best recognized for
their ability to control activation of caspase-1, which in turn
regulates the maturation of interleukin-1 β (IL-1β) and interleukin 18
(IL-18). IL-1β was originally identified as a pro-inflammatory cytokine
able to induce both local and systemic inflammation and a febrile
reaction in response to infection or injury. Excessive production of
IL-1β is associated with autoimmune and inflammatory diseases.
Microbial
derivatives, bacterial pore-forming toxins,extracellular ATP and other
pathogen-associated molecular patterns trigger activation of NLRP3
inflammasomes.
Recent studies have reported that viroporin activity is
capable of inducing inflammasome activity and production of IL-1β, where
NLRP3 is shown to be regulated by fluxes of K+, H+ and Ca2+
in addition to reactive oxygen species, autophagy and endoplasmic
reticulum stress. The aim of this review is to present an overview of
the key findings on viroporin activity with special emphasis on their
role in virus immunity and as possible activators of inflammasomes.
https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-020-00404-4
On nimittäin josain mielessä havaittu SARS CoV2002 pahemmaksi kuin nykyinen SARS CoV 2-2019, vaikka minusta sen tappavuus ei kyllä mikään " vähempi patogeenisuus" mielestäni ollenkaan. koska virus on hankkinut sen pandemisen kykynsä tässä aikojen kuluessa.
Kuitenin sanotaan että SARS 1 tekijöillään ORF3a ja ORF8b indusoi NLRP3 inflammasomia samoja ORF.eja taas ei niissä muodoissaan ole tässä viruksessa, sen sijaan uudella viruksella on jokin lisä proteiinipätkäkin näistä ORF-alueista eikä tiedetä niiden funktiosta kovin paljoja. Ne ovat varmaan nsp- kaltaisia tekijöitä. ja maintiaan vain "ORF3" ja " ORF8"oletettavaa on , että ne tehostavat kaikkien 16 tunnetun polyproteiiniperäisen nsp:n monipuolista funktiota ehkä viruksen virioninkehittämisohjelman ajoituksessa tarvitavaia tekijöitä. Koko nsp-kirjo on ajoituksesta suuresti riippuvaista. vähän tyrmäystaktiikalla, hyvä alkutyrmäys ja sitten työrauhaa vikkelään toimintaan. En oikeiastaan vielä odotakaan löytäväni karttoja uuden viruksen vaikutuksesta inflammasomitasoon. muta koetan löytää ensin karttoja ja tekstejä vanhoissta SARS- viruksista inflammasomiympäristössä. .
The ninth question concerns why SARS-CoV-2 is less pathogenic. If the
reduced pathogenicity of SARS-CoV-2 is the result of adaptation to
humans, it will be of great importance to identify the molecular basis
of this adaptation. The induction of a cytokine storm is the root cause
of pathogenic inflammation both in SARS and COVID-19. SARS-CoV is known
to be exceedingly potent in the suppression of antiviral immunity and
the activation of proinflammatory response. It is therefore intriguing
to see how SARS-CoV-2 might be different from SARS-CoV in
interferon-antagonizing and inflammasome-activating properties. It is
noteworthy that some interferon antagonists and inflammasome activators
encoded by SARS-CoV are not conserved in SARS-CoV-2. Particularly, ORF3
and ORF8 in SARS-CoV-2 are highly divergent from ORF3a and ORF8b in
SARS-CoV that are known to induce NLRP3 inflammasome activation. ORF3 of
SARS-CoV-2 is also significantly different from the interferon
antagonist ORF3b of SARS-CoV. Thus, these viral proteins of SARS-CoV and
SARS-CoV-2 should be compared for their abilities to modulate antiviral
and proinflammatory responses. The hypothesis that SARS-CoV-2 might be
less efficient in the suppression of antiviral response and the
activation of NLRP3 inflammasome should be tested experimentally.
Selaillessani KARTTOJA INFLAMMASOMISTA HAVAITSIN YHDEN ARTIKKELIN JOSSA OLI ASSOSIOITU Covid-19 ja NLRP3 MYÖS KUTEN AIEMMIN ASSOSIOITIIN Sars coV ja NLRP3.
Luin artikkelin. se vaikuttaa yhden henkilön teorialta. https://www.evolutamente.it/category/doris-loh/Tässä on sarja näitä eri näkökohtia. Otan sen NLRP3:n yhteydessä mainitun kohdan. Yllätyksekseni se assosioidaan melatoniiniin.
Monessa kohtaa olen samaa mieltä, patisi ACEI ja ARb lääkityksen suhteen, koska ne eivät kohdistu entsyymi ACE2- molekyyliin ollenkaan ja ovat mielestäni hyödyksi koska mahdollisesti kehittyy hypoertensiota jos ACE2- molekyyliä pääsee paljon tuhtuumaan ja ACE-entsyymi pääsee vallalle , ja juuri sitä ylivaltaa vastaan ACEI ja ARB ovatkin, järjestelmän vasokonstrikipuolen ylisäätymistä vastaan, ACE2 vastaa dilataatiofunktiosta. Hyvä maininta on NO, sillä se kuuluu RAAS järjestelmään ja verisuoniston tilavuuden ylläpitoon. Mitä tulee Melatoniiniin, mielstäni kaikki sadat tuhannet karanteeniin määrätyt voivat nostaa melatoniininsa vain nukkumalla yönsä pimeässä huoneessa ilman yövaloa. Melatoniin säätöä tehostaa jos aamulla vilkaisee valoisaa ulkoilmaa kun hengittää raikasta aamuilmaa ja tuulettaa keuhkojaan. Melatoniini muodostuu aminohapoista. ja aivoon siirtyy aromaattisia (AA) ja haaraketjuisia (BCAA) aminohappoa eli isoja neutraaleja aminohappoja (LNAA) circadisen rytmin mukaan ja siihen sopii että syö aamuisi maitoproteiineja aamiaisella, munaa, maitoa, leipää, ym ja keskipäivällä esim lpapusoppaa, kalaa, linsejä ym josita tulee runsaasti näitä laatuja, sillä niillä on sitten kilpailunsa aivoon pääsystä ja se on tasapainoisinta vuorokaudelle jos niitä on syöty päiväsaikaan jo aamusta. Sitten on materiaalia sille melatoniinia muodostua pimeässä. Aminohappojen keskinäisessä kilpailussa tryptofaani josta melatoniini lopulta muodostuu, on eräänlainen rajoittava tekijä, sitä on aika vähän joissain ruoissa, että on paras katsoa ravintonsa sen verran monipuoliseksi, että sitäkin tulee. Ei pitäisi harrastaa proteiinia vain kaikken maukkaimmassa ja kulinaarisimmassa muodossaan, sillä siinä arvokkaat aminohapot ovat monta kertaa pelkkää muistoa omasta itsestään, eli itsensä aminimuotoja, joista ei voi rakentaa kehon proteiinimuotoja. Sen takia tuollaiset kylmät proteiinit, kuten jogurtit, rahkat, maidot, tuorejuustot, pähkinät, mantelit, hiutaleet, myslit, ovat eduksi. Kananmunakin voi keittää vähälläkin ajalla ettei se nyt ole aivan kivikova tai paistaa niin että se juuri ja juuri muuttuu hyväksi omeletiksi eikä ole mikään tärkätty ruskeareunainen pitsi.
Bioorg Med Chem. 2015 Sep 1;23(17):6036-48. doi: 10.1016/j.bmc.2015.06.039. Epub 2015 Jun 19.
Targeting
zoonotic viruses: Structure-based inhibition of the 3C-like protease
from bat coronavirus HKU4--The likely reservoir host to the human
coronavirus that causes Middle East Respiratory Syndrome (MERS).
The
bat coronavirus HKU4 belongs to the same 2c lineage as that of the
deadly Middle East Respiratory Syndrome coronavirus (MERS-CoV) and shows
high sequence similarity, therefore potentiating a threat to the human
population through a zoonotic shift or 'spill over' event. To date,
there are no effective vaccines or antiviral treatments available that
are capable of limiting the pathogenesis of any human coronaviral
infection. An attractive target for the development of anti-coronaviral
therapeutics is the 3C-like protease (3CL(pro)), which is essential for
the progression of the coronaviral life cycle. Herein, we report the
screening results of a small, 230-member peptidomimetic library against
HKU4-CoV 3CL(pro) and the identification of 43 peptidomimetic compounds
showing good to excellent inhibitory potency of HKU4-CoV 3CL(pro) with
IC50 values ranging from low micromolar to sub-micromolar. We
established structure-activity relationships (SARs) describing the
important ligand-based features required for potent HKU4-CoV 3CL(pro)
inhibition and identified a seemingly favored peptidic backbone for
HKU4-CoV 3CL(pro) inhibition. To investigate this, a molecular
sub-structural analysis of the most potent HKU4-CoV 3CL(pro) inhibitor
was accomplished by the synthesis and testing of the lead peptidomimetic
inhibitor's sub-structural components, confirming the activity of the
favored backbone (22A) identified via SAR analysis. In order to
elucidate the structural reasons for such potent HKU4-CoV 3CL(pro)
inhibition by the peptidomimetics having the 22A backbone, we determined
the X-ray structures of HKU4-CoV 3CL(pro) in complex with three
peptidomimetic inhibitors. Sequence alignment of HKU4-CoV 3CL(pro), and
two other lineage C Betacoronaviruses 3CL(pro)'s, HKU5-CoV and MERS-CoV
3CL(pro), show that the active site residues of HKU4-CoV 3CL(pro) that
participate in inhibitor binding are conserved in HKU5-CoV and MERS-CoV
3CL(pro). Furthermore, we assayed our most potent HKU4-CoV 3CL(pro)
inhibitor for inhibition of HKU5-CoV 3CL(pro) and found it to have
sub-micromolar inhibitory activity (IC50=0.54±0.03μM). The X-ray
structures and SAR analysis reveal critical insights into the structure
and inhibition of HKU4-CoV 3CL(pro), providing fundamental knowledge
that may be exploited in the development of anti-coronaviral
therapeutics for coronaviruses emerging from zoonotic reservoirs.
Inhibition of SARS-CoV 3C-like Protease Activity by Theaflavin-3,3'-digallate (TF3)
Chia-Nan Chen,1Coney P. C. Lin,1Kuo-Kuei Huang,1Wei-Cheng Chen,1Hsin-Pang Hsieh,1Po-Huang Liang,2 and John T.-A. Hsu1,3
1Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Taipei, Taiwan 2Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan 3Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan
BACKGROUND:
Since December 2019, novel coronavirus (SARS-CoV-2)-infected pneumonia (COVID-19) occurred in Wuhan, and rapidly spread throughout China. This study aimed to clarify the characteristics of patients with refractory COVID-19.
METHODS:
In this retrospective single-center study, we included 155 consecutive patients with confirmed COVID-19 in Zhongnan Hospital of Wuhan University from January 1st to February 5th. The cases were divided into general and refractory COVID-19 groups according to the clinical efficacy after hospitalization, and the difference between groups were compared.
RESULTS:
Compared with general COVID-19
patients (45.2%), refractory patients had an older age, male sex, more
underlying comorbidities,lower incidence of fever, higher levels of
maximum temperature among fever cases,higher incidence of breath
shortness and anorexia, severer disease assessment on admission, high
levels of neutrophil, aspartate aminotransferase (AST), lactate
dehydrogenase (LDH) and C-reactive protein, lower levels of platelets
and albumin, and higher incidence of bilateral pneumonia andpleural effusion (P<0 .05="" nbsp="" p="">Refractory COVID-19
patients were more likely to receive oxygen, mechanical ventilation,
expectorant, and adjunctive treatment including corticosteroid,
antiviral drugs and immuneenhancer (P<0 .05="" adjustment="" after="" class="highlight" refractory="" span="" those="" with="">COVID-19
were also more likely to have a male sex and manifestations of anorexia
and fever on admission, and receive oxygen, expectorant and adjunctive
agents (P<0 .05="" admission="" and="" considering="" disease="" factors="" icu="" mechanical="" of="" on="" p="" severity="" the="" transfer.="" ventilation="" when="">CONCLUSION:
Nearly 50% COVID-19
patients could not reach obvious clinical and radiological remission
within 10 days after hospitalization. The patients with male sex,
anorexia and no fever on admission predicted poor efficacy.
BACKGROUND:
The pneumonia caused by the 2019 novel coronavirus (SARS-CoV-2, also called 2019-nCoV) recently break out in Wuhan, China, and was named as COVID-19.
With the spread of the disease, similar cases have also been confirmed
in other regions of China. We aimed to report the imaging and clinical
characteristics of these patients infected withSARS-CoV-2 in Guangzhou, China.
METHODS:
All patients with laboratory-identified SARS-CoV-2
infection by real-time polymerase chain reaction (PCR) were collected
between January 23, 2020, and February 4, 2020, in a designated hospital
(Guangzhou Eighth People's Hospital). This analysis included 90
patients (39 men and 51 women; median age, 50 years (age range,
18-86 years).
All the included SARS-CoV-2-infected
patients underwent non-contrast enhanced chest computedtomography
(CT). We analyzed the clinical characteristics of the patients, as well
as the distribution characteristics, pattern, morphology, and
accompanying manifestations of lung lesions. In addition, after 1-6 days
(mean 3.5 days), follow-up chest CT images were evaluated to assess
radiological evolution FINDINGS:
The majority of infected patients had a history of exposure in Wuhan
or to infected patients and mostly presented with fever and cough.
More
than half of the patients presented bilateral, multifocal lung lesions,
with peripheral distribution, and 53 (59%) patients had more than two
lobes involved.
Of all included patients, COVID-19
pneumonia presented with ground glass opacities in 65 (72%),
consolidation in 12 (13%), crazy paving pattern in 11 (12%),
interlobular thickening in 33 (37%), adjacent pleura thickening in 50 (56%), and linear opacities combined in 55 (61%). Pleural effusion, pericardial effusion,and lymphadenopathy were uncommon findings. In addition, baseline chest
CT did not show any abnormalities in 21 patients (23%), but 3 patients
presented bilateral ground glass opacities on the second CT after
3-4 days.
CONCLUSION:
SARS-CoV-2
infection can be confirmed based on the patient's history, clinical
manifestations, imaging characteristics, and laboratory tests. Chest CT
examination plays an important role in the initial diagnosis of the
novel coronavirus
pneumonia. Multiple patchy ground glass opacities in bilateral multiple
lobular with periphery distribution are typical chest CT imaging
features of the COVID-19 pneumonia.
Keuhkoja ympäröi keuhkopussi jossa on kaksilehtinen pleurakalvo. Kahden pleurakalvon välillä on lubrikanttinestettä sisältävä tila, joka vastaa fysiologisesta liikkuvuudesta rntakehän seinämän ja keuhkon välillä hengitysliikkeiden aikana.
Koetan löytää tästä lubrikanttinesteestä molekulaarista tietoa. Jos muistellaan vanhoja aikoja, kun tu oli yleinen, tähän tilaan muodostui paljon effusiota, jota sitten tyhjejnnettiin ja josta viljeltiin tubibakteeriakin.
Vanhaa hyvää tietoa ensin vuodelta 1997
Eur Respir J. 1997 Jan;10(1):219-25. Physiology and pathophysiology of pleural fluid turnover. Miserocchi G1. Abstract
The
pleural space contains a tiny amount (approximately 0.3 mL.kg-1) of
hypooncotic fluid (approximately 1 g.dL-1 protein). Pleural fluid
turnover is estimated to be approximately 0.15 mL.kg-1.h-1. Pleural
fluid is produced at parietal pleural level, mainly in the less
dependent regions of the cavity. Reabsorption is accomplished by
parietal pleural lymphatics in the most dependent part of the cavity, on
the diaphragmatic surface and in the mediastinal regions. The flow rate
inpleural lymphatics can increase in response to an increase in
pleural fluid filtration, acting as anegative feedback mechanism to
control pleural liquid volume. Such control is very efficient, as a 10
fold increase in filtration rate would only result in a 15% increase in
pleural liquid volume. When filtration exceeds maximum pleural lymphatic
flow, pleural effusion occurs: as an estimate, in man, maximum pleural
lymph flow could attain 30 mL.h-1, equivalent to approximately 700
mL.day-1 (approximately 40% of overall lymph flow). Under physiological
conditions, the lung interstitium and the pleural space behave as
functionally independent compartments, due to the low water and solute
permeability of the visceral pleura. Pleural fluid circulates in the
pleural cavity and intrapleural fluid dynamics may be represented by a
porous flow model. Lubrication betweenlung and chest wall is assured by
oligolamellar surfactant moleculesstratified on mesothelial cells of
the opposing pleurae. These molecules carry a charge of similar sign
and, therefore, repulse each other, assuring a graphite-like
lubrication.
mpia tietoja pleuran mesoteliaalisen joustavuuden parantamisesta molekulaarisesti lubrikantilla. Jopa antibiottia, antiviruslääkettä voidaan asentaa tällaisen kantaja-aineen avulla intrapleuraaliseen tilaan pleuralehtien välisen liikkuvuuden parantamiseksi.
To examine effects of lung motion on the separation of pleural surfaces during breathing, we modeled the pleural space
in two dimensions as a thin layer of fluid separating a stationary
elastic solid and a sliding flat solid surface. The undeformed elastic
solid contained a series of bumps, to represent tissue surface features,
introducing unevenness in fluid layer thickness. We computed the extent
of deformation of the solid as a function of sliding velocity, solid elastic modulus,
and bump geometry (wavelength and amplitude). For physiological values
of the parameters, significant deformation occurs (i.e. bumps are
‘flattened’) promoting less variation in fluid thickness and decreased
fluid shear stress. In addition, deformation is persistent; bumps of
sufficient wavelength, once deformed, require a recovery time longer
than a typical breath-to-breath interval to return near their undeformed
configuration. These results suggest that in the pleural space during
normal breathing, separation of pleural surfaces is promoted by the
reciprocating sliding of lung and chest wall.
COVID on ottanut insertion - PRRA- tuohon kohtaan missä se tekee biosynteesinä S1/S2 pilkkoutuman Siinä on tullainen juuri insertio. -prra- sivumennen sanoen, jonka kaltainen löytyy intereronista joka voisi tunnistaa tuon viruksen. Sattumalöytö vain. Muistiin)
Abstract
The recently discovered IFN‐λ4 has been found to have
antiviral activity against several viruses. However, it's unknown
whether IFN‐λ4 can inhibit HIV infection. Here, we show that IFN‐λ4
could suppress HIV infection of macrophages. This IFN‐λ4‐mediated HIV
inhibition was compromised by the antibodies against IFN‐λ receptor
complex, IFN‐λR1/IL‐10R2. IFN‐λ4 enhanced the phosphorylation of STAT1,
and induced antiviral interferon‐stimulated genes. These findings
indicated that IFN‐λ4 can inhibit HIV via JAK/STAT signalling pathway.
.. IFNL4 genome contains a dinucleotide variant, IFNL4‐ΔG/TT (rs368234815,
originally designated as ss469415590) in exon 1 of IFNL4, upstream of
IFN‐λ3 on chromosome 19q13.13. The IFNL4‐ΔG allele generates a
functional IFN‐λ4 protein p179 (179 aa) by introducing a frameshift
mutation that enables transcription, and the homozygous TT genotype
creates a premature stop codon and thus knockouts this gene. IFN‐λ4
expresses in a small fraction of Asian and about half of European
populations, but in most of Africans.4
Genetic studies have demonstrated that IFNL4‐TT allele has a strong
positive correlation with HCV clearance, treatment outcome of HCV
infection, and innate resistance to HIV infection, on the contrary,
IFNL4‐ΔG allele is associated with the impairment of HCV clearance, and
unfavourable clinical and immunological status in HIV/HCV co‐infected
subjects.4-6
But there was also evidence supported that IFNL4 genotype is not
associated with the antiviral interferon‐stimulated genes (ISGs)
expression and HIV load in chronic HIV infection.7
