Gugliano said, so she found Gregg competent to stand trial

it could have been her own inner dialogue and she didn’t recognize it

blackouts, she said she thought that was what had happened during the incident

patient can keep producing insulin naturally in the coming years, s

Two and a half months later, the woman's lifelong dependence on injected insulin came to an end – completely reversing her long-term, hard-to-control diabetes.

reversal of inflammation and fibrosis

achieved complete B-cell depletion, including B cells implicated in the pathophysiology of their autoimmune disorders.

the formation of specialized vesicles

Rarely, vigorous exercise triggers a widespread, potentially severe allergic (anaphylactic) reaction. In some people, this reaction occurs only if they eat a specific food (especially wheat or shrimp) before exercising. Breathing becomes difficult or blood pressure falls, leading to dizziness and collapse. An anaphylactic reaction can be life threatening.

Iron is a potential therapeutic target for IRI (Fig. 4). Clinical studies have shown that children with following severe ischemic-anoxic insult have significantly increased iron levels in multiple areas of the brain

Probably the long-term health effects we see in people who are supposed to be recovered from an acute infection are actually due to persistence of virus

Once the infected immune cells were eliminated, the signs of damage diminished

Moreover, the presence of the virus changed the behavior of the infected immune cells, causing them to become more inflammatory than the uninfected immune cells

destroys RNA within the cells to further reduce protein synthesis of both viral and host genes.

to reduce protein synthesis within the cell

Monocytes and macrophages can also produce large amounts of type I interferons when stimulated by viral molecular patterns

fibroblast growth factors and vascular endothelial growth factors stimulate blood vessel

, epidermal growth factor (EGF)

promote cell differentiation and maturation,

HSV-1 tends to reside in the trigeminal ganglia,

When vascular dysfunction is present, vasodilation is impaired

hypoxia also inhibits chicken ovalbumin upstream

Treatment with inhibitors of TGF β1 receptor and ANTXR2 significantly attenuates hypoxia-induced cell adhesio

produce collagens,

Hypoxia is common at the beginning

initiation of hypoxia is one of the main causes of AKI

rapid failure of kidney function, usually caused by decreased blood flow

capacity of Hif-1 to downregulate fatty acid β-oxidation

overexpressing Hif-1α in adipocytes have elevated obesity and insulin resistance associated with increased inflammation and fibrosis

Hypoxia alters several key metabolic processes including glucose uptake, glycolysis, oxidative metabolism, lipolysis, and lipogenesis in adipocytes.

leptin, visfatin, apelin, TNF-α, IL-1, IL-6, VEGF, MMP2, MMP9, angiopoietin-like protein-4, macrophage migration inhibitory factor, and PAI-1 expression

show that HIF-1α and HIF-2α inhibit insulin signaling

inhibition of proteolytic enzymes

pronounced circadian variation in PAI-1 plasma levels with the highest concentration present in the morning a

Rapid fluctuations in t-PA concentration can be observed in response to exercise, venous occlusion, alcohol and drugs

Tissue-type plasminogen activator (t-PA) is the principal endogenous activator of plasminogen in blood. It is produced as a single-chain molecule by the vascular endothelial cells and is secreted into the plasma continuously or by an acute release reaction following stimulation of certain endothelial cell receptors

The opposite effect is observed in the presence of anions, in particular with Cl-, which stabilizes the closed form of Glu-plasminogen rendering plasminogen poorly activatable.

point-of-care ultrasound can be used to measure optic nerve sheath diameter for detection of increased intracranial pressure

Unless specific tests are used to detect hypoperfusion (transcranial Doppler, perfusion CT, or direct cerebral blood flow measurement) it will go unnoticed, low PbtO2 will be deemed unreliable, or no causes will be identified

Awakening was in fact reported as the cause of low PbtO

it must be realized that PaO2 required for a few days after brain injury to overcome a diffusion barrier is probably higher than 100 mm Hg. 20,24

Diffusion of oxygen from the capillary to the neuron is actually the rate-limiting step of oxygen delivery 22

switch from carbohydrate metabolism to lipid metabolism for cellular energy supply.[30][31][32] This metabolic switch limits anaerobic metabolism and the formation of lactate, a herald of poor prognosis and multi-organ failure (MOF) after I/R injury. In addition, the increase in lipid metabolism generates ketone bodies and activates peroxisome proliferating-activated receptors (PPARs), both of which have been shown to be protective against I/R injury

Superoxide dismutase edit Superoxide dismutase is an effective anti-oxidant enzyme which converts superoxide anions to water and hydrogen peroxide. Recent researches have shown significant therapeutic effects on pre-clinical models of reperfusion injury after ischemic stroke

resulting in mitochondrial dysfunction and collapse. Upon collapse, the calcium is then released to overwhelm the next mitochondria in a cascading series of events that cause mitochondrial energy production supporting the cell to be reduced or stopped completely

Hypothermia has been shown to help moderate intracranial pressure and therefore to minimize the harmful effect of a patient's inflammatory immune responses

hypothermia

FMN loss by complex I and I/R injury can be alleviated by the administration of FMN precursor, riboflavin

brain ischemia/reperfusion injury is mediated via complex I redox-dependent inactivation.[5] It was found that lack of oxygen leads to conditions in which mitochondrial complex I loses its natural cofactor, flavin mononucleotide (FMN) and become inactive.[6] When oxygen is present the enzyme catalyzes a physiological reaction of NADH oxidation by ubiquinone, supplying electrons downstream of the respiratory chain (complexes III and IV). Ischemia leads to dramatic increase of succinate level.[7] In the presence of succinate mitochondria catalyze reverse electron transfer so that fraction of electrons from succinate is directed upstream to FMN of complex I.[8] Reverse electron transfer results in a reduction of complex I FMN, increased generation of ROS, followed by a loss of the reduced cofactor (FMNH2) and impairment of mitochondria energy production.[8]

Repeated bouts of ischemia and reperfusion injury also are thought to be a factor leading to the formation and failure to heal

major part in the biochemistry of hypoxic brain injury in stroke

White blood cells may also bind to the endothelium of small capillaries, obstructing them and leading to more ischemia.[2]

oxygen within cells that damages cellular proteins, DNA, and the plasma membrane.

. White blood cells, carried to the area by the newly returning blood, release a host of inflammatory factors such as interleukins as well as free radicals in response to tissue damage.[2

often associated with microvascular injury, particularly due to increased permeability of capillaries and arterioles that lead to an increase of diffusion and fluid filtration across the tissues

showing a possible reduction in the overall systemic inflammatory process

but antioxidant drugs, control of blood glucose levels, and hemodilution (thinning of the blood) coupled with drug-induced hypertension are some treatment techniques currently under investigation

excitotoxicity

promotes calcium influx through N-methyl-D-aspartate (NMDA) receptors. Calcium influx exacerbates neuronal injury by activating lytic enzymes, precipitating free radical formation, and interfering with mitochondrial function.

contributes to intracellular sodium accumulation and cytotoxic edema

reductions in motivational deficits were associated with heightened responses in a brain network

improved motivation was mediated by the observed changes in TNF signaling

alterations in brain activity

greater willingness to exert effort in pursuit of rewards

effort-based decision-making task,

Over two weeks,

potent anti-inflammatory medication used to treat rheumatoid arthritis

persistent inflammation, which suppresses activity

circuits in the brain.

improved motivation in depressed

Brain activity in motivation-related areas increased

Anti-inflammatory Drug Boosts Motivation in Depression

correlating with changes in brain activity in key motivation regions.

infliximab

This research highlights the potential of targeting inflammation as a treatment for depression-related motivation issues.

The study links TNF-mediated inflammation to motivation deficits in depression

Motivational impairments are a core component of depression and have long been linked with poor treatment outcomes, diminished quality of life and heightened suicide risk

such as aminocaproic acid (ε-aminocaproic acid) and tranexamic acid are used as inhibitors of fibrinolysis

Angiotensin II increases the synthesis of plasminogen activator inhibitor-

PAI-1 can also be a component of the senescence-associated secretory phenotype (SASP).[8]

inhibiting mTORC1, rapamycin reduces SASP production by senescent cells.[67]

For this reason, senolytic therapy has been proposed as a generalized treatment for these and many other diseases.[2] The flavonoid apigenin has been shown to strongly inhibit SASP production.[5

In fact, SASP from senescent cells is associated with many aging-associated diseases

Despite the fact that cellular senescence likely evolved as a means of protecting against cancer early in life, SASP promotes the development of late-life

SASP cytokines can result in an inflamed stem cell niche, leading to stem cell exhaustion and impaired stem cell function.[36]

accumulation of unfolded proteins, resulting in proteotoxic impairment of cell function

SASP factors from senescent cells reduce nicotinamide adenine dinucleotide (NAD+) in non-senescent cells,[

Transforming growth factor beta family members secreted by senescent cells impede differentiation

SASP disrupts normal tissue function by producing chronic inflammation, induction of fibrosis and inhibition of stem cells.[4

SASP factors induce insulin resistance.[

which is why senescent cells consisting of only 2% or 3% of tissue cells can be a major cause of aging-associated diseases.

cGAS is essential for induction of cellular senescence

upregulating SASP by induction of interferon type I.[

Soluble urokinase plasminogen activator surface receptor is part of SASP, and has been used to identify senescent cells for senolytic therapy.[5] In

inhibits M-CDKs which are a key component of progression into mitosis.

the process of reconsolidation, in contrast, is DSB-dependent.

Stimulation of neuronal activity, as previously mentioned in IEG expression, is another mechanism through which DSBs are generated.

can change gene function or regulation of gene expression and possibly contribute to progression to cancer.

The hallmarks of mitochondrial disease are almost always multisystem involvement and unambiguous lactate acidemia or acidosis.

Any inborn error of metabolism that involves the tightly coupled and regulated process of mitochondrial energy metabolism may have profound effects on health and disease, because oxidative phosphorylation is the process by which we convert nutrients into energy

by administration of inotropic agents.

type A lactic acidosis can become self-perpetuating unless vigorous measures are undertaken to reverse the disturbance and treat the underlying cause.

prompt diagnosis and correction of the underlying disease state are crucial.

tissue perfusion

When the blood flow decreases so does the destruction of aldosterone by liver enzymes

jaundice, pruritus, gastrointestinal bleeding, coagulopathy, increased abdominal girth, renal failure, and changes in mental status

teens need to hear messages about how people experiencing suicidal ideation may not always make the best decisions for themselves.

They take their responsibility as a friend very, very seriously,” she said.

The hurt will never go away, but we all deserve to live and be happy — with or without our adult children in our lives.

I've given up on trying to have a relationship with them. It's not going to happen. No matter what I do,

was able to identify one overarching theme in family estrangement: a severe, and sometimes total, breakdown in communication

We also found that rifts can result from family members' strong, and sometimes unrealistic, expectations for one another,"

The second factor is when an adult child has differences in values and expectations.

The first reason, which Pillermer calls "the long arm of the past," is when an adult child feels that childhood experiences in the family were "very adverse, including harsh discipline, parental favoritism, or even verbal or physical abuse

One of the things

mouth filled with bloody mucus and fluid

in every patient

no two long COVID patients are alike."

Perry Wilson

has

are linked

mental health services,

some individuals have extensive behavioral health needs. In these cases, we partner with local mental health agencies on a referral basis to ensure all the medical and emotional needs of our patients are met.

also has a case manager

side-by-side with your primary care

family-related issues

behavioral health care as part of any medical appointment.

behavioral health professional,

dental care

full-service

but their confidence level is still below that of high performers

Nor does it claim that people lacking a given skill are as confident as high performers

which people with limited competence

positive prior beliefs about one's skills are the source of false self-assessment

inhibit people from addressing their shortcomings

engaging in dangerous behavior

systematic tendency to engage in erroneous forms of thinking and judging

the tendency of highly skilled people to underestimate their abilities relative to the abilities of others

incompetence often includes being unable to tell the difference between competence and incompetence

people with low intelligence

key role in causing the various pathologies; it can activate clotting factors [13], it is itself amyloidogenic [14], and it may have direct protein-protein interactions with the main plasma clotting protein, fibrinogen [2,15].

presence of clotting pathology in the form of fibrinaloid microclots, hyperactivated platelets and endothelial dysfunction represents a key target for both the diagnosis and the treatment of the condition [1,8,11,12].

signals indicating the presence of microclots should be easily detectable using a conventional flow cytometer

combining cell imaging and the high-event-rate and full-sample analysis nature of a conventional flow cytometer, imaging flow cytometry can eliminate erroneous results and increase accuracy in gating and analysis beyond what pure quantitative measurements from conventional flow cytometry can provide.

we have used imaging flow cytometry for the first time to show a significantly increased concentration and size of these microclots

demonstrated a significant amyloid microclot load in Long COVID patients

One of the major pathophysiological factors contributing to Long COVID is the presence of hypercoagulability; this results in insoluble amyloid microclots that are resistant to fibrinolysis

This suggests that there may be a replicating viral reservoir remaining long term, in some cases.

Various adjuvant medications may also assist

clinicians have embarked upon clinician-initiated treatment regimens that include such treatments

Oral anticoagulants

treatments will be to prevent microclots from forming and to prevent platelet hyperactivation

easy place to break it is the microclots because they’re really the chief bad guys

got to break the cycle somewhere

due directly to hypoxia, but also ischemia reperfusion injury, which causes so-called post-exertional malaise

a lot of sequelae is caused by microclots that lead to a variety of problems

The microclots account for all the obvious symptoms like fatigue, where patients are gasping for oxygen

If you’ve got these microclots, they block up the microcapillaries, preventing red blood cells from going through so oxygen doesn’t get to the tissues. The tissues that have been blocked from getting oxygen are the ones that are going to manifest disease

hese microclots are the central element to everything,

The general principle is that if you acquire a scientific understanding of what’s gone wrong with a disease, you can use that knowledge to fix it

P-selectin on CD40L-activated platelet surfaces can form complexes with monocytes and neutrophils.

platelets express P-selectin

form a platelet-T cell complex

found that microclots and platelet pathologies were present in all 80 patients

All patients were experiencing lingering symptoms of shortness of breath, low oxygen levels, heart palpitations, constant fatigue, joint and muscle pain, brain fog, sleep disturbances, digestive problems, or kidney problems.

samples from 80 patients

Long COVID, they found that no thrombin was needed to start the fibrinogen amyloid microclot process because the SARS-CoV-2 Spike protein was capable of starting the microclot process.

when we added thrombin to a blood sample from someone with asthma, it induced clotting into the amyloid form

We found that this was happening in a variety of chronic inflammatory diseases, such as Alzheimer disease or Parkinson disease

these deposits could be induced by things like unliganded iron, and later, we discovered, also by very low concentrations of bacterial cell wall components.

University of Liverpool

Stellenbosch Universit

dense matted deposits resulting from fibrin polymerization

had been looking at clots with an electron microscope

Over 10 years ago now

help to explain why some patients experience long-term symptoms and why COVID-19 affects so many tissues and organ systems

vascular4,8 disease

However, it is now accepted that COVID-19 is primarily an endothelial4,

was thought to be a typical viral pneumonia with acute disseminated intravascular coagulopathy

known as Long COVID

persistent sequelae, typically manifesting as fatigue, shortness of beath, sleep difficulties, and central nervous system symptoms.

respiratory failure and hypoxia

multi-organ failure

Thrombotic Disorders Are Amyloid Fibrin Microclots Central to Long COVID? Jessica Nye, PhD | July 8, 2022

understanding and treatment of Long COVID

it has been shown that suitable and closely monitored ‘triple’ anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms

Consistent with

Although the symptoms of Long COVID are multifarious, we here argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms

microclots are more-or-less easily measured in PPP with the stain thioflavin T and a simple fluorescence microscope

extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies.

result, as is strongly manifested

A few years ago, we discovered that fibrinogen in blood can clot into an anomalous ‘amyloid’ form of fibrin

bears similarities to other post-viral syndromes, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

symptoms such as breathlessness, fatigue, ‘brain fog’, tissue damage, inflammation, and coagulopathies (dysfunctions of the blood coagulation system) persist long after the initial infection

Biochem J. 2022 Feb 25; 479(4): 537–559. Published online 2022 Feb 23. doi: 10.1042/BCJ20220016PMCID: PMC8883497PMID: 35195253A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications

A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications

Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/Post-Acute Sequelae of COVID-19 (PASC) Etheresia Pretorius  ORCID: orcid.org/0000-0002-9108-23841,5, Chantelle Venter1, Gert Jacobus Laubscher2, Maritha J Kotze3, Sunday O. Oladejo4, Liam R. Watson  ORCID: orcid.org/0000-0002-7016-92294, Kanshu Rajaratnam4, Bruce W. Watson  ORCID: orcid.org/0000-0003-0511-18374 & …Douglas B. Kell  ORCID: orcid.org/0000-0001-5838-79631,5,6 Show authors Cardiovascular Diabetology volume 21, Article number: 148 (2022) Cite this article

Research Article| August 20 2021 SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19 In Collection Coronavirus Lize M. Grobbelaar; Lize M. Grobbelaar Sample analysis, Visualization, Writing—original draft 1Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, Private Bag X1, Matieland 7602, South Africa Search for other works by this author on: This Site PubMed Google Scholar Chantelle Venter; Chantelle Venter Data curation, Project administration 1Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, Private Bag X1, Matieland 7602, South Africa Search for other works by this author on: This Site PubMed Google Scholar Mare Vlok; Mare Vlok Software, Formal analysis, Investigation 2Central Analytical Facility: Mass Spectrometry Stellenbosch University, Tygerberg Campus, Room 6054, Clinical Building, Francie van Zijl Drive, Tygerberg, Cape Town 7505, South Africa Search for other works by this author on: This Site PubMed Google Scholar Malebogo Ngoepe 0000-0002-3639-9063 ; Malebogo Ngoepe Methodology 3Department of Mechanical Engineering, Faculty of Engineering and the Built Environment, University of Cape Town, Cape Town, Rondebosch 7701, South Africa4Stellenbosch Institute for Advanced Study, Wallenberg Research Centre, Stellenbosch University, Stellenbosch, South Africa Search for other works by this author on: This Site PubMed Google Scholar Gert Jacobus Laubscher; Gert Jacobus Laubscher Writing—review and editing 5Private practice clinician, Mediclinic Stellenbosch, Stellenbosch 7600, South Africa Search for other works by this author on: This Site PubMed Google Scholar Petrus Johannes Lourens; Petrus Johannes Lourens Writing—review and editing 5Private practice clinician, Mediclinic Stellenbosch, Stellenbosch 7600, South Africa Search for other works by this author on: This Site PubMed Google Scholar Janami Steenkamp; Janami Steenkamp Project administration, Writing—review and editing 1Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, Private Bag X1, Matieland 7602, South Africa6PathCare Laboratories, PathCare Business Centre, PathCare Park, Neels Bothma Street, N1 City 7460, South Africa Search for other works by this author on: This Site PubMed Google Scholar Douglas B. Kell 0000-0001-5838-7963 ; Douglas B. Kell Writing—review and editing 1Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, Private Bag X1, Matieland 7602, South Africa7Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, U.K.8The Novo Nordisk Foundation Centre for Biosustainability, Technical University of Denmark, Kemitorvet 200, Kgs Lyngby 2800, Denmark Correspondence: Etheresia Pretorius (resiap@sun.ac.za) or Douglas B. Kell (dbk@liv.ac.uk) Search for other works by this author on: This Site PubMed Google Scholar Etheresia Pretorius

However, there was a complete failure to dislodge or disturb COVID-19 PPP clots from the channels.

COVID-19 clots, on the contrary, could not be displaced or dislodged and remained intact, even with the force of high-speed water flow in a small flow channel.