Aims of our presentation 1 Crash vaccine dogmas

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Aims of our presentation 1. Crash vaccine dogmas. 2. Explore the behavior of WHO

Aims of our presentation 1. Crash vaccine dogmas. 2. Explore the behavior of WHO and Drug Regulatory Agencies with respect to vaccines. 3. Investigate the Relationship between vaccines and neuro-inflammation. 4. Post-vaccination inflammatory syndrome.

Between dogmas and dogmatic scientism 1. Dogma A fixed, especially religious, belief or set

Between dogmas and dogmatic scientism 1. Dogma A fixed, especially religious, belief or set of believes that people are expected to accept without any doubts. 2. Dogmatic scientist If you are dogmatic, you are certain that you are right and that everyone else is wrong. 3. Conclusion So, the vaccines are certainly safe (Dogma) and who says it is right (Dogmatic Scientist) and others are wrong (True Scientists? ).

Some Vaccine Dogmas 1. Vaccines are safe and efficient. 2. Vaccines are thoroughly tested

Some Vaccine Dogmas 1. Vaccines are safe and efficient. 2. Vaccines are thoroughly tested in rigorous scientific studies… 3. Doctors know the properties of vaccines very well. 4. Paul Offit’s dogmas.

Crash the dogmas.

Crash the dogmas.

 • No vaccine is however 100% safe or effective. • Safety concerns for

• No vaccine is however 100% safe or effective. • Safety concerns for a vaccine include those due to inherent toxicities of the antigen and adjuvant, toxicities of impurities and contaminants and toxicities due to interactions of the vaccine components present in the vaccine formulation. • Reversion to virulence after multiplication in the human host might be of particular concern for some live attenuated vaccines. • Preservatives and stabilisers may not be as immunologically inert as previously thought (e. g. polygeline). • Removal of a preservative and/or stabiliser from a well-established vaccine may also have an impact on the safety profile of the vaccine as seen with a recent tick-bone encephalitis vaccine.

Presence of adventitious agents in a marketed product

Presence of adventitious agents in a marketed product

The four cases are: 1. SV 40 in polio vaccines. 2. Bacteriophage in measles

The four cases are: 1. SV 40 in polio vaccines. 2. Bacteriophage in measles and polio vaccines. 3. Reverse transcriptase in measles and mumps vaccines. 4. Porcine circovirus and porcine circovirus DNA sequences in rotavirus vaccines.

John Petricciani et al. In all four cases, and after consideration of scientific advice,

John Petricciani et al. In all four cases, and after consideration of scientific advice, the vaccines concerned were not removed from the market, or were only temporarily suspended, since the benefits of immunization were believed to be much more beneficial than the risk of any potential adverse effects.

MMR and MMRV Vaccines • Priorix-Tetra GSK package insert. • Each virus strain is

MMR and MMRV Vaccines • Priorix-Tetra GSK package insert. • Each virus strain is separately produced in either chick embryo cells (mumps and measles) or MRC 5 human diploid cells (rubella and varicella). • MMRV II Merck package insert. • the Wistar RA 27/3 strain of live attenuated rubella virus propagated in WI-38 human diploid lung fibroblasts.

Conclusions: vaccines are not safe 1. 2. 3. 4. 5. Adventitious agents in some

Conclusions: vaccines are not safe 1. 2. 3. 4. 5. Adventitious agents in some vaccines. The MRC-5 cell line is old 53 years. The WI-38 cell line is old 55 years. These Cell lines are in cancer age. These cell lines are intended exclusively for research. They are not intended for any human or therapeutic or diagnostic use.

It is not intended for use in humans.

It is not intended for use in humans.

It is not intended for use in humans.

It is not intended for use in humans.

Dogma number 2 • Vaccines are thoroughly tested in rigorous scientific studies… But •

Dogma number 2 • Vaccines are thoroughly tested in rigorous scientific studies… But • A lot of vaccine studies are produced by scientists with conflicts of interest and / or are employees in the Pharmaceutical Vaccine Companies.

Cohort study

Cohort study

No evidences, no causality.

No evidences, no causality.

What are the problems? 1. Cohort studies start with two groups of subjects: the

What are the problems? 1. Cohort studies start with two groups of subjects: the exposed and the non-exposed (vaccinated vis non-vaccinated). 2. The only valid studies to test the safety of a drug are RCTs studies (Randomized Controlled Trials). The only RCT vaccine studies concern HPV vaccines, and almost all are scientific oxymorons. 3. Invalid RCT studies make systematic reviews and meta-analyzes false.

Dogma number 3 Doctors know the properties of vaccines very well. But 1. Doctors

Dogma number 3 Doctors know the properties of vaccines very well. But 1. Doctors often confuse vaccination (injection of the mixture) with immunization (desired effect). 2. Many doctors believe that all the people vaccinated become immunized for life. 3. Doctors easily introject dogmas (herd Immunity). 4. Very few doctors know the action mechanism of the vaccines.

Paul Offit’s dogmas • A child can get any number of doses without any

Paul Offit’s dogmas • A child can get any number of doses without any harm. • The neonate is capable of mounting a protective immune response to vaccines within hours of birth. • Each infant would have theoretical capacity to respond to about 10, 000 vaccines at any one time.

Paul Offit’s errors 1. He exchanges the tasks of B lymphocytes. 2. There are

Paul Offit’s errors 1. He exchanges the tasks of B lymphocytes. 2. There are specific memory B cells against specific antigens (specific immune memory). 3. There are long-lived plasma cells (producers of specific antibodies) that prevent infection. 4. Having memory B cells does not prevent the infection (eg adolescents with anti-Hs. Ag memory B cells, but without specific antibodies, can be infected by the Hepatitis B virus).

Long-lived plasma cells

Long-lived plasma cells

Another big mistake • Paper Maternal pertussis vaccination and its effects on the immune

Another big mistake • Paper Maternal pertussis vaccination and its effects on the immune response of infants aged up to 12 months in the Netherlands: an open-label, parallel, randomised controlled trial. • Interpretation In view of the high pertussis toxin antibody concentrations at age 3 months, maternal vaccination supports a delay of the first pertussis vaccination in infants until at least age 3 months. Maternal antibody interference affects antibody concentrations after primary and booster vaccinations. The clinical consequences of this interference remain to be established. https: //www. thelancet. com/journals/laninf/article/PIIS 1473 -3099(18)307175/fulltext

The greatest factor • Is it possible to understand if a vaccination has caused

The greatest factor • Is it possible to understand if a vaccination has caused damage or represents • a danger signal for possible future damage?

Post-Vaccination Reactive Brain Inflammation • After vaccine injection, especially if multiple doses are given

Post-Vaccination Reactive Brain Inflammation • After vaccine injection, especially if multiple doses are given to a young child during a single office visit, significant systemic immune activation may occur with signs suggesting reactive brain inflammation, such as acute crying, fever, restlessness and failure to eat (Blaylock, 2008; Blaylock, 2013).

Infanrix-Hexa vaccine (GSK) Very Common Adverse Events (≥ 1/10 doses) 1. 2. 3. 4.

Infanrix-Hexa vaccine (GSK) Very Common Adverse Events (≥ 1/10 doses) 1. 2. 3. 4. Appetite lost. Crying abnormal and pain. Irritability. Fever ≥ 38°C.

WHO: The big problem • In January 2018, the WHO produces a document on

WHO: The big problem • In January 2018, the WHO produces a document on how to catalog the adverse reactions that are indicated by the acronym AEFI. • The WHO states: “Causality assessment is the systematic review of data about an AEFI case; it aims to determine the likelihood of a causal association between the event and the vaccine(s) received”. • It also specifies: “At the individual level it is usually not possible to establish a definite causal relationship between a particular AEFI and a particular vaccine on the basis of a single AEFI case report”.

An unhealthy act 1. Since all adverse reactions are case reports (because they occur

An unhealthy act 1. Since all adverse reactions are case reports (because they occur in a single vaccinated individual), excluding them results in the consequent elimination of all post-vaccine AEs. 2. Furthermore, the report cases form the series of reports that will never exist with this evaluation system that excludes the individual case reports.

A practical example shows that the reports of AEs do not end up on

A practical example shows that the reports of AEs do not end up on the reports of the regulatory agencies.

AE Reporting to AIFA

AE Reporting to AIFA

2017 VACCINE REPORT POSTMARKETING SURVEILLANCE IN ITALY

2017 VACCINE REPORT POSTMARKETING SURVEILLANCE IN ITALY

Can vaccines cause autism? • We do not know the causes of autism. •

Can vaccines cause autism? • We do not know the causes of autism. • Epidemiological investigations do not identify the causes of the diseases, but only the risk factors for that disease. • There are not RCT vaccines studies that compare unvaccinated vs vaccinated subjects. • The vaccine-favorable cohort studies do not compare unvaccinated vs vaccinated subjects (vaccines exposed vs not exposed).

Royal dogma: vaccines do not cause autism. Final question: Vaccines can cause autism? Final

Royal dogma: vaccines do not cause autism. Final question: Vaccines can cause autism? Final Answer: Yes, vaccines can cause autism.

The biological plausibility of danger

The biological plausibility of danger

A protected and insecure building.

A protected and insecure building.

HPV VACCINES What’s the mistery?

HPV VACCINES What’s the mistery?

Fooling is better than informing CONCLUSIONS: • We provide research-tested messages that providers can

Fooling is better than informing CONCLUSIONS: • We provide research-tested messages that providers can use to address parents’ HPV vaccination questions and concerns about 7 common topics. • Important principles for increasing message effectiveness are to include information on the benefits of vaccination (including cancer prevention)… • Shah PD et al. Questions and Concerns About HPV Vaccine: A Communication Experiment. Pediatrics February 2019, VOLUME 143 / ISSUE 2.

The mistification: The HPV cancer-preventing vaccine. • This is a vaccine which prevents some

The mistification: The HPV cancer-preventing vaccine. • This is a vaccine which prevents some HPV infections. • This vaccine is not a cancer-preventing vaccine. • Cancer is the magic word of marketing. • The magic word becomes medical dogma.

Australia: a country with powerful mystificators.

Australia: a country with powerful mystificators.

Incidence rate from 2007 to 2018 • Incidence rate from 2014 to 2018: from

Incidence rate from 2007 to 2018 • Incidence rate from 2014 to 2018: from 7. 4 cases per 100, 000 femals to 7. 1 cases per 100, 000 femals. • Only 0. 3% reduction after 10 years of intense HPV-vaccination program. • Incidence 7, 04 per 100, 000 femals in 2007 against 7, 1 estimated in 2018.

Stop HPV, Stop Cervical Cancer.

Stop HPV, Stop Cervical Cancer.

Freddy Mercury: Don't Stop Me Now

Freddy Mercury: Don't Stop Me Now

Let us just remember that: • It was shown that vaccinated young women have

Let us just remember that: • It was shown that vaccinated young women have had a higher prevalence of any HPV type infection (type with high and low risk for cancer). • Vaccinated young women have a higher prevalence of virus infection with high risk of non-vaccine types despite having a lower prevalence of vaccination types (Guo et al. , 2015).

The biological plausibility of HPV Ae. S https: //www. oatext. com/pdf/CCRR-5 -454. pdf

The biological plausibility of HPV Ae. S https: //www. oatext. com/pdf/CCRR-5 -454. pdf

Pain in the center of the syndrome. 1. 2. 3. 4. 5. 6. 7.

Pain in the center of the syndrome. 1. 2. 3. 4. 5. 6. 7. History of adverse reactions. HPV vaccines and pain. Proinflammatory cytokines. From injection to neuroinflammation. Pain processing. Neuroinflammation and pain. Post-vaccination inflammatory syndrome.

History of adverse reactions • In Japan, the period of HPV vaccination overlapped with

History of adverse reactions • In Japan, the period of HPV vaccination overlapped with the development of HPV vaccine -related symptoms in vaccinated patients, which include chronic regional pain syndrome (CRPS), autonomic and cognitive dysfunctions (Ozawa et al. , 2017). • Brinth et al. (2015) reported the characteristics of a number of patients with a syndrome of orthostatic intolerance, headaches, fatigue, cognitive dysfunction, and neuropathic pain starting in close relation to HPV vaccination.

HPV vaccines and pain • In the Cervarix Package insert (GSK, 2019) it is

HPV vaccines and pain • In the Cervarix Package insert (GSK, 2019) it is reported that: 20% of subjects were in pain. • In the Gardasil 4 Package insert (Merck, 2019) it is reported that: headache, fever, nausea, and dizziness; and local injection site reactions (pain, swelling, erythema, pruritus, and bruising) occurred after the administration of Gardasil.

Gardasil 9: Package Insert

Gardasil 9: Package Insert

Gardasil 9: Package Insert • In girls and women from 16 to 26 years

Gardasil 9: Package Insert • In girls and women from 16 to 26 years of age: injection-site pain (89. 9%) • In girls from 9 to 15 years of age: injection-site pain (89. 3%)

Proinflammatory cytokines. • Vaccination always produces inflammation. During inflammation, tissue resident and recruited immune

Proinflammatory cytokines. • Vaccination always produces inflammation. During inflammation, tissue resident and recruited immune cells secrete molecular mediators that act on the peripheral nerve terminals of nociceptor neurons to produce pain sensitization (Pinho-Ribeiro et al. , 2016). • High circulating plasma cytokine/chemokine levels were observed after the first dose of Gardasil 4® vaccine and the proinflammatory cytokines were elevated after the 1 st and 3 rd injection of the Cervarix® vaccine (Herrin et al. , 2014).

DRG neurons: Cytokine Receptors

DRG neurons: Cytokine Receptors

From injection to neuroinflammation 1. The injection of the vaccines determine a strong production

From injection to neuroinflammation 1. The injection of the vaccines determine a strong production of proinflammatory cytokines. 2. These cytokines activate nociceptors. 3. The anterograde signal progresses centrally to activate spinal microglia. 4. Neuroinflammatory changes have been identified in the sensory ganglia and in the nerves as well. 5. Neuroinflammation in dorsal root ganglion and at the spinal cord contributes to the transition from acute to chronic pain.

Pain processing • Understanding pain processing is fundamental to identify the roots of post-vaccination

Pain processing • Understanding pain processing is fundamental to identify the roots of post-vaccination inflammatory syndrome caused by HPV vaccines. • This is a complicated path that begins with the expression of proinflammatory cytokines on the vaccine injection site, and then arrives at the somatosensory cortex.

Peripheral component of nociception • Nociceptors (pain receptors) are bare nerve endings of primary

Peripheral component of nociception • Nociceptors (pain receptors) are bare nerve endings of primary sensory neurons which innerve skin, muscles and viscera. • Pain receptors are selectively activated by mechanical, thermal or chemical stimuli that open sodium channels and elicit axonal depolarization.

DRG neurons: specific receptors.

DRG neurons: specific receptors.

Nociceptors • Nociceptors by responding directly to cytokines can directly “sense” the immune response

Nociceptors • Nociceptors by responding directly to cytokines can directly “sense” the immune response in inflamed tissue; essentially they are, therefore, not only noxious stimulus detectors, but also inflammation sensors (Binshtok et al. , 2008). • Moreover, TNF-α is a key regulator of the inflammatory response and is involved in the increased production of proalgesic agents (Xu and Yaksh, 2011).

Nociceptive pain processing

Nociceptive pain processing

Neurophatic and inflammatory pain • Peripheral nerve injury activates spinal microglia. This leads to

Neurophatic and inflammatory pain • Peripheral nerve injury activates spinal microglia. This leads to lasting changes in the properties of dorsal horn neurons that initiate central sensitization and the onset of neuropathic pain (Biggs et al. , 2010). • Vice versa, inflammatory pain is initiated by tissue damage/inflammation. Both are characterized by hypersensitivity at the site of damage and in adjacent normal tissue (Woolf and Salter, 2000).

Chronic pain • The rules of perception and pain management change in chronic pain.

Chronic pain • The rules of perception and pain management change in chronic pain. • In fact, at peripheral level, nociceptors undergo sensitization and hyper-excitability (peripheral sensitization); while at central level, excitatory synaptic transmission is increased in spinal cord, brainstem, and cortical neurons (central sensitization), caused by transcriptional, translational, and post-translational regulation (Ji et al. , 2013).

Chronic pain • It is now well established that chronic pain, such as inflammatory

Chronic pain • It is now well established that chronic pain, such as inflammatory pain, neuropathic pain, and cancer pain, is an expression of neural plasticity both in the peripheral nervous system, as peripheral sensitization (Basbaum et al. , 2009; Gebhart, 2010; Gold and Gebhart, 2010), and in the central nervous system (CNS), as central sensitization (Ji et al. , 2003; Kuner, 2010).

Peripheral sensitization • The International Association for the Study of Pain (IASP) definition of

Peripheral sensitization • The International Association for the Study of Pain (IASP) definition of peripheral sensitization is: “Increased responsiveness and reduced threshold of nociceptive neurons in the periphery to the stimulation of their receptive fields” (IASP, 2019). • Then, Peripheral sensitization induces a hyperexcitability of afferent nociceptive neurons (Woller et al. , 2017).

Central Sensitization • The IASP definition of central sensitization is: “Increased responsiveness of nociceptive

Central Sensitization • The IASP definition of central sensitization is: “Increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input” (IASP, 2019). • Central sensitization increases response to pain sensation. Heightened sensitivity results in the perception of pain from non painful stimuli (allodynia) and greater pain than what one would be expected to get from normal painful stimuli (hyperalgesia).

Effects of Peripheral and central sensitization • While peripheral sensitization in nociceptors is essential

Effects of Peripheral and central sensitization • While peripheral sensitization in nociceptors is essential for the development of chronic pain (Gold and Gebhart, 2010), and transition from acute pain to chronic pain (Reichling and Levine, 2009), central sensitization regulates the chronicity of pain, it causes the spread of pain beyond the site of injury, and influences the emotional and affective aspects of pain (Woolf and Salter, 2000).

Spinal cord microglia • The spinal cord microglia, can respond to peripheral injuries which

Spinal cord microglia • The spinal cord microglia, can respond to peripheral injuries which are distant from the spinal cord to produce neuroinflammation in the central nervous system (Ji et al. , 2013). • Spinal glia activation is necessary and sufficient to induce neuropathic pain (Howard and Smith, 2010).

Nociceptors activates microglia and astrocytes • In the case of strong and repetitive noxious

Nociceptors activates microglia and astrocytes • In the case of strong and repetitive noxious stimuli, larger quantities and additional signaling molecules are released from the spinal terminals of nociceptive nerve fibers which lead to the activation of microglia and astrocytes (Sandkühler, 2017).

Neuroinflammation in chronic pain • Neuroinflammation (in the peripheral and central nervous system) drives

Neuroinflammation in chronic pain • Neuroinflammation (in the peripheral and central nervous system) drives to a widespread chronic pain via central sensitization and mantains it. This is linked to a phenomenon of synaptic plasticity and the increasment of neuronal responsiveness in central pain pathways after painful insults (Ji et al. , 2018).

Ji RR, Chamessian A, Zhang YQ. Pain regulation by non-neuronal cells and inflammation. Science.

Ji RR, Chamessian A, Zhang YQ. Pain regulation by non-neuronal cells and inflammation. Science. 2016; 354(6312): 572 -577.

 • The anterograde signalling progresses centrally to activate spinal microglia with possible up

• The anterograde signalling progresses centrally to activate spinal microglia with possible up regulation of glialderived proinflammatory/pronociceptive mediators. • Neuroinflammatory changes have not only been identified in the spinal cord and brainstem, but more recently, in the sensory ganglia and in the nerves as well. • The present perspective paper indicates that neuroinflammation and the associated release of proinflammatory cytokines in dorsal root ganglion and at the spinal cord contribute to the transition from acute to chronic pain.

Vaccination always produces inflammation • Nociceptor peripheral nerve terminals possess receptors and ion channels

Vaccination always produces inflammation • Nociceptor peripheral nerve terminals possess receptors and ion channels that detect molecular mediators released during inflammation. • During inflammation, tissue resident and recruited immune cells secrete molecular mediators that act on the peripheral nerve terminals of nociceptor neurons to produce pain sensitization. • Nociceptor neurons are also sensitized by tumor necrosis factor alpha (TNF-α), IL-1β and IL-6 produced by mast cells, macrophages, and neutrophils.

Neuroinflammation and pain • Mechanistically, neuroinflammation drives to a wide-spread chronic pain via central

Neuroinflammation and pain • Mechanistically, neuroinflammation drives to a wide-spread chronic pain via central sensitization, which can be induced and maintained by cytokines, chemokines, and other glia-produced mediators that circulate in the cerebrospinal fluid. • Chronic pain is commonly associated to depression, anxiety, and sleep disorders. • Ru-Rong Ji, Andrea Nackley, Yul Huh, Niccolò Terrando, William Maixner; Neuroinflammation and Central Sensitization in Chronic and Widespread Pain. Anesthesiology 2018; 129(2): 343 -366. doi: 10. 1097/ALN. 0000002130.

We must stop neuroinflammation • Neuroinflammation resulting from neuroglial and neuroimmune interactions do not

We must stop neuroinflammation • Neuroinflammation resulting from neuroglial and neuroimmune interactions do not only serve as a driving force for chronic pain but it is also implicated in other neurologic and psychiatric diseases such as Alzheimer disease, Parkinson disease, multiple sclerosis, autism, major depression, and schizophrenia.

Pain, Citokines, and Neuroinflammation 1. Activation of microglia and astrocytes, in the spinal cord

Pain, Citokines, and Neuroinflammation 1. Activation of microglia and astrocytes, in the spinal cord and brain, lead to the release of proinflammatory cytokines and chemokines. 2. Central sensitization is also driven by neuroinflammation in the peripheral and central nervous system. 3. Chronic pain is maintained in part by central sensitization.

Central component of nociception • After synapsing at the spinal cord, the second neuron

Central component of nociception • After synapsing at the spinal cord, the second neuron travels in the spinal tracts, it crosses the midline and runs up the spinothalamic tract to the thalamus where it synapses again and the next neuron travels to the somatosensory cortex. • Here the impulses are processed in distinct areas, known, collectively, as the “pain matrix” so the nature of the pain can be perceived.

CENTRAL SENSITIZATION • Central Sensitization refers to the amplification of pain by central nervous

CENTRAL SENSITIZATION • Central Sensitization refers to the amplification of pain by central nervous system mechanisms. • On a cellular level, Central Sensitization results from multiple processes altering the functional status of nociceptive neurons. • Central Sensitization increases response to pain sensation. • Heightened sensitivity results in the perception of pain from non-painful stimuli (allodynia) and greater pain than what one would be expected to get from normal painful stimuli (hyperalgesia). • Fleming KC, Volcheck MM. Central sensitization syndrome and the initial evaluation of a patient with fibromyalgia: a review. Rambam Maimonides Med J. 2015; 6(2): e 0020. Published 2015 Apr 29. doi: 10. 5041/RMMJ. 10204

Mary Holland’s girls

Mary Holland’s girls

Kesia enlisted in Study Protocol 015 • • • Pain Sleep problems (Systemic Effects)

Kesia enlisted in Study Protocol 015 • • • Pain Sleep problems (Systemic Effects) Fatigue (Systemic Effects) Flu-like symptoms (Systemic Effects) Arm weak (Movement Effects) She felt exhausted (Systemic Effects)

Rikke symptoms • Pain • Headaches • Fainting without any warning • Insomnia (sleep

Rikke symptoms • Pain • Headaches • Fainting without any warning • Insomnia (sleep disorders)

Abbey’s story • Pain • Jerking movements (Movement Effects) • Fatigue (Systemic Effects) •

Abbey’s story • Pain • Jerking movements (Movement Effects) • Fatigue (Systemic Effects) • Panic attack

Alexis • • Relentless pain Sleep disorders (Systemic Effects) Seizures Chronic fatigue (Systemic Effects)

Alexis • • Relentless pain Sleep disorders (Systemic Effects) Seizures Chronic fatigue (Systemic Effects)

Christina • Arrhythmia • Feeling really tired • Fatigue (Systemic Effects) • Sudden death

Christina • Arrhythmia • Feeling really tired • Fatigue (Systemic Effects) • Sudden death

Japanese girls • Chronic regional pain syndrome type I • Cognitive dysfunctions • Autonomic

Japanese girls • Chronic regional pain syndrome type I • Cognitive dysfunctions • Autonomic dysfunctions

Nociceptive pain and Central sensitization

Nociceptive pain and Central sensitization

Central Sensitization • Malignant process of upregulation. • Pain be getting more painful, becoming

Central Sensitization • Malignant process of upregulation. • Pain be getting more painful, becoming autonomous. • Other effects are associated with pain.

Secondary Hyperalgesia • Reduced threshold • Hyperpathia • Paresthesia • Numbness

Secondary Hyperalgesia • Reduced threshold • Hyperpathia • Paresthesia • Numbness

Modality Effects • Allodynia • For example: 1. Pouring a drop of alcohol on

Modality Effects • Allodynia • For example: 1. Pouring a drop of alcohol on the skin causes pain. 2. Touching the skin causes pain. 3. Exerting a slight skin pressure causes pain.

Systemic Effects • • • Sleep disturbance Fatigue Circadian Rhythm disruption Development of Additional

Systemic Effects • • • Sleep disturbance Fatigue Circadian Rhythm disruption Development of Additional Pain Syndromes Sickness Behavior

Sympathetic System • • Dysautonomia Persistent hyperactivation Paradoxical hyporeactivity to stress Psychological problem

Sympathetic System • • Dysautonomia Persistent hyperactivation Paradoxical hyporeactivity to stress Psychological problem

Autonomic effects • Hyperhydrosis • Arousal/Non-arousal • Local Changes, Neurogenic Edema, Temperature changes, Hypoalgesia

Autonomic effects • Hyperhydrosis • Arousal/Non-arousal • Local Changes, Neurogenic Edema, Temperature changes, Hypoalgesia • Onset of stress- induced hyperalgesia • Vascular changes • Trophic changes: Hair and Nails problems

Psychological effects • • Fear, Anger, Social login, Pain Behaviors, Motivation, Helplessness effects, Depressive

Psychological effects • • Fear, Anger, Social login, Pain Behaviors, Motivation, Helplessness effects, Depressive effects, Preoccupation of body pain.

Movement Effects • Difficulty in initiation, maintenance, and precision of small movements. • Weakness,

Movement Effects • Difficulty in initiation, maintenance, and precision of small movements. • Weakness, Dystonia, Decreased range of motion, • Tremor, Spasm, Myclonic Jerks, • Neglect-like syndrome, • Pathophysiology of complex regional pain syndrome (CRPS).

What is CRPS? • CRPS type I (Complex Regional Pain Syndrome) is a syndrome

What is CRPS? • CRPS type I (Complex Regional Pain Syndrome) is a syndrome that usually develops after an initiating noxious event. It is not limited to the distribution of a single peripheral nerve and it is disproportionate to the inciting event. • It is associated to oedema, changes in skin blood flow, abnormal sudomotor activity in the region of pain, allodynia and hyperalgesia and it commonly involves the distal aspect of arms and legs or a distal to proximal gradient. • In addition to weakness of the involved limb, CRPS patients may develop symptoms akin to a neurological neglect-like syndrome, whereby the limb may feel foreign (“cognitive neglect”) and direct mental and visual attention is needed to move the limb (“motor neglect”).

Complex Regional Pain Syndrome (CRPS) • Complex Regional Pain Syndrome (CRPS), is a neuroinflammatory

Complex Regional Pain Syndrome (CRPS) • Complex Regional Pain Syndrome (CRPS), is a neuroinflammatory condition that is characterized by a combination of sensory, autonomic, vasomotor, and motor dysfunctions. • During neuroimmune activation, TLR 4 (Toll-Like Receptor 4) is upregulated in microglia. • Activation of TLR 4 in both microglia and CNS neurons augments the production of pro-inflammatory cytokines via the NF-κB pathway. • Chopra P, Cooper MS. Treatment of Complex Regional Pain Syndrome (CRPS) using low dose naltrexone (LDN). J Neuroimmune Pharmacol. 2013; 8(3): 470 -6.

Cytokines in CRPS Type I • Cytokines including IL-1β, IL-6, TNF-α, and others are

Cytokines in CRPS Type I • Cytokines including IL-1β, IL-6, TNF-α, and others are reliably identified during the acute phases of the syndrome. • HPV vaccines determines a strong prodution of proinflammatory cytokines, such as IL-1β, IL-6, TNF-α. • Patients with CRPS typically progress from an acute stage, in which the affected limb is painful, warm, and edematous to a chronic stage in which warmth and edema resolve, but the pain remains. • David Clark J, Tawfik VL, Tajerian M, Kingery WS. Autoinflammatory and autoimmune contributions to complex regional pain syndrome. Mol Pain. 2018; 14: 1744806918799127.

Proinflammatory cytokines and CRPS • High levels of the proinflammatory cytokines (TNF-α and IL-6)

Proinflammatory cytokines and CRPS • High levels of the proinflammatory cytokines (TNF-α and IL-6) have been found in skin blister fluid of the affected limbs versus the unaffected limbs of CRPS patients. • In patients with CRPS, the levels of IL-1β and IL-6 were significantly increased in cerebrospinal fluid (CSF), compared to other subjects. • Thus, CRPS type I is associated with high levels of IL-1β and IL-6 in CSF, and high levels of TNF-α in the blood.

Vaccines and immune system • Each vaccine injection determines the mandatory intervention, at the

Vaccines and immune system • Each vaccine injection determines the mandatory intervention, at the injection site, of dendritic cells that are, at the same time, antigen presenting cells (APC) and tissue macrophages. • Macrophages secrete pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, when activated.

Pro-inflammatory cytokines 1. Each vaccine injection results in a strong expression of pro-inflammatory cytokines.

Pro-inflammatory cytokines 1. Each vaccine injection results in a strong expression of pro-inflammatory cytokines. 2. Cytokines take center stage in orchestrating immune responses (Essen, 2016). 3. They act in most cases at shorter distances (with exceptions such as IL-1, IL-6 and TNF).

Cytokines and Central Nervous System • The peripheral pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α),

Cytokines and Central Nervous System • The peripheral pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), expressed after the injection of all vaccines, can reach the brain and can cause neuroinflammation after microglia activation. • Elevated proinflammatory cytokines, particularly TNF-α, have been described in studies regarding the cytokines profile in autistic children.

Neuroinflammation in ASD • A subgroup of children with ASD have developed neuroinflammation. •

Neuroinflammation in ASD • A subgroup of children with ASD have developed neuroinflammation. • Several postmortem studies have confirmed the activation of microglia and neuroinflammation. • A recent study shows the presence of aluminum in brain tissue in ASD. Aluminium was also found in microglia cells (Mold et al. , 2018).

HPV vaccines and CRPS type I • It is now evident that the pro-inflammatory

HPV vaccines and CRPS type I • It is now evident that the pro-inflammatory response to the injections of the HPV vaccines is identical, under the common citokines substrate, to the inflammatory profile of the CRPS type I. • CRPS type I is associated to high levels of IL 1β and IL-6 in CSF, and high levels of TNF-α in the blood. • These pro-inflammatory cytokines are strongly expressed after the injection of HPV vaccines.

Post-vaccination inflammatory syndrome 1. 2. 3. 4. 5. 6. 7. 8. HPV vaccines Proinflammatory

Post-vaccination inflammatory syndrome 1. 2. 3. 4. 5. 6. 7. 8. HPV vaccines Proinflammatory cytokines Microglia Neuroinflammation Nociceptors Peripheral sensitization Central sensitization Girls damaged and mocked by science

Conclusions • The molecular mechanisms presented here demonstrate how peripheral cytokines, expressed after vaccination,

Conclusions • The molecular mechanisms presented here demonstrate how peripheral cytokines, expressed after vaccination, can cause neuroinflammation in some subjects, after microglia activation, depending on the immunogenetic background and the innate immune memory.

Conclusions 1. All vaccines can cause neuroinflammation. 2. HPV vaccines can cause a post-vaccination

Conclusions 1. All vaccines can cause neuroinflammation. 2. HPV vaccines can cause a post-vaccination inflammatory syndrome characterized by chronic pain and neuroinflammation. 3. In this case, the phenomena of central sensitization is responsible for all the symptoms associated with chronic pain. 4. The strong expression of proinflammatory cytokines, secreted after HPV vaccinations, brings to a process that can produce irreversible neurological results in HPV vaccinated girls.

Conclusions 1. The existence of extensive lines of communication between the nervous system and

Conclusions 1. The existence of extensive lines of communication between the nervous system and immune system represent a fundamental principle underlying neuroinflammation. 2. Immune memory in the brain is an important modifier of neuropathology. 3. Systemic inflammation generates signals that communicate with the brain and lead to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype.

Conclusions The effects produced by the activation of the microglia, and the subsequent neuroinflammation,

Conclusions The effects produced by the activation of the microglia, and the subsequent neuroinflammation, are diversified according to age: 1. before the first two years of life they can contribute to produce ASD (in some subjects with ASD, there is neuroinflammation and aluminum accumulation in the brain); 2. while a different neurological symptomatology can arise in girls vaccinated with HPV vaccines.

Thank you very much 1. We have provided you with the molecular biology evidence

Thank you very much 1. We have provided you with the molecular biology evidence of your girls' suffering. 2. The others will attack us and say we are crazy. 3. We prefer to be crazy but not corrupt.

Yes, we can stop this syndrome.

Yes, we can stop this syndrome.