We start our paper observing that in past centuries physicians in some cardiologic disease were used to prescribe to the patient to take a long rest in order to recuperate their health status. In past centuries it wasn’t available high efficient drugs strategies and so to take a long rest without physical and psychological stress contributes to this process.
Also in oriental medicine we can see body balances strategies, and also in some psycoaanalitc techniques we can see that time is relevant to re-equilibrate some conditions (in example acute stress). We can think that the main factors involved are TIME and LONG REST in order to balance the physiologic functions. In some case it was observed complete resolve in some situations. In example we can think that a metabolic unbalances can create this situation and the time make possible to restore.
In example what happen in sudden death heart syndrome in untrained?  Why in this condition physical training can reduce this event? We can think a condition of intra- toxicity time related. Other example can be some immune shock  or what happen in septic shock.
We think in this condition is relevant observe the time related intra- toxicity situation involved in some
Metabolic- catabolic –electrical cell membrane - immune status and other. In example involved in some heart aritmia, epilectic status, septic shock and other situation high time related (ischemic coronaric spasm etc). In embryology, oncology, toxicology, some heart and brain pathologies time is relevant added to local micro environment and inters cellular
communication (crisis). We can consider an intra- local
toxicology aspect time related to better verify some pathologic process under a new light.
According to K Michael Pollard et al. in example “Susceptibility to most autoimmune diseases is dependent on polygenic inheritance, environmental factors, and poorly defined stochastic events. One of the significant challenges facing autoimmune disease research is in identifying the specific events that trigger loss of tolerance and autoimmunity. Although many intrinsic factors, including age, sex, and genetics, contribute to autoimmunity, extrinsic factors such as drugs, chemicals, microbes, or other environmental factors can also act as important initiators. This review explores how certain extrinsic factors, namely drugs and chemicals, can promote the development of autoimmunity, focusing on a few better characterized agents that, in most instances, have been shown to produce autoimmune manifestations in human populations. Mechanisms of autoimmune disease induction are discussed in terms of research obtained using specific animal models. Although a number of different pathways have been delineated for drug/chemical-induced autoimmunity some similarities do exist and a working model is proposed .”
Blatt et al.  writed that: “Autism is defined neuro developmental disorder that affects over 1% of new births in the USA, about 2% of boys. The etiologies are unknown and they are genetically complex. There may be epigenetic effects, environmental influences, and other factors that contribute to the mechanisms and affected neural pathway. Involved brain specific areas in the cerebellum, limbic system, and cortex. Part of structures appears to be affected most rather than the entire
structure, for example, select nuclei of the amygdala, the fusiform
face area, and so forth. Altered cortical organization, frequent
and narrower minicolumns and early overgrowth of the frontal
portion of the brain, affects connectivity. Abnormalities include
cytoarchitectonic laminar differences, excess white matter
neurons, decreased numbers of GABAergic cerebellar Purkinje
cells, and other events that can be traced developmentally and
cause anomalies in circuitry. Problems in neurotransmission
are evident according recent receptor/binding site studies
especially in the inhibitory GABA system transmission likely
contributing to an imbalance of the system of excitatory/
inhibitory transmission. As postmortem findings are related to
core behavior symptoms, and technology improves, researchers
are gaining a much better perspective of contributing factors to
the disorder ”.
According WEI H. et al “the mechanisms responsible of
autism pathogenesis are not understood, studies
have suggested that localized inflammation of the CNS may
contribute to the development of autism. Recent evidence shows
that IL-6 has a crucial role in the development and plasticity of
CNS  Katritsis et al.  write that “CAD is the predominant
cause of SCD in older athletes.
Vigorous exertion can trigger cardiac arrest or SCD,
especially in untrained persons, but habitual vigorous exercise
diminishes the risk of sudden death during vigorous exertion
. “According the recent paper “Brain and Transmission Signal
Modulation “ 2017 “As observed in other scientific or medical
discipline controlling some non physiological cellular activity
Results in reducing of abnormal organ activation ”.
According to Hung et al.  “Coronary artery spasm (CAS),
an intense vasoconstriction of coronary arteries that causes
total or subtotal vessel occlusion, plays an important role in
myocardial ischemic syndromes including stable and unstable
angina, acute myocardial infarction, and sudden cardiac death.
Coronary angiography and provocative testing usually is required
to establish a definitive diagnosis. While the mechanisms
underlying the development of CAS are still poorly understood,
CAS appears to be a multifactorial disease but is not associated
with the traditional risk factors for coronary artery disease.
The diagnosis of CAS has important therapeutic implications,
as calcium antagonists, not β-blockers, are the cornerstone
of medical treatment. The prognosis is generally considered
benign; however, recurrent episodes of angina are frequently
observed. We provide a review of the literature and summarize
the current state of knowledge regarding the pathogenesis of
And “Precipitating factors may contribute to the onset of
CAS and act in the same patient to cause angina in different
conditions. CAS can be precipitated by physical and/or mental
stress 54, magnesium deficiency 55, alcohol consumption
56, the cold pressure test, hyperventilation, the Valsalva
maneuver, remnant lipoproteins 57, and the administration of
pharmacological agents such as cocaine 58, sympathomimetic
agents (epinephrine, norepinephrine, etc.), beta-blocking agents
(propranolol, etc.), parasympathomimetic agents (methacholine,
pilocarpine, etc.), and ergot alkaloids (ergonovine, ergotamine,
etc.), particularly in the morning when spontaneous CAS is
most likely to occur 26. Activated platelets may trigger CAS by
releasing vasoconstrictor substances, including thromboxane
and serotonin, both of which are found to be associated with
CAS 59-61. It is important to differentiate CAS from Kounis
syndrome because there is some overlap between the 2 entities.
Kounis syndrome is characterized by the concurrence of acute
coronary events with allergic or hypersensitivity reactions
62. To differentiate Kounis syndrome from CAS, knowledge of
individual hypersensitivity is crucial .”
“Pathogenesis: The causes and the mechanisms underlying
the development of CAS are still poorly defined and are likely
multifactorial. In the 1980s, the autonomic nervous system was
found to play an important role in the pathophysiology of CAS
27,63,64. In the 1990s, inflammation, endothelial dysfunction,
oxidative stress, respiratory alkalosis and magnesium deficiency
were identified as predisposing factors 27. In the late 1990s
and early 2000s, genetic mutations were found to be associated
with CAS 27. Nonetheless, coronary vascular smooth muscle cell
hyper reactivity seems to constitute the substrate for CAS .”
“Individual differences in ability to control fear have
been linked to activation of dorsal anterior cingulate cortex,
ventromedial prefrontal cortex, and amygdala. This study
investigated whether functional variance in this network can be
predicted by resting metabolism in these same regions.
Healthy subject volunteers were studied with positron
emission tomography using [18F]-deoxyglucose to measure
resting brain metabolism. This was followed by a two-day fear
conditioning and extinction training paradigm in a functional
magnetic resonance imaging scanner to measure brain activation
during fear extinction and its recall. Skin conductance response
was used to index conditioned responding. Resting metabolism
in amygdala, dorsal anterior cingulate cortex and ventromedial
prefrontal cortex were used to predict responses during fear
extinction and extinction recall.
During extinction training, resting amygdala metabolism
positively predicted ventromedial prefrontal cortex, and
negatively predicted dorsal anterior cingulate cortex, activation.
In contrast, during extinction recall, resting amygdala
metabolism negatively predicted ventromedial prefrontal
cortex, and positively predicted dorsal anterior cingulate cortex,
activation. Resting dorsal anterior cingulate cortex metabolism
predicted fear expression (skin conductance response) during
extinction recall. Brain metabolism at rest predicts neuronal reactivity and skin conductance changes associated with recall
of the fear extinction memory .”
In toxicology usually are high considered the external
environmental factors but we think we must observe under
toxicological methods also the inside intra-extra cellular local
microenvironment (paraphysiologic-pathologic conditions).
In some pathology the time is relevant added to local micro
environment and inters cellular communication situations. We
must consider an intra- local toxicology aspect time related to
better verify some pathologic process under a new light.
In some time related local metabolic-catabolic-toxic status
we can observe some cellular effect resulting in some organ
failure. The time involved in resolve some temporary gradients
or the velocity involved in this process can be fundamental.
The same effect related to too much rapid evolution or too
slow reduction in balancing equilibrates physiologic systems.
(The same the reduced effect showed in example in sports trained
in SCD vs not trained activate platelet in trigger coronary artery
spams, amygdala temporal iper activation or other examples).
We need to introduce more toxicological methods in some
pathologies in order to clear some relevant aspect in etiology,
diagnosis and therapy.