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11.
In this article, we discuss molecular mechanisms involved in the evolution of amygdala kindling and the episodic loss of response
to pharmacological treatments during tolerance development. These phenomena allow us to consider how similar principles (in
different neurochemical systems) could account for illness progression, cyclicity, and drug tolerance in affective disorders.
We describe the phenomenon of amygdala-kindled seizures episodically breaking through effective daily pharmacotherapy with
carbamazepine and valproate, suggesting that these observations could reflect the balance of pathological vs compensatory
illness-induced changes in gene expression. Under certain circumstances, amygdala-kindled animals that were initially drug
responsive can develop highly individualized patterns of seizure breakthroughs progressing toward a complete loss of drug
efficacy. This initial drug efficacy may reflect the combination of drug-related exogenous neurochemical mechanisms and illness-induced
endogenous compensatory mechanisms. However, we postulate that when seizures are inhibited, the endogenous illness-induced
adaptations dissipate (the “time-off seizure” effect), leading to the re-emergence of seizures, a re-induction of a new, but
diminished, set of endogenous compensatory mechanisms, and a temporary period of renewed drug efficacy. As this pattern repeats,
an intermittent or cyclic response to the anticonvulsant treatment emerges, leading toward complete drug tolerance.
We also postulate that the cyclic pattern accelerates over time because of both the failure of robust illness-induced endogenous
adaptations to emerge and the progression in pathophysiological mechanisms (mediated by long-lasting changes in gene expression
and their downstream consequences) as a result of repeated occurrences of seizures. In this seizure model, this pattern can
be inhibited and drug responsivity can be temporarily reinstated by several manipulations, including lowering illness drive
(decreasing the stimulation current.), increasing drug dosage, switching to a new drug that does not show crosstolerance to
the original medication, or temporarily discontinuing treatment, allowing the illness to re-emerge in an unmedicated animal.
Each of these variables is discussed in relation to the potential relevance to the emergence, progression, and suppression
of individual patterns of episodic cyclicity in the recurrent affective disorders. A variety of clinical studies are outlined
that specifically test the hypotheses derived from this formulation. Data from animal studies suggest that illness cyclicity
can develop from the relative ratio between primary pathological processes and secondary endogenous adaptations (assisted
by exogenous medications). If this proposition is verified, it further suggests that illness cyclicity is inherent to the
neurobiological processes of episode emergence and amelioration, and one does not need to postulate a separate defect in the
biological clock. The formulation predicts that early and aggressive long-term interventions may be optimal in order to prevent
illness emergence and progression and its associated accumulating neurobiological, vulnerability factors. 相似文献
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B Balkau E Eschwège L Papoz J L Richard J R Claude J M Warnet P Ducimetière 《BMJ (Clinical research ed.)》1993,307(6899):295-299
OBJECTIVE--To identify risk factors for all cause mortality according to glucose tolerance status. DESIGN--Cohort study with an average 15.6 years'' follow up. SETTING--Paris, France. SUBJECTS--7166 working men aged 44-55 in 1968-72 in the Paris prospective study cohort, with non-insulin dependent diabetes or known result of two hour 75 g oral glucose tolerance test. MAIN OUTCOME MEASURES--Risk factors for death from all causes. RESULTS--128 men were known to be diabetic, 180 had diabetes diagnosed, and 697 had impaired glucose tolerance diagnosed. Compared with normoglycaemic men the relative risks of death in these groups were 2.0 (95% confidence interval 1.4 to 3.0), 2.7 (2.0 to 3.6), and 1.6 (1.3 to 2.0) respectively. Obesity, smoking, high blood pressure, and high non-esterified fatty acid concentration were risk factors for death in all subjects and were unaffected by glucose tolerance. The risks for fasting and two hour insulin concentrations and mean corpuscular volume were two times higher in known diabetic men than in men not known to be diabetic. Central obesity was significant only in men not known to be diabetic (1.6 (1.4 to 1.9)). In known diabetic men a two hour glucose concentration higher than 11.1 mmol/l carried a relative risk of death of 3.8 (1.4 to 9.4). CONCLUSIONS--Diabetic men have similar risk factors for early mortality to other men but are at higher risk from hyperinsulinaemia, hyperglycaemia, and high mean corpuscular volume. 相似文献
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An investigation on the influence of lead toxicity on some of the hepatic enzymes was studied in rats both after a shorter
interval of 15 d and after longer intervals of 60 and 90 d. Three different doses of lead as 5, 10, and 50 mg/kg body wt were
administered orally on every alternate day. Whereas significant inhibition of succinic dehydrogenase was seen following lead
poisoning, the activity acid and alkaline phosphatase increased with lead intoxication. The histoarchitecture of the liver
was grossly intact. Liver accumulated less lead compared to kidney at 60 and 90 d. 相似文献
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Regulation of Escherichia coli secA mRNA translation by a secretion-responsive element. 总被引:6,自引:2,他引:4 下载免费PDF全文
The Escherichia coli secA gene, whose translation is responsive to the proficiency of protein export within the cell, is the second gene in a three-gene operon and is flanked by gene X and mutT. By using gene fusion and oligonucleotide-directed mutagenesis techniques, we have localized this translationally regulated site to a region at the end of gene X and the beginning of secA. This region has been shown to bind SecA protein in vitro. These studies open the way for a direct investigation of the mechanism of secA regulation and its coupling to the protein secretion capability of the cell. 相似文献