Urinary lithium: distribution shape, reference values, and evaluation of exposure by inductively coupled plasma argon-emission spectrometry.
Inductively coupled plasma argon-emission spectrometry (ICPAES) was used to evaluate the lithium content of undiluted urine samples. The method can be performed with 1 mL of urine in a single tube using a routine ICPAES analysis for rapid and convenient assessment of lithium exposure in humans. Urine samples obtained from male workers (n = 86) who had not been exposed to lithium were used for the determination of this element by ICPAES. The obtained concentrations were corrected using a specific gravity of 1.024. The particular frequency distribution resulted in a log-normal distribution diagram for anatomical spread. Geometric mean value for urinary lithium in the nonexposed male workers was 23.5 microg/L, and the confidence interval from a log-normal distribution was 11.0 to 50.5 microg/L. Taking into consideration a short biological half-life and the massive urine excretion of lithium, urinary lithium was considered to be a useful index for monitoring of exposure. Calibration curves obtained for lithium standards had good sensitivity and linearity. Good reproducibility was assessed by lithium addition to urine samples. It was concluded that the obtained lithium reference values would be useful for the early diagnosis of lithium intoxication or in the assessment of the degree of exposure to lithium in subjects at risk. (+info)
The social and economic effects of manic depressive illness and of its treatment in lithium clinics.
Advising about the employment of those who have had manic depressive episodes requires Occupational Health Physicians to obtain, with consent, an objective account of previous episodes and to appreciate the enormous range of manic and depressive manifestations. Familiarity is needed with the likely effects of treatment of episodes and the benefits and problems of prophylaxis--not just in general but in individual cases, for example, where driving is required. This article summarizes research into the effects of lithium preparations on the course of the illness, thyroid and renal function and the risk of suicide. The author found that changing from treatment of episodes to continuous prophylaxis benefited employment and personal relationships without causing body weight problems. Many patients do well in life if supported by an experienced professional team, with 61% requiring no further admissions once on lithium, and with an 86% reduction in admissions achieved in our local clinic. (+info)
Allosteric regulation of even-skipped repression activity by phosphorylation.
The Drosophila homeodomain protein Even-skipped (Eve) is a well characterized transcriptional repressor. Here, we show that Eve's ability to function in vitro is negatively regulated by phosphorylation. DNA-binding activity was unaffected by phosphorylation, but phosphorylated Eve was unable to interact with the TATA-binding protein (TBP), a known target for repression. Unexpectedly, phosphorylation of the Eve N terminus, which is dispensable for repression and TBP binding, was necessary and sufficient to inactivate Eve. LiCl, which specifically inhibits glycogen synthase kinase-3 (GSK-3), reduced Eve phosphorylation in nuclear extract and blocked inhibition of repression. In addition, Eve was phosphorylated and inactivated by purified GSK-3 beta plus casein kinase II. Our results suggest a novel mechanism of transcriptional control involving phosphorylation-induced allosteric interference with a repressive protein-protein interaction. (+info)
Regulation of AMP deaminase from chicken erythrocytes. A kinetic study of the allosteric interactions.
The allosteric properties of AMP deaminase [EC 126.96.36.199] from chicken erythrocytes have been qualitatively and quantitatively accounted for by the concerted transition theory of Monod et al., on the assumption that this enzyme has different numbers of binding sites for each ligand. Theoretical curves yield a satisfactory fit for all experimental saturation functions with respect to activation by alkali metals and inhibition by Pi, assuming that the numbers of binding sites for AMP, alkali metals, and Pi are 4, 2, and 4, respectively. The enzyme was inhibited by concentrations of ATP and GTP below 0.1 and 0.25 mM, respectively, whereas activation of the enzyme was observed at ATP and GTP concentrations above 0.4 and 1.5 mM, respectively. These unusual kinetics with respect to ATP and GTP could be also accounted for by assuming 2 inhibitory and 4 activating sites for each ligand. (+info)
Correlation between hypermetabolism and neuronal damage during status epilepticus induced by lithium and pilocarpine in immature and adult rats.
The correlation between seizure-induced hypermetabolism and subsequent neuronal damage was studied in 10-day-old (P10), 21-day-old (P21), and adult rats subjected to lithium-pilocarpine status epilepticus (SE). Local CMRglc (LCMRglc) values were measured by the [14C]2-deoxyglucose method for a duration of 45 minutes starting at 60 minutes after the onset of SE, and neuronal damage was assessed by cresyl violet staining at 6 days after SE. In P21 and adult rats, LCMRglc values were increased by 275 to 875% in all thalamic, cortical, forebrain, and hypothalamic regions plus the substantia nigra. In addition, at P21 there were also large increases in LCMRglc in brainstem regions. In P10 rats, metabolic increases were mostly located in cortical and forebrain regions plus the substantia nigra but did not affect hypothalamic, thalamic, or brainstem areas. In adult rats, there was an anatomical correlation between hypermetabolism and neuronal damage. At P21, although hypermetabolism occurred in regions with damage, the extent of damage varied considerably with the animals and ranged from an almost negligible to a very extended degree. Finally, in P10 rats, although quite pronounced hypermetabolism occurred, there was no neuronal damage induced by the seizures. Thus, in the present model of epilepsy, the correlation between marked hypermetabolism and neuronal damage can be shown in adult rats. Conversely, immature rats can sustain major metabolic activations that lead either to a variable extent of damage, as seen at P21, or no damage, as recorded at P10. (+info)
Sodium reabsorption and distribution of Na+/K+-ATPase during postischemic injury to the renal allograft.
BACKGROUND: A loss of proximal tubule cell polarity is thought to activate tubuloglomerular feedback, thereby contributing to glomerular filtration rate depression in postischemic acute renal failure (ARF). METHODS: We used immunomicroscopy to evaluate the segmental distribution of Na+/K+-ATPase in tubules of recipients of cadaveric renal allografts. Fractional excretion (FE) of sodium and lithium was determined simultaneously. Observations were made on two occasions: one to three hours after graft reperfusion (day 0) and again on post-transplant day 7. An inulin clearance below or above 25 ml/min on day 7 was used to divide subjects into groups with sustained (N = 15) or recovering (N = 16) ARF, respectively. RESULTS: In sustained ARF, the fractional excretion of sodium (FENa) was 40 +/- 6% and 11 +/- 5%, and the fractional excretion of lithium (FELi) was 76 +/- 5% and 70 +/- 2% on days 0 and 7, respectively. Corresponding findings in recovering ARF were 28 +/- 2% and 6 +/- 2% for the FENa and 77 +/- 4% and 55 +/- 3% (P < 0.05 vs. sustained) for FELi. Na+/K+-ATPase distribution in both groups was mainly basolateral in distal straight and convoluted tubule segments and collecting ducts. However, Na+/K+-ATPase was poorly retained in the basolateral membrane of proximal convoluted and straight tubule segments in sustained and recovering ARF on both days 0 and 7. CONCLUSIONS: We conclude that loss of proximal tubule cell polarity for Na+/K+-ATPase distribution is associated with enhanced delivery of filtered Na+ to the macula densa for seven days after allograft reperfusion. Whether an ensuing activation of tubuloglomerular feedback is an important cause of glomerular filtration rate depression in this form of ARF remains to be determined. (+info)
Role of mitochondrial dysfunction in the Ca2+-induced decline of transmitter release at K+-depolarized motor neuron terminals.
The present study tested whether a Ca2+-induced disruption of mitochondrial function was responsible for the decline in miniature endplate current (MEPC) frequency that occurs with nerve-muscle preparations maintained in a 35 mM potassium propionate (35 mM KP) solution containing elevated calcium. When the 35 mM KP contained control Ca2+ (1 mM), the MEPC frequency increased and remained elevated for many hours, and the mitochondria within twitch motor neuron terminals were similar in appearance to those in unstimulated terminals. All nerve terminals accumulated FM1-43 when the dye was present for the final 6 min of a 300-min exposure to 35 mM KP with control Ca2+. In contrast, when Ca2+ was increased to 3.6 mM in the 35 mM KP solution, the MEPC frequency initially reached frequencies >350 s-1 but then gradually fell approaching frequencies <50 s-1. A progressive swelling and eventual distortion of mitochondria within the twitch motor neuron terminals occurred during prolonged exposure to 35 mM KP with elevated Ca2+. After approximately 300 min in 35 mM KP with elevated Ca2+, only 58% of the twitch terminals accumulated FM1-43. The decline in MEPC frequency in 35 mM KP with elevated Ca2+ was less when 15 mM glucose was present or when preparations were pretreated with 10 microM oligomycin and then bathed in the 35 mM KP with glucose. When glucose was present, with or without oligomycin pretreatment, a greater percentage of twitch terminals accumulated FM1-43. However, the mitochondria in these preparations were still greatly swollen and distorted. We propose that prolonged depolarization of twitch motor neuron terminals by 35 mM KP with elevated Ca2+ produced a Ca2+-induced decrease in mitochondrial ATP production. Under these conditions, the cytosolic ATP/ADP ratio was decreased thereby compromising both transmitter release and refilling of recycled synaptic vesicles. The addition of glucose stimulated glycolysis which contributed to the maintenance of required ATP levels. (+info)
Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity.
This study was undertaken to investigate the molecular mechanisms underlying the neuroprotective actions of lithium against glutamate excitotoxicity with a focus on the role of proapoptotic and antiapoptotic genes. Long term, but not acute, treatment of cultured cerebellar granule cells with LiCl induces a concentration-dependent decrease in mRNA and protein levels of proapoptotic p53 and Bax; conversely, mRNA and protein levels of cytoprotective Bcl-2 are remarkably increased. The ratios of Bcl-2/Bax protein levels increase by approximately 5-fold after lithium treatment for 5-7 days. Exposure of cerebellar granule cells to glutamate induces a rapid increase in p53 and Bax mRNA and protein levels with no apparent effect on Bcl-2 expression. Pretreatment with LiCl for 7 days prevents glutamate-induced increase in p53 and Bax expression and maintains Bcl-2 in an elevated state. Glutamate exposure also triggers the release of cytochrome c from the mitochondria into the cytosol. Lithium pretreatment blocks glutamate-induced cytochrome c release and cleavage of lamin B1, a nuclear substrate for caspase-3. These results strongly suggest that lithium-induced Bcl-2 up-regulation and p53 and Bax down-regulation play a prominent role in neuroprotection against excitotoxicity. Our results further suggest that lithium, in addition to its use in the treatment of bipolar depressive illness, may have an expanded use in the intervention of neurodegeneration. (+info)