Differential effect of human chorionic gonadotrophin on lymphocyte proliferation induced by mitogens

Human chorionic gonadotrophin (hCG) inhibits the lymphoproliferative responses of human peripheral blood mononuclear cells (PBM) to phytohaemagglutinin (PHA) and concanavalin A (Con A) at 10-50 IU of hCG/ml (P less than 0.05). hCG inhibited poorly the response of PBM to pokeweed mitogen (PWM) at concentration up to 100 IU/ml. When monocytes were removed from the PBM population with columns of Sephadex G10 the inhibitory effect of hCG on PHA- and Con A-induced lymphoproliferation was reduced, with inhibition occurring only at a level of 100 IU of hCG/ml. These results suggest that hCG does not inhibit equally the proliferative response of all lymphocyte subsets and further that cells of the monocyte/macrophage series may play a role in its action on lymphocyte proliferation.     

The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers

RATIONALE: Cognitive impairment is a common feature of depressive illness. While accumulating evidence suggests that brain serotonin (5-HT) pathways play an important role in the neurobiology of depression, the extent to which altered 5-HT function is responsible for the associated changes in cognition and emotion remains unclear. OBJECTIVE: The present study examined the effects of acute dietary depletion of tryptophan (TRP) on cognitive and affective processing in healthy volunteers and explored the putative role of 5-HT in the neuropsychology of depression. METHODS: We administered computerised cognitive tests to healthy control participants following ingestion of TRP-free and nutritionally balanced amino acid drinks in a double-blind, placebo-controlled, crossover design. RESULTS: The TRP-free amino acid mixture significantly lowered plasma total and free TRP concentrations relative to baseline values and produced selective deficits similar to those observed previously in cases of clinical depression. In particular, TRP depletion increased response times for happy but not sad targets in an affective go/no-go task and slowed responding in a visual discrimination and reversal learning task. These deficits were not due to a global sedative effect, as planning ability was unimpaired. CONCLUSIONS: The present data indicate that serotonergic factors may be more involved in the disrupted inhibitory and emotional processing characteristic of depression than in other aspects of executive function, such as planning ability. These findings support the recent proposal that serotonergic manipulation may have greater effects on tasks mediated by frontal circuitry that includes the orbitofrontal cortex than by dorsolateral prefrontal cortex circuitry.     

Acute tryptophan depletion decreases intensity dependence of auditory evoked magnetic N1/P2 dipole source activity

Abstract Rationale. Intensity dependence of the N1/P2 components may be regulated by serotonergic neurons in the primary auditory cortex, where low activity leads to a high intensity dependence and vice versa. Depletion of tryptophan (TRP), a precursor for serotonin has been described to reduce serotonin content in brain of animals and humans. Objective. We investigated the intensity dependence of magnetic and electric N1/P2 components in ten subjects in a double-blind, controlled, cross-over design study after oral mixture of amino-acids leading to acute tryptophan depletion (ATD) and control. Methods. Auditory evoked magnetic fields (AEF) and potentials (AEP) were recorded with 122-channel magnetoencephalography simultaneously with 64-channel EEG 5 h after ingestion of mixtures. The AEF sources and strength were estimated by a least-squares fit of a single equivalent current dipole. The amplitudes and latencies of N1 and P2 recorded with EEG were analyzed at frontal electrode site. Results. TRP depletion decreased the total and free TRP levels by 76 and 45% and control mixture increased it by 48 and 28%. ANOVA showed that ATD had a significant main effect on the N1m/P2m dipole moments at the contralateral (P=0.02), but failed significantly to influence the ipsilateral responses. A significant mixture ingestion-by-stimulus intensity interaction was observed on the N1m/P2m dipole moments at the contralateral hemisphere (P=0.01). The N1/P2 slope for intensity dependence function was decreased following ATD compared with the control experiment (P=0.01) at the contralateral hemisphere. For EEG, a significant mixture ingestion-by-stimulus intensity interaction on the N1 latencies at the Fz electrode position was observed (P=0.01). Conclusion. ATD decreased the intensity dependence of N1m/P2m source dipole moments in the primary auditory cortex at the hemisphere contralateral to the ear stimulated. These results suggest that serotonin participates in the regulation of intensity of auditory stimulation. Electronic Publication     

Skin cancer and ultraviolet-B radiation under the Antarctic ozone hole: southern Chile, 1987-2000

BACKGROUND: Punta Arenas, Chile, the southernmost city in the world (53 degrees S), with a population of 154,000, is located near the Antarctic ozone hole (AOH) and has been regularly affected by high levels of ultraviolet-B (UV-B) radiation each spring for the last 20 years. Large increases in UV-B associated with the AOH have been measured with increases in UV-B at 297 nm of up to 38 times those of similar days with normal ozone. Recently we reported significant increases in sunburns during the spring of 1999 on days with low ozone because of the AOH. METHODS: A surveillance of skin cancers occurring from 1987 to 2000 was performed. Age, sex, location, type of skin cancer and skin phototype were recorded. A Brewer Spectrophotometer was used in order to obtain in situ measurements of ozone and UV-B. Total Ozone Mapping Spectrometer (TOMS) data from National Aeronautics and Space Administration (NASA) was used in order to establish pre-ozone hole climatology. RESULTS: Ozone levels as low as 145 DU (Dobson Units) were recorded, a 56% decrease in ozone, and UV-B levels up to 4.947 J/m2. These levels are close to summertime levels at mid latitudes. For the 14-year period--from 1987 to 2000--173 cases of skin cancer were diagnosed, 65 during the first 7 years, 108 during the second, an increase of 66%. Cutaneous malignant melanoma (CMM), 19% of the cases, increased by 56%, raising the rate from 1.22 to 1.91 per 100,000. Non-melanoma skin cancer (NMSC), 81% of the total, increased the rate from 5.43 to 7.94 per 100 000 (P < 0.05), a 46% increase. Patients with CMM and NMSC had skin phototypes I-II in 59% and 54% of cases, respectively. Days with more than 25% ozone loss occurred in 143 days during the last 20 springs. Significant increases of UV-B were observed under ozone hole conditions, especially around 300 nm, the most carcinogenic wavelengths. CONCLUSIONS: Highly unusual ozone loss and UV-B increases have occurred in the Punta Arenas area over the past two decades resulting in the non-photoadapted population being repeatedly exposed to an altered solar UV spectrum with a greater effectiveness for erythema and photocarcinogenesis. This phenomenon has not previously been reported over other populated areas and an additional increase in the skin cancer rate attributable to the AOH may be occurring. Research on the clinical and subclinical impact of these abnormalities is urgently needed.     

ATP缺失时大鼠近端肾小管上皮细胞骨架重组与ERM蛋白的重分布相关

目的:探讨ATP缺失时大鼠近端肾小管上皮细胞(NRK52E细胞)肌动蛋白细胞骨架重组情况及其可能机制.方法:用含0.1 μmol/L antimycin A的ATP缺失缓冲液处理培养的NRK52E细胞,建立细胞的体外ATP缺失模型;采用FITC标记的鬼笔环肽标记纤维型肌动蛋白(F-actin),用流式细胞仪检测技术分析肌动蛋白细胞骨架的重组情况;用Western blot及免疫印迹技术检测ATP缺失后NRK52E细胞内骨架组分(Triton不溶组分)及上清组分(Triton可溶组分)中ERM(Ezrin/Radixin/Moesin)蛋白的分布改变.结果:体外ATP缺失模型建立,各实验组细胞内ATP浓度呈时间依赖性的下降(P＜0.05);ATP缺失后,NRK52E细胞内纤维型肌动蛋白的量渐增,且肌动蛋白的聚合程度随ATP缺失时间延长而增加(P＜0.05);ATP缺失后,ERM蛋白从细胞骨架解离进入胞浆,且ERM蛋白从细胞骨架的解离程度随ATP缺失的程度的增加而增加(P＜0.05).结论:ATP缺失后NRK52E细胞骨架重组可能与ERM蛋白的重分布相关.     

Amine accumulation in behavioural pathology

When nigro-striatal and meso-cortical neurons degenerate there is a loss of dopamine in the terminal fields and an accumulation of amines in the axons of these systems as they traverse the hypothalamus through the medial forebrain bundle. Traditional lines of thought have attributed the occurrence of motor and consummatory deficits which occur after dopamine neuron degeneration to the loss of functional dopamine neurotransmitter in the terminal fields. However we have hypothesized that hypothalamic amine accumulation represents an area of brain tissue where processes such as neurotransmitter release ephaptic transmission or local axon swelling may be affecting adjacent neurons and may thereby participate in the production of behavioural deficits. There is a considerable amount of evidence from studies on both peripheral and central catecholamine-containing neurons indicating that when their axons degenerate a release of functional neurotransmitter can occur. Information from neuropharmacological studies indicates that several drugs which facilitate behavioural recovery from dopamine-depleting lesions may do so by affecting amine release or receptor sensitivity near areas of accumulation rather than depleted terminal fields. We conclude that amine accumulation is a component of dopamine neuron degeneration which should be considered when assessing the role of the central catecholamine systems in the control of various behavioural and physiological processes.     

The dependence of the anti-nociceptive effect of morphine and other analgesic agents on spinal motor activity after central monoamine depletion

The interference of central monoamine depletion with the anti-nociceptive effect of morphine, pethidine and aminophenazone was studied in rats with regard to the changes in spinal motor activity induced by reserpine, tetrabenazine and α-methyl-p-tyrosine.All three analgesic agents prolonged the time of the tail-flick reaction in intact rats. This effect was abolished by reserpine, which prolonged the reaction time. Bilateral lesioning of the substantiae nigrae with microinjections of 6-hydroxydopamine prolonged the reaction time and abolished the anti-nociceptive effect of morphine. In spinal rats, the time of the tail-flick reaction was prolonged by morphine and reduced by aminophenazone. Reserpine did not abolish the effect of morphine in spinal rats.Morphine, pethidine and aminophenazone inhibited the α-reflex discharges facilitated by conditioning stimulation in intact and spinal rats. Pethidine and aminophenazone, but not morphine, depressed the facilitation of α-reflex discharges produced by central monoamine depletion in intact rats. The increase in the amplitude of monosynaptic mass reflexes produced by reserpine in intact rats was not reduced by morphine, whereas the depression of polysynaptic mass reflexes after reserpine was antagonized by morphine.The three analgesic agents differ markedly in their action on spinal motor activity altered by monoamine depletion. It is concluded that the antagonizing effect of central monoamine depletion on the anti-nociceptive effect of morphine, pethidine and aminophenazone in the rat is due to a change in the basal motor activity on which the spinal nociceptive reflex is elicited.     

The effects of guanethidine, bretylium and debrisoquine on the accumulation of noradrenaline in constricted postganglionic sympathetic nerves in vitro

The accumulation of noradrenaline proximal to a constriction applied to cat hypogastric nerves in vitro has been studied in preparations treated with bretylium, guanethidine and debrisoquine. All three drugs reduced the accumulation of the amine. This was paralleled by a decrease in the accumulation of dense vesicles seen with the electron microscope. Evidence is presented which suggests that the drugs e xert a noradrenaline-depleting action upon the amine-storage vesichles. At leat 18 hrs' treatment with bretylium and debrisoquine were necessary before the amine-depleting action of these drugs was evident. It is suggested that the method employed is of value in the correlation of the ultrastructural and biochemical effects of drugs on sympathetic nerves.     

Combined D1/D2 receptor stimulation under conditions of dopamine depletion impairs spatial working memory performance in humans

Rationale The mesocortical dopamine system is regarded as an important modulator of working memory. While it has been established that stimulation of the D₁/D₂ receptor in primates can improve spatial working memory performance, findings in humans are less consistent. Recent studies in humans suggest that global depletion of dopamine via tyrosine/phenylalanine depletion may impair spatial working memory performance, although these results are also inconsistent, and it has been suggested that task differences may partly underlie the inconsistent findings. Objectives This study had two aims: (1) to investigate the effects of acute tyrosine depletion (TPD) on a number of working memory tasks and (2) to examine whether stimulation of D₁/D₂ receptors under conditions of TPD can attenuate or “reverse” TPD-induced working memory impairments. Methods Eighteen healthy male participants performed a spatial working memory delayed-recognition task, non-spatial working memory task and spatial n-back task on three separate occasions, after TPD, TPD and pergolide (D₁/D₂ agonist), and placebo. Results TPD did not impair working memory performance on any of the tasks administered. However, stimulation of D₁/D₂ receptors under TPD conditions caused a subtle impairment in spatial working memory performance. Conclusions The finding that D₁/D₂ stimulation under TPD conditions impairs working memory highlights the complexity of functional effects of augmenting dopaminergic transmission within a dopamine-depleted state. The lack of TPD-related effects on a range of working memory tasks questions the reliability of TPD as a modulator of dopamine function and working memory performance in humans.     

Reduced serotonin synthesis during early embryogeny changes effect of subsequent prenatal stress on persistent pain in the formalin test in adult male and female rats

The considerable evidence supporting a role for serotonin (5-HT) in the embryonic formation of CNS, mediation of prenatal stress, and pain processing is reviewed. Long-term influences of prenatal 5-HT depletion as well as its combination with prenatal stress effects on tonic nociceptive system in 90-day-old Wistar rats were studied in the formalin test. Pregnant dams were injected with para-chlorophenylalanine (pCPA, 400 mg/kg/2 ml, ip), producing 5-HT depletion during the early period of fetal serotonergic system development. The adult offspring from pCPA-treated dams revealed changes in behavioral indices of persistent pain (flexing + shaking and licking) in the formalin test (2.5%, 50 microl) that were accompanied by irreversible morphological alterations in the dorsal raphe nuclei. In the other series of experiments, the role of 5-HT in the mediation of prenatal stress on the behavioral indices of persistent pain was investigated in the adult offspring from dams with 5-HT depletion followed by restraint stress. Stress during the last embryonic week caused much more increase in flexing + shaking and licking in the second tonic phase of the response to formalin in offspring from pCPA- than saline-treated (control) dams. The former was characterized by alterations in the durations of the interphase, the second phase, and the whole behavioral response too. In offspring from pCPA-treated dams, sex dimorphism was revealed in tonic pain evaluated by licking. Together with our previous results in juvenile rats demonstrating the necessity of definite level of prenatal 5-HT for normal development of tonic nociceptive system, the present pioneering findings obtained in adult rats indicate that prenatal 5-HT depletion causes long-term morphological abnormalities in the dorsal raphe nuclei accompanied by alterations in behavioral indices of tonic pain. Early prenatal 5-HT depletion increases vulnerability of tonic nociceptive circuits to the following prenatal stress.