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Biomedical subjects

J Littleton

Publications and source records attributed to J Littleton.

At least 19 recordsLinked to original sources
PubMed2005

Linear enamel hypoplasia and historical change in a central Australian community.

BACKGROUND: The current study extends the use of linear enamel hypoplasia (LEH) to examine the historical changes in living conditions encountered by Aboriginal people at Yuendumu who were born between 1890 and 1960. LEH provides health information beyond written records and gives information beyond written records and gives insight into the relationship between individual health and living conditions during initial and ongoing contact with Europeans. MATERIALS AND METHODS: The dental casts of 446 people, collected as part of the University of Adelaide longitudinal study of growth and development, were recorded for the presence of hypoplastic defects. Defects were recorded according to the Development Defects of the Enamel (DDE) standards and assigned to developmental units based on their crown position. RESULTS: The frequency of LEH on the permanent dentitions increased five-fold from the 1890-1929 birth cohort to the 1955-1960 cohort. LEH also affected earlier developing enamel units. Deciduous defects did not show a strong temporal trend but overall prevalence was comparable to other disadvantaged groups. CONCLUSION: The changes in permanent LEH frequency and age distribution correspond to altered living conditions with the worst hypoplasia recorded after settlement of Aboriginal people at Yuendumu. Prior to that period LEH was comparable to precontact Australian populations indicating that resettlement had a dramatic impact on childhood morbidity.

Child, Preschool↗
PubMed2001

Receptor regulation as a unitary mechanism for drug tolerance and physical dependence--not quite as simple as it seemed!

This review examines the development of the unitary hypothesis that both drug tolerance and the drug withdrawal syndrome arise from adaptive regulation of drug receptors in the brain. Although there is still considerable merit in this hypothesis, the author explains that careful evaluation of some of the changes that have been reported suggests that many of these are not good explanations for both aspects of drug dependence. In addition, modern developments in the understanding of receptor mechanisms show that the original hypothesis represents a gross oversimplification of the true situation. Adaptive changes in post-receptor mechanisms are now believed to be at least as important as alterations in the receptors themselves. Equally some receptor proteins, by altering their subunit composition, may be able to adapt to the presence of drugs without producing major changes in the action of the natural transmitter. In conclusion, receptor regulation still seems to play an important role in drug dependence but this role is more complex than was once believed.

Adaptation, Physiological↗
PubMed2001

Acamprosate is neuroprotective against glutamate-induced excitotoxicity when enhanced by ethanol withdrawal in neocortical cultures of fetal rat brain.

BACKGROUND: Acamprosate reduces relapse, and the drug may interact with glutamate transmission and with glutamate/NMDA receptors. Because these systems are implicated in excess calcium entry leading to alcohol withdrawal-induced neurotoxicity, we evaluated the effects of acamprosate on these parameters in neuronal cultures. METHODS: Primary cultures of neocortical neurons from fetal Sprague-Dawley rats were maintained either in normal medium or in medium containing 100 mM ethanol for 4 days. After this time, cultures were challenged with glutamate for 10 min and then returned to medium (all in the absence of ethanol). 45Ca2+ uptake was measured during the challenge, and glutamate-induced toxicity was assessed after 20 hr. The effects of acamprosate present during the glutamate challenge were measured on both parameters. RESULTS: In controls, acamprosate did not significantly affect glutamate-induced neurotoxicity but produced a significant inhibition of calcium entry. The NMDA receptor antagonists dizocilpine and d-amino-phosphonovalerate (D-APV) inhibited both glutamate neurotoxicity and calcium entry. In cultures previously exposed to ethanol, glutamate-induced neurotoxicity and calcium entry were both significantly enhanced. Dizocilpine reduced both these parameters to unstimulated control values, and D-APV reduced both calcium entry and neurotoxicity with the same relation that we obtained in control cultures. In the ethanol-withdrawn cultures, acamprosate reduced both the enhanced glutamate-induced calcium entry and the enhanced neurotoxicity in a concentration-dependent manner. Acamprosate also significantly reduced calcium entry caused by 80 mM K+ in control and ethanol-exposed cultures. CONCLUSIONS: Acamprosate had protective effects against glutamate-induced neurotoxicity only in ethanol-withdrawn cultures. The neuroprotective effects of the drug did not correlate with its effects on calcium entry, making it unlikely that acamprosate directly affects NMDA receptors via the glutamate binding site or the receptor-operated calcium channel. The results are, however, compatible with other inhibitory effects on NMDA receptor function.

Acamprosate↗
PubMed2000

Can craving be modeled in animals? The relapse prevention perspective.

The mechanism that underlies craving is unknown, and this makes it difficult to model craving in any general way in animals. However, there is considerable evidence that conditioned "drug-like" and "drug-opposite" responses play a part in relapse during abstinence. In so much as these conditioned responses represent one type of mechanism that leads to craving, they can be used to develop animal models of craving. Indeed, there are several types of model already available that are based on drug-conditioned responses, and that are relevant. However, most current "drug conditioning models" have not been developed with the specific intention of modeling factors that predispose to relapse, and they have deficiencies for this purpose as a result. In addition, some of the drug-conditioning models are unsuitable for the study of alcohol rather than for more positively reinforcing drugs such as cocaine. This commentary considers first whether the existing models, and the concepts behind them, can be adapted to provide "craving models" and, secondly, whether the resulting models may be used to evaluate anti-relapse drugs. This purpose requires two levels of complexity, simple "screening tests" that suggest that a drug may be worth evaluating further, and models of more complex behavior that have face validity to relapse in the human subject, and have predictive value for therapeutic use in relapse. Finally, rather different animal models, based on the concepts of extinction and reinstatement, might be used to answer fundamental questions as to the mechanisms of relapse into use of alcohol. All the proposed types of animal models of craving are based on conditioned reinforcements, rather than being based on reinforcing effects of the drugs themselves (as are most of the current models). However, if the development of "craving models" based on conditioning will help us better understand relapse, then the therapeutic benefits that can be expected will make the effort worthwhile.

Alcohol-Related Disorders↗
PubMed1999

Paleopathology of skeletal fluorosis.

Skeletal fluorosis is one of a range of conditions causing excessive ossification and joint ankylosis in skeletons. It is rarely considered, however, in differential diagnoses of palaeopathological lesions. This paper considers the identification of skeletal fluorosis in a skeletal sample from the island of Bahrain, Arabian Gulf, dating to ca. 250 BC-AD 250. Approximately 4% of 255 adult skeletons in the sample have hyperostosic lesions resulting in joint ankylosis primarily of the lumbar vertebrae, as well as the major joints. These lesions most frequently occur among males in the 50+ age group. Chemical analysis on a small series of bone and dental samples confirmed the presence of high levels of fluoride, while staining of the teeth is evidence of dental fluorosis. The level of dental fluorosis is comparable with a naturally occurring fluoride level in water of between 1-2 ppm. The prevalence of hyperostosic lesions, however, appears higher than expected, and two possible reasons are suggested: confusion between a diagnosis of diffuse idiopathic skeletal hyperostosis and skeletal fluorosis on partial or less severely affected skeletons; and the presence of predisposing factors for skeletal fluorosis on the island in the past.

Adult↗
PubMed1998

Neurochemical mechanisms underlying alcohol withdrawal.

More than 50 years ago, C.K. Himmelsbach first suggested that physiological mechanisms responsible for maintaining a stable state of equilibrium (i.e., homeostasis) in the patient's body and brain are responsible for drug tolerance and the drug withdrawal syndrome. In the latter case, he suggested that the absence of the drug leaves these same homeostatic mechanisms exposed, leading to the withdrawal syndrome. This theory provides the framework for a majority of neurochemical investigations of the adaptations that occur in alcohol dependence and how these adaptations may precipitate withdrawal. This article examines the Himmelsbach theory and its application to alcohol withdrawal; reviews the animal models being used to study withdrawal; and looks at the postulated neuroadaptations in three systems-the gamma-aminobutyric acid (GABA) neurotransmitter system, the glutamate neurotransmitter system, and the calcium channel system that regulates various processes inside neurons. The role of these neuroadaptations in withdrawal and the clinical implications of this research also are considered.

Alcoholism↗
PubMed1998

Mechanism of action of acamprosate. Part II. Ethanol dependence modifies effects of acamprosate on NMDA receptor binding in membranes from rat cerebral cortex.

Acamprosate is a putative anticraving drug used to maintain abstinence in alcohol-dependent patients. Its mechanism of action is uncertain, but the drug is thought to interact with neuronal NMDA receptors and calcium channels, and these proteins are implicated in the induction of alcohol dependence. In these experiments, the effects of acamprosate were studied on the binding of the NMDA receptor ligand [3H]dizocilpine to rat brain membranes under nonequilibrium conditions; 10 microM glutamate and 1 microM glycine were present in the binding assays to partially activate the receptor. At clinically relevant concentrations (in the micromolar range), acamprosate significantly enhanced [3H]dizocilpine binding to cortical membranes from control animals (suggesting that acamprosate may increase the rate of association of the radioligand), whereas at higher concentrations binding was inhibited. This effect is consistent with a partial agonist effect of acamprosate on the NMDA receptor protein. However, when rats were made dependent on ethanol (exposure to the drug for 10 days by inhalation) and cortical membranes were prepared from these animals, acamprosate in vitro no longer produced any enhancement of [3H]dizocilpine binding. Similar results were obtained when membranes were used from rats that had received 400 mg/kg/day of acamprosate in their drinking water with or without concurrent ethanol inhalation for 10 days. Thus, in brain membranes from all these treatment groups, acamprosate in vitro caused inhibition of [3H]dizocilpine binding only. The results suggest that acamprosate may have excitatory or inhibitory effects on NMDA receptors, depending on the experimental conditions. The effects of the drug on this system appear to be shifted toward inhibition in alcohol dependence, and this finding may be important to its clinical mechanism.

Acamprosate↗
PubMed1995

Acamprosate in alcohol dependence: how does it work?

Acamprosate is a relatively new drug that appears to be clinically useful in the treatment of alcohol dependence. Although it has proved effective in reducing relapse into drinking in clinical trials its exact mechanism of action is uncertain. Evidence is presented that the drug does not act in any of the conventional ways to reduce alcohol intake and it is proposed that it may be a novel kind of agent that suppresses "craving". On the basis of its known pharmacological effects in pre-clinical studies it is suggested that acamprosate may reduce craving that is associated with conditioned withdrawal. In addition to the potential therapeutic value of acamprosate, the drug may be useful because work directed toward understanding its mechanism of action may shed light on some of the fundamental processes that govern alcohol abuse and relapse in weaned alcohol dependent patients.

Acamprosate↗
PubMed1994

Current concepts of ethanol dependence.

Alcohol dependence is considered to be divisible into two types (although the divisions between these are indistinct). These are psychological dependence, in which the rewarding effects of alcohol play a primary role, and chemical dependence, in which adaptive changes in the brain initiate punishing effects on withdrawal of alcohol, and suppression of these becomes the primary motive for using the drug. The neurochemical basis for the rewarding effects of alcohol may be the potentiation of GABA at GABAA receptors (causing relaxation) and release of dopamine from mesolimbic neurones (causing euphoria). The adaptive changes which cause the alcohol withdrawal syndrome are not known for certain, but alterations in GABAA receptors, NMDA receptors and voltage-operated calcium channels all have a claim. However, it is distinctly doubtful whether these all contribute to the negatively reinforcing effects of alcohol that are important in chemical dependence, although they may be important in other pathological effects of alcohol abuse. Current research badly needs better communication between basic scientists and clinicians to establish research goals and to improve current models.

Alcohol Drinking↗
PubMed1993

Fish-eaters and farmers: dental pathology in the Arabian Gulf.

Twelve skeletal samples, previously published, from the Arabian Gulf have been used to trace differences in diet and subsistence patterns through an analysis of dental pathology. The skeletons date from 3,000 BC to AD 1,500 and cover a variety of geographical locations: off-shore islands, Eastern Arabia, and Oman. The dental conditions analyzed are attrition, caries, calculus, abscessing, and antemortem tooth loss (AMTL). Results indicate four basic patterns of dental disease which, while not mutually exclusive, correspond to four basic subsistence patterns. Marine dependency, represented by the Ras el-Hamra population, is indicated by severe attrition, low caries rates, wear-caused abscessing, and a lack of AMTL. The second group of dental diseases--moderate attrition and calculus, low rates of caries, wear-caused abscessing, and low-moderate rates of AMTL--affects populations subsisting on a mixture of pastoralism or fishing and agriculture (Failaka, Umm an-Nar, Bronze Age Maysar, Bronze Age Shimal, and Iron Age Galilah). Mixed farming populations (Iron Age Maysar and Islamic Bahrain) experienced low-moderate attrition, high rates of caries and calculus, abscessing due to caries, and severe AMTL. The final group of dental diseases affects populations practicing intensive gardening (Bronze and Iron Age Bahrain, and Sites 3 and 5, Ras al-Khaimah). These groups experienced slight attrition, high rates of caries, low rates of calculus deposition, and severe AMTL.

Adult↗
PubMed1993

Hyperexcitability in adrenal cells after culture in ethanol: withdrawal or excitotoxicity.

Experiments on bovine adrenal chromaffin cells maintained in culture medium containing ethanol (200 mM for a period of 5 days) show evidence of cellular hyperexcitability upon removal of the drug. This appears to be due to an adaptive response to the initial depressant effects of ethanol. In this model system excitatory amino acids (EAA) have greater toxicity during this state of cellular hyperexcitability promoting the view that the same mechanisms which lead to cellular withdrawal may also be linked with processes of neurodegeneration. Recent findings suggest the increased toxicity of amino acids may be due to several different mechanisms: consequently, the investigation of this hypothesis is not straightforward.

Adaptation, Physiological↗
PubMed1993

Adaptive changes in numbers of calcium channels in drug dependence.

Adrenal-derived cells in culture slowly upregulate numbers of putative calcium channel proteins in response to inhibitory drugs including ethanol, benzodiazepines and morphine. This appears to be an adaptive response to cell inhibition involving second messengers and protein phosphorylation and culminating in alterations in expression of the calcium channel gene (Fig. 1). These increases in calcium channels lead to rebound increases in cell excitability when the depressant drugs are withdrawn (a characteristic feature of chemical dependence on depressant drugs) so that this change in numbers of calcium channels may provide a model for one mechanism of chemical dependence. Similar findings have been reported in the brains of animals made dependent on depressant drugs, and genetic and pharmacological manipulations of dependence and withdrawal further support a role for calcium channels in these phenomena.

Adaptation, Physiological↗
PubMed1989

Increased plasma carnitine in severe alcohol dependence.

Carnitine plays a central role in lipid metabolism. There have been several suggestions that carnitine metabolism is affected in alcoholism. In the present study plasma carnitine levels in severely dependent alcoholic patients were investigated. The results show that total and free plasma carnitine in 11 out of 14 patients were raised above those found in normal control subjects. This may be indicative of changes central to the disease process. We suggest that plasma free carnitine represents a useful test which can be added to those currently used to assess alcohol dependence.

Adult↗
PubMed1983

Alpha-adrenoceptor number and function in rat cortex after ethanol and immobilization stress.

Alpha-Adrenoceptor number and function were assessed in rat cortex after ethanol and immobilization stress. Rats subjected to immobilization stress for 2 h/day/7 days showed a significant reduction in alpha 2-adrenoceptors in cortex ( [3H]clonidine binding) but no change in alpha 1-adrenoceptors ( [3H]prazosin binding). The inhibitory effect of clonidine (500 nM) on 3H efflux from cortical slices preincubated with [3H]norepinephrine was reversed in the stressed animals. These effects on alpha 2-adrenoceptor number and function were reduced when stress was accompanied by chronic administration of ethanol (35% of calories in a liquid diet) although when given alone ethanol produced small changes in the same direction as those produced by stress. It is suggested that, in its effects on cortical alpha-adrenoceptors, chronic ethanol administration attenuates the effects of severe stress though itself perhaps acting as a mild stressor when given as part of a liquid diet regimen.

Animals↗