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Biomedical subjects

S S Smith

Publications and source records attributed to S S Smith.

At least 19 recordsLinked to original sources
PubMed2004

A preliminary investigation of the effectiveness of a sleep apnea education program.

OBJECTIVES: This study aimed to evaluate a standardised sleep apnea patient education program and develop a study design that may be used to evaluate other such education programs. METHOD: Thirty-four adults diagnosed with obstructive sleep apnea hypopnea syndrome (OSAHS) underwent a standard sleep apnea education program and completed measures of knowledge of and beliefs about sleep apnea before, after, and 3 months following education. Two outcome measures were used: the Apnea Knowledge Test (AKT) and the Apnea Beliefs Scale (ABS). RESULTS: AKT results showed significant knowledge gains posteducation, which were maintained at follow-up. Patients also reported more positive beliefs about their ability to change their behaviour and comply with continuous positive airway pressure (CPAP) treatment recommendations after education. DISCUSSION: Findings from this preliminary investigation suggest that the education program used in this study may improve patients' knowledge of CPAP and promote functional beliefs about OSAHS treatment. This program clearly warrants further research, and ultimately such programs may prove important in improving CPAP compliance.

Attitude to Health↗
PubMed2003

Anxiogenic effects of neurosteroid exposure: sex differences and altered GABAA receptor pharmacology in adult rats.

Acute exposure to progesterone or its neurosteroid derivative allopregnanolone (3alpha,5alpha-THP) is anxiolytic, consistent with the GABA modulatory effects of 3alpha,5alpha-THP at the GABA(A) receptor. However, continuous exposure to progesterone increases anxiety in association with increased expression of the benzodiazepine-insensitive GABA(A) receptor alpha4 subunit. Furthermore, negative mood symptoms and altered GABA(A) receptor pharmacology in patients with premenstrual dysphoric disorder occur in the early luteal phase in association with peak circulating levels of progesterone and 3alpha,5alpha-THP. Because sex differences have been reported in steroid-regulated anxiety responses, the present study investigated the role of sex and development in the regulation of anxiety after short-term exposure to 3alpha,5alpha-THP. To this end, we compared the effects of hormone administration in adult male, adult female, and juvenile female rats. Increased anxiety in the elevated plus maze was evident in all groups after 48-h exposure to either 3alpha,5alpha-THP or progesterone. At this time point, alterations in the anxiolytic profile of benzodiazepine agonists and antagonists were also observed in both adult males and females in the elevated plus maze. However, sex differences in the acoustic startle response were observed after short-term hormone treatment such that only female rats displayed an increased response indicative of higher anxiety levels. These results suggest that although neurosteroid exposure may influence both the pharmacological properties of the GABA(A) receptor and the manifestation of anxiety in both sexes, the effects of neurosteroids may be modulated in a sex- and task-specific manner.

Acoustic Stimulation↗
PubMed2003

Progesterone withdrawal increases the anxiolytic actions of gaboxadol: role of alpha4betadelta GABA(A) receptors.

Hippocampal alpha4betadelta GABA(A) receptors (GABA(A)-R) are increased following progesterone withdrawal (PWD) in a rodent model of premenstrual anxiety. This alpha4betadelta receptor isoform uniquely responds to the GABA agonist gaboxadol (THIP) with a maximum current greater than that gated by GABA, and is potentiated more by pentobarbital than are other GABA(A)-R. We therefore investigated the anxiolytic effects of these drugs using the elevated plus maze. Gaboxadol (1.25 mg/kg) was markedly more anxiolytic in animals undergoing PWD than in controls. Pentobarbital (10 mg/kg) also produced a greater anxiolytic effect during PWD. These results suggest that the pharmacological properties of alpha4betadelta GABA(A)-R following PWD are evident behaviorally. Alterations in the alpha4betadelta GABA(A)-R population may have implications for the etiology and treatment of premenstrual syndrome.

Animals↗
PubMed2003

Sex differences in anxiety, sensorimotor gating and expression of the alpha4 subunit of the GABAA receptor in the amygdala after progesterone withdrawal.

In a progesterone withdrawal (PWD) model of premenstrual anxiety, we have previously demonstrated that increased hippocampal expression of the alpha4 subunit of the GABAA receptor (GABAA-R) is closely associated with higher anxiety levels in the elevated plus maze. However, several studies indicate that sex differences in regulation of the GABAA-R in specific brain regions may be an important factor in the observed gender differences in mood disorders. Thus, we investigated possible sex differences in GABAA-R subunit expression and anxiety during PWD. To this end, we utilized the acoustic startle response (ASR) to assess anxiety levels in male and female rats undergoing PWD as the ASR is also applicable to the assessment of human anxiety responses. We also investigated GABAA-R alpha4 subunit expression in the amygdala, as the amygdala directly regulates the primary startle circuit. Female rats exhibited a greater ASR during PWD than controls, indicating higher levels of anxiety and arousal. In contrast, male rats undergoing PWD did not demonstrate an increased ASR. The sex differences in the ASR were paralleled by sex differences in the expression of the GABAA-R alpha4 subunit in the amygdala such that alpha4 subunit expression was up-regulated in females during PWD whereas alpha4 levels in males undergoing PWD were not altered relative to controls. These findings might have implications regarding gender differences in human mood disorders and the aetiology of premenstrual anxiety.

Acoustic Stimulation↗
PubMed2003

Psychiatric treatment in prison: a missed opportunity?

National Health Service Executive guidelines require psychiatric services to maintain links with prisoners previously subject to the Care Programme Approach (CPA) and to participate in discharge planning. We are unaware of previous studies assessing the involvement of general psychiatric services with patients in prison or prisoners' perceptions of their needs. Consecutive referrals to a prison psychiatric liaison service over a three-month period were screened for previous psychiatric contact. Half of those interviewed reported previous psychiatric contact. Two-thirds were in contact with services at the time of detention. One-third believed services knew of their imprisonment. Ninety-three per cent believed they would require psychiatric support after release. Few patients received input from general psychiatric services during imprisonment despite a high level of perceived need. Improved liaison would help facilitate both care in prison and discharge planning in the spirit of CPA and the government directive.

Criminal Psychology↗
PubMed2002

Progesterone withdrawal increases the alpha4 subunit of the GABA(A) receptor in male rats in association with anxiety and altered pharmacology - a comparison with female rats.

Withdrawal from the neurosteroid 3alpha,5alpha-allopregnanolone after chronic administration of progesterone increases anxiety in female rats and up-regulates the alpha4 subunit of the GABA(A) receptor (GABA(A)-R) in the hippocampus. We investigated if these phenomena would also occur in male rats. Progesterone withdrawal (PWD) induced higher alpha4 subunit expression in the hippocampus of both male and female rats, in association with increased anxiety (assessed in the elevated plus maze) comparable to effects previously reported. Because alpha4-containing GABA(A)-R are insensitive to the benzodiazepine (BDZ) lorazepam (LZM), and are positively modulated by flumazenil (FLU, a BDZ antagonist), we therefore tested the effects of these compounds following PWD. Using whole-cell patch clamp techniques, LZM-potentiation of GABA ((EC20))-gated current was markedly reduced in CA1 pyramidal cells of male rats undergoing PWD compared to controls, whereas FLU had no effect on GABA-gated current in control animals but increased it in PWD animals. Behaviorally, both male and female rats were significantly less sensitive to the anxiolytic effects of LZM. In contrast, FLU demonstrated significant anxiolytic effects following PWD. These data suggest that neurosteroid regulation of the alpha4 GABA(A)-R subunit may be a relevant mechanism underlying anxiety disorders, and that this phenomenon is not sex-specific.

Animals↗
PubMed2001

Short-term exposure to a neuroactive steroid increases alpha4 GABA(A) receptor subunit levels in association with increased anxiety in the female rat.

Previous work from this laboratory has demonstrated that withdrawal from the neuroactive steroid 3alpha,5alpha-THP (3alpha-hydroxy-5alpha-pregnan-20-one) after 3-week exposure to its parent compound, progesterone (P), increases anxiety and produces benzodiazepine (BDZ) insensitivity in female rats. These events were linked to upregulation of the alpha4 subunit of the GABA(A) receptor (GABAR) in the hippocampus [Brain Res. 507 (1998) 91; Nature 392 (1998) 926; J. Neurosci. 18 (1998) 5275]. The present study investigates the role of shorter term hormone treatment on alpha4 subunit levels as well as relevant behavioral and pharmacological end-points related to GABAR function. After 2-3 days of P exposure, two- to threefold increases in alpha4 protein levels were observed, which declined to control values after 5-6 days of hormone exposure. This effect was due to the GABA-modulatory metabolite of P, 3alpha,5alpha-THP. alpha4 upregulation was inversely correlated with BDZ potentiation of GABA-gated current, assessed using whole cell patch clamp techniques on acutely isolated hippocampal pyramidal cells. A near total BDZ insensitivity was observed by 2-3 days of hormone exposure in association with the maximal increase in alpha4 levels. Up-regulation of the alpha4 GABAR subunit was also reflected by an increase in anxiety in the elevated plus maze. A significant decrease in open arm entries was observed after 72-h exposure to P, an effect which recovered by 6 days of P treatment. As demonstrated in vitro, alpha4 upregulation also resulted in a relative insensitivity to the anxiolytic actions of BDZ. These results suggest that short-term exposure to 3alpha,5alpha-THP produces changes in GABAR subunit composition similar to those that occur after chronic exposure and withdrawal from the steroid.

Animals↗
PubMed2001

Age- and concentration-dependent neuroprotection and toxicity by TNF in cortical neurons from beta-amyloid.

The induction of an inflammatory response and release of cytokines such as TNF may be involved in the age-related etiology of Alzheimer disease (AD). In the brain, microglia have been shown to produce a wide variety of immune mediators, including the pro-inflammatory cytokine tumor necrosis factor (TNF). We hypothesize that with age there is increased ability of microglia to produce TNF or that age decreases the neuroprotective effect of TNF against beta-amyloid (Abeta) toxicity in neurons. We investigated the effects of Abeta(1-40) on TNF secretion from forebrain cultures of microglia from embryonic, middle-age (9-month) and old (36-month) rats. Over the first 12 hr of exposure to 10 microM Abeta (1-40), microglia from embryonic and old rats increase TNF secretion, although microglia from middle-age rats did not produce detectable levels of TNF. When low concentrations of TNF are added to neurons together with Abeta (1-40) in the absence of exogenous antioxidants, neuroprotection for old neurons is significantly less than neuroprotection for middle-age neurons. In neurons from old rats, high levels of TNF together with Abeta are more toxic than in neurons from middle-age or embryonic rats. These results are discussed in relation to neuroprotection and toxicity of the age-related pathology of AD.

Age Factors↗
PubMed2001

Pre-menstrual steroids.

A number of steroid hormones and their metabolites fluctuate in the circulation across the human menstrual cycle. In addition to their classic actions on the hypothalamo-pituitary-gonadal axis, many of these hormones act as 'neuroactive steroids' to alter the function of neurotransmitters, such as GABA, within central nervous system circuits. Clinically, these steroids are important because they have not only acute but also long-term effects, and 'withdrawal' properties. This review discusses the effects of steroids such as 3alpha-OH-5alpha-pregnan-20-one (3alpha,5alpha-THP or allopregnanolone) which alter GABA function in distinct ways dependent upon the time course of exposure, to either enhance or decrease inhibition in the brain. These effects are discussed in light of recent clinical findings which seek to further characterize the steroid milieu which underlies pre-menstrual dysphoria.

Animals↗
PubMed2001

Strike while the iron is hot: can stepped-care treatments resurrect relapsing smokers?

The efficacies of 2 group counseling step-up treatments for smoking cessation, cognitive-behavioral/skill training therapy (CBT) and motivational interviewing/supportive (MIS) therapy, were compared with brief intervention (BI) treatment in a sample of 677 smokers. Differential efficacy of the 2 step-up treatments was also tested in smokers at low and high risk for relapse (no smoking vs. any smoking during the first postquit week. respectively). All participants received 8 weeks of nicotine patch therapy. BI consisted of 3 brief individual cessation counseling sessions; CBT and MIS participants received BI treatment and 6 group counseling sessions. Neither CBT nor MIS treatment improved long-term abstinence rates relative to BI. Limited support was found for the hypothesis that high-risk smokers would benefit more from MIS than CBT. Other hypotheses were not supported.

Administration, Cutaneous↗
PubMed2001

CFTR: covalent and noncovalent modification suggests a role for fixed charges in anion conduction.

The goal of the experiments described here was to explore the possible role of fixed charges in determining the conduction properties of CFTR. We focused on transmembrane segment 6 (TM6) which contains four basic residues (R334, K335, R347, and R352) that would be predicted, on the basis of their positions in the primary structure, to span TM6 from near the extracellular (R334, K335) to near the intracellular (R347, R352) end. Cysteines substituted at positions 334 and 335 were readily accessible to thiol reagents, whereas those at positions 347 and 352 were either not accessible or lacked significant functional consequences when modified. The charge at positions 334 and 335 was an important determinant of CFTR channel function. Charge changes at position 334--brought about by covalent modification of engineered cysteine residues, pH titration of cysteine and histidine residues, and amino acid substitution--produced similar effects on macroscopic conductance and the shape of the I-V plot. The effect of charge changes at position 334 on conduction properties could be described by electrodiffusion or rate-theory models in which the charge on this residue lies in an external vestibule of the pore where it functions to increase the concentration of Cl adjacent to the rate-limiting portion of the conduction path. Covalent modification of R334C CFTR increased single-channel conductance determined in detached patches, but did not alter open probability. The results are consistent with the hypothesis that in wild-type CFTR, R334 occupies a position where its charge can influence the distribution of anions near the mouth of the pore.

Animals↗
PubMed2001

CFTR: covalent modification of cysteine-substituted channels expressed in Xenopus oocytes shows that activation is due to the opening of channels resident in the plasma membrane.

Some studies of CFTR imply that channel activation can be explained by an increase in open probability (P(o)), whereas others suggest that activation involves an increase in the number of CFTR channels (N) in the plasma membrane. Using two-electrode voltage clamp, we tested for changes in N associated with activation of CFTR in Xenopus oocytes using a cysteine-substituted construct (R334C CFTR) that can be modified by externally applied, impermeant thiol reagents like [2-(trimethylammonium)ethyl] methanethiosulfonate bromide (MTSET+). Covalent modification of R334C CFTR with MTSET+ doubled the conductance and changed the I-V relation from inward rectifying to linear and was completely reversed by 2-mercaptoethanol (2-ME). Thus, labeled and unlabeled channels could be differentiated by noting the percent decrease in conductance brought about by exposure to 2-ME. When oocytes were briefly (20 s) exposed to MTSET+ before CFTR activation, the subsequently activated conductance was characteristic of labeled R334C CFTR, indicating that the entire pool of CFTR channels activated by cAMP was accessible to MTSET+. The addition of unlabeled, newly synthesized channels to the plasma membrane could be monitored on-line during the time when the rate of addition was most rapid after cRNA injection. The addition of new channels could be detected as early as 5 h after cRNA injection, occurred with a half time of approximately 24-48 h, and was disrupted by exposing oocytes to Brefeldin A, whereas activation of R334C CFTR by cAMP occurred with a half time of tens of minutes, and did not appear to involve the addition of new channels to the plasma membrane. These findings demonstrate that in Xenopus oocytes, the major mechanism of CFTR activation by cAMP is by means of an increase in the open probability of CFTR channels.

Amino Acid Substitution↗
PubMed2001

Using brain MERMER testing to detect knowledge despite efforts to conceal.

This experiment examined the accuracy and reliability of the memory and encoding related multifaceted electroencephalographic response (MERMER) technique for detecting information related to events subjects have experienced, despite subjects' efforts to conceal that knowledge. Information obtained through interviews was used to develop stimulus sets consisting of words and phrases presented to subjects visually by computer. Sets were composed of three types of stimuli: life experience-related (Probes), stimuli the subject was asked to memorize and respond to (Targets), and irrelevant information (Irrelevants). Each set of stimuli was tested on two individuals: (1) one individual who had participated in the event in question--and thus had the relevant information stored in his/her brain, and (2) one who had not. Six subjects were tested. Electrical brain responses to the stimuli were recorded non-invasively from the scalp and analyzed. MERMERs, (memory and encoding related multifaceted electroencephalographic responses), of which the P300 is a sub-component, were used to determine whether the subject had the relevant information stored in his brain (information present) or not (information absent), thus indicating whether or not each subject had participated in the real-life event in question. Bootstrapping was used to analyze and compare the responses to the three types of stimuli. As predicted, MERMERs were elicited by Probe stimuli only in the subjects who had participated in the investigated event, by Target stimuli in all subjects, and in no case by Irrelevant stimuli. For each of the six subjects, brain MERMER testing correctly determined whether the subject had participated in and consequently knew about the event in question (information present) or had not participated (information absent). The statistical confidence for this determination was 99.9% in five cases and 90.0% in one case. The article concludes with a discussion of areas of future research and the potential for using this new technology as an investigative tool in criminal cases.

Adult↗
PubMed2000

Gilbert's conjecture: the search for DNA (cytosine-5) demethylases and the emergence of new functions for eukaryotic DNA (cytosine-5) methyltransferases.

In 1985 Walter Gilbert challenged members of the DNA methylation community assembled at a National Institutes of Health meeting organized by Giulio Cantoni and Ahron Razin with the following words: "The most exciting aspect about the methyl groups on DNA is the thought that they might provide a locally inherited change in a DNA structure. However, for that to be interesting, those changes have to be different in different cells. Furthermore, the alterations in methylation have to be freely imposable and have to be maintained. It is not yet clear that all these properties are true. So I don't think one will find that methylation ever is one of the primary, top-level controls on gene expression."In essence, Gilbert's conjecture, that DNA methylation is not one of the top-level controls on gene expression, assumes that evidence in favor of both of its testable propositions will not be obtained. Evidence for the first proposition, that alterations in methylation status associated with gene-expression states have to be maintained, was already available in 1985 and has been strengthened by a number of very recent experiments. However, the extensive effort to obtain evidence for the second proposition, that alterations in methylation status be freely imposable, has not been successful in its original intent. The effort has, on the other hand, resulted in the emergence of new functions for 5-methylcytosine and the cytosine methyltransferases in eukaryotic DNA repair, recombination and chromosome stability.

Alleles↗
PubMed2000

Oestrogen effects in olivo-cerebellar and hippocampal circuits.

17 beta-oestradiol (E2) is known to exert activating effects on CNS excitability, which are in part mediated by increases in glutamate responses, as we have shown in cerebellum. In addition, this steroid is known to facilitate rapid, rhythmic limb movement. Because the inferior olive is believed to be a timer of rapid movement, we have investigated effects of E2 on patterns of discharge recorded from dorsal accessory olive (DAO) using chronically implanted microwires. E2 increases the frequency of rhythmic olivary discharge as well as the number of synchronized neurons in association with facilitation of rhythmic limb and vibrissae movement. One possible mechanism for this effect is via an increase in gap junction proteins, as olivary cells are electrotonically coupled. Levels of connexin 32 (Cx32) and the dendritic lamellar body, both markers for gap junction-associated proteins, are increased threefold after 48 h E2 exposure (2 micrograms, i.p.), compared to control in both ventral medulla and hippocampal neurons. Gap junction conductance has also been shown to be decreased by gamma-aminobutyric acid (GABA)ergic input. For this reason, we tested effects of 48 h E2 treatment on GABAA receptor subunit proteins and GABAergic synaptic current. E2 increased levels of the alpha 4 subunit in hippocampus via an increase in the GABA-modulatory progesterone metabolite 3 alpha-OH-5 alpha-pregnan-20-one. This effect was correlated with a decrease in decay time of tetrodotoxin-resistant miniature inhibitory postsynaptic currents (mIPSCs) recorded from pyramidal cells in CA1 hippocampus, an effect which would tend to reduce total GABA inhibition. In sum, these effects of E2 are consistent with the concept that E2 exerts primarily activating effects on CNS excitability.

Animals↗
PubMed2000

Interarch tooth size relationships of 3 populations: "does Bolton's analysis apply?".

This study evaluates whether Bolton's interarch ratios extend across populations and genders. The data were derived from systematically collected preorthodontic casts of 180 patients, including 30 males and 30 females from each of 3 populations (black, Hispanic, and white). Forty-eight mesiodistal contact points were digitized on each model, and the lengths of the anterior, posterior, and overall arch segments were calculated. The results showed significant (P <.05) ethnic group differences in all 6 arch segment lengths and in all 3 interarch ratios. Whites displayed the lowest overall ratio (92.3%), followed by Hispanics (93.1%), and blacks (93.4%). The group differences were due primarily to the relationships between the posterior segments. The arch segments of males were significantly larger than females; the overall and posterior ratios were also significantly larger in males than in females. Multiple regression analyses showed that individual differences in the overall ratio were most closely associated with the size of the lower second premolar, followed by the upper lateral incisors, upper second premolars, and the lower central incisors. In combination, these 4 teeth explained approximately 50% of the variation in the overall ratio between subjects. We conclude that interarch tooth size relationships are population and gender specific. Bolton ratios apply to white females only; the ratios should not be indiscriminately applied to white males, blacks, or Hispanics.

Adolescent↗
PubMed2000

Blastocyst transfer: a useful tool for reduction of high-order multiple gestations in a human assisted reproduction program.

OBJECTIVE: We evaluated the efficacy of blastocyst transfer in decreasing the incidence of high-order multiple gestations after in vitro fertilization. STUDY DESIGN: We conducted a retrospective analysis of 218 patients who were undergoing in vitro fertilization and by our criteria of three 8-cell embryos on day 3 could receive either a day 3 transfer of cleaved embryos or a day 5 transfer of blastocysts. Ongoing pregnancy rates, implantation rates (determined by the total number of visualized gestational sacs), and multiple pregnancy rates were compared between the 2 groups. RESULTS: Respective day 3 and day 5 ongoing pregnancy rates (61% and 51%) and implantation rates (35% and 33%) were not significantly different. There were 9 triplet or higher gestations in the day 3 group and 0 in the day 5 group. CONCLUSION: Blastocyst transfer can be used to reduce the number of embryos transferred and the resultant incidence of high-order multiple pregnancies while maintaining high pregnancy rates.

Adult↗