Biomedical subjects

K E Williams

Publications and source records attributed to K E Williams.

At least 19 recordsLinked to original sources

PubMed2006

Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid.

The preclinical pharmacology of the alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline, a novel smoking cessation agent is described. Varenicline binds with subnanomolar affinity only to alpha4beta2 nAChRs and in vitro functional patch clamp studies in HEK cells expressing nAChRs show that varenicline is a partial agonist with 45% of nicotine's maximal efficacy at alpha4beta2 nAChRs. In neurochemical models varenicline has significantly lower (40-60%) efficacy than nicotine in stimulating [(3)H]-dopamine release from rat brain slices in vitro and in increasing dopamine release from rat nucleus accumbens in vivo, while it is more potent than nicotine. In addition, when combined with nicotine, varenicline effectively attenuates the nicotine-induced dopamine release to the level of the effect of varenicline alone, consistent with partial agonism. Finally, varenicline reduces nicotine self-administration in rats and supports lower self-administration break points than nicotine. These data suggest that varenicline can reproduce to some extent the subjective effects of smoking by partially activating alpha4beta2 nAChRs, while preventing full activation of these receptors by nicotine. Based on these findings, varenicline was advanced into clinical development and recently shown to be an effective and safe aid for smoking cessation treatment.

Animals↗

PubMed2006

Multiple vaccine and pyridostigmine interactions: effects on EEG and sleep in the common marmoset.

Following active service during the 1990/1991 Gulf conflict, a number of UK and US veterans presented with a diverse range of symptoms, collectively known as Gulf Veterans' Illnesses (GVI). The administration of vaccines and/or the pretreatment against possible nerve agent poisoning, pyridostigmine bromide (PB), given to Armed Forces personnel during the Gulf conflict has been implicated as a possible factor in the aetiology of these illnesses. The possibility that long-term health effects may result from the administration of these vaccines (anthrax, pertussis, plague, yellow fever, polio, typhoid, tetanus, hepatitis B, meningococcal meningitis and cholera) and/or PB, have been investigated using a non-human primate model, the common marmoset. This paper reports the results from two aspects of the study, brain electrical activity (EEG, collected during performance of a touchscreen mediated discrimination task) and sleep. There were no marked long-term changes in EEG or sleep patterns that could be attributed to vaccines and/or PB administration. The changes that were detected were predominantly time related and independent of treatment. Where statistical differences were detected between treatments, the magnitudes of the difference were relatively minor and therefore not regarded as having long term biological significance.

Animals↗

PubMed2005

A novel method for activity monitoring in small non-human primates.

Patterns of spontaneous activity are valuable reflections of well-being in animals and humans and, because of this, investigations have frequently incorporated some form of activity monitoring into their studies. It is widely believed that activity monitoring, alongside assessments of general behaviour, should be included in initial CNS safety pharmacology screening. As the number of marmoset studies having actimetry as their focus, or as an adjunct, is increasing, we wished to evaluate an alternative approach to those commonly used. The method is based on miniaturized accelerometer technologies, currently used for human activity monitoring.Actiwatch-Minis were used to monitor the activity of two groups of differently housed marmosets for 14 consecutive days. Group A consisted of four mixed-sex pairs of animals and group B comprised eight group-housed males. Activity profiles were generated for weekday and weekend periods. The devices captured quantifiable data which showed differences in total activity between the two differently housed groups and revealed intragroup variations in the temporal spread of activity between weekdays and weekends. The Actiwatch-Mini has been shown to generate retrospective, data-logged activity counts recorded from multiple animals in a single arena by means of non-invasive monitoring.

Activity Cycles↗

PubMed2004

Specificity and functional impact of post-exercise depression of cortically evoked motor potentials in man.

Magnetic stimulation of the motor cortex with electromyographic recordings from exercising muscles has shown corticospinal excitability to be depressed following exercise. We now investigate whether this depression spreads to non-exercising muscles and its influence on performance. Healthy volunteers made unilateral biceps curls to exhaustion and, in another later session, for 25% of the time to exhaustion. Bilateral motor-evoked potentials (MEPs) in biceps brachii and first dorsal interosseus muscles were measured at 2-min intervals before and after exercise. In another experiment, subjects performed exhaustive curls and, in addition to MEP areas, force production in biceps, hand-grip force, simple reaction times and movement times were measured bilaterally. MEPs were depressed after exhaustive exercise in the exercising biceps for over 60 min; depression was also observed 10-15 min after exercise in the non-exercising biceps but not in the first dorsal interosseus of either hand. The shorter exercise period produced depression of MEPs only in the exercising muscle. After exhaustive exercise maximum voluntary contraction fell in the exercising biceps and this correlated with MEP areas. No reduction in force was seen in the non-exercising biceps but hand-grip force fell slightly in both arms. There was no change in reaction times or movement times. Depression of MEPs can occur in non-exercising homonymous muscles but not in heteronymous muscles and only when exercise levels are high. There was no measurable functional deficit in the non-exercising limb, so we conclude that the reduced corticospinal excitability observed in this limb has little or no consequence on the performance parameters measured.

Adaptation, Physiological↗

PubMed2001

The eukaryotic response regulator Skn7p regulates calcineurin signaling through stabilization of Crz1p.

To survive ionic, pH and pheromone stress, the yeast Saccharomyces cerevisiae activates signaling through the Ca2+-activated phosphatase calcineurin to the transcription factor Crz1p/Tcn1p. We show that the overexpression of SKN7, a response-regulator transcription factor, activates transcription from a calcineurin/Crz1p-dependent response element (CDRE). Ca2+-induced, calcineurin/Crz1p-dependent activation of several genes is reduced in skn7 mutants. Skn7p modulates CDRE-dependent transcription by affecting Crz1p protein levels. Specifically, the rate of Crz1p turnover is increased in skn7 mutants. Calcineurin, but not its phosphatase activity, is required for Skn7p-mediated Crz1p stabilization. Skn7p binds to both calcineurin and Crz1p in vitro, and we suggest that this interaction is required for Skn7p regulation of Crz1p. The DNA-binding and internal coiled-coil domains, but not the response- regulator phosphorylation of Skn7p, are necessary for Crz1p-dependent transcriptional activation and Crz1p stabilization by Skn7 in vivo. The DNA-binding domain of Skn7p is also required for binding to Crz1p and calcineurin in vitro. Thus, we propose that Skn7p protects Crz1p from degradation by binding to it and calcineurin through its DNA-binding domain.

Calcineurin↗

PubMed2001

Multimodality therapy for patients with clinical Stage I and II malignant mixed Müllerian tumors of the uterus.

BACKGROUND: The role of adjuvant therapy in the management of patients with malignant mixed Müllerian tumors (MMMT) of the uterus has not been defined. The outcome of planned multimodality therapy for patients with apparent early stage disease was assessed. METHODS: A pilot study was performed on 38 patients with clinical Stage I or II MMMTs of the uterus who were offered treatment according to a standard protocol. The protocol consisted of removal of the uterus, fallopian tubes, and ovaries and surgical staging followed by tailored radiation therapy and chemotherapy, consisting of cisplatin and epirubicin. RESULTS: The overall survival was 74% (28 of 38 patients), with a mean duration of follow-up for survivors of 55 months (range, 17-121 months). The mean time to death from disease was 26 months (range, 7-87 months). The survival rate for those patients who completed treatment according to the multimodality protocol was 95% (20 of 21 patients), with a disease free survival rate of 90% (19 of 21 patients). The overall survival of patients who did not receive the recommended treatment protocol for various reasons was 47% (8 of 17 patients). An analysis of survival curves demonstrated that there was a significant survival advantage for those patients who completed the treatment according to the multimodality protocol (P = 0.01). CONCLUSIONS: In this pilot study, patients with clinical Stage I or II MMMTs who underwent surgical staging and aggressive adjuvant radiation and chemotherapy had an excellent survival rate. The results justify a randomized prospective study of this approach.

Adult↗

PubMed1999

Orally administered dextran sulfate is absorbed in HIV-positive individuals.

Preliminary in vivo studies suggested that oral dextran sulfate was poorly absorbed, but investigations were limited by inadequate methods for measuring the drug in the body. To determine absorption in HIV-positive subjects, hydrogenated dextran sulfate, average molecular weight 8000 (Usherdex 8), was orally administered in a short-term (single dose, 4 g/day for 5 days, 7 subjects) and in a long-term study (1 g, 4 times per day for 29 to 335 days, 8 subjects), which was a continuation of the short-term study with the inclusion of an additional subject. When an agarose gel electrophoresis technique with toluidine blue staining was used, the drug was recovered from plasma (67%, peak 2.2 microg/mL) and circulating peripheral blood lymphocyte (PBL) samples (50%, peak 333 microg/L blood) obtained at 5 and 15 minutes and 1, 3, 6, and 24 hours after the first day's dose and from plasma (56%) and PBL samples (38%) obtained 5 minutes after administration on 4 subsequent days in the short-term study. In the long-term study, the drug was found in plasma (67%, peak 2.4 microg/mL) and PBL samples (25%, peak 126 microg/L blood) obtained at monthly visits within 4 hours of the last dose. The drug was found in all urine samples from all subjects in both studies (short-term study, 24-hour samples up to 4 days after the final dose; long-term study, monthly samples within 4 hours of the last dose). In the long-term study, bone marrow preparations from 3 subjects showed metachromatic inclusions present in reticular cells when the cells were stained with toluidine blue, indicating the presence of sulfated polyanions. A significant rise in activated partial thromboplastin time and a drop in platelet count (P < .025) were demonstrated, with thrombocytopenia developing in 3 patients. Mild-to-moderate gastrointestinal disturbances were experienced by 6 subjects in the short-term study and by all subjects in the long-term study. One subject experienced mild central nervous system symptoms in the short-term study. These results indicate that dextran sulfate is absorbed after oral administration; therefore, further studies on its efficacy, particularly in the early stages of the disease, along with additional observations on its toxicity, are warranted.

Absorption↗

PubMed1999

Activation of the Saccharomyces cerevisiae filamentation/invasion pathway by osmotic stress in high-osmolarity glycogen pathway mutants.

Mitogen-activated protein kinase (MAPK) cascades are frequently used signal transduction mechanisms in eukaryotes. Of the five MAPK cascades in Saccharomyces cerevisiae, the high-osmolarity glycerol response (HOG) pathway functions to sense and respond to hypertonic stress. We utilized a partial loss-of-function mutant in the HOG pathway, pbs2-3, in a high-copy suppressor screen to identify proteins that modulate growth on high-osmolarity media. Three high-copy suppressors of pbs2-3 osmosensitivity were identified: MSG5, CAK1, and TRX1. Msg5p is a dual-specificity phosphatase that was previously demonstrated to dephosphorylate MAPKs in yeast. Deletions of the putative MAPK targets of Msg5p revealed that kss1delta could suppress the osmosensitivity of pbs2-3. Kss1p is phosphorylated in response to hyperosmotic shock in a pbs2-3 strain, but not in a wild-type strain nor in a pbs2-3 strain overexpressing MSG5. Both TEC1 and FRE::lacZ expressions are activated in strains lacking a functional HOG pathway during osmotic stress in a filamentation/invasion-pathway-dependent manner. Additionally, the cellular projections formed by a pbs2-3 mutant on high osmolarity are absent in strains lacking KSS1 or STE7. These data suggest that the loss of filamentation/invasion pathway repression contributes to the HOG mutant phenotype.

Cloning, Molecular↗

PubMed1998

p53 protein overexpression: a strong prognostic factor in uterine papillary serous carcinoma.

Uterine papillary serous carcinoma (UPSC) is an uncommon but aggressive type of endometrial cancer associated with rapid progression of disease and poor prognosis. We investigated 23 cases of UPSC. p53 expression was studied in archival paraffin-embedded tissue by immunohistochemistry. Eleven tumors (47.8%) showed p53 overexpression whereas 12 tumors (52.2%) were p53 negative. One of 8 stage I/II (12.5%) and 10/15 stage III/IV (66.6%) tumors revealed p53 staining (P = 0.027). The median overall survival was 43.3 months. Patients with advanced-stage (III, IV) disease had a 5-year overall survival probability (5-year OS%) of 24% compared to 100% in those in stages I and II (log-rank, P = 0.018). Myometrial invasion, lymphatic space invasion, or lymph node involvement did not correlate with the 5-year OS of these patients. Patients whose tumors overexpressed p53 had a significantly shorter survival than those whose tumors did not (P = 0.033). This study confirms the influence of p53 overexpression on survival in UPSC patients.

Aged↗

PubMed1998

Influence of postoperative treatment on survival in patients with uterine papillary serous carcinoma.

BACKGROUND: Uterine papillary serous carcinoma (UPSC) is an uncommon, aggressive type of endometrial cancer associated with an advanced stage at initial presentation, rapid progression of disease, and poor prognosis. METHODS: Twenty-three patients with UPSC were included in this study. History, treatment, follow-up, and 5-year overall survival probability (5-yr OS%) were evaluated. RESULTS: All women underwent total hysterectomy and bilateral salpingo-oophorectomy. Positive lymph nodes were found in 10 of 17 patients who underwent pelvic lymphadenectomy. Eight patients had FIGO Stage I/II, whereas 15 patients showed Stage III or IV tumors. After surgery 5 women underwent radiotherapy, 5 chemotherapy, and 8 both radiotherapy and chemotherapy. Chemotherapy consisted of cisplatin/carboplatin plus cyclophosphamide. Adjuvant irradiation consisted of vault and external beam irradiation. The median duration of follow-up was 39.4 months (25th and 75th percentiles; 26. 1, 68.1). The median overall survival was 43.3 months (12.9, 75th percentile not reached). Three of 10 patients who received only chemotherapy or radiotherapy are alive, whereas 7/8 patients who received a combination of both are alive with no evidence of disease at the time of reporting. The 5-yr OS% was 80% in those who received radio- and chemotherapy and only 30% in those who were treated with radiotherapy alone (log rank = 0.05). CONCLUSION: These results stress the need to study and evaluate the usefulness of combined chemo- and radiation therapy in patients with uterine serous papillary cancer.

Aged↗

PubMed1998

Behavioral treatment of obsessive-compulsive disorder in African Americans: clinical issues.

African Americans with obessive-compulsive disorder are underrepresented in behavioral treatment outcome studies. This paper consists of a clinical discussion of issues arising during the treatment with exposure plus response prevention of two African-American women with obessive-compulsive disorder. Clinical issues, such as excessive shame, insanity fears, and a sense of uniqueness, complicated the treatment process. However, both clients made significant improvement as assessed by behavioral testing, target ratings and the Yale-Brown Obsessive-Compulsive Scale.

Adult↗

PubMed1998

Use of texture fading in the treatment of food selectivity.

Children with feeding disorders often display severe food selectivity. For many of these children, consuming highly textured foods may be aversive or potentially dangerous because of frequent gagging. The purpose of this study was to demonstrate the efficacy of texture fading in the treatment of food selectivity displayed by 4 children. Treatment involved the gradual addition of higher textures based on the results of periodic probes. In addition, food acceptance and swallowing were reinforced, while food refusal and food expulsion were placed on extinction. Results showed that all participants successfully advanced to consumption of age-appropriate texture and volume. The results suggest that texture fading with intermittent probes at higher textures may be an effective method for the treatment of food selectivity by texture.

Barium↗

PubMed1997

Are emotions frightening? An extension of the fear of fear construct.

Proposed in this paper is an expansion of the concept of fear of fear to include fear of other emotions (anger, depression, and positive emotions). In Study 1, initial evidence of the reliability and validity of a questionnaire designed to measure this construct, the Affective Control Scale, is provided. In Study 2, an analogue experiment of susceptibility to panic disorder was conducted. The ability of fear of anger, depression, and positive emotions to predict fear of laboratory-induced bodily sensations in a population with no history of panic attacks was demonstrated.

Adult↗

PubMed1997

Silver-resistant mutants of Escherichia coli display active efflux of Ag+ and are deficient in porins.

Silver-resistant mutants were selected by stepwise exposure of silver-susceptible clinical strains of Escherichia coli, two of which did not contain any plasmids, to either silver nitrate or silver sulfadiazine. These mutants showed complete cross-resistance to both compounds. They showed low-level cross-resistance to cephalosporins and HgCl2 but not to other heavy metals. The Ag-resistant mutants had decreased outer membrane (OM) permeability to cephalosporins, and all five resistant mutants tested were deficient in major porins, either OmpF or OmpF plus OmpC. However, the well-studied OmpF- and/or OmpC-deficient mutants of laboratory strains K-12 and B/r were not resistant to either silver compound. Resistant strains accumulated up to fourfold less (110m)AgNO3 than the parental strains. The treatment of cells with carbonyl cyanide m-chlorophenylhydrazone increased Ag accumulation in Ag-susceptible and -resistant strains, suggesting that even the wild-type Ag-susceptible strains had an endogenous Ag efflux activity, which occurred at higher levels in Ag-resistant mutants. The addition of glucose as an energy source to starved cells activated the efflux of Ag. The results suggest that active efflux, presumably coded by a chromosomal gene(s), may play a major role in silver resistance, which is likely to be enhanced synergistically by decreases in OM permeability.

Adenosine Triphosphate↗

PubMed1997

Prevalence of dementia and depression among elderly people in black and ethnic minorities.

BACKGROUND: This study was designed to identify all elderly people of ethnic minorities living in a defined geographical area in inner-city Liverpool and to identify psychiatric morbidity and barriers to use of services. This paper reports the prevalence of dementia and depression. METHOD: A survey of the community was carried out using the Geriatric Mental State Examination, AGECAT and ethnically matched interviewers. The sampling frame consisted of Family Health Services Authority lists as a basis, with additional information from community lists, 'snow-balling' and a door-to-door survey. RESULTS: 418 people were interviewed, with a high percentage (55%) of young elderly (65-74) men. The prevalence of dementia ranged from 2 to 9% and of depression from 5 to 19%, and there were no significant differences in levels between English-speaking ethnic groups and the indigenous population. Higher levels of dementia were found among non-English-speaking groups. CONCLUSIONS: A complete enumeration of the elderly in ethnic minority groups is best achieved by using several different methods. Diagnosis of dementia may be misleading among those who do not speak the dominant language.

Africa↗

PubMed1997

Use of extinction and reinforcement to increase food consumption and reduce expulsion.

Extinction and reinforcement contingencies were used to treat 2 children with feeding disorders. Positive reinforcement and avoidance extinction effectively increased food acceptance but also increased food expulsion. Reduced expulsion and increased swallowing were achieved by repeated presentation of expelled food, a second extinction component

Behavior Therapy↗

PubMed1997

Obsessive-compulsive disorder in pregnancy, the puerperium, and the premenstruum.

BACKGROUND: Recent reports suggest that pregnancy and the puerperium may precipitate or exacerbate obsessive-compulsive disorder (OCD). The influence of this illness on other reproductive events, such as the premenstruum, is unknown. We examined retrospectively the relationships of pregnancy, the puerperium, and premenstruum to the course of OCD in 57 women. METHOD: Women outpatients with OCD meeting DSM-III-R criteria completed a standardized telephone interview administered by a psychiatric resident. They were asked retrospectively about the clinical course of their illness premenstrually and during and after pregnancy. RESULTS: Of 72 women eligible for the study, 79% (N = 57) completed the interview. Premenstrual worsening of OCD was described by 24 (42%) of the 57 women, and 12 (21%) described premenstrual dysphoria. Of the 57 women, 38 (67%) had been pregnant at least once; 31 (54%) had delivered at least one child. Pregnancy was associated with the onset of OCD in only 5 (13%) of the 38 women. Of the 29 women with preexisting OCD who became pregnant, 20 (69%) described no change in symptoms during pregnancy, 5 (17%) described worsening, and 4 (14%) described improvement. Postpartum exacerbation of OCD symptoms was reported by 7 (29%) of the 24 women with preexisting OCD who completed full-term pregnancies. Nine (37%) of the 24 women with both preexisting OCD and completed pregnancies also reported postpartum depression. CONCLUSION: The premenstrual and postpartum exacerbation of OCD symptoms in some women suggests that the course of this disorder may, in some cases, be influenced by changes in gonadal hormones. Our finding that women with OCD may be at increased risk for postpartum depression underscores the importance of careful postpartum evaluation of women with OCD to prevent maternal and infant morbidity.

Adult↗

PubMed1996

Concordance between p53 protein overexpression and gene mutation in a large series of common human carcinomas.

Immunohistochemical (IHC) detection of p53 protein was compared with the presence of p53 gene mutation in many colorectal (n = 100), breast (n = 92), endometrial (n = 122), and gastric (n = 116) carcinomas. Two commercially available antibodies, DO7 and CM1, were used for IHC analysis of paraffin-embedded tissue sections. Screening for gene mutations in frozen and paraffin-embedded tumor samples was carried out using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP). The frequency of nuclear staining with DO7 or CM1 for each tumor type, respectively, was colorectal (36%, 23%); breast (15%, 19%); endometrial (21%, 33%); and gastric (23%,-). Overall correlation between the two antibodies for nuclear staining was 90% for the 314 tumors analyzed. Cytoplasmic staining was observed with DO7 in 7% of breast and 5% of gastric carcinomas and with CM1 in 17% of breast and 54% of endometrial carcinomas. p53 gene mutation was found in 39% of colorectal, 28% of breast, 13% of endometrial, and 25% of gastric cancers. The concordance between p53 nuclear overexpression and gene mutation (both positive or both negative) was 68% for colorectal, 79% for breast, 76% for endometrial, and 73% for gastric carcinomas. This study provides further evidence that IHC detection of p53 protein accumulation does not always indicate the presence of a gene mutation and vice versa. Discordant results were observed in approximately 20% to 30% of the tumors studied, highlighting the need for careful characterization of both p53 gene and protein alterations when assessing the relationship between p53 status and tumor behavior.

Breast Neoplasms↗