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Biomedical subjects

J Milton

Publications and source records attributed to J Milton.

At least 19 recordsLinked to original sources
PubMed2006

Subcutaneous administration of ghrelin stimulates energy intake in healthy lean human volunteers.

BACKGROUND: The gastric hormone ghrelin appears a useful agent to stimulate food intake in people with anorexia of illness. The loss of ghrelin's acyl group renders it inactive, thus it has been thought that subcutaneous administration may be problematic. OBJECTIVE: To investigate whether human subjects are sensitive to the effects of ghrelin administered by single subcutaneous injection. STUDY DESIGN: Randomized, double-blind, placebo-controlled trial. SUBJECTS: Sixteen healthy lean volunteers (eight men and eight women). PROTOCOL: Fasted subjects received subcutaneous injections of ghrelin (3.6 nmol/kg) or saline. After 30 min, a buffet breakfast was served. RESULTS: Ghrelin injection increased energy intake by 27% (ghrelin 5076 +/- 691 kJ versus saline 4230+/-607 kJ, P = 0.04). Ghrelin appeared to enhance the perceived palatability of the food offered (palatability score: ghrelin 81.1 +/- 3.6 versus saline 70.0 +/- 4.4; P = 0.03). CONCLUSIONS: These results suggest that subcutaneous ghrelin is effective at stimulating energy intake and improving palatability and may be of direct use in the treatment of appetite loss.

Adult↗
PubMed2002

Medico-legal reports and gatekeeping: one year of referrals to a forensic service.

Forensic psychiatrists and the services they provide have been subject to recent scrutiny and high public profile. This study examined part of the work of a regional and district forensic service by looking at a one-year cohort of referrals, and the factors contributing to patient admission, including requests for medico-legal reports. The sample consisted of all referrals to the East Midlands Centre for Forensic Mental Health, Leicester from 1 January 1998 to 31 December 1998. Information on referrals was collected retrospectively using a proforma to collate data from referral letters and the reports prepared by assessing clinicians. Two hundred and eighty referrals relating to 260 individuals were received. The sample characteristics were broadly similar to those reported in previous studies. The finding that 70% of those assessed were referred for medico-legal reports by courts or solicitors, and the fact that only 20% of this group finally entered the forensic service, led us to consider whether this work was legitimate use of National Health Service time. We examined this group more closely, and found that referral for a medico-legal report could be considered as a screening test for entry into the forensic services and there are good arguments for this work continuing.

Cohort Studies↗
PubMed2001

Aggressive incidents in first-episode psychosis.

BACKGROUND: Recent research has reported increased risk of aggressive incidents by individuals with psychotic illness. AIMS: To examine acts of aggression in first-episode psychosis. METHOD: Subjects with a first-episode psychosis were ascertained from a defined catchment area (Nottingham, UK) and reassessed at 3 years (n=166) using clinical interview, informants, health care and forensic records. RESULTS: Of the subjects, 9.6% demonstrated at least one act of serious aggression (defined as weapon use, sexual assault or victim injury) during at least one psychotic episode and 23.5% demonstrated lesser acts of aggression (defined as all other acts of aggression). For all aggressive subjects (33.1%), unemployment (OR=3.6, 95% C11.6-8.0), comorbid substance misuse (OR=3.1, C1 1.1-8.8) and symptoms of overactivity at service contact (OR=6.9,C1 2.7-17.8) had independent effects on risk of aggression. CONCLUSIONS: We confirmed some previously reported demographic and clinical associations with aggression in first-episode psychosis but no relationship with specific psychotic symptoms or diagnostic groups was observed.

Adolescent↗
PubMed2001

Psychoanalysis and cognitive behaviour therapy--rival paradigms or common ground?

The author suggests that contemporary enthusiasm for cognitive-behavioural therapy reflects our longing for swift, rational help for psychological suffering. Competition for funding threatens the psychoanalytic presence in the public sector. The psychoanalytic and cognitive-behavioural models are contrasted, and the relative richness of the psychoanalytic paradigm outlined. The author suggests that a cognitive model is commonsensical, but less complex, with less potential explanatory and therapeutic power. She discusses how the analytic stance is always under pressure to 'collapse' into simpler modes, one of which resembles a cognitive one. This also occurs inevitably, she argues, when attempts are made to 'integrate' the two models. Cognitive and 'integrated' treatments nevertheless have the advantage that they are less intrusive and hence more acceptable to some patients. Selected empirical process and outcome research on cognitive and psychoanalytic therapies is discussed. Brief psychotherapies of either variety have a similar, modestly good outcome, and there is some evidence that this may be based more on 'dynamic' than 'cognitive' elements of treatment. Formal outcome studies of more typical psychoanalytic psychotherapy and of psychoanalysis itself begin to suggest that these long and complex treatments are effective in the more comprehensive ways predicted by the model.

Cognitive Behavioral Therapy↗
PubMed2001

Interaction between bacterial peptides, neutrophils and goblet cells: a possible mechanism for neutrophil recruitment and goblet cell depletion in colitis.

Goblet cell depletion occurs in various forms of colitis, but its mechanism is unknown. We have investigated two linked hypotheses: (i) that bacterial peptides, such as formyl-methionyl-leucyl-phenylalanine (fMLP), interact with epithelial cells inducing the release of chemokines, including interleukin-8 (IL-8), which in turn leads to the recruitment of neutrophils which release mucin secretagogues; (ii) that fMLP acts directly on epithelial cells to cause mucus secretion. Studies were performed to measure the effects of fMLP on the synthesis and secretion of IL-8 and mucus by the goblet cell differentiated colon cancer cell lines HT29-MTX (methotrexate-conditioned HT29 colonic adenocarcinoma cell line) and LS174T, and to assess the effects of neutrophil-derived secretagogues on goblet cell secretion in these cell lines. fMLP (0.1 microM) increased the secretion of IL-8 by 105% (P<0.0001) in HT29-MTX cells and by 401% (P<0.0001) in LS174T cells. fMLP also increased the synthesis and secretion of mucins by these cell lines, with maximal effects of 65% above control values for synthesis (P<0.01) and 73% for secretion (P<0.01). A dose-related increase (up to 67%; P<0.01) in mucin secretion was demonstrated in HT29-MTX cells in response to incubation with supernatant from activated neutrophils. This effect was largely (83%; P<0.02) inhibited by ICI 200,355, a specific inhibitor of neutrophil elastase. In conclusion, the bacterial peptide fMLP and neutrophil elastase are both potent mucus secretagogues for colon epithelial cells. fMLP also elicits release of the potent neutrophil chemoattractant IL-8 from colon epithelial cells. These findings support the hypothesis that the mucosal inflammation and mucus depletion seen in ulcerative colitis could result from interaction between bacterial peptides and the mucosa.

Bacterial Proteins↗
PubMed2001

Whatever it takes.

Explore the source record for details and available documents.

Case Management↗
PubMed2000

Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase.

BACKGROUND: Efavirenz is a second-generation non-nucleoside inhibitor of HIV-1 reverse transcriptase (RT) that has recently been approved for use against HIV-1 infection. Compared with first-generation drugs such as nevirapine, efavirenz shows greater resilience to drug resistance mutations within HIV-1 RT. In order to understand the basis for this resilience at the molecular level and to help the design of further-improved anti-AIDS drugs, we have determined crystal structures of efavirenz and nevirapine with wild-type RT and the clinically important K103N mutant. RESULTS: The relatively compact efavirenz molecule binds, as expected, within the non-nucleoside inhibitor binding pocket of RT. There are significant rearrangements of the drug binding site within the mutant RT compared with the wild-type enzyme. These changes, which lead to the repositioning of the inhibitor, are not seen in the interaction with the first-generation drug nevirapine. CONCLUSIONS: The repositioning of efavirenz within the drug binding pocket of the mutant RT, together with conformational rearrangements in the protein, could represent a general mechanism whereby certain second-generation non-nucleoside inhibitors are able to reduce the effect of drug-resistance mutations on binding potency.

Alkynes↗
PubMed2000

Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases. Structural and biochemical analyses.

Most non-nucleoside reverse transcriptase (RT) inhibitors are specific for HIV-1 RT and demonstrate minimal inhibition of HIV-2 RT. However, we report that members of the phenylethylthiazolylthiourea (PETT) series of non-nucleoside reverse transcriptase inhibitors showing high potency against HIV-1 RT have varying abilities to inhibit HIV-2 RT. Thus, PETT-1 inhibits HIV-1 RT with an IC(50) of 6 nM but shows only weak inhibition of HIV-2 RT, whereas PETT-2 retains similar potency against HIV-1 RT (IC(50) of 5 nM) and also inhibits HIV-2 RT (IC(50) of 2.2 microM). X-ray crystallographic structure determinations of PETT-1 and PETT-2 in complexes with HIV-1 RT reveal the compounds bind in an overall similar conformation albeit with some differences in their interactions with the protein. To investigate whether PETT-2 could be acting at a different site on HIV-2 RT (e.g. the dNTP or template primer binding site), we compared modes of inhibition for PETT-2 against HIV-1 and HIV-2 RT. PETT-2 was a noncompetitive inhibitor with respect to the dGTP substrate for both HIV-1 and HIV-2 RTs. PETT-2 was also a noncompetitive inhibitor with respect to a poly(rC).(dG) template primer for HIV-2 RT. These results are consistent with PETT-2 binding in corresponding pockets in both HIV-1 and HIV-2 RT with amino acid sequence differences in HIV-2 RT affecting the binding of PETT-2 compared with PETT-1.

Binding, Competitive↗
PubMed2000

Identification of genes regulated by UV/salicylic acid.

PURPOSE: Previous work from the authors' group and others has demonstrated that some of the effects of UV irradiation on gene expression are modulated in response to the addition of salicylic acid to irradiated cells. The presumed effector molecule responsible for this modulation is NF-kappaB. In the experiments described here, differential-display RT-PCR was used to identify those cDNAs that are differentially modulated by UV radiation with and without the addition of salicylic acid. MATERIALS AND METHODS: Differential-display RT-PCR was used to identify differentially expressed genes. RESULTS: Eight such cDNAs are presented: lactate dehydrogenase (LDH-beta), nuclear encoded mitochondrial NADH ubiquinone reductase 24 kDa (NDUFV2), elongation initiation factor 4B (eIF4B), nuclear dots protein SP100, nuclear encoded mitochondrial ATPase inhibitor (IF1), a cDNA similar to a subunit of yeast CCAAT transcription factor HAP5, and two expressed sequence tags (AA187906 and AA513156). CONCLUSIONS: Sequences of four of these genes contained NF-kappaB DNA binding sites of the type that may attract transrepressor p55/p55 NF-kappaB homodimers. Down-regulation of these genes upon UV irradiation may contribute to increased cell survival via suppression of p53 independent apoptosis.

Adenosine Triphosphatases↗
PubMed2000

Multistability in recurrent neural loops arising from delay.

The dynamics of a recurrent inhibitory neural loop composed of a periodically spiking Aplysia motoneuron reciprocally connected to a computer are investigated as a function of the time delay, tau, for propagation around the loop. It is shown that for certain choices of tau, multiple qualitatively different neural spike trains co-exist. A mathematical model is constructed for the dynamics of this pulsed-coupled recurrent loop in which all parameters are readily measured experimentally: the phase resetting curve of the neuron for a given simulated postsynaptic current and tau. For choices of the parameters for which multiple spiking patterns co-exist in the experimental paradigm, the model exhibits multistability. Numerical simulations suggest that qualitatively similar results will occur if the motoneuron is replaced by several other types of neurons and that once tau becomes sufficiently long, multistability will be the dominant form of dynamical behavior. These observations suggest that great care must be taken in determining the etiology of qualitative changes in neural spiking patterns, particularly when propagation times around polysynaptic loops are long.

Action Potentials↗
PubMed2000

Psychoanalysis and the moral high ground.

The author reflects on the power and ubiquity of moral issues in the human psyche and thus inevitably in psychoanalysis, and suggests that our moral sense may be an adaptive biological strategy. Goodness is sought in others and aspired to in the self, as part of an innate need to build the ego upon experiences of good objects. Kleinian theory suggests a 'natural morality' that can be discerned in the move towards the 'depressive position', involving increasing care and concern for others. The hunger for goodness within is experienced as a moral quest, with strivings both to approve of, and to be approved of by, one's objects. Goodness, felt as moral rightness, is highly prized, and may be claimed falsely for the self or for objects in the form of the 'moral high ground'. Derailments of the analytic standpoint easily occur, away from the search for objective truth towards assumption of the moral high ground, on the part of the patient, the analyst or both. The author shows this occurring clinically and reflects also on how psychoanalytic theory can be misused in the pursuit of moral superiority.

Adult↗
PubMed1999

Risk assessment and suicide prevention in primary care.

General practitioners (GPs) are assumed to occupy an important position in the prevention of suicide through the introduction of risk assessment techniques commonly used in psychiatric practice. Despite this theoretical role for primary care services, it remains unclear how frequently GPs implement risk assessment in patients who may be vulnerable to suicide. To address this, a retrospective survey of probable suicides was conducted within a primary care setting utilizing a questionnaire of GPs who had experienced a patient suicide and was augmented by hospital and coroners' records. 85% of questionnaires were returned and 61 deaths were adjudged as suicides during the year long census period. 75% of suicides were male and 54% were aged under 35.28% were in contact with psychiatric services prior to death, although 60% had some diagnosis of mental disorder. GPs had little knowledge of a patient's life circumstances in up to half of cases. Recording of risk assessment occurred in 38% of subjects, was positively associated with prior psychiatric contact (p = 0.001) but negatively associated with presence of physical illness (p = 0.004), older patient age (p = 0.04), and GPs length in practice (p = 0.05). One GP felt their suicide case was preventable. The low rate of risk assessment and limited knowledge of patient lifestyle point to the need for active engagement of GPs in future suicide prevention strategies and should influence the content of training programs in primary care.

Adult↗
PubMed1999

Does Psi exist? Lack of replication of an anomalous process of information transfer.

D. J. Bem and C. Honorton (1994) recently presented in this journal a set of ganzfeld extrasensory perception (ESP) experiments conducted by C. Honorton that appeared to support the existence of a communication anomaly. In this article, the authors present a meta-analysis of 30 ganzfeld ESP studies from 7 independent laboratories adhering to the same stringent methodological guidelines that C. Honorton followed. The studies failed to confirm his main effect of participants scoring above chance on the ESP task, Stouffer z = 0.70, p = .24, one-tailed; M effect size (z/N1/2) = 0.013, SD = 0.23. The new studies included replication attempts of 3 out of 5 internal effects reported as statistically significant by D. J. Bem and C. Honorton. Only 1 was confirmed, and the authors found that D. J. Bem and C. Honorton were mistaken in describing the original effect as being statistically significant. The authors conclude that the ganzfeld technique does not at present offer a replicable method for producing ESP in the laboratory.

Bias↗
PubMed1999

Modulation of retinal pigment epithelial cell behavior by Agaricus bisporus lectin.

PURPOSE: To determine whether Agaricus bisporus lectin (ABL) binds retinal pigment epithelial cells (RPEs), to conduct a preliminary viability study of RPEs exposed to ABL, and to evaluate the effects of ABL on RPE proliferation and RPE-mediated matrix contraction in vitro. METHODS: Using cultured bovine RPEs, immunohistochemistry was used to study ABL binding. Morphologic and trypan blue exclusion techniques were used for toxicity studies. The effect of ABL on RPE proliferation was investigated by [methyl-3H]-thymidine incorporation. The effect of ABL on RPE-mediated matrix contraction was evaluated with RPE-populated three-dimensional collagen matrices. RESULTS: ABL bound to RPE cells. This binding was inhibited by asialomucin. No change in RPE morphology or trypan blue exclusion compared with controls was observed in RPEs incubated with 5 to 60 microg/ml ABL for 3 days. Twenty-four-hour incubations of RPEs with ABL significantly inhibited RPE proliferation in a dose-dependent way, 40 microg/ml ABL inhibited proliferation by 83% (SE 14, P<0.05). ABL showed a dose-dependent significant inhibition of RPE-mediated collagen matrix contraction over 3 days, with 93% inhibition compared with controls by 40 microg/ml lectin (P<0.05). The inhibitory effect of ABL on proliferation and gel contraction was partly reversible after eliminating ABL from the culture medium. CONCLUSIONS: Bovine RPE cells bind ABL, and preliminary evaluations suggest that levels of ABL that are nontoxic to the cells potently inhibit RPE proliferation and RPE-mediated matrix contraction. ABL deserves further investigation as a potential inhibitor of RPE proliferation and cell-mediated matrix contraction in anomalous reparative processes such as proliferative vitreoretinopathy and as a laboratory tool for RPE behavioral studies.

Animals↗
PubMed1998

Biaryl acids: novel non-nucleoside inhibitors of HIV reverse transcriptase types 1 and 2.

A series of biaryl acids has been found to show micromolar inhibition of the HIV reverse transcriptase (RT) from types 1 and 2 with IC50S in the micromolar range. The series was discovered by consideration of the polymerase active site and sub-structure searching of the company compound collection. Synthesis of analogues to investigate the SAR is described. Two of these compounds have shown inhibition of HIV-2 RT only.

Anti-HIV Agents↗
PubMed1998

Identification of the sensory/motor area and pathologic regions using ECoG coherence.

An electrophysiologic mapping technique which enables identification of the central sulcus and pathologic cortical regions is described. Electrocorticographic recordings of 1 min duration were recorded from 25 patients who were undergoing resection of tumors in the sensory-motor region or being evaluated for temporal lobectomy for epilepsy. Analysis of the patterns of subdural inter-electrode coherence revealed low coherence across the central sulcus for 11/12 cases where its location could be verified with direct cortical stimulation and/or somatosensory evoked potential mapping. Regions of high coherence identified the location of tumors in the sensory-motor region for 10/10 cases. Over the temporal lobe, localized areas of high coherence were evident in 8/9 epilepsy patients, but were not indicative of the location of mesial temporal lobe tumors or inter-ictal spiking, when present. We conclude that analysis of cortical coherence patterns may be helpful for revealing the location of pathologic processes relative to critical cortical areas.

Adolescent↗
PubMed1998

Can animals detect when their owners are returning home? An experimental test of the 'psychic pet' phenomenon.

In his book, Seven Experiments That Could Change The World, Rupert Sheldrake suggested that the public carry out experiments to test whether pets can psychically detect when their owners are returning home. The first of these tests was undertaken by an Austrian television company and involved an owner in the north-west of England, Pam Smart (PS) and her dog (Jaytee). The test appeared remarkably successful and seemed to show Jaytee responding when PS set off to return home from a remote location. Rupert Sheldrake and PS asked the authors if they would like to carry out their own investigation into Jaytee's abilities. This paper outlines various 'normal' explanations that might account for the phenomenon and presents an experimental design that minimizes these possibilities. The paper then details the procedure and results of four experiments. Analysis of the data did not support the hypothesis that Jaytee could psychically detect when his owner was returning home. Finally, the paper discusses a possible reason for the difference in results of these studies and those carried out by the Austrian television company.

Animals↗