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Biomedical subjects

P Salmon

Publications and source records attributed to P Salmon.

At least 19 recordsLinked to original sources
PubMed2006

Adult rat liver cells transdifferentiated with lentiviral IPF1 vectors reverse diabetes in mice: an ex vivo gene therapy approach.

AIMS/HYPOTHESIS: We examined a clinical model of ex vivo transdifferentiation of primary adult hepatocytes to insulin-secreting cells for the treatment of type 1 diabetes. MATERIALS AND METHODS: Isolated rat hepatocytes were transduced in primary culture with a human lentivirus containing pancreatic duodenal homeobox 1 (PDX1, now known as insulin promoter factor 1, homeodomain transcription factor [IPF1]). Insulin expression and secretion of the newly engineered cells were assessed in vitro by RT-PCR, in situ hybridisation, immunostaining and radioimmunoassay. PDX1-transduced hepatocytes were further studied in vivo by injecting them under the renal capsule of diabetic SCID mice. RESULTS: Isolated rat hepatocytes were efficiently transduced with the lentiviral vector, as assessed by green fluorescent reporter gene expression. The transduced cells exhibited insulin at both mRNA (RT-PCR, in situ hybridisation) and protein levels (immunostaining and radioimmunoassay). Moreover, insulin secretion by the engineered cells was dependent on glucose and sulfonylurea. Other beta cell genes, including those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (Slc2a2), glucokinase (Gck), ATP-binding cassette, sub-family C (CFTR/MRP), member 8 (Abcc8), the potassium inwardly-rectifying channel, subfamily J, member 11 (Kcnj11) and proprotein convertase subtilisin/kexin type 1 (Pcsk1) were also expressed. The PDX1-transduced hepatocytes expressed several pancreatic transcription factors related to early pancreatic endocrine development (endogenous Pdx1, neurogenic differentiation factor 1 [Neurod1], and NK6 transcription factor related, locus 1 [Nkx6-1]) as well as the late-stage pancreatic transcription factors (paired box gene 4 [Pax4], paired box gene 6 [Pax6], and v-maf musculoaponeurotic fibrosarcoma oncogene homolog A [Mafa]). Transplantation of 3 x 10(6) transdifferentiated liver cells under the renal capsule of seven streptozotocin-induced diabetic SCID mice resulted in significant reduction of non-fasting blood glucose levels from 30.7 +/- 1.3 to 8.7 +/- 3.7 mmol/l (mean +/- SEM, p = 0.01), in 6 to 8 weeks. Removal of the graft resulted in severe hyperglycaemia. CONCLUSIONS/INTERPRETATION: Ex vivo lentiviral-mediated PDX1 expression in isolated adult liver cells represents a potential model for type 1 diabetes mellitus therapy.

Animals↗
PubMed2006

Asymmetric reduction of alpha, beta-unsaturated ketone to (R) allylic alcohol by Candida chilensis.

A pilot scale whole cell process was developed for the enantioselective 1,2-reduction of prochiral alpha,beta-unsaturated ketone to (R) allylic alcohol using Candida chilensis. Initial development showed high enantiomeric excess (EE > 95%) but low product yield (10%). Process development, using a combination of statistically designed screening and optimization experiments, improved the desired alcohol yield to 90%. The fermentation growth stage, particularly medium composition and growth pH, had a significant impact on the bioconversion while process characterization identified diverse challenges including the presence of multiple enzymes, substrate/product toxicity, and biphasic cellular morphology. Manipulating the fermentation media allowed control of the whole cell morphology to a predominantly unicellular broth, away from the viscous pseudohyphae, which were detrimental to the bioconversion. The activity of a competing enzyme, which produced the undesired saturated ketone and (R) saturated alcohol, was minimized to < or =5% by controlling the reaction pH, temperature, substrate concentration, and biomass level. Despite the toxicity effects limiting the volumetric productivity, a reproducible and scaleable process was demonstrated at pilot scale with high enantioselectivity (EE > 95%) and overall yield greater than 80%. This was the preferred route compared to a partially purified process using ultra centrifugation, which led to improved volumetric productivity but reduced yield (g/day). The whole cell approach proved to be a valuable alternative to chemical reduction routes, as an intermediate step for the asymmetric synthesis of an integrin receptor antagonist for the inhibition of bone resorption and treatment of osteoporosis.

Biotransformation↗
PubMed2004

Pre-operative information and patient-controlled analgesia: much ado about nothing.

We examined whether pre-operative information benefited patients receiving patient-controlled analgesia (PCA) after major surgery. We investigated whether patients felt better informed about PCA and also whether pre-operative information altered the use of PCA, the adequacy of pain relief, worries about addiction and safety, and knowledge of side-effects. We investigated the effectiveness of information provided in two ways, namely by a patient-determined leaflet or an interview by a trained nurse from the pain team, compared with routine pre-operative information. We studied 225 patients, 75 in each group. Patients in the leaflet group were better informed about PCA, became familiar with using PCA more quickly and were less confused about PCA than the control group. However, there were no effects on pain relief, worries about addiction and safety, and knowledge of side effects. The pre-operative interview resulted in no benefits. Our findings indicate that the detailed provision of pre-operative information failed to improve patients' experiences of PCA.

Adolescent↗
PubMed2003

Ectopic expression of the beta-cell specific transcription factor Pdx1 inhibits glucagon gene transcription.

AIMS/HYPOTHESIS: The transcription factor Pdx1 is required for the development and differentiation of all pancreatic cells. Beta-cell specific inactivation of Pdx1 in developing or adult mice leads to an increase in glucagon-expressing cells, suggesting that absence of Pdx1could favour glucagon gene expression by a default mechanism. METHOD: We investigated the inhibitory role of Pdx1 on glucagon gene expression in vitro. The glucagonoma cell line InR1G9 was transduced with a Pdx1-encoding lentiviral vector and insulin and glucagon mRNA levels were analysed by northern blot and real-time PCR. To understand the mechanism by which Pdx1 inhibits glucagon gene expression, we studied its effect on glucagon promoter activity in non-islet cells using transient transfections and gel-shift analysis. RESULTS: In glucagonoma cells transduced with a Pdx1-encoding lentiviral vector, insulin gene expression was induced while glucagon mRNA levels were reduced by 50 to 60%. In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3. CONCLUSION/INTERPRETATION: Cell-specific expression of the glucagon gene can only occur when Pdx1 expression extinguishes from the early alpha cell precursor.

Animals↗
PubMed2003

Novel proline hydroxylase activities in the pneumocandin-producing fungus Glarea lozoyensis responsible for the formation of trans 3- and trans 4-hydroxyproline.

Novel proline 3-hydroxylase (P3H) and proline 4-hydroxylase (P4H) activities that convert free l-proline to both trans 3- and trans 4-hydroxy- l-proline were detected in protein extracts of the anamorphic fungus Glarea lozoyensis. The enzymatic conversion of l-proline to trans 3- and trans 4-hydroxy- l-proline was strictly dependent on alpha-ketoglutarate, ascorbate, and dithiothreitol. Ferrous iron was required for optimal P3H and P4H activity. These substrate and co-factor requirements indicate these enzyme activities belong to the class of 2-oxoglutarate-dependent dioxygenases. Both P3H and P4H were inhibited by zinc and other trace metals. The addition of proline to the fermentation medium resulted in an increase in the specific activity of P4H and a decrease in the synthesis of pneumocandin C(0). Additionally, the synthesis of trans 3- and trans 4-hydroxy- l-proline in vivo was affected differently by the proline concentration in the medium. This result suggested that two enzymes may be responsible for the regio- and stereospecific hydroxylation of l-proline.

Anti-Bacterial Agents↗
PubMed2003

Clinical decision guidelines for NHS cosmetic surgery: analysis of current limitations and recommendations for future development.

Because of increasing demand for publicly funded elective cosmetic surgery, clinical decision guidelines have been developed to select those patients who should receive it. The aims of this study were to identify: the main characteristics of such guidelines; whether and how they influence clinical decision making; and ways in which they should be improved. UK health authorities were asked for their current guidelines for elective cosmetic surgery and, in a single plastic surgery unit, we examined the impact of its guidelines by observing consultations and interviewing surgeons and managers. Of 115 authorities approached, 32 reported using guidelines and provided sufficient information for analysis. Guidelines mostly concerned arbitrary sets of cosmetic procedures and lacked reference to an evidence base. They allowed surgery for specified anatomical, functional or symptomatic reasons, but these indications varied between guidelines. Most guidelines also permitted surgery 'exceptionally' for psychological reasons. The guidelines that were studied in detail did not appreciably influence surgeons' decisions, which reflected criteria that were not cited in the guidelines, including cost of the procedure and whether patients sought restoration or improvement of their appearance. Decision guidelines in this area have several limitations. Future guidelines should: include all cosmetic procedures; be informed by a broad range of evidence; and, arguably, include several nonclinical criteria that currently inform surgeons' decision-making.

Cosmetics↗
PubMed2003

Activity analysis of housekeeping promoters using self-inactivating lentiviral vector delivery into the mouse retina.

For most retinal degeneration disorders, no efficient treatment exists to preserve photoreceptors (PRs) and, consequently, to maintain vision. Gene transfer appears to be a promising approach to prevent PR loss. In order to design adequate vectors to target specific retinal cell types, we have analyzed the expression pattern of three different promoters (mouse phosphoglycerate kinase 1 (PGK), elongation factor-1 (EFS), rhodopsin (Rho)) in newborn and adult DBA/2 mice retinas using self-inactivating lentiviral vectors. At 7 days after intraocular injection and in optimal conditions, cell transduction was observed up to 1.5 mm from the injection site. PGK promoter expression was predominant in the retinal pigment epithelium (RPE), especially in adult mice, whereas the EFS promoter allowed a broad expression in the retina. Finally, as expected, the Rho promoter was specifically expressed in PRs. Differences in the cell types transduced and in transduction efficiency were observed between newborn and adult injected eyes emphasizing the importance of such basic studies for further gene therapy approaches as well as for understanding the transcriptional changes during retinal maturation. Thus, for future attempts to slow or rescue retinal degeneration by lentiviral delivery, PGK and EFS are more suitable to control the expression of a supporting secreted factor, PGK being mainly expressed in RPE and EFS in different cell types throughout the entire retina, whereas Rho should allow to specifically deliver the therapeutic gene to PRs.

Animals↗
PubMed2003

Relationship of sexual abuse to motivation for strenuous exercise.

AIM: Sources of motivation for intense physical exercise are poorly understood. Based on views that link such behaviour to preexisting psychopathology, we tested the hypotheses that history of childhood sexual abuse would be greater in intense exercisers than in non-exercisers, and that effects of abuse on self-esteem, perfectionism and body dissatisfaction would help to explain any link between abuse and exercise. METHODS: Consecutive attenders at two types of exercise were recruited: weight training and running. Sedentary attenders at a further education college provided a third, comparison group. Each group contained 64 men and 64 women. Participants completed questionnaires to record history of sexual and physical abuse in childhood and adulthood, body dissatisfaction, self-esteem, and positive and negative perfectionism. RESULTS: Adult, but not childhood abuse, was reported by more weight-trainers than others. Abused individuals were more anxious and depressed, were more negative about themselves and were more concerned with avoiding failure in general. Women abused in childhood were more concerned with avoiding failure at exercise in particular. CONCLUSION: These results suggest hypotheses that link adult abuse to intense weight training habits and, in women, that link child abuse to feelings of failure in exercise.

Adult↗
PubMed2002

Glucocorticoid-induced osteopenia in the mouse as assessed by histomorphometry, microcomputed tomography, and biochemical markers.

Glucocorticoids are potent anti-inflammatory molecules used in the treatment of asthma, rheumatoid arthritis, inflammatory bowel disease, and other inflammatory and dermatological diseases, as well as in posttransplantation immunotherapy. Although glucocorticoids have been prescribed for many years, their potential side effects, when administered orally, can prevent their long-term use. The most serious side effect observed in the clinic is glucocorticoid-induced osteoporosis (GIOP). To develop a small animal model to characterize glucocorticoid-induced bone loss, we carried out a series of experiments using BALB/c mice given daily intraperitoneal doses of the synthetic glucocorticoid, dexamethasone. Following dexamethasone treatment, the mice became osteopenic, with highly significant decreases in bone formation rate and mineral apposition rate, as assessed by standard histomorphometry. Moreover, 3 week treatment with dexamethasone resulted in a decrease in trabecular thickness and trabecular number with an increase in surface-to-volume ratio of trabeculae in the distal femur, as measured using microcomputed tomography (micro-CT). The serum bone formation marker, osteocalcin, was dose-dependently decreased in all mice treated with dexamethasone and showed a parallel extent of regulation to the bone formation rate changes. In addition, serum levels of leptin, recently identified as playing a role in the regulation of bone mass, increased following dexamethasone treatment. BALB/c mice therefore represent a useful model system in which the detrimental effects of glucocorticoids on bone can be studied.

Animals↗
PubMed2001

Defending against patients' pain: a qualitative analysis of nurses' responses to children's postoperative pain.

OBJECTIVE: Cognitive approaches to clinical communication attribute deficits in communication to lack of skill. We examined, instead, emotional influences on communication by finding out how nurses construed patients who were in pain, and how these constructions were related to the emotional challenge of patients' pain and to deficits in clinical communication. METHODS: Data, analyzed qualitatively, included: (i) direct observations of verbal interactions of 13 nurses with 16 children after orthopedic surgery; (ii) standardized open-ended interviews with the nurses, patients and parents. RESULTS: Nurses tried to prevent children from displaying pain behavior. When pain behavior did occur, they construed pain as unreal, unwarranted or not deserving help. These findings were apparent in observations of, and interviews with, nurses and also in parents' and children's accounts of nurses' behavior. CONCLUSION: We identified behavioral and cognitive strategies whereby clinicians defend themselves emotionally against patients' pain, and which compromise communication with patients in pain.

Adolescent↗
PubMed2001

Psychological characteristics of women presenting with breast pain.

OBJECTIVE: Extensive evidence links unexplained physical symptoms in adults with childhood abuse. This study investigated a possible link between unexplained breast pain, recalled childhood abuse and emotional and somatic distress. METHODS: Consecutive female out-patients presenting with breast pain were categorised as treatment-resistant (n=20), newly diagnosed and requesting treatment (n=37), or newly diagnosed but reassured and not seeking treatment (n=32) and compared with pain-free patients with breast lumps (n=31). RESULTS: All breast pain groups were more anxious and depressed, somatised more and recalled a higher incidence of emotional abuse by comparison with breast lump patients. Logistic regression confirmed that emotional abuse and anxiety were independently associated with breast pain. CONCLUSION: Clinical management of patients who present breast pain should be sensitive to the evidence that pain is a marker of emotional abuse in some women and is associated with widespread somatic and emotional distress.

Adolescent↗
PubMed2001

Postoperative fatigue is a component of the emotional response to surgery: results of multivariate analysis.

OBJECTIVE: To test the theory that postoperative fatigue is an aspect of the emotional, not physiological, response to surgery, we examined whether fatigue is a component of subjective experience after surgery and whether it is related to subjective physical or emotional state. METHODS: Patients (N=160) undergoing hip or knee arthroplasty were assessed preoperatively, 1 and 7 days and 1 and 6 months postoperatively using multiple indicators of fatigue and subjective emotional and physical state. Covariance structure modeling was used to find out the structure of patients' experience on each occasion. RESULTS: At each time, data indicated four latent variables: negative mood, positive mood, dysfunction and pain. Scales measuring fatigue indicated negative or positive mood but were unrelated to dysfunction and pain. DISCUSSION: In surgical patients, the language of fatigue and energy describes empirically distinct components of emotional state. Explanations for postoperative fatigue should therefore be sought in emotional, not physiological, mechanisms.

Affect↗
PubMed2001

Effects of physical exercise on anxiety, depression, and sensitivity to stress: a unifying theory.

Until recently, claims for the psychological benefits of physical exercise have tended to precede supportive evidence. Acutely, emotional effects of exercise remain confusing, both positive and negative effects being reported. Results of cross-sectional and longitudinal studies are more consistent in indicating that aerobic exercise training has antidepressant and anxiolytic effects and protects against harmful consequences of stress. Details of each of these effects remain unclear. Antidepressant and anxiolytic effects have been demonstrated most clearly in subclinical disorder, and clinical applications remain to be exploited. Cross-sectional studies link exercise habits to protection from harmful effects of stress on physical and mental health, but causality is not clear. Nevertheless, the pattern of evidence suggests the theory that exercise training recruits a process which confers enduring resilience to stress. This view allows the effects of exercise to be understood in terms of existing psychobiological knowledge, and it can thereby provide the theoretical base that is needed to guide future research in this area. Clinically, exercise training continues to offer clinical psychologists a vehicle for nonspecific therapeutic social and psychological processes. It also offers a specific psychological treatment that may be particularly effective for patients for whom more conventional psychological interventions are less acceptable.

Anxiety↗
PubMed2001

Influence of the emotional response to surgery on functional recovery during 6 months after hip arthroplasty.

We examined whether the emotional response to hip arthroplasty predicted functional recovery after controlling for preoperative function and surgical trauma. Mood and fatigue were measured in 102 consecutive patients preoperatively and 3 days postoperatively. Time of achievement of functional milestones indicated recovery in hospital, and functional status was measured preoperatively and 1 and 6 months postoperatively. Circulating C-reactive protein and interleukin-6 levels indicated trauma. Recovery in hospital was slower in patients with greater trauma. Recovery at follow-up was slower in patients with poorer preoperative function and with greater anxiety and fatigue, but the apparent influence of anxiety was explained by its association with preoperative function and fatigue. Whereas short-term recovery is predicted by surgical trauma, long-term recovery is predicted by preexisting function and the emotional response to surgery. However, the influence of the emotional response is small and the important aspect of emotion is fatigue rather than anxiety.

Aged↗
PubMed2001

Effects of amino acid and trace element supplementation on pneumocandin production by Glarea lozoyensis: impact on titer, analogue levels, and the identification of new analogues of pneumocandin B(0).

Addition of the amino acids threonine, serine, proline, and arginine to fermentations of the fungus Glarea lozoyensis influenced both the pneumocandin titer and the spectrum of analogues produced. Addition of threonine or serine altered the levels of the "serine analogues" of pneumocandins B(0) and B(5) and allowed for their isolation and identification. Proline supplementation resulted in a dose-dependent increase in the levels of pneumocandins B(0) and E(0), whereas pneumocandins C(0) and D(0) decreased as a function of proline level. Moreover, proline supplementation resulted in an overall increase in the synthesis of both trans-3- and trans-4-hydroxyproline while maintaining a low trans-4-hydroxyproline to trans-3-hydroxyproline ratio compared to the unsupplemented culture. Pneumocandin production and the synthesis of hydroxyprolines was also affected by addition of the proline-related amino acid arginine but not by the addition of glutamine or ornithine. Zinc, cobalt, copper, and nickel, trace elements that are known to inhibit alpha-ketoglutarate-dependent dioxygenases, affected the pneumocandin B(0) titer and altered the levels of pneumocandins B(1), B(2), B(5), B(6), and E(0), analogues that possess altered proline, ornithine, and tyrosine hydroxylation patterns.

Amino Acids↗
PubMed2001

Recovery from hip and knee arthroplasty: Patients' perspective on pain, function, quality of life, and well-being up to 6 months postoperatively.

OBJECTIVE: To provide a more detailed description from patients' perspectives than is yet available of recovery from hip and knee arthroplasty and to use this information to test 2 assumptions about recovery from these procedures: that recovery from knee arthroplasty, as assessed by patients, routinely reaches the level achieved by hip arthroplasty; and that fatigue is prolonged after major orthopedic surgery. DESIGN: A cohort study. SETTING: University teaching hospitals. PARTICIPANTS: Consecutive patients undergoing hip (n = 107) or knee (n = 53) arthroplasty. INTERVENTIONS: Unilateral hip or knee arthroplasty. MAIN OUTCOME MEASURES: Standardized self-rated measurements of pain, function, quality of life, and well-being from preoperatively to 6 months follow-up. RESULTS: Pain and function improved significantly less after knee arthroplasty than after hip arthroplasty, but the 2 procedures led to similar improvements in life evaluation, mood, and subjective health. Fatigue was only transiently increased. CONCLUSION: The findings were inconsistent with both assumptions. Nevertheless, despite poorer recovery in pain and function, patients receiving knee arthroplasty felt that life had improved as much as did patients with hip arthroplasty. Detailed information about how major joint arthroplasty in routine practice affects patients' lives can be used to advise patients and clinicians and can invalidate influential, but inaccurate, assumptions.

Activities of Daily Living↗
PubMed2001

Relationship of the functional recovery after hip arthroplasty to the neuroendocrine and inflammatory responses.

We studied the relationship between the neuroendocrine and inflammatory responses to hip arthroplasty and functional recovery in 102 patients undergoing elective arthroplasty for osteoarthritis. Blood samples were collected for up to 7 days after surgery and analysed for concentrations of norepinephrine, epinephrine, cortisol, interleukin-6 and C-reactive protein. The primary outcome measures were milestones in hospital, times to walk 10 and 25 m, pain on discharge from hospital, and function 1 and 6 months after surgery. Walking distances in hospital were significantly delayed in patients with greater interleukin 6 and C-reactive protein concentrations, but few neuroendocrine measures had significant correlations with functional recovery in hospital. Multivariate analysis showed that the interleukin 6 concentration on day 1 was the unique predictor of time to walk 10 and 25 m, and that the day 2 concentration of C-reactive protein was the unique predictor of pain on discharge from hospital. No significant correlations were found between the inflammatory and neuroendocrine variables and recovery at 1 and 6 months. We conclude that the inflammatory response affects immediate functional recovery after hip arthroplasty.

Adult↗