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Biomedical subjects

D A Lane

Publications and source records attributed to D A Lane.

At least 19 recordsLinked to original sources
PubMed2006

Association of protein S p.Pro667Pro dimorphism with plasma protein S levels in normal individuals and patients with inherited protein S deficiency.

A dimorphism in PROS1 gene (c.A2,001G, p.Pro667Pro) has been associated with significantly reduced levels of both free and total protein S in carriers of the GG genotype. It is not known how the GG genotype could influence PS levels in normals, whether it could influence the levels of protein S in carriers of mutations in PROS1 gene and whether this genotype acts as an isolated or additive risk factor for venous thrombosis. With this as background, we evaluated the association of p.Pro667Pro dimorphism with free and total protein S centrally measured in a panel of 119 normal controls, 222 individuals with low protein S and 137 individuals with normal PS levels belonging to 76 families with protein S deficiency enrolled in the ProSIT study. Transient expression of recombinant wild type protein S and p.Pro667Pro protein S was performed to evaluate the role of the A to G transition at position 2001 in vitro. The p.Pro667Pro polymorphism was also expressed together with a p.Glu67Ala variant to assess a possible influence on protein S levels in protein S deficient subjects. Free and total protein S levels were significantly lower in normal women. In normal women only was the GG genotype associated with significantly lower free protein S levels in comparison to AA and AG genotypes (P=0.032). No significant influence of GG genotype was observed in patients, either with known mutations or with low protein S levels. These data were confirmed by in vitro transient expression, showing no difference in secretion levels of the p.Pro667Pro variant (even in association with the p.Glu67Ala mutation), compared to the wild type protein S. The genotype in itself was neither a significant risk factor for venous thrombosis nor a risk modifier in patients with known mutations.

Adolescent↗
PubMed2005

Psychological interventions for depression in heart failure.

BACKGROUND: Heart failure is a common and growing health problem. Depression is prevalent among these patients and is associated with an increased risk of mortality, in some, but not all, studies. Depression may increase the risk of recurrent cardiac events and death, either through direct pathophysiological mechanisms such as thrombogenesis or ventricular arrhythmias, or through behavioural mechanisms. Depressed patients are less likely to adhere to their medication regimen and modify their lifestyle appropriately, thereby increasing the likelihood of recurrent cardiac events and death. The effects of psychological interventions for depression in terms of reducing depression and improving prognosis in patients with heart failure are unknown. OBJECTIVES: To assess the effects of psychological interventions for depression in people with heart failure on depression and quality of life, morbidity, and mortality in these patients. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials and The Database of Abstracts of Reviews of Effects on The Cochrane Library (Issue 3, 2003), MEDLINE (1951 to August 2003), PsycINFO (1887 to August 2003), CINAHL (1980 to August 2003) and EMBASE (1980 to August 2003). Searches of reference lists of retrieved papers were also made and expert advice was sought. Abstracts from national and international cardiology, psychology, and psychiatry conferences in 2003 and dissertation abstracts were also searched. All relevant foreign language papers were translated. SELECTION CRITERIA: RCTs of psychological interventions for depression in adults (18 years or older) with heart failure. The primary outcome was a significant reduction in depression. The secondary outcomes were the acceptability of treatment, quality of life, cardiac morbidity (hospital re-admission for heart failure and non-fatal cardiovascular events), reduction of cardiovascular behavioural risk factors, health economics, and death. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened titles and abstracts of potential studies. Two reviewers independently assessed the full papers for inclusion criteria. Further information was sought from the authors where papers contained insufficient information to make a decision about eligibility. MAIN RESULTS: No RCTs of psychological interventions for depression in patients with heart failure were identified. AUTHORS' CONCLUSIONS: Depression is common among patients with heart failure. Randomised controlled trials of psychological interventions for depression in heart failure patients are needed to investigate the impact of such interventions on depression, quality of life, behavioural CVD risk factors, cardiac morbidity, health economics and mortality, given the paucity of such trials in this area and the increasing prevalence of heart failure.

Depression↗
PubMed2005

Evidence for an intrinsic mechanism of antinociceptive tolerance within the ventrolateral periaqueductal gray of rats.

Repeated microinjections of morphine into the ventrolateral periaqueductal gray produce antinociceptive tolerance. This tolerance may be a direct effect of morphine on cells within the ventrolateral periaqueductal gray or may require activation of downstream structures such as the rostral ventromedial medulla or spinal cord. Experiment 1 examined whether tolerance develops when opioid receptors in the ventrolateral periaqueductal gray are blocked prior to repeated systemic morphine administration. Microinjections of naltrexone hydrochloride (1microg/0.4microl) into the ventrolateral periaqueductal gray blocked antinociception and significantly attenuated the development of antinociceptive tolerance produced from systemic morphine administration. Experiment 2 examined whether tolerance develops when the effects of morphine are isolated to the ventrolateral periaqueductal gray. This was accomplished by microinjecting morphine (5microg/0.4microl) into the ventrolateral periaqueductal gray while simultaneously blocking the descending output through the rostral ventromedial medulla. Inhibition of neurons within the rostral ventromedial medulla by microinjecting the GABA(A) agonist muscimol (10ng/0.5microl) blocked the antinociception produced by microinjection of morphine into the ventrolateral periaqueductal gray but did not block the development of tolerance. These data demonstrate that the ventrolateral periaqueductal gray is both necessary and sufficient to produce tolerance to the antinociceptive effect of morphine. The ventrolateral periaqueductal gray is necessary in that tolerance does not develop if opiate action within the ventrolateral periaqueductal gray is blocked (experiment 1). The ventrolateral periaqueductal gray is sufficient in that tolerance occurs even when morphine's effects are restricted to the ventrolateral periaqueductal gray (experiment 2).

Analgesics↗
PubMed2004

Oestradiol dampens reflex-related activity of on- and off-cells in the rostral ventromedial medulla of female rats.

The present study was conducted to determine whether the ovarian steroid oestradiol alters the activity of nociceptive modulatory neurons in the rostral ventromedial medulla (RVM). Adult female rats were ovariectomized and implanted s.c. with an oestradiol-filled or placebo capsule. Sixteen to 37 days later, rats were anaesthetised for single unit recording from RVM neurons. On-cells were characterised by a burst of activity, and off-cells by a pause in activity immediately preceding reflexive withdrawal of the tail from 51 and 54 degrees C water. Although on- and off-cells were evident in both oestradiol- and placebo-treated rats, the reflex-related on-cell burst and off-cell pause were dampened in oestradiol-treated rats. On-cells from oestradiol-treated rats had a mean activity burst of 9.1+/-2.2 Hz in the 2 s preceding the tail withdrawal reflex to 51 degrees C water, compared with 17.9+/-4.3 Hz for on-cells in placebo controls. Off-cell activity during the 2 s preceding tail withdrawal was 4.8+/-2.2 vs. 0.1+/-0.1 Hz in oestradiol vs. placebo-treated females, respectively. Similar changes in on- and off-cell activity occurred when the tail was placed in 54 degrees C water. The present data demonstrate that oestradiol constrains the magnitude of the shift in RVM on- and off-cell activity associated with nociceptive reflexes.

Animals↗
PubMed2004

Behavioral and electrophysiological evidence for tolerance to continuous morphine administration into the ventrolateral periaqueductal gray.

Repeated microinjections of morphine into the ventrolateral periaqueductal gray (vPAG) produce tolerance to the antinociceptive effect of morphine [Behav Neurosci 113 (1999) 833]. These results may be a direct effect of morphine on cells within the vPAG or be caused by cues linked to the microinjection procedure (i.e. associative tolerance). The objective of this paper was to determine whether continuous administration of morphine into the vPAG (i.e. no cues) would produce tolerance. Tolerance was assessed by measuring changes in behavior and changes in the activity of neurons in the rostral ventromedial medulla (RVM), the primary output target of the PAG. Rats were implanted with an osmotic minipump that released morphine (2.5 or 5 microg/h) or saline into the vPAG continuously. Continuous administration of morphine produced an increase in hotplate latency when measured 6 h after initiation of treatment. Tolerance to this antinociception was evident within 24 h. After 3 days, rats were anesthetized and the activity of RVM neurons was assessed. Although acute morphine administration into the RVM inhibits the activity of RVM on-cells and enhances the activity of off-cells, these neurons appeared normal following 3 days of continuous morphine administration. Systemic naloxone administration produced hyperalgesia that was associated with a marked increase in on-cell activity and a complete cessation of off-cell activity. The loss of morphine inhibition of nociception, measured behaviorally and electrophysiologically, demonstrates that tolerance is caused by a direct action of morphine on vPAG neurons.

Analgesics, Opioid↗
PubMed2004

Ethnicity and tracking blood pressure in children.

There is growing evidence that hypertension, one of the major modifiable risk factors for cardiovascular disease (CVD), is established early in life. Given this, it is important to discover when hypertension first becomes apparent. Further, it is of particular importance to examine the ethnic differences in blood pressure (BP) in children, given the variation in rates of CVD morbidity and mortality among adults from different ethnic groups.

Adolescent↗
PubMed2003

Psychological interventions for depression in adolescent and adult congenital heart disease.

BACKGROUND: Adult and adolescent congenital heart disease is increasing in prevalence as better medical care means more children are surviving to adulthood. People with chromic disease often also experience depression. There are several non-pharmacological treatments that might be effective in treating depression and improving quality of life for adults and young adults with congenital heart disease. The aim of this review was to assess the effects of treatments such as psychotherapy, cognitive behavioural therapies and talking therapies for treating depression in this population. OBJECTIVES: To assess the effects (both harms and benefits) of psychological interventions for treating depression in young adults and adults with congenital heart disease. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (CCTR) (on The Cochrane Library issue 4, 2002), MEDLINE (1966 to August 2002), EMBASE (1980 to August 2002), PsycLIT (1887 to August 2002), the Database of Abstracts of Reviews of Effectiveness (DARE) (Issue 4, 2002 of the Cochrane Library), Biological Abstracts (January 1980 to August 2002), and CINAHL (January 1980 to August 2002). Abstracts from national and international cardiology and psychology conferences and dissertation abstracts were also searched. SELECTION CRITERIA: Randomised controlled trials comparing psychological interventions with no intervention for people over 15 years with depression who have congenital heart disease. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened titles and abstracts of studies that were potentially relevant to the review. Studies that were clearly ineligible were rejected. Two reviewers independently assessed the abstracts or full papers for inclusion criteria. Further information was sought from the authors where papers contained insufficient information to make a decision about eligibility. MAIN RESULTS: No randomised controlled trials were identified. REVIEWER'S CONCLUSIONS: Depression is common in patients with congenital heart disease and can exacerbate the physical consequences of the illness. There are effective pharmacological and non-pharmacological treatments for depression, but we have not been able to identify any trials showing the effectiveness of non-pharmacological treatments. A well designed randomised controlled trial is needed to assess the effects of psychological interventions for depression in congenital heart disease.

Adolescent↗
PubMed2003

Behavioral evidence linking opioid-sensitive GABAergic neurons in the ventrolateral periaqueductal gray to morphine tolerance.

Tolerance develops to the antinociceptive effects of morphine with repeated microinjections into the ventrolateral periaqueductal gray (PAG). This tolerance could be caused by adaptations within the PAG or anywhere along the descending pathway (rostral ventromedial medulla to spinal cord). If tolerance is caused by a change along the descending pathway, then tolerance should develop to direct activation of PAG output neurons. However, if tolerance is caused by a change to neurons within the PAG, then tolerance will not occur with repeated direct activation of PAG output neurons. This hypothesis was tested by assessing antinociception following repeated microinjections of the GABA antagonist bicuculline and the excitatory amino acid kainate into the ventrolateral PAG. Microinjection of bicuculline and kainate produces antinociception by disinhibition and direct excitation of ventrolateral PAG output neurons, respectively. Repeated administration of these drugs into the ventrolateral PAG produced antinociception with no evidence of tolerance. That is, the hot-plate latency and responsiveness to intraplantar formalin administration was comparable whether rats received the drug for the first or fifth time. Moreover, microinjection of bicuculline or kainate produced comparable antinociception in rats pretreated with these drugs and saline-treated control rats. These data demonstrate that repeated activation of ventrolateral PAG output neurons is not sufficient to produce tolerance. Thus, tolerance must be caused by a change in neurons preceding output neurons in this circuit, presumably opioid-sensitive GABAergic neurons.

Analgesics, Opioid↗
PubMed2003

Altered expression of 3 alpha-hydroxysteroid dehydrogenases in human glaucomatous optic nerve head astrocytes.

3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) isoforms (AKR1C1-AKR1C4) are aldo-keto reductases that metabolize steroids and other substances in many tissues including the CNS. Here we demonstrated that in glaucomatous human optic nerve heads, increased expression of 3alpha-HSD was localized to reactive astrocytes in the lamina cribrosa. Similar, optic nerve head astrocytes exhibited increased expression of 3alpha-HSD in response to elevated intraocular pressure in a monkey model of experimental glaucoma, but not in monkeys with unilateral optic nerve transection. In vitro, glaucomatous optic nerve head astrocytes expressed higher levels of AKR1C1, AKR1C2, and AKR1C3 mRNA, than normal astrocytes, with significant differential increase of AKR1C2 expression, and exhibited higher enzymatic activity forming 3alpha-androstanediol a well-recognized neurosteroid. Normal astrocytes exposed to elevated hydrostatic pressure selectively increased AKR1C2 expression. Our findings of increased expression of 3alpha-HSDs in glaucomatous optic nerve head astrocytes offer new insights into possible roles for neurosteroids in the pathophysiology of glaucoma.

3-Hydroxysteroid Dehydrogenases↗
PubMed2002

Quality of life in adults with congenital heart disease.

OBJECTIVE: To examine the quality of life of adults with congenital heart disease. DESIGN AND SETTING: Observational, cross sectional study conducted at one general hospital in Birmingham, UK. PATIENTS: All 471 patients registered at the adult congenital heart disease clinic were sent the 36 item short form health survey (SF-36) to assess their quality of life. Questionnaires were completed by 276 (58.6%) patients (41.7% men; median (interquartile range) age 31.0 (26.3-36.0) years, range 16-85 years). RESULTS: Surprisingly, patients deemed surgically cured (for example, atrial septal defect repair) had significantly poorer quality of life in all domains (all p < 0.05), except for pain, than the general population, as determined from population normative data. Patients who had received palliative treatment reported quality of life scores similar to those who had never required cardiac surgery and to the general population, although both patient groups had significantly poorer physical functioning and overall general health perception than the general population (all p < 0.01). Patients with inoperable conditions had significantly poorer physical functioning (all p < 0.01) and overall general health perception (all p < 0.05) than all other patients, and significantly worse quality of life in all domains than the similarly aged general population. Patients with cyanotic conditions had significantly worse quality of life than age and sex matched acyanotic patients (all p < 0.01). CONCLUSIONS: Patients with inoperable or cyanotic conditions and, paradoxically, those deemed surgically cured, had the poorest quality of life among adults with congenital heart disease. However, all adults with congenital heart disease had significantly poorer levels of physical functioning and overall general health perception then similarly aged people in the general population.

Adolescent↗
PubMed2001

Haemostatic genetic risk factors in arterial thrombosis.

Haemostasis plays an integral role in arterial thrombotic disease. However, establishing which of the factors are risk factors has proven surprisingly difficult. Because of its technical simplicity and digital nature, the study of haemostatic polymorphisms as risk factors has grown in popularity. Once established as a risk factor, a genetic polymorphism has the potential to aid selective prophylaxis and therapy of disease. Numerous reports have now been published on polymorphisms of coagulation and fibrinolytic factors, of coagulation and fibrinolytic inhibitory proteins, and of platelet membrane glycoprotein receptors. This article describes the polymorphisms and evaluates the results of these studies using the premises of consistency of within-report genotype/phenotype/disease relationships and consistency of outcome between studies. Many studies have been only of association between polymorphisms and disease, a type of study that is prone to error. Furthermore, the collective outcome of these studies has primarily been inconsistent. It is concluded that despite the early promise of polymorphisms as risk factors, fresh approaches differing in scale and design are now required to clarify their possible importance.

Arteriosclerosis↗
PubMed2001

Homozygous antithrombin deficiency type II (99 Leu to Phe mutation) and childhood thromboembolism.

We report 5 children from 3 families with homozygous antithrombin deficiency type II affecting the heparin binding site (99 Leu to Phe mutation). Four children had severe spontaneous thromboembolic events (deep leg or caval vein thrombosis, ischaemic stroke) at one week, 3 months, 13 and 14 years of age. The fifth patient, a 17 year-old boy was asymptomatic. Early manifestation of homozygous deficiency calls for prompt and accurate diagnosis. In doubtful cases genetic analysis is required. Long-term oral anticoagulation should be considered in affected individuals.

Adolescent↗
PubMed2000

The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure.

Factor XIII on activation by thrombin cross-links fibrin. A common polymorphism Val to Leu at position 34 in the FXIII A subunit is under investigation as a risk determinant of thrombosis. Because Val34Leu is close to the thrombin cleavage site, the hypothesis that it would alter the function of FXIII was tested. Analysis of FXIII subunit proteolysis by thrombin using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and high-performance liquid chromatography showed that FXIII 34Leu was cleaved by thrombin more rapidly and by lower doses than 34Val. Mass spectrometry of isolated activation peptides confirmed the predicted single methyl group difference and demonstrated that the thrombin cleavage site is unaltered by Val34Leu. Kinetic analysis of activation peptide release demonstrated that the catalytic efficiency (k(cat)/K(m)) of thrombin was 0.5 for FXIII 34Leu and 0.2 (micromol/L)(-1) x sec(-1) for 34Val. Presence of fibrin increased the catalytic efficiency to 4.8 and 2.2 (micromol/L)(-1) x sec(-1), respectively. Although the 34Leu peptide was released at a similar rate as fibrinopeptide A, the 34Val peptide was released more slowly than fibrinopeptide A but more quickly than fibrinopeptide B generation. Cross-linking of gamma- and alpha-chains appeared earlier when fibrin was incubated with FXIII 34Leu than with 34Val. Fully activated 34Leu and 34Val FXIII showed similar cross-linking activity. Analysis of fibrin clots prepared using plasma from FXIII 34Leu subjects by turbidity and permeability measurements showed reduced fiber mass/length ratio and porosity compared to 34Val. The structural differences were confirmed by electron microscopy. These results demonstrate that Val34Leu accelerates activation of FXIII by thrombin and consequently affects the structure of the cross-linked fibrin clot.

Blood Coagulation↗
PubMed2000

Relationships between homocysteine, factor VIIa, and thrombin generation in acute coronary syndromes.

BACKGROUND: It has been suggested by clinical, epidemiological, and experimental in vitro studies that homocysteine potentiates thrombin generation. This prothrombotic effect however has not previously been demonstrated in patients presenting with acute coronary syndromes (ACS). METHODS AND RESULTS: Patients with ACS (n =117) presenting with confirmed acute myocardial infarction (MI) (n =57) or unstable angina pectoris (UAP) (n =60) were consecutively recruited together with patients (n =18) in whom the presenting chest pain was not of cardiac origin (NCP), included as controls. Plasma samples were collected on admission and before clinical intervention. Homocysteine was assayed by high performance liquid chromatography, and both Factor VIIa and prothrombin fragment F1+2 were analyzed by ELISA. There were significant elevations in F1+2 in MI (P<0.001) and UAP (P=0.003), and modest elevations in Factor VIIa in UAP (P<0.05) compared with NCP but no differences in homocysteine levels among those groups. On dividing patients with ACS into quartiles of homocysteine, there was a stepwise increase in F1+2 (P<0.0001) and of Factor VIIa (P<0.05). There were significant correlations in ACS between homocysteine and F1+2 (r=0.46, P<0.0001), homocysteine and Factor VIIa (r=0.24, P<0.01), and F1+2 and Factor VIIa (r=0.41, P<0.0001). There was no correlation between homocysteine and either F1+2 (r=-0.15, P=0.57) or Factor VIIa (r=0. 22, P=0.37) in the NCP patients. CONCLUSIONS: Elevated plasma homocysteine is associated with and may cause elevated Factor VIIa and thrombin generation in patients presenting with ACS. These findings suggest an explanation for the prothrombotic effect of homocysteine in ACS.

Acute Disease↗