Search PubMed⌕ Search

Biomedical subjects

M R Johnson

Publications and source records attributed to M R Johnson.

At least 37 records · Page 2Linked to original sources
PubMed2004

Rotation-libration and rotor-rotor coupling in 4-methylpyridine.

The low temperature rotational dynamics of methyl groups in 4-methylpyridine is analyzed in terms of a model potential including rotation-libration and rotor-rotor coupling. The parameters of the model potential are adjusted by comparison of calculated with published and newly recorded inelastic neutron scattering spectra. Initial evaluations of the potential parameters of the model are obtained from molecular mechanics calculations. Experimental spectra are calculated from these potentials by numerical solution of Schrödinger's equation for clusters of coupled rotors embedded in a bigger ensemble of rotors treated in the mean field approximation. Adjustment of the potential parameters leads to excellent agreement with the experimental spectra of protonated 4-methylpyridine, measured at well-defined spin temperatures. At higher levels of deuteration, agreement with experiment is qualitative, only. The observed deviations are attributed to the increasing frustration of the system of coupled methyl groups and mutual localization, effects leading to a phase transition around 5.5 K in isotopic mixtures, as shown in diffraction experiments.

Journal Article↗
PubMed2004

Functional genomics-based studies of the microbial ecology of hyperthermophilic micro-organisms.

Although much attention has been paid to the genetic, biochemical and physiological aspects of individual hyperthermophiles, how these unique micro-organisms relate to each other and to their natural habitats must be addressed in order to develop a comprehensive understanding of life at high temperatures. Phylogenetic 16 S rRNA-based profiling of samples from various geothermal sites has provided insights into community structure, but this must be complemented with efforts to relate metabolic strategies to biotic and abiotic characteristics in high-temperature habitats. Described here are functional genomics-based approaches, using cDNA microarrays, to gain insight into how ecological features such as biofilm formation, species interaction, and possibly even gene transfer may occur in native environments, as well as to determine what genes or sets of genes may be tied to environmental functionality.

Biofilms↗
PubMed2004

Impaired retrograde transmission of vasodilatory signals via the endothelium in pre-eclampsia: a cause of reduced tissue blood flow?

There is evidence that tissue blood flow is regulated by retrograde transmission of signals initiated at capillary and post-capillary sites, and transmitted via the endothelium to modulate pre-capillary resistance. We have used pre-eclampsia as a model to test the hypothesis that normal endothelium is required to enable adjustment of blood flow to match tissue requirements. Integrity of the endothelial pathway was assessed by measuring calf blood flow at increasing venous pressures, using an established small cumulative-step venous-congestion plethysmography protocol in ten women with pre-eclampsia, 17 normal pregnant controls and ten non-pregnant women. Endothelial cell activation was assessed by measuring plasma levels of the cell adhesion molecules, intercellular cell-adhesion molecule-1 (ICAM-1), vascular cell-adhesion molecule-1 (VCAM-1) and E-selectin. Baseline calf blood flow was significantly lower in pre-eclampsia than in the other two groups (P<0.0001; ANOVA). In the pre-eclampsia group, there was a fall in blood flow as venous congestion pressure was raised (P<0.0001; ANOVA). No such change was observed in the other two groups. A significant inverse correlation was observed between the reduction in blood flow in pre-eclampsia and the levels of E-selectin (r=-0.92, P=0.0002), VCAM-1 (r=-0.93, P=0.0008) and ICAM-1 (r=-0.86, P=0.001). The differences between the pre-eclamptic women and the other two groups support the notion that the failure to sustain blood flow during a cumulative pressure step protocol in the pre-eclamptic group might be influenced by interference with the retrograde transmission of signals via the endothelium in these patients.

Adult↗
PubMed2004

Insulin resistance and pre-eclampsia: a role for tumor necrosis factor-alpha?

Insulin resistance occurs in pre-eclampsia, but the cause is unknown. Furthermore, it is uncertain whether women destined to develop pre-eclampsia have a pre-existing insulin resistance or whether it is acquired with the development of the disease. We carried out this study to test the hypotheses that the increase in insulin resistance associated with pre-eclampsia is related to higher levels of tumor necrosis factor (TNF)-alpha, and that the increase in insulin resistance precedes the clinical onset of the disease. Fasting plasma samples were obtained from ten women who subsequently developed pre-eclampsia and ten normal pregnant controls at 16, 20, 24, 28, 32 and 36 weeks' gestation to measure circulating levels of insulin, glucose and TNF-alpha. Fasting insulin resistance index (FIRI) was calculated from insulin and glucose concentrations. In the normal controls, fasting insulin and TNF-alpha levels, and FIRI increased with gestation, and these were significantly greater than baseline values from 24, 28 and 28 weeks, respectively. In the group of women who developed pre-eclampsia, plasma levels of insulin and the FIRI were significantly higher than baseline from 20 and 24 weeks, respectively, but both were significantly higher than in the control group at 32 and 36 weeks. The increase in TNF-alpha in the pre-eclampsia group was significantly greater than in normal pregnant controls (p < 0.001). However, there was no significant association between TNF-alpha levels and FIRI in either normal pregnancy or pregnancies developing pre-eclampsia. These data suggest that insulin resistance in pre-eclampsia precedes the clinical onset of the disease, but that it is not related to elevated levels of TNF-alpha.

Adult↗
PubMed2004

Mechanical stretch activates type 2 cyclooxygenase via activator protein-1 transcription factor in human myometrial cells.

The uterus is subject to stretch throughout pregnancy, which, in the presence of progesterone, is a potent stimulus for uterine growth. However, in the absence of progesterone or when stretch is excessive, as in multiple pregnancy, it may provoke the onset of labour. We have investigated the effect of stretch on prostaglandin synthesis in primary human uterine myocytes [non-pregnant (NP), pregnant not in labour (NL) and pregnant in labour (L)]. The cells were grown on flexible bottom culture plates and subjected to 1 or 6 h static stretch. Expression of type 2 cyclooxygenase (COX-2) mRNA was similar in samples obtained from NP and L groups and both were significantly greater than those found in the NL group. Stretch of cells from all groups resulted in increased COX-2 mRNA expression. In further studies carried out on cells taken from the NL group, 6 h of stretch resulted in increased COX-2 protein levels and, in the media, increases in prostaglandin (PG) I(2) metabolite and PGE(2) concentrations and a reduction in the concentration of PGF(2)alpha metabolites. After stretch, EMSA studies showed increased activator protein-1 (AP-1) nuclear protein DNA binding activity but not of nuclear factor kappaB. These data demonstrate that stretch of human myocytes results in increased COX-2 activity and suggest that this may occur through activation of the AP-1 system.

Adult↗
PubMed2004

Neurofibromatous neuropathy in neurofibromatosis 1 (NF1).

BACKGROUND: Neurofibromatosis 1 (NF1) is a common, autosomal dominant, neurocutaneous disease that is clinically and genetically distinct from the rare condition neurofibromatosis 2 (NF2). Neurofibromatous neuropathy has been regarded as a common feature of NF2, but is an unusual and unexplained complication of NF1. The clinical and histological features of the NF1 neuropathy are distinct from those encountered in NF2. We describe eight patients with a symmetrical polyneuropathy, which has been called neurofibromatous neuropathy. METHODS: Clinical assessments, laboratory investigations, neuroimaging, and neurophysiology were undertaken in eight individuals with neurofibromatous neuropathy. None were referred because of neuropathic symptoms. Two subjects underwent sural nerve biopsy and three agreed to mutational analysis. RESULTS: The patients had an indolent symmetrical predominantly sensory axonal neuropathy and unusually early development of large numbers of neurofibromas. The biopsied nerves showed diffuse neurofibromatous change and disruption of the perineurium. Two patients developed a high grade malignant peripheral nerve sheath tumour. Disease causing mutations were detected in two individuals and molecular studies did not reveal any whole gene deletions. CONCLUSIONS: Neurofibromatous neuropathy occurred in 1.3% of 600 patients with NF1. Its cause may be a diffuse neuropathic process arising from inappropriate signalling between Schwann cells, fibroblasts, and perineurial cells.

Adult↗
PubMed2003

Adsorption of argon on carbon nanotube bundles and its influence on the bundle lattice parameter.

We report experimental studies of the adsorption characteristics and structure of both 36Ar and 40Ar on single-wall carbon nanotube bundles. The structural studies make use of the large difference in coherent neutron scattering cross section for the two Ar isotopes to explore the influence of the adsorbate on the nanotube lattice parameter. We observe no dilation of the nanotube lattice with 40Ar, and explain the apparent expansion of this lattice upon 36Ar adsorption by the location of the adsorbed Ar atoms on the outer bundle surface.

Journal Article↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed2002

A longitudinal study of biochemical markers of bone turnover during normal pregnancy and pregnancies complicated by pre-eclampsia.

OBJECTIVES: To test the hypothesis that the increased bone turnover observed in established pre-eclampsia is present earlier in pregnancy prior to the diagnosis of pre-eclampsia. DESIGN: A prospective longitudinal study. SETTING: Obstetric Unit at Chelsea and Westminster Hospital, London. POPULATION: Nine women who subsequently developed pre-eclampsia and 17 normal pregnant controls. METHODS: Maternal plasma levels of the cross-linked carboxyl terminal telopeptide of the type I collagen (ICTP), a marker of bone resorption, and of the carboxy-terminal propeptide of type I collagen (PICP), a marker of bone formation, were measured longitudinally in nine women who developed pre-eclampsia and 17 women with normal pregnancy. Serial blood samples were obtained at 16, 20, 24, 28, 32 and 36 weeks of gestation and the levels of ICTP and PICP were measured by radio-immunoassay. RESULTS: ICTP and PICP increased progressively in the normal pregnant and pre-eclampsia groups, but the rate of increase was significantly greater in the latter (P = 0.00002 and 0.0008, unpaired t test, for ICTP and PICP summary measures, respectively). In the pre-eclampsia group, positive correlation were observed between ICTP levels at 36 weeks of gestation and plasma uric acid (r = 0.9, P = 0.001) and degree of proteinuria (r = 0.78, P = 0.04). No correlation was observed between the two bone markers and other variables during normal pregnant group. CONCLUSION: These data show that biochemical markers of bone turnover are greater in pregnancies complicated by pre-eclampsia compared with normal pregnancy but only when the disease is clinically evident.

Adult↗
PubMed2002

Does endothelial cell activation occur with intrauterine growth restriction?

It is possible that in fetal growth restriction without pre-eclampsia endothelial cell activation does not occur. This might be either because there is no release of 'factor X' or because of maternal resistance to its effects. To test this hypothesis, we took blood samples from 26 women with pre-eclampsia (without fetal growth restriction), 13 women with fetal growth restriction (without pre-eclampsia) and 24 normal pregnant controls, and measured the circulating levels of three markers of endothelial cell activation (soluble VCAM, ICAM and E-selectin) and three cytokines [tumour necrosis factor-a (TNF-alpha), interleukin-6 (IL-6) and -8 (IL-8)]. The levels of the markers of endothelial cell activation were raised in both pre-eclampsia and fetal growth restriction pregnancies compared with controls; however, the levels of TNF-alpha, IL-6 and IL-8 were significantly raised in pregnancies complicated by pre-eclampsia, but not in fetal growth restriction, compared with controls. These data show that endothelial cell activation is common to both pre-eclampsia and fetal growth restriction, but that the circulating levels of cytokines are elevated only in pre-eclampsia. Thus, it seems likely that endothelial cell activation is a consequence of a failure of trophoblast invasion and that a further step is required, possibly involving cytokine release, for the expression of the full clinical picture of pre-eclampsia.

Adult↗
PubMed2001

Coronary endothelial dysfunction after heart transplantation predicts allograft vasculopathy and cardiac death.

BACKGROUND: Coronary endothelial dysfunction may be an early marker for cardiac allograft vasculopathy (CAV) in orthotopic heart transplant recipients. Using serial studies with intravascular ultrasound and Doppler flow-wire measurements, we have previously demonstrated that annual decrements in coronary endothelial function are associated with progressive intimal thickening. The present study tested whether endothelial dysfunction predicts subsequent clinical events, including cardiac death and CAV development. METHODS AND RESULTS: Seventy-three patients were studied yearly beginning at transplantation until a prespecified end point was reached. End points were angiographic evidence of CAV (>50% stenosis) or cardiac death (graft failure or sudden death). At each study, coronary endothelial function was measured with intracoronary infusions of adenosine (32-microgram bolus), acetylcholine (54 microgram over 2 minutes), and nitroglycerin (200 microgram) into the left anterior descending coronary artery; intravascular ultrasound images and Doppler velocities were recorded simultaneously. Of the 73 patients studied, 14 reached an end point during the study (6 CAV and 8 deaths, including 4 with known CAV, 1 graft failure, and 3 sudden). On the last study performed, the group with an end point had decreased epicardial (constriction of 11.1+/-2.9% versus dilation of 1.7+/-2.2%, P=0.01) and microvascular (flow increase of 75+/-20% versus 149+/-16%, P=0.03) endothelium-dependent responses to acetylcholine compared with the patients who did not reach an end point. Responses to adenosine and nitroglycerin did not differ significantly. CONCLUSIONS: Endothelial dysfunction, as detected by abnormal responses to acetylcholine, preceded the development of clinical end points. These data implicate endothelial dysfunction in the development of clinically significant vasculopathy and suggest that serial studies of endothelial function have clinical utility.

Acetylcholine↗
PubMed2001

Intracellular inhibition of human neutrophil elastase by orally active pyrrolidine-trans-lactams.

Described are the acylation binding of trans-lactam 1 to porcine pancreatic elastase, the selection of the SO2Me activating group for the lactam N which also confers metabolic stability in hamster liver microsomes, the introduction of aqueous solubility through the piperidine salt 9, the in vivo oral activity of 9 and its bioavailability, and the introduction of 9 as an intracellular neutrophil elastase inhibitor.

Acylation↗
PubMed2001

Paroxetine for social anxiety and alcohol use in dual-diagnosed patients.

The objective of this study was to compare the efficacy and tolerability of paroxetine to matched placebo in adults with co-occurring social anxiety disorder and alcohol use disorder. Outcome measures included standardized indices of social anxiety and alcohol use. Fifteen individuals meeting DSM-IV criteria for both social anxiety disorder and alcohol use disorder were randomized to treatment. Paroxetine (n = 6) or placebo (n = 9) was given in a double-blind format for 8 weeks using a flexible dosing schedule. Dosing began at 20 mg/d and increased to a target dose of 60 mg/d. There was a significant effect of treatment group on social anxiety symptoms, where patients treated with paroxetine improved more than those treated with placebo on both the Clinical Global Index (CGI) and the Liebowitz Social Anxiety Scale (Ps < or = 0.05). On alcohol use, there was not a significant effect of treatment on quantity/frequency measures of drinking, but there was for the CGI ratings (50% paroxetine patients versus 11% placebo patients were improvers on drinking, P < or = 0.05). This pilot study suggests that paroxetine is an effective treatment for social anxiety disorder in individuals with comorbid alcohol problems, and positive treatment effects can be seen in as little as 8 weeks. Further study is warranted to investigate its utility in helping affected individuals reduce alcohol use.

Adolescent↗
PubMed2001

A longitudinal study of resting peripheral blood flow in normal pregnancy and pregnancies complicated by chronic hypertension and pre-eclampsia.

OBJECTIVES: To investigate the hypothesis that reduced resting tissue blood flow precedes the clinical onset of pre-eclampsia in women at risk of the disease. METHODS: We used venous occlusion plethysmography to compare resting calf muscle blood flow in 18 normal pregnant controls, 18 pregnant women with chronic hypertension, and 23 pregnant women at increased risk of developing pre-eclampsia. Calf blood flow was measured at 16, 20, 24, 28, 32 and 36 weeks of gestation. RESULTS: Blood flow increased with gestation in normal pregnancy (P = 0.004) and chronic hypertension (P = 0.006), but not in the 'at risk' women who did not develop pre-eclampsia (P = 0.36). In contrast, blood flow decreased significantly in eight out of the 23 women 'at risk', who developed pre-eclampsia (P < 0.00001, ANOVA). The decrease in flow preceded the clinical diagnosis of the pre-eclampsia by several weeks. Moreover, a significant inverse correlation was observed between resting blood flow and plasma uric acid concentrations (r = -0.86, P = 0.03) in the women that developed pre-eclampsia. CONCLUSIONS: We have shown that reduced resting blood flow precedes the clinical onset of pre-eclampsia independently of hypertension per se. These findings support the notion that impaired tissue blood flow may be involved at an early stage in the pathophysiology of the disease.

Chronic Disease↗
PubMed2001

The challenge of rejection and cardiac allograft vasculopathy.

Since the first human heart transplantation was performed in 1967, the field of heart transplantation has advanced to the point where survival and acceptable quality of life are commonplace. Despite remarkable progress in the clinical management of rejection, rejection continues to limit survival and quality of life in the heart transplant population. This review will discuss the biologic processes involved in hyperacute rejection, acute rejection, and humoral (vascular) rejection. The development of endomyocardial biopsy techniques represented a significant advancement in the diagnosis of cardiac rejection, and endomyocardial biopsy remains the 'gold standard' in the diagnosis of cellular rejection. To date, no noninvasive parameters will diagnose rejection with adequate sensitivity and specificity. Biopsy frequency and immunosuppressive therapies may be tailored to the risk of rejection. Immunosuppression for cardiac transplantation can be divided into three major phases: 1) perioperative immunosuppression; 2) maintenance immunosuppression, and; 3) treatment of rejection. The strategy for treating transplant rejection should be influenced by several variables: 1) Histologic grade of rejection; 2) Evidence of hemodynamic compromise by ejection fraction or right heart catheterization; 3) Severity of previous rejection episodes and types of immunosuppressives used; and 4) Risk factors for rejection, including time after transplantation. Future rejection therapy will involve more sophisticated attempts to alter host responses toward the donor organ in a more specific and selective way. Despite considerable advances in the care of the heart transplant recipient, long-term survival is limited by cardiac allograft vasculopathy. The final section of this chapter will review the pathology, immunopathology, nonimmunologic risk factors, diagnosis, prevention and treatment of allograft vasculopathy.

Cardiovascular Diseases↗