Showing papers by "Leicester Royal Infirmary published in 2000"

Increased Matrix Metalloproteinase-9 Activity in Unstable Carotid Plaques A Potential Role in Acute Plaque Disruption

Abstract: Background and Purpose —Acute disruption of atherosclerotic plaques precedes the onset of clinical syndromes, and studies have implicated a role for matrix metalloproteinases (MMPs) in this process. The aim of this study was to establish the character, level, and expression of MMPs in carotid plaques and to correlate this with clinical status, cerebral embolization, and histology. Methods —Plaques were obtained from 75 consecutive patients undergoing carotid endarterectomy and divided into 4 groups according to symptomatology (group 1, asymptomatic; group 2, symptomatic >6 months before surgery; group 3, symptomatic within 1 to 6 months; group 4, symptomatic within 1 month). All patients underwent preoperative and intraoperative transcranial Doppler monitoring. Plaques were subjected to histological examination and quantification of MMPs by zymography and ELISA. Results —The level of MMP-9 was significantly higher in group 4 (median 125.7 ng/mL for group 4, median <32 ng/mL for all other groups; P =0.003), with no difference in the levels of MMPs 1, 2, or 3. Furthermore, the MMP-9 concentration was significantly higher in plaques undergoing spontaneous embolization ( P =0.019) and those with histological evidence of plaque instability ( P <0.03). In situ hybridization demonstrated increased MMP-9 expression in highly symptomatic plaques in areas of intense inflammatory infiltrate. Conclusions —The concentration, production, and expression of MMP-9 is significantly higher in unstable carotid plaques. If this proves to be a causal relationship, MMP-9 may be a strong candidate for pharmacotherapy aimed at stabilizing plaques and preventing stroke.

Does ethnic origin influence the incidence or severity of keratoconus

Abstract: Purpose Keratoconus affects all races, yet very little infonnation exists as to the relative frequency in patients of different ethnic origin. We aimed to establish the incidence and severity of keratoconus in Asian and white patients. Methods The hospital records of the ophthalmology department of a large Midlands hospital with a catchment population of approximately 900 000 (87% white, 11% Asian, 2% other) were examined retrospectively for the 10 year period from 1989 to 1998. Results For the age group 10-44 years the prevalence of keratoconus in Asians and whites was 229 and 57 per 100 000 respectively, a relative prevalence of 4 to 1. The incidence of keratoconus in the same age group was 19.6 and 4.5 per 100 000 per year respectively, a relative incidence of 4.4 to 1. Asians were significantly younger at presentation compared with whites (mean 22.3 ± 6.5 vs 26.5 ± 8.5 years, p < 0.0001). A first corneal graft was carried out on 14% of the Asian and 15% of the white patients. Of those having grafts, Asians were significantly younger than white patients at the time of diagnosis (mean 19.1 ± 4.8 vs 25.7 ± 7.3 years, p=0.005) and at operation (mean 21.4 ± 5.0 vs 28.7 ± 7.7 years, p=0.004). The interval from diagnosis to operation, though shorter for Asians, was not significantly different (mean 1.8 ± 1.4 vs 2.5 ± 1.7 years, p=0.2). Conclusion The results show previously unrecognised racial differences in the hospital presentation of keratoconus in the UK. Compared with white patients, Asians have a fourfold increase in incidence, are younger at presentation and require corneal grafting at an earlier age.

Vascular endothelial growth factor, platelet-derived endothelial cell growth factor and angiogenesis in non-small-cell lung cancer.

Abstract: High microvessel density, an indirect measure of angiogenesis, has been shown to correlate with increased tumour size, lymph node involvement and poor prognosis in non-small-cell lung cancer (NSCLC). Tumour cell vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) expression correlate with angiogenesis and a poor outcome in this disease. In a retrospective study VEGF and PD-ECGF expression and microvessel density were evaluated immunohistochemically in surgically resected specimens (T1-3, N0-2) from 223 patients with operable NSCLC using the VG1, P-GF.44C and JC70 monoclonal antibodies respectively. High VEGF immunoreactivity was seen in 104 (46.6%) and PD-ECGF in 72 (32.3%) cases and both were associated with high vascular grade tumours (P= 0.009 and P= 0.05 respectively). Linear regression analysis revealed a weak positive correlation between VEGF and PD-ECGF expression in cancer cells (r= 0.21; P = 0.002). Co-expression of VEGF and PD-ECGF was not associated with a higher microvessel density than VEGF or PD-ECGF only expressing tumours. Furthermore a proportion of high vascular grade tumours expressed neither growth factor. Univariate analysis revealed tumour size, nodal status, microvessel density and VEGF and PD-ECGF expression as significant prognostic factors. Tumour size (P < 0.02) and microvessel density (P < 0.04) remained significant on multivariate analysis. In conclusion, VEGF and PD-ECGF are important angiogenic growth factors and have prognostic significance in NSCLC. Furthermore the study underlines the prognostic significance of microvessel density in operable NSCLC.

Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy.

Abstract: Cyclosporin (CyA) has been shown to be highly effective and well tolerated in the short-term treatment of severe childhood atopic dermatitis; however, there is limited experience in its longer-term use. The aim of this study was to compare multiple short courses of CyA with continuous therapy for 1 year, with respect to efficacy, safety, tolerability and quality of life. Children aged 2-16 years, with a diagnosis of severe atopic dermatitis refractory to topical steroid therapy, were randomly assigned to receive short course therapy (multiple courses of 12 weeks) or continuous therapy. The starting dose and maximum dose for all patients was 5 mg/kg per day. Disease activity was monitored using the Six Area Six Sign Atopic Dermatitis score and the 'Rule of Nines' area score. Pruritus, sleep disturbance and irritability were measured using visual analogue scales, and topical therapy was monitored. Safety measurements included monitoring of serum creatinine, blood pressure and adverse events. Forty patients were included in the efficacy analysis, 21 of whom were randomized to the short course group (of whom six were withdrawn) and 19 to the continuous group (of whom five were withdrawn). Significant improvements were seen in all efficacy parameters at every time-point. There were no significant differences between groups, although the improvement was more consistent in the continuous arm. In the short course arm, 7 out of 21 patients could be managed by at least two short courses. The remaining 14 patients includes 12 who could not be controlled by at least two short courses, one patient who failed to return after week 12 and another patient who was withdrawn at week 4 due to an adverse event. Quality of life improved for both the children and their families. Tolerability was considered good or very good in at least 80% of the patients at week 12 and at the end of the study. No clinically significant change was seen in mean serum creatinine and no change was seen in mean blood pressure in either group. CyA is effective in controlling severe atopic dermatitis in children over a 1-year period and is well tolerated. More consistent control is achieved with continuous treatment; however, short course therapy was adequate for some patients, indicating that treatment should be tailored to the individual patient's needs. Short course treatment may produce prolonged remission in some cases and reduce the cumulative exposure to the drug.

Analysis of ciliary beat pattern and beat frequency using digital high speed imaging: comparison with the photomultiplier and photodiode methods

Abstract: BACKGROUND—The aim of this study was to determine the relationship of the power and recovery stroke of respiratory cilia using digital high speed video imaging. Beat frequency measurements made using digital high speed video were also compared with those obtained using the photomultiplier and modified photodiode techniques. METHOD—Ciliated epithelium was obtained by brushing the inferior nasal turbinate of 20 healthy subjects. Ciliated edges were observed by microscopy and the deviation of cilia during their recovery stroke relative to the path travelled during their power stroke was measured. Beat frequency measurements made by digital high speed video analysis were compared with those obtained using the photomultiplier and modified photodiode. RESULTS—Cilia were found to beat with a forward power stroke and a backward recovery stroke within the same plane. The mean angular deviation of the cilia during the recovery stroke from the plane of the forward power stroke was only 3.6°(95% CI 3.1 to 4.1). There was a significant difference in beat frequency measurement between the digital high speed video (13.2 Hz (95% CI 11.8 to 14.6)) and both photomultiplier (12.0 Hz (95% CI 10.8 to 13.1), p = 0.01) and photodiode (11.2 Hz (95% CI 9.9 to 12.5), p<0.001) techniques. The Bland-Altman limits of agreement for the digital high speed video were -2.75 to 5.15 Hz with the photomultiplier and -2.30 to 6.06 Hz with the photodiode. CONCLUSION—Respiratory cilia beat forwards and backwards within the same plane without a classical sideways recovery sweep. Digital high speed video imaging allows both ciliary beat frequency and beat pattern to be evaluated.

Cerebral venous sinus thrombosis

Abstract: Cerebral venous sinus thrombosis is a challenging condition because of its variability of clinical symptoms and signs. It is very often unrecognised at initial presentation. All age groups can be affected. Large sinuses such as the superior sagittal sinus are most frequently involved. Extensive collateral circulation within the cerebral venous system allows for a significant degree of compensation in the early stages of thrombus formation. Systemic inflammatory diseases and inherited as well as acquired coagulation disorders are frequent causes, although in up to 30% of cases no underlying cause can be identified. The oral contraceptive pill appears to be an important additional risk factor. The spectrum of clinical presentations ranges from headache with papilloedema to focal deficit, seizures and coma. Magnetic resonance imaging with venography is the investigation of choice; computed tomography alone will miss a significant number of cases. It has now been conclusively shown that intravenous heparin is the first-line treatment for cerebral venous sinus thrombosis because of its efficacy, safety and feasability. Local thrombolysis may be indicated in cases of deterioration, despite adequate heparinisation. This should be followed by oral anticoagulation for 3-6 months. The prognosis of cerebral venous sinus thrombosis is generally favourable. A high index of clinical suspicion is needed to diagnose this uncommon condition so that appropriate treatment can be initiated.

Urinary 8-oxo-2'-deoxyguanosine--source, significance and supplements.

Abstract: Oxidative damage to cellular biomolecules, in particular DNA, has been proposed to play an important role in a number of patholgical conditions, including carcinogenesis. A much studied consequence...

Dynamic but not static cerebral autoregulation is impaired in acute ischaemic stroke.

Abstract: It remains unclear as to whether dynamic and static cerebral autoregulation (CA) are impaired in acute ischaemic stroke, and whether these changes are related to stroke subtype. This could have important implications with regard to post-stroke prognosis and the management of blood pressure (BP) in the acute post-ictal period. Using transcranial Doppler ultrasonography and non-invasive manipulation of BP, we compared both mechanisms in 61 patients with ischaemic stroke within 96 h of ictus, and 54 age- and sex-matched controls. There was no difference in static and dynamic CA indices between the various stroke subtypes. Combining all stroke subtypes dynamic autoregulation, as measured using thigh cuff release, was significantly impaired in both the affected and non-affected stroke hemispheres compared to controls (mean autoregulation index 4.1 +/- 3.3, 4.8 +/- 3.1 and 6.2 +/- 2.3, respectively, p < 0.05). By comparison static autoregulation, assessed using isometric hand grip and thigh cuff inflation, was not significantly different. In conclusion, dynamic but not static CA appears to be globally impaired in acute ischaemic stroke. This deserves further study and may identify possibilities for therapeutic intervention.

Vitamin D Receptor Polymorphisms Are Associated with Altered Prognosis in Patients with Malignant Melanoma

Abstract: Calcitriol[ 1,25(OH) 2 D 3 ], the hormonal derivative of vitamin D 3 , is an antiproliferative and prodifferentiation factor for several cell types, including cultured melanocytes and malignant melanoma (MM) cells. Several polymorphisms of the vitamin D receptor (VDR) gene have been described including a Fok I RFLP in exon 2, Bsm I, and Apa I polymorphisms in intron 8 and an adjacent Taq I RFLP in exon 9. Alterations in vitamin D/1,25(OH) 2 D 3 levels and polymorphisms of the VDR have been shown to be associated with several systemic malignancies. We hypothesize that polymorphism in this gene may be associated with altered susceptibility and outcome in patients with MM. A hospital-based case-control study, using 316 MM cases and 108 controls, was used to assess associations with MM susceptibility. Breslow thickness, the most important single prognostic factor in MM, was used as the outcome measure. Polymorphisms at the Fok I and Taq I restriction sites were determined using PCR-based methods. Polymorphism at the Fok I, but not Taq I, RFLP was associated with an altered risk of MM ( P = 0.014). More importantly, variant alleles were associated with increased Breslow thickness. Thus, homozygosity for variant alleles at both RFLP ( ttff genotype combination) was significantly associated with thicker tumors. (≥3.5 mm; P = 0.001; odds ratio = 31.5). Thus, polymorphisms of the VDR gene, which would be expected to result in impaired function, are associated with susceptibility and prognosis in MM. These data suggest that 1,25(OH) 2 D 3 , the ligand of the VDR, may have a protective influence in MM, as has been proposed for other malignancies.

Characterization of [Nphe1]nociceptin(1-13)NH2, a new selective nociceptin receptor antagonist

Abstract: Nociceptin (orphanin FQ) is a novel neuropeptide capable of inducing a variety of biological actions via activation of a specific G-protein coupled receptor However, the lack of a selective nociceptin receptor antagonist has hampered our understanding of nociceptin actions and the role of this peptide in pathophysiological states As part of a broader programme of research, geared to the identification and characterization of nociceptin receptor ligands, we report that the novel peptide [Nphe1]nociceptin(1-13)NH2 acts as the first truly selective and competitive nociceptin receptor antagonist and is devoid of any residual agonist activity [Nphe1]nociceptin(1-13)NH2 binds selectively to recombinant nociceptin receptors expressed in Chinese hamster ovary (CHO) cells (pKi 84) and competitively antagonizes the inhibitory effects of nociceptin (i) on cyclic AMP accumulation in CHO cells (pA2 60) and (ii) on electrically evoked contractions in isolated tissues of the mouse, rat and guinea-pig with pA2 values ranging from 60 to 64 [Nphe1]nociceptin(1-13)NH2 is also active in vivo, where it prevents the pronociceptive and antimorphine actions of intracerebroventricularly applied nociceptin, measured in the mouse tail withdrawal assay Moreover, [Nphe1]nociceptin(1-13)NH2 produces per se a dose dependent, naloxone resistant antinociceptive action and, at relatively low doses, potentiates morphine-induced analgesia Collectively our data indicate that [Nphe1]nociceptin(1-13)NH2, acting as a nociceptin receptor antagonist, may be the prototype of a new class of analgesics British Journal of Pharmacology (2000) 129, 1183–1193; doi:101038/sjbjp0703169

The relationship between angiogenesis and the immune response in carcinogenesis and the progression of malignant disease.

Abstract: Recent studies have demonstrated that angiogenesis and suppressed cell-mediated immunity (CMI) play a central role in the pathogenesis of malignant disease facilitating tumour growth, invasion and metastasis. In the majority of tumours, the malignant process is preceded by a pathological condition or exposure to an irritant which itself is associated with the induction of angiogenesis and/or suppressed CMI. These include: cigarette smoking, chronic bronchitis and lung cancer; chronic oesophagitis and oesophageal cancer; chronic viral infections such as human papilloma virus and ano-genital cancers, chronic hepatitis B and C and hepatocellular carcinoma, and Epstein-Barr virus (EBV) and lymphomas; chronic inflammatory conditions such as Crohn's disease and ulcerative colitis and colorectal cancer; asbestos exposure and mesothelioma and excessive sunlight exposure/sunburn and malignant melanoma. Chronic exposure to growth factors (insulin-like growth factor-I in acromegaly), mutations in tumour suppressor genes (TP53 in Li Fraumeni syndrome) and long-term exposure to immunosuppressive agents (cyclosporin A) may also give rise to similar environments and are associated with the development of a range of solid tumours. The increased blood supply would facilitate the development and proliferation of an abnormal clone or clones of cells arising as the result of: (a) an inherited genetic abnormality; and/or (b) acquired somatic mutations, the latter due to local production and/or enhanced delivery of carcinogens and mutagenic growth factors. With progressive detrimental mutations and growth-induced tumour hypoxia, the transformed cell, to a lesser or greater extent, may amplify the angiogenic process and CMI suppression, thereby facilitating further tumour growth and metastasis. There is accumulating evidence that long-term treatment with cyclo-oxygenase inhibitors (aspirin and indomethacin), cytokines such as interferon-alpha, anti-oestrogens (tamoxifen and raloxifene) and captopril significantly reduces the incidence of solid tumours such as breast and colorectal cancer. These agents are anti-angiogenic and, in the case of aspirin, indomethacin and interferon-alpha have proven immunomodulatory effects. Collectively these observations indicate that angiogenesis and suppressed CMI play a central role in the development and progression of malignant disease.

Rapid flow cytometric test for the diagnosis of membrane cytoskeleton-associated haemolytic anaemia.

Abstract: The flow cytometric test measures the fluorescence intensity of intact red cells labelled with the dye eosin-5-maleimide, which reacts covalently with Lys-430 on the first extracellular loop of band 3 protein. In this study, red cells from patients with hereditary spherocytosis (HS), congenital dyserythropoietic anaemia type II, South-east Asian ovalocytosis and cryohydrocytosis have produced a greater degree of reduction of mean channel fluorescence readings than those for other patient groups and normal controls. The predictive value of this test for membrane abnormality was compared with the results obtained from the sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) method, which is currently the reference laboratory test for the identification of membrane protein deficiencies in hereditary spherocytosis and for the detection of spectrin variants in hereditary elliptocytosis. The dye method is a reliable, speedy diagnostic test (2 h from sample collection to result) for HS with a sensitivity of 92.7% and a specificity of 99.1%. Thus, it will serve well as a first-line screening test for the diagnosis of hereditary spherocytosis in routine haematology.

The relationship between angiogenesis and the immune response in carcinogenesis and the progression of malignant disease

Abstract: Recent studies have demonstrated that angiogenesis and suppressed cell- mediated immunity (CMI) play a central role in the pathogenesis of malignant disease facilitating tumour growth, invasion and metastasis. In the majority of tumours, the malignant process is preceded by a pathological condition or exposure to an irritant which itself is associated with the induction of angiogenesis and/or suppressed CMI. These include: cigarette smoking, chronic bronchitis and lung cancer; chronic oesophagitis and oesophageal cancer; chronic viral infections such as human papilloma virus and ano-genital cancers, chronic hepatitis B and C and hepatocellular carcinoma, and Epstein- Barr virus (EBV) and lymphomas; chronic inflammatory conditions such as Crohn's disease and ulcerative colitis and colorectal cancer; asbestos exposure and mesothelioma and excessive sunlight exposure/sunburn and malignant melanoma. Chronic exposure to growth factors (insulin-like growth factor-I in acromegaly), mutations in tumour suppressor genes (TP53 in Li Fraumeni syndrome) and long-term exposure to immunosuppressive agents (cyclosporin A) may also give rise to similar environments and are associated with the development of a range of solid tumours. The increased blood supply would facilitate the development and proliferation of an abnormal clone or clones of cells arising as the result of: (a) an inherited genetic abnormality; and/or (b) acquired somatic mutations, the latter due to local production and/or enhanced delivery of carcinogens and mutagenic growth factors. With progressive detrimental mutations and growth-induced tumour hypoxia, the transformed cell, to a lesser or greater extent, may amplify the angiogenic process and CMI suppression, thereby facilitating further tumour growth and metastasis. There is accumulating evidence that long-term treatment with cyclo-oxygenase inhibitors (aspirin and indomethacin), cytokines such as interferon-α, anti-oestrogens (tamoxifen and raloxifene) and captopril significantly reduces the incidence of solid tumours such as breast and colorectal cancer. These agents are anti-angiogenic and, in the case of aspirin, indomethacin and interferon-α have proven immunomodulatory effects. Collectively these observations indicate that angiogenesis and suppressed CMI play a central role in the development and progression of malignant disease. (C) 2000 Elsevier Science Ltd.

Plasma N terminal pro-brain natriuretic peptide and cardiotrophin 1 are raised in unstable angina.

Abstract: OBJECTIVE To compare circulating concentrations of N terminal pro-brain natriuretic peptide (N-BNP) and cardiotrophin 1 in stable and unstable angina. DESIGN AND SETTING Observational study in a teaching hospital. PATIENTS 15 patients with unstable angina, 10 patients with stable angina, and 15 controls. MAIN OUTCOME MEASURES Resting plasma N-BNP and cardiotrophin 1 concentrations. RESULTS N-BNP concentration (median (range)) was 714 fmol/ml (177–3217 fmol/ml) in unstable angina, 169.5 fmol/ml (105.7–399.5 fmol/ml) in stable angina (p = 0.005 v unstable angina), and 150.5 fmol/ml (104.7–236.9 fmol/ml) in controls (p v unstable angina; NS v stable angina). Cardiotrophin 1 concentration was 142.5 fmol/ml (42.2–527.4 fmol/ml) in unstable angina, 73.2 fmol/ml (41.5–102.1 fmol/ml) in stable angina (p v unstable angina), and 27 fmol/ml (6.9–54.1 fmol/ml) in controls (p v stable angina; p v unstable angina). Log cardiotrophin 1 correlated with log N-BNP in unstable angina ( r = 0.93, p CONCLUSIONS Both circulating N-BNP and cardiotrophin 1 are raised in unstable angina, while cardiotrophin 1 alone is raised in stable angina. The role of cardiotrophin 1 and the relation between cardiotrophin 1 and N-BNP in myocardial ischaemia remain to be defined.

Müllerian agenesis: etiology, diagnosis, and management.

Abstract: Mullerian agenesis, a congenital malformation of the genital tract is the second most common cause of primary amenorrhea. Its etiology is poorly understood but it may be associated with renal, skeletal, and other abnormalities. The diagnosis is often made either radiologically or laparoscopically in patients in whom hormonal and karyotypic investigations for primary amenorrhea are normal. Two-dimensional ultrasound is not a reliable method of diagnosis, as exemplified by the two cases presented in this review; however, three-dimensional ultrasound may be a more sensitive diagnostic tool. The management is varied, but we conclude that the treatment of choice should be a nonsurgical approach aimed at creating a neovagina. Because of the implications for reproduction, these patients require psychological support, which should be offered as part of therapy. Target audience: Gynecologists and Family Physicians Learning objectives: After completion of this article, the reader will be able to describe the patho

Activating and inactivating mutations in the human GNAS1 gene.

Abstract: GNAS1 on chromosome 20 is a complex locus, encoding multiple proteins, of which Gsα, the α-subunit of the heterotrimeric stimulatory G protein Gs, is of particular interest clinically. Amino acid substitutions at two specific codons lead to constitutive activation of Gsα. Such gain-of-function mutations are found in a variety of sporadic endocrine tumors and in McCune-Albright syndrome, a sporadic condition characterized by multiple endocrine abnormalities. Heterozygous loss of Gsα function results in the dominantly inherited condition, Albright hereditary osteodystrophy (AHO). Here we present a review of published GNAS1 mutations and report 19 additional mutations, of which 15 are novel. A diverse range of inactivating mutations has been detected, scattered throughout the gene but showing some evidence of clustering. Only one, a recurring 4 bp deletion in exon 7, could be considered common among AHO patients. The parental origin of the mutation apparently determines whether or not the patient shows end-organ resistance to hormones such as parathyroid hormone. Gsα is biallelically expressed in all tissues studied to date and thus there is no direct evidence that this transcript is imprinted. However, the recent identification of other imprinted transcripts encoded by GNAS1 and overlapping Gsα, together with at least one imprinted antisense transcript, raises intriguing questions about how the primary effect of mutations in GNAS1 might be modulated. Hum Mutat 16:183–189, 2000. © 2000 Wiley-Liss, Inc.

Mutation Analysis and Embryonic Expression of the HLXB9 Currarino Syndrome Gene

Abstract: The HLXB9 homeobox gene was recently identified as a locus for autosomal dominant Currarino syndrome, also known as hereditary sacral agenesis (HSA). This gene specifies a 403-amino acid protein containing a homeodomain preceded by a very highly conserved 82-amino acid domain of unknown function; the remainder of the protein is not well conserved. Here we report an extensive mutation survey that has identified mutations in the HLXB9 gene in 20 of 21 patients tested with familial Currarino syndrome. Mutations were also detected in two of seven sporadic Currarino syndrome patients; the remainder could be explained by undetected mosaicism for an HLXB9 mutation or by genetic heterogeneity in the sporadic patients. Of the mutations identified in the 22 index patients, 19 were intragenic and included 11 mutations that could lead to the introduction of a premature termination codon. The other eight mutations were missense mutations that were significantly clustered in the homeodomain, resulting, in each patient, in nonconservative substitution of a highly conserved amino acid. All of the intragenic mutations were associated with comparable phenotypes. The only genotype-phenotype correlation appeared to be the occurrence of developmental delay in the case of three patients with microdeletions. HLXB9 expression was analyzed during early human development in a period spanning Carnegie stages 12-21. Signal was detected in the basal plate of the spinal cord and hindbrain and in the pharynx, esophagus, stomach, and pancreas. Significant spatial and temporal expression differences were evident when compared with expression of the mouse Hlxb9 gene, which may partly explain the significant human-mouse differences in mutant phenotype.

Impaired glucose tolerance and fasting hyperglycaemia have different characteristics

Abstract: Summary Aims Use of the oral glucose tolerance test (OGTT) to define glucose intolerance in the general population may bias towards selection of those with insulin resistance. Beta cell function and insulin resistance markers were analysed in four groups: controls (n = 101); fasting hyperglycaemia (FH, n 45); impaired glucose tolerance; (IGT, n = 16) and those with features of both FH and IGT (‘Both’, n = 30). Methods Subjects underwent an OGTT. Plasma glucose, fasting lipid profiles, fasting, 30 and 120 min insulin were measured and beta cell function (% B) and insulin sensitivity (% S) assessed by homeostatic model assessment (HOMA) Results The FH group compared to controls had a significantly lower % B. The IGT group compared to controls had features of insulin resistance (higher body mass index (BMI), systolic blood pressure and 2 h insulin concentration). Subjects with ‘both’ IGT and FH had features of insulin resistance (higher BMI, systolic and diastolic blood pressure and triglyceride concentration) as well as beta cell dysfunction with a lower % B and 30 min insulin–glucose ratio compared to controls. There was a preponderance of males in this group. In all, 192 subjects' 30-min insulin concentration and incremental insulin response showed only a significantly negative correlation with fasting glucose concentration. In a linear regression analysis, a low 30-min insulin–glucose ratio was only a significant factor in the fasting glucose model. Thus, higher fasting glucose concentrations appear to be associated with beta cell dysfunction. However, HbA1 only showed a significant correlation with 120-min glucose, not fasting glucose concentration. Conclusions In those with milder degrees of glucose intolerance, FH is associated with beta cell dysfunction and those with IGT and a relatively ‘normal’ fasting glucose have features of the insulin resistance syndrome.

Multivariate dynamic analysis of cerebral blood flow regulation in humans

Abstract: The contributions of beat-to-beat changes in mean arterial blood pressure (MABP) and breath-by-breath fluctuations in end-tidal CO/sub 2/ (EtCO/sub 2/) as determinants of the spontaneous variability of cerebral blood flow velocity (CBFV) were studied in 16 normal subjects at rest. The two input variables (MABP and EtCO/sub 2/) had significant cross-correlations with CBFV but not between them. Transfer functions were estimated as the multivariate least mean square finite impulse response causal filters. MABP showed a very significant effect in explaining CBFV variability (p<10/sup -11/, Fisher's aggregated-p test) and the model mean square error was significantly reduced (p<0.001) by also including the contribution EtCO/sub 2/. The estimated mean CBFV step response to MABP displayed the characteristic return to baseline caused by the cerebral autoregulatory response. The corresponding response to EtCO/sub 2/ showed a gradual rise taking approximately 10 s to reach a plateau of 2.5%/mmHg. This study demonstrated that spontaneous fluctuations in EtCO/sub 2/ can help to explain the CBFV variability at rest if appropriate signal processing techniques are employed to address the limited power and bandwidth of the breath-by-breath EtCO/sub 2/ signal.

Comparison of different doses of remifentanil on the cardiovascular response to laryngoscopy and tracheal intubation.

Abstract: We have compared three bolus and infusion regimens of remifentanil on the cardiovascular response to laryngoscopy and orotracheal intubation in three groups of 20 ASA I-II female patients, in a randomized, double-blind study. Patients in group 1 received glycopyrolate 200 micrograms i.v. followed by a bolus dose of remifentanil 1 microgram kg-1 over 30 s and an infusion of remifentanil at a rate of 0.5 microgram kg-1 min-1. The other patients received remifentanil 0.5 microgram kg-1 over 30 s and an infusion of 0.25 microgram kg-1 min-1 with (group 2) or without (group 3) pretreatment with glycopyrrolate 200 micrograms. All patients then received a sleep dose of propofol, rocuronium 0.6 mg kg-1 and 1% isoflurane with 67% nitrous oxide in oxygen. Laryngoscopy and tracheal intubation were performed 3 min later. Heart rate and arterial pressure were recorded at 1-min intervals from before induction of anaesthesia until 5 min after intubation. Baseline heart rate was similar in all groups, but decreased in group 3 (no glycopyrrolate) after induction and remained significantly lower after intubation compared with the other groups (P < 0.05). Heart rate and arterial pressure increased slightly after intubation in each group but there were no significant differences in mean arterial pressure between groups at any time. The incidence of bradycardia (one patient in group 2) and hypotension (two patients in groups 1 and 2 and three patients in group 3) was low.

Assessment of the Thigh Cuff Technique for Measurement of Dynamic Cerebral Autoregulation

Abstract: Background and Purpose—Dynamic methods of measuring cerebral autoregulation have become an accepted alternative to static evaluation. This article aims to describe a set of data collected from healthy volunteers by a dynamic method, the purpose being to qualify and quantify expected results for those who may be designing a study using this technique. Methods—Cerebral blood flow velocity (CBFV) (measured by transcranial Doppler) and arterial blood pressure (Finapres) were recorded in 16 normal subjects before, during, and after the induction of a blood pressure drop (release of bilateral thigh cuffs). This procedure was repeated 6 times for each subject. A mathematical model was applied to the data to generate an autoregulatory index (ARI) with values between 0 and 9. Results—The ARI values for this sample population follow a normal distribution, with a mean±SD of 4.98±1.06 (n=15). Analysis of the cumulative mean ARI values of all subjects showed an exponential-type convergence of ARI toward the sample mea...

Endometrial protection from tamoxifen-stimulated changes by a levonorgestrel-releasing intrauterine system: a randomised controlled trial

Abstract: Summary Introduction Tamoxifen is currently the most commonly used adjuvant treatment for breast cancer, however, it frequently causes episodes of unscheduled uterine bleeding, which could be associated with proliferative changes of the endometrium, or even endometrial cancer. We aimed to assess whether a levonorgestrel intrauterine system could modulate the uterine responses to tamoxifen. We also aimed to assess women's tolerance of the screening procedures, the insertion, removal, and potential side-effects of the device. Methods We did a randomised controlled trial, in which postmenopausal women who had had at least 1 year of adjuvant tamoxifen treatment and who were undergoing regular follow-up for breast cancer were randomly assigned to either endometrial surveillance alone, or endometrial surveillance before and after insertion of the levonorgestrel intrauterine system for 12 months. We assessed tolerance of the surveillance procedures and the device with visual analogue scales. Findings Baseline assessment showed only benign uterine changes in all women (n=122). Hysteroscopic assessment indicated a uniform decidual response (confirmed histologically in 40 of 41 cases) in all women fitted with the intrauterine system; there were no new polyps in these women and 13% had fewer fibroids than in controls. Both screening procedures and device were well tolerated. There was an excess of bleeding in the women fitted with intrauterine systems but this resolved to a baseline similar to those receiving surveillance only. Interpretation The levonorgestrel-releasing intrauterine system had a protective action against the uterine effects of tamoxifen. The effectiveness of this device in preventing uterine changes in the endometrium needs to be assessed in the context of decreasing the need for repeated investigations of postmenopausal bleeding in women taking tamoxifen.

The treatment of Wilms' tumour: results of the United Kingdom Children's cancer study group (UKCCSG) second Wilms' tumour study.

Abstract: The aims of the UKW2 study were: (1) to further refine treatment for stage I and II favourable histology (FH) patients; (2) to consolidate the UKW1 results for stage III FH patients; (3) to improve the outlook for patients with inoperable primary tumours and those patients with stage IV and unfavourable histology disease Treatment consisted of primary nephrectomy, wherever possible, followed by chemotherapy and radiotherapy, as dictated by stage and histology Treatment was refined successfully for stage I and II FH patients The 4-year event-free survival for these two groups was 94% and 91%, respectively Stage III FH patients had a 4-year event free survival of 84% The outlook for patients with clear cell sarcoma of the kidney is as good as for patients with favourable histology, whilst that for patients with anaplastic or rhabdoid variants remains poor The outlook for the majority of children with Wilms' tumour is now excellent

Relative roles of pneumolysin and hydrogen peroxide from Streptococcus pneumoniae in inhibition of ependymal ciliary beat frequency.

Abstract: Ciliated ependymal cells line the ventricular system of the brain and the cerebral aqueducts. This study characterizes the relative roles of pneumolysin and hydrogen peroxide (H(2)O(2)) in pneumococcal meningitis, using the in vitro ependymal ciliary beat frequency (CBF) as an indicator of toxicity. We have developed an ex vivo model to examine the ependymal surface of the brain slices cut from the fourth ventricle. The ependymal cells had cilia beating at a frequency of between 38 and 44Hz. D39 (wild-type) and PLN-A (pneumolysin-negative) pneumococci at 10(8) CFU/ml both caused ciliary slowing. Catalase protected against PLN-A-induced ciliary slowing but afforded little protection from D39. Lysed PLN-A did not reduce CBF, whereas lysed D39 caused rapid ciliary stasis. There was no effect of catalase, penicillin, or catalase plus penicillin on the CBF. H(2)O(2) at a concentration as low as 100 microM caused ciliary stasis, and this effect was abolished by coincubation with catalase. An additive inhibition of CBF was demonstrated using a combination of both toxins. A significant inhibition of CBF at between 30 and 120 min was demonstrated with both toxins compared with either H(2)O(2) (10 microM) or pneumolysin (1 HU/ml) alone. D39 released equivalent levels of H(2)O(2) to those released by PLN-A, and these concentrations were sufficient to cause ciliary stasis. The brain slices did not produce H(2)O(2), and in the presence of 10(8) CFU of D39 or PLN-A per ml there was no detectable bacterially induced increase of H(2)O(2) release from the brain slice. Coincubation with catalase converted the H(2)O(2) produced by the pneumococci to H(2)O. Penicillin-induced lysis of bacteria dramatically reduced H(2)O(2) production. The hemolytic activity released from D39 was sufficient to cause rapid ciliary stasis, and there was no detectable release of hemolytic activity from the pneumolysin-negative PLN-A. These data demonstrate that D39 bacteria released pneumolysin, which caused rapid ciliary stasis. D39 also released H(2)O(2), which contributed to the toxicity, but this was masked by the more severe effects of pneumolysin. H(2)O(2) released from intact PLN-A was sufficient to cause rapid ciliary stasis, and catalase protected against H(2)O(2)-induced cell toxicity, indicating a role for H(2)O(2) in the response. There is also a slight additive effect of pneumolysin and H(2)O(2) on ependymal toxicity; however, the precise mechanism of action and the role of these toxins in pathogenesis remain unclear.