Showing papers by "Leicester Royal Infirmary published in 2008"

Mutations in the Pericentrin (PCNT) Gene Cause Primordial Dwarfism

Abstract: Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin (PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism type II (MOPD II) in 25 patients. Adults with this rare inherited condition have an average height of 100 centimeters and a brain size comparable to that of a 3-month-old baby, but are of near-normal intelligence. Absence of PCNT results in disorganized mitotic spindles and missegregation of chromosomes. Mutations in related genes are known to cause primary microcephaly (MCPH1, CDK5RAP2, ASPM, and CENPJ).

The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential

Abstract: Identification of the enigmatic nociceptin/orphanin FQ peptide (N/OFQ) in 1995 represented the first successful use of reverse pharmacology and led to deorphanization of the N/OFQ receptor (NOP). Subsequently, the N/OFQ-NOP system has been implicated in a wide range of biological functions, including pain, drug abuse, cardiovascular control and immunity. Although this could be considered a hurdle for the development of pharmaceuticals selective for a specific disease indication, NOP represents a viable drug target. This article describes potential clinical indications and highlights the current status of the very limited number of clinical trials.

Cerebral Autoregulation: From Models to Clinical Applications

Abstract: Short-term regulation of cerebral blood flow (CBF) is controlled by myogenic, metabolic and neurogenic mechanisms, which maintain flow within narrow limits, despite large changes in arterial blood pressure (ABP). Static cerebral autoregulation (CA) represents the steady-state relationship between CBF and ABP, characterized by a plateau of nearly constant CBF for ABP changes in the interval 60–150 mmHg. The transient response of the CBF–ABP relationship is usually referred to as dynamic CA and can be observed during spontaneous fluctuations in ABP or from sudden changes in ABP induced by thigh cuff deflation, changes in posture and other manoeuvres. Modelling the dynamic ABP–CBFV relationship is an essential step to gain better insight into the physiology of CA and to obtain clinically relevant information from model parameters. This paper reviews the literature on the application of CA models to different clinical conditions. Although mathematical models have been proposed and should be pursued, most studies have adopted linear input–output (‘black-box’) models, despite the inherently non-linear nature of CA. The most common of these have been transfer function analysis (TFA) and a second-order differential equation model, which have been the main focus of the review. An index of CA (ARI), and frequency-domain parameters derived from TFA, have been shown to be sensitive to pathophysiological changes in patients with carotid artery disease, stroke, severe head injury, subarachnoid haemorrhage and other conditions. Non-linear dynamic models have also been proposed, but more work is required to establish their superiority and applicability in the clinical environment. Of particular importance is the development of multivariate models that can cope with time-varying parameters, and protocols to validate the reproducibility and ranges of normality of dynamic CA parameters extracted from these models.

DNAI2 mutations cause primary ciliary dyskinesia with defects in the outer dynein arm.

Abstract: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by chronic destructive airway disease and randomization of left/right body asymmetry. Males often have reduced fertility due to impaired sperm tail function. The complex PCD phenotype results from dysfunction of cilia of the airways and the embryonic node and the structurally related motile sperm flagella. This is associated with underlying ultrastructural defects that frequently involve the outer dynein arm (ODA) complexes that generate cilia and flagella movement. Applying a positional and functional candidate-gene approach, we identified homozygous loss-of-function DNAI2 mutations (IVS11+1G > A) in four individuals from a family with PCD and ODA defects. Further mutational screening of 105 unrelated PCD families detected two distinct homozygous mutations, including a nonsense (c.787C > T) and a splicing mutation (IVS3-3T > G) resulting in out-of-frame transcripts. Analysis of protein expression of the ODA intermediate chain DNAI2 showed sublocalization throughout respiratory cilia. Electron microscopy showed that mutant respiratory cells from these patients lacked DNAI2 protein expression and exhibited ODA defects. High-resolution immunofluorescence imaging demonstrated absence of the ODA heavy chains DNAH5 and DNAH9 from all DNAI2 mutant ciliary axonemes. In addition, we demonstrated complete or distal absence of DNAI2 from ciliary axonemes in respiratory cells of patients with mutations in genes encoding the ODA chains DNAH5 and DNAI1, respectively. Thus, DNAI2 and DNAH5 mutations affect assembly of proximal and distal ODA complexes, whereas DNAI1 mutations mainly disrupt assembly of proximal ODA complexes.

Extracorporeal membrane oxygenation for severe respiratory failure in newborn infants.

Abstract: Background Neonatal extracorporeal membrane oxygenation (ECMO) is a complex procedure of life support used in severe but potentially reversible respiratory failure in term infants. Although the number of babies eligible for ECMO is small and the use of ECMO invasive and potentially expensive, its benefits may be high. Objectives To determine whether ECMO used for neonatal infants with severe respiratory failure is clinically and cost effective compared to conventional ventilatory support. Search methods The Cochrane Neonatal Group Specialised Register, the Cochrane Controlled Trials Register, and MEDLINE were searched for 1974 to 2007. Selection criteria All randomised trials comparing neonatal ECMO to conventional ventilatory support. Data collection and analysis The authors independently evaluated the trials for methodological quality and appropriateness for inclusion in the Review (without consideration of their results) and independently extracted the data. Main results The four trials (three USA and one UK) recruited clinically similar groups of babies. Two trials excluded infants with congenital diaphragmatic hernias. In two trials, transfer for ECMO implied transport over long distances. Two trials had follow-up information. One study included economic evaluation. The three USA trials had very small numbers of patients. Two trials used conventional randomisation with low potential for bias. Two used less usual designs, which led to difficulties in their interpretation. All four trials showed strong benefit of ECMO on mortality (typical RR 0.44; 95% CI 0.31 to 0.61), especially for babies without congenital diaphragmatic hernia (typical RR 0.33, 95% CI 0.21 to 0.53). The UK trial provided follow up information about death or severe disability, and cost-effectiveness, and showed benefit of ECMO at one year (RR 0.56, 95% CI 0.40 to 0.78), four years (RR 0.62, 95% CI 0.45 to 0.86), and seven years (RR 0.64, 95% CI 0.47 to 0.86). Overall nearly half of the children recruited had died or were severely disabled by seven years of age, reflecting the severity of their underlying conditions. A policy of ECMO is as cost-effective as other intensive care technologies in common use. Authors' conclusions A policy of using ECMO in mature infants with severe but potentially reversible respiratory failure results in significantly improved survival without increased risk of severe disability. The benefit of ECMO for babies with diaphragmatic hernia is unclear. Further studies are needed to consider the optimal timing for introducing ECMO; to identify which infants are most likely to benefit; and to address the implications of neonatal ECMO during later childhood and adult life.

Haematological toxicity of drugs used in psychiatry.

Abstract: Almost all classes of psychotropic agents have been reported to cause blood dyscrasias. Mechanisms include direct toxic effects upon the bone marrow, the formation of antibodies against haematopoietic precursors or involve peripheral destruction of cells. Agranulocytosis is probably the most important drug-related blood dyscrasia. The mortality from drug-induced agranulocytosis is 5-10% in Western countries. The manifestations of agranulocytosis are secondary to infection. Aggressive treatment with intravenous broad-spectrum antimicrobials and bone marrow stimulants may be required. Of drugs encountered in psychiatry, antipsychotics including clozapine (risk of agranulocytosis approximately 0.8%, predominantly in the first year of treatment) and phenothiazines (chlorpromazine agranulocytosis risk approximately 0.13%), and antiepileptics (notably carbamazepine, neutropenia risk approximately 0.5%) are the most common causes of drug-related neutropenia/agranulocytosis. Drugs known to cause neutropenia should not be used concomitantly with other drugs known to cause this problem. High temperature and other indicators of possible infection should be looked for routinely during treatment. Clozapine is well known as a drug that can cause blood dyscrasias, but olanzapine and other atypicals may also cause similar problems. In addition to genetic factors, there are likely to be dose-related and immunological components to these phenomena. Important lessons have been learnt from the haematological monitoring that is necessary with clozapine and the monitoring has been very successful in preventing deaths related to clozapine-induced agranulocytosis. Continuing research into the mechanisms of drug-induced neutropenia and agranulocytosis may serve to further enhance the safe use not only of clozapine, but also of other agents.

Blood leucocyte telomere DNA content predicts vascular telomere DNA content in humans with and without vascular disease.

Abstract: Aims Previous studies have suggested that reduced telomere length in circulating leucocytes in humans is associated with premature vascular disease and by implication, accelerated vascular ageing. Importantly, a link between telomere length in circulating leucocytes and the blood vessel wall has never been established. We, thus, investigated the relationship between vascular wall and circulating leucocyte telomere length in humans with and without overt vascular disease. Methods and results Aortic biopsies and paired blood leucocytes were obtained from 20 patients with asymptomatic abdominal aortic aneurysms (AAAs), undergoing elective open repair, and 12 morphologically normal aortas from a group of cadaveric organ donors of similar mean age. Telomere content was compared by quantitative PCR and expressed as telomere:genomic DNA ratio. The telomere:genomic DNA content was significantly reduced in wall biopsies of AAA vs. normal aorta, and this difference remained after adjusting for age and gender. There were strong correlations between leucocyte and vascular telomere content when the AAA and control groups were analysed either separately or grouped irrespective of the presence of vascular disease ( r = 0.62, P < 0.001). Conclusion The findings demonstrate that leucocyte DNA content is predictive of vascular telomere content and is an accurate surrogate for human vascular age.

Are family factors universally related to metabolic outcomes in adolescents with Type 1 diabetes

Abstract: AIMS: To assess the importance of family factors in determining metabolic outcomes in adolescents with Type 1 diabetes in 19 countries. METHODS: Adolescents with Type 1 diabetes aged 11-18 years, from 21 paediatric diabetes care centres, in 19 countries, and their parents were invited to participate. Questionnaires were administered recording demographic data, details of insulin regimens, severe hypoglycaemic events and number of episodes of diabetic ketoacidosis. Adolescents completed the parental involvement scale from the Diabetes Quality of Life for Youth--Short Form (DQOLY-SF) and the Diabetes Family Responsibility Questionnaire (DFRQ). Parents completed the DFRQ and a Parental Burden of Diabetes score. Glycated haemoglobin (HbA(1c)) was analysed centrally on capillary blood. RESULTS: A total of 2062 adolescents completed a questionnaire, with 2036 providing a blood sample; 1994 parents also completed a questionnaire. Family demographic factors that were associated with metabolic outcomes included: parents living together (t = 4.1; P < 0.001), paternal employment status (F = 7.2; d.f. = 3; P < 0.001), parents perceived to be over-involved in diabetes care (r = 0.11; P < 0.001) and adolescent-parent disagreement on responsibility for diabetes care practices (F = 8.46; d.f. = 2; P < 0.001). Although these factors differed between centres, they did not account for centre differences in metabolic outcomes, but were stronger predictors of metabolic control than age, gender or insulin treatment regimen. CONCLUSIONS: Family factors, particularly dynamic and communication factors such as parental over-involvement and adolescent-parent concordance on responsibility for diabetes care appear be important determinants of metabolic outcomes in adolescents with diabetes. However, family dynamic factors do not account for the substantial differences in metabolic outcomes between centres

Stockpiling prepandemic influenza vaccines: a new cornerstone of pandemic preparedness plans

Abstract: The history of pandemic influenza, along with the evolving epizootic of the highly pathogenic avian influenza A (H5N1) virus and the severity of associated human infections, serve as a warning to the world of the threat of another influenza pandemic Conservative estimates suggest that up to 350 million people could die and many more would be affected, causing disruption to health-care systems, society, and the world's economy WHO has encouraged countries to prepare in advance by developing influenza pandemic preparedness plans that involve public-health and pharmaceutical interventions Vaccination is a cornerstone of these plans; however, a pandemic vaccine cannot be manufactured in advance because the next pandemic virus cannot be predicted The concepts of vaccine stockpiling and prepandemic vaccination have thus become attractive Human H5N1 vaccines are currently available and can induce heterotypic immunity WHO and governments should give urgent consideration to the use of these vaccines for the priming of individuals or communities who would be at greatest risk of infection if an H5N1 influenza pandemic were to emerge

HER2 testing in the UK - further update to recommendations

Abstract: These guidelines update the previous UK HER2 testing guidelines and have been formulated to give advice on methodology, interpretation and quality assurance to ensure that HER2 testing results are accurate, reliable and timely with the expansion of testing to all patients with breast cancer at the time of primary diagnosis. The recommendations for testing are the use of immunohistochemistry but with analysis of equivocal cases by in situ hybridisation to clarify their HER2 status or the use of frontline fluorescence in situ hybridisation (FISH) testing for those laboratories wishing to do so; the inclusion of a chromosome 17 probe is strongly recommended. Laboratories using chromogenic or silver in situ hybridisation should perform an initial validation against FISH. For immunohistochemistry and in situ hybridisation there must be participation in the appropriate National External Quality Assurance scheme.

The natural history of the severe form of Hunter's syndrome: a study based on 52 cases.

Abstract: SUMMARY During a national survey of Hunter's syndrome, 52 boys with the severe form were ascertained. The averageages of onset and death were 2. 47 and 11.77 years respectively. Most patients had a large head and short stature. Persistent diarrhoea was noted in 65 per cent of the patients. 76 per cent had an umbilical hernia. Right and left inguinal herniae were noted in 51 and 32 per cent respectively. Evidence of cardiovascular disease was found in 65 per cent of cases; and serious lower respiratory-tract disease ocurred in 84 per cent. Induction of anaesthesia proved difficult or impossible in five boys. The disease pattern was dominated by the effects of neurological involvement, with initial developmental delay and behavioural disturbance, followed by regression, with convulsions and pyramidal tract signs. Death was due primarily to this neurodegenerative cachexia, with superimposed respiratory disease. RESUME Histoire naturelle des formes severes du syndrome de Hunter: etudes hasees sur 52 cas 52 garcons presentant un syndrome de Hunter a forme severe ont fait I'object d'une etude dans le cadre d'une approche nationale du syndrome de Hunter. Les âges moyens de debut et de deces ont ete respectivement 2 47 et 11. 77 ans. De nombreux malades ont presente les signes suivants: tete large et courte statur: diarrhee persistante (65 pour cent): hernie ombilicale (76 per cent), hernies inguinales droite et gauche (51 et 32 pour cent): signes d'affection cardio-vasculaire (65 pour cent) et des voies respiratoires inferieures (84 pour cent). La mise en place d'une anesthesie s'est revelee impossible chez cinq garcons. L'allure de la maladie a ete dominee par les consequences de I'atteinte neurologique avec retard du developpement initial et troubles du comportement, suivis par regression avec convulsions et signes pyramidaux. La mort fut provoquee principalement par cette cachexie neurodegenerative avec affection respiratoire surimposee. ZUSAMMENFASSUNG Anamnese der schweren Form des Hunter Syndroms: eine Studie basierend auf 52 Fallen 52 Jungen mit der schweren Form des Hunter Syndroms wurden in einer nationalen Ubersicht uber das Hunter Syndrom ermittelt. Das Durchschnittsalter des Krankheitsbeginns und des Todes lag bei 2 47 bzw. 11. 77 Jahren. Viele Patienten zeigten folgende Symptome: groser Kopf und kleine Statur, persistierende Diarrhoe (65 Prozent), Nabelhernie (76 Prozent), beidseitige Inguinalhernie (51 und 32 Prozent), Anzeichen einer kardiovaskularen Erkrankung (65 Prozent) und Bronchopulmonalerkrankungen (84 Prozent). Bei funf Jungen erwies sich die Einleitung einer Narkose als schwierig bzw. unmoglich. Das Krankheitsmuster wurde bestimmt durch die Folgen der neurologischen Beteiligung, mit anfanglichen Entwicklungsverzogerungen und Verhaltensstorungen, gefolgt von Anfallen und Pyramidenbahnzeichen. Als Todesursache stand diese neurodegenerative Kachexie mit einer dazukommenden Erkrankung der Atemwege im Vordergrund. RESUMEN Historia natural de la forma grave del sindrome de Hunter; estudio basado en 52 casos Cincuenta y dos muchachos con una forma grave del sindrome de Hunter fueron estudiados en un estudio nacional del sindrome de Hunter. La edad promedio de comienzo y de defuncion fue de 2, 47 y 11, 77 anos respectivamente. Muchos pacientes mostraban siguiente: cabeza grande y estatura pequena; diarrea persistente (65 por ciento), hernia umbilical (76 por ciento), hernias inguinales derecha e izquierda (51 e 32 por ciento), evidencia de enfermedad cardiovascular (65 por ciento) enfermedad del tracto respiratorio bajo (84 per ciento). La inducion anestesica se mostro dificil o imposible en cinco ninos. En la enfermedad dominaban los efectos de la alteracion neurologica con retraso en el inicio del desarrollo y alteracion en el comportamiento, seguidos de una regresion con convulsioncs y signos piramidales. La muerte se debio primariamente a esta caquexia neurodegenerativa con enfermedades respiratorias sobreanadidas.

Plasma tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9: novel indicators of left ventricular remodelling and prognosis after acute myocardial infarction

Abstract: Aims Matrix metalloproteinase (MMP) activity is central to the development of left ventricular (LV) remodelling and dysfunction after acute myocardial infarction (AMI). We assessed the relationships with LV structure and function and outcome, of tissue inhibitors of metalloproteinase-1 (TIMP-1) and MMP-9, and compared with N-terminal pro-B-type natriuretic peptide (NTproBNP). Methods and results We studied 404 patients with AMI. Primary outcome measures were the associations of TIMP-1, MMP-9, and NTproBNP with death or heart failure, and with LV dimensions, function and remodelling (ΔLVEDV, change in LV end-diastolic volume between discharge and follow-up). Cut-off concentrations for prediction of death or heart failure were identified from receiver operator characteristic (ROC) curves. In multivariable analysis, TIMP-1 and NTproBNP had predictive value for LV ejection fraction pre-discharge (TIMP-1 P = 0.023; N-BNP P = 0.007) and at follow-up (TIMP-1 P = 0.001; N-BNP P = 0.003). MMP-9, TIMP-1, and NTproBNP correlated directly with LV volumes. MMP-9 ( P = 0.005) and TIMP-1 ( P = 0.036), but not NTproBNP, correlated with ΔLVEDV. For the combined endpoint of death or heart failure the area under the ROC curve was 0.640 for MMP-9, 0.799 for NTproBNP and 0.811 for TIMP-1. Patients with TIMP-1 > 135 ng/mL ( P 1472 fmol/mL ( P < 0.001) had increased risk of endpoint. Consideration of both NTproBNP and TIMP-1 further improved risk stratification. Conclusion TIMP-1 and MMP-9 correlate with echocardiographic parameters of LV dysfunction and remodelling after AMI and may identify patients at risk of subsequent LV remodelling and adverse prognosis.

Isolation and Extraction of Circulating Tumor DNA from Patients with Small Cell Lung Cancer

Abstract: There is no consensus on the optimal protocol for isolation of circulating tumor DNA. We report our comparison of several extraction methods and variables that may affect yield, quality, and contamination of tumor DNA. DNA was extracted from the plasma and serum of five healthy volunteers by means of four different commercially available kits and DNA yield was quantified by real-time PCR. DNA was extracted using the optimum kit from the plasma and serum of an additional 10 healthy volunteers and 10 patients with small cell lung cancer (SCLC) to compare yield and DNA fragment size in plasma versus serum and in those with SCLC versus controls. Time to sample processing was also examined. We found that DNA yield was greatest using the QIAamp Viral Spin Kit. Delayed time to processing led to increased DNA concentrations in serum, but not plasma. The plasma DNA concentration in SCLC patients was significantly higher than in healthy volunteers (24.5 ng/mL versus 5.1 ng/mL, P= 0.002). In contrast, there was no significant difference in serum DNA concentrations between controls and patients that may be explained by the wide variability and range of DNA concentrations in serum. A significantly higher proportion of longer fragments (272 bp/60 bp) was observed in the plasma DNA extracted from patients with SCLC than in healthy controls (13% versus 8%, P= 0.04). There was absence of DNA fragments of 512 bp in healthy control plasma, but faint bands were observed in serum, which is thought to be due to cellular contamination. We conclude that plasma is a more reliable source of tumor DNA then serum and have optimized a robust procedure for plasma tumor DNA isolation that can be applied to translational research studies.

Are one or two simple questions sufficient to detect depression in cancer and palliative care? A Bayesian meta-analysis

Abstract: The purpose of this study is to examine the value of one or two simple verbal questions in the detection of depression in cancer settings. This study is a systematic literature search of abstract and full text databases to January 2008. Key authors were contacted for unpublished studies. Seventeen analyses were found. Of these, 13 were conducted in late stage palliative settings. (1) Single depression question: across nine studies, the prevalence of depression was 16%. A single 'depression' question enabled the detection of depression in 160 out of 223 true cases, a sensitivity of 72%, and correctly reassured 964 out of 1166 non-depressed cancer sufferers, a specificity of 83%. The positive predictive value (PPV) was 44% and the negative predictive value (NPV) 94%. (2) Single interest question: there were only three studies examining the 'loss-of-interest' question, with a combined prevalence of 14%. This question allowed the detection of 60 out of 72 cases (sensitivity 83%) and excluded 394 from 459 non-depressed cases (specificity of 86%). The PPV was 48% and the NPV 97%. (3) Two questions (low mood and low interest): five studies examined two questions with a combined prevalence of 17%. The two-question combination facilitated a diagnosis of depression in 138 of 151 true cases (sensitivity 91%) and gave correct reassurance to 645 of 749 non-cases (specificity 86%). The PPV was 57% and the NPV 98%. Simple verbal methods perform well at excluding depression in the non-depressed but perform poorly at confirming depression. The 'two question' method is significantly more accurate than either single question but clinicians should not rely on these simple questions alone and should be prepared to assess the patient more thoroughly.

Superiority of reduced-intensity allogeneic transplantation over conventional treatment for relapse of Hodgkin's lymphoma following autologous stem cell transplantation.

Abstract: This study compares outcome of reduced-intensity conditioned transplant (RIT) with outcome of conventional non-transplant therapy in patients with Hodgkin's lymphoma relapsing following autograft. There were 72 patients in two groups who had relapsed, and received salvage therapy with chemotherapy±radiotherapy. One group (n=38) then underwent alemtuzumab-containing RIT. The second group—historical controls (n=34), relapsing before the advent of RIT—had no further high-dose therapy. This group was required to respond to salvage therapy and live for over 12 months post-relapse, demonstrating potential eligibility for RIT, had this been available. Overall survival (OS) from diagnosis was superior following RIT (48% at 10 years versus 15%; P=0.0014), as was survival from autograft (65% at 5 years versus 15%; P⩽0.0001). For the RIT group, OS at 5 years from allograft was 51%, and in chemoresponsive patients was 58%, with current progression-free survival of 42%. Responses were seen in 8 of 15 patients receiving donor lymphocyte infusions (DLI) for relapse/progression, with durable remission in five patients at median follow-up from DLI of 45 months (28–55). These data demonstrate the potential efficacy of RIT in heavily pre-treated patients whose outlook with conventional therapy is dismal, and provide evidence of a clinically relevant graft-versus-lymphoma effect.

μ-Opioid Receptor Stimulation of Inositol (1,4,5)Trisphosphate Formation via a Pertussis Toxin-Sensitive G Protein

Abstract: The cellular mechanisms underlying opioid action remain to be fully determined, although there is now growing indirect evidence that some opioid receptors may be coupled to phospholipase C. Using SH-SY5Y human neuroblastoma cells (expressing both mu- and delta-opioid receptors), we demonstrated that fentanyl, a mu-preferring opioid, caused a dose-dependent (EC50 = 16 nM) monophasic increase in inositol (1,4,5)trisphosphate mass formation that peaked at 15 s and returned to basal within 1-2 min. This response was of similar magnitude (25.4 +/- 0.8 pmol/mg of protein for 0.1 microM fentanyl) to that found in the plateau phase (5 min) following stimulation with 1 mM carbachol (18.3 +/- 1.4 pmol/mg of protein), and was naloxone-, but not naltrindole- (a delta antagonist), reversible. Further studies using [D-Ala2, MePhe4, Gly(ol)5]enkephalin and [D-Pen2,5]enkephalin confirmed that the response was specific for the mu receptor. Incubation with Ni2+ (2.5 mM) or in Ca(2+)-free buffer abolished the response, as did pretreatment (100 ng/ml for 24 h) with pertussis toxin (control plus 0.1 microM fentanyl, 26.9 +/- 1.5 pmol/mg of protein; pertussis-treated plus 0.1 microM fentanyl, 5.1 +/- 1.3 pmol/mg of protein). In summary, we have demonstrated a mu-opioid receptor-mediated activation of phospholipase C, via a pertussis toxin-sensitive G protein, that is Ca(2+)-dependent. This stimulatory effect of opioids on phospholipase C, and the potential inositol (1,4,5)trisphosphate-mediated rises in intracellular Ca2+, could play a part in the cellular mechanisms of opioid action.

Anthropological measurement of lower limb and foot bones using multi-detector computed tomography.

Abstract: Anthropological examination of defleshed bones is the gold standard for osteological measurement in forensic practice. However, multi-detector computed tomography (MDCT) offers the opportunity of three-dimensional imaging of skeletal elements, allowing measurement of bones in any plane without defleshing. We present our experiences of the examination of 15 human lower limbs in different states of decomposition using MDCT. We present our method of imaging and radiological measurement of the bones including sex assessment. The radiological measurements were undertaken by three professional groups--anthropology, radiology, and forensic pathology--both at the site of scanning and at a remote site. The results were compared to anthropological oestological assessment of the defleshed bones. We discuss the limitations of this technique and the potential applications of our observations. We introduce the concept of remote radiological anthropological measurement of bones, so-called tele-anthro-radiology and the role that this could play in providing the facility for standardization of protocols, international peer review and quality assurance schemes.

8p23.1 duplication syndrome; a novel genomic condition with unexpected complexity revealed by array CGH

Abstract: The 8p23.1 deletion syndrome is established but not an equivalent duplication syndrome. Here, we report five patients; a de novo prenatal case and two families in which 8p23.1 duplications have been directly transmitted from mothers to children. Dual-colour fluorescent in situ hybridisation, multiplex ligation-dependent probe amplification analysis and customised oligonucleotide array comparative genomic hybridisation (oaCGH) indicated an approximately 3.75 Mb duplication of most of band 8p23.1 between the olfactory receptor/defensin repeats (ORDRs) in all cases. However, oaCGH revealed an additional duplication of 500 kb adjacent to the proximal ORDR in Family 1 and an additional deletion of 3.14 Mb within the Nablus Mask-Like Facial Syndrome region of 8q22.1 in Family 2. Copy number variation at introns 4-5 of the GATA4 gene was also identified. This 8p23.1 duplication syndrome is associated with a characteristic facial phenotype including a prominent forehead and arched eyebrows. Adrenal insufficiency, Tetralogy of Fallot, partial 2/3 syndactyly of the toes and cleft palate in some individuals may be explained by ascertainment bias, incomplete penetrance and/or the presence of the microdeletion in Family 2. The duplication is compatible with normal early childhood development but, although our adult cases live independent lives with varying degrees of support, learning difficulties have been experienced by some family members. We conclude that the 8p23.1 duplication syndrome is a genomic condition with an emerging but variable phenotype that may be under-diagnosed. Our results demonstrate that direct transmission does not distinguish genuine duplications from euchromatic variants and illustrate the power of array CGH to reveal unexpected additional imbalances in affected patients.

Surgical versus non-surgical treatment of chronic low back pain: a meta-analysis of randomised trials

Abstract: We performed a meta-analysis of randomised controlled trials to investigate the effectiveness of surgical fusion for the treatment of chronic low back pain compared to non-surgical intervention. Several electronic databases (MEDLINE, EMBASE, CINAHL and Science Citation Index) were searched from 1966 to 2005. The meta-analysis comparison was based on the mean difference in Oswestry Disability Index (ODI) change from baseline to the specified follow-up of patients undergoing surgical versus non-surgical treatment. Of the 58 articles identified, three studies were eligible for primary analysis and one study for sensitivity analysis, with a total of 634 patients. The pooled mean difference in ODI between the surgical and non-surgical groups was in favour of surgery (mean difference of ODI: 4.13, 95%CI: −0.82 to 9.08, p = 0.10, I2 = 44.4%). Surgical treatment was associated with a 16% pooled rate of early complication (95%CI: 12–20, I2 = 0%). Surgical fusion for chronic low back pain favoured a marginal improvement in the ODI compared to non-surgical intervention. This difference in ODI was not statistically significant and is of minimal clinical importance. Surgery was found to be associated with a significant risk of complications. Therefore, the cumulative evidence at the present time does not support routine surgical fusion for the treatment of chronic low back pain.

Iatrogenic malnutrition in neonatal intensive care units: urgent need to modify practice.

Abstract: Background: Extrauterine growth retardation is a major clinical problem in very-low-birth-weight infants. Parenteral nutrition (PN) serves to achieve rapid maximal nutrition in early postnatal life. There is a lack of uniformity with regard to neonatal PN practice. The objective of this study is to ascertain current practice regarding neonatal PN prescription in the early postnatal period in the United Kingdom. Methods: A study questionnaire was e-mailed to neonatal pharmacists serving level 3 and major level 2 units in the United Kingdom between October 2005 and March 2006. Static numerical information regarding glucose, amino acids, and lipid prescription during the first 10 days of life was collected and compared with current recommendations. Results: Fifty-two (81%) units responded to the questionnaire; 4 units were excluded for incomplete data. Twenty-six units (54%) initiated PN on day 1. Full PN was achieved by the median age of 6 days. Twelve units (25%) achieved full PN only by day 7 or later. Ma...

Survivorship Analysis at 15 Years of Cemented Press-Fit Condylar Total Knee Arthroplasty

Abstract: We performed a survival analysis on 354 cemented primary press-fit condylar total knee arthroplasties in 277 patients with prospective follow-up (mean, 8.8 years; range, 0.3-16.9 years). The number of patients alive reaching 15 years at follow-up for survival analysis was 15. The cumulative survival rate at 15 years was 81.7% (95% confidence interval, 72.1%-88.5%), using revision for all causes as our end point. Indications for revision in our patient group were aseptic loosening 4.5%, infection 2.3%, and exchange of polyethylene insert 1.1%. Our results indicate that the cemented press-fit condylar total knee arthroplasty has a good long-term survival, at 15 years, based on revision as the end point.

Curcumin in cancer management: recent results of analogue design and clinical studies and desirable future research.

Abstract: The ability of the curry constituent curcumin to delay the onset of cancer has been the topic of extensive research for many years. Abundant literature is devoted to mechanisms by which curcumin may mediate this activity. These insights have prompted investigations in which curcumin as lead molecule serves as a scaffold for synthetic chemical attempts to optimize pharmacological potency. Among the published analogues with notable efficacy are dimethylcurcumin, 1,5-bis(3-pyridyl)-1,4-pentadien-3-one and 3,5-bis-(2-fluorobenzylidene)-piperidinium-4-one acetate. Results of a small number of clinical pilot studies conducted with curcumin at doses of up to 12 g suggest tentatively that it is safe in humans. Prevention of adenoma recurrence constitutes a clinical paradigm worthy of further investigation for curcumin. Future clinical study should include measurement of mechanism-based pharmacodynamic parameters.

Delayed hypothermia as selective head cooling or whole body cooling does not protect brain or body in newborn pig subjected to hypoxia-ischemia.

Abstract: The neuroprotective efficacy of hypothermia (HT) after hypoxia-ischemia (HI) falls dramatically the longer the delay in initiating HT. Knowledge is scarce regarding protective or adverse effects of HT in organs beyond the brain. In addition, the relative effectiveness of selective head cooling (SHC) and whole body cooling (WBC) has not been studied. We aimed to examine whether 24 h HT, initiated 3 h after global HI is brain- and/or organ-protective using pathology, neurology, and biochemical markers. Fifty,