Commentary on the Olivieri symposium.
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Bioethical Issues↗
Biomedical subjects
E Connolly
Publications and source records attributed to E Connolly.
Unusual cause of a perforated stomach.
A case of gastric perforation 2 months following insertion of a gastric balloon is reported. The literature is reviewed regarding the complications and success rates inherent in such balloon devices. This is the first case report of an intra-gastric balloon causing gastric perforation.
Female↗
Randomised controlled trial of specialist nurse intervention in heart failure.
OBJECTIVES: To determine whether specialist nurse intervention improves outcome in patients with chronic heart failure. DESIGN: Randomised controlled trial. SETTING: Acute medical admissions unit in a teaching hospital. PARTICIPANTS: 165 patients admitted with heart failure due to left ventricular systolic dysfunction. The intervention started before discharge and continued thereafter with home visits for up to 1 year. MAIN OUTCOME MEASURES: Time to first event analysis of death from all causes or readmission to hospital with worsening heart failure. RESULTS: 31 patients (37%) in the intervention group died or were readmitted with heart failure compared with 45 (53%) in the usual care group (hazard ratio=0.61, 95% confidence interval 0.33 to 0.96). Compared with usual care, patients in the intervention group had fewer readmissions for any reason (86 v 114, P=0.018), fewer admissions for heart failure (19 v 45, P<0.001) and spent fewer days in hospital for heart failure (mean 3.43 v 7.46 days, P=0.0051). CONCLUSIONS: Specially trained nurses can improve the outcome of patients admitted to hospital with heart failure.
Aged↗
Angiography of fluoresceinated anti-vascular endothelial growth factor antibody and dextrans in experimental choroidal neovascularization.
OBJECTIVE: To determine if anti-vascular endothelial growth factor antibody and a range of dextrans with varying diffusion radii and molecular weights are permeable through experimental choroidal neovascularization (CNV). METHODS: Choroidal neovascularization was induced in 10 cynomolgus monkey retinas by means of argon laser injury. Digital fundus fluorescein angiograms were performed with fluorescein sodium, fluoresceinated IgG antibodies (anti-vascular endothelial growth factor and a control antibody), and fluoresceinated dextrans with molecular weights of 4, 20, 40, 70 and 150 kd. The 40- and 70-kd dextrans straddle the effective diffusion radius of IgG. For each reagent, early and late angiograms were performed in a standardized fashion, with follow-up images obtained to monitor residual fluorescence. RESULTS: Perfusion of retinal vessels and choroidal vasculature was seen with all reagents. Fluorescein and 4- and 20-kd dextran leaked rapidly from the CNV within the first minute. Angiography with the use of 40-kd dextran and fluoresceinated antibody, either anti-vascular endothelial growth factor or control IgG, showed fluorescence within the CNV that increased during the first 1 to 5 hours, with mild leakage from the CNV. By 24 hours, fluorescence in the CNV was minimal, although in some cases persistent fluorescence in the surrounding tissue was evident up to 2 weeks. The 70-kd dextran showed fluorescence within the CNV and leakage in 1 of 3 eyes. The 150-kd dextran showed fluorescence within the CNV but did not demonstrate leakage. CONCLUSIONS: Fluoresceinated antibodies and dextran with smaller effective diffusion radii showed CNV perfusion and leakage. Dextrans with larger effective diffusion radii (70 kd and 150 kd) perfused into CNV but did not show leakage consistently. CLINICAL RELEVANCE: Determining the permeablity of antibodies and molecules of similar size through CNV can help ascertain the feasibility of using intravenously administered antibodies against angiogenic growth factors as a future treatment for choroidal neovascularization.
Animals↗
Induced and accidental hypothermia.
OBJECTIVE: To review human thermoregulation and the pathophysiology and management of induced and accidental hypothermia. DATA SOURCES: A review of studies reported over ten years from 1990 to 2000 and identified through a MEDLINE search of the English-language literature on thermoregulation and induced and accidental hypothermia. SUMMARY OF REVIEW: Hypothermia is defined as a core temperature less than 35 degrees C, and may be therapeutic (i.e. induced for clinical benefit) or accidental. Hypothermia induced prior to cardiovascular or neurosurgical procedures (i.e. therapeutic hypothermia) allows for a greater hypotensive operative period with less risk of cerebral or cardiac ischaemic injury. Hypothermia induced following tissue injury (e.g. closed head injury, cerebrovascular accident, adult respiratory distress syndrome) has also been used to reduce ischaemic tissue injury, although significant clinical benefits have not yet been demonstrated. Inadvertent hypothermia (i.e. accidental hypothermia) is classed as mild from 33 degrees C-35 degrees C, moderate from 30 degrees C-33 degrees C and severe if less than 30 degrees C. Treatment includes surface and core warming methods, all of which have a valid basis from experimental studies. However, no prospective, randomised controlled clinical trials exist that have compared the various rewarming methods. Currently, passive rewarming methods (e.g. reflective metalloplastic sheets, blankets) are recommended for patients with mild hypothermia (> 33 degrees C), active surface rewarming (e.g. heated blankets, hot air circulators) for moderate hypothermia (> 30 degrees C), active core rewarming (e.g. heated haemodialysis, haemodiafiltration or peritoneal dialysis) for severe hypothermia (< 30 degrees C), and heated cardiopulmonary bypass for severe hypothermia with cardiopulmonary arrest. CONCLUSIONS: Operative hypothermia reduces ischaemic injury during cardiac and neurosurgical procedures. Hypothermia induced following tissue injury has not yet been shown to be of benefit. Management of accidental hypothermia requires passive and active warming methods, the indication of each depending on the availability of the method and severity of hypothermia.
Journal Article↗
Acute complications in the operative treatment of isolated ankle fractures in patients with diabetes mellitus.
Using a computer database, we conducted a retrospective review of all ankle fractures treated at our institution from March 1985 to October 1996. Twenty-one patients with diabetes mellitus and isolated ankle fractures that were treated operatively met all inclusion criteria. Seven had insulin-dependent diabetes, and 14 had non-insulin-dependent diabetes. A randomly selected control group of 46 patients without diabetes who also underwent operative treatment of ankle fractures during this same time period were matched for age, sex, and fracture severity. The complication rate was 43% with 13 complications in nine patients with diabetes. There were seven (15.5%) complications in the control group. Complications in the diabetic group included seven infections (five deep, two superficial) and three losses of fixation. The complications were more severe in our diabetic population, requiring seven additional procedures including two below-knee amputations; a third patient refused an amputation. No additional procedures were required in our control group. All complications in our control group resolved with treatment. The relative risk for postoperative complications in patients with diabetes who sustained ankle fractures that were treated operatively was 2.76 times greater than the control group's (95% confidence interval, 1.57-3.97).
Acute Disease↗
MDMA toxicity presenting with severe hyperpyrexia: a case report.
Ingestion of even small amounts of MDMA ('ecstasy') by a small subset of the population may result in a potentially fatal clinical syndrome of severe hyperpyrexia, cardiovascular collapse, coagulopathy, rhabdomyolysis and multiple organ failure. Rapid and aggressive temperature control is of utmost importance in the management of these patients. We report a case of MDMA toxicity presenting with severe hyperpyrexia (43 degrees C) who survived after a rapid reduction in temperature to 36 degrees C within 60 minutes following active surface cooling, cooled (approximately 4 degrees C) intravenous solutions, urinary and gastric lavage solutions and replacement fluids for continuous veno-venous diafiltration.
Journal Article↗
Intravenous magnesium.
OBJECTIVE: To review the function and use of intravenous magnesium in magnesium depleted and non-magnesium depleted patients. DATA SOURCES: A review of studies reported from 1966 to 1998 and identified through a MEDLINE search of the English-language literature on the use of intravenous magnesium. SUMMARY OF REVIEW: Magnesium is a metalo-coenzyme that participates in numerous enzymatic reactions including all reactions that involve the formation and utilization of ATP. The cardiovascular, neurological and metabolic disorders caused by magnesium deficiency are associated with an increase in morbidity and mortality and can be rapidly corrected by magnesium therapy. There is also evidence that intravenous magnesium alters ion channels, NMDA receptors, and calcium metabolism, causing effects that are beneficial in a range of cardiovascular, respiratory and metabolic disorders, in the absence of magnesium deficiency. In these disorders intravenous magnesium sulphate is usually administered as an initial bolus varying between 8 - 16 mmol over 5 min, followed by an infusion of 2 - 4 mmol/h, to keep the plasma magnesium between 1.5 - 3 mmol/L. CONCLUSIONS: Magnesium is required in patients who are magnesium depleted and is also of benefit in non-magnesium depleted patients with pre-eclampsia. It may also be of benefit in non-magnesium depleted patients with acute coronary syndromes, arrhythmias, acute asthma, stroke, seizures and spinal cord injury.
Journal Article↗
Abnormal regulation of the leptin gene in the pathogenesis of obesity.
A subset of obese humans has relatively low plasma levels of leptin. This finding has suggested that in some cases abnormal regulation of the leptin gene in adipose tissue is etiologic in the pathogenesis of the obese state. The possibility that a relative decrease in leptin production can lead to obesity was tested by mating animals carrying a weakly expressed adipocyte specific aP2-human leptin transgene to C57BL/6J ob/ob mice (which do not express leptin). The transgene does not contain the regulatory elements of the leptin gene and is analogous to a circumstance in which the cis elements and/or trans factors regulating leptin RNA production are abnormal. The ob/ob mice carrying the transgene had a plasma leptin level of 1. 78 ng/ml, which is approximately one-half that found in normal, nontransgenic mice (3.72 ng/ml, P < 0.01). The ob/ob animals expressing the leptin transgene were markedly obese though not as obese as ob/ob mice without the transgene. The infertility as well as several of the endocrine abnormalities generally evident in ob/ob mice were normalized in the ob/ob transgenic mice. However, the ob/ob transgenic mice had an abnormal response when placed at an ambient temperature of 4 degreesC, suggesting that different thresholds exist for the different biologic effects of leptin. Leptin treatment of the ob/ob transgenic mice resulted in marked weight loss with efficacy similar to that seen after treatment of wild-type mice. In aggregate these data suggest that dysregulation of leptin gene can result in obesity with relatively normal levels of leptin and that this form of obesity is responsive to leptin treatment.
Adipocytes↗
Identification of a family of zinc transporter genes from Arabidopsis that respond to zinc deficiency.
Millions of people worldwide suffer from nutritional imbalances of essential metals like zinc. These same metals, along with pollutants like cadmium and lead, contaminate soils at many sites around the world. In addition to posing a threat to human health, these metals can poison plants, livestock, and wildlife. Deciphering how metals are absorbed, transported, and incorporated as protein cofactors may help solve both of these problems. For example, edible plants could be engineered to serve as better dietary sources of metal nutrients, and other plant species could be tailored to remove metal ions from contaminated soils. We report here the cloning of the first zinc transporter genes from plants, the ZIP1, ZIP2, and ZIP3 genes of Arabidopsis thaliana. Expression in yeast of these closely related genes confers zinc uptake activities. In the plant, ZIP1 and ZIP3 are expressed in roots in response to zinc deficiency, suggesting that they transport zinc from the soil into the plant. Although expression of ZIP2 has not been detected, a fourth related Arabidopsis gene identified by genome sequencing, ZIP4, is induced in both shoots and roots of zinc-limited plants. Thus, ZIP4 may transport zinc intracellularly or between plant tissues. These ZIP proteins define a family of metal ion transporters that are found in plants, protozoa, fungi, invertebrates, and vertebrates, making it now possible to address questions of metal ion accumulation and homeostasis in diverse organisms.
Amino Acid Sequence↗
Absence of soluble leptin receptor in plasma from dbPas/dbPas and other db/db mice.
The leptin receptor (Ob-R) is alternatively spliced into at least five different RNAs designated Ob-R(a-e). Ob-R(a-d) predict receptors with a single transmembrane domain, and Ob-Re predicts a secreted form of the receptor. The presence of an approximately 120-kDa soluble leptin receptor in mouse plasma was confirmed by precipitation with leptin-Sepharose beads followed by immunobloting with anti-leptin receptor antibodies. The soluble leptin receptor is larger than that predicted by the primary sequence. Deglycosylation of the receptor with peptide N:glycosidase F results in a decrease in molecular mass to a size consistent with that of the primary sequence. The secreted receptor was present in plasma from wild type mice but was truncated in plasma from db3J/db3J and absent in dbPas/dbPas plasma. Although db3J/db3J mice are known to have a frameshift mutation at amino acid 625, the basis for the mutation in dbPas/dbPas mice was not known. Further studies indicated that dbPas/dbPas mice carry a duplication of exons 4 and 5 of Ob-R. This mutation introduces a premature stop codon into the protein at amino acid 281. The absence of Ob-R in db3J/db3J and dbPas/dbPas mice confirm the identify of the 120-kDa plasma protein as Ob-Re.
Alternative Splicing↗
Incidence and occupational pattern of leukaemias, lymphomas, and testicular tumours in western Ireland over an 11 year period.
STUDY OBJECTIVE: To determine incidence of the following malignancies, testicular tumours, all leukaemias and all lymphomas in the West of Ireland in an 11 year period. Secondly, to examine the relation between disease patterns and available occupational data in male subjects of working age. DESIGN: A census survey of all cases occurring in the three counties in the Western Health Board (WHB) area, Galway, Mayo and Roscommon, for the 11 year period 1980 to 1990 inclusive. Average annual age standardised incidence rates for the period were calculated using the 1986 census data. Rates for the area are compared with rates from the southern region of Ireland, which had a tumour registry. Trends over the time period are evaluated. All male subjects for whom occupational data were available were categorised using the Irish socioeconomic group classification and incidence rates by occupation were compared using the standardised incidence ratio method. In one of the counties, Galway, a detailed occupational history of selected cases and an age matched control group was also elicited through patients' general practitioners. SETTING: All available case records in the West of Ireland. RESULTS: There are no national incidence records for the period. Compared with data from the Southern Tumour Registry, the number of cases of women with myeloid leukaemias was significantly lower. Male leukaemia rates were significantly lower as a group (SIR 84 (95% CI 74, 95) but not when considered as individual categories. Regression analysis revealed an increasing trend in the number of new cases of non-Hodgkin's lymphoma among both men (r = 0.47, p = 0.02) and women (r = 0.90, p = 0.0001) and of chronic lymphocytic leukaemia in men (r = 0.77, p = 0.005) and women (r = 0.68 p = 0.02) in the WHB region over the last decade. Four hundred and fifty six male cases over the age of 15 years were identified and adequate occupational information was available for 74% of these. Standardised incidence ratios of testicular tumours 100, 938) and agriworkers other than farmers (SIR 377, 95% CI 103, 967). There were also significantly increased incidence ratios for both non-Hodgkin's lymphoma (SIR 169, 95% CI 124, 266) and three categories of leukaemias among farmers. Hodgkin's disease and acute myeloid leukaemias were significantly increased among semi-skilled people. Interview data with 90 cases and 54 controls of both sexes revealed that among farmers, cases (n = 31) were significantly less likely than controls (n = 20) to use tractor mounted spraying techniques (OR = 0.19 (95% CI 0.04, 0.80)) and less likely to wear protective masks (OR 0.22 (95% CI 0.05, 0.84)). CONCLUSIONS: Trends of increase in non-Hodgkin's lymphoma and some leukaemias are consistent with studies elsewhere. The study provides further evidence of the relation between agricultural work and certain lymphoproliferative cancers. The possible carcinogenic role of chemicals used in agricultural industries must be considered as an explanation.
Adolescent↗
Conserved promoter elements in the CYP6B gene family suggest common ancestry for cytochrome P450 monooxygenases mediating furanocoumarin detoxification.
Despite the fact that Papilio glaucus and Papilio polyxenes share no single hostplant species, both species feed to varying extents on hostplants that contain furanocoumarins. P. glaucus contains two nearly identical genes, CYP6B4v2 and CYP6B5v1, and P. polyxenes contains two related genes, CYP6B1v3 and CYP6B3v2. Except for CYP6B3v2, the substrate specificity of which has not yet been defined, each of the encoded cytochrome P450 monooxygenases (P450s) metabolizes an array of linear furanocoumarins. All four genes are transcriptionally induced in larvae by exposure to the furanocoumarin xanthotoxin; several are also induced by other furanocoumarins. Comparisons of the organizational structures of these genes indicate that all have the same intron/exon arrangement. Sequences in the promoter regions of the P. glaucus CYP6B4v2/CYP6B5v1 genes and the P. polyxenes CYP6B3v2 gene are similar but not identical to the -146 to -97 region of CYP6B1v3 gene, which contains a xanthotoxin-responsive element (XRE-xan) important for basal and xanthotoxin-inducible transcription of CYP6B1v3. Complements of the xenobiotic-responsive element (XRE-AhR) in the dioxin-inducible human and rat CYP1A1 genes also exist in all four promoters, suggesting that these genes may be regulated by dioxin. Antioxidant-responsive elements (AREs) in mouse and rat glutathione S-transferase genes and the Barbie box element (Bar) in the bacterial CYP102 gene exist in the CYP6B1v3, CYP6B4v2, and CYP6B5v1 promoters. Similarities in the protein sequences, intron positions, and xanthotoxin- and xenobiotic-responsive promoter elements indicate that these insect CYP6B genes are derived from a common ancestral gene. Evolutionary comparisons between these P450 genes are the first available for a group of insect genes transcriptionally regulated by hostplant allelochemicals and provide insights into the process by which insects evolve specialized feeding habits.
Amino Acid Sequence↗
Cryptosporidiosis in children who visited an open farm.
In the summer of 1995, cryptosporidiosis was diagnosed in a child in hospital. This child had taken part in a summer activity project involving 161 children and nine adults. Reports of a similar illness among a number of other participants prompted an outbreak investigation. A cohort study was conducted in two phases. Thirteen children (aged 6 to 15 years) out of 161 respondents to the first questionnaire met the case definition for illness and cryptosporidium was detected in stools from seven of the 13. Illness was significantly associated with child participants who had visited an open farm (p < .000005). Nine of the cases sought medical attention, and two were admitted to hospital. The second phase of the cohort study was conducted among 52 of the 55 people who had visited the open farm. Illness was significantly associated with playing in sand to which animals had access, at the edge of a stream beside a picnic area (p < .005). Contact with various animals was not associated with illness. This outbreak emphasises the risk for children of visiting open farms. Managers of open farms need to be aware of the potential for transmission of infectious diseases to visiting children. Strict implementation of hygiene measures is essential to minimise risk.
Adolescent↗
Intravenous infusion of liposomal benzoporphyrin derivative for photodynamic therapy of experimental choroidal neovascularization.
OBJECTIVE: To compare the effectiveness of photodynamic therapy to close experimental choroidal neovascularization using an intravenous infusion of liposomal benzoporphyrin derivative (verteporfin) with previous work using a rapid intravenous injection, before initiating clinical trials. METHODS: Choroidal neovascularization was induced in cynomolgus monkey eyes using argon laser. Liposomal benzoporphyrin derivative was delivered by an intravenous infusion pump for 10 or 32 minutes at a dose of 0.375 mg/kg. Irradiation was performed with 689- or 692-nm laser light (600-mW/cm2 irradiance and 150-J/cm2 fluence) in 7 normal eyes and 11 eyes with choroidal neovascularization between 30 and 105 minutes after the start of dye infusion. Findings were documented by fundus photography, fluorescein angiography, and light and electron microscopy. RESULTS: Irradiation within 32 to 50 minutes of the start of the fast (10 minutes) or slow (32 minutes) dye infusion resulted in closure of choroidal neovascularization. In normal eyes, this technique caused choriocapillaris closure and retinal pigment epithelium damage with minimal damage to surrounding tissues. CONCLUSION: Photodynamic therapy using intravenous infusion of liposomal benzoporphyrin derivative selectively closed experimental choroidal neovascularization. This may be a suitable modality for clinical use.
Animals↗
Subarachnoid hemorrhage diagnosis: lumbar puncture is still needed when the computed tomography scan is normal.
OBJECTIVES: To determine the sensitivity of third-generation CT scanners for diagnosed nontraumatic subarachnoid hemorrhage (SAH) and to assess the impact of symptom duration on sensitivity. METHODS: A retrospective chart review was performed in a university-affiliated tertiary care hospital with an annual ED volume of > 100,000 patients. The target population was all patients who presented to the ED from January 1991 to September 1994 with symptoms suggestive of SAH and who had a final diagnosis of nontraumatic SAH based on either a positive CT scan or positive spinal fluid analysis. Patients referred from outside facilities were included if they had a CT done at the study site. All CT scans were done using third-generation scanners. Official CT scan reports were used to categorize scans as positive or negative. RESULTS: There were 140 patients identified with SAH, with a mean age of 56 years (range 10-88). The sensitivity of CT in the diagnosis of nontraumatic SAH when performed at or before 12 hours of symptom duration was 100% (80/80), and 81.7% (49/60) after 12 hours of symptom duration (95% CI 95-100% and 69.5-90.4%, respectively; p < 0.0001). Eleven of the 140 patients had a negative CT and positive spinal fluid analysis, yielding an overall sensitivity of 92.1% (129/140). CONCLUSION: The sensitivity of third-generation CT scans for SAH decreases with time from the onset of symptoms. In this sample population, CT was able to detect all patients scanned < or = 12 hours after symptom onset. Although the study demonstrated good sensitivity of CT scan reports for SAH when the scan was performed after < or = 12 hours of symptom onset, additional real-time experience is needed to better define the potential risk of a missed SAH should this population not receive the customary lumbar puncture examination in the setting of a negative CT scan.
Adolescent↗
Alpha 1-adrenergic stimulation of Cl- efflux in isolated brown adipocytes.
Unidirectional 36Cl- efflux from preloaded isolated brown adipocytes was studied. A norepinephrine-stimulated 36Cl- efflux pathway was found which approximately doubled the rate of 36Cl- efflux from the cells. The response to norepinephrine was fully inhibited by the alpha 1-adrenergic antagonist prazosin, but was unaffected by the beta-adrenergic antagonist propranolol, showing that norepinephrine stimulated the 36Cl- efflux pathway via the alpha 1-adrenoceptor. The stimulation of 36Cl- efflux could not be mimicked by the Ca2+ ionophore A23187, indicating that the effect was not mediated by elevation of the intracellular Ca2+ level. It is concluded that brown fat cells possess a specific mechanism for alpha 1-adrenergic stimulation of Cl- efflux. The possibility is discussed that this Cl- efflux pathway could be the basis for the early alpha-adrenergic depolarization seen in brown fat cells.
Adipose Tissue, Brown↗
Beta-adrenergic modulation of Ca2+ uptake by isolated brown adipocytes. Possible involvement of mitochondria.
Rapid, unidirectional Ca2+ influx was examined in isolated brown adipocytes by short incubations (30 s) with 45Ca2+. Ca2+ uptake was found to be large in the resting brown adipocyte, but was markedly inhibited when the cells were presented with norepinephrine. Specific alpha 1-adrenergic stimulation was without effect on Ca2+ uptake. The effect of norepinephrine (which had an EC50 of 140 nM) could be inhibited by beta-adrenergic blockade and could be mimicked by forskolin (an adenylate cyclase activator) and theophylline (a phosphodiesterase inhibitor). Exogenous free fatty acids such as octanoate and palmitate (classical stimulators of respiration in brown adipocytes) were also able to dramatically inhibit Ca2+ uptake by the cells. The artificial mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) induced a large reduction in cellular Ca2+ uptake (even in the presence of the ATPase inhibitor oligomycin), and in the presence of FCCP the inhibitory effect of norepinephrine on Ca2+ uptake was significantly reduced. The effect of beta-adrenergic stimulation on Ca2+ uptake was not directly caused by the large increase in respiration that occurs in response to norepinephrine because the respiratory inhibitor rotenone did not affect the Ca2+ response of the cells to the hormone. The evidence suggests that beta-adrenergic stimulation of brown adipocyte metabolism leads to a partial inhibition of Ca2+ uptake into the mitochondrial Ca2+ pool and we discuss the possibility that this represents the effect of a reduced membrane potential (and thus reduced Ca2+ uniport activity) in the partially uncoupled mitochondria of the thermogenically active brown adipocyte.
Adipose Tissue, Brown↗