Influence of cardiac output on the correlation between mixed venous and central venous oxygen saturation. The influence of cardiac output on the correlation between central venous oxygen saturation and mixed venous oxygen saturation was assessed in 51 patients who had both a pulmonary artery catheter and separate central venous catheter in situ. Seventy-six paired samples were taken from the catheters and oxygen saturation measured immediately in a Ciba Corning 2500 Co-oximeter. Cardiac output was measured using a standard thermodilution technique. The data were separated into groups with low cardiac index (< 2.5 litre min-1 m-2; n = 20), medium cardiac index (2.5-4.0 litre min-1 m-2; n = 36) and high cardiac index (> 4.0 litre min-1 m-2; n = 20). The correlation coefficients of the three groups were: low cardiac index 0.95, medium cardiac index 0.88 and high cardiac index 0.95 (P < .001 for all three groups). All measurements were made before any x-ray and necessary repositioning of the central venous catheter. These results suggest that central venous oxygen saturation is a useful estimate of mixed venous oxygen saturation and that the influence of cardiac output on that estimate is minimal.


A method to facilitate regional anaesthesia by detection of mixed nerve action potentials. We have studied conduction anaesthesia of the median and ulnar nerves at the axilla using mixed nerve action potentials (MNAP) as a guide to needle position in three volunteers. The median and ulnar nerves were stimulated distally at the wrist using surface electrodes and MNAP were detected proximally in the axilla using an insulated needle electrode. The increase in amplitude of MNAP to maximum as the insulated needle electrode approached the nerve trunk was taken as an indication that the tip of the needle was in close proximity to the nerve trunk. Instillation of 1% lignocaine plain 4 ml decreased the amplitude of the MNAP with the onset of nerve block. We conclude that this method may be of potential use as an aid to peripheral regional anaesthesia by allowing accurate localization of needle position close to specific nerve trunks.


Lumbovertebral syndrome after extradural blood patch. We describe a patient who developed an immobilizing lumbovertebral syndrome after an extradural blood patch and who was hospitalized with a suspected extradural abscess. An infectious aetiology of the persistent backache could be excluded and the patient recovered with analgesics and physiotherapy. The probable aetiology is discussed.


Accidental subdural catheterization: radiological evidence of a possible mechanism for spinal cord damage. We describe the inadvertent subdural insertion of a lumbar extradural catheter in a primiparous woman in labour. A small quantity of local anaesthetic resulted in extensive motor and sensory block. Computed tomography performed after contrast injection demonstrated unequivocally that the catheter was in the subdural space. The catheter and injected fluid produced considerable displacement of the arachnoid within the thecal sac. We postulate that this could result in arterial compression or direct damage to the spinal nerve roots. Such a mechanism might explain some of the cases of permanent neurological damage associated with extradural analgesia.


Life-threatening acute respiratory distress in late pregnancy. Acute severe ventilatory failure from any cause is always a critical emergency. In advanced pregnancy, such an episode is particularly hazardous. The management of a pregnant patient who presented with an acute episode of respiratory distress is described. Although this was though initially to be an asthmatic attack, there was evidence of upper airway obstruction caused by an enlarged thyroid. The major complicating factors and aetiology are discussed.


Selective activation of extrathymic T cells in the liver by glycyrrhizin. Extrathymic pathways for T cell differentiation were recently demonstrated in the liver, intestine and omentum. In this study, glycyrrhizin (GL), a plant extract was investigated as to its effect on extrathymic T cells in the liver of mice. A new method using anti-LFA-1 mAb in conjunction with anti-TCR or -CD3 mAbs to sensitively identify such extrathymic T cells is included. Single injection and repeated injections of GL increased not only the number of total hepatic MNC but also the proportion of intermediate TCR cells, which are extrathymic T cells uniquely seen in the liver. In contrast to other tested reagents (e.g., lymphotoxin and estrogen) that activated the extrathymic T cells and simultaneously induced profound thymic atrophy, GL did not affect regular T cells in the thymus. The present results suggest that the selective activation of extrathymic T cells in the liver might be intimately related to the clinical effects of GL.


The potential improvement of thrombolytic therapy by targeting with bispecific monoclonal antibodies: why they are used and how they are made. The generation of the proteolytic enzyme plasmin from its inactive precursor plasminogen, mediated by so called plasminogen activators, is the essential step in thrombolytic therapy. Plasmin is responsible for the degradation of the insoluble fibrin, the major component of a thrombus, to soluble fibrin degradation products. So far, the use of the more recently developed thrombolytic agents single-chain urokinase-type plasminogen activator (scu-PA) and tissue-type plasminogen activator (t-PA) were disappointing, mainly due to some of their negative properties in vivo, i.e., rapid inhibition and/or hepatic clearance. Besides some background information on the haemostatic balance; t-PA and scu-PA structure; and mechanisms of action, we here review some reported attempts to improve on these agents for thrombolytic therapy following various strategies. One of the more potential strategies, antibody-targeted thrombolytic therapy using bispecific monoclonal antibodies, is discussed somewhat more extensively, as are the several procedures that can be followed for bispecific antibody preparation.


Chinese medicine, Coix seeds increase peripheral cytotoxic T and NK cells. Coix seeds, a Chinese medicine have been used in Japan and reported to be effective in patients with verruca vulgaris and verrucae planae juveniles. We investigated the in vivo effects on lymphocyte subsets in seven healthy volunteers who took six tablets of Coix seeds three times a day (a typical dose) for four weeks. Leukocyte counts and the percentage of total lymphocytes did not change but the percentages of CD3+CD56+ cells and CD16+CD57- cells increased significantly. These results indicate that Coix seeds increase peripheral cytotoxic lymphocytes and may be effective to viral infection through the enhancement of cytotoxic activity.


Early and late hormonal modulation of cholinergic maturation in culture of embryonic mesencephali. Dissociated cells from 13- and 17-day-old embryonic rat mesencephali have grown in primary cultures in order to compare the early and late influences of different agents--insulin, dexamethasone and nerve growth factor (NGF)--on the expression of cholinergic maturation process. We have studied cholin acetyltransferase (ChAT) activity, which is regarded as a specific marker for cholinergic function of the brain, and a widely used differentiation marker, the acetyl-cholinesterase (AchE) enzyme. Biochemical maturation of increasing specific activity of ChAT in both younger and older cells was taken into consideration. During cultivation the AchE activity was slightly increased in younger cells, but a dramatic decrease could be noted in older ones. Insulin in concentration from 10 to 27 micrograms mL-1 causes a significant inhibition in ChAT activity in comparison with the enzyme activity measured in control cultures (insulin ranging from 1 to 100 ng), independently of embryos age. This polypeptide hormone is able to enhance AchE activity in the cultured cells, especially in older ones. With continuous treatment of the culture with dexamethasone, a synthetic glucocorticoid, the ChAT activity in younger cells reaches a maximum curve by day 9 (nine). At this time the AchE activity shows a slighter, no significant increase than at any other time during cultivation. In cell cultures taken from 17-day-old embryos however dexamethasone treatment evoked a significant decrease in ChAT activity with a concomitant increase of AchE activity which was compared to insulin treatment. In spite of the fact that the NGF is able to enhance the ChAT activity, no significant alteration in AchE activity can be measured in younger cell cultures. These results suggest an uneven expression of the enzymes in embryonic rat mesencephali in the presence of above agents depending on the age of cells.


Administration of milk from cows immunized with intestinal bacteria protects mice from radiation-induced lethality. Oral administration of "immune milk", that had been obtained from cows immunized with a variety of human gut bacteria containing E. coli, S. typhimurium, S. dysenteriae and 23 others, protected AKR/J mice from the lethal effect of radiation, when immune milk was orally given to mice at 150 g kg-1 day-1 for 7 days prior to gamma-irradiation of 8 Gy. Mean survival times were 24.8 days for the group given immune milk but only 16.8 days for the group given control milk from unimmunized cows. Enterobacteriaceae were detected in various organs such as liver, lung and kidney on day 13 after irradiation, whereas the numbers were significantly fewer in the study group as compared with the control group. And fewer number of intestinal Enterobacteriaceae were detected in the study group compared with the control group prior to irradiation. Immune milk also enhanced the mitogenic response to mesenteric lymph node cells, the redirected cytolytic activity of intestinal intraepithelial lymphocytes to P815 tumor cells with anti-CD3 mAb, and in vitro killing activities of the phagocytes in mesenteric lymph nodes to E. coli as compared with control milk. These results suggest that immune milk may reduce the number of bacteria translocating from the intestinal-tract and augment the activities of the gut-associated lymphoid tissues against the invasion of intestinal bacteria, causing protection against the lethal effect of radiation.


Systemic IL-1 and adjuvant treatment of an experimental tumor. I. Immune status following tumor rechallenge. Local adjuvant therapy of weakly immunogenic tumors protects against primary tumor challenge. However, this form of therapy does not produce long-lasting immunity to the tumor. In this study, local adjuvant therapy combined with systemic IL-1 administration produced not only primary tumor protection, but also long lasting immunity to the tumor. IL-1 and adjuvant protected animals resisted rechallenge with tumor as much as 180 days after initial tumor administration. Resistance to tumor rechallenge was IL-1 dose dependent. IL-1 and adjuvant protected animals also exhibited delayed type hypersensitivity reactions which were tumor-specific. Splenic and lymph node cell populations from IL-1 and adjuvant protected animals mounted tumor-specific lymphoproliferative responses. No such responses were observed in animals which had been administered either IL-1 or adjuvant alone. These results demonstrate that systemic IL-1 functions to augment specific immune protection when administered in conjunction with local adjuvant, resulting in long-lasting tumor immunity.


Excitatory amino acid antagonists and their potential for the treatment of ischaemic brain damage in man. 1. A wide range of therapeutic strategies has been explored in humans and experimental animals with the aim of improving outcome after brain ischaemia but few have shown convincing clinical benefit. 2. The massive increase in the extracellular concentration of glutamate which occurs in cerebral ischaemia is a key component in the sequence of neurochemical events which leads to neuronal death. Pharmacological blockade of the action of glutamate at the N-methyl-D-aspartate (NMDA) receptor, (the glutamate receptor subtype principally involved in the neurotoxic effects of the amino acid) provides a novel therapeutic approach to cerebral ischaemia. 3. The effects of NMDA receptor antagonists in animal models of focal cerebral ischaemia are uniquely consistent, viz, a marked reduction in the amount of irreversible ischaemic damage irrespective of the species, the model of cerebral ischaemia, when the animals are sacrificed after the ischaemic episode, whether ischaemia is permanent or temporary and followed by reperfusion and which particular NMDA antagonist was employed. 4. NMDA receptor antagonists have marked effects on brain function in normal animals. The balance between these potential adverse effects and the anti-ischaemic efficacy of these drugs will ultimately determine the clinical utility of this class of drugs. 5. The data which are reviewed provide the basis for the current clinical evaluation of NMDA receptor antagonists in stroke and head trauma.


Studies with low dose intravenous diacid ACE inhibitor (perindoprilat) infusions in normotensive male volunteers. 1. Intravenous ACE inhibitor therapy is of increasing importance in the treatment of patients with unstable heart failure after myocardial infarction. Available pharmacokinetic and concentration effect data with this route of administration are limited. 2. The pharmacokinetics and blood pressure responses to perindoprilat were studied during prolonged low dose (1 mg) infusions in eight normotensive salt replete male volunteers. 3. Subjects received randomised, single (subject) blinded therapy with saline placebo (30 ml) over 3 h or active treatment (1 mg in 30 ml) over 1 h, 3 h or 6 h by constant rate infusion. 4. Significant falls in blood pressure greater than placebo were noted with active infusions without changes in heart rate. Mean maximal plasma perindoprilat concentrations reflected the rate of infusion (1 h, 51.5 +/- 11.4 ng ml-1; 3 h, 30.4 +/- 8.4 ng ml-1; 6 h 19.0 +/- 4.0 ng ml-1) and mean maximal plasma ACE inhibition was less with slower infusions (1 h, 95.7 +/- 0.5%; 3 h 92.3 +/- 2.7%; 6 h 87.4 +/- 5.1%, P less than 0.013). 5. Concentration-time profiles showed a sigmoid drug accumulation profile with delay in the early accumulation of drug particularly during the 3 h and 6 h infusions. The pharmacokinetic data was assessed by statistical comparison of a hierarchy of standard compartmental models and non linear saturable binding models. A non linear model incorporating elements to describe both tissue and plasma binding of the drug provided the best fit to observed data. 6. Low dose constant rate infusions are a means of optimising intravenous ACE inhibitor therapy to allow individual dose titration.(ABSTRACT TRUNCATED AT 250 WORDS)


The analgesic activity of morphine-6-glucuronide. 1. The pharmacokinetics, cardio-respiratory effects and analgesic effects of intravenous morphine-6-glucuronide were studied in 20 cancer patients with pain. Four different dose levels (0.5, 1, 2, and 4 mg 70 kg-1) were studied. Plasma concentrations of morphine-6-glucuronide were measured for 12 h after dosing. Pulse rate, respiratory rate and blood pressure were monitored, and pain relief was measured using two rating scales and a visual analogue scale. 2. The mean elimination half-life (+/- s.d.) of morphine-6-glucuronide was 3.2 +/- 1.6 h. The mean AUC standardised to a dose of 1 mg 70 kg-1 was 390 +/- 263 nmol l-1 h. Mean morphine-6-glucuronide clearance was 96 +/- 38 ml min-1. There was a direct relationship between morphine-6-glucuronide plasma clearance and calculated creatinine clearance (r = 0.81, P less than 0.001). 38 +/- 22% of the dose of morphine-6-glucuronide was recovered unchanged in the urine in 24 h. No morphine or morphine-3-glucuronide was detected in the plasma or urine of any patient after morphine-6-glucuronide treatment. 3. Morphine-6-glucuronide exerted a useful analgesic effect in 17/19 assessable patients for periods ranging between 2 and 24 h. No correlation was observed between dose or plasma morphine-6-glucuronide concentrations, and duration or degree of analgesia. No clinically significant changes in cardio-respiratory parameters were observed. No patients reported sedation or euphoria. Nausea and vomiting were notably absent in all cases. 4. Morphine-6-glucuronide is an effective and well-tolerated analgesic. It is likely that the majority of the therapeutic benefit of morphine is mediated by morphine-6-glucuronide.(ABSTRACT TRUNCATED AT 250 WORDS)


Passage of S(+) and R(-) gamma-vinyl-GABA across the human isolated perfused placenta. 1. The maternal to foetal transfers of S(+)- and R(-)-gamma-vinyl-GABA (VGB) across the human isolated perfused placenta were low and comparable with those of acidic alpha-amino acids. 2. The placental uptake of the active S(+)-isomer from the maternal circulation exceeded that of the R(-)-isomer and this was reflected by a corresponding difference in placental tissue concentrations. 3. During perfusion with recirculation of the foetal medium, the two enantiomers were present at a similar concentration and did not concentrate in foetal perfusate, indicating that the excess amount of S(+)-VGB cleared from the maternal circulation was not accessible to the foetal perfusate. Furthermore, stable concentrations of both isomers in the foetal perfusate suggested a lack of placental metabolism. 4. Possible explanations of these findings include the operation of a stereoselective sodium-dependent-GABA placental uptake system on the maternal side, similar to that observed in neuronal tissue, or stereoselective binding to a placental GABA transaminase.


Alterations in G-protein expression, Gi function and stimulatory receptor-mediated regulation of adipocyte adenylyl cyclase in a model of insulin-resistant diabetes with obesity. The stimulatory effect of Mn2+ (1.5-fold), forskolin (1.6-fold) and low (1 microM) concentrations of GTP (1.9-fold) on the adenylyl cyclase of adipocyte membranes from obese, diabetic CBA/Ca mice was markedly enhanced compared to that seen using membranes prepared from their lean littermates. In contrast, receptor-mediated stimulation, achieved with either isoprenaline or secretin was reduced and that by glucagon abolished in membranes from diabetic animals. The levels of expression of alpha-subunits of Gi-1, Gi-2 and Gi-3 were reduced to some 49, 76 and 54%, respectively, in membranes from diabetic animals compared with those from normal animals. Levels of G-protein beta-subunits and Gs alpha-subunits were similar. Receptor-mediated inhibition of adenylate activity elicited by either nicotinic acid or prostaglandin E1 (PGE1) was of a similar magnitude in membranes from normal and diabetic animals but the inhibitory action of N6-(L-2-phenylisopropyl)adenosine (PIA) was greater in membranes from diabetic animals by about 30%. Gi function was similarly evident in membranes from both lean and diabetic animals, as assessed using low concentrations of guanylyl 5'-imidodiphosphate to inhibit forskolin-stimulated adenylyl cyclase activity. However, assessing Gi function using GTP showed marked dissimilarities in that the elevated GTP concentrations expected to occur physiologically were incapable of reversing the stimulation achieved at low concentrations of GTP in membranes from diabetic but not normal animals. The adipocytes of CBA/Ca mice, as do other animal models of insulin resistance, show lesions in adenylyl cyclase regulation, Gi function and G-protein expression.


Involvement of pertussis toxin-sensitive and -insensitive GTP-binding proteins in luteinizing hormone exocytosis distal to second messenger generation. Inhibition of luteinizing hormone (LH) exocytosis by guanosine 5'-[gamma-thio]triphosphate (GTP gamma S) in permeabilized pituitary cells has indicated the involvement of one or more GTP-binding proteins in the exocytotic mechanism distal to second messenger generation. We now report that two inhibitory sites of action of GTP gamma S can be distinguished by their dependence on GTP gamma S concentration and their sensitivity to pertussis toxin. Ca(2+)-stimulated exocytosis was half-maximally inhibited by 6.8 microM GTP gamma S, a six-fold higher concentration than that required for inhibition of exocytosis stimulated by phorbol ester plus cAMP. In addition, GTP gamma S inhibition of Ca(2+)-stimulated exocytosis was insensitive to pertussis toxin, in contrast to the inhibition of exocytosis stimulated by phorbol ester plus cAMP, which was abolished by pretreatment with pertussis toxin. These results indicate that at least two stimulus-specific GTP-binding proteins are involved in regulating LH exocytosis distal to second messenger generation.


Protein kinase C initially inhibits the induction of meiotic cell division in Xenopus oocytes. We have used one activator and two inhibitors of protein kinase C (PKC) to examine the role of this enzyme in the induction of meiotic cell division. At 1 U/ml, phosphatidylcholine-specific phospholipase C increases DAG, alters intracellular pH and inhibits the induction of meiosis by insulin or progesterone. However, when added about 1.6 h after progesterone, the enzyme speeds the induction of cell division. Microinjection of inhibitor peptide (19-36) of PKC has little effect on progesterone action but stimulates the induction of meiosis by insulin. When the inhibitor peptide is injected about 2h after insulin addition, the peptide inhibits. A second PKC inhibitor, staurosporine, decreases PKC-dependent intracellular pH and in vitro oocyte PKC activity. At similar concentrations, staurosporine stimulates insulin or progesterone action, but, when added after about 2 h, the drug inhibits induction by insulin. We conclude that PKC is initially inhibitory to the induction of meiotic cell division but then may become synergistic.


Two protein kinase C activators, bryostatin-1 and phorbol-12-myristate-13-acetate, have different effects on haemopoietic cell proliferation and differentiation. Primary B lymphocytes can be induced to proliferate and certain haemopoietic cell lines such as HL60 and U937 can be induced to differentiate by the addition of phorbol esters, which have been shown to activate protein kinase C. Several non-phorbol esters, such as the bryostatins, have also been shown to bind to and activate protein kinase C. Although bryostatin-1 and 12-O-tetradecanoylphorbol-13-acetate (TPA) compete for and activate protein kinase C to the same degree and with similar kinetics and also induce similar levels of expression of the CD23 cell-surface antigen, bryostatin-1 is a weak mitogen for B lymphocytes and fails to induce the differentiation of both HL60 and U937 cells. Such an outcome suggests that these two activators have different binding properties for the enzyme that have a physiological consequence which may be useful for analysing the role that protein kinase C plays in both differentiation and proliferation. Analysis of competition assays between bryostatin-1 and TPA leads us to put forward a model where protein kinase C is required to be constantly reactivated and recycled during proliferation and differentiation which can be accomplished by TPA but not by bryostatin, although we cannot exclude the differential activation of some of the sub-species of the kinase by the two agonists.


Microinjection of the alpha-subunit of the G protein Go2, but not Go1, reduces a voltage-sensitive calcium current. Calcium currents can be modulated by receptor activation of the GTP-binding protein G(o). We have determined whether the two forms of G(o), Go1 and Go2, differentially regulate calcium current magnitude. Using identified neurons of the pond snail Helisoma, we demonstrate that a high-voltage-activated (HVA) calcium current is reduced by addition of the neuropeptide Phe-Met-Arg-Phe-amide (FMRFamide) and that this inhibition is mediated by a pertussis toxin (PTX)-sensitive G protein pathway. Using this calcium current as an assay for G protein activity, we microinjected GTP gamma S-activated alpha-subunits of G proteins into neuronal somata. We demonstrate that the calcium current is differentially regulated by the two forms of alpha o. Microinjection of alpha o2*, but not alpha o1*, reduces calcium current magnitude.


Autophosphorylation of Mucor rouxii cAMP-dependent protein kinase and its role in holoenzyme activation. Two phosphoproteins of 53,000 and 63,000 mol. wt detected in partially purified preparations of Mucor rouxii cAMP-dependent protein kinase submitted to phosphorylation conditions with [gamma-32P]ATP are demonstrated to be the result of the autophosphorylation of its regulatory subunit, according to the following criteria: (1) linearity of phosphate incorporation with enzyme sample; (2) independence of phosphate incorporation on temperature; (3) correlation of the phosphoproteins with enzymatic activity in a DEAE-Sepharose chromatography; (4) specific elution of the phosphorylated proteins from cAMP-agarose; (5) phosphorylation of the purified regulatory subunit. Antibodies specific against Mucor regulatory subunit detected an intact subunit of 72,000 mol. wt in crude extracts. Autophosphorylation of the fungal protein kinase A promotes activation of the holoenzyme by cAMP since: (1) under conditions of partial activation, increase of activity is observed when using the phosphoform of the enzyme; (2) release of free catalytic subunit from cAMP-agarose is enhanced when the holoenzyme is previously phosphorylated.


Signalling across the endoplasmic reticulum membrane: potential mechanisms. The endoplasmic reticulum (ER) is a membrane-bound organelle responsible for the synthesis, assembly and post-translational modification of proteins destined for the lysosomes, Golgi and for secretion. The processes which occur in the lumen of the ER are vital to the correct functioning of the cell, and mechanisms must exist to enable the cell to monitor events within the lumen of the ER. How the cell is able to do this is not known, but it would apparently require the passage of signals from the lumen of the ER to the cytosol, from where signals can be sent to, for example, the nucleus to effect changes in transcription. Here, it is suggested that the membrane of the ER may contain the components (i.e. receptors, kinases, etc.) required for transmembrane signalling in much the same way as the plasma membrane does. This hypothesis will be discussed in relation to known ER proteins which might act as signalling proteins.


Granulocyte-macrophage colony-stimulating factor primes phospholipase D activity in human neutrophils in vitro: role of calcium, G-proteins and tyrosine kinases. The addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to human peripheral blood neutrophils primes phospholipase D (PLD) to subsequent stimulation by N-formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol myristate acetate (PMA). The present investigation was directed at the elucidation of the pathway(s) involved in the regulation of the activity of PLD in untreated as well as in GM-CSF-primed neutrophils. Pretreatment with pertussis toxin (PT) totally inhibited fMLP-induced activation of PLD in control or GM-CSF-treated cells. PT did not affect the activation of PLD by PMA but inhibited the priming effect of GM-CSF. Activation of PLD by fMLP was dose-dependently inhibited by erbstatin, an inhibitor of tyrosine kinases. Furthermore, pre-incubation with GM-CSF accelerated the tyrosine phosphorylation response to fMLP (as analysed by protein immunoblot with antiphosphotyrosine antibodies). In PMA-stimulated neutrophils, erbstatin antagonized the priming effect of GM-CSF on PLD without affecting the direct effects of the phorbol ester. Buffering cytoplasmic calcium with the chelator BAPTA inhibited fMLP-induced activation of PLD as monitored by the formation of phosphatidylethanol. The stimulation of PLD by PMA was partially attenuated in BAPTA-loaded cells while the priming effect of GM-CSF was abolished. Thus, priming of human neutrophil PLD by GM-CSF may be mediated by G-proteins, by increases in the levels of cytosolic free calcium, and by stimulation of protein kinase C and/or tyrosine kinase(s).


Differential up-regulation of specific and azurophilic granule membrane markers in electropermeabilized neutrophils. We have developed an alternative method to study the degranulation in electropermeabilized human neutrophils by measuring the up-regulation of the specific membrane markers CD63 (residing in the azurophilic granules of resting neutrophils) and CD67 (present in specific granules). The expression of these marker proteins was measured by the binding of specific antibodies to paraformaldehyde-fixed cells and subsequent flow cytometry. We first investigated whether the changes in CD63 and CD67 expression after stimulation of intact cells were comparable with earlier measurements of neutrophil degranulation, in which the release of soluble marker proteins was measured. These experiments indicated that this new method compares favourably with earlier studies, both with respect to kinetics and stimulus dependency. Subsequently, we applied this method (which does not include centrifugation of the cells) to study degranulation in electropermeabilized neutrophils. In permeabilized neutrophils, a clear up-regulation of the specific granule marker CD67 was observed upon incubation with a free Ca2+ concentration of 1 microM, a value of the cytosolic free Ca2+ concentration occurring in formylmethionyl-leucyl-phenylalanine (FMLP)-activated neutrophils. The azurophilic granule marker CD63 required GTP-gamma-S besides 1 microM Ca2+ for a significant up-regulation. Hence, our study indicates a different requirement for intracellular signals of the two main types of granules in human neutrophils.


Evidence on the role of three calcium pools in Ca-ionophore A23187-stimulated rat blood platelet aggregation. The effect of Ca-ionophore A23187 on activation of rat blood platelets was investigated to elucidate the involvement of extracellular and intracellular Ca2+ ions. Platelet aggregation induced by 10 concentrations of the stimulus was studied in Ca-free medium as well as in the presence of EGTA and/or calcium. In Ca-free medium, A23187 induced platelet aggregation in a dose-dependent way; the mean effective concentration was 1.43 +/- 0.08 mumol/l. The stimulatory effect of ionophore was potentiated by addition of 0.01 and 0.1 mM calcium and inhibited when the calcium concentration was increased to 1 mmol/l. In the presence of EGTA, A23187-stimulated aggregation of isolated rat platelets was recorded only at a 10-times higher ionophore concentration and was then reduced to 30% in comparison with aggregation in Ca-free medium. The inhibitory effect of 1 mM EGTA was abolished by addition of 2 mM calcium. We suggest the participation of at least three calcium pools in the stimulation of rat platelets by A23187, i.e. the extracellular pool, the membrane-associated pool and the pool displacing calcium intracellularly.


Adenosine inhibits divalent cation influx across human neutrophil plasma membrane via surface adenosine A2 receptors. Adenosine and its analogues inhibited increases in divalent cation influx stimulated by platelet-activating factor (PAF) and formyl-methionyl-leucyl-phenylalanine (FMLP) in a dose-dependent fashion. This effect was antagonized by theophylline, an adenosine receptor antagonist. When extracellular adenosine was removed by adenosine deaminase, the effect of adenosine was completely abolished. Two adenosine analogues with different affinities for adenosine receptor subtypes, 5'-N-ethylcarboxamideadenosine (NECA) and L-N6-phenylisopropyladenosine (PIA), also inhibited divalent cation influx, NECA being more potent than PIA. These results suggest that adenosine and its analogues inhibit divalent cation influx across neutrophil plasma membranes via surface adenosine A2 receptors. Adenosine had little effect on the initial peaks of intracellular free calcium rises induced by chemoattractants, but it inhibited the subsequent rise in free calcium. Since calcium influx through the divalent cation channels or neutrophil plasma membranes is responsible for maintaining free calcium concentration following the initial peaks, we suggest that adenosine modulates neutrophil function by interfering with this calcium influx.


Modulation of human growth hormone binding to somatogenic and lactogenic receptors by monoclonal antibodies to human growth hormone. The relationship between the structure of human growth hormone (hGH) and the hormone-receptor interaction was investigated by studying the effects of specific monoclonal antibodies (MAbs) to hGH on the binding of [125I]hGH to rabbit liver and mouse liver microsomes. Receptor binding assays were carried out using a constant dose (1 ng) of [125I]hGH and varying concentrations of MAbs. The assay was carried out in the presence of either excess ovine prolactin for the measurement of somatogenic (SOM) binding sites, or excess bovine growth hormone for the determination of lactogenic (LAC) binding sites. Anti-hGH MAbs were found to have a whole spectrum of effects on hGH binding, including inhibitory, non-effect and enhancing activities. Enhancement of the binding of [125I]hGH to both SOM and LAC receptors was observed in liver membranes of rabbit or mouse. The observed amplified signal of [125I]hGH binding to various receptors in the presence of MAb no. 8 may be due to conformational changes which occur following MAb binding to hGH. On the other hand, most of the other MAbs caused inhibition of [125I]hGH binding. A negative correlation exists between the cross-reaction of various MAbs with the N-terminus truncated forms of hGH (Met14-hGH or Met8Leu-hGH) and their respective KD/IC50 values enabled the evaluation of the crucial role of the N-terminus region in hGH binding to both LAC and SOM receptors. MAb nos 1 and 19, which are directed towards acid residues 95-134 and the C-terminus, inhibited SOM binding more potently than LAC binding. Thus, it seems that these mid-molecule and C-terminus regions are also important in hGH binding, and that they play a role in the partial overlap of SOM and LAC binding.


Immunological identification of protein kinase C-alpha and protein kinase C-delta in cultured rat mesangial cells: differential sensitivity of the two isoforms towards the protein kinase inhibitor H7. Rat mesangial cells contain both calcium-dependent protein kinase C (PKC) activity, which phosphorylates histone H1 and endogenous proteins, and calcium-independent, phospholipid-dependent PKC activity, which phosphorylates only endogenous proteins. The calcium-dependent PKC was identified as PKC alpha by immunoblot analysis and hydroxyapatite chromatography (HPLC). The calcium-insensitive, phospholipid-dependent isoform was identified as PKC delta using similar techniques. The inhibition of these two PKC isoforms by the protein kinase inhibitor H7 [1-(iso-quinolinyl sulphonyl)-2-methyl piperazine] was examined using both histone H1 and endogenous proteins as substrates. Phosphorylations catalyzed by the calcium-dependent PKC isoform alpha were almost 90% inhibited when histone H1 was used, and only 55% when endogenous proteins were the substrate. In contrast, the phosphorylation of endogenous proteins catalysed by the calcium-insensitive, phospholipid-dependent PKC delta was not significantly affected by the inhibitor.


Low molecular mass phosphoproteins from the frog rod outer segments form a complex with 48 kDa protein. Upon separation of cAMP-dependent low molecular mass phosphoproteins [Components I and II; Polans et al. (1979) J. gen. Physiol. 74, 595-613] from the frog rod outer segments by gel-chromatography, isoelectric focusing, non-denaturating electrophoresis and ion-exchange chromatography, they behave like subunits of the oligomeric complex. Apparent molecular mass of the complex determined by gel-chromatography is 52-57 kDa and by non-denaturating gradient electrophoresis is 62-66 kDa. The isoelectric point of the complex is 5.5. The elution profile of Components I and II upon gel-chromatography and ion-exchange chromatography coincides with that of major rod outer segment 48 kDa protein. The isoelectric point for them also coincides with the isoelectric point of 48 kDa protein. The amount of low molecular mass phosphoproteins is sealed rods is equal to one molecule per 60 rhodopsin molecules and coincides with that of a 48 kDa protein. It is suggested that in solution Components I and II form an oligomeric complex with 48 kDa protein.


Murine models of autoimmunity: T-cell and B-cell defects. The lpr gene has been identified as a defect in the Fas gene, which encodes a lymphocyte surface protein associated with apoptosis and shares homology with the tumor necrosis factor-alpha receptor. This finding is important as it may quickly lead to identification of the gld gene product, which is thought to be a ligand for Fas. Also, it clearly identifies autoimmune disease as originating from a defect in the ability to induce cell death in lymphocytes. The major challenge in the future will be to directly demonstrate the relationship of abnormal apoptosis pathways to the development of autoimmunity and, in the case of lpr and gld mice, to lymphadenopathy, and to eventually determine if this is a fundamental defect at the root of all autoimmune diseases in both mice and humans.


Murine models of autoimmune disease.

Murine models of autoimmune disease. Animal models of autoimmunity are used to identify important immunologic factors and pathways involved in the different autoimmune diseases. Identification of the role of cytokines and development of new disease models have led to new possibilities for treatment.


Autoantibodies and their idiotypes.

Autoantibodies and their idiotypes. Antinuclear antibodies occur prominently in systemic lupus erythematosus and serve as markers of underlying pathogenetic disturbances. Although these antibodies display features indicative of genetic control and in vivo selection by self-antigen, other mechanisms shaping the B-cell repertoire may influence their production. Provocative new animal models provide systems for analyzing the cellular and genetic disturbances promoting these responses, as well as the role of pathogenic specificities in inducing tissue injury.


The molecular genetics of systemic lupus erythematosus and Sjögren's syndrome. Refinements in molecular genetic technology as well as in the organization of the major histocompatibility complex and the genes contained therein continue to lead the way to elucidation of the immunogenetics of systemic lupus erythematosus and Sjögren's syndrome. In this article, recent advances in these areas are reviewed, and major histocompatibility complex associations with systemic lupus erythematosus and Sjögren's syndrome will be explored with particular emphasis on autoantibody subsets of these diseases. Data thus far support the hypothesis that systemic lupus erythematosus and Sjögren's syndrome are clinically and serologically heterogeneous disorders of major histocompatibility complex class II allele-associated autoantibody subsets, to which other major histocompatibility complex genes (C4 null alleles) and non-major histocompatibility complex genes (such as T-cell receptor genes) may contribute in susceptibility.


New developments in Sjögren's syndrome.

New developments in Sjögren's syndrome. Sjögren's syndrome is an autoimmune exocrinopathy with characteristics of both organ-specific and generalized autoimmune disease. The main features are keratoconjunctivitis sicca and xerostomia, but patients may also show signs of extraglandular involvement. Sjögren's syndrome can occur in the absence (primary Sjögren's syndrome) or in the presence of other connective tissue disease (secondary Sjögren's syndrome). Sjögren's syndrome has often been considered a link in the spectrum between autoimmune disease and lymphoproliferative disorders. The cause of Sjögren's syndrome is still unknown, although the role of viruses in the pathogenesis is disputed. There is still no consensus about the diagnostic criteria, due to lack of specificity and sensitivity of the diagnostic procedures performed thus far. Recent studies using immunohistochemical and molecular biologic techniques highly suggest that disturbances in the target organs, such as salivary glands, are the consequence of local processes, rather than the reflection of systemic alterations. This underlines the importance of implementing these techniques for diagnostic purposes. Based on increasing understanding of the pathogenetic processes, new therapeutic possibilities will come into the picture. Over the past few years, interesting studies have contributed to our knowledge of the disease.


Antiphospholipid antibody and antiphospholipid antibody syndrome. Over the past year, many reports have been published on a variety of clinical manifestations related to antiphospholipid antibodies. The low prevalence of anticardiolipin antibodies with the rare occurrence of thrombosis and a low rate of fetal loss in studies in Malaysia and China showed a potential role for local factors. A study of cross-reactive idiotype of the anticardiolipin antibody suggested that anticardiolipin antibodies are derived from a set of natural autoreactive clones. Regarding the pathogenic role of the antiphospholipid antibody, evidence has been presented that the epitopes formed between cardiolipin and beta 2 glycoprotein I are the targets of the antiphospholipid antibody. Complement activation, abnormalities of natural anticoagulants such as protein S deficiency, and genetic association with DR4, DR7, and DRw53 have also been studied.


Clinical manifestations of systemic lupus erythematosus, measures of disease activity, and long-term complications. Studies of renal involvement in systemic lupus erythematosus continue to dominate the clinical literature. Reports of the prognostic significance of both clinical and histologic parameters at the time of renal biopsy are discussed. The potential impact of anticardiolipin antibodies on the development of renal insufficiency is described. The outcome of renal transplantation in patients with systemic lupus erythematosus is assessed in a study concerned with both allograft survival and recurrence of active nephritis in the transplanted kidney. The incidence and prognosis of various features of neuropsychiatric systemic lupus erythematosus are discussed, while the search for an accurate indicator of lupus involvement of the central nervous system continues. Magnetic resonance imaging and single-photon-emission computed tomography are considered. Abnormalities of pulmonary gas exchange are featured in several reports. Features of the antiphospholipid antibody syndrome are presented, stressing predisposition to thrombosis. The definition and characteristics of systemic lupus erythematosus disease flares is discussed, in relation to several recently developed disease activity indexes. The attempt to distinguish systemic lupus erythematosus activity from infection and preeclampsia is also considered. Finally, the association of systemic lupus erythematosus with the development of cancer is discussed.


Prognosis of systemic lupus erythematosus and factors that affect it. The prognosis of systemic lupus erythematosus has improved over the past four decades. We now have data for 15-year survival, which has also improved. Several factors may be associated with improved survival, including earlier diagnosis, better treatment, and improved medical therapy. Specific organ damage continues to be an issue, primarily with regard to kidney disease and to neurocognitive impairment and lung involvement. Infection and vascular disease emerge as important factors. With improved survival, other outcome measures, including specific organ function and health status, need to be considered.


Role of drugs and environmental agents in lupus syndromes. It is increasingly accepted that a broad range of drugs and environmental factors can give rise to lupus syndromes and other types of connective tissue disease syndromes. This chapter reviews the drugs and environmental agents reported during this past year. Considerable research efforts are now focused on understanding the possible mechanisms, particular specificities of the antibody responses, new patterns of antibody responses, and biochemical pathways. These potentially important contributors to the expression of disease are reviewed.


Treatment of systemic lupus erythematosus. The past year continued to see both major studies and interesting case reports slowly add suggestions, if not absolute knowledge, concerning the treatment of systemic lupus erythematosus. The Lupus Nephritis Collaborative Study Group published two papers, one of which concerned the lack of efficacy of plasmapheresis in treating severe lupus nephritis. A related paper documented the utility of initial serum creatinine in predicting renal failure in patients enrolled in both arms of the plasmapheresis study. Patients in the study received high-dose oral prednisone and low-dose oral cyclophosphamide. Whether this approach is superior to pulse intravenous cyclophosphamide is yet to be determined. Two other approaches to treatment were also reported: anti-CD4, based on success in case reports, merits further study; the modified androgen, 19-nortestosterone, was unfortunately not effective. Other case reports provide additional evidence for specific treatments in certain situations, such as the use of tetracycline pleurodesis for recurrent pleural effusions. Finally, reports of new side effects for old medicines and new ones are a reminder that the treatment can be part of the problem when a lupus patient develops complications.


Juvenile rheumatoid arthritis, juvenile chronic arthritis, and juvenile spondyloarthropathies. Immunogenetics are supporting the marked heterogeneity of chronic arthritis in children. Thus DRw13-DRw18 and DQw6-DQw18 were associated with persistent pauciarticular disease in children with an early onset of disease. Several studies have shown DPw2 as an additional susceptibility factor in this subgroup. Standardization of diagnostic criteria for juvenile onset spondyloarthropathy and psoriatic arthritis is necessary; various studies are in progress, and although HLA-B27 provides the common marker, this may only apply to a small group of juvenile psoriatics who have spondyloarthropathy. In the management of juvenile rheumatoid arthritis, methotrexate in moderate doses has been shown to be superior to lower doses of methotrexate and placebo in controlling polyarthritis. Methotrexate may be of particular value in treating the polyarthritis that follows a pauciarticular onset. The possible value of sulfasalazine in a B27 group with persistent polyarthritis has been suggested. Highlights of corticosteroid therapy were intra-articular injections, particularly in pauciarticular disease, the suggestion that deflazacort has a calcium sparing effect, and the possible role of intravenous methylprednisone in the management of severe disease.


Rheumatic fever and disorders of the musculoskeletal system. New information provided on the pathogenesis and management of rheumatic fever is of current interest. Invasive disease by group A streptococci has been shown to be due to production of toxin A. The natural history and immunopathologic basis for chronic Lyme arthritis are reported. Attention is drawn to pyomyositis and clinical presentation of chronic fatigue syndrome in children. Patients with Sweet's syndrome often have antineutrophil cytoplasmic autoantibodies. Biopsy specimens of panniculitis should be taken to aid treatment. Long-term outcome in chronic osteomyelitis is favorable; recommendations on the rational use of imaging have been reported.


Musculoskeletal signs of metabolic and systemic diseases in childhood. Many metabolic and systemic disorders affect the musculoskeletal system in growing children. This review surveys some of the recent literature in several diverse areas, including new radiologic methods to determine bone mineralization and their use in children with juvenile arthritis and other systemic diseases, bone disorders in childhood, and the association of endocrinopathies and musculoskeletal symptoms.


Heritable disorders of connective tissue and disability and chronic disease in childhood. The heritable disorders of connective tissue encompass a broad range of diseases, many of which occur in childhood and present to the pediatric rheumatologist's attention. The underlying theme of these disorders is fragility of connective tissue components such as bone, cartilage, and blood vessels. Over the past few years, investigations of patients with the major forms of heritable disorders of connective tissue, osteogenesis imperfecta, Marfan syndrome, and Ehlers-Danlos syndrome have revealed genetic mutations of collagen genes as the cause of the diseases. Review of the newest genetic information in these three disorders is presented. The rheumatic disorders of childhood present a paradigm for the effects of chronic disease on children and families. New work, discussed in this review, continues to suggest changes in psychosocial adaptation in children with chronic rheumatic diseases and their families, but these data are conflicting. The development of arthritis impact measures may help workers in pediatric rheumatology care to have a broader and more in-depth understanding of the effect of this chronic disease on functioning, psychosocial development, and family and peer interactions.


Musculoskeletal tumors in childhood.

Musculoskeletal tumors in childhood. As treatment strategies improve, the ability to cure children with musculoskeletal tumors is growing. The stage of a given malignancy, representing the degree of spread of the tumor to its local surroundings or distant sites, is the best predictor of long-term survival. Unfortunately, the insidious nature of the presentation of these tumors leads to their late recognition in advanced stages. This review will present scenarios suggesting the need for consideration of malignancy in the differential diagnosis of clinical problems related to the musculoskeletal system. Pitfalls in diagnosis and therapeutic approaches will also be discussed.


Pain of musculoskeletal origin in children. Pain in infants and children may be manifest by deformity, altered function, or discomfort. These manifestations are highly age related. Pseudoparalysis may be the only manifestation of septic arthritis of the hip in the neonate; a limp is often the presenting complaint in Perthes' disease, and scoliosis may be the primary manifestation of a herniated disc in an adolescent. New imaging methods aid in diagnosis. Ultrasound is helpful in assessing joint effusions; bone scans localize the cause of a limp; and magnetic resonance imaging shows spinal cord and root lesions. The traditional methods of assessment have not been replaced. History and physical examination are most essential to provide a rational basis on which to select the appropriate imaging study.


[Surgical treatment of post-thyroidectomy laryngeal paralysis]. A not infrequent complication of thyroid surgery is laryngeal nerve palsy with transitory or permanent deficiency of cordal motility. A very frequent cause of this condition is total thyroidectomy. Peripheral mono-or bilateral palsy in these cases may either occur, in adduction or abduction, and be complete or not complete. Therefore, different strategies in order to restore respiratory and phonatory functions are required. The Authors describe the main otorhinolaryngologic procedures used for the surgical treatment of laryngeal palsy, particularly for bilateral adducted ones. Their 10-year experience is also reported.


[Therapeutic trends in adrenal incidentaloma]. The term incidentally discovered adrenal mass or incidentaloma includes several tumors, mainly benign, involving the adrenal space. From 1983 to 1990, at the 1st Surgical Department of the Careggi Hospital of Florence, 10 patients (8 females and 2 males), with age ranging from 31 to 66 years, were found to have an incidentaloma. The size of the mass ranged from 2 to 10 cms; the left side was interested in 2 cases and the right one in 8 cases. The first diagnostic approach was abdominal ultrasound scanning in 8 out of 10 patients, whereas computerized tomography was the first used in the remaining 2 patients. Overall, all patients underwent CT scanning, while abdominal ultrasound scanning was performed in 9, urography in 2, and MNR in 1. Fine needle aspiration was performed in one case of adrenal cyst both for diagnostic and therapeutic purposes. The Authors suggest a therapeutic-diagnostic program in which cytology, obtained through fine needle aspiration, may have a prominent role in reducing the need for surgical interventions, as it recently happened for thyroid disorders. Although technically more complex compared to thyroid fine needle aspiration, adrenal ultrasound-guided FNA may bring to a better classification of the different adrenal disorders reducing at the same time the need for surgery, which at present has a prevalent diagnostic intent.


[Cystic tumors of the pancreas: a case of cystadenocarcinoma of the pancreatic head]. Cystic tumors of the pancreas are important, although rare, lesions representing nearly 1% of all neoplasms and 10-15% of pancreatic cysts. The Authors compare clinical data of the case observed with those reported in literature. The described case confirms the peculiar characteristics of pancreatic mucinous cystoadenomas: slow growth, not specific symptoms, poor trend to give local or distant metastases, difficult preoperative differential diagnosis and satisfying oncological resection. Taking into account these parameters and the potential malignant evolution of such tumors, the Authors underline the importance of a radical surgical therapy.


[Carcinoma of the splenic flexure].

[Carcinoma of the splenic flexure]. The Authors report their experience in the management of 25 cancers of the splenic flexure corresponding to 4.8% of large bowel cancers overall observed. Twelve patients underwent elective surgery consisting in a left hemicolectomy, which in 1 of the 12 cases required an associated distal splenopancreatectomy. Operative mortality was null, whereas morbidity involved 1 case of anastomotic dehiscence. Thirteen patients presenting with complete obstruction underwent emergency surgery: a two-stage resection with primary colostomy was performed in 5 cases, a sub-total colectomy with one-stage ileo-rectal anastomosis or ileo-sigmoid anastomosis was performed in 8 cases. In this last group of 8 patients mortality rate was 12.5% (1 pt.) and diarrhoea was the most important sequela. On this regard the Authors point out the opportunity to perform an ileo-sigmoidostomy, which reduces the incidence of such complication.


[Emergency endoscopic sphincterotomy in acute lithiasic cholangitis]. Emergency endoscopic sphincterotomy in acute cholangitis for bile duct stones should be the first choice treatment in patients with and without gallbladder. In fact, emergency surgery carries higher mortality and morbidity rates. Urgent biliary drainage, easily and quickly obtainable by endoscopy is the major goal. Bile duct stone clearance can be attempted subsequently, when the patient general conditions are stable. Elective open surgery can be performed thereafter, if indicated, with less risk. This experience is clearly shown by many surgical and endoscopic, mainly retrospective, studies.


[New trends in the diagnosis of Crohn's disease]. The Authors in reviewing the diagnostic techniques commonly used in Crohn's disease, focus their attention on Indium-111 scanning. The method seems useful, not only to point out the complications of the disease (stenosis, abscess, fistula) but especially for the follow up of patients after surgery with early diagnosis of a possible relapse.


[Revascularization of distal arteries of the leg: critical considerations on more than 2000 cases reported in the literature]. The Authors review the results of more than 2000 cases of lower extremity revascularization, treated from 1969 to 1991 and reported in the literature. They evaluate indications, contraindications and results at 12 and 24 months from operation performed with saphenous vein "in situ" and reversed. Finally they stress the greater reliability of by-passes performed with "in situ" saphenous vein graft.


Existing and emerging foodborne diseases. Foodborne diseases, i.e. illnesses due to contaminated food, are one of the most widespread problems of the contemporary world. They are toxic or infectious by nature and are caused by agents which enter the body through the ingestion of contaminated food or water. These agents can be chemical like pesticide residues and toxic metals or biological like pathogenic microorganisms. Foods contaminated by biological agents are, however, the major cause of foodborne disease. Data recorded in different countries show that the incidence of some of these diseases has increased dramatically over the past few years, but because of under-reporting the data are of limited value and cannot be compared between countries. In most countries, individual cases of illness are usually not reported. A sentinel surveillance system, started as a pilot study in the Netherlands, was shown to be feasible for the registration of some foodborne infections. Based on this study, it can be estimated that each year Salmonella and Campylobacter cause respectively about 12,000 and 25,000 cases of acute enteritis per million. Case-control studies clearly implicate poultry products as an important source of acute enteritis. New developments in food production and changing trends in food consumption lead to the emergence of new hazards. Additionally, because the population is aging and there has been an increase in the number of individuals with underlying diseases, the state of public health is deteriorating. Campylobacter, Salmonella enteritidis and enterohemorrhagic Escherichia coli are examples of microorganisms that have the opportunity to increase as a consequence of intensive husbandry. Listeria monocytogenes is an example of an organism that causes disease in immunosuppressed individuals.


The economic impact of poultry-borne salmonellosis: how much should be spent on prophylaxis? Foodborne salmonellosis constitutes a major health problem in many countries. Moreover, the costs associated with salmonellosis could be considerable. There are thus strong arguments for preventive efforts. Ambitious, often government-sponsored, programmes aimed at preventing and controlling salmonellosis in for instance, poultry production represent one alternative to lower salmonellosis-related illness and economic costs. On the other hand, such comprehensive programmes are rather resource-demanding. From the economic point of view the key problem is to find the optimal level for prophylactic measures. The purpose of this study is to compare two different approaches to preventing poultry-borne salmonellosis among humans. We identify and compare the economic costs of illness due to poultry-borne salmonellosis and the costs of salmonella control in England and Wales and Sweden, respectively. An alternative option is then introduced: the concept of competitive exclusion (CE). Our results show that the cost of illness constitutes the major part of the total cost in England and Wales, whereas in Sweden, the control cost amounts to 95% of the total cost. By using the CE concept, the cost of illness due to poultry-borne salmonellosis in England and Wales could be reduced by at least GB pound 12.6 million. These advantages apply to individuals, producers, and to society, and we thus conclude that the CE concept is a very cost-effective way of using scarce resources.


A voluntary Salmonella control programme for the broiler industry, implemented by the Danish Poultry Council. In the light of data and experience gained over the last two decades, initiatives made to combat and control Salmonella in the Danish broiler industry are described and the results obtained so far are discussed. The main elements include evaluation of the establishments, procedures and processes used, including bacteriological assessment, advice and guidance, routine bacteriological monitoring, and also research. Results obtained are used in the control of breeding stock, parent stock, hatcheries, broiler farms, slaughterhouses, feedmills and transport systems.


Problems of Salmonella sampling.

Problems of Salmonella sampling. Modern husbandry practices, regional concentration of the industry, high stocking densities, uniform age-distribution of birds and continuous feeding promote the spread of poultry diseases. Moreover, the immature state of the intestinal microflora or disturbance of the developing flora by antibiotics increases susceptibility of chicks to salmonellas. If an estimate of the number of salmonella-positive birds in a flock is needed, then the required number of samples can be assessed by using the binomial distribution function. Whenever a qualitative result is sufficient, the samples can be pooled or the flock litter can be sampled using an 'overshoe method', which is a novel, low-cost and rapid technique. An optimal pooling factor can be assessed at low prevalence levels (less than 10%). Serological methods will only detect the presence of antibodies to invasive strains of Salmonella. The sampling interval depends on the strategy of the Salmonella Control Programme. Breeder flocks should be sampled more frequently than meat flocks and laying flocks. The new salmonella standard, ISO 6579-1990, is applicable in the poultry industry. When bacterial numbers are likely to be low, or the organisms in a stressed condition, a pre-enrichment step should be included. In the case of faecal samples, however, pre-enrichment should be omitted. A whole carcass rinsing and massaging method is preferred for the examination of finished carcasses.


The competitive exclusion concept: development and future. The origin of the competitive exclusion (CE) concept in controlling a Salmonella infantis outbreak in poultry in 1971 and the subsequent development of a commercial treatment product are described. The possible role of CE in salmonella control, current status of the concept and theories relating to the bacteria involved and mechanisms of protection are reviewed. Some observations are made on the need for methodological development and possibilities for extending the scope of CE to other pathogens and types of domestic animal.


Competitive exclusion in the young bird: challenge models, administration and reciprocal protection. The competitive exclusion (CE) concept has been tested against both non-invasive and invasive salmonella serotypes. Studies with different challenge models indicate that CE treatment is likely to protect the young bird against all serotypes that are capable of intestinal colonization. Spray or 'droplet' application of the CE-treatment material was compared with administration in the first drinking water. Both methods gave a similar degree of protection against Salmonella infantis. A study was made to compare protection of newly hatched chicks and turkey poults by the one commercial CE product Broilact, and two similar preparations involving intestinal microorganisms from an adult turkey. Each preparation protected both avian species when administered orally prior to challenge, but the degree of protection obtained varied with the type of preparation and its host origin.


Antimicrobials and competitive exclusion. The compatibility of commonly used antimicrobial feed additives with CE treatment are examined. It appears that additives permitted in the U.K. are without effect on CE, with the possible exception of avoparcin. However, a sharp difference has been found with the effect of antimicrobials on CE treatment cultures in vitro, and the in vivo effect; and it is postulated that these differences may be accounted for by the fact that the substances may not be 'caecum available' in the bird. When effects are observed in the bird they appear to be largely due to dose variation. In the case of adult birds already infected with Salmonella, the time lapse between completion of antimicrobial treatment and the administration of Broilact will be examined; as well as the selection of appropriate antimicrobial treatment in infected birds prior to the administration of replacement microflora.


Experience of a 10-year use of competitive exclusion treatment as part of the Salmonella control programme in Sweden. In Sweden, competitive exclusion (CE) treatment has been used since 1981 as a part of the national control programme for Salmonella. According to the programme all broiler flocks are tested for Salmonella before slaughter thus providing an evaluation of CE treatment. The CE culture used is mainly for the two consecutive flocks raised in a unit after a Salmonella-infected flock has been identified. During the period 1981-1990 Ce culture has been given to 179 flocks, involving 3.82 million chickens. Only one of the treated flocks was found to be Salmonella-positive. A special study during a period when Salmonella was spread by contaminated feed demonstrated that CE treatment was effective in controlling Salmonella under field conditions. A likely contributory factor is that the hatcheries in Sweden can be claimed to be Salmonella-free. In addition, the control programme and related action, have led to a very low incidence of Salmonella in broiler chickens. A nationwide study carried out in 1990 demonstrated that less than 1% of broiler chickens was contaminated with Salmonella after slaughter.


Long-term experience with competitive exclusion and salmonellas in Finland. Poultry production is under strict official control in Finland. Fifteen years after the introduction of 'competitive exclusion' treatment the majority of growers (over 70%) use it routinely. The number of Salmonella-positive flocks is less than 5% and the incidence of Salmonella-contaminated broiler carcasses has been 5-11% in the last two years. The average number of Salmonella cells on contaminated carcasses is very low, generally less than 5 per carcass. Between 70 and 80% of human Salmonella infections are contracted abroad, mainly outside the Nordic countries. It is estimated that only 15-20% of some 1200 cases of domestic origin are caused by contaminated poultry.


Defined cultures and prospects.

Defined cultures and prospects. Resistance of young chicks to Salmonella colonization can be increased by treating them with suspensions or anaerobic cultures of gut content from healthy, adult birds. Unfortunately, such treatments have an unknown bacterial composition and are therefore not acceptable to regulatory agencies in some countries. Efforts are continuing to identify components in the gut microflora that are involved in the protective process. The ultimate aim is to identify bacteria that may be used, either alone or in mixtures (defined cultures), as a prophylactic treatment of chicks against Salmonella colonization. Although much research has been done in this area, a defined culture treatment with a potency and stability equivalent to that of undefined culture has not been developed. Since the mechanism of protection is not clear, there are no reliable criteria for selecting potentially protective strains. The most effective mixtures contain large numbers of bacterial cultures (about 50 isolates). These mixtures are comparable to undefined faecal cultures in protecting chicks against challenge levels of up to 10(4) Salmonella/chick. However, they are not protective for turkey poults. Mixtures containing lower number of strains are generally less protective. It appears that obligate and facultative anaerobes from different genera are required for protection. Mixtures containing strains from only one genus, e.g. Lactobacillus or Bifidobacterium, are generally not effective. Maintenance of intestinal isolates on laboratory media, as well as in storage at -70 degrees C, results in a progressive decrease in their protective ability. The protective ability of mixtures or individual strains can be partially restored by in vivo passage. A promising criterion for isolating and/or screening potentially protective isolates is based on the adherence of native microflora to the caecal wall of treated chicks. Despite substantial efforts and some progress in the development of defined cultures, the prospects are not very encouraging. Until the exact mechanism of protection is elucidated, the basis for selecting the required strains will be difficult to define.


The use of an antimicrobial and competitive exclusion combination in Salmonella-infected pullet flocks. Replacement pullets which had been found infected with Salmonella were treated with antibiotics for 12 days, moved to a clean house by the 11th day and given 2 treatments with a competitive exclusion (CE) preparation on the 13th and 15th day. It was found necessary to supply a small amount of feed to generate a thirst in the birds and ensure efficient and rapid consumption of the CE preparation. Salmonella could not be grown from the intestines or other organs of birds after this procedure had been carried out.


Competitive exclusion of campylobacters from poultry with K-bacteria and Broilact. The competitive exclusion (CE) product (Broilact) which is effective against Salmonellas, was found to be inactive against campylobacters. Microecological concepts were applied in the search of a new competitive flora and two novel strains ('K-bacteria') were isolated. These strains resembled campylobacters but differed from them in morphology, enzyme profiles (API), cellular fatty acid profiles and when tested with a ribosomal RNA hybridization probe (Gene-Trak). Two-week laboratory trials on broiler chickens showed that CE treatment may protect the birds against campylobacters but revealed the need for facultatively anaerobic bacteria in establishing a protective flora. A 5-week pilot scale trial was carried out. The trial involved 1800 newly hatched chicks in 30 groups. K-bacteria and Broilact, which provided the necessary facultatively anaerobic bacteria, were administered to some of the birds in the first drinking water. A seeder bird technique was used to challenge experimental and control birds with Campylobacter jejuni biotype 2 (broiler origin). Three seeder birds were placed in each group of 60 birds. Groups were sampled weekly for campylobacters and finally at the slaughterhouse. From each group, the caecal contents of two birds were examined quantitatively for campylobacters. The performance of the birds was also monitored during the trial. The results showed a 1.5 week delay in the onset of campylobacter infection in treated chicks and a consistently lower level of colonization in comparison with control birds. At slaughter, levels of carriage in caecal contents of treated birds were 1.5-2.0 log10 units lower than those of controls, despite apparent stress from harvesting and transportation. The treatment had no economically important effects on the performance of the birds during rearing.


Prevention of colonization by Salmonella enteritidis PT4 in broiler chickens. Field experiments in The Netherlands and in Scandinavian countries have shown that an undefined microflora originating from SPF adult poultry will reduce considerably the colonization of young chicks by Salmonella. A commercial product from this so-called Nurmi concept, Broilact, was studied for its effectiveness in preventing infection of broilers with Salmonella enteritidis PT4 (S.e.). Two trials were carried out, in which the birds were exposed to S.e. via 'seeder' birds placed among them. The trial period was 21 days and each week one third of the chicks was killed and their caecal contents examined for salmonellas. The results of the first trial can be summarized as follows. (1) After 2 weeks the number of 'seeder' birds carrying the Salmonella decreased sharply; (2) the proportion of infected chicks in the Broilact-treated group was lower than in the non-treated group; (3) Counts of S.e. in the non-treated group were higher than in the Broilact group. Results of the second trial were comparable, although no salmonellas could be isolated after the second week.


Evaluation of the efficacy of Broilact in preventing infection of broiler chicks with Salmonella enteritidis PT4. A study was conducted to evaluate treatment of day-old broiler chicks with Broilact, a live-culture preparation, for preventing intestinal colonization by a non-host-specific Salmonella (S. enteritidis PT4, with high resistance to nalidixic acid). Newly hatched broiler chicks were sprayed with Broilact at a commercial hatchery and delivered on the same day to Huntingdon Research Centre. Control chicks from the same source (i.e. chicks not treated with Broilact) were sent separately. Chicks were maintained in floor pens in groups of 40. The challenge was introduced by means of seeder birds infected with S. enteritidis PT4 (nalr) at a nominal dose level of 10(4) CFU per bird (3 seeder birds per pen of 40 contact birds). Groups of birds were killed 7, 28 and 40 days after challenge, and in each case caecal contents were examined culturally for the test organism. A total of 18 deaths occurred including 13 untreated contact birds, 3 Broilact-treated contact birds and 2 seeder birds. These were attributed to the experimental infection. Results of the examination of caecal contents from untreated control birds indicated that the challenge organism was successfully established in contact chicks via the seeder birds. The overall results for birds treated with Broilact showed a clear protective effect, with little indication of any significant infection by the challenge organism. It was concluded therefore that under the conditions of this study, Broilact was largely effective in preventing intestinal colonization by the non-host-specific s. enteritidis PT4.


Use of a competitive exclusion product (Broilact) to prevent Salmonella colonization of newly hatched chicks. The study described here was carried out at the request of a French company to utilize the authors' experience of 'competitive exclusion' treatment for poultry. The objective of the study was to determinate the safety and efficacy of a particular treatment product (Broilact) in protecting chicks against Salmonella infection.


Survey of thermotolerant Campylobacter spp. and Yersinia spp. in three surface water sources in Norway. We investigated the occurrence of thermotolerant Campylobacter and Yersinia spp. in three surface water sources in Norway which represented different levels of pollution and eutrophication. Samples were collected every fortnight during a 14-month period. In addition, samples from 100 private wells were examined for campylobacters only. Campylobacter was recovered from 42 (43.8%) of the 96 samples of surface water, whereas Yersinia spp. were isolated from four (4.2%) of the samples. Campylobacter was not isolated from the well water samples. The highest isolation rate of Campylobacter was obtained from the two most polluted water sources. The proportion of positive samples was significantly higher in the autumn (71.4%) than in the spring (36.4%) or summer (22.2%). The highest overall isolation rate was obtained at water temperatures ranging from 2.1 to 8.0 degrees C, and the lowest at temperatures greater than 15 degrees C. Logistic regression analysis showed a highly significant relationship between the prevalence of Campylobacter and the number of three types of indicator bacteria: faecal coliforms, faecal streptococci and sulphite-reducing clostridia. Of the 60 Campylobacter isolates obtained, 51.7% belonged to C. jejuni biotype 1, 20.0% belonged to C. jejuni biotype 2, 21.7% to C. coli, 3.3% to C. lari and 3.3% were non-typable. All four Yersinia isolates were non-pathogenic variants.


An audit of trauma deaths in Newcastle upon Tyne. The TRISS methodology was applied to identify unexpected trauma deaths during a one-year period. Out of a total of 104 deaths, 50 were hospital deaths (M = 0.6837). Twelve (27%) of these deaths were judged to be unexpected, ie, had a probability of survival (Ps) > or = 0.50 (Z = +4.80). Those deaths deemed to be unexpected were subject to further analysis. The implications of these findings are discussed.


Behavior of Listeria monocytogenes during processing and storage of experimentally contaminated hot-smoked trout. Hot-smoked fish like smoked trout is quite frequently contaminated with Listeria monocytogenes. In order to estimate the potential health hazard for the consumer eating such products, the behavior of L. monocytogenes was studied during processing and storage of artificially-inoculated hot-smoked trout. Four trials were performed; in trials 1 and 3 a wild-type strain was used, while in trials 2 and 4 a serological reference strain, SLCC 2755, was used. In the first two trials, raw trout was surface inoculated with L. monocytogenes, marinated, hot-smoked (core temperature 65 degrees C during 20 min), and stored at 4 and 8-10 degrees C, respectively, for up to 20 days. At different times during processing and storage, samples were taken and, by means of a MPN-method, quantitatively analysed for L. monocytogenes. The initial Listeria levels in the trout were 10(6) MPN/g. Until smoking, the concentrations remained about the same. After the hot-smoking process and during storage, however, L. monocytogenes could no longer be detected. In trials 3 and 4, the trout were inoculated after hot-smoking at a final concentration of 4.5 x 10(1) MPN/g and 3.1 x 10(1) MPN/g, respectively. During storage at 4 degrees C, neither an increase nor a decrease of L. monocytogenes was observed. At 8-10 degrees C, however, a significant increase up to 10(7) MPN/g occurred. By hot-smoking, low level contaminations of raw fish with L. monocytogenes will easily be eliminated. Nevertheless, it is of great importance to prevent postprocessing contamination, because during storage at refrigeration temperatures growth of L. monocytogenes is possible.(ABSTRACT TRUNCATED AT 250 WORDS)


A survey of head injuries in a general hospital. This paper reports the incidence of head injuries as patients attended a general hospital Accident & Emergency Department. The survey was carried out over a twelve-month period. The Accident & Emergency Department of Luton & Dunstable Hospital sees approximately 60,000 new patients every year. It is situated in close proximity to the M1 motorway and other major road systems. Facilities are available on site for computerised tomography from Monday to Friday between 9:00 am and 5:00 pm. At other times, if it is considered necessary after consultations with our neurosurgical colleagues, they are referred to the Royal Free Hospital, 30 miles away.


Childhood chronic renal failure in Qatar. Thirty children below the age of 12 with chronic renal failure (CRF) were studied. In 21 patients (70%) the renal failure was secondary to congenital or familial aetiology. Obstructive uropathy (53.3%), mostly due to posterior urethral valves (40%), comprised the majority of cases. Four cases (13.3%) were secondary to reflux nephropathy. It is concluded that the majority of cases of CRF in the state of Qatar are secondary to potentially treatable or preventable conditions. Use of antenatal ultrasonography combined with aggressive management of obstruction and urine infection may help reduce morbidity and mortality.


Glucose and sucrose fermenting capacity of homofermentative lactic acid bacteria used as starters in fermented salads. Salads, i.e., vegetables and/or meat in an oil-in-water emulsion with a low pH due to the addition of acids, are popular in western countries. The shelf life of these salads is influenced mainly by storage temperature and the use of preservatives, i.e., sorbic and benzoic acid. Lactic acid fermentation could be an interesting novel approach to salad preparation. As part of an investigation on fermented salads, lactic acid bacteria from the genera Lactobacillus, Pediococcus and Streptococcus were screened for their capacity to ferment glucose and sucrose in a model system and in a standard salad. The temperature optimum of these strains was in the range of 34-48 degrees C. Most of these strains produced about equal amounts of L(+)- and D(-)-lactic acid. To determine the specific sugar fermenting capacity (mmol lactic acid produced per min per g dry weight) of non-growing cells of lactic acid bacteria, a semi-automated model system was used, based on monitoring the pH decrease in a phosphate buffer during conversion of sugars to lactic acid. The strains tested showed acid production rates on glucose varying between 0.03 and 0.39 mmol of acid produced per min per g dry weight (average 0.23). These glucose-grown cells showed varying, but lower fermentation rates on sucrose (0-0.25 mmol/min/g d.w., average 0.04) than sucrose-grown cells (0-0.33 mmol/min/g d.w., average 0.19). Results obtained with the model system were in good agreement with those of fermentation tests, carried out with a standard salad. Inhibition of spoilage bacteria in the standard salad could be achieved by using starter cultures with high fermenting capacity.


Infectivity of Toxoplasma gondii in mutton following curing, smoking, freezing or microwave cooking. To investigate the effects of curing with sodium chloride and sucrose, low temperature smoking, freezing at -20 degrees C, and cooking in a microwave oven, respectively, on the infectivity of Toxoplasma gondii encysted in mutton, meat from three experimentally and one naturally infected sheep was used. Samples of meat prepared accordingly as well as untreated, raw meat from each animal were assayed by mouse inoculation. Infective T. gondii was isolated from untreated samples from all animals used, but in no case from cured, smoked or frozen meat. However, in two of four steaks processed in a microwave oven, according to a standard household recipe, the parasite remained infective, possibly due to uneven heating of the meat.


Fluvoxamine in the treatment of depressive illness. A series of double-blind hospital based comparative studies carried out in the UK. A series of double-blind hospital based studies comparing fluvoxamine with other antidepressants in depressed patients is reviewed. Overall there were no significant differences in terms of efficacy between fluvoxamine and the comparators (amitriptyline, dothiepin, lofepramine and mianserin). Fluvoxamine was shown to be associated with a low incidence of anticholinergic, cardiovascular or sedative effects. This profile of activity, together with low toxicity in overdosage, has established the place of fluvoxamine in the treatment of depressive illness.


Simple and economical culture of Campylobacter jejuni and Campylobacter coli in CO2 in moist air. Strains of Campylobacter jejuni and C. coli representing the 18 serogroups (Lior) most commonly isolated from humans in Canada were grown on solid media in an atmosphere of 10% CO2 in moist air, 99% relative humidity. When the growth of all 18 serogroups on Mueller Hinton agar in a microaerobic atmosphere (5% O2, 10% CO2 and 85% N2) was compared with the growth of all 18 serogroups on the same media in 10% CO2 in moist air, colony sizes were significantly larger (p less than 0.05) for strains grown in 10% CO2 in moist air. No significant difference in colony numbers was seen between the two atmospheres. The addition of blood to the media significantly enhanced the growth of the campylobacters in both types of atmospheres (p less than 0.05). This simple CO2 atmosphere permitted the use of a common CO2 incubator thereby reducing the cost and difficulty of culturing these organisms.


Comparative efficacy and tolerability of cephradine and cefuroxime axetil in the treatment of acute dysuria and/or frequency in general practice. One hundred and thirteen patients with dysuria and/or frequency were treated randomly with either 500 mg cephradine 12-hourly or 125 mg cefuroxime axetil 12-hourly, for seven days. A total of 71 patients were found to have urinary infection: bacteriological cure rates were 97% one week post-treatment, and 96% five weeks post-treatment, for both antibiotics. On direct questioning, adverse events were reported by eight patients out of 59 taking cephradine and by three of 54 who had received cefuroxime axetil. However, only three and one respectively stopped taking the antibiotic due to the adverse event. Analysis of diary cards, completed by 109 patients, showed a significantly higher incidence of increased frequency of bowel movements in those taking cefuroxime axetil. It is concluded that both antibiotics are of equal value in the treatment of simple acute urinary infections in general practice.


Doctors' knowledge of socio-legal aspects of patient care. Doctors' knowledge of socio-legal aspects of patient care is poor. To quantify this a questionnaire on certain socio-legal topics was sent to 400 general practitioners and 250 hospital doctors. The responses were compared to a group of social workers. Both hospital doctors and general practitioners did badly on all topics considered. Social workers' knowledge was significantly better overall, (P < 0.01). Our results confirm the lack of knowledge amongst a broad spectrum of doctors. We suggest that this may be related to a lack of emphasis on these aspects in both undergraduate and postgraduate education.


Growth of fermentative and non-fermentative yeasts in natural yoghurt, stored in polystyrene cartons. Permeation of oxygen through polystyrene packaging is a factor in the growth of yeasts in natural yoghurt. Diffusion of oxygen through the packaging material can permit the growth of non-fermentative yeasts in yoghurt stored at refrigeration temperatures. Yarrowia lipolytica, a non-fermentative yeasts which does not utilize lactose was isolated from yoghurt. The growth in natural yoghurt of Yarrowia lipolytica and the lactose-fermenting yeast Kluyveromyces marxianus was investigated. Both yeasts grew in yoghurt with reduced fat content. Storage of yoghurt in an anaerobic atmosphere eliminated growth of Yarrowia lipolytica but permitted fermentative growth of Kluyveromyces marxianus.


Ofloxacin versus trimethoprim and co-trimoxazole in the treatment of uncomplicated urinary tract infection in general practice. A large-scale, randomised, multicentre single-blind clinical trial was conducted to assess the comparative efficacy and tolerance of ofloxacin, trimethoprim and co-trimoxazole in the treatment of uncomplicated urinary tract infection in general practice. A total of 1,069 patients from 76 centres across the UK were enrolled in the study, and randomised to one of the following treatment groups: ofloxacin (200 mg od), trimethoprim (200 mg bd) or co-trimoxazole (trimethoprim 160 mg and sulphamethoxazole 800 mg bd). Each patient received five days of medication. Clinically, ofloxacin was as effective as trimethoprim and co-trimoxazole. However, the bacteriological cure rate was significantly better for ofloxacin, with eradication of the initial causative pathogen by the end of treatment in 92% of patients in the ofloxacin group, compared with 81% for trimethoprim and co-trimoxazole (P = 0.0002). There was also a lower relapse rate for ofloxacin. Ofloxacin was well tolerated: adverse events were reported by 67 (12.4%) patients in the ofloxacin group, compared with 48 (18.7%) patients in the co-trimoxazole group and 37 (13.6%) patients in the trimethoprim group. Ofloxacin can therefore be considered a suitable alternative for the treatment of uncomplicated urinary tract infection.


Sleep apnoea: causes, consequences and treatment. An awakening has taken place over the last 25 years to the science of sleep disorders. Foremost amongst these, both in the medical world and the public eye, has been Sleep Apnoea Syndrome (SAS). The prevalence is thought to be the order of 1-2%. Males are eight times more commonly affected than females, although after the menopause the gap narrows considerably. Sleep apnoea occurs in children, usually in relation to large tonsils and adenoids, but in adult life patients usually present between the age of 40 and 60 and the prevalence increases with age. Numerous apnoeas or hypopnoeas during the night's sleep result in disordered sleep architecture and unrefreshing sleep. This is usually accompanied by night-long snoring which may lead to marital discord and even complaints from neighbours. Symptoms on waking may be a headache and a feeling of not being refreshed by sleep. Sleepiness during the day can interfere with work and social activities and may produce risks to the patient and others if it occurs while operating dangerous machinery or driving. Over a longer time scale SAS results in intellectual and memory deterioration, a higher incidence of ischaemic heart disease, hypertension, polycythemia and pulmonary hypertension. Right heart failure is particularly likely if there is chronic airflow obstruction contributing to a low arterial oxygen level. Asystolic periods and tachyarrhythmias may occur during apnoeic periods. The increased mortality of SAS relates to coronary and cerebrovascular disease and arrhythmias. Sudden death occurs with greater frequency in patients with SAS, mainly at night.


Coronary intervention: where are we now? Coronary interventional techniques are used widely in the treatment of patients with coronary artery disease. With modern dilatation equipment the angiographic success rate of coronary balloon angioplasty may exceed 90%, but complications due to acute coronary occlusion may require emergency coronary artery bypass surgery (2-4%), or result in acute myocardial infarction (2-5%) or in-hospital death (0-2%). In most patient groups the long-term outcome of successful coronary angioplasty is good, but restenosis of a successfully dilated stenosis occurs in about 30% of cases, necessitating re-intervention in a significant proportion of patients. Other interventional methods of treating coronary artery stenosis, including directional and rotational coronary atherectomy, endoluminal stenting, and laser angioplasty, have been used in preliminary clinical studies. The acute results of these techniques are encouraging but the restenosis rate remains high and the long-term results are uncertain. The results of randomised clinical trials comparing coronary interventional techniques with alternative treatment methods are awaited.


Conservative therapy for tennis elbow.

Conservative therapy for tennis elbow. Tennis elbow is a common overuse syndrome. It is accompanied by degenerative changes in the enthesis of the extensor carpi radialis brevis muscle. It may be best diagnosed clinically by eliminating other possible causes of lateral elbow pain. Physical methods should always be selected as initial treatment. Immobilisation is the initial advice that most doctors give: ultrasound has been shown to be effective in a placebo-controlled, double-blind trial, and low energy laser has been found to reduce objective but not subjective symptoms. Other forms of physical treatment like electrotherapy, thermotherapy and massages can be tried, even though proof of their efficacy needs to be established more firmly. When physical treatments have failed, steroid injections can help. If symptoms still persist, then surgery is called for. There are still many open questions surrounding the syndrome of tennis elbow. Research into this common soft tissue disease should be intensified.


Which calcium channel blocker for ischaemic heart disease? Calcium channel blockers have been available since the early 1960s. Extensive research has been undertaken to evaluate their usefulness in the treatment of patients with ischaemic heart disease. We have reviewed the pharmacology of these drugs and the major clinical trials. In particular, we have examined the effect of calcium channel blockers on the progression of atheroma, and their role in the following clinical settings: following myocardial infarction, following non-Q-wave myocardial infarction, and in unstable angina.


Artificial ventilatory management in a severe, pregnant asthmatic--a case report. A 33-year-old pregnant atopic woman, who had never suffered from asthma or atopic-related disorder, was admitted on three occasions during her fifth pregnancy with severe asthma. On her last admission she required more intensive monitoring and artificial ventilation. We report this patient and discuss the pathogenesis of asthma during pregnancy. Asthma in pregnancy is not uncommon and it may take a severe course in some pregnancies. In one prospective study 42% of the patients required aggressive management, but none required artificial ventilation. However, there was no difference in the outcome of pregnancies between asthmatic and control subjects. Here we describe a patient with severe asthma who required artificial ventilation with a successful outcome.


Paradoxical emboli in elderly patients.

Paradoxical emboli in elderly patients. We report two elderly patients who each had a patent foramen ovale (PFO) and were considered to have had paradoxical emboli. In one patient the PFO was detected by contrast two-dimensional echocardiography, whereas in the other it was demonstrated at post-mortem examination. This is an unusual but treatable condition, particularly difficult to diagnose in older people and probably occurring more frequently than is generally suspected.


Spontaneous rupture of normal spleen: an enigma recalled. That a normal spleen can rupture spontaneously has long been a point of debate. A definitive case is reported here in an attempt to resolve the issue in its favour. Spleen involved in tropical diseases like malaria, infectious mononucleosis and typhoid fever is prone to rupture spontaneously as well as in cases follow minor trauma. In contrast, normal spleen ruptures almost always following severe trauma, such as road accidents or fall from significant heights. Though cases of spontaneous rupture of normal spleens have appeared off and on in the past, doubt has always surrounded the very existence of such an entity. We are reporting a definitive case of spontaneous rupture of normal spleen. This is only the second case of its kind since 1958 and the first ever from the Indian subcontinent.


Recurrent endometrial adenocarcinoma presenting as an umbilical metastasis (Sister Mary Joseph's nodule). A case of recurrent endometrial adenocarcinoma metastatic to the umbilicus is reported. The possible modes of spread, management and prognosis of this rare manifestation of visceral malignancy are discussed.


Extra cranial arteriovenous malformations presenting as pulsatile tinnitus. We present two cases of extra cranial arteriovenous malformations, which presented as pulsatile tinnitus. They were originally diagnosed by clinical examination and both lesions were subsequently confirmed by angiography and their feeding vessels defined. One case was managed by surgical excision, which produced relief of symptoms. The diagnosis and management of arteriovenous malformations is discussed.


Ruptured abdominal aortic aneurysm presenting with acute urinary retention. Ruptured abdominal aortic aneurysm classically presents with abdominal pain radiating to the back, a pulsatile abdominal mass and circulatory collapse. However, other symptoms may be the only presenting complaint. We report the case of a patient who presented with a history of acute retention of urine relieved by catheterisation, but who then developed clinical features more typical of abdominal aortic aneurysm rupture.


Cancer prevention education in United States medical schools. Cancer Education Survey II: cancer education in United States medical schools. The Cancer Education Survey collected data from 126 of 128 US Medical Schools on the current status of cancer-related educational activities for undergraduate medical students. The study was conducted by a Supervisory Committee of the American Association for Cancer Education, with funding from the American Cancer Society. The survey obtained data concerning institutional characteristics in support of undergraduate medical student cancer education, ie, administrative structures, current cancer-related curricula, sources of financial support, and anticipated changes in these characteristics. Institutions were also queried on specific topics of cancer prevention, detection, and diagnosis that might be taught as identifiable areas of instruction for medical students. Three-fourths of the institutions had a lecture on the principles of cancer screening, and, among those, nearly three-fourths classified it as a part of a required course or rotation. Detection of common cancers is taught in virtually all institutions. The least likely cancer prevention lecture topics are related to prevention and cessation of smoking, a well-verified cancer risk. Also, no consistent pattern emerges that might indicate that association with a cancer center imparts to a medical school a greater emphasis on delivery of cancer prevention topics.


Changing the cancer curriculum: a curriculum committee's response to the results of the AACE Cancer Education Survey II. Cancer Education Survey II: cancer education in United States medical schools. The AACE Cancer Education Survey-II offers an unusual opportunity based on data from 125 medical schools and 1,035 experienced cancer educators to effect constructive change with regard to cancer education. The changes suggested include more coordination; integration; and a shift of emphasis to include more on topics of prevention, early diagnosis, tumor biology, rehabilitation, palliative care, and psychosocial issues. Ample opportunities, especially in the ambulatory care arena, exist at most medical schools, and there is a great deal of interest in improving the situation. This article reviews the factors contributing to resistance to change, the data on adult learning, and the major movements and dilemmas facing medical education today. It also discusses some of the external forces like the Liaison Committee on Medical Education (LCME) and foundation support, which are being harnessed to effect change. Given these barriers, forces, and opportunities, the article ends with a possible action plan for an individual, an institution, and national bodies interested in cancer education. The knowledge, skills, values, and attitudes must be defined, taught effectively, and evaluated. It is an opportune time, armed with this useful data, to bring about change in how cancer subjects are taught. The ultimate goal is more knowledgeable and effective practitioners and scientists who can decrease the morbidity and mortality from cancer.