Beta thalassaemia in the indigenous British population. We have analysed the molecular basis of beta-thalassaemia in 22 Anglo-Saxon individuals, all of whom were heterozygous for beta-thalassaemia except for one, who was a compound heterozygote. Using a combination of allele-specific priming of the polymerase chain reaction (PCR) and direct sequencing of genomic DNA amplified by the PCR, 20/23 beta-thalassaemic genes were characterized. Nine different mutations were identified; four are commonly found in the Mediterranean, one in Asia, one has been described previously in both Europe and Asia, and three are rare mutations associated with a dominant beta-thalassaemia phenotype. In three individuals the mutation remains uncharacterized despite sequence analysis of the beta-globin gene and its immediate flanking regions. We report our findings and discuss the diversity of these mutations.


Homozygosity for dominant form of hereditary spherocytosis. A 6-month-old male infant with hereditary spherocytosis (HS) who was the first child of a cousin marriage is presented. The patient had splenomegaly and severe anaemia. Examination of the peripheral blood smear revealed spherocytes and the osmotic fragility of red blood cells was greatly increased. Physical examination of the parents revealed that both parents had mild anaemia, jaundice and splenomegaly. Their peripheral blood smears showed spherocytes and a few acanthocytes. Osmotic fragility of red blood cells of both parents were increased. Red cell membrane electrophoresis indicated a deficiency of ankyrin in the propositus; mild deficiency was also detected in both parents. Electrophoretic patterns of red cell membrane proteins suggested that the child was homozygous for the dominant form of HS associated with ankyrin deficiency, while both parents had the simple dominant form of the disease. Red blood cell transfusions were given to the patient starting at the age of 1 month until splenectomy was performed at the age of 1 year that resulted in complete haematological response. This observation indicates that homozygosity for dominant type of HS associated with ankyrin deficiency is life compatible and splenectomy may cure the anaemia.


Serum immunoreactive erythropoietin in patients with idiopathic aplastic and Fanconi's anaemias. In patients with idiopathic aplastic anaemia (n = 34) and Fanconi's anaemia (n = 8), sampled once or on several occasions, serum erythropoietin (Epo) increased with increasing severity of anaemia with apparently similar rates of increase in each group. However, after adjustment for Hb, log Epo values for the Fanconi's anaemics tended to be greater than those for the idiopathic aplastic anaemics (P < 0.01). Erythropoietin concentrations in serum samples from patients with Fanconi's and idiopathic aplastic anaemias tended to be greater than in samples from patients with anaemias from protein energy malnutrition, myelodysplasia and iron deficiency. The results suggest that there is no deficiency of erythropoietin in Fanconi's and idiopathic aplastic anaemias and that if exogenous erythropoietin is of any benefit it would need to be administered in doses large enough to induce a significant increase in log Epo. Results of the study illustrate the need to take account of the assumptions which underlie interpretation of the statistical analysis. Use of erythropoietin values in place of log Epo gives misleading conclusions demonstrable as invalid as the conditions for normality of distribution of the data and homogeneity of variances were not satisfied.


Serum erythropoietin levels in anaemic patients with advanced human immunodeficiency virus infection. This study attempts to evaluate the adequacy of the erythropoietin (EPO) response in 42 anaemic patients with advanced human immunodeficiency virus (HIV) infection [30 with acquired immunodeficiency syndrome (AIDS) and 12 with AIDS-related conditions] by comparing their serum EPO levels with those found in a non-HIV reference population consisting of 36 patients with anaemia of chronic disorders (ACD) and 57 with iron deficiency anaemia (IDA). Although the average Hb concentration was similar in the three groups, the EPO level for HIV patients (mean +/- SEM, 64.3 +/- 7.7 mU/ml) did not differ significantly from that in ACD patients (45.3 +/- 8.3 mU/ml, P > 0.1), and both groups had a lower mean EPO level (P < 0.05 and P < 0.01 respectively) than IDA subjects (133.5 +/- 18.7 mU/ml). Thirteen HIV patients on zidovudine therapy showed similar mean Hb and EPO levels to those in the untreated patients. A significant inverse correlation between the log of serum EPO and the Hb values was observed in the three groups. However, this relationship was found to be stronger in IDA patients than in either HIV or ACD subjects (P < 0.001), with no difference between the two latter groups (P > 0.2). These data suggest that the EPO response is blunted in the anaemia associated with advanced HIV infection.


Prevalence of thrombocytopenia in HIV-infected and non-HIV infected drug users and homosexual men. We studied the prevalence and risk factors for thrombocytopenia among 299 drug users and 461 homosexual men. The prevalence of thrombocytopenia was 3.3% in HIV-negative homosexual men, 8.7% in HIV-negative drug users, 16.4% in HIV-positive homosexual men, and 36.9% in HIV-positive drug users. With multivariate logistic regression HIV-seropositivity (odds ratio 3.3), a history of injecting drugs (OR 3.9), an increased number of lymphocytes (OR 0.44), an increased number of neutrophils (OR 0.53) and a larger mean platelet volume (OR 2.8) were independently and significantly associated with thrombocytopenia. The results obtained with linear regression analysis were consistent with the results of the logistic regression. The higher prevalence of thrombocytopenia among drug users was related to a history of intravenous drug use but not to recent injecting. The mechanisms causing thrombocytopenia among HIV-positives and HIV-negatives seem to be related, but HIV-infection seems to enhance thrombocytopenia in an independent way.


A cross-cultural evaluation of expectations about psychological counselling. This study investigated differences in British Asian and white people's expectations about psychological counselling. Ninety-eight general practice subjects not anticipating counselling completed the Expectations About Counselling (EAC) questionnaire. There were significant differences on 10 of 18 EAC subscales relating to client and counsellor attitudes and characteristics, and counselling process and outcome.


Critique of a Kleinian case presentation. An account of Kleinian analysis illustrating the concept of the pathological organization is discussed from an alternative theoretical position, that of cognitive analytic therapy. It is suggested that the alternative model of development, while still essentially an object relations theory, produces a different understanding and that the therapeutic method associated with it offers a more powerful means of aiding personality integration.


The psychodynamics of the STD clinic: secrecy, splitting and isolation. We introduce the idea of a professionally isolated and apparently disconnected agency. We describe how health professionals working in settings with good multi-agency links may not recognize the effect of the isolated agency system on the presentation of problems. In particular, we describe the setting of the Sexually Transmitted Diseases clinic (STD) in which confidentiality can be turned into secrecy by the patients at the service of their denial of the seriousness of their problems. The isolation of the STD clinic as an agency resonates with the patients' isolation from their own feelings and emotional contact with people. It also isolates the professional and the therapeutic network. By way of clinical examples, we describe how this may deskill the staff and lead to dangerous situations.


Facilitators and regulators: cross-cultural and methodological considerations. In a model of motherhood Raphael-Leff (1983) delineated two basic orientations: the Facilitator who adapts to the baby and the Regulator who expects the baby to adapt. The FR questionnaire was completed by 97 Israeli mothers of six-month-old infants; 34 per cent were classified as Facilitators, 34 per cent Regulators, 15 per cent Intermediates and 17 per cent were labelled Bipolars. Future research should explore the characteristics of this latter group and its prevalence in other societies.


Psychodynamic aspects of delayed abortion decisions. Multiple regression analysis of a wide range of variables for a sample of 58 women obtaining elective abortion identified psychodynamic factors as the only statistically significant explanations for seeking abortion at later gestational ages. Delay among these women was associated with greater disturbance in the basic sense of self as noted in indications of gender/sexual conflict on their drawings of a human figure, and lower achievement orientation ('striving') as expressed by lower levels of striving attributed to parents or other primary (early) caretakers. These findings are discussed as an active taking charge of an unintended pregnancy for women who present early for abortion; for those who delay, attempts to affirm a deficient feminine identification and/or reunite psychologically with the early caretaker are discussed as underlying dynamics.


Psychological theories of delusional thinking: in search of integration. Psychological theories approach the problem of delusional thinking in psychosis from a range of perspectives. Recent attention has focused on the attributional style of sufferers; research points towards the relevance of cognitive deficits; the potential value of cognitive therapy in reducing delusional thinking is being explored; and psychodynamic theories argue for the role of defence mechanisms. Aspects of these approaches are reviewed and ideas for integration discussed within the vulnerability-stress model of psychosis. Implications for therapy are noted.


Defining delusion and the serving of professional interests: the case of 'paranoia'. This paper examines the related concepts of paranoia and delusion from a broadly social constructionist perspective. Through an analysis of the American Psychiatric Association's (1987) definition of delusion, inherent inconsistencies and implied philosophical assumptions are highlighted. It is argued that psychiatric definitions are not merely academic and clinical but are a site of political and professional interest. The implications of such an analysis are discussed with particular reference to developing new directions for research and clinical practice.


Paranoia and the defensive attributional style: deluded and depressed patients' attributions about their own attributions. A data set of Attributional Style Questionnaire responses collected by Kaney & Bentall (1989) from persecutory deluded, normal and depressed subjects was added to a similar data set collected by the first author. The attributions made for hypothetical positive and negative events by the combined pool of subjects were then blind rated for internality by five independent judges. Whereas the internality ratings made by the subjects for their own attributions showed evidence of an exaggerated self-serving bias in the case of the deluded subjects, and an absence of such a bias in the case of the depressed subjects, the independent ratings showed no such group differences. These findings suggest that the differences in internality for positive and negative events observed on the ASQ between deluded, normal and depressed subjects may not reflect differences in the types of causal statements made by these subjects but differences in their attributions about their attributions. The relevance of this observation for attribution theory in general and attributional accounts of psychopathology in particular are discussed.


Psychosis precipitated by marriage: a culture-bound syndrome? A retrospective study of 258 psychiatric out-patients in Jerusalem compared 122 patients from an ultra-orthodox Jewish community with 136 other Jewish patients. It was found that six patients who had a psychosis within a month of marriage all belonged to the ultra-orthodox community. The possible links between cultural and educational practice in the ultra-orthodox community and the vulnerability to the stress of marriage are discussed. It seems feasible to regard the precipitation of major mental illness by marriage as a largely culture-bound phenomenon.


Brightness versus apparent contrast. 2: Large-field asymmetry. Experiments were performed on the quasi-static perception of brightness and of apparent contrast of a foveal 1-deg disk, presented either as a luminance increment or decrement against a 300 cd.m-2 background. Results suggest that the perceptual attributes of brightness and apparent (or subjective) contrast should be distinguished. For an equal brightness difference with respect to the background, luminance increments are more effective than decrements. For an equal apparent contrast it is found that increments and decrements, up to 100 cd.m-2, are about equally effective; for higher values luminance decrements are more effective. Brightness increments and decrements can both be described by a Stevens power function of the respective luminance increments and decrements. Apparent contrast can, apart from applying a usual luminance contrast formula, also be described as a power function of the luminance difference with the background.


Brightness versus apparent contrast. 3: Blurred disks and concentric cosine gratings. Matching either the centre-brightness or the apparent contrast of incremental 1-deg disks, with varying edge-sharpness, yields quite different results. These suggest that the maximum brightness gradient at the edge determines apparent-contrast perception. However, no significant differences are found in matching the brightness maxima, the brightness minima, or the apparent contrast of concentric cosine gratings with varying spatial frequency. This means that spatial frequency influences both brightness extremes in the same way, and that apparent contrast is a function of the difference between the brightness extremes. The grating results therefore deviate from the results obtained with sharp as well as blurred disks. These contradictions complicate the construction of a model which unifies suprathreshold disk and grating perception.


Sensitivity to colour- and to orientation-carried motion respectively improves and deteriorates under equiluminant background conditions. This study presents two distinct effects produced by manipulation of the background illumination on the directional sensitivity to colour- and orientation-carried motion. The two motion percepts were produced with two of a class of stimuli extensively used by the first and last authors in apparent-motion studies. The stimuli were designed to produce motion perception by virtue of spatiotemporal matching of (a) colour with orientation systematically mismatched (Colour across Orientation, CxO) and of (b) orientation with colour systematically mismatched (OxC). An increase in background illumination from dark to the equiluminance point (relative to the luminance of the discrete stimulus microelements) entails a significant increase and decrease of directional performances with CxO and OxC stimuli, respectively. It is proposed that these anti-symmetrical background effects have distinct neurophysiological origins. For CxO stimuli, improvement of directional performances at the equiluminant point is presumably due to the inactivation of the inhibitory effect of the luminance-motion pathway on the chromatic-motion pathway. The opposite effect obtained with OxC stimuli, previously referred to as the veto effect (Gorea and Papathomas, 1988 Invest. Ophthal. Vis. Sci. Suppl., 29, 265), is supposed to be entailed by the inactivation of the luminance-oriented mechanism, the only motion sensitive mechanism activated by this stimulus configuration.


Comparing local and remote motion aftereffects. A new method, using phase-reversing sinusoidal gratings to cancel perceived motion, was developed to measure the motion aftereffect (MAE). This technique was used to show the existence of a remote MAE, i.e. an MAE in areas that were not directly stimulated during adaptation. In several experiments, this remote MAE was compared to the local MAE. The remote effect was generally weaker and of shorter duration. It showed no directional tuning within the investigated range, as compared to a tuning of +/- 60 deg of the local MAE. There was no adaptation effect to the component gratings of a plaid, indicating that the plaid was treated as a coherent pattern. The local MAE showed clear spatial frequency tuning, whereas the remote MAE varied little with spatial frequency difference, although there was a tendency towards frequencies lower than the adaptation frequency. The possibility is considered that both local and remote MAEs are generated in extrastriate areas.


Biostability and blood-contacting properties of sulfonate grafted polyurethane and Biomer. Sulfonate-containing polyurethanes were evaluated for in vivo biodegradation using subcutaneously implanted tensile bars. In addition, these anionically charged polyurethanes were evaluated for in vivo activation of human complement C3a and ex vivo platelet deposition in arteriovenously-shunted canines. The sulfonate derivatized polymers included laboratory synthesized polyurethane and Biomer. Other polymers used for references included Intramedic polyethylene, Silastic and a poly(ethylene oxide) based polyurethane. The biodegradation results indicated that Biomer and the laboratory sulfonated Biomer (both manufactured with stabilizers), remained mechanically stable, retaining both tensile strength and elasticity after 4 weeks of subcutaneous implantation. The unstabilized polyurethanes (with or without sulfonation), however, showed marked cracking and a loss of mechanical properties after the same period of subcutaneous implantation. Sulfonated polyurethanes depressed human complement C3a activation in plasma, as indicated by decreased levels of anaphylatoxin production. The results of canine ex vivo blood contacting experiments were conducted in both an acute and chronic model and demonstrated decreased platelet deposition and activation for the sulfonated polyurethanes.


Iron(III) chelating resins II. 3-Hydroxy-4(1H)-pyridinones-sepharose gels. 3-Hydroxy-4(1H)-pyridinones(HP)-Sepharose gels were prepared to study their iron(III) chelating properties. As ligands, derivatives of 3-hydroxy-4(1H)-pyridinone were coupled to CNBr-activated Sepharose gels. HP-Sepharose gels were obtained with HP densities of 23-28 mumol/ml gel and iron(III) chelating capacities of 19-23 mumol/ml gel at pH 6.8. From preliminary experiments, it was found that with the gels 19-27% iron could be removed from milk. In addition, 74% of iron(III) was removed from 100% iron(III) saturated lactoferrin within 24 h at pH 6.8 in the presence of citrate and a Sepharose gel, onto which 1-(2-aminoethyl)-3-hydroxy-2-methyl-4(1H)-pyridinone had been immobilized as a ligand. The properties of the gels make them potentially useful as water-insoluble iron(III) chelating agents.


In vivo protein adsorption on polymers: visualization of adsorbed proteins on vascular implants in dogs. The absorption of plasma proteins is an important event at the blood-material interface, and strongly affects subsequent cellular interaction and thrombus formation. Although considerable efforts have been expended to elucidate the mechanism of protein adsorption and the role of absorbed protein layer at the blood-material interface, there has been little knowledge of how the initial adsorbed proteins are maintained or changed in a time-variant process in in vivo long-term implantation. In this study, we described detailed analyses concerning the characterization of adsorbed proteins on HEMA--styrene block copolymer surfaces (HEMA-st) and poly(ethylene oxide) (PEO) grafted Biomer (B-PEO4K) for in vivo long-term canine vascular graft implants as well as in vitro short-term experiments. Biomer vascular grafts (6 mm I.D., 7 cm in length) were fabricated by a dip coating and the luminal surface was modified with PEO grafting, HEMA-st coating, or Biomer coating (control). These surface modified grafts were recirculated for different time intervals (5, 15, 30, 60 and 120 min) using citrated canine whole blood. The grafts were then implanted in the abdominal aortas of dogs and evaluated for graft patency and protein adsorption. The adsorbed proteins (albumin, IgG and fibrinogen) were quantified using an in situ radioimmunoassay. Surface protein layer thickness was measured by transmission electron microscopy (TEM). Visualization of absorbed plasma proteins (albumin, IgG and fibrinogen) was performed with TEM using an immunoperoxidase double antibody technique. In in vitro recirculation systems, albumin and IgG showed similar Langmuir type pattern onto all test surfaces. On B-PEO4K surfaces, fibrinogen adsorption kinetics demonstrated 'Vroman effect'. The Biomer and B-PEO4K grafts occluded within 1 month, while HEMA-st grafts were patent for over 3 months. Biomer and B-PEO4K showed thick multilayers of adsorbed proteins, and the thickness increased with implantation periods and the composition altered with time. In contrast, HEMA-st showed a monolayer-like adsorbed protein pattern, and the composition and thickness were consistent regardless of implantation time including in vitro short-time experiments, which may attribute to less conformational change of adsorbed proteins on HEMA-st surfaces. In terms of nonthrombogenicity, the stable monolayer-like adsorbed protein layer on HEMA-st surfaces exhibited improved blood compatibility over thick multilayered adsorbed proteins on Biomer and B-PEO4K surfaces.


Iron(III) chelating resins--I. Preparation and properties of Sepharose-desferrioxamine gels. For the removal of iron(III), Sepharose-desferrioxamine gels were prepared by the coupling of CNBr-activated Sepharose with desferrioxamine (DFO) at pH 7.8-8.3. DFO densities of the gels were 12-23 mumol/ml gel with iron(III) chelating capacities of 8.5-18 mumol/ml gel. The Sepharose-DFO gels with a high affinity for iron(III) were used for the removal of iron(III) from aqueous iron(III) solutions, wine, milk and whey.


Seasonal variations in the onset of retinal vein occlusion. Seasonal variation in the development of retinal vein occlusion in 1003 consecutive patients with various types of retinal vein occlusion was studied prospectively from 1973 to 1990. No seasonal variation in the onset of any type or combination of types of retinal vein occlusion was found. This refutes previous reports of such seasonal variation, which were based on small retrospective series.


Acyclovir ointment plus topical betamethasone or placebo in first episode disciform keratitis. Thirty patients with first episode disciform keratitis and with no previous steroid exposure were randomly assigned to double blind treatment with 3% acyclovir ointment and 0.1% betamethasone (Betnesol) drops or acyclovir ointment and matching placebo. In the steroid group 14 of the 15 patients healed in a mean time of 21.8 days. In the placebo group eight of the 13 patients healed in a mean time of 34.5 days. The difference in mean healing time between the two groups was significant (p < 0.05). The cumulative rate of healing was also quicker in the steroid group when compared with the placebo group (p < 0.001). Other clinical parameters improved more favourably in the combination treatment group. Four patients, two in either group, experienced a mild transient punctate epitheliopathy, but no other serious adverse effects were noted. There has been no significant difference in the recurrence rate between the two groups after a mean follow-up period of approximately 3 years.


Topical ofloxacin compared with gentamicin in the treatment of external ocular infection. Ofloxacin Study Group. In a double-masked, randomised, controlled study the effectiveness and safety of 0.3% ofloxacin solution were compared with those of 0.3% gentamicin ophthalmic solution in treating external bacterial ocular infections. The clinical improvement rate for patients treated with ofloxacin was 98% (51/52) and 92% (48/52) for those treated with gentamicin. Microbiological improvement was achieved in 78% (40/51) of the ofloxacin patients, compared with 67% (35/52) of the gentamicin group. Ofloxacin treatment eradicated or controlled 85% (86/101) of the Gram positive and 89% (17/19) of the Gram negative organisms cultured, compared with 83% (103/124) and 78% (29/37), respectively, after gentamicin treatment. None of these differences were statistically significant. The incidence of adverse effects attributable to ofloxacin treatment (3.2%) was less than that reported for gentamicin (7.1%). Ofloxacin proved to be an effective, safe, and comfortable therapy for external bacterial ocular infection.


Contrast sensitivity and glare in cataract using the Pelli-Robson chart. There is a need for a convenient, clinically applicable test of glare disability which can be used in the preoperative evaluation of patients with cataract. In this study, contrast sensitivity (using the Pelli-Robson letter chart), near vision, and visual acuity were compared, with and without the introduction of a glare source in 70 patients with cataract, 15 with intraocular lenses, and 19 controls. A disposable pen torch was shone at the pupillary margin to induce glare. Contrast sensitivity demonstrated the most marked reduction during glare testing. Cortical cataracts were most affected followed by posterior subcapsular opacities. The glare disability was significantly less in pseudophakic patients and was absent from patients with non-cataractous phakic eyes. Glare testing with a disposable pen torch and a Pelli-Robson contrast sensitivity letter chart provides a rapid test of glare disability which can be easily incorporated into the clinical appraisal of patients with cataract.


Refraction changes in children developing convergent or divergent strabismus. Strabismus and amblyopia were studied in a cohort of children born in 1979 or 1980 in the area of Västerås, Sweden. Forty percent of the children had participated in a voluntary eye examination at 1 year of age. All children diagnosed as strabismic and/or amblyopic between 1979 and 1988 at any of the three eye clinics in the area were included in this study. Strabismic cases were mostly detected by the parents while microstrabismus and straight eye amblyopia were found at the general 4 years of age screening at children's health centres. In 57 cases with (n = 31) and without amblyopia (n = 41) it was possible to obtain several refraction values between 1 and 6 years of age. In this study we concentrated on manifest esotropia and exotropia. The aim of the study was to describe changes of refraction before and after onset of strabismus and to establish risk indicators that identified populations at risk of developing strabismus. We found that patients with esotropia show a more pronounced hypermetropia than exotropic cases at the time of detection of strabismus. This difference becomes more definite over time, since hypermetropia increased in the deviating eye in the esotropic cases while refractive errors remained stationary in most of the exotropic eyes. It was also apparent that anisometropia frequently developed after onset of strabismus in esotropic cases in contrast to exotropic cases. An increasing refractive error in the deviating esotropic eye could be combined with an emmetropisation of the fixating eye.


Magnetic resonance imaging of the optic nerve in extremes of gaze. Implications for the positioning of the globe for retrobulbar anaesthesia. Orbital magnetic resonance imaging was carried out in nine directions of gaze in a normal subject. The findings are presented and discussed especially in relation to retrobulbar injections. Atkinson's position is confirmed to be hazardous and a new position for the globe at retrobulbar injections is suggested.


Vertical transposition of the horizontal recti (Knapp procedure) for the treatment of double elevator palsy: effectiveness and long-term stability. Full tendon width vertical transposition (Knapp procedure) of the horizontal recti is an established treatment for double elevator palsy (DEP) but the long-term stability of the surgical results have not been well studied. We undertook a retrospective study to determine the overall effectiveness of the Knapp procedure, the postoperative stability of alignment, and the influence of prior inferior rectus muscle recession (IRc) on the magnitude of correction. Nineteen patients with DEP underwent a Knapp procedure. Eight were corrected to within 5 delta of orthophoria, six were undercorrected, and five were overcorrected by at least 5 delta after a mean follow-up of 3 years (to last visit or to further surgical intervention). The average vertical correction was 37.5 delta in patients who underwent a prior IRc compared with 21.1 delta in patients with no prior IRc (p = < 0.0017). Over and undercorrections were more likely to occur in patients with prior IRc. Postoperative drift was towards increased effect in all patients. The seven patients with long-term (> 36 months) follow-up demonstrated an increased magnitude of correction (average = 12.6 delta) over an average follow-up of 76 months. The Knapp procedure had an increasing effect over time but the amount of vertical correction did not correlate with the size of the preoperative vertical deviation and was less predictable when a prior IRc had been performed.


A method for assessing the accuracy of surgical technique in the correction of astigmatism. Surgical results can be assessed as a function of what was aimed for, what was done, and what was achieved. One of the aims of refractive surgery is to reduce astigmatism; the smaller the postoperative astigmatism the better the result. Determination of what was done--that is, the surgical effect, can be calculated from the preoperative and postoperative astigmatism. A simplified formulation is described which facilitates the calculation (magnitude and direction) of this surgical effect. In addition, an expression for surgical accuracy is described, as a function of what was aimed for and what was achieved.


Localisation of corneal foreign bodies.

Localisation of corneal foreign bodies. Of 50 patients attending the eye casualty department with a corneal foreign body (FB), 41 were able to say where they felt the FB and 78% of these were localised correctly for side or level of cornea. Patient handedness did not influence FB location. Indicating the upper lid was a particularly poor guide to localisation, whereas FB sensations within the palpebral fissure, in the lower lid or medially or laterally were good guides to actual FB location. A simple method of recording FB location by zone and clock hour is proposed.


Horner's syndrome: an electron microscopic study of a human iris. Electron microscopy was performed on the irides of a man with a history of a long standing Horner's syndrome which resulted in iris heterochromia. Comparison of his normal brown iris with the depigmented blue iris showed depletion of anterior border cells and absence of sympathetic nerve fibres. Stromal melanocyte numbers were also diminished but melanosome numbers within the residual cells were not significantly different. Postnatal maintenance of stromal and anterior border zone pigmentation, derived from the neural crest, would appear to be dependent on an intact sympathetic nerve supply in contrast to the iris pigment epithelium which remains normally unaffected in Horner's syndrome.


Neurilemmoma of the anterior ethmoidal nerve encroaching upon the nasolacrimal duct. The clinical, light microscopic, ultrastructural, and immunohistologic findings of a neurilemmoma encroaching upon the nasolacrimal duct are presented. This is the first reported case of this rare tumour of the nasolacrimal duct where the diagnosis has been confirmed by electron microscopy and immunohistochemical techniques.


Anthrax of the eyelids.

Anthrax of the eyelids. Anthrax is a disease caused by Bacillus anthracis. The disease affects primarily herbivores including sheep, cattle, horses, and other domestic animals. Humans may rarely be affected. We examined one male and two female patients with a localised itchy erythematous papule of the eyelid. A necrotising ulcer formed in each of the three cases resulting in a black lesion. Scraping in each case showed Gram positive rods and culture grew Bacillus anthracis. All three patients responded to the intravenous administration of penicillin G, and the lesion resolved leaving scars in two cases. Anthrax is a rare disease but should be considered in the differential diagnosis of ulcers or pustules of the eyelids.


Bilateral Kimura's disease of the eyelids. A case of Kimura's disease affecting the eyelids bilaterally is reported in a 5-year-old boy of Afro-Caribbean extraction who has been followed for 12 years with repeat biopsies. He initially presented at 5 years of age with swelling of the left upper eyelid, left cervical lymphadenopathy, and eosinophilia. One year later he developed swelling of the right upper eyelid. There has been no change in the clinical appearance over the next 12 years. Repeated biopsies of the eyelids showed a diffuse inflammatory infiltrate with many eosinophils and lymphocytes. A lymph node biopsy showed reactive lymphoid hyperplasia. Immunohistochemistry using lymphoid markers showed a polyclonal pattern. Kimura's disease is a rare cause of eyelid swelling, particularly at such a young age and with bilateral involvement. This case demonstrates that bilateral orbital lymphoid lesions with cervical node involvement do not always imply lymphoma, but may have a benign pathogenesis. The unusually long follow up in this case confirms an excellent prognosis for Kimura's disease with conservative management. Accurate diagnosis in small orbital biopsies may spare the patient unnecessary radical surgery.


Progressive myopia in early onset chronic angle closure glaucoma. A 19-year-old girl presented with advanced unilateral chronic angle closure glaucoma and myopia with gross cupping and field loss in a previously hyperopic eye with a marked increase in corneal curvature. This emphasises that a marked myopic shift may be an important sign of glaucoma in a young patient.


Dermochondral corneal dystrophy (of François). Dermochondral corneal dystrophy (of François) has been reported rarely in the literature. It consists of a triad of findings characterised by the development of skin nodules, acquired deformities of the extremities, and a corneal dystrophy. The corneal dystrophy is central and superficial with whitish subepithelial opacities. We present two brothers who display previously unreported ocular findings. Specifically, they developed confluent opacification of their central corneas with anterior stromal involvement, and peculiar anterior cortical cataracts. These findings should be added to the spectrum of findings seen in this rare disorder.


Anterior subcapsular plaque cataract in hyperornithinaemia gyrate atrophy--a case report. Hyperornithinaemia gyrate atrophy (HOGA) is a rare autosomal recessive disorder in which chorioretinal degeneration occurs with cataracts, myopia, and hyperornithinaemia. We report the case of an 18-year-old female who presented with the typical features of HOGA, including posterior subcapsular cataracts and elevated plasma ornithine. She later developed distorted vision in both eyes owing to wrinkling of the anterior lens capsules. Histological examination following lens extraction showed the wrinkling was caused by focal distortion from capsular fibrosis (anterior subcapsular plaque cataract). This specific lens change has not been linked previously with HOGA.


Pink hypopyon: a sign of Serratia marcescens endophthalmitis. Endogenous bacterial endophthalmitis in infants is uncommon. We recently examined and treated an infant who presented with pink hypopyon which followed a Serratia marcescens septicaemia. Culture of the aspirate from the anterior chamber showed no red blood cells, and grew Serratia marcescens, which was also isolated from the tip of the child's umbilical artery catheter. The presence of a pink hypopyon in the absence of hyphaema may suggest the diagnosis of Serratia marcescens endophthalmitis.


Electroencephalographic sleep and mood during cocaine withdrawal. We report on nine patients between the ages of 21 and 39 years who were admitted to an inpatient substance abuse treatment unit for cocaine treatment. The patients' sleep was studied in the laboratory for 4 nights during the first week, and 2 nights during the second and third weeks of their hospitalization. Daily mood ratings, cocaine craving scores and sleep logs were also recorded on each patient. During the first week of withdrawal, these patients had a markedly shortened REM latency, an increased REM sleep percentage, a very high REM density and a long total sleep period time. During the third week, REM latencies were very short and total percentage of REM sleep was increased. By week three of withdrawal the sleep continuity pattern was similar to that found in chronic insomnia, with a long sleep latency, an abnormally increased total time awake after sleep onset and a poor sleep efficiency. The subjects' ratings of cocaine craving, total POMS scores and depression fell precipitously after the first week of withdrawal and were at sub-clinical levels by week three of withdrawal.


Neuropsychiatric effects of cocaine: SPECT measurements. Cocaine causes serious neurologic and neuropsychiatric complications. Cocaine-induced seizures are common and appear to be due to the local anaesthetic actions of this compound. Cocaine induced stroke has varied mechanisms. With ischemic stroke there is severe vasospasm induced by rises in brain catecholamines. These changes can persist for many weeks and can be demonstrated using single-photon emission computerized tomography (SPECT). In many patients with psychiatric symptoms such as psychosis or mania, SPECT demonstrates similar changes in cerebral blood flow. In fact, some of the psychiatric symptoms induced by cocaine may be due to decreases in cerebral blood flow. In cocaine abuse, treatment strategies based on decreasing cerebral vasospasm need to be developed.


Respiratory effects of cocaine freebasing among habitual cocaine users. Smoking of alkaloidal cocaine ("crack") has become increasingly prevalent in our society. Recent evidence suggests that crack smoking can cause acute respiratory symptoms, abnormalities in lung function and, in some instances, severe, life-threatening acute lung injury. To evaluate further the relationship between frequent cocaine smoking and respiratory symptoms and lung dysfunction, we studied a sample of 177 heavy, habitual smokers of freebase cocaine (mean 6.6 gm/wk for an average of 27 months) with or without concomitant smoking of tobacco and/or marijuana. Results in this sample were compared with those in a control sample of 75 age-, sex- and race-matched nonsmokers of cocaine who did or did not also smoke tobacco and/or marijuana. After controlling for the use of other smoked substances, heavy, habitual cocaine smoking was associated with the following: (1) a high frequency of acute respiratory symptoms (cough, black sputum, chest pain) in temporal association with freebase use; (2) an obstructive ventilatory abnormality involving the large airways; and (3) a mild but significant impairment in the diffusing capacity of the lung. These findings suggest that heavy, habitual crack smoking produces (1) respiratory tract injury manifested by acute respiratory symptoms and evidence of chronic airflow obstruction in large airways, and (2) an abnormality in diffusion of gas at the alveolar-capillary level. The mechanism of the diffusion defect is unknown but could reflect damage to the alveolar-capillary membrane. Further study of the magnitude, persistence, reversibility, mechanism and clinical significance of the abnormality in diffusing capacity is needed.


Cardiovascular effects and toxicities of cocaine. Cocaine exerts a myriad of adverse cardiovascular effects which are dependent on the dose, rate of administration, and duration of use. The drug has two primary pharmacologic actions: it is a powerful sympathomimetic agent and a local anesthetic. The drug blocks the presynaptic reuptake of catecholamines resulting in the marked hormonal increase at the postsynaptic receptor sites. These effects, in turn, lower the threshold for coronary vasoconstriction and vasospasm, myocardial ischemia and infarction. In addition, the drug's multiple pharmacologic and electrophysiologic cardiovascular actions can promote arrhythmias, myocarditis, cardiomyopathy, as well as unmasking subclinical diseases. Long-term cocaine use can cause autonomic disturbances and alter catecholamine homeostasis: chronic cocaine addicts face serious cardiovascular sequelae from the drug's multiple adverse effects. It is important to assess the prevalence of cocaine-related cardiovascular diseases, to understand how the drug affects the autonomic nervous system, and to determine its long-term effects on the cardiovascular system.


Observations on increased CPK levels in "asymptomatic" cocaine abusers. In order to assess increased creatinine phosphokinase (CPK) among medically asymptomatic active crack cocaine abusers, retrospective analysis of daily supervised urine data collected in a 20 day daily visit plus 12 week followup weekly visit study of heavy crack cocaine abusers was performed. The subjects were 36 black male chronic crack cocaine users unmotivated in drug abuse treatment, willing to be studied for daily payment, who were recruited by word of mouth on the street. Of the 464 CPK results obtained, the mean CPK value was 397 (SD = 784) IU/L. Two-thirds of the results were greater than 200; 19% were greater than 500 IU/L. CPK test results were systematically eliminated if related to medical causes or concurrent other drug use. The relative contribution of recent alcohol use versus recent cocaine use in raising CPK was assessed by dividing the remaining 435 observations into sequential use groups. With alcohol use instances excluded, a statistically significant relationship between urine cocaine metabolite and elevated CPK was found. When all other possible causes of elevated CPK levels were controlled, crack cocaine use was associated with a significant quantitative effect on CPK level.


Pathophysiological effects of cocaine in humans: review of scientific issues. Almost all data on pathophysiological abnormalities associated with human cocaine use comes from clinical observation and testing of cocaine abusers seeking treatment. Such data are subject to several confounding factors which preclude drawing definitive conclusions about the pathophysiological mechanism for the observed abnormality, its prevalence and prognosis, and individual differences in susceptibility. Confounding factors include the unknown purity of cocaine used, uncertainty as to quantity and duration of cocaine exposure, effects of other substances frequently used by cocaine users, abnormalities associated with drug route of administration and the drug abuse lifestyle, and selection bias. Future studies can address these issues by employing more sophisticated research designs, such as prospective, longitudinal follow-up of large, representative samples of cocaine users, case-control comparisons of well characterized cocaine users with appropriately matched groups, and experimental administration of cocaine under safe, controlled conditions.


The undertreatment of depression.

The undertreatment of depression. In spite of considerable progress in the establishment of physical and psychological treatments for major depression in clinical trials, little is known of the impact of treatment on the prevalence and course of depression in the population. Improved methods for assessing need for care have not yet been applied systematically to such a population. One hundred and thirty men and women attending psychiatric hospitals with depressive disorders were interviewed at the time of their initial contact. After a mean 4-month interval, 119 were reassessed in order to determine the extent to which potentially effective treatments were being fully deployed in those who had not made a complete recovery. Half had made a good recovery. At least 78% of those remaining at threshold level or above apparently had not been offered alternative, potentially effective physical or psychosocial treatment, and were therefore rated as having unmet need. Older male patients were less likely to have unmet need. This study thus raises doubts about the effectiveness of routine clinical management of depression. However, we will remain uncertain of how far the routine falls below the ideal until systematic needs for care procedures (Brewin et al. 1987) are applied prospectively to depressed populations.


First onset and early symptomatology of schizophrenia. A chapter of epidemiological and neurobiological research into age and sex differences. In the frame of the ABC (Age, Beginning and Course) Schizophrenia Project we studied the influence of age and sex on first-ever onset, symptom manifestation and early course up to first admission in schizophrenia by using a large, representative sample of first-admitted schizophrenic patients. The results showed that the two variables had surprisingly little bearing upon the core symptoms, particularly on negative and other most frequent symptoms and on first-rank symptoms. In 70% of the cases schizophrenia started solely with negative symptoms, in 20% with negative and positive and in 10% with positive symptoms only. In most of the cases symptoms accumulated exponentially up to the first acute episode with positive symptoms appearing considerably later. The age differences observed concerned secondary phenomena associated with developmental factors. Such phenomena, i.e. anxiety, depression and the cognitive formation of delusions, can be interpreted as responses to the psychosis. Also the sex differences, which culminated in far more frequent socially negative disease behaviour in males, were limited to secondary phenomena. This positive and negative core symptomatology of schizophrenia seems to be astonishingly uniform and fairly independent of age and sex at this early stage of the disease. The only remarkable difference was a three to four years higher mean age of onset in females. We were able to show in animal experiments and to confirm in a clinical study that this finding is attributable to a neuromodulatory effect of estrogens on the sensitivity of D2 receptors in the brain. Apparently, estrogens raise the vulnerability threshold until menopause and have a slight neuroleptic-like effect on the symptomatology in acute schizophrenic episodes.


A follow-up and family study of DSM-III-R schizophreniform disorder with good prognostic features. A follow-up and family study was carried out of 16 first episode, DSM-III-R schizophreniform disorder patients with good prognostic features. Mean length of follow-up was 52.3 months. It was found that 62.5% had affective episodes, 31.2% had schizophreniform episodes. No case of schizophrenia was observed. Outcome was good. Morbid risk for affective disorder among first degree relatives was 25%, morbid risk for schizophrenia was 0%. These findings suggest a link between DSM-III-R schizophreniform disorder with good prognostic features and affective disorder, and no relationship with schizophrenia.


Are CSF or serum ganglioside antibodies related to peripheral nerve demyelination in neuroborreliosis, Guillain-Barré syndrome, or chronic inflammatory demyelinating polyradiculoneuropathy? Cerebrospinal fluid (CSF) and serum IgG and IgM antibodies to seven gangliosides were determined in patients with neuroborreliosis (NB) (n = 20), Guillain-Barré syndrome (GBS) (n = 13), and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (n = 10). The incidence of elevated antibodies was highest in NB and lowest in CIDP. Correlation between CSF and serum antibodies was only observed for IgG antibodies to GM1, GD1b and GT1b in GBS. The strong IgM antibody reactivity to gangliosides in the CSF of NB patients may be involved in the variety of neurological disorders attributed to Borrelia burgdorferi infection. Since one CIDP and three GBS patients had serologic evidence of prior or concurrent borrelia infection, this infection may belong to the infections that can trigger GBS or CIDP. The lack of specific ganglioside antibody patterns in these four patients suggests that ganglioside antibodies are not the link between Borrelia burgdorferi infection and the demyelination of peripheral nerves in GBS and CIDP.


Psychological functioning and psychiatric morbidity in an elderly urban population in Greece. As part of a systematic epidemiological survey of mental disorders in two Athenian boroughs, a probability sample of 251 elderly community residents was examined by a psychiatrist. For the assessment of their mental health, symptom screening scales were used (Langner and CES-D). Cognitive functioning was also evaluated. An overall psychological functioning profile was composed from previously derived mental health levels. Clinical diagnostic examination was based on a semi-structured schedule (PEF) supplemented by DSM-III criteria. A higher proportion of females than males were characterised as psychologically impaired, reporting non-specific symptoms of distress. Older respondents of lower socioeconomic status experiencing stressful life events, such as living alone or having been exposed to migration in the past, exhibited a significant degree of psychopathology. Of the sample, 20.3% was diagnosed as suffering from a specific psychiatric illness. The prevalence of organic mental disorders was 5.6% and affective disorders of any type constituted nearly half of the diagnosed psychiatric "cases". The implications of this survey are of great importance for the design and the development of preventive strategies and community-based interventions.


The Zurich Study: XV. Suicide attempts in a cohort from age 20 to 30. The life-time prevalence of suicide attempts in a Swiss population, interviewed four times between the ages of 20 and 30 years, was 3.8% (females 5.4%, males 2.1%). One fifth of the 30-year-olds reported persistent suicidal ideation. In comparison with controls, attempters reported a more disturbed childhood, and subjects with multiple attempts reported more sexual abuse. Over 10 years attempters persistently showed more negative affectivity, more feelings of helplessness and lower self-esteem. At age 30 they were higher on the scales neuroticism, masculinity and aggressivity in a personality test. Over ten years, a higher than expected comorbidity appeared of suicide attempts with depressive and anxiety disorders, with substance abuse, and with sociopathic features.


The Zurich Study. XVI. Early antecedents of depression. A longitudinal prospective study on incidence in young adults. The purpose of this study was to investigate antecedents of first incidence of major depressive disorder and recurrent brief depression with the help of a cohort of 20 year-old Swiss, who was interviewed four times up to age 30. Cases diagnosed as depressed at the third or fourth interview (age 28 or 30) were compared with never diagnosed controls for antecedents at the first and second interview (age 21 and 23). Besides retrospectively assessed childhood precursors, later depressives showed slight differences in their relationship to parents and friends and early symptoms of subclinical depression, persistent helplessness and a surplus of life events. These antecedents were mainly found in females. The most persistent antecedent of later depression for both sexes was a higher score than controls' on the SCL-90R ("negative affectivity"). Whether this finding signifies that proneness to the milder depressions in young adults is rooted in personality is subject to discussion.


The co-occurrence of depressive symptoms and cognitive impairment in a French community: are there gender differences. The cross-sectional data are reported for co-occurrence of depressive symptomatology and cognitive impairment from the first wave of a longitudinal study of normal and pathological aging in a representative sample of 2792 older adults (> or = 65) residing in the Aquitaine Region (Bordeaux) of Southwest France. The prevalence rate for co-occurrence was 4.2% for men and 6.2% for women. Co-occurrence was associated with age, no or little education, functional impairment and dissatisfaction with social support for both men and women, though men were at higher risk than women for the latter two factors, and women were at higher risk than men for no or little education. Women over the age of 85 years were at increased risk whereas men were not, and marital status was associated with co-occurrence for men but had no effect for women. These findings indicate that the risk of co-occurrence differs for men and women, and that, with the exception of social support, the correlates we examined play different roles according to gender.


The factor structure of the 28-item General Health Questionnaire when used in Japanese early adolescents and adult employees: age- and cross-cultural comparisons. The principal-component analysis (PCA) with varimax rotation on the 28-item General Health Questionnaire (GHQ-28) in Japanese translation was performed separately for two samples of the Japanese population: early adolescents (junior high school students) and adult employees. The initial PCA yielded different number of components across sub-samples. The later PCA, however, with restriction of the number of components four generally produced a similar structure across sub-samples by means of visual inspection and the coefficient of factor similarity between the components calculated by using the loadings matrices, while a slight different structure emerged for the employees aged 40-49 years. Then, based on these two ways of comparison, the factor structure of GHQ-28 was compared between the present Japanese samples and the European and Turkish school-aged adolescent populations with three ethnic backgrounds. The results showed that its structure was highly stable across age (generation) and several cultural backgrounds, at least among these nations. The internal consistency reliability of the GHQ-28 was at a high level among the present sample of Japanese.


All-night electroencephalographic sleep and cranial computed tomography in depression. A study of unipolar and bipolar patients. All-night electroencephalographic (EEG) sleep recording and cranial computed tomography were performed in 24 inpatients with major depression (14 unipolar, 10 bipolar). The patients showed the characteristic "depression-like" EEG sleep alterations and their ventricular brain ratio (VBR) was increased compared with the control subjects. No major differences were found between the unipolar and the bipolar groups. There was a close and positive association between the VBR values and several measures of slow wave sleep. It is hypothesized that this relationship is due to an altered function of the limbic-hypothalamic-pituitary-adrenocortical axis in depression that affects both EEG sleep and brain morphology.


Marchiafava-Bignami disease. A case studied by structural and functional brain imaging. Marchiafava-Bignami disease (MBD) is a rare complication of chronic alcoholism. The clinical features, X-ray, CT and MRI findings are well documented. However, functional brain imaging has not been used in cases of MBD. We used single-photon emission computed tomography (SPECT) to monitor the regional cerebral blood flow in a patient suffering from a acute form of MBD, from which he subsequently recovered. Several abnormalities were found. A more frequent use of functional brain imaging in MBD could improve our knowledge of pathogenesis and prognosis for MBD.


Hypnotizability in bulimic patients and controls. A pilot study. Various studies have indicated that bulimics are more easily hypnotized and dissociate more readily than control groups and patients with other eating disorders. A comparison is reported of 15 inpatients with bulimia nervosa (DSM III-R) with 15 subjects in a control group comparable in age and education. The instrument used was the Harvard Group Scale of Hypnotic Susceptibility/Form A (HSGHS:A), which includes 12 standardized test suggestions. The results show that bulimics have higher scores in hypnotizability than the control group. A method study (comparison of self-evaluation with a video recording) shows that this is a result of the behaviour itself and not of the answering pattern used by the subjects in the questionnaire. It is possible that differing expectations regarding the experiment may have influenced the results. Considerations concerning the increased ability of bulimics to dissociate as a causal factor versus an accompanying phenomenon of the disorder are discussed.


The Munich Diagnostic Checklist for the assessment of DSM-III-R Personality Disorders for use in routine clinical care and research. Diagnostic checklists for the assessment of DSM-III-R Axis I diagnoses have proven to be a reliable and feasible instrument in research and routine clinical care. Therefore, a checklist for the assessment of the DSM-III-R Personality Disorders (MDCL-P) has been developed. An English version of the MDCL-P is available. The MDCL-P has been tested for reliability in a test-retest design. The average duration of the interview was 36 min. Of the patients, 48% received a diagnosis of at least one personality disorder. The Kappa value concerning the distinction personality disorder as opposed to no personality disorder was 0.62. The range of Kappa values of specific personality disorders, which were diagnosed at least five times, was from 0.35 to 0.79.


Acceptance, attrition, and outcome in an outpatient treatment programme for alcoholics. A comparison between a randomized and a non-randomized process-outcome study. Acceptance, attrition and outcome of the same outpatient treatment programme for alcoholics was studied first in a non-randomized and later in a randomized study. There was a lower (15%) rate of acceptance and a higher (19%) rate of attrition in the randomized study. Among treatment completers drinking outcome during the third year after commencement of treatment did not differ between the non-randomized and the randomized study. It is concluded that the characteristics of subjects accepting a randomly assigned study should always be clearly presented. The absence of a patient-therapist matching in a randomized design could negatively effect attrition and probably also acceptance of treatment, while it seems to be less influential on outcome in those completing therapy.


Alopecia and mood stabilizers: two case reports. Two cases of alopecia observed during treatment with lithium and valproate are described, and the recent literature on this subject is reviewed. Our clinical observations confirm earlier reports. These toxic alopecias are characterized by a diffuse but rarely total hair loss. After stopping medication, the hair grows back generally and completely. Two cases of toxic alopecia are presented where hair grew back following a substitution of lithium by valproate in the first case and after stopping valproate in the second. The evaluation and therapeutic attitude in the presence of alopecia in patients needing mood stabilizers are also discussed.


The risk of minor depression in families of probands with major depression: sex differences and familiality. Currently it is not clear whether minor forms of unipolar depression not matching the criteria of "major depression" should be considered as a separate diagnostic category. A controlled family study examined the familial aggregation of minor depression among probands with unipolar major depression. In the families of these probands the relative risk for minor depression was elevated by a similar magnitude to the risk for major depression. Therefore, the diagnostic category "minor depression" would not increase diagnostic sensitivity at the expense of diagnostic specificity as far as familiality is the criterion. In agreement with recent epidemiological studies, minor depression did not reveal a similar excess prevalence in females compared with males as major depression does. The variation of the sex ratio for any subtype of unipolar depression was not associated with the familiality of this disorder.


Automatic-voluntary dissociation: an unusual facial paresis in a patient with probable multiple sclerosis. A patient with multiple sclerosis is described who presented with a unilateral loss of voluntary function of his lower face muscles. However, in an emotional situation, there was strong involuntary innervation of these muscles: automatic-voluntary dissociation. The subcortical afferents to the facial motor nucleus are discussed. It is hypothesized that cortical disinhibition of midbrain nuclei underlies the accentuated involuntary innervation.


Treatment of multiple sclerosis with mitoxantrone. Ten multiple sclerosis patients, all with a rapid deteriorating disease profile, were treated with 12 mg/m2 of the cytostatic agent mitoxantrone, administered every 3 months. This dosage is only 25% of what a patient with a solid tumour would normally receive during the same time period. In all treated patients the deterioration was stopped following the initial dosage; in four out of ten patients there was even an immediate improvement of the neurological status. Eight out of nine patients showed an improvement after 1 year as compared with their enrollment status; the other one remained stabile. In correlation with the clinical improvement, the mean P100 latencies of visual evoked potentials showed a reduction after 1 year. However, the changes identified through magnetic resonance imaging were even clearer than those seen clinically. At admission, this group of patients presented with a total of 169 gadolinium (Gd)-enhancing lesions. Only 10 lesions were enhancing in nine patients 12 months after the initiation of treatment. It appears that mitoxantrone accelerates the disappearance of Gd-enhancing lesions and prevents the development of new ones. Minimal side effects such as mild nausea and a slight faintness were evident in six patients and then for only 1-2 days.


Thallium-201: what do we gain from new clinical protocols and acquisition procedures? The Italian Study on Thallium Reinjection/SIRT). Nine medical centers, equipped with the same gamma camera and computer software, participated in this multicenter study on thallium-201 reinjection imaging. Preliminary findings for the first 143 patients with ischemic heart disease and perfusion defects at stress imaging are reported. Eighty-eight patients were reinjected at rest after conventional stress-redistribution imaging. Another 55 patients were reinjected at rest on a separate day. After segmental comparison of conventional redistribution versus stress imaging, differences > 1 in the segmental scores on a reduced 3 point scale identified 58 patients with irreversible or mainly irreversible defects (dominant scar pattern) and 85 patients with reversible or mainly reversible defects (dominant ischemic pattern). When reinjection was compared to stress images, 24 patients out of 58 with a dominant scar pattern at the conventional analysis were then assigned to the group with a dominant ischemic pattern. No clinical variables or exercise stress data were found to be significantly different in this patient subgroup. Only 4 out of 85 patients with a dominant ischemic pattern were reassigned to a dominant scar pattern after reinjection scoring. These preliminary results of the SIRT study confirm the consistent problem of scar overestimation by conventional stress-redistribution imaging and the clinical value of the thallium-201 reinjection procedure for differentiating viable from necrotic myocardium.


99mTc-sestamibi: its clinical role as a viability agent. The correlation between the presence of viable myocardium and 99mTc-sestamibi uptake is still to be defined. Preliminary studies indicate that: 1) reduced 99mTc-sestamibi uptake at rest is not necessarily evidence of scar tissue, and 2) its uptake is correlated to the severity of coronary stenosis. To define the relationship between rest thallium-201 and 99mTc-sestamibi uptake in dyssynergic segments, we studied 10 patients with ventricular dysfunction. 99mTc-sestamibi uptake was higher than thallium-201 uptake in normal segments but was similarly reduced in segments perfused by stenotic coronary arteries with or without wall motion abnormalities. Post-revascularization studies of regional wall motion showed that 99mTc-sestamibi had a positive and a negative predictive accuracy in identifying viable segments of 88 and 69%, respectively; these values were significantly lower than that provided by Thallium-201. 99mTc-sestamibi appears to be a primary perfusion agent with a high sensitivity to blood flow reduction at rest; it can be cautiously used as a viability agent in segments with wall motion abnormalities at rest.


Computer simulation of the segmental neural network generating locomotion in lamprey by using populations of network interneurons. Realistic computer simulations of the experimentally established local spinal cord neural network generating swimming in the lamprey have been performed. Populations of network interneurons were used in which cellular properties, like cell size and membrane conductance including voltage dependent ion channels were randomly distributed around experimentally obtained mean values, as were synaptic conductances (kainate/AMPA, NMDA, glycine) and delays. This population model displayed more robust burst activity over a wider frequency range than the more simple subsample model used previously, and the pattern of interneuronal activity was appropriate. The strength of the reciprocal inhibition played a very important role in the regulation of burst frequency, and just by changing the inhibitory bias the entire physiological range could be covered. At the lower frequency range of bursting the segmental excitatory interneurons provide stability as does the activation of voltage dependent NMDA receptors. Spike frequency adaptation by means of summation of afterhyperpolarization (AHP) serves as a major burst terminating factor, and at lower rates the membrane properties conferred by the NMDA receptor activation. The lateral interneurons were not of critical importance for the burst termination. They may, however, be of particular importance for inducing a rapid burst termination during for instance steering and righting reactions. Several cellular factors combine to provide a secure and stable motor pattern in the entire frequency range.


Coronary revascularization and recovery of function: the ultimate target. Recovery of contraction in the akinetic segments represents an important target of coronary revascularization, and the preoperative recognition of viable dyssynergic (hibernating) myocardium is a crucial point in the preoperative investigation of patients with chronically depressed left ventricular function. Dobutamine-echocardiography was utilized in 14 patients to study the contractile reserve retained by viable segments. Redistribution of thallium-201 after rest injection was also used to assess the viability of these areas. The wall motion response to dobutamine infusion predicted immediate postoperative improvement in 85 of 93 segments (sensitivity 91%) and identified 25 of 32 segments which did not exhibit early postoperative improvement (specificity 78%). Rest-redistribution of thallium-201 demonstrated high sensitivity (93%) but low specificity (44%) for predicting the early recovery of regional wall motion. When late recovery was also considered, the specificity of this method increased to 64%. Recovery of function following coronary revascularization can be predicted in patients in whom hibernating myocardium is recognized preoperatively.


A simple vector implementation of the Laplace-transformed cable equations in passive dendritic trees. Transient potentials in dendritic trees can be calculated by approximating the dendrite by a set of connected cylinders. The profiles for the currents and potentials in the whole system can then be obtained by imposing the proper boundary conditions and calculating these profiles along each individual cylinder. An elegant implementation of this method has been described by Holmes (1986), and is based on the Laplace transform of the cable equation. By calculating the currents and potentials only at the ends of the cylinders, the whole system of connected cylinders can be described by a set of n equations, where n denotes the number of internal and external nodes (points of connection and endpoints of the cylinders). The present study shows that the set of equations can be formulated by a simple vector equation which is essentially a generalization of Ohm's law for the whole system. The current and potential n-vectors are coupled by a n x n conductance matrix whose structure immediately reflects the connectivity pattern of the connected cylinders. The vector equation accounts for conductances, associated with driving potentials, which may be local or distributed over the membrane. It is shown that the vector equation can easily be adapted for the calculation of transients over a period in which stepwise changes in system parameters have occurred. In this adaptation it is assumed that the initial conditions for the potential profiles at the start of a new period after a stepwise change can be approximated by steady-state solutions.(ABSTRACT TRUNCATED AT 250 WORDS)


A theory of maximizing sensory information. A theory is developed on the assumption that early sensory processing aims at maximizing the information rate in the channels connecting the sensory system to more central parts of the brain, where it is assumed that these channels are noisy and have a limited dynamic range. Given a stimulus power spectrum, the theory enables the computation of filters accomplishing this maximizing of information. Resulting filters are band-pass or high-pass at high signal-to-noise ratios, and low-pass at low signal-to-noise ratios. In spatial vision this corresponds to lateral inhibition and pooling, respectively. The filters comply with Weber's law over a considerable range of signal-to-noise ratios.


On the performance of single-layered neural networks. This paper studies the performance of single-layered neural networks. This study begins with the performance of single-layered neural networks trained using the outer-product rule. The outer-product rule is a suboptimal learning scheme, resulting under certain assumptions from optimal least-squares training of single-layered neural networks with respect to their analog output. Extensive analysis reveals the improvement on the network performance caused by its optimal least-squares training. The effect of the training scheme on the performance of single-layered neural networks with binary output is exhibited by experimentally comparing the performance of single-layered neural networks trained with respect to their analog and binary output.


A computational model of vertical signal propagation in the primary visual cortex. A computational model of the flow of activity in a vertically organized slab of cat primary visual cortex (area 17) has been developed. The membrane potential of each cell in the model, as a function of time, is given by the solution of a system of first order, coupled, non-linear differential equations. When firing threshold is exceeded, an action potential waveform is "pasted" in. The behavior of the model following a brief simulated stimulus to afferents from the dorsal lateral geniculate nucleus (dLGN) is explored. Excitatory and inhibitory post-synaptic potential (E and IPSP) latencies, as a function of cortical depth, were generated by the model. These data were compared with the experimental literature. In general, good agreement was found for EPSPs. Many disynaptic inhibitory inputs were found to be "masked" by the firing of action potentials in the model. To our knowledge this phenomenon has not been reported in the experimental literature. The model demonstrates that whether a cell exhibits disynaptic or polysynaptic PSP latencies is not a fixed consequence of anatomical connectivity, but rather, can be influenced by connection strengths, and may be influenced by the ongoing pattern of activity in the cortex.


Formation of a stable 99mTc-tri-hydrazidophosphine oxide (99mTc-THP) chelate. Atri-hydrazidophosphine oxide (THP) ligand was synthesized and used to complex 99mTc in high yield (> 95%) by Sn(II) reduction of 99mTcO4-. 99mTc-THP has excellent stability in both 0.9% acqueous NaCl at neutral pH and in human serum at 37 degrees C. Biodistribution studies indicate minimal organ specificity and no significant in vivo release of 99mTcO4-. The ease of 99mTc complexation with THP and the high stability of 99mTc-THP suggests that this ligand may be used as a basis for the development of new imaging agents.


Basic functions of variability of simple pre-planned movements. A model of a pre-planned single joint movements performed without feedback is considered. Modifications of this movement result from transformation of a trajectory pattern f(t) in space and time. The control system adjusts the movement to concrete external conditions specifying values of the transform parameters before the movement performance. The pre-planned movement is considered to be simple one, if the transform can be approximated by an affine transform of the movement space and time. In this case, the trajectory of the movement is x(t) = Af (t/tau + s) + p, were A and l/tau are space and time scales, s and p are translations. The variability of movements is described by time profiles of variances and covariances of the trajectory x(t), velocity v(t), and acceleration a(t). It is assumed that the variability is defined only by parameters variations. From this assumption follows the main finding of this work: the variability time profiles can be expanded on a special system of basic functions corresponding to established movement parameters. Particularly, basic functions of variance time profiles, reflecting spatial and temporal scaling, are x2(t) and t2v2(t) for trajectory, v2(t) and (v(t)+t.a(t))2 for velocity, and a2(t) and (2a(t)+t.j(t))2, where j(t) = d3x(t)/dt3, for acceleration. The variability of a model of a reaching movement was studied analytically. The model predicts certain peculiarities of the form of time profiles (e.g., the variance time profile of velocity is bi-modal, the one of acceleration is tri-modal, etc.). Experimental measurements confirmed predictions. Their consistence allows them to be considered invariant properties of reaching movement. A conclusion can be made, that reaching movement belongs to the type of simple pre-planned movements. For a more complex movement, time profiles of variability are also measured and explained by the model of movements of this type. Thus, a movement can be attributed to the type of simple pre-planned ones by testing its variability.


A new algorithm for the identification of multiple input Wiener systems. Multiple-input Wiener systems consist of two or more linear dynamic elements, whose outputs are transformed by a multiple-input static non-linearity. Korenberg (1985) demonstrated that the linear elements of these systems can be estimated using either a first order input-output cross-covariance or a slice of the second, or higher, order input-output cross-covariance function. Korenberg's work used a multiple input LNL structure, in which the output of the static nonlinearity was then filtered by a linear dynamic system. In this paper we show that by restricting our study to the slightly simpler Wiener structure, it is possible to improve the linear subsystem estimates obtained from the measured cross-covariance functions. Three algorithms, which taken together can identify any multiple-input Wiener system, have been developed. We present the theory underlying these algorithms and detail their implementation. Simulation results are then presented which demonstrate that the algorithms are robust in the presence of output noise, and provide good estimates of the system dynamics under a wide set of conditions.


Multiplying with neurons: compensation for irregular input spike trains by using time-dependent synaptic efficiencies. A leaky integrate-and-fire (LIF) neurons can act as multipliers by detecting coincidences of input spikes. However, in case of input spike trains with irregular interspike delays, false coincidences are also detected and the operation as a multiplier is degraded. This problem can be solved by using time dependent synaptic weights which are set to zero after each input spike and recover with the same time constant as the decay time of the corresponding excitatory postsynaptic potentials (EPSP). Such a mechanism results in EPSP's with amplitudes independent on the input interspike delays. Neuronal computation is then performed without frequency decoding.


Adaptive feedback control models of the vestibulocerebellum and spinocerebellum. We extend the cerebellar learning model proposed by Kawato and Gomi (1992) to the case where a specific region of the cerebellum executes adaptive feedback control as well as feedforward control. The model is still based on the feedback-error-learning scheme. The proposed adaptive feedback control model is developed in detail as a specific neural circuit model for three different regions of the cerebellum and the learning of the corresponding representative movements: (i) the flocculus and adaptive modification of the vestibulo-ocular reflex and optokinetic eye-movement responses, (ii) the vermis and adaptive posture control, and (iii) the intermediate zones of the hemisphere and adaptive control of locomotion. As a representative example, simultaneous adaptation of the vestibulo-ocular reflex and the optokinetic eye-movement response was successfully simulated while the Purkinje cells receive copies of motor commands through recurrent neural connections as well as vestibular and retinal-slip parallel-fiber inputs.


Doublet-split-scaling of correlation integrals in non-linear dynamics and in neurobiology. The search for the low-dimensional attractor behaviour and the dynamic self-organization of neuronal systems, from an analysis of electroencephalographic (EEG) signals, must be carried out under conditions in which the signals are not stationary for more than a few seconds. We employ a technique that we have introduced for analyzing short signals obeying a differential equation and develop it further. The technique uses the fact that in plots of "slope curves" of d log C(r)/d log r against log C(r), C(r) = correlation integral, for short time sequences, the dynamics may be "trans-embedding-scaled", i.e. a horizontal power-law structure builds up, that is constructed from different slope curves (different embeddings), and appears at the right value of the correlation dimension, although no single slope curve exhibits scaling. Patterns of the family of slope curves are described exhibiting the "doublet-split-scaling" of the correlation integrals. Examples include a solution of the Mackey and Glass delay differential equation and EEG signals. The two components of a doublet differ in the dimensions of the embeddings of which they are formed, i.e. low- and high-dimensions, respectively. The advantages subsequent to recognizing trans-embedding-scaled correlation integrals and doublet-split-scaling are illustrated for EEG delta sleep signals, with emphasis on ideal doublet-split-scaling. Unambiguous evidence of attractor behaviour in delta sleep is presented.


Associative learning in a network model of Hermissenda crassicornis. I. Theory. A time-varying Resistance-Capacitance (RC) circuit computer model was constructed based on known membrane and synaptic properties of the visual-vestibular network of the marine snail Hermissenda crassicornis. Specific biophysical properties and synaptic connections of identified neurons are represented as lumped parameters (circuit elements) in the model; in the computer simulation, differential equations are approximated by difference equations. The model's output, membrane potential, an indirect measure of firing frequency, closely parallels the behavioral and electrophysiologic outputs of Hermissenda in response to the same input stimuli presented during and after associative learning. The parallelism of the computer modeled and the biologic outputs suggests that the model captures the features necessary and sufficient for associative learning.


Control of rabbit nictitating membrane movements. I. A computer model of the retractor bulbi muscle and the associated orbital mechanics. Our objective in this study is to synthesize existing experimental data by constructing a realistic neuromechanical control model of rabbit nictitating membrane (NM) movements. We model the retractor bulbi muscle at the motor unit level because this is the level of nervous system control and also facilitates comparison with experimental data. Our motor unit model is derived from an earlier model of muscle activation based on calcium kinetics and includes a post-activation potentiation mechanism. Motor units are combined into a model of whole muscle that includes length-tension and force-velocity effects. Finally, we incorporate the muscle model into a biomechanical model in which the globe and NM are represented as a system of inertial, viscous, and elastic elements. The model takes patterns of neural signals (in the form of impulses) as input and produces movement of the NM as output. Our muscle model quantitatively accounts for data on isometric force development and decay for twitch, double shock, and tetanic stimulation. The complete model may be used for analysis of the relationship of motoneuron activity to behavior or as a realistic response generator in models of NM conditioning. This study also highlights gaps in the experimental data on the rabbit NM effector system.


Control of rabbit nictitating membrane movements. II. Analysis of the relation of motoneuron activity to behavior. The objective of this study is to understand more precisely the relationship of motoneuron activity to movements of the rabbit nictitating membrane (NM). We use a model of the oculomotor plant to investigate what NM movements are generated by a given pattern of neural input and what inputs are required to generate particular NM movements. Simulated peak NM extensions can occur well over 50 ms after the end of motoneuron activity. The neural input required for the model to generate full amplitude NM extension responses is more consistent with single accessory abducens unit recordings from awake rabbits than recordings from anesthetized rabbits. An initial high frequency burst of neural activity followed by a rapid decay is required for simulations of conditioned responses (CRs) trained at a 125 ms interstimulus interval (ISI). For CRs trained with a 250 ms ISI, a more slowly rising and decaying neural activity is required. Model simulations show that the linear correlation between the shape of histogrammed motoneuron activity and the shape of NM movements can be high for long duration responses (> 400 ms) but is low for short duration responses (< 200 ms). Simulations are also consistent with the hypothesis that NM retraction is generally passive.


The relationship between short-term memory capacity and EEG power spectral density. Multiplying memory span by mental speed, we obtain the information entropy of short-term memory capacity, which is rate-limiting for cognitive functions and corresponds with EEG power spectral density. The number of EEG harmonics (n = 1, 2,..., 9) is identical with memory span, and the eigenvalues of the EEG impulse response are represented by the zero-crossings up to the convolved fundamental, the P300. In analogy to quantum mechanics the brain seems to be an ideal detector simply measuring the energy of wave forms. No matter what the stimulus is and how the brain behaves, the metric of signal and memory can always be understood as a superposition of n pi states of different energy and their eigenvalues.


A self-organising neural network model of image velocity encoding. A self-organising neural network has been developed which maps the image velocities of rigid objects, moving in the fronto-parallel plane, topologically over a neural layer. The input is information in the Fourier domain about the spatial components of the image. The computation performed by the network may be viewed as a neural instantiation of the Intersection of Constraints solution to the aperture problem. The model has biological plausibility in that the connectivity develops simply as a result of exposure to inputs derived from rigid translation of textures and its overall organisation is consistent with psychophysical evidence.


A neural network model rapidly learning gains and gating of reflexes necessary to adapt to an arm's dynamics. Effects of dynamic coupling, gravity, inertia and the mechanical impedances of the segments of a multi-jointed arm are shown to be neutralizable through a reflex-like operating three layer static feedforward network. The network requires the proprioceptively mediated actual state variables (here angular velocity and position) of each arm segment. Added neural integrators (and/or differentiators) can make the network exhibit dynamic properties. Then, actual feedback is not necessary and the network can operate in a pure feedforward fashion. Feedforward of an additional load can easily be implemented into the network using "descendent gating", and a negative feedback control loop added to the feedforward control reduces errors due to external noise. A training, which combines a least squared error based simultaneous learning rule (LSQ-rule) with a "self-imitation algorithm" based on direct inverse modeling, enables the network to acquire the whole inverse dynamics, limb parameters included, during one short training movement. The considerations presented also hold for multi-jointed manipulators.


A computational model of four regions of the cerebellum based on feedback-error learning. We propose a computationally coherent model of cerebellar motor learning based on the feedback-error-learning scheme. We assume that climbing fiber responses represent motor-command errors generated by some of the premotor networks such as the feedback controllers at the spinal-, brain stem- and cerebral levels. Thus, in our model, climbing fiber responses are considered to convey motor errors in the motor-command coordinates rather than in the sensory coordinates. Based on the long-term depression in Purkinje cells each corticonuclear microcomplex in different regions of the cerebellum learns to execute predictive and coordinative control of different types of movements. Ultimately, it acquires an inverse model of a specific controlled object and complements crude control by the premotor networks. This general model is developed in detail as a specific neural circuit model for the lateral hemisphere. A new experiment is suggested to elucidate the coordinate frame in which climbing fiber responses are represented.


Hypersecretion of melatonin following diurnal exposure to bright light in seasonal affective disorder: preliminary results. Night-time melatonin secretion was measured in five depressed inpatients with seasonal affective disorder before and after 1-week of morning and evening exposure to bright (3000 lux) and dim (300 lux) light. Analysis of variance by ranks showed no differences in timing of melatonin secretion but statistically significant differences in plasma melatonin levels. There was a decrease of the area under the curve after bright light and a very robust rebound after exposure to dim light. The failure to constitute a parallel group of patients in a crossover design did not permit to control for an ordering effect of light exposure. These findings raise many questions concerning the diurnal sensitivity to different intensities of light in seasonal affective disorder.


Effects of hypothyroidism on rat circadian activity and temperature rhythms and their response to light. Male rats made hypothyroid by administration of propylthiouracil plus sodium ipodate in drinking water were compared to controls in terms of period of circadian activity and temperature rhythms, amount of gross motor activity, and mean temperature. Animals were studied under entrainment, constant darkness (DD), and constant dim light (LL). There was no difference in the period of the circadian activity rhythm between groups in DD. However, hypothyroid rats showed significant blunting of the period-lengthening response to increasing ambient illumination. As expected, the period of the circadian temperature rhythm increased in controls with increasing ambient illumination. In contrast, the period of the circadian temperature rhythm in hypothyroid animals actually shortened under LL compared to DD. This blunting of the period-lengthening response to increasing ambient illumination of both activity and temperature rhythms in hypothyroid animals could not be explained by differences in activity level or mean temperature between the groups.


Multidiagnostic evaluation of prolactin response to haloperidol challenge in schizophrenia: maximal blunting in Kraepelinian patients. We have previously reported that prolactin (PRL) responses to haloperidol 0.5 mg IV were blunted in subjects characterized by several diagnostic systems of schizophrenia compared to controls (Keks et al 1990). However, an attempt to find a diagnostic system most different from controls was unsuccessful due to inherent difficulties in the statistical analysis of multidiagnostic data. In this paper we present new methodologies. A test for differences in dependent correlations demonstrated that most of the variance in stimulated PRL was accounted for by Kraepelinian, and least by Schneiderian and M. Bleulerian, schizophrenias (p < 0.001). The main symptomatic difference between nonKraepelinian and Kraepelinian patients was the presence of association disturbance and feelings of passivity. Patients with both symptoms had a lower stimulated PRL than controls. Further findings and possible implications are discussed.


Lateralized effects of diazepam on frontal brain electrical asymmetries in rhesus monkeys. A growing body of literature has documented the differential role of the frontal regions of the two cerebral hemispheres in certain positive and negative affective processes. This corpus of evidence has led to the hypothesis of a possible differential effect of diazepam on asymmetry of frontal activation. To examine this question, nine infant rhesus monkeys were tested on two occasions during which brain electrical activity was recorded from left and right frontal and parietal scalp regions. During one session, recordings were obtained under a baseline restraint condition and then after an injection of diazepam (1 mg/kg). In the other session, following the same baseline restraint condition, a vehicle injection was given. In response to diazepam, the animals showed an asymmetrical decrease in power in the 4-8 Hz frequency band, which was most pronounced in the left frontal region. No change in electroencephalogram (EEG) activity was observed in response to vehicle. Asymmetry in parietal EEG activity was also unchanged by diazepam. Diazepam also produced overall reductions in power across different frequency bands in both frontal and parietal regions. Good test-retest stability of EEG measures of activation asymmetry was also found between the two testing sessions separated by three months. The possible proximal cause of the asymmetrical change in frontal brain electrical activity in response to diazepam, as well as the implications of these findings for understanding the mechanism of action of benzodiazepines are discussed.


Cerebrospinal fluid neuropeptides in dementia. Cerebrospinal fluid concentrations of corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH) and somatostatin (SRIF) were measured in 77 female inpatients with moderate to extreme dementia and in 17 elderly female controls. Both multi-infarct (MID) and Alzheimer-type (SDAT) demented patients had equally elevated CSF CRH and TRH but not SRIF levels as compared with the controls. This elevation was, however, not seen in patients with simple dementia while it was most prominent in those exhibiting marked depressive symptoms. It is concluded that depression rather than dementia itself may be associated with CSF CRH and TRH elevation in elderly patients with cognitive impairment.


Review article: urease, gastric ammonium/ammonia, and Helicobacter pylori--the past, the present, and recommendations for future research. The presence of ammonium in gastric contents was described in 1852; urease activity in the stomach was identified 70 years later. The discovery of gastric urease resulted in intense research activity to discover its origin, function, and relation to the gastric levels of ammonium and urea. Interest in urease waned in the 1960s as most pertinent questions appeared to have been addressed and there was strong evidence that gastric urease was not a property of the stomach but was of microbial origin. Identification of Helicobacter pylori as the source of urease in the stomach in the last decade has resulted in a rebirth of interest in gastric urease and its products. There is little actual evidence to support a role for toxicity of ammonia in relation to H. pylori and the bulk of the evidence suggests that the products of urease activity are not toxic and may even be beneficial. The purpose of this review is to examine the older literature and to examine new findings in the perspective of what is already known and to suggest areas remaining to be examined. We ask, 'What is old, what is new, and what needs to be done?'


The effects of 5-aminosalicylic acid and acetyl-5-aminosalicylic acid on lipid peroxidation in erythrocytes and prostaglandin production by mononuclear cells. In parallel studies, the effects of 5-aminosalicylic acid (5-ASA) and acetyl-5-aminosalicylic acid (acetyl-5-ASA) on peroxidation of red-cell membrane lipids and production of prostaglandins by peripheral blood mononuclear cells were assessed. 5-ASA at concentrations of 10(-5), 10(-4) and 10(-3) M significantly inhibited erythrocyte lipid peroxidation, measured as malondialdehyde production, by 20%, 56% and 63%, respectively, (P < 0.05, P < 0.002, P < 0.001, respectively) while acetyl-5-ASA had no effect. 10(-5) and 10(-4) M 5-ASA significantly increased production by stimulated peripheral blood mononuclear cells of PGE2 (by 31% and 30%, P < 0.01, P < 0.05, respectively) and PGF2 alpha (by 30% and 25%, P < 0.05, P < 0.01, respectively). 10(-4) M 5-ASA also significantly stimulated prostacyclin production measured as 6KF1 alpha by 10% (P < 0.05). At 10(-3) M 5-ASA there were significant falls in 6KF1 alpha (by 37%) PGE2 (by 45%) and PGF2 alpha (by 47%) (P < 0.01, P < 0.001, P < 0.001, respectively) although this was accompanied by a decrease in cell viability. Acetyl-5-ASA had little effect upon prostaglandin production. 5-ASA scavenges free radicals and stimulates production of cytoprotective prostaglandins.


Absorption of polar drugs following caecal instillation in healthy volunteers. We have investigated colonic drug absorption in man by the caecal instillation of a multi-component solution of atenolol, cimetidine, frusemide, hydrochlorothiazide and salicylic acid. We found that salicylic acid absorption from this solution was delayed but complete whereas the absorption of atenolol, cimetidine, frusemide and hydrochlorothiazide was four- to five-fold lower than expected from oral bioavailability studies.


Ranitidine: differential effects on gastric bleeding and mucosal damage induced by aspirin. This study investigated the influence of ranitidine on mucosal injury and gastric bleeding in 20 normal volunteers taking 600 mg aspirin q.d.s. This study was a double-blind placebo controlled crossover study comparing ranitidine, as 150 mg b.d., 300 mg q.d.s. and 600 mg b.d. with placebo. Gastric mucosal injury was assessed at unsedated endoscopy by counting haemorrhagic and non-haemorrhagic erosions; bleeding was measured in gastric washings. Aspirin alone increased mucosal injury from 0 to 11.4 erosions (mean, P < 0.01) and bleeding from 1.77 to 9.11 microliters blood/10 min (mean P < 0.001). Ranitidine prophylaxis reduced bleeding to 5.34, 3.18 and 3.47 microliters/10 min with 150 mg b.d., 300 mg q.d.s. and 600 mg b.d. respectively (overall effect of ranitidine P < 0.001) and also reduced haemorrhagic erosions though it had no effect on the total number of erosions. Ranitidine is effective at reducing aspirin-induced gastric bleeding and whilst not reducing aspirin-induced gastric erosions, it does reduce the number that appear haemorrhagic. Ranitidine may have a role in the prophylaxis of aspirin-induced gastric bleeding.


A comparison of upper gastrointestinal mucosal damage by standard and delayed-release indomethacin. Forty-five patients taking long-term indomethacin and with endoscopic erosions or superficial ulcers in the oesophagus, stomach or duodenal bulb were randomized in a double-blind study to continue with standard indomethacin or receive a 'delayed-release' formulation. This consisted of microgranules of indomethacin coated with an acrylic resin, Eudragit L, which releases drug in the small intestine. Endoscopy was repeated after 8 weeks and biopsies taken on both occasions. Changes in endoscopic lesions and histological appearances were similar in both groups, although mucosal erythema was less in those given Eudragit L indomethacin. Systemic, rather than topical, effects of indomethacin may therefore be responsible for persistence of gastro-duodenal mucosal lesions in these patients. There is reason to question the clinical practice of using expensive, delayed-release preparations.