Imaging and movement of iron-oxide-bound antibody microparticles in brain and cerebrospinal fluid.

Therapy with monoclonal antibody conjugates has been proposed for patients with malignant intracranial tumors and meningeal carcinomatosis. One obstacle to successful immunotherapy has been the inability of adequate quantities of antibody to reach and bind malignant cells. The use of superparamagnetic antibody microparticles offers a potential solution to the problem of inadequate antibody delivery. In this report, studies of the imaging characteristics and magnetically-induced movement of iron oxide-bound antibody (IOAb) microparticles [BioMag] are described. 1 mg/ml IOAb was readily visualized using conventional CT scan technique, but produced image artifacts on MRI. Rapid movement of IOAb in vitro was noted to occur in response to a magnetic field gradient. This property was exploited in in vivo studies using laboratory animals. IOAb injected into the intrathecal space of sedated rats could be transported through the CSF and localized to the medial aspect of one cerebral hemisphere or the other, using an external magnet. Construction of specific microparticles may allow for improved delivery of therapeutic substances to specific sites within CSF pathways.


Modulation of protein kinase C activity by palmitoyl esters of maltose.

Mixtures of maltose palmitates containing predominantly maltose tetrapalmitate (designated MTP) possess immune potentiating and antitumor properties. Immune potentiation derives from macrophage activation and B lymphocyte mitogenicity and antitumor action from anti-angiogenic activity. Their mode of action at the cellular level is not known. Since high performance liquid chromatography (HPLC) provided purified maltose palmitates, we tested whether they individually and as a mixture could modulate activity of protein Kinase C (PKC), an enzyme implicated in mitogenic and release reactions. MTP activated crude lymphocyte and purified brain PKC in the absence of phosphatidyl serine (PS). It also augmented labeled dibutyryl phorbol (PDBu) binding to the brain enzyme in the absence of phospholipid. HPLC purified maltose tetrapalmitates (two isomers) were insoluble in aqueous solvent, and activated PKC slightly after incorporation into PS liposomes. Purified maltose di- and tri-palmitates were inhibitory to the enzyme. The activation of PKC was, therefore, due to higher saturated maltose palmitates, well dispersed by less substituted maltose palmitates acting as emulsifiers.


Metabolism of benzo[a]pyrene in human skin xenografts.

Although a human neonatal foreskin graft to a nude mouse has been shown to be morphologically intact for several months after establishment, the feasibility of using this system for carcinogenesis studies has not been widely investigated. In this study, we have investigated the metabolism of benzo[a]pyrene (BaP) in human skin xenografts after the topical application of different concentrations of [3H]BaP (0.5 microgram-10.0 micrograms and 20 muCi/graft) for 2 h and 1.0 micrograms [3H]BaP for various intervals of time up to 4 h. Significant amounts of different organic solvent soluble metabolites were observed in all the different samples. The increase in the amounts of the organic solvent soluble metabolites was linear over the 0.5 microgram to 5.0 micrograms/graft range. When 1.0 microgram [3H]BaP was applied to each graft, the maximum production of the organic solvent soluble metabolites was observed 10 minutes after treatment and it then decreased with time. Diols were the major metabolites detected in each of the experiments, followed by phenols, and then tetrols. The levels of water soluble glucuronide and sulfate conjugates were almost equivalent for each treatment over the same range of application of BaP per graft. The combined levels of these conjugates and the non-extractable organic soluble metabolites in the residue, generally ranged between 7-24% of the total metabolites in the various experiments.


Regulation of M2-type pyruvate kinase from human meningioma by allosteric effectors fructose 1,6 diphosphate and L-alanine.

In the present study the mechanism of action of M2-type pyruvate kinase from human meningioma in the simultaneous presence of fructose 1,6 diphosphate and L-alanine was investigated. Purified pyruvate kinase from human meningioma was allosterically inhibited by L-alanine with respect to substrates phosphoenolpyruvate and ADP. The inhibitory effects of L-alanine was partially removed by fructose 1,6 diphosphate. The purified enzyme was slightly susceptible to ATP inhibition.


Mixed function oxidase demethylase and dealkylase activity in an electromagnetic field.

In contrast to the increase in reaction rate of microsomal NADPH-cytochrome-P450 reductase activity resulting from low-level microwave perturbation (reported earlier) transformations involving the entire MFO-pathway were inhibited by a microwave field. Dealkylation of 7-ethoxycoumarin was inhibited 25% and demethylation of p-nitroanisole was inhibited 40% when the reaction was carried forward in a 9.14 GHz CW field. Microsomal preparations from the liver of mature chickens had enzymic characteristics (kinetic constants, inhibitor-response spectrum) for these substrates similar to those reported for rodent and human MFO complex.


Sialic acid levels in various types of cancer.

Serum or plasma total sialic acid (TSA) and lipid bound sialic acid (LSA) are useful markers for human cancer. In this study, sialic acid levels have been demonstrated in various types of human cancer including brain, thyroid and Hodgkin's. TSA was found to be significantly elevated in various human brain tumors, especially in the microsomal fraction. Also serum and tissue LSA levels indicated significant increases when compared to the normals in various brain and thyroid tumors. TSA levels were significantly higher in the plasma and leucocyte in patients with Hodgkin's. The results show that sialic acid can be advisable as a beneficial marker for detecting malignancies. But it can not be used as a criteria for identifying tumor types.


Spin-trapping of free radicals during phthalocyanine photosensitization of lymphoma cells in vitro.

Spin-trapping and electron spin resonance (ESR) spectroscopy were used to detect free radicals generated during light exposure of lymphoma cells sensitized in vitro by metallotetrasulfophthalocyanines (Al-PcS4 and Zn-PcS4). 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) and alpha-phenyl-beta-tert-butylnitrone (PBN) were used as spin-trapping agents. Hydroxyl radical spin-adducts were detected under conditions of both extracellular and intracellular photosensitization. In addition, organic radicals of different origin and/or variable yields were trapped, depending on the photosensitization conditions and the spin-trap used. For comparison, analogous experiments were carried out with another tumor-localizing photosensitizer, Photofrin II.


Stimulation of amino acid efflux from cells by extracellular serine.

P388 (murine) and CEM (human) leukemia cells were exposed in vitro to a serine-deprived medium. Cultivation was carried out at 37 degrees C, 5% CO2. Proliferation assay was conducted with a RPMI 1640 medium (control) and a serine-deprived medium for 3 days. The deprivation of serine reduced the proliferation of both cells, and the necessity of serine for the cell proliferation was thus recognized. The effects of the substance on the level and pattern of intracellular amino acids were observed. P388 cells exposed to serine-deprived medium for 3 h were then transferred to the control medium. The cellular amino acid levels were determined at the time of medium change and 1, 2, 3 h thereafter. Serine-deprivation improved intracellular amino acids in comparison with those from control, and the medium change to control reduced their levels. Therefore, extracellular serine appeared to regulate the efflux of amino acids from cells. This suggests that serine-deprivation may be useful for anticancer drug retention in the cells.


Radioprotective properties of ATP and modification of acid phosphatase response after a lethal dose of whole body p(66MeV)/Be neutron radiation to BALB/c mice.

The intraperitoneal administration of exogenous ATP prior to a lethal dose (7 Gy) of whole body neutron irradiation increased the radioresistance of BALB/c mice. This radiation used the beam from a neutron therapy facility produced by the reaction p(66 MeV)/Be. Survival of the mice, determined 7 days post-irradiation as the endpoint, was increased from 26% to 86% by the action of the exogenous ATP. Furthermore, the response of acid phosphatase activity as an indicator of the acute radiation effects showed a marked augmentation in both tissues studied, testes and small intestine. The activity of the enzyme after neutron irradiation with prior administration of ATP showed smaller increases when compared with the increases observed after neutron irradiation alone. This implies that exogenous ATP reduces the effect of the lytic enzyme and, hence, damage. Finally, changes were observed in the activity of acid phosphatase in the testes and intestine with different concentrations of exogenous ATP. In both tissues there was a monotonic decrease in the activity of the enzyme with increase of the concentration of exogenous ATP administrated before radiation. These results reflect the protective ability of exogenous ATP as an adaptive defence mechanism to reduce radiation damage in normal tissues after a lethal dose of neutron radiation.


The fluidity of DOPC bilayers and membrane fractions prepared from murine plasmacytoma cells is unchanged after incorporation of pristane (2,6,10,14-tetramethylpentadecane) as assessed by fluorescence polarization analysis.

The nature of the plasmacytomagenic activity of pristane (2,6,10,14-tetramethylpentadecane) is poorly defined. However, evidence for tumor promoting properties of pristane has recently come forward that includes direct cellular effects on B lymphocytes; i.e., the plasmacytoma precursor cell. Bly et al. (Cancer Biochem. Biophys. 11, 1990, 145-154) observed changed membrane fluidities in lymphocytes after administration of pristane in vivo. We measured steady-state fluorescence polarization using DPH (1,6-diphenyl-1,3,5-hexatriene) and APCL (1-acyl-2-[12-(9-anthryl)-11-trans-dodecenoyl]-sn-glycero-3- phosphocholine) as probes in DOPC (L-alpha-dioleoylphosphatidylcholin) model membranes and membrane fractions derived from plasmacytoma cells after incorporation of pristane in vitro. In a previous investigation, we verified the in vitro uptake of pristane into DOPC bilayers under the conditions employed here (Gawrisch and Janz, Biochim. Biophys. Acta 1070, 1991, 409-418). However, neither in DOPC bilayers nor in plasmacytoma membrane fractions could we detect changes in fluorescence polarization after in vitro incorporation of pristane within reasonable error limits. Therefore, we suggest that the observed alterations in membrane fluidity in lymphocytes from pristane-treated animals are the indirect result of the in vivo treatment but not a direct effect of pristane on membrane fluidity.


Effects of diabetes and insulin on phosphoinositide metabolism in R3230AC mammary tumors.

The effects of diabetes and insulin administration on certain aspects of phosphoinositide metabolism in R3230AC mammary tumors were studied in vivo. Three weeks after diabetes was induced by streptozotocin, [3H]myoinositol incorporation into PI, PIP and PIP2 was increased in R3230AC tumors, whereas the formation of [3H]IP, [3H]IP2 and [3H]IP3 was decreased. Administration of protamine zinc insulin (3IU, twice daily, for 3 days) to diabetic rats decreased [3H]myoinositol incorporation into phosphoinositides and inositol phosphates in these mammary tumors. The R3230AC tumor from insulin-treated diabetic hosts had lower levels of unmetabolized [3H]-myoinositol compared to tumors from diabetic animals. Enzymatically-dissociated tumor cells from insulin-treated animals displayed decreased myoinositol transport in vitro. These findings suggest that the insulin-induced decrease in the turnover of inositol lipids in vivo in R3230AC mammary tumors could have resulted from the decreased level of [3H]myoinositol in these cells.


Vigabatrin--plasma enantiomer concentrations and clinical effects.

Plasma concentrations of the [R]- and [S]- enantiomers of the new anticonvulsant vigabatrin were measured by an enantiospecific gas-liquid chromatographic assay in a group of therapy-resistant epileptic patients in whom racemic vigabatrin was added to their existing antiepileptic drug regimens. The peak plasma concentrations of the biologically active [S]-enantiomer of vigabatrin were correlated with those of the [R]-enantiomer, with drug dose, seizure frequency and change in score on various tests of psychological function administered prior to and when the subjects were under steady-state conditions following vigabatrin therapy. Plasma [S]-vigabatrin concentrations correlated with drug dose, [R]-vigabatrin concentration and change in score of certain psychological tests reflecting verbal memory, recall and speed of information processing. No definite pharmacokinetic interactions were detected, though plasma phenobarbitone concentrations tended to fall during vigabatrin administration. There were too few data to assess the relation between [S]-vigabatrin concentrations and seizure frequency.


Predicting survival after stroke: experience from the Perth Community Stroke Study.

Survival is the most fundamental measure of the outcome from stroke, the magnitude of the burden being strongly reflected in case-fatality and survival rates. Although the literature is rich with follow-up studies examining survival after stroke, most are based on selected series of patients and factors which correlated with time to death have usually been determined in univariate analyses. We examined the factors associated with a high risk of death during the acute phase of stroke. Analyses were based on data from a population based study of acute cerebrovascular disease undertaken in Perth, Western Australia, during an 18 month period 1989-1990. Using logistic regression modelling techniques only 2 factors, severe loss of consciousness, odds ratio 14.7 [95% confidence limits (CL), 4.0-53.6], and severe paresis, odds ratio 7.2 [95% CL, 1.6-32.0], independently predicted death by 28 days after the onset of stroke. The implication is that 2 simple measures, level of consciousness and motor power, may help direct management. Furthermore, age is not an independent risk factor for death early after stroke. Therefore the elderly should not be denied therapy purely on the basis of their age.


Thrombolytic therapy in vertebrobasilar occlusion.

Since 1983 at the Alfred Hospital 4 patients with thrombotic or embolic vertebrobasilar occlusions have been treated with intra-arterial streptokinase (SK) infusions for the effects of persisting brainstem ischaemia despite anticoagulation with heparin. In 3 cases there was immediate and dramatic neurological improvement, in all cases associated with arteriographically demonstrated reperfusion of a blocked vessel. Two of these patients suffered further thromboembolic vertebral or basilar artery occlusions (3 days and 2 years later) but recovered fully without further thrombolytic therapy. The other patient was given intra-arterial SK 12 days after an apparently completed brainstem stroke: the therapy failed to cause reperfusion of a vertebral occlusion or produce any clinical improvement. Complications from the therapy were nausea requiring the termination of the SK infusion in one case, easily controlled bleeding from a recent surgical wound, and a clinically insignificant haemorrhagic transformation of cerebellar infarction in a third. The benefits of thrombolytic therapy in vertebrobasilar ischaemia and the dose of streptokinase required are discussed.


Confounding factors in non-invasive tests of neurovascular function in diabetes mellitus.

Disturbances of neurovascular function in the extremities may occur in patients with diabetes mellitus, exposure to toxic substances and chronic exposure to vibrating hand tools, as well as in Raynaud's phenomena. In these conditions symptoms of paraesthesia, finger numbness and blanching occur, so nerve conduction studies, vibration and temperature threshold measurements and neurovascular function tests are used for objective assessment of neurological dysfunction. The aim of the present study was to examine some factors which may confound quantitative neuro-vascular function measurements if used to assess neuropathy in diabetics. All subjects were consenting volunteers without exposure to known neurotoxic chemicals. The 5 groups were (a) healthy non-diabetic subjects not exposed to vibration (n = 10, mean age 52.3 yrs) (b) 2 insulin dependent and 8 non-insulin dependent diabetic subjects with a mean of 6 years treatment (n = 10, mean age 55.7 yrs) (c) maintenance employees exposed to high frequency pneumatic hand tools (n = 10, mean age 52.2 yrs) (d) subjects who were not diabetic or exposed to vibrating tools, but were being treated with the ACE-inhibitor enalapril 20 mg daily for hypertension (n = 5, mean age 54 yrs) (e) subjects who had smoked more than 10 cigarettes daily for at least 15 yrs (n = 10, mean age 51 yrs). Neurovascular tests included axon reflex responses measured by laser Doppler velocimeter evoked on the dorsum of the finger by iontophoresis of acetylcholine 16 mC in a circumferential chamber: cutaneous microvascular dilator responses to endothelial stimulation by iontophoretic application of the muscarinic agonist pilocarpine 16 mC and to direct nitrodilator sodium nitroprusside 16 mC. The skin temperature of the digits was held between 33 degrees and 34 degrees C during testing and dilator responses were measured as flux change by on-line computer analysis using 'Perisoft'. There was a significant reduction (P < 0.05) in the neurovascular responses of both diabetics and vibration--exposed subjects to acetylcholine and, in the case of vibration-exposed subjects, to pilocarpine, but nitroprusside responses were not significantly different. Our findings of reductions in neurovascular responses in diabetics and in subjects exposed to higher frequency vibration is consistent with recent epidemiological findings. Furthermore, subjects treated with an ACE-inhibitor (enalapril) showed significant reduction in acetylcholine-evoked axon reflex responses, while the test group of smokers showed a significant reduction in their dilator response to pilocarpine.(ABSTRACT TRUNCATED AT 400 WORDS)


Frontal signs following subcortical infarction.

Subcortical cerebral infarction is associated with impaired performance on tests of cognitive function which are sensitive to frontal lobe damage. In a cohort of 82 patients with multiple subcortical cerebral infarcts diagnosed on the basis of CT scan appearances, physical signs presumed to be sensitive to frontal lobe dysfunction were elicited. Associations between physical findings and CT scan changes were determined. The snout reflex was present in 38 patients and correlated significantly with the number of lesions, the presence of periventricular lucency and the presence of ventricular enlargement, while the grasp reflex occurred in 33 and correlated with the number of lesions and the presence of ventricular enlargement, and gait impairment in 54 correlated with the number of lesions and the presence of ventricular enlargement. It is assumed that multiple subcortical infarcts disrupt frontal association pathways, resulting in frontal disconnection which produces frontal cognitive dysfunction and frontal release signs.


The molecular genetics of mitochondrial cytopathies: the Melbourne experience.

Mitochondrial DNA is a unique, maternally inherited molecule encoding several subunits of the respiratory enzyme chain. In several mitochondrial cytopathies mutations have been described in this genome viz. large-scale heteroplasmic deletions in syndromes with progressive external ophthalmoplegia and point mutations in MELAS and MERRF encephalomyopathies. We here report Southern blot analyses in the cases of CPEO we have seen and describe the search for point mutations in MELAS and MERRF. Mitochondrial genetic sequencing in normal and disease controls as well as in patients has confirmed the pathogenic nature of a tRNA Lys point mutation in MERRF. We propose a novel mitochondrial structural gene mutation in a MELAS--like encephalomyopathy: an A-->G substitution at position 11084 leading to a Thr to Ala replacement in the ND4 subunit of complex I.


Anti-ganglioside antibodies in peripheral neuropathy.

There have recently been reports that patients with motor neuropathy with multifocal conduction block have high circulating levels of antibodies to the ganglioside GM1. Other reports have described the presence of these antibodies in patients with inflammatory demyelinating neuropathy and patients with lower motor neurone forms of motor neurone disease. We have established an ELISA assay for IgG and IgM antibodies to asialo-GM1 (Sigma). We used this assay to measure such antibodies in serum from normal subjects and from patients with various neurological conditions. In normal subjects, antibodies to asialo-GM1 were present only in low levels. An arbitrary scale with an upper limit of normal was established. Initial studies have found that abnormally high levels of IgG antibodies to asialo-GM1 were present in 4 of 9 patients with inflammatory demyelinating neuropathies (Guillain-Barré syndrome or chronic inflammatory demyelinating polyradiculoneuropathy). We found one patient with a monoclonal IgM circulating paraprotein and a motor neuropathy who had a high titre of antibody to asialo-GM1. As yet we have found no patients with motor neurone disease with antibodies to asialo-GM1.


Hereditary sensory radicular neuropathy: defective neurogenic inflammation.

Hereditary sensory radicular neuropathy exhibits autosomal dominant inheritance with complete penetrance in males and incomplete penetrance in females. Newer tests of small sensory nerve function were used in screening 8 family members aged between 14 and 66 years. All exhibited some frequent features of the disorder with an onset in the 2nd or 3rd decade, foot ulceration, foot callus, loss of pin prick, thermal and light touch sensation, and some reduction in vibration acuity and proprioception in the lower limbs. The hands were involved in 3 of 8, muscle involvement was present in 5 of 8, but deafness was not detected by audiometry. Nerve conduction velocity, sensory action potentials, latency and amplitude, thermal acuity, vibration acuity and axon reflex flares were measured in all patients. One sural nerve biopsy confirmed the presence of peripheral fibre loss in this predominantly sensory neuropathy. Chemically evoked axon reflex tests were used to evaluate the extent of primary sensory nerve fibre involvement. All patients were tested using a Moor MBF 3-D dual channel laser Doppler velocimeter. Acetylcholine or phenylephrine iontophoretically applied as 16 mC doses evoked absent or tiny axon reflexes in areas of impaired pin prick sensation. By contrast, direct microvascular dilator responses to nitroprusside (smooth muscle dependent) and acetylcholine (endothelium-dependent) were present but somewhat reduced in areas with defective neurogenic inflammation. These results differ significantly from the responses obtained in age-matched healthy controls (P < 0.05). Foot pressure analysis was performed for orthoses in 2 affected members with foot ulceration using the Musgrave Footprint system.(ABSTRACT TRUNCATED AT 250 WORDS)


Enigmatic trigeminal sensory neuropathy diagnosed by facial skin biopsy.

Facial paraesthesia due to perineural malignant infiltration is a well recognised complication of basal and squamous cell carcinomas of the head and neck. Perineural involvement was originally attributed to involvement of the perineural lymphatics; however subsequent studies have demonstrated conclusively that these lymphatics do not exist and that the invasion occurs along the line of least resistance. Previous studies on perineural spread of carcinomas of the head and neck have emphasised diagnostic biopsy of an involved nerve (e.g. the infraorbital, mental or major branches of the trigeminal nerve), or at times craniectomy with exploration of the gasserian ganglion. We suggest that in many cases the diagnosis can be obtained by biopsy of the anaesthetic skin alone, without recourse to more involved biopsy techniques. The following case report illustrates this point.


Late radiation associated neurological injury.

Late radiation-associated neurological injury is a recognised and often fatal complication of therapeutic ionising radiation. This retrospective study outlines its highly variable presentation, radiological findings and prognosis over a 6 year period in a major teaching hospital.


Postinfectious myelitis, encephalitis and encephalomyelitis.

Six cases of post-infectious encephalomyelitis are described. A preceding non-specific viral-like illness occurred 4 to 20 days before the onset of the neurological deficits. The clinical syndromes included transverse myelitis, focal encephalitis and encephalomyelitis (each in one case) and diffuse encephalitis in 3. Magnetic resonance imaging appeared to be the investigation of choice. High dose corticosteroids were given to 4 patients who recovered partially or fully. The patient with focal encephalitis had a spontaneous and complete recovery. The remaining patient with diffuse encephalitis died 3 days after the onset; autopsy showed prominent lymphocytic perivascular cuffing in the white matter and lymphocytic infiltration of the meninges.


XIXth century pre-Jacksonian concepts of epileptogenesis.

By the beginning of the XIXth Century the old belief that epilepsy was due to demonic possession or to malevolent influences emanating from a variety of sources had largely given way to an acceptance that the disorder was a physical illness which arose in the brain, though in some not very precisely defined way. No even reasonably satisfactory hypotheses about epileptogenesis were available till Marshall Hall (1790-1857), from 1836 onwards, popularised the concept of reflex action which had earlier been described by Robert Whytt (1714-1776) under the name 'sympathy'. Marshall Hall interpreted epilepsy as due to abnormal irritability in the afferent limb or central section of what later came to be called the reflex arc, loss of consciousness in the seizures being the result of secondary cerebral venous congestion. This concept of epileptogenesis was refined by Brown-Séquard, who in 1858 ascribed a more important role to overt or occult peripheral afferent nerve irritability, considered that the central element of the relevant reflex mechanism involved the medulla oblongata, and believed that reflex cerebral vasospasm, rather than cerebral venous congestion, caused loss of consciousness in the seizures. Almost contemporaneously, Schroeder van der Kolk placed considerably greater emphasis on the medullary element in causing the increased excitability of the reflex arc that produced epileptic seizures. These ideas of exaggerated reflex activity as the mechanism of epilepsy were made redundant by the work of Hughlings Jackson (1837-1911), who from 1860 onwards demonstrated that epilepsy arose in the cerebrum itself, rather than from altered function at lower levels of the nervous system.


The cervical spine in fatal motor vehicle accidents.

Of 100 fatal accident cases involving motor vehicles, 60 showed damage to the cervical spine, involving bony or disc damage in 31 and focal haemorrhages in another 29. In 8 cases, pre-autopsy radiology failed to detect lesions which were found by radiology and pathological examination of the post-autopsy specimen. Most of the lesions missed were at the C6-7 region. In some cases, the initial pathological examination 'missed' laterally placed fractures and small chip fractures. Narrow cervical canals in the elderly indicated advanced spondylosis.


Low osmolar and non-ionic X-ray contrast media and cortical blindness.

Six cases of contrast neurotoxicity with cerebral visual disturbance following angiography are presented. The typical clinical features, putative mechanisms and usual outcome of this uncommon but distinctive syndrome are discussed.


Effect of ritanserin, a highly selective 5-HT2 receptor antagonist, on Parkinson's disease.

There is both experimental and clinical evidence to suggest a role for 5-hydroxytryptamine (5-HT) in Parkinson's disease. The effect of ritanserin, a highly selective 5-HT2 receptor antagonist, on Parkinsonian symptomatology was investigated in 10 patients in a single-blind placebo-controlled study. Akinesia and gait improved significantly in a dose-dependent manner in 5 and 7 patients respectively. However there was no significant improvement in tremor. The effects of ritanserin on akinesia and gait are consistent with a role for 5-HT in Parkinson's disease.


The influence of other anticonvulsants on the plasma concentration of E-2-en-valproate.

E-2-en-valproate is a major metabolite present in the blood of humans treated with valproate. In animals it is a potent anticonvulsant. We have measured concentrations of valproate and E-2-en-valproate in 102 plasma samples obtained from 75 adult patients (20 taking valproate only; 55 taking valproate and other anticonvulsants) under steady-state conditions. The two groups' mean ages and weights were comparable. The average valproate daily dose was lower (p < 0.002) in the monotherapy group (1152 +/- S.D. 661 mg/d) than in the polypharmacy group (1902 +/- S.D. 874 mg/d). Despite this, the mean plasma levels of valproate and E-2-en-valproate were significantly higher (p < 0.05, p < 0.0001, respectively) in the monotherapy group (60.0 +/- S.D. 22.6 micrograms/ml; 3.00 +/- S.D. 1.40 micrograms/ml, respectively) than in the polypharmacy group (49.5 +/- S.D. 24.8 micrograms/ml; 1.73 +/- S.D. 0.95 microgram/ml). While the mean plasma valproate level was 17.5% lower in the polypharmacy group, the mean plasma E-2-en-valproate level was 42% lower. The co-administration of other anticonvulsants significantly reduced the concentration of valproate and, more so, of E-2-en-valproate in plasma.


Video-audio/EEG monitoring in epilepsy--the Queen Elizabeth Hospital experience.

Our experience of using video-audio/EEG monitoring in the diagnosis and management of epilepsy at The Queen Elizabeth Hospital Comprehensive Epilepsy Service from March 1987 to December 1990 is described. We performed 75 long term monitoring studies on a total of 66 patients. Following monitoring, a change in seizure diagnosis was made in 21 of 66 patients (32%). Pseudoseizures were diagnosed in 17 patients. A change in management as a consequence of monitoring occurred in 53 of the 66 patients (80%). The referring neurologists considered that 56 of the 75 studies (75%) were successful. The investigational technique is effective and is particularly useful for the diagnosis of pseudoseizures.


Salivary concentrations of antiepileptic drugs, oestradiol and progesterone throughout pregnancy in epileptic women.

Epileptic women may experience an increase in seizure frequency during pregnancy. To explore the relationship between seizures, simultaneous antiepileptic drug and sex hormone concentrations, 8 pregnant epileptic women collected saliva each week throughout their pregnancies and for up to 6 weeks after delivery. The ratio of the drug dose to the drug's body fluid concentration at steady state (dose:Css), as measured by high performance liquid chromatography (HPLC), increased throughout pregnancy and fell in the 3rd to 4th week postpartum. There was no correlation between the dose:Css ratio and the salivary oestradiol concentration, nor between the number of seizures and the antiepileptic drug or sex hormone concentrations, and there was only a weak positive correlation between the dose:Css ratio and the salivary progesterone concentration. The possible interactions between sex hormone concentrations, antiepileptic drug concentrations and seizures are complex, and warrant further study in a greater number of pregnant subjects.


Automatisms--the current legal position related to clinical practice and medicolegal interpretation.

The interface between medicine and the law is an area which demands further investigation. There can be no criminal capability for an act unless the perpetrator had both the will to so act and the capacity to differentiate and choose whether or not to conform the particular behaviour to that dictated by the law. The capacity for choice must remain the fundamental issue. The range of conditions which can raise volition as a defence include: Somnambulism; post-traumatic syndromes; epilepsy; arteriosclerosis; or acts secondary to cerebral neoplasia. There is need to differentiate between reflex actions and automatisms and it is imperative that terms such as automatism or automatic behaviour are not perverted to allow an excuse for that which is inexcusable. Cases such as that of Cogdon, who was acquitted of murdering her daughter; Ramsbottom who was found guilty of causing a traffic accident despite having a stroke; Dennison in which a driver was found guilty despite epilepsy or Jenkins where the driver was initially found innocent of dangerous driving because of the unpredictable nature of diabetes are discussed. Special attention will be focused upon the case of Sullivan, a landmark in consideration of automatism in epilepsy. The paper examines insane verses non-insane automatism and the Australian legal system as it affects modern neurological practice. Suggestions are proffered as to how the law should be modified to better reflect justice as required within the context of modern medical knowledge. 'The social and psychological pressures that shape our criminals also shape-those who make and remake the laws which aim to control, punish or rehabilitate them, and those who try to change their behaviour.'


Video EEG analysis of non-ictal events in children.

Over a 3 year period 186 children aged 3 weeks to 17 years were studied by telemetry (prolonged video and EEG monitoring) at the Prince of Wales Children's Hospital: 74 had events considered at referral to possibly represent seizures but which were shown by clinical analysis and telemetry to be non-ictal. Nine such patients were developmentally delayed, one was neurologically impaired and 16 were both developmentally delayed and neurologically impaired. A specific diagnosis of the non-ictal events was reached in 24 subjects-postures of spasticity in children with neurological impairment (6), Münchausen-by-proxy (5), pseudoseizures (3), breathholding (2), masturbation (2), reflux (2), shudder (1), movement disorder (1), motor tic (1) and pertussis (1). Specific descriptive patterns were assigned to the remaining 51 events. These included staring (20) and jerks (16) or unusual behaviour (15). 49 inter-event EEGs were normal; 7 displayed abnormal background rhythms and 19 showed epileptiform activity. We discourage use of the term 'pseudoseizure' for the majority of the events described and prefer that a specific diagnosis be made or a descriptive analysis be provided. The events seen illustrate the wide spectrum of childhood behaviour and on occasions suggest the need for telemetry to determine their true nature.


P300 event-related potentials correlated with cerebral blood flow in nondemented patients with lacunar infarction.

We have studied the relationship between the P300 latency and regional cerebral blood flow (rCBF) in 25 nondemented patients who had lacunar infarctions in the territory of the deep perforating branches of the internal carotid artery system. A significant prolongation of the P300 latency with advancing age was observed. There was a negative correlation between the P300 latency and the rCBF. These results indicate that a combination of P300 latency and rCBF measurements might prove more sensitive in detecting mental decline than rCBF studies alone in nondemented patients with lacunar infarctions.


Brazilian contributions to epidemiological aspects of schistosomiasis mansoni.

A review of epidemiological aspects of endemic areas for schistosomiasis, especially in Brazil, will be presented. These studies, performed by several authors from different states of the country, have been very useful in indicating the relative efficacy of control measures. For example quoting only one aspect, specific treatment was demonstrated by Brazilian researchers to be the most important individual tool for morbidity control. More recently the study of risk factors in endemic areas has been seen to be a very important approach when transmission control is the final goal.


T cell derived cytokines in lung-phase immunity to Schistosoma mansoni.

In C57Bl/6 strain mice vaccinated with radiation-attenuated cercariae of Schistosoma mansoni immune elimination of challenge parasites occurs in the lungs. Leucocytes were recovered from the lungs of such mice by bronchoalveolar lavage and cultured in vitro with larval antigen; the profile of cytokines released was then analyzed. From 14 days after vaccination, BAL cultures contained infiltrating lymphocytes which produced abundant quantities of IFN-g and IL-3. Challenge of vaccinated mice resulted in a second influx of IFN-g and IL-3--producing cells, earlier than after vaccination or in the appropriate controls. Ablation studies revealed that CD4+ T cells were the source of IFN-g. The timing of cytokine production after vaccination, and challenge was coincident with the phases of macrophage activation previously reported. At no time could lymphocytes in BAL cultures be stimulated to proliferate with either larval Ag or mitogen, in contrast to splenocytes from the same mice. Furthermore, T cell growth factor activity was not detected in BAL cultures stimulated with Ag. We suggest that the lymphocytes recruited to the lungs are memory/effector cells. When Ag released from challenge schistosomula is presented to these cells, they respond by secreting cytokines which mediate the formation of cellular aggregates around the parasites, blocking their onward migration.


Molecular and cellular basis of hepatic fibrogenesis in experimental schistosomiasis mansoni infection.

Morbidity in schistosomiasis mansoni occurs primarily as a result of the complications of hepatic fibrosis. Yet, the pathogenesis of schistosomal hepatic fibrosis is poorly understood. The fact that the hepatic egg granuloma is the hallmark of this infection suggests a potential role for granulomatous inflammation in hepatic fibrogenesis. Our studies in a murine schistosomiasis model indicate that hepatic granuloma cells secrete a variety of fibrogenic cytokines that may initiate the scarring process. Among these cytokines, we identified a novel protein that we designated fibroblast stimulating factor-1 (FsF-1). FsF-1 is a lymphokine that can stimulate fibroblast growth and matrix synthesis. A notable feature of hepatic fibrosis in this model is that production of FsF-1 and other granuloma-derived fibrogenic cytokines is down-regulated in chronic infection, an event that may be under immunological control. The spontaneous reduction of FsF-1 secretion presumably accounts for reduced scar formation late in infection of mice. In the context of relevant clinical studies, our findings engender the hypothesis that Symmer's fibrosis may develop in a small subpopulation of individuals as a result of immunogenetically-determined dysregulation of fibrogenic cytokine production.


Serum laminin in hepatosplenic human schistosomiasis.

Serum laminin level was measured in chronic hepatic schistosomiasis. A significant increase in the mean serum laminin levels was observed in patients with hepatosplenic (HS) schistosomiasis (2.57 +/- 0.83 U/ml), as compared to those in patients with the hepatointestinal (HI) form of the disease (1.38 +/- 0.45-U/ml) and in the control group (1.15 +/- 0.31 U/ml). In the HS patients there was a significant direct relation between serum laminin and percutaneous splenic pulp pressure (r = 0.68). These findings are compatible with an increased production of laminin in hepatosplenic schistosomiasis with may be related to the observed enlarged liver and spleen basement membranes in such disease.


Morphological features of collagen degradation in advanced hepatic schistosomiasis of man.

Optical and electron microscopical evidences of focal matrix degradation were frequently seen in liver sections taken from patients with periportal ("pipe-stem") fibrosis caused by schistosomiasis mansoni. Besides the presence of focal areas of rarefaction, fragmentation and dispersion of collagen fibers, the enlarged portal spaces also showed hyperplasia of elastic tissue and disarray of smooth muscle fibers following the destruction of portal vein branches. Ultrastructural changes represented by focal lytic and/or electron dense alterations of collagen fibrils were similar to those first seen in experimental material and designated as "chronic collagen degradation". Elastin and related microfibrils were also affected by focal condensation, fragmentation, distortion and dissolution. Schistosome eggs were scanty in the tissue sections examined. Matrix degradation represented involuting changes related to the progressive diminution of parasite aggression, which occurs spontaneously with age or after cure by chemotherapy. Changes of focal matrix degradation now being described represent the basic morphological counterpart of periportal fibrosis involution documented clinically, especially by ultrasonography, in patients with hepatosplenic schistosomiasis submitted to curative chemotherapy.


Immunological profiles of patients from endemic areas infected with Schistosoma mansoni.

Crude extracts of eggs (SEA) adult worms (SWAP) or cercariae (Cerc) have been used to stimulate Peripheral Blood Mononuclear cells (PBMC) and have provided rather distinct profiles of responses in different types of patients. In general it is clear that patients with early infections respond strongly to SEA while response to SWAP are develop more slowly. As infection progresses into the more chronic phases, a general pattern is seen which leads to lower anti-SEA proliferative responses in the face of higher responses to SWAP and variable anti-cerc responsiveness. Cured not re-exposed patients express very high levels of anti-SEA proliferation. It has recently been seen that those individuals who live in endemic areas and have continued water contact, but are repeatedly stool-negative (who are presumed to have self-cured or be putatively resistant; endemic normals) are strongly responsive to antigenic extracts, particularly to SEA. Furthermore, our results show that endemic normal individuals have significantly higher IFN gamma production upon PBMC stimulation with schistosome antigens than infected individuals. With the emergence of more studies it is becoming apparent that both the intensity and the prevalence of a given area may influence or shape the general responsiveness of the population under study.


The value of ultrasonography in assessment of portal hypertension in hepatosplenic schistosomiasis.

Ultrasonography can reveal most of the manifestations of portal hypertension complicating hepatosplenic schistosomiasis. However, direct demonstration of gastroesophageal varices by ultrasonography is still very difficult. An attempt was done to correlate sonographic features of portal hypertension with the degree of fibrosis to screen patients having varices and predicting their chance of bleeding. The results obtained were found to be consistent with the esophagogastric endoscopy and with history of hematemesis. Four parameters were used, size of spleen, degree of periportal fibrosis, presence of collaterals and portal vein diameter. A pilot field survey was also done adopting the same principle.


Duplex hemodynamic evaluation of hepatosplenic mansoni schistosomiasis.

Conventional ultrasonography highly contributes to a non invasive diagnosis of HS schistosomiasis (Cerri et al., 1984). The introduction of Doppler allowed new advances in the knowledge of the portal dynamics of this disease (Taylor et al. 1985; Moriyasu et al., 1986). The aim of this paper was to analyze the hemodynamic behavior of the portal vessels, considering caliper, maximum flow speed, direction of flow and preferential disposition of the collateral vessels. Thirty two patients with schistosomiasis mansoni with confirmed hepatosplenic form (HSSM), were analyzed. Fourteen patients with the intestinal form, have been analyzed as a control group. The results demonstrated that the maximum speed of the portal vein in the two groups has not been significantly different. Nevertheless, the diameter of the PV in the hepatosplenic group has been larger. The splenic vein presented speed and caliper larger than the superior mesenteric vein. The hepatic artery has been detected in only 40% of the cases. The hepatic veins presented normal caliper and spectral pattern. The duplex proved to be an useful technic complementary and non-invasive, in the study of HSSM.


Schistosomiasis research funding: the TDR (Special Programme for Research and Training in Tropical Diseases) contribution.

In spite of the recent decline in financial support on the part of some major donors, the overall international support for schistosomiasis research in current US dollars has been holding steady. However, when adjusted for inflation, a clear decline-during the last decade appears and only in a few countries has this decline been balanced by increased national or bilateral funding. The prevailing level of support for schistosomiasis research is barely sufficient to maintain established laboratories and researchers, and highlights the need to attract young investigators. The important goal of bringing a new generation of scientists into the field of schistosomiasis can only be achieved by a considerable long-term increase in funding, both at the national and the international levels. A break-through in current research emphasizing improved techniques for control is needed to encourage donors and governments to improve the situation.


New approaches to social and economic research on schistosomiasis in TDR (Special Programme for Research and Training in Tropical Diseases).

This paper describes new approaches to social and economic research being developed by the Social and Economic Research component of the Special Programme for Research and Training in Tropical Diseases of the World Health Organization. One of these is a study to assess the possibility of identifying high risk communities for urinary schistosomiasis through a "mailed" questionnaire approach distributed through an existing administrative system, thereby eliminating the need for face-to-face interviews by the research or disease control team. This approach, developed by the Swiss Tropical Institute in Ifakara, Tanzania, is currently being tested in seven other African countries. The paper also describes a change of emphasis of economic research on schistosomiasis, focusing on the intra-household effects of the disease on rural households, rather than, as previously done, studying the impact of the disease on the productivity of individual wage labourers. Other priorities involve the identification of epidemiological information needed for improved decision-making regarding acceptable treatment strategies in endemic areas with limited financial capacity, as well as research on how the adverse effects of economic development projects can be alleviated.


Effector functions of eosinophils in schistosomiasis.

The dual function of eosinophils is clearly illustrated in schistosomiasis. Well equipped in membrane receptors for immunoglobulins and complement, and due to the presence of granule basic proteins, eosinophils can become cytotoxic for parasite larvae and thus participate to protective immunity. However, mediators can also exert their cytolytic effect on normal cells or tissues, inducing therefore pathology. through ADCC mechanisms against schistosome larvae in vitro involving different antibody isotypes (IgG, IgE and IgA) and also in experiments performed in vivo, eosinophils have been clearly involved in protective immunity. Although no direct evidence of the protective role of eosinophils were brought in humans, the striking association of eosinophil-dependent cytotoxic antibody isotypes with resistance to reinfection (for instance IgE and IgA antibodies), whereas in vitro blocking antibody isotypes (IgG4, IgM) were detected in susceptible subjects, strongly, suggested the participation of eosinophils in antibody-dependent protective immune response. However eosinophils could also participate to granuloma formation around S. mansoni eggs and consequently to the pathological reactions induced by schistosomiasis.


Experimental murine schistosomiasis mansoni: establishment of the chronic phase of the disease.

After the acute hyperergic phase of schistosomal infection, the chronic phase of the disease corresponds to the establishment of a relative equilibrium between the host and the parasite. This involves: (1) A shift from the predominance of the TH2 response observed in the acute phase, to the predominance of the TH1 response in the chronic phase of the disease, with modification of lymphokine and immunoglobulin secretions patterns. (2) Redistribution of hosts responses to parasite, with predominance of systemic controls in the acute phase, and a shift towards local tissue responses in the chronic phase. This redistribution relieves the hyperergic response involving the whole body of the host, and delimits cellular and molecular reactions to parasites to only those tissues that are directly involved by the adult parasites and their eggs. Mobilization of eosinophil granulocytes in schistosomal periovular granulomas is one of examples of this redistribution.


Cross-sectional and evolutive studies of schistosomiasis mansoni in untreated and mass treated endemic areas in the southeast and northeast of Brazil.

Cross-sectional and evolutive studies on schistosomiasis mansoni were carried out before and after mass treatment in the endemic areas of Capitão Andrade and Padre Paraiso, state of Minas Gerais, Riachuelo, state of Sergipe, Alhandra, state of Paraiba, and Aliança, Alegre and Coroatá, lowland of the state of Maranhão, Brazil, in the last eighteen years. The studies included clinical and fecal examination by the Kato-Katz quantitative technique, skin test for Schistosoma mansoni infection, evaluation of man-water contact and other epidemiological investigations such as infection rate and dynamic of the snail population. Results showed: (1) Higher prevalence of S. mansoni infection, greater egg load elimination and higher and earlier morbidity of the chronic forms of the disease in the southeast areas of Capitão Andrade and Padre Paraiso; (2) The incidence of hepatosplenic form is higher in some family clusters, in whites and mulattos in all the endemic areas but develop earlier in the southeast; (3) The prevalence and morbidity of schistosomiasis are decreasing both in the mass treated northeast and in the untreated southeast areas; (4) The mass treatment reduces rapidly the prevalence of the infection and the morbidity of the disease but can not control it because of the frequent reinfections due to the intensity of man-water contact.


Portal hypertension in schistosomiasis: pathophysiology and treatment.

In heavily infected young patients, there is a "non-congestive" phase of the disease with splenomegaly which can improve after chemotherapy. A strong correlation between hepatosplenic form and worm burden in young patients has been repeatedly shown. The pattern of vascular intrahepatic lesions, seems to depend on two mechanisms: (a) egg embolization, with a partial blocking of the portal vasculature; (b) the appearance of small portal collaterals along the intrahepatic portal system. The role played by hepatitis B virus (HBV) and C virus infections in the pathogenesis of liver lesions is variably considered. Selective arteriography shows a reduced diameter of hepatic artery with thin and arched branches outlining vascular gaps. A rich arterial network, as described in autopsy cases, is usually not seen in vivo, except after splenectomy or shunt surgery. An augmented hepatic arterial flow was demonstrated in infected animals. These facts suggest that the poor intrahepatic arterial vascularization demonstrated by selective arteriography in humans is due to a "functional deviation" of arterial blood to the splenic territory. The best results obtained in treatment of portal hypertension were: esophagogastric devascularization and splenectomy (EGDS), although risk of rebleeding persists; classical (proximal) splenorenal shunt (SRS) should be abandoned; distal splenorenal shunt may complicate with hepatic encephalopathy, although later and in a lower percentage than in SRS. Propranolol is currently under investigation. In our Department, schistosomatic patients with esophageal varices bleeding are treated by EGDS and, if rebleeding occurs, by sclerosis of the varices.


Experiences with the control of schistosomiasis mansoni in two foci in central Africa.

Experiences with population-based chemotherapy and other methods for the control of schistosomiasis mansoni in two subsaharan foci are described. In the forest area of Maniema (Zaire), intense transmission of Schistosoma mansoni, high prevalences and intensities of infection, and important morbidity have been documented. Taking into account the limited financial means and the poor logistic conditions, the control strategy has been based mainly on targeted chemotherapy of heavily infected people (> 600 epg). After ten years of intervention, prevalences and intensities have hardly been affected, but the initial severe hepatosplenic morbidity has almost disappeared. In Burundi, a national research and control programme has been initiated in 1982. Prevalences, intensities and morbidity were moderate, transmission was focal and erratic in time and space. A more structural control strategy was developed, based on screening and selective therapy, health education, sanitation and domestic water supply. Prevalences and intensities have been considerably reduced, though the results show focal and unpredictable variations. Transmission and reinfection were not significantly affected by chemotherapy alone, and the eventual outcome of repeated selective treatment appears to be limited by the sensitivity of the screening method. Intestinal morbidity was strongly reduced by community-based selective treatment, but hepatosplenic enlargement was hardly affected; this is possibly due to the confounding impact of increasing malaria morbidity. The experiences show the importance of local structures and conditions for the development of an adapted control strategy. It is further concluded that population-based chemotherapy is a highly valid tool for the rapid control of morbidity, but should in most operational conditions not be considered as a tool for transmission control.(ABSTRACT TRUNCATED AT 250 WORDS)


Vaccine strategies against schistosomiasis.

In this review the authors analyze the effector and regulatory mechanisms in the immune response to schistosomiasis. To study these mechanisms two animal models were used, mouse and rat. The mouse totally permissive host like human, show prominent-T cell control in the acquisition of resistance. But other mechanisms like antibody mediated cytotoxicity (ADCC) involving eosinophils and IgG antibodies described in humans, are observed in rats. Also in this animal, it is observed specific IgE antibody high production and blood and tissue eosinophilia. Using the rat model and schistosomula as target, some ADCC features have emerged: the cellular population involved are bone marrow derived inflammatory cell (mononuclear phagocytes, eosinophils and platelets), interacting with IgE through IgE Fc receptors. Immunization has been attempted using the recombinant protein Sm28/GST. Protection has been observed in rodents with significant decrease of parasite fecundity and egg viability affecting the number, size and volume of liver egg granulomas. The association of praziquantel and immunization with Sm28/GST increases the resistance to infection and decreases egg viability. The authors suggest the possibility of the establishment of a future vaccine against Schistosoma mansoni.


[Specific treatment as a weapon for controlling schistosomiasis].

The specific treatment of schistosomiasis has been thought to prevent or revert severe forms of the disease, since 1957. Starting in 1977, prospective and controlled studies performed in different endemic areas of Brazil were able to confirm such facts. The new drugs, of high efficacy and well tolerated--Oxamniquine and Praziquantel--can actually prevent and cure the severe forms of some patients, contributing to change the morbidity pattern of the disease, thus being considered as important weapons in its control. Analysis of the principal Brazilian articles on the subject is presented.


Age-targeted chemotherapy for control of urinary schistosomiasis in endemic populations.

Severity of urinary tract morbidity increases with intensity and duration of Schistosoma haematobium infection. We assessed the ability of yearly drug therapy to control infection intensity and reduce S. haematobium-associated disease in children 5-21 years old in an endemic area of Kenya. In year 1, therapy resulted in reduced prevalence (66% to 22%, P < 0.001) and intensity of S. haematobium infection (20 to 2 eggs/10 mL urine), with corresponding reductions in the prevalence of hematuria (52% to 19%, P < 0.001). There was not, however, a significant first-year effect on prevalence of urinary tract abnormalities detected by ultrasound. Repeat therapy in years 2 and 3 resulted in significant regression of hydronephrosis and bladder abnormalities (41% to 6% prevalence, P < 0.01), and further reductions in proteinuria. Repeat age-targeted therapy was associated with decreased prevalence of infection among young children (< 5 yr) entering into the targeted age group. Two years after discontinuation of therapy, intensity of S. haematobium infection and ultrasound abnormalities remained suppressed, but hematuria prevalence began to increase (to 33% in 1989). Reinstitution of annual therapy in 1989 and 1990 reversed this trend. We conclude that annual oral therapy provides an effective strategy for control of morbidity due to S. haematobium on a population basis, both through regression of disease in treated individuals, and prevention of infection in untreated subjects.


Genetic complementation analysis of two independently isolated hycanthone-resistant strains of Schistosoma mansoni.

The objective of this study is to determine whether various hycanthone resistant strains of schistosomes which have been independently isolated are all affected in the same gene. A strain obtained from a Brazilian patient was compared with a strain of Puerto Rican origin selected in the laboratory. If the mutation conferring resistance involved two different genes, one would expect that progeny of a cross between the two strains would show complementation, i.e. it would be sensitive to the drug. We have performed such a cross and obtained F1 hybrid worms which were essentially all resistant, thus suggesting that the mutation conferring resistance in the two strains involves the same gene.


Alternative approaches in schistosomiasis control.

Measures for the control of schistosomiasis were implemented in Egypt beginning 1922. This shows that developing endemic countries are facing this problem for near 70 years. However, results in the control of this infection have not been satisfactorily obtained in spite of the technologies and strategies recently developed. The idea that social and economic components are relevant in the control of schistosomiasis is not new although its extension and profundity have not usually been well understood. More recently, most of the workers have recognized that the focal distribution of the prevalence rates of schistosomiasis should not be neglected in the control of the infection. At present, field work projects on the control of schistosomiasis are being developed in rural areas of two Brazilian studies (Espírito Santo and Pernambuco). The adopted strategy aims to interfere in the complex relationships between man and his bio-social-cultural environment, without forgetting that the unequal distribution of the space is a consequence of the political and economic organization of the Society.


Some personal views on the control of schistosomiasis mansoni.

Our views are based, among other, on a recent study of a district of União dos Palmares (Alagoas). Although being a very compact community (32 city blocks holding two thousand families), transmission is very uneven, the geometric mean egg counts in the various blocks ranging between extremes of 96 and 1920. (Results do not correlate with the availability of domestic water supply). We thus are led to conclude that: (a) transmission is primarily peridomestic, resulting from pollution of open ditches and other collections of water; (b) control of transmission can be done on a selective basis, requiring quite modest investments. Given the inefficacy of population-based chemotherapy, when used alone, the author insists that this alternative cannot any longer be overlooked. He also regrets the emphasis placed upon vaccine development; allegations that this would, at any rate, prevent severe morbidity can be dismissed, since-whatever the cause-morbidity due to schistosomiasis has been rapidly declining in Northeast Brazil.


New approaches for the control and eradication of schistosomiasis in Venezuela.

Schistosomiasis in America with the exception of Brazil, behaves as a chronic mild disease with few clinical manifestations due to low parasite burden. These features restrict the clinical and parasitological diagnosis. The most commonly used stool examination method, Kato-Katz, becomes insensitive when the majority of individuals excrete less than 100 eggs/g of feces. In view that antigen-detecting techniques have not been able to reveal light infections, the antibody detecting assays remain as a very valuable diagnostic tool for epidemiological surveillance. The Venezuelan Schistosomiasis Research Group (CECOICE) has designed a mass chemotherapy strategy based on sero-diagnosis. Since blood sampling is one of the important limiting factors for large seroepidemiological trials we developed a simple capillary technique that successfully overcame most of the limitations of blood drawing. In this sense, ELISA seems to be the most adequate test for epidemiological studies. Soluble egg Schistosoma mansoni antigen (SEA) has been largely used in Venezuela. The sensitivity of ELISA-SEA in our hands is 90%, moreover its specificity reach 92% when populations from non-endemic areas but heavily infected with other intestinal parasites are analyzed. The Schistosomiasis Control Program is currently carrying out the surveillance of endemic areas using ELISA-SEA as the first screening method, followed by the Circumoval Precipitin test for validation assay. The results with these two serological techniques allowed us to defined the criteria of chemotherapy in populations of the endemic areas. On the search of better diagnostic technique, Alkaline Phosphatase Immunoenzyme Assay (APIA) is being evaluated in field surveys.


[Control of schistosomiasis mansoni in an area of low transmission].

The schistosomiasis is transmitted by Biomphalaria tenagophila in our study area (Pedro de Toledo, São Paulo, Brazil). From 1980 to 1990 epidemiological surveys in a population of 4,000 inhabitants, has shown that: prevalences by Kato-Katz (KKT), immunofluorescence (FT) and intradermal (IDT) techniques were 22.8%, 55.5% and 51.8%, respectively; intensity of infection was low, 58.5 eggs per gram of faeces (epg); there were no symptomatic cases; prevalences were higher in mates, children and rural zone; index of potential contamination was 57.5% in the age group 5 to 20 years; 2/3 of patients were autochthonous; cases were no-randomly aggregated; transmission was focal and only 0.4% of snails were infected; water contacts through recreation showed the most important odds ratio; knowledge, attitudes and practices were satisfactory. From the epidemiological findings a control programme was carried out: yearly faeces exams, chemotherapy, molluscocide, health education and sanitation. Thus, the prevalence decreased sharply to 3.3% and intensity of infection to 30.3 epg; the incidence rates ranged between 0.4% and 2.5% annually; the sanitation became better and the youngsters were the main target in prophylaxis. To improve control, immunodiagnosis has to be conducted and the involvement of the population should be increase. However, we cannot forget that re-infection, therapeutic failure, etc, could play a major role in the maintenance this residual prevalence.


Epidemiological features and control of schistosomiasis japonica in China.

Achievements and successes have been obtained in schistosomiasis control in China. An epidemic survey was carried out and its results analyzed.


Identification of schistosome-infected snails by detecting schistosomal antigens and DNA sequences.

Cercarial shedding tests do not provide species identification of the schistosomes concerned and cannot detect prepatent schistosomal infections. We have demonstrated that both immunodetection by ELISA of schistosomal antigens in snail hemolymph, and dot hybridization of snail extracts by a DNA probe representing highly repeated sequences, proved suitable for detecting infected snails during prepatency as well as patency. A group-specific monoclonal antibody was found to be suitable for detecting Schistosoma mansoni infection in Biomphalaria sp., but not for positive identification of S. haematobium in Bulinus sp. Comparative evaluation of the diagnostic qualities, and technical aspects and cost of these tests, point to the superiority of the immunodetection approach for large scale detection of snails prepatently infected with S. mansoni. This approach is potentially useful for providing extended information on schistosome-snail epidemiology that may facilitate rapid evaluation of the danger of post-control reinfection, and help make decisions on the time and place of supplementary control measures. In this context the potential usefulness of the immunodetection or DNA probing approach for facilitating catalytic model representation of schistosome-snail epidemiology warrants further evaluation. Specific identification of S. haematobium in Bulinus by either of these approaches may be possible depending on the development of suitable antibodies or DNA probes.


Ecological studies on the intermediate host snails and the relevance to schistosomiasis control.

A detailed knowledge of distribution patterns of schistosome intermediate hosts and their population dynamics and factors affecting these patterns will provide useful information about the possibilities and desirability of conducting snail control measures in various transmission situations. On the basis of various case studies the association between the occurrence of human water contacts and the presence of schistosome intermediate hosts or infections in the intermediate hosts is illustrated. Other parameters affecting snail distribution patterns and density fluctuations are discussed. It is concluded that ecological studies on the intermediate hosts are extremely relevant, either to optimally apply existing control measures or to develop alternative measures of snail control, such as ecological or biological control.


Holochilus brasiliensis and Nectomys squamipes (Rodentia-Cricetidae) natural hosts of Schistosoma mansoni.

After several Brazilian researchers, the author examines the capacity of two species of rodents Cricetidae, Holochilus brasiliensis and Nectomys squamipes, to maintain the biological cycle of Schistosoma mansoni in the field and to be parasite reservoir: (a) the role they are able to play in human endemy; (b) the methods necessary to characterize the population of Schistosoma mansoni related either to man, either to rodents, either to both.


Further development of the baboon as a model for acute schistosomiasis.

Baboons develop a syndrome, including eosinophilia and transient fever, after infection with cercariae of Schistosoma mansoni that is consistent with the human syndrome of acute schistosomiasis. Radiotelemetry can be used to follow the course of fever in infected baboons. Individual variations in intensity of disease were noted in baboons. These symptoms and signs were more closely linked to the onset of oviposition by the newly matured worms than they were to the presence of migrating schistosomula or maturing worms. The baboon is concluded to be a suitable and useful model for human acute schistosomiasis mansoni.


Pre- and post-treatment immunodiagnostic evaluation in human schistosomiasis mansoni.

Schistosomiasis control seems to be different in countries were low parasitic burden and asymptomatic clinical patients are the features of majority of cases. Immunological methods must substitute the traditional coprologic techniques used for some decades in the Control Program. Circumoval Precipitin Test (COPT), intradermal test and ELISA with soluble egg antigen (SEA) are evaluated for using as tools for seroepidemiologic studies. COPT and ELISA were performed after treatment to known their utility when impact of chemotherapy must be assessed. One hundred sixty five persons were followed up 3, 6, 9 and 12 months after treatment. The mean sensitivity of COPT studied by age groups was 95.6% which is very important considering that 88.4% of the studied population excreted less than 100 eggs/gr of feces, while sensitivity of intradermal test was 58.2%. Children showed the highest reactivity to COPT. When treatment is effective, COPT reactivity progressively diminish until become negative one year later. In the non cure group, the COPT reactivity diminished but never below 20%. ELISA-SEA did not modify one year after treatment. Effort should be made to isolate fractions of eggs of Schistosoma mansoni whose antibodies disappear after treatment.


Mini-review: the ultrasonographical and serological changes and their improvement after praziquantel treatment in Schistosoma japonicum infected patients in Leyte, Philippines.

We have identified the specific ultrasonographical (US) changes in Schistosoma japonicum infected patients with the serological changes in general liver function markers. The US examination with the following haematological and biochemical serum analysis was performed on 102 patients in Schistosomiasis Hospital, Leyte, Philippines. The US liver images were classified into 4 patterns according to the development of periportal fibrosis and the patterns of echogenic bands. Among various haematological and biochemical serum parameters of liver damage. The serum levels of total bile acid (TBA) and procollagen-III-peptide (P-III-P) correlated well with the development of hepatic fibrosis and the portal hypertension. These patients were subsequently treated with praziquantel (3 x 20 mg/kg), and the improvement of the thickening of the portal vein wall and the intensity of the echogenic band formation was detected 6 months after treatment. The significant US changes could not be detected in the patients with severe hepatic fibrosis caused in the long term infection. The results revealed that the US examination with the serum TBa level would provider a sensitive tool to monitor the severity of the infection and also the improvement occurred shortly after praziquantel treatment.


Efficacy of Niclosamide as a potential topical antipenetrant (TAP) against cercariae of Schistosoma mansoni in monkeys.

A 1% (W/V) formulation of Niclosamide (2', 5-Dichloro-4-nitrosalicylanilide) (TAP) was tested on Cebus apella monkeys as a topical prophylactic against schistosomiasis mansoni. Two experiments were conducted using the same formulation. In the first experiment, the TAP provided complete protection against schistosomiasis for 3 days. Of the 4 monkeys treated with TAP 7 days before exposure to Schistosoma mansoni cercariae, 2 were completely protected. The remaining 2 monkeys of the 7 day treatment group had a 78% or greater reduction in adult worm burdens when compared to the placebo treated monkeys. The second experiment was designed to determine the time between day 3 and 7 when the TAP no longer provided complete protection. However, all of the TAP treated monkeys in this experiment were completely protected, even the monkeys treated 7 days earlier. In both experiments, all monkeys used as infection controls and those receiving only the placebo became infected and showed typical experimental schistosomiasis. These results demonstrate that the TAP could provide fast acting, short-term protection to people who must enter cercariae infested water.


Present aspects of immunodiagnosis of schistosomiasis.

Facilitated and improved by advances in molecular biology, techniques for the immunodiagnosis of schistosomiasis, including assays based on the detection of antigens circulating in the serum and/or excreted in the urine, have now reached the stage of multi-centre trials. There is a need to complement parasitological techniques as some national programmes are becoming increasingly successful in establishing control of the disease and the classical approach frequently fails to reveal low-intensity infection. Epidemiological survey teams in some areas have tentatively started to use serology and their experience indicates that antibody detection suffices in eradicated or controlled areas with low expected prevalence but that detection of circulating antigens is needed for assessment of the incidence of infection or reinfection in areas recently brought under control. Before reagents and procedures can be recommended for routine use of national control programmes, the assays must be standardized with sera from clinically well-characterized patients in geographically defined regions, hence emphasizing the need for a reference serum bank. Implementation of serological testing, carried out by national public health laboratories using standardized testing systems, would permit valid comparisons between different areas providing support for decisions regarding national health policies.


Interrelationship between schistosomiasis and concomitant diseases.

The biological literature contains many examples of mutual influences between different species of parasites, especially with respect to concomitant helminth infections. Several situations are known in which the association of infection by Schistosoma mansoni with other pathogens in the same host results in a type of disease which differs from the simple summation of the individual effects of each infection. The present study concerns concomitant infections involving S. mansoni and enterobacteriaceae; S. mansoni and other helminths such as Ascaris lumbricoides, Ancylostomids, Toxocara canis and species of the genus Hymenolepis; S. mansoni and different protozoa such as Trypanosoma cruzi, T. brucei, Toxoplasma gondii and Plasmodium berghei. The interaction between hepatitis B virus and S. mansoni, leading to prolonged viremia and worsening of liver damage, is also discussed. The paper also treats the simultaneous occurrence of schistosomiasis and other aggravating factors such as malnutrition and neoplasias which may alter the host's response to the trematode.


Nutrition and acute schistosomiasis.

In northeast Brazil, nutritional deficiency diseases and schistosomiasis mansoni overlap. An experimental model, which reproduces the marasmatic clinical form of protein-energy malnutrition, was developed in this laboratory to study these interactions. Albino Swiss mice were fed with a food association ingested usually by human populations in northeast Brazil. This diet (Regional Basic Diet - RBD) has negative effects on the growth, food intake and protein utilization in infected mice (acute phase of murine schistosomiasis). Nitrogen balance studies have also shown that infection with Schistosoma mansoni has apparently no effect on protein intestinal absorption in well nourished mice. However, the lowest absorption ratios have been detected among RBD--fed infected animals, suggesting that superimposed schistosome infection aggravated the nutritional status of the undernourished host. The serum proteins electrophoretic pattern, as far as albumins are concerned, is quite similar for non-infected undernourished and infected well-fed animals. So, the significance of albumins as a biochemical indicator of the nutritional status of human populations residing in endemic foci of Manson's schistosomiasis, is discussable.


Seroepidemiology of schistosomiasis mansoni.

In population surveys in which the Schistosoma mansoni intensity of infection is low, or in localities where the schistosomiasis control program had success, the parasitologic methods lack in sensitivity. Despite of some limitations, the immunological methods are useful to provide valuable information in such field conditions. Thus, the prevalence of schistosomiasis in untreated population can be determined by the detection of IgG or IgM antibodies, as well as the incidence by the IgA antibodies, employing mainly immunofluorescence (IF) and immunoenzymatic (ELISA), and in some extent hemagglutination (HA) or even skin test. The true prevalence and incidence of schistosomiasis can be estimated using a probabilistic model equation, since knowing before-hand the sensitivity and specificity of employed test. The sensitivity and the specificity of serologic test become higher in low aged group, under 14. The geometric mean IF titers also gives a positive correlation with the intensity of infection. Presently, there are need of serologic tests which are economic and practical in seroepidemiologic inquiries, requiring no specialized personnel to collect population blood or serum samples, and also easily interpret the test results. The reagents for such tests are desired to be stable and reproducible. Moreover, it is expected that the tests can distinguish an active infection.


Intermediate hosts of Schistosoma mansoni in Brazil.

The Brazilian planorbidical chart is slowly but progressively been increased by new data. Distribution of vector species of Schistosoma mansoni, according to Paraense, 1986, may be thus resumed: Biomphalaria glabrata--delimited by parallels 13 and 21 degrees S and meridians 39 and 45 degrees W, area of greater dominance (Southeast Bahia, oriental hal of Minas Gerais and Espírito Santo). It is observed along the coast line of the states of Sergipe, Alagoas, Pernambuco, Paraiba and Rio Grande do Norte. Starting from there, it is found towards the southwest, in the direction to the São Francisco River and South-Center of Minas Gerais. Isolated population may be observed in other states. Its presence is probably, associated to the transmission of schistosomiasis in all areas where it occurs. B. tenagophila--extends it self through a wide strip of coast-line from the South of Bahia (17 degrees 45'S; 39 degrees 15'W), RS (33 degrees 41'S, 53 degrees 27'W). In São Paulo and Rio Grande do Sul states it is found further inland. It is important in schistosomiasis transmission in the Paraiba valley (SP). Isolated populations are observed in the Federal District and Minas Gerais state. B. straminea--better adapter species to climatic variation, having a more dense distribution in the northeast (41 degrees W and 110 degrees S), south of Bahia and northeast of Minas Gerais (150 and 180 degrees S, 400 and 440 degrees W). It is less susceptible than the B. glabrata, being however, the most important responsible for the transmission of S. mansoni in the northeast, chiefly in the northeastern dry area, where it is almost the only transmissive species.


[Malacologic diagnostic methods].

Specific identification of the snail vectors: (a) shell features; (b) animal features (genital organs); (c) biochemical techniques (electrophoresis). The snail infection rates: (a) exposure to light and cercarial identification; (b) snail crushing and identification or the larval forms in the tissues.


[Measures for control of schistosomiasis adopted by the National Health Foundation].

The control measures used by the Ministério da Saúde/Fundação Nacional de Saúde for 1990/1991, started to have a new focus when significant advances were evidenced in the two last decades and after internal meetings with participation of the scientific community interested in accompanying the actions directed to the control of schistosomiasis in our country. Since then, the priority started to be the suppressing of the occurrence of advanced clinical forms, having as an objective, the detection and treatment of all carrier of Schistosoma mansoni. Beyond the control measures, factors that may interfere in the application of those measures were also studied, the diverse phases of field operations, the work methodology and results obtained in the first semester of 1991.


[Acute or toxemic form of schistosomiasis mansoni].

The acute or toxemic form of schistosomiasis mansoni is studied under the anatomic and clinical point of view, according to classification made by Neves, Raso and Bagliolo in 1975. The first phase is characterised by the following facts: cutaneous (immediate and late) manifestations; high fever or in progressive elevation; intense diaphoresis abdominal discomfort; intense aqueous diarrhea; dehydration; loss of weight, dry cough; painful hepatosplenomegaly; discreet lymphadenomegaly, progressive increase of blood leucocytes and eosinophiles; radiological pulmonary alterations; absence of alterations in serum protein and hepatic functional tests; the hepatic function biopsy shows focus of acute hepatitis. The second stage or properly named toxemic period was clinically characterized by the neat aggravation of the previously observed phenomena. At last, the evolutive course of the disease has implication derived not only the worm's presence, but from the intense dissemination of eggs in the tissue. In the pre-laying phase one studied the forms of cercarian dermatitis, prodromic and inapparent. In the post laying phase, the properly named acute toxemic form, with its types: pseudocholeraic, pseudotyphous, pseudodysenteric-bacillary, pseudonephritic, pseudoenterovirotic, the reactivated, the ischemic enterocolitis and others; whenever possible clinical and anatomic correlation will be made.


Parasitological diagnosis of schistosomiasis mansoni: fecal examination and rectal biopsy.

Even with all progress in the search of sensitive and specific methods for the immunological diagnosis of schistosomiasis, the microscopic detection of eggs of the parasite in the stool still remains the most widely used tool for the actual diagnosis of active infection. Among the coproscopic methods, Kato's technic modified by Katz et al (Kato/Katz) has the advantages of higher sensitivity, the possibility of egg quantification, its low operational cost and its feasibility in areas with minimal infra-structure. The oogram of the rectal mucosa is valuable in initial clinical trials of schistosomicides, when it is needed to observe egg morphology in tissue. It could be an alternative method for individual diagnosis, being more sensitive than a single stool exam in low intensity infection. However, the increased sensitivity of a higher number of fecal exams makes that invasive procedure unnecessary. In the assessment of cure of schistosomiasis, Kato/Katz method (three fecal samples in one, three and six months after treatment) and the rectal biopsy four months after treatment, are equally reliable.


[Immunodiagnosis of schistosomiasis mansoni].

In the last years, the knowledge about immunodiagnosis in schistosomiasis has increased considerably. This was due to a better immunologic understanding of the host-parasite interaction and the evolution of the technical procedures by the introduction of new concepts and techniques. The search of more sensitive, specific, practical and less expensive diagnostic tests has led to the development of a great number of immunological tests that could complement the limitations of the parasitological diagnosis. The antigens of different life cycle stages of Schistosoma mansoni may be used as target for immunodiagnostic tests and the anti-schistosome antibodies in the sera of infected patients can be detected. The research of circulating schistosome antigens, the production of specific antisera and the application of these antibodies in immunodiagnostic tests have also been discussed.


Pathogenesis of Schistosoma mansoni infection.

In this paper a discussion is made on the pathogenesis of schistosomiasis mansoni in mice, presented from the perspectives of "processes", "mediators", "strategies for study" and "disease". These concepts overlap considerably. Regarding "processes", granulomas, fibrosis and vasculitis are discussed. The role of mediators, including cells, antibodies and immune complexes, cytokines and distal mediators is commented as related to the pathological processes occurring in schistosomiasis. Finally, strategies for study are presented, followed by a discussion on the etiopathogenesis of the different clinical stages and pathologic manifestations of schistosomiasis mansoni.


[Schistosomiasis mansoni--drug treatment].

It is the specific treatment of mansoni schistosomiasis that aims to act directed on the parasite, through chemotherapy. Constitutes fundamental indication to the treatment of schistosomiasis active forms, that is, these determined by the presence of living eggs in the feces or in material from rectal biopsy, since eventual contra indications are respected. Two are the medicaments actually used: oxamniquine, used in the single dosage of 15 mg/kg, V.O. for adults and 20 mg/kg V.O. for children divided in two doses, offers a percentage of 30 to 40% of cures, evaluated by quantitative "oogram" and praziquantel, in the single dose of 60 mg/kg V.O., presents a cure index of 30%, however in sequential doses, of 60 mg/kg during 3 days or 30 mg/kg, 6 days, cure percentage is elevated to 95%, evaluated by oogram. The evaluation of the treatment by quantitative or qualitative examination methods does not show the same sensibility. The percentage of cure according to feces examination, the quantitative of Kato-Katz or the qualitative (sedimentation), showed indexes from 90 to 100%, for either one of the drugs, even in single dose, which evidences the difference of methodology of therapeutic evaluation. Tolerance to both medicaments is from good to regular, with collateral effects in 30 to 40% of the patients.


[Sclerotherapy of esophageal varices in schistosomiasis patients].

To assess the therapeutic possibilities of injection sclerosis in schistosomotic portal hypertension, a 5-year prospective study was conducted in northeast Brazil, where this parasitosis is endemic. Fifty patients undergoing endoscopy for upper gastrointestinal hemorrhage from rupture of esophageal varices from July through December 1981 were chosen for the study. The 32 consenting patients were submitted to injection sclerotherapy paravariceally, using ethanolamine oleate; the 18 refusing to participate were assigned to the control group. The incidence of rebleeding was 28.1% in the former and 44.5% in the latter, a difference which was not statistically significant (Fisher's test, p = 0.375). Mortality from rupture of esophageal varices was 3.1% in the sclerotherapy group and 27.7% in the control group, a statistically significant difference (Fischer's test, p = 0.017). Since sclerotherapy markedly improved the long-term survival rate of the patients, this procedure is advocated for the treatment of esophageal varices in cases of portal hypertension due to schistosomiasis.


[Critical evaluation of schistosomiasis portal hypertension surgery].

There are over 100,000 patients affected by schistosomotic portal hypertension, that may suffer rupture of the esophageal varices. Besides the portal hypertension, local factors must be emphasized as responsible for the three distal centimeters of the esophagus, called "zona vulnerável" (vulnerable zone). The better liver functional reserve of these schistosomotic patients as compared to the cirrhotic, present two favorable conditions: (1) better possibility of conservative treatment during acute hemorrhage; (2) elective surgical treatment may be undergo without a mandatory step of large portal decompression. The Author only indicate surgical treatment in patients with hemorrhage antecedent and his preference consist in splenectomy plus obliterative suture of the varices at the "vulnerable zone" and when possible, ligature of left gastric vein also; 358 patients were undergone surgery with operative mortality 3.07%; 347 were followed during 1 to 25 years; late mortality 8.38%; recurrence hemorrhage 11.58%; none porto-systemic encephalopathy was observed.


Influence of the host related factors in the development of the hepatosplenic form of schistosomiasis mansoni.

The frequency of hepatosplenomegaly in endemic areas is not proportional to the fecal ova count. This may be explained by epidemiological genetic. The occurrence of two or more cases of schistosomal hepatosplenomegaly in nuclear family is much higher than expected. The concentration is higher among siblings than it is among mothers and children of father and children. It is not significant between father and mother. If the mother, instead of the father, has hepatosplenic schistosomiasis the relative risk for the child to acquire hepatosplenomegaly is at least five times (the maternal affect). The inbreeding is higher in the hepatosplenic than in the hepato-intestinal patients. In some areas in Brazil the hepatosplenic form of the schistosomiasis mansoni occurs with much higher frequency in whites than in blacks. After treatment, reversion of hepatosplenic schistosomiasis occurs more frequently in non-whites. It seems that the resistance of blacks to the hepatosplenic form of schistosomiasis may be related to the glyoxalase system, perhaps associated to another genetic marker. The hepatosplenic schistosomiasis is less frequent in longilineal individuals. In some areas the hepatosplenic form of schistosomiasis is more frequent in A blood group of ABO system. The family heredograms do not suggest a single mendelian inheritance, but probably a multifactorial and possibly polygenic one.


Harmonization of research and control in schistosomiasis.

I have been employed by several different organizations during over 30 years working on schistosomiasis, the majority spent in endemic areas of the Caribbean, South America, Africa and the Western Pacific. Much of the work is best classified as applied research but sometimes it strayed to the extremes of either public health control programmes or pure research. Over this period, there have been several significant research developments that have altered our whole approach to control. Ideally, research and control should complement each other but, in reality, they sometimes have conflicting objectives. Public health workers understandably wish to provide immediate, short-term protection to the communities in their care, but research workers may, within ethical limits, reasonably want to observe untreated communities for extended periods in order to understand the underlying processes of transmission, disease pathogenesis and immunity to help develop more effective control measures. An example of this situation has occurred recently in Senegal where water development projects seem to have favoured the introduction and spread of Schistosoma mansoni in the Senegal River Basin. I have been asked to be the scientific consultant to the newly formed ESPOIR programme, linking European research organizations and the Senegal Ministry of Health, to reconcile the conflicting aims of public health workers, wishing to use whatever funds can be obtained for an immediate chemotherapy to try to eliminate the focus, at present confined to the vicinity of a relatively small, commercially run sugar irrigation scheme; and research workers who see a rare chance to study the development of immune mechanisms in a adults in a community not previously exposed to the infection.(ABSTRACT TRUNCATED AT 250 WORDS)


Parasite enzymes as a tool to investigate immune responses.

Previous evidences reported by us and by other authors revealed the presence of IgG in sera of Schistosoma mansoni-infected patients to immunodominant antigens which are enzymes. Besides their immunological interest as possible inductors of protection, several of these enzyme antigens might be also interesting markers of infection in antibody-detecting immunocapture assays which use the intrinsic catalytic property of these antigens. It was thus thought important to define some enzymatic and immunological characteristics of these molecules to better exploit their use as antigens. Four different enzymes from adult worms were partially characterized in their biochemical properties and susceptibility to react with antibodies of infected patients, namely alkaline phosphatase (AKP, Mg2+, pH 9.5), type I phosphodiesterase (PDE, pH 9.5), cysteine proteinase (CP, dithiothreitol, pH 5.5) and N-acetyl-beta-D-glucosaminidase (NAG, pH 5.5). The AKP and PDE are distinct tegumental membrane-bound enzymes whereas CP and NAG are soluble acid enzymes. Antibodies in infected human sera differed in their capacity to react with and to inhibit these enzyme antigens. Possibly, the specificity of the antibodies related to the extent of homology between the parasite and the host enzyme might be in part responsible for the above differences. The results are also discussed in view of the possible functional importance of these enzymes.


Protein-DNA associations in a gender-specific gene of Schistosoma mansoni: characterization by UV cross-linking, DNase I footprinting and band shift assays.

Protein extracts obtained from male and female schistosomes were incubated with a gender-specific gene, F-10, transcribed only in adult females and encoding a major egg-shell protein. The protein/DNA interaction was measured using the band shift, DNase-I-footprinting and UV cross-linking techniques. The results showed a clear band shift when a 302 bp restriction fragment containing the 3' end of the gene was incubated with either female or male proteins. This fragment also contained a putative steroid hormone regulatory element (HRE). In contrast, only the male proteins produced a shift with the 495 bp fragment corresponding to the middle region of the gene. DNase I footprinting showed that proteins from males and females interacted with the F-10 gene by binding to multiple adjacent sites along the DNA, thus generating relatively long protected fragments of approximately 100 bp. This result suggested that the adjacent binding of several moles of protein occurred at the 5' end of the gene. UV cross-linking between schistosome proteins and a 21 bp synthetic oligonucleotide containing the F-10 HRE, evidenced proteins having MWS of 30, 45 and 65 kDa. These proteins are presumably involved in the regulation of transcription of the F-10 gene.


The p53 gene expression and its developmental regulation in schistosomes.

We have studied the gene expression, especially of the oncoproteins, and its regulation in schistosomes. Schistosomes have a complex life cycle with a defined dimorphic lifestyle. The parasite are so far unique in biology in expressing oncogene products in their adult stage. In order to characterize the expression and developmental regulation, a lambda gt 11 cDNA library and lambda EMBL4 genomic DNA library of each growth stage of Schistosoma mansoni and S. japonicum was constructed, and was screened with various monoclonal antibodies against oncogene products. One positive plaque reacted to anti-p53 antibody (Ab-2, Oncogene Science, Inc.) was further analyzed. This fusion protein was about 120 KDa in molecular weights, and expressed as 1.4 Kb RNA in the adult stage. P53 gene is well-known as the negative regulator of the cell cycle, and the mutations in the gene are turning out to be the most common genetic alterations in human cancers. The comparison of the gene structure among species and stages were being conducted. Chromosome structures, C-band formation, and the results of in situ hybridization using the phage probe would be discussed.


The role of egg antigens, cytokines in granuloma formation in murine schistosomiasis mansoni.

The induction of granuloma formation by soluble egg antigens (SEA) of Schistosoma mansoni is accompanied by T cell-mediated lymphokine production that regulates the intensity of the response. In the present study we have examined the ability of SDS-PAGE fractionated SEA proteins to elicit granulomas and lymphokine production in infected and egg-immunized mice. At the acute stage of infection SEA fractions (< 21, 25-30, 32-38, 60-66, 70-90, 93-125, and > 200 kD) that elicited pulmonary granulomas also elicited IL-2, IL-4 lymphokine production. At the chronic stage a diminished number of fractions (60-66, 70-90, 93-125, and > 200 kD) were able to elicit granulomas with an overall decrease in IL-2, IL-4 production. Granulomas were elicited by larval-egg crossreactive and egg-specific fractions at both the acute and chronic stage of the infection. Examination of lymphokine production from egg-immunized mice demonstrated that as early as 4 days IL-2 was produced by spleen cells stimulated with < 21, 32-38, 40-46, 93-125, and > 200 kD fractions. By 16 days, IL-2 production was evoked by 8 of 9 fractions. IL-4 production at 4 days in response to all fractions was minimal while at 16 days IL-4 was elicited with the < 21, 25-30, 50-56, 93-125, and > 200 kD fractions. The present study reveals differences in the range of SEA fractions able to elicit granulomas and IL-2, IL-4 production between acute and chronic stages of infection.(ABSTRACT TRUNCATED AT 250 WORDS)