Improving patient access and choice: Assisted Bibliotherapy for mild to moderate stress/anxiety in primary care.

Current traditional methods of mental healthcare service delivery, based on 'specialists' providing 'outpatient appointments' for formal therapy, are often inappropriate for the needs of patients in primary care. The estimated numbers of adults with mental health problems are immense, and it is this, combined with Department of Health initiatives aimed at improving choice and access, which make it essential that new ways of delivering services are explored. This trial examines the use of an assisted self-help treatment package for mild to moderate stress/anxiety [Assisted Bibliotherapy (AB)] with an adult clinical population referred by their general practitioner. Assisted Bibliotherapy is a brief intervention (8 weeks), with limited therapist contact (20-min sessions). Non-parametric statistical testing of scores from the Zung Anxiety Scale and the Clinical Outcomes in Routine Evaluation (CORE) questionnaire indicated positive results. There was significant improvement at post-treatment, which was maintained at 3 month follow-up. The results from this trial and a previous trial of AB by Kupshik & Fisher in 1999, indicate that it is an effective treatment which could be used as part of a stepped care approach to managing and treating stress/anxiety in primary care.

Chemoprophylaxis against malaria in Papua New Guinea: a trial of amodiaquine and a combination of dapsone and pyrimethamine.

A placebo-controlled chemoprophylaxis trial was carried out in 1980 in 318 semi-immune school children in the Madang area of Papua New Guinea, where there was a high prevalence of strains of Plasmodium falciparum resistant to 4-aminoquinolines. Since prophylaxis with amodiaquine at 5 mg/kg weekly had failed, amodiaquine at a dose of 10mg/kg weekly and Maloprim (half a tablet or one tablet depending on body weight, which gave ranges of dapsone of 1.7-3.3mg/kg and pyrimethamine 0.2-0.4 mg/kg) weekly were tried. Neither regimen was completely successful in preventing parasitaemia, though after 13 weeks of prophylaxis the slide positivity rate was 16% for the amodiaquine group and 2% for the Maloprim group, which was in each case significantly lower than the normal baseline rate in the controls of 42%. Amodiaquine was completely successful in suppressing Plasmodium vivax infections. Breakthrough parasitaemia occurred, with either P. falciparum or P. vivax, in 5% of subjects on Maloprim at some time during the 13-week period of prophylaxis. Significantly more children in both the amodiaquine and Maloprim groups than in the placebo group showed a reduction in spleen size. All groups showed an unexplained fall in haemoglobin level over the study period but the fall was significantly less in both the prophylaxis groups. There was no adverse effect on white cell counts by either drug regimen. Chemoprophylaxis as a component of an integrated malaria control program should not be overlooked, provided that compliance can be maintained. However, in this particular case the principal purpose of the study had been to evaluate the proposed chemoprophylactic regimens in school children before embarking on an intervention study in young children. As a result of this study it was decided not to go ahead with the chemoprophylactic intervention in young children but to adopt an approach based on early presumptive treatment.

Characterisation of the host response to Plasmodium falciparum infection. I. Cerebral malaria.

Cerebral malaria is a major form of complicated malaria consequent upon cerebral damage associated with endothelial cell necrosis. We have used assays of Plasmodium falciparum growth inhibition in vitro to study serum inhibitory factors in patients with cerebral malaria. Serum from children with cerebral malaria inhibited parasite growth in a non-synchronised 72-hour assay to a greater extent than did sera from immune adults or asymptomatic children (p less than 0.001). The high level of non-specific inhibition of parasite growth was particularly evident when sera were tested against three P. falciparum isolates, and contrasted with the inhibitory effect of sera from non-malaria febrile controls. In this study, serum from patients with cerebral malaria was more inhibitory than serum from the other groups (p less than 0.001) and its between-isolate variation, when tested against a panel of P. falciparum isolates in growth assays, was significantly less than that of the other groups tested (p less than 0.005). These results are consistent with the hypothesis of toxin-induced endothelial cell damage, with the sequence of pathogenic events involving host-derived serum factors capable of damaging P. falciparum.

Characterisation of the host response to Plasmodium falciparum infection in acute non-complicated malaria.

In this study we have examined serum from patients with Plasmodium falciparum malaria, collected at the time of acute attack and 14 days later. We have also examined sequential samples of sera taken from children living in Madang Province, Papua New Guinea, an area endemic for malaria. The total amount of antibody directed against P. falciparum in acute phase sera was less than that found in matched controls. An in vitro assay measuring inhibition of penetration of uninfected erythrocytes by merozoites of P. falciparum revealed less inhibitory activity in acute phase sera than in matched controls. The longitudinal study of sera from village children demonstrated that non-specific inhibition of intracellular parasite growth was fairly stable, while merozoite inhibiting activity was unstable and varied with time. A cloned P. falciparum species has been used to directly demonstrate the specific growth enhancement by serum in vitro.

Pharmacokinetics of quinine in children.

Serum quinine concentrations were measured in seven children after intravenous infusion of quinine dihydrochloride, in eight children after intramuscular injection of quinine dihydrochloride, and in six children after nasogastric administration of a solution of quinine dihydrochloride. The mean (+/- SD) half-life of quinine was 11.1 +/- 4.8 hours, and the volume of distribution was 1.39 +/- 0.37 L/kg. To attain a serum level of 10 microgram/ml quinine, we suggest that children with severe malaria be given a loading dose of 20 mg/kg quinine dihydrochloride parenterally, followed by 7.5 mg/kg every 8 hours. Once recovery begins, quinine sulphate 10 mg/kg may be given orally every 8 hours. Serum concentrations should be monitored, if possible, because they vary greatly from person to person. Quinine is rapidly and completely absorbed after either intramuscular or nasogastric administration.

The development and ultrastructure of Plasmodium falciparum damaged in vitro by human "crisis" sera and by chloroquine.

P. falciparum malaria was cultured in vitro in the presence of sera from patients with cerebral malaria, meningitis and also after chloroquine administration. Intra-erythrocytic parasite damage was seen by light and electron microscopy. The significance of the results is discussed with relevance to non-specific immune mechanisms, and the damage induced by these mechanisms compared with that from chloroquine.

Specificities of antibodies boosted by acute Plasmodium falciparum infection in man.

In the search for antibodies correlating with host-protective immunity to Plasmodium falciparum in man, sera from individuals in Papua New Guinea were analyzed at the time of infection and in the convalescent period following infection. Titers of antibody were determined by enzyme linked immunoassay (ELISA), and the specificities of antibodies was examined by gel electrophoresis of immunoprecipitates. In the majority of cases, convalescence was associated with an increase in antibody titer and one-dimensional gel analysis of immunoprecipitated biosynthetically labeled parasite antigens demonstrated the variability in specificity of the antibody response in the two types of serum samples from different individuals. A protein of Mr 96,000 which has previously been identified as a candidate host-protective antigen was not clearly seen in immunoprecipitates generated with acute serum, even in samples with high titers of antibody assessed by ELISA. Antibodies to a protein Mr 96,000 were present in some, but not all convalescent sera. Two-dimensional gel analysis was more sensitive in detecting a boost in antibody response to minor antigens (e.g., an acidic protein Mr approximately equal to 230,000). This approach has not led to identification of antibody specificities to major antigens which are invariably boosted by infection and drug cure, but has identified antibody specificities in acute sera which are inadequate in quantity or quality to inhibit parasite growth.

Serum levels of quinine following intramuscular administration to children.

The serum quinine level was assayed in 31 children four hours after receiving an intramuscular injection of quinine dihydrochloride; in 14 children the level was also assayed 2 hours after the injection. The quinine was quickly absorbed from muscle, with serum quinine levels being significantly higher at 2 hours than at 4 hours. The injections were not particularly painful, and muscle necrosis was not observed. Quinine is rapidly absorbed following intramuscular injection, and is a safe and reliable method of administering the drug to children with severe malaria. In most situations in Papua New Guinea (PNG), intramuscular administration of quinine is preferable to intravenous infusion.

Cerebral malaria in children: a retrospective study of admissions to Madang Hospital, 1980.

A review was undertaken of sixty-eight children admitted with cerebral malaria to Madang Hospital, Madang, Papua New Guinea (PNG) in 1980. Children with cerebral malaria were significantly older than those with uncomplicated malaria, and older than children admitted with other conditions causing fits or coma. The nutritional status of children with cerebral malaria did not differ from that of children admitted with other diagnoses. The cerebrospinal fluid was normal in 80% of children with cerebral malaria, and in 20% mildly elevated protein or leukocytes were noted. Of the 68 children with cerebral malaria, four died (5.9%). This is a low mortality rate in comparison wih other centres in PNG and with reports from other countries.

Sulfadoxine-pyrimethamine for the treatment of acute malaria in children in Papua New Guinea. I. Plasmodium falciparum.

Chloroquine-resistant Plasmodium falciparum malaria is increasing in prevelance in Papua New Guinea and alternative therapies for acute malaria are being sought. A trial of sulfadoxine-pyrimethamine for the treatment of acute falciparum malaria in children has been carried out in Madang, Papau New Guinea. Eighty-five children were treated with sulfadoxine-pyrimethamine, either alone or in combination with a single 10 mg/kg dose of chloroquine. Of 78 children completing 28-days follow-up, treatment failures occurred in 15 (19.2%) and of these, 8 (10.3%), are believed to be sulfadoxine-pyrimethamine resistant; the others remain equivocal. There was no advantage in this study in combining a single dose of chloroquine with sulfadoxine-pyrimethamine; indeed, this combination was associated with an increased incidence of vomiting. It is argued that sulfadoxine-pyrimethamine should not become the standard presumptive treatment for acute malaria in Papua New Guinea.

Sulfadoxine-pyrimethamine for the treatment of acute malaria in children of Papua New Guinea. II. Plasmodium vivax.

In Papua New Guinea, Plasmodium falciparum and P. vivax are common causes of acute malaria in children and P. malariae an uncommon cause. The increasing prevelance of chloroquine-resistant strains of P. falciparum in Papua New Guinea has prompted the search for alternatives to chloroquine as standard presumptive treatment. Sulfadoxine-pyrimethamine, either alone or in combination with a single dose of chloroquine, was compared with chloroquine alone for treatment of acute vivax malaria in children in Madang. Fever resolution was slowest in the group treated with sulfadoxine-pyrimethamine alone, and time to clearance of parasitemia was significantly longer in this group (P less than 0.001). Where possible, species identification should be undertaken in acute malaria and cases of P. vivax treated with chloroquine.

Reduction in malaria parasite rate in young children by distribution of prophylactic amodiaquine through voluntary village workers.

In Madang Province PNG voluntary dispensers in 36 villages distributed weekly amodiaquine to young children over 12 month period (July 1977 - June 1978). The tablets were distributed each week for over 70% of the study period. The slide positive rate for malarial parasites was markedly reduced from 29% to 3.7%.

PIP: A pilot project was conducted in which 1300 young children received weekly amodiaquine from voluntary villages dispensers. The project involved 40 villages within a radius of 50 km of Madang town from June 1977-June 1978. The tablets were distributed each week for over 70% of the study period. In the treatment villages, the slide positive rate fell markedly and significantly after 12 months prophylaxis. All species showed the same significant response. The slide positive rates in the control villages failed to change significantly. In the treatment villages, the slide positive rate declined for all age groups but no change was recorded in the control villages. The reduction in parasite rate in the prophylaxis villages did not appear to be the result of the simultaneous spraying of DDT. In the prophylaxis villages, spraying had an effect, but it was not significant. In the sprayed villages, prophylaxis had a highly significant effect. In non-sprayed villages, prophylaxis had a highly significant effect. Of the children in the prophylaxis programs, 21% did not take the tablets on the Sunday prior to the 1978 blood collection and had a parasite rate of 5.4%. Of the children who took to prophylaxis on the preceding Sunday (79%), the parasite rate was 2.9%. For the July-December 1977 period, 929 children (62%) attended more than 80% of the time and 1197 children (79.9%) attended more than 60% of the time. The compliance did not deteriorate as the trial progressed; median compliance was slightly higher in the 2nd 6 months (78%) than in the 1st 6 months (75%). The Madang program has 2 phases: the 1st phase protected children (0-5 years) from malaria by prophylaxis; the 2nd phase will be the provision of rapid access to treatment doses of antimalarials for older children. In sum, the study results show that young children in villages with voluntary village dispensers had a marked fall in parasite rates and in spleen rates.

Studies on malaria in Papua New Guinea: comparison of the surface glycoproteins on red blood cells from infected and uninfected individuals.

The levels of erythrocyte membrane sialic acid from 17 patients with Plasmodium falciparum malaria and 1 with Plasmodium vivax malaria, in Papua New Guinea, have been compared with 9 uninfected controls. The amounts of radioactivity incorporated into the major erythrocyte glycoproteins by the periodate/NaB3H4 or galactose oxidase plus neuraminidase/NaB3H4 methods were unchanged by malaria infection. The electrophoretic mobilities of these proteins also were unaffected. Several new glycoprotein bands with molecular weights (mol. wt) of 160,000, 89,000, 46,000, 42,000 and 33,000 Daltons were labelled on the surface of erythrocytes from infected individuals; however, none of these bands appeared in all malarious samples. Sialic acid levels on the erythrocyte membrane were also measured by exhaustive neuraminidase treatment and quantitative assay of released sialic acid. The amount of sialic acid was raised in 1 infected individual, within the normal range for Europeans in 4 others, and below this range with 3 patients. Apparently, extensive removal or modification of sialic acid on the surface of uninfected erythrocytes does not occur in human malaria, in contrast to the results obtained in earlier studies with the lethal murine malarias.

Acute malaria in children in Madang: endemicity, clinical presentation and treatment.

Much of the present knowledge of the status of malaria in Papua New Guinea stems from a few studies carried out in the past. In the present situation there are many areas of uncertainty not least the effects of poor acceptance of residual spraying programmes and the emergence of chloroquine-resistant falciparum malaria. New anti-malarials are being developed, new methods of vector control may become useful and immunization may soon become possible. In order to assess the impact of these measures it is essential that they are studied in an area with a well defined population and where the current epidemiological situation is known.

Immunoprecipitation of biosynthetically-labelled proteins from different Papua New Guinea Plasmodium falciparum isolates by sera from individuals in the endemic area.

The human serum antibody response to Plasmodium falciparum infection in Papua New Guinea has been studied by electrophoretic analysis of immunoprecipitated biosynthetically-labelled malaria proteins from three different isolates maintained in long-term in vitro culture. Differences in protein antigenic composition in different lines have been described and simplified by examination of antigens recognized only by hyperimmune serum. An in vitro assay has been used to screen various human sera containing antimalarial antibody for their ability to inhibit parasite growth and the immunoprecipitation profiles of non-inhibitory sera have been compared with those of a hyperimmune serum pool. In the discussion, emphasis is placed on the value of immunoprecipitation analyses using clinically-defined sera with known in vitro function in the identification of antigens which may be responsible for the induction of host-protective immunity.