The sick placenta-the role of malaria.

The human placenta is an ideal site for the accumulation of Plasmodium falciparum malaria parasites, and as a consequence serious health problems arise for the mother and her baby. The pathogenesis of placental malaria is only partially understood, but it is clear that it leads to a distinct epidemiological pattern of malaria during pregnancy. The objectives of this review are: (1) To review recent data on the epidemiology of malaria in pregnancy, with emphasis on placental malaria; (2) to describe the pathological changes and immunological factors related to placental malaria; and (3) to discuss briefly the functional consequences of this infection for the mother and her baby. The review attempts to bring together local events at the maternal-fetal interface which encompass immunological and pathological processes which relate to the epidemiological pattern of malaria in pregnancy in areas of both high and low malaria transmission. An integrated understanding of the epidemiological, immunological and pathological processes must be achieved in order to understand how to control malaria in pregnancy. The yearly exposure of at least 50 million pregnancies to malaria infection makes it the commonest and most recurrent parasitic infection directly affecting the placenta. These statistics and our limited understanding of its pathogenesis suggest the research priorities on this subject.

Haematological profiles of the people of rural southern Malawi: an overview.

An integrative review of the results of two published and two unpublished studies of anaemia in children, adolescent females, pregnant women and adults living in southern Malawi is presented. Anaemia was universally present in all age-groups, with the higher prevalences in infants (100%) and adolescent primigravidae (93.8%). Nutritional deficits of iron and vitamin A were major contributory factors but chronic malarial haemolysis also significantly contributed to the anaemia. Among boys, anaemia was more common among those with glucose-6-phosphate-dehydrogenase (G6PD) deficiency than in those without this deficiency (P<0.002). This enzymopathy, which occurred in 23.5% [95% confidence interval (CI)=16.7%-30.1%] of the male and 30% (CI=17.3%-42.7%) of the female infants examined, was also associated with neonatal jaundice. The overall prevalences of the-alpha(3.7)/alphaalpha and -alpha(3.7)/-alpha(3.7) thalassaemia genotypes were estimated at 41.0% (CI=28.3%-53.7%) and 8.7% (CI=1.5%-15.9%), respectively. Haemoglobin AS was present in 18.1% (CI=12.8%-23.4%) of the infants and haemoglobin SS in 2.5% (CI=1.4%-3.6%). As the prevalence of infection with Plasmodium falciparum was significantly higher in infants with haemoglobin AS than in those with AA (21.4% v. 6.7%; P<0.001), an increased risk of early-onset moderate parasitaemias in young infants probably stimulates the development of immunity, protecting older heterozygotes from severe malarial infection. Innovative community approaches are required to break the cycle of ill health that anaemia supports in those living in rural areas of southern Malawi. Interventions in adolescent girls could be of particular importance, as they could break the cycle in both pregnant women and their infants.

Identification of neonatal hearing impairment: a multicenter investigation.

OBJECTIVES: This article describes the design of a multicenter study sponsored by the National Institutes of Health. The purpose of this study was to determine the accuracy of three measures of peripheral auditory system status (transient evoked otoacoustic emissions, distortion product otoacoustic emissions, and auditory brain stem responses) applied in the perinatal period for predicting behavioral hearing status at 8 to 12 mo corrected age. The influences of the infant's medical status, the test environment, and test and response parameters on test performance were examined. DESIGN: Seven institutions participated in this study. There were 7179 infants evaluated in the perinatal period. All graduates of the neonatal intensive care unit (4478) and well babies with one or more risk factor for hearing loss (353) were targeted for follow-up testing using visual reinforcement audiometry (VRA) at 8 to 12 mo corrected age. Well babies without any risk indicators (N = 2348) were not targeted for follow-up VRA testing. However, 80 of these well babies did not pass the screening protocol and thus were targeted for follow-up VRA testing as well. Perinatal test performance was evaluated using the VRA data as the "gold standard." RESULTS: The results of this study are described in a series of 11 articles following this introductory article. CONCLUSIONS: The evaluation of newborn hearing tests required a longitudinal study in which newborn test results were compared with a gold standard based on behavioral audiometric assessment. Such an evaluation was possible because all newborns, passes as well as refers, were followed up long enough to permit reliable behavioral measurements. In addition, prenatal, perinatal, and maternal history information, test environment, and test parameter information were collected to provide data that led to a complete description of factors affecting test outcomes. All of these data were obtained in a sample of sufficient ethnic, medical, and geographic diversity in efforts to increase the generalizability of the results. Finally, the data were combined in a relational data base to examine the factors that influence test performance. Specific information related to these issues is presented in the articles that follow.

Identification of neonatal hearing impairment: transient evoked otoacoustic emissions during the perinatal period.

OBJECTIVES: 1) To describe transient evoked otoacoustic emission (TEOAE) levels, noise levels and signal to noise ratios (SNRs) for a range of frequency bands in three groups of neonates who were tested as a part of the Identification of Neonatal Hearing Impairment multi-center consortium project. 2) To describe the relations between these TEOAE measurements and age, test environment, baby state, and test time. DESIGN: TEOAEs were measured in 4478 graduates of neonatal intensive care units (NICUs), 353 well babies with at least one risk indicator, and 2348 well babies without risk factors. TEOAE and noise levels were measured for frequency bands centered at 1.0, 1.5, 2.0, 3.0, and 4.0 kHz for a click stimulus level of 80 dB SPL. For those ears not meeting "passing" stopping criteria at 80 dB pSPL, a level of 86 dB pSPL was included. Measurement-based stopping rules were used such that a test did not terminate unless the response revealed a criterion SNR in four out of five frequency bands or no response occurred after a preset number of averages. Baby state, test environment, and other test factors were captured at the time of test. RESULTS: TEOAE levels, noise levels and SNRs were similar for NICU graduates, well babies with risk factors and well babies without risk factors. There were no consistent differences in response quality as a function of test environment, i.e., private room, unit, open crib, nonworking isolette, or working isolette. Noise level varied little across risk group, test environment, or infant state other than crying, suggesting that the primary source of noise in TEOAE measurements is infant noise. The most significant effect on response quality was center frequency. Responses were difficult to measure in the half-octave band centered at 1.0 kHz, compared with higher frequencies. Reliable responses were measured routinely at frequencies of 1.5 kHz and higher. CONCLUSIONS: TEOAEs are easily measured in both NICU graduates and well babies with and without risk factors for hearing loss in a wide variety of test environments. Given the difficulties encountered in making reliable measurements for a frequency band centered at 1.0 kHz, its inclusion in a screening program may not be justified.

Identification of neonatal hearing impairment: summary and recommendations.

OBJECTIVES: This article summarizes the results of a multi-center study, "Identification of Neonatal Hearing Impairment," sponsored by the National Institutes of Health. The purpose of this study was to determine the performance characteristics of three measures of peripheral auditory system status, transient evoked otoacoustic emissions (TEOAEs), distortion product otoacoustic emissions (DPOAEs), and auditory brain stem responses (ABR), applied in the neonatal period in predicting hearing status at 8 to 12 mo corrected age. DESIGN: The design and implementation of this study are described in the first two articles in this series. Seven institutions participated in this study; 7179 infants were evaluated. Graduates of the neonatal intensive care unit and well babies with one or more risk factors for hearing loss were targeted for follow-up testing using visual reinforcement audiometry (VRA) at 8 to 12 mo corrected age. Neonatal test performance was evaluated using the VRA data as the "gold standard." RESULTS: The major results of the study are described in the nine articles preceding this summary article. TEOAEs in response to an 80 dB pSPL click, DPOAEs in response to L1 = 65 and L2 = 50 dB SPL and ABR in response to a 30 dB nHL click performed well as predictors of permanent hearing loss of 30 dB or greater at 8 to 12 mo corrected age. All measures were robust with respect to infant state, test environment and infant medical status. No test performed perfectly. CONCLUSIONS: Based on the data from this study, the 1993 National Institutes of Health Consensus Conference-recommended protocol-an OAE test followed by an ABR test for those infants failing the OAE test-would result in low referral rate (96 to 98%). TEOAEs for 80 dB pSPL, ABR for 30 dB nHL and DPOAEs for L1 = 65 dB SPL and L2 = 50 dB SPL perform well in predicting hearing status based on the area under the relative operating characteristic curve. Accuracy for the OAE measurements are best when the speech awareness threshold or the pure-tone average for 2.0 kHz and 4 kHz are used as the gold standard. ABR accuracy varies little as a function of the frequencies included in the gold standard. In addition, 96% of those infants returning for VRA at 8 to 12 mo corrected age were able to provide reliable ear-specific behavioral thresholds using insert earphones and a rigorous psychophysical VRA protocol.

Spectrochemical investigations of fluorescence quenching agents. Part 5. Effect of surfactants of the ability of nitromethane to selectively quench fluorescence emission of alternant PAHs.

Applicability of the nitromethane selective quenching rule for discriminating between alternant vs. nonalternant polycyclic aromatic hydrocarbons (PAHs) is examined for 18 representative PAH solutes dissolved in micellar cetyltrimethylammonium chloride (CTACl), micellar dodecyltrimethylammonium bromide (DTAB), micellar Brij-35 and micellar sodium octanoate (SO) solvent media. Experimental results show that nitromethane quenched fluorescence emission of only the 10 alternant PAHs in the two cationic (CTACl and DTAB) and nonionic Brij-35 surfactant solvent media as expected. Emission intensities of nonalternant PAHs, except for the few exceptions noted previously, were unaffected by nitromethane addition. Unexpected quenching behavior was observed, however, in the case of nonalternant PAHs dissolved in micellar sodium octanoate solvent media. Nitromethane quenched fluorescence emission of all nonalternant PAHs studied in the SO solvent media, which is contrary to the selective quenching rule.

Clinical and echocardiographic features of intermittent atrial fibrillation that predict recurrent atrial fibrillation. Stroke Prevention in Atrial Fibrillation (SPAF) Investigators.

In addition to antithrombotic therapy, 2 treatment strategies for intermittent atrial fibrillation (AF) are evolving: suppression of AF or control of the ventricular response during AF. Clinical and echocardiographic features that predict recurrent AF may influence the choice of management. In this study, clinical, echocardiographic, and electrocardiographic data from 486 patients with intermittent AF enrolled in the Stroke Prevention in Atrial Fibrillation studies were analyzed. Patients with intermittent AF were younger (p < 0.001), had fewer incidences of systemic hypertension (p < 0.007) and heart failure (p < 0.001), and had more recent-onset AF than patients with constant AF. They also had a smaller mean left atrial diameter, a lower prevalence of a large (> 5 cm) left atrium, better left ventricular performance by echo, and less mitral regurgitation. After a mean follow-up of 26 months, 51% of patients remained in sinus rhythm and 49% of patients developed recurrent AF, including 12% who had AF, as seen on all follow-up electrocardiograms. Clinical factors predicting recurrent AF were age, heart failure, and myocardial infarction. An enlarged left atrium was associated with recurrent intermittent AF; an enlarged left ventricle predicted conversion to constant AF. Thus, clinical and echocardiographic parameters predict recurrent AF in patients with intermittent nonvalvular AF.

Blood glucose levels in Malawian children before and during the administration of intravenous quinine for severe falciparum malaria.

Hypoglycemia may develop in patients with severe untreated malaria and can complicate the course of treatment with parenteral quinine as a result of quinine-induced hyperinsulinemia. Intravenous quinine is used increasingly as the therapy of choice in patients with severe malaria, most of whom are children. To assess the importance of both pretreatment and quinine-related hypoglycemia in children in an area in which the disease is endemic, we prospectively studied 95 Malawian children with falciparum malaria and altered consciousness who were treated with intravenous quinine. Nineteen patients had hypoglycemia before treatment. Seven (37 percent) died, and five of the survivors (26 percent) had neurologic sequelae. The corresponding values for patients who were initially normoglycemic were 4 percent and 4 percent, respectively (P less than 0.0001). Hypoglycemia was associated with low plasma insulin concentrations and with elevated plasma concentrations of lactate, alanine, and 5'-nucleotidase--a finding that suggests that impaired hepatic gluconeogenesis but not hyperinsulinemia contributes to the pathogenesis of pretreatment hypoglycemia. All patients were given quinine dihydrochloride in a 5 percent dextrose infusion, and those with hypoglycemia received 50 percent dextrose. Hypoglycemia recurred in seven of the patients with pretreatment hypoglycemia, but these episodes were also not associated with hyperinsulinemia. Of the 76 children who were initially normoglycemic, none became hypoglycemic during the course of treatment with intravenous quinine. We conclude that hypoglycemia is a frequent complication of falciparum malaria in children and that it reflects severe disease and is associated with a poor prognosis. We did not find it to be a complication of quinine treatment.

Current pharmacologic management of narcolepsy.

Narcolepsy is an incurable sleep disorder characterized by attacks of sleepiness and a series of auxiliary symptoms: cataplexy, sleep paralysis and hypnagogic hallucinations. Classic treatment has included stimulants to control sleepiness and tricyclic antidepressants to control the auxiliary symptoms. Polysomnography is necessary to confirm the diagnosis and to detect other sleep disorders. Recent developments in treatment include the use of codeine for sleepiness and gamma-hydroxybutyrate for auxiliary symptoms.

Studies on the mechanisms of oxidation in the erythrocyte by metabolites of primaquine.

The interaction of certain metabolites of the 8-aminoquinoline antimalarial primaquine with both normal and glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes and with haemoglobin preparations was studied in an attempt to elucidate the mechanisms of methaemoglobin formation and haemolytic anaemia associated with the use of primaquine. Studies using erythrocytes revealed that oxidation of haemoglobin and reduced glutathione (GSH) was due to the metabolites rather than the parent drug. Incubation of free haemoglobin with 5-hydroxylated metabolites of primaquine also led to oxidation of oxyhaemoglobin and GSH. Oxidation of GSH also occurred in the absence of oxyhaemoglobin. The results suggest a dual mechanism for these oxidative effects, involving autoxidation of the 5-hydroxy-8-aminoquinolines and their coupled oxidation with oxyhaemoglobin. The initial products of these processes would be drug metabolite free radicals, superoxide radical anions, hydrogen peroxide and methaemoglobin. Further free radical reactions would lead to oxidation of GSH, more haemoglobin and probably other cellular constituents. NADPH had no effect on the oxidative effects of the primaquine metabolites in these experiments. In the G6PD-deficient erythrocyte, the oxidation of haemoglobin and GSH leads to Heinz body formation and eventually to haemolysis, the mechanisms of which are as yet unclear. The possible role of oxygen free radicals in the mode of action of 8-aminoquinolines against the malaria parasite is also briefly discussed.

The pharmacokinetics of proguanil in human subjects following a single oral dose.

The pharmacokinetics of orally administered 200-mg dose of proguanil in volunteers, one African and one Caucasian, is described. The drug was rapidly absorbed reaching a peak concentration in the blood within 3 h, and declining slowly thereafter to give a terminal phase elimination half life of 11.20 +/- 4.10 h and a systemic clearance of 1.270 +/- 0.020 l/h/kg. The small apparent volume of distribution shows that the drug is confined mainly to the blood and is not extensively bound to tissues; it undergoes cyclic oxidation in the liver to cycloguanil--the active metabolite responsible for antimalarial activity. Cycloguanil was detected in the plasma 3 h after proguanil ingestion and reached peak concentration between 5 h and 6 h. Excretion of proguanil was rapid, 60% of the single dose passing through the renal system within 24 h.

Carbohydrate metabolism of malarial parasites--I. Metabolism of lactate in Plasmodium knowlesi infected monkey erythrocytes.

Lactate metabolism by Plasmodium knowlesi infected erythrocytes was examined after careful removal of leucocytes from cell preparations. Infected cells were able to metabolize glucose, pyruvate and lactate. Respiration of infected erythrocytes was maximally stimulated by lactate and to a lesser degree by pyruvate and glucose. Respiration of infected cells was insensitive to stimulation by succinate or glutamate or inhibition by malonate. Mepacrine was found to be a potent respiratory inhibitor. Chromatographic analysis of end products of lactate metabolism showed incorporation of carbon from [2-C14]lactate into phosphoenol pyruvate, 3-phosphoglycerate and malate. Experimental data failed to provide evidence for the presence of a functional citric acid cycle activity in infected cells.