Molecular genetics: Bloodthirsty amazons?
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Aedes↗
Biomedical subjects
M J Donnelly
Publications and source records attributed to M J Donnelly.
Co-occurrence of East and West African kdr mutations suggests high levels of resistance to pyrethroid insecticides in Anopheles gambiae from Libreville, Gabon.
Point mutations in the voltage-gated sodium channel gene involved in knockdown resistance to DDT and pyrethroid insecticides have been described in several insect species. In the malaria vector Anopheles gambiae Giles sensu stricto (Diptera: Culicidae) two mutations have been identified. The first, consisting of a leucine-phenylalanine substitution at amino acid position 1014, is widespread in West Africa. The second, a leucine-serine substitution at the same position, has to date only been detected in western Kenya. Analysis of the kdr polymorphism in a sample of 106 An. gambiae s.s. of the rDNA S-form/Type I collected in Libreville (Gabon) surprisingly revealed the presence of both East and West African kdr mutations with frequencies of 63% and 37%, respectively. No wild-type alleles were detected and there was an excess of heterozygous genotypes (P = 0.04). In addition, an inconsistency was found during the kdr genotyping procedures by polymerase chain reaction, which could have lead to an underestimation of resistance alleles. The implications of these findings are discussed.
Animals↗
Revisiting the role of introgression vs shared ancestral polymorphisms as key processes shaping genetic diversity in the recently separated sibling species of the Anopheles gambiae complex.
The role of interspecific hybridisation in the evolution of pest species is poorly understood. In mosquito disease vectors this is of particular importance due to the evolution of insecticide resistance and the proposed release of transgenic strains that are refractory to the malaria parasite. In this study, we apply population genetic methods in a novel manner to determine whether mitochondrial DNA sequences have introgressed between the closely related African malaria vectors Anopheles gambiae and A. arabiensis. Our results suggest that speciation was geologically recent and ancestral haplotypes at the ND5 locus are retained in both species. In addition, comparing haplotype frequencies in allopatric and sympatric populations, suggest locale specific unidirectional introgression of mitochondria from A. arabiensis into A. gambiae.
Africa↗
Species abundance and insecticide resistance of Anopheles gambiae in selected areas of Ghana and Burkina Faso.
The Ghanaian National Malaria Control Programme has prioritized insecticide-treated materials as a key strategy for malaria control. We report on a survey of the distribution of the molecular forms of Anopheles gambiae Giles (Diptera: Culicidae) and insecticide resistance (the kdr mutation), carried out by sampling mosquitoes from 11 locations in Ghana and one additional site in Burkina Faso. The molecular M and S forms of An. gambiae were found to occur in sympatry in southern Ghana. The S form predominated throughout its distribution in the coastal savannah, except at one location in the strand and mangrove zone where rice was cultivated. The M form was the only form collected in northern Ghana and was the predominant form (97.5%) in Burkina Faso. No M/S hybrids were detected. The kdr mutation was observed at very high frequencies (98-100%) within the S form but reached a maximum of only 3.38% in the M form in one population at an irrigation scheme in the Ghanaian coastal savannah zone.
Animals↗
An island within an island: genetic differentiation of Anopheles gambiae in São Tomé, West Africa, and its relevance to malaria vector control.
Islands are choice settings for experimental studies of vector control strategies based on transgenic insects. Before considering this approach, knowledge of the population structure of the vector is essential. Genetic variation at 12 microsatellite loci was therefore studied in samples of the malaria vector Anopheles gambiae s.s., collected from six localities of São Tomé island (West Africa). The objectives were (i) to assess the demographic stability and effective population size of A. gambiae from these sites, (ii) to determine population differentiation and (iii) to relate the observed patterns of population structure with geographic, ecological and historical aspects of the vector on the island. Significant population differentiation, revealed by FST and RST statistics, was found between the southernmost site, Porto Alegre, and northern localities. The observed patterns of population substructure are probably a result of restrictions to gene flow in the less inhabited, more densely forested and mountainous south. In all localities surveyed, A. gambiae appeared to be experiencing a demographic expansion, consistent with a relatively recent (ca. 500 years) founder effect. The results are discussed with respect to current and future prospects of malaria vector control.
Africa, Western↗
Genetic structure of Anopheles gambiae (Diptera: Culicidae) in São Tomé and Príncipe (West Africa): implications for malaria control.
The impact of a vector eradication programme, conducted in the 1980s, on Anopheles gambiae populations from the islands of São Tomé and Príncipe, was evaluated by microsatellite DNA analysis. Significant genetic differentiation was observed within and between the two islands and between the islands and a population from Gabon, suggesting a degree of isolation between them. Large estimates of long-term N(e) suggested that the control programme did not affect the effective population size of the vector. Heterozygosity tests were also not consistent with a recent bottleneck.
Africa, Western↗
Evidence for recent population expansion in the evolutionary history of the malaria vectors Anopheles arabiensis and Anopheles gambiae.
Gene flow in malaria vectors is usually estimated based on differentiation indices (e.g., F(ST)) in order to predict the contemporary spread of genes such as those conferring resistance to insecticides. This approach is reliant on a number of assumptions, the most crucial, and the one most likely to be violated in these species, being mutation-migration-drift equilibrium. Tests of this assumption for the African malaria vectors Anopheles gambiae and Anopheles arabiensis are the focus of this study. We analyzed variation at 18 microsatellite loci and the ND5 region of the mitochondrial genome in two populations of each species. Equilibrium was rejected by six of eight tests for the A. gambiae population from western Kenya and by three tests in eastern Kenya. In western Kenya, all departures from equilibrium were consistent with a recent population expansion, but in eastern Kenya, there were traces of a recent expansion and a bottleneck. Equilibrium was also rejected by two of the eight tests for both A. arabiensis populations; the departure from equilibrium was consistent with an expansion. These multiple-locus tests detected a genomewide effect and therefore a demographic event rather than a locus-specific effect, as would be caused by selection. Disequilibrium due to a recent expansion in these species implies that rates of gene flow, as inferred from differentiation indices, are overestimates as they include a historical component. We argue that the same effect applies to the majority of pest species due to the correlation of their demography with that of humans.
Africa↗
Macrofilaricidal activity of tetracycline against the filarial nematode Onchocerca ochengi: elimination of Wolbachia precedes worm death and suggests a dependent relationship.
Filarial nematodes are important and widespread parasites of animals and humans. We have been using the African bovine parasite Onchocerca ochengi as a chemotherapeutic model for O. volvulus, the causal organism of 'river blindness' in humans, for which there is no safe and effective drug lethal to adult worms. Here we report that the antibiotic, oxytetracycline is macrofilaricidal against O. ochengi. In a controlled trial in Cameroon, all adult worms (as well as microfilariae) were killed, and O. ochengi intradermal nodules resolved, by nine months' post-treatment in cattle treated intermittently for six months. Adult worms removed from concurrent controls remained fully viable and reproductively active. By serial electron-microscopic examination, the macrofilaricidal effects were related to the elimination of intracellular micro-organisms, initially abundant. Analysis of a fragment of the 16S rRNA gene from the O. ochengi micro-organisms confirmed them to be Wolbachia organisms of the order Rickettsiales, and showed that the sequence differed in only one nucleotide in 858 from the homologous sequence of the Wolbachia organisms of O. volvulus. These data are, to our knowledge, the first to show that antibiotic therapy can be lethal to adult filariae. They suggest that tetracycline therapy is likely to be macrofilaricidal against O. volvulus infections in humans and, since similar Wolbachia organisms occur in a number of other filarial nematodes, against those infections too. In that the elimination of Wolbachia preceded the resolution of the filarial infections, they suggest that in O. ochengi at least, the Wolbachia organisms play an essential role in the biology and metabolism of the filarial worm.
Animals↗
Evidence for extensive genetic differentiation among populations of the malaria vector Anopheles arabiensis in Eastern Africa.
We describe the geographical population structure of the malaria vector Anopheles arabiensis in Eastern Africa. Allelic variation at eight microsatellite loci was scored in samples from nine localities along a 4500 km transect from Sudan to Mozambique. Highly significant differences in genotype frequencies were found between all populations separated by more than 200 km. Populations within Malawi separated by 191 km were indistinguishable, as were those within Sudan separated by 134 km. FST and rhoST gave significant estimates of isolation by distance. These data, lead us to conclude that there are extensive barriers to gene flow in this region. The high estimates of Nm (9.4 from FST and 5.2 from rhoST) indicate recent range expansion in this species rather than extensive contemporary gene flow.
Africa, Eastern↗
Head and neck schwannomas--a 10 year review.
Schwannomas of the head and neck are uncommon tumours that arise from any peripheral, cranial or autonomic nerve. Twenty-five to 45 per cent of extracranial schwannomas occur in the head and neck region and thus are usually in the domain of the otolaryngologist. They usually present insidiously and thus are often diagnosed incorrectly or after lengthy delays, however, better imaging and cytological techniques have lessened this to some degree more recently. For benign lesions conservative surgical excision is the treatment of choice bearing in mind possible vagal or sympathetic chain injury. Malignant schwannomas are best treated with wide excision where possible. The role of adjuvant therapy remains uncertain and irrespective of treatment modality prognosis is poor with an overall survival of 15 per cent. However, recent advances in ras oncogene inhibitors may hold hope for the future.
Adult↗
Population structure in the malaria vector, Anopheles arabiensis patton, in East Africa.
The population structure of the malaria vector Anopheles arabiensis was investigated using data from six microsatellite loci in samples from localities in Mozambique and Tanzania. Genotype frequencies were neither significantly different between houses in a village in Tanzania nor between villages within a 20-km radius in Mozambique. Thus a deme has an area greater than 20 km in radius. At five of the six loci the heterozygosity of the population from Mozambique was lower than that from Tanzania, implying a lower effective population size (Ne) at this southern edge of the species range. There were significant differences in genotype frequencies between the Tanzanian and Mozambique populations at five of the six loci (P<0.05). Values for both FST (mean=0.069) and RST (mean=0.025) were significantly different from zero (P<0.05) at four and three out of five loci, respectively, but there was no significant correlation between the two statistics. The wide variation in values of FST and RST across loci suggests that care should be taken in interpreting values derived from averaging across loci. Whether the variation results from sampling effects or selectional constraints on some loci is unclear. Although there is evidence for significant differentiation between these populations, estimates of gene flow (Nm) calculated from mean FST and RST statistics were relatively high, 3.4 and 4.9, respectively. We argue that this is more likely to reflect recent separation of these populations and/or large effective population size rather than large-scale present day migrations.
Animals↗
Second malignancies in patients treated for childhood acute lymphoblastic leukemia.
PURPOSE: Second malignant neoplasms (SMN) are devastating late complications of childhood acute lymphoblastic leukemia (ALL) and its treatment. We evaluated the incidence and type of SMN diagnosed before leukemic relapse in a large series of patients with ALL. PATIENTS AND METHODS: We reviewed the outcome of all patients treated for childhood ALL between 1972 and 1995 on Dana-Farber Cancer Institute (DFCI) and DFCI ALL Consortium protocols. The follow-up time from diagnosis of ALL to induction failure, relapse, remission death, or SMN, whichever occurred first, ranged from 0 to 24.0 years (median, 7.6 years; mean, 6.7 years). RESULTS: Thirteen SMNs were diagnosed among 1,597 patients. Eight tumors occurred in a radiation field (five in the CNS and three in the head and neck), two occurred outside of a radiation field (one adenocarcinoma of the sigmoid colon and one epithelioid sarcoma of the chest wall), and three were hematopoietic malignancies. The median time to occurrence was 6.7 years (range, 1.0 to 17.2 years) and the cumulative incidence of second malignancy before another first event was 2.7% (95% confidence interval, 0.7 to 4.7). The risk of a first event, which included induction failure, relapse, or remission death, was 31.0% (95% confidence interval, 28.5 to 33.5). CONCLUSION: We found a more than 10-fold risk of other first events when compared with SMN. Thus, we conclude that SMN before first relapse is a relatively uncommon occurrence among survivors of childhood ALL. Future therapeutic regimens must focus on reducing leukemia relapse and enhancing quality of life, as well as preventing SMNs.
Child↗
Intensified therapy for infants with acute lymphoblastic leukemia: results from the Dana-Farber Cancer Institute Consortium.
BACKGROUND: Infants with acute lymphoblastic leukemia (ALL) have a very poor prognosis. Since 1985, we have intensified therapy for infants with ALL by including a month of high dose multiagent chemotherapy after remission induction. METHODS: Between 1985 and 1995, we treated 23 infants (age < 12 months). We compared the presenting characteristics and outcomes of these infants with the 11 infants treated on our protocols between 1973 and 1985, an era prior to the intensification of therapy. Available bone marrow samples from infants treated since 1985 were analyzed for the presence of MLL gene rearrangements by Southern blot analyses and for TEL-AML1 gene fusion by reverse transcriptase-polymerase chain reaction. RESULTS: With a median follow-up of 5.6 years, the 50-month event free survival (EFS) (+/- standard error) for the 23 infants was 54 +/- 11%, a significant improvement (P = 0.001) compared with the outcome for the 11 infants treated on our protocols prior to 1985 (EFS = 9 +/- 9%). Of the seven infants found to have a rearranged MLL gene, three (43%) remained in first complete remission. None of the nine infant bone marrow specimens tested had evidence of TEL-AML1 gene fusion. The intensified therapy was complicated by a high incidence of infections, including septicemia in 52% of patients and Pneumocystis carinii pneumonitis in 22% of patients. Late effects identified in the 13 long term survivors (median age, 6 years) included developmental delay and learning disabilities of varying severity (82% of evaluable patients), asymptomatic cataracts (67%), asymptomatic echocardiographic abnormalities (30%), obesity (27%), and short stature (18%). CONCLUSIONS: Intensification of therapy significantly improved the EFS of infants with ALL compared with previous, less intensive regimens and with the experience of other investigators. Future treatment for infants should attempt to improve efficacy while minimizing toxicity.
Antineoplastic Combined Chemotherapy Protocols↗
Tonsillitis, tonsillectomy and weight disturbance.
To determine the relationship between tonsillitis, tonsillectomy and abnormalities in body weight, we have analyzed pre- and post-operative weights in a population of 55 children who underwent adenotonsillectomy in our department. Pre-operative mean weight was 9.8% heavier than the standard mean normal weight for age and post-operative mean weight was 22% greater than standard mean weight for age. The mean weight gain during the follow-up period was 12% greater than that which would be normally expected (p < 0.001). This study suggests that children undergoing tonsillectomy are slightly heavier than their peers and that following the procedure this discrepancy increases.
Acute Disease↗
Improvements in health and behaviour following childhood tonsillectomy: a parental perspective at 1 year.
To determine subjective parental impressions following routine tonsillectomy we have interviewed the parents of 80 children 1 year following the procedure. Results show that the procedure carried a 100% parental satisfaction rating. All parents felt their child's symptoms of recurrent acute tonsillitis had improved and over 90% of parents felt their child's general health had improved. Sixty-four percent of the parent population reported a noticeable improvement in their child's sleeping pattern and over 30% described an improvement in their child's general behavior. Although this study reports subjective data, and we do not have a comparable control population, these findings provide an interesting insight into parental impressions regarding alterations in their child's health, sleep pattern and behaviour following this procedure.
Adenoidectomy↗
Acute food bolus impaction: aetiology and management.
A prospective study into the aetiology of acute food bolus obstruction (AFBO) was carried out on 17 consecutive patients who presented with this complaint. There were nine males and eight females. Twelve patients (71 per cent) had symptoms of oesophageal disease and 10 patients (59 per cent) had prior food bolus obstruction. Investigations included endoscopy, barium swallow, oesophageal pH and manometry studies. Evidence of oesophageal pathology was found in 12/14 (86 per cent) of patients investigated. No patients had malignancy and the most common abnormality, gastroesophageal reflux (GOR) was found in eight out of 14 (57 per cent) of cases. Oesophageal dysmotility was seen in five out of 12 (42 per cent) patients who had manometric studies. With such a high incidence of recurrence of AFBO, we suggest that patients with this condition be investigated to exclude malignancy and to identify benign oesophageal pathology using techniques such as oesophageal pH and manometry. Appropriate treatment of oesophageal disease may help prevent recurrence of this distressing condition.
Adult↗
The effect of tonsillectomy on eustachian tube function.
A two-part study was designed to investigate the effect of tonsillectomy on eustachian tube function and to identify if any change is related to postoperative pain. Middle ear pressure was measured by tympanometry and results were classified as type A (+50 daPa to -99 daPa), type B (flat) or type C (-100 daPa to -350 daPa). Thirty-one patients with type A tympanograms, undergoing tonsillectomy enrolled in study A. Patients had tympanometry the next day and filled in a questionnaire incorporating visual analogue pain scores. In study B, 30 patients underwent a similar protocol and were followed up at 1 week tympanometry and a questionnaire. A control group of 26 patients undergoing appendicectomy was recruited. Follow-up was available on 23 patients from study B. Combining A and B, on the first postoperative day 39% of patients developed type C tympanograms. No member of the control group developed any change in middle ear pressure. There was no significant relationship between pain scores for throat pain or otalgia and the development of negative middle ear pressure. By day 7 all patients had type A tympanograms. Otalgia was a delayed symptom significantly associated with increased throat pain. Transient negative middle ear pressure commonly occurs following tonsillectomy.
Acoustic Impedance Tests↗
Malaria-treatment-seeking behaviour in the southern Punjab, Pakistan.
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Female↗