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Biomedical subjects

N Alexander

Publications and source records attributed to N Alexander.

At least 19 recordsLinked to original sources
PubMed2006

Insecticide-treated bednets for the prevention of Plasmodium falciparum malaria in Cambodia: a cluster-randomized trial.

OBJECTIVES: To validate and quantify the impact of insecticide-treated bednets (ITN) on malaria morbidity and mortality in Cambodia. METHODS: A paired, cluster-randomized trial of ITN was conducted in Rattanakiri, North East Cambodia. Thirty-four villages with a total population of 10,726 were randomized to receive deltamethrin-impregnated bednets or to control (no net provision). Cross-sectional surveys measured Plasmodium falciparum prevalence at baseline and 10 months after ITN distribution. Village malaria volunteers in control and intervention villages treated dipstick-positive P. falciparum cases with artesunate and mefloquine. The resulting passive surveillance data were used as an estimate of the incidence of clinical P. falciparum infections. RESULTS: There was a protective efficacy of 28% in P. falciparum incidence (adjusted rate ratio 0.72, 95% CI 0.47-1.08) and 9% in P. falciparum prevalence (adjusted prevalence ratio 0.91, 95% CI 0.65-1.28) in ITN relative to control villages; however, neither of these estimates reached statistical significance. Individual-level analysis indicated a greater reduction in P. falciparum prevalence among under 5-year-olds (adjusted OR = 0.63, 95% CI 0.26-1.53) compared to older individuals (interaction P = 0.042). The protective efficacy of 35% (95% CI -28, 67%) with respect to clinical P. falciparum incidence in under 5-year-olds was more pronounced than the corresponding estimates for prevalence but was again not significant. CONCLUSIONS: Lack of statistical significance in the results is likely to be due to a lack of power. The analysis provides further evidence for ITN effectiveness in South East Asia, particularly among individuals under 5 years of age.

Adolescent↗
PubMed2006

Near-hanging as presenting to hospitals in Queensland: recommendations for practice.

Near-hanging is an increasing presentation to hospitals in Australasia. We reviewed the clinical management and outcome of these patients as they presented to public hospitals in Queensland. A retrospective clinical record audit was made at five public hospitals between 1991 and 2000. Of 161 patients enrolled, 82% were male, 8% were indigenous and 10% had made a previous hanging attempt. Chronic medical illnesses were documented in 11% and previous psychiatric disorders in 42%. Of the 38 patients with a Glasgow Coma Scale score (GCS) of 3 on arrival at hospital, 32% returned to independent living and 63% died. Fifty-two patients received CPR, of whom 46% had an independent functional outcome. Independent predictors of mortality were a GCS on hospital arrival of 3 (AOR 150, CI 95% 12.4-1818, P<0.001), taking plain X-rays of the cervical spine (AOR 0.06, CI 95% 0.004-0.97, P=0.047) and contact with the ground (AOR 0.03, CI 95% 0.002-0.62, P=0.02). Only 66% had imaging of the cervical spine performed with other imaging performed infrequently. There were three laryngeal, two hyoid bone and three cervical spine injuries and one carotid dissection. The number of cervical spine X-rays required to find a significant cervical spine fracture was 54. Near-hanging presenting to hospital with a poor conscious state or even cardiac arrest can have a favourable clinical outcome. Radiological investigations are infrequently performed despite a low GCS precluding early accurate assessment. Given the general favourable outcome, an aggressive approach to searching for correctable injuries is recommended.

Adolescent↗
PubMed2006

Sample sizes for identifying the key types of container occupied by dengue-vector pupae: the use of entropy in analyses of compositional data.

A method has been developed for estimating the sample sizes needed to identify categories that comprise a large proportion of a compositional data-set. The method is to be used in the design of surveys of mosquito pupae, for identifying the key container types from which the majority of adult dengue vectors emerge. Although a finite-population correction was devised for estimating the mean of a negative binomial distribution, other complications of parametric approaches make them unlikely to yield methods simple enough to be practically applicable. The Shannon-Wiener index was therefore investigated as a more useful alternative, at the cost of theoretical generalizability, in an approach based on re-sampling methods in conjunction with the use of entropy. This index can be used to summarize the degree to which pupae are either concentrated in a few container types, or dispersed among many. An empirical relationship between the index and the repeatability of surveys of differing sample sizes was observed. A step-wise rule, based on the entropy of the cumulative data, was devised for determining the sample size, in terms of the number of houses positive for pupae, at which a pupal survey might reasonably be stopped.

Aedes↗
PubMed2004

Elastofibroma: a rare soft tissue tumour with a pathognomonic anatomical location and clinical symptom.

BACKGROUND: Elastofibromas are rare benign soft tissue tumours that are almost always located at the inferior pole of the scapula, deep to the serratus anterior muscle. Their anatomical location and a distinctive clinical symptom distinguish them from malignant soft tissue tumours. PATIENTS AND METHODS: A prospective histo-pathological database of all soft tissue tumours referred for treatment to the Royal Marsden Hospital between 1995 and 2003 was searched. Seven patients treated in this institution with a histological diagnosis of elastofibroma were identified. RESULTS: The usual presenting symptoms were that of a mass at the angle of the scapula (7/7), and clunking of the scapula on shoulder abduction (5/7). Pain was an infrequent symptom (1/7). Imaging by CT or MR usually indicated an indeterminate soft tissue neoplasm deep to the peri-scapular muscles, but the histological diagnosis was confirmed pre-operatively by core biopsy in all patients. Subsequent surgical excision was only performed if symptoms were severe. CONCLUSIONS: The clinical presentation of these benign neoplasms is typical and the suspected clinical diagnosis can be confirmed easily by core biopsy. Surgery can be safely reserved for symptomatic patients.

Aged↗
PubMed2001

Diaminoindanes as microsomal triglyceride transfer protein inhibitors.

The synthesis and biological activities of biarylamide-substituted diaminoindanes as microsomal triglyceride transfer protein (MTP) inhibitors are described. One of the more potent compounds, 8aR, inhibited both the secretion of apoB from Hep G2 cells and the MTP-mediated transfer of triglycerides between synthetic acceptor and donor liposomes with IC(50) values of 0.7 and 70 nM, respectively. In normolipidemic rats and dogs, oral administration of 8aR dose-dependently reduced both plasma triglycerides and total cholesterol. Moreover, in rats and dogs, 8aR also prevented the postprandial rise in plasma triglycerides following a bolus administration of a fat load. Because MTP inhibitors decrease very low density lipoprotein assembly in the liver, the potential for hepatic lipid accumulation was evaluated. In normolipidemic rats, hepatic cholesterol and triglyceride contents were dose-dependently increased by 8aR. However, hepatic lipid accumulation resulted in negligible change in total liver weight and was reversible after withdrawal of the compound.

Animals↗
PubMed2000

Should trichiasis surgery be offered in the village? A community randomised trial of village vs. health centre-based surgery.

INTRODUCTION: Surgery for trachomatous trichiasis prevents blindness and is advocated by the WHO as part of the SAFE strategy for the global elimination of trachoma. We conducted a randomised community trial to investigate the effect of providing surgery in villages on surgical uptake in The Gambia. METHODS: 56 villages from two divisions were assigned to eight pairs of clusters matched by geographical division and proximity. One cluster from each pair was randomly assigned to receive village-based surgery and the other cluster health centre-based surgery. Outcome measures were uptake rates and surgical results after 1 week and 3 months. The paired t-test was used to analyse the results. RESULTS: Overall uptake was 66% in the village-based clusters and 44% in the health centre-based clusters. Subjects in the village-based surgery arm had significantly shorter journey times (P = 0.01) and lower costs (P = 0.002). The mean difference in absolute acceptance rates of surgery was 20% better in village-based clusters (95% CI -9 to + 49%, P = 0.15), which would equate to an improvement of 45% (95% CI -20% to 120%) on the average acceptance rates of 44% in the health centre-based group. CONCLUSION: These results strongly suggest better surgical uptake when surgery is provided in patients' villages due to lower cost to the patient, time saved and less fear of the operation.

Blindness↗
PubMed2000

Spatial modelling of individual-level parasite counts using the negative binomial distribution.

We present a spatial model for the mean and correlation of highly dispersed count data, and apply it to individual-level counts of the nematode Wuchereria bancrofti, a parasite of humans which causes the disease lymphatic filariasis. Our model uses the negative binomial distribution, whose shape parameter is a convenient index of over-dispersion. Spatial association is quantified in terms of a characteristic length, which has an intuitive interpretation as the distance over which correlation decreases by half. Demographic surveillance and mapping enable us to include individual-level covariates such as age and sex. We discuss the distinctive features of our model and interpret the results in terms of the epidemiology of lymphatic filariasis and possible implications for control programmes.

Journal Article↗
PubMed1999

CRE DNA binding proteins bind to the AP-1 target sequence and suppress AP-1 transcriptional activity in mouse keratinocytes.

Previously, we have shown that nuclear extracts from cultured mouse keratinocytes induced to differentiate by increasing the levels of extra-cellular calcium contain Fra-1, Fra-2, Jun B, Jun D and c-Jun proteins that bind to the AP-1 DNA binding sequence. Despite this DNA binding activity, AP-1 reporter activity was suppressed in these cells. Here, we have detected the CREB family proteins CREB and CREMalpha as additional participants in the AP-1 DNA binding complex in differentiating keratinocytes. AP-1 and CRE DNA binding activity correlated with the induction of CREB, CREMalpha and ATF-1 and CREB phosphorylation at ser133 (ser133 phospho-CREB) in the transition from basal to differentiating keratinocytes, but the activity of a CRE reporter remained unchanged. In contrast, the CRE reporter was activated in the presence of the dominant-negative (DN) CREB mutants, KCREB and A-CREB, proteins that dimerize with CREB family members and block their ability to bind to DNA. The increase in CRE reporter activity in the presence of these mutants suggests that CRE-mediated transcriptional activity is suppressed in keratinocytes through protein-protein interactions involving a factor that dimerizes with the CREB leucine zipper. In experiments where the A-CREB mutant was co-transfected with an AP-1 reporter construct, transcriptional activity was also increased indicating that a CREB family member binds AP-1 sites and represses AP-1 transcriptional activity as well. Exogenous expression of the transcriptional repressor CREMalpha down-regulated both CRE and AP-1 reporters in keratinocytes suggesting that this factor may contribute to the suppression of AP-1 transcriptional activity observed in differentiating keratinocytes.

Animals↗
PubMed1998

HIV quantitation in spiked vaginocervical secretions: lack of non-specific inhibitory factors. DATRI 005 Study Team. Division of AIDS Treatment Research Initiative.

The objective of this study was to assess the effect of menstrual phase on the ability to quantitate HIV-1 in vaginocervical secretions (VCS) through reconstruction experiments with HIV seronegative VCS collected throughout the menstrual cycle. Measurement of HIV-1 inoculated into both fresh and frozen VCS was undertaken by quantitative micro co-culture, p24 antigen assay and polymerase chain reaction (PCR) for both HIV-1 RNA and pro-viral DNA. Two laboratories carried out these assays over a range of viral concentrations. The study involved a randomized factorial design and the factors were: (1) diluents (phases of the menstrual cycle and controls); (2) laboratories; (3) stock concentrations; and (4) frozen versus fresh VCS samples. Each assay was assessed independently using a random effects analysis of variance (ANOVA) model. No statistical differences due to menstrual cycle were seen in the assay results of p24 antigen (P = 0.08), PBMC culture (P = 0.74), plasma culture (P = 0.13), cell-free RNA (P = 0.44), cell-associated RNA (P = 0.58) and cell-associated DNA (P = 0.43). Inter-laboratory differences were statistically significant for cell-free RNA (P < 0.001), cell-associated DNA (P < 0.001) and p24 (P < 0.001). It is concluded that VCS obtained throughout the menstrual cycle from HIV-uninfected women lacks intrinsic inhibitory factors which could limit detection and quantification by antigen, culture or nucleic acid-based technologies for HIV-1 in VCS throughout the menstrual cycle. Using a standardized collection procedure, we suggest that variation in HIV quantity over time, when reported in VCS of infected women, should be attributed to HIV-associated biologic factors, rather than non-specific or other technical factors.

Analysis of Variance↗
PubMed1998

Diarrhoea morbidity in children in the Asaro Valley, Eastern Highlands Province, Papua New Guinea.

A morbidity study of diarrhoea covering 1926 children aged less than 5 years was carried out in Goroka town and the Lowa and Asaro Census Divisions, Eastern Highlands Province between 1986 and 1989. The study involved weekly demographic surveillance of the total population and morbidity surveillance of children by lay reporters who enquired about the presence or absence on any of the preceding 8 days of a range of symptoms associated with diarrhoeal and respiratory diseases. A three-day symptom-free period was used to define distinct episodes of diarrhoea. The average number of episodes/child-year for all children in the study population was 3.0. Boys suffered a significantly higher incidence of diarrhoea under 48 months of age than girls (4.4 episodes compared to 3.6/child-year). Incidence was highest among those aged 6-17 months (5.5/child-year) with a rapid decline after age 35 months. Incidence of diarrhoea was highest in the more remote Asaro Census Division and was higher in periurban areas than in Goroka town. Incidence also varied significantly between villages, some villages experiencing up to 10 times the incidence of diarrhoea found in Goroka town. The incidence of diarrhoea was significantly higher in January than at other times of year. Duration of diarrhoea varied with age, the longest duration being an average of 4.7 days in the 12-17 months age group. In order to reduce diarrhoea morbidity, it is necessary to improve access to water, encourage improved hygiene practices and breastfeeding and warn people about the risks of sleeping with pigs.

Age Distribution↗
PubMed1997

Targeted disruption of the epidermal growth factor receptor impairs growth of squamous papillomas expressing the v-ras(Ha) oncogene but does not block in vitro keratinocyte responses to oncogenic ras.

We have assessed the role of epidermal growth factor receptor (EGFR) signaling in biological responses to the v-ras(Ha) oncogene using primary keratinocytes from Egfr -/- mice and wild-type littermates. On the basis of several criteria, Egfr -/- keratinocytes were unresponsive to either acute or chronic exposure to several EGFR ligands but were stimulated to proliferate in response to several other mitogens. Although conditioned medium from primary keratinocytes transduced with v-ras(Ha) retrovirus (v-ras(Ha) keratinocytes) was a potent mitogen for wild-type but not Egfr -/- keratinocytes, v-ras(Ha) transduction of primary keratinocytes of either genotype resulted in a strong mitogenic response, arguing against an obligatory role for EGFR activation in v-ras(Ha)-mediated stimulation of keratinocyte proliferation. Infection with high-titer v-ras(Ha) retrovirus altered the keratin expression pattern in keratinocytes of both genotypes, suppressing differentiation-specific keratins K1 and K10 while activating aberrant expression of K8 and K18. In wild-type but not Egfr -/- cultures, K1 and K10 were also suppressed following infection at lower retroviral titers, presumably as a result of paracrine EGFR activation on uninfected cells present in these cultures. Squamous papillomas produced by grafting Egfr -/- v-ras(Ha) keratinocytes onto nude mice were only 21% of the size of wild-type v-ras(Ha) tumors, and a striking redistribution of S-phase cells was detected by immunostaining for bromodeoxyuridine. In Egfr -/- v-ras(Ha) papillomas, the fraction of total labeled nuclei detected in suprabasal layers was increased from 19 to 39%. In contrast, the basal layer labeling index of Egfr -/- papillomas was reduced to 34%, compared to 43% in wild-type tumors. Our results indicate that, although autocrine EGFR signaling is not required for keratinocyte responses to oncogenic ras in culture or benign tumor formation in nude mouse grafts, disruption of this pathway impairs growth of v-ras(Ha) papillomas by a mechanism that may involve alterations in keratinocyte cell cycle progression and/or migration in vivo.

Animals↗
PubMed1997

Single and repeated environmental stress: effect on plasma oxytocin, corticosterone, catecholamines, and behavior.

Rat studies were done to further characterize an environmental model of stress designated shaker stress (SS). Plasma oxytocin (OT), corticosterone (CS), norepinephrine (NE), and epinephrine (E) were measured before and after 5 or 30 min of SS applied one time or applied 10 times over a 2-week period. The major findings were partial adaptation of plasma E within 30 min of acute SS, adaptation of plasma CS baselines but not responses to chronic SS, and complete adaptation of plasma OT responses to chronic SS. Poststress behavior during chronic SS was affected in the following ways: freezing time habituated, defecation and rearings increased, and grooming and teeth chattering remained relatively constant. The results show that SS produces consistent patterns of hormonal and behavioral responses; some aspects of the patterns are similar to those elicited by other environmental stresses, whereas some aspects are unique to SS. We conclude that rats do not adapt to repeated SS but rather that most hormonal and behavioral defense mechanisms are renewable on a daily basis.

Animals↗
PubMed1997

Transmission intensity and its relationship to infection and disease due to Wuchereria bancrofti in Papua New Guinea.

This study describes the relationship between transmission intensity and infection and disease due to Wuchereria bancrofti in an endemic area of Papua New Guinea. The prevalence of microfilaremia in the entire study population was 66%. Of 1892 persons examined, 6.2% and 12.3% had lymphedema of the legs and hydroceles, respectively. The prevalences of microfilaremia and clinical morbidity were lowest in persons <20 years old and increased progressively with age. Annual transmission potential and annual infective biting were monitored in five villages where Anopheles punctulatus and Anopheles koliensis are the only vectors of W. bancrofti. Both measures of the entomologic inoculation rate were positively associated with the village-specific microfilarial rate, mean intensity of microfilaremia, and prevalence of leg edema. These data indicate that transmission intensity is a major determinant of patent infection and morbidity rates in bancroftian filariasis.

Adolescent↗
PubMed1997

Spatial and temporal variation in abundance of Anopheles (Diptera:Culicidae) in a malaria endemic area in Papua New Guinea.

Abundance of anophelines in 10 villages in the Wosera area of Papua New Guinea was monitored during 1990-1993. Of 85,197 anophelines collected in 1,276 paired indoor and outdoor landing catches, 40.4% were Anopheles koliensis Owen, 36.7% An. punctulatus Donitz, 14.3% An. karwari (James), 4.9% An. farauti s.l. Laveran, 3.1%, An, longirostris Brug, and 0.7% An. bancroftii Giles. Maps of average indoor biting rates were produced using a Bayesian conditional autoregressive model which allowed for heterogeneities in sampling effort over time and space. Differences in spatial distributions among species were observed among and within villages and were related to the distribution of larval habitats and vegetation. Abundance of An. punctulatus and An. koliensis decreased with distance from the main waterway and probably from a sago swamp forest at 6 villages in North Wosera. Abundance of An. punctulatus was associated negatively with those of An. farauti s.l., An. longirostris, and An. bancroftii. The latter 3 species also had relatively low ratios of indoor-to-outdoor biting rates, and earlier biting times than An. punctulatus. Human blood indices of at least 0.79 were observed for all species except An. bancroftii. Abundance of all 6 species was correlated temporally with recent rainfall, but An. koliensis, An. karwari, and An. longirostris showed greater temporal variability than the other species. An punctulatus and An. koliensis tended to occur together in time and space (index of association, I = 0.85). Weaker associations were seen between An. farauti s.l. and An. longirostris (I = 0.44) and An. koliensis and An. karwari (I = 0.34). The most frequently collected species occurred together and were concentrated near the Amugu river; the remaining species tended to occur together but in different parts of the Wosera area. The importance of understanding ecological requirements of the different Anopheles vectors and their association with key household and landscape features are discussed in relation to malaria transmission and control.

Animals↗
PubMed1997

Central nitric oxide donors attenuate cardiovascular and central norepinephrine responses to stress.

An earlier study showed that norepinephrine (NE) was released in the paraventricular nucleus (PVN) and posterior hypothalamus (PH) along with increases of mean arterial pressure (MAP) and heart rate (HR) during shaker stress (SS). Here we investigated the possibility that nitric oxide (NO) donors, infused into hypothalamus, could modulate responses to SS. In conscious rats, an injector-microdialysis probe, for direct application of donor and collection of extracellular NE, respectively, was inserted into PVN or PH; MAP and HR were recorded continuously from conscious rats. The NO donor, molsidomine (Mol), infused 5 or 30 min before SS, did not alter baseline values of NE, MAP, or HR, but did attenuate changes elicited by 5 min of SS; methylene blue blocked the effects of Mol. The NO donor, sodium nitroprusside, was much less effective than Mol as a modulator of stress-related effects. The results indicate that MAP, HR, and hypothalamic NE responses to environmental stress, but not baseline values, can be modulated by NO donors in the hypothalamus.

Animals↗
PubMed1997

Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development.

Mice harboring a targeted disruption of the epidermal growth factor receptor (EGFR) allele exhibit a severely disorganized hair follicle phenotype, fuzzy coat, and systemic disease resulting in death before 3 weeks. This skin phenotype was reproduced in whole skin grafts and in grafts of EGFR null hair follicle buds onto nude mice, providing a model to evaluate the natural evolution of skin lacking the EGFR. Hair follicles in grafts of null skin did not progress from anagen to telogen and scanning electron micrografts revealed wavy, flattened hair fibers with cuticular abnormalities. Many of the EGFR null hair follicles in the grafted skin were consumed by an inflammatory reaction resulting in complete hair loss in 67% of the grafts by 10 weeks. Localization of follicular differentiation markers including keratin 6, transglutaminase, and the hair keratins mHa2 and hacl-1 revealed a pattern of premature differentiation within the null hair follicles. In intact EGFR null mice, proliferation in the interfollicular epidermis, but not hair follicles, was greatly decreased in the absence of EGFR. In contrast, grafting of EGFR null skin resulted in a hyperplastic response in the epidermis that did not resolve even after 10 weeks, although the wound-induced hyperplasia in EGFR wild-type grafts had resolved within 3 to 4 weeks. Thus, epithelial expression of the EGFR has complex functions in the skin. It is important in delaying follicular differentiation, may serve to protect the hair follicle from immunological reactions, and modifies both normal and wound-induced epidermal proliferation but seems dispensable for follicular proliferation.

Age Factors↗
PubMed1996

Lanreotide reduces serum free and total insulin-like growth factor-I after angioplasty.

BACKGROUND: Several experiments point to a participating role of insulin-like growth factor-I (IGF-I) in the vascular events leading to restenosis after percutaneous transluminal coronary angioplasty (PTCA). METHODS AND RESULTS: We measured fasting serum total (extractable) IGF-I in 553 patients in a controlled clinical trial. Half of the patients received continuous subcutaneous infusion of the somatostatin analogue lanreotide from the day before (baseline) and for 4 days after PTCA. We also measured ultrafiltrated serum free IGF-I and IGF-II, total IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and insulin in a subgroup of 18 placebo-treated and 20 lanreotide-treated patients. Total IGF-I had decreased by 7% (P < .0001) 1 day after initiation of lanreotide infusion and stayed reduced, whereas no early changes occurred in placebo-treated patients. The same pattern was observed in the subgroup. Free IGF-I decreased significantly from baseline by 22% to 27% (P < .05) in lanreotide-treated patients and increased insignificantly by 10% to 30% (P = .054) in placebo-treated patients. IGFBP-1 increased (P < .05) in both groups postoperatively, but levels in lanreotide-treated patients exceeded (P < .05) those of placebo-treated patients. Lanreotide treatment resulted in minor reductions (P < .05) in free and total IGF-II and IGFBP-3, whereas insulin was unaltered. CONCLUSIONS: Lanreotide administration acutely decreases circulating total and free IGF-I, the latter relatively more, and increases IGFBP-1. These alterations in the IGF system may participate in the improvement of the long-term outcome after PTCA noted with lanreotide treatment.

Adult↗