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Biomedical subjects

E J Sanders

Publications and source records attributed to E J Sanders.

At least 37 records · Page 2Linked to original sources

O'nyong-nyong fever in south-central Uganda, 1996-1997: description of the epidemic and results of a household-based seroprevalence survey.

O'nyong-nyong (ONN) fever, an acute, nonfatal illness characterized by polyarthralgia, is caused by infection with a mosquito-borne central African alphavirus. During 1996-1997, south-central Uganda experienced the second ONN fever epidemic ever recognized. During January and early February 1997, active case-finding and a household cluster serosurvey were conducted in two affected and two comparison areas. A confirmed case was defined as an acute febrile illness with polyarthralgia occurring within the previous 9 months plus serologic confirmation or isolation of ONN virus from blood. In affected (n=129) and comparison (n=115) areas, the estimated infection rates were 45% and 3%, respectively, and the estimated attack rates were 29% and 0%, respectively, for an apparent:inapparent infection ratio of nearly 2 in affected areas. In villages sampled near Lake Kijanebalola, Rakai District, the estimated infection and attack rates were 68% and 41%, respectively, and 55% of sampled households had >/=1 case of ONN fever. In conclusion, this epidemic was focused near lakes and swamps, where it was associated with high infection and attack rates.

Adolescent↗

International multicenter evaluation of the clinical utility of a dipstick assay for detection of Leptospira-specific immunoglobulin M antibodies in human serum specimens.

We performed a multicenter evaluation of a robust and easily performed dipstick assay for the serodiagnosis of human leptospirosis. The assay is aimed at the detection of Leptospira-specific immunoglobulin M (IgM) antibodies. The study involved 2,665 serum samples collected from 2,057 patients with suspected leptospirosis in 12 countries on five continents with different levels of endemicity and different surveillance systems. The patients were grouped as laboratory-confirmed leptospirosis case patients and noncase patients based on the results of culturing and the microscopic agglutination test. Paired samples from 27.7% of the subjects were tested. Of the 485 case patients, 87.4% had a positive dipstick result for one or more samples. Of the 1,513 noncase patients, only 7.2% had a positive result. Whereas most (88.4%) of the positive samples from the case patients showed moderate to strong (2+ to 4+) staining in the dipstick assay, most (68.1%) of the positive samples from the noncase patients showed weak (1+) staining. The sensitivity of the dipstick assay increased from 60.1% for acute-phase serum samples to 87.4% for convalescent-phase samples. The specificities for these two groups of samples were 94.1 and 92.7%, respectively. The dipstick assay detected a broad variety of serogroups. The results of the dipstick assay were concordant (observed agreement, 93.2%; kappa value, 0.76) with the results of an enzyme-linked immunosorbent assay for the detection of specific IgM antibodies, a test which is often used in the laboratory diagnosis of current or recent leptospirosis. This study demonstrated that this easily performed dipstick assay is a valuable and useful test for the quick screening for leptospirosis; has a wide applicability in different countries with different degrees of endemicity; can be used at all levels of the health care system, including the field; and will be useful for detecting and monitoring outbreaks of leptospirosis.

Agglutination Tests↗

Increase of leptospirosis in dengue-negative patients after a hurricane in Puerto Rico in 1996 [correction of 1966].

Leptospirosis has rarely been reported in Puerto Rico, although in the period from 1948 to 1952, 208 cases of leptospirosis and an island-wide seroprevalence of antibody to Leptospira of 14% were documented. In Puerto Rico in October 1996, following rainfall and a period of flooding generated by Hurricane Hortense, serum specimens of 4 patients with suspected dengue fever that were negative for dengue tested positive for Leptospira-specific IgM antibodies in a dipstick assay. Subsequently, we used an island-wide dengue laboratory-based surveillance system to determine the increase in leptospirosis after hurricane-generated floods. All anti-dengue IgM-negative patients (n = 142) with disease onset from August 8 to October 6, 1996 from prehurricane and posthurricane groups were investigated for leptospirosis. Laboratory-confirmed leptospirosis cases were defined as microscopic agglutination test titers > or = 1 :400 to 1 or more serovars, or positive immunohistochemistry in autopsy tissues. Four (6%) of 72 prehurricane and 17 (24%) of 70 posthurricane patients had laboratory-confirmed cases of leptospirosis (relative risk [RR] = 4.4, 95% confidence interval [CI] = 1.6-12.4). The mean age of case-patients was 34 years (range = 13-64). Eighteen (86%) of 21 confirmed case-patients were males, including one patient who died (31 years old). Patients were located in 18 (38%) of 48 municipalities that submitted serum samples. Clinical features significantly associated with leptospirosis were eye pain (RR = 1.5, 95% CI = 1.3-1.9), joint pain (RR = 1.4, 95% CI = 1.1-1.6), diarrhea (RR = 1.7, 95% CI = 1.2-2.5), and jaundice (RR = 3.3, 95% CI = 1.5-7.2). This study demonstrates the utility of a dengue laboratory-based surveillance system for the detection of an increase of leptospirosis, which most likely would have gone unrecognized. Leptospirosis is treatable with antibacterial agents; knowledge of this diagnosis may significantly reduce morbidity and mortality.

Adolescent↗

Dengue and dengue haemorrhagic fever.

The incidence and geographical distribution of dengue have greatly increased in recent years. Dengue is an acute mosquito-transmitted viral disease characterised by fever, headache, muscle and joint pains, rash, nausea, and vomiting. Some infections result in dengue haemorrhagic fever (DHF), a syndrome that in its most severe form can threaten the patient's life, primarily through increased vascular permeability and shock. The case fatality rate in patients with dengue shock syndrome can be as high as 44%. For decades, two distinct hypotheses to explain the mechanism of DHF have been debated-secondary infection or viral virulence. However, a combination of both now seems to be the plausible explanation. The geographical expansion of DHF presents the need for well-documented clinical, epidemiological, and virological descriptions of the syndrome in the Americas. Biological and social research are essential to develop effective mosquito control, medications to reduce capillary leakage, and a safe tetravalent vaccine.

Dengue↗

Nuclear degeneration in the developing lens and its regulation by TNFalpha.

DNA fragmentation in lens fibre cell nuclei undergoing programmed degeneration was identified by terminal deoxynucleotidyl transferase (TdT)-mediated biotin-dUTP nick end labelling (TUNEL). Lens epithelial cells in culture were induced to differentiate into lens fibre-like clumps of cells (lentoids) by insulin and it was shown that the TUNEL method was also an effective means of labelling degenerating nuclei in lentoid cells in lens epithelial cell cultures. Using immuno-fluorescence and confocal microscopy, it was shown that TNFalpha and TNF receptor (TNFR1, and TNFR2) immunoreactivity was present in sections of chick embryo lenses. TNFalpha immunoreactivity was associated with the lens epithelium and lens fibres. TNFR1 immunoreactivity was present in lens epithelial cells, cortical lens fibres, and lens fibre cell nuclei, while TNFR2 immunoreactivity had a similar distribution to that of TNFR1, but was not associated with nuclei. Similar patterns of TNFalpha, TNFR1, and TNFR2 immunoreactivity were observed in lens epithelial cell cultures. When added to lens epithelial cell cultures, TNFalpha, at concentrations of 50 to 100 ng ml-1, and agonistic antibodies to both TNFR1 and TNFR2 significantly (P<0.05) enhanced the number of degenerating (TUNEL-positive) nuclei. On the other hand, a neutralising antibody to TNFalpha significantly (P<0. 05) reduced the number of TUNEL-positive nuclei. These results demonstrate that TUNEL is an effective means of labelling degenerating lens fibre nuclei during lens fibre and lentoid differentiation, and suggest a potential role for TNFalpha-like factors and their receptors in the degeneration of lens fibre cell nuclei during lens differentiation. We further suggest that the nuclear degeneration of lens fibre cells is analogous to the nuclear events that occur during apoptosis, and that in lens cells the nuclear degeneration is uncoupled from the plasma membrane events of apoptosis that normally lead to cell death.

Animals↗

Growth hormone: a paracrine growth factor in embryonic development?

Although pituitary growth hormone is obligatory for normal postnatal growth and development, early embryonic and fetal growth is generally considered to be independent of pituitary GH. Indeed, in chickens, somatotrophs and serum GH are not detectable until late in embryogenesis, and neither partial decapitation nor pre-hatch GH administration greatly affects embryonic growth. However, since it is now known that GH can be produced and act in many extra-pituitary tissues, early embryonic growth may be independent of pituitary GH but dependent upon the paracrine actions of extra-pituitary GH. The possibility that growth hormone may be a paracrine growth factor during early development will therefore be considered in this brief review, which is based on the embryogenesis of the domestic fowl.

Animals↗

First recorded outbreak of yellow fever in Kenya, 1992-1993. I. Epidemiologic investigations.

Outbreaks of yellow fever (YF) have never been recorded in Kenya. However, in September 1992, cases of hemorrhagic fever (HF) were reported in the Kerio Valley to the Kenya Ministry of Health. Early in 1993, the disease was confirmed as YF and a mass vaccination campaign was initiated. Cases of suspected YF were identified through medical record review and hospital-based disease surveillance by using a clinical case definition. Case-patients were confirmed serologically and virologically. We documented 55 persons with HF from three districts of the Rift Valley Province in the period of September 10, 1992 through March 11, 1993 (attack rate = 27.4/100,000 population). Twenty-six (47%) of the 55 persons had serologic evidence of recent YF infection, and three of these persons were also confirmed by YF virus isolation. No serum was available from the other 29 HF cases. In addition, YF virus was isolated from a person from the epidemic area who had a nonspecific febrile illness but did not meet the case definition. Five patients with confirmed cases of YF died, a case-fatality rate of 19%. Women with confirmed cases of YF were 10.9 times more likely to die than men (P = 0.010, by Fisher's exact test). Of the 26 patients with serologic or virologic evidence of YF, and for whom definite age was known, 21 (81%) were between 10 and 39 years of age, and 19 (73%) were males. All patients with confirmed YF infection lived in rural areas. There was only one instance of multiple cases within a single family, and this was associated with bush-clearing activity. This was the first documented outbreak of YF in Kenya, a classic example of a sylvatic transmission cycle. Surveillance in rural and urban areas outside the vaccination area should be intensified.

Adolescent↗

First recorded outbreak of yellow fever in Kenya, 1992-1993. II. Entomologic investigations.

The first recorded outbreak of yellow fever in Kenya occurred from mid-1992 through March 1993 in the south Kerio Valley, Rift Valley Province. We conducted entomologic studies in February-March 1993 to identify the likely vectors and determine the potential for transmission in the surrounding rural and urban areas. Mosquitoes were collected by landing capture and processed for virus isolation. Container surveys were conducted around human habitation. Transmission was mainly in woodland of varying density, at altitudes of 1,300-1,800 m. The abundance of Aedes africanus in this biotope, and two isolations of virus from pools of this species, suggest that it was the principal vector in the main period of the outbreak. A third isolate was made from a pool of Ae. keniensis, a little-known species that was collected in the same biotope. Other known yellow fever vectors that were collected in the arid parts of the valley may have been involved at an earlier stage of the epidemic. Vervet monkeys and baboons were present in the outbreak area. Peridomestic mosquito species were absent but abundant at urban sites outside the outbreak area. The entomologic and epidemiologic evidence indicate that this was a sylvatic outbreak in which human cases were directly linked to the epizootic and were independent of other human cases. The region of the Kerio Valley is probably subject to recurrent wandering epizootics of yellow fever, although previous episodes of scattered human infection have gone unrecorded. The risk that the disease could emerge as an urban problem in Kenya should not be ignored.

Adolescent↗

Cellular phenotype transformation during early embryogenesis: a role for focal adhesion kinase?

We have used the gastrulating chick embryo as a model for studying the potential role of focal adhesion kinase (FAK) in phenotypic transformation. In the gastrulating embryo, there is a well-defined epithelial to mesenchymal transformation as the upper epithelial epiblast layer of cells ingresses at the primitive streak to form the invasive mesenchymal mesoderm layer and the epithelioid endoderm layer. Immunolocalization showed that FAK was expressed primarily in the apical cytoplasm of the epiblast layer, together with some regions of the mesoderm and endoderm. Hensen's node and the primitive streak, where the transformation occurs, showed very low immunoreactivity. Levels of FAK in these individual tissues were quantified by densitometric analysis of Western blots, and FAK activation was quantified by stripping these blots and reprobing for phosphotyrosine. Immunoprecipitation indicated that the phosphotyrosine bands corresponded with the FAK bands on the blots. Although the blots confirmed that FAK was highly expressed in the epiblast, the level of FAK activation was highest in the endoderm, despite relatively low expression of the protein, Similar quantitative blotting was carried out using cells from each of the three layers cultured on different substrata. The results indicated that cells cultures on fibronectin, laminin, and Matrigel expressed differing levels of FAK, with differing levels of tyrosine phosphorylation, depending on the cell type and the substratum. We conclude that FAK is developmentally regulated during gastrulation, and that this regulation could be influenced by the changing substratum encountered by the differentiating cells during this process. However, the apical localization of FAK in much of the epiblast appears to preclude a consistent focal contact-like association of this molecule with integrins in vivo, and we therefore suggest that in the embryo, FAK may be involved in integrin-mediated signalling pathways without physical association with cell-substratum contacts.

Animals↗

Localization and translocation of MMP-2 during aggregation of human platelets.

We have previously shown that human platelets express matrix metalloproteinase-2 (MMP-2) and that the release of this enzyme during platelet activation mediates the ADP- and thromboxane-independent part of aggregation. We have now used immunogold electron microscopy, flow cytometry. Western blot analysis and zymography methods to study the ultrastructural localization of MMP-2 in human washed platelets. Platelet aggregation was stimulated by collagen and the MMP-2 immunoreactivity of platelets was followed during various stages of aggregation. In resting platelets, MMP-2 was randomly distributed in the platelet cytosol without detectable association with platelet granules. Platelet aggregation caused the translocation of MMP-2 from the cytosol to the extracellular space. During the early stages of aggregation, MMP-2 remained in close association with the platelet plasma membrane. We conclude that the interactions of MMP-2 with platelet surface membranes mediate the aggregatory response induced by this enzyme.

Adenosine Diphosphate↗

Cell death in the avian sclerotome.

In this study the occurrence of apoptotic cells in chick embryo trunk somites, between 2.5 and 4 days of development, has been examined using an in situ nick-end-labeling method (TUNEL) to identify nuclei in which DNA is undergoing fragmentation. At 2.5 days of development, apoptotic cells were found in the sclerotome with a distribution that depended on the rostrocaudal level in the trunk. At the most rostral levels (somites 1-18), dying cells were present primarily in the rostral half of the ventral sclerotome; at midlevels (somites 19-26), they were present throughout the ventral sclerotome; and at caudal levels (somites 27-32), no dying cells were present. By 4 days of development, the number of dying cells in the sclerotome was sharply reduced, and those present were primarily distributed to the caudal side of the intrasclerotomal fissure. Double labeling of cells for both TUNEL and the HNK-1 epitope, at 2.5 days, indicated that the majority of the dying cells were not neural crest cells. Further, dying cells in the rostral somite half were present largely in regions of the sclerotome that labeled poorly for HNK-1. It was confirmed that apoptotic neural crest cells retain the HNK-1 epitope and therefore would have been observed if present. Neural crest cells only appeared to be apoptotic in relatively small numbers and only at the ventral border of the sclerotome. Examination of DiI-labeled neural crest cells confirmed that the dying cells in the body of the somite were not primarily neural crest cells. Two hypotheses regarding the TUNEL-positive cells in the sclerotome were experimentally tested. First, that they originate from the somitocoel compartment of the somite, because their distribution patterns at 4 days were similar to those of somitocoel cells. To test this, somitocoel cells were labeled with carboxyfluorescein and grafted into host embryos in ovo. Results showed that these cells did not become apoptotic and that the dying cells were therefore not derived from the somitocoel. Second, the hypothesis was tested that the distribution patterns of the dying cells in the sclerotome are determined by factors outside the somite itself. Somites and segmental plates were transplanted into hosts in ovo with reversed orientation, after which the patterns of dying cells were examined using nile blue sulfate staining. The results indicated that the patterns were unchanged after a further 2 days incubation, suggesting that the patterns of cell death in the sclerotome are not determined solely from within the somite. The distribution of the cell death-associated gene products, bcl-2, bax, and interleukin-1 beta converting enzyme, indicates that although these proteins are segmentally distributed in the dermomyotome and in the rostrodorsal quadrant of the sclerotome, their patterns are not directly correlated with the distribution of dying cells.

Animals↗

Patterns of cell death during gastrulation in chick and mouse embryos.

We have examined the distribution of cells at an early stage of the cell death process in gastrulating chick and mouse embryos, using a DNA nick end-labelling technique to label nuclei that are undergoing DNA fragmentation in situ. In the chick embryo, the incidence of nuclei showing DNA fragmentation was mapped by digitizing the occurrence of these nuclei from sections, and reconstructing the three separate layers of the entire embryo at several stages of gastrulation. In the chick, DNA fragmentation was found in nuclei throughout the embryo, in cells of all three germ layers, but most especially in the epiblast in the rostral germinal crescent and in the lateral marginal zones. This region of greatest cell death formed an arc rostrally and laterally in the epiblast, and was consistent through gastrulation and into the early neurulation stage. While the extensive cell death in the chick embryo may be due to cell redundancy, it is also possible that the pattern of death observed could be related to the compression of the embryo against the barrier of yolk at the periphery of the area pellucida during expansion. In a number of cases in the chick, local regions of elevated cell death were also observed in the primitive streak. This may be associated with the changing cell-cell and cell-matrix interactions experienced by cells traversing the primitive streak. In the gastrulating mouse embryo, by contrast, nuclei undergoing DNA fragmentation showed no consistent regions of elevated incidence, in any of the embryonic layers. DNA fragmentation in these embryos was, however, observed in nuclei of cells in the visceral endoderm and in the epiblast. The lack of any clear pattern of DNA fragmentation in the mouse embryo at this stage of development leaves the roles of the dying cells enigmatic. The death may, however, be lineage-related or be a reflection of a cellular redundancy necessary in a developing system that is undergoing extensive cell rearrangement and cellular adhesive change.

Animals↗

Cell death in the gastrulating chick embryo: potential roles for tumor necrosis factor-alpha (TNF-alpha).

We have examined the expression of TNF-alpha and its receptors, TNFR1 and TNFR2, during gastrulation in the chick embryo, and have investigated the possible role of this factor in the control of cell death at this early stage of development. TNF-alpha, immunoreactive at approximately 17 kD, was found both in vivo and in vitro, most intensely associated with the cell surface and cytoskeleton of endoderm cells. TNFR2 was especially immunoreactive in endoderm cells of the marginal zone. TNFR1 was found in nuclei throughout the embryo. Embryos also showed widespread expression of both the bcl-2 and Bax gene products, which are both associated with cell death pathways. Intact embryos in culture were sensitive to the addition of TNF-alpha (approx. 110 ng/ml), responding by significantly increasing the incidence of DNA fragmentation in cells from all tissues of the embryo. This effect was abrogated by immunological pre-absorption of the cytokine. Cultured cells from these embryos also responded to the addition of agonistic antibodies to TNF-alpha receptors by increasing DNA fragmentation. A similar response to TNF-alpha antiserum by cultured cells appeared to be related to a concomitant decrease in cell-substratum adhesion caused by the antibody. Decreased cell adhesion, induced non-specifically with anti-integrin antiserum, also resulted in increased DNA fragmentation. TNF-alpha, synthesized and secreted by the embryo itself, may be able to exert a paracrine effect on the incidence of cell death in tissues of the embryo, and the cell death process may be related to the expression of bcl-2 and Bax gene products. The influence of TNF-alpha may be exerted by the activation of cell death signalling pathways directly, or indirectly through perturbation of the cytoskeleton or of integrin-mediated cell adhesion.

Journal Article↗

Roles for growth and differentiation factors in avian embryonic development.

We review the evidence for a role for transforming growth factor-beta (TGF-beta) and for tumor necrosis factor-alpha (TNF-alpha) in the development of the avian embryo. Transforming growth factor-beta is expressed in a number of locations in the early embryo with a distribution consistent with a function in epithelial-mesenchymal transformation and modulation of the composition of the extracellular matrix. During gastrulation, this factor is found in the mesoderm cell layer as well as in the endoderm underlying the primitive streak. In vivo and in vitro investigations suggest that TGF-beta may be involved in the regulation of phenotypic transformation, matrix deposition, and cell proliferation. Tumor necrosis factor-alpha and its two receptors are also located with distributions that suggest important involvement for this pleiotropic factor in early morphogenetic processes. Tumor necrosis factor-alpha is found in several cell populations from the time of gastrulation onwards, including the lens. In vitro investigations, using tissue from the gastrulating embryo as well as from the lens, suggest that this factor may be associated with the extensive cell death that occurs throughout the first 6 d of development, and with nuclear degeneration in the lens. We hypothesize that TNF-alpha, acting in a paracrine or autocrine fashion, may be involved in the signalling pathways that effect the regulation of cell death in development.

Animals↗

Methods for detecting apoptotic cells in tissues.

In this review, methods currently available for the detection of cell death in tissues are surveyed, with special reference to techniques that allow the recognition of apoptotic cells in situ, either in whole mount specimens or in tissue sections. The techniques considered include: several variations on in situ DNA nick-end labelling methods, vital dyes, lysosomal enzyme histochemistry, transglutaminase expression, and immunocytochemical detection of several death-associated antigens. These methods are discussed in relation to their utility in detecting different stages of cell death, and also to their ability to distinguish between apoptotic and necrotic cell death.

Animals↗

Yellow fever in Kenya: the need for a country-wide surveillance programme.

Since the emergence of yellow fever (YF) as a public health threat in Kenya in 1992-1993, low level transmission of the virus to humans has continued to occur. A programme of YF surveillance has been instrumental in the monitoring of YF activity and has clearly demonstrated an expansion of the zone of virus activity into regions that were not affected in the 1992-1993 epidemic. This is of major concern for the approximately 29 million Kenyans who are unvaccinated and therefore at risk of infection. A revision of the surveillance programme is underway to create a more efficient system of recognition of suspect YF cases, laboratory diagnosis and reporting to the appropriate authorities for action. In addition, a research programme to study YF ecology in Kenya will benefit the surveillance programme, enabling it to target potential 'hotspots' of YF activity. As it may not be possible, for financial reasons, to incorporate YF vaccination into the Kenya Expanded Programme of immunization in the immediate future, the need for continued surveillance to monitor the emergence of YF in Kenya is vital.

Education, Graduate↗

Laboratory investigations in the diagnosis of septicaemia and malaria.

During a three month prospective study, 229 in-patients with fever, admitted to St. Mary's Hospital, Mumias, were examined for bacterial and malarial causes of fever. Blood cultures taken from patients appeared to contain true pathogens in 51 (22%) cases. Nine different bacterial species were identified from positive blood cultures of which four predominated: Salmonella typhi (46%), Streptococcus pneumoniae (19%), Salmonella enteritidis (12%), Salmonella typhimurium (8%). S. enteritidis and S. typhimurium isolates were mostly multi-antibiotic resistant, compared to S. typhi isolates which were relatively susceptible to the antibiotics used in the hospital. Only 70% of the S. pneumoniae isolates were susceptible to penicillin. Among 227 patients in whom a thick blood-film for malaria parasites and HIV serology were performed, only 25 (11%) revealed malaria parasites. HIV-1 antibodies were detected in 51 (22%) patients. Without appropriate laboratory examinations, the majority of the diagnoses would have been missed and no optimal treatment would have been administered. This may increase resistance to antimalarials and antibiotics.

Child↗

Ultrastructural identification of apoptotic nuclei using the TUNEL technique.

We describe an ultrastructural adaptation of the method of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) for the identification of DNA fragmentation. Thin sections of tissue embedded in hydrophilic resin were nick end labelled with biotinylated dUTP which was subsequently labelled with avidin conjugated to gold particles. The technique was validated by labelling the nuclei of L929-8 cells treated with tumour necrosis factor alpha. These cells are known to respond to treatment with the factor by undergoing apoptosis. The method was then used on tissue from the chick embryo which is known to be undergoing programmed cell death. This tissue was from the neural tube and the posterior necrotic zone of the limb bud, where cells can be identified as undergoing apoptosis based on the morphology of their nuclei. The method specifically labelled heterochromatin adjacent to the nuclear envelope as well as that associated with the nucleolus of cells from regions of the embryo where programmed cell death was expected. In addition to labelling the nuclei of cells that were clearly undergoing apoptosis, the method also identified nuclei of apparently normal cells. This method, used in conjunction with corroborating techniques, provides a means for the early detection of cells undergoing DNA fragmentation, before the onset of gross apoptotic morphology, and in cells that do not show classical apoptotic characteristics.

Animals↗