Ivermectin improves the skin condition and self-esteem of females with onchocerciasis: a report of two cases.
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Adult↗
Biomedical subjects
B Benton
Publications and source records attributed to B Benton.
Partnership and promise: evolution of the African river-blindness campaigns.
This article describes the evolution of the partnership, between various health and developmental agencies, that has sustained the campaign against river blindness in Africa. The international community was oblivious to the devastating public-health and socio-economic consequences of onchocerciasis until towards the end of the 1960s and the beginning of the 1970s. Then a 'Mission to West Africa', supported by the United Nations Development Programme, and a visit to the sub-region by the president of the World Bank culminated, in 1974, in the inauguration of the Onchocerciasis Control Programme in West Africa (OCP). OCP was a landmark event for the World Bank as it represented its first ever direct investment in a public-health initiative. The resounding success of the OCP is a testimony to the power of the partnership which, with the advent of the Mectizan Donation Programme, was emboldened to extend the scope of its activities to encompass the remaining endemic regions of Africa outside the OCP area. The progress that has been made in consolidating the partnership is discussed in this article. The prospects of adapting the various strategies of the African Programme for Onchocerciasis Control, to entrench an integrated approach that couples strong regional co-ordination with empowerment of local communities and thereby address many other health problems, are also explored.
Africa↗
APOC's strategy of community-directed treatment with ivermectin (CDTI) and its potential for providing additional health services to the poorest populations. African Programme for Onchocerciasis Control.
Since its inauguration in 1995, the African Programme for Onchocerciasis Control (APOC) has made significant progress towards achieving its main objective: to establish sustainable community-directed treatment with ivermectin (CDTI) in onchocerciasis-endemic areas outside of the remit of the Onchocerciasis Control Programme in West Africa (OCP). In the year 2000, the programme, in partnership with governments, non-governmental organizations and the endemic communities themselves, succeeded in treating 20,298,138 individuals in 49,654 communities in 63 projects in 14 countries. Besides the distribution of ivermectin, the programme has strengthened primary healthcare (PHC) through capacity-building, mobilization of resources and empowerment of communities. The community-directed-treatment approach is a model that can be adopted in developing other community-based health programmes. The approach has also made it possible to bring to the poor some measure of intervention in some other healthcare programmes, such as those for malaria control, eye care, maternal and child health, nutrition and immunization. CDTI presents, at all stages of its implementation, a unique window of opportunity for promoting the functional integration of healthcare activities. For this to be done successfully and in a co-ordinated manner, adequate funding of CDTI within PHC is as important as an effective sensitization of the relevant policy-makers, healthworkers and communities on the value of integration (accompanied by appropriate training at all levels). Evaluation of the experiences in integration of health services, particularly at community level, is crucial to the success of the integration.
Africa↗
PARP determines the mode of cell death in skin fibroblasts, but not keratinocytes, exposed to sulfur mustard.
Sulfur mustard is cytotoxic to dermal fibroblasts as well as epidermal keratinocytes. We demonstrated that poly(ADP-ribose) polymerase (PARP) modulates Fas-mediated apoptosis, and other groups and we have shown that PARP plays a role in the modulation of other types of apoptotic and necrotic cell death. We have now utilized primary dermal fibroblasts, immortalized fibroblasts, and keratinocytes derived from PARP(-/-) mice and their wildtype littermates (PARP(+/+)) to determine the contribution of PARP to sulfur mustard toxicity. Following sulfur mustard exposure, primary skin fibroblasts from PARP-deficient mice demonstrated increased internucleosomal DNA cleavage, caspase-3 processing and activity, and annexin V positivity, compared to those derived from PARP(+/+) animals. Conversely, propidium iodide staining, PARP cleavage patterns, and random DNA fragmentation revealed a dose-dependent increase in necrosis in PARP(+/+) but not PARP(-/-) cells. Using immortalized PARP(-/-) fibroblasts stably transfected with the human PARP cDNA or with empty vector alone, we show that PARP inhibits markers of apoptosis in these cells as well. Finally, primary keratinocytes were derived from newborn PARP(+/+) and PARP(-/-) mice and immortalized with the E6 and E7 genes of human papilloma virus. In contrast to fibroblasts, keratinocytes from both PARP(-/-) and PARP(+/+) mice express markers of apoptosis in response to sulfur mustard exposure. The effects of PARP on the mode of cell death in different skin cell types may determine the severity of vesication in vivo, and thus have implications for the design of PARP inhibitors to reduce sulfur mustard pathology.
Apoptosis↗
Cloning and functional characterization of an NAD(+)-dependent DNA ligase from Staphylococcus aureus.
A Staphylococcus aureus mutant conditionally defective in DNA ligase was identified by isolation of complementing plasmid clones that encode the S. aureus ligA gene. Orthologues of the putative S. aureus NAD(+)-dependent DNA ligase could be identified in the genomes of Bacillus stearothermophilus and other gram-positive bacteria and confirmed the presence of four conserved amino acid motifs, including motif I, KXDG with lysine 112, which is believed to be the proposed site of adenylation. DNA sequence comparison of the ligA genes from wild type and temperature-sensitive S. aureus strain NT64 identified a single base alteration that is predicted to result in the amino acid substitution E46G. The S. aureus ligA gene was cloned and overexpressed in Escherichia coli, and the enzyme was purified to near homogeneity. NAD(+)-dependent DNA ligase activity was demonstrated with the purified enzyme by measuring ligation of (32)P-labeled 30-mer and 29-mer oligonucleotides annealed to a complementary strand of DNA. Limited proteolysis of purified S. aureus DNA ligase by thermolysin produced products with apparent molecular masses of 40, 22, and 21 kDa. The fragments were purified and characterized by N-terminal sequencing and mass analysis. The N-terminal fragment (40 kDa) was found to be fully adenylated. A fragment from residues 1 to 315 was expressed as a His-tagged fusion in E. coli and purified for functional analysis. Following deadenylation with nicotinamide mononucleotide, the purified fragment could self-adenylate but lacked detectable DNA binding activity. The 21- and 22-kDa C-terminal fragments, which lacked the last 76 amino acids of the DNA ligase, had no adenylation activity or DNA binding activity. The intact 30-kDa C terminus of the S. aureus LigA protein expressed in E. coli did demonstrate DNA binding activity. These observations suggest that, as in the case with the NAD(+)-dependent DNA ligase from B. stearothermophilus, two independent functional domains exist in S. aureus DNA ligase, consisting of separate adenylation and DNA binding activities. They also demonstrate a role for the extreme C terminus of the ligase in DNA binding. As there is much evidence to suggest that DNA ligase is essential for bacterial survival, its discovery in the important human pathogen S. aureus indicates its potential as a broad-spectrum antibacterial target for the identification of novel antibiotics.
Amino Acid Motifs↗
Orphan G protein-coupled receptors: from DNA to drug targets.
Although G protein-coupled receptors (GPCRs) are the most numerous therapeutic targets to date, ligands remain unknown for approximately two-thirds of these receptors. The challenge in the post-genomic era is to evaluate the role of these 'orphan' GPCRs in normal physiology and disease, and to develop new therapeutics based on this information. A prevalent strategy to determine the function of these orphan GPCRs is to identify specific ligands that conditionally modulate their function. These ligands can then be used to explore the role of the receptor-ligand pair in relevant models of disease. Some promise is emerging from this infant field of functional genomics as several recently deorphanized GPCRs may be potential drug targets for many diseases, including obesity, cardiovascular disease, inflammation and cancer.
Animals↗
Economic impact of onchocerciasis control through the African Programme for Onchocerciasis Control: an overview.
This note overviews several studies that have been conducted on the economic impact of onchocerciasis (river blindness) control through the African Programme for Onchocerciasis Control (APOC). A cost-benefit analysis of the APOC concludes that the programme is highly cost-effective. The economic rate of return (ERR) is 17% if benefits are considered in accordance with the stated objective of the programme (i.e. the achievement of long-term, sustainable, ivermectin-delivery systems). However, the cost-benefit analysis significantly under-estimates the net benefits from the APOC, since it considers, for ease of quantification, only the reduction in blindness as the principal benefit accruing from control activities. Recent studies, summarized here, have shown that there may be substantial benefits (in terms of enhanced productivity, increased household-level welfare, and reduced health-related expenditure, for instance) resulting from the reduction of the skin-related symptoms associated with the disease.
Africa↗
Cost-benefits of onchocerciasis control.
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Africa, Western↗
N-Nitroso compounds and childhood brain tumors: a case-control study.
We questioned mothers of 209 young brain tumor patients and mothers of 209 controls about experiences of possible etiological relevance which they had during pregnancy or which their children had while growing up. Long-suspected brain tumor risk factors such as head trauma and X-rays appeared to be factors for relatively few cases. Increased risk was associated with maternal contact with nitrosamine-containing substances such as burning incense (odds ratio, 3.3; p = 0.005), sidestream cigarette smoke (odds ratio, 1.5; p = 0.03), and face makeup (odds ratio, 1.6; p = 0.02); with maternal use of diuretics (odds ratio, 2.0; p = 0.03) and antihistamines (odds ratio, 3.4; p = 0.002); and with the level of maternal consumption of cured meats (p = 0.008). These drugs contain nitrosatable amines and amides, and the cured meats contain nitrites, chemicals which are precursors of N-nitroso compounds. We propose a hypothesis that brain tumors in these young people are related to in utero exposure to N-nitroso compounds and their precursors, the most potent nervous system carcinogens known in experimental animals.
Adolescent↗
Risk factors for cancer of the testis in young men.
An individual matched case-control study of testis cancer in 131 men under age 40 was conducted to investigate antecedent risk factors including events during prenatal life. Ten patients were born with an undescended testis compared to only two controls (p less equal to 0.02), a previously reported risk factor. Two new risk factors were uncovered: six patients-mothers received hormones during the index pregnancy compared to only one control-mother, and eight patient-mothers and two control-mothers reported excessive nausea as a complication of the index pregnancy. A hypothesis linking these three factors is presented: viz, that a major risk factor for testis cancer is a relative excess of certain hormones (in particular estrogen) at the time of differentiation of the testes.
Adolescent↗
Male genitourinary abnormalities and maternal diethylstilbestrol.
In view of the risk of vaginal cancer developing in young female subjects exposed in utero to maternally ingested diethylstilbestrol a pilot study was undertaken of male subjects similarly exposed. A healthy questionnaire was mailed to 306 male subjects whose mothers were known to have taken diethylstilbestrol in the early part of their pregnancies and to 231 age and sex-matched controls identified from the same record source. Although there was no increased history of cancer, heart disease or asthma when the groups were compared there was a higher incidence of reported urinary tract symptoms and genital abnormalities in the group exposed to diethylstilbestrol. The presence of these abnormalities was confirmed by physical examination of 15 respondents. Studies in experimental animals also have shown that in certain species maternally ingested stilbestrol may result in abnormalities of the genitaltensive clinical studies be undertaken to determine the level of risk, if any, to which many thousands of young men are subject.
Abnormalities, Drug-Induced↗
Regression of liver cell adenomas associated with oral contraceptives.
The regression of liver cell adenomas that follow the use of oral contraceptives when steroids are withdrawn was observed in three patients. At diagnosis by needle biopsy in patients without pain or evidence of hemorrhage, prompt cessation of steriod use is suggested as the preferable form of treatment. The same is true for the diagnosis made at surgery if the tumor or tumors are difficult to remove.
Adenoma↗
Letter: Hepatocellular carcinoma and oral contraceptives.
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Carcinoma, Hepatocellular↗
Liver-cell adenomas associated with use of oral contraceptives.
During the past six years an increasing number of liver-cell adenomas in women were diagnosed, and we undertook a study of possible etiologic factors, including use of oral contraceptives, in 42 women. There was a significant difference between cases and matched controls in mean months of oral-contraceptive use: 73.4 as compared to 36.2 (P less than 0.001). The women with adenomas took mestranol-containing pills much more commonly than the controls (P less than 0.0001). Hemorrhage into the tumor was often associated with the onset of menstruation in women taking oral contraceptives. Long-term use of oral contraceptives, especially those containing a high total dose of steroids or mestranol as the synthetic estrogen, should be balanced against risks of side effects of the drugs.
Adult↗
Histopathologic spectrum of vaginal adenosis and related changes in stilbestrol-exposed females.
A total of 98 colposcopically directed biopsies were obtained from the vagina, cervix, and cervicovaginal ridge (hood) of 80 young women believed to have had intrauterine exposure to stilbestrol (DES). Specific investigation of the patient's medical records corroborated the history of maternal stilbestrol administration in 36 patients (45%), while in the remainder the drug history was regarded as presumptive since medical records were unavailable for review. The findings did not differ significantly in those biopsies taken from patients with confirmed or presumptive drug histories. Histologic evidence of vaginal adenosis was detected in vaginal biopsies from 43 patients. In 30 cases (70%) benign Müllerian-type glandular epithelium was in the superficial vaginal wall, residing on the mucosal surface and/or in the lamina propria. The glandular epithelium predominantly was of endocervical type, but in six instances it resembled endometrial or fallopian tubal epithelium. The glands were accompanied by varying degrees of squamous metaplasia in 22 cases. When extensive the metaplasia produced transformation zones similar to those seen in the normal cervix. Vaginal biopsies of adenosis from the other 13 patients (30%) revealed squamous metaplasia without demonstrable glands due to complete transformation of all antecedent glandular epithelium by squamous metaplasia. Our studies indicate that squamous metaplasia is a component of major importance in the natural history of adenosis and that the concept of adenosis should be broadened to include those examples comprised exclusively of metaplastic epithelium. In such examples metaplasia is identified by the immaturity and poor glycogenation of the squamous cells and their accompanying squamous pegs which often contain residual gland openings or squamous "eddies." Similar findings were present in biopsies of seven cervicovaginal ridges and in cervical biopsies from 37 patients, except for the absence of endometrial or tubal type glands in the latter site. Although no adenocarcinomas were detected, six patients had squamous dysplasia of the vagina and/or cervix. In no case were premalignant or dysplastic changes of glandular cells found. Our findings support the thesis that stilbestrol-associated adenosis represents anomalous embryologic localization of the original squamocolumnar junction in the vagina rather than in the cervix. It is closely related to so-called cervical "erosions." The development of squamous metaplasia accounts for modifications in the clinical and histologic appearances by producing transformation zones which then may be subject to the same oncogenic stimuli for squamous neoplasia as are their counterparts in the cervix.
Adolescent↗
Urogenital tract abnormalities in sons of women treated with diethylstilbestrol.
Since in utero exposure to diethylstilbestrol (DES) is known to cause abnormalities of the female genital tract later in life, exposed male offspring were located, surveyed by mail, and compared with unexposed male offspring from the same period and medical practices. The exposed and unexposed respondents appeared comparable and did not differ in their response to most medical questions. However, a larger proportion of exposed than of unexposed boys had experienced problems in passing urine (12.9% vs. 1.8%, P = .0003) and abnormalities of the penile urethra (4.4% vs. 0%; P = .017).
Abnormalities, Drug-Induced↗
Environmental exposure and bladder cancer in young males.
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Carcinogens↗
Cytologic findings in stilbestrol exposed females with emphasis on detection of vaginal adenosis.
This prospective study of 271 females believed to have had prenatal exposure to stilbestrol documents the cytologic findings in separate vaginal and cervical preparations. In 233 patients, direct circumferential scrapings of the upper vaginal wall were taken after potentially contaminating mucous secretions had been removed. These specimens were considered evaluable for the cytologic detection of vaginal adenosis. Cellular evidence of vaginal adenosis was observed in 105 (45%) of these patients as determined by the identification of columnar cells and/or metaplastic squamous cells in the vaginal samples. Columnar cells were observed in 87 (37%) of the 233 patients. Metaplastic squamous cells accompanied the columnar cells in 54 cases. In an additional 18 patients (8%) metaplastic squamous cells were the only cytologic evidence of adenosis. Similar cellular changes were observed in 88 per cent of the vaginal samples from 25 patients with biopsy-proven vaginal adenosis. Malignant cells were not found in any of the cytologic or histologic specimens. Dysplastic squamous cells, however, were present in cytosmears from four patients. Biopsies from two of these patients confirmed the diagnosis of squamous dysplasia. Dysplasia also was identified by biopsy in four others. We believe cytology is a valuable aid in the evaluation of patients with a history of intrauterine exposure to stilbestrol. Vaginal adenosis as well as neoplastic and dysplastic lesions can be reflected in properly obtained cellular specimens.
Adolescent↗