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PubMed2006

Bcr interacts with components of the endosomal sorting complex required for transport-I and is required for epidermal growth factor receptor turnover.

Virtually all patients with chronic myelogenous leukemia (CML) express an aberrant protein (p210 Bcr-Abl) that contains NH2-terminal sequences from Bcr fused to COOH-terminal sequences from Abl. In a yeast two-hybrid screen, we have identified TSG101 as a binding partner for Bcr. Because TSG101 is a subunit of the mammalian endosomal sorting complex required for transport (ESCRT), which regulates protein sorting during endosomal trafficking, this association suggests that Bcr may have a related cellular function. The docking site for TSG101 has been mapped to the COOH terminus of Bcr, indicating that this interaction may be disrupted in CML. Overexpression studies with full-length TSG101 and Bcr reveal that this interaction can be recapitulated in mammalian cells. The association can also be observed between natively expressed proteins in a panel of hematopoietic and nonhematopoietic cell lines, where a second subunit of the ESCRT complex, vacuolar sorting protein 28 (Vps28), was also found to interact with Bcr. Both Bcr and TSG101 exhibit a punctate cytoplasmic distribution and seem to colocalize in HeLa cells, which would be consistent with an in vivo association. Bacterially purified Bcr and TSG101 also bind, suggesting that the interaction is direct and is not dependent on ubiquitination. Disruption of the endosomal pathway with an ATPase-defective Vps4 mutant results in the cellular redistribution of Bcr, and suppression of Bcr in HeLa cells by small interfering RNA impairs epidermal growth factor receptor turnover. Taken together, these observations suggest that Bcr is a component of the mammalian ESCRT complexes and plays an important role in cellular trafficking of growth factor receptors.

3T3 Cells↗
PubMedDate not supplied

Trauma radiology: Part V. Imaging of acute cervical spine trauma.

Cervical spine injury constitutes a major cause of morbidity resulting from trauma. The consequences of a missed "significant" injury can be devastating for the patient and can create potential medical legal consequences for involved physicians. Multiple imaging modalities can be applied to imaging of the cervical spine after trauma, including radiography, computed tomography (CT), myelography, CT myelography and magnetic resonance imaging (MRI). Controversy exists concerning the appropriate number of radiographic views required for the screening assessment of cervical spine injuries. CT clarifies uncertain radiological findings, identifies subtle fractures in patients with neck pain or with neurological deficits but with normal radiographs, determines details of injury, and assists in operative planning. MRI has virtually replaced myelography and CT myelography in evaluating the traumatized cervical spine. MRI is more accurate than CT with intrathecal contrast in delineating epidural pathology, ligament injury, soft-tissue edema, and cord parenchymal injury. Information derived from MRI guides appropriate management and has value in predicting injury outcome. We consider indications for and relative merits of these various diagnostic modalities, and we describe imaging features of major patterns of cervical spine injury.

Algorithms↗
PubMed1999

Techniques of CT colonography (virtual colonoscopy).

Colorectal cancer is a leading cause of death in older adults, which usually involves a long-term progressive change of normal mucosa into adenomatous polyps and then cancer. The detection and treatment of this disease in an early stage can lead to a cure in most cases by simply removing the polyp. Computed tomographic colonography (CTC), also referred to as virtual colonoscopy (VC), is a recent advance that gives an intraluminal visualization of the colon that is similar to endoscopy. VC requires fast 3D display (at least 10 frames/sec) of the colon's mucosal surface on a computer screen. Spiral/helical computer tomography is used to gather 3D volume data prior to display. CTC has been demonstrated to be promising for colorectal cancer screening. Studies on unraveling of the colon are underway to map the convoluted tubular structure into a straightened and flattened image volume for global visualization. In this article, we review the current status of CTC with an emphasis on image processing and visualization algorithms. Clinical assessment results of existing techniques are summarized. Practical issues and future perspectives are also discussed.

Colonic Neoplasms↗
PubMed1988

[Preparation of human monoclonal antibodies reactive with human melanoma and the possibility of clinical application].

Human monoclonal antibodies (mAbs) were prepared from the lymph node and peripheral blood lymphocytes (PBL) of the patients with melanoma. NS-1 fusion with lymph node lymphocytes resulted in a higher number of growing hybrids than LICR-LON-HMy2 (LICR-2) fusion. Virtually no hybrids were obtained from NS-1 or LICR-2 fusions with PBL. Epstein-Barr virus transformed the lymphocytes from lymph node and periphered blood with equal efficiency, and the yield of proliferating cultures for antibody screening was more than 10 to 30-fold greater than that obtained by fusion techniques. However, once antibody-producing cultures had been identified, stability and clonability of EBV-transformed cells were poorer than that of NS-1 hybrid cells. To combine the strengths of both methods, cultures of EBV-transformed cells were fused with NS-1, and hybrid clones were isolated that showed vigorous growth, clonability, and stable antibody secretion. Detailed specificity analysis of four mAbs indicated detection of a class 1 (unique) melanoma antigen (GXM1), a class 2 (shared) melanoma antigen (HJM1) and two class 3 (widely distributed) antigen (FCM1 and DSM1). HJM1 reacted most strongly with GD3 and would be a candidate for immunotherapy of melanoma.

Antibodies, Monoclonal↗
PubMed1978

The effect of thyrocalcitonin therapy and phosphate deprivation on tumoral calcinosis.

Six siblings were screened for clinical and biochemical evidence of tumoral calcinosis. The 3 brothers showed all the characteristic manifestations of this entity. Two of them were treated for an initial period of 6 months with large doses of thyrocalcitonin, with virtually no response. After a 9-month equilibration period they were treated by phosphate depletion, and at the end of 6 months they were re-investigated. There was no appreciable objective or radiological difference in the extent of the masses. It was concluded that, in these 2 patients, surgical excision of the tumours was the only feasible form of therapy.

Adult↗
PubMed1995

Sequence analysis of mitochondrial DNA in a new maternally inherited encephalomyopathy.

A heteroplasmic insertion of a 9-bp tandem repeat element was detected in the mitochondrial DNA of the maternal members of a large family. The mutation was contained within the non-coding region between the genes specifying subunit II of cytochrome c oxidase and tR-NA(Lys). The proband and most of his maternal relatives were affected by a late-onset mitochondrial encephalomyopathy of variable severity, characterized by a unique combination of symptoms. Extensive screening of a large series of DNA samples, collected from unrelated normal individuals as well as patients affected by different neurological disorders, consistently failed to detect the 9-bp insertion, with two exceptions: a patient suffering from a syndrome virtually identical to that described in our original family and a child affected by bilateral striatal necrosis, a disorder which has been attributed to impairment of mitochondrial oxidative phosphorylation. These considerations suggest that the 9-bp insertion is pathogenic and that the region affected by the mutation may play a previously unsuspected functional role in mtDNA gene expression.

Aged↗
PubMed1992

Restriction site generating-polymerase chain reaction (RG-PCR) for the probeless detection of hidden genetic variation: application to the study of some common cystic fibrosis mutations.

In this report we describe the use of a DNA amplification technique in which modified primers introduce a base substitution adjacent to the codon of interest and create an artificial restriction site for the detection of mutations which do not produce or modify a naturally occurring restriction site (restriction site generating-polymerase chain reaction, RG-PCR). RG-PCR was developed and applied to the screening in an Italian population sample of several relatively common cystic fibrosis mutations which are not amenable to analysis with a known restriction endonuclease: G542X, 2869insG, Y913C, N1303K, and 1717-1GA. This method, which allows the identification of virtually any single base change by restriction enzyme analysis and without the need for molecular probes, is rapid and easy to perform. The combined use of RG-PCR for several different CF mutations in multiplex tests further expands the advantages of this approach.

Base Sequence↗
PubMed2005

Anti-A and anti-B activity in batches of different intravenous immunoglobulin products determined using a direct haemagglutination method.

The European Pharmacopoeia requires that manufacturers assess intravenous immunoglobulin (IVIG) products for antibodies against blood groups A and B using an indirect anti-globulin test (AGT). However, this method suffers from the disadvantage that the anti-globulin reagent may be neutralised by excess IgG and invalidate the data generated. In view of this, we have used a direct microtitre-based haemagglutination method to screen batches of IVIG products from five manufacturers for anti-A and anti-B, and compared the titres with those reported by the manufacturers. The range of reported titres varied 32-fold across the different products, whereas virtually all the direct method titres fell within a 4-fold range for each specificity. This indicated that the discrepancies in reported titres were due to inconsistencies in manufacturers' testing methodology and/or interpretation of results. Our finding that the anti-globulin reagent used to bring about agglutination of anti-A- or anti-B-sensitised erythrocytes in the AGT was neutralised by excess IgG at least down to a 1 in 8 dilution of IVIG (from 5% (w/v) IgG) casts serious doubts on the suitability of the AGT for testing high immunoglobulin concentration products.

ABO Blood-Group System↗
PubMed2002

Reducing malaria by mosquito-proofing houses.

Sometimes, valuable lessons from history are forgotten, remain unknown, or worse, are ignored. This article reminds us of the pioneering work of Angelo Celli at the end of the 19th century, who demonstrated that people could be protected from malaria by screening their homes against mosquitoes. Since then, public health scientists have continued to show that simple changes in house design have the potential for protecting people against this life-threatening disease. Yet today, this type of intervention remains virtually ignored. The literature reviewed here demonstrates the enormous potential of these methods to reduce malaria, in the hope that it will stimulate scientific debate and further research.

Animals↗
PubMed2004

A gene cluster encoding resistomycin biosynthesis in Streptomyces resistomycificus; exploring polyketide cyclization beyond linear and angucyclic patterns.

Resistomycin is a pentacyclic polyketide metabolite of Streptomyces resistomycificus that exhibits a variety of pharmacologically relevant properties. While virtually all bacterial aromatic polyketides can be grouped into linear and angular polyphenols, resistomycin has a unique "discoid" ring system. We have successfully identified the entire gene cluster encoding resistomycin biosynthesis by heterologously expressing a pooled cosmid library and screening for the fluorescence of the metabolite produced. The rem gene cluster exhibits several unusual features of the type II PKS involved, most remarkably a putative MCAT with highest homology to AT domains from modular PKSs. In addition, we provide the first insight into the molecular basis of a unique mode of cyclization giving rise to a discoid polyketide.

Benzopyrenes↗
PubMed2001

GenEST, a powerful bidirectional link between cDNA sequence data and gene expression profiles generated by cDNA-AFLP.

The release of vast quantities of DNA sequence data by large-scale genome and expressed sequence tag (EST) projects underlines the necessity for the development of efficient and inexpensive ways to link sequence databases with temporal and spatial expression profiles. Here we demonstrate the power of linking cDNA sequence data (including EST sequences) with transcript profiles revealed by cDNA-AFLP, a highly reproducible differential display method based on restriction enzyme digests and selective amplification under high stringency conditions. We have developed a computer program (GenEST) that predicts the sizes of virtual transcript-derived fragments (TDFs) of in silico-digested cDNA sequences retrieved from databases. The vast majority of the resulting virtual TDFs could be traced back among the thousands of TDFs displayed on cDNA-AFLP gels. Sequencing of the corresponding bands excised from cDNA-AFLP gels revealed no inconsistencies. As a consequence, cDNA sequence databases can be screened very efficiently to identify genes with relevant expression profiles. The other way round, it is possible to switch from cDNA-AFLP gels to sequences in the databases. Using the restriction enzyme recognition sites, the primer extensions and the estimated TDF size as identifiers, the DNA sequence(s) corresponding to a TDF with an interesting expression pattern can be identified. In this paper we show examples in both directions by analyzing the plant parasitic nematode Globodera rostochiensis. Various novel pathogenicity factors were identified by combining ESTs from the infective stage juveniles with expression profiles of approximately 4000 genes in five developmental stages produced by cDNA-AFLP.

Animals↗
PubMed1996

Homocystinuria: what about mild hyperhomocysteinaemia?

Hyperhomocysteinaemia is associated with an increased risk of atherosclerotic vascular disease and thromboembolism, in both men and women. A variety of conditions can lead to elevated homocysteine levels, but the relation between high levels and vascular disease is present regardless of the underlying cause. Pooled data from a large number of studies demonstrate that mild hyperhomocysteinaemia after a standard methionine load is present in 21% of young patients with coronary artery disease, in 24% of patients with cerebrovascular disease, and in 32% of patients with peripheral vascular disease. From such data an odds ratio of 13.0 (95% confidence interval 5.9 to 28.1), as an estimate of the relative risk of vascular disease at a young age, can be calculated in subjects with an abnormal response to methionine loading. Furthermore, mild hyperhomo-cysteinaemia can lead to a two- or three-fold increase in the risk of recurrent venous thrombosis. Elevated homocysteine levels can be reduced to normal in virtually all cases by simple and safe treatment with vitamin B6, folic acid, and betaine, each of which is involved in methionine metabolism. A clinically beneficial effect of such an intervention, currently under investigation, would make large-scale screening for this risk factor mandatory.

Cardiovascular Diseases↗
PubMed1995

Hypokalemia in outpatients with eating disorders.

OBJECTIVE: The literature on the prevalence and importance of hypokalemia in persons with eating disorders in contradictory and confusing. The authors investigated the frequency of hypokalemia and its relationship to symptoms in a group of outpatients with eating disorders. METHOD: Diagnostic evaluations and electrolyte studies were performed for 945 outpatients meeting the DSM-III-R criteria for eating disorders at the time of their intake evaluations at a suburban clinic for eating disorders. RESULTS: Clinically significant hypokalemia was comparatively rare. A total of 43 subjects (4.6%) were hypokalemic; of these, seven (0.7% of all subjects) were borderline hypokalemic (serum potassium = 3.4 mmol/liter). The hypokalemic subjects had a significantly lower mean weight and body mass index at entry than the normokalemic subjects. Significantly more of the hypokalemic subjects purged by abusing laxatives, either alone or with vomiting. The patients with restricting (nonpurging) anorexia nervosa, even those whose weights were very low, were generally normokalemic. CONCLUSIONS: The low frequency of hypokalemia in this group of eating disordered outpatients suggests that routine electrolyte determination is a poor screening tool for occult or denied bulimia. Hypokalemia occurred almost invariably in lower-weight bulimic (or anorectic/bulimic) patients who were vomiting and/or abusing laxatives. Indeed, the study suggests that hypokalemia in a patient with an eating disorder is virtually certain evidence that the patient is purging at least daily. In addition, it appears that a patient with purely restricting anorexia nervosa is not at risk for hypokalemia even if his or her weight is very low.

Adolescent↗
PubMed1999

The parasitological and serological prevalence of tsetse-transmitted bovine trypanosomosis in the Eastern Caprivi (Caprivi District, Namibia).

Between August 1995 and June 1997 a survey to determine the distribution of tsetse-transmitted trypanosomosis was conducted in the Eastern Caprivi (Caprivi District, Namibia). A total of 1,481 adult cattle was examined at 33 sampling sites. Direct parasitological diagnostic tests were used and eluted blood spots were screened for the presence of anti-trypanosomal antibodies. Tsetse-transmitted trypanosomal infections were detected in 66 animals (4.5%) from 14 different locations. The parasitological and serological prevalence of trypanosomosis was highest in the Mamili area. Trypanosomosis was virtually absent in the Linyanti/Chobe area and the target barrier along the Kwando River had significantly reduced the prevalence of trypanosomosis in cattle grazing to the east of it. This suggests that anti-trypanosomal antibody prevalence data can be used to evaluate and monitor the effectiveness of tsetse control measures. Survey results suggest that in the Katima Mulilo area, trypanosomal infections were being acquired when cattle grazed along the Zambezi River. Moreover, survey results indicate that tsetse have not been able to establish themselves in the Katima Mulilo area. The parasitological prevalence in a herd and the respective prevalence of anti-trypanosomal antibodies was significantly correlated to the percentage of anaemic animals in that herd. Furthermore, the parasitological prevalence in a herd was positively correlated with the prevalence of anti-trypanosomal antibodies of that herd. It is concluded that the prevalence of anti-trypanosomal antibodies in a herd can be used as an additional indicator of the extent of infection in that particular herd.

Animals↗
PubMed1976

The epidemiological situation of brucellosis in Africa.

Brucellosis, as a geomedical literature survey has shown, is spread to a higher of lesser degree of incidence virtually over the whole African continent. Its epidemiological spectrum of host animals is especially rich amongst the domestic and wild animal species. All domestic animal species and 21 of 26 herbivorous and 5 of 12 carnivorous wild animal species screened yielded positive brucella antibody serotitres. Thus self-maintaining natural foci independent of the domestic stock have firmly been established. The mapping of the epidemiological situation must be based on survey data which should have been planned, exactly performed, analyzed and reported according to statistical rules. Unfortunately Africa is especially badly covered in the world literature in the field of brucellosis. Representing itself 32.0% (49/153) of the countries of the world, their Medical and Veterinary Departments contributed only 2.1% of the computerized world literature on brucellosis in the period 1969-74. This picture can be considerably changed by including the non-computerized "grey literature" of Department and Laboratory Annual Reports into the screening process. By introducing objective, mathematical criteria for determining the degree of incidence from the available data, the following results were obtained from the literature survey: brucellosis is known or suspected to exist in 40 of the 49 African countries (82%). In 20 (41%) of these countries it represents a major problem, in 10 (20.4%) a moderate problem in the other 10 countries a minor problem to human health and economy. Following the rule that brucellosis can be expected to exist everywhere in the world (with the exception of a few islands) where cattle, sheep and/or goats are kept unless it has been eliminated by vigourous measures of control, it may be expected that the remaining 9 African countries not yet reporting also harbour this chronic, zoonotic disease. 35 of the 40 countries reporting have found brucellosis regularly, 1 exceptionally among domestic animals, 5 among game animals. Only 17 of these 35 (48.5%) have scheduled the disease, even if its incidence has been reported to be high. Only 32 of the 49 countries report on human brucellosis. The main reservoirs of disease and risks of infection vary from place to place with the different main kinds of domestic stock, the animal husbandry and human consumption methods and habits. Thus mainly the cattle herds are the source of infection for those countries where large numbers of cattle are kept and the drinking of raw milk is the custom; however, there is no strict correlation between these two factors. Goats and sheep fill the epidemiological place in all those countries where the lack of marketable milk curtails its consumption; the small ruminants are kept as the main source of meat supply and in close contact with the farmers family within the compound or house.

Africa↗
PubMed1997

Common cancers--genetics, origin, prevention, screening: Parts I and II.

Carcinogenesis is a stepwise process that occurs through mutations of cancer-related genes. Five or more genes must be mutated before malignant transformation occurs in most adult cancers; in some childhood cancers as few as two mutated genes may be sufficient. A rare inherited mutation of a critical gene may predestine cancer to occur in one or more sites. This germline mutation is present in virtually every cell in the body, except half of the germ cells, which do not contain the mutated gene in their haploid chromosome set. These and other genes have been used to piece together a puzzle of regulatory systems that govern cell division and proliferation, as well as apoptosis or programmed cell death. Mutations of these genes result not only in increased cell proliferation but also in diminished cell death. Most genetic changes that occur during carcinogenesis are not inherited or germline. They are acquired after birth and are called somatic mutations. A somatic mutation affects only the mutated cell and its progeny. Each time a cell divides, there is a chance of somatic mutation, and therefore there always is a low, background risk for cancer and other malignant lesions. A far more prevalent cause of cancer-related death in the United States is environmental exposure. Such exposure causes somatic mutations of cancer-related genes through direct damage to DNA or through alteration of proliferation or cell death, which enhances the baseline risk for mutation. As carcinogenesis becomes understood, interventions may be designed that selectively interfere in important steps. Screening for cancer is based on the premise that one can treat a patient for a cancer that has not spread from its primary site. Nevertheless, cancer screening is controversial and often confusing. Issues of costs, risks versus benefits, physical time and effort, and patient compliance all affect the clinician's view of screening, often to the extent that the true value of this approach to cancer control is underappreciated and underutilized. A clinician should consider the following questions when assessing the priority, scope, and intensity of cancer screening. Is the cancer an important public health problem? Can preclinical stages be detected and cured? Are effective screening tests available? Are the tests feasible and acceptable? Have screening programs reduced cancer-specific mortality? Is the screening program cost effective? Is screening generally recommended? There is clear-cut evidence of benefit from screening for cancer of the cervix, breast, colon and rectum, and skin and some specific genetic syndromes. Evidence of survival benefit from screening for prostate cancer is lacking, although prostate specific antigen screening is widely used. Screening for lung and ovarian cancer is ineffective.

Adult↗
PubMed2003

Racial/ethnic differences in the self-reported use of screening mammography.

The efficacy of mammography in reducing breast cancer mortality among women 50-69 years of age has been demonstrated in randomized controlled studies, but many women, especially ethnic minorities, have not been receiving regular mammographic screening. The current study investigated racial/ethnic differences in mammography use and their association with demographic characteristics and other factors. The study population consisted of 4,444 women aged 40 years and older who participated in the 1996 Medical Expenditure Panel Survey. Outcome measures studied included the self-reporting of mammography within the past two years and past year. Multivariate logistic regression modeling was used to examine the effect of race while controlling for other factors. In the univariate analysis, there was virtually no difference between white, black, and Hispanic women in mammography rates within either one or two years. However, multivariate logistic regression suggested that both blacks and Hispanics were more likely than whites to have received recent mammography, as black women were 31% and Hispanic women were 43% more likely than white women to have had a mammogram within the previous two years. Our results suggest that white women are no longer more likely to receive periodic screening mammography than black and Hispanic women, and in fact, might even be less likely to undergo the procedure. This reversal might indicate, at least in part, that programs and other activities to promote screening mammography among ethnic minority women have been successful and should now be expanded to include other women.

Adult↗