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PubMed2002

HPV induced cervical carcinogenesis: molecular basis and vaccine development.

Association of infection with papillomavirus and dysplasia of the cervix uteri has been firmly established. There are only few cervical cancers where no HPV DNA is detectable. The mechanism of epithelial cell immortalization by interaction with tumour suppressor genes p53 and pRb by viral oncogenes E6 and E7 is elucidated. Progression of the HPV infected cell to a malignant phenotype involves further modification of host gene expression and/or mutations. The appearance of chromosomal aberrations can lead to mutational inactivation or loss of tumour suppressor genes (TSG), activation and amplification of oncogenes, with importance for the process of carcinogenesis. Oncogene amplification, with exception of few reports, seems not to be a major mechanism in cervical carcinogenesis. In contrast, cytogenetic and loss of heterozygosity (LOH) results from CIN and invasive cancer demonstrate alterations at specific chromosomal regions, pointing at localisation of TSG. Genetic alterations at chromosomes 3p, 6p, 1lq were frequently found early in tumour development Primary invasive carcinoma showed additional allelic losses at chromosome arms 6q, 17p and 18q. Useful biological diagnostic and prognostic markers for high-risk HPV infection and malignant progression may be p16NK4 p27Kip, and NET-I/C4.8. Putative senescence genes relevant for HPV-induced carcinogenesis are localized on chromosomes 2, 4 and 10. Genes for Telomerase suppression are presumably located on chromosomes 3, 4 and 6. Natural immune responses to HPV infection exist Therefore, immune therapy is an attractive possibility for prevention and therapy of HPV infection. To date, vaccine development has reached clinical evaluation. Prophylaxis aims at the induction of virus neutralizing antibodies to capsid proteins. Virus-like particle vaccines are currently tested in clinical trials. Due to the long lag period between infection and clinical manifestation trials will take a long time until conclusive results are obtained. Mandatory expression of viral and perhaps certain cellular genes in infected epithelial and tumour cells offers targets for therapeutic approaches. Since most dysplasia clears spontaneously the viral infection is immunogenic to some extent. However, in some individuals the immune response has to be stimulated by vaccination in order to be effective. Several strategies are being tested in clinical trials and others are in preclinical development The task will be to circumvent immunosuppressive features of the HPV infected cells.

Chromosome Mapping↗
PubMedDate not supplied

Drugs of abuse and abuse of drugs in sportsmen: the role of in vitro models to study effects and mechanisms.

A particular field of analytical chemistry applied to forensic toxicology is represented by the anti-doping analysis, where biological samples (urine and in some instances blood) collected, either "in competition" or "out of competition", from athletes ruled for national/international sport federations, are analyzed to detect the putative use of prohibited substances and methods. Together with the official anti-doping activity to test the athletes (i.e. who engages in competitive sport) for the non-physiological enhancement of sport performance, it is mandatory to activate a new strategy of doping control, that should necessarily comprise a deep and exhaustive toxicological evaluation of the entire spectrum of doping substances and methods. An outline of the present status and of the future trends of the antidoping research is here presented, showing that most of the new tasks could greatly benefit from an approach based on in vitro methods, ranging from specific toxicity studies to the possible detection of new forms of doping.

Cells, Cultured↗
PubMed2006

Prospects for the BCG vaccination programme in France.

Until recently, the French BCG vaccination programme consisted of a mandatory BCG vaccination before children started at daycare centres, and of re-vaccination of tuberculin-negative children. A re-assessment of this programme has been undertaken in recent years. It has led in 2004 to the discontinuation of all revaccinations and post-vaccination tuberculin tests except those post-vaccination tuberculin tests performed as part of a diagnosis of tuberculosis infection or disease or of the follow-up of health or social workers for whom BCG vaccination remains mandatory. Based on an estimate of the epidemiological impact of either selective vaccination of high risk children or discontinuation of BCG vaccination, and taking into account the risk-benefit balance that can be made of the two options, the Conseil Supérieur d'Hygiène Publique de France (CSHPF, national high committee of public hygiene) has recommended a change to selective vaccination. However, the committee has proposed the strengthening of other control measures aimed at decreasing the risk of infection for children, as a pre-requisite to the implementation of this strategy. This position is made more complex by the withdrawal of the multipuncture technique in early 2006, previously used in France in more than 90% of BCG primary vaccinations.

Adolescent↗
PubMed2006

Dynamic tests and basal values for defining active acromegaly.

Acromegaly is a rare disease caused by excess secretion of growth hormone (GH), usually from a pituitary somatotrope adenoma. The prevalence of acromegaly is 38-40 cases/1,000,000 subjects, while the annual incidence is 3 new cases/1,000,000 subjects. The increase in morbidity and mortality associated with acromegaly is the result of GH and insulin-like growth factor (IGF)-I oversecretion and the direct mass effect of the pituitary tumor. Once the disease is clinically suspected, laboratory evaluation is mandatory to establish diagnosis. The standard method for the diagnosis of acromegaly has been the measuring of GH nadir (GHn) during an oral glucose tolerance test (OGTT) which in normal individuals is undetectable, while acromegalics failed to suppress GH levels. Determination of IGF-I levels is useful as they correlate with clinical features of acromegaly and with the 24-hour mean GH levels. According to the more recent consensus, a random GH <0.4 microg/l and IGF-I in the age- and gender-matched normal range exclude the diagnosis of acromegaly. If either of these levels are not achieved, an OGTT should be performed, and then GHn <1 microg/l during OGTT excludes acromegaly. The therapeutic goals for acromegaly include the relief of sings and symptoms, the control of the tumor mass, the correction of the biochemical markers to normal levels, and the reduction in morbidity and mortality to the expected rate for the normal population. According to the 2000 consensus criteria, biochemical control of acromegaly is achieved when circulating IGF-I is reduced to an age- and sex-adjusted normal range and GHn during OGTT is <1 microg/l. There is debate in the literature whether GHn or IGF-I levels are more reliable to evaluate treatment of acromegaly. It has been reported that 15% of acromegalics with GHn <1 microg/l after treatment demonstrate abnormal IGF-I levels, while 15% of patients with normal IGF-I fail to suppress GH levels <1 microg/l during the OGTT. Probably, GHn and IGF-I levels represent two different aspects of disease activity in acromegaly. While IGF-I evaluates the secretory function of the somatotropes, GHn provides evidence of the presence or absence of functional autonomy of these cells.

Acromegaly↗
PubMed1995

Presentation of acute Wernicke's encephalopathy and treatment with thiamine.

Thirty two cases of acute Wernicke's encephalopathy were observed in a period of 33 months, and prior to the mandatory thiamine enrichment of Australian bread-making flour in 1991. These cases were carefully assessed by multiple tests at specified intervals prior to, and following thiamine administration until discharge from hospital. Structured scoring of neurological signs and symptoms, CT scans, psychometry, nutritional measurements, and liver biopsies were performed. There was variation in the presentation and severity of clinical signs and symptoms and in response to treatment. All patients had alcohol-related liver disease, and the results indicated that fatty liver was important in presentation and in response to treatment with thiamine. Other forms of alcohol related brain damage were present in these patients, most of whom were in the 4th or 5th decade of life and had been drinking beer to excess for more than 20 years.

Alcoholic Intoxication↗
PubMed2005

[Management of pulmonary embolism].

Venous thromboembolism is often triggered by transient episodes of increased risk but may occur spontaneously in patients with permanently increased risk. Pulmonary embolism may cause impairment of respiratory and circulatory function which can vary in severity from silent to catastrophic. The diagnosis can be feasibly established by detecting vein thrombosis. If this approach fails, demonstration of pulmonary emboli by lung scans becomes necessary to establish the diagnosis. A D-dimer-test can select patients in whom imaging of pulmonary perfusion is required. Immediate therapeutic anticoagulation with heparins is mandatory in confirmed thromboembolism, and is followed by a vitamin K antagonist. In the initial work-up, patients also have to be evaluated for systemic thrombolytic therapy by hemodynamic parameters and echocardiography. In a triggered episode of venous thromboembolism, duration of anticoagulation is confined to several months while spontaneous or recurrent events require prolonged or indefinite treatment.

Anticoagulants↗
PubMed1999

Colorectal carcinoma: recent advances in its biology and treatment.

Recent advances in the molecular biology and treatment of rectal carcinoma were reviewed mainly on the basis of our own experience. Remarkable improvement in molecular biology has been achieved in the colorectal diseases, and the new knowledge derived from molecular genetics is now being used in the clinical field. The deeper understanding of colorectal carcinogenesis and wider clinical use of molecular diagnosis is one of the examples, and further advances are expected in the next century. Surgical advances are noted particularly in the field of rectal surgery. Various modalities make it possible to assess the clinical stage more precisely, which leads to careful application of the fine surgical procedures used to maintain urinary and sexual functions with low rates of local recurrence and prolonged survival. This decision making should be conducted and can be accomplished by experienced colorectal surgeons with the team members supporting them. The earlier the detection of disease, the easier the operation, with a lower risk of recurrence and longer survival; therefore, early detection of colorectal cancer by means of occult blood test is essential for this purpose. Establishment of the proper training system for appropriate colorectal surgery is also mandatory for this most common gastrointestinal cancer in the Western world, and this is also the case for Japan. The Japan Society for Cancer of the Colon and Rectum is expected to play an important role in this respect.

Colorectal Neoplasms↗
PubMed1992

The stigma of disease: implications of genetic screening.

As the field of human genetics successfully continues to unravel the secrets of an individual's genetic makeup, the social processes of stigmatization and ostracism of those with "undesirable" traits have the potential to increase. An historical example that may shed light on the problems of applying genetic technology to disease prevention is the institution of quarantine. This essay discusses the concept of "quarantine mentality" and the desire for healthy society to separate itself from those labeled "ill" or abnormal, and addresses two episodes in American history when genetics was applied to the formulation of social policy toward the "diseased": the eugenics movement of the early 20th century and the early attempts of genetic screening programs for sickle cell anemia during the 1970s.

Anemia, Sickle Cell↗
PubMed1991

Indomethacin increases the sensitivity of the monocyte migration inhibition assay.

In ophthalmo-immunological investigations only small samples of ocular tissues and fluid are available and assays which are feasible with very small volumes or cell numbers are mandatory. Indomethacin, which is known to augment the immune response both in vivo and in vitro was therefore tested for its effect on the monocyte migration inhibition (MIF) assay using low cell or antigen doses. The sensitivity of the MIF assay may be greatly increased by adding indomethaci during the first step of the assay. Titration of either the antigen dose, the mononuclear cells number or both per assay, resulted in a 10-50-fold increase in sensitivity of the assay, with a broad inter-individual variability. Increasing the sensitivity of the MIF assay with indomethacin has clear advantages with regard to the number of cells required but also confronts us with a new problem: activation of specific cells that circulate at very low frequencies in non-immunized individuals. The enhanced response could be reversed to some extent by adding prostaglandin E2 together with indomethacin to the first step of the assay. Moreover, adding leukotriene B4 to the first step of the assay had an enhancing effect over a limited concentration range. We conclude that in the presence of indomethacin, the MIF assay provides a highly sensitive technique for the demonstration of cellular immune responses in small samples of biological fluids containing very small numbers of antigen-specific lymphocytes.

Cell Migration Inhibition↗
PubMed1996

Itraconazole and leishmaniasis: a randomised double-blind trial in cutaneous disease.

Cutaneous leishmaniasis (CL) is a vector-borne parasitic disease of the skin. Previous open controlled studies with oral itraconazole suggest that it was effective for CL in India. Twenty patients with localised CL participated in this trial. Patients were allocated randomly to receive capsule itraconazole and matching placebo for 6 weeks. No topical medicines were used. Demonstration of Leishmania by slit smear was mandatory. Prior to, periodically during and 3 months after completion of therapy an overall clinical assessment, liver function tests and urinalysis were performed. On decoding, out of the 10 cases receiving drug itraconazole, 7 were declared cured by clinical and parasitological criteria. No major side-effects were noted. Spontaneous remission was observed in 1 case in the placebo group at 3 months follow up. Oral itraconazole has a promising antileishmanial thus secure CL patient from the hazards of antimonials.

Antiprotozoal Agents↗
PubMed2002

Gelatinase B, PECAM-1 and MCP-3 gene polymorphisms in Belgian multiple sclerosis.

Polymorphic microsatellite markers in the genes for gelatinase B, PECAM-1 and MCP-3 have previously been analysed in Swedish and Sardinian individuals to test for association with multiple sclerosis (MS). Confirmation and comparison of genetic associations in various ethnic populations is mandatory and, therefore, we studied these three gene polymorphisms in 216 clinically definite MS patients and 193 normal controls, and in 148 simplex MS families, all of Belgian origin. No allelic associations were found between MS and the CA microsatellite marker in the promoter region of the gelatinase B gene, and the polymorphic CA repeat in the sixth intron of PECAM1. However, the two most abundant alleles of the CA/GA microsatellite polymorphism in the promoter-enhancer region of the MCP-3 gene, A2 (109 bp) and A3 (111 bp), were found to be significantly associated with disease in the case-control study [OR (95% CI)=0.68 (0.51-0.92), p (1 df)=0.015 and OR (95% CI)=1.62 (1.22-2.14), p (1 df)=0.0010, respectively], but not in the family study. These results are in agreement with previous findings in the Swedish and Sardinian populations and reinforce the possibility of a role for chemokines in MS pathogenesis.

Adult↗
PubMed2000

Stimulation protocols for poor responders and aged women.

There is a general consensus on the clinical fact that the more embryos replaced the higher pregnancy rates are achieved. For this reason those IVF cycles with a low response and a reduced number of oocytes and embryos will have very few chances of producing a pregnancy. It is very important to diagnose, by means of the anamnesis and hormonal tests which patients are most likely to present a poor response to conventional ovarian stimulation protocols. It is mandatory to know the patient's plasmatic levels of FSH and estradiol together with personal data such as the age and the previous history of the patient. Only young poor responders with a normal basal hormonal profile will have some chances that by applying new protocols and combining new drugs, improve their response and have higher pregnancy rates. For the old poor responders who have already failed to alternative protocols including natural cycles, oocyte donation is the last and best hope.

Adult↗
PubMed2004

ANCA-GBM dot-blot: evaluation of an assay in the differential diagnosis of patients presenting with rapidly progressive glomerulonephritis.

Rapidly progressive glomerulonephritis (RPGN) is characterized by rapid and progressive loss of renal function and the presence of crescentic glomerulonephritis (CGN). Early diagnosis and appropriate treatment is mandatory to prevent death and/or renal failure. We have evaluated an ANCA-GBM dot-blot diagnostic test in terms of sensitivity, specificity, and inter-observer effect in consecutive patients with RPGN ( n = 82). Control sera ( n = 34) included healthy and relevant disease controls. Dot-blots were independently evaluated by nine observers. Proteinase 3 (PR3)-ANCA, myeloperoxidase (MPO)-ANCA, and both were detected by ELISA in 36, 32, and 3 samples of 71 patients with pauci-immune CGN, respectively. Two additional samples were ANCA negative. The dot-blot revealed a sensitivity of 92-95% for PR3-ANCA and 80-86% for MPO-ANCA. The specificity of the dot-blot for PR3- and MPO-ANCA was 100%. In the patients with anti-GBM nephritis ( n = 9) anti-GBM was detected by both ELISA and dot-blot (sensitivity: 100%). The specificity of the anti-GBM dot-blot was 91-94%. However, the inter-observer effect was relatively high for detection of anti-GBM antibodies (24%). In conclusion, the ANCA-GBM dot-blot is a useful screening tool in situations where conventional ANCA testing is not readily available with excellent performance for PR3-ANCA detection, but less optimal sensitivity for MPO-ANCA and specificity for anti-GBM detection. Therefore, it is recommended to include the following advises in the report to the physicians: 1) patients with a high clinical suspicion for MPO-ANCA-associated RPGN and negative dot-blot must have conventional analysis for MPO-ANCA, and 2) negative anti-GBM dot-blot makes anti-GBM disease very unlikely, but positive samples should be confirmed by conventional anti-GBM tests.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2000

Recurrent hepatitis C after liver transplantation: clinical and therapeutical issues.

Hepatitis C virus (HCV) reinfection after liver transplantation is almost constant, assessed by the persistence of HCV RNA in 90% of cases. Acute hepatitis appeared in 75% of patients at a median of 4 months' post-transplantation. The 5-year actuarial rate of acute and chronic hepatitis on the graft is 75% and 60%, respectively. The rate of HCV cirrhosis on the graft is variable from 8 to 25% at 5 years. After transplantation, HCV viraemia is dramatically increased and correlates with the occurrence of acute hepatitis on the graft. Intrahepatic levels of HCV are high at the time of acute hepatitis, and decrease with constitution of chronic graft hepatitis lesions, implying an immunological response to the viral infection. A relationship between genotype 1b and the prevalence of HCV hepatitis on the graft has been suggested in European but not American series. The influence of the age of the recipient, quasispecies, viral compartmentalization, immunosuppressive treatment, and of HLA matching is being evaluated. The 5-year patient survival is around 65-80%. However, the occurrence of cirrhosis with a risk of graft failure may decrease the 10 and 15-year patient survival. Attempts to give prophylactic post-transplant antiviral treatment are under evaluation. Antiviral treatment of post-transplant graft lesions with combination therapy interferon-ribavirin gave promising results but indications and duration of treatment should be evaluated. In conclusion, HCV reinfection is frequent, but medium-term survival is good. However, the long-term graft and patient survival remains unknown, and efficient prevention and treatment of HCV graft is mandatory.

Age Factors↗
PubMed1984

Genetic screening: marvel or menace?

Genetic screening is a systematic search in the population for persons of certain genotypes. The usual purpose is to detect persons who themselves or whose offspring are at risk for genetic diseases or genetically determined susceptibilities to environmental agents. Is genetic screening a marvel about to free us from the scourge of genetic disease or a menace about to invade our privacy and determine who may reproduce? There are three different types of genetic screening. Newborn screening identifies serious genetic disease at birth, permitting prompt treatment to prevent mental and physical retardation. Fetal screening and prenatal diagnosis identify genetic disease in the fetus permitting selective termination of pregnancy and the opportunity to have children free of defects detectable in utero. Carrier screening identifies individuals heterozygous for a gene for a serious recessive disease who may be at risk for affected offspring. The challenge to society is to provide (by way of cost-effective programs) expert services, including genetic counseling and follow-up, to all who may benefit, to ensure confidentiality and freedom of choice, and to avoid misunderstanding and stigmatization. It is recommended that the objective of screening programs should be to maximize the options available to families at risk rather than to reduce the incidence of genetic diseases. Whenever possible, the providers of these services should be the providers of primary health care. Urgently needed are a greater awareness of avoidable genetic diseases on the part of primary care providers and efforts to familiarize the public with the basic concepts of human genetics through the public school system.

Amniocentesis↗
PubMed2000

Evaluation of F-specific RNA bacteriophage as a candidate human enteric virus indicator for bivalve molluscan shellfish.

Escherichia coli is a widely utilized indicator of the sanitary quality of bivalve molluscan shellfish sold for human consumption. However, it is now well documented that shellfish that meet the E. coli standards for human consumption may contain human enteric viruses that cause gastroenteritis and hepatitis. In this study we investigated using F-specific RNA bacteriophage (FRNA bacteriophage) to indicate the likely presence of such viruses in shellfish sold for consumption. FRNA bacteriophage and E. coli levels were determined over a 2-year period for oysters (Crassostrea gigas) harvested from four commercial sites chosen to represent various degrees of sewage pollution. Three sites were classified as category B sites under the relevant European Community (EC) Directive (91/492), which required purification (depuration) of oysters from these sites before sale. One site was classified as a category A site, and oysters from this site could be sold directly without further processing. Samples were tested at the point of sale following commercial processing and packaging. All of the shellfish complied with the mandatory EC E. coli standard (less than 230 per 100 g of shellfish flesh), and the levels of contamination for more than 90% of the shellfish were at or below the level of sensitivity of the assay (20 E. coli MPN per 100 g), which indicated good quality based on this criterion. In contrast, FRNA bacteriophage were frequently detected at levels that exceeded 1,000 PFU per 100 g. High levels of FRNA bacteriophage contamination were strongly associated with harvest area fecal pollution and with shellfish-associated disease outbreaks. Interestingly, FRNA bacteriophage contamination exhibited a marked seasonal trend that was consistent with the trend of oyster-associated gastroenteritis in the United Kingdom. The correlation between FRNA bacteriophage contamination and health risk was investigated further by using a reverse transcription-PCR assay for Norwalk-like virus (NLV). NLV contamination of oysters was detected only at the most polluted site and also exhibited a seasonal trend that was consistent with the trend of FRNA bacteriophage contamination and with the incidence of disease. The results of this study suggest that FRNA bacteriophage could be used as viral indicators for market-ready oysters.

Animals↗
PubMed1991

There's no quick fix for AIDS.

The epidemiology of AIDS reflects interactions among biological, psychological and social factors. The immune response to the infectious agent is relatively ineffectual; the course of the disease it produces is chronic. The long interval between HIV infection and the appearance of clinical disease maximizes "silent" transmission. The infection is transmitted behaviourally; that is, primarily via specific sexual acts and contaminated paraphernalia employed by IV drug users. The virus entered human populations in an era when such behaviours had become very much more prevalent in response to social change. The public health response to the epidemic was seriously compromised by the stigma attached to the persons victimized by the disease; thus, the mobilization of adequate resources was markedly delayed. Irrational fears of contamination led to proposals for mandatory population-wide screening, in utter disregard of the high false to true positive ratio in screening tests when prevalence is low. Welcome as a vaccine to prevent HIV infection would be, it is not likely to be available, if it can be produced at all, before the end of the century. Control of the epidemic demands that stigma be vigorously combated and that all groups of the population be educated about ways to minimize the likelihood of becoming infected and of transmitting the virus.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Legal and ethical issues of newborn screening.

Newborn screening raises many ethical and legal concerns, from the bioethics issues commonly faced with genetic testing and the practice of informed consent to the classical medical ethics questions that surround resource allocation. This mandatory, state-based healthcare intervention has not met with the resistance that one might have anticipated, yet it is still not integrated into society to its full potential. While there is room for newborn screening programs to improve on the technical, ethical, and legal fronts, this should not discourage policymakers, physicians, scientists, and other stak-holders from learning from the successful aspects of its implementation and applying these lessons to other, related technologies.

Biological Specimen Banks↗

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