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PubMed1994

Regulation of translation by specific protein/mRNA interactions.

This review will focus on cases of specific translational control by protein/RNA interactions in the 5'- or 3'-UTR of eukaryote mRNA where either the cis-acting RNA determinant or the trans-acting protein (or preferably both) have been identified with fair certainty. Examples of messages that are regulated by 5' motifs, which are proposed to occlude ribosome binding when bound by their specific factors, include ferritin and ribosomal protein mRNAs and the autoregulated thymidylate synthase and poly(A)-binding mRNAs. However, it has become increasingly evident recently that 3' UTR determinants and their specific binding proteins also regulate translation efficiency either directly, or indirectly via an influence on the polyadenylation status of the mRNA. It is still unclear how events at the 3' end of mRNA influence ribosome binding. Most, if not all, of the mRNAs known to be regulated by 3' UTR motifs are subject to regulation during early development or during differentiation such as several spermatocyte and oocyte mRNAs and erythroid lipoxygenase mRNA. To date, in all cases where translation is controlled directly by specific protein/mRNA interactions, the protein seems to act as a negative regulator, a translational repressor, whose binding to the specific site on the mRNA results in inhibition of initiation. The only cases of translational activation known so far concern internal initiation of translation of picornaviral RNAs, but this topic is beyond the scope of this review.

Animals↗

PubMed1993

Mass spectrometric investigations of drug-receptor interactions.

Mass spectrometric (MS) detection of biologically important noncovalent complexes is reviewed within the scope of on-going studies on this topic from this laboratory. The merits of ion spray MS and tandem MS are demonstrated in this area with examples that show systemic studies of several receptor-ligand, enzyme-substrate, and enzyme-product complexes associated with both an established well-characterized biological system (lysozyme hydrolysis of N-acetylglucosamine) and an important modern receptor-ligand complex (FKBP-FK-506 and FKBP-rapamycin). These examples and recent applications of negative ion MS and MS/MS with DNA adducts, heme-globin complexes, and antibiotic-binding proteins suggest an exciting new area of applications for MS that have not been previously available to investigators.

Animals↗

PubMed1995

Medical genetics in Singapore.

This paper is a brief review of the scope of research and clinical work in human genetics in Singapore. Clinical genetics and karyotyping were established in the early sixties. G6PD deficiency was discovered then as the commonest cause of kernicterus in the newborn. Screening of all newborns was instituted. The measures taken have been very successful and kernicterus is virtually unknown since the early 1970s. Numerous G6PD variants have been discovered and characterized. During the 1980s the emphasis shifted to molecular genetics. Work on the molecular genetics of alpha- and beta-thalassemias, Duchenne muscular dystrophy, hemophilia and retinoblastoma have been established, and good progress on diseases such as neurofibromatosis, leukemias, and lymphoid malignancies. The diagnosis of tuberculosis by DNA amplification (PCR) has been successfully implemented. Numerous papers have been published on the molecular genetics of coronary artery disease, as well as in population genetics.

Adult↗

PubMed2005

18F-fluoro-2-deoxy-D-glucose positron emission tomographic imaging: recent developments in head and neck cancer.

PURPOSE OF REVIEW: Positron emission tomography using 18F-fluoro-2-deoxy-D-glucose (18FDG-PET) is well established in clinical routine as a metabolism-based whole-body imaging tool for cancer diagnosis and follow-up. Several reports have appeared indicating the potential and limitations of this technique in head and neck cancer (HNC). This review limits its scope to the recent advances using 18FDG-PET in the clinical management of HNC. RECENT FINDINGS: The combination of 18FDG-PET and sentinel node biopsy has been explored for the surgical treatment planning of oral and oropharyngeal cancer. Recent reports indicate that multimodality imaging combining PET with high-end CT scanning increases the diagnostic accuracy. 18FDG-PET has a potential for use in radiation treatment planning and for the prediction of response and early evaluation of treatment efficacy. SUMMARY: Increasingly 18FDG-PET is used as a clinical imaging modality in the different stages of the management of HNC. In particular, its clinical value in initial staging of neck lymph nodes and in the evaluation of recurrent or residual disease is well established. In these settings 18FDG-PET has been shown to be more accurate than conventional imaging. Recent studies indicate that 18FDG-PET could be of additional value in staging the N0 neck, in radiation treatment planning, and in prediction of treatment efficacy.

Fluorodeoxyglucose F18↗

PubMed1994

Helping pregnant teenagers.

Teenagers who are pregnant face many difficult issues, and counseling by physicians can be an important source of help. We suggest guidelines for this counseling, beginning with a review of the scope and consequences of adolescent pregnancy. Communication strategies should be aimed at building rapport with techniques such as maintaining confidentiality, avoiding judgmental stances, and gearing communication to cognitive maturity. Techniques for exploring family relationships are useful because these relationships are key influences on subsequent decisions and behaviors. We discuss topics related to abortion and childbearing, such as safety, facilitation of balanced decision making, the use of prenatal care, and the formulation of long-term plans. Physicians who can effectively discuss these topics can help pregnant teenagers make informed decisions and improve their prospects for the future.

Abortion, Legal↗

PubMed1995

Functional magnetic resonance imaging of the brain.

This conference reviewed the potential scope of application of recently developed techniques for functional magnetic resonance imaging (fMRI) of the brain. The most successful technique is based on the sensitivity of magnetic resonance imaging (MRI) to magnetic effects caused by the modulation of the oxygenation state of hemoglobin, which is induced by local variations in blood flow during task activation. Typically, the MRI signal increases by a few percentage points during brain activation because blood flow and oxygen supply sharply increase. Brain activation images with excellent combined spatial and temporal resolution have been obtained noninvasively using visual, sensorimotor, or auditory stimuli, or during higher-order cognitive processes such as language or mental imagery. Although sensitive to misregistration artifacts and macroscopic vessels, MRI permits both the direct correlation of function with underlying anatomy and repeated studies on the same person. It may become the method of choice for studies of mental and cognitive processes, presurgical mapping, monitoring recovery from stroke or head injuries, exploration of seizure disorders, or monitoring the effects of neuropharmaceuticals.

Animals↗

PubMed2002

Peripheral neuropathies and anti-glycolipid antibodies.

This review charts the progress of anti-glycolipid antibodies in neuropathy, from their original discovery 20 years ago in immunoglobulin M paraproteinaemic neuropathy through to current discoveries mapping their relationship to subtypes of Guillain-Barré syndrome. Antibodies to >20 different glycolipids have now been associated with a wide range of clinically identifiable acute and chronic neuropathy syndromes. Particular progress has been achieved in understanding the link between acute motor axonal neuropathy and antibodies to GM1, GD1a, GM1b and GalNAc-GD1a, and between the cranial, bulbar and sensory variants of GBS and antibodies to the disialylated gangliosides GQ1b, GT1a, GD1b and GD3. In addition to clinical and serological studies, the origins and measurement of anti-glycolipid antibodies and their relationships to similar carbohydrate structures on infectious organisms, particularly Campylobacter jejuni, are discussed in the context of a molecular mimicry hypothesis. The structure and nomenclature of relevant glycolipids are outlined, along with information on their localization in nerve, and the influence this has on clinical phenotypes. Major advances have been made in animal modelling of anti-glycolipid antibody-associated diseases, both in vitro and in vivo. This has advanced our understanding of the role of anti-GQ1b antibodies in Miller Fisher syndrome with particular respect to the motor nerve terminal as a potential site of injury, and led to the creation of rabbit models of anti-GD1b and anti-GM1 antibody-mediated sensory and motor neuropathy, respectively. With such information in place, it will now be possible to determine the precise mechanisms by which antibodies injure the different compartments of peripheral nerve and establish how a range of immunomodulating therapies, including current treatments, exert their therapeutic effects. Despite these very significant advances, considerable gaps in our knowledge persist, and it is likely that other pathogenic pathways operate in inflammatory neuropathy that are unrelated to glycolipid antibodies, although these are outside the scope of this review.

Animals↗

PubMed1987

Arterial involvement in genetic diseases.

Whereas the information on the subject of arterial status is sketchy and haphazard with respect to any one genetic disorder, the number of these diseases would have precluded the provision of a critical review within the scope of this presentation. Thus, it was deemed more meaningful to approach the subject selectively. A brief summary was provided on the nature of the arterial wall and its involvement in genetic diseases either as a primary target or a secondarily affected organ, and on "affinity" of various genetic disorders for a type (elastic, muscular, or smallest), segment (proximal, distal), and layer (intimal, medial, adventitial) of the arterial tree or the arterial wall, respectively. Genetic diseases may affect arteries by "causing" (a) congenital malformations, (b) alteration of the arterial "makeup" without necessarily producing definable lesions, and (c) modification of a nongenetic arterial disease (e.g., atherosclerosis), or by "producing" (d) arterial lesions that are characteristic of (even specific for?) a given genetic disorder. A few examples were selected to illustrate (b) (tuberous sclerosis; infantile GM1-gangliosidosis), (c) Wolman's disease; familial hyperlipoproteinemias), and (d) [Hurler's disease, neurofibromatosis; Ehlers-Danlos syndrome (type IV)]. Whenever available, the results of electron microscopic studies carried out in our laboratories were included. Some of these have not been reported in the literature to date. The need for a coordinated multidisciplinary approach to the study of genetic diseases in general is stressed in closing.

Arteries↗

PubMed2004

Positron emission tomography in gastric and esophageal cancer.

PURPOSE OF REVIEW: Positron emission tomography using the positron emitting glucose analogue 18F-fluorodeoxyglucose has recently emerged as a promising metabolism-based whole-body imaging tool for cancer diagnosis and follow-up. Several reports have recently appeared indicating the potential and limitations of this technique. The review limits its scope to the recent advances of 18F-fluorodeoxyglucose positron emission tomography in the clinical management of gastric and esophageal cancer. RECENT FINDINGS: New studies have been reported on the use of 18F-fluorodeoxyglucose positron emission tomography to assess the early and late metabolic response of a gastroesophageal tumor to chemo(radiation) therapy. The metabolic response as measured by serial 18F-fluorodeoxyglucose positron emission tomography, performed before and during treatment or some weeks thereafter, can be used to predict the clinical and histopathologic response. Moreover, the metabolic positron emission tomography response seems to be related to overall and disease-free survival. SUMMARY: Gastroesophageal 18F-fluorodeoxyglucose positron emission tomography could add significant diagnostic information to the different phases of patient management. At initial diagnosis of esophageal cancer, positron emission tomography detects more distant lymph node and organ metastases compared with conventional diagnostics, allowing a more accurate selection of the most appropriate treatment. Serial 18F-fluorodeoxyglucose positron emission tomography performed before and during chemotherapy allows early identification of nonresponding tumors. 18F-fluorodeoxyglucose positron emission tomography performed after a treatment allows accurate assessment of the residual tumor load. 18F-fluorodeoxyglucose positron emission tomography allows accurate detection and restaging of recurrent disease.

Adenocarcinoma↗

PubMed1998

The neuropathology of adult HIV infection.

Since the onset of the acquired immune deficiency syndrome (AIDS) epidemic fifteen years ago, much has been learned about the effects of the human immunodeficiency virus (HIV) in the nervous system. This review summarizes the pathology findings in the central nervous system (CNS). There is now abundant evidence that HIV can infect the CNS directly, leading to a characteristic HIV encephalitis (HIVE) which occurs in 10-50 p. 100 of AIDS autopsy series. Multinucleated giant cells are the pathognomonic feature of HIVE and are found predominantly in the central white matter and deep grey matter. Evidence of productive HIV infection in the CNS is confined to cells of the microglial/macrophage lineage, from which the giant cells are almost certainly derived. These cells are known to express both CD4 and beta-chemokine receptors, which act in conjunction to permit HIV entry. Restricted infection of astrocytes has also been identified by a variety of methods. HIVE is frequently associated with white matter damage ranging from inflammatory (microglia, macrophages and sparse lymphocytes) to degenerative (myelin loss and axonal damage) pathology. Although giant cells are seen less frequently in neocortical grey matter, significant neuronal loss has been established in a number of studies. Recent investigations using markers of apoptosis, (including TUNEL, Bcl-2 and BAX), have established the presence of DNA damage in some neurons and in other cell types. Axonal damage has also been confirmed by evidence of amyloid precursor protein expression. The CNS is also vulnerable to opportunistic infections and high grade B-cell lymphomas as a result of the immune suppression of advanced HIV infection. Cytomegalovirus (CMV) infection is reported in 10-30 p. 100 of AIDS cases at autopsy, toxoplasma in 10-25 p. 100, progressive multifocal leucoencephalopathy in about 5 p. 100 and lymphomas, usually primary, in up to 10 p. 100. A wide variety of other infections has also been reported. These may coexist with HIVE and may be difficult to diagnose in life. CMV gives rise to microglial nodular encephalitis, ventriculitis, necrotising encephalitis and myelo-radiculitis. Presymptomatic HIV positive patients do not show HIVE or opportunistic infections or lymphomas in the CNS. They frequently display a low-grade T-cell infiltrate in the leptomeninges and parenchyma, particularly around vessels. This lymphocytic infiltrate has been attributed to presumed early invasion of the CNS by HIV although the exact timing of entry is uncertain. It is possible that reported abnormalities in presymptomatic cases such as gliosis, microglial activation and rising proviral load may anticipate the onset of HIVE but most studies show that significant CNS damage and HIV-related pathology is confined to patients with AIDS. HIV-related pathology in the spinal cord includes not only HIV myelitis, opportunistic infections and lymphomas, but also vacuolar myelopathy (VM) which affects predominantly the dorsolateral white matter tracts. The cause of VM is not understood and has not been unequivocally linked with HIV infection. It is noted that none of these neuropathological features (including HIVE) correlates exactly with the clinical expression of AIDS-related dementia (ARD). The exact contribution of macrophage activation and cytokine release, astrocytic infection, neuronal loss and axonal damage to the neuropsychiatric syndromes of advanced HIV infection remain to be determined. While the current understanding of the pathogenesis of HIVE and ARD is beyond the scope of this review it is axiomatic that accurate documentation of neuropathology findings will help to resolve the outstanding dilemmas relating to HIV infection of the CNS. There is considerable optimism that progress in therapeutic regimes for HIV-infected patients will succeed in eliminating the virus from the blood and from lymphoid tissue. (ABSTRACT TRUNCATED)

AIDS-Related Opportunistic Infections↗

PubMed2000

Prophylactic vitamin K for vitamin K deficiency bleeding in neonates.

BACKGROUND: Vitamin K deficiency can cause bleeding in an infant in the first weeks of life. This is known as Hemorrhagic Disease of the Newborn (HDN). HDN is divided into three categories: early, classic and late HDN. Early HDN occurs within 24 hours post partum and falls outside the scope of this review. Classic HDN occurs on days one to seven; common bleeding sites are gastrointestinal, cutaneous, nasal and from a circumcision. Late HDN occurs from week 2-12; the most common bleeding sites are intracranial, cutaneous, and gastrointestinal. Vitamin K is commonly given prophylactically after birth for the prevention of HDN, but the preferred route is uncertain. OBJECTIVES: To review the evidence from randomized trials in order to determine the effectiveness of vitamin K prophylaxis in the prevention of classic and late HDN. Main questions are: Is one dose of vitamin K, given after birth, able to significantly reduce the incidence of classic and late HDN? Is there a significant difference between the oral route and the intramuscular route in preventing classic and late HDN? Are multiple oral doses of vitamin K, given after birth, able to significantly reduce the incidence of classic and late HDN? SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. SELECTION CRITERIA: All trials using random or quasi-random patient allocation, in which methods of vitamin K prophylaxis in infants were compared to each other, placebo or no treatment, were included. DATA COLLECTION AND ANALYSIS: Data were extracted independently by each author and were analysed with the standard methods of the Cochrane Collaboration and its Neonatal Review Group, using relative risk, risk difference and weighted mean difference. MAIN RESULTS: Two eligible randomized trials, each comparing a single dose of intramuscular vitamin K with placebo or nothing, assessed effect on clinical bleeding. One dose of vitamin K reduced clinical bleeding at 1-7 days, including bleeding after circumcision, and improved biochemical indices of coagulation status. Eleven additional eligible randomized trials compared either a single oral dose of vitamin K with placebo or nothing, a single oral with a single intramuscular dose of vitamin K, or three oral doses with a single intramuscular dose. None of these trials assessed clinical bleeding. Oral vitamin K improved biochemical indices of coagulation status at 1-7 days. There was no evidence of a difference between the oral and intramuscular route in effects on biochemical indices of coagulation status. A single oral compared with a single intramuscular dose resulted in lower plasma vitamin K levels at two weeks and one month, whereas a 3-dose oral schedule resulted in higher plasma vitamin K levels at two weeks and at two months than did a single intramuscular dose. REVIEWER'S CONCLUSIONS: A single dose (1.0 mg) of intramuscular vitamin K after birth is effective in the prevention of classic HDN. Either intramuscular or oral (1.0 mg) vitamin K prophylaxis improves biochemical indices of coagulation status at 1-7 days. Neither intramuscular nor oral vitamin K has been tested in randomized trials with respect to effect on late HDN. Oral vitamin K, either single or multiple dose, has not been tested in randomized trials for its effect on either classic or late HDN.

Humans↗

PubMed2007

Cellular pathways to beta-cell replacement.

In the twenty-first century, diabetic patients are likely to be one of the major beneficiaries from the advancement of regenerative medicine through cellular therapies. Though the existence of a specific self-renewing stem cell within the pancreas is still far from clear, a surprising variety of cells within the pancreas can differentiate towards a beta-cell phenotype: ductular cells, periductular mesenchymal cells and beta-cells themselves can all give rise to new beta-cells. Extra-pancreatic adult somatic stem cells, in particular, those originating from bone marrow may also be capable of differentiating to beta-cells, though equally well the beneficial effects of bone marrow cells may reside in their contribution to the damaged islet vasculature. Forced expression of the beta-cell-specific transcription factor Pdx1 in hepatocytes also holds promise as a therapeutic strategy to increase insulin levels in diabetic individuals. Embryonic stem (ES) cells are clearly another possible source for generating beta-cells, but ES cells are beyond the scope of this review, which focuses on adult stem and progenitor cells capable of producing beta-cells. Despite considerable endeavour, we still have much to learn in the field of pancreatic regeneration prior to any clinically applicable therapy based upon adult stem cells.

Animals↗

PubMedDate not supplied

Role of chemotherapy in head and neck cancer: systemic use of single agents and combinations in advanced disease.

Chemotherapy of head and neck cancer has recently been receiving increasing attention as a treatment modality. The basis for this interest has been the availability of at least three agents with reproducible antitumor activity: methotrexate, bleomycin, and cisplatinum (diamminedichloroplatinum). These agents alone or in combination have been demonstrated to be of palliative value in patients whose disease recurs or is too advanced for other therapeutic modalities. Although the multiple drug regimens used have not been curative, their relative effectiveness has raised hopes that, in combination with other modalities, they may lead to improvements in survival and in local control in earlier stages of disease. In addition, as a result of multimodality approaches, it is hoped that it may be possible to identify the role of chemotherapy and specific agents in the treatment of various sites of origin of these tumors. The interaction of chemotherapy and radiation--and the use of intraarterial chemotherapy--fall beyond the scope of this review but constitute another important aspect for investigation in the treatment of these malignancies.

Bleomycin↗

PubMed2005

Nuclear inositol lipid metabolism: more than just second messenger generation?

A distinct polyphosphoinositide cycle is present in the nucleus, and growing evidence suggests its importance in DNA replication, gene transcription, and apoptosis. Even though it was initially thought that nuclear inositol lipids would function as a source for second messengers, recent findings strongly indicate that lipids present in the nucleus also fulfil other roles. The scope of this review is to highlight the most intriguing advances made in the field over the last few years, such as the possibility that nuclear phosphatidylinositol (4,5) bisphosphate is involved in maintaining chromatin in a transcriptionally active conformation, the new emerging roles for intranuclear phosphatidylinositol (3,4,5) trisphosphate and phosphoinositide 3-kinase, and the evidence which suggests a tight relationship between a decreased level of nuclear phosphoinositide specific phospholipase C-beta1 and the evolution of myelodisplastic syndrome into acute myeloid leukemia.

Animals↗

PubMed1999

Communicating their individual results to participants in an environmental exposure study: insights from clinical ethics.

The objective of this study was to formulate a framework for determining what information to communicate to individual subjects of a study measuring biomarkers of exposure, consistent with the principles of ethical clinical and research practice. Methods consisted of review of the scope of environmental exposure studies, including the use of biomarker measurement in clinical medicine and environmental research and the relevant principles of clinical ethics and research practice. An exposure biomarker study is designed to elucidate constitutional, behavioral, and environmental determinants of tissue concentrations of exogenous substances. Of itself, it is not designed to measure risk relations, those being the relation between biomarker levels and health outcomes. In many settings, measured tissue biomarker concentrations fall below those known or reasonably predicted to cause disease. Ethical clinical and research practice, aiming to maximize autonomy and beneficence and to minimize harm, requires that study findings concerning the determinants of exposure be communicated to study participants. In addition, investigators should reference clinical action levels beyond which individual biomarker results are routinely communicated to participants. When biomarkers have no known relation to risk, or when levels fall below action levels, it may be preferable not to communicate individual results, if this arrangement has been formalized at the time of informed consent.

Biomarkers↗

PubMed2001

Characterization and application of plant hairy roots endowed with photosynthetic functions.

The scope of this review includes the physiological properties of the hairy roots induced by light irradiation and the kinetic analysis considering the effects of light intensity on hairy root cultures. The cell lines of photomixotrophic and photoautotrophic hairy roots of pak-bung are established from heterotrophic ones by improving the photosynthetic ability of hairy roots through acclimation cultures under light irradiation. Comparisons of physiological properties of derived photoautotrophic cell line with photomixotrophic and heterotrophic ones are also made through histological examination. Moreover, the effect of photosynthesis inhibitor on the photoautotrophic growth of the hairy roots is described. By elucidating the influences of light intensity on growth and chlorophyll formation of photoautotrophic and photomixotrophic hairy roots, a kinetic model was applied to describe the hairy root growth and chlorophyll formation of these cell lines of hairy roots.

Cell Culture Techniques↗

PubMed1995

Transgenic and gene knockout mice in cancer research.

Transgenic animal technology, and the use of germline manipulation for the creation of targeted gene mutations, has resulted in a plethora of murine models for cancer research. Our understanding of some of the important issues regarding the mechanisms controlling cell division, differentiation and death has dramatically advanced in recent years through exploitation of these techniques to generate transgenic mice. In particular, the generation of mice with targeted mutations in genes encoding proteins of oncological interest has proved to be a useful way of elucidating the function of these gene products in vivo. Transgenic mouse models have provided some insight into the complex oncogenic events contributing to cellular dysregulation and the loss of growth control that can lead to tumorigenesis. These animal studies have highlighted the fact that there are many different stages at which the loss of cell cycle control can occur, as a result of mutations affecting proteins anywhere from the cell surface to the nucleus. Although mutations affecting growth factors, growth factor receptors, signal transduction molecules, cytoplasmic proteins or nuclear proteins might appear to be very distinct, the end result of these changes may be accelerated and unchecked cell growth ultimately leading to cancer. It is beyond the scope of this review to mention every animal model that has been developed for cancer research, especially since many of the early studies have been covered extensively in previous reviews. This article will instead focus on a small selection of transgenic and knockout animal models which exemplify how proteins from distinct localisations along multiple pathways can contribute to loss of cell cycle control and the pathogenesis of cancer.

Animals↗

PubMed1990

The initial hemodynamic response to newer antihypertensive agents at rest and during exercise: review of visacor, doxazosin, nisoldipine, tiapamil, perindoprilat, pinacidil, dilevalol, and carvedilol.

Antihypertensive drugs may lower blood pressure through very different mechanisms, initially as well as during chronic use. This article is a review of the immediate hemodynamic changes induced by a beta blocker (visacor), an alpha-receptor blocker (doxazosin), two calcium antagonists (tiapamil and nisoldipine), an angiotensin-converting enzyme inhibitor (perindoprilat), two double-acting compounds (dilevalol and carvedilol), and placebo studied in 126 patients with mild to moderately severe essential hypertension. The patient populations of the different treatment groups were comparable. The invasive hemodynamic technique, including intraarterial blood pressure (BP) recording and measurements of cardiac output by cardiogreen, was the same in all studies. All antihypertensive compounds examined induced a rapid reduction in blood pressure both at rest and during exercise, while no significant changes occurred in the placebo group. This review shows the scope of hemodynamic responses, ranging from peripheral vasodilation to a reduction of heart rate and blood flow. Furthermore, different counterregulatory effects blunting the immediate BP reduction are demonstrated.

Adult↗