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Gallium-67 scintigraphy: a cornerstone in functional imaging of lymphoma.

Until recently, gallium-67 scintigraphy (GS) has been the best available functional imaging modality for evaluating patients with non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). The diagnostic accuracy of GS in detecting lymphoma is based on optimisation of the imaging protocol, knowledge of potential physiological and benign sites of (67)Ga uptake, and the Ga avidity characteristics of the individual lymphoma. As (67)Ga is a tumour viability agent, the role of GS is primarily at follow-up. A residual mass persisting on CT after treatment poses a common clinical dilemma: it may indicate the presence of viable lymphoma, which requires further treatment, or it can be benign, consisting of only fibrotic and necrotic tissues. GS can successfully differentiate between these conditions. Routine follow-up with GS may allow early diagnosis of recurrence and early institution of treatment. Reversion of a positive GS to a negative test, and the rapidity with which this occurs has a high predictive value for the outcome of the individual patient. Lymphoma showing a normal GS early during treatment has a better prognosis than lymphoma with persistence of pathological findings. Other tumour-seeking single-photon emitting agents, such as thallium-201, technetium-99m methoxyisobutylisonitrile and indium-111 octreotide, have been investigated in lymphoma, primarily as an alternative to GS in specific clinical settings, but are of limited value. The role of radioimmunoscintigraphy is gaining importance in conjunction with radioimmunotherapy. Fluorine-18 fluorodeoxyglucose (FDG) imaging of lymphoma using either dedicated or camera-based PET systems is gradually replacing GS for assessment of lymphoma. FDG overcomes some of the limitations of GS while sharing its tumour viability characteristics. The extensive clinical knowledge and experience accumulated over three decades with GS in lymphoma provides a solid background as well as a model for the assessment of new functional imaging techniques.

Female↗

Portrait of multifaceted transporter, the multidrug resistance-associated protein 1 (MRP1/ABCC1).

MRP1 (ABCC1) is a peculiar member of the ABC transporter superfamily for several aspects. This protein has an unusually broad substrate specificity and is capable of transporting not only a wide variety of neutral hydrophobic compounds, like the MDR1/P-glycoprotein, but also facilitating the extrusion of numerous glutathione, glucuronate, and sulfate conjugates. The transport mechanism of MRP1 is also complex; a composite substrate-binding site permits both cooperativity and competition between various substrates. This versatility and the ubiquitous tissue distribution make this transporter suitable for contributing to various physiological functions, including defense against xenobiotics and endogenous toxic metabolites, leukotriene-mediated inflammatory responses, as well as protection from the toxic effect of oxidative stress. In this paper, we give an overview of the considerable amount of knowledge which has accumulated since the discovery of MRP1 in 1992. We place special emphasis on the structural features essential for function, our recent understanding of the transport mechanism, and the numerous assignments of this transporter.

Adenosine Triphosphate↗

Vascular injury and complication in neurosurgical spine surgery.

Vascular injury is an uncommon, but not rare complication of spine surgery. The consequence of vascular injury may be quite devastating, but its incidence can be reduced by understanding the mechanisms of injury. Properly managing vascular injury can reduce mortality and morbidity of patients. A review of the literature was conducted to provide an update on the etiology and management of vascular injury and complication in neurosurgical spine surgery. The vascular injuries were categorized according to each surgical procedure responsible for the injury, i.e., anterior screw fixation of the odontoid fracture, anterior cervical spine surgery, posterior C1-2 arthrodesis, posterior cervical spine surgery, anterolateral approach for thoracolumbar spine fracture, posterior thoracic spine surgery, scoliosis surgery, anterior lumbar interbody fusion (ALIF), lumbar disc arthroplasty, lumbar discectomy, and posterior lumbar spine surgery. The incidence, mechanisms of injury, and reparative measures were discussed for each surgical procedure. Detailed coverage was especially given to vascular injury associated with ALIF, which may have been underestimated. The accumulation of anatomical knowledge and advanced imaging studies has made complex spine surgery safer and more reliable. It is not clear, however, whether the incidence of vascular injury has been reduced significantly in all procedures of spine surgery. Emerging new techniques, such as microendoscopic discectomy and lumbar disc arthroplasty, seem to be promising, but we need to keep in mind their safety issues, including vascular injury and complication.

Blood Vessels↗

Ischaemic preconditioning of the brain, mechanisms and applications.

BACKGROUND: The concept of ischaemic preconditioning was introduced in the late 1980s. The concept emerged that a brief subcritical ischaemic challenge could mobilize intrinsic protective mechanisms that increased tolerance against subsequent critical ischaemia. Tissues with a high sensitivity against ischaemia, i.e. myocardium and central nervous system, present the most promising targets for therapeutic application of ischaemic preconditioning. During the last years the mechanisms of neuronal preconditioning were systematically studied and a number of molecular regulation pathways were discovered to participate in preconditioning. The purpose of the present review is to survey the actual knowledge on cerebral preconditioning, and to define the practical impact for neurosurgery. METHODS: A systematic medline search for the terms preconditioning and postconditioning was filed. Publications related to the nervous system were selected and analysed. FINDINGS: Preconditioning can be subdivided into early and late mechanisms, depending on whether the effect appears immediately after the nonlethal stress or with a delay of some hours or days. In general early effects can be linked to adaptation of membrane receptors whereas late effects are the result of gene up- or downregulation. Not only subcritical ischaemia can trigger preconditioning but also hypoxia, hyperthermia, isoflurane and other chemical substances. Although a vast amount of knowledge has been accumulated regarding neural preconditioning, it is unknown whether the effects can be potentiated by pharmacological or hypothermic neuroprotection during the critical ischaemia. Furthermore, although the practical importance of these findings is obvious, the resulting protective manipulations have so far not been transferred into clinical neurosurgery. Postconditioning and remote ischaemic preconditioning are additional emerging concepts. Postconditioning with a series of mechanical interruptions of reperfusion can apparently reduce ischaemic damage. Remote ischaemic preconditioning refers to the concept that transient ischaemia for example of a limb can lead to protection of the myocardium and possibly the brain. CONCLUSION: Possible cumulative neuroprotection by preconditioning and pharmacological protection during critical ischaemia should be studied systematically. Easy to apply methods of preconditioning, such as the application of volatile anaesthetics or erythropoietin some hours or days prior to planned temporary ischaemia, should be introduced into the practice of operative neurosurgery.

Brain↗

National Institutes of Health State-of-the-Science Conference Statement : Preventing Violence and Related Health-Risking, Social Behaviors in Adolescents, October 13-15, 2004.

NIH consensus and state-of-the-science statements are prepared by independent panels of health professionals and public representatives on the basis of (1) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality (AHRQ), (2) presentations by investigators working in areas relevant to the conference questions during a 2-day public session, (3) questions and statements from conference attendees during open discussion periods that are part of the public session, and (4) closed deliberations by the panel during the remainder of the second day and morning of the third. This statement is an independent report of the panel and is not a policy statement of the NIH or the Federal Government. The statement reflects the panel's assessment of medical knowledge available at the time the statement was written. Thus, it provides a "snapshot in time" of the state of knowledge on the conference topic. When reading the statement, keep in mind that new knowledge is inevitably accumulating through medical and behavioral research.

Adolescent↗

Application of advances in molecular biology to the treatment of brain tumors.

Recent advances in molecular biology have substantially improved our understanding of the molecular genetics of primary brain neoplasms. Soon each histopathologic category of glioma will be further divided into subgroups according to similar genetic background, gene expression profile, and similarity of biologic responses to radiotherapy or chemotherapy. Identification of key molecules that are specifically altered in neoplastic cells will provide candidate molecular targets for tumor treatment. Novel therapeutic tools for targeting tumor cells, such as viral vectors for gene therapy, have been created. In the near future, the accumulation of new knowledge in brain tumor biology and genetics, combined with rational drug design, will revolutionize the treatment of malignant gliomas, which are among the most lethal human cancers.

Apoptosis↗

Method of analysis of local neuronal circuits in the vertebrate central nervous system.

Although a considerable amount of knowledge has been accumulated about the activity of individual nerve cells in the brain, little is known about their mutual interactions at the local level. The method presented in this paper allows the reconstruction of functional relations within a group of neurons as recorded by a single microelectrode. Data are sampled at 10 or 13 kHz. Prominent spikes produced by one or more single cells are selected and sorted by K-means cluster analysis. The activities of single cells are then related to the background firing of neurons in their vicinity. Auto-correlograms of the leading cells, auto-correlograms of the background cells (mass correlograms) and cross-correlograms between these two levels of firing are computed and evaluated. The statistical probability of mutual interactions is determined, and the statistically significant, most common interspike intervals are stored and attributed to real pairs of spikes in the original record. Selected pairs of spikes, characterized by statistically significant intervals between them, are then assembled into a working model of the system. This method has revealed substantial differences between the information processing in the visual cortex, the inferior colliculus, the rostral ventromedial medulla and the ventrobasal complex of the thalamus. Even short 1-s records of the multiple neuronal activity may provide meaningful and statistically significant results.

Animals↗

Huntington's disease.

Early in 1993, an unstable, expanded trinucleotide repeat in a novel gene of unknown function was identified on HD chromosomes. This discovery unleased a flurry of experimentation that has established the expanded CAG repeat the almost universal cause of the characteristic neurologic symptoms and pathology of this neurodegenerative disorder of midlife onset. The biochemical basis for the specific neuronal loss of HD remains uncertain, but the genetic lesion probably acts via its consequent polyglutamine segment in the protein product, huntingtin. This review will describe the basic parameters of the HD repeat's behavior and the knowledge that has accumulated concerning its potential mechanisms of action.

Age of Onset↗

Expression of noncoding mRNA in human blood cells activated with synthetic peptide of HIV.

T cells activation includes several steps such as translational events, activation of transcription for different genes, expression of surface molecules, secretion of cytokines, effectors functions. Knowledge has been accumulated on various nontranslatable RNA transcripts that are synthesized. In this context, a member of T cell noncoding transcripts (NTT) has been identified. It has been known that this gene is selectively expressed in activated T cells, as a 17-kb transcript. In this study, we investigate cell activation using RT-PCR to detect NTT. We investigated the expression of IFNgamma mRNA, a cytokine produced by activated blood mononuclear cells treated with HLA-A2 restricted synthetic peptide of HIV (p9) by RT-PCR detecting a fragment of 300 bp. This finding demonstrated that human HLA-A2 blood mononuclear cells have been activated in the presence of synthetic peptide of HIV (p9) and can induce expression of mRNA of NTT and IFNgamma which was confirmed by direct sequencing. For the first time, we have demonstrated an endogenous noncoding human RNA molecule, NTT mRNA, suggesting its implication in the cellular immune response.

Blood Cells↗

An RNA-centered view of eukaryotic cells.

Emerging evidence suggests that the introns and intergenic sequences of the genomes of higher eukaryotes (the "junk" DNA) codes for a vast, RNA-based, genetic regulatory network. It is believed that this network is responsible for the variety and complexity of terrestrial life. We conjecture that this regulatory network is more properly viewed as an RNA "community", composed of a rich and largely unexplored biochemical web of RNA interactions. Viewed as an RNA-community, we hypothesize that the RNA regulatory network of higher eukaryotes can re-wire itself, and employ various and evolvable mutational strategies in response to external pressures. Thus, we argue that much evolutionary change is due to intracellular, RNA-mediated learning processes. Successful strategies and pathways are then recorded (hard-wired) into the DNA genome via reverse transcriptase. We present evidence, which is consistent with this viewpoint, and make specific theorems, which could be used to test the utility of our framework. If essentially correct, the RNA-community view of eukaryotic cells could reconcile measured point mutation and gene duplication rates with actual rates of evolutionary change. Futhermore, the RNA-community view of eukaryotic cells suggests that agent-based modeling techniques, used in mathematical economics, game theory, and neuroscience, will likely be as useful in understanding the functioning of eukaryotic cells as the pathway-based approaches of systems biology. We conclude this paper by arguing that a sufficient amount of biological knowledge has been accumulated to initiate a systematic program of experimental and computational studies of the origins and macroevolution of terrestrial life.

Animals↗

P53 and prognosis: new insights and further complexity.

Despite the massive amount of knowledge that has accumulated about p53, there is still much to learn about its role in tumor suppression. New papers now provide evidence that levels of Mdm2 in humans or presence of mutant forms of p53 in mice can have profound impacts on survival and tumorigenesis. These findings may lead to new diagnostic and therapeutic approaches to treating cancer patients.

Animals↗

Transuranic and fission product contamination in lake sediments from an alpine wetland, Boréon (France).

Transuranics and fission products have been measured in lake sediment samples, collected in an alpine wetland, to determine their vertical distribution and calculate inventories. The radionuclides considered are 90Sr, 137Cs, 238Pu, 239/240Pu and 241Am. From the results, a better knowledge of radionuclide accumulation mode and behaviour was obtained. In addition, the origins of the individual pollutants could be deduced from activity ratios. Analyses were made on different sediment cores. The sampling sites were chosen to enable future determination of the mass balances of the radiopollutants. As the selected study area is in a recreational area used by urban populations, a rough estimate was made of the mean external dose from 137Cs for comparison with the French regulation.

Americium↗

Comparative genomics and evolution of the tailed-bacteriophages.

The number of completely sequenced tailed-bacteriophage genomes that have been published increased to more than 125 last year. The comparison of these genomes has brought their highly mosaic nature into much sharper focus. Furthermore, reports of the complete sequences of about 150 bacterial genomes have shown that the many prophage and parts thereof that reside in these bacterial genomes must comprise a significant fraction of Earth's phage gene pool. These phage and prophage genomes are fertile ground for attempts to deduce the nature of viral evolutionary processes, and such analyses have made it clear that these phage have enjoyed a significant level of horizontal exchange of genetic information throughout their long histories. The strength of these evolutionary deductions rests largely on the extensive knowledge that has accumulated during intensive study into the molecular nature of the life cycles of a few 'model system' phages over the past half century. Recent molecular studies of phages other than these model system phages have made it clear that much remains to be learnt about the variety of lifestyle strategies utilized by the tailed-phage.

Base Sequence↗

Adolescent depression: challenges and opportunities: a review and current recommendations for clinical practice.

Many aspects of the treatment for adolescent depression are still uncertain. However, our body of knowledge continues to accumulate, and our approaches continue to be refined. When we remember that 40 years ago the field was still arguing about the existence of depression in youth, it is clear that significant progress has been made. Recent controversies have provided another opportunity to step back and re-evaluate. Given the chronicity, morbidity, and mortality associated with adolescent depression, the risks of doing nothing are too great. Evidence-based research has provided us with some direction during this unsettling time. After careful reviews, the major professional organizations representing pediatric medicine and psychiatry all support the continued use of SSRI antidepressant medications but emphasize close monitoring. The debates also have heightened interest in effective psychotherapy approaches, particularly CBT and IPT. Given the risk for suicidality in depressed adolescents, assessment and management of safety concerns remain critical, regardless of medication usage. Above all, it is most important that we remain hopeful about our ability to guide adolescents and families through the struggles with depression toward recovery.

Adolescent↗

Indications for coronary angiography: changes in laboratory practice over a decade.

The indications for coronary angiography have been changing in recent years. To characterize these changes, we examined the records of Mayo Clinic patients referred for 400 coronary angiography procedures in 1973 and 1983 (200 procedures in each study year). We retrospectively assigned patients to one of seven general indication categories to determine the changes in indications used for referral during that decade. We observed a relative increase in angiographic studies related to acute myocardial infarction and percutaneous transluminal coronary angioplasty and a relative decrease in studies for nonspecific chest pain. No change was noted in the relative frequencies of indications related to assessment of anginal chest pain, possible coronary artery disease but no chest pain, assessment after coronary artery bypass grafting procedures, major ventricular arrhythmias, and investigational protocols. We believe that the differences noted primarily reflect the accumulation of new knowledge and new technologic capabilities.

Adolescent↗

Environmental controls in the management of allergic asthma.

Environmental allergen control is one of the four primary goals of good asthma management. The American Academy of Allergy, Asthma, and Immunology has published a position statement [78] that endorses the National Asthma Education and Prevention Program management guidelines [23] and recommends that every patient with persistent asthma be evaluated for environmental allergen sensitivity. Patients who have sensitivities should receive practical advice on allergen avoidance. An accumulating body of knowledge indicates that such measures, when strictly applied for a sufficient period of time, can indeed reduce asthma symptoms, need for medication, and airway hyperresponsiveness. Ongoing prospective trials in large numbers of patients are being conducted and should enhance the ability to make proper recommendations to patients.

Asthma↗

The experience with oxaliplatin in the treatment of upper gastrointestinal carcinomas.

The treatment for advanced gastroesophageal tumors is still largely based on 5-fluorouracil and cisplatin combinations, and the treatment for advanced pancreatic tumors principally relies on gemcitabine. The need for more active agents is evident in light of the poor outcomes for patients with these tumors. Oxaliplatin is an important chemotherapeutic agent currently being investigated in the treatment of gastrointestinal carcinomas. This diaminocyclohexane-platinum compound has significant differences from cisplatin and carboplatin with respect to its activity and toxicity. It appears to have activity in tumors believed to be marginally sensitive to the other platinum agents, and it is neither ototoxic nor nephrotoxic. The main side effect of oxaliplatin is a sensory neuropathy exacerbated by cold exposure. After extensive clinical development, oxaliplatin has become an important option in the treatment of colorectal cancer. Its role in the treatment of upper gastrointestinal cancers is less well established, but is the focus of intense investigation. Much of what we currently know is based on small phase I and II studies, but knowledge is rapidly accumulating. The fact that cisplatin remains an important drug in the treatment of several upper gastrointestinal cancers raises the hope that oxaliplatin will contribute significantly to the treatment of those malignancies as well. Larger randomized phase III trials are being designed and conducted to fully define the role of oxaliplatin in the treatment of upper gastrointestinal tumors in the relatively near future.

Antineoplastic Agents↗

Mild hypothermia--a revived countermeasure against ischemic neuronal damages.

Although hypothermia as a means of cerebral protection against and resuscitation from ischemic damage has a history of approximately six decades, extensive studies, both in basic and clinical fields, on the mechanisms, effects and methods of mild hypothermia at temperatures no less than 31 degrees C have started only in the last decade. In experiments on rodents, hypothermia in the postischemic period that is introduced up to several hours after reperfusion and is maintained for one day followed by a slow rewarming, significantly protects hippocampal neurons against damage. The mode of action of hypothermia is apparently non-specific and multi-focal in widely progressing cascade reactions in ischemic cells; namely, suppressing: (1) glutamate surge followed by; (2) intraneuronal calcium mobilization; (3) sustained activation of glutamate receptors; (4) dysfunction of blood brain barrier; (5) proliferation of microglial cells; and (6) production of superoxide anions and nitric oxide. In addition, mild hypothermia modulates processes in ischemic condition at the level of cell nucleus, such as the binding of transcription factor AP-1 to DNA, and ameliorates the depression of protein synthesis. This non-specific and widely affecting manner might explain why hypothermia is superior to any medicine developed. Recent clinical trials of mild hypothermia in various individual institutions have revealed significantly beneficial outcomes in some cases, along with an accumulation of practical knowledge of techniques and treatments. Large scale randomized studies involving multiple institutions as well as exchange of informations and ideas are needed for further development of hypothermia treatment.

Animals↗