Second surgery for progressive glioblastoma: a multi-centre questionnaire and cohort-based review of clinical decision-making and patient outcomes in current practice.

PURPOSE: Glioblastoma prognosis is poor. Treatment options are limited at progression. Surgery may benefit, but no quality guidelines exist to inform patient selection. We sought to describe variations in surgical management at progression, highlight where further evidence is needed, and build towards a consensus strategy. METHODS: Current practice in selection of patients with progressive GBM for second surgery was surveyed online amongst specialists in the UK and Europe. We complemented this with an assessment of practice in a retrospective cohort study from six United Kingdom neurosurgical units. We used descriptive statistics to analyse the data. RESULTS: 234 questionnaire responses were received. Maintaining or improving patient quality of life was key to decision making, with variation as to whether patient age, performance status or intended extent of resection was relevant. MGMT methylation status was not important. Half considered no minimum time after first surgery. 288 patients were reported in the cohort analysis. Median time to second surgery from first surgery 390 days. Median overall survival 815 days, with no association between time to second surgery and time to death (p = 0.874). CONCLUSIONS: This is the most wide-ranging examination of contemporaneous practice in management of GBM progression. Without evidence-based guidelines, the variation is unsurprising. We propose consensus guidelines for consideration, to reduce heterogeneity in decision making, support data collection and analysis of factors influencing outcomes, and to inform clinical trials to establish whether second surgery improves patient outcomes, or simply selects to patients already performing well.

Neuroinflammation and Functional Connectivity in Alzheimer's Disease: Interactive Influences on Cognitive Performance.

Neuroinflammation is a key part of the etio-pathogenesis of Alzheimer's disease (AD). We tested the relationship between neuroinflammation and the disruption of functional connectivity in large-scale networks, and their joint influence on cognitive impairment. We combined [11C]PK11195 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in 28 patients (12 females/16 males) with clinical diagnosis of probable AD or mild cognitive impairment with positive PET biomarker for amyloid, and 14 age-, sex-, and education-matched healthy controls (8 females/6 males). Source-based "inflammetry" was used to extract principal components of [11C]PK11195 PET signal variance across all participants. rs-fMRI data were preprocessed via independent component analyses to classify neuronal and non-neuronal signals. Multiple linear regression models identified sources of signal covariance between neuroinflammation and brain connectivity profiles, in relation to the diagnostic group (patients, controls) and cognitive status.Patients showed significantly higher [11C]PK11195 binding relative to controls, in a distributed spatial pattern including the hippocampus, frontal, and inferior temporal cortex. Patients with enhanced loading on this [11C]PK11195 binding distribution displayed diffuse abnormal functional connectivity. The expression of a stronger association between such abnormal connectivity and higher levels of neuroinflammation correlated with worse cognitive deficits.Our study suggests that neuroinflammation relates to the pathophysiological changes in network function that underlie cognitive deficits in Alzheimer's disease. Neuroinflammation, and its association with functionally-relevant reorganization of brain networks, is proposed as a target for emerging immunotherapeutic strategies aimed at preventing or slowing the emergence of dementia.SIGNIFICANCE STATEMENT Neuroinflammation is an important aspect of Alzheimer's disease (AD), but it was not known whether the influence of neuroinflammation on brain network function in humans was important for cognitive deficit. Our study provides clear evidence that in vivo neuroinflammation in AD impairs large-scale network connectivity; and that the link between neuro inflammation and functional network connectivity is relevant to cognitive impairment. We suggest that future studies should address how neuroinflammation relates to network function as AD progresses, and whether the neuroinflammation in AD is reversible, as the basis of immunotherapeutic strategies to slow the progression of AD.

Induction of flowering in tropical trees by a 30-min reduction in photoperiod: evidence from field observations and herbarium specimens.

During the late rainy season in October 1997 we observed. over a range of >100 km, the highly synchronous emergence of flower buds in several deciduous tree species of the semi-deciduous tropical forest in Guanacaste, Costa Rica. Synchronous flowering soon after the rapid decline in day length around the September equinox and in the absence of any notable climatic cues suggested flower induction by declining photoperiod. By combining field observations and the analysis of flowering herbarium collections, we established highly synchronous flowering periods with low interannual and latitudinal variation predicted for photoperiodic flower induction for more than 25 tree species and a few herbs. We describe morphogenetic changes at the shoot apex of three species during flower induction and the suppression and induction of flowering in several herbaceous species by experimental daylight extension. The combined observations provide strong, mainly indirect evidence for photoperiodic induction of flowering in many tropical tree species. At low latitudes with annual variation in day length of 1 hour, flower induction must be caused by a decline in photoperiod of 30 min or less. This is the first report of photoperiodic control of flowering in trees.

Photoperiodic control of seasonal development and dormancy in tropical stem-succulent trees.

Tropical stem-succulent trees store large quantities of water in their trunks yet remain leafless during the early and mid dry season. In contrast to most other tropical trees, bud break of vegetative buds is not induced in fully hydrated stem succulents between the winter solstice and the spring equinox by leaf abscission, abnormal rain showers or irrigation. Vegetative buds of leafless trees are therefore in a state of endo-dormancy similar to that of temperate perennial plants during early winter. Highly synchronous bud break regularly occurs soon after the spring equinox, often weeks before the first rainfalls of the wet season. These observations suggested that endo-dormancy and bud break might be induced by declining and increasing photoperiods after the autumn and spring equinoxes, respectively. In phenological field observations, we confirmed highly synchronous bud break after the spring equinox in many trees of five stem-succulent species in the northern and southern hemispheres. Shoot growth of potted saplings of Plumeria rubra L. was arrested by a decline in day length below 12 h after the autumn equinox, but continued in saplings maintained in a 13-h photoperiod. Conversely, exposure to a 13-h photoperiod induced bud break of dormant apical buds in saplings and cuttings in January, whereas plants maintained in the natural day length of < 11.7 h remained dormant. Photoperiodic control of endo-dormancy of vegetative buds in stem succulents is thus supported by field observations and experimental variation of the photoperiod. At low latitudes, where annual variation of day length is less than 1 h, bud dormancy is induced and broken by variations in photoperiod of less than 30 min.

Electric resistance as a measure of tree water status during seasonal drought in a tropical dry forest in Costa Rica.

Variation in electric resistance of stem tissues was used to measure differences and changes in water status among trees in a tropical dry forest in Costa Rica during the dry season. For more than 30 tree species, stem water content (SWC), measured as electric resistance between nails driven 20 mm deep into tree trunks, correlated well with wood density, saturation water content, dehydration, measured with the pressure chamber, and tree development during drought. At dry sites, SWC was lowest in hardwood trees (characterized by high wood density) and highest in stem-succulent lightwood trees (characterized by low wood density). Among hardwood trees, SWC varied with soil water availability. During the dry season, SWC declined before leaf shedding and increased during rehydration preceding bud break. The time course of seasonal changes in SWC apparently constitutes an indirect measure of variation in the relative water content of outer stem tissues, which determines development of dry-forest trees during the dry season.

The bacterial endotoxin test in the PET facility.

A method by which the gel-clot Limulus amebocyte lysate test may be performed in 20 rather than 60 min with sufficient sensitivity to satisfy the needs of the nuclear medicine or positron emission tomography laboratories has been developed and validated for use as a substitute for the Bacterial Endotoxin Test described in the United States Pharmacopeia, 22nd revision. Using this method, results may be obtained from the test prior to the human administration of radiopharmaceuticals without extensive loss of activity and with increased safety when compared to tests performed after administration. Additionally, studies on the shelf-lives of the reagents used in the test were conducted. When refrigerated between use, control standard endotoxin dilutions of 5 EU/ml or greater may be used for at least 1 mo after preparation and reconstituted lysate retains its labeled sensitivity for at least 10 days, considerably longer than the manufacturer's stated shelf-lives.

The value of urine creatinine analysis in the evaluation on Schilling tests.

We performed a prospective study to assess the clinical value of evaluating the adequacy of 24-hour urine specimens submitted for Schilling tests. A total of 121 specimens were evaluated of which 51 had abnormal vitamin B12 excretion values. Of those 51, there were 23 with apparently inadequate total creatinine content (implying a collection of less than 24 hours). Six of 12 specimens with less than 600 ml had adequate total creatinine content as well as normal vitamin B12 excretion. Compared with evaluation of specimen volume alone, these data support the inexpensive urine creatinine assay as a valuable source of information regarding the adequacy of 24-hour urine collections thereby improving the specificity of the Schilling test.

Ca(2+) as developmental signal in the formation of Ca-oxalate crystal spacing patterns during leaf development inCarya ovata.

Changes in the spacing patterns of Ca-oxalate crystals during enlargement ofCarya ovata Mill. leaves were quantified by computerized image-analysis. Single Ca-oxalate crystals form in the vacuoles of young mesophyll cells transformed into crystal cells Crystals are very small in newly induced crystal cells and increase in size throughout leaf development. Crystal patterns thus reflect both induction and relative age of crystal cells. Shortly after the emergence of young leaves from the bud, very small crystals are formed in the mesophyll at high density. As leaves expand, these crystals grow larger and become separated by increasing distances. New small crystals appear in the gaps between the older, larger crystals. Later crystal patterns consist of widely spaced, larger crystals only. Finally, clusters of small crystals are formed again in the gaps between large crystals. No crystals were observed in young leaves expanding in a moist chamber, but large numbers of crystal cells were induced experimentally in sections of immature leaves floating on 4 mM Ca-acetate. The observations support the following mechanism of crystal-pattern formation: Ca(2+) carried into leaves with the transpiration stream acts as the developmental signal inducing transdifferentiation of a few mesophyll cells into crystal cells when apoplastic [Ca(2+)] rises. Crystal cells precipitate absorbed Ca(2+) as oxalate and, acting as Ca(2+) sinks, inhibit crystal-cell induction in their vicinity by depleting apoplastic Ca(2+). This prevents close spacing of crystal cells. New crystal cells form in the gaps between the depletion zones of older crystal cells when these move apart during leaf expansion. Later changes in crystal patterns result from increasing sink strength of crystal cells, lowered inducibility of mesophyll cells, and increased Ca(2+) influx into leaves during intensive transpiration. Throughout leaf development, spacing of crystal cells permits rapid secretion of apoplastic Ca(2+) as Ca-oxalate.

Absent platelet aggregation with normal fibrinogen binding in basset hound hereditary thrombopathy.

Platelets from dogs with Basset Hound Hereditary Thrombopathy (BHT) initially displayed a thrombasthenia-like aggregation defect but have been shown to have normal amounts of platelet membrane glycoproteins IIb and IIIa (GPIIb-IIIa), and therefore are more accurately described as thrombopathic. The presence of normal quantities of GPIIb-IIIa, however, did not rule out the possibility of a functionally abnormal glycoprotein complex which would be unable to bind radio-labeled fibrinogen. Therefore, fibrinogen binding in BHT platelets was evaluated. Platelets from BHT and normal dogs were activated with 1 x 10(-5) M ADP in the presence of 125I-fibrinogen and the surface-bound radioactivity was quantitated. The amount of fibrinogen bound by BHT dog platelets was not significantly different than that bound by normal dog platelets. Platelets from dogs with BHT bound 30,282 +/- 3,133 and normal dog platelets bound 31,664 +/- 2,772 molecules of fibrinogen per platelet. The quantitatively normal GPIIb-IIIa complex binds fibrinogen in normal amounts and does not seem to represent the abnormality responsible for the aggregation defect in BHT platelets. Therefore, other factors central to normal platelet function and related to platelet aggregation must be considered.

Prevention of motion artifacts on dual isotope subtraction parathyroid scintigraphy.

A simple, effective technique is described to identify and eliminate motion artifacts which might potentially invalidate dual isotope subtraction parathyroid scintigraphy. Cobalt-57 markers, appropriately placed on the patient, allow detection of movement and permit realignment if movement occurs between imaging sequences. This technique should assure the accuracy of dual isotope parathyroid subtraction scintigraphy.

C nuclear magnetic resonance study of acetate incorporation into malate during ca-uptake by isolated leaf tissues.

(13)C Nuclear magnetic resonance spectroscopy of leaflets of Gleditsia triacanthos and Albizia julibrisin was used to determine the fate of acetate taken up during the absorption of calcium from (13)C-labeled Ca-acetate solution. Small amounts of acetate accumulated temporarily in the leaf tissues, but the bulk of acetate was incorporated into malate. The initial rate of malate synthesis was very low, but increased rapidly during acetate treatment and reached its maximum after 8 hours; the enzymes involved in malate synthesis thus appear to be substrate induced. Use of acetate-2-(13)C yielded malate labeled in C-3, indicating that vacuolar malate accumulating during Ca-uptake might be synthesized via malate synthase from acetate and glyoxalate. However, a source of glyoxalate condensing with acetate during malate synthesis could not be identified. Glycolate produced in photorespiration is an unlikely source, because glycolate-2-(13)C was absorbed and metabolized by the leaf tissues into products of the glycolate pathway, but was not a major precursor in malate synthesis. Malate synthesis via the glyoxalate cycle is also unlikely, because no evidence for the recycling of a (13)C-labeled 4-carbon organic acid was found. Malate synthesis in the leaflets of Gleditsia and Albizia thus appears to involve the inducible condensation of acetate with a 2-carbon compound of unidentified nature and origin.

Radioiodine therapy of hyperthyroidism precludes thallium-201 myocardial scintigraphy.

The authors attempted to perform Tl-201 myocardial perfusion scintigraphy in a 42-year-old man 23 and 35 days after he received 9.8 mCi of oral I-131 for documented Graves' disease. Interference from primary and scattered photons from residual thyroid I-131 made Tl-201 myocardial scintigraphy technically impossible. A series of phantom and patient studies using I-131 and Tl-201 were performed, yielding guidelines for planning Tl-201 myocardial scintigraphy following radioiodine therapy.

Severe systemic reaction to diphosphonate bone imaging agents: skin testing to predict allergic response and a safe alternative agent.

We describe a severe systemic reaction which occurred in a patient on two occasions after i.v. injection of chemically related diphosphonate bone imaging agents. Skin testing showed reactivity to multiple commercially available diphosphonate compounds but no significant response to pyrophosphates. A subsequent pyrophosphate bone scan resulted in no adverse reaction. Severe systemic reactions to diphosphonates can occur, skin testing may prove useful in evaluating allergic reactions, and pyrophosphates appear to be a safe alternative agent in patients proven or suspected allergic to diphosphonates.

Calcium acetate induces calcium uptake and formation of calcium-oxalate crystals in isolated leaflets of Gleditsia triacanthos L.

During treatment of isolated, peeled leaflets of Gleditsia triacanthos with 0.5-2 mM [(45)Ca]acetate, saturation of the cell-wall free space with Ca(2+) occurred within 10 min and was followed by a period of 6-10 h during which there was no significant Ca-uptake into the protoplast, but apoplastic Ca(2+) was periodically released into the medium. Later, Ca(2+) was absorbed for 3-4 d at rates of up to 2.2 µmol Ca(2+)·h(-1)·(g FW)(-1) to final concentrations of 350 µmol Ca(2+)· (g FW)(-1). The distribution of absorbed Ca(2+) between cell wall, vacuole and Ca-oxalate crystals was determined during Ca-uptake. Wheras intact, cut leaflets deposited absorbed Ca(2+) as Ca-oxalate in the crystal cells, peeled leaflets lacking crystal cells accumulated at least 40-50 µmol·(g FW)(-1) soluble Ca(2+) before the absorbed Ca(2+) was precipitated as Ca-oxalate. These observations indicate that the mechanisms for the continuous uptake of Ca(2+), the synthesis of oxalate and the precipitation of Ca(2+) as Ca-oxalate are operational in the crystal cells of intact leaflets, but not in the mesophyll cells of peeled leaflets where they must be induced by exposure to Ca(2+). The precipitation of absorbed Ca(2+) as Ca-oxalate by the crystal cells of isolated Gleditsia leaflets illustrates the role of these cells in the excretion of surplus Ca(2+) which enters normal, attached leaves with the transpiration stream.In addition to acetate, only Ca-lactate and Ca-carbonate lead to Ca-uptake, but at rates well below those observed with Ca-acetate. Other small organic anions (citrate, glycolate, glyoxalate, malate) and inorganic anions (chloride, nitrate, sulfate) did not permit Ca-uptake. Acetate-(14)C was rapidly absorbed during Ca-uptake, but less than 20% was incorporated into Ca-oxalate; the rest remained mostly in the soluble fraction or was metabolized to CO2. Acetate, as a permeable weak acid, may enable rapid Ca-uptake by stimulating proton extrusion at the plasmalemma and by serving as a counterion during Ca-accumulation in the vacuole, but is unlikely to function as the principal substrate for oxalate synthesis.

Thyroid uptake and imaging with iodine-123 at 4-5 hours: replacement of the 24-hour iodine-131 standard.

A study was carried out to determine the suitability of utilizing a 4 to 5 hr interval from administration of iodine-123 to imaging and uptake measurement as a replacement for the 24-hr standard originally established with iodine-131. In 55 patients who underwent scintigraphy at 4 and 24 hr, there was no discrepancy between paired images. In 55 patients who had uptake measured at 4 and 24 hr and in 191 patients who had uptake measured at 5 and 24 hr, the early measurements proved equal or better discriminants of euthyroid from hyperthyroid patients. In our institutions, these findings and the logistical advantages of completing the exam in 4-5 hr led us to abandon the 24-hr study in the majority of patients.

Calcium-induced patterns of calcium-oxalate crystals in isolated leaflets of Gleditsia triacanthos L. and Albizia julibrissin Durazz.

For experimental induction of crystal cells (=crystal idioblasts) containing calcium-oxalate crystals, the lower epidermis was peeled from seedling leaflets of Gleditsia triacanthos L., exposing the crystal-free mesophyll and minor veins to the experimental solutions on which leaflets were floated for up to 10 d under continous light. On 0.3-2.0 mM Ca-acetate, increasing numbers of crystals, appearing 96 h after peeling, were induced. The pattern of crystal distribution changed with Ca(2+)-concentration ([Ca(2+)]): at low [Ca(2+)], crystals formed only in the non-green bundlesheath cells surrounding the veins, believed to have a relatively low Ca(2+)-extrusion capacity; at higher [Ca(2+)], crystals developed in up to 90% of the mesophyll cells, and at supraoptimal [Ca(2+)], large extracellular crystals formed on the tissue surface. By sequential treatments with solutions of different [Ca(2+)], the following three phases were identified in the induction of crystal cells: (1) during the initial 24-h period (adaptive aging), Ca(2+) is not required and crystal induction is not possible; (2) during the following 48 h (induction period), exposure to 1-2 mM Ca-acetate induces the differentiation of mesophyll cells into crystal cells; (3) crystal growth begins 72 h after the start of induction. In intact leaflets of Albizia julibrissin Durazz., calcium-oxalate crystals are found exclusively in the bundle-sheath cells of the veins, but crystals were induced in the mesophyll of peeled leaflets floating on 1 mM Ca-acetate. Exposure to inductive [Ca(2+)] will thus trigger the differentiation of mature leaf cells into crystal cells; the spatial distribution of crystals is determined by the external [Ca(2+)] and by the structural and functional properties of the cells in the tissue.

Time course and spatial distribution of phenylalanine ammonia-lyase and peroxidase activity in wounded potato tuber tissue.

The time course and spatial distribution of wound-induced activities of phenylalanine ammonia-lyase and peroxidase were determined to establish correlations between molecular and cellular aspects of the wound-induced pattern of cell differentiation in potato (Solanum tuberosum L.) tissue. A high correlation between peroxidase activity and suberization was observed. Peroxidase activity increased for several days after wounding. Peroxidase content of suberizing cells was more than 10 times higher than that of the immediately adjacent dividing cells. Suberizing and dividing cells contained different isoperoxidases. Neither time course nor spatial distribution of the wound-induced activity of phenylalanine ammonia-lyase was directly correlated with the wound-induced pattern of cell differentiation.

Simultaneous separation of acidic and basic isoperoxidases in wounded potato tissue by acrylamide gel electrophoresis.

Preparation and use of a newly developed pH 4.3 horizontal thin layer acrylamide gel which permits the simultaneous separation of acidic and basic isoperoxidases in up to 30 samples is described. Use of cytochrome c, horseradish peroxidase, and a purified potato isoperoxidase as internal standards for a range in isoelectric points of peroxidases from pH 3 to 11 is introduced to facilitate comparison of results obtained with different materials and different methods. Distribution of tissue-specific isoperoxidases in different cell layers of wounded potato (Solanum tuberosum L.) tissue is shown and their purification described. Evidence for the in vitro degradation of basic potato isoperoxidases resulting in more acidic forms similar to isoperoxidases occurring in wounded potato tissue is presented. The significance of this observation for the postulated differential function of different isoperoxidases is discussed.