Underlying sources of cognitive-anatomical variation in multi-modal neuroimaging and cognitive testing.

Healthy adults have robust individual differences in neuroanatomy and cognitive ability not captured by demographics or gross morphology (Luders, Narr, Thompson, & Toga, 2009). We used a hierarchical independent component analysis (hICA) to create novel characterizations of individual differences in our participants (N=190). These components fused data across multiple cognitive tests and neuroanatomical variables. The first level contained four independent, underlying sources of phenotypic variance that predominately modeled broad relationships within types of data (e.g., "white matter," or "subcortical gray matter"), but were not reflective of traditional individual difference measures such as sex, age, or intracranial volume. After accounting for the novel individual difference measures, a second level analysis identified two underlying sources of phenotypic variation. One of these made strong, joint contributions to both the anatomical structures associated with the core fronto-parietal "rich club" network (van den Heuvel & Sporns, 2011), and to cognitive factors. These findings suggest that a hierarchical, data-driven approach is able to identify underlying sources of individual difference that contribute to cognitive-anatomical variation in healthy young adults.

Call-Fleming syndrome associated with subarachnoid haemorrhage: three new cases.

BACKGROUND: The Call-Fleming syndrome (CFS) comprises acute severe recurrent (thunderclap) headaches, occasional transient or fluctuating neurological abnormalities and reversible segmental cerebral vasoconstriction. It is a benign condition with an excellent prognosis, yet because it is often clinically and radiologically similar to a number of commonly encountered conditions, diagnostic difficulties may arise, leading to inappropriate, and even potentially harmful, investigative and therapeutic approaches. CASES: Three personal cases are presented to highlight the occurrence of subarachnoid haemorrhage (SAH) as part of CFS. In two patients with a positive CT head, SAH involved the sulci in the upper cerebral convexity, an unusual location in aneurysmal SAH. RESULTS: SAH is not an uncommon feature of CFS, occurring in approximately 25% of reported cases, and may pose a diagnostic challenge. CFS has a relatively characteristic spectrum of features, allowing a confident diagnosis in most cases, even when atypical features such as SAH are present. CONCLUSIONS: Recognising the spectrum of abnormalities seen in CFS, including particularly SAH, allows a sound approach to a safe diagnosis.

Osteoblastoma of the temporal articular tubercle misdiagnosed as a temporomandibular joint disorder.

The case of a 17-year-old female with a benign osteoblastoma in the temporomandibular joint (TMJ) is reported. The patient had a 2.5-year history of reduced mouth opening accompanied by tenderness and swelling in the left TMJ. Initial treatment included stabilization of the occlusion with a splint, jaw exercises, and analgesics. At first the patient's symptoms decreased, but they then increased 18 months later, prompting a cone beam computed tomography (CBCT) evaluation of the joint. The radiographic findings showed a somewhat ill-defined, radiolucent, expansile lesion containing small scattered calcifications located in the temporal articular tubercle. The lesion was removed under general anaesthesia and sent for histopathological examination. At the 12-month follow-up, the patient had normal TMJ function without clinical symptoms. CBCT examination showed a small recurrence of 3mm. Another 12 months later, CBCT showed a 1-mm increase in the recurrence. Her function was normal, with slight tenderness lateral to the left TMJ. The decision from a multidisciplinary meeting was further annual follow-up. The present case illustrates the importance of initial radiographic examination together with clinical examination in patients with TMJ dysfunction.

Cognitive and anatomical data in a healthy cohort of adults.

We present data from a sample of 190 healthy adults including assessments of 4 cognitive factor scores, 12 cognitive tests, and 115 MRI-assessed neuroanatomical variables (cortical thicknesses, cortical and sub-cortical volumes, fractional anisotropy, and radial diffusivity). These data were used in estimating underlying sources of individual variation via independent component analysis (Watson et al., In press) [25].

Lipid activation of undecaprenol kinase from Lactobacillus plantarum.

Extraction of membranes of Lactobacillus plantarum with Triton X-100/glycerol solubilized up to 80% of the undecaprenol kinase activity. Fractionation of the extract by gel chromatography separated endogenous phospholipid from the enzyme but simultaneously inactivated the enzyme. The kinase was reactivated by reconstitution with various synthetic phosphatidylcholines and purified L. plantarum phospholipids. Ditetradecanoylphosphatidylcholine and lysylphosphatidylglycerol were the best activators. Furthermore, the optimal environment for enzyme stimulation was provided by different defined molar ratios of Triton X-100/phospholipid. The ratios for the phospholipids tested ranged from 1.25 to 6.3. Similar substrate specificity and kinetic constants were observed for both the solubilized and reconstituted enzymes suggesting that no fundamental changes in the enzyme activity occurred during the delipidation-reconstitution process.

Characterization of undecaprenol kinase from Lactobacillus plantarum.

A membrane-bound undecaprenol kinase from Lactobacillus has been identified by observing the ATP-dependent phosphorylation of [14C]undercaprenol. The product of this reaction was shown to be [14C]undecaprenyl monophosphate by comparison of its chromatographic mobilities with authentic undecaprenyl monophosphate. It was shown that 32P from [gamma-32P]ATP was incorporated into undecaprenyl monophosphate. The kinase was partially solubilized by a variety of methods utilizing Triton X-100. Both the membrane-associated and solubilized enzymes required Mg2+, Triton X-100 and dimethylsulfoxide for activity. The enzyme preferentially phosphorylated the C34, C50 AND C 55 polyprenols. Geranylgeraniol (C20) and dolichol (C100), however, were utilized only 6% and 13% as well as undecaprenol, respectively. Despite the 8-fold difference in apparent V values, the apparent Km values for dolichol and undecaprenol were both 14 microM. The apparent Km for the nucleotide cosubstrate, ATP, was 2 mM. No other nucleoside triphosphate could substitute for ATP.

Hydrophobic chromatography of prenyl transferases.

Several prenyl transferases were examined with respect to their affinity for C0--C10 alkyl-Agarose columns. C10-alkyl Agarose was effective in adsorbing each of the prenyl transferases tested but only undecaprenyl pyrophosphate and octaprenyl pyrophosphate synthetases could be effectively eluted with Triton X-100.

Fibric acid derivatives: effects on the synthesis of isoprenoid lipids in cultured human lymphocytes.

Fibric acid derivatives have been demonstrated to reduce circulating lipoprotein and triacylglycerol concentrations and to inhibit hydroxymethylglutaryl CoA reductase, a key regulatory enzyme of cholesterol biosynthesis. This study describes the effect of four fibric acid derivatives on the biosynthesis of isoprenoid products from acetate and mevalonate in Molt-4 cells, a human leukemic T-lymphocyte cell line. The isoprenoids analyzed were cholesterol as well as dolichol and ubiquinone, alternative products of the branched isoprenoid biosynthetic pathway. None of the fibric acid derivatives showed significant effects on the synthesis of cholesterol from acetate or mevalonate and there was little change in the flux of these metabolites into either dolichol and ubiquinone compared to cells grown in drug-free medium. Therefore, in contrast to the reported inhibitory effects of fibric acids on hepatic sterol synthesis in rats and humans and on hydroxymethylglutaryl CoA reductase activity in human nonmalignant lymphocytes, our results show that these drugs do not significantly affect any of the post-reductase enzymes in the branched metabolic pathways leading from acetate to dolichol, ubiquinone and cholesterol in short term culturing of human malignant lymphocytes.

Extraction and detergent/lipid activation of dolichol kinase.

The CTP-dependent dolichol kinase from bovine liver microsomes was optimally extracted using either 0.5% sodium deoxycholate or 0.5% Triton X-100 containing 0.5 M NH4Cl. All activity was found in the supernatant fraction following high-speed centrifugation. This fraction was depleted of phospholipid (phospholipid remaining, less than 5% of total) by gel chromatography of the 0.5% deoxycholate extract. This partially purified enzyme was maximally activated 9- or 53-fold over controls in the presence of 0.1% deoxycholate or 0.1% Triton X-100, respectively. Stimulation of the kinase was also observed with mixtures of dimyristoylphosphatidylcholine and deoxycholate. The level of stimulation by these mixtures was up to 20-fold higher than that observed in controls having deoxycholate alone. Dimyristoylphosphatidylcholine alone was not stimulatory. A 1:1 molar ratio of Triton X-100 or deoxycholate to dimyristoylphosphatidylcholine was optimal for enzyme activation. The half-maximum velocity of the dephospholipidated enzyme at 1:1 molar ratio of detergent to dimyristoylphosphatidylcholine was obtained at 150 or 550 microM CTP in the presence of deoxycholate or Triton X-100, respectively. It has been observed, therefore, that dolichol kinase may be extracted from liver microsomes, depleted of endogenous phospholipids and activated by specific molar ratios of detergent to phospholipid.

Hemoglobin concentration in white, black, and Oriental children: is there a need for separate criteria in screening for anemia?

The concentration of hemoglobin in blacks was found to be 0.5 to 1.0 g/dl lower than that of income-matched whites in several large surveys. This difference could be a racial characteristic of blacks, or it might be due to a higher frequency of genetic traits such as thalassemia minor and hemoglobinopathies, or to environmental factors such as iron deficiency. To help in making this distinction, we analyzed the data from multiphasic examinations (1973 to 1975) on 1718 white, 741 black, and 315 Oriental healthy, nonindigent children between 5 and 14 years of age. In the entire population, the median hemoglobin concentration averaged 0.5 g/dl lower in blacks than in whites of both sexes (t test, P less than 0.001). The differences still averaged 0.5 g/dl (P less than 0.001) after exclusion of all those with abnormal hemoglobin by electrophoresis (Hgb S and C) and those whose mean corpuscular volume was more than 5% below the normal mean for age (to exclude iron deficiency or thalassemia minor). The data strengthen the impression that blacks normally have a concentration of hemoglobin averaging about 0.5 g/dl less than in whites. If this is the case, about 10% of normal blacks will be mistakenly designated anemic, if the same norms are applied.

Protein prenyl transferase activities of Plasmodium falciparum.

Prenylated proteins have been shown to function in important cellular regulatory processes including signal transduction. The enzymes involved in protein prenylation, farnesyl transferase and geranylgeranyl transferase, have been recent targets for development of cancer chemotherapeutics. We have initiated a systematic study of protein prenyl transferases of the malaria parasite, Plasmodium falciparum, to determine whether these enzymes can be developed as targets for antimalarial chemotherapy. We report here the identification of protein farnesyl transferase and protein geranylgeranyl transferase-I in the malaria parasite, P. falciparum. The farnesyl transferase has been partially purified from the cytosolic fraction through ammonium sulfate precipitation and Mono-Q chromatography. Farnesyl and geranylgeranyl transferase-I activities are present at all stages of P. falciparum intraerythrocytic development with maximum specific activity in the ring stage. Geranylgeranyl transferase-I specific activity is two times that of farnesyl transferase in the ring stage. Peptidomimetics and prenyl analogues of protein farnesyl transferase substrates were tested as in vitro inhibitors of partially purified P. falciparum prenyl transferase and of malaria parasite growth. The peptidomimetics were significantly more potent inhibitors than lipid substrate analogues of both the activity of Mono-Q purified enzyme and parasite growth in intraerythrocytic cultures. Exposure of the parasite to the peptidomimetic L-745,631 also showed significant inhibition of morphological development beyond the trophozoite stage. These studies suggest the potential of designing or identifying differential inhibitors of P. falciparum and mammalian prenyl transferases as an approach to novel malaria therapy.

Non-invasive screening for renal artery stenosis with ultrasound contrast enhancement.

OBJECTIVE: Our aim was to evaluate duplex ultrasound imaging in the identification of renal artery stenosis using a new technique to enhance the recorded Doppler signal. DESIGN: Colour Doppler studies of interlobar renal arteries were performed before and after enhancement using an intravenous contrast of galactose microparticle suspension containing microbubbles (Levovist, Schering) in patients with angiographically confirmed renal artery stenosis. SETTING: Blood Pressure Unit, St. George's Hospital Medical School, and Department of Radiology. The Middlesex Hospital, London, UK. PARTICIPANTS: Twenty-one consecutive hypertensive patients in whom the diagnosis of renal artery stenosis was made on digital subtraction angiography. MAIN OUTCOME MEASURES: The diagnosis of haemodynamically significant renal artery stenosis (> or = 60% on angiography). RESULTS: With Levovist, there was a 20 db increase in the Doppler intensity and, as a result, intrarenal signals were much more clearly delineated and distinct spectral waveforms were obtained from all but one kidney, which was occluded. Significant associations were found between the degree of stenosis (as assessed by angiography) and the following Doppler parameters: diastolic velocity (F = 7.6; P < 0.01), acceleration time (F = 33.5, < 0.0001), peak systolic velocity (F = 37.7, P < 0.0001) and acceleration (F = 60.0; P < 0.0001). Without enhancement, there were five false-positive and two false-negative examinations (sensitivity 85%; specificity 79%) using the acceleration cut-off value of 3.5 m/s2 to identify haemodynamically significant renal artery stenosis (> or = 60% on angiography). After contrast enhancement, there were only three false-positive and one false-negative examinations (sensitivity 94% and specificity of 88%) using the acceleration cut-off value of 3.75 m/s2 and the examination time was reduced by approximately half (sensitivity and specificity of 90% using the acceleration cut-off value of 3.5 m/s2). CONCLUSIONS: Our results suggest that renal duplex scanning using contrast enhancement is a promising new non-invasive technique in screening patients with suspected renal artery stenosis. Contrast enhancement produces more reproducible spectral waveforms, improves accuracy and halves the examination time.

Restraint stress differentially affects anti-viral cellular and humoral immune responses in mice.

Physical restraint administered to C57BL/6 mice significantly altered the inflammatory response to influenza virus infection and depressed anti-viral cellular immunity. Restraint-stressed animals showed a pattern of reduced mononuclear cell infiltration and lung consolidation which coincided with elevated plasma corticosterone levels. Furthermore, cellular immunity to virus was significantly depressed; interleukin-2 secretion was reduced by 96% and 59% in the mediastinal lymph nodes and spleens, respectively, as compared to a non-restrained group. However, the magnitude of the humoral immune response to influenza virus was unaffected by restraint stress. Anti-viral IgG antibody levels in restrained/infected mice did not differ when compared to a non-restrained/infected control group 14 days post-infection.

A pediatric screening examination for psychosocial problems.

In an effort to avert the cumulative effects of unresolved emotional problems on children's social and school adjustment, a psychosocial phase was added to a pediatric multiphasic examination. Based upon a cumulative stress concept, the screening procedures included child behavior and family stress questionnaires for parents, and abbreviated standard psychological tests for children, administered by specially trained aides. Computerized results were reported to the child's pediatrician. Follow-up by mental health counselors attached to the pediatric clinic was provided for patients identified as being at high risk of serious psychosocial problems. Evidence of validity of the screen, factors affecting the scores, and effectiveness of clinical follow-up of high-risk patients are discussed. Valid semicomputerized screening of school-age children for serious psychosocial problems can be carried out routinely and at relatively low cost by paraprofessional personnel in a pediatric setting. Impediments to effective use of the screening results on the part of both health care provider and patient are discussed.

Sulfophthalocyanines for photodynamic inactivation of viruses in blood products: effect of structural modifications.

Transmission of infectious disease through blood transfusions is well known. Ultraviolet irradiation, solvents, and detergents provide a means of sterilizing noncellular blood components. However, these harsh methods are not applicable to cellular blood products. Recently, attempts have been made to sterilize biological fluids using photodynamic treatment and phthalocyanine (Pc) dyes have been advanced as photosensitizers for this purpose. We have evaluated a series of water-soluble Pc, chelated with different central metal ions, substituted to different degrees with sulfonato and t-butyl groups, for their effectiveness to reduce virus infectivity in red blood cell suspensions. Vaccinia virus cytopathogenicity was determined by endpoint serial dilutions in the CV-1 cell line. Anti-viral activity increased with the central metal ion in the following: Ga(III) < Al(III) < Zn(II), and varied inversely with the degree of sulfonation. Furthermore, addition of a t-butyl group onto the trisulfonated dyes (PcS3[t-Bu]) resulted in a 5-40-fold increase in anti-viral potency, suggesting that amphiphilicity enhances the photodynamic activity of the dye. Strong anti-viral photosensitizing properties cannot be the sole selection criterion. Of equal importance is the preservation of blood component integrity. Accordingly, the photohemolytic activity of the dyes was evaluated using the rate of hemolysis as a parameter and a toxicity index was defined. Among the most active dyes, the AlPcS3(t-Bu) complex exhibited the most favorable anti-viral properties combined with a low toxicity index. Our results suggest that trisulfophthalocyanines, bearing an additional t-butyl group to enhance amphiphilicity, are particularly promising dyes for photodynamic blood sterilization.

Photodynamic therapy: tumor targeting with adenoviral proteins.

A brief summary of the mechanisms involved in photodynamic therapy (PDT) and the role of delivery vehicles for photosensitizer targeting is addressed. Phthalocyanines (Pc) have been coupled to adenovirus type 2 capsid proteins including the hexon, the penton base and the fiber to enhance their target selectivity. Adenovirus penton base proteins contain the arginine-glycine-aspartic acid peptidic sequence (RGD) motif known to bind with great affinity and high specificity to integrin receptors, expressed by several types of cancer. Tetrasulfonated aluminum phthalocyanine (AlPcS4) was covalently coupled to the various capsid proteins via one or two caproic acid spacer chains (A1 or A2) in 7:1 up to 66:1 molar ratios. The capacity of the bioconjugates for singlet oxygen production, as measured by an L-tryptophan oxidation assay, was strongly reduced, likely reflecting scavenging by the carrier. Cell adsorption and in vitro photocytotoxicity assays were carried out using the A549 and HEp2 human cell lines expressing integrin receptors, and one murine, the EMT-6 cell line, which lacks receptors for the RGD sequence. The AlPcS4A2-protein complexes induced greater cytotoxicity as compared to the analogous AlPcS4A1 preparations. The penton base-AlPcS4A2 derivative was the more phototoxic for all cell lines tested. Tumor response studies using Balb/c mice with EMT-6 tumor implants demonstrated that the free AlPcS4A2 induced complete tumor regression at a dose of 1 mumol/kg and 400 J/cm2, which is comparable to the activity of the known AlPcS2adj. A mixture of adenovirus type 2 soluble proteins covalently labeled with AlPcS4A2 required 0.5 mumol/kg to induce the same response with the same light dose, suggesting that the high affinity RGD/receptor complex is able to target Pc for PDT.

Nephrotic syndrome with renal vein thrombosis: pathogenetic importance of a plasmin inhibitor (alpha 2-antiplasmin).

Tests of fibrinolysis were measured by fibrin plate methods in 44 patients with nephrotic syndrome, in 14 of whom renal vein thrombosis was demonstrated. In both groups the level of total fibrinolytic activity was normal, that of vascular plasminogen activator was decreased, and that of an inhibitor of plasminogen activation was elevated. The level of a plasmin inhibitor, measured by the fibrin plate method, was elevated in 13 of 14 patients with, but only in 12 of 30 without, renal vein thrombosis (p less than 0.005). The plasmin inhibitor was identical with alpha 2-antiplasmin. The data suggest that an increased level of alpha 2-antiplasmin may be a factor in determining susceptibility to the development and persistence of renal vein thrombosis in patients with nephrotic syndrome.

3-dimensional reconstruction of ultrasound images of the uterine cavity.

We report our experience of 3-dimensional (3-D) reconstruction of ultrasound images of the uterine cavity. This is the first time that mapping of the contours of the uterine cavity with 3-D reconstruction has been achieved using standard clinical equipment for image acquisition. Ultrasound contrast hysterography was performed on 10 patients using both negative and positive intrauterine contrast media. 3-D image acquisition was performed during uterine cavity distension. The manipulation of the 3-D data sets is described and examples are shown. We believe that in some circumstances 3-D reconstructed images may be easier to interpret than 2-dimensional ultrasound images. We anticipate that this new technique will have a role in the preoperative assessment of uterine fibroids and endometrial polyps.

Ultrasound contrast hysterosalpingography--evaluation as an outpatient procedure.

Ultrasound contrast hysterosalpingography (HSG) uses intrauterine contrast media to increase the diagnostic value of plain transvaginal ultrasound enabling the uterine cavity contour to be assessed and allowing tubal patency to be determined. We present our experience using both negative (sterile saline) and positive (Echovist, Schering) contrast media in 27 patients presenting with a wide range of gynaecological disorders. This is the first report comparing the use of the two contrast media with plain ultrasound on a purely outpatient basis. We have found ultrasound saline HSG to be superior for the delineation of the uterine cavity and we predict that this will become a first line investigation for assessing the configuration of the uterine cavity. However, although Echovist could be demonstrated flowing through patent fallopian tubes, we found ultrasound contrast HSG to be insufficiently accurate in the determination of tubal patency and do not feel that it can replace conventional X-ray HSG. We review the literature on this technique and discuss its future role in gynaecological imaging.

Training improves medical student performance in image interpretation.

The aim of this study was to objectively quantify the effects of radiological teaching on student performance in interpreting radiological images, and to establish whether training location affects performance. 114 clinical students were asked to anonymously interpret radiological cases before and after 26 weeks clinical training. Improvements were assessed by comparing performance on the median question in each assessment using the Kruskal-Wallis analysis. Variations according to different placements were assessed by the Mann-Whitney U-test. There was a highly significant (p<0.001) improvement in the performance of the group with training. The proportion of correct answers to the median question improved from 8% to 43%. Differences between training placements were non-significant. Our study suggests that radiology teaching significantly improves student performance. Future work should look to define the contribution of "clinical exposure" towards this improvement, as well as the various teaching methods employed.