Tau positron emission tomography imaging in C9orf72 repeat expansion carriers.

BACKGROUND AND PURPOSE: AV-1451 (18 F-AV-1451, flortaucipir) positron emission tomography was performed in C9orf72 expansion carriers to assess tau accumulation and disease manifestation. METHODS: Nine clinically characterized C9orf72 expansion carriers and 18 age- and gender- matched cognitively normal individuals were psychometrically evaluated and underwent tau positron emission tomography imaging. The regional AV-1451 standard uptake value ratios from multiple brain regions were analyzed. Spearman correlation was performed to relate the AV-1451 standard uptake value ratio to clinical, psychometric and cerebrospinal fluid measures. RESULTS: C9orf72 expansion carriers had increased AV-1451 binding in the entorhinal cortex compared to controls. Primary age-related tauopathy was observed postmortem in one patient. AV-1451 uptake did not correlate with clinical severity, disease duration, psychometric performance or cerebrospinal fluid markers. CONCLUSION: C9orf72 expansion carriers exhibited increased AV-1451 uptake in entorhinal cortex compared to cognitively normal controls, suggesting a propensity for primary age-related tauopathy. However, AV-1451 accumulation was not associated with psychometric performance in our cohort.

Phospholipase D-mTOR requirement for the Warburg effect in human cancer cells.

A characteristic of cancer cells is the generation of lactate from glucose in spite of adequate oxygen for oxidative phosphorylation. This property - known as the "Warburg effect" or aerobic glycolysis - contrasts with anaerobic glycolysis, which is triggered in hypoxic normal cells. The Warburg effect is thought to provide a means for cancer cells to survive under conditions where oxygen is limited and to generate metabolites necessary for cell growth. The shift from oxidative phosphorylation to glycolysis in response to hypoxia is mediated by the production of hypoxia-inducible factor (HIF) - a transcription factor family that stimulates the expression of proteins involved in glucose uptake and glycolysis. We reported previously that elevated phospholipase D (PLD) activity in renal and breast cancer cells is required for the expression of the α subunits of HIF1 and HIF2. We report here that the aerobic glycolysis observed in human breast and renal cancer cells is dependent on the elevated PLD activity. Intriguingly, the effect of PLD on the Warburg phenotype was dependent on the mammalian target of rapamycin complex 1 (mTORC1) in the breast cancer cells and on mTORC2 in the renal cancer cells. These data indicate that elevated PLD-mTOR signaling, which is common in human cancer cells, is critical for the metabolic shift to aerobic glycolysis.

Design and synthesis of porphyrins bearing rigid hydrogen bonding motifs: highly versatile building blocks for self-assembly of polymers and discrete arrays.

Two aldehydes, 2,6-diacetamido-4-formylpyridine (7) and 1-butyl-6-formyluracil (11), are used to synthesize five pyridyl and four uracyl meso-subsituted porphyrins. With these complementary porphyrin building blocks, it is possible to build various types of multi-porphyrin supramolecules with different spatial relationships in predefined geometries. The formation and properties of self-complementary dimers and a closed tetrameric square are presented as a basis of comparison to the latter system in the solid state. An X-ray structure of 5,10-bis(4-tert-butylphenyl)-15,20-bis(3,5-diacetamido-4-pyridyl)porphyrin confirms its molecular structure and reveals a hydrogen-bonded supramolecular organization mediated by water molecules.

Genome-wide search for schizophrenia susceptibility loci: the NIMH Genetics Initiative and Millennium Consortium.

Schizophrenia has a complex pattern of inheritance, indicative of interactions among multiple genes and environmental factors. The detection and replication of specific susceptibility loci for such complex disorders are facilitated by the availability of large samples of affected sib pairs and their nuclear families, along with standardized assessment and systematic ascertainment procedures. The NIMH Genetics Initiative on Schizophrenia, a multisite collaborative study, was established as a national resource with a centralized clinical data base and cell repository. The Millennium Schizophrenia Consortium has completed a genome-wide scan to detect susceptibility loci for schizophrenia in 244 individuals from the nuclear families of 92 independent pairs of schizophrenic sibs ascertained by the NIMH Genetics Initiative. The 459 marker loci used in the scan were spaced at 10-cM intervals on average. Individuals of African descent were higher than those of European descent in their average heterozygosity (79% vs. 76%, P < .0001) and number of alleles per marker (9.2 vs. 8.4, P < .0001). Also, the allele frequencies of 73% of the marker loci differed significantly (P < .01) between individuals of European and African ancestry. However, regardless of ethnic background, this sample was largely comprised of schizophrenics with more than a decade of psychosis associated with pervasive social and occupational impairment.

Physiology of respiratory system related to anesthesia.

All inhalational anesthetic agents depress respiratory function. They also depend largely on the respiratory system to facilitate an induction and emergence from anesthesia. The other anesthetic agents, such as intravenous agents, also depress respiration. Much of the morbidity and mortality that occurs in the perioperative period can be attributed to an alteration in lung mechanics and dysfunctions in airway dynamics. In fact, it is postulated that 70% to 80% of the morbidity and mortality occurring in the perioperative period is associated with some form of respiratory dysfunction. Consequently, a detailed discussion of the many facets of respiratory anatomy and physiology will be presented. If the CRNA incorporates this information into anesthesia practice, care of the surgical patient will be enhanced.

Pathophysiology of the respiratory system related to anesthesia.

The pathophysiology of the respiratory system can be viewed by simply evaluating the status of a functional residual capacity (FRC). More specifically, patients with airways that are characterized as extremely compliant or "floppy" will have an increased FRC, which is the hallmark of chronic obstructive pulmonary disease. Patients with noncompliant, "stiff" lungs suffer from a form of restrictive disease with a resultant reduction in the FRC. Hence, the implications for anesthesia care focus on the FRC; that is, raising the FRC in the restrictive disease patient and normalizing or preventing further increase in the FRC in the patient with chronic obstructive pulmonary disease.

The pharmacology of respiratory disorders related to anesthesia.

The pharmacology of disorders of the respiratory system focuses on one major parameter--bronchodilatation. Drugs are rated as effective purely on how well they reverse brochoconstriction. Patients' conditions are considered reversible if there is a 20% increase in flow rates after a bronchodilator is administered. This article evaluates many of the drugs used in the treatment of reactive airway diseases such as asthma. Particular emphasis is placed on the anesthetic drugs used during the perioperative period.

Anesthesia care of the patient with reactive airways disease.

The clinical characteristics of reactive airways disease have been recognized for centuries. Any bronchospastic respiratory disease process that has a degree of reversibility can be considered a reactive airways disease. More specifically, any of the chronic obstructive pulmonary disease components--asthma, emphysema, and chronic bronchitis--that are reversible can be considered a form of reactive airways disease. Asthma is the prototypical reactive airways disease. Accounts of asthmatic symptoms have appeared in the medical literature from the time of Hippocrates. In fact, the word asthma is derived from the Greek word "asthma," which means panting. Certainly, the anesthetic management of a patient with asthma can be challenging for the anesthetist. Serious complications, of which 75% are pulmonary, can occur both during and after surgery.

Photogating of ionic currents across lipid bilayers. Electrostatics of ions and dipoles inside the membrane.

The conductances of the lipophilic ions tetraphenylboride and tetraphenylphosphonium across a lipid bilayer can be increased or decreased, i.e., gated, by the photoformation of closed-shell metalloporphyrin cations within the bilayer. The gating can be effected by pulsed or continuous light or by chemical oxidants. At high concentrations of lipophilic anions where the dark conductance is saturated due to space charge in the bilayer, the photogated conductance can increase 15-fold. The formation of porphyrin cations allows the conductance to increase to its nonspace charge limited value. Conversely, the decrease of conductance in the light of phosphonium cations diminishes toward zero as the dark conductance becomes space charge limited. We present electrostatic models of the space charge limited conductance that accurately fit the data. One model includes an exponentially varying dielectric constant for the polar regions of the bilayer that allows an analytical solution to the electrostatic problem. The exponential variation of the dielectric constant effectively screens the potential and implies that the inside and outside of real dielectric interfaces can be electrically isolated from one another. The charge density, the distance into the membrane of the ions, about one-quarter of its thickness, and the dielectric constant at that position are determined by these models. These calculations indicate that there is insufficient porphyrin charge density to cancel the boride ion space charge and the following article proposes a novel ion chain mechanism to explain these effects. These models indicate that the positive potential arising from oriented carbonyl ester groups, previously used to explain the 10(3)-fold larger conductance of hydrophobic anions over cations, is smaller than previously estimated. However, the synergistic movement of the positive choline group into the membrane can account for the large positive potential.

Photogating of ionic currents across lipid bilayers. Hydrophobic ion conductance by an ion chain mechanism.

The photogating of hydrophobic ion currents across the lipid bilayer membrane allows the direct study of their kinetics by symmetrically forming charge within the membrane and across each interface, rather than across the membrane. We find that the photoinduced conductance continues to increase beyond the region where the tetraphenylboride charge density in the membrane exceeds the estimated porphyrin cation density. This photoconductance is proportional to the tetraphenylboride charge density raised to the second to third power. The risetime of the photogating effect increases with increasing concentration of tetraphenyl boride. The porphyrin cation mobility is increased when the tetraphenylboride anion is present, and low concentrations of tetraphenylphosphonium cation increase the dark conductivity while inhibiting the photoconductivity. The activation energy for both the porphyrin and phosphonium cation induced conductance is more positive than that of the tetraphenylboride conductance. From these results we conclude that in addition to some cancellation of space charge within the membrane, the mechanism of increased conductance involves the transport of these hydrophobic anions via an alternating anion-cation chain, analogous to the Grotthuss mechanism for excess proton conduction in water. This ion chain conductance can be viewed as an evolutionary prototype of an ion channel across the membrane. It also underscores the importance of the counter ion in the transport of large ions such as peptides across the lipid bilayer.

Comparison of two instructional methods on the levels of physiologic and psychologic stress as measured by blood cortisol and the State-Trait Anxiety Inventory.

This study was designed to determine whether a systematic or nonsystematic instructional strategy affected the levels of physiologic and psychologic stress as measured by blood cortisol levels and the State-Trait Anxiety Inventory (STAI) in students in the postsecondary educational setting. A convenience sample consisting of 43 subjects was randomly assigned to either a systematic or nonsystematic teaching group. The blood cortisol and STAI were measured 1 and 2 weeks before the treatment and following the treatment on the day of the study. Results of the study demonstrated that there were differential posttreatment increases in the amount of physiologic stress, as measured by blood cortisol levels produced by either instructional method. However, between the control measurement 1 week before the treatment and the posttreatment measurement, there were no effects observed for the psychologic STAI measures for either group. Accounting for the circadian rhythm effect of cortisol, there was a significant "buffering effect" in stress experienced by the subjects in the systematic teaching group. More specifically, the nonsystematic teaching group experienced a 55.42% rate increase in cortisol compared to a 10.74% rate increase for the systematic teaching group which was statistically significant. The systematic teaching method may be more effective in preventing physiologic stress in the educational setting and possibly in the clinical practice of anesthesia nursing. Additionally, the results suggested that the STAI may be inappropriate when used as an index of stress in certain educational settings.

All-D amino acid-containing channel-forming antibiotic peptides.

The D enantiomers of three naturally occurring antibiotics--cecropin A, magainin 2 amide, and melittin--were synthesized. In addition, the D enantiomers of two synthetic chimeric cecropin-melittin hybrid peptides were prepared. Each D isomer was shown by circular dichroism to be a mirror image of the corresponding L isomer in several solvent mixtures. In 20% hexafluoro-2-propanol the peptides contained 43-75% alpha-helix. The all-D peptides were resistant to enzymatic degradation. The peptides produced single-channel conductances in planar lipid bilayers, and the D and L enantiomers caused equivalent amounts of electrical conductivity. All of the peptides were potent antibacterial agents against representative Gram-negative and Gram-positive species. The D and L enantiomers of each peptide pair were equally active, within experimental error. Sheep erythrocytes were lysed by both D- and L-melittin but not by either isomer of cecropin A, magainin 2 amide, or the hybrids cecropin A-(1-13)-melittin-(1-13)-NH2 or cecropin A-(1-8)-melittin-(1-18)-NH2. The infectivity of the bloodstream form of the malaria parasite Plasmodium falciparum was also inhibited by the D and L hybrids. It is suggested that the mode of action of these peptides on the membranes of bacteria, erythrocytes, plasmodia, and artificial lipid bilayers may be similar and involves the formation of ion-channel pores spanning the membranes, but without specific interaction with chiral receptors or enzymes.

Photogating of ionic currents across a lipid bilayer.

Photoformation of metalloporphyrin cations in a lipid bilayer increases the ionic currents of negative and decreases those of positive hydrophobic ions. At low concentrations of the mobile hydrophobic ion, a 30% change in conductivity is observed that decreases with increasing concentration of positive tetraphenylphosphonium ion and increases drastically with increasing concentration of negative tetraphenylboride ion. In the region of saturated conductance of boride ion, the increase in conductivity is 3.6-fold. A 15-fold increase is observed with the protonophore carbonyl cyanide 3-chlorophenylhydrazone. In this case the net charge gated is 300 times greater than the photogenerated charge in the bilayer membrane. Thus there is a net gain in this organic field effect phototransistor. The gating can also be accomplished by continuous light or chemical oxidants. Photogating is explained as space charge effects inside the bilayer.