The Practice of Cranial Neurosurgery and the Malpractice Liability Environment in the United States

Object

The potential imbalance between malpractice liability cost and quality of care has been an issue of debate. We investigated the association of malpractice liability with unfavorable outcomes and increased hospitalization charges in cranial neurosurgery.

Methods

We performed a retrospective cohort study involving patients who underwent cranial neurosurgical procedures from 2005-2010, and were registered in the National Inpatient Sample (NIS) database. We used data from the National Practitioner Data Bank (NPDB) from 2005 to 2010 to create measures of volume and size of malpractice claim payments. The association of the latter with the state-level mortality, length of stay (LOS), unfavorable discharge, and hospitalization charges for cranial neurosurgery was investigated.

Results

During the study period, there were 189,103 patients (mean age 46.4 years, with 48.3% females) who underwent cranial neurosurgical procedures, and were registered in NIS. In a multivariable regression, higher number of claims per physician in a state was associated with increased ln-transformed hospitalization charges (beta 0.18; 95% CI, 0.17 to 0.19). On the contrary, there was no association with mortality (OR 1.00; 95% CI, 0.94 to 1.06). We observed a small association with unfavorable discharge (OR 1.09; 95% CI, 1.06 to 1.13), and LOS (beta 0.01; 95% CI, 0.002 to 0.03). The size of the awarded claims demonstrated similar relationships. The average claims payment size (ln-transformed) (Pearson’s rho=0.435, P=0.01) demonstrated a positive correlation with the risk-adjusted hospitalization charges but did not demonstrate a correlation with mortality, unfavorable discharge, or LOS.

Conclusions

In the present national study, aggressive malpractice environment was not correlated with mortality but was associated with higher hospitalization charges after cranial neurosurgery. In view of the association of malpractice with the economics of healthcare, further research on its impact is necessary.     

Altered Activation of Innate Immunity Associates with White Matter Volume and Diffusion in First-Episode Psychosis

First-episode psychosis (FEP) is associated with inflammatory and brain structural changes, but few studies have investigated whether systemic inflammation associates with brain structural changes in FEP. Thirty-seven FEP patients (median 27 days on antipsychotic medication), and 19 matched controls were recruited. Serum levels of 38 chemokines and cytokines, and cardiovascular risk markers were measured at baseline and 2 months later. We collected T1- and diffusion-weighted MRIs with a 3 T scanner from the patients at baseline. We analyzed the association of psychosis-related inflammatory markers with gray and white matter (WM) volume using voxel-based morphometry and WM diffusion using tract-based spatial statistics with whole-brain and region-of-interest (ROI) analyses. FEP patients had higher CCL22 and lower TGFα, CXCL1, CCL7, IFN-α2 and ApoA-I than controls. CCL22 decreased significantly between baseline and 2 months in patients but was still higher than in controls. The association between inflammatory markers and FEP remained significant after adjusting for age, sex, smoking and BMI. We did not observe a correlation of inflammatory markers with any symptoms or duration of antipsychotic treatment. Baseline CCL22 levels correlated negatively with WM volume and positively with mean diffusivity and radial diffusivity bilaterally in the frontal lobes in ROI analyses. Decreased serum level of ApoA-I was associated with smaller volume of the medial temporal WM. In whole-brain analyses, CCL22 correlated positively with mean diffusivity and radial diffusivity, and CXCL1 associated negatively with fractional anisotropy and positively with mean diffusivity and radial diffusivity in several brain regions. This is the first report to demonstrate an association between circulating chemokine levels and WM in FEP patients. Interestingly, CCL22 has been previously implicated in autoimmune diseases associated with WM pathology. The results suggest that an altered activation of innate immunity may contribute to WM damage in psychotic disorders.     

Some Neurophysiological Correlates of Altered Mental States in Labor: Report II. Features of the Superslow Phasic Processes

A group of parturient women (n= 45) was divided into subgroups of subjects with a large and small number of signs of an altered mental state (AMS and NAMS, respectively) during and after labor, according to data of a special psychological questionnaire. The background EEG and the superslow phasic electric processes (SSPP) of the head surface were recorded simultaneously in 16 monopolar leads before and after labor. The parameters of autocorrelation and cross-correlation functions of the processes were calculated. Highly significant differences were found among the subgroups in the parameters of dynamics and spatial synchronization of the SSPP, related, in particular, to the activity of the anterofrontal zones of both hemispheres and of the temporal zones of the right hemisphere. The differences between the AMS and NAMS subgroups were revealed on the basis of the different extents of the unidirectional deviations from the SSPP parameters in the reference group of healthy nulliparous women. The pattern of interrelations of the investigated parameters of the EEG and the SSPP confirms the hypothesis that functional changes in the brain during the adaptation of women to pregnancy termination and physiological labor correlate with a special mental state.     

Role of the Environment in the Interaction of Nonintercalators with Z-DNA

Abstract

Interaction of the DNA binding nonintercalators Netropsin, Distamycin and the mPD derivative with Z-DNA has been studied. It has been found that environmental factors like the solvent and added cations significantly modulate the interaction of these ligands with ZDNA However no definite Z to B transition in presence of these ligands was found in any case, in contrast to previously reported results (Ch.Zimmer, C.Marek and W.Guschlbauer, FEBS Lett. 154, 156–160(1983)).     

Analyses of Conformational States of the Transporter Associated with Antigen Processing (TAP) Protein in a Native Cellular Membrane Environment

The transporter associated with antigen processing (TAP) plays a critical role in the MHC class I antigen presentation pathway. TAP translocates cellular peptides across the endoplasmic reticulum membrane in an ATP hydrolysis-dependent manner. We used FRET spectroscopy in permeabilized cells to delineate different conformational states of TAP in a native subcellular membrane environment. For these studies, we tagged the TAP1 and TAP2 subunits with enhanced cyan fluorescent protein and enhanced yellow fluorescent protein, respectively, C-terminally to their nucleotide binding domains (NBDs), and measured FRET efficiencies under different conditions. Our data indicate that both ATP and ADP enhance the FRET efficiencies but that neither induces a maximally closed NBD conformation. Additionally, peptide binding induces a large and significant increase in NBD proximity with a concentration dependence that is reflective of individual peptide affinities for TAP, revealing the underlying mechanism of peptide-stimulated ATPase activity of TAP. Maximal NBD closure is induced by the combination of peptide and non-hydrolysable ATP analogs. Thus, TAP1-TAP2 NBD dimers are not fully stabilized by nucleotides alone, and substrate binding plays a key role in inducing the transition state conformations of the NBD. Taken together, these findings show that at least three steps are involved in the transport of peptides across the endoplasmic reticulum membrane for antigen presentation, corresponding to three dynamically and structurally distinct conformational states of TAP. Our studies elucidate structural changes in the TAP NBD in response to nucleotides and substrate, providing new insights into the mechanism of ATP-binding cassette transporter function.     

Interaction of glycophorin A with lectins as measured by surface plasmon resonance (SPR)

Glycophorin A (GPA), the major sialoglycoprotein of the human erythrocyte membrane, was isolated from erythrocytes of healthy individuals of blood groups A, B and O using phenol-water extraction of erythrocyte membranes. Interaction of individual GPA samples with three lectins (Psathyrella velutina lectin, PVL; Triticum vulgaris lectin, WGA and Sambucus nigra I agglutinin SNA-I) was analyzed using a BIAcore biosensor equipped with a surface plasmon resonance (SPR) detector. The experiments showed no substantial differences in the interaction between native and desialylated GPA samples originating from erythrocytes of either blood group and each of the lectins. Desialylated samples reacted weaker than the native ones with all three lectins. PVL reacted about 50-fold more strongly than WGA which, similar to PVL, recognizes GlcNAc and Neu5Ac residues. SNA-I lectin, recognizing alpha2-6 linked Neu5Ac residues, showed relatively weak reaction with native and only residual reaction with desialylated GPA samples. The data obtained show that SPR is a valuable method to determine interaction of glycoproteins with lectins, which potentially can be used to detect differences in the carbohydrate moiety of individual glycoprotein samples.     

Interaction of the polyelectrolyte heparin with copper(II) and calcium

The binding of copper(II) ions by heparin was investigated using equilibrium dialysi techniques, and the effects of this binding on solution properties determined. In neus tral Tris buffer solutions, heparin binds a maximum of twenty-three to twenty-four copper ions in two classes of sites, one containing three to four binding sites, the other containing twenty to twenty-one sites. Cooperative binding is associated with the larger class of sites. In more acidic citrate buffer solution, only one class of sites is observed, containing about four to five binding sites. Association constants are calculated for the classes and the possible chemical nature of the sites is discussed. The binding of calcium ions in neutral buffer is also examined, and these ions appear to be bound by a group of twenty to twenty-one binding sites, with a larger association constant than that for the copper ions. Definite effects on the solution properties of heparin, such as intrinsic viscosity, sedimentation coefficients, and partial specific volume, can be observed only in the cooperative binding of copper ions in neutral buffer. The interpretation of these solution properties in terms of molecular size and shape is analyzed, and it is concluded that the metal ion interactions cause no major change in the apparently random coil conformation of heparin in buffered solution, although some minor changes can be associated with the cooperative uptake of copper ions.     

Interaction of copper(II) with hemoglobins in the unliganded conformation

The interaction of exogenous Cu(II) with stable T-state Ni(II)- and Cu(II)-reconstituted hemoglobins has been studied. The relative binding affinities for the two human hemoglobin Cu(II) binding sites are found to be reversed in these hemoglobins relative to native iron(II) hemoglobin A. Nickel hemoglobin, modified by N-ethylmaleimide (NEM), iodoacetamide, and carboxypeptidase A, is used to establish that the observed differences can be attributed to the protein quaternary conformation and not to the metal substitution. Magnetic interactions between the Cu(II) responsible for oxidation and the metal-heme center suggest that the Cu(II) is closer to the heme in T-state hemoglobin than R-state hemoglobin. This finding suggests a pathway for T-state heme oxidation which does not require the beta-93 sulfhydryl group, consistent with rapid Cu(II) oxidation for NEM-reacted deoxyhemoglobin.     

(Lysyl-Glycyl-Glycyl)5 and (Lysyl-Glycyl-Glycyl)10 as models of histone. Interaction with DNA and acetylation by calf thymus enzyme

Sequential polypeptides (Lys-Gly-Gly)5 and (Lys-Gly-Gly)10 were synthesized as models for the N-terminal region of H4 histone and their interactions with DNA were studied. The ability of (Lys-Gly-Gly)10 to precipitate DNA was found to be much higher than that of (Lys-Gly-Gly)5. For example, at the physiological salt concentration, (Lys-Gly-Gly)10 precipitates DNA but (Lys-Gly-Gly)5 does not. Both peptides could be acetylated by a partially purified histone acetyltransferase preparation derived from calf thymus. epsilon-Amino groups of lysyl residues were the sites of the acetylation. DNA-cellulose chromatography of the products indicated that acetylation weakened the interaction of the peptides with DNA.     

Reviewing the Role of DNA (Cytosine-5) Methyltransferase Overexpression in the Cortical GABAergic Dysfunction Associated with Psychosis Vulnerability

In this review, we discuss changes in the regulation of gene expression in the central nervous system (CNS) associated with DNA (cytosine-5) methylation, chromatin remodeling and post-translational covalent modifications of histones.

During brain development, abnormal intrinsic or extrinsic cues may compromise epigenetic processes regulating neural stem cell proliferation and differentiation and thus directly or indirectly could contribute to altered epiphenotypes leading to psychiatric disorders. These mechanisms, that include chromatin remodeling and reversible changes in promoter methylation patterns, are largely expressed by terminally differentiated cortical GABAergic neurons. These neurons are unique among various brain cell subtypes because they express high levels of DNA-methyltransferase-1 (DNMT1). Moreover, DNMT1 expression is further increased in schizophrenia (SZ) and bipolar (BP) disorder brains.

To unravel how this pathological DNMT1 overexpression induces GABAergic neuronal dysfunction in SZ and in other psychoses, we report on how alterations in methylation modify the expression of susceptible vulnerability genes such as reelin or GAD67 in these neurons. The results encourage the view that promoter hypermethylation in GABAergic neurons that occurs in SZ represents a testable target for novel therapeutic strategies to treat this disorder.     

Interaction of the vanadyl (IV) cation with carnosine and related ligands

The interaction of the vanadyl (IV) (VO²⁺) cation with carnosine (the dipeptide β-alanyl-histidine) has been investigated by electron absorption spectroscopy at high ligand-to-metal ratios and at different pH values. The results show that in the range 6.0–8.5, the cation interacts with the imidazole group of four different carnosine molecules and points to the presence of an axially coordinated water molecule. These suppositions were confirmed by the behavior of the VO²⁺/imidazole system, which was investigated under similar experimental conditions, and supported by previous ENDOR (electron-nuclear double resonance) results. The study was complemented with additional measurements using the glycylglycine, glycylglycine/imidazole, and histidine systems as ligands.     

Interaction of phospholipids (Lysophosphatidylethanolamines) with water and sodium cation

We have performed detailed ab initio SCF calculations on the intermolecular interaction energies for one Na⁺ ion and one water molecule with two molecular fragments, one exemplifying a phospholipid (PL) head (PLHD) and the other, a phospholipid tail (PLTL). A 6-12-1 atom-atom pair potential for the interaction of a Na⁺ ion and water with a lysophosphatidyl-ethanolamine (LPEA) was derived from these results by a fitting procedure. This fitted potential was used to obtain isoenergy maps that provide energy profiles of the Na⁺ ion and the water around the phospholipids. The interaction of the Na⁺ ion with PL, as well as the interaction of water with the PL, can be visualized from these maps, which, as expected, show regions of hydrophilicity and hydrophobicity for the water and indicate a very strong binding site for the Na⁺ ion on the phosphate. It appears to be a stationary site that would limit the Na⁺ ion mobility. This binding site is located near the double-bonded oxygen atom of the phosphate group; its binding energy for Na⁺ is 67 kcal/mol. On the other hand the NH⁺ group of PLHD ahows strong electrostatic repulsion of Na⁺ while interacting with water with a binding energy of 13 kcal/mol. This potential energy well region for water is separated from another of similar depth near the phosphate by a barrier and both regions are expected to act as binding sites for water.     

The Interaction of Chromium(VI) with Urease in Solution

The interaction between K₂Cr₂O₇ and urease was investigated using fluorescence, UV-vis absorption, and circular dichroism (CD) spectroscopy. The experimental results showed that the fluorescence quenching of urease by K₂Cr₂O₇ was a result of the formation of K₂Cr₂O₇–urease complex. The apparent binding constant K _A between K₂Cr₂O₇ and urease at 295, 302, and 309 K were obtained to be 2.14?×?10⁴, 1.96?×?10⁴, and 1.92?×?10⁴ L mol^?1, respectively. The thermodynamic parameters, ΔH° and ΔS° were estimated to be ?5.90 kJ mol^?1, 43.67 J mol^?1 K^?1 according to the Van’t Hoff equation. The electrostatic interaction played a major role in stabilizing the complex. The distance r between donor (urease) and acceptor (K₂Cr₂O₇) was 5.08 nm. The effect of K₂Cr₂O₇ on the conformation of urease was analyzed using UV-vis absorption, CD, synchronous fluorescence spectroscopy, and three-dimensional fluorescence spectra, the environment around Trp and Tyr residues were altered.     

NMR Studies of the Interaction of Bleomycin with (dC-dG)3

Abstract

The interaction of bleomycin A₂ and Zn(II)-bleomycin A₂ with the oligonucleotide (dC-dG)₃ has been monitored by nuclear magnetic resonance spectroscopy. Binding of the drug to the oligonucleotide is indicated by an upfield shift of the bithiazole proton resonances consistent with partial intercalation of this group between base pairs. The effect of temperature and ionic strength on the binding of both free bleomycin and the Zn(II) complex has been studied. Consistent with earlier studies on polynucleotides, the rate of exchange between the free drug and the drug-oligonucleotide complex is rapid on the ¹H NMR chemical shift time scale. Binding of the oligonucleotide induced changes in resonances assigned to protons in the metal-binding region of Zn(II)-bleomycin. Intermolecular nuclear Overhauser effect enhancements between bleomycin and the oligonucleotide have not been detected.     

Interaction of sodium decyl sulfate with poly(L-ornithine) and poly(L-lysine) in aqueous solution

The binding isotherms of sodium decyl sulfate to poly(L -ornithine), poly(D ,L -ornithine), and poly(L -lysine) at neutral pH were determined potentiometrically. The nature of a highly cooperative binding in all three cases suggests a micelle-like clustering of the surfactant ions onto the polypeptide side groups. The hydrophobic interaction between the nonpolar groups overshadows the coulombic interaction between the charged groups. The titration curves can be interpreted well by the Zimm–Bragg theory. The average cluster size of bound surfactant ions is sufficiently large to promote the β-structure of (L -Lys)_n even at a very low binding ratio of surfactant to polypeptide residue, whereas the onset of the helical structure for (L -Orn)_n begins after about 7 surfactant ions are bound to two turns of the helix. The CD results are consistent with this explanation.     

Interaction of 5-iminodaunorubicin with Fe(III) and with cardiolipin-containing vesicles

5-Iminodaunorubicin is an anthracycline derivative exhibiting promising antitumor activity. Using potentiometric and spectroscopic measurements we have shown that 5-iminodaunorubicin forms with Fe(III) a complex in which three molecules of drug are bound to one Fe(III) ion. Each molecule is chelated through the C-12-carbonyl and the C-11-phenolate oxygen atoms. The stability constant is 1.6 X 10(34). Using circular dichroism measurements we have studied the interactions of 5-iminodaunorubicin with cardiolipin-containing vesicles. We have shown that cardiolipin could bind one molecule of drug without penetration of the dihydroanthraquinone moiety into the bilayer.