Disease burden and patient characteristics associated with systemic therapy utilization among adults with atopic dermatitis: data from CorEvitas Atopic Dermatitis Registry.

BACKGROUND: The decision to initiate advanced systemics in patients with atopic dermatitis (AD) is complex. OBJECTIVES: To explore disease burden and clinical characteristics of patients with moderate-to-severe AD and identify characteristics associated with initiating new systemics. METHODS: Data from prospective, longitudinal, non-interventional CorEvitas AD Registry were evaluated. Differences in demographic and clinical characteristics, comorbidities, disease severity (vIGA-AD™; body surface area (BSA); Eczema Area and Severity Index (EASI); SCORing AD [SCORAD]), and patient-reported outcomes (PROs) were assessed between systemic and non-systemic therapy groups. RESULTS: Of 883 patients, 673 were newly prescribed systemics and 210 were not. Non-systemic therapy group had higher than expected rates of severe disease at enrollment based on vIGA-AD = 4 (39%), mean BSA involvement (31%), and mean EASI (19). PROs for non-systemic therapy group indicated elevated burden from AD on quality of life and poor disease control. SCORAD, peak pruritus in the past 24 h, history of biologics, and facial pallor, were significantly associated with initiation of systemics at enrollment. CONCLUSION: While disease burden likely influences the initiation of systemic therapy, many patients with significant burden are not treated with systemics for unclear reasons. Further research is needed to identify other factors, beyond disease severity, that influence this decision.

Comparing the burden of illness in patients with alopecia areata vs atopic dermatitis in the US population from a payer perspective.

BACKGROUND: Alopecia areata (AA) is an autoimmune disease characterized by nonscarring hair loss. AA frequently co-occurs with other inflammatory autoimmune conditions, presenting a significant clinical burden. OBJECTIVE: To compare the burden of illness, direct and indirect costs in adult patients with AA vs atopic dermatitis (AD). METHODS: This retrospective cohort study used US administrative claims data from the Merative MarketScan Commercial Claims and Encounters Database to compare commercially insured adults with AA to those with AD. Patients with an AA diagnosis between January 2017 and September 2019 were propensity score matched to patients with AD. Comorbidity burden, medication use, health care resource utilization, health care costs, and indirect costs during a 12-month follow-up period were compared between cohorts. RESULTS: Overall, 25,446 adult patients with AA were selected for the matched analysis with the AD cohort. Patients with AA generally had lower comorbidity burden than patients with AD; mean Deyo-Charlson Comorbidity Index scores were 0.36 (SD = 0.99) and 0.39 (SD = 0.92), for AA and AD, respectively (P = 0.007). Patients with AA had significantly lower proportions of allergic rhinitis, asthma, pruritus, skin infections, and urticaria, but higher proportions of thyroid disease, when compared with patients with AD (all P < 0.001). A smaller proportion of patients with AA had prescriptions for topical (45.3% vs 64.8%; P < 0.001) and oral (20.3% vs 29.6%; P < 0.001) corticosteroids and antianxiety and/or antidepressants (24.7% vs 29.7%; P < 0.001), but a significantly larger proportion for intralesional corticosteroids (triamcinolone) (49.6% vs 21.7%; P < 0.001), compared with patients with AD. Despite a lower comorbidity burden and generally less medication usage in patients with AA, total all-cause health care costs did not significantly differ between the AA and AD cohorts ($10,705 vs $10,816; P = 0.712), and outpatient costs were higher in patients with AA ($6,297 vs $5,859; P = 0.014). Female patients with AA had significantly greater costs for both outpatient and outpatient pharmacy when compared with female patients with AD. Patients with AA were more likely to have a claim for long-term disability (0.6% vs 0.3%; P = 0.001) and higher long-term disability-associated indirect costs ($73 [SD = $1,442] vs $25 [SD = $774]; P = 0.004) compared with patients with AD. CONCLUSIONS: We found similar total health care costs in patients with AA and AD, despite a lower proportion of comorbidities and prescription use in patients with AA. Outpatient costs were also significantly higher overall in patients with AA. Although often dismissed as a cosmetic condition, AA, an autoimmune disease, has a similar level of medical expenditure as AD. DISCLOSURES: This study was funded by Eli Lilly and Company. Mr Fenske and Drs Ding, Morrow, and Smith are employed by Eli Lilly and Company. Drs Manjelievskaia, Moynihan, and Silver are employed by Merative. Drs Manjelievskaia, Moynihan, and Silver were employed by IBM Watson Health at the time of study completion. IBM Watson Health received funding from Eli Lilly and Company to conduct this study.

Giant core-shell nanospherical clusters composed of 32 Co or 32 Ni atoms held by 6 p-tert-butylthiacalix[4]arene units.

Using combinations of p-tert-butylthiacalix[4]arene (TCA) and [M(DMSO)(6)(BF(4))(2)] salts (M = Co(II) or Ni(II)), two almost isostructural core-shell-type thermally stable giant nanoclusters, composed of 32 metal centers, 6 deprotonated calix units binding the metal centers by both their O and S atoms, 24 µ-oxo or µ-hydroxo bridging groups, and 6 MeOH molecules, have been prepared under mild and reproducible conditions. For both giant clusters, the oxidation state II [M(II)(32)O(16)(OH)(8)(CH(3)OH)(6)TCA(6) (M = Co or Ni)] for the metal center was demonstrated by X-ray photoelectron and electronic absorption spectroscopies.

Alopecia Areata Treatment Patterns, Healthcare Resource Utilization, and Comorbidities in the US Population Using Insurance Claims.

INTRODUCTION: Alopecia areata (AA) is an autoimmune disorder causing sudden, non-scarring hair loss. There are currently no drugs approved for AA treatment. This study assessed prevalence of comorbidities, treatments, and healthcare costs and resource utilization among patients with AA in the USA. METHODS: Patients diagnosed with AA between January 2011 and December 2018 were identified in IBM MarketScan® Research Databases. Eligible patients had no other hair loss-related disorders and were continuously enrolled with medical and pharmacy benefits at least 12 months before and after AA diagnosis. Descriptive statistics were used to summarize comorbid conditions, treatments related to AA or other autoimmune/inflammatory conditions, and all-cause and AA-specific healthcare costs and resource utilization identified from claims data. RESULTS: A total of 68,121 patients with AA were identified. Mean (SD) age was 40.3 (17.8) years and 61.0% were female. The most common comorbidities included hyperlipidemia (22.4%), hypertension (21.8%), thyroid disorders (13.1%), contact dermatitis or eczema (10.8%), depression (9.5%), and anxiety (8.4%). Comorbid autoimmune diseases included atopic dermatitis (2.8%), psoriasis (2.1%), chronic urticaria (1.5%), and rheumatoid arthritis (1.1%). During the 12-month follow-up period, 37,995 patients (55.8%) were prescribed treatment for their AA or other comorbid autoimmune/inflammatory disease; 44.9% of treated patients were prescribed therapy within 7 days of AA diagnosis. Of patients receiving treatment, 80.3% received topical steroids and 30.0% received oral steroids. Mean (SD) total healthcare costs were $11,241.21 ($43,839.69) for all-causes and $419.12 ($1534.99) for AA. AA-related expenses were driven by outpatient and prescription costs. CONCLUSION: Patients with AA have a high comorbidity burden and lack of treatment. Current AA treatments, including systemic therapies other than oral steroids, were not frequently utilized in this study population. Healthcare costs incurred by patients with AA went beyond AA-related expenses. Longitudinal data are needed to better understand treatment trajectories and the disease burden in patients with AA.

Systematic Review of Brain Metastases in Patients With Non-Small-Cell Lung Cancer in the United States, European Union, and Japan.

Brain metastases (BRM) occur frequently in non-small-cell lung cancer (NSCLC) and present a substantial unmet medical need. Previous literature on global BRM prevalence, treatment patterns, costs, and outcomes typically has described a subset of these factors. The primary objective of this systematic literature review was to summarize BRM-related epidemiology, treatment patterns, costs, and survival of patients with NSCLC in the United States, European Union, and Japan. The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards. Literature searches were conducted in PubMed, Ovid MedLine, and Embase to identify studies published between 2003 and 2014. Peer-reviewed, English language, and human observational studies of patients with NSCLC and BRM were identified. Demographic characteristics, treatment patterns, histology subtype, costs, and survival data were extracted into Microsoft Excel and descriptively analyzed using SAS version 9.2 (SAS Institute, Inc). Of 8257 studies, 243 were eligible. Data from 46,422 patients with NSCLC and 27,907 patients with BRM were summarized. Radiation therapy was used by 70.7% (n = 19,736) of the total BRM population, followed by systemic therapy (8.9%, n = 2497), and surgery (6.1%, n = 1690). Reported median survival was 9.78 months ranging from 2.5 to 38 months. Radiation therapy had the best outcome at 10.0 months with 41.6% (n = 101) of the studies reporting the use of stereotactic radiosurgery. Highly variable median survival and treatment patterns were reported between countries. Costs and histology subtype data were not reported for most countries, highlighting the need for additional research to describe the economic burden of BRM and improve the diagnosis, prognosis, and prescription of effective therapies.

Chemical exchange between lamellar and non-lamellar lipid phases. A one- and two-dimensional 31P-NMR study.

One- and two-dimensional 31P-exchange NMR has been used to investigate chemical exchange between coexisting lamellar (L alpha) and non-lamellar (hexagonal HII and cubic I2) lipid phases. Samples of DOPE, DOPE/DOPC (9:1 and 7:3), DOPE/cholesterol sulfate (9:1), DOPC/monoolein (MO) (3:7 and 1:1), and DOPC/DOPE/cholesterol (1:1:2) were macroscopically oriented on glass plates and studied at the 0 degree orientation (angle between the bilayer normal and the external magnetic field), where the L alpha, HII, and I2 resonances are resolved. A reversible L alpha to HII transition was observed for all of the samples except for the DOPC/MO mixtures, which displayed a reversible L alpha to I2 transition. Near-equilibrium mixtures of L alpha and either HII or I2 were obtained after prolonged incubation at a given temperature. Two-dimensional exchange experiments were performed on DOPE at 9-14 degrees C for mixing times ranging from 500 ms to 2 s. For all samples, one-dimensional exchange experiments were performed for mixing times ranging from 100 ms to 4 s, at temperatures ranging from 3 degrees C to 73 degrees C. No evidence of lipid exchange between lamellar and non-lamellar phases was observed, indicating that if such a process occurs it is either very slow on the seconds' timescale, or involves an undetectable quantity of lipid. The results place constraints on the stability or kinetic behaviour of proposed transition intermediates (Siegel, D.P. (1986) Biophys. J. 49, 1155-1170).

Glycosphingolipid interdigitation in phospholipid bilayers examined by deuterium NMR and EPR.

Glycosphingolipid fatty acids commonly have up to eight methylene carbons more than do their surrounding phospholipid-attached counterparts. The resultant 'extra' segment may very well modulate glycosphingolipid function as receptor and structural element. As part of an investigation of this phenomenon, galactosylceramide was prepared with a deuterated 18-carbon fatty acid chain. Deuterium-labelled galactosylceramide was assembled at 10 mol% into unsonicated phosphatidylcholine bilayers having all 14-carbon or all 18-carbon saturated fatty acid chains (DMPC and DSPC, respectively). The systems were studied by 2H-NMR spectroscopy above and below the phase transition temperatures, Tm, of the host matrices. At comparable reduced temperatures in fluid membranes the degree of motional order exhibited by the glycolipid fatty acid was significantly higher in the phospholipid host matrix that was four carbons shorter. The fatty acid chain segment least affected by the change from long to short chain host matrix was the terminal (deutero)methyl group (an increase of 8% in quadrupolar splitting for the terminal methyl vs. 16% for deuterons at C17 and 23-28% for the remainder of the chain). Order parameter profiles for galactosylceramide were qualitatively very similar in the two host membranes, arguing against any major conformational difference between the arrangement of the 18-carbon glycolipid fatty acid in the 18-carbon vs. 14-carbon host matrices. Similarly a nitroxide spin probe covalently attached to carbon-12 of the galactosylceramide fatty acid gave clear indication of greater order in the fluid 14-carbon fatty acid phospholipid bilayer. These results are consistent with 'tethering' of the extra length of fatty acid via interdigitation into the opposing monolayer. There was no spectroscopic evidence of any intrinsic difference in glycolipid behaviour in the two fluid host matrices. 2H-NMR spectra of galactosylceramide at comparable reduced temperatures below Tm of the phospholipid bilayer were very different for 14-carbon vs. 18-carbon host matrices. The glycolipid fatty acid showed evidence of relatively reduced mobility in the shorter chain matrix.

Cationic poly(ethyleneglycol) lipids incorporated into pre-formed vesicles enhance binding and uptake to BHK cells.

This paper describes a new method for enhancing the interaction of liposomes with cells. A novel class of cationic poly(ethyleneglycol) (PEG)-lipid (CPL) conjugates have been characterized for their ability to insert into pre-formed vesicles and enhance in vitro cellular binding and uptake of neutral and sterically-stabilized liposomes. The CPLs, which consist of a distearoylphosphatidylethanolamine (DSPE) anchor, a fluorescent dansyl moiety, a heterobifunctional PEG polymer (M(r) 3400), and a cationic headgroup composed of lysine derivatives, have been described previously [Bioconjug. Chem. 11 (2000) 433]. Five separate CPL, possessing 1-4 positive charges in the headgroup (referred to as CPL(1)-CPL(4), respectively), were incubated (as micellar solutions) in the presence of neutral or sterically-stabilized cationic large unilamellar vesicles (LUVs), and were found to insert into the external leaflet of the LUVs in a manner dependent on temperature, time, CPL/lipid ratio, and LUV composition. For CPL/lipid molar ratios < or =0.1, optimal insertion levels of approximately 70% of initial CPL were obtained following 3 h at 60 degrees C. The insertion of CPL resulted in aggregation of the LUVs, as assessed by fluorescence microscopy, which could be prevented by the presence of 40 mM Ca(2+). The effect of CPL-insertion on the binding of LUVs to cells was examined by fluorescence microscopy and quantified by measuring the ratio of rhodamine fluorescence to protein concentration. Neither control LUVs or LUVs containing CPL(2) displayed significant uptake by BHK cells. However, a 3-fold increase in binding was observed for LUVs possessing CPL(3), while for CPL(4)-LUVs values as high as 10-fold were achieved. Interestingly, the increase in lipid uptake did not correlate with total surface charge, but rather with increased positive charge density localized at the CPL distal headgroups. These results suggest that incorporation of CPLs into existing liposomal drug delivery systems may lead to significant improvements in intracellular delivery of therapeutic agents.

Effects of fatty acid alpha-hydroxylation on glycosphingolipid properties in phosphatidylcholine bilayers.

The role of glycosphingolipid fatty acid alpha-hydroxylation as a modulator of glycolipid organization and dynamics was considered by 2H-NMR in bilayer membranes. For these experiments, galactosylceramides were prepared in which the natural fatty acid mixture was replaced with perdeuterated 18-carbon hydroxylated or non-hydroxylated stearic acid. The L-stereoisomer of N-(alpha-OH-stearoyl-d34)galactosylceramide and its naturally-occurring D-alpha-OH analogue, were isolated for independent study. Bilayers were formed using 10 mol% galactosylceramide in a shorter chain phospholipid, dimyristoylphosphatidylcholine, in an attempt to reproduce several features of glycolipid-phospholipid interactions typical of cell membranes. Spectra of deuterated galactosylceramide in gel phase phospholipid membranes indicated that alpha-hydroxylation led to greater motional freedom and/or conformational disorder, with no measurable difference between D- and L-alpha-OH fatty acid derivatives. In fluid phosphatidylcholine bilayers the effects were modest. Glycolipid fatty acid hydroxylation led to broadening of the range of order parameters associated with methylene groups near the membrane surface (frequently referred to as the 'plateau region') - this effect being more marked for the naturally-occurring (D) stereoisomer. The degree of overall molecular order sensed by the glycolipid fatty acid chain in a fluid host matrix was minimally affected by alpha-hydroxylation; although the plateau region of the D isomer was slightly more ordered than that of the L isomer and the non-hydroxylated species. These results suggest that a significant aspect of the alpha-hydroxy group effect on glycosphingolipid behaviour in bilayer membranes with low glycolipid content was interference with glycolipid packing amongst host phospholipids in the upper portion of the acyl chains. For the D stereoisomer, there was some evidence that the hydroxy group led to strengthening of interlipid interaction near the membrane surface.

Factors influencing uptake and retention of amino-containing drugs in large unilamellar vesicles exhibiting transmembrane pH gradients.

The level of uptake and retention of amino-containing drugs in large unilamellar vesicles (LUVs) following uptake in response to a transmembrane pH gradient (DeltapH) can vary dramatically depending on the drug. For example, the anticancer drugs doxorubicin and epirubicin can be readily retained, whereas the anticancer drug vincristine and the antibiotic ciprofloxacin tend to leak out rapidly. In this investigation, we examine the influence of the hydrophobicity of the entrapped amines (that induce the DeltapH) and the anionic lipid content of the LUV on drug retention. It is shown that entrapment of increasingly hydrophobic monoamines (methylamine to amylamine) all lead to an induced DeltapH of 3 units and essentially complete drug uptake under the conditions employed, but do not lead to improved retention of vincristine and ciprofloxacin. However, significantly improved retention could be achieved by substitution of the anionic lipid distearoylphosphatidylglycerol (DSPG) for distearoylphosphatidylcholine (DSPC) in the LUV bilayer. Further, it is shown that if the induced DeltapH is reduced to 1.4 units (driven by entrapped diamine) nearly 100% accumulation of doxorubicin and epirubicin could be achieved, whereas only 25% loading for vincristine and ciprofloxacin was observed. Taken together these results provide methodology for improving (weak base) drug retention in liposomes and indicate that drugs that can partition into the lipid bilayer exhibit improved uptake and retention characteristics.

Ionophore-mediated uptake of ciprofloxacin and vincristine into large unilamellar vesicles exhibiting transmembrane ion gradients.

A new method, based on the ion-translocating properties of the ionophores nigericin and A23187, is described for loading large unilamellar vesicles (LUVs) with the drugs vincristine and ciprofloxacin. LUVs composed of distearoylphosphatidylcholine/cholesterol (DSPC/Chol) (55:45 mol/mol) or sphingomyelin (SPM)/Chol (55:45 mol/mol) exhibiting a transmembrane salt gradient (for example, internal solution 300 mM MnSO4 or K2SO4; external solution 300 mM sucrose) are incubated in the presence of drug and, for experiments involving divalent cations, the chelator EDTA. The addition of ionophore couples the outward movement of the entrapped cation to the inward movement of protons, thus acidifying the vesicle interior. External drugs that are weak bases can be taken up in response to this induced transmembrane pH gradient. It is shown that both nigericin and A23187 facilitate the rapid uptake of vincristine and ciprofloxacin, with entrapment levels approaching 100% and excellent retention in vitro. Following drug loading, the ionophores can be removed by gel exclusion chromatography, dialysis, or treatment with biobeads. In vitro leakage assays (addition of 50% mouse serum) and in vivo pharmacokinetic studies (in mice) reveal that the A23187/Mn2+ system exhibits superior drug retention over the nigericin/K+ system, and compares favorably with vesicles loaded by the standard DeltapH or amine methods. The unique features of this methodology and possible benefits are discussed.

The effects of arachidonic acid and non-steroidal anti-inflammatory drugs on intrapulmonary airways of the guinea-pig.

A method is described in which changes in intrapulmonary airway tone of guinea-pig isolated lungs are reflected by changes in intraluminal perfusion pressure. A supramaximal dose of arachidonic acid (AA) (61 microM) was found to have little on no action on baseline perfusion pressure. However, following elevation of perfusion pressure with histamine, AA caused a dose-dependent pressure decrease. This was also mimicked by prostaglandin E1 (PGE1) and PGE2. AA induced a reduction of histamine elevated perfusion pressure which was inhibited, dose-dependently, by several non-steroidal anti-inflammatory agents including indomethacin, phenylbutazone, aspirin, benoxaprofen, BW755C and phenidone. Their respective rank order of potency appeared to correlate with their activity against microsomal cyclo-oxygenase. Indomethacin, phenylbutazone and aspirin induced augmentation of the elevated perfusion pressure due to histamine, whereas BW755C did not. We suggest that the primary arachidonate metabolite present in intrapulmonary airways following histamine-induced constriction is probably a relaxant of the E series. However, our data suggest that both cyclo-oxygenase and lipoxygenase products are associated with the maintenance of airway tone.

Long-circulating vectors for the systemic delivery of genes.

The development of vectors capable of treating systemic diseases is an important goal for gene therapy protocols. In order for a carrier system to preferentially accumulate at sites of systemic disease, such as tumors, sites of inflammation and sites of infection, the carrier must exhibit long circulation lifetimes following intravenous injection. Unfortunately, most gene delivery systems, including viral vectors as well as non-viral vectors, e.g., lipoplexes, polyplexes and lipopolyplexes, are rapidly cleared from the circulation and are preferentially taken up by the 'first-pass' organs such as liver, lung and spleen. Here we review recent literature concerning the ability of non-viral vectors to act as systemic gene therapy agents. The most promising systemic vectors are liposomal systems in which plasmid DNA is encapsulated within a lipid bilayer. The stabilized plasmid-lipid particle (SPLP) system, for example, exhibits circulation half-lives of the order of 6 h following intravenous injection, and preferentially accumulates in distal tumors with gene expression primarily localized to the tumor site.

Developments in liposomal drug delivery systems.

Liposomes are the leading drug delivery systems for the systemic (iv.) administration of drugs. There are now liposomal formulations of conventional drugs that have received clinical approval and many others in clinical trials that bring benefits of reduced toxicity and enhanced efficacy for the treatment of cancer and other life-threatening diseases. The mechanisms giving rise to the therapeutic advantages of liposomes, such as the ability of long-circulating liposomes to preferentially accumulate at disease sites including tumours, sites of infection and sites of inflammation are increasingly well understood. Further, liposome-based formulations of genetic drugs such as antisense oligonucleotides and plasmids for gene therapy that have clear potential for systemic utility are increasingly available. This paper reviews the liposomal drug delivery field, summarises the success of liposomes for the delivery of small molecules and indicates how this success is being built on to design effective carriers for genetic drugs.

Synthesis, structures and theoretical investigation of

The silylated derivative of thiophosphoric acid (S)P(SSiMe3)3 is used as a convenient starting compound for the synthesis of multinuclear Cu and Au cluster complexes. (S)P(SSiMe3)3 reacts with CuCI/PPh3 and [AuCClPPh3] to give the following compounds: [Cu4(P2S6)(PPh3)4] (1), [Cu6(P2S6)Cl2-(PPh3)6] (2) and [Au4(P2S6)(PPh3)4](3). According to X-ray structure determination, these compounds contain P2S6(4-) ions, in which S atoms act as ligands for Cu+ and Au+ ions. Although 1 and 3 have the same stoichiometry, bonding of the metal ions to the P2S6 skeleton displays small but remarkable differences. Au is twofold coordinated, whereas Cu shows a threefold coordination. Ab initio calculations have been carried out to rationalise these structural differences. The theoretical treatment of the corresponding Ag compound indicates the latter to be less stable.

Multiple expression of molecular information: enforced generation of different supramolecular inorganic architectures by processing of the same ligand information through specific coordination algorithms

The multisubunit ligand 2 combines two complexation substructures known to undergo, with specific metal ions, distinct self-assembly processes to form a double-helical and a grid-type structure, respectively. The binding information contained in this molecular strand may be expected to generate, in a strictly predetermined and univocal fashion, two different, well-defined output inorganic architectures depending on the set of metal ions, that is, on the coordination algorithm used. Indeed, as predicted, the self-assembly of 2 with eight CuII and four CuI yields the intertwined structure D1. It results from a crossover of the two assembly subprograms and has been fully characterized by crystal structure determination. On the other hand, when the instructions of strand 2 are read out with a set of eight CuI and four MII (M = Fe, Co, Ni, Cu) ions, the architectures C1-C4, resulting from a linear combination of the two subprograms, are obtained, as indicated by the available physico-chemical and spectral data. Redox interconversion of D1 and C4 has been achieved. These results indicate that the same molecular information may yield different output structures depending on how it is processed, that is, depending on the interactional (coordination) algorithm used to read it. They have wide implications for the design and implementation of programmed chemical systems, pointing towards multiprocessing capacity, in a one code/ several outputs scheme, of potential significance for molecular computation processes and possibly even with respect to information processing in biology.

Insoluble complex formation between low density lipoprotein and heparin. A 31P-NMR study.

31P-NMR has been used to probe the motions of the phosphate moiety of phospholipid head-groups in samples of human low density lipoprotein (LDL) in which particle tumbling has been greatly reduced by increasing the viscosity of the medium, by forming an LDL gel by ultracentrifugation, or by precipitation with heparin. The 31P-NMR spectra of LDL gel give broad "powder-like" lineshapes, with the sign and magnitude of the anisotropy characteristic of the bilayer mesophase, which narrow as the temperature is raised from 5 to 45 degrees C. This narrowing occurs over the same temperature range as the core cholesteryl ester liquid-crystalline to liquid phase transition, suggesting interactions between the surface and core. The 31P lineshapes of LDL-heparin insoluble complexes are also "powder-like", but are broader than native LDL at all temperatures studied. The spectra were simulated assuming an axially-symmetric shielding tensor motionally narrowed by Brownian isotropic diffusion [Burnell et al. (1980) Biochim. Biophys. Acta 603, 63-69], allowing determination of the lateral diffusion coefficients, DT, and the chemical shift anisotropy, delta sigma, of the monolayer phospholipids. Relative to LDL gel, the temperature-dependence of DT was reduced in the LDL-heparin insoluble complexes, and delta sigma was increased from 50 to 60 ppm. The results suggest that insoluble complex formation slows phospholipid lateral diffusion in the LDL monolayer and alters the orientation and/or order of the head-group.

Soluble complex formation between low-density lipoprotein and glycosaminoglycans. A 2H and 31P-NMR, and quasi-elastic light scattering study.

Soluble complex formation between LDL and heparin (HEP) and chondroitin sulfate (CS) has been studied by 2H- and 31P-NMR and light scattering. The 2H-NMR linewidths of [2H]HEP and [2H]C4S increase substantially upon binding to LDL, with the [2H]HEP linewidths broader at low glycosaminoglycan (GAG)/low density lipoprotein (LDL) ratios. Preliminary analysis of the bound C2H3 group correlation times suggests that the observed linewidths are determined by the complex size, and that both [2H]GAGs have similar motions when bound to LDL. The 31P-NMR data demonstrate that large LDL-HEP complexes (diameter approx. 50 nm) are formed only over a narrow range of HEP concentrations, whereas the size of LDL-CS complexes increases continuously over the range of CS concentrations studied, reaching values of 32-35 nm for both C4S and C6S. At the lower protein concentrations studied by light scattering (less than or equal to 1 mg/ml), the same trends are observed, although the mean diameters are less than those estimated by 31P-NMR. Soluble complex formation was unaffected by the presence of 2 mM Ca2+. Dilution studies demonstrate that complex size varies with protein concentration. The binding of GAGs to LDL was also examined by HEP-CS competition studies. HEP has the higher affinity while no differences in binding could be detected between C4S and C6S.

[In]

Near C(3) symmetry is displayed by the 19-atom In-P polyhedron that forms the central structural unit in the title compound (see structure), which was synthesized by reaction of InCl(3) with PEt(3) and PhP(SiMe(3))(2). In addition to In-P bonds, the cage has In-In and P-P bonds. Six terminal chloro ligands and three PEt(3) ligands surround the cluster core which itself encloses a central chloride anion.

The Rx to ease a community's burdens. A Detroit hospital helps low-income patients obtain prescription medication.

St. John Hospital and Medical Center found itself with an increasing volume of indigent and low-income patients who had few or no resources with which to purchase prescription medications. With funding cutbacks in various federal, state, and local programs, the hospital's pharmaceutical resources had diminished to the point at which it could only occasionally meet a patient's needs. The Indigent Pharmaceutical Fund was established in 1992. Once a staff member from the hospital's Social Work and Discharge Planning Department has exhausted all patient or community resources, he or she requests assistance for a patient. In the first year of operation, the fund assisted 278 patients at a cost of just under $5,000.