Implementation of a primary care physician network obesity management program.

Most primary care physicians do not treat obesity, citing lack of time, resources, insurance reimbursement, and knowledge of effective interventions as significant barriers. To address this need, a 10-minute intervention delivered by the primary care physician was coupled with individual dietary counseling sessions delivered by a registered dietitian via telephone with an automated calling system (House-Calls, Mobile, AL). Patients were seen for follow-up by their physician at weeks 4, 12, 24, 36 and 52. A total of 252 patients (202 women and 50 men) were referred by 18 primary care physicians to the program. The comorbid conditions reported for all patients at baseline included low back pain, 29% (n = 72); hypertension, 45% (n = 113); hypercholesterolemia, 41% (n = 104); type 2 diabetes, 10% (n = 26); and sleep apnea, 5% (n = 12). When offered a choice of meal plans based on foods or meal replacements, two-thirds of patients (n = 166) chose to use meal replacements (Ultra Slim-Fast; Slim-Fast Foods Co., West Palm Beach, FL) at least once daily. Baseline weights of subjects averaged 200 +/- 46 lb for women (n = 202) and 237 +/- 45 lb for men (n = 50). Patients completing 6 months in the program lost an average of 19.0 +/- 4.0 lb for women (n = 94) and 15.5 +/- 8.2 lb for men (n = 26). Physicians reported a high degree of satisfaction with the program, suggesting that a brief, effective physician-directed program with nutritionist support by telephone can be implemented in a busy primary care office.

Attitudes of patients and staff to the implementation of an open door policy in a psychiatric unit of a general hospital [Abstract]

OBJECTIVE: To document the changing attitudes of staff and patients to the implementation of an open door policy (ODP) in the custodial psychiatry unit at the University Hospital of the West Indies. METHOD: The implementation of the changing therapeutic activities between October 2000 and January 2001 was followed using qualitative methods. Patients, their relatives and staff were interviewed around the time of implementation of each changing activity, and their attitudes documented. Patients attitudes to the transformed ward were sampled from May 2001 using the Verona Satisfaction Scale. The ODP had five separate components. The first was the opening of the main gate of the ward, which took place in October 2000. This was followed by a rationalization in stages of patients clinical status and their assignment to specific therapeutic activities. The implementation of daily therapeutic community group meetings was followed shortly afterwards by the implementation of an art therapy programme and other occupational activities. The opening of the Occupational Centre was the final phase of the programme in June 2001. RESULTS: The initial response of staff members to the opening of the main gate was angry and hostile with acts of passive resistance. Patient response was cautious but favourable, and they soon took advantage of leaving the ward unacompanied. Demarcation of the patients into groups of clinical severity soon allowed the staff to rationalize therapuetic activities for the patients. Both staff and patients were cooperative to this change. Implementation of the therapuetic community group meetings had a profound resocializing effect on patients and staff. Finally, the implementation of the art and activity therapy was warmly received by the patients, and proudly acclaimed by the staff. Analysis of the Verona Satisfaction Scores indicated a general acceptance and appreciation by the patients. CONCLUSIONS: The general consensus has been that the ward atmosphere was positively transformed by the ODP with patients being more satisfied with their care and being less hostile in their interactions with staff. Staff have cooperated with the changes, and have expressed appreciation of the benefits derived from the process. (AU)

First examples of oxidizing secondary alcohols to ketones in the presence of the disulfide functional group: synthesis of novel diketone disulfides.

The disulfide functionality is present in a number of organic compounds of interest in the fields of both chemistry and biology. Because the disulfide group is known to be highly susceptible to further oxidation by a wide range of agents, performing a chemoselective oxidation without further oxidizing the disulfide moiety poses a synthetic challenge. Reported herein are the first examples of such a chemoselective oxidation in which a series of novel secondary alcohol disulfides 2a-f have been converted to the corresponding symmetrical diketones 3a-f utilizing a modified Swern oxidation.

Nitrosothiol esters of diclofenac: synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs.

Despite its widespread use, diclofenac has gastrointestinal liabilities common to nonsteroidal antiinflammatory drugs (NSAIDs) that might be reduced by concomitant administration of a gastrointestinal cytoprotectant such as nitric oxide (NO). A series of novel diclofenac esters containing a nitrosothiol (-S-NO) moiety as a NO donor functionality has been synthesized and evaluated in vivo for bioavailability, pharmacological activity, and gastric irritation. All S-NO-diclofenac derivatives acted as orally bioavailable prodrugs, producing significant levels of diclofenac in plasma within 15 min after oral administration to mice. At equimolar oral doses, S-NO-diclofenac derivatives (20a-21b) displayed rat antiinflammatory and analgesic activities comparable to those of diclofenac in the carrageenan-induced paw edema test and the mouse phenylbenzoquinone-induced writhing test, respectively. All tested S-NO-diclofenac derivatives (20a-21b) were gastric-sparing in that they elicited markedly fewer stomach lesions as compared to the stomach lesions caused by a high equimolar dose of diclofenac in the rat. Nitrosothiol esters of diclofenac comprise a novel class of NO-donating compounds having therapeutic potential as nonsteroidal antiinflammatory agents with an enhanced gastric safety profile.

Structure-activity studies on a novel series of cholinergic channel activators based on a heteroaryl ether framework.

Analogs of compound 1 with a variety of azacycles and heteroaryl groups were synthesized. These analogs exhibited Ki values ranging from 0.15 to > 10,000 nM when tested in vitro for cholinergic channel receptor binding activity (displacement of [3H](-) cytisine from whole rat brain synaptic membranes).

Design and evaluation of nitrosylated alpha-adrenergic receptor antagonists as potential agents for the treatment of impotence.

We designed and evaluated a new class of molecules, nitrosylated alpha-adrenergic receptor antagonists, as potential agents for the treatment of impotence. In in vitro studies with human and rabbit corpus cavernosum strips in organ chambers, the alpha-adrenergic receptor antagonists (alpha-ARAs) moxisylyte and yohimbine and their corresponding nitrosylated compounds, SNO-moxisylyte (NMI-221) and SNO-yohimbine (NMI-187), concentration-dependently relaxed endothelin-induced contraction. The nitrosylated compounds were significantly more potent than the parent alpha-ARA. In human tissues, the specific phosphodiesterase type 5 inhibitor zaprinast potentiated the relaxing effects of the nitrosylated compounds. Only nitrosylated compounds induced accumulation of cyclic GMP in rabbit corpus cavernosum strips. Yohimbine and NMI-187 demonstrated a potent alpha2-blocking activity, with no significant differences in pA2 values (8.9 versus 8.2, respectively). Moxisylyte and NMI-221 showed moderate potency in antagonizing phenylephrine contraction, with comparable pA2 values for both molecules (6.5 versus 6.6, respectively). alpha-Adrenergic receptor-binding studies showed similar binding affinities for the alpha-ARA and their corresponding nitrosylated compounds. In vivo, intracavernosal injection of nitrosylated molecules caused greater increases in intracavernosal pressure (NMI-221 versus moxisylyte) that were more long lasting than those of moxisylyte or yohimbine. There were no significant differences between nitrosylated and non-nitrosylated compounds in the magnitude of systemic mean arterial pressure decrease after intracavernosal injection. alpha-ARA and the nitrosylated compounds showed no pain-inducing activity as evaluated with the paw-lick model in mice. In summary, nitrosylated alpha-ARA have the dual functionalities of nitric oxide donors and alpha-ARA. These drugs induced penile erection in animals, suggesting their possible therapeutic value as agents for the local pharmacological treatment of impotence.

Atmospheric particulate absorption and black carbon measurement.

It is convenient to measure the optical attenuation A of the combination of a layer of atmospheric particulate matter and the quartz fiber filter on which it has been collected. The problem of relating A to the absorption and scattering coefficients k and s of the particulate matter itself is treated as a problem in diffuse reflectance spectroscopy using the KubelkaMunk theory. The results show that although, in general, A is a nonlinear function strongly dependent on both s and k, for a limited range of s and sample thickness d, A can be a practically linear function of k. Fortunately, this range includes that common to atmospheric particulate samples. Furthermore, it is shown that if the filter's reflectance is sufficiently high, A can be nearly independent of s. This is in agreement with experimental and, for the limiting case when the substrate filter reflectance is unity, theoretical results obtained by other researchers. Use of such measurements of A as a means of determining the black carbon mass loading C on a filter is also investigated. It is shown that when the black carbon mass fraction f(c) is high, as it is for samples collected in large urban areas, A is a predictable and practically linear function of C. However, when f(c) is low, as it is for many rural locations, then the slope of the function A(C) is strongly dependent on f(c), leading to possible overestimates of C. This problem can be alleviated by making the measurement of A at near-infrared wavelengths rather than in the visible spectrum.

Cyclopentanedi- and tricarboxylic acids as squalene synthase inhibitors: syntheses and evaluation.

Based on earlier lead squalene synthase inhibitor A-87049 (3) and zaragozic acids, a series of cyclopentanedi- and tricarboxylic acids were synthesized and evaluated against the enzyme. Some exhibited good potency and SAR revealed the importance of conformation and substitution pattern of these synthetic inhibitors.

Fabrication and characterization of single-mode electro-optic polymer optical fiber.

We report on what we believe is the first demonstration of single-mode polymer optical fiber with embedded electrodes. We show that the electrodes can be used to pole the dye-doped core and to electro-optically phase modulate the light in the waveguide.

Nitrosylated bovine serum albumin derivatives as pharmacologically active nitric oxide congeners.

Although nitrosothiols have been suggested to act as regulators of cell (patho)physiology, little is known about the pharmacology of nitrosylated proteins as nitric oxide (NO.) congeners. We describe the molecular consequences of nitrosylating bovine serum albumin (BSA) at multiple specific sites and demonstrate that the product S-nitrosoproteins exert NO.-like activity. The content of nucleophilic nitrosylation sites (i.e., free sulfhydryl groups) in native BSA was increased by either reduction with dithiothreitol or thiolation with N-acetylhomocysteine. Fourteen moles of nitrogen monoxide (NO)/mol BSA equivalent were then selectively positioned on either the endogenous sulfhydryl groups of reduced BSA or the homocysteine moieties of thiolated BSA, respectively. Each resulting S-nitrosoprotein adduct was an oligomeric mixture across the >2000 kDa to approximately 66 kDa molecular mass range. The BSA-derived S-nitrosoproteins were immunoreactive with antibodies against native BSA but evidenced compromised long-chain fatty acid binding. Both types of BSA-derived S-nitrosoproteins suppressed human coronary artery smooth muscle cell proliferation to a similar degree (IC50 approximately 70 microM NO. equivalents) and were significantly more effective antiproliferative agents than a standard NO. donor, DETA NONOate. Antiproliferative bioactivity reflected the NO functionalities carried by each protein, but was independent of molecular mass of the nitrosylated BSA adducts. These data exemplify the rational design and characterization of protein-based S-nitrosothiols as NO. congeners and suggest that such agents could have therapeutic potential as NO delivery systems.

Reactivity of nitrogen monoxide species with NADH: implications for nitric oxide-dependent posttranslational protein modification.

Nitric oxide (NO.) and NO. donors incite NAD- [i.e., mono(ADP-ribosylation)] and NADH-dependent posttranslational protein modifications by an as yet unknown mechanism. A route of pyridine nucleotide-dependent, NO.-stimulated protein modification has recently been hypothesized [S. Dimmeler, and B. Brune, (1992) Eur. J. Biochem. 210, 305-310; J. S. Stamler (1994) Cell 78, 931-936]. An essential feature of this proposed mechanism is NADH nitrosation, for a nitroso-NADH adduct is considered to be a key reactant in the generation of pyridine nucleotide-modified protein. To evaluate at the molecular level the ability of NADH to act as a nitrosation substrate, the potential effects of NO., the nitrosothiols S-nitrosoglutathione and S-nitrosocysteine, the nitrosating agent tert-butyl-nitrite, and the NO. metabolite peroxynitrite on the molecular and functional (i.e., hydride-transfer) properties of NADH have been directly assessed at physiological pH. Exposure of NADH to NO. or nitrosothiol altered neither the hydride-transfer capability of the pyridine nucleotide nor its ultraviolet spectrum in ways suggestive of NADH nitrosation. As determined by NMR spectroscopy, NADH was refractory to the well-recognized nitrosating agent tert-butyl nitrite. Consequently, it appears that NADH is an unfavorable substrate for nitrosation under physiological conditions. These data are inconsistent with the proposal that NO. or a NO.-derived nitrosating agent interacts with NADH to generate the nitroso-NADH hypothesized to be essential to NO.-stimulated, pyridine nucleotide-dependent protein modification. Peroxynitrite, a possible source of nitrosating compounds, readily oxidized NADH to NAD, but demonstrated no potential to form a nitroso-NADH adduct. The facility with which NADH is oxidized to NAD has implications for peroxynitrite-mediated tissue damage.

Nephelometer optical response model for the interpretation of atmospheric aerosol measurements.

A numerical model evaluating the response of a typical integrating nephelometer is described. The model incorporates the actual scattering geometry as well as the effects of a finite light source, detector size, and a nonideal Lambertian diffuser. An angular scattering weighting function is introduced to provide a tractable approach in numerical calculations and easy application. Using established size distribution ensembles associated with a few representative aerosol types, we compare the calculated response of a real nephelometer with that of an ideal, or perfect, nephelometer. The results indicate that, frequently, the nephelometer-produced aerosol-scattering coefficient is of the order of 10-20% too small; but for some naturally occurring aerosols, the difference may be as large as 40-50%. For a multiple-wavelength nephelometer, the response model can be employed to estimate the expected error in the aerosol-scattering coefficients directly from the measurements themselves.

Structure-activity studies on 2-methyl-3-(2(S)-pyrrolidinylmethoxy) pyridine (ABT-089): an orally bioavailable 3-pyridyl ether nicotinic acetylcholine receptor ligand with cognition-enhancing properties.

2-Methyl-3-(2(S)-pyrrolidinylmethoxy)pyridine, ABT-089 (S-4), a member of the 3-pyridyl ether class of nicotinic acetylcholine receptor (nAChR) ligands, shows positive effects in rodent and primate models of cognitive enhancement and a rodent model of anxiolytic activity and possesses a reduced propensity to activate peripheral ganglionic type receptors. The profiles of S-4, its N-methyl analogue, and the corresponding enantiomers across several measures of cholinergic channel function in vitro and in vivo are presented, together with in vitro metabolism and in vivo bioavailability data. On the basis of its biological activities and favorable oral bioavailability, S-4 is an attractive candidate for further evaluation as a treatment for cognitive disorders.

S-nitrosylated tissue-type plasminogen activator protects against myocardial ischemia/reperfusion injury in cats: role of the endothelium.

S-Nitrosylated tissue plasminogen activator (tPA) is formed by S-nitrosylation of the clinically important agent tPA by nitric oxide, thus conferring nitric oxide donor properties to the molecule. Cats were subjected to 90 min of myocardial ischemia and 270 min of reperfusion and were treated with either tPA or S-nitrosylated tPA 10 min before reperfusion. S-Nitrosylated tPA-treated cats demonstrated marked attenuation of cardiac necrosis after myocardial ischemia/reperfusion, compared with cats receiving only tPA (13 +/- 3% vs. 28 +/- 3%, P < .01). Relaxation of ischemic/reperfused left anterior descending coronary artery rings in response to the endothelium-dependent dilators acetylcholine and A23187 was greater in the S-nitrosylated tPA-treated group, compared with the cats receiving only tPA, indicating that coronary vascular endothelial function was preserved by S-nitrosylated tPA. S-Nitrosylated tPA also resulted in markedly reduced adherence of neutrophils to the coronary vascular endothelium, compared with nonnitrosylated tPA (P < .01). Immunohistochemical localization of P-selectin in the ischemic region was also significantly reduced by S-nitrosylated tPA, compared with the control group (P < .01). These data indicate that S-nitrosylated tPA is a cardioprotective agent, likely exerting its effect by site-specific nitric oxide donation resulting in inhibition of neutrophil-endothelium interaction via a P-selectin-dependent mechanism.

A-85380 [3-(2(S)-azetidinylmethoxy) pyridine]: in vitro pharmacological properties of a novel, high affinity alpha 4 beta 2 nicotinic acetylcholine receptor ligand.

The in vitro pharmacological properties of a novel cholinergic channel ligand, A-85380 [3-(2(S)-azetidinylmethoxy)pyridine], were examined using tissue preparations that express different putative nAChR subtypes. In radioligand binding studies, A-85380 is shown to be a potent and selective ligand for the human alpha 4 beta 2 nAChR subtype (Ki = 0.05 + 0.01 nM) relative to the human alpha 7 (Ki = 148 +/- 13 nM) and the muscle alpha 1 beta 1 dg subtype expressed in Torpedo electroplax (Ki = 314 +/- 12 nM). The R-enantiomer of A-85380, A-159470, displays little enantioselectivity towards the alpha 4 beta 2 and alpha 1 beta 1 delta gamma subtypes but does not display 12-fold enantioselectivity towards the alpha 7 subtype (Ki = 1275 +/- 199 nM). (+)- and(-)-Epibatidine display similar potencies at the human human alpha 4 beta 2 (Ki = 0.04 +/- 0.02 nM and 0.07 +/- 0.02 nM, respectively), human alpha 7 (Ki = 16 +/- 2 nM and 22 +/- 3 nM, respectively) and muscle alpha 1 beta 1 delta gamma g (Ki = 2.5 +/- 0.9 nM and 5.7 +/- 1.0 nM, respectively) nAChRs. Functionally, A-85380 is a potent activator of cation efflux through the human alpha 4 beta 2 (EC50 = 0.7 +/- 0.1 microM) and ganglionic (EC50 = 0.8 +/- 0.09 microM) subtypes, effects that are attenuated by pretreatment with mecamylamine (10 microM). Further, A-85380 can activate (EC50 = 8.9 +/- 1.9 microM) currents through channels formed by injection of the human alpha 7 subunit into Xenopus oocytes, effects that are attenuated by pretreatment with the alpha 7 nAChR antagonist, methyllycaconitine (10 nM). In all cases, A-85380 is more potent than (-)-nicotine but less potent than (+/-)-epibatidine. In neurotransmitter release studies, A-85380 stimulates the release of dopamine with an EC 50 value of 0.003 +/- 0.001 microM which is equipotent to (+/-)-epibatidine, and 20-fold more potent than (-)-nicotine (EC50 = 0.04 +/- 0.009 microM). Thus, A-85380 displays a profile of robust activation of a number of nAChR subtypes with substantially less affinity for [125I] alpha-BgT sites than [3H](-)-cytisine sites, suggesting that it may serve as a more selective pharmacologic probe for the alpha 4 beta 2 subtype relative to the alpha 7 and alpha 1 beta 1 delta g nAChRs than (+/-)-epibatidine.

Novel 3-Pyridyl ethers with subnanomolar affinity for central neuronal nicotinic acetylcholine receptors.

Recent evidence indicating the therapeutic potential of cholinergic channel modulators for the treatment of central nervous system (CNS) disorders as well as the diversity of brain neuronal nicotine acetylcholine receptors (nAChRs) have suggested an opportunity to develop subtype-selective nAChR ligands for the treatment of specific CNS disorders with reduced side effect liabilities. We report a novel series of 3-pyridyl ether compounds which possess subnanomolar affinity for brain nAChRs and differentially activate subtypes of neuronal nAChRs. The synthesis and structure-activity relationships for the leading members of the series are described, including A-85380 (4a), which possesses ca.50 pM affinity for rat brain [(3)H]-(-)-cytisine binding sites and 163% efficacy compared to nicotine to stimulate ion flux at human alpha4beta2 nAChR subtype, and A-84543 (2a), which exhibits 84-fold selectivity to stimulate ion flux at human alpha4beta2 nAchR subtype compared to human ganglionic type nAChRs. Computational studies indicate that a reasonable superposition of a low energy conformer of 4A with (S)-nicotine and (-)-epibatidine can be achieved.

Sagnac interferometric intensity-dependent refractive-index measurements of polymer optical fiber.

We have applied a new modified Sagnac interferometric technique to measure the real part of the intensitydependent refractive index of a single-mode polymer optical fiber. For a 0.1% by weight squaraine dye in a poly(methyl methacrylate) core, Re([chi((3))1111]) is 12(+/-7) x 10(-13) cm(3)/erg at lambda = 1064 nm. We discuss the effect of these measurements on all-optical devices.