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S B Jones

Publications and source records attributed to S B Jones.

At least 55 records · Page 3Linked to original sources

What is driving health system change?

Socially amoral economic forces now drive health system change. The authors, assisted by a panel of experts on employers, health plans, providers, and consumers, discuss current drivers such as (1) employers' price-focused purchasing, without good quality/value measures; (2) health plans' growing successes and market clout; (3) providers declining prospects and fears about their future; and (4) consumers' worries about less choice. Future influences will include Medicare reforms, better information, and pro-consumer regulation of managed care, as well as rising social distress. The health system's future is now open for resolution in an evolving, imperfect market.

Choice Behavior↗

Virtual endoscopy of the head and neck. Diagnosis using three-dimensional visualization and virtual representation.

BACKGROUND: Although flexible endoscopy is only 25 years old, a new technology may soon be used to provide the same view of internal organs without inserting an instrument. This is virtual endoscopy. METHODS: By acquiring patient specific high resolution digital images with a helical CT scan or MRI, individual organs can be graphically isolated or "segmented" into fully interactive 3-D reconstructions on a computer monitor. Applying sophisticated flight-tracking programs from military pilots, the organs can be "flown through", giving a view identical to endoscopy. CONCLUSIONS: In the future we will fly through data instead of inserting endoscopic instruments for gastrointestinal endoscopic diagnosis.

Computer Simulation↗

Why not the best for the chronically ill?

Premium adjustors to neutralize risk selection among health plans are the weakest component in the technology for assuring competitive markets. It will be many years before we have adjustors adequate to free health plans to invest in and market improved managed care to predictably high-cost chronically ill persons. For want of a fair premium, health plans are driven by risk selection to underinvest in and otherwise "demarket" care to these very employees and beneficiaries whose costs and care most need to be managed. To achieve best value for the chronically ill, large employer coalitions, Medicare, and Medicaid should consider radical new approaches, such as establishing separate prices for care to people with specific chronic conditions and purchasing such care both from health plans and directly from provider systems.

Chronic Disease↗

Paradigm shifts in Medicare reform.

Reforms passed by Congress and vetoed by the president during the past year would have accelerated initiatives already transforming Medicare. Operating in a rapidly changing insurance marketplace, Medicare is shifting from a social insurance model toward a private individual insurance model-expanding the number and type of alternative health plans it offers-and growing numbers of beneficiaries are enrolling in these plans. Such reforms, especially if bolstered by legislative reforms that are likely to resurface after the November elections, will rewrite the social contract enacted more than 30 years ago. They require fundamental shifts in ways of thinking about the federal government's responsibilities; the Medicare program's management; relations between the Medicare program and doctors, hospitals, and other health care providers; and the role of beneficiaries in the Medicare program. The likely deferral of further legislative attempts to reform Medicare affords an opportunity to step back and consider these ongoing changes. It is not easy to describe paradigm shifts accurately, but there are advantages to trying. First, conceptual comparisons can allow public discussion to go beyond budget scorekeeping and media soundbites to consider how different the Medicare program will be if it evolves in the new ways being proposed. Second, a conceptual framework can assist health policy analysts to target what to watch for in tracking changes, to assess the tradeoffs involved, and to advise about the needs for refining legislation. This paper includes examples of what to watch for in tracking the implemented changes. The paradigm shifts are summarized below, then described individually in terms of directions of change along a number of continuums. Note that complete paradigm shifts, from one end of a continuum to the other, are seldom completely realized nor even far advanced. But Medicare's ongoing reforms, accelerated by legislative proposals, seem likely predecessors of future changes. For developing this framework, the authors have drawn on the Medicare provisions of the Conference Agreement on the Balanced Budget Act of 1995, the president's proposals as presented in December 1995, and current and proposed Health Care Financing Administration practices.

Consumer Behavior↗

5,7-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H- pyrrolo[3,2-f]-1,2-benzisoxazol-6-one: a potent and centrally-selective inhibitor of acetylcholinesterase with an improved margin of safety.

A series of N-benzylpiperidines (2a-d, 10) with novel isoxazole-containing tricycles has been prepared. This series has shown potent in vitro inhibition of the enzyme acetylcholinesterase (AChE), with IC50S = 0.33 - 3.6 nM. Compound 2a was the most potent inhibitor with an IC50 = 0.33 +/- 0.09 nM. Derivatives 2a-d and 10 displayed weak in vitro inhibition of butyrylcholinesterase (BuChE) with IC50S = 600 - 23,000 nM. The most selective compound was 2a with a BuChE/AChE ratio in excess of 4 orders of magnitude (> 10,000). Pyrrolobenzisoxazole 2a also displayed a favorable profile in vivo. In microdialysis experiments, 2a produced a 200% increase in extracellular levels of acetylcholine (ACh) at a dose of 0.4 mg/kg in freely moving, conscious rats. Peripheral side effects (salivation ED50 = 26 +/- 1.5 mg/kg) and acute lethality (LD50[1 h] = 42 mg/kg) were observed at > 60-fold higher doses. These data indicate that 2a is an AChE inhibitor with good central selectivity and a favorable margin of safety. Compound 2a, designated as CP-118,954, is currently in clinical development for the treatment of cognitive disorders.

Animals↗

Design and synthesis of 1-heteroaryl-3-(1-benzyl-4-piperidinyl)propan-1-one derivatives as potent, selective acetylcholinesterase inhibitors.

Herein is described the synthesis and structure--activity relationship of a novel series of aromatic and heteroaromatic 3-(1-benzyl-4-piperidinyl)propan-1-one derivatives that display potent and selective inhibition of the enzyme acetylcholinesterase (AChE). 1-(2-Methyl-6-benzothiazolyl)-3-(N-benzyl-4-piperidinyl)propan-1-one hydrochloride, 6d, is one of the most active compounds within this series exhibiting an IC50 for the inhibition of the AChE enzyme equal to 6.8 nM. Compound 6d has shown a dose-dependent elevation of total acetylcholine (ACh) levels in the mouse forebrain with an oral ED50 = 9.8 mg/kg. In addition, in vivo microdialysis experiments in the rat demonstrate that 6d increases extracellular ACh (100% over basal) 1-3 h postdose with an oral ED50 = 4.8 mg/kg.

Animals↗

Muscarinic cholinergic receptors in brain and atrial membranes of adult brook trout (Salvelinus fontinalis) measured by radioligand binding techniques.

Muscarinic cholinergic receptors were measured by radioligand binding techniques in crude membrane particulate preparations of brain and atrial tissues from laboratory reared brook trout (Salvelinus fontinalis). The radioligand [3H]N-methyl scopolamine was used to determine number and affinity of receptors in saturation experiments. The affinity of the radioligand did not differ in brain and atrial preparations (96 +/- 8 and 60 +/- 4 pM, respectively). However, the number of binding sites was greater in atrium compared with brain (269 +/- 19 and 166 +/- 7 fmol/mg protein, respectively). The rank order of potency of competing drugs in inhibition experiments was similar for antagonists with atropine > or = scopolamine > pirenzepine. Pirenzepine, an M1-selective drug had a 3-fold higher affinity in brain than atrium. The agonists oxotremorine and carbachol each bound to two sites in both tissues. In contrast, pilocarpine bound to only one site in brain and two in atrial tissue. These results are compared with those observed in other nonmammalian species and discussed with reference to conservation of proteins that serve important cellular roles.

Animals↗

Phorbol ester-stimulated 6-keto-prostaglandin F1 alpha in aortas from control and aldosterone-salt rats.

OBJECTIVE: To assess the contribution of protein kinase C to the production of 6-keto-prostaglandin F1 alpha by stimulating protein kinase C directly. RESULTS: Phorbol myristate acetate caused a time-dependent increase in 6-keto-prostaglandin F1 alpha and thromboxane B2. The time course was slower than for norepinephrine-stimulated production of these metabolites, but the pattern was similar, with thromboxane B2 appearing before 6-keto-prostaglandin F1 alpha. The phorbol myristate acetate concentration-response curves for 6-keto-prostaglandin F1 alpha production for control-salt and aldosterone-salt hypertensive rats were equivalent. Staurosporine inhibited phorbol myristate acetate-stimulated 6-keto-prostaglandin F1 alpha production in control-salt and aldosterone-salt hypertensive rats concentration-dependently. The staurosporine median inhibitory concentration for phorbol myristate acetate-stimulated 6-keto-prostaglandin F1 alpha production was twofold greater in aldosterone-salt hypertensive than in control-salt rats, but was similar for norepinephrine-stimulated 6-keto-prostaglandin F1 alpha. CONCLUSION: Activation of protein kinase C results in increases in arachidonic acid metabolites, but alterations in this pathway do not seem to be responsible for the differences observed with norepinephrine-stimulated 6-keto-prostaglandin F1 alpha production. The present data offer some support for the concept of direct coupling between the alpha 1-adrenoceptor and phospholipase A2.

6-Ketoprostaglandin F1 alpha↗

Calcitonin gene-related peptide release in endotoxicosis may be mediated by prostaglandins.

Three cyclo-oxygenase inhibitors (ibuprofen, indomethacin, and high dose aspirin) and two inhibitors of thromboxane biosynthesis (imidazole and low dose aspirin) were used to evaluate the role of prostaglandins and thromboxane in the release of calcitonin gene-related peptide (CGRP) during endotoxicosis. Endotoxin (lipopolysaccharide B from Salmonella Enteritidis, 5 mg/kg, intravenously) was administered to rats lightly anesthetized with ether during injection. After 3 h, endotoxin significantly elevated plasma CGRP levels by 3-fold. Ibuprofen (50 mg/kg, subcutaneously), indomethacin (10 mg/kg, subcutaneously) and high dose aspirin (100 mg/kg, intraperitoneally (i.p.)), but not imidazole (30 mg/kg, i.p.) or low dose aspirin (15 mg/kg, i.p.), significantly blocked endotoxin-induced CGRP elevations, suggesting that a prostaglandin, but not thromboxane, served as a mediator of CGRP release during endotoxicosis. Because endotoxin-induced production of prostaglandins is greatly diminished in endotoxin-tolerant rats (following multiple exposures to low dose endotoxin), we tested whether endotoxin-induced CGRP release also becomes diminished in tolerant rats. Accumulation of plasma CGRP was greatly diminished in endotoxin-tolerant rats exposed to endotoxin (5 mg/kg, intravenously), consistent with a mediator role for prostaglandins in the CGRP release during endotoxicosis.

Animals↗

Clozapine is a potent and selective muscarinic M4 receptor agonist.

Clozapine was studied in functional assays at human muscarinic M1-M5 receptors expressed in Chinese hamster ovary cells. Clozapine was a full agonist at the muscarinic M4 receptor (EC50 = 11 nM), producing inhibition of forskolin-stimulated cAMP accumulation. In contrast, clozapine potently antagonized agonist-induced responses at the other four muscarinic receptor subtypes. Selective stimulation of M4 receptors may, in part, explain the hypersalivation observed clinically with clozapine. Moreover, the unique overall muscarinic profile of clozapine may contribute to its atypical antipsychotic efficacy.

Animals↗

Novel benzisoxazole derivatives as potent and selective inhibitors of acetylcholinesterase.

A series of N-benzylpiperidine benzisoxazoles has been developed as potent and selective inhibitors of the enzyme acetylcholinesterase (AChE). The benzisoxazole heterocycle was found to be an appropriate bioisosteric replacement for the benzoyl functionality present in the N-benzylpiperidine class of inhibitors. The title compounds were synthesized by alkylating 3-methyl-1,2-benzisoxazoles with an iodo piperidine derivatives as the key step. Benzisoxazoles 1b-j,o displayed potent inhibition of AChE in vitro with IC50's = 0.8-14 nM. Particularly interesting were N-acetyl and morpholino derivatives 1g (IC50 = 3 nM) and 1j (IC50 = 0.8 nM), respectively, which displayed outstanding selectivity for acetyl-over butyrylcholinesterase, in excess of 3 orders of magnitude. N-Acetyl 1g also displayed a favorable profile in vivo. This analog showed a dose-dependent elevation of total acetylcholine in mouse forebrain after oral administration with an ED50 = 2.4 mg/kg. In addition, 1g was able to reverse amnesia in a mouse passive avoidance model at doses of 3.2 and 5.6 mg/kg with an average reversal of 89.7%. Molecular dynamics simulations were used to study the possible binding modes of N-benzylpiperidine benzisoxazoles to AChE from Torpedo californica. Key structural insights were obtained regarding the potency of this class of inhibitors. Specifically, Asp-72, Trp-84, Trp-279, Phe-288, and Phe-330 are implicated in the binding of these inhibitors. The N-benzylpiperidine benzisoxazoles may be suitable compounds for the palliative treatment of Alzheimer's Disease.

Acetylcholine↗

An open access bone densitometry service: report of first year's operation.

Medical treatment of symptomatic osteoporosis is unsatisfactory. Treatment of patients with low bone density but without history of fracture includes hormone replacement therapy (HRT) which offers the prospect of reduced fracture risk. Dual energy X-ray absorptiometry (DXA) offers a safe and accurate technique available for the measurement of bone mineral density at a district general hospital level. All open access service providing densitometry measurements for general practitioners and hospital consultants was instigated at South Cleveland Hospital in February 1991. A major purpose of the service was to provide density measurements in order to 'inform' the discussion between the patient and doctor with regard to the use of anti-resorptive and other medical agents. We report our experience of operating such a service. The report analyses the main reasons for referrals. Nine hundred and thirty female subjects and 63 male subjects were scanned. The main reason for female referral were early menopause, consideration for HRT, personal history of fracture and family history of fracture--these account for 54.7% of all referrals. In men, there was a high incidence of fracture, back pain and the use of steroids given as reasons for referral. Sixty-seven per cent of patients were referred by general practitioners. Eighteen per cent of female lumbar spinal BMD values were between 1 and 2 S.D. below the Leeds normative mean and 9.0% below 2 S.D. Figures for the femoral neck were 22.0 and 9.0%.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗

Endotoxin enhances norepinephrine release in the rat by peripheral mechanisms.

The study was designed to investigate the effects of endotoxin administration on norepinephrine release in vivo in the rat. The norepinephrine release rate was calculated from the steady-state concentration of endogenous norepinephrine and [3H]norepinephrine in the central venous pool after infusion of [3H]norepinephrine intra-arterially. This method corrects for both metabolism and disposition as the infused tracer closely follows the normal pathway of neuronally released norepinephrine. Measurements were made in anesthetized intact rats as well as in pithed rats with electrically stimulated sympathetic outflow (3 Hz). Comparisons were made before and for 60 min following administration of bacterial endotoxin (10 mg/kg intravenously) or an equal volume of saline (vehicle). Plasma levels of norepinephrine and epinephrine increased significantly in both anesthetized and pithed preparations after endotoxin, whereas plasma norepinephrine clearance decreased only in anesthetized rats. Norepinephrine release rates were significantly increased in anesthetized as well as in pithed rat preparations after endotoxin. Plasma epinephrine was elevated more in pithed than anesthetized rats. The blood pressure fall was more rapid in pithed compared to anesthetized rats following endotoxin, which probably indicates that the central nervous system is able to compensate to some extent for the blood pressure fall in the anesthetized rat. Heart rate was unchanged in both preparations following endotoxin. Significant increases in norepinephrine release rates induced by bacterial endotoxin in pithed rats with constant frequency sympathetic nerve stimulation suggests that some factor in endotoxicosis enhances the release of norepinephrine by an action at peripheral nerve terminals.

Analysis of Variance↗

Distinct expression patterns of insulin-like growth factor binding proteins 2 and 5 during fetal and postnatal development.

Insulin-like growth factors (IGFs), when isolated from serum or tissue fluids, are usually found as part of a protein complex which also contains one of several IGF binding proteins (IGFBPs). Although some IGFBPs have been shown to alter interactions of IGFs with their receptors in vitro and can modify the responses of cultured cells to exogenous IGFs, the in vivo functions of IGFBPs remain unclear. This study examines expression of a recently described IGFBP gene, IGFBP-5, in the rat embryo and fetus and in selected adult tissues. Embryonic IGFBP-5 messenger RNA (mRNA) can be detected as early as embryonic day 10.5 and has an mRNA expression pattern distinct from the previously characterized pattern of IGFBP-2 mRNA expression. Major sites of IGFBP-5 expression during early postimplantation stages of development include the notochord, the floor plate, regions of the surface ectoderm, muscle precursor cells, and specific axial regions of neuroepithelium. Later in development IGFBP-5 mRNA is found in several regions of the central nervous system, including the proliferative zone of the external granule layer of the cerebellum and the mitral neurons of the olfactory bulb, as well as in muscle precursor populations of the developing limb, and in most cells of the anterior pituitary. In addition, only a subset of pituicytes in the adult posterior pituitary express IGFBP-5, which provides the first evidence that this cell population is biochemically heterogeneous. Taken together, these data suggest functions for IGFBP-5 during development of several organ systems.

Aging↗

A highly conserved insulin-like growth factor-binding protein (IGFBP-5) is expressed during myoblast differentiation.

Insulin-like growth factor-binding proteins (IGFBPs) are a family of secreted proteins that bind insulin-like growth factors I and II (IGFs I and II) and are capable of modulating IGF actions on target cells. We have shown previously that C2 myoblasts secrete a single approximately 29-kDa IGFBP during their terminal differentiation (Tollefsen, S. E., Lajara, R., McCusker, R. H., Clemmons, D. R., and Rotwein, P. (1989) J. Biol. Chem. 264, 13810-13817). In this study, we have purified the protein from C2 cell-conditioned media by conventional and IGF-affinity chromatography, cloned its cDNA by PCR-based and traditional library screening, and identified it as mouse IGFBP-5. The resultant 5561 nucleotide cDNA encodes a 252-amino acid mature protein (predicted M(r) approximately 28,400) that is 97% identical to rat and human IGFBP-5. In differentiating C2 myoblasts and in F3 azamyoblasts the > 6-kilobase IGFBP-5 mRNA accumulates concomitantly with induction of myogen mRNA, an early marker of muscle differentiation. Ligand blot analysis shows that IGFBP-5 protein is secreted within 12 h of the onset of differentiation in these cells and that it is the only IGFBP produced in several fusing skeletal muscle cell lines. In vivo, IGFBP-5 transcripts are expressed in a variety of mouse tissues including striated muscle, but, unlike other IGFBPs, it is barely detectable in liver. IGFBP-5 is more conserved than other IGFBPs in mammals; its conserved structure and sequence also extends to non-mammalian vertebrates. Hybridization of a mouse BP5 coding region probe to RNA from several chicken and Xenopus tissues demonstrated similarly sized transcripts in these species. A partial Xenopus cDNA is identical in 38/45 deduced amino acids to the mammalian proteins. Identification of an IGF-binding protein that is produced during myoblast differentiation provides a model system in which to study the potential modulatory role of IGFBPs in development.

Amino Acid Sequence↗

Immune cells mediate epinephrine secretion from bovine chromaffin cells in vitro.

Potential immunological influences on peripheral catecholamine secretion were investigated by measuring epinephrine secretion from chromaffin cells in vitro in response to cell-free conditioned media from mononuclear cells. Chromaffin cells were isolated from bovine adrenals whereas mononuclear cells were isolated from bovine spleen tissue or whole bovine blood. In secretion experiments epinephrine release and epinephrine remaining in cells was determined such that secretion was expressed as % of total cell content. After 90 minutes exposure to conditioned media, 22.8 +/- 1.1% of content was released compared to 1.7 +/- 0.2% with RPMI media. Secretion after filtration (< 3,000 MW cutoff) was 21.6 +/- 0.9% whereas after boiling and boiling in acid, secretion was 10.2 +/- 0.2 and 4.3 +/- 0.1% respectively. Dialysis (< 3,000 MW cutoff) reduced the 90 min conditioned media-stimulated epinephrine secretion from 22.5 +/- 3.8% to 2.3 +/- 0.3%. Neither atropine nor hexamethonium blockade altered the conditioned media-stimulated epinephrine secretion. These results suggest that mononuclear cells produce a low molecular weight substance--most likely a peptide--that contributes to the stimulation of epinephrine secretion.

Adrenal Glands↗

Quantitation of the levels of tyrosine hydroxylase and preproenkephalin mRNAs in nigrostriatal sites after 6-hydroxydopamine lesions.

Expression of the striatal proenkephalin gene is modulated by dopaminergic input from the substantia nigra (SN). We have used rapid, specific and sensitive solution hybridization assays for the quantitation of tyrosine hydroxylase (TH) mRNA, preproenkephalin (PPenk) mRNA and total cellular RNA to compare ipsilateral and contralateral levels of these RNAs in tissue dissected from the origin and termination of the nigrostriatal pathway of individual rats following sham (vehicle) or 6-hydroxydopamine (6-OHDA) induced lesions of the SN. Three weeks after treatment the rats that had received 6-OHDA, but not sham treated controls, demonstrated a characteristic contralateral rotation in response to apomorphine. Four weeks after 6-OHDA treatment, TH mRNA levels were reduced below the limits of sensitivity of the assay (1 pg/ug RNA) in ipsilateral SN while the levels of TH mRNA in contralateral SN (4.8 pg/ug RNA) did not differ from that in sham treated animals. PPenk mRNA levels in striatum were increased 3 fold to 64.9 pg/ug RNA on the side of the 6-OHDA lesions while the contralateral PPenk mRNA levels (21.6 pg/ug RNA) did not differ from sham treatment. The 6-OHDA treatment did not alter the levels of total cellular RNA in either SN or striatum. These results provide quantitative evidence for the tonic inhibition of striatal proenkephalin gene expression by the dopaminergic nigrostriatal pathway.

Animals↗