Economic notes: definitions of efficiency.
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Efficiency, Organizational↗
Biomedical subjects
S Palmer
Publications and source records attributed to S Palmer.
Highly drug-resistant HIV-1 clinical isolates are cross-resistant to many antiretroviral compounds in current clinical development.
OBJECTIVES: To assess the in-vitro drug susceptibility of a panel of five well-characterized drug-resistant HIV variants to recently developed anti-HIV compounds including seven reverse transcriptase (RT) inhibitors and seven protease inhibitors. METHODS: Drug-resistant viral strains were selected on the basis of the prevalence of these mutants in patient samples from local area HIV clinics. The isolates included one multinucleoside-resistant virus containing the Q151M mutation, and four clinical isolates containing multiple RT and protease resistance mutations. The activity of the experimental compounds against these isolates was determined using drug susceptibility assays and measuring the viral antigen p24 end-point. RESULTS: These clinically relevant highly drug-resistant viruses were resistant to many of the new compounds in clinical development. In most cases the resistance mutations of the clinical isolate were different from those selected in vitro for the particular experimental compound. CONCLUSIONS: It is critical to expand the preclinical development of new drugs to include the assessment of their activity against currently circulating highly drug-resistant clinical strains, in order to develop appropriate salvage therapies for patients harboring resistant strains.
Drug Resistance, Microbial↗
Cost-effectiveness of brief psychodynamic-interpersonal therapy in high utilizers of psychiatric services.
BACKGROUND: It is known that a small number of patients with mental health problems have chronic disorders and account for a disproportionate amount of mental health costs. This randomized controlled trial evaluated the cost-effectiveness of psychodynamic-interpersonal therapy vs treatment as usual in patients with mental health problems who were unresponsive to usual treatment. METHOD: Subjects (N = 110) with nonpsychotic disorders unresponsive to 6 months of routine specialist mental health treatment were enrolled in a randomized controlled trial. Sixty-three percent were women, the mean age was 41.4 years, the median duration of illness was 5 years, 68% were unemployed or receiving state benefits because of illness, and 75.5% had a depressive illness. Intervention patients received 8 weekly sessions of psychodynamic-interpersonal psychotherapy. Control patients received usual care from their psychiatrist. Outcome measures included ratings of psychological distress and health status and a detailed economic evaluation. Analysis was conducted on an intent-to-treat basis. RESULTS: Subjects randomized to psychotherapy had a significantly greater improvement than controls in psychological distress and social functioning 6 months after the trial. Baseline treatment costs were similar for both groups. Subjects who received psychotherapy showed significant reductions in the cost of health care utilization in the 6 months after treatment compared with controls. The extra cost of psychotherapy was recouped within 6 months through reductions in health care use. CONCLUSION: These preliminary findings suggest that brief psychodynamic-interpersonal therapy may be cost-effective relative to usual care for patients with enduring nonpsychotic symptoms who are not helped by conventional psychiatric treatment.
Adult↗
The relationship between health and human services and the personal goal-directed activities of persons living with AIDS.
This study evaluates the relationship between the social climate from different services and the personal goal-directed activities of 224 individuals with AIDS. The study's results supported the main hypothesis that "recipient" and "participatory" service involvement uniquely influence personal goal-directed activities, even after considering individuals with AIDS' physical symptoms, psychological distress, income, and recruitment site. Income and involvement with participatory services were both positively related to the amount of personal goal-directed activity. Longitudinal analyses suggest that personal initiative contributes to the subsequent amount of personal goal-directed activities a person pursues. These results suggest further examination of factors contributing to the selection of different service types and of the processes underlying the relationship between participatory services and positive outcomes for clients with AIDS.
Acquired Immunodeficiency Syndrome↗
Should we be doing more to prevent Group C meningococcal infection in school age children? How can we decide?
Meningococcal Group C infections are potentially preventable by vaccination in most cases. Population immunization has not been adopted because the disease is rare and the vaccine effective for only about three years. However, the recent rise in cases in school age children has prompted an assessment of the cost-effectiveness of alternative strategies for management of a case of Group C infection. Chemoprophylaxis and vaccination of close contacts is the most cost-effective strategy but will prevent relatively few cases. Population vaccination prevents considerably more cases, but at a much higher total and marginal cost. An intermediate strategy of giving antibiotics to and vaccinating the school population following a single case, in addition to contact tracing, has intermediate cost-effectiveness. Policy decisions will take into account other important factors but the approach we have taken makes explicit key assumptions so that wider debate including profession and public can be developed.
Adolescent↗
Diverse effects of tyrosine kinase inhibitors on follicle-stimulating hormone-stimulated estradiol and progesterone production from rat granulosa cells in serum-containing medium and serum-free medium containing epidermal growth factor.
Epidermal growth factor (EGF) has been shown to influence FSH-stimulated estradiol (E2) and progesterone (P4) production from granulosa cells. RG 50810, a tyrosine kinase inhibitor (TKI), has previously been shown to inhibit the EGF-receptor tyrosine kinase. RG 50810 has also been shown to inhibit FSH-stimulated increases in mRNA for steroidogenic enzymes, implying a functional role of tyrosine kinases in FSH action in granulosa cells. However, inhibition of FSH-stimulated steroidogenesis by TKIs has not been evaluated in connection with the effects of EGF in granulosa cells. In the present studies, FSH-stimulated E2 production was inhibited similarly by inhibitors of protein kinase A (H-89) and protein kinase C (calphostin C) and by TKIs, and none of the inhibitors were capable of reversing the EGF-induced inhibition of FSH-stimulated E2 production. FSH-stimulated P4 production was enhanced dramatically in serum-containing medium with concentrations of TKI that were near previously reported IC50s. The enhancing effect of TKIs was less evident in serum-free medium. Addition of EGF to serum-free medium enhanced FSH-stimulated P4 production, and the TKIs reversed EGF-enhanced P4 production, but in a manner similar to that of protein kinase A inhibitor H-89. Compared to results in serum-free medium, the potency of RG 50810 and genistein to inhibit the effects of EGF on P4 production was 3- to 8-fold greater relative to H-89. These studies have demonstrated that TKIs RG 50810 and genistein selectively inhibit the effects of EGF on FSH-stimulated P4 production in granulosa cell cultures. In contrast, these studies have demonstrated nonselective inhibition of FSH-stimulated E2 and P4 production by TKIs in serum-free medium, in which it is not clear which enzyme system is affected by the compounds tested.
Animals↗
Automated rubella antibody screening:a cautionary tale.
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Antibodies, Viral↗
Hydroxyurea enhances the activities of didanosine, 9-[2-(phosphonylmethoxy)ethyl]adenine, and 9-[2-(phosphonylmethoxy)propyl]adenine against drug-susceptible and drug-resistant human immunodeficiency virus isolates.
We assessed the effects of hydroxyurea (HU) at a concentration of 50 microM on the in vitro activities of 2',3'-dideoxyinosine (ddI), 9-[2-(phosphonylmethoxy)ethyl]adenine (PMEA), and 9-[2-(phosphonylmethoxy)propyl]adenine (PMPA) against a wild-type human immunodeficiency virus (HIV) type 1 (HIV-1) laboratory isolate and a panel of five well-characterized drug-resistant HIV isolates. Fifty micromolar HU significantly increased the activities of ddI, PMEA, and PMPA against both the wild-type and the drug-resistant HIV-1 isolates. In fixed combinations, both ddI and PMEA were synergistic with HU against wild-type and drug-resistant viruses.
Adenine↗
Microbial desulfurization of alkylated dibenzothiophenes from a hydrodesulfurized middle distillate by Rhodococcus erythropolis I-19.
Rhodococcus erythropolis I-19, containing multiple copies of key dsz genes, was used to desulfurize alkylated dibenzothiophenes (Cx-DBTs) found in a hydrodesulfurized middle-distillate petroleum (MD 1850). Initial desulfurization rates of dibenzothiophene (DBT) and MD 1850 by I-19 were 5.0 and 2.5 micromol g dry cell weight(-1) min(-1), more than 25-fold higher than that for wild-type bacteria. According to sulfur K-edge X-ray absorption near-edge structure (XANES) analysis, thiophenic compounds accounted for >95% of the total sulfur found in MD 1850, predominantly Cx-DBTs and alkylated benzothiophenes. Extensive biodesulfurization resulted in a 67% reduction of total sulfur from 1,850 to 615 ppm S. XANES analysis of the 615-ppm material gave a sulfur distribution of 75% thiophenes, 11% sulfides, 2% sulfoxides, and 12% sulfones. I-19 preferentially desulfurized DBT and C1-DBTs, followed by the more highly alkylated Cx-DBTs. Shifting zero- to first-order (first-order) desulfurization rate kinetics were observed when MD 1850 was diluted with hexadecane. Apparent saturation rate constant (K(0)) and half-saturation rate constant (K(1)) values were calculated to be 2.8 micromol g dry cell weight(-1) min(-1) and 130 ppm, respectively. However, partial biocatalytic reduction of MD 1850 sulfur concentration followed by determination of initial rates with fresh biocatalyst led to a sigmoidal kinetic behavior. A competitive-substrate model suggested that the apparent K(1) values for each group of Cx-DBTs increased with increasing alkylation. Overall desulfurization rate kinetics with I-19 were affected by the concentration and distribution of Cx-DBTs according to the number and/or lengths of alkyl groups attached to the basic ring structure.
Alkylation↗
Subcallosal striations: early findings of multiple sclerosis on sagittal, thin-section, fast FLAIR MR images.
PURPOSE: To determine how sensitive and specific the magnetic resonance (MR) imaging finding of subcallosal striations is for multiple sclerosis (MS). MATERIALS AND METHODS: In 18 patients with clinically suspected MS and 32 age-matched patients without MS, sagittal 2-mm fast fluid-attenuated inversion-recovery (FLAIR) imaging was added to the routine MR studies of the brain. The images were reviewed for the presence of subcallosal striations, that is, linear, 1-mm-thick foci of hyperintensity perpendicular to the ependyma, like a stack of coins. The images were masked to exclude the hemispheric white matter and were interpreted without knowledge of patient age or medical history. RESULTS: Seventeen patients with clinical MS had subcallosal striations; one did not. Of the 32 patients without MS, five had subcallosal striations and 27 did not. Subcallosal striations were highly associated (P < .001) with clinical MS. CONCLUSION: Subcallosal striations are thought to represent perivenular demyelination, that is, the same process that later produces the "ovoid" lesions visible on routine MR images. Subcallosal striations are not seen on routine axial MR images and can be seen only on 2-mm sagittal FLAIR images.
Adult↗
Pharmacological profile of ZD1611, a novel, orally active endothelin ETA receptor antagonist.
The endothelins (ETs), potent vasoconstrictor peptides, have been implicated in the pathogenesis of various cardiovascular disorders. In the present study, we describe the novel, potent, orally active, selective ET(A) receptor antagonist ZD1611 [3-(4-[3-(3-methoxy-5-methylpyrazin-2-ylsulfamoyl)-2-pyridyl ]phenyl)- 2,2-dimethylpropanoic acid]. ZD1611 competitively inhibited (125)I-labeled ET-1 binding at human cloned ET(A) and ET(B) receptors with pIC(50) values of 8.6 +/- 0.1 and 5.6 +/- 0.1, respectively, showing 1000-fold selectivity for the ET(A) receptor. ZD1611 caused a parallel rightward shift of the concentration response curve to ET-1 in the rat isolated aorta yielding a concentration of antagonist that caused a 2-fold rightward shift in the ET-1-response curve (pA(2)) of 7.5 +/- 0.3. When administered i. v. to anesthetized rats and dogs, ZD1611 caused dose-related rightward shifts of partial dose-response curves to the precursor of ET-1, big ET-1. Threshold doses for significant antagonist activity were determined as 0.1 mg/kg and 0.3 mg/kg in the rat and dog, respectively. Importantly, ZD1611 was able to reverse an established big ET-1-induced pressor response in pithed rats in the presence of continuous big ET-1 infusion. Failure of ZD1611 to inhibit the BQ3020 (ET(B)-selective)-induced depressor response in pithed rats indicated a lack of activity at the endothelial ET(B) receptor. ZD1611 was orally active in the rat at 0.3 mg/kg and had a duration of action of more than 7 h, and, in the dog, a dose of 0.6 mg/kg p.o. was active for at least 6 h. In conclusion, these data demonstrate that ZD1611 is a potent and orally active, selective ET(A) receptor antagonist with a long duration of action which may be of therapeutic use.
Administration, Oral↗
Neuroprotection by (R)-deprenyl and 7-nitroindazole in the MPTP C57BL/6 mouse model of neurotoxicity.
The neurodegenerative properties of the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are thought to result from inhibition of complex I of the mitochondrial respiratory chain by the monoamine oxidase-B (MAO-B) generated 1-methyl-4-phenylpyridinium metabolite MPP+. 7-Nitroindazole (7-NI) both a reversible MAO-B inhibitor and a neuronal nitric oxide synthase (nNOS) inhibitor, and (R)-deprenyl a potent MAO-B inactivator, provide neuroprotection in the C57BL/6 mouse model of MPTP neurotoxicity. The results reported here demonstrate the complexities of the effects of 7-NI in this model and examine the possibility of other mechanisms of neuroprotection by (R)-deprenyl.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
[Functional complementation of intra- and extra-oral implants. Apropos of a case of extensive loss of substance of the face].
The respective indications for oral or extra-oral implants lead to no confusion: stabilization of dental prostheses for the first, stabilization of maxilo-facial epitheses for the others. We demonstrate that the complementarity of the two types of implants can prove to be very useful in maintaining the maxillary dental prosthesis and the epithesis in a case of severe loss of facial substance affecting particularly the pre-maxilla. This complementary characteristic made it possible to recover fairly rapidly phonation and deglutition, and to remedy somewhat the esthetic damage. In other words to create the essential conditions for a return to everyday life.
Aged↗
Patchy fur, a mouse coat mutation associated with X-Y nondisjunction, maps to the pseudoautosomal boundary region.
Patchy fur is a semidominant X-linked mutation in the mouse, resulting in a sparse coat. The Paf mutation also alters the normal segregation of the X and the Y chromosomes during male meiosis by causing nondisjunction at anaphase I. Analysis of 1139 female meioses from an intersubspecific backcross using 15 PCR-based markers localizes Paf to an approximately 0.2-cM interval that includes the pseudoautosomal boundary. The meiotic nondisjunction phenotype may result from a chromosomal rearrangement that includes pseudoautosomal sequences and affects XY pairing.
Animals↗
Large-scale sequence comparisons reveal unusually high levels of variation in the HLA-DQB1 locus in the class II region of the human MHC.
Comparison of genomic sequences flanking the HLA-DQB1 locus in the human MHC class II region reveals local sequence variation of up to 10%, which is the highest level of sequence variation found in the human genome so far. The variation is haplotype-specific and extends far beyond the transcriptional unit of the DQB1 gene, suggesting hitch-hiking along with functionally selected alleles as the most likely mechanism. All major insertions/deletions (indels) were found to be of retroviral origin and in the immediate upstream region of DQB1. Possible cis-acting effects of these indels on the transcriptional regulation of DQB1 are discussed.
Ataxin-1↗
From public health to the health of the public. Modern public health problems will not be solved by anything as simple as sewers.
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History, 19th Century↗
Bereavement in adult life. Psychotropic drugs may be appropriate treatment.
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Adult↗
Roles of Ca2+ and crossbridge kinetics in determining the maximum rates of Ca2+ activation and relaxation in rat and guinea pig skinned trabeculae.
We examined the influences of Ca2+ and crossbridge kinetics on the maximum rate of force development during Ca2+ activation of cardiac myofibrils and on the maximum rate of relaxation. Flash photolysis of diazo-2 or nitrophenyl-EGTA was used to produce a sudden decrease or increase, respectively, in [Ca2+] within Triton-skinned trabeculae from rat and guinea pig hearts (22 degrees C). Trabeculae from both species had similar Ca2+ sensitivities, suggesting that the rate of dissociation of Ca2+ from troponin C (k(off)) is similar in the 2 species. However, the rate of relaxation after diazo-2 photolysis was 5 times faster in the rat (16.1 +/- 0.9 s(-1), mean +/- SEM, n = 11) than in the guinea pig (2.99 +/- 0.26 s(-1), n = 7). This indicates that the maximum relaxation rate is limited by crossbridge kinetics rather than by k(off). The maximum rates of rapid activation by Ca2+ after nitrophenyl-EGTA photolysis (k(act)) and of force redevelopment after forcible crossbridge dissociation (k(act)) were similar and were approximately 5-fold faster in rat (k(act)= 14.4 +/- 0.9 s(-1), k(tr)= 13.0 +/- 0.6 s(-1)) than in guinea pig (k(act)= 2.57 +/- 0.14 s(-1), k(tr)= 2.69 +/- 0.30 s(-1)) trabeculae. This too may be mainly due to species differences in crossbridge kinetics. Both k(act) and k(tr) increased as [Ca2+] increased. This Ca2+ dependence of the rates of force development is consistent with current models for the Ca2+ activation of the crossbridge cycle, but these models do not explain the similarity in the maximal rates of activation and relaxation within a given species.
Actomyosin↗