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Biomedical subjects

S Brown

Publications and source records attributed to S Brown.

At least 91 records · Page 5Linked to original sources

Depressive symptoms modulate the subjective and physiological response to cocaine in humans.

The goal of this study was to examine the relationship between the presence of subclinical depressive symptoms and physiological and subjective responses to smoked cocaine in humans. Cocaine users without major depression, who participated in various inpatient studies, received a single 0.4 mg/kg of smoked cocaine. When the relationship between the Beck Depression Inventory (BDI) scores and various subjective and physiological responses to cocaine was examined, similar trends were found. Low BDI scores of 0-7 were associated with a smaller physiological and subjective cocaine response. In contrast, BDI ranges of 8-13 were associated with enhanced cocaine response which plateaued or declined in the higher (> 14) BDI group. These group differences were not explained by sex or body weight differences among groups. The implication of these results is that the presence of depressive symptoms may affect cocaine use behavior partly by being associated with an enhanced response to cocaine.

Administration, Inhalation↗

Xenopus Bcl-X(L) selectively protects Rohon-Beard neurons from metamorphic degeneration.

Amphibian metamorphosis involves extensive, but selective, neuronal death and turnover, thus sharing many features with mammalian postnatal development. The antiapoptotic protein Bcl-X(L) plays an important role in postnatal mammalian neuronal survival. It is therefore of interest that accumulation of the mRNA encoding the Xenopus Bcl-X(L) homologue, termed xR11, increases abruptly in the nervous system, but not in other tissues, during metamorphosis in Xenopus tadpoles. This observation raises the intriguing possibility that xR11 selectively regulates neuronal survival during postembryonic development. To investigate this hypothesis, we overexpressed xR11 in vivo as a green fluorescent protein (GFP)-xR11 fusion protein by using somatic and germinal transgenesis. Somatic gene transfer showed that the fusion protein was effective in counteracting, in a dose-dependent manner, the proapoptotic effects of coexpressed Bax. When GFP-xR11 was expressed from the neuronal beta-tubulin promoter by germinal transgenesis we observed neuronal specific expression that was maintained throughout metamorphosis and beyond, into juvenile and adult stages. Confocal microscopy showed GFP-xR11 to be exclusively localized in the mitochondria. Our findings show that GFP-xR11 significantly prolonged Rohon-Beard neuron survival up to the climax of metamorphosis, even in the regressing tadpole tail, whereas in controls these neurons disappeared in early metamorphosis. However, GFP-xR11 expression did not modify the fate of spinal cord motoneurons. The selective protection of Rohon-Beard neurons reveals cell-specific apoptotic pathways and offers approaches to further analyze programmed neuronal turnover during postembryonic development.

Animals↗

Policy considerations for using forests to mitigate carbon dioxide emissions.

A recent article in Nature, "Soil Fertility Limits Carbon Sequestration by Forest Ecosystems in a CO2-Enriched Atmosphere" by Oren and colleagues, has been widely reported on, and often misinterpreted, by the press. The article dampens enthusiasm for accelerated forest growth due to CO2 fertilization and puts in question the fringe theory that the world"s forests can provide an automatic mitigation feedback. We agree that these results increase our understanding of the global carbon cycle. At the same time, their relevance in the context of the international climate change negotiations is much more complicated than portrayed by newspapers such as the New York Times ("Role of Trees in Curbing Greenhouse Gases is Challenged", May 24, 2001) and the Christian Science Monitor ("Trees No Savior for Global Warming", May 25, 2001).

Atmospheric Pressure↗

Influence of topological constraints on the statics and dynamics of ring polymers.

We report a computer simulation study of the influence of topological constraints on the statics and dynamics of single ring polymers and ring polymers in the melt. We show that single rings have identical static and dynamic scaling behavior regardless of the presence of topological constraints. For rings in the melt we find that the scaling behavior is significantly influenced by the presence of topological constraints.

Journal Article↗

HIV-1 reverse transcriptase sequence in plasma and cerebrospinal fluid of patients with AIDS dementia complex treated with Abacavir.

OBJECTIVE: To assess HIV-1 RNA levels and the relationship between HIV-1 reverse transcriptase (RT) genotype from plasma and cerebrospinal fluid (CSF) during treatment with abacavir (Ziagen, ABC) or placebo in combination with stable background therapy (SBG) in subjects with AIDS dementia complex (ADC) (study CNA3001). DESIGN: One-hundred and five HIV-1 infected adults with ADC were randomized to receive either ABC (600 mg twice daily) or ABC-matched placebo (twice daily) in addition to SBG for 12 weeks. METHODS: Plasma and CSF were collected for population sequencing at baseline and week 12 (CSF optional). Sequences were analyzed for mutations associated with resistance to nucleoside reverse transcriptase inhibitors (NRTI). RESULTS: Sixty out of sixty-seven subjects with baseline plasma HIV-RT sequence data harbored virus with > or = 1 NRTI-associated mutations; 50 out of 67 had the M184V mutation. At week 12, more subjects in the ABC group had plasma HIV-1 RNA < or = 400 copies/ml than the SBG group (46% versus 13%, P = 0.002). Non-response to ABC was associated with multiple baseline zidovudine (ZDV)/stavudine (d4T)-associated mutations. Baseline RT mutation patterns differed in 14 out of 21 (67%) paired samples from plasma and CSF. Four subjects experienced > 1 log10 copies/ml reductions in CSF HIV-1 RNA, two in the absence of reductions in plasma HIV-1 RNA and two with undetectable plasma HIV-1 RNA at baseline. CONCLUSIONS: Substantial decreases in plasma and CSF HIV-1 RNA following addition of ABC were not precluded by baseline HIV-1 NRTI-associated mutations, including the M184V mutation, but non-responders commonly harbored multiple ZDV/d4T-associated mutations. HIV-1 RNA responses and RT genotype appear to be discordant between CSF and plasma in some subjects.

AIDS Dementia Complex↗

Quantitative analysis of myocardial perfusion changes with transmyocardial laser revascularization.

Transmyocardial laser revascularization (TLR) is a technique of creating left ventricular transmural channels in patients with refractory angina. We aimed to measure perfusion changes quantitatively using technetium-99m methoxyisobutyl isonitrile. Perfusion scans were performed on 94 TLRs and in 94 control patients at rest and during exercise at assessment, and 3-, 6-, and 12-month follow-up. A serial set of scans allowed direct comparison of each patient over all visits. Bull's-eyes were divided into 5 anatomic regions and a 20-region model. Severity values were calculated for rest, stress, and each cardiac region using a threshold of 1 for analysis. Higher scores indicated greater severity of ischemia and lower perfusion. At 3-month follow-up, the severity was significantly worse during TLR than in control patients both during stress (0.172 +/- 0.003 and 0.161 +/- 0.003, respectively, p = 0.007) and at rest (0.170 +/- 0.003 and 0.158 +/- 0.003, respectively, p = 0.002). At 6 months, severity during stress was 0.176 +/- 0.003 with TLR and 0.162 +/- 0.003 in controls (p = 0.001), with no significant difference at rest. At 12 months, there was no significant difference between TLR and control groups at stress and rest. Regional severity deteriorates during TLR compared with control patients anteriorly (p = 0.001, p = 0.0016, p = 0.005 at 3, 6, and 12 months), apically (p = 0.005, p = 0.0046, p = 0.032, respectively), and laterally (p <0.0001, p = 0.001, p = 0.002, respectively). An apparent improvement is observed in the inferoseptal region at 6- and 12-month follow-up-an area not lasered. Thus, TLR appears to produce deterioration in resting myocardial perfusion in lasered regions, and improvement in nonlasered regions, with no difference in exercise-induced myocardial ischemia compared with that in control patients.

Angina Pectoris↗

How are abnormal results for liver function tests dealt with in primary care? Audit of yield and impact.

OBJECTIVE: To determine whether abnormal results for liver function tests are investigated in primary care and findings on full investigation. DESIGN: Retrospective audit and prospective clinical investigation. SETTING: University hospital and surrounding general practices serving around 330 000 people. SUBJECTS: Adults with abnormal results for liver function based on tests requested by their doctor between 1 January and 30 June 1995. INTERVENTIONS: All patients with gamma-glutamyltransferase, alanine aminotransferase, or alkaline phosphatase concentrations at least twice the upper limit of the reference range were studied. A median of 15 months later (range 12-21) records of hospital attendances and further investigations were examined. Where investigations were incomplete the records from the general practice were examined, and suitable patients were invited to attend the liver clinic. MAIN OUTCOME MEASURES: Investigations requested by the doctor and final diagnoses reached. RESULTS: 933 patients with abnormal liver function tests were identified; follow up data were obtained in 873 (94%). 531 patients were already under hospital review. Of the remaining 342 patients, 157 were suitable for investigation; the others had died, moved away, were elderly, or had repeat liver function tests with normal results. No further tests were requested for 91 (58%) of these patients. 66 had been partially investigated by their doctor, and in seven patients results suggesting a treatable chronic liver disease had not been followed up. On investigation, 97 (62%) had an identifiable diagnosis requiring hospital intervention or follow up, or both. CONCLUSIONS: Abnormal results for liver function are often not adequately investigated, missing an important chance of identifying treatable chronic liver disease.

Alanine Transaminase↗

X-ray absorption studies of human matrix metalloproteinase-2 (MMP-2) bound to a highly selective mechanism-based inhibitor. comparison with the latent and active forms of the enzyme.

Malignant tumors express high levels of zinc-dependent endopeptidases called matrix metalloproteinases (MMPs), which are thought to facilitate tumor metastasis and angiogenesis by hydrolyzing components of the extracellular matrix. Of these enzymes, gelatinases A (MMP-2) and B (MMP-9), have especially been implicated in malignant processes, and thus, they have been a target for drugs designed to block their activity. Therefore, understanding their molecular structure is key for a rational approach to inhibitor design. Here, we have conducted x-ray absorption spectroscopy of the full-length human MMP-2 in its latent, active, and inhibited states and report the structural changes at the zinc ion site upon enzyme activation and inhibition. We have also examined the molecular structure of MMP-2 in complex with SB-3CT, a recently reported novel mechanism-based synthetic inhibitor that was designed to be highly selective in gelatinases. It is shown that SB-3CT directly binds the catalytic zinc ion of MMP-2. Interestingly, the novel mode of binding of the inhibitor to the catalytic zinc reconstructs the conformational environment around the active site metal ion back to that of the proenzyme.

Absorptiometry, Photon↗

Murine high-fat diet and laser photochemical model of basal deposits in Bruch membrane.

OBJECTIVE: To examine the histologic, histochemical, and ultrastructural changes in Bruch membrane in mice on a high-fat diet with and without laser photochemical injury. METHODS: Five groups of C57BL/6 mice were studied. Group 1 included 2-month-old mice on a normal diet; group 2 included 8-month-old mice on a normal diet; group 3 included 8-month-old mice on a high-fat diet; groups 4 and 5 included 8-month-old mice on a normal diet or high-fat diet, respectively, that underwent laser application of one eye with argon blue laser (488 nm). The mice were killed and plasma lipid levels were measured. The eyes were examined by standard electron microscopy, filipin histochemistry for unesterified cholesterol (UC) and esterified cholesterol (EC), and the osmium-tannic acid-phenylenediamine method for preserving extracellular lipid particles. RESULTS: The plasma cholesterol level was significantly higher in the mice on the high-fat diet than the controls (P<.001). Bruch membrane was thicker in group 2 than group 1 (P =.04) and group 3 had a thicker Bruch membrane than group 2 (P =.003). All eyes in group 3 exhibited accumulation of electron-lucent debris. There was no histochemical and ultrastructural evidence that this material represented accumulated UC or EC. Seven of 9 laser-injured eyes in group 5 accumulated basal laminar deposit (BlamD)-like material in Bruch membrane (P =.02). CONCLUSIONS: Electron-lucent debris accumulates in murine Bruch membrane, and the amount correlates with age and high-fat diet. This debris has some similarities with basal linear deposits, although the debris does not form a discrete layer external to the basement membrane of the retinal pigment epithelium as occurs in basal linear deposits. These deposits do not appear to be UC or EC. Laser photochemical injury of the retinal pigment epithelium may result in the appearance of BlamD-like deposits in eyes with electron-lucent debris. The BlamD-like deposits in this model are similar to the basal laminar deposits that occur in age-related macular degeneration. CLINICAL RELEVANCE: This is an animal model of ultrastructural BlamD-like material in Bruch membrane that is very similar to the deposits that occur in age-related macular degeneration.

Animals↗

Prenatal diagnosis of a familial Xq deletion in a female fetus: a case report.

X chromosome deletion is an infrequent finding in prenatal diagnosis and presents a difficult counseling challenge when it occurs. We present a case of a familial X chromosome long arm deletion discovered in a routine amniocentesis and subsequently in the mother. The pregnancy resulted in the birth of a normal girl, and X chromosome inactivation skewing was demonstrated in both mother and daughter. Xq deletion phenotypes and counseling issues are reviewed.

Adult↗

Benefits of thickened feeds in previously healthy infants with respiratory syncytial viral bronchiolitis.

Infants with respiratory syncytial virus (RSV) bronchiolitis have an increased risk of aspiration. The optimal feeding strategy for these patients has not been described. Fifteen previously healthy and clinically stable infants with RSV bronchiolitis underwent video-fluoroscopy studies to assess swallowing using thin barium. Those with abnormal studies underwent a repeat study, using barium that was thickened with rice cereal. Nine of 15 infants had abnormal studies with thin barium. Laryngeal or tracheal penetration with thin barium was seen in 3 and 2 infants, respectively, but not with thickened barium. Aspiration of thin barium was seen in 4 infants, but it corrected in 3 of these 4 infants with thickened barium. Thickened feeds provide a simple, safe, and cost-effective intervention to improve swallowing dysfunction and prevent aspiration in infants with RSV bronchiolitis.

Barium↗

Development of a retinoic acid receptor-binding assay with rainbow trout tissue: characterization of retinoic acid binding, receptor tissue distribution, and developmental changes.

Retinoic acid (RA) regulates the transcription of various genes required for several essential functions in vertebrates through binding to two classes of nuclear receptors, the retinoic acid receptors (RAR) and retinoid X receptors (RXR). We investigated nuclear RA binding in tissues from rainbow trout using the radiolabeled all-trans and 9-cis isomers of RA. Specific binding (indicative of receptor binding) of both all-trans- and 9-cis-RA was found in all tissues tested, including the adult trout ovary, testis, gill, liver, kidney, blood, white muscle, and heart. The kinetics and absolute amount of RA binding were dependent on both the tissue and the isomer of RA used. All-trans-RA bound with high affinity (K(d) approximately 1.0-3.9 nM), and low capacity (B(max) approximately 75-484 fmol RA/mg protein), while 9-cis-RA bound with lower affinity (K(d) approximately 7-56 nM), but with a greater capacity (B(max) approximately 214-1076 fmol RA/mg protein). The B(max) results were used to estimate RAR and RXR levels and revealed that the gill possesses primarily RARs while the liver possesses primarily RXRs. The RAR-specific competitor TTNPB was able to effectively displace all-trans-[3H]RA in most tissues, and the RXR-specific competitor AGN 194204 was able to effectively displace 9-cis-[3H]RA. However, TTNPB and AGN 194204 could not displace all of the RA in the kidney and testis, suggesting the existence of another nuclear RA binding protein. Binding of all-trans- and 9-cis-RA was also found in developing trout embryos and fry. Kinetic analysis revealed that RAR levels predominated at the eyed-embryo stage, but decreased 87% by the swim-up fry stage, while RXR levels remained relatively constant over the same time period. These findings suggest that RA and its receptors may play a key role in early trout development. This study has provided a simple and rapid radioligand binding assay that can identify RAR and RXRs in trout tissues.

Alitretinoin↗

Molecular characterization of Tclabial and the 3' end of the Tribolium homeotic complex.

The homeotic selector gene labial is located at the 3' end of the Antennapedia complex (ANTC) and is required for proper head development in Drosophila. We have cloned and characterized the Tribolium ortholog of labial, Tclabial (Tclab). Similar to Drosophila labial, Tclab contains a single large intron upstream of the homeobox. In contrast, Tclab lacks an intron within the homeobox. The Tribolium ortholog of chaoptic, Tcchaoptic, transcribed from the opposite strand, is located immediately downstream of the homeotic complex, and its 3'UTR overlaps that of Tclab by 50 nucleotides. We have also sequenced the 13.5 kb interval between Tclab and maxillopedia (the Tribolium ortholog of Drosophila proboscipedia). In contrast to Drosophila, there is not a cluster of cuticle genes in this region. Finally, we have examined the expression of Tclab transcripts in Tribolium embryos. As previously described for Drosophila and other insects, the expression of Tclab is specific to the intercalary segment.

Amino Acid Sequence↗

Cytochrome c is not essential for viability of the fungus Aspergillus nidulans.

The filamentous fungus Aspergillus nidulans is an obligate aerobe, which is capable of anaerobic survival, but not anaerobic growth. Since cytochrome c forms an essential part of the oxidative respiratory pathway it was expected that mutants lacking this component would be non-viable. Gene replacement of one homologue of the cycA (cytochrome c) gene was carried out in a diploid strain. Benomyl-induced haploidisation of this diploid yielded all cycA+ haploid colonies, initially suggesting that loss of cycA was indeed lethal. However, use of an alternative unbiased method to recover haploids yielded viable, but slow-growing, cycA- mutants. Replacement of the cycA locus in the cycA- mutants was verified by Southern blotting. Spectral analysis confirmed the absence of detectable levels of cytochrome c, and respiratory insensitivity to cyanide suggested the absence of cytochrome c-dependent respiration. Growth parameters were consistent with those expected of a CycA- mutant. Compared to the wild type, the mutants grew slowly on fermentable carbon sources, did not grow on non-fermentable carbon sources, and produced higher levels of ethanol. To our knowledge, this is the first report of a filamentous fungus that remains viable after complete elimination of a functional cytochrome c gene. We propose that the mutants are viable due to their ability to ferment and to use alternative respiratory pathways.

Aspergillus nidulans↗