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Biomedical subjects

R Friedman

Publications and source records attributed to R Friedman.

At least 19 recordsLinked to original sources
PubMed2006

Cardiovascular responses to combined treatment with selective monoamine oxidase type B inhibitors and L-DOPA in the rat.

BACKGROUND AND PURPOSE: Postural hypotension is a common side-effect of L-DOPA treatment of Parkinson's disease, and may be potentiated when L-DOPA is combined with selegiline, a selective inhibitor of monoamine oxidase B (MAO-B). Rasagiline is a new, potent and selective MAO-B inhibitor, which does not possess the sympathomimetic effects of selegiline. We have studied the effects of these selective MAO inhibitors, L-DOPA and dopamine on the cardiovascular system of the rat. EXPERIMENTAL APPROACH: Blood pressure and heart rate was measured in conscious rats following acute or chronic administration of rasagiline, selegiline and L-DOPA, by comparison with the selective MAO-A inhibitor clorgyline, or the MAO-A/B inhibitor tranylcypromine. Cardiovascular responses, catecholamine release, and modification of pressor response to dopamine were studied in pithed rats. KEY RESULTS: In conscious rats neither rasagiline nor selegiline caused significant potentiation of the effects of L-DOPA (50, 100, 150 mg.kg(-1)) on blood pressure or heart rate at doses which selectively inhibited MAO-B, but L-DOPA responses were potentiated by clorgyline and tranylcypromine. In rats treated twice daily for 8 days with L-DOPA and carbidopa, selegiline (5 mg.kg(-1)) but not rasagiline (0.2 mg.kg(-1)) caused a significant hypotensive response to L-DOPA and carbidopa, although both drugs caused similar inhibition of MAO-A and MAO-B. In pithed rats, selegiline but not rasagiline increased catecholamine release and heart rate, and potentiated dopamine pressor response at MAO-B selective dose. CONCLUSIONS AND IMPLICATIONS: The different responses to the two MAO-B inhibitors may be explained by the amine releasing effect of amphetamine metabolites formed from selegiline.

Animals↗
PubMed2006

The dynamics of proton transfer between adjacent sites.

The mechanism of proton transfer at the interface is the most prevalent reaction in the biosphere, yet its modeling at atomic level is still technically impossible. The difficulties emerge from the quantum mechanical nature of the proton, the modulation of the local electrostatic potential by the protein-water dielectric boundary and the formation of covalent bonds with proton binding sites whenever encounters take place. To circumvent some of these difficulties, and to identify the effect of the local electrostatic field, we present molecular dynamics simulations, where Na+ and Cl- ions diffuse at the surface of a small model protein, the S6 of the bacterial ribosome. The analysis reveals the presence of a detained state, where an ion is located for a relatively long period within the immediate environment of certain attractor residues. In the detained state the ion retains its ability to diffuse, yet the local field deters it from leaving to the bulk. When an ion is detained inside a Coulomb cage, it has a high probability to be transferred between nearby attractors, thus forming a mechanism similar to that responsible for the proton collecting antenna present on proton proteins.

Ion Transport↗
PubMed2002

Pain and the body schema: effects of pain severity on mental representations of movement.

Previous research suggests that response times for imagined movements provide a sensitive measure of the integrity of the motor system. In a group of 12 patients with chronic unilateral arm pain, the authors demonstrate that response times for imagined movements are influenced by the severity of pain. Simulated large-amplitude arm movements were slower for the painful as compared with the unaffected arms before, but not after, effective music therapy entrainment, suggesting that mental representations of movement are influenced by the current state of nociceptive feedback.

Arm↗
PubMed2001

Changing chairs: anticipating problems in prescribing wheelchairs.

PURPOSE: This article presents a framework for prescribing, ordering, and adapting a new wheelchair, focusing on individual, environmental and wheelchair factors that must be taken into consideration to ensure optimal function. METHOD: A review and analysis was conducted of all factors relevant to the transition to a new wheelchair. Without appropriate planning and implementation, this transition can result in unnecessary expenses, duplication of effort, and possibly even injury to the user and abandonment of the wheelchair. RESULTS: Recommendations are provided to manufacturers, therapists, technicians, users, insurers and physicians, who must work together throughout this process. To the extent feasible, the authors suggest that major changes from the previous wheelchair should be avoided, particularly for people with substantial functional limitations. Therapists and technicians must measure the user accurately, and anticipate those factors that can impede a smooth transition. Insurers and other payors must recognize that changing wheelchairs will often require substantial professional assistance, including several fittings to adjust the new chair to the needs of the user. CONCLUSION: Additional research and case reporting on outcomes of adjusting to a new wheelchair appear warranted.

Equipment Design↗
PubMed2001

PEA3 sites within the progression elevated gene-3 (PEG-3) promoter and mitogen-activated protein kinase contribute to differential PEG-3 expression in Ha-ras and v-raf oncogene transformed rat embryo cells.

Transformation of normal cloned rat embryo fibroblast (CREF) cells with cellular oncogenes results in acquisition of anchorage-independent growth and oncogenic potential in nude mice. These cellular changes correlate with an induction in the expression of a cancer progression-promoting gene, progression elevated gene-3 (PEG-3). To define the mechanism of activation of PEG-3 as a function of transformation by the Ha-ras and v-raf oncogenes, evaluations of the signaling and transcriptional regulation of the approximately 2.0 kb promoter region of the PEG-3 gene, PEG-Prom, was undertaken. The full-length and various mutated regions of the PEG-Prom were linked to a luciferase reporter construct and tested for promoter activity in CREF and oncogene-transformed CREF cells. An analysis was also performed using CREF cells doubly transformed with Ha-ras and the Ha-ras specific suppressor gene Krev-1, which inhibits the transformed phenotype in vitro. These assays document an association between expression of the transcription regulator PEA3 and PEG-3. The levels of PEA3 and PEG-3 RNA and proteins are elevated in the oncogenically transformed CREF cells, and reduced in transformation and tumorigenic suppressed Ha-ras/Krev-1 doubly transformed CREF cells. Enhanced tumorigenic behavior, PEG-3 promoter function and PEG-3 expression in Ha-ras transformed cells were all dependent upon increased activity within the mitogen-activated protein kinase (MAPK) pathway. Electrophoretic mobility shift assays and DNase I footprinting experiments indicate that PEA3 binds to sites within the PEG-Prom in transformed rodent cells in an area adjacent to the TATA box in a MAPK-dependent fashion. These findings demonstrate an association between Ha-ras and v-raf transformation of CREF cells with elevated PEA3 and PEG-3 expression, and they implicate MAPK signaling via PEA3 as a signaling cascade involved in activation of the PEG-Prom.

Animals↗
PubMed2001

Oral ketamine for opioid-resistant acute pain.

We report successful treatment of opioid-resistant postoperative pain in this case report. Oral ketamine reduced the doses of opioids needed for pain control. Opioid/N-methyl-D-aspartate receptor antagonist combinations should be studied further for acute pain treatment.

Journal Article↗
PubMed2001

Pain and the body schema: evidence for peripheral effects on mental representations of movement.

Some accounts of body representations postulate a real-time representation of the body in space generated by proprioceptive, somatosensory, vestibular and other sensory inputs; this representation has often been termed the 'body schema'. To examine whether the body schema is influenced by peripheral factors such as pain, we asked patients with chronic unilateral arm pain to determine the laterality of pictured hands presented at different orientations. Previous chronometric findings suggest that performance on this task depends on the body schema, in that it appears to involve mentally rotating one's hand from its current position until it is aligned with the stimulus hand. We found that, as in previous investigations, participants' response times (RTs) reflected the degree of simulated movement as well as biomechanical constraints of the arm. Importantly, a significant interaction between the magnitude of mental rotation and limb was observed: RTs were longer for the painful arm than for the unaffected arm for large-amplitude imagined movements; controls exhibited symmetrical RTs. These findings suggest that the body schema is influenced by pain and that this task may provide an objective measure of pain.

Adult↗
PubMed2001

How should we measure blood pressure in the doctor's office?

BACKGROUND: Blood pressure is the most ubiquitous diagnostic recording made in the doctor's office, but the measurement is subject to a number of sources of bias, which may lead to over- or underestimation. The current study examined the systematic influence of the way in which the measurements were taken - by the physician, by a nurse, or with the patient sitting alone, using an automated device. SUBJECTS AND METHODS: Blood pressure was measured in 17 essential hypertensive and 10 white-coat hypertensive individuals. On separate clinic visits, measurements were taken by the attending physician, by a nurse and using an automated device (Arteriosonde 1216). RESULTS: A repeated-measures ANOVA revealed that, for systolic pressure, there was a significant effect of measurement modality on blood pressure. Physician systolic pressures were on average approximately 10 mmHg higher than those taken by a nurse, nurse pressures being approximately 7 mmHg higher than those recorded using Arteriosonde. The effect on diastolic pressure was similar but smaller, and no nurse-Arteriosonde difference was observed. CONCLUSIONS: We conclude that the routine clinical assessment of blood pressure would be more representative of daily ambulatory pressure if an automated device, without doctor or nurse present, were used.

Aged↗
PubMed2001

Gene duplication and the structure of eukaryotic genomes.

A simple method for understanding how gene duplication has contributed to genomic structure was applied to the complete genomes of Caenorhabditis elegans, Drosophila melanogaster, and yeast Saccharomyces cerevisiae. By this method, the genes belonging to gene families (the paranome) were identified, and the extent of sharing of two or more families between genomic windows was compared with that expected under a null model. The results showed significant evidence of duplication of genomic blocks in both C. elegans and yeast. In C. elegans, the five block duplications identified all occurred intra-chromosomally, and all but one occurred quite recently. In yeast, by contrast, 39 duplicated blocks were identified, and all but one of these was inter-chromosomal. Of these 39 blocks, 28 showed evidence of ancient duplication, possibly as a result of an ancient polyploidization event. By contrast, three blocks showed evidence of very recent duplication, while seven others showed a mixture of ancient and recent duplication events. Thus, duplication of genomic blocks has been an ongoing feature of yeast evolution over the past 200--300 million years.

Animals↗
PubMed2001

Pattern and timing of gene duplication in animal genomes.

Duplication of genes, giving rise to multigene families, has been a characteristic feature of the evolution of eukaryotic genomes. In the case of vertebrates, it has been proposed that an increase in gene number resulted from two rounds of duplication of the entire genome by polyploidization (the 2R hypothesis). In the most extensive test to date of this hypothesis, we compared gene numbers in homologous families and conducted phylogenetic analyses of gene families with two to eight members in the complete genomes of Caenorhabditis elegans and Drosophila melanogaster and the available portion of the human genome. Although the human genome showed a higher proportion of recent gene duplications than the other animal genomes, the proportion of duplications after the deuterostome-protostome split was constant across families, with no peak of such duplications in four-member families, contrary to the expectation of the 2R hypothesis. A substantial majority (70.9%) of human four-member families and four-member clusters in larger families showed topologies inconsistent with two rounds of polyploidization in vertebrates.

Animals↗
PubMed2001

Ancient genome duplications did not structure the human Hox-bearing chromosomes.

The fact that there are four homeobox (Hox) clusters in most vertebrates but only one in invertebrates is often cited as evidence for the hypothesis that two rounds of genome duplication by polyploidization occurred early in vertebrate history. In addition, it has been observed in humans and other mammals that numerous gene families include paralogs on two or more of the four Hox-bearing chromosomes (the chromosomes bearing the Hox clusters; i.e., human chromosomes 2, 7, 12, and 17), and the existence of these paralogs has been taken as evidence that these genes were duplicated along with the Hox clusters by polyploidization. We tested this hypothesis by phylogenetic analysis of 42 gene families including members on two or more of the human Hox-bearing chromosomes. In 32 of these families there was evidence against the hypothesis that gene duplication occurred simultaneously with duplication of the Hox clusters. Phylogenies of 14 families supported the occurrence of one or more gene duplications before the origin of vertebrates, and of 15 gene duplication times estimated for gene families evolving in a clock-like manner, only six were dated to the same time period early in vertebrate history during which the Hox clusters duplicated. Furthermore, of gene families duplicated around the same time as the Hox clusters, the majority showed topologies inconsistent with their having duplicated simultaneously with the Hox clusters. The results thus indicate that ancient events of genome duplication, if they occurred at all, did not play an important role in structuring the mammalian Hox-bearing chromosomes.

Animals↗
PubMed2001

Phylogenetic analysis of culturable dimethyl sulfide-producing bacteria from a spartina-dominated salt marsh and estuarine water.

Dimethylsulfoniopropionate (DMSP), an abundant osmoprotectant found in marine algae and salt marsh cordgrass, can be metabolized to dimethyl sulfide (DMS) and acrylate by microbes having the enzyme DMSP lyase. A suite of DMS-producing bacteria isolated from a salt marsh and adjacent estuarine water on DMSP agar plates differed markedly from the pelagic strains currently in culture. While many of the salt marsh and estuarine isolates produced DMS and methanethiol from methionine and dimethyl sulfoxide, none appeared to be capable of producing both methanethiol and DMS from DMSP. DMSP, and its degradation products acrylate and beta-hydroxypropionate but not methyl-3-mecaptopropionate or 3-mercaptopropionate, served as a carbon source for the growth of all the alpha- and beta- but only some of the gamma-proteobacterium isolates. Phylogenetic analysis of 16S rRNA gene sequences showed that all of the isolates were in the group Proteobacteria, with most of them belonging to the alpha and gamma subclasses. Only one isolate was identified as a beta-proteobacterium, and it had >98% 16S rRNA sequence homology with a terrestrial species of Alcaligenes faecalis. Although bacterial population analysis based on culturability has its limitations, bacteria from the alpha and gamma subclasses of the Proteobacteria were the dominant DMS producers isolated from salt marsh sediments and estuaries, with the gamma subclass representing 80% of the isolates. The alpha-proteobacterium isolates were all in the Roseobacter subgroup, while many of the gamma-proteobacteria were closely related to the pseudomonads; others were phylogenetically related to Marinomonas, Psychrobacter, or Vibrio species. These data suggest that DMSP cleavage to DMS and acrylate is a characteristic widely distributed among different phylotypes in the salt marsh-estuarine ecosystem.

DNA, Bacterial↗
PubMed2001

A telephone-linked computer system for COPD care.

The current revolution in communications technology provides an opportunity for novel approaches to management of medical illness. As economic imperatives lead to a progressive reduction in the time that health-care providers spend with their patients, computerized, telephone-linked communication systems offer an inexpensive, widely available alternative with which patients and providers can maintain contact. Such systems may be particularly useful for providing ongoing monitoring and education of patients with chronic illnesses such as COPD. In this article, we describe the general application of telephone-linked communication systems in the health-care setting. We then present in detail one such system, which provides telephone-linked care for COPD (TLC-COPD). The operation of the system is described, as are its theoretical underpinnings in social learning theory. A randomized clinical trial currently is being performed to study the effects of the TLC-COPD system. The rationale for expected improvements in disease control and quality of life, and for a reduction in acute health-care utilization, is discussed.

Algorithms↗
PubMed2000

Methamphetamine selectively alters brain glutathione.

As methamphetamine-induced neurotoxicity has been proposed to involve oxidative stress, reduced and oxidized glutathione (GSH and GSSG, respectively), vitamin E and ascorbate were measured in the striata of rats killed 2 or 24 h after a neurotoxic regimen of methamphetamine. At 2 h, methamphetamine increased GSH and GSSG (32. 5% and 43.7%, respectively) compared to controls at 2 h. No difference was seen in glutathione at 24 h, and in vitamin E and ascorbate at either time point. These findings indicate selectivity of methamphetamine for the glutathione system and a role for methamphetamine in inducing oxidative stress.

Animals↗
PubMed2000

Genetically modified anthrax lethal toxin safely delivers whole HIV protein antigens into the cytosol to induce T cell immunity.

Bacillus anthrax lethal toxin can be engineered to deliver foreign proteins to the cytosol for antigen presentation to CD8 T cells. Vaccination with modified toxins carrying 8-9 amino acid peptide epitopes induces protective immunity in mice. To evaluate whether large protein antigens can be used with this system, recombinant constructs encoding several HIV antigens up to 500 amino acids were produced. These candidate HIV vaccines are safe in animals and induce CD8 T cells in mice. Constructs encoding gag p24 and nef stimulate gag-specific CD4 proliferation and a secondary cytotoxic T lymphocyte response in HIV-infected donor peripheral blood mononuclear cells in vitro. These results lay the foundation for future clinical vaccine studies.

AIDS Vaccines↗
PubMed2000

Oral ketamine in hepatocellular carcinoma.

Ketamine, an NMDA antagonist, has been used in pain treatment for a number of years. Recent reports have suggested its utility in a variety of pain states including post-herpetic neuralgia [1], cancer [2], and postoperative pain [5]. While a variety of neuropsychologic side effects are observed with parenteral ketamine, in oral use these side effects have been less pronounced [2,3]. We report a patient with severe hepatic disease who developed hallucinations following a 75-mg oral dose of ketamine for treatment of severe cancer pain unresponsive to morphine.

Journal Article↗
PubMed2000

Evolutionary diversification of protein-coding genes of hantaviruses.

Phylogenetic analyses of the S:, M, and L: genes of the hantaviruses (Bunyaviridae: Hantavirus) revealed three well-differentiated clades corresponding to viruses parasitic on three subfamilies (Murinae, Arvicolinae, and Sigmodontinae) of the rodent family Muridae. In rooted trees of M: and L: genes, the viruses with hosts belonging to Murinae formed an outgroup to those with hosts in Arvicolinae and Sigmodontinae. This phylogeny corresponded with a phylogeny of the murid subfamilies based on mitochondrial cytochrome b sequences, supporting the hypothesis that hantaviruses have coevolved with their mammalian hosts at least since the common ancestor of these three subfamilies, which probably occurred about 50 MYA. The nucleocapsid protein (encoded by the S: gene) differentiated among the viruses parasitic on the three subfamilies in such a way that a high frequency of amino acid residue charge changes occurred in a hypervariable (HV) portion of the molecule, and nonsynonymous nucleotide differences causing amino acid charge changes in the HV region occurred significantly more frequently than expected under random substitution. Along with evidence that at least in some hantaviruses the HV region is a target for host antibodies and the known importance of charged residues in determining antibody epitopes, these results suggest that changes in the HV region may represent adaptation to host-specific characteristics of the immune response.

Animals↗