By P. Vatras. Temple University.
INTRODUCTION Theories of the role of the basal ganglia within the functional circuitry of the basal ganglia-thalamic-cortical system are entering a state of ﬂux buy 250 mg famvir hiv infection rate statistics. Current theories buy famvir 250mg mastercard lemon antiviral, while of heuristic value in explaining many observations, are now inconsistent with an expanding body of knowledge. Most likely, observations supportive of the current theories and their associated circumstances will be found to be special cases of a larger new theory. There is no new general theory yet proposed that is a clear successor. Consequently, there is considerable value in analyzing the epistemic basis of current theories, if for no other reason than avoiding the types of inferences that, in retrospect, are erroneous. Also, such an exercise may help to form a framework by which new theories can develop and be judged. As Charcot said, ‘‘we see only what we are ready to see’’ (1). Typically this statement is made in retrospect to explain why observations and insights are missed or late in being made. A better use would be to prepare prospectively to facilitate new observations and insights. Such preparation must necessarily be theoretical and, to some extent, philosophical because such discussions precede recognition of data. Understanding the functional circuitry of the basal ganglia-thalamus- cortex in terms of neuronal activities and interrelationships within a large- Copyright 2003 by Marcel Dekker, Inc. The resurgence of functional stereotactic surgery, both ablative and utilizing deep brain stimulation (DBS), has been fueled by improvement in surgical techniques such as image-based and microelectrode navigation, a realization of the limitations of pharmacological therapy, as well as a justifying rationale based on better understanding of neuronal pathophysiology. Systems physiology and pathophysiology will play an ever-increasing role in developing new electrophysiologically based techni- ques such as DBS. Systems physiology and pathophysiology also will play a large role in the further development of neurotransplantation of both fetal dopamine and stem cells. The occurrence of ‘‘runaway’’ dyskinesia in patients who underwent neurotransplantation with fetal cells emphasizes the importance of physiological controls on the implanted cells (2). Considerable research is underway to develop methods to dynamically control transplanted neurons, as well as a greater understanding of the importance of the physiological context or environment. For example, fetal dopamine neurons extracted from the region of the substantia nigra pars compacta (SNpc) have been transplanted into the striatum. However, this is not the normal location for these neurons, and the usual efferents to SNpc that control dopamine neuron function are not located in the striatum. ANATOMY: THE BASICS FOR CIRCUITRY This section reviews the basic anatomical interconnections between neurons that make up the basal ganglia-thalamic-cortical circuits. The anatomy is discussed only to a level of detail necessary for conceptual understanding of current models of function and dysfunction and for possible future theories. This section will not cover a ﬁne-grained analysis of interconnections nor the histology (3,4). Traditional approaches to the anatomy of the basal ganglia have divided it into input and output stages. This approach will be avoided here because such a description implies a sequential and hierarchical organiza- tion, which probably is misleading from a physiological perspective. Just as it is hard to say where a circle starts and an arbitrary starting point must be selected, this description will begin with the striatum. The caudate nucleus and putamen (Pt) make up the striatum. The major sources of input to the striatum come from the cerebral cortex and thalamus. Virtually the entire cortex projects to the striatum in a topographic fashion. Frontal cortex projects to the head of the caudate and anterior putamen while motor and somatosensory cortex project to the postcommissural Pt and temporal cortex projects to the tail of the caudate. Inputs from the thalamus include projections from the centromedian (CM) and parafasciculus (PF) nuclei of the thalamus.
A Multicenter double-blind placebo controlled trial of pergolide as adjunct to Sinemet in the treatment of Parkinson’s disease generic famvir 250mg hiv-1 infection cycle. Bromocriptine for levodopa-induced motor complications in Parkinson’s disease buy famvir 250 mg lowest price antiviral zdv. Falling asleep at the wheel; motor vehicle mishaps in persons taking pramipexole and ropinirole. Pathologic gambling in patients with Parkinson’s disease. Pramipexole in patients with early Parkinson’s disease. Pramipexole versus levodopa as initial treatment for Parkinson’s disease: a four-year randomized controlled trial. Clinical evaluation of pramipexole in advanced Parkinson’s disease: results of a randomized, placebo-controlled, parallel group study. Ropinirole for the treatment of early Parkinson’s disease. Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A ﬁve-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. The development of dyskinesias in Parkinson’s disease patients receiving ropinirole and given supplemental l-dopa. A multicenter trial of ropinirole as adjunct treatment for Parkinson’s disease. Multicenter, placebo-controlled trial of cabergoline taken once daily in Parkinson’s disease. Cabergoline versus bromocriptine for levodopa- induced complications in Parkinson’s disease. Efﬁcacy and dose response of the novel transdermally applied dopamine agonist rotigotine CDS in early Parkinson’s disease. A comparison of the therapeutic efﬁcacy of pergolide and pramipexole in Parkinson’s disease. An algorithm for the management of Parkinson’s disease. Should treatment of Parkinson’s disease be started with a dopamine agonist? The role of dopamine agonists in the treatment of early Parkinson’s disease. A HISTORY Monoamine oxidase (MAO) is an enzyme involved in the breakdown of catecholamines including dopamine, norepinephrine, and serotonin. MAO inhibitors were discovered in the late 1950s and were ﬁrst utilized in the treatment of depression. In 1962 Bernheimer showed that MAO inhibitors could potentiate the antiparkinsonian effect of levodopa but caused severe hypertensive crisis (1). In 1968, Johnston identiﬁed two types of monoamine oxidase: A and B (2). Each has a separate afﬁnity for various catecholamines and works in different parts of the body. MAO-B is found predominantly in the human brain (3) and platelets and has an afﬁnity for dopamine and benzylamine. MAO-A is found predominantly in the intestinal tract and has an afﬁnity for serotonin and norepinephrine. Both types can oxidize tyramine, though MAO-B does so only at higher concentrations. They also showed that at low doses selegiline did not potentiate the pressor effect of tyramine also known as the ‘‘cheese effect. In autopsied brains, 10 mg of selegiline was found to be sufﬁcient to selectively inhibit 90% of MAO-B in such areas as the caudate, substantia nigra, globus pallidus, and thalamus (5). Hence, it was shown that selective MAO-B inhibitors such as selegiline could inhibit the MAO that has strong afﬁnity for the basal ganglia.
The surface of a small chip is dotted with thousands of pieces of single-stranded Bioinformatics also provides the scientist DNA order famvir 250mg on line hiv infection rates male female, each representing a different gene or segment of a gene generic famvir 250mg with amex hiv infection first 24 hours. The chip is then with the capability of organizing vast incubated with a sample of a patient’s DNA, and the pattern of hybridization is amounts of data in a manageable form that allows easy access and retrieval of data. The results of the hybridization analysis could be Powerful computers are required to perform used, for example, to determine which one of the many known mutations for a par- these analyses. As an example of an experi- ticular genetic disease is the specific defect underlying a patient’s problem. An indi- ment requiring these tools, suppose you vidual’s gene chip also may be used to determine which alleles of drug-metaboliz- want to compare the effects of two different ing enzymes are present and, therefore, the likelihood of that individual having an immunosuppressant drugs on gene expres- adverse reaction to a particular drug. Lymphocytes would be Another use for a DNA chip is to determine which genes are being expressed. If treated with either nothing (the control) or the mRNA from a tissue specimen is used to produce a cDNA by reverse transcrip- with the drugs (experimental samples). RNA tase, the cDNA will hybridize with only those genes being expressed in that tissue. The treatment then could be more specifically analog. The cDNA produced from your tailored to the individual patient. This technique also can be used to identify the three samples would be used as probes for genes required for tissue specificity (e. Experiments using gene chips are helping us to understand differentia- would be allowed to hybridize to the chips, tion and may open the opportunity to artificially induce differentiation and tissue and you would then have 15,000 results to regeneration in the treatment of disease. USE OF RECOMBINANT DNA TECHNIQUES FOR THE can group genes showing similar levels of PREVENTION AND TREATMENT OF DISEASE stimulation or inhibition in the presence of the drugs and compare the two drugs with A. Vaccines respect to which genes have activated or inhibited expression. Before the advent of recombinant DNA technology, vaccines were made exclu- sively from infectious agents that had been either killed or attenuated (altered so that they can no longer multiply in an inoculated individual). Both types of vaccines were potentially dangerous because they could be contaminated with the live, infec- tious agent. In fact, in a small number of instances, disease has actually been caused by vaccination. The human immune system responds to antigenic proteins on the surface of an infectious agent. By recombinant DNA techniques, these antigenic proteins can be produced, completely free of the infectious agent, and used in a vac- cine. The first successful recombinant DNA vaccine to be produced was for the hepatitis B virus. When Erna Nemdy began working with patients, she received the hepatitis B vaccine. The hepatitis B virus (HBV) infects the liver, causing severe damage. The virus contains a surface antigen (HBsAg) or coat protein for which the gene has been isolated. How- ever, because the protein is glycosylated, it could not be produced in E. The viral protein, separated from the small amount of contaminating yeast protein, is used as a vaccine for immunization against HBV infection. CHAPTER 17 / USE OF RECOMBINANT DNA TECHNIQUES IN MEDICINE 311 B. Production of Therapeutic Proteins Di Abietes is using a recombinant human insulin called lispro (Huma- 1. INSULIN AND GROWTH HORMONE log) (see Chapter 6, Fig.
Thus buy famvir 250mg on-line anti viral hand gel, energy from the electrochemical gra- ATP dient is used to change the conformation of the ATP synthase subunits so that the newly synthesized ATP is released buy generic famvir 250 mg on line antiviral eye drops. Twelve c subunits are hypothesized, and it takes 12 pro- 2 ADP + Pi tons to complete one turn of the rotor and synthesize three ATP. Oxidation–Reduction Components of the Electron Transport Chain Electron transport to O2 occurs via a series of oxidation–reduction steps in which each successive component of the chain is reduced as it accepts electrons and oxidized as it passes electrons to the next component of the chain. The ATP oxidation–reduction components of the chain include flavin mononucleotide (FMN), Fe-S centers, CoQ, and Fe in the cytochromes b, c1, c, a, and a3. Binding change mechanism for a component of cytochromes a and a (Fig. The three subunit pairs of these electron acceptors are tightly bound to the protein subunits of the carriers. This energy is used to move protons against their concentration gradient, unit. Step 1: When ADP Pi bind to an open site and the proton influx rotates the spindle so that they become concentrated on the cytosolic side of the inner membrane. Bound ADP and Pi combine to form ATP at another site. Step 2: site for NADH, several FMN and iron-sulfur (Fe-S) center binding proteins, and As the ADP Pi bind to the new open site, binding sites for CoQ (see Fig 21. An FMN accepts two electrons from NADH and the shaft rotates, the conformations of and is able to pass single electrons to the Fe-S centers (Fig. Fe-S centers, the sites change again, and ATP is released. Fe-S centers are also present in other enzyme systems, such as other proteins, which transfer electrons to CoQ, in the cytochrome b–c1 complex, and in aconitase in the TCA cycle. SUCCINATE DEHYDROGENASE AND OTHER FLAVOPROTEINS the vitamin riboflavin. It contains In addition to NADH dehydrogenase, succinic dehydrogenase and other flavopro- the electron-accepting flavin ring teins in the inner mitochondrial membrane also pass electrons to CoQ (see structure, but not the adenosine monophos- phate (AMP) portion of FAD (see Fig. ETF-CoQ oxidore- Severe riboflavin deficiency decreases the ductase accepts electrons from ETF (electron transferring flavoprotein), which ability of mitochondria to generate ATP from acquires them from fatty acid oxidation and other pathways. Both of these flavo- oxidative phosphorylation due to the lack of proteins have Fe-S centers. CHAPTER 21 / OXIDATIVE PHOSPHORYLATION AND MITOCHONDRIAL FUNCTION 385 Intermembrane Glycerol 4H+ 2H+ space + 3-phosphate 4H dehydrogenase Cyt c CoQH CoQH Fe-s Cyt c CuA 2 FAD 2 1 Fe-S Cyt a I Cyt b CoQ II CoQ Cyt a3 FMN Fe-S Fe-S CuB FAD (FAD) IV NADH NAD+ III Succinate + 1/2 O2 + 2H H2O NADH Succinate ETF: Q Cytochrome b-c1 Cytochrome c dehydrogenase dehydrogenase oxidoreductase complex oxidase Matrix Fig. NADH dehydrogenase (complex I) spans the membrane and has a proton pumping mech- anism involving CoQ. The electrons go from CoQ to cytochrome b–c1 complex (complex III), and electron transfer does NOT involve complex II. Succinate dehydrogenase (complex II), glycerol 3-phosphate dehydrogenase, and ETF:Q oxidoreductase (shown in blue) all transfer electrons to CoQ, but do not span the membrane and do not have a proton pumping mechanism. As CoQ accepts protons from the matrix side, it is con- verted to QH2. Electrons are transferred from complex III to complex IV (cytochrome c oxidase) by cytochrome c, a small cytochrome in the intermembrane space that has reversible binding sites on the b–c1 complex and cytochrome c oxidase. The free energy drop between NADH and CoQ of approximately 13 to 14 PrPr kcal is able to support movement of four protons. However, the FAD in succinate Cys dehydrogenase (as well as ETF-CoQ oxidoreductase and -glycerophosphate dehy- SS S Fe drogenase) is at roughly the same energy level as CoQ, and there is no energy Pr Cys S Fe S released as they transfer electrons to CoQ. These proteins do not span the membrane and consequently do not have a proton pumping mechanism. COENZYME Q SS S Fe CysCys SS CoQ is the only component of the electron transport chain that is not protein bound. PrPr CysCys The large hydrophobic side chain of 10 isoprenoid units (50 carbons) confers lipid PrPr solubility, and CoQ is able to diffuse through the lipids of the inner mitochondrial membrane (Fig. When the oxidized quinone form accepts a single electron, Fig. In Fe-S centers, the Fe 4 4 it forms a free radical (a compound with a single electron in an orbital).
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