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The specific transcription factors bind mediator proteins (co-activators or corepressors) that interact with the general transcription factors of the basal transcription complex buy suhagra 100 mg with amex. The basal transcription complex contains RNA polymerase and associated general transcription factors (TFII factors) and binds to the TATA box of the promoter purchase 100mg suhagra otc, initiating gene transcription purchase suhagra 100 mg amex. TRANSCRIPTION FACTORS THAT ARE STEROID HORMONE/THYROID HORMONE RECEPTORS In the human discount suhagra 100 mg fast delivery, steroid hormones and other lipophilic hormones activate or inhibit tran- scription of specific genes through binding to nuclear receptors that are gene-specific transcription factors (Fig. The nuclear receptors bind to DNA regulatory In a condition known as testicular sequences called hormone response elements and induce or repress transcription of feminization, patients produce target genes. The receptors contain a hormone (ligand) binding domain, a DNA bind- androgens (the male sex steroids), ing domain, and a dimerization domain that permits two receptor molecules to bind to but target cells fail to respond to these each other, forming characteristic homodimers or heterodimers. A transactivation steroid hormones because they lack the domain binds the coactivator proteins that interact with the basal transcription com- appropriate intracellular transcription factor plex. The receptors also contain a nuclear localization signal domain that directs them receptors. Therefore, the transcription of the to the nucleus at various times after they are synthesized. A patient with this condition has in different ways. The glucocorticoid receptor, which binds the steroid hormone an XY (male) karyotype (set of chromo- somes) but looks like a female. External cortisol, resides principally in the cytosol bound to heat shock proteins. As cortisol male genitalia do not develop, but testes are binds, the receptor dissociates from the heat shock proteins, exposing the nuclear present, usually in the inguinal region. The receptors form homodimers that are translocated to the nucleus, where they bind to the hormone response elements (glu- cocorticoid response elements–GRE) in the DNA control region of certain genes. The transactivation domains of the receptor dimers bind mediator proteins, thereby activating transcription of specific genes and inhibiting transcription of others. Domains of the steroid hormone receptor Dimerization sites Inhibitor binding sites NLS + O H3N C O– Transactivation DNA binding Ligand binding domain (TAD) domain (DBD) domain (LBD) B. Transcriptional regulation by steroid hormone receptors Cytosol GRE DNA HSP GR GR Cortisol DBD Nuclear GR pore TAD GR NLS Coactivators + HSP Basal TAD GR NLS transcription GR complex DBD TATA GR dimer Increased gene transcription Fig. The transactivation domain (TAD) binds coactivators; DNA- binding domain (DBD) binds to hormone response element in DNA; ligand-binding domain (LBD) binds hormone; NLS is the nuclear local- ization signal; the dimerization sites are the portions of the protein involved in forming a dimer. The inhibitor binding site binds heat shock pro- teins and masks the nuclear localization signal. Transcriptional regulation by steroid hormone receptors. Additional abbreviations: HSP, heat shock proteins; GRE, glucocorticoid response element; GIZ, glucocorticoid receptor. Other members of the steroid hormone/thyroid hormone family of receptors are also gene-specific transactivation factors but generally form heterodimers that con- stitutively bind to a DNA regulatory sequence in the absence of their hormone lig- and and repress gene transcription (Fig. For example, the thyroid hormone receptor forms a heterodimer with the retinoid X receptor (RXR) that binds to thy- roid hormone response elements and to corepressors (including one with deacety- lase activity), thereby inhibiting expression of certain genes. When thyroid hormone binds, the receptor dimer changes conformation, and the transactivation domain binds coactivators, thereby initiating transcription of the genes. The RXR receptor, which binds the retinoid 9-cis retinoic acid, can form het- erodimers with at least eight other nuclear receptors. Each heterodimer has a dif- ferent DNA binding specificity. This allows the RXR to participate in the regulation of a wide variety of genes, and to regulate gene expression differently, depending on the availability of other active receptors. STRUCTURE OF DNA BINDING PROTEINS Several unique structural motifs have been characterized for specific transcription factors. Each of these proteins has a distinct recognition site (DNA binding domain) that binds to the bases of a specific sequence of nucleotides in DNA. Four of the best-characterized structural motifs are zinc fingers, b-zip proteins (including leucine zippers), helix-turn-helix, and helix-loop-helix. CHAPTER 16 / REGULATION OF GENE EXPRESSION 287 To regulate gene transcription, two estrogen receptors combine to form a dimer that binds to a palindrome in the promoter region of certain genes (see TR RXR Figs.

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As a consequence of the nature of exercise therapy buy cheap suhagra 100mg line, blinding of both providers and patients is not possible buy suhagra 100 mg visa. However suhagra 100 mg on line, in only half of the trial reports order 100 mg suhagra with amex, was blinding outcome assessment explicitly reported. Another potential source of bias was the frequently occurring absence of information on adherence to the intervention. This hampers the interpretation of a study with negative results. It remains unclear whether the exercise therapy intervention was ineffective due to the intervention itself or due to participants’ failure to adhere to therapy. Summary: Key findings and clinical implications • Exercise is indicated for patients with mild/moderate osteoarthritis of the knee but there are limited studies available • Standard interventions and outcomes measures are needed • Physicians should stress behaviour change to engage long-term benefit • Long-term efficacy has not been established • Strategies to promote exercise adoption for general health should be the goal of physicians and their patients In conclusion, the available evidence indicates beneficial short- term effects of exercise therapy in patients with OA of the knee. Given the limited number of studies available, this conclusion applies to patients with mild to moderate OA who were recruited from both outpatient settings and the community. Beneficial effects have been found for various types of exercise therapy and recommended for patients with OA of the knee with mild to moderate stage of disease. Physicians should promote physical activity among their patients with OA of the knee. Exercise can improve symptoms, potentiate concomitant medications and improve health in general. In particular, additional clinical trials are needed to study the long-term 191 Evidence-based Sports Medicine effectiveness of exercise therapy. In the design and conduct of these trials, specific attention should be paid to a sufficient sample size, adherence to exercise therapy, controls for co-interventions, blinded outcome assessment, and an adequate data analysis including an intention to treat analysis. The incorporation of a standard set of outcome measures29 in combination with the adoption of a standard for reporting results30 will greatly enhance evidence synthesis in this area. The patient is the mother of three teenage children, works as a grocery clerk part-time and has been physically active in a bowling league during the winter and a slopitch baseball league during the summer months. She describes her pain as initially in her right knee (which she claims to have injured playing baseball 24 years prior while sliding, successfully into home-plate) primarily at the end of the day. This pain has gradually progressed to being present with any weight bearing. This pain has gradually progressed to being present with activity and has resulted in her requiring a chair at work, her failing to join recreational activities this past year, and limiting walking to less than one city block. She has tried acetomenophen, icing and a brace with no effect. She now has similar pain and dysfunction in the left knee. On examination, she has a BMI of 29, has valgus deformity of both knees (right>left) and audible crepitus, pain with knee flexion to 40 degrees. There were bilateral small effusions and positive joint line tenderness medially>laterally. Radiograph shows mild joint space narrowing medially with osteophytes and a small 2×3 mm loose body. Her goals are to return to recreational activity and experience less pain at work. She is concerned also that her reduced activity has added a few kilograms of body weight that she would like to lose. She is concerned however that physical activity may have led to her knee problem and may have also exacerbated it as well. Sample examination questions Multiple choice questions (answers on p 561) 1 What are primary outcomes appropriate for determination of efficacy of exercise in osteoarthritis of the knee? A Pain (VAS or WOMAC) B Flexibility (Passive/active ROM) 192 Exercise and osteoarthritis of the knee C Function (Walking/stepping, ADL) D Pain with function 2 Exercise is best targeted at patients with which traits?

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If phosphate pathway begins with glucose 6-phosphate buy discount suhagra 100 mg line, and feeds back into the the patient is thiamine deficient suhagra 100mg overnight delivery, transketo- lase activity will be low suhagra 100mg amex, and adding thiamine pyrophosphate will greatly stimulate the reaction suhagra 100mg online. Al Martini was diagnosed in Chap- ter 19 as having beriberi heart disease result- CH2OH ing from thiamine deficiency. The diagnosis C was based on laboratory tests confirming HO the thiamine deficiency. H H H CH OPO2– 2 3 Sedoheptulose 7–phosphate + H O C H CH OPO2– 2 3 Glyceraldehyde 3–phosphate transaldolase H O C H H CH OPO2– 2 3 Erythrose 4–phosphate + CH2OH C HO H C OH H C OH CH OPO2– 2 3 Fructose 6–phosphate Fig. Transaldolase transfers a 3-carbon fragment that contains an alcohol group next to a keto group. A balanced sequence of reactions in the pentose phosphate pathway. The interconversion of sugars in the pentose phosphate path- way results in conversion of 3 glucose 6-phosphate to 6 NADPH, 3 CO2, 2 fructose 6-phosphate, and one glyceraldehyde 3-phosphate. The reaction sequence starting from glucose-6-P, and involving both the oxidative and nonoxidative phases of the path- way, is shown in Figure 29. GENERATION OF RIBOSE 5-PHOSPHATE FROM INTERMEDIATES OF GLYCOLYSIS The reactions catalyzed by the epimerase, isomerase, transketolase, and transal- dolase are all reversible reactions under physiologic conditions. Thus, ribose 5-phosphate required for purine and pyrimidine synthesis can be generated from intermediates of the glycolytic pathway, as well as from the oxidative phase of the pentose phosphate pathway. The sequence of reactions that generate ribose 5-phos- phate from intermediates of glycolysis is indicated below. Transketolase (1) Fructose-6-P glyceraldehyde-3-P Erythrose-4-P Xyulose-5-P Transaldolase (2) Erythrose-4-P Fructose-6-P Sedoheptulose-7-P Glyceraldehyde-3-P Transketolase (3) Sedoheptulose-7-P Glyceraldehyde-3-P Ribose-5-P Xyulose-5-P Epimerase (4) 2 Xyulose-5-P 2 Ribulose-5-P Isomerase (5) 2 Ribulose-5-P 2 Ribose-5-P Net Equation : 2 Fructose-6-P Glyceraldehyde-3-P 3 Ribose-5-P CHAPTER 29 / PATHWAYS OF SUGAR METABOLISM: PENTOSE PHOSPHATE PATHWAY, FRUCTOSE, AND GALACTOSE METABOLISM 537 C. Role of the Pentose Phosphate Pathway in the Table 29. Pathways That Require NADPH Generation of NADPH In general, the oxidative phase of the pentose phosphate pathway is the major Detoxification source of NADPH in cells. NADPH provides the reducing equivalents for biosyn- • Reduction of oxidized glutathione thetic reactions and for oxidation–reduction reactions involved in protection against • Cytochrome P450 monooxygenases the toxicity of ROS (see Chapter 24). The glutathione-mediated defense against Reductive synthesis oxidative stress is common to all cell types (including the red blood cell), and the • Fatty acid synthesis requirement for NADPH to maintain levels of reduced glutathione probably • Fatty acid chain elongation accounts for the universal distribution of the pentose phosphate pathway among dif- • Cholesterol synthesis ferent types of cells. NADPH is also used for ana- • Neurotransmitter synthesis bolic pathways, such as fatty acid synthesis, cholesterol synthesis, and fatty acid • Nucleotide synthesis chain elongation (Table 29. It is the source of reducing equivalents for • Superoxide synthesis cytochrome P450 hydroxylation of aromatic compounds, steroids, alcohols, and drugs. The highest concentrations of glucose 6-phosphate dehydrogenase are found in phagocytic cells, where NADPH oxidase uses NADPH to form superoxide from molecular oxygen. The superoxide then generates hydrogen peroxide, which kills the microorganisms taken up by the phagocytic cells (see Chapter 24). The entry of glucose 6-phosphate into the pentose phosphate pathway is con- How does the net energy yield trolled by the cellular concentration of NADPH. NADPH is a strong product from the metabolism of 3 moles of inhibitor of glucose 6-phosphate dehydrogenase, the first enzyme of the pathway. Glucose Glucose 6–phosphate Glucose dehydrogenase deficiency Oxidant stress • Infections Glucose • Certain drugs 6–phosphate 1 2 Erythrocyte • Fava beans Hemolysis 4 Glucose Glucose NADP+ 2 GSH H O HO• 3 2 2 6–phosphate 6–phosphate glucose 6–phosphate glutathione glutathione (ROS) dehydrogenase reductase peroxidase – Glycolysis 6–Phospho- NADPH GS–SG 2 H2O O2 gluconate + H+ 2 ATP NADH Pentose phosphate pathway 5 Heinz bodies met Hb oxy Hb 2 Lactate Fig. Maintenance of the integrity of the erythrocyte membrane depends on its ability to generate ATP and NADH from glycolysis. NADPH is generated by the pentose phosphate pathway. NADPH is used for the reduction of oxidized glutathione to reduced glutathione. Glutathione is necessary for the removal of H2O2 and lipid peroxides generated by reactive oxygen species (ROS). In the erythrocytes of healthy individuals, the continuous generation of superoxide ion from the nonenzymatic oxidation of hemoglobin provides a source of reactive oxygen species. The glutathione defense system is compromised by glucose 6-phosphate dehydroge- nase deficiency, infections, certain drugs, and the purine glycosides of fava beans.

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