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Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal INFLUENCE IN TRAUMATIC quality isoptin 240mg hypertension age 60, OPERATIVE purchase 240 mg isoptin free shipping blood pressure medication and lemon juice, cyclooxygenase inhibition. In the acute postoperative model, most of Rheumatoid Arthritis and Juvenile Chronic Arthritis. Non-steroidal anti-inflam- Likely because of their analgesic, antipyretic, and matory drugs and the risk of serious coronary heart disease: sodium-retaining effects, NSAIDs attenuate An observational cohort study. Association between NSAIDS reduce opioid requirements, fevers, and, naproxen use and protection against acute myocardial infarc- perhaps, fluid loss. Nonsteroidal anti- of NSAIDs on platelet adhesion and the potential of inflammatory drug use and acute myocardial infarction. Lower risk of throm- that ended with the introduction of selective COX-2 boembolic cardiovascular events with naproxen among patients agents that do not appreciably affect bleeding times. Inhibition of traumatic immunosuppression, nitrogen balance, and cyclooxygenase attenuates the metabolic response to endo- acute-phase reactant proteins. Inhibition of neous activity in dorsal root ganglion cells) to spe- prostaglandin synthesis improves postoperative nitrogen bal- cific features of pain phenomenology could improve ance Clin Nutr. Topical flurbiprofen decreases burn wound induced hypermetabolism and sys- temic lipid peroxidation. Immunoprotective PHARMACOLOGIC MECHANISMS OF effects of cyclooxygenase inhibition in patients with major ANTINOCICEPTION surgical trauma. Effect of DESCENDING INHIBITION ibuprofen in patents with severe sepsis: A randomized dou- ble blind multicenter study. Indomethacin and the pressants is mediated primarily by the blockade of stress response to hysterectomy. Prophylactic diclofenac infu- enhances the activation of descending inhibitory neu- sions in major orthopedic surgery: Effects of analgesia and acute phase proteins. The effects of periop- Antidepressants, however, may produce antinocicep- erative ketorolac infusion on postoperative pain an endocrine tive effects through a variety of pharmacologic mech- metabolic response. Clark, MD, MPH MONOAMINE MODULATION INTRODUCTION Investigations have demonstrated differential effects of ANTIDEPRESSANTS AND PAIN monoamine receptor subtypes in antidepressant- induced antinociception in the rat formalin test. The Since the first report of imipramine use for trigeminal effects of antidepressants with varying degrees of nor- neuralgia was published in 1960, antidepressants, par- epinephrine and serotonin reuptake inhibition as well as ticularly tricyclic antidepressants (TCAs), have been those of their antagonists indicate that α1 adrenoceptors commonly prescribed for the treatment of many and several serotonin receptor subtypes (5-HT2, 5-HT3, chronic pain syndromes, especially those involving and 5-HT4) contribute to antinociception. OPIOID INTERACTIONS MONOAMINE RECEPTORS CLASSIFICATION SYSTEMS Because they interact with opioids or their antago- nists, antidepressants may interact with opioid recep- Neuropathic pain has been classified according to tors or stimulate endogenous opioid peptide release. In contrast, systemic kappa-3, and delta opioid receptor subtypes as well as and spinal administration of antidepressants produce by the α2 adrenergic receptor. CLINICAL APPLICATIONS SYNERGISTIC EFFECTS SEROTONIN AND NOREPINEPHRINE In the rat tail-flick model, the antinociception produced by individual intrathecal administration of serotonin, Antidepressants are typically characterized according desipramine, and morphine can be achieved with sub- to the specificity of their neurotransmitter reuptake threshold doses of combinations of these agents. For example, TCAs Fluoxetine (Prozac) 10–80 mg 5-HT NE reuptake may reduce hyperalgesia but not tactile allodynia inhibition because different neuronal mechanisms underlie dif- Sertraline (Zoloft) 50–200 mg ferent manifestations of neuropathic pain. Paroxetine (Paxil) 10–40 mg The blocking by caffeine of this effect induced with Fluvoxamine (Luvox) 100–300 mg Citalopram (Celexa) 20–40 mg amitriptyline indicates a role for endogenous adeno- sine systems. ATYPICAL ANTIDEPRESSANTS Venlafaxine (Effexor) 75–450 mg 5-HT NE DA reup- ION CHANNELS take inhibition 2+ + (dose dependent) The opening of voltage-gated and Ca -gated K Nefazodone (Serzone) 100–600 mg 5-HT NE reuptake channels has been implicated in the central antinoci- Trazodone (Desyrel) 100–600 mg inhibition with ception induced by amitriptyline and clomipramine in 5-HT2 receptor the mouse hot plate test. Intravenous amitriptyline blockade + Bupropion (Wellbutrin) 100–450 mg DA and NE reuptake impairs the function of tetrodotoxin-resistant Na inhibition channels in rat dorsal root ganglia, particularly in con- Mirtazapine (Remeron) 15–90 mg α2-NE and 5-HT2 ditions of repetitive firing and depolarizing mem- presynaptic agonist with 5-HT2/3 receptor brane potential, which may reduce firing frequency in blockade ectopic sites of damaged nociceptive fibers. The fact that 73% of treated patients were prescribed the equivalent of 50 mg or less of SELECTIVE SEROTONIN amitriptyline, however, suggests there is a potential REUPTAKE INHIBITORS for additional pain relief with higher doses. This antinociception is blocked by sero- guidelines have been established. TERTIARY VERSUS SECONDARY In human clinical trials, the efficacy of SSRIs in Generally, the tertiary TCAs with balanced effects on chronic pain syndromes has been variable and incon- 5-HT and NE reuptake (imipramine, amitriptyline, sistent:14 doxepin) are considered more effective analgesic Desipramine was superior to fluoxetine in the treat- agents than the secondary TCAs with more selective ment of painful diabetic peripheral neuropathy. NE reuptake inhibition (desipramine, nortriptyline, Paroxetine and citalopram were beneficial in maprotiline). A 12-week course of fluoxetine also decreased gastrointestinal motility and urinary reten- improved a variety of self-reported outcome meas- tion. The fact that desipramine and nortriptyline had ures in women with fibromyalgia. Nor- In a study of chronic tension-type headache, triptyline, the major metabolite of amitriptyline, amitriptyline significantly reduced the duration of causes less sedation, orthostatic hypotension, and headache, headache frequency, and the intake of falls than does imipramine and is as effective as analgesics, but citalopram, an SSRI, did not. Studies of mianserin, an older analog of mir- serotonin and norepinephrine and, to a lesser extent, tazapine, produced mixed results. Additional analyses suggested that response improved with higher doses of venlafaxine. FUTURE ANTIDEPRESSANTS Reboxetine is a selective noradrenaline reuptake NEWER ANTIDEPRESSANTS inhibitor not yet available in the United States. In a placebo-controlled study of laser-evoked somato- Norepinephrine and dopamine reuptake inhibitors, sensory potentials in healthy humans, reboxetine such as bupropion, produced antinociception in stud- reduced N1 and P2 amplitudes along with subjec- ies of thermal nociception. In a randomized, double- tive pain feelings and measurements, suggesting blind, placebo-controlled, crossover study of patients central and peripheral mechanisms of antinoci- with neuropathic pain but without depression, bupro- ception.

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John P Kugler discount isoptin 40 mg arrhythmia ketosis, MD buy cheap isoptin 40mg blood pressure levels up and down, MPH W hile there is a definite increased risk for certain sus- Ralph P Oriscello, MD, FACC ceptible individuals, particularly middle-aged persons with coronary artery disease (CAD) and a sedentary lifestyle, there is abundant evidence (Maron, 2000) of net cardiovascular benefits from consistent exercise as a INTRODUCTION primary-prevention recommendation for coronary dis- ease in asymptomatic middle-aged and older persons. Regular physical activity promotes THE ATHLETIC HEART SYNDROME cardiovascular fitness and lowers the risk of disease. These changes are nonpathologic and represent until the adverse event occurs. Of note, detraining for 2–3 months can result in a reversal of CARDIOVASCULAR BENEFITS athletic heart syndrome changes, which is not seen in OF EXERCISE pathologic conditions. Colditz, 1990) have clearly identified physical inac- For endurance-trained athletes, the heart has to tivity and a sedentary lifestyle as significant risk fac- adapt to principally a chronic volume overload that tors for the development and progression of coronary results in an increase in both left ventricular end- heart disease. Moreover, studies (Pate et al, 1995; diastolic diameter and left ventricular wall thickness. Electrocardiograms of the General Population and Athletes The strength-trained athlete adapts by developing a GENERAL concentric hypertrophy with an increase in absolute ARRHYTHMIA POPULATION (%) ATHLETES (%) and relative wall thickness without significant Sinus bradycardia 23. An S3 may be noted in endurance-trained athletes secondary to the increased SUDDEN DEATH IN EXERCISE rate of left ventricular filling associated with the rela- tive left ventricular dilatation (Zeppilli, 1988). Functional mur- has clearly shown, there is a “paradox of exercise” murs may be noted in 30–50% of athletes on careful that requires a clinical assessment of risk prior to the examination (Huston, Puffer, and Rodney, 1985). Estimates from various studies (Siscovick et al, 1984; ELECTROCARDIOGRAPHIC CHANGES Ragosta et al, 1984; Thompson et al, 1982; Maron, Poliac, and Roberts, 1996; Van et al, 1995; Maron, Several minor electrocardiogaphic variations have Gohman, and Aeppli, 1998) range from 1:15,000 jog- been commonly noted in highly trained athletes and gers per year (Siscovick et al, 1984; Thompson et al, are considered to be consistent with the athlete’s heart 1982) to 1:50,000 marathon participants (Maron, syndrome (Huston, Puffer, and Rodney, 1985; Oakley Poliac, and Roberts, 1996). In a recent Italian study The specific etiologies contributing to sudden cardiac (Pelliccia et al, 2000), 1005 athletes were consecu- death are most closely related to age. This primarily stems study found that 40% of the athletes had abnormal from the observation that for sudden deaths over age 35, EKGs, not including the minor alterations associated over 75% are associated with coronary artery disease. Of The high prevalence of atherosclerosis in this age group these athletes, 36% had distinctly abnormal patterns. In European studies (Tabib et al, 1999; Firoozi et al, 2002; Priori et al, 2002), arrhythmogenic right ven- TABLE 25-1 Common ECG Findings in Athletic tricular cardiomyopathy (ARVC) is more commonly Heart Syndrome recognized as an etiology than it is in the United Sinus bradycardia Sinus arrhythmia States. Other less common etiologies include aortic First-degree AV block Wenckebach AV block Incomplete RBBB Notched P waves rupture from Marfan’s syndrome, genetic conductive RVH by voltage criteria LVH by voltage criteria system abnormalities, idiopathic concentric left ven- Repolarization changes QTc interval at upper limit tricular hypertrophy, substance abuse (cocaine or Tall, peaked and inverted t waves steroids), aortic stenosis, mitral valve prolapse, CHAPTER 25 CARDIOVASCULAR CONSIDERATIONS 143 sickle cell trait, and blunt chest trauma (commotio TABLE 25-4 Features of Marfan Syndrome cordis). Joint laxity It is recommended that a complete personal and family Cardiovascular history and physical examination be done for all ath- Systolic murmur (mitral valve prolapse) letes. It should focus on identifying those cardiovascu- Evidence of easing bruising lar conditions known to cause sudden death. It should Diastolic murmur (aortic regurgitation) be done every 2 years with an interim history between Ocular examinations. The 26th Bethesda Conference specifies Myopia participation guidelines for different conditions Retinal detachment Lens subluxation (Maron and Mitchell, 1994). Cardiac auscultation should be performed in hypertension, hyperlipidemia, smoking, or on the pres- the supine and standing positions and murmurs ence of HCM, ARVC, Marfan’s syndrome, prolonged should be assessed with Valsava and position QT syndrome, or significant arrhythmias. The murmur of aortic stenosis inten- Contraindications to Vigorous Exercise sifies with squatting, and decreases with Valsalva. Hypertrophic cardiomyopathy Femoral pulses should be assessed and blood pres- Idiopathic concentric left ventricular hypertrophy sure measured with the appropriately sized cuff in Marfan’s syndrome the sitting position. Coronary heart disease Uncontrolled ventricular arrhythmia’s Ancillary testing should be directed by the patient’s his- Severe valvular heart disease (especially aortic stenosis and pulmonic tory, physical, and age. Lipid profiles should be checked stenosis) in the older athlete and should be considered in athletes Coarctation of the aorta of any age. Exercise stress testing is not recommended as Acute myocarditis Dilated cardiomyopathy a routine screening device for the detection of early coro- Congestive heart failure nary artery disease because of low predictive value and Congenital anomalies of the coronary arteries high rates of false positive and false negative results. Cyanotic congenital heart disease Exercise testing may be required prior to beginning an Pulmonary hypertension Right ventricular cardiomyopathy exercise program in select cases (see chapters 15 and 20) Ebstein’s anomaly of the tricuspid valve EKG and echocardiograms are not currently recom- Idiopathic long Q-T syndrome mended as screening tools (Basilico, 1999; Kugler and Require Close Monitoring and Possible Restriction O’Connor, 1999; Kugler, O’Connor and Oriscello, Uncontrolled hypertension 2001). As mentioned above, the normal adaptations of Uncontrolled atrial arrhythmia’s the “athletic heart” make interpretation of the routine Hemodynamic significant valvular heart disease (aortic insufficiency, EKG and echocardiogram problematic (Pelliccia et al, mitral stenosis, mitral regurgitation) 2000). High rates of false positivety, high relative costs, SOURCE: (Maron and Mitchell, 1994; Kugler and O’Connor, 1999) limited availability, and low prevalence of disease make 144 SECTION 3 MEDICAL PROBLEMS IN THE ATHLETE these modalities impractical as screening devices, at this The first step involves determining if the event was a point in time. The second in sarcomere formation; Long QT syndrome-autoso- step is to differentiate between syncope that occurs mal dominant sodium channel defect; Marfan’s during the event (suggesting a more ominous Syndrome-autosomal dominant mutation of FBN1 arrhythmic etiology) and syncope that occurs fol- fibrilin gene; Brugada Syndrome-autosomal dominant lowing the event, usually associated with orthostatic SCN5A channelopathy; ARVC-autosomal dominant hypotension on exercise cessation (suggesting a less defect), genetic testing is not routinely recommended. It is also critical to identify pro- dromal symptoms that may have occurred during exercise such as palpitations (arrhythmia), chest pain SYNCOPE-AND EXERCISE-ASSOCIATED (ischemia or aortic dissection), nausea (ischemia or COLLAPSE vagal activity), wheezing, or pruritus (anaphylaxis). Exercise-associated collapse An EKG should be ordered in most cases and should (EAC) refers to athletes who are unable to stand or be evaluated closely for rate, rhythm, QT interval, walk unaided because of lightheadedness, faintness, repolarization abnormalities, left or right hypertrophy, dizziness, or outright syncope. The potential differen- preexcitation evidence, and complications of ischemic tial diagnosis is extensive and includes multiple car- heart disease. Further testing, including blood work, diovascular and neurologic etiologies (Kapoor, 1992; echocardiogram, and stress testing may be done Manolis et al, 1990).

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By eliminating the fog discount 240 mg isoptin with mastercard hypertension case study, the meaning of the sentence becomes much clearer cheap 40mg isoptin with amex blood pressure explained. In the third example, the two long word clusters can be written more directly. In the fourth example, 16 words (46% of the original sentence) are removed to achieve a short, clear sentence. In examples five and six, 57% and 32% of words are removed respectively. Most of us can think more clearly if we have to explain a concept to another person in verbal rather than in written form. If you are unsure of what you are trying to write, it is best to leave the keyboard and find someone with whom you can discuss your thoughts. This is the first study to demonstrate a statistically significant effect of this drug compared with a placebo in patients with seizures. Once you have spoken your thoughts in a simple and straightforward way, it is often much easier to write them clearly. For this reason, studies that have been presented at conferences are more easily written up as papers than studies that have not had this advantage. Say what you mean There goes the man that writ a book that neither he nor anybody else understands. Although we all know what we mean and can describe what we mean when questioned, writing can be more difficult. In scientific writing, it is important to select words that have a clear meaning and that are not open to different interpretations. You may know what you mean when you write being exposed to environmental tobacco smoke and sex were important risk factors for childhood infections but the words gender or being male would have been a better word choice than sex. Also reordering the phrases would help so that the sentence is Gender and being exposed to environ- mental tobacco smoke were important risk factors for childhood infections. In each example, you can see how the meaning becomes clearer when the correct words are used. In the first example, diagnosis is not an event that can recur in an individual and so the term less often diagnosed is inappropriate. The second example suggests that a rat can be culled more than once, which is clearly impossible. The third example suggests that atopy, symptoms, and asthma increase in adults as they put on more weight rather than saying that overweight people have a higher prevalence of symptoms, as is intended. The word correlate has a specific statistical meaning and should only be used in this context. The word should not be used in a general sense to suggest that two factors are related in some way. Word order For your born writer, nothing is so healing as the realization that he has come upon the right word. The following classified advertisement which appeared in a local newspaper is a good example of incorrect word order: Stock horse stallions standing at stud: Reverlee and Freckles Oak. Readers should not have to reorganise words to decipher the correct meaning. Neither should readers have to get to the end of a sentence to find out what they needed to know at the beginning. In the first example, the word asthma is used incorrectly as an adjective and, because the increase in prevalence is the topic of the sentence, this phrase is better placed at the beginning. This sentence benefits from making the sentence into one main clause and from removing some of the prepositions. In the fourth example, the transition word however is misplaced within the sentence. Transition words or conjunctions do their job in maintaining flow better if they are used at the beginning of a sentence rather than interrupting the subject–verb–object flow. Also, the word current is better used as an adjective to further describe the type of information than as the adverb currently to describe the verb. The order in which you present the information in each sentence also depends on the context in which you are writing and the audience you are writing for. Sentences that work best 198 Writing style are those in which the subject of the sentence is the main topic of your study. In this way, you provide the most important information at the beginning of the sentence and you set the context correctly. For example, you may have conducted a cross-sectional study in which you measured the risk of children developing gastrointestinal infections and investigated whether this was associated with breastfeeding. The data may be from the same study but your choice of word order is important for delivering a clear message to your audience. Infant feeding context Breastfeeding significantly reduced the incidence of gastrointestinal infections in infancy.

A statistician’s role may vary from the development of the study design and study protocol to helping prepare the grant application purchase 240mg isoptin otc blood pressure medication metoprolol, implementing the study isoptin 240mg generic blood pressure medication helps ed, planning and performing the data analyses, and/or interpreting the results. In general, authorship is not warranted when the statistician has contributed to only one or two aspects of the paper in an entirely consultative way. However, authorship is often warranted when the statistician has been more actively involved and has made a fundamental, intellectual contribution that fulfils at least some of the Vancouver guidelines. Author order There is intense international competition in science these days which is a kind of substitute for war. Gordon Lil and Arthur Maxwell (Science, 1959) An additional problem in deciding authorship can be the order in which coauthors are listed. The last author is usually the senior member of the team and is often the person who conceived the initial idea for the study and/or obtained funding. It is common policy that the authors in between the first and last are ranked in order of the magnitude of their input into the paper. On some papers, the last author may be the person who contributed the least in intellectual terms rather than the most. The Cochrane Collaboration specifically asks that the order reflects the size of the contribution made by each author so that the last author is the person who makes the smallest contribution. In some cases, authorship lists are extremely long but are justified by the need for collaboration between centres as 37 Scientific Writing happens, for example, in international and multicentre studies. In recent years, new methods of acknowledging teams rather than individuals and of grouping contributors have been developed as shown in Box 2. However, teams should be aware that bibliographic databases vary in the way in which they list authors of multicentre studies. MEDLINE® often puts “no authors listed” and includes the name of the collective authorship in the title. At the other end of the scale, EMBASE® lists the names of up to 19 authors drawn from the byline before et al. Some suggestions include dividing the author’s rank in the authorship list by the sum of the ranks for all authors,51 dividing each publication unit by the number of authors,52 or attributing a proportion of the productivity to each author. However, it is ironical that attempts to minimise author lists contradicts the current trend of universities, hospitals, and granting bodies to promote collaboration between research groups. Some research groups write their own formal policies for deciding authorship. A policy entitled “The money, fame and 38 Getting started happiness document” has been developed by a clinical research unit in Sydney and is given to all new researchers who join the unit (www12). This policy acknowledges the Vancouver guidelines for authorship but includes an algorithm for allocating points for specific contributions to a research project as shown in Box 2. The policy states that the Vancouver guidelines do not need to be used for most papers but that they are helpful at times when authorship decisions are difficult to make. The policy also gives advice on how to circumvent and resolve authorship problems and includes a statement that the organisation reserves the right to publish important reports without an author rather than waste the product of research conducted using public money. What is important is that policies are developed in a collaborative way, are regularly revisited and revised if necessary, and are available to all potential authors. Senior researchers are occasionally criticised for being only second or final authors when the system of using author order as an acknowledgement of mentoring, intellectual, and/or management credentials is not recognised. Until a consensus on the meaning of author order is achieved, researchers who strive to gain recognition for their own intellectual contribution whilst mentoring junior staff in the processes of writing and publication will always be disadvantaged. To deal with this issue, researchers applying for promotion often specify the exact contributions that they made to publications listed in their curriculum vitae. Gift, ghost, and guest authors Ghost writing is what you do for a football player when it is painfully obvious from his every utterance on and off the field that he has little to say but still needs help to say it. David Sharp55 “Gift” authorship occurs when someone who has not made an intellectual contribution to a paper accepts an authorship. This type of authorship often develops because both the author and the “gift” author benefit from the relationship. Senior “gift” authors are often enrolled because they tend to confer a stamp of authority on a paper. Many researchers are willing to cite senior authors if they think that this will facilitate the publication of their work or enhance their career prospects. Most of all, gift authors should definitely not be included “because everyone does it”. In a survey of journal articles published in three peer-reviewed journals (Annals of Internal Medicine, JAMA, and the New England Journal of Medicine) in 1996, 11% of articles involved the use of ghost authors and 19% had evidence of honorary authors. Although “guest” authors may have final control over the manuscript, they may not thoroughly review the paper if it does not have high priority in their workload.

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