By N. Achmed. Davenport College.
Inhibition of COMT within both peripheral and CNS structures provides some theoretical advantages over peripheral inhibition alone since discount female cialis 20mg mastercard menstrual blood spells, in addition to the peripheral levodopa-sparing capability generic 20mg female cialis overnight delivery women's health nursing issues, concomitant central COMT inhibition would not only reduce metabolism of levodopa to 3-OMD within the striatum, but would also block one route of metabolism of dopamine itself. Single-dose studies demonstrated tolcapone to be a noticeably more potent COMT inhibitor than entacapone. At a dose of 200 mg, tolcapone increases the levodopa AUC by anywhere from 50 to 100%, prolongs the levodopa T1/2 by 60–80%, and reduces the AUC of 3-OMD by 64% (18,47,68,69). No appreciable increase in Cmax or Tmax is seen with 200 mg of tolcapone, although some delay in the Tmax becomes evident at higher doses (68). A number of double-blind, placebo-controlled clinical trials have conﬁrmed the efﬁcacy of tolcapone in reducing motor ﬂuctuations in individuals with PD (70–73). In each of these multicenter trials, which varied in length from 6 weeks to 6 months, signiﬁcant increases in ‘‘on’’ time and reductions in ‘‘off’’ time were documented in the tolcapone-treated groups compared to the placebo groups. Reduction in both total daily levodopa dosage and number of levodopa doses taken was often evident in the tolcapone-treated groups. In these four multicenter studies, in which 517 patients (out of 745 enrolled), received tolcapone in various doses ranging from 50 to 400 mg TID, adverse effects were generally mild and most often felt to be dopaminergic in character (70–73). In the three studies where the treatment groups consisted of placebo vs. Diarrhea, at times unresponsive to medication and of sufﬁcient severity to warrant drug discontinuation, was reported in a relatively small percentage of individuals receiving tolcapone, possibly in a dose-related pattern (47,72,73). The mechanism of the diarrhea is uncertain, although tolcapone has been noted to trigger intestinal ﬂuid and electrolyte secretion, Copyright 2003 by Marcel Dekker, Inc. As with entacapone, yellowish urine discoloration also occurred in some individuals. In these initial multicenter trials, elevation of liver transaminase levels occurred in a small number of individuals, but all were clinically asymptomatic and the laboratory abnormalities sometimes returned to normal despite continued treatment. In all clinical trials of tolcapone the reported incidence of transaminase elevations greater than three times the upper limit of normal was approximately 1% at a dose of 100 mg TID and 3% at a dose of 200 mg TID (75). However, following introduction of tolcapone into routine clinical use, three cases of fulminant hepatic failure with a fatal outcome occurred, which led regulatory agencies in Europe and Canada to withdraw tolcapone from the market and the Food and Drug Administration in the United States to severely limit its use to situations in which other drugs have not provided sufﬁcient beneﬁt. Baseline liver function tests must be normal, and monitoring of liver function studies must be performed on a regular basis in patients receiving tolcapone. Similar hepatotoxicity has not occurred with entacapone. CURRENT STATUS OF COMT INHIBITORS Two COMT inhibitors are currently available for use as adjunctive therapy in PD, to be used in conjunction with levodopa and an AAAD inhibitor in patients who have developed motor ﬂuctuations with end of dose failure. Tolcapone is the more potent of the two and, with its longer T1/2, can be given on a TID basis. However, its potential to produce hepatic failure has severely restricted its clinical utility. Because of this, the ﬁeld has largely been ceded to entacapone, which is a somewhat less potent, but a safer alternative. Because of its short T1/2, entacapone must be administered with each dose of levodopa. The additional 1–2 hours of ‘‘on’’ time per day a COMT inhibitor typically affords to a ﬂuctuating patient can be beneﬁcial. A recent cost-effectiveness analysis of entacapone concluded that the additional drug costs when entacapone is employed are offset by reductions in other costs and improvement (6%) in ‘‘quality-adjusted life years’’ (76). While it is clear that COMT inhibitors provide quantiﬁable improve- ment in function for PD patients with motor ﬂuctuations, their potential beneﬁt in stable PD patients who have not yet developed motor ﬂuctuations has received much less attention. Two clinical trials have addressed this question with tolcapone (77,78). In the larger of the two trials (77), statistically signiﬁcant improvement in both Part II (activities of daily living) and Part III (motor exam) of the UPDRS were documented. Improvement was most evident in more severely affected patients. Fewer patients in the tolcapone-treated group developed motor ﬂuctuations during the duration Copyright 2003 by Marcel Dekker, Inc. Adverse events were similar to those encountered in earlier trials described above. The second, smaller trial actually did not examine nonﬂuctuating PD patients, but rather evaluated individuals who had previously experienced wearing-off of levodopa efﬁcacy, which had been successfully controlled by levodopa dosage adjustment (78).
This is an issue that buy female cialis 10 mg 45 menstrual cycle, if addressed buy female cialis 10 mg on line xeloda menopause, will take sports epidemiology further. Partnerships can be made with medical students and public health schools to alleviate this problem. Currently there is no common operational definition of sports injuries in existence, which constitutes one of the biggest problems in sports injury data collection. What constitutes an injury in some sports may not be what is considered an injury in another sport. Some studies define an injury as “an incident requiring medical attention following a sport related activity (typical to that sport)”1, 5–7 others only define it as an injury “if it requires the athlete to miss the rest of that session or a subsequent training or participation session”. These guidelines can be a set definition of what constitutes an injury, with a sub-division of definitions (codes) expansive enough to incorporate all sporting diagnoses and subcategories for specific injury definitions, which can be supplemented for some of the atypical sports. Furthermore, there is no set definition of severity. Some studies classify severe injuries as those “requiring five weeks out of competitive competition” others classify severe injuries as those “requiring five games to be missed”. For example, if a team-player missed three games with an ankle sprain and another team-player (examined by the same physician) missed five games, but both injuries were considered to be 14 Methodology in research exactly the same grade and had the exact same rehabilitation, would the conclusion be that one ankle sprain was wrongly diagnosed initially or wrongly rehabilitated? However, consider the fact that both the injuries were exactly the same and the second team-player missed more games simply due to the fact that his team had two additional midweek fixtures as well as the regular weekend game. Dependent on the definition of injury if the classification of severe is five or more games missed one sprain is severe and the other is moderate, even though these injuries are the same. When collecting and reporting on data these considerations have to be taken into account. They can be controlled by collecting data in two ways, by total games/competition days missed and total days/weeks missed with both reported in the results. Currently there is no set format for data collection across sports. Largely this is due to the fact that there are no set definitions of diagnoses and severity. If these were to be defined then an inclusion criteria of data variables for universal collection could also be set. This would help solve some of the problems of the data collections that exist. The criteria would be standardised allowing comparisons like for like, whilst also allowing clinicians or scientists to collect in a variety of formats as long as the criteria were adhered to. These formats could initially be paper or electronic, although undoubtedly the way forward is electronic databases. An additional problem is that the sizes of the samples vary. Some studies into team sports refer to only one team, others use multiple teams. For example, if a paper comparing two different types of team sports reported that at the same stadium, on the same day, the first team sport had 12 injuries and second team sport had only 10 injuries and concluded the first sport was more dangerous than the second, the conclusion would not be acceptable unless the authors had also shown “how long each sport was played for” i. Also the reader should be told “how many players were playing in each team of the different sports. It does not give any indication of risk and cannot conclude one sport has more injuries in comparison to another. Sample size will influence the results, as explained above. Studies concerned with one particular sporting team, however, can be powerful studies if the number of injuries incurred is large enough to show statistical significance. This is clinical in nature and the practicalities of RCT are not well suited to the study of sports injury data at present. Cohort studies rated next, which monitor both the injured and non-injured athletes showing the results of participation and are ideally prospective in nature. Cohort design enables the risk factors to be established before the injuries occur. Case control was the third, monitoring only those athletes who suffered an injury and are typically more retrospective in nature. The latter make up the vast majority of sports injury studies at present, yet we should be aware that multiple anecdotes do not add up to an evidence-base.
LBs have not been described in the cerebellar cortex purchase female cialis 20mg online women's health clinic queen elizabeth gateshead. In the spinal cord proven female cialis 10mg women's health clinic grafton, the neurons of the intermediolateral cell column are most vulnerable. LBs can be found in the autonomic ganglia, including submucosal ganglia of the esophagus. While not usually numerous in typical PD, LBs can be found in cortical neurons, especially in the limbic lobe. Cortical LBs can be difﬁcult to detect with routine histology, but they are visible with special staining techniques and are usually most numerous in small nonpyramidal neurons in lower cortical layers. Similar lesions in the substantia nigra are referred to as ‘‘pale bodies’’ or as ‘‘pre-Lewy bodies. The chemical composition of LBs has been inferred from immuno- histochemical studies. While antibodies to neuroﬁlament were ﬁrst shown to label LBs (10), ubiquitin (11) and more recently a-synuclein (12) (Fig. Lewy neurites have the same immunoreactivity proﬁle as LBs (13). Biochemical studies of puriﬁed LBs have not been accomplished, but evidence suggests that they may contain a mixture of proteins including neuroﬁlament and a-synuclein (14–16). DEMENTIA IN PD Pathological ﬁndings considered to account for dementia in PD include severe pathology in monoaminergic and cholinergic nuclei that project to the cortex producing a ‘‘subcortical dementia’’ (39%), coexistent Alzhei- mer’s disease (AD) (29%) and diffuse cortical LBs (26%) (17). The basal forebrain cholinergic system is the subcortical region most often implicated in dementia, and neurons in this region are damaged in both AD and LBD. Neuronal loss in the basal nucleus is consistently found in PD, especially PD with dementia (18). Cholinergic deﬁcits are common in PD (19), and they may contribute to dementia in PD in those cases that do not have concurrent AD or cortical LBs. While virtually all PD brains have a few cortical LBs (17), they are usually neither widespread nor numerous in PD patients who are not demented. Several recent studies have shown, however, that cortical LBs are numerous and widespread in PD with dementia (20–22) and that the density of cortical LBs and Lewy neurites, especially in the medial temporal lobe (23), correlates with the severity of dementia (24). MULTIPLE SYSTEM ATROPHY The term multiple system atrophy refers to a neurodegenerative disease characterized by parkinsonism, cerebellar ataxia, and autonomic dysfunc- tion (25). The average age of onset is between 30 and 50 years, and the disease duration runs in the decades (25). There is no known genetic risk factor or genetic locus for MSA. The MSA brain shows varying degrees of atrophy of cerebellum, cerebellar peduncles, pons and medulla, as well as atrophy and discoloration of the posterolateral putamen and pigment loss in the substantia nigra. The histopathological ﬁndings include neuronal loss, gliosis, and microvacuolation, involving the putamen, substantia nigra, cerebellum, olivary nucleus, pontine base, and intermediolateral cell column of the spinal cord. White matter inevitably shows demyelination, with the brunt of the changes affecting white matter tracts in cerebellum and pons (Fig. Lantos and coworkers ﬁrst described oligodendroglial inclusions in MSA and named them glial cytoplasmic inclusions (GCIs) (26). GCIs can be detected with silver stains, such as the Gallyas silver stain, but are best seen with antibodies to synuclein, where they appear as ﬂame- or sickle-shaped inclusions in oligodendrocytes (Fig. Like LBs, GCIs are also immunostained with antibodies to ubiquitin (26). At the ultrastructural level, GCIs are non–membrane-bound cytoplasmic inclusions composed of ﬁlaments (7–10 nm) and granular material that often coats the ﬁlaments, making precise measurements difﬁcult (27). GCIs are speciﬁc for MSA and have not been found in other neurodegenerative diseases. In addition to GCIs, synuclein immunoreactive lesions are also detected in some neurons in MSA. Biochemical studies of synuclein in MSA have shown changes in its solubility (27). NEUROPATHOLOGY OF PROGRESSIVE SUPRANUCLEAR PALSY PSP, an atypical parkinsonian disorder associated with progressive axial rigidity, vertical gaze palsy, dysarthria, and dysphagia, was ﬁrst described by Steele-Richardson-Olszewski (28). Frontal lobe syndrome and subcortical Copyright 2003 by Marcel Dekker, Inc. FIGURE 3 MSA: Substantia nigra neuronal loss in MSA is obvious in the cluster of pigment-laden macrophages (arrow in a), but neuronal inclusions are not present.
Expected injuries are calculated by dividing the total injuries (for example over four seasons) by the total exposure (for example for the same four seasons) and multiplying the result by the exposure for the period under consideration (for example one season only) giving an expected injury case for that one season generic female cialis 20 mg overnight delivery menstrual like cramps at 34 weeks. The relevance of recording and analysing data this way is demonstrated below order 10 mg female cialis mastercard menstruation joint pain, taking data from a previous study conducted by 20 Methodology in research 300 Number of injuries 250 200 150 100 50 0 1993/4 1994/5 1995/6 1996 Figure 2. An obvious increasing incidence of injury is demonstrated. The message is further highlighted when the facts are considered that during the 1993/4 season there were 35 games played (605·15 exposure hours) and in 1996 only 21 games were played (363·09 exposure hours) – yet observe the difference in injury incidence again. Not adjusting for exposure/risk hours but only commenting on total injury cases is a fatal flaw in sports injury data presentation. Summary: Weaknesses and strengths in sports injury epidemiology research Weaknesses • Retrospective data is utilised which may lead to bias. Strengths • Using one recorder to diagnose and document injuries improves inter-rater reliability. If the above is applied to what is already known clinically, then we as researching clinicians may help to predict and prevent future injury occurrence. Thus accurate data collection could be essential in the prevention of injuries. If specific influences are identified as a contributing factor to the risk of injury and supported by scientific data collection then the rules of the sport may be changed to prevent this happening again. Preventative measures can then be initiated 22 Methodology in research and the effect of those measures can be monitored through further analysis. This will have the effect of making our athletes as injury free as possible and may even help lengthen their time in competitive participation. Summary: The ideal future study • Cohort design (injured and non-injured athletes observed). The future National guidelines should be established with set, universal definitions and codes for injury and severity, plus guidelines on the minimum data sets to be collected (allowing a few variations such as time loss weeks or games; mechanism or not; exposure per hour or mile, etc. Data could be collected (paper or electronic) as long as the definitions and minimum data set were adhered to. This would give clinicians/researchers the flexibility to choose a data set and software that met their own clinical/scientific needs while still fulfilling the requirement for data collection. This means more importantly that data across sport can be compared, analysed and evaluated. The true cost of a sporting injury is still not known. This is an area of research that is lacking in sport. What is the true cost of an athlete obtaining an injury? This will take sports medicine further to show managers and boards of directors what having an athlete on the sideline does to their finances and how having the best care at the appropriate time by the best qualified practitioner can reduce their losses. This will stop the cost cutting that goes on in medical rooms at clubs where qualified staff are replaced by students, newly qualified staff or non-professionals who come cheaper to the game. Below is an example of a working database in action (this is shown as a means to highlight a present working database, not to imply it is a gold standard). Do not look at this till you have attempted the above. A database in action The following section highlights a contact-team sports database in action. This database was developed by the author (LHP) and has been in use since 1993. Initially the database was developed solely for the purposes of medical record keeping. In 1996 the database became a research tool and was expanded slightly, whilst still keeping the core elements for retrospective analysis of the other three seasons’ data collected. Since the 1996 season all the data collected has been prospective in nature. Whilst this database has principles specific to the sport for which it was developed, the principles of epidemiology are the same and can be extrapolated to any sport whether team or individual orientated. Variables and categories utilised for the purpose of injury recording The injury definition used was “Pain, discomfort, disability or illness reported after participation in a Rugby related activity (game or training). Rates per 1 000 hours were calculated taking player exposure risk hours into account (as described in this chapter).
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