By M. Bandaro. Cleveland Chiropractic College.
The post-test probability – the probability of each disease given the information – is a function of two variables order 10mg female cialis visa, pretest probability and the strength of the evidence purchase female cialis 20 mg with amex. The latter is measured by a “likelihood ratio”, the ratio of the probabilities of observing a particular finding in patients with and without the disease of interest. Using Bayes’ theorem becomes hopelessly complicated and impractical when this assumption is violated and more than two correlated cues are involved in a diagnostic judgement, as is often the case in clinical medicine. In these situations, linear and logistic regression techniques are commonly used to derive an equation or clinical prediction rule. We simply point out that the coefficients (weights) in a regression equation depend on the composition of the derivation sample. Bayes’ theorem distinguishes the effect of disease prevalence and the strength of the evidence on the diagnostic judgement, but ordinary regression analytical methods confound these variables in the regression coefficients. If the index disease is overrepresented in the derivation sample, a prediction rule should be applied cautiously to populations where the prevalence of that disease is different. Clinical applications of statistically derived prediction rules can outperform human judgement37; this is the rationale for a range of clinical prediction rules that have been developed during the past two decades. Reports of the accuracy of such rules and the reasons for their success have been available in the psychological literature on judgement for over 40 years,38 but application in clinical practice has been slow because of continuing concerns about: q whether a rule derived from a particular population generalises accurately to another q eroding the professional authority and responsibility of clinicians, and q whether guidelines (at least in the United States) are intended more to ration care and contain costs than to improve quality. Formally, if T1 and T2 are conditionally independent tests for a disease D, then: p(T2 |D and T1 ) p(T2 |D ) and p(T2 |D and T1 ) p(T2 |D ) 185 THE EVIDENCE BASE OF CLINICAL DIAGNOSIS substantial role for clinical judgement. Decision analysis proposes to offer the clinician insight into the crucial variables in a decision problem, together with a recommended strategy that maximises expected utility (for example, see42). Both attempt to avoid quasimandatory prescriptive guidelines and to leave room for professional discretion. Bayes’ theorem is a normative rule for diagnostic reasoning: it tells us how we should reason, but it does not claim that we use it to revise opinion. It directs attention to two major classes of error in clinical reasoning: in the assessment of either pretest probability or the strength of the evidence. The psychological study of diagnostic reasoning from the bayesian viewpoint has focused on errors in both components. Errors in probability estimation Availability People are prone to overestimate the frequency of vivid or easily recalled events and to underestimate the frequency of events that are either very ordinary or difficult to recall. This psychological principle is exemplified clinically in overemphasising rare conditions. The clinical aphorism “When you hear hoofbeats, think horses, not zebras” calls attention to this bias. Representativeness Earlier, clinical diagnosis was viewed as a categorisation process. The strategy of estimating the probability of disease by judging how similar a case is to a diagnostic category or prototype can lead to an overestimation of the probability of a disease in two ways. Second, representativeness neglects base rates and implicitly considers all hypotheses as equally likely. This is an error, because if a case resembles disease A and disease B equally well, and there are 10 times as many cases of A as of B, then the case is more likely an instance of A. This heuristic drives the “conjunction fallacy”: incorrectly concluding that the probability of a joint event (such as the combination of multiple symptoms to form a typical clinical picture) is greater than the probability of any one of those events alone. The joint event may be more representative (typical) of the diagnostic category, but it cannot be more probable than a single component.
Refill practices must be clearly defined for the benefit of patients and pharmacists female cialis 20mg cheap. The pharmacist must understand the physician’s policy concerning controlled substances buy generic female cialis 20mg line. Steps must be taken to prevent hoarding and then overdosing at a later date. The patient must understand in advance the physician’s policy regarding lost pre- scriptions and drugs destroyed by the dog or flushed down the toilet or stolen from a woman’s purse. Some drugs that patients are permitted to refill require close monitoring. If a patient fails to comply with monitoring instructions, the privilege to refill may have to be withdrawn. Finally, there must be systems in place to warn patients of drug recalls. Procedures It is clearly a breach of the standard of care for physicians or their assistants to perform procedures for which they are not adequately trained. In one case, a woman’s face was badly scarred by a physician who was trained in the use of a laser by a salesperson. Soft tissue injections around the scapula or into an intercostal muscle have perforated lungs. Joint injections by those not properly trained have caused destructive septic arthritis. These and similar misadventures have led to lawsuits that are very difficult to defend. The Language Barrier The problems related to language barriers are well known to phy- sicians. Patients with limited English skills cannot be denied health care or in any way be discriminated against by health care providers. In 2000, President Clinton issued Executive Order 13166, requiring equal access to federally funded health care services for patients with limited English proficiency. A language barrier will probably not shield a physician from allegations of negligence. In one recent case, a physician failed to diagnose a subarachnoid hemorrhage because he could not understand the history of onset or severity of a headache. Interpreters on the telephone or, bet- ter still, in the office are invaluable. Before discharging a patient, a physician should be certain that he or she understands the medical problems and that the patient understands the necessary advice and follow-up. SUMMATION At any given time, 15–20% of physicians are defendants in malprac- tice lawsuits. The average lawsuit takes more than 3 years from incep- tion to resolution. The experience can destroy a physician’s health, family relationships, standing in the community, self-confidence, and financial security. There have even been suicides where objective evaluation indicated that the physician was not guilty of wrongdoing. Risk managers have been criticized for advising strategies that are too time-consuming. New laws, rules, and court decisions continue to create additional responsibilities and risks for physicians. Finally, it should be kept in mind that a family physician’s best friends in a malpractice lawsuit are the contemporaneous, thoughtful, clearly written medical record and a supportive, competent, caring nurse.
On balance it seems buy discount female cialis 20 mg, however discount female cialis 10 mg on-line, that DA stimulates the neurons of the Dir Path so that the GPint is inhibited and thalamo-cortical flow facilitated. Whatever the precise activity of these pathways, DA obviously has a pivotal role in their control. The fact that lesion of GPext causes some rigidity in animals supports this. Also if the Dir Path is not driven in the absence of DA, this will also free GPint to inhibit motor activity. So how can the abnormal pattern of striatal activity that causes akinesia be restored to normal? THERAPY Parkinsonism is unique among diseases of the CNS, in that it results from the known loss of a particular NT, i. DA, resulting from the degeneration of a particular path- way, the nigrostriatal. Dopamine also has a relatively limited distribution in the brain and few peripheral effects. It should therefore be amenable to therapy based on augmenting its function. Also since the role of DA appears to be to maintain a tonic inhibitory control on GABA output pathways from the striatum, possibly in part by an extra synaptic action (Chapter 6), it may not be necessary for it to be released physiologically from nerve terminals. Nevertheless it must also be expected that anything which increases DA function not only controls extrapyramidal function but also reproduces the other central effects of DA; i. Despite these problems, the therapy of PD is one of the success stories of neurology. It is generally assumed that DA itself cannot be used because it does not cross the blood±brain barrier although some recent mocrodialysis studies following intravenous DA indicates that this may not be so, in rats anyway. Thus PD may be treated by 304 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION DISEASES OF THE BASAL GANGLIA 305 (A) Augmenting the action of DA (Fig. The DA neuronal uptake transporter can be distinguished from that for NA and is blocked preferentially by nomifensine. Also unlike NA, which is a substrate for MAOA, dopamine is a substrate for MAOB for which selegiline (deprenyl) is an effective inhibitor. The efficacy of both nomifensine and selegiline might be augmented initially by supersensitivity to the remaining DA (increased receptor number) but this decreases with time and augmenting synaptic DA increases the likelihood of stimulating terminal autoreceptors and inhibiting DA release. In view of these problems and the progressive degeneration of DA neurons it is not surprising that nomifensine has little effect but selegiline does produce some improvements in the early stages of the disease and there has been much interest in the possibility that it can prevent, or at least reduce, further degeneration (see section on Aetiology). O-methylation of DA is a secondary line of metabolism and its inhibition has little effect on the removal of DA but drugs that block this enzyme are gaining a place in prolonging the action of levodopa. Levodopa, by contrast, is not a good substrate for MAO, although metabolised by COMT (Fig. Early attempts to treat PD with dopa failed because the doses used were too small. This arose partly from the fear that it would be converted to NA as well as DA and so 306 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION Figure 15. After oral administration alone most dopa is rapidly decarboxylated to DA in the gut and blood with some o-methylated (COMT) to o-methyl/dopa (OMD). Blocking just the peripheral dopa decarboxylase (DD) with inhibitors like carbidopa and benserazide, that cannot enter the CNS (extra cerebral dopa decarboxylase inhibitors, ExCDDIs), stops the conversion of levodopa to DA peripherally, so that more enters the CNS or is o-methylated peripherally to OMD. The deamination of DA to DOPAC can be prevented by MAOB inhibitors such as selegiline while COMT inhibitors stop its further o-methylation to HVA and the conversion of dopa to OMD.
Ca2+-INDEPENDENT RELEASE OF TRANSMITTER CARRIER-MEDIATED RELEASE It is now well established that transmitter in the cytoplasm of neurons can be released by a process which is not dependent on Ca2 discount female cialis 10mg. For monoamines buy female cialis 10mg visa, this is best illustrated 100 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION by the actions of amphetamine and its analogues. Studies of a range of substituted amphetamines, using cultured serotonergic neurons, have confirmed that this release is not prevented by either N-type or L-type Ca2 channel blockers, or removal of Ca2 from the incubation medium, or depletion of the vesicular pool of transmitter. The release is blocked by inhibitors of the axolemma 5-HT transporter on the axolemma that normally carries 5-HT back into the nerve terminals from the synaptic cleft. This suggests that amphetamine-induced release of 5-HT represents a reversed efflux of transmitter on the membrane-bound carrier (Rudnick and Wall 1992). Whether this process of reverse transport accounts for all the 5-HT which is released by amphetamine, or whether this drug has additional actions which affect transmitter release, remains unclear (see also Chapter 9). Such carrier-mediated release could explain the massive Ca2-independent release of noradrenaline during ischaemia which increases intracellular Na concentration and reduces intracellular K. Amino acids might also be released in this way (see Attwell, Barbour and Szatkowski 1993). There is evidence that depolarisation of retinal horizontal cells and cultured type 2 astrocytes by glutamate increases intracellular [Na] concentration sufficiently to drive the membrane transporter to carry GABA (together with Na and Cl7)out of the neurons (Fig. Glutamate release during ischaemia is also thought to involve such carrier-mediated transport. A similar process might also explain a glutamate-induced increase in glycine release from astrocytes in the hippocampus. HETEROCARRIER-MEDIATED RELEASE Finally, there is evidence that transporters for GABA are found on the terminals of neurons releasing other types of transmitters. This suggestion arises from findings that exposure of brain synaptosomes to GABA can trigger release of noradrenaline, dopamine and acetylcholine. This release is prevented by inhibitors of GABA uptake but not by GABA receptor antagonists or monoamine uptake blockers. Unlike the carrier-mediated release described above, this form of release is thought to be Ca2-dependent and to involve vesicular exocytosis. However, the contribution of this process to the physiological control of neurotransmission has not yet been resolved. CONCLUSION That impulse-evoked release of neurotransmitters depends on a Ca2-dependent extrusion from storage vesicles is beyond dispute. However, many details concerning the supply of vesicles that participate in this process, as well as the processes which regulate the docking and fusion of synaptic vesicles with the axolemma, remain uncertain. Nevertheless, it is clear that the amount of transmitter that is released in this NEUROTRANSMITTER RELEASE 101 Figure 4. Depolarization of a neuronal, or glial cell process by glutamate, with a concomitant rise in [Na]i reverses the operation of the GABA uptake carrier, raising [GABA]o. Activation of these receptors is coupled to the release process through their respective second messengers. It is also evident that vesicular exocytosis is not the only process which leads to release of transmitter from nerve terminals. Under certain conditions, axolemma-bound transporters can export transmitters from neurons or even evoke exocytosis. It seems that a range of processes contribute to release of neurotransmitters, all of which could have a vital role in the regulation of neurotransmission. REFERENCES Attwell, D, Barbour, B and Szatkowski, M (1993)Nonvesicular release of neurotransmitter. Basbaum, CB and Heuser, JE (1979)Morphological studies of stimulated adrenergic axon varicosities in the mouse vas deferens. Benfanati, F, Onofri, F and Giovedi, S (1999)Protein±protein interactions and protein modules in the control of transmitter release.