Rafael Tamargo, M.D.

• Walter E. Dandy Professor of Neurosurgery
• Professor of Neurosurgery

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0000358/rafael-tamargo

An association which is not causal between the disease and a marker allele may then be present in the pooled sample blood sugar fluctuations symptoms proven precose 25 mg, even if no association is present in any of the subpopulations metabolic disease child cheap precose amex. Non-related diabetes prevention trial type 2 purchase 50 mg precose overnight delivery, and ideally randomly chosen cases and controls from the same random mating population are used diabetes symptoms 8dpo trusted precose 25mg. Usually controls have been chosen from convenient available samples thought to be representative of the population from which the cases were selected diabetes mellitus type 2 definition who buy generic precose 25 mg line. As one can really never be sure of this diabetes type 2 patient information buy 50 mg precose overnight delivery, even after matching controls for ethnicity and geography, other approaches including the use of family controls have been proposed. The use of such methods has been strongly recommended for genetic mapping of susceptibility genes (Risch and Merikangas 1996, 1997). Furthermore, patients with available and participating parents may repre sent a selected and atypical sample of patients also concerning psychiatri cally relevant risk genes (Bruun and Ewald 1999). In large outbred populations there will be linkage disequilibrium in only a small chromosomal area of less than one million base pairs around the marker. At least a few thousand markers are required to make a systematic search in such populations. Currently association studies therefore usually are performed with markers in or near candidate genes. Once there is evidence of close linkage, and no more recombinants can be detected, the demonstration of linkage disequilibrium in a population asso ciation study may be helpful in the final identification of the relevant gene in the chromosome region (Bodmer 1986). It has been estimated that in 1999 around 5% of the human genome has been sequenced and that at least parts of the sequence of half of the 70 000 genes or so are known. Following the discovery of presenilin 1 a second candidate gene, presenilin 2, was found on chromosome 1 by search ing databases for sequence homology with presenilin 1. A number of textbooks and papers describe methods for genetic mapping and their interpretation in detail (Lander and Kruglyak 1995, Ott 1991, Terwilliger and Ott 1994, Sham 1998, Houwen et al. What constitutes a sufficient amount of markers to be tested in order to have covered all chromosome regions 256 H. Later the positive report of linkage in the Amish population was followed by decreased evidence (Kelsoe et al. However, the Amish study group has consistently reported low positive lod scores, around 0. Positive lod scores and some evidence of increased allele sharing for a few markers on each of chromosomes 6p25, 13q13 and 15q21 were presented. They reported some evidence of increased haplotype shar ing distal on chromosome 6p and on chromosome 9p. Byerley has tested many candidate genes and in 1993 reported an investigation of 328 markers in eight families (Coon et al. A haplotype may be defined as a group of closely linked alleles on a single chromosome which very often are inherited as a unit. Formal lod scores were not reported but were below the level of significant linkage (Escamilla et al. Allele frequencies for four markers were different comparing the affected family members with a population control sample (Freimer et al. Inspection of the most likely haplotype revealed that only two out of 16 patients with recurrent depression had not inherited the relevant haplotype. A number of studies have been performed on a collection of more than 20 North American pedigrees of European descent. More informative markers on chromosome 7 implied that this was a spurious positive finding. Other studies including these pedigrees have provided possible evidence for linkage to chromosome 18p near the centromere (Berrettini et al. Some evidence of increased allele sharing was also found on chromosome 21q (Detera-Wadleigh et al. A number of studies have been performed on a collection of Australian pedigrees of European descent (Mitchell et al. Lander and Kruglyak (1995) have suggested specific criteria for suggestive and signifi cant linkage using extended families as lod scores above 1. It is worth remembering that even false-positive findings may receive support from independent studies, that some risk genes may be too weak to be found by linkage strategies and that it perhaps may be quite difficult to replicate a true finding (Suarez et al. Concerning replications of significant and suggestive findings on chromo somes 4p, 12q, 18, 21q and the X chromosome a brief survey follows below. Though this formally replicates the Scottish findings according to the criteria suggested by Lander and Kruglyak (1995) some caution is warranted, as the modes of inheritance which yielded the highest lod score in the two studies were different. Searching for protective loci in Old Order Amish pedigree 110 and other Amish pedigrees, Ginns et al. Weaker and / or preliminary support has been reported by other research groups on chromosome 4p and 4q (Kennedy et al. Though the region implied by these studies may be around 20 cM wide these findings may represent the same locus (Ewald et al. Preliminary findings of significant linkage to this region have also been reported in Canadian families (Barden et al. In the genome scan of two large Costa Rican families the second-highest lod score found in one of the families was 1. The p-values were not very different from their p-values obtained at D18S37 mentioned above. In 11 pedigrees with probable pater nal transmission the highest affecteds-only lod scores found were at D18S41 in the paternal pedigrees, 3. This study found linkage disequilibrium to D18S1121 which is part of the haplotype reported in 1996 by Freimer et al. Chromosome 18q23 has also received some support from a cytogenetic study (Calzolari et al. Testing additional markers and including additional families the highest homogeneity lod score is still found on chromosome 21q22 (Aita et al. This region has received some support from a number of other research groups (Byerley et al. Evidence for linkage has been reported with classical, less polymorphic markers such as colour blindness (Xq28) (Mendlewicz and Fleiss 1974) and glucose-6-phosphate dehydrogenase deficiency (Xq28, very close to the colour blindness loci) (Mendlewicz et al. Progress has been accomplished despite fears that limitations concerning phenotypic knowledge and genetic mapping methods would hinder this. These findings seem plausible as they have mainly been detected in large families con sidering patients with bipolar disorder as affected, and supported also by relatively large lod scores, low empirical p-values and a shared haplotype. Sequencing of the exons has been done in patients with bipolar and unipolar affective disorder. Ewald presence or absence of 44 base pairs of probable functional significance (Heils et al. Apart from the studies on the Old Order Amish, mentioned earlier, a few linkage studies have found relatively low lod scores in the region (Byerley et al. A number of such regions have been reported (Table 5), and some studies have investigated a large number of cases based on nationwide cytogenetic registers (Mors et al. Cytogenetic abnormalities among family members may perhaps be related to illness if they are present among all or almost all affected individuals or Genetics of bipolar affective disorder 265 arise de novo in a single affected case. This is at odds with current trends of large-scale high throughput search for linkage disequilibrium with a very large number of polymorphisms (Risch and Merikangas 1996, Kruglyak 1999, Nothen et al. However, for complex diseases the identification of genes at chromo somal breakpoints, in regions implied by linkage or other genetic mapping studies, seems very promising compared to searching for linkage disequilibrium. Though concor dance rates less than 100% might be due to non-genetic aetiology in some discordant monozygous twin pairs, studies of the offspring of discordant monozygous bipolar affective or schizophrenic twins have indicated that reduced penetrance is also a possibility (Bertelsen and Gottesman 1986, Gottesman and Bertelsen 1989). Reduced penetrance is traditionally ascribed to unknown external environmental factors, but may be due to random cellular events during neural development (McGuffin et al. So the environment as implied from classical genetic studies includes a range of non-inherited factors ranging from cellular changes to external environmen tal factors. Classical twin studies have also been used for estimation of variance components to heritability, shared and non-shared environment. Genetic factors seem to influence the probability of development of major depression after severe stressful events (Kendler et al. Furthermore, the environ ment may not be randomly distributed in relation to the genotype. Genes may influence the way people interact with and experience their environ ment, so that what is traditionally viewed as external to the individual may be partly under genetic influence. A study has suggested that genes involved in major depression may act through predisposing individuals to place themselves in stressful environments (Kendler and Karkowski-Shuman 1997) and that this perhaps explains one-third of the association between stressful life events and major depressive episodes (Kendler et al. Another study has suggested that genetic factors may influence how people experience life events (Thapar and McGuffin 1996). Knowledge of specific environmental risk factors may help the identification of specific risk genes and vice-versa, and perhaps guide specific interventions. However, counselling will still be sought, and some patients may be willing to buy commercially available genetic tests even if they only convey very little and imprecise information. The initial molecular target is known for at least the antipsychotic drugs, cyclic antidepressants and selective serotonin reup take inhibitors. The slow onset of therapeutic action of these drugs indicates that the therapeutic mechanism of action is different. Such genes may also be different from the risk genes, though perhaps related to the same functional or a counterbalancing pathway. Antidepressants block the reuptake of serotonin and / or noradrenaline from the synapse. More studies on antidepressant treatment response are necessary, including genes involved in intracellular pathways of possible significance for this response. A few studies have investigated polymorphism in relation to neuroleptic treatment response. Among schizophrenic patients clozapine response and side-effects seem to be independent of variations in the very polymorphic dopamine D4 receptor (Rao et al. Putative candidate genes involved in the action of lithium such as tyrosine hydroxylase (Cavazzoni et al. Concerning drug metabolism many polymorphisms have been found in relation to a subset of the around 60 cytochrome P450 genes which catalyse the metabolism of many drugs including neuroleptics, antidepressants and monoamine oxidase inhibitors (Nebert 1997). It is hoped that future knowl edge of gene polymorphism may guide the choice of drugs, and perhaps dosage, in order to reduce the possibility of side-effects and toxicity. Judged from experience of monogenic and other complex diseases this may take several years. It is uncertain to which additional benefits these findings will contribute, and how fast these benefits will be available. Knowledge of which persons might be genetically susceptible to environmental factors may make it possible to detect these environmental factors. If carriers can be detected with a reason able certainty, preventive measures may be directed at such persons. It may perhaps be possible to predict course and severity of patients who have had their first episode. Environment and vulnerability to major psychiatric illness: a case control study of early parental loss in major depression, bipolar disorder and schizophrenia. A comprehensive linkage analysis of chromosome 21q22 supports prior evidence for a putative bipolar affective disorder locus. Genome-wide microsatellite marker linkage study of bipolar affective disorders in a very large pedigree derived from a homogeneous population in Quebec. High-density maker map supports bipolar affective disorder susceptibility locus on chromosome 12 in a homogeneous pop ulation in Quebec. The impact of phenotypic variation on genetic analysis: application to X-linkage in manic-depressive illness. Diminished support for linkage between manic depressive illness and X chromosome markers in three Israeli pedigrees. A pedigree series for mapping disease genes in bipolar affective disorder: sampling, assessment, and analytic considerations. Diagnosis and classification of mental disorders in relation to molecular research. Contested boundaries of bipolar disorder and the limits of categorical diagnosis in psychiatry. Linkage studies utilizing P300 and eye tracking data in bipolar and schizophrenic pedigrees. Implications of comorbidity for genetic studies of bipolar disorder: P300 and eye tracking as biological markers for illness. Abnormal beha vior associated with a point mutation in the structural gene for monoamine oxidase A. Selection bias of susceptibility genes possible when using parent-offspring trios in genetic association studies. Tyrosine hydroxylase gene not linked to manic depression in seven of eight pedigrees. Psychiatric disorder in a familial 15;18 transloca tion and sublocalization of myelin basic protein of 18q22.

Characteristic features: high urine output (polyuria) with low urine osmolality blood glucose record buy cheap precose line, and (in the conscious patient) craving for water (polydipsia) metabolic disorder known as g-a 1 generic precose 25mg visa, especially ice-water search keywordblocks signs diabetes generic 25 mg precose with amex. If severe diabetes test machine price in india discount precose 25 mg overnight delivery, t h e p at ien t m ay n ot be able t o m ain t ain ad e qu at e in t ake of flu id or t olerate t h e frequ en t trips to bathroom blood glucose 99 25mg precose for sale. Hyp on at re m ia managing type 1 diabetes in childhood and adolescence buy generic precose 50 mg online, Con vu lsion s, Re sp irat ory An t id iu r e t ic Hor m o n. Hyponatremia in of Inappropriate Secretion of Antidiuretic Hormone Acu the Bra in Dise ase. Administration of Intrave tremia: Rapid Correction and Possible Relation to nous Urea and Normal Saline for the Treatment of Ce n t r a l Po n t in e Myelin o lys is. In: Antidiuret Management and Relation to Central Pontine Myeli ic Horm one: Regulation, Disorders, and Clinical nolysis. Lympho Sym p t o m at ic Hyp on a t r e m ia an d It s Re lat io n t o cytic Hypophysitis: Case Report. Treating Hyponatremia: What is All the Con [34] Imura H, Nakao K, Shimatsu A, et al. Dr u g in fo: La b e t a lo l (No r m o d yn e , Tr a n d a t e ) 2 Blo c ks 1 selective, non-selective (potency<propranolol). Th e a c t ive m e t a b o lit e o f t h e o r a lly a d m in is t e r e d drug enalapril (see below). Re p e a t lo a d in g d o s e a n d in c r e m e n t in fu s io n r a t e b y 5 0 m c g / kg / m in q 5 m in s. In cludes: a) hemorrhage (external or internal) b) bowel obstruction (with third spacing) 2. Pulse increases >10%may exacerbate myocardial ische mia, more common at doses>20 mcg/kg/min. Phosphodiest erase inhibit or, e ects similar to dobutamine (including exacerbation of myocardial ischemia). Dr u g in fo: Ph e n yle p h r in e (Ne o -Syn e p h r in e ) Pure alpha sym pathom im et ic. Useful in hypot ension associat ed wit h t achycardia (at rial t achyarrhyth mias). Lack of action means non-inotropic, no cardiac acceleration, and no relaxation of bronchial smooth muscle. To prepare: put 40 mg (4 amps) in 500 ml D5 W to yield 80 mcg/ml; a rate of 8 ml/hr = 10 mcg/min. Dr u g in fo: Is o p r o t e r e n o l (Is u p r e l) Positive chronot ropic and inot ropic, > in crease d card iac O2 consumption, arrhythmias, vasodilatation (by 1 action) skeletal muscle >cerebral vessels. Dr u g in fo: Le vo p h e d 6 Direct stimulation (positive inotropic and chronotropic). This m ay increase the risk of pneum onia from aspira 7 tion, and there is a suggestion that mortality may also be increased. There is 7 insu cient data to determine the net result of sucralfate compared to no treatm ent. They block acid secretion regardless of the stim ulus (Zollinger-Ellison syndrome, hypergas trinemia). Not indicated for long-term treatm ent as the trophic e ects of the resultant elevated levels of gastrin may lead to gastric carcinoid tumors. Dr u g in fo: Om e p r a zo le (Pr ilo s e c) In h ib it io n o f so m e h e p a t ic P-4 5 0 e n zym e s re su lt s in re d u ce d c le a ra n c e o f wa r fa rin a n d p h e n yt o in. Act s b y co a t in g u lce ra t e d a re as o f m u co sa, d o e s n o t in h ib it a cid secretion. This may actually result in a lower incidence of pneumonia and mortality than agents that a ect gastric pH (see above). A Review of In duced by Sodium Nitropru sside in Patients w ith Stress Ulcer Prophylaxis in th e Neurosurgical In ten In tracran ial Mass Lesion s. Use fu l fo r q u a n t it a t in g t h e d e s ir e d le ve l o f se d a t io n w h e n t it r a t in g se d a t ive s for agit at ed p at ien t s. Doses are gen erally lower than those used by anesthesiologists for general anesthesia. Dr u g in fo: Th io p e n t a l (Pe n t o t h a l) A s h o r t a c t in g b a r b it u r a t. Sid e e ects: dose related respiratory depression, irritation if extravasated, intra-arterial injection > necrosis, agitation if injected slowly, an antianalgesic, myocardial depressant, hypotension in hypo volem ic pat ient s. Metabolism: non-hepatic hydrolysis by nonspecific blood and tissue esterases, no accumulation. Synergy with thiopental, propofol, isoflurane, midazo lam re q uire s re d ucin g d ose s of t he se ag e nt s b y up t o 75 %. Sid e e ects: bradycardia, hypotension (these side e ects may be blunted by pretreatment with anticholinergics), N/V, muscle rigidity, pruri this (aspecially facial) dose dependent respiratory depression at doses>0. Su p p lie d: vials of 1, 2 or 5 mg powder to be reconstituted to 1 mg/ml solution. Dr u g in fo: Fe n t a n yl (Su b lim a ze ) Narcot ic, pot e ncy 100 morphine. Sid e e ects: dose dependent respiratory depression, large doses given rapidly may cause chest wall rigidity. Als o u s e fu l in h ig h d o s e s d u r in g a n e u r ysm su r g e r y a s a n e u ro p ro t e c t a n t (p. Sid e e ects: includ e Prop ofol Infusion Synd rom e: hype rkale m ia, he p at om e g aly, lip e m ia, m e t ab ol 3 ic acid o sis, m yocard ial failure, rh ab d om yolo sis, re nal failu re an d som e tim e s d e at h. The bottle and tubing must be changed every 12 hours since it contains no bacteriostatic agent. Ha s b o t h s e d a t ive and analgesic properties and dramatically reduce the risk of respiratory depression and the amount of narcotic analgesics required. Sid e e ects: clinically significant bradycardia and sinus arrest have occurred in young, healthy volunteers with incre ase d vag al t one (ant icholine rg ics such as at rop ine 0. Use with caution in patients with advanced heart block, baseline bradycardia, using other drugs that lower heartrate, and hypovolemia. Re m in d e r: p a r a lyz e d p a t ie n t s m ay still be conscious and therefore able to feel pain, the simultaneous use of sedation is thus required for con sciou s p at ien t s. Ad d it io n a l in fo r m a t io n fo r so m e a ge n t s follow s t h e t a b le a lo n g with some considerations for neurosurgical patients. In d ica t io n s Due t o significant side e ects (see below), use is now limited primarily to the following indications. Ad u lt s: g e n e r a lly r e c o m m e n d e d o n ly fo r e m e r g e n c y in t u b a t io n s w h e r e t h e a ir w a y is n o t c o n t r o lle d. In ch ild re n: o n ly wh e n in t u b a t io n is n e e d e d wit h a fu ll st o m a ch, o r if la r yn g o sp asm o c cu rs d u rin g attempted intubation using other agents. Do not use for routine intubations in adolescents and children (may cause cardiac arrest even in apparently healthy youngsters, many of whom have undiagnosed myopathies). Ma y ca u se d ysrh yt h m ia s, e sp e cia lly sin u s b ra d yca rd ia (t re a t wit h a t ro p in e). Due to active metabo lit e s, p aralysis h as b e e n re p ort e d t o t ake 6 hrs t o 7 d ays t o re ce d e fo llowin g d isco nt inu at io n of t he 7 drug after 2 days use in patients with renal failure. Dr u g in fo: Cis a t r a c u r iu m (Nim b e x ) Nondepolarizing (com pet it ive) blocker. This isom er of at racurium does not release hist am ine unlike it s pare nt com p ound (se e be low). Also und e rg oe s Hofm ann de g ra dation, with laudanosine as one of its metabolites. Non opioid analgesics should be continued as more potent medications and invasive techniques are utilized. Ca r b a m a z e p in e (The g r e t o l) m ay b e u s e fu l fo r p a r o x y s m a l, la n cin a t in g p a in. Ch a r a ct e r is t ics o f n o n s e le ct ive n o n s t e r o id a l a n t i in fla m m a t o r y d r u g s: 1. Fo r p a t ie n t we ig h t < 5 0 kg, a g e > 6 5 yrs, o r re d u ce d re n a l fu n c t io n (c re a t in in e cle a ra n c e < 5 0 m l/ min), all of the above dosages are halved (maxdaily dose: 60 mg). Creatinine clearance can be esti mated using the Cockcroft-Gault equation14 shown in Eq (7. For moderately severe acute pain, an initial dose of 100 mg followed by 50 mg doses may su ce. Ad u lt: OxyCo n t in t a b le t s a r e t a ke n wh o le a n d a r e n o t t o b e d ivid e d, c h e we d or crushed. For patients on narcotic medications, a conversion table is provided below for some medications. Use should be limited to physicians with experience using these drugs cmay not be practical for use in severe pain since 1 Tylox contains only 5mg oxycodone (the acetaminophen lim its the dosage), m ay use OxyContin for higher doses of oxycodone d should not be used as routine post-op analgesic (risk of respiratory depression). How ever, the contents of the capsule (the beads) may be sprinkled on apple-sauce for those unable to swallow the capsules, but the beads are not to be chewed or crushed. Tr i c y c l i c a n t i d e p r e s s a n t s: 7 Tr y p t o p h a n: a n a m i n o a c i d a n d a p r e c u r s o r o f s e r o t o n i n, m a y w o r k b y i n c r e a s i n g s e r o t o n i n l e v e l s. An t ih is t a m in e s, w h ich a r e a ls o a n x io lyt ic, antiemetic, and mildly hypnotic, are e ective as analgesics or as adjuvants. An t ico n vu ls a n t cla ss d r u gs: ca r b a m a z e p in e, clo n a ze p a m, p h e n yt o in, ga b a p e n t in o r p r e g a b a lin tend to be more e ective in neuropathic pain. Best known for this use is fluphenazine (Prolixin), usually given with a tricyclic antidepressant for neuro pathic pain, Diabet ic n eu ropat hy, Treatm en t (p. Co r t ico s t e r o id s: in a d d it io n t o t h e r e d u ct io n o f t o x ic e ects of radiation or chemotherapy, they may potentiate narcotic analgesics. There are also a number of nonspecific beneficial e ects: increased appetite, sense of well being, antiem etic. Physiologic replacem ent (in the absence of stress) can be accom plished w ith either: 1. Because of m ineralocorticoid activity, use for chronic therapy of other conditions. Suppression is unlikely with <40 mg prednisone (or equivalent) giv en in the morning for less than 7 days, or with every-other-day therapy of <40 mg for 5 1 weeks. Measuring morning plasma hydrocortisone can evaluate the degree of recovery of basal adreno cortical function, but does not assess adequacy of stress response. For longer treatment, or when withdrawal problems develop, use the following con servative taper: 1. Patient may experience mild withdrawal symptoms of:3 a) fatigue b) anorexia c) nausea d) orthostatic dizziness 2. The need for st ress d oses of steroid s ce ases w h en a p osit ive test is obtain ed. Th e risk for ad ren al insu ciency persist 2 years after cessation of chronic steroids (especially the first year) Ta b le 8. Some evidence suggests that low-dose glucocor ticoids ( 10 mg/d of prednisolone or prednisone equivalent) for rheumatoid arthritis does not 5 increase osteoporotic fractures, blood pressure, cardiovascular disease, or peptic ulcers, but weight 3,6 gain and skin changes are common. Since steroids may mask signs of peritonitis, this should be considered in patients on steroids with abdominal discomfort, especially in the elderly and those with a history of diverticular disease. Ea ch la b should provide a lower limit of normal for their lab, which may be broken down further by age and gender. Sy m p t o m s: m e n t a l s t a t u s ch a n g e s (co n fu s io n, le t h a r g y, o r a git a t io n), m u s cle w e a k n e s s. Tr e a t m e n t o f Ad d i s o n i a n c r i s i s If p ossible, d raw se r u m for cort isol d eter m in at ion (d o n ot w ait for t h ese resu lt s t o in st it u t e t h erapy). Wound healing and cardiac function may be compromised, and surgery 8 under general anesthesia should be postponed if possible until thyroid levels are normalized. E ects of anesthesia may be markedly prolonged, and dosages should be adjusted accordingly.

Radiotherapy is indicated to cure or improve survival in nearly 85% of the cases where radiotherapy is indicated [3 diabetes mellitus type 2 care plan buy discount precose 25 mg on line. A criterion based benchmarking method has been used to estimate need on the basis of utilization in regions where radiotherapy was assumed to be optimal [3 blood glucose tolerance test buy precose 50 mg low cost. This method uses the highest utilization rates as a benchmark metabolic disease drug development generic precose 50mg on line, but does not relate this to the clinical evidence diabetes medications starting with j cheap precose 25 mg visa. In developed countries diabetes signs in urdu buy precose amex, radiotherapy demand is dominated by prostate diabetes test every 3 months order genuine precose on-line, breast and lung cancer, and the three methods for estimating demand have been compared with uptake in British Columbia, Canada. This is something of a self-fulfilling prophecy and is not directly translatable to other populations [3. In addition, these cancers are often diagnosed at a more advanced stage, which limits surgical options. To demonstrate the effect of differences in types of cancers, the model by Delaney et al. Because the types of cancer vary from region to region, the proportion with an indication for radiotherapy varies from 48% of new cases of cancer in Mexico and Central America, and the Middle East, to 55% in the Caribbean (Table 3. This shows the larger number of cases of lung cancer and stomach cancer in East Asia. More advanced cancers are less likely to be amenable to surgery and therefore are more likely to be treated by radiotherapy. It shows that there is a 59% need for radiotherapy for cancers in indigenous Australians compared with 52% for the general population. This is because indigenous Australians present with later stage cervical, breast and colorectal cancers. Advanced stage cervical cancer was seen in 39% of cases, compared with 12% of non-indigenous cases; advanced stage breast cancer was seen in 55% of cases, compared with 38% of non-indigenous cases; and advanced colorectal cancer was seen in 57% of cases, compared with 48% of non-indigenous cases. Lung cancer was the only cancer where indigenous patients presented with earlier stage cancers, perhaps because of detection by chest X rays taken as part of tuberculosis screening. About 50% of new cases of cancer would benefit from radiotherapy and about 25% of these may benefit from further treatments [3. These courses will include new patients, re-treatments (second or subsequent treatment) and treatment of non-malignant disease cases such as pituitary tumours or those not notified to a cancer registry such as non-melanomatous skin cancer. This can be compared against the actual supply of units in a country or region to determine the shortfall. Thus, the radiotherapy utilization rate will be higher, the number of courses per machine will be higher and the re-treatment rate will be lower (Table 3. The intuitive answer is that radiotherapy centres should follow the population concentration distribution in a country [3. A single centre may suffice in small countries or even in large countries with a small population if transportation services between centres of population are adequate. In general, however, a network of oncology services will be required, with a radiotherapy centre within each region of a country. For those patients living at a distance from the radiotherapy centre, funding will have to be set aside to pay for the costs of transportation and accommodation. Countries where a significant proportion of the population are living at a distance or geographically isolated from the main centres may also consider either the implementation of consultation clinics as focal points for further referral (primary care clinics can fulfil this role) or, alternatively, facilitate patient commuting through an organized transportation service. In this study, the radiotherapy utilization rate was 29%, which is much lower than the generally accepted rate for a developed country. A similar study from the north of England showed socioeconomic gradients in access to services [3. They may also record data about stage at presentation, which has a critical influence on outcomes. Screening tests sort out apparently well persons who probably have a disease from those who probably do not. Persons with positive or suspicious findings must be referred to their physicians for diagnosis and necessary treatment. Certainly in developing countries, and even in developed countries, involvement of a physician is neither practical nor necessary. The concept of screening for cancers in their preclinical stages is an appealing one, at least for those sites and geographical areas where screening is effective. The results can be interpreted accurately and quickly, and appropriate therapy can be instituted, allowing a more effective response than that which can be offered when the preclinical tumour is diagnosed later. This is precisely 59 the intention of disease screening; namely, to detect a disease and lead to rapid treatment and a meaningful reduction in mortality. Detecting pre-cancers should reduce the number of new cases (the incidence) and thereby reduce mortality. Even in optimal circumstances, controversy exists about the screening of asymptomatic patients for most cancer sites. Annual mammography and breast self-examination have been subject to unresolved discussion, and even the age at which Papanicolaou (Pap) smears are first performed, and the interval between tests, is controversial. In this chapter, the discussion of screening is limited to those cancers for which: there is a screening test with high sensitivity and specificity; the predictive value of a positive or negative test is high; and the test has high acceptability. In addition to the aforementioned limitations, it is further restricted to those sites which respond well to radiotherapy. Therefore, the following sites are included: breast, uterine cervix, prostate, rectum and oral cavity. Technically, the characteristics of screening tests and screening programmes are not measured on symptomatic individuals. However, the need for follow-up of individuals who screen positive is the same for both groups, although the type, extent and speed of follow-up are likely to differ. Furthermore, once someone has become symptomatic, it may be prudent to skip a screening procedure and go immediately to a more definitive diagnostic assessment. This often happens during a clinical examination, in which case screening may cause a delay and unnecessary expenditure. Once a screening programme is established and people return on a regular basis. Sometimes, if surgery is impossible, or the patient opts not to have surgery, radiation may be used as the primary treatment for breast cancer. Radiotherapy is also used to treat cancer which has metastasized to the bone or brain. For many years, mammography was recommended for women aged 50 and older, on either a yearly or biennial follow-up basis. More recently, however, the effectiveness of mammography has been questioned in a number of high income countries. Breast cancer mortality in women who are treated with adjuvant therapy has a similar survival rate, whether or not they participated in screening programmes [4. An inquiry into benefits versus harms of mammographic screening has just been initiated in the United Kingdom, which is one country where analyses have shown little benefit from mammographic screening [4. Women in whom abnormalities are detected by mammographic screening are exposed to the harms of false positive mammograms and overdiagnosis with unnecessary treatment. Evidence does not support the effectiveness of breast self-examination as a means of detecting early cancers. Its effectiveness at reducing the stage at presentation has been demonstrated, and its effectiveness at decreasing mortality has been suggested by statistical simulation studies. However, a population based screening intervention remains a very resource intensive health programme regardless of which tool is used [4. There is also a place for surgical treatment of early and in situ cervical cancer. Regardless of the test used, the key to an effective programme is to reach the largest proportion of women at risk with quality screening and treatment [4. False positive results increase the costs of screening, the burden of anxiety for women and morbidity from unnecessary diagnostic and treatment procedures. For example, if the Pap smear is positive, a colposcopy is required for biopsy and, if this is positive, excision or cryotherapy of the abnormal area is usually needed. In resource poor settings, this series of procedures requires at least three visits and expertise in pathology and gynaecology, which are frequently not available. Effective management of these women would be expected to have an impact on population mortality from cervical cancer. The Pap test, when combined with a regular program of screening and appropriate follow-up, can reduce cervical cancer deaths by up to 80% [4. They found good evidence from multiple observational studies that screening with cervical cytology (Pap smears) reduces the incidence of, and mortality from, cervical cancer. Indirect evidence suggests most of the benefit can be obtained by beginning screening within three years of the onset of sexual activity or age 21 (whichever comes first) and screening at least every three years. It recommends against routinely screening women older than age 65 for cervical cancer if they have had adequate recent screening with normal Pap smears and are not otherwise at high risk for cervical cancer [4. It gave the service a D recommendation, which means there is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits, and the task force discourages use of the service [4. It recommends that men have an opportunity to make an informed decision with their health care provider about whether or not to be screened for prostate cancer [4. This includes African Americans and men who have a first degree relative (father, brother or son) diagnosed with prostate cancer at an early age. Overall health status, and not age alone, is important when making decisions about screening. Annual screening has been the standard; however, two screening studies demonstrate that screening is beneficial every two to four years. If there is a higher risk of prostate cancer, such as family history of prostate cancer or if the patient is of African descent, screening should be offered at age 40 years. This is predominantly related to the relatively low incidence of oral cancer in the United States of America, even if screening is limited to adults who smoke. However, the British Columbia Cancer Agency has made the following recommendations for adult patients beginning at age 40 [4. In Sri Lanka and India, large studies of screening for oral cancer have proven the feasibility of screening by primary health care workers. A randomized controlled trial of screening for oral pre-cancers and early cancers by visual inspection in Kerala, South India, showed a significant 34% reduction in mortality in high risk groups. However, these would still need to be linked to definitive follow-up and treatment, in order to see a decrease in incidence or mortality. However, for rectal cancer, radiation is often given 66 either before or after surgery to make the cancer more operable and/or prevent local recurrence [4. There may be considerations that support colorectal cancer screening in an individual patient. Unless high compliance with the test can be achieved, however, the benefit that could be obtained in the general population would be much less, and not commensurate with the expense of the screening programme. Given these principles, screening for cancers which are responsive to radiotherapy should be limited to breast, cervical and rectal cancers. However, even published guidelines from developed countries must be interpreted with caution, because of differences in populations, age specific incidence, the availability of adequately trained personnel and of equipment and supplies, universal access to health care, education, economic factors, etc. Much of the evidence for effectiveness of screening for cancer has been based on trials or studies conducted among Caucasians, so applying these to racial or ethnic groups with a different natural history of the cancers. When initiating either a population based screening programme or an opportunistic programme (such as one offered at a health fair), both symptomatic and asymptomatic individuals will be present. Similarly, cryotherapy has been selected as the treatment option for the eligible test-positive cases. However, unless high compliance with the test can be achieved, the benefit that could be obtained in the general population would be much less, and not commensurate with the expense of the screening programme. However, even published guidelines from developed countries must be interpreted with caution because of differences in populations, age specific incidence, the availability of adequately trained personnel and of equipment and supplies, universal access to health care, education and economic factors. The vast majority of cancers in adults are not genetically inherited, but rather are related to associated co-morbidities and exposure to carcinogenic substances. Historically, the incidence of cancer has been higher in developed countries than in developing countries [5. The recent demographic growth observed in the developing world as a consequence of the successful management of communicable diseases, which had caused substantial premature death, is inevitably making these populations more susceptible to cancer. In fact, of the estimated 14 million new cancer cases every year, 8 million are predicted to occur in the developing world [5. Although early detection and optimal treatment have already proved to have a demonstrable effect on the decline of the cancer mortality rate in most developed countries [5.

However metabolic disease in animals 50mg precose visa, more magnetic stimulator diabetes 1 cure order cheapest precose, many thousands of patients advances in coil design show promise in improving and normal individuals throughout the world have the precision and thus the utility of magnetic periph undergone magnetic stimulation without ill effect blood sugar se x magik cheap precose 50mg. Adult values for central motor conduction can concern but there have only been a few reports of usually be attained by 4 years of age diabetes type 1 cure discount precose 50 mg on line. However diabetic diet breakfast ideas buy generic precose 50 mg on-line, cor seizures occurring at or shortly after the time of mag tical threshold remains high until the end of the first 35 diabete 91 quality precose 25mg,64,66 92 netic stimulation. The disparity between attainment of adult epileptics have failed to induce either clinical sei values of central motor conduction velocity and cor zures or electroencephalographic epileptiform activ tical threshold is consistent with the notion that cen 139 ity. Injury to the included possible brain cell damage with cognitive motor cortex in young children can be followed by and other dysfunction and complications from dis excellent functional recovery of the affected limb(s). It is In such situations, magnetic stimulation of the unaf possible that magnetically induced currents could fected cortex induces not only the usual contralater damage the internal electronics of biomedical de al response but also a large ipsilateral one. The coils should probably the result of corticospinal sprouting within therefore not be placed in the vicinity of cardiac the pyramidal tract leading to an elaboration of ip 18 pacemakers. It has been morphologically with the magnetic coil if it is placed directly over the confirmed that sprouting of central fibers can occur, open heart; applying a magnetic coil over the lateral using labeling of corticospinal cells. For routine clinical practice, 10 to 15 stimuli are usually more than sufficient to achieve Amyotrophic Lateral Sclerosis. Adult values for cen abnormalities and with clinical upper motor neuron tral motor conduction velocity are attained a few signs (hyperreflexia, finger flexion, impaired fine 117 years after central sensory conduction. Demyelination induces conduc tion block, slowed conduction, and inability to faith fully sustain rapid trains of impulses. Slowing of central motor conduction, the most commonly seen abnormality, can be very marked and correlates to some degree with the pres ence of upper motor neuron signs and clinical defi 69 cit. Note the causes transcallosal inhibition of a contracting target late component with a latency of 45. A significantly and may reflect activation of slow conducting cortical motor neu increased excitability threshold in resting or preac ronal connections. This is usually associated with prolonged central conduction but may also oc to stimulate the motor cortex with a magnetic coil is cur as an isolated abnormality. For example, the cortical silent period, a measure of cor ticospinal inhibition, is shortened compared to nor mal subjects (Fig. Over time, the dispersion in creases and double primary peaks occur, suggesting activation of slow-conducting indirect pathways. A poral dispersion is caused by selective loss of large, similar pattern can be seen in patients with heredi 135 fast-conducting pyramidal neurons. Responses in the lower limbs typically tested at short conditioning test intervals and with show marked prolongation. In is likely that future studies will reveal useful insight tracortical inhibition in epilepsy is reduced, but this into the pathophysiological mechanisms and mode is a nonspecific finding which can be seen in many of drug action. It is unclear whether changes in cor tical excitability are due to medication or to epilepsy Stroke. Antiepileptic drugs which act on sodium chan 106 cal stimulation is often absent. The cortical threshold is ileptic drugs or medication modulating activity of 25 commonly found to be raised. The finding of an increased threshold correlates the response latency is reproducible but the stimu with the presence of brisk tendon jerks. This precludes, amongst other value of magnetic root stimulation to evaluate ra things, accurate detection of conduction block. As with other conduc However, there are at least two situations in which tion techniques used to evaluate radiculopathies (F use of the coil is advantageous. To elicit responses from muscles innervated through the cranial nerves at their intra Plexopathy. Although magnetic stimulation can be cranial-extramedullary portion, the magnetic coil used in plexopathies, the technique has not been should be positioned over the occiput ipsilateral to able to substitute for electrical stimulation. Evidence indicates that the nerves magnetic stimulation at the plexus level, supramaxi are excited close or just distal to their exit foramina. However, cording electrodes can be a problem, a concentric magnetic stimulation provides certain advantages in needle electrode is often preferred for recording the some types of plexus lesions. The coil is optimally placed 4 cm lateral to electrical stimulation of the spinal roots through a the vertex on a line joining the vertex (Cz) and the monopolar needle. An unexplained phenomenon is equina is also possible with magnetic stimulation, the greater transdiaphragmatic twitch pressure that but, like stimulation of the brachial plexus, it some occurs with magnetic rather than electrical stimula times fails to elicit reproducible, maximal re tion. Normal values for the latency to sessment of lumbosacral radiculopathies and the diaphragm using electrical stimulation in the 31 plexopathies. Transcranial mag netic stimulation of the human brain: responses in muscles sponses. Facilitation of muscle tients with high cervical cord lesions or central hy evoked responses after repetitive cortical stimulation in poventilation. Responses of single spinal tests that can be used to monitor and prevent the motoneurons to magnetic brain stimulation in healthy sub 5,20 jects and patients with multiple sclerosis. Inter that may damage the motor pathways independently hemispheric inhibition in patients with multiple sclerosis. Optimal focal transcranial magnetic activation of cerebral blood vessels, and resection of tumors and the human motor cortex: effects of coil orientation, shape of arteriovenous malformations involving the motor the induced current pulse, and stimulus intensity. Variability of cortically Electrical stimulation of the cortex with record evoked motor responses in multiple sclerosis. Magnetic trodes) is the most reliable method because it is in stimulation of the sacral roots. Altered corticospinal projections to esthetics such as ketamine or fentanyl and obtain lower limb motoneurons in subjects with cerebral palsy. Direct comparison of corticospinal volleys in produced helps overcome the effects of some anes human subjects to transcranial magnetic and electrical stimulation. Cantello R, Civardi C, Cavalli A, Varrasi C, Tarletti R, Mo lation in ischemic stroke. Clinical evalu responses to magnetic brain stimulation in patients with cen ation of conduction time measurements in central motor tral motor disorders. Electroencephalogr Clin Neurophysiol pathways using magnetic stimulation of human brain. Non-invasive magnetic netic transcranial stimulation in acute stroke: early excita stimulation of human motor cortex. Motor and somatosensory evoked potentials in cer ity by low-frequency transcranial magnetic stimulation. Evidence marker of amyotrophic lateral sclerosis as revealed by from epidural recordings. Di Lazzaro V, Oliviero A, Profice P, Insola A, Mazzone P, umn: site of stimulation and clinical application. Electroencephalogr Clin stimulation in the diagnosis of lumbosacral radiculopathy. Magnetic stimulation of the peripheral nervous up with focal magnetic transcranial stimulation. Central motor conduction: method and normal Mood improvement following daily left prefrontal repetitive results. The sensitivity of multimodal evoked cerebral cortex, an indicator of reorganization in motor potentials in multiple sclerosis. Central motor conduction time by gitudinal study of central motor conduction time following magnetic stimulation of the cortex and peripheral nerve stroke. Electroencephalogr Clin tion with a double coil: the importance of coil orientation. Magnetic and electrical Activation of the epileptic focus by transcranial magnetic transcranial brain stimulation: physiological mechanisms stimulation of the human brain. Corticomotor threshold is reduced in Activation of epileptic foci by transcranial magnetic stimula early sporadic amyotrophic lateral sclerosis. A new method for reproducible coil positioning in vealed by transcutaneous magnetic stimulation of the brain. Motor cortex plasticity during constraint brachial plexus injury: segmental demyelination and axonal induced movement therapy in stroke patients. The glu invasive differentiation of motor cortical representation of tamate antagonist riluzole suppresses intracortical facilita hand muscles by mapping of optimal current directions. Measurement of the electric arrest and counting errors with rapid-rate transcranial mag field induced into inhomogeneous volume conductors by netic stimulation. Lumbosacral nerve root evoked by transcranial magnetic stimulation during the ac stimulation comparing electrical with surface magnetic coil quisition of new fine motor skills. Pennisi G, Rapisarda G, Bella R, Calabrese V, Maertens de brain stimulation study with focal magnetic pulses. Motor recovery following stroke: a transcranial mag Oxford: Clarendon Press; 1993. Ugawa Y, Uesaka Y, Terao Y, Suzuki M, Sakai K, Hanajima R, Changes in the balance between motor cortical excitation Kanazawa I. Clinical utility of magnetic corticospinal tract and inhibition in focal, task specific dystonia. The course of cortico-hypoglossal projections in tical reorganization in patients with facial palsy. Motor cortex ment of postexcitatory inhibition in patients with focal dys excitability in patients with focal epilepsy. Low-frequency re of the late excitatory potential in the hand following mag petitive transcranial magnetic stimulation of the motor cor netic stimulation of the motor cortex. Facilitation of human first magnetic stimulation: its current role in epilepsy research. It is an overview of the most important endocrine diseases, it helps to learn the correct endocrine diagnostics and offers an effective treatment of endocrine diseases. I wish it would be a principal aid in basic medicine study for students of medicine, but also a concise endocrinology guide for physicians who exert a medical practice. The system is based on a number of glands, which secrete hormones into internal medium to act on target tissues. 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