Blockchain Papers

Gilbert H. Daniels

Appropriate therapy for amiodarone-induced thyrotoxicosis (AIT) requires a diagnostic precision that may be difficult to achieve (1). Individual cases are rarely straight forward. On June 14, 1999, a 71-yr-old man was hospitalized with a 1-week history of exertional shortness of breath, foot swelling, and feeling poorly. In 1982, he was hospitalized with congestive heart failure and atrial fibrillation, attributed to myocarditis. In 1985, atrial fibrillation recurred and responded to chronic quinidine therapy. In early 1996, quinidine was stopped, followed by paroxysmal and then persistent atrial fibrillation with congestive heart failure (ejection fraction, 20–25%). Amiodarone (200 mg/day) and coumadin were prescribed. In May 1996, his serum TSH was 0.9 μU/mL. In September 1996, he suffered an acute myocardial infarction and underwent angioplasty of stenoses of the left anterior descending and diagonal coronary arteries. He remained in normal sinus rhythm; coumadin was discontinued. Amiodarone was discontinued in 1997 but successfully restarted in March 1998 when atrial fibrillation recurred (TSH 2.3μ U/mL). Atrial fibrillation recurred and persisted, and amiodarone was discontinued in September 1998, 9 months before admission. On admission (June 1999) he was in atrial fibrillation with a ventricular response of 180. His blood pressure was 90 systolic. He had mild proptosis (left greater than right), lid retraction, neck vein distension, and a slightly enlarged (20–25 g) thyroid. Although bilateral pleural effusions were present on the chest x-ray, interstitial edema was absent. A myocardial infarction was ruled out. His ventricular response was difficult to control despite escalating doses of β-blockers. Laboratory studies are summarized in Table 1. Laboratory data Normal range: T4, 4.5–10.9 μg/dL; free T4 index, 4.5–10.9; T3 RIA, 60–180 ng/dL; TSH, 0.5–5.0 μU/mL. Free T4, 0.7–1.5 (ng/dl); TSI, 0–129%; TBII, 0–9.9%; urine iodide, 42–350 μg/L. Laboratory data Normal range: T4, 4.5–10.9 μg/dL; free T4 index, 4.5–10.9; T3 RIA, 60–180 ng/dL; TSH, 0.5–5.0 μU/mL. Free T4, 0.7–1.5 (ng/dl); TSI, 0–129%; TBII, 0–9.9%; urine iodide, 42–350 μg/L. His 20-min 99m pertechnetate uptake was low at 0.19% (normal range, 0.5–3.75). AIT was diagnosed, possibly secondary to Graves’ disease. He was begun on methimazole (10 mg, po, tid), prednisone (40 mg, po, daily), iopanoic acid (500 mg, po, bid), metoprolol (200 mg, 4 id), and heparin, coumadin, and verapamil in doses up to 120 mg, tid. At the time of discharge his heart rate was 100–120. He was discharged on June 23, 1999, on methimazole (10 mg, po, tid), prednisone (40 mg, po, daily), iopanoic acid (500 mg, po, bid), lopressor (75 mg, 4 id), verapamil (20 mg, tid), lasix (20 mg, po, qd), and coumadin. Prednisone was discontinued after June 24. On July 2, he was in atrial fibrillation with a ventricular response of 104–108; his blood pressure was 90/60. He had lost 12 lbs since his hospital admission and noted less exertional shortness of breath. Mild proptosis, left greater than right, was noted (Hürthle exophthalmometer: left, 20 mm; right, 19 mm). TSH-binding inhibitory immunoglobulin titers (TBIIs) had been completed and were weakly positive. Graves’ disease was considered likely. On July 22, his pulse was 120 (AF). His dyspnea was unchanged, but he had a single episode of angina relieved by nitroglycerine. He noted increased fatigue and heat sensitivity. Methimazole was increased to 20 mg three times daily. Iopanoic acid was continued. On August 6, his radial pulse was 116–120. His ventricular rate on electrocardiogram was 139, increased compared with his previous electrocardiogram, and worsening ST segment depression was present. Although his dyspnea was stable, edema had increased to the mid-calf. His cardiologist considered hospital admission, but careful outpatient observation was the final recommendation. On August 17, thyroidectomy was recommended, in part, based on a serum T4 of 25.9 μg/dL, although his serum T3 had fallen to 140 ng/mL. A bilateral thyroidectomy was performed on September 10 without incident or complications. Pathological examination revealed an enlarged thyroid gland (right lobe, 5 × 2.5 × 1.5 cm; left lobe, 4.5 × 2.5 × 3 cm), but no weight was recorded. The final pathology report read: “Enlarged thyroid with fibrosis and mild chronic inflammation. There is no evidence of malignancy.” We asked to have the pathological material re-assessed. An addendum was reported: “The thyroid is diffusely affected with the lesions described as follows. Approximately half of the areas contained islands of dilated thyroid follicles that were lined by attenuated follicular epithelial cells. These islands are separated by areas of collapsed thyroid follicles admixed with fibrosis and prominent vasculature. Nonspecific findings including histocytes and eosinophilic bodies were present. These changes are consistent with those described in amiodarone-associated thyrotoxicosis” (2). Subsequent hypothyroidism was treated with levothyroxine. In December 1999, he remained in atrial fibrillation, but his ventricular response was 60. Amiodarone is an iodinated benzofuran derivative that is approved for the therapy of life-threatening recurrent ventricular arrhythmias (3) but is also used to treat angina, paroxysmal supraventricular tachycardia, and atrial fibrillation and to maintain normal sinus rhythm after cardioversion for atrial fibrillation (4). Amiodarone contains 75 mg iodine per 200-mg tablet and releases∼ 10% of the iodine as free iodide daily (5). Amiodarone is highly lipophilic and is concentrated in adipose tissue, cardiac and skeletal muscle, as well as the thyroid (6). With prolonged use, amiodarone has an elimination half-life as long as 100 days (6) Amiodarone effects on thyroid function result from iodine release and intrinsic drug properties (7). Pharmacologic iodide administration to euthyroid individuals with intrinsically normal thyroid glands results in transient inhibition of thyroid hormone synthesis and release, decreased thyroidal iodide trapping, and enhanced T4 (3,3′,5,5′ tetraiodothyronine) rather than T3 (3,3′,5 triiodothyronine) production by the thyroid, so-called autoregulatory functions (8). The net effect is a slight serum TSH increase that occasionally exceeds the normal range (9, 10). With chronically higher iodide intake, the prevalence of Hashimoto’s thyroiditis increases in genetically susceptible human and animal populations (11–13). In addition, pharmacologic iodide administration may precipitate hypothyroidism in patients with Hashimoto’s thyroiditis (14). Approximately 6% of patients receiving amiodarone develop iodine-induced hypothyroidism; the prevalence is higher in areas of iodine sufficiency and lower in iodine-deficient areas (15). Hypothyroidism may develop as soon as 2 weeks and as long as 39 weeks after starting amiodarone (7). Iodide supplementation in iodine-deficient endemic goiter populations triggers epidemics of hyperthyroidism in a minority of the population, the so-called Jod-Basedow phenomenon (16). Eighty-five percent of these hyperthyroid patients have nodular goiters. Autonomous areas within the nodular thyroid gland overproduce thyroid hormone when exposed to excess substrate (iodide) but are relatively impervious to the autoregulatory effects of iodine (17). However, some hyperthyroid patients have diffuse thyroidal uptake suggestive of Graves’ disease (18). As in the Hashimoto’s thyroiditis example above, excess iodide seems to trigger or facilitate an immunological attack on the thyroid (19). Additionally, borderline iodine-deficient patients with Graves’ disease in remission commonly relapse after adding 500 μg iodide daily (20), an amount comparable with the daily iodide intake in many iodide-sufficient areas. Pharmacologic doses of iodide may also precipitate hyperthyroidism in euthyroid individuals with nodular thyroid glands in iodine-sufficient regions (21). Case reports (22) and the amiodarone experience suggest that iodine excess may also precipitate Graves’ hyperthyroidism in iodine-sufficient areas, but this conclusion is uncertain. Amiodarone also has powerful effects on thyroid hormone metabolism (7). Amiodarone inhibits the peripheral conversion of T4 to T3 and may inhibit T3 receptor binding and action (23–25). In euthyroid individuals, T4 and free T4 concentrations increase by 42% due to decreased T4 clearance (7). Reverse T3 (3,3′5′ triiodothyronine) concentration rises by 172%. Efficacy and toxicity of amiodarone may be proportional to reverse T3 concentration (26). Serum T3 concentrations initially decline by 20–25%, subsequently an average 16% below baseline, but may be frankly low in some patients (7, 27). Serum TSH rises, occasionally out of the normal range, but with chronic administration generally remains in the normal to high normal range. It is uncertain whether TSH elevation in the 10–20 μU/mL range represents peripheral subclinical hypothyroidism or is a pituitary specific effect of amiodarone. Some authors accept subnormal serum TSH concentrations with normal T3 concentrations as compatible with the euthyroid state. However, I interpret these findings as evidence of amiodarone-induced subclinical hyperthyroidism. The 24-h radioiodine uptake decreases to low levels (<4%) in euthyroid individuals taking amiodarone (28). This is to be expected because 15 mg inorganic iodide daily, after a loading dose of 30 mg, decreases mean 24-h radioiodine uptake to less than 2% after 12 days (10). When added to antithyroid drugs, amiodarone facilitates the treatment of severe hyperthyroidism (29), by inhibiting T4 to T3 conversion, thyroid hormone release, and possibly T3 receptor binding and action. Unfortunately, 3% of patients exposed to amiodarone develop hyperthyroidism (30), with a higher prevalence in iodine-deficient regions (15). AIT may have a male predominance (31), reflecting the higher cardiovascular disease prevalence in men. Hyperthyroidism may occur 4 months to 3 yr after initiating therapy or after drug withdrawal (28) and is not related to cumulative drug dosage (7). Knowledge of three distinct types of AIT is required to understand this case (1, 30). Amiodarone-induced toxic nodular goiter, a form of iodine-induced thyrotoxicosis, was described in Europe where large nodular goiters are more prevalent than in the United States. Despite antithyroid drug therapy, some patients demonstrated refractory hyperthyroidism (28). The addition of perchlorate to antithyroid drugs decreased the time to euthyroidism in uncontrolled trials (32, 33). Perchlorate inhibits the thyroidal iodide trap and permits the back diffusion of free (nonorganified) iodide from the thyroid gland, so-called perchlorate “discharge” (34). Doses of perchlorate higher than 1.5 g per day may cause aplastic anemia, whereas doses of 1 g per day used in these studies are apparently safe. Emergency thyroidectomy was required in some patients, a courageous approach in these critically ill patients. The mechanism of refractory hyperthyroidism is uncertain. Thyroidal iodine stores are much higher in hyperthyroid compared with euthyroid patients receiving amiodarone (34A ). The expanded iodide pool is invoked to explain refractory hyperthyroidism, because antithyroid drugs prevent thyroid hormone synthesis but not hormone release. However, pharmacologic iodide inhibits thyroid hormone release from autonomous nodular thyroid glands when new hormone production is blocked by antithyroid drugs (35). Although amiodarone was often discontinued at the onset of thyrotoxicosis, a continued high iodide environment persisted due to its long half-life. A second group of patients treated with amiodarone developed Graves’ hyperthyroidism characterized by diffuse thyroid enlargement, a prolonged course, and the presence of thyroid autoantibodies (30). T-cell populations specific for Graves’ disease have been demonstated as well (36). Most authors infer that “latent” Graves’ disease was made overt by an iodine-stimulated immune attack on the thyroid. Proof of this assumption requires specific markers for genetic Graves’ disease. Toxic nodular goiter and Graves’ disease comprise Type I AIT, hyperthyroidism in patients with preexisting or “latent” thyroid disease. Type II AIT is a form of “destructive thyroiditis” (37), which develops in patients with baseline normal thyroid glands. Hyperthyroidism is due to release of stored thyroid hormone. The thyroid is usually nontender, but pain may occur. The sedimentation rate is generally within normal limits. Amiodarone, its metabolites, and intrathyroidal iodide have all been implicated in cellular toxicity, however, amiodarone is also toxic to cells that do not incorporate iodine (38, 39). Hyperthyroidism lasts for 1–3 months, until thyroid hormone stores are depleted, but resolves more quickly after glucocorticoid therapy. Transient and rarely permanent hypothyroidism may ensue, but the prevalence is uncertain (37). Subacute lymphocytic thyroiditis (“silent thyroiditis”) and subacute granulomatous thyroiditis (“painful subacute thyroiditis”, de Quervain’s thyroiditis) are worthy of study as other examples of destructive thyroiditis that follow a similar course (40). Hyperthyroidism with a nil 24-h radioiodine uptake is often followed by hypothyroidism. Subacute lymphocytic thyroiditis is an autoimmune disorder with a predilection for the postpartum period (postpartum thyroiditis). Thyroid autoantibodies are generally present, diffuse lymphocytic infiltration is found on biopsy, and permanent hypothyroidism occurs in a significant minority of patients. Subacute granulomatous thyroiditis is characterized by intense thyroid pain, a very high sedimentation rate, severe thyroid follicle disruption, and multinucleate giant cells. Permanent hypothyroidism is rare (41). Amiodarone-induced destructive thyroiditis seems not to be an autoimmune disorder because antithyroid antibodies are generally absent. Hypothyroidism, when it occurs, is usually transient. Although limited numbers of such thyroids have been examined, follicular disruption, zones of fibrosis, and mild inflammatory changes are usually present, but dense lymphocytic infiltration and multinucleated giant cells are usually absent (2, 38). Type II AIT was diagnosed on histological examination of our patient’s thyroid gland; hyperplastic changes of Graves’ disease were absent. Type II is the most common variety of AIT in our clinic. Type I AIT is more common in Europe; the geographic differences likely reflect the higher iodine intake in the United States. Many patients with AIT II demonstrate minimal transient hyperthyroidism, diagnosed by fully suppressed TSH alone (personal observation). Permanent hypothyroidism is rare, even when amiodarone is continued (personal observation). Some episodes of Type II AIT may represent subacute lymphocytic thyroiditis precipitated by amiodarone (42). Occasional patients develop repeated cycles of hypothyroidism, followed by hyperthyroidism (43) Appropriate therapy of AIT requires a clear distinction between Type I and Type II AIT. How can this be accomplished (Table 2)? AIT-differential diagnosis and therapy Based on European experience (see text). AIT-differential diagnosis and therapy Based on European experience (see text). Given the high iodine content of amiodarone, a nil 24-h radioiodine uptake might be expected in all patients taking this drug. However, detectable or normal 24-h radioiodine uptake is found in 80% of patients with amiodarone-associated hypothyroidism in Europe (44). Furthermore, in Europe type I AIT is accompanied by low, normal, or high 24-h radioiodine uptake, a possible consequence of baseline borderline low iodide intake (45, 46). The radioiodine uptake is near zero in all patients with Type II AIT. A normal or high radioiodine uptake effectively excludes Type II AIT, however, a nil uptake cannot distinguish between Type I or Type II. All patients with Type I and Type II AIT seen in our Thyroid Clinic have a near nil uptake. Systemic radiodine studies of Type I AIT are needed in the United States. If confirmed, our observations suggest that 24-h radioiodine uptakes are superfluous in AIT in the United States. A low (0.19%) 20-min 99m pertechnetate uptake was measured in our patient. In contrast to the 24-h radioiodine uptake, this test can be performed while receiving antithyroid drugs, allowing therapy to begin immediately. Thyroid ultrasonography may allow us to discriminate between Type I and Type II AIT. Thyroid nodules are easily diagnosed by ultrasound and in their toxic nodular goiter is effectively However, destructive thyroiditis may with a nodular thyroid Thyroid ultrasound with can thyroid blood Type I AIT with Graves’ disease has normal or increased blood whereas Type II AIT a with decreased In patients with Type I from Type II AIT Many studies on thyroid nodules but not When ultrasonography in patients with AIT, thyroid gland studies be Thyroid as the but experience in iodine-sufficient areas such as the United be before it can be fully other studies antibodies are present in at of patients with Graves’ hyperthyroidism and are generally absent in AIT II. antibodies and are considered specific for Graves’ disease. When thyroid autoantibodies are no can be were found in our Graves’ disease. Serum is a that and T-cell is in Type II AIT and normal to at most slightly in Type in Type II AIT are and in Type I AIT I are However, have seen low concentrations in patients with Type II AIT, reflecting of was not measured in our patient. T3 is a of Graves’ hyperthyroidism. The of serum T3 to T4 concentration is a that can be in Graves’ hyperthyroidism from destructive when radioiodine uptakes cannot be In of patients with Graves’ hyperthyroidism had a T3 to T4 greater than whereas of those with “destructive thyroiditis” and 6% of euthyroid individuals were in this range This has not been in AIT. A low is to be because amiodarone inhibits T4 to T3 conversion, however, a high AIT patients receiving amiodarone have a mean T3 to T4 of whereas AIT patients have a mean of 12 (7). of I and II AIT have not been patient’s T3 to T4 of the diagnosis of Graves’ hyperthyroidism. Type I AIT with Graves’ disease and Type II AIT present with a normal to diffusely enlarged thyroid. or a thyroid Graves’ disease. However, pharmacologic doses of iodide mg/day) thyroidal blood in Graves’ disease and a may within days of iodide administration (personal In our thyroid was to Graves’ hyperthyroidism was diagnosed based on findings and TBII, although this to be We not an ultrasound or in our studies that in might have been The of is uncertain because pathological changes in Type II AIT are often Table 2 the therapy of I and II AIT. of toxic nodular goiter methimazole or perchlorate may be With prolonged hyperthyroidism, or continued amiodarone be considered The of radioiodine therapy in patients with normal or high 24-h radioiodine uptake is uncertain. Type I AIT due to Graves’ disease is treated in a similar 12 patients with Type I AIT (10 with toxic nodular goiters and 2 with Graves’ were treated with a of methimazole and perchlorate All normal free T3 concentrations by 4 weeks A diagnosis of Graves’ hyperthyroidism was made in our patient. Methimazole was and iopanoic acid was added to hormone release and inhibit T4 to T3 conversion, functions also by amiodarone. The 24-h urine iodide was perchlorate was not It is to amiodarone for weeks after starting antithyroid drugs in Type I AIT patients, but this is of Although amiodarone serum half-life is the of T4 to T3 inhibition after drug is Hyperthyroidism in Type II AIT is but some patients critically ill with cardiovascular therapy the hyperthyroidism of Type II AIT and may be treated 12 Type II AIT patients with prednisone (40 mg/day) for with a 3 Free T3 and after an average of and In our many patients euthyroid after weeks of However, hyperthyroidism then prednisone be A response to glucocorticoid therapy is an in difficult a diagnosis seems therapy at Type I and Type II AIT including when from and antibodies often days to weeks to was ill on admission. Amiodarone had been discontinued. Although Graves’ disease was the diagnosis based on his methimazole and iopanoic were all prescribed. When the results prednisone was discontinued. The was attributed to iopanoic acid but may have been due to prednisone therapy. In a course of prednisone therapy have been and might have been A for was made when the was When for the was but the and his a The diagnosis was in and therapy with antithyroid drugs might have been In more with a diagnostic approach might have been amiodarone be discontinued in all cases of When the cardiac amiodarone in AIT but therapy for weeks after starting antithyroid Many authors amiodarone in Type II AIT, however, this is the diagnosis is cases of Type II are had been amiodarone for 9 months, Type II thyroid before starting The drug is usually begun in an or by without for thyroid disease. However, a approach be to a history of autoimmune thyroid disease and serum TSH and antithyroid These studies might be in amiodarone-associated hypothyroidism and possibly allow of “latent” Graves’ disease. Thyroid ultrasound patients with nodular thyroid glands at for AIT but its might be more in Europe where AIT I is more AIT to our Although clear are diagnosis and therapy for an may be studies in the United and in AIT are or 99m pertechnetate uptake is but may be superfluous in the United States. Although in some this case the that with AIT.

Katherine A. Kovacs, Y. Miu Lam, Joseph L. Pater

Introduction Bilateral massive adrenal hemorrhage (BMAH) is a rare catastrophic condition that manifests with acute adrenal insufficiency due to irreversible destruction of the adrenal cortices (19–20). It is uniformly fatal if glucocorticoid treatment is not initiated shortly after onset of the crisis but can be very difficult to diagnose prospectively because of its nonspecific symptoms. Numerous case reports have identified plausible risk factors for the development of this condition, and animal studies lend support to some of them (1, 10, 17, 19, 20, 22, 28). These include advanced age, serious underlying medical illness (such as, congestive heart failure and sepsis), postoperative state (especially cardiovascular or orthopedic surgery, suggested to be due to the common practice of using anticoagulants), significant hypotension, spontaneous or iatrogenic coagulopathies, certain prothrombotic disorders, trauma, adrenocorticotropin (ACTH) administration, vasculitis, adrenal venography, and pheochromocytoma. Anticoagulant use (mainly heparin) has been incriminated in most recent case reports. With heparin use becoming more common, it is useful to identify those at greatest risk for this catastrophic side effect. Since there have been no analytical epidemiologic studies, this case-control study was designed to study the strength of the association between most of these putative risk factors and BMAH. Other exploratory factors were studied, including hypertension, diabetes, cardiovascular disease, atrial fibrillation, radiologic procedures, and smoking. By identifying the profile of a high-risk patient, it becomes feasible to initiate lifesaving glucocorticoid treatment more promptly while awaiting confirmation of BMAH. Methods Design/source of cases and controls This was a multicenter, hospital-based, case-control study comprising case and control patients from acute care hospitals in Kingston (Kingston General Hospital and Hotel Dieu Hospital), Ottawa (Ottawa Civic Hospital and Ottawa General Hospital), Toronto (Sunnybrook Health Science Centre, The Toronto Hospital, and St. Michael’s Hospital), and London (St. Joseph’s Health Centre, LHSC-Victoria Campus, and LHSC-University Campus), Ontario, Canada. All are teaching hospitals providing secondary and tertiary care, with similar record-keeping practices and approaches to patient care. Admission requires a detailed admission note outlining history of the present illness, review of systems, medications, past medical history, and physical examination. We chose to do a hospital-based study not only for convenience and thrift, but also due to the fact that almost all cases of BMAH occur during or shortly after hospitalization for another condition. The critical nature of the condition would not allow for cases in the population to survive undiagnosed for very long. Furthermore, once diagnosed, the condition requires admission for close observation and treatment. In using hospital controls, one can try to answer the question, “what is different about the baseline characteristics and/or hospital exposures in those who eventually become BMAH cases compared with those who do not?” It is reasonable to assume that control patients admitted to the same hospital as the cases belong to the same study base (24). As opposed to using non-hospital controls, one could be better assured that there would be similar quantity and quality of exposure data available for the controls (such as, list of medical conditions and platelet counts). Drawing control patients from all other possible diagnostic admission categories helped eliminate bias should 1 control disease be linked to 1 or more of the study exposures (24). Definition of cases and controls Case definition: The inclusion criteria are listed below (patient must fit all of the criteria): 1) Appearance consistent with bilateral adrenal hemorrhage by radiologic studies (ultrasound, computerized tomography [CT], or magnetic resonance imaging [MRI]), surgery, or autopsy 2) Adrenal insufficiency proven by biochemical criteria (low serum cortisol and/or flat response on rapid ACTH stimulation test) or death 3) Age ≥ 18 years 4) Availability of medical record 5) Admission during the time period 1989–1998 The exclusion criteria are listed below (patient excluded if 1 or more of the following applies): 1) Bilateral adrenal hemorrhage demonstrated to be associated with other bilateral primary adrenal pathology such as tuberculosis, histoplasmosis, amyloid, or neoplasia 2) Adrenal hemorrhage occurring in association with Gram-negative septicemia (Waterhouse-Friderichsen syndrome) 3) Adrenal hemorrhage secondary to adrenal rupture during thoracoabdominal trauma Cases were identified through a computerized search at the Medical Records Departments (1989 and beyond) in each hospital for those with the diagnosis “adrenal hemorrhage.” Since “adrenal hemorrhage” is coded under the same ICD code as undifferentiated adrenal insufficiency, the latter patients first had to be excluded by examination of the medical record. Cases were required to fit the “case definition” defined above. Based on power considerations, 4 control patients per case were randomly chosen from computerized lists of all hospital admissions. There is usually little marginal benefit to including more than this (25). Each control was individually matched to his or her respective case by hospital, year of admission (within 1 year), and age (within 1 year). This matching was felt to be important to avoid bias related to varying quality of record-keeping and changing medical practice over time (such as, anticoagulant use) and between hospitals. It is already known from descriptive studies that most cases of BMAH occur in those past middle age. Because age was not of scientific interest and was a potentially strong confounder (25), it was 1 of the matching criteria for complete control of its potential confounding, possibly improving the efficiency in the estimation of the effect of other exposures (25). Potential controls would be excluded if they had a history of adrenal hemorrhage, bilateral primary adrenal pathology, or adrenalectomy. When there were multiple admissions during the same year, the admission closest in time to that of the case was chosen for data extraction. Data collection Ethics approval was received in each hospital before proceeding with data gathering by way of a retrospective chart review. All volumes of the hospital record for each patient were reviewed to avoid missing pertinent details in the past medical history. An identical database form was filled out for all subjects and the information was gathered by the unblinded principal investigator with the same attention to detail for cases and controls. Data collected for the defined exposure period included demographics, preadmission and admission medications, past and active medical problems, past and recent surgeries or procedures, history of the present illness, course in hospital, and laboratory data. Note that hypertension referred to a prior history of hypertension (BP > 140/90) that may be controlled with medication. Data from the database form were then entered by the same investigator into a computerized data set. “Exposure period” was defined as the 30 days preceding the index hospital admission until the onset of BMAH in cases and until the end of admission in controls. The “latency period” was defined as the duration in days post index admission until the first clear manifestations attributable to BMAH in cases (not until death in some, when it was confirmed at autopsy). Specific details collected and coded in the data set are listed in Table 1.TABLE 1: Data collected and coded for the exposure periodMinor amounts of heparin used in flushes, often not reliably recorded in the medical record, were not noted. The checklist was proofed several times to ensure no misclassifications were made. In the rare situation where incomplete information was sent along from the peripheral hospital upon transfer to the teaching hospital, the pertinent Medical Records Departments were contacted to supply the missing details. Statistical analysis Preliminary analysis of the data was by univariate logistic regression (8, 23). Parameters were estimated by the maximum-likelihood method. A value of p ≤ 0.05 was considered statistically significant and 95% confidence intervals were derived for the odds ratios. Stem and leaf plots were examined for the continuous variables (duration of hospitalization, duration of coumadin, and duration of heparin) without attention to case-control status. Because they were highly skewed in their distributions, they were converted into categorical variables according to quantiles of exposure, and univariate logistic regression was used on these design variables to analyze and derive odds ratios and regression coefficients. The results were scrutinized, including graphically to assess departures from linearity in the logit, and categories were simplified accordingly for further use in the multivariate model. For all variables, both unmatched and matched univariate analyses were performed for comparison. Furthermore, to show that the matching variables were conditionally independent of case-control status given the risk factors (3), average ages and years of admission were compared for cases and controls according to levels of the risk factors appearing to have greatest importance. An unmatched analysis was then deemed appropriate for the multivariate analysis (3) to improve the study’s power and make it more feasible for the investigator. Any bias that may have resulted from using the unmatched analysis would tend to be in the direction of conservatism for estimates of odds ratios. Multivariate modeling by forward stepwise unconditional logistic regression (8, 23) proceeded with those variables felt to be important by previous animal studies and for those of the additional variables that had p < 0.20. Parameters were estimated by the maximum-likelihood method and 95% confidence intervals were derived for the adjusted odds ratios. Once the final model was formed, each excluded variable was individually added into the and the performed and examined to ensure that the variable should be The final model was on for all the variables in the final in to age, were for All analyses were performed by There were cases of BMAH identified that fit the “case definition” as defined cases were from Kingston General Hospital, 1 from Hotel Dieu Hospital, from Ottawa Civic Hospital, from Ottawa General Hospital, 4 from Health Science Centre, from The Toronto Hospital, from St. Michael’s Hospital, from St. Joseph’s Health Centre, from LHSC-Victoria Campus, and from LHSC-University for exclusion of 4 other potential cases included with and with hemorrhage into bilateral adrenal There were no present to potential controls. The cases and the controls on age, hospital, and year of were for complete data collection and The ages for both cases and controls from to with a of The period until clear of BMAH in the cases from to days post admission with a of days patient skewed the results by a admission before cases not have clear until when BMAH was demonstrated at In patients had the of BMAH in but BMAH was already demonstrated in of cases on the of the index admission with BMAH it at and following a recent hospitalization for another As the medical record was for each admissions that the preceding 30 days of the index for cases and controls, were available for data extraction. The duration of hospitalization in the exposure period defined from to days in the cases and 1 to days in the controls Table the results of the univariate analysis the between potential risk factors and development of BMAH. The factors that to be associated with BMAH included hospital heparin and The estimated odds ratios were similar for the matched and unmatched Furthermore, of average ages and years of admission for cases and controls according to levels of the most important exposure variables were similar not of univariate analysis and matched variable was in its 4 categories as it was in the was in its categories as the was in a For was also in the logit, the first categories were as the odds ratios were both close to and further analysis of the The categories for to be close to in the graphically and the of was also highly analyses in multivariate analyses as both categorical and continuous the BMAH cases who were to received heparin or received or heparin and received both heparin and or from exposure to heparin was more important in risk of BMAH than other of or There were only subjects in there was exposure to other and in 1 in 1 and in 1 In all of there was additional exposure to heparin and the were to assess independent to platelet included and a patients with or The to BMAH was in the direction to that as there were cases of BMAH in those to platelet The same can be for diabetes, as there were no cases of BMAH in patients with The variables and were excluded from further analysis because of and the of a hypertension and disease association to was In case these were for some other they were included in further multivariate unconditional logistic regression proceeded with those variables in Table that had p < and and/or were felt to be important by previous animal The unconditional was chosen over the matched analysis because the latter was due to as a of the were entered by forward stepwise regression and were for on adjusted coefficients. Table the adjusted odds ratios and 95% confidence intervals for those variables that in the of multivariate analysis logistic of the association between potential risk factors and of to the univariate heparin and were to be associated with risk of BMAH after for the effect of other The for each of these variables in the cases are in Table There not to be significant between the variables in the final model or with age. a risk of BMAH. to heparin for and those for over were about and more to BMAH than those who had than 4 days or no the risk of BMAH radiologic was associated with it as continuous or by categorical design variables, was no of BMAH as it was with heparin and and was on during the stepwise duration of hospitalization its ensure that there was no effect of the excluded variables, they were added in individually to the final model and not to have significant on the estimated of and in analysis suggested that disease was highly development of and hypertension, and diabetes, also may have been of post of variables for other the of disease but not the odds and also not the variables chosen in the final model Table state of adrenal insufficiency becomes once of the adrenal has been The most common is disease, in destruction the other bilateral adrenal is usually associated with a more acute it is to occur in “adrenal of the and in Gram-negative septicemia (Waterhouse-Friderichsen syndrome) it also in the of these conditions and has been bilateral massive adrenal of the adrenal by hemorrhage than the Once a and other radiologic studies have it possible to diagnose BMAH in its course due to for other by BMAH BMAH with nonspecific and it difficult to diagnose cases from the that had case to the of these In the patients present with a of in the or or manifestations (such as, or laboratory include a significant in the of with the of the adrenal and of adrenal insufficiency that often several days to can occur a or after days of but nonspecific those who survive after of glucocorticoid complete and irreversible of adrenal associated with adrenal is almost In autopsy the of adrenal hemorrhage from to of those in autopsy a of of BMAH. bilateral adrenal hemorrhage may more to the of patients than The diagnosis of BMAH can be confirmed in the course by of hemorrhage or and biochemical of adrenal insufficiency (low serum cortisol levels or response on rapid ACTH stimulation both to be often in with the the in and show a in characteristics are with and studies model for development of the adrenal is to adrenal hemorrhage The supply a of through that into a in the This highly into in the by at the a potential the adrenal is only by a further to in adrenal such as that by during or in could the and in hemorrhage into the In the are from the supply and would be to be most to from when the examination in patients following of significant this to be (1, 28). then through the at the time of when is The of the adrenal that are known to platelet and The adrenal is to the of in the and this during times of This could in and of the to as above. As a the can and their into the further In the in the may make it to development of platelet in of and under the of that adrenal hemorrhage and/or can be by and The from massive to or with little or no The usually the adrenal and the is by of and into the and are at the of and there are of secondary time and a in the to between and both and anticoagulant conditions may adrenal hemorrhage by ACTH from the or ACTH in the adrenal in to of 20, 28). show that stimulation with ACTH results in and hemorrhage of the adrenal similar to in from to are to hemorrhage into the adrenal with heparin or the risk of adrenal hemorrhage to in by of through the risk factors defined by case In and other case reports of BMAH (1, 10, 17, putative risk factors identified included advanced age, serious underlying medical illness or congestive heart and postoperative state (especially cardiovascular or orthopedic surgery, suggested to be due to the common practice of using anticoagulants), significant hypotension, spontaneous or iatrogenic time or and anticoagulant certain prothrombotic and and trauma, ACTH administration, with adrenal venography, and with In the case of and disease, the to BMAH could be through the use of of the recent cases of BMAH with heparin or another form of at the time of adrenal hemorrhage spontaneous was not and studies were usually not the is As its is there are multiple reports of BMAH occurring in the of In this condition, are that and in the of usually in and a risk of The state is felt to be due to of and the with in the usually are not and and may be the in BMAH. can be by or of of but to be more common after of or The risk of after of heparin but may for about a after exposure As the risk factors for BMAH by descriptive studies have a by about the and and from animal It is usually possible to from the record the time of onset of adrenal by of acute (such as, or that is a days by a in the and/or radiologic of adrenal hemorrhage to the The and usually would not have been prospectively as due to BMAH because of the nonspecific nature of the and the of the condition. the of the most appropriate way to the strength of the association between the putative risk factors and BMAH was by of a case-control factors at that could be linked through or included hypertension, diabetes, cardiovascular disease, atrial fibrillation, radiologic and smoking. study The case-control study demonstrated that the of and exposure to heparin are and associated with development of BMAH in These are in with suggested by descriptive studies and animal The of in and very odds ratios for each of these variables a There not to be significant these variables, the may have a By plausible risk factors and in of the the nature of the multivariate analysis the out of from independent risk factors and variables in the duration of hospitalization not in the multivariate that there were no other exposures associated with hospitalization that were not As multiple variables were with one another important in the univariate their in the multivariate of this include and other with heparin and with heparin exposure and hypotension, highly important in the animal studies and in the univariate was no significant after for other of the detailed case suggested that the response in and it is also a to in It may be that was by only because of these to the of disease, hypertension and diabetes, was associated with development of BMAH. The only plausible that is that of these patients were and other may development of such as by in in the case of post of these variables into the multivariate analysis not have on the odds ratios. from the epidemiologic it can be that these were a of bias by the use of hospital controls because patients are more to have other medical conditions that them to admitted (24). In other a association is between these and case-control status because of the of admission to hospital for and exposure characteristics in the This has been demonstrated For the situation where the case disease has a very of hospitalization as compared with the control disease, as is the case with exposure or characteristics can be associated with the control In effect in more it that heparin use must days to risk of BMAH. This is with about duration of heparin exposure for development of in most this association was with the included in the model. the be to for all of the association It may be that the anticoagulant heparin the side effect during It that of heparin was not as important as and case exposures included both and the was to a of risk between An is that the as a of of the association of heparin and BMAH this has a case of acute bilateral adrenal in a patient with confirmed due to This that anticoagulant effect is not a for the of bilateral adrenal and cases of adrenal may have been by this As the adrenal on the of in this confirmed primary adrenal insufficiency, this the in a case-control study on adrenal The greatest to this study is the may have resulted in or It also resulted in confidence for the odds ratios. Furthermore, multiple were the risk of for the risk factors heparin exposure, and sepsis), the results were to be of a This study the about a retrospective but were to similar quality of data. The fact that all of the data gathering was by the same investigator and at teaching of the about bias in between and between study Furthermore, the medical from all was of similar quality and of similar attention to detail for data gathering for cases and controls, could that was in the It was not feasible in this study to randomly to to this Furthermore, has been as a possible for the association with disease and possibly and hypertension, could be as as in the in this the of the other variables examined not conditions or exposures risk of hospitalization, and were of exposures for the most Because this was a hospital-based the odds ratios be to the population in This may not be very important most cases of BMAH in bias may have resulted from patients of BMAH and not autopsy of In this were to the effect of on risk of BMAH because it was not in a is usually by the and of the examined and of hypotension, and there are no with ACTH is the of greatest of (duration of was examined and not to be important while the of the other variables were Case reports and case have identified putative risk factors for the development of bilateral massive adrenal hemorrhage (BMAH) in The and of the adrenal allow development of a model to fit the these risk these risk factors were not using analytical epidemiologic A case-control study was using of cases and controls from multiple teaching hospitals in Ontario, Canada. The results of multivariate logistic regression that 95% confidence intervals p < heparin exposure of or days > p < and p were most and associated with development of BMAH. association included radiologic p or duration of hospitalization were independent risk disease and possibly and hypertension to be for risk of this may be a of bias by using hospital controls as the effect was not by a effect of a of the high-risk patient should include a patient who has been with heparin or days and has had (not by heparin) during the course of the or or or disorders, should not to with lifesaving while awaiting results of The of the Medical Records at the following hospitals was Kingston General Hospital, Hotel Dieu Hospital Ottawa Civic Hospital, Ottawa General Hospital, Health Science The Toronto Hospital, St. Michael’s Hospital St. Joseph’s Health LHSC-Victoria and LHSC-University

Faith T. Campbell

Invasive exotic or alien species cause enormous damage to the natural environment. Indeed, 49% of all imperiled species in the United States are threatened in part by alien species (Wilcove et al. 1998). The toll may be even higher: Additional plant species have been harmed by alien species but have not yet been designated as imperiled (e.g., the American chestnut, Fraser fir, American elm, flowering dogwood). Losses in the agriculture, forestry, and other sectors of the US economy and control costs associated with invasive alien species total $137 billion annually. Approximately $80 billion of that amount is associated with alien plants, insects, and disease pathogens subject to phytosanitary regulations (Pimentel et al. 1999), which are the subject of this article. Because attempts to eradicate established invasive alien species have met with little success, scientists recommend that governments put the highest priority on preventing introduction of such species. This article examines US policies governing the structure and implementation of prevention programs aimed at alien plants and those insects and disease pathogens considered to be plant pests. Whereas many invasive plants have been imported deliberately, insects and fungal pathogens usually hitch a ride with imported cargo. As Chris Bright noted during a presentation at the Worldwatch Institute on 8 October 1998, international trade “leaks” exotic species. Many others also have predicted that severe damage would follow introduction of insects and fungal pathogens from forests in Europe, Mexico, Asia, or other regions that trade heavily with the United States (Forest Service 1991, 1998, Campbell and Schlarbaum 1994, Niemela and Mattson 1996, APHIS 1998c, 1998d). Some types of imports are particularly likely to transport hitchhikers. Live plants imported for horticultural use, for example, have been called a “uniquely efficient pest introduction pathway” (Regelbrugge 1998). Between 45% and 86% of various categories of pests introduced to California in recent decades came in on horticultural imports (OTA 1993). Among forest pests that were most likely introduced on imported live plants are dogwood anthracnose (Discula destructiva Redlin) (Campbell and Schlarbaum1994), Melampsora fungus on larch and poplar, and pine pitch canker (Fusarium subglutinans f. sp. pini) on Monterrey pine (Pinus radiata) (Haleamau 1998). Like live plants, “green” wood—raw or unprocessed wood—is a high-risk import. Crates, pallets, spools for cable, and other packaging are often made from low-quality, pest-damaged wood. When not in use, these items are usually piled in the open air, thus facilitating pests' establishment (APHIS 1998d). As US imports have grown—by more than 50% just since 1990 (GAO 1997)—so too has the quantity of solid wood packaging in which they are shipped, thus presenting more opportunities for exotic species to travel to North America. Another wood pathway for pests is through imported logs, unprocessed lumber, and wood chips. Those US imports once came almost exclusively from Canada, which is a low-risk source because forests in these two nations are contiguous. However, beginning in the 1990s, US wood processors have imported increasing quantities of green wood from geographically separate areas that harbor pests inimical to US forests. Although Canada still supplies more than 70% of US wood imports, Mexico supplies more than 3%, China more than 2%, Chile nearly 2%, and New Zealand about 0.6%; the remainder comes from tropical countries. These imports are expected to increase in the future now that a court injunction limiting imports has been lifted. Some knowledgeable observers, including scientists working with horticultural and forest pests (La Fage and Williams 1979, Niemela and Mattson 1996), as well as the National Plant Board (National Plant Board 1999), have concluded that the phytosanitary safeguards set out by the US Department of Agriculture (USDA) are inadequate to prevent introductions at current trade levels. According to the National Plant Board, “Recent breaches of the APHIS-PPQ [Animal and Plant Health Inspection Service, Plant Protection and Quarantine] safeguarding system that led to entry of dangerous invasive plant pests in the U.S. have raised concerns that current organizational policies and procedures are inadequate to execute Agency functions…. Clearly, the current safeguarding system cannot meet the changes thrust upon it by rapidly transforming global circumstances” (National Plant Board 1999, p. 40). Yet with imports rising, the danger of alien organisms reaching America is increasing, and phytosanitary controls would have to be tightened commensurately to ensure the same level of protection. APHIS has begun to strengthen its regulations for wood packing (APHIS 1998e, 1999a) and lumber from Mexico (APHIS 1999b); both of these rulemakings are still in process. Nonetheless, it has fought in court against scientists who argue that regulations should be strengthened also for logs and lumber from New Zealand and Chile; it has rejected similar pleas from the Oregon Department of Agriculture for regulation strengthening. Moreover, the USDA has relaxed controls for certain horticultural imports. To be “science based,” a phytosanitary program should reflect the serious threat posed by exotic species to agriculture, horticulture, and forestry, and to the myriad natural ecosystems and biotic communities found from Alaska to Florida and from Maine to Hawaii. It should also reflect practical realities. First, ecologists realize that their knowledge of the millions of insects, fungi, and disease pathogens living in the habitats of US trading partners is limited. Indeed, probably less than 5% of the Earth's fungi have even been named by science; fewer still have been studied enough to determine their ecological role. Scientists know more about exotic insects and plants, but even among these groups are tens of thousands of species that have not been well studied. Given these large information gaps, it may well be impossible for scientists to predict which foreign species might cause devastating damage if introduced to a new ecosystem. Second, biological invasions are usually irreversible, given current scientific knowledge, limited funding, and burgeoning pest problems. In other words, it is far easier—and less expensive—to prevent an invasion than to combat one. It follows that a sound phytosanitary program should seek to bar entry to all exotic organisms except those that have been evaluated and determined to be very unlikely to be invasive. Two slogans express this goal: “If in doubt, keep it out” and “Guilty until proven innocent.” To put this objective into practice, the responsible government agency—USDA's APHIS—could combine technological treatments with stringent regulatory requirements that importers act to minimize the likelihood that living, unapproved insects, fungal pathogens, viruses, or weeds will hitchhike to this country on imported goods. This approach obviates several problems. First, it reduces the burden on port inspectors, who would otherwise have to search millions of shipments for tiny, even microscopic, organisms. Second, it reduces the risk that an erroneous assessment of the potential impacts of an organism will result in a decision to allow entry of a species that turns out to be highly damaging. An appropriately serious phytosanitary program should also seek out and utilize all available and emerging information on pests, pathways, and exclusion or mitigation technologies, and rapidly adapt regulations to reflect that new information. However, USDA officials have rejected the “If in doubt, keep it out” policy (Isi Siddiqui [US Deputy Under Secretary of Agriculture], personal communication, 1998), finding it incompatible with trade promotion; APHIS is now trying to “balance” protection and trade promotion. Thus, rising trade volume is not the sole reason that the threat of introduction of harmful bioinvaders is growing. Although USDA policy that proves ineffective can be changed through domestic political channels, pro-trade policies now have the force of international law through US adherence to global trade rules enforced by the World Trade Organization (WTO). Thus, if these policies do result in too high a risk of introduction of pests, international treaties adopted by 135 countries must be changed—a daunting challenge. Phytosanitary measures are no longer adopted unilaterally in response to a country's perception of risk. Phytosanitary safeguards are now subject to international standards and review. In 1994 more than 100 countries concluded the Uruguay Round of the General Agreement on Tariffs and Trade by forming the World Trade Organization, which sets the rules for international trade. To prevent member nations from using phytosanitary safeguards to protect domestic agricultural producers from foreign competition, the signatories simultaneously adopted the Agreement on the Application of Sanitary and Phytosanitary Measures (SPS agreement; see www.wto.org). In November 1997, the 46-year-old International Plant Protection Convention (IPPC), which was formed to control plant pests and diseases and prevent their spread across national borders, was revised to bring it into compliance with the SPS agreement. (The IPPC revisions have not yet come into force, however, because too few nations have ratified the changes.) Under the SPS agreement and revised IPPC, countries may impose trade restrictions to the extent necessary to protect human, animal, or plant health—including wild fauna and flora—as long as they apply the same standards for protection across the board, domestically as well as internationally. Phytosanitary measures must be based on scientific principles and supported by scientific evidence, as documented in a risk assessment. When scientific information is insufficient to meet the requirements for risk assessment laid out in the SPS agreement, a country may adopt a provisional regulation while seeking more information. Taking into account available scientific evidence, the risk assessment should address processing or production methods; inspection and sampling methods; prevalence of the target organism—or the existence of pest- or disease-free areas—in the exporting and importing countries; ecological and environmental conditions; and quarantine or treatment measures that could control any pest that is introduced. A risk assessment should also take into consideration the potential damages from introduction of a pest or disease (such as losses in production or sales and the cost of control or eradication) and the cost-effectiveness of alternative approaches to limiting risks. The SPS agreement states that phytosanitary regulations should not be more restrictive than necessary to achieve a country's chosen level of protection—which could be set at zero risk—and that the process of their promulgation must be transparent. Finally, the SPS agreement grants developing countries more time to comply with international phytosanitary standards and calls on WTO member countries to give them technical assistance. Countries that believe their exports have been discriminated against may challenge the importing country's phytosanitary protections as nontariff barriers to trade; if the challenger wins its case, the importer must either revise the phytosanitary regulations or pay a penalty. The penalty can be substantial: For example, after the European Communities (EC) refused to accept a WTO Appellate Body ruling allowing entry of US beef from cattle treated with growth hormones, the United States imposed a $116.8 million tariff on various European food exports (Williams 1999). The SPS agreement is only now being interpreted—often through official decisions of WTO dispute settlement bodies—thus many questions remain to be answered about what the agreement allows. USDA is wrestling also with questions about how it will apply certain provisions. For example, what level of protection should the United States strive to maintain? Which agencies, in addition to APHIS, should weigh in on this policy? Because any pests introduced as a result of APHIS policies will affect everyone in the United States, as well as the environment, all of the issues surrounding the SPS agreement should be the subject of broad discussion. Two topics in particular—determination of an appropriate level of protection and “quarantine pests”—should be part of that discussion. As mentioned above, each country has the right to set its own level of protection, even if that level is zero risk. However, a country must consistently apply comparable levels of protection in comparable situations; a further limitation to this right to determine an appropriate level of protection, according to the WTO Appellate Body, is that the country is obligated to demonstrate a scientific justification for the selected level of risk (Victor 1999). The consistency requirement exposes any phytosanitary safeguard to comparison with other domestic or international statutes aimed at managing a comparable risk or—importantly—to comparison with the absence of such statutes. A gap in the protection provided by these statutes could be cited as proof that a stringent phytosanitary regulation is inconsistent with existing standards. Indeed, the Appellate Body ruled against Australia when that country banned imports of salmon largely because the sanitary measure for salmon imports was more stringent than that for other fish imports judged—by the WTO dispute panel—to pose an equal or greater risk (WTO AB-1998-5). For stringent phytosanitary safeguards to survive a challenge under the SPS agreement, then, countries must close any loopholes in regulations governing comparable situations. Of course, tightening these statutes takes time and may prove difficult because of political pressures. Until these steps are taken, however, differences in a country's approach to various risks to health and to the environment might be challenged as or are to be (WTO The SPS dispute have also ruled that a country's of its level of risk be supported by a risk that assessment must be even scientists have little to predict which foreign species may prove when introduced to a new environment. In the from US the dispute supported by the Appellate Body, noted that the scientific on which the European Communities based their level of risk were in the of they not as the Appellate Body they the potential of the at levels found more or when the are for growth in (WTO p. this level of to a risk assessment for potential plant pests might restrictions on imports by both that a fungus has the potential to damage in the importing country and that the fungus might be on an imported The risk assessment would probably have to address each species or to logs for the Appellate Body that is not is a of A risk the the of or (WTO p. Although the Appellate Body imposed it that the not have to be must it prove that the damage would any (WTO AB-1998-5). Given current levels of scientific knowledge and funding, can APHIS be expected to the likelihood or that any of the of insects, fungi, or plant of which could hitch a ride on any from any of US trading any of the agricultural or natural ecosystems of the United Moreover, the Appellate Body not the that many other potential pests cannot be evaluated at because they are either to or or in their APHIS can apply phytosanitary an organism for control must have been designated a “quarantine must be based on a risk the in and scientific just In practice, for example, APHIS might well be to predict that certain insects on imports of pose a threat to in do scientists have information to how those insects might in natural to the potential for invasion by other species of or pathogens on the same It is that APHIS can these the time to risk that imports of to pose severe pest risks can for several APHIS can the process and impose new For example, APHIS in that it considered solid wood packing to be of the pest of all wood imports (APHIS it its risk assessment regulations only in October APHIS the in The only a country can the to the and its with such is through of provisional measures under the of article In ruling on the US challenge regulations on imports of and the Appellate Body that a measure cannot as provisional the country is seeking the information and will the provisional measure a (Victor 1999). The is in the many in which APHIS with it must either to allow the organism with invasive potential into the it will not prove to impose a provisional on its and to trying to the standards of the SPS agreement. The to for the of information on species may well be to on of it has been determined that pests may be introduced a certain of or its country of APHIS should to the available to that or as as to insects, fungi, and the SPS agreement allow a country to adopt such an safeguard on the of a risk assessment that examines a of pests that might be associated with that and not Although pathway regulation has not yet been at in a the on in the of the agreement and in Appellate Body that such an approach would be found when an organism has been designated a “quarantine the still phytosanitary to ensure that their phytosanitary requirements cause the to trade. In other words, of the most measure to against or a country must accept risk of that and adopt those measures that a level of protection. For example, in the of logs and lumber imported from New Zealand and APHIS the less of alternative measures in to the burden on APHIS with that treatments would be more than with in preventing pest its of by that is to the agricultural and its forest from exotic plant pests, but it also has the ensure international only to the to meet plant protection of plant pest risk to a To this would be considered trade restrictions under and subject to challenge by other trading partners in the World Trade (APHIS p. The SPS agreement and revised IPPC the right of the United States to protect from introduction of the thousands of species of pests and weeds that are natural ecosystems in the country insects, see Niemela and Mattson 1996, APHIS for plants, see and the Plant at more organisms to these species into the country several The the species to the new imports may a in an not and the imported organisms may a that is to control than established from the New Zealand see et al. 1999). the SPS agreement and IPPC allow a country to phytosanitary barriers for pests in the country only when the species is not and an official control program the or when the introduced organism from its in the United States in a that the potential to cause greater which as an control will affect the types and of established pests and weeds against which APHIS can protect US ecosystems from imports. however, the to control programs for more than a few species. A of could for phytosanitary controls at US borders, provided that regulatory and programs are considered control Given the that could result from allowing introductions of established it would be appropriate to all in the of which of are to be official control As noted above, the SPS agreement also governments to of an established pest when the new in from in the However, phytosanitary have been to in their attempts to determine such that can have serious the spread of of disease by several fungi in the which when phytosanitary imports of logs, based on their that the disease only that was in their countries. APHIS policies and procedures to be which may the threat from of the SPS agreement. For example, according to the National Plant Board, APHIS-PPQ risk assessment process not the in the it on which or are Many of the process are (National Plant Board 1999). In response to this APHIS has a of its risk assessment October 1999, the a in the seeking on the and on November 1999, it a the an in risk on a process and noted in APHIS the for with the process to ensure that no is also noted that APHIS too on the of an introduction and too little on the of such an introduction 1999). APHIS is also a to and existing international standards and the current of the APHIS to a with of changes in ensure and The SPS agreement was almost by in trade and not in the new of invasion Under the it is not that the SPS agreement phytosanitary safeguards and the danger of harmful The danger from to heavily on risk when the are the priority to trade protection from biological invasion not the of species and biological subject to its on and a few species than on preventing any introductions the of the differences in risk of associated with shipments from as to producers A for American scientists to the issues raised in this article and to for changes in policies that to pest exclusion In US an Invasive and it with developing for US programs to prevent and to The Invasive should the SPS agreement and IPPC allow countries to adopt phytosanitary programs to the structure in In the APHIS can its pest exclusion program the imposed by the SPS agreement and IPPC by zero which it should appropriate level of protection. Although this new would not “If in doubt, keep it out” or “Guilty until proven as the in it would the to be as as when for example, which organisms should be considered “quarantine As above, APHIS is to its risk assessment assessment may be an appropriate for to set for search and on pests, but the process is too and too to to a scientific for an exclusion

Robert Silverman

With increasing demands for internet security, the demand for distribution of public key certificates and certificate authorities spreads. This brings up the new problem of public key validation. This problem can arise in different contexts and can be adressed in some of them using novel zero knowledge protocols, while in other contexts it can be only poorly solved. The purpose of this paper is to give an overview of the topic of key validation and to discuss the possible solutions to the different instances in which it appears. We also present a new zero knowledge protocol for correctness of an RSA public exponent and a simple protocol (not zero-knowledge) for primality of a discrete logarithm. We use the latter to give a proof protocol (not zero knowledge) that an RSA key is the product of strong primes These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Mark S. Miller, Chip Morningstar, Bill Frantz

No abstract is available for this record.

Annette Søberg Roed, Hanne Sjuneson

The Danish health care system The Danish health care system is characterized by free and equal access to health care services. This principle has the same high priority regardless of the party in office. Free and equal access to health care services and universal coverage go hand in hand with a strong determination to control costs. Within the last fifteen years, the freedom to select the hospital of one's choice has also become a very important part of the health care system. The health care system in Denmark is mainly publicly financed through taxes, and is decentralized, with three administrative levels: state, county and municipality. The state's task in health care provision is, first and foremost, to initiate, coordinate, advise, and legislate. The counties are responsible for providing health care services within the limits set by the state. The municipalities are responsible for district nursing, public health care, school health care, and child dental treatment. The provision of health care services by municipalities and counties is negotiated every year in the national budget negotiation. The budget negotiation takes place between the government on the one hand, and the Danish regions (counties) and Local Government Denmark (LGDK) on the other. Agreements are typically in the form of recommendations for local and country tax rates and agreements on injecting capital into specific health care areas or projects, such as cancer treatment or waiting times. Introduction of activity-based financing has also been agreed on in budget negotiations.

William H. Tietjen, Winfred P. Cowgill, Martha H. Maletta, Peter J. Nitzsche · 5 authors

The effect of disease forecasting systems and stake or ground culture on foliar and postharvest disease control for tomato ( Lycopersicon esculentum ) was evaluated during two growing seasons in northern New Jersey. Foliar disease was reduced and marketable yield increased by stake culture. Percent of postharvest losses, including loss due to anthracnose, was significantly reduced by stake culture. Effectiveness of disease control schedules, weekly or forecaster-generated, was not affected by cultural system. Disease forecasting was shown to have potential for optimizing fungicide use in tomato production by controlling foliar disease and fruit anthracnose with fewer applications than a weekly schedule.

Rikard Lindqvist

Introduction Sweden, with about nine million inhabitants, has a decentralized public health care system. Three political and administrative levels – central government, county councils and local municipalities – are involved in financing, providing and evaluating health care activities. The central government has only a legislative supervisory role, while county councils and municipalities are responsible both for financing and providing health services (Figure 4.1). The county councils are entitled to collect direct income tax revenues as their major financial source, but they are also politically accountable through their directly elected political assemblies. The vast majority of Swedish hospitals are public, owned and financed by the county councils. Primary care settings are also financed by the county councils but they are both publicly and privately owned. Swedish hospitals have traditionally been financed via global budgeting. This is due to the fact that Sweden has a tradition of publicly owned hospitals and that cost control has been an important issue. Moreover, before the introduction of DRGs, there was no accepted system in use to describe performance. The counties had poor knowledge of hospital activity and productivity. There was a great need to find ways to measure productivity. In Sweden, DRGs have been used as a prospective payment system, to describe performance and increase the transparency of hospital activities, as an analyzing tool and to measure productivity.

Takeru Miyazaki

No abstract is available for this record.

Gallina Andronova Vincelette

The article points to two major reasons for the delay of the reforms in the Bulgarian financial sector. First, the unwillingness of the state to facilitate its own retreat: powerful insider groups were fully capable of misallocating the flows of resources within the existing institutions of the banking system, leading to the state’s never-ending (in scope and time) micro-involvement in the banking industry. The failure of the state to execute the macro-aspect of the reform process, i.e. to provide for the establishment of the institutional environment and its rules in the sphere of banking and finance, allowed for the insiders to prey upon it. This brings us to the second reason for the delays, spelled out broadly as inconsistency in following the market creed for the development of the banking industry in Bulgaria. The lack of continuity in the reform policy process provided for an unstable institutional environment in the sector. Adequate banking sector regulation and supervision, decentralization, privatization and fair competition were not among the assets of the financial sector transformation in Bulgaria in the 1990s.

John P. Burns

ABSTRACT Administrative reform in China has followed a different path from reform in OECD countries. Because of its different point of departure (relatively underdeveloped, centrally planned economy, and one party monopoly) reform in China has included establishing a market economy, strengthening market regulations, and institutionalizing civil service. There are some similarities between China and OECD countries, however. Both China and developed capitalist democracies have tried to downsize their public sectors, corporatize some government departments, and decentralize administration. Contrary to stated policy goals of Chinese government, net result of these changes has been to strengthen state. Moreover, reform has left both developmental and predatory natures of Chinese state intact. There is some evidence, however, that Chinese state is now seeking to become more neutral vis-a-vis INTRODUCTION Spared by economic crises and informed by New Right, public-sector reform in developed capitalist democracies has involved decentralization, deregulation, privatization, and marketization (Lane, 1997:1; Rainey, 1998: 19; Hood, 1991). The implication of these changes was that size and role of state would shrink. According to this scenario, a lean core state would remain to manage most activities indirectly. Most public goods and services would be provided by business-like executive agencies or by private sector and non-profit organizations under contract. Globalization and need to compete in an increasingly integrated market have had an impact on developing countries as well and they, too, have been encouraged to reform their public sectors. Because China has come to public sector reform from a radically different starting point from developed capitalist democracies (relatively underdeveloped, centrally planned, and ruled by a one-party monopoly), reform in world's most populous country has taken its own path. Still, reform in China has also sought a smaller, less intrusive state. This goal is neatly captured in official Chinese slogan: small government, large society. The evidence now indicates, however, that in spite if years of reform both in China and overseas, position of state remains relatively strong. The statist orientation of public-sector reform is evident in western democracies. In OECD countries, for example, although size of civil service has shrunk in many cases (including Australia, Canada, New Zealand, UK, and USA), public expenditure as a percentage of gross national product has remained remarkably stable (Ferlie et al. 1996:2-3) because the public sector continues to finance and deliver core goods and services that are of major significance to as a whole: health, education, research and development, criminal justice, and social security (Ibid., 3). In China, case is even clearer. Not only has size of public sector, especially government, been immune to years of attempted downsizing but also position of state as a result of public sector reform, especially local state, remains as strong as ever. The goal of small government, large society has yet to be realized. CONTEXT China is divided into 30 provinces or provincial-level units ranging in population from 2 million (Tibet) to over 110 million (Sichuan) people. Average provincial population is 30 to 40 million, larger than population of many countries. Provinces are subdivided into prefectures (there were 110 such units by end of 1997) or prefectural cities (22 in 1997). Prefectures in turn are subdivided into counties (1,693 in 1997) or county-level cities (442). Cities are further divided into 727 districts (State Statistical Bureau, 1998:3). Territorially based party committees, each with its own bureaucracy, manage government and economy at each administrative level (Lieberthal, 1995). …

Dimitrios G. Katehakis, Manolis Tsiknakis, Stelios C. Orphanoudakis

Healthcare is usually delivered within certain organ- izational boundaries and information produced at each site is managed by isolated autonomous clinical information systems. In some cases point-to-point communication is enabled, facilitat- ing the exchange of information. In contrast, integrated re- gional health telematics networks enable accessibility to infor- mation and services without visible organizational boundaries, to provide decentralized healthcare through integrated services for seamless and personalized information delivery. This has the advantage that enables informed citizens to have an impact on the healthcare system and to be more concerned and care for their own health. The current vision comprises affordable ac- cess to healthcare resources and services for all citizens, thus making medical expertise a shared resource wherever and whenever needed. Important areas in which information society technologies are likely to have a significant impact include those of pre-hospital health emergencies, remote monitoring of pa- tients with chronic conditions, and medical collaboration through sharing of health-related information resources. Acces- sibility to these and other media-rich, user-oriented services, in the context of the emerging global information society, will be supported by a healthcare information infrastructure, which can achieve effective horizontal integration of networked infor- mation sources. Keywords - Healthcare Information Infrastructure, Regional Health Telematics Networks, Component-based Architecture

José Murari Bovo

After the 1988 Constitution, as a consequence of an unplanned decentralization process, the increase of social expenditures by local governments has contributed to aggravate the financial situation of these governments. This aggravation poses a serious problem to the financing of social policies, thus threatening their future implementation and implying the worsening of social inequalities. This paper discusses the decentralization process of public policies and the federative equilibrium in Brazil.

Scott Norris

Of the various brewing biological crises of our time, the issues of declining biodiversity and emerging disease are among the most complex and far-reaching. In many respects they are also different sides of the same coin, a perspective that is central to the new field of conservation medicine. The product of a growing coalition of conservation biologists and ecologists, wildlife veterinarians, and biomedical researchers, conservation medicine explicitly addresses the interlinked and transdisciplinary nature of many of today's most urgent health and conservation issues. The field is being advanced most forcefully by researchers associated with the recently established Consortium for Conservation Medicine (CCM). Originally established in 1998 within the School of Veterinary Medicine at Tufts University, CCM consists of three partner organizations representing the veterinary, wildlife conservation, and human health components of conservation medicine. Collaborating with Tufts are Wildlife Trust, a US-based wildlife conservation organization, and the Center for Health and the Global Environment at Harvard Medical School. The advent of conservation medicine is timely. In this era of widespread environmental degradation, declining biodiversity, and emerging diseases in both humans and animals, many medical experts and conservationists agree with conservation medicine's defining theme: The concept of health—for both humans and animals—must be understood in an ecological context. One of the aims of conservation medicine is to formalize and advance this multidisciplinary perspective. “Health connects all species on the planet,” said Philip Kosch, dean of the Tufts University School of Veterinary Medicine, in introducing a special symposium on conservation medicine at the June 2000 meeting of the Society for Conservation Biology in Missoula, Montana. Much of the focus at the symposium was on the complex problem of emerging diseases—that is, those with increasing incidence or geographic range. “There are almost no examples of emerging wildlife diseases not driven by human environmental change,” said Peter Daszak, a disease ecologist at the University of Georgia. “And few human emerging diseases don't include some domestic animal or wildlife component.” Proponents of conservation medicine argue that, just as an ecological perspective can aid health workers in understanding the mechanisms of disease, adopting a medical model can benefit conservationists. Most directly, the integration of the veterinary community's biomedical perspective with the theoretical, ecological focus of conservation biologists can inform efforts to preserve biodiversity. At the same time, a focus on human health may be an effective way to “sell” biodiversity protection programs to the public, both in the United States and around the world. Some conservation biologists hope that their basic environmental message will garner greater authority and respect when delivered by doctors and public health officials. Despite the enthusiasm of ecologists for the concept of conservation medicine, other observers take issue with a few of the field's claims and assumptions. Members of some veterinary and biomedical organizations point out that they already have a long history of dealing with issues at the interface of public health, wildlife health, and conservation. Beyond these mostly territorial disputes are other, more serious concerns. Some biologists, for example, question the assumption that conservation efforts can only benefit from a strong linkage with human health issues. Clearly, conservation medicine is a field that is still trying to define itself. But whether it is new in substance or in name only, the problems it has staked out are substantial ones. “Human and animal populations are more mobile than ever before,” notes Mark Pokras, a Tufts University veterinarian who helped organize CCM. “At the same time, wildlife habitat is decreasing and populations are declining and under stress. We're seeing an accelerating trend of exchange of disease among taxonomic groups, and it's going to get a lot worse over the next hundred years.” Richard Ostfeld, an ecologist at the Institute of Ecosystem Studies in Millbrook, New York, says conservation medicine has an important role to play in making explicit the linkages between wildlife veterinary medicine, conservation biology, and epidemiology. “There really hasn't been any unified field that combines these perspectives,” he says. Conservation medicine provides a formal disciplinary framework within which scientists can piece together an understanding of the processes—spanning all levels of biological organization, from cells to ecosystems—that comprise the ecological context of health. Such an approach is a radical shift away from viewing diseases solely in terms of the response of individual organisms to infection or the spread of infection through populations. Consider Lyme disease, for example. Ostfeld has spent years unraveling the ecology of this tick-transmitted disease, which affects tens of thousands of people annually in North America and Europe. “To a physician,” he says, “a case of Lyme disease begins when a patient enters a clinic complaining of symptoms. But to an ecologist, that visit to the clinic is the culmination of a series of events that began one to two years earlier and involved several different species—ticks, mice, deer, oak trees, bacteriain nature.” In forests of the northeastern United States, the white-footed mouse is the most efficient host for transmitting Borrelia burgdorferi, the Lyme disease bacterium, to ticks. Lyme disease risk is governed by two factors: the percentage of tick nymphs infected with the disease organism and the absolute density of infected nymphs. The greater the summer abundance of white-footed mice, the greater the abundance of infectious tick nymphs the following year. When mouse populations are low, chances are greater that a larval tick will parasitize some other, nondisease-carrying species and thus will remain uninfected. The same is true when mice coexist with a diverse assembly of potential tick hosts. Through this “dilution effect,” Ostfeld has shown, increased biodiversity directly reduces the infection rate of ticks. When species diversity is reduced—and especially when predators of mice are eliminated—both mouse and tick densities climb steeply, and disease risk to humans increases. Ostfeld's data show that the small habitat patches in fragmented forests support few vertebrate species and large mouse populations with a high rate of B. burgdorferi infection. The work is still in progress, but if Ostfeld's data continue to support his hypothesis, the implication for land management is significant: Maintaining forests with high vertebrate diversity and healthy predator populations can directly benefit human health. Ostfeld and coworker Felicia Keesing are also investigating the possibility that a diverse assemblage of potential hosts might reduce the risk of other vector-borne diseases. Although more data are needed, Ostfeld says, “We think this dilution effect is likely to be very widespread.” The case of Lyme disease is unusual only in the degree to which its ecology is understood. The emergence or reemergence of vector-borne diseases worldwide is nearly always the result of ecological changes affecting human, animal, and pathogen populations. Habitat loss and fragmentation, the disruption of food webs and other ecological relationships, environmental contamination, and climate change all contribute to new patterns in the manifestation and spread of disease. Thus, complete understanding of the human health risk posed by emerging diseases must include knowledge of causes that lie outside the traditional domain of physicians and epidemiologists. Most emerging infectious diseases in humans result from exposure to zoonotic pathogens, organisms that invade and complete some portion of their life cycle in other animals. Any changes in the density, distribution, population dynamics, or ecological interactions of host animal or insect vector species may result in new patterns of disease incidence. For example, work by Jonathan Patz of the Johns Hopkins School of Public Health has shown how deforestation in northern Peru has produced vast areas of prime habitat for Anopheles darlingi, the mosquito species that is the main vector for the malaria parasite in South America. Dense forest habitat, which favored other Anopheles species less likely to carry the disease, has given way to sunlit areas with a thin soil layer and standing pools of water—conditions in which the malaria-carrying A. darlingi thrives. From 1987 to 1997, the incidence of malaria in the region increased sixfold. Climate change is another factor driving the expansion of malaria, encephalitis, and other diseases into new geographic regions. In the southwestern United States, recent changes in rainfall patterns have been linked to increases in rodent populations, which in turn lead to outbreaks of vector-borne diseases such as plague and hantavirus pulmonary syndrome. Morover human populations are changing and expanding, and the increased movement of people and materials around the world are creating new opportunities for the transfer of disease from wildlife to humans. Human encroachment into formerly isolated habitats has been associated with the emergence in people of previously unknown pathogens such as the Ebola virus and the human immunodeficiency virus. The recent appearance of West Nile virus in the eastern United States is a perfect example of a disease agent emerging in a novel location and ecological setting. First discovered in the Western Hemisphere in 1999, the virus was passed from infected birds to humans by mosquitoes. Over a dozen birds species, including a number of wide-ranging migrants, carry the virus. Ostfeld says the outbreak vividly illustrates the need for a transdisciplinary approach to disease research. A traditional medical and epidemiological investigation of West Nile virus, he notes, leaves many questions unresolved: “What role do American crows play in disease transmission? Why do mosquitoes in New York City's Central Park show very high infection prevalence, whereas mosquitoes in rural upstate New York show little or no infection? What impact does the pathogen have on wildlife populations? Answers to these questions require interdisciplinary or collaborative approaches, and conservation medicine can provide an important framework for such explorations.” Conservation medicine, proponents claim, does more than recognize the ecological context of health. It may also play an important role in protecting biodiversity. Although a small but active group of veterinarians have long focused on the health and conservation needs of wildlife populations, coordinated efforts drawing on the expertise of both field veterinarians and ecologists have been more the exception than the rule. Proponents believe that conservation medicine can both clarify the need for such a unified approach and provide the theoretical and logistical foundation for such efforts. At the same time, by emphasizing the human health costs of environmental damage, conservation medicine has the potential to leverage public understanding and support for protecting species and natural systems. In an October 1999 editorial in Conservation Biology, journal editor and University of Florida ecologist Gary Meffe wrote that “an added biomedical perspective surely would give conservation biology a higher public profile and offer even stronger arguments for biodiversity protection…. Strong scientific links between conservation biology and human health could be our most powerful tool in reaching larger expanses of humanity.” The need for a biomedical perspective in conservation efforts can be seen most clearly in the case of emerging diseases that threaten wildlife. Just as cholera, malaria, and tuberculosis pose a resurgent threat to human beings, a growing number of infectious diseases in both captive and wild animal populations now threaten wildlife species. In a recent review article (Science 287: 443–449) Peter Daszak and several coauthors surveyed a large number of terrestrial wildlife diseases that can be classified as “emerging” on the basis of criteria such as increased geographic range, appearance in new populations, and increased incidence. Perhaps the best example is the fungal disease chytridio mycosis in amphibians. Outbreaks of the disease have caused mass die-offs of frogs and salamanders in different parts of the world, including Central America and Australia. “This is probably the most significant emerging disease in wildlife,” Daszak commented. Chytridiomycosis is particularly alarming because it has appeared in relatively undisturbed habitats, can affect a wide variety of amphibian hosts, and has caused population declines and possibly extinctions in widely separated geographic regions. Just as European expansion in previous centuries introduced novel pathogens such as smallpox to aboriginal populations in the Americas and Australia, the growing international movement of people and livestock has resulted in the spread of diseases affecting wildlife. This globalization of infectious diseases is continuing at an accelerating rate, and the transfer of pathogens among humans, domestic animals, and wildlife occurs in all directions. Daszak describes a “host–parasite ecological continuum” within which various environmental changes and disruptions facilitate the spread of disease across taxonomic boundaries. Mountain and lowland gorillas, for example, are susceptible to many human diseases. Among them is the measles virus, which tourists may unwittingly introduce to gorilla populations, with devastating consequences. A greater threat to wildlife may be diseases spread by domestic animals. Canine distemper and rabies, spread by domestic dogs, have led to declines and local extinctions in African wild dogs. A domestic chicken pathogen is believed to be the cause of myco plasmal conjunctivitis in wild house finches, a fatal disease that has spread throughout the eastern United States since its introduction in 1994. The global exchange of agricultural materials, domestic animals, food products, timber, and biologically contaminated wastes has resulted in a phenomenon Daszak terms “pathogen pollution.” Pathogens introduced into immunologically naive host populations can have catastrophic effects on wildlife. In the late 1800s an outbreak of the morbillivirus disease rinderpest, originating in cattle imported from India, swept through Africa, decimating native ungulate populations. Introduced diseases contributed to the extinction of several native Hawaiian bird species. Like other forms of pollution, exotic pathogens now appear in remote and seemingly pristine habitats, as exemplified by the presence of a domestic chicken pathogen, the infectious bursal disease virus, in Antarctic penguins. As health pressures on both humans and wildlife mount, scientists from the biomedical and conservation communities are responding by joining forces. Although some issues clearly demand expertise from multiple disciplines, forging a coalition among ecologists, conservation workers, and health professionals is not easy. “We need to develop a common respect, a common language, and a common set of priorities,” Pokras says. “We have to bridge the gap between the people in muddy boots and jeans and those in white coats.” Forging a new coalition of health researchers is part of the goal of CCM. The consortium began as an outgrowth of established Tufts programs in international veterinary medicine and wildlife medicine. Pokras says that Tufts veterinarians were seeking ways to expand their involvement in conservation issues when they were approached by Wildlife Preservation Trust International (now Wildlife Trust), a group with over two decades of experience out field and conservation programs around the world. said to are wildlife conservation work in a number of and are wildlife health issues that as conservation biologists are not to Pokras says. Wildlife Trust that many of field workers an accelerating trend of health problems that both wildlife and humans. seen in the that is going says. some of our field were more The two partner organizations were by Center for Health and the Global a on the potential human health of global environmental Beyond the work in of defining and conservation medicine, CCM and its organizations a number of field and says that through its involvement with Wildlife Trust has its in field veterinary and conservation who Wildlife international field wildlife veterinary says of the is on and programs at field approach has been in trying to local veterinarians and and other who are to wildlife,” he says. 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But its greater in its with new and a new in some of the new ecological and public health In North the white-footed mouse is the host for the Lyme disease bacterium, which is to and to humans. vertebrate species diversity may reduce the potential for the disease. University of Wildlife health veterinary provides on the presence of infectious levels of and other of health basic health for wildlife populations researchers to environmental change and conservation and Wildlife in the in from For many wild species, these have to be and Wildlife with in threaten around the world. The disease is to be caused by an virus, but caused by may be a of Wildlife Trust of the Wildlife Conservation veterinarians and biologists in for Such conservation and health programs that are B. Wildlife Conservation Society

Pino Caballero‐Gil, Candelaria Hernández‐Goya

No abstract is available for this record.

Laksono Trisnantoro

Background: Health system in Indonesia is experiencing a reform due to decentralisation policy. This policy causes a big change on public and private sector's roles in health services. The great impact will be on the regional economy. In turn the regional economy change will influence local health system. This study aims to make a projection on the influence of decentralisation policy to the regional health system due to the change of regional economy.\nMethods: This study is a case study with 7 provinces in Indonesia, including their districts, as the subjects of the study. The simulation of change in district economic situational as the impact of decentralization in 7 provinces is shown by secondary data.The local government economic strength is determined based on Regional Original Revenue (PAD), General Allocation Fund (DAU), and the simulation of Local Shared Fund (Dana Bagian Daerah). The community economioc strength is determined by Gross Domestic Regional Income (PDRB).\nResults: This study shows that there will be 4 groups of region based on their economy strength. The results shows that there are four types of district government and community situation: (1) strong district government financial resources with strong community finance

Sukarjo Kasut, SU Kristiani

No abstract is available for this record.

Jeffrey P. Cohn

In June the Office of Management and Budget proposed new, congressionally mandated guidelines to ensure the quality of the data gathered and disseminated by federal agencies. The new law augments the Paperwork Reduction Act, which already requires federal agencies to adopt processes to ensure data quality. Many scientists, however, worry that the guidelines—which require agencies to devise and implement procedures that make it possible for individuals to challenge the accuracy of agency information—could impede or prevent the flow of scientific information and undermine the peer review process. Comments submitted to OMB by 55 scientific societies and academic institutions, including the American Institute of Biological Sciences, supported the intent of the law. “As biomedical researchers whose work depends on the excellence of our own data, we are acutely aware of and sensitive to the importance of accurate data,” wrote Robert Rich, M.D., president of the Federation of American Societies for Experimental Biology (FASEB). The problem, scientists say, is not with the intent of the law but with the vagueness of the guidelines OMB proposes for implementing it. In particular, scientists argue that challengers seeking a correction of an agency's data should have expertise in the subject matter and should disclose any financial interest at stake in the outcome of the challenge. There should be a clear burden of proof on the person or group who made the initial charge to demonstrate why the data being challenged are inaccurate or wrong, added Elaine Hoagland, national executive officer for the Council on Undergraduate Research. Further, the OMB rules should contain adequate safeguards against frivolous challenges of scientific information. Those safeguards should allow government agencies to insist on the same degree of rigor and objectivity required of the original science, says Stephen Heinig, senior staff associate at the Association of American Medical Colleges (AAMC). “Scientists can fight out issues of data and methodology in the literature,” Heinig says. “That's the standard. We don't see any reason to change it.” And, noted AAMC President Jordan Cohen, the procedures mandated by the guidelines will be burdensome to agencies, whose staff—already struggling to meet core missions—will have to shoulder supervisory and reporting tasks that contribute little to the agencies' missions. Citing “errors” in Environmental Protection Agency data, as well as the sheer volume of information that EPA and other government agencies post on the Internet, Jim Tozzi explains that “we felt the need to ensure the quality of government data.” Tozzi, a former OMB official who is now a board advisor to the Center for Regulatory Effectiveness, an independent policy group that helped draft the new law, calls the debate over OMB's data quality proposals “a big hullabaloo over nothing.” Not so, say Washington's scientific and educational groups. “There is plenty of potential here for mischief,” notes Richard Harpel, director of federal relations for the National Association of State Universities and Land Grant Colleges. In part, that is because the draft guidelines are very subjective, says Joanne Carney, director of the Center for Science, Technology and Congress at the American Academy for the Advancement of Science. Robert Wells, president of the American Society for Biochemistry and Molecular Biology, expressed the views of many scientific societies when he pointed out that key terms in the guidelines are not defined: “OMB asked for comment on the definitions of the terms ‘quality,’ ‘utility,’ ‘objectivity,’ and ‘integrity’…· [but] we are unable to find any definitions of these terms in the proposed guidelines…·. It may seem to the drafters of this proposal that these terms are self-explanatory, but in fact they are not, at least as far as science and regulatory policy are concerned.” It isn't even clear who will be covered by the guidelines, which are silent on the question of applicability to federal grant recipients. “Any attempted federal restriction on dissemination of academic research would be wholly unacceptable in principle and would likely raise First Amendment considerations,” Heinig wrote. The guidelines “should specifically exclude academic and other non-federal institutions performing research under federal grants.” FASEB's Rich questioned OMB's proposal that government data “be substantially reproducible upon independent analysis.” “Who will conduct these [independent] studies and who will pay for them?” he wondered. “How can research studies [that] may have taken place over a period of years and used biological substances be ‘substantially reproduced’?” Rich also faulted OMB's proposal that federal agencies report the number and nature of complaints regarding their compliance with the guidelines. “The number of complaints received rather than the validity of the complaints could unfairly impact the reputation of an agency and//or its funded investigators,” he wrote. “A large number of complaints on a scientific matter could simply reflect a controversial issue…·rather than the excellence of the science.” The bottom line, Harpel says, is that by seeking to ensure high-quality scientific data, OMB could interrupt ongoing research and leave government agencies and their researchers open to harassment by special interests. That, he states, would “make it harder to be a scientist.”

Imrana Qadeer, Kasturi Sen, Kesavan Rajasekharan Nayar

Introduction PART ONE: THE POLITICAL ECONOMY OF HEALTH AND DEVELOPMENT Landmarks in the Development of Health Services in India - Debabar Banerji Structural Adjustment and the Poor in Pakistan - Jennifer Bennett Donor-Driven Family Planning Services in Bangladesh - Farida Akhter Impact on Women's Health Changes in Health Care Systems in Europe - Meri Koivusalo Focus on Finland Structural Adjustment Policies and Health in the Plantation Sector in Sri Lanka - Indira Hettiarachchi Dilemmas for Research in Primary Health Care in the Era of Reforms - Marc De Bruycker PART TWO: CONCEPTS AND EVIDENCE Impact of Structural Adjustements Programs on Concepts in Public Health - Imrana Qadeer Health Reforms and Developing Countries - Kasturi Sen A Critique Disability Adjusted Life Years as a Tool for Public Health Policy - Ritu Priya A Critical Assessment Re-Thinking Public Health - Sheila Zurbrigg Food, Hunger and Mortality Decline in South Asian History Biological Stress and History from Below - Lalita Chakravarty The Millet Zone of India, 1970-92 PART THREE: SHIFTS IN HEALTH SERVICES AND HEALTH FINANCING Health Sector Reforms and Structural Adjustment - Rama V Baru A State-Level Analysis Reforms and Their Relevance - V Raman Kutty The Kerala Experience Health Sector and Economic Reforms - K Seeta Prabhu A Study of Maharashtra and Tamil Nadu Structural Adjustment and Economic Slowdown - S Akbar Zaidi Likely Impact on Health Outcomes in Pakistan Health Services in Bangladesh - A Q Khan Development and Structural Reforms Structural Adjustment Programs and Health Care Services in Sri Lanka - Dulitha N Fernando An Overview Evolution of India's Leprosy Program from Control to Elimination - B R Chatterjee Tuberculosis Program in India - A K Chakraborty Current Operational Issues PART FOUR: DECENTRALIZATION IN HEALTH CARE Politics of Decentralization - K R Nayar Lessons from Kerala Promises and Problems of Panchayati Raj - Anwar Jafri Experiences from Madhya Pradesh An Assessment of the Effectiveness of Decentralization of Health Services in Sri Lanka - Nimal Attanayake People's Health Care Initiative in Chhattisgarh District, Madhya Pradesh - Binayak Sen PART FIVE: PERSPECTIVES OF CLINICIANS Prescribing Practices - Anant R Phadke A Comparison of Public and Private Sectors Revisiting the Community Health Worker - Shyam Ashtekar Disturbing Trends in the Treatment of Malaria - Yogesh Jain Public Health in Vellore - Anand Zachariah Experiences with Malaria and Cholera The Revised National Tuberculosis Control Program - Anurag Bhargava A Critical Perspective PART SIX: EXPERIENCES AT THE MICRO-LEVEL The Plague, the Poor and the Health Services - Ghanshyam Shah Public Health Issues of Small Towns - K S Sebastian The Case of Alleppey The Labor Process and Its Impact on the Lives of Women Workers - Meena Gopal The Reproductive Health Package - Alpana Sagar A Chimera for Women's Health The Rhetoric of Reproductive Rights - Mohan Rao Quinacrine Sterilization in India

Cary Deck

Trade developed through barter, an institution requiring the double coincidence of wants. Fiat money subsequently arose to provide traders with a mechanism for exchange in decentralized markets while avoiding the problems associated with commodity monies. Currently, every major modern economy uses fiat money and numerous Internet economies are developing private fiat monies, yet traditional economic theories, such as general equilibrium or Walrasian models, provide little insight. This work develops the concept of a coordination equilibrium model, which maintains fiat money's role as a medium of exchange. The potential instability of fiat money is apparent from observed hyperinflationary episodes. Civil unrest and real purchases financed by printing money are also associated with hyperinflations. These factors lead to an experimental design addressing the stability of intrinsically valueless money. Via controlled laboratory experiments, subjects trade fictitious commodities for fiat money in a circular flow economy. The experimental results indicate that under a long trading horizon with no money creation, fiat money provides a stable medium of exchange and the economy realizes almost maximum efficiency, a result consistent with the coordination equilibrium model but not with standard economic models. Shortening the trade horizon causes a decrease in efficiency. However, the ability to create money leads to hyperinflationary trade patterns independent of the horizon. Further, the experimental results demonstrate that the collapse is not caused by an increasing money supply but rather the result of interference in the real price discovery process. As the party issuing money is often an active participant, this economic instability creates a problem in the design of decentralized economic systems. Forcing the monetary authority to balance fiscal spending with the level of tax collection is a potential solution. Experimental evidence demonstrates that a balanced budget results in a pattern of market activity similar to that observed in fiat money economies when the government is inactive. This level of trade is achieved by private agents "crowding out" the government. Further, this effect is not due to the introduction of inside money, money that derives value within the system as tender for tax payment.

Ivan Damgård, Eiichiro Fujisaki

No abstract is available for this record.

Massimo Pigliucci

Icons of Evolution: Science or Myth? Why Much of What We Teach about Evolution Is Wrong. Jonathan Wells. Regnery, Washington (DC), 2000. 338 pp. $27.95 (ISBN 0895262762 cloth). Because there are omissions, simplifications, and inaccuracies in some general biology textbooks, obviously the modern theory of evolution must be wrong. This is the astounding line of reasoning that is the backbone of Jonathan Wells's Icons of Evolution. It is the latest book in a series of neocreationist productions (this one dressed with the slightly more respectable label of “intelligent design theory” [Pigliucci 2000a]) to drive a stake into the perceived perniciousness of modern science, and of biology in particular. This is another astonishing example of the fact that evolution deniers seem to consider attacks on science popularizing to be genuine intellectual feats, as if they had found huge holes in the primary literature that constitutes the core of any respectable science. Wells is a fellow of the Center for the Renewal of Science and Culture, which has been at the forefront of the neocreationist assault on science over the last few years. Predictably, his book is endorsed by other fellows of the same institution and by luminaries of the evolution-deniers movement such as Michael Behe (author of Darwin's Black Box), Phillip Johnson (Darwin on Trial and The Wedge of Truth, among others), and Dean Kenyon (Biochemical Predestination and Of Pandas and People). Wells himself seems particularly well positioned to engage in this never-ending debate, given his double PhD in theology and molecular biology. Alas, Icons falls far short of a critique of evolutionary theory, or indeed of any significant contribution to the “evolution wars.” Wells's idea is simple: In the 10 chapters that make up most of the book, he tackles an equal number of what he calls “icons”—that is, myths—of evolutionary biology, attempting to show that biology textbooks don't tell the whole story, are out of date, or oversimplify what is known. From there he concludes that because these icons are the best “proofs” of evolution, biologists don't have a leg to stand on and they should once and for all abandon their ideological positions and open their minds to a truer and better science, which of course must include the possibility of intelligent supernatural design (Dembski 1998). There are several flaws with this line of reasoning, which I shall examine in turn. First, textbook examples are no proof of anything. Second, Wells's critique of the ten icons is much less devastating than he seems to think. and third, science simply doesn't work the way Wells apparently conceives it. The fact that science (not only biology) textbooks contain plenty of oversimplifications and inaccuracies, and occasionally even major conceptual errors, is not news to anybody and has always been decried by professional scientists and educators. There are sadly understandable reasons for this state of affairs. For one thing, general science textbooks are written by people who either are not practicing scientists or are directly competent in only a fraction of the topics covered. Even when several authors collaborate, the situation does not improve significantly. Second, textbooks (unlike technical research books) are written largely to make money, both for publishers and for authors, and academic rigor sometimes gets sacrificed to accommodate more pressing matters, such as publishing deadlines. Third, pedagogical efficacy is often considered—rightly or not—more important than scientific rigor; after all, the audience is made of young students with little background in the discipline to be studied, not of professionals who understand the subtleties of the subject matter. Regrettable as these facts may be, to conclude from them that evolutionary biology is a big lie constructed on thin evidence is analogous to the preposterous suggestion of abandoning, say, quantum mechanics because many physics textbooks do not portray it accurately or may even make egregious conceptual mistakes in explaining it. It just doesn't follow, and it is pure wishful thinking on Wells's part to pretend otherwise. As for the icons themselves, I will limit myself to a brief discussion of a couple of them (I provide a more detailed, chapter-by-chapter analysis at the Web site fp.bio.utk.edu/skeptic/Debates/Wells%20guide.htm). Let me therefore consider the first and last—and perhaps the most important—of the icons: the Miller–Urey experiments on the origin of life, and the current status of the research on the origin of humans. As is well known, in 1953 Stanley Miller—at the time a student of Harold Urey—published a historic paper in which he demonstrated the possibility of the inorganic synthesis of some of the fundamental building blocks of life, given conditions that were thought to resemble those of the ancient earth. This experiment is still presented in many textbooks as the scientific answer to the question of the origin of life. and Wells is right in maintaining that it shouldn't be. For one thing, even if we do accept Miller's results at face value, they are far from constituting an answer to the origin-of-life question. At most they provide an interesting beginning. More important, the recent consensus among geochemists is that the ancient earth atmosphere was essentially chemically neutral, not reducing like the one Miller simulated. However, textbooks should still devote space to Miller's experiment for its historical (and pedagogical) value: It was not only the first modern piece of empirical research on the origin of life, thus moving the whole field out of metaphysical speculation, but also a great example of how science progresses by questioning its own assumptions and results. As for this being an icon of evolution in Wells's sense, there are two problems with his position. First, Wells gives his readers the completely misleading impression that the field of research on the origin of life is still at the level of Miller's 1953 experiment and that, given the questionable validity of the latter, the whole enterprise is in disarray. Au contraire, this is an area of extremely fecund theoretical and empirical activity, with new hypotheses, findings, and experiments being published at a very rapid pace (Lahav 1999, Fry 2000). More to the point of the creation–evolution debate, the Miller experiments and the whole question of the origin of life have nothing to do with the truth, or lack thereof, concerning evolutionary theory. By definition, evolution is something that happens after life originates on a planet and cannot be invoked to answer the question of how this happened. By the same token, evolutionary theory cannot be blamed for not being able to answer the questions of the origin of life, even if that question might remain a mystery forever. It is certainly true, as creationists are fond of saying, that evolution requires life to have originated, but the two are entirely discrete scientific questions addressed by different fields of research. For that matter, evolution also requires a universe to exist beforehand, but nobody would say that failure to understand the origin of the universe deals a fatal blow to Darwinism (actually, naive young-earth creationists such as Duane Gish do, but that is another story; Pigliucci 2000b, Chapter 11). The “ultimate” icon in Wells's book concerns the story of human descent. This is perhaps one of the most peculiar chapters in the entire book, because even Wells is forced to concede ample ground to the evolutionists! He begins the chapter with the usual complaint about the naive scientists that were fooled by the Piltdown man hoax in 1912. I know of several scientists who feel the sting of shame—which Wells wants them never to forget—because science was duped by a fraudulent fossil. But Piltdown man was neither the first nor the last practical joke scientists will ever face. Furthermore, it is yet another beautiful example, one that textbooks should promote, of how science really works. It is true that this alleged missing link between humans and chimps was more or less accepted (though not without challenge) for several decades. However, it is also true that the human fossil record at the time was so scant that it was very difficult to raise substantive objections to the Piltdown findings. More important, scientists—not creationists—uncovered the hoax, a development prompted by the very fact that more and more discoveries of genuine human and protohuman fossils made it quite clear that Piltdown didn't fit anywhere in the emerging picture. Because science works through consilience of evidence (Wilson 1998), it was the progress of science in virtue of its self-correcting mechanisms that prompted evolutionists to reject Piltdown and eventually uncover the fraud. I have yet to find a similar example of acknowledgment of error in the evolution-denying literature, despite the fact that such errors have been ubiquitous in that literature. Wells, as much as he desperately tries to debunk what to him is the most crucial component of evolutionary theory—the history of human descent—is backed against a wall by his own knowledge of biology. Unlike more naive creationists, he has to grudgingly admit that “many human-like fossils have been found since 1912, and unlike Piltdown they appear to be genuine. Some have distinctively ape-like features, while others are more human-like” (p. 218), and that “obviously, the human species has a history” (p. 223). So much for destroying the ultimate icon. But perhaps the most damning point about Wells's book is the general conception of science that emerges from it. Given his scientific training, Wells should have known better. It is clear that the education system at Berkeley has failed in his case or that Wells does indeed have an ideological agenda (which he was forced to admit in a public debate with me at the University of Tennessee; see http://burns.tns.utk.edu/research/cb/evdebate.htm). Wells's whole argument hinges on the idea of the crucial proof of a scientific theory. If that pillar fails, the whole enterprise is useless. Now, Wells is far from showing that any of the icons are in fact fundamentally flawed or represent an insurmountable obstacle for evolutionists. But even if he succeeded, Wells's conception of science is so simplistic as being labeled by philosophers of science as naive falsificationism. Falsificationism, it may be recalled, is the idea proposed by philosopher Karl Popper (1968) that no amount of positive evidence is enough to sustain a theory unless such theory also makes predictions that could—in principle—be demonstrated to be wrong, that is, the theory is potentially falsifiable. Popper, however, did not advocate discarding a scientific theory at the first sign of trouble. Indeed, Thomas Kuhn (1970) clearly showed that real science is a lot more messy and that before switching paradigms the amount of trouble has to be substantial, or one risks living in a perennial state of flux in which no progress is actually possible. The real “evidence” for evolution is not to be found in individual experiments, and it is certainly not to be expected in textbooks for beginning students. Rather, it is found in the plethora of facts about the biotic world that accumulate every year in the primary literature, facts that make no sense outside of the evolutionary paradigm. Components of this paradigm are constantly being tested in countless laboratories around the world, and—for the most part—the theory has withstood the test of time. More important, this is the way science really works, regardless of Wells's naive and ideologically motivated views that it should be otherwise (he admits in an online article, available at http://www.tparents.org/library/unification/talks/wells/DARWIN.htm, that he enrolled in his second PhD program—in molecular biology—for the express purpose of “destroying Darwinism”). What have we to learn from this latest attempt at debunking evolution? Two things. First, that it is indeed a good idea to pay more attention to how our textbooks are written. This is not just so that individuals like Wells will not be able to use their cheap ammunition in a public debate, but because the so-called icons can be properly used to show students that science is an engaging and ever-changing enterprise, not a monolithic block of static knowledge. Second, we should finally get the message that evolution deniers are always at work, and that they are making inroads with both the public and politicians. How long until we climb down from the ivory tower and start defending—and doing a better job of teaching—reason and science? I wish to thank the following people for a critical reading of this manuscript and for providing me with valuable insights and suggestions: Wesley Elsberry, Jim Foley, Carl Johnson, Niall Shanks, Frank Steiger, and Dave Ussery.

Zhai Xin

Through the analysis of geotechnical section of the drilled holes, the results of the shear wave velocity tests, the background,active rift and effects of the earthquake geology and the main earthquake proof parameter,the authors consider that construction site of the university belongs to medium soft soil which does not have the possibility of liquification and type of site can be classified as Type Ⅱ. At the same time,the authors hold that 6 or less than 6 degrees earthquake background exists in the neighborhood and its earthquake intensity can be estimated as seven degrees. In view of this,the authors suggest a series of earthquake proof measures:foundation of the site can be reinforced by changing soil cushion;a large diameter concentrated stake base and frame pillars, one pillar with one stake may be used for high buildings;base roof beams should be set for shear wall;the building should be properly set in the earth and basements should be built.

Wenbo Mao

Let n be a large composite number. Without factoring n, the computation of a 2 t (mod n)given a, t with gcd(a# n) = 1 and t!n can be done in t squarings modulo n.For t n (e.g., n?2 1024 and t!2 100 ), no lower complexity than t squarings is known to fulfill this task. Rivest et al suggested to use such constructions as good candidates for realising timed-release crypto problems. We argue the necessity for a zero-knowledge proof of the correctness of such constructions and propose the first practically efficient protocol for a realisation. Our protocol proves, in log 2 t standard crypto operations, the correctness of (a e ) 2 t (mod n) with respect to a e where e is an RSA encryption exponent. With such a proof, a Timed-release Encryption of a message M can be given as a 2 t M (mod n) with the assertion that the correct decryption of the RSA ciphertext M e (mod n) can be obtained by performing t squarings modulo n starting from a. Timed-release RSA signatures can be constructed analogously. Keywords Timed-release cryptography, Time-lock puzzles, Non-parallelisability, Efficient zero-knowledge protocols. 1