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      In Vitro Effects of Pumpkin ( Cucurbita moschata) Seed Extracts on Echinococcus granulosus Protoscoleces

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          Abstract

          Background:

          Echinococcus granulosus parasite causes a zoonotic disease which is important for public and veterinary health. Since pumpkin seeds ( Cucurbita sp.) are used as traditional vermifuge in Iran, they may be a potential herbal anthelmintic.

          Methods:

          This study was designed in 2016 to evaluate the in vitro scolicidal effect of Cucurbita moschata seeds form northern part of Iran. Hydroalcoholic and petroleum ether extracts were prepared by maceration and soxhlet respectively. Both extracts with four different concentrations (100, 10, 1, 0.1 mg/ml) were incubated against protoscoleces in 5, 15, 30 and 60 min.

          Results:

          Maximum mortality was 16% with 1% hydroalcoholic extract in 60 min. The highest mortality with organic extract was 4% with 10% concentration in 60 min ( P=0.015).

          Conclusion:

          Since highest mortality was 16%, the extract did not reach to LD50 (50% mortality). Therefore, the potency of the total extract is not sufficient as potential scolicidal drug.

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          Most cited references17

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          The Monetary Burden of Cystic Echinococcosis in Iran

          Introduction Cystic echinococcosis (CE), a chronic disease caused by the larval form of the tapeworm Echinococcus granulosus, is one of the most important helminth-associated zoonoses globally [1], [2]. The parasite's domestic life cycle involves livestock and dogs as the primary intermediate and definitive hosts, respectively. Canids harboring adult E. granulosus worms excrete eggs into the environment, where intermediate hosts become infected through ingestion of the eggs. Humans can also act as aberrant intermediate hosts if they ingest infective parasite eggs either through contaminated food or directly from an infected canid. A cystic larval form (metacestode) gradually develops, most commonly in the liver or lungs. However, other organs can also be affected. Clinical signs typically develop as a result of this space-occupying lesion exerting pressure on surrounding tissues. Rupture of the cyst and spillage of the contents may cause anaphylactic shock and secondary CE. In many parts of the world, including Iran, surgery remains the treatment of choice for most individuals suffering from CE [2]. Cystic echinococcosis is a cosmopolitan zoonosis, with highly endemic areas especially prevalent in regions of South America, North Africa, China, and the Middle East [2]. Iran is an important endemic focus of CE where several species of intermediate host are commonly infected with E. granulosus [3]. High infection prevalences, with different strains of E. granulosus, have been reported in various domestic livestock including sheep (5.1%–74.4%), goats (2%–20%), cattle (3.5%–38.3%), buffalo (11.9%–70%), and camels (25.7%–59.3%) [4], [5], [6]. Between 5% and 45% of dogs is reported to be infected with E.granulosus in different provinces of Iran (reviewed in [7]). Human CE cases are also regularly reported from medical centers in different parts of the country and the incidence of CE is estimated 1.18-3 per 100,000 populations in different regions [7]. Recently, the World Health Organization (WHO) included CE in a subgroup of selected Neglected Tropical Diseases (NTDs) to be addressed within its 2008–2015 strategic plan for control of NTDs [8], [9]. The WHO recommends that the impact of zoonotic infections be assessed before implementation of any control measure [10], [11]. Costs associated with CE have been shown to have a great impact on affected individuals, their families, and the community as a whole [12], [13]. Monetary losses due to CE have been estimated for Uruguay [14], Wales [15], Jordan [16], Tunisia [17], Turkey [18], Spain [19], Peru [20] and for a highly endemic area of the Tibetan plateau [21], [22]. In addition, the non-monetary burden of CE has been assessed for a highly endemic region of China and globally utilizing the disability adjusted life year (DALY) [23]. Although CE is assumed to be a significant public health and economic problem in Iran, the extent of its socioeconomic impact is not fully understood. Economic losses due to CE in ruminants have been previously estimated in three provinces of Iran (Khuzestan, North Khorasan, and Ardabil) [24], [25], [26]. However, these studies were not concerned with human CE and used potentially biased methods to estimate livestock-related losses. Accurate assessment of the disease burden is crucial to raise awareness of decision-makers and to prioritize use of limited resources to provide timely preventive measures [27], [28]. The purpose of the present study is to estimate the monetary burden of CE in Iran using existing country-level data on human and animal CE. Materials and Methods Human epidemiological data Population data for Iran for 2010 were extrapolated from the 2006 population census, with 71.8% of the population living in urban areas [29]. Due to a lack of surveillance data, the number of CE patients, by age and gender, that underwent surgery between 2000 and 2009 in 34 referral hospitals in seven of the country's most populous provinces (representing 51.4% of the total population) was collected to determine average annual surgical incidence. In total, 5,993 CE surgeries were identified over this 10-year period. For the remaining 23 provinces, data from individual scientific reports were used when available [30], [31], [32], [33]. For those provinces with no data, information from neighboring provinces with similar socioeconomic status was applied. Based on these sources, an annual number of 1,295 CE surgeries was calculated. All CE recurrences with re-operations were regarded as new surgical cases. Approximately 80% of surgical CE cases in Iran are treated in public hospitals, with the remaining 20% treated in private hospitals. Only surgical cases of CE were included in this study due to a lack of data on cases that seek treatment, but that are treated medically. In order to estimate the number of undiagnosed or asymptomatic cases of CE in Iran, data on ultrasound prevalence of CE (1.2% and 0.2%) were used (Table 1) [34], [35]. Lengths of hospital stay and mortality rates were based on available literature (Table 1). 10.1371/journal.pntd.0001915.t001 Table 1 Human epidemiological parameters associated with CE in Iran. Category Value Unit Distribution Range Reference Population (2010) 74,733,230 Individuals Fixed - [29] Urban/Rural 71.8/28.2 Percent Fixed - [29] Average income per day-urban 23.48 US$ Fixed - [29] Average income per day-rural 14.09 US$ Fixed - [29] Annual surgical incidence of CE 1.27 Per 100,000 Uniform 0.80–1.73 See Methods Hepatic cysts 55.5 Percent Fixed - See Methods Pulmonary cysts 30.9 Percent Fixed - [25], [31], [33], [51], [52]* Hepatic and pulmonary involvement 4.1 Percent Fixed - See Methods Other organs 9.5 Percent Fixed - See Methods Undiagnosed cases of CE 0.85 Percent Uniform 0.2–1.5 [34], [35] Length of hospital stay 11.4 Days Uniform 7–15.8 [53], [54], [55] Mortality among surgical cases 2.5 Percent Uniform 1–5 [56], [57], [58] No of absentee days for recovery 18 Days Uniform 8–28 [53], [54] Age and sex distribution ¶ 947 Individuals Uniform 599–1295 See Methods Male patients 0–9 4.6 Percent - - 10–19 14.5 Percent - - 20–29 20.4 Percent - - 30–39 16.9 Percent - - 40–49 13.9 Percent - - 50–59 10.5 Percent - - 60–69 10.1 Percent - - 70–79 7.5 Percent - - 80+ 1.6 Percent - - Total 100 Percent - - Female patients 0–9 3.6 Percent - - 10–19 9.7 Percent - - 20–29 19.0 Percent - - 30–39 19.2 Percent - - 40–49 16.8 Percent - - 50–59 13.9 Percent - - 60–69 10.3 Percent - - 70–79 6.3 Percent - - 80+ 1.2 Percent - - Total 100 Percent - - ¶ Based on surgical incidence. Livestock epidemiological data The livestock species primarily involved in the domestic cycle of CE in Iran are sheep, goats, cattle, buffalo, and camels. Data for livestock populations and annual numbers of slaughtered animals were obtained from official government reports (Table 2) [29]. The low percentage of the total sheep and goat population slaughtered annually (12.8% and 8.5%, respectively) may reflect the practice of slaughtering outside of abattoirs. To account for home slaughtering, losses were also evaluated assuming that slaughter rates are twice what are reported at the abattoirs, assuming a mean of 1.25 offspring per ewe/doe per year. Milk, wool, and hide/skin production values were based on either Statistical Center of Iran (SCI) reports or United Nation's Food and Agriculture Organization (FAO) FAOSTAT data [29], [36]. Livestock prevalence data were obtained from abattoir-based studies available from the literature. Only studies where a researcher confirmed the presence of CE cysts were included because abattoir-reported cases are not considered reliable in Iran. Prevalence data obtained from 3 or more studies were combined for cattle, sheep, and goats using a meta-analysis for proportions in R statistical data analysis software, ver. 2.12.0 (META package version 1.6-1; by Guido Schwarzer) (Table 2) [37]. Due to the limited available data for buffalos, a meta-analysis could not be performed for this species. Therefore, the mean prevalence from two studies on CE in buffalo in Iran (12.4% and 11.9%) was used [5], [26]. 10.1371/journal.pntd.0001915.t002 Table 2 Epidemiological parameters and annual livestock production values for Iran. Category Value (CI) Unit Distribution Reference SHEEP Population 49,976,138 Animals Fixed [29] *No of slaughtered animals/year 6,446,354 Animals Fixed [29] Prevalence of CE at abattoir 23.5 (8–39) Percent Normal [5], [26], [59], [60], [61], [62], [63], [64], [65] Meat production 390,000 Tonne Fixed [36] Milk production 444,004 Tonne Fixed [29] Skin/hide production 64,800 Tonne Fixed [36] Wool production 52,455 Tonne Fixed [29] GOAT Population 22,333,547 Animals Fixed [29] *No of slaughtered animals/year 1,912,640 Animals Fixed [29] Prevalence of CE at abattoir 8 (5–11) Percent Normal [5], [26], [59], [60], [61], [62], [63], [64], [65] Meat production 106,000 Tonne Fixed [36] Milk production 270,157 Tonne Fixed [29] Skin/hide production 18,875 Tonne Fixed [36] Wool production 2,905 Tonne Fixed [29] CATTLE Population 7,088,984 Animals Fixed [29] No of slaughtered animals/year 1,432,270 Animals Fixed [29] Prevalence of CE at abattoir 20 (13–27) Percent Normal [5], [26], [59], [60], [61], [62], [63], [64], [65] Meat production 360,000 Tonne Fixed [36] Milk production 5,965,728 Tonne Fixed [29] Hide/leather production 47,700 Tonne Fixed [36] BUFFALO Population 191,438 Animals Fixed [29] No of slaughtered animals/year 30,926 Animals Fixed [29] Prevalence of CE at abattoir 12.5 Percent Fixed [5], [26] Meat production 14,900 Tonne Fixed [36] Milk production 245,000 Tonne Fixed [29] Hide/leather production 2,048 Tonne Fixed [36] CAMEL Population 151,932 Animals Fixed [29] No of slaughtered animals/year 45,127 Animals Fixed [29] Prevalence of CE at abattoir 32 (15–49) Percent Normal [66], [67], [68], [69], [70], [71] Meat production 1,680 Tonne Fixed [36] * Assuming government-reported slaughter rates for sheep and goats. Human economic data Costs associated with direct and indirect losses associated with human surgical CE were assessed. Direct costs included cost of surgery, hospital accommodation, diagnostic imaging, clinical laboratory and histopathology testing, and drug costs in both public and private hospitals. The Puncture Aspiration Injection Re-aspiration (PAIR) technique, which is widely used in other parts of the world, is rarely used in Iran. Therefore, the procedure was not costed in this study. Unit costs of services were obtained from official tariffs established by the Iranian Ministry of Health and Medical Education [38]. Service costs were calculated by multiplying the unit cost of an individual parameter by its frequency in the course of disease. Expert attending surgeons from Afzalipour Medical Center in Kerman, Iran were asked to estimate the frequency of common CE-associated procedures and services when these data were not available elsewhere. Indirect costs associated with human CE included lost wages due to work absenteeism during hospitalization and recovery, due to time off to stay with a child with CE, and due to CE-related mortality. Income data for urban and rural populations were obtained from official reports of the CBI. Gender specific wage data were not available for Iran or its neighboring countries. Therefore, based on studies conducted in other regions, it was assumed that women earn approximately 0.70 times as much as men [19]. Breakdown of wages by age was also not available for Iran. Therefore, it was assumed that this breakdown would also be similar to the findings from other studies [19]. Unemployment figures were based on SCI data. Productivity for females who do not work outside of the home was assumed to be equivalent to 30% of the daily income of an officially employed female of the same age group [15]. A 100% loss of daily wages or productivity was assumed for CE surgical patients for the period of hospitalization. However, no losses were evaluated for unemployed patients since government unemployment benefits, which are received by all members of society whether they work in the public or private sector, were assumed to remain unchanged during the treatment period. Since unemployment benefit coverage is most likely not complete, the cost estimation is probably underestimated, especially in rural populations. For CE patients under the age of 18 years, a 30% wage loss for a man 30–39 years of age was applied for the period of hospitalization. This was based on the assumption that a parent would need to devote a proportion of his or her time to caring for the child [17], [19]. It was assumed that premature mortality causes an annual income loss of between 1 and 364 days in any given year. Therefore, a uniform distribution was defined for the number of lost days due to CE-related deaths. In asymptomatic individuals, lost wages were calculated in terms of annual monetary income and a productivity loss of 0–5% for one year (Table 1). Livestock economic data Direct and indirect costs due to CE-associated losses in livestock species were evaluated. Direct costs associated with CE in livestock are due to the condemnation of livers and lungs during carcass inspections in abattoirs. A uniform distribution was applied to liver and lungs losses based on market prices across Iran (Table 3). It was assumed that the entire liver and/or lungs of infected cattle, sheep, goats, and buffalo would be condemned. The cost of infected camel livers, but not lungs, was included in the estimate because camel lungs are not traditionally consumed in Iran. 10.1371/journal.pntd.0001915.t003 Table 3 Value of livestock parameters (per Kg) used to estimate the monetary burden of CE in Iran. Category Value (US$) Distribution Range Reference SHEEP Live animal 2.86 Uniform 2.46–3.26 [29], [36] Liver 10.12 Uniform 8.67–11.56 [72] Lung 10.12 Uniform 8.67–11.56 [72] Milk 0.50 Fixed - [36] Hide/skin 1.64 Fixed - [73] Wool 0.59 Fixed - [29] GOAT Live animal 2.78 Uniform 2.40–3.16 [29], [36] Liver 10.12 Uniform 8.67–11.56 [72] Lung 10.12 Uniform 8.67–11.56 [72] Milk 0.48 Fixed - [36] Hide/skin 1.14 Uniform 0.63–1.64 [73] Wool 0.59 Fixed - [29] CATTLE Live animal 2.54 Uniform 2.26–2.81 [29], [36] Liver 8.67 Uniform 7.71–9.63 [72] Lung 0.27 Uniform 0.24–0.29 [72] Milk 0.38 Fixed - [36] Hide/leather 1.14 Uniform 0.63–1.64 [73] BUFFALO Live animal 2.54 Uniform 2.26–2.81 [29], [36] Liver 8.67 Uniform 7.71–9.63 [72] Lung 0.27 Uniform 0.24–0.29 [72] Milk 0.51 Fixed - [36] Hide/leather 1.14 Uniform 0.63–1.64 [73] CAMEL Live animal 1.21 Fixed - [36] Liver 8.67 Uniform 7.71–9.63 [72]* Milk 0.38 Fixed - [36]* • Assumed to be similar to that of cattle. Indirect losses due to decreased carcass weight, reduction in milk production, decreased wool production, decreased hide/skin value, and reproductive losses were estimated. Values of livestock parameters used to estimate economic losses associated with CE were assumed to be similar to those used in previous assessments of livestock-associated CE losses [16], [17], [19], [21]. Based on these values, a 2.5% decrease in milk production, 15% reduction in wool quality, 5.5% reduction in fecundity, 10% decrease in hide/skin production, and 6.25% reduction in carcass weight were utilized for this study. Farmers' investment was not taken into account in the presented cost estimates due to lack of data on this topic available from Iran or other countries in this region. Uncertainty and sensitivity analysis Data were compiled in Excel spreadsheets (Microsoft Corp, Redmond, WA). The risk analysis and simulation software @RISK (Palisade corp., Ithaca, NY, ver. 4.5) for Excel was used to estimate monetary costs attributed to CE infection in humans and livestock. Output variables were defined according to parameters involved in the estimation of direct and indirect costs associated with CE in humans and livestock intermediate hosts (Table 4). Distributions were assigned based on the most likely range for each variable. Median and 2.5 and 97.5 percentiles (95% credible intervals, CIs) were calculated for each output variable. Monte Carlo simulation using a Latin Hypercube approach with 10,000 iterations was performed to model parameter uncertainty. A sensitivity analysis was conducted using stepwise linear regression of the estimated costs against the input parameter values to assess the impact of each input parameter on the overall cost estimate. A separate sensitivity analysis was run excluding losses related to asymptomatic/non-healthcare seeking human CE cases. 10.1371/journal.pntd.0001915.t004 Table 4 Annual direct and indirect costs associated with CE in humans and livestock in Iran. Category Median cost (US $) 95% CI HUMAN Costs of hepatic CE 593,485 410,640–818,157 Costs of pulmonary CE 261,800 189,390–340,775 Costs of CE in liver and lung 75,420 53,198–100,919 Costs of CE in other organs 101,456 70,080–139,730 Direct costs of CE 1,097,950 855,548–1,381,656 Indirect costs of CE§ 372,613 188,873–576,448 Indirect costs of CE¶ 97,527,670 9,712,122–206,574,100 Total costs of human CE§ 1,470,564 1,158,458–1,817,444 Total costs of human CE¶ 98,625,620 10,739,470–207,912,300 * SHEEP Direct costs of CE 12,524,960 4,047,542–22,354,430 Indirect costs of CE 59,036,660 4,047,542–22,354,430 Total costs of sheep CE 71,551,620 16,585,770–152,227,400 * GOAT Direct costs of CE 1,074,601 608,845–1,610,484 Indirect costs of CE 6,031,210 1,271,019–12,306,230 Total costs of goat CE 7,105,811 2,235,714–13,586,770 CATTLE Direct costs of CE 9,992,240 6,412,567–13,777,960 Indirect costs of CE 47,920,830 18,608,570–84,215,220 Total costs of cattle CE 57,913,070 27,012,570–96,117,080 BUFFALO Direct costs of CE 131,108 114,636–148,589 Indirect costs of CE 787,311 314,762–1,273,489 Total costs of buffalo CE 918,418 445,066–1,403,014 CAMEL Direct costs of CE 13,433 6,201–20,886 Indirect costs of CE 586,974 175,347–1,140,535 Total costs of camel CE 600,406 184,034–1,158,064 All animals Direct costs 23,726,340 14,323,200–34,387,130 Indirect costs 114,363,000 51,049,920–196,475,100 Total costs of animal CE 138,089,300 69,524,500–226,669,800 Direct costs of CE in human and animals 24,824,290 15,425,180–35,444,500 Indirect costs of CE in human and animals § 114,735,600 51,377,930–196,922,400 Indirect costs of CE in human and animals ¶ 211,890,700 96,003,140–344,185,200 TOTAL MONETORY COSTS OF CE IN IRAN § 139,559,900 71,095,360–228,152,000 TOTAL MONETORY COSTS OF CE IN IRAN ¶ 236,714,900 117,690,300–373,694,500 * Assuming government-reported slaughter rates for sheep and goats. § Excluding asymptomatic/non-healthcare seeking human population. ¶ Including asymptomatic/non-healthcare seeking human population. Results Human CE costs Table 4 contains estimates of the annual direct and indirect costs associated with CE in humans in Iran. The cost of surgical treatment for a case of hepatic or pulmonary CE in a public hospital was estimated at US$1,027 (95% CI US$676–1,379) and US$851 (95% CI US$528–1,173), respectively. The corresponding values for surgical treatment of CE in a private hospital were estimated at US$1,911 (95% CI US$1,431–2,387) for hepatic and US$2,458 (95% CI US$1,976–2,939) for pulmonary involvement. The overall annual cost of CE in Iran was estimated at US$232.25 million (95% CI US$103.11–397.84 million). The cost associated with human CE was estimated at US$93.39 million (95% CI US$6.11–222.72 million), of which US$1.09 million (95% CI US$820,000–1.44 million) and US$92.34 million (95% CI US$5.01–221.55 million) were attributed to direct and indirect costs, respectively. Human CE contributed to more than 40% of the total annual cost of CE in Iran. This was mainly due to the impact of human productivity losses in the asymptomatic/non-healthcare seeking population. This figure decreased to 1.1% of the total estimated cost when productivity losses in the asymptomatic/non-healthcare seeking population were excluded. Direct costs of human CE were estimated at 1.2% of the total cost of human disease. However, direct costs accounted for three quarters of the economic losses in surgical CE cases. Livestock associated CE costs Assuming government slaughter values, the median annual cost associated with CE in livestock was estimated at US$132.0 million (95% CI US$61.8–246.5 million), of which US$23.5 million (95% CI US$12.7–36.5 million) was direct and US$108.4 million (95% CI US$45.0–216.9 million) was indirect cost. Sheep and cattle CE were responsible for 48% and 42% of the total economic losses due to livestock CE in Iran, respectively. Direct costs associated with CE in livestock accounted for 10.1% of the overall cost of the disease. Indirect costs associated with CE in livestock were primarily due to losses in fecundity and milk reduction. Indirect costs due to CE in livestock intermediate hosts comprised more than 80% of the total livestock-associated costs of CE and approximately 47% of the overall cost of CE in Iran. Costs associated with sheep and goat CE, assuming the practice of home slaughtering, are found in Table 5. 10.1371/journal.pntd.0001915.t005 Table 5 Estimated monetary losses associated with CE in Iran based on two scenarios for home slaughtering. Scenarios Direct costs, US$ (95% CI) Indirect costs, US$ (95% CI) Direct and indirect costs, US$ (95% CI) Government reported values assuming that 12.8% of sheep and 8.5% of goats are slaughtered annually. Sheep 12,524,960 (4,047,542–22,354,430) 59,036,660 (9,746,846–133,468,100) 71,551,620 (16,585,770–152,227,400) Goat 1,074,601 (608,845–1,610,484) 6,031,210 (1,271,019–12,306,230) 7,105,811 (2,235,714–13,586,770) Total 13,589,560 (5,037,907–23,589,440) 65,067,870 (15,316,950–139,935,100) 78,657,420 (22,988,640–159,876,500) Adjusting for home slaughtering assuming that 25% of sheep and 17% of goats are slaughtered annually. Sheep 25,048,910 (8,168,014–44,242,900) 63,456,400 (12,570,030–140,369,500) 88,505,300 (24,126,530–177,011,800) Goat 2,149,359 (1,225,908–3,259,446) 6,400,930 (1,580,594–12,635,600) 8,550,289 (3,359,383–15,273,460) Total 27,198,270 (10,138,330–46,741,520) 69,857,330 (18,569,920–146,739,300) 97,055,590 (32,653,080–186,131,500) Sensitivity analysis The impact of uncertain parameters on the total monetary burden of CE in Iran and the corresponding regression coefficient values are shown in Figure 1. Productivity losses in asymptomatic individuals, CE prevalence in sheep, and fecundity losses in sheep and cattle had the largest impact on overall cost of the disease (Figure 1a). When productivity losses in asymptomatic/non-healthcare seeking individuals were excluded, fecundity losses and CE prevalence in sheep and cattle had the largest overall impact (Figure 1b). 10.1371/journal.pntd.0001915.g001 Figure 1 Regression coefficients of parameters associated with the total cost of CE in Iran. Discussion Estimating the economic impact of a zoonotic disease is a way of quantifying the significance of the disease in both human and livestock populations. In addition, this type of analysis helps decision-makers prioritize resources for disease control and prevention. The aim of the present study was to estimate the economic impacts of CE in Iran. Findings indicated that CE costs Iran more than US$230 million per year. This is a considerable burden as this equates to about 0.03% of the country's Gross Domestic Product (GDP). A value of 0.03% of the country's GDP is in line with the findings of other studies where this value ranged from 0.003% to 0.04% of GDP (Table 6). 10.1371/journal.pntd.0001915.t006 Table 6 Human and livestock population and the proportion of GDP lost due to CE in different countries. Country Human population (million humans) Livestock population (million animals) Total cost of CE (US$ million) % GDP lost Reference Sheep Goat Cattle Iran 74.7 49.9 22.3 7.1 232.3 0.03 Present study Spain 43.0 22.7 2.9 6.5 200 0.01 [19] Turkey 74.7 25.5 6.3 11.0 89¶ 0.01¶ [18] Tunisia 9.6 7.2§ 1.3 0.8 14.7 0.03 [17] Uruguay 3.2 25.0 0.016§ 10.4 9.0 0.04 [14] Peru 26.2 14.2§ 1.9§ 5.5§ 6.3 0.003* [20] Jordan 4.4 1.2 0.5 0.7§ 3.9 0.04 [16] ¶ Cost of animal CE only. § From FAOSTAT, 2010. * Indirect human losses not accounted for. The overall cost of CE in Iran was estimated to be higher than the CE-associated monetary losses for other countries, including Jordan (US$ 3.9 million), Uruguay (US$ 9.0 million), Tunisia (US$ 14.7 million), Turkey (US$ 89 million- livestock losses only), and Spain (US$ 200 million) [14], [15], [16], [18], [19]. This is partly the result of larger human and livestock populations in Iran compared to the other studied countries (Table 6). Iran is the third most populous and second largest country in the Middle East and has the fourth largest sheep population in the world [36]. However, direct comparison of economic losses associated with CE from different countries is difficult since past studies have used a variety of methodologies to arrive at cost estimates. In previous studies on ruminant echinococcosis economic losses due to CE have been estimated using conventional calculation methods. Livestock CE-related losses were estimated at US$459,660 in the city of Ahwaz [25], at US$421,826 in nine districts of North Khorasan province [24] and at US$51,900 in Ardabil province [26]. Based on the results of this study, the monetary burden of CE in Iran is substantial, especially when indirect costs due to productivity losses in the asymptomatic/non-healthcare seeking population were taken into consideration. Productivity losses for asymptomatic/non-healthcare seeking individuals added about US$ 100 million to the overall cost estimate of CE in the country. This estimate was based on the two community-based ultrasound studies that have been carried out in Iran. However, this was not optimal since both of the studies were conducted in rural/nomadic populations. Nevertheless CE cases are increasingly reported from urban regions. The number of CE cases from rural and urban areas was shown not be significantly different in Iran. Several studies have shown that CE is equally prevalent in rural and urban regions, especially due to the increased recreational/camping activities of the urban population and large migrations of people from rural to the urban/peri-urban regions of the country during last three decades [31], [39]. This same phenomenon has been documented in other countries, including Serbia [40], Croatia [41] and Libya [42]. Like other NTDs prevalent in less developed countries, it appears that CE is being urbanized and can no longer be considered solely as a rural disease [43], [44]. The ratio of community ultrasound prevalence to the annual surgical incidence of CE was 669.3, which is higher than the ratio of 45.4 found in Florida, Uruguay [45], the ratio of 22 to 344 for Turkey [46], [47], and the ratio of 241 for Morocco [47]. However, the value is comparable with the ratio of 405 to 1,889 determined for Libya [47], [48]. While this may mean that the number of asymptomatic/non-healthcare seeking individuals in Iran was overestimated, it also could indicate that health-seeking behavior of Iranians is different from that of people in other countries. Compared to Uruguayans, Turks, and Moroccans, Iranians may have either less access to health care or do not seek health care services provided in the country due to different health-seeking behaviors. Differences in the pathogenicity of E. granulosus genotypes/strains may also explain this dissimilarity since it is generally believed that genotypes of E. granulosus can differ in infectivity and/or clinical severity [49]. By applying the ratios for Turkey (334) and Uruguay (45.4) to the incidence rate of surgical cases in Iran, the prevalence of asymptomatic/non-healthcare seeking cases of CE would be 0.23% and 0.06%, respectively compared to the estimated 0.85% used in this study. A limitation of this study was how to assess productivity losses for those individuals who were not formally employed. Based on limited available data, a 30% productivity loss was assumed for women who are not officially employed outside of the home. This value was chosen because a sick homemaker indirectly affects the entire family's productivity and increases living costs of the family. Indirect costs of CE in humans and livestock accounted for more than 80% of overall monetary losses in this study, which is in agreement with the results of other studies in endemic areas [14], [15], [16], [17], [18], [19], [21]. Indirect costs reflect economic effects of the disease that are often not taken into consideration by agriculture and health officials. Indirect costs associated with human CE treatment were probably underestimated in this study. Additional indirect costs may include expenses associated with travel from a rural area to the city, or from one urban area to another urban area to seek appropriate health care, as well as expenses due to an accompanying spouse or other member of the family. Additional studies are needed in order to provide better evidences of the true impact of indirect losses due to CE in both humans and livestock intermediate hosts. Availability of high quality epidemiological and economic data is crucial for improving the accuracy of the estimation. Lack of age-stratified CE prevalence data for livestock was another limitation of the present study. However, abattoir-based CE prevalence data tends to be underestimated due to the fact that, in Iran, animals that are slaughtered in abattoirs tend to be young and, therefore, have a lower chance of being infected compared to older animals. Another important issue is the unexpectedly low proportion of the sheep and goat population reported to be slaughtered each year (12.8% and 8.5%, respectively). These figures reflect animals that are slaughtered in registered abattoirs, which is almost definitely an underestimation. Many people, especially those living in rural/suburban areas, practice home slaughter. In addition, a number of unregulated abattoirs also exist within the country. However, the extent of slaughtering outside official channels is not fully understood and needs to be investigated. To account for the practice of home slaughter, a second scenario was considered assuming that 25% and 17% of sheep and goat populations are slaughtered every year, respectively. As expected, this second scenario resulted in both increased direct and indirect costs for these species (Table 5). However, the overall effect of the second scenario on the total monetary cost of human and animal CE was relatively small (i.e., a 7.7% increase from US$236.7 million to US$254.9 million). Regarding the high proportion of camel population reported to be slaughtered each year (29.7%) that seems very high for such a long-lived animal, we retrieved camel data from official sources (Statistical Center of Iran). Underestimation of the total population of camels is quite probable because of the very traditional nature of camel farming in the country and illegal import of camels across the eastern border. Findings of the present study indicate that CE imposes a substantial economic impact on Iran. Reduction of human and livestock infection through implementation of CE control programs is necessary to reduce the economic burden of CE on the country. Cost-benefit analysis of different control programs is now possible in light of present knowledge on the economic losses associated with CE in Iran. However, because comparing monetary costs in different countries with different socioeconomic statuses is often not optimal, a complementary analysis of the non-monetary burden of CE is recommended to compare CE burden in different geographical regions. In addition, evaluation of the non-monetary burden of the disease and measurement of cost per DALY averted by the control campaigns is recommended. Therefore, a paper evaluating CE-associated DALYs in Iran is currently in preparation. This is the first study to evaluate monetary losses due to human and livestock CE in Iran. However, additional research is needed to improve CE monetary burden estimates and to develop uniform methodologies for assessment [17], [50]. Supporting Information Checklist S1 STROBE checklist. (DOC) Click here for additional data file.
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            Cystic Echinococcosis: Chronic, Complex, and Still Neglected

            The Overall Scene Cystic echinococcosis (CE), an infection with the larval form of the dog tapeworm Echinococcus granulosus, still causes serious lung and liver disease with a worldwide geographical distribution. This parasitic infection is preventable, eliminable, and treatable—in theory. The biological cycle can be attacked at various points: regular dog deworming, controlled sheep slaughtering, vaccination of the intermediate (sheep) animal host, and possibly in the future, vaccination of the definitive (dog) animal host (Figure 1). However, breaking the cycle in practice is difficult and requires long-lasting efforts. Control programs are expensive to set up and sustain. With the currently available options, a period of 20 years is needed to reach elimination, a goal that, unsurprisingly, has only been reached in rich countries [1]. 10.1371/journal.pntd.0001146.g001 Figure 1 Life cycle of Echinococcus granulosus in a community of the Middle Atlas region, Morocco. (We thank M. Kachani, College of Veterinary Medicine, Western University of Health Sciences, for the pictures.) At the current pace of control, patients suffering from CE will be seen for many decades to come. CE disease is chronic, complex, and neglected [2]–[4]. It is still poorly understood, and recommendations for diagnosis and treatment have not progressed beyond expert opinions and are not necessarily adopted by clinicians because of lack of grade I evidence. The critical issues are: 1. CE may develop silently over years and even decades until it surfaces with signs and symptoms or as a chance finding on an ultrasound (US) scan or chest X-rays requested for unrelated reasons. Clinical manifestations may mean that the cyst is already complicated, e.g., ruptured into the biliary or bronchial tree, secondarily infected with bacteria, or leaking and causing allergic reactions if not anaphylactic shock. 2. Screening large samples of populations to detect asymptomatic cases is expensive. As with all screening procedures, ethical issues arise: do all patients in whom cysts are found require treatment? Is the treatment which we then offer well established and safe? And is it available at all? Screening projects in endemic areas are often inadequately prepared, as the clinical management is not provided locally for those who are found positive. Problems start with the screening tool. With the exception of liver US, the available methods are far from satisfactory. In regards to serology, the sensitivity and specificity of several antigens have been well defined [5], [6], but available assays still lack standardization, sensitivity, and specificity [7]. Controversies on the usefulness for clinical diagnosis and screening remain unresolved [8]. Serodiagnostic performance depends on several factors, such as cyst location, cyst stage, and even cyst size, but these and other variables have not been thoroughly assessed to date. Ultrasound is an indispensable tool, but will likely miss very small cysts, and its efficacy is mostly restricted to intraabdominal organs. Additionally, some cyst stages may be difficult to distinguish from non-parasitic cysts, which are common. The problem continues when an echinococcal cyst has been diagnosed. In settings where health care facilities are several days of travel away from the rural areas where patients live and work, and as long as we have doubts on what the natural evolution of their cysts will be, clinical decision making is difficult. It has to be done in each case individually based on current standards, clinicians' experience, and local technical possibilities, supported by embarrassingly poor evidence. 3. Not all CE patients are similar, even at a population level. Broadly speaking, there are two defined groups of patients, each with a different set of problems: mainly asymptomatic patients (detected in screening programs or by chance), or clinically apparent cases (mostly patients with complicated cysts). (a) Patients with cysts detected during screening activities or as a chance finding. They mostly receive the treatment with which the attending clinician is familiar. This is not necessarily the best option relative to the cyst stage and clinical situation of the patient. Preliminary results from a survey on knowledge, attitudes, and practices regarding clinical management of CE in European, North African, and Middle Eastern countries yielded alarming results [9]. Patients may be put at risk of interventions that may be completely unnecessary. This certainly applies to a sizeable number of cysts that have become inactive and do not cause any symptoms or complications. A significant proportion of cysts stop growing and follow a path to spontaneous involution. Long-term follow-up suggests that these cysts and the patients harbouring them should be left alone. This is an appealing perspective for patients and health services, if evidence can be gathered in its support. CE4 and CE5 cysts appear to be very good candidates for this approach if they do not compromise any vital structures. It is, however, unclear if and under which circumstances this concept can be extended to other cyst types. (b) Patients developing complications. Successful management depends on equipment, skills, and quality of available health services. The most common complications are biliary obstruction with or without cholangitis, bronchial obstruction, bacterial infection of the cyst cavity with abscess formation, rupture with anaphylactic reactions that range from mild to lethal anaphylactic shock, secondary echinococcosis (growth of new cysts caused by seeding of protoscolices, generally in a cavity such as the peritoneal space) following spillage of fluid from a cyst that ruptured either spontaneously or because of a therapeutic maneuver, and impaired function of organs and blood vessels compressed by growing adjacent cysts (Figure 2). In most endemic countries, the required setup is only met in major cities a long way off from where patients experiencing complications live. 10.1371/journal.pntd.0001146.g002 Figure 2 Severe and life threatening complications of CE. (A) Biliary obstruction/obstructive cholangitis due to biliary fistulas. (B) Liver abscess formation due to secondary bacterial infection of cysts. (C) Cyst rupture (*) followed by anaphylaxis and secondary echinococcosis. (D) Cysts exerting pressure on vital neighbouring structures (e.g., liver veins resulting in Budd-Chiari Syndrome). (E) Embolism of the right pulmonary artery (arrow) caused by cardiac CE and vascular invasion. (F) CE infestation of the posterior wall of the left heart replacing the myocardial layer at the base of the heart. (We thank W. Hosch, Department of Radiology, and A. Stiehl, Department of Gastroenterology, University Hospital Heidelberg, for the images.). What Is Available Today to Diagnose and Treat CE Patients? Ultrasound is well established as a tool to diagnose, stage, and follow up CE cysts in the liver and other locations. Gharbi and colleagues developed the first widely adopted US classification in 1981 [10]. Other classifications were subsequently produced but were not as widely used. In 1994, the World Health Organization (WHO)-Informal Working Group started developing an international standardised US classification that could be universally applied to replace the plethora of classifications previously used (Figure 3) [11]. Even with all the obvious advantages of a standardised classification, some important issues still need to be resolved, one being the right sequence of cyst stages seen as the effect of natural or treatment-induced involution. A recent assessment of metabolic profiles of cyst stages with high-field proton magnetic resonance spectroscopy (1H MRS) has shown that the WHO IWGE classification of active, inactive, and transitional stages is perfectly in line with the metabolic activity profiles of the cysts, with the exception of CE3b, which appears vigorously active in 1H MRS, a finding that corresponds well with clinical experience [12]. US has been confirmed as an invaluable tool to assess cysts both with respect to viability and potential complications (Figure 2). 10.1371/journal.pntd.0001146.g003 Figure 3 Comparison of Gharbi's and WHO-IWGE ultrasound classifications of CE cysts. CL, as a potentially parasitic cyst, was not in Gharbi's classification and needs to be differentiated from non-parasitic cysts. This may also happen with CE1 cysts, when the double layer sign is not evident. Also, WHO CE3b had not been explicitly described by Gharbi but could likely be classified as Type III. There are basically four management options: surgery, percutaneous sterilization techniques, anti-parasitic treatment, and observation (“watch & wait”). Their individual roles were recently reviewed [2]–[4]. Each of the four strategies certainly has its place, but the specific places and boundaries are still not well defined. Surgery, the oldest form of treatment, keeps its place in most of the complicated forms of the disease. There is some competition between surgery and percutaneous approaches, in particular modified catheterization techniques, to be resolved, but this comparison requires carefully designed studies and cannot be decided on the basis of exclusively non-comparative small clinical studies, which are the only ones currently available. Proponents of classical PAIR (punction, aspiration, injection, reaspiration) [13] have lost a bit of their enthusiasm after realizing that some cyst stages, such as CE2 and CE3b, are quite tedious to needle with too many compartments to be individually approached. But most importantly, these stages tend to relapse after PAIR. It remains to be seen whether large modified catheterization techniques can substitute for PAIR in these stages. Over the past decade, several studies have been published suggesting that medical therapy (mebendazole, albendazole) could be an alternative to invasive treatment options in patients with uncomplicated cysts, broadening the indication for medical treatment over the years. The individual studies were all small and heterogeneity precluded appropriate meta-analysis. A recently published pooled analysis of individual patient data collected from six treatment centres suggests that the overall efficacy of benzimidazoles has been overrated [14]. Clinical trials stratified by cyst stage are needed to define the place of anti-parasitic treatment in the treatment of CE since it appears that it works better in some cyst stages (e.g., small CE1 cysts) than in others. The rate and nature of side effects of prolonged application of benzimidazole also deserves to be investigated more rigorously. Other anthelmintics, old and new (praziquantel, nitazoxanide), and combinations of anthelmintics (e.g., albendazole plus praziquantel) need to be properly investigated, too. Though so far not systematically studied, experience with leaving certain cysts completely alone and only following them up over years, points to a fourth managing option, watch & wait. Apart from being biologically plausible, long term follow-up of patients with CE4 and CE5 cysts in anatomically silent corners of the body looks good. This holds great promise for patients in whom cysts have reached this stage and needs to be urgently systematically studied. Reasons for Arrested Progress in CE Difficult, chronic diseases with a low case fatality rate clustering in poor rural areas are particularly “unattractive” to researchers and funders who depend on quick results to maintain the momentum of their activities. CE shares this fate with other communicable diseases, such as neurocysticercosis and Buruli disease. Health services also turn a blind eye on them since they plainly lack the means to manage patients with complex diseases such as CE appropriately. This is reflected in the low attention national and international institutions are paying to CE despite its substantial global burden, which is estimated at over 1 million DALYs per year [15], [16]. Additionally, due to its global distribution pattern, CE is not taking advantage of the attention that is being paid to “tropical” diseases. Interestingly, CE never made it to the list of the “TDR diseases” (from the WHO Special Programme for Research and Training in Tropical Diseases). The scarcity of resources and lack of momentum leads research to develop in niches with research communities too small to plan and conduct projects on a scale that allows conclusive answering of the relevant questions on efficacy, effectiveness, adverse reactions, and costs of a given treatment in comparison to other options. Currently available data arise from a multitude of small underpowered studies carried out over years, leading to contradicting results and recommendations, and, consequently, to controversies and difficulties (e.g., randomization) when planning appropriately designed clinical trials. What Do We Need to Improve CE Management in the Short Term? Here is a most clinically neglected parasitic disease that urgently needs attention. A valuable tool for diagnosing, staging, and following up patients, ultrasound, is readily available. Four management procedures, surgery, percutaneous sterilization techniques, anti-parasitic treatment, and watch & wait, have “evolved” over decades, and been recently summarized [4], but without adequate comparative evaluation of efficacy, effectiveness, rate of adverse events, relapse rates, and cost. Clinical decision making is on even shakier ground for extrahepatic and extrapulmonary locations, which are rarer (see [4] for a list of extrahepatic and extrapulmonary locations with related treatments), and numbers needed to build comparative trials hard to come by. There is an obligation to put at least what we have on an appropriate evidence base by conducting comparative clinical trials at the scale and quality that allow answering these important questions. As one of the expected results, clear criteria for the watch & wait option alone might already save a substantial proportion of patients from unnecessary interventions and save health services money. Difficult chronic diseases clustering in poor rural areas need intelligent, creative approaches, and this one urgently needs operational research incorporating the particularities of resource-poor settings into consideration.
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              Echinococcosis--an international public health challenge.

              This review aims to summarise some of the recent studies that have been undertaken on parasites of the genus Echinococcus and the diseases which they cause. Although the adult parasite, which inhabits the intestine of various carnivore species is not pathogenic, the larval or metacestode stages can be highly pathogenic, causing economic losses to livestock and various forms of echinococcosis in humans, some of which have a high fatality rate. There is growing evidence that there are at least 5 species of Echinococcus rather than the generally accepted 4 species. Within these species there are a number of genotypes or strains. This can have implications for surveillance and control. In some wealthy countries, cystic echinococcosis caused by Echinococcus granulosus has been successfully controlled or indeed eradicated. However, in most parts of the world it remains a serious threat to human health. In the former Soviet Union, the disease has rapidly increased in incidence after the end of communist administration. Human alveolar echinococcosis, caused by Echinococcus multilocularis, is more sporadic. However, in some Chinese communities there is a disturbingly high human prevalence and in Europe there has been an increase in the detection rate of E. multilocularis in animals in the last 10 years. Echinococcosis can present diagnostic challenges, particularly in the definitive host in areas of low endemicity. Much of the recent work relating to the use of coproantigen and PCR to overcome these difficulties is summarized. New ideas for controlling the parasite are becoming available and these include both the use of vaccination and the application of mathematical models to determine the most cost effective means of control. Effective measures that are affordable are vital if the parasite is to be controlled in poor countries.
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                Author and article information

                Journal
                Iran J Parasitol
                Iran J Parasitol
                IJPA
                IJPA
                Iranian Journal of Parasitology
                Tehran University of Medical Sciences
                1735-7020
                2008-238X
                Jan-Mar 2020
                : 15
                : 1
                : 76-83
                Affiliations
                [1. ] Department of Pharmaceutics, School of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran
                [2. ] Department of Medical Parasitology and Mycology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
                [3. ] Zoonosis Research Center, Tehran University of Medical Sciences, Tehran, Iran
                [4. ] Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
                [5. ] School of Traditional Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
                [6. ] Department of Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
                Author notes
                [* ] Correspondence Email: b-nikmanesh@ 123456tums.ac.ir
                Article
                IJPA-15-76
                7244846
                3297ee40-fe99-44fb-a8fe-2b0c8e1baa5d
                Copyright© Iranian Society of Parasitology & Tehran University of Medical Sciences

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 13 March 2019
                : 20 July 2019
                Categories
                Original Article

                Parasitology
                cucurbita moschata,pumpkin seed extract,echinococcus granulosus,scolicidal effect
                Parasitology
                cucurbita moschata, pumpkin seed extract, echinococcus granulosus, scolicidal effect

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