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Cardinale V, Semeraro R, Torrice A, Gatto M, Napoli C, Bragazzi MC, Gentile R, Alvaro D. Intra-hepatic and extra-hepatic cholangiocarcinoma: New insight into epidemiology and risk factors. World J Gastrointest Oncol 2010; 2(11): 407-416
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Domenico Alvaro, MD, Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy. firstname.lastname@example.org
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Vincenzo Cardinale, Rossella Semeraro, Alessia Torrice, Manuela Gatto, Cristina Napoli, Maria Consiglia Bragazzi, Raffaele Gentile, Domenico Alvaro, Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza University of Rome, 00185 Rome, Italy
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Author contributions: Cardinale V and Alvaro D provided substantial contributions to conception and design, drafting and revising the article; Semeraro R, Torrice A, Gatto M, Napoli C, Bragazzi MC and Gentile R provided contributions to literature evaluation and collection and to revising the manuscript.
Correspondence to: Domenico Alvaro, MD, Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy. email@example.com
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Received: August 3, 2010 Revised: November 4, 2010 Accepted: November 11, 2010 Published online: November 15, 2010
Cholangiocarcinoma (CCA) is a malignant tumour that arises from biliary epithelium at any portion of the biliary tree. CCA is currently classified as intra-hepatic or extra-hepatic CCA (EH-CCA). Recent evidences suggest that intra-hepatic CCA (IH-CCA) and EH-CCA are biologically different cancers, giving further support to a number of recent epidemiological studies showing large differences in terms of incidence, mortality and risk factors. The purpose of this manuscript is to review recent literature dealing with the descriptive epidemiology and risk factors of CCA with a special effort to compare IH- with EH-CCA.
Citation: Cardinale V, Semeraro R, Torrice A, Gatto M, Napoli C, Bragazzi MC, Gentile R, Alvaro D. Intra-hepatic and extra-hepatic cholangiocarcinoma: New insight into epidemiology and risk factors. World J Gastrointest Oncol 2010; 2(11): 407-416
Cholangiocarcinoma (CCA) is a malignant tumour that arises from biliary epithelium at any portion of the bile duct system, from bile ductules to the ampulla of Vater[1,2]. Intra-hepatic cholangiocarcinoma (IH-CCA) develops within the liver parenchyma while extra-hepatic cholangiocarcinoma (EH-CCA) involves the biliary tree within the hepatoduodenal ligament. EH-CCAs are further divided into hilar or distal tumours. Hilar CCA, also called Klatskin tumour, is located within 2 cm from the bifurcation of the common duct. Distal EH-CCA may affect the middle or the distal portion of main bile duct. A number of recent studies have focused on the role of stem cells in the origin of cancer. It has been elucidated that stem cells, due to their biologic features, are particularly prone to be involved in the carcinogenic process. When a liver stem/progenitor cell on its way to differentiation develops into cancer (maturation arrest), this can give rise to tumours with a whole range of phenotypes with varying hepatocellular and cholangiocellular differentiation characteristics. Stem cell niches have been identified in the canals of Hering/bile ductules[6-8]. They can differentiate into hepatocytes and cholangiocytes and, as postulated by different authors, can give rise to hepatocarcinoma (HCC), IH-CCA and combined hepato-cholangiocarcinoma (cHCC-CCA), a rare form of intrahepatic cancer formed by cancer cells sharing features of both HCC and CCA. More recently, we have found convincing evidence of the presence of additional stem cell niches located at the base of peribiliary glands (PBGs), distributed along the wall of the biliary tree. PBGs start intrahepatically at the level of the segmental ducts and are particularly dense in the extrahepatic biliary tree at the level of cystic duct, hilum and periampullary region, the sites where most EH-CCAs emerge. As intra-hepatic and extra-hepatic PBGs are indistinguishable from one another, we assume that these stem cell niches are the source of cells for cell turnover in all bile ducts distal to the interlobular bile ducts as well as sites vulnerable to oncogenic transformation. This allows us to hypothesize that IH-CCA could arise from two distinct cellular lineages: one lineage originating from liver stem cells residing in the canals of Hering and one originating from the stem cells within the PBGs (Figure 1). These advances in stem cells location and other recent evidences suggest that IH-CCA and EH-CCA are biologically different cancers, giving further support to a number of recent epidemiological studies showing large differences in terms of incidence, mortality and risk factors. The purpose of this manuscript is to review recent literature dealing with the descriptive epidemiology and risk factors of CCA with a special effort to compare IH- with EH-CCA.
Figure 1 Hypothesized origin of intra-hepatic cholangiocarcinoma and extra-hepatic cholangiocarcinoma.
Stem cell niches have been identified within the liver in the canals of Hering (red stars). Hepatic stem cells can differentiate into hepatocytes and cholangiocytes and can give rise to hepatocarcinoma (HCC), intra-hepatic cholangiocarcinoma (IH-CCA) and combined hepato-cholangiocarcinoma (cHCC-CCA). Convincing evidences are achieved on the presence of additional stem cell niches located at the bottom of peribiliary glands (PBGs) (blue stars). PBGs are mucous tubulo-alveolar glands, found deep within the ducts wall distributed along the biliary tree, starting intra-hepatic from the septal ducts. Proliferation of cells within PBGs, observed in chronic diseases or associated with malignancies, follow a pattern similar to that with typical stem cell compartment activation. PBGs are particularly dense in cystic duct, hilum and periampullary region, which are sites where extra-hepatic cholangiocarcinoma (EH-CCAs) typically emerge (encircled blue stars). As the intra-hepatic PBGs are indistinguishable from the extra-hepatic ones, we assume that these stem cells niches are sources for cell turnover of entire bile ducts distal to the interlobular bile ducts as well as sites vulnerable to oncogenic transformation. When a liver or biliary stem/progenitor cell on its way to differentiation develops into cancer, this can give rise to tumours with a whole range of phenotypes. This allows us to hypothesize that IH-CCA could arise from two distinct cellular lineages: the lineage originating from the liver stem cells residing in the canal of Hering, giving rise to a range of phenotypes from HCC to CCA comprising cHCC-CCA and the one originating from stem cells within the PBGs, giving rise to a range of phenotypes from CCA to mucinous adenocarcinoma. CCA risk factors associated to IH-CCA rather than EH-CCA are demonstrate to involve differently and specifically each of the two lineages, with the chronic parenchimal liver diseases affect the one from canals of Hering and chronic biliary disease (excluded PBC) and liver fluke affect the one from the PBGs.
CLASSIFICATION OF CHOLANGIOCARCINOMA IN EPIDEMIOLOGIC STUDIES
CCA is classified by the International Classification of Diseases for Oncology (ICD-O) according to their anatomic site (topography) and histology (morphology). Welzel et al elegantly highlighted that until 2006 hilar CCA, Klatskin tumour, may have been mistakenly classified as IH-CCA under all versions of ICD-O. Before this report, some authors described the epidemiology and the risk factors for CCA, clearly considering the Klatskin tumours (8162) as IH-CCA. The conclusions of these studies[13,14] must be considered with caution in evaluating the differences in the epidemiology and risk factors of the IH- and EH-CCA. Pathological examination is generally considered the “gold standard” for the diagnosis and, consequently, a high degree of confidence is placed in microscopically verified cancer registrations. In an Italian series of clinically diagnosed CCA, tissue-proven diagnosis was obtained in 78.45% of IH-CCAs and in 80.40% of EH-CCAs. As described by West et al in England and Wales, the proportion of IH-CCAs verified by microscopy has declined dramatically from 80.5% in the period 1968-1972 to 37.6% in the period 1993-1997, relatively more than what observed in the case of the EH-CCA (from 51.0% to 44.1%). An additional bias in CCA classification is cHCC-CCA, a biologically different subtype, which is considered to represent 1.0%-3.5% of primary liver cancers. However, in a population of clinically diagnosed (ordinary or enhanced CT, ultrasonography, and hematological marker detection) cases of IH-CCA, the proportion of the cHCC-CCA has been reported to be 30%, as definitively demonstrated in surgically resected cases. Donato et al, in a case–control study investigating several risk factors for IH-CCA (hepatitis C and B virus infection, alcohol intake, and hepatolithiasis), identified 2 cases of cHCC-CCAs among the 26 histologically verified IH-CCAs (7.6%), suggesting a bias in the interpretation of the results relative to the risk factors of IH-CCA. On this basis, non-histologically verified cases of IH-CCA have to be considered to be a mixed population of CCAs and cHCC-CCAs. The true proportion of the two cancers, remains to be evaluated. The lack of histological verification could affect the ability to evaluate the relative weight of a risk factor. In addition, some reports evaluating the epidemiology[20-22], the risk factors[23-25] and the mortality rate[26-28] are based exclusively on topographic classification (ICD-9; ICD-10 or others classification). In contrast, in more recent studies, the criteria used to identify IH-CCA or EH-CCA are those described by the European RARECARE project where, IH-CCA has been identified by specific topographical (C22.0, C22.1) and morphological codes (8000–8005, 8010, 8011, 8020-8022, 8050-8084, 8140-8141, 8160, 8161, 8480-8500, 8550, 8560, 8570-8572) while EH-CCA has been identified by the topographical code C24.0 and the morphological codes 8000-8005, 8010, 8011, 8020-8022, 8140-8141, 8144, 8160-8161, 8162 (Klatskin tumour), 8190, 8230-8231, 8260, 8310, 8480-8500, 8550, 8560, 8570-8573, 8575-8576. CCA with not otherwise specified (NOS) localization is identified by topographical code 24.9, irrespective of histology.
We searched the literature for case series of IH-CCA and EH-CCA diagnosed according the currently recognized criteria, described by the European RARECARE. Welzel et al reported how the incidence of IH-CCA (excluding hilar CCA) in the USA over the period from 1992 to 2000, showed a 4% annual increase. The incidence of EH-CCA (including code 8162/3) remained constant (annual percent changes = 1%), as did the incidence of hilar CCA reported under the code 8162/3. Between 1973 and 1991, the increase in incidence of IH-CCA was similar to that for the 1992 to 2000 period (annual percent changes = 5%) while, in contrast, there was a 1%/year decrease in EH-CCA incidence. Consistent with the data from US registers, the AISF “Cholangiocarcinoma” committee reporting comprehensive national data from Italian National Cancer Registries, described 5517 histologically confirmed CCAs. For EH-CCA, an increasing trend of age standardised incidence rates from 11.5 to 13.5 cases per million was observed between 1988 and 2002. In the same period, a consistently increasing trend was also observed for IH-CCA: from 5 to 12 cases per million (average increase = 6% per year). Between 1995 and 2006 a progressive increase in incidence with age was seen for EH-CCA, IH-CCA and NOS. EH-CCA incidence rates were similar to those for IH-CCA for ages 45-54 years (6.5 vs 6.8), while EH-CCA showed a more pronouncing increase of incidence rate in the subsequent age classes. For all ages and for both sub-sites, incidence was more than 50% higher in men than in women. Interestingly, the proportion of NOS cases also increased with age. Jepsen et al identified, in Denmark, a cases series of 1335 IH-CCAs and 1269 EH-CCAs and reported, in contrast to observations in the US and Italy, an incidence rate decrease of 3.7% (95% CI: 3.0%-4.4%) and 2.7% (95% CI: 1.9%-3.4%) per year for IH- and EH-CCAs, respectively. The incidence rates for IH- and EH-CCAs in 1978 were 1.27 (95%CI: 0.96-1.58) and 1.05 (95% CI: 0.77-1.34) per 100 000 people, respectively. From the mid-1980s, incidence rates started to decrease and by 2002 the incidence rates for IH- and EH-CCAs were 0.46 (95%CI: 0.29-0.62) and 0.74 (95% CI: 0.53-0.95) per 100 000 people, respectively. The decrease in incidence was observed in both sexes and in all three arbitrarily defined age-groups (i.e. < 60, 60-79 and ≥ 80 years).
In summary, with the exception of data from Denmark, studies investigating CCA epidemiology indicate a progressive worldwide increase of incidence and mortality for IH-CCA, whereas EH-CCA seems to be stable or slightly decreasing[12,13,21,30,32]. Large differences in incidence and mortality between IH-CCA and EH-CCA observed in these studies suggest that these two types of CCA emerge from pathological conditions (risk factors) which are largely different.
Some final considerations are needed. CCA is still considered a rare cancer. However, considering the hepatobiliary system as a whole, cancers of the gallbladder, intra-hepatic and extra-hepatic biliary tree together represent approximately 30% of the total primary liver cancers with incidence rates approaching that of HCC. Moreover, among patients transplanted for liver cirrhosis of various aetiologies (n = 496), an incidental CCA was diagnosed in 10/82 (12.2%) explanted livers. This means that CCA remains frequently undiagnosed.
We searched the literature for case series of IH-CCA and EH-CCA diagnosed according the currently recognized criteria (i.e. European RARECARE), or case series with appropriate topographic classification of histologically verified CCA. Most series are case-control studies with multivariate analysis. The results of the 10 studies selected on the basis of these criteria are summarized in Table 1[19,34-42]. Several putative risk factors have been evaluated including, biliary diseases [choledochal cysts, cholangitis, primitive sclerosing cholangitis (PSC), biliary cirrhosis, primary biliary cirrhosis (PBC), cholelithiasias, choledocholithiasis, hepatolithiasis, cholecystitis], surgery (cholecystectomy), liver flukes, gastrointestinal diseases [inflammatory bowel diseases (IBD), duodenal ulcer, chronic pancreatitis], type II diabetes, cigarette smoking, alcohol intake, obesity and parenchymal liver diseases (chronic liver diseases, alcoholic liver disease, nonspecific cirrhosis, hemochromatosis, chronic non alcoholic liver disease, HCV infection, HBV infection). Of course, the geographic distribution of the risk factors had a strong influence on the study design, with liver flukes almost exclusively investigated in the endemic area such as Far East and South East Asia. Conversely, the studies performed in the US, Europe, Japan and China mainly focused on viral hepatitis, cirrhosis, PSC and other biliary disease (with exclusion of liver flukes), type II diabetes mellitus, alcohol intake and smoking. Moreover, through the years, IH-CCA has been more extensively studied than EH-CCA. The investigated risk factors could be classified on the basis of the cells primarily targeted or activated by the diseases and therefore involved in the carcinogenic process. Biliary diseases such as choledochal cysts, cholangitis/PSC, secondary biliary cirrhosis, choledocholithiasis, hepatolithiasis, cholecystitis, and liver flukes are pathologic conditions primarily affecting large intra-hepatic bile ducts and/or extra-hepatic bile ducts. As might be expected, these pathological conditions are risk factors for both IH- and EH-CCA, as shown in Table 1. Cholelithiasias and cholecystectomy primarily affect extra-hepatic bile ducts.Consequently, these conditions are recognized risk factors mainly for EH-CCA (Table 1). Parenchymal liver diseases including, chronic viral and non-viral liver diseases, have the interlobular bile ducts, bile ductules and the canals of Hering as their primary targets. In fact, interlobular bile ducts, bile ductules and the canals of Hering are the main players involved in ductular reaction, a phenomenon shared by all these pathologies. Consequently, these conditions are recognized risk factors mainly for IH-CCA (Table 1). Type II diabetes and alcohol intake, are probably general cancer risks and, therefore, don’t affect IH- and EH-CCA differently, as shown in Table 1.
Table 1 Summary of risk factors significantly associated to intra-hepatic cholangiocarcinomaa and/or extra-hepatic cholangiocarcinomab as assessed by case control studies (Odd ratios by multivariate analyses).
aHistological verified cases; bHistological verified cases comprise Klatskin tumour; cIH-CCA cases comprise 2 cases of cHCC-CCA. The table is prepared summarizing findings by case control studies investigating risk factors associated to IH-CCA and/or EH-CCA as assessed by multivariate analyses. The case-control studies are selected from the papers individuated by the follow terms searched on PubMed: ["cholangiocarcinoma"(MeSH Terms) OR "cholangiocarcinoma"(All Fields)] AND ["risk factors"(MeSH Terms) OR ["risk"(All Fields) and "factors"(All Fields)] OR "risk factors"(All Fields) OR ["risk"(All Fields) AND "factor"(All Fields)] OR "risk factor"(All Fields)]] NOT ["review"(Publication Type) OR "review literature as topic"(MeSH Terms) OR "review"(All Fields)] AND English(lang). The criteria selections of the works comprise moreover the case definition of CCA: Histological verified cases series of IH-CCA and/or EH-CCA with appropriate topographic classification (Klatskin tumours classified as EH-CCA and excluded from the IH-CCAs). In the 10 case control studies selected, several putative risk factors have been evaluated. The risk factors are collected together based on the patho-physiologic mechanisms lead to CCA (cells primarily targeted or activated by the diseases and therefore involved in the carcinogenic process) and on the homogeneity of the risk factors. IH-CCA: Intra-hepatic cholangiocarcinoma; EH-CCA: Extra-hepatic cholangiocarcinoma.
The evidence for a possible association between liver flukes and CCA has been evaluated by the International Agency for Research on Cancer (IARC) since 1994. Opisthorchis viverrini infestation, endemic in South East Asia, was considered definitively carcinogenic. Three studies (in Thailand) allow estimation of the relative risk associated with infection although none of them evaluates the discrete risk of IH-CCA and/or EH-CCA correlated to Opisthorchis viverrini[44-46]. Clonorchis sinensis infection revealed by radiologic evidence or stool examination was shown as an independent risk factor both for IH-CCA and for EH-CCA as assessed by multivariate analysis (Table 1). Other case-control studies from Korea[43,47] allow estimation of the role of Clonorchis sinensis in CCA development, however there was no evaluation of the discrete risk of IH-CCA and/or EH-CCA. Liver flukes inhabit mainly the intra- and extra-hepatic bile ducts and, rarely, in the gallbladder and pancreatic duct. The infection is associated with a number of hepatobiliary diseases, including cholangitis, cholecystitis and hepato-cholelithiasis and is associated with several pathological changes in the liver, gallbladder and extra-hepatic bile ducts. Microscopically, the intra-hepatic lesions are confined to the biliary tree, particularly to the large and medium-sized bile ducts where the flukes are harboured. During liver fluke infection, inflammation, periductal fibrosis, and proliferative responses, may represent predisposing lesions that enhance the susceptibility of DNA to carcinogens including several N-nitroso compounds and their precursors[48,49].
Biliary diseases (cholangitis, PSC, choledochal cysts, biliary cirrhosis, choledocholithiasis and cholecystitis) are also indicated to be independent strong risk factors for both IH-CCA and EH-CCA as assessed by multivariate analysis (Table 1).
PSC, a disease affecting both intra-hepatic and extra-hepatic bile ducts, represents the strongest independent risk factor both for IH-CCA and for EH-CCA as evaluated by multivariate analysis (Table 1). In addition, IBD possibly associated with or preceding PSC, may significantly influence this risk since IBD was indicated as an independent risk factor for both IH-CCA and EH-CCA (Table 1). Unfortunately, definitive conclusions on how the coexistence of IBD with PSC may increase CCA risk compared to IBD or PSC alone are still lacking. Several older studies have evaluated the cumulative risk of CCA in PSC patients but none of these studies evaluated separately the discrete risk of IH-CCA and/or EH-CCA correlated to PSC[25,50-53]. More recently, Erichsen et al demonstrated that the risk of both IH-CCA and EH-CCA in IBD patients, 65% percent with ulcerative colitis (UC), 25% with Crohn’s disease (CD), and 10% with ICD codes for both diseases (incidence rates of 7.6 per 100 000 person years), was 4 times higher than in IBD-free population controls, RR = 4.0 (95%CI: 2.5-6.4). CCA occurred nearly twice as frequently in UC patients as in CD patients; the incidence rate was 8.2 (95%CI: 5.4-12.5) per 100 000 person years among UC patients versus 4.3 (95%CI: 1.8-10.3) per 100 000 person years among CD patients. Interestingly, the incidence of CCA was highest within the first year at risk but decreased with time. Approximately 4% of IBD patients with colonic involvement develop PSC, which increased the risk of both IH-CCA and EH-CCA (Table 1). In the study by Erichsen et al, it was found that at least half of patients with IBD and CCA had been diagnosed with PSC and the authors discuss how the remaining patients may already have or later develop PSC. Several case-control studies were conducted to evaluate differences between PSC patients with or without CCA in order to identify risk factors which could differentiate the two groups and thus helping in identification of PSC patients at high risk of CCA development[50,51,55,56]. Unfortunately, no statistical difference in the frequency or duration of IBD between PSC patients with and without CCA was found. Finally, as assessed by Kornfeld et al, PSC patients who experienced a cumulative risk to develop CCA of 11.2% 10 years after diagnosis, when diagnosed with associated IBD had a somewhat better prognosis: 10-year survival of 71.8%, compared with 60% for patients without IBD. Duration of IBD, and colectomy had no influence on survival and CCA risk. In summary PSC and IBD are currently considered risk factors for both IH- and EH-CCA. Whether or not, the association of IBD with PSC further increases the risk of IH- or EH-CCA with respect to IBD or PSC alone is still debated.
Inflammation and biliary stasis are common features shared by different pathologies that increase CCA risk. These include PSC, cholangitis, choledochal cysts, secondary biliary cirrhosis, choledocholithiasis, hepatolithiasis and cholecystitis. Recently, the role of the inflammation in CCA pathogenesis has been elucidated. The activation of NF-κB via Toll-like receptor ligands (lipopolysaccharide, flagellin) or bile acids (deoxycholate, taurodeoxycholate, and glycodeoxycholate) and Sonic Hedgehog signalling have been considered of relevance in inducing neoplastic cholangiocyte transformation during chronic inflammation. Furthermore, it was highlighted how oncogenic signals (Hedgehog, myc), innate immune activation (TLR), and bile acids all converge to suppress mir-29 promoter activity and expression. Mir-29 is a down-regulator of prosurvival protein Mcl-1. Multipotent stem/progenitors are located at the base of the peribiliary glands and differentiate into mature cholangiocytes during migration from the bottom to the top of the glands, recapitulating in the biliary tree the intestinal model where proliferation of multipotential stem cells within Lieberkuhn’s crypts, cellular migration and differentiation along the crypt-villus axis, are critical for development and maintenance of intestinal architecture. The development of PSC and UC appears to precede dysplasia respectively of the biliary and of the colonic mucosa and represents a marker of patients at risk for developing CCA and colorectal adenocarcinoma. The common embryologic origin of biliary tree and intestine and the similarities in the stem cell niches residing in the two organs lead to the suggestion that the inflammatory immune-mediated processes underlining PSC and UC could target cells originating from biliary and intestinal lineage indistinguishably. This opens new perspectives on current knowledge of these pathologies and on the similarities between colorectal adenocarcinoma and CCA.
The association between PBC and EH-CCA, described by Welzel et al, deserves some comment. PBC does not affect extra-hepatic bile ducts and, therefore, the reasons for increased susceptibility of cancer transformation in these large ducts are unclear. The absence of diagnostic confirmation and the possibility that some secondary biliary cirrhosis were included in the investigated population must be considered. The same authors discussed how, because of the small numbers of PBC, the reported association should be confirmed by other studies.
Hepatolithiasis has been indicated as a strong independent predictor of IH-CCA development (OR range 50-4.8), whereas none of the case-control studies have investigated the role of hepatolithiasis in EH-CCA (Table 1).
Cholelithiasias was indicated as an independent predictor of EH-CCA development (OR range 2.6-11), but not of IH-CCA (Table 1). These data are in accordance with the finding that the risk of EH-CCA increases with size of gallstones, calcification of gallbladder epithelium (“porcelain gallbladder”) and duration of disease. Gallbladder cancer arises usually as a consequence of chronic inflammation associated with gallstones. Persistent inflammation is thought to promote carcinogenesis by causing DNA damage, activating tissue reparative proliferation, and by creating a local environment that is enriched with cytokines, other growth factors and oxysterols[61,62].
Cholecystectomy was shown to be highly significant as a predictor of EH-CCA (OR range 12-5.8) and also IH-CCA (OR range 5.4-3.6) (Table 1). However, a single study failed to confirm the association for both EH-CCA and IH-CCA. In different human pathologies including gallstone and chronic liver diseases[62,63], bile contains oxygenated derivatives of cholesterol (oxysterols) which possess diverse biological properties. After cholecystectomy, changes in the profile of lipids circulating in bile along the gut-liver axis (enterohepatic circulation) have been described with increased levels of oxysterols. It was proposed that enhanced COX-2 protein expression by oxysterols may participate in the genesis and progression of CCA. Thus, the continued exposure of extra-hepatic ducts to constituents, such as oxysterols, which are enriched in the bile of cholecystectomized patients, could represent the basic mechanism responsible for the association of this condition with EH-CCA. Recently, it was observed that obese patients have a stronger acute inflammatory response to cholecystectomy where, increased biliary levels of oxysterols could play a role. As obesity represents a risk factor for gallstones as well as a risk factor for several inflammatory and neoplastic conditions, it could be hypothesized that, in the specific setting of cholecystectomized patients, the obesity sustains high levels of oxysterols in bile with increased risk of EH-CCA development.
Type II diabetes has been indentified as an independent predictor of IH-CCA in 2/4 studies and of EH-CCA in 2/3 studies (Table 1).
Heavy alcohol intake (> 80 g/d) has been identified by multivariate analysis as an independent risk factor associated with both IH-CCA (range of OR 5.9-6.6) and EH-CCA (OR 3.6), as showed in Table 1, while 12 or more g/d of alcohol was not significant[34,39].
Type II diabetes and heavy alcohol intake, they probably reflect a general cancer risk.
Obesity was considered to represent an independent predictor of IH-CCA (Table 1), whereas the same study failed to demonstrate an association with EH-CCA.
Smoking was suggested as an independent predictor of IH-CCA in 1 of 4 studies (Table 1), while 3 different studies failed to demonstrate an association with EH-CCA[34,35,38].
Hemochromatosis and non-alcoholic fatty liver disease were identified as independent predictors of IH-CCA development, even if with a lower strength of association than other risk factors (viral hepatitis, cirrhosis) and they failed to predict EH-CCA (Table 1).
Cirrhosis of unspecified aetiology and alcoholic liver disease are independent risk factors significantly associated, according to multivariate analysis, with both IH-CCA and EH-CCA (Table 1). Specifically, cirrhosis showed an OR significantly higher for IH-CCA than EH-CCA (10-16.5 vs OR 5.4). However, it was not possible to determine whether the group of non specific cirrhosis included a fraction of biliary cirrhosis secondary to undetected pathologies of the extra hepatic biliary tree. This introduces a potential bias which may possibly invalidate the apparent association between non specific cirrhosis and EH-CCA. Many biliary diseases leading to secondary biliary cirrhosis are associated with EH-CCA development, as showed in Table 1. However, a possible physiopathological basis for the apparent association could be the high level of oxysterols in cirrhotic patients, compared to both control and viral hepatitis patients, which could affect the extra hepatic biliary tree via bile or via peribiliary plexus blood flow.
In the last few years, hepatitis viruses (HCV, HBV) have been extensively investigated and debated because of the recognized global health burden of infection-associated cancer. So far, there is no evidence which actually supports a role for viral hepatitis in EH-CCA development (Table 1). In contrast, many well conceived case-report studies and one cohort study have demonstrated the association between hepatitis viruses and IH-CCA, with ranges of OR from 2.7 to 9.7 (Table 1). It is interesting to note that the highest OR relative to HCV (i.e. 9.7) resulted from a study incorporating a few cases of cHCC-CCA in the IH-CCA group corroborating the suggestion that the mixed subtype of primary liver cancer is induced by hepatitis virus. In addition, it is important to note confounding factors that could affect the results of different studies including age of investigated population and the degree of liver damage (i.e. chronic hepatitis, cirrhosis etc.). A few authors have investigated the role of HBV and HCV infection as CCA risk factors independent of liver cirrhosis. Excluding the IH-CCA associated with cirrhosis Tao et al showed that HBsAg was independently associated with IH-CCA (OR: 7.3; 95%CI: 3.1-17.2). Also, in a cohort study of asymptomatic subjects, those who tested HBsAg-positive had a significantly higher risk for IH-CCA (histological and/or clinical diagnosed) than those who tested negative for both HBsAg and anti-HCV. The risk was further increased in HBsAg positive patients with ALT levels of 40 KU or higher. Yamamoto et al revealed by multivariate analysis that during chronic hepatitis C infection without cirrhosis the adjusted OR for ICC was 2.32. Several other case-control studies evaluated viral related liver disease by investigating HBV[37,39] or HCV infection without clarifying the stage of the associated liver disease. It was demonstrated, as showed in Table 1, that HBsAg seropositivity and anti-HCV seropositivity with unspecified liver disease represent independent risk factors for development of IH-CCA. Recently, a large cohort study (follow-up 8 years) demonstrated that HCV infection significantly increased the risk of clinically diagnosed HCC (155.0) and IH-CCA (155.1 ICD-9), with OR for HCC more than 5 fold higher than for IH-CCA. Results indicated that EH-CCA (156.1, 156.2, 156.8 and 156.9) and pancreatic adenocarcinoma (157.0, 157.1, 157.2, 157.3, 157.8 and 157.9), were not associated with HCV infection. In relation to HBV infection (HBsAg seropositivity), the range of the OR, in the positive study ranged from 2.3 to 9.7 (Table 1). However, there is not conclusive agreement since further two studies failed to demonstrate a definitive association between anti-HCV seropositivity and IH-CCA[37,39]. Similarly, two studies on HBV failed to demonstrate HBsAg seropositivity as a risk factor for IH-CCA[19,38]. It is interesting to note that the two negative studies on HCV patients were conducted on populations of IH-CCA patients with an average age of 53.2 and 60.7 years respectively[37,39], whereas Lee et al recently reported that the age at the diagnosis of the HCV related IH-CCA was 64.9 years. In contrast, a strong agreement exists that viral cirrhosis is a significant risk factor for IH-CCA. Lee et al demonstrated that cirrhosis increased the risk for IH-CCA by 3.2 fold in HCV patients. Yamamoto et al revealed by multivariate analysis that as liver status worsened during HCV infection, the adjusted OR for IH-CCA tended to increase (chronic hepatitis, 2.32 vs cirrhosis, 5.03). As for HCV, it was observed that the presence of HBV-related cirrhosis increases the OR for IH-CCA development from 7.3 to 18 according to Tao et al, and from 9.7 to 13, according to Zhou et al. Consistent with this evidence Lee et al demonstrated that cirrhosis increased the risk for IH-CCA by 3.2 fold in HBV patients. These authors reported that the mean age of IH-CCA patients with hepatitis B (56.4 ± 11.1 years) was 9 years younger than that of IH-CCA patients with hepatitis C (65.6 ± 9.17 years), similar to results observed in HCC. Taken together the current literature suggests that the association between IH-CCA and hepatitis viruses (HBV, HCV) is markedly stronger when cirrhosis is present, suggesting that the background of enhanced proliferation and cell cycle acceleration, together with chronic inflammation, represents a significant pathogenic determinant. The occurrence of HCC, IH-CCA and cHCC-CCA in chronic liver diseases, exemplifies the postulated (see Roskams) wide spectrum of histological presentation of stem cell derived liver cancer. Liver stem cell activation accompanies many forms of liver damage irrespective of aetiology, making such cells very probable carcinogen targets. HBV and HCV components have been demonstrated in bile duct epithelial cells during chronic infection. The infection of resident hepatic stem cells by HBV and HCV could explain the subsequent transmission of the viruses both to hepatocytes and to cholangiocytes. However, the hypotheses of a direct mutagenic role of HBV and HCV on liver stem cells is not actually sustained by the existing literature. The role of hepatitis viruses as risk factors for IH-CCA, independently of liver cirrhosis, needs to be further addressed together with the possible pathogenic mechanism responsible for this association.
The magnitude of the association between HBV and HCV positivity (with or without liver diseases) with IH-CCA is markedly lower than for the association with HCC[72,73] and the same is evident for hemochromatosis. While HCC arises from cells directly infected by HCV or HBV (resident stem cells or adult hepatocytes), IH-CCA histogenesis is more heterogeneous, originating from resident liver stem cells or from cells not primarily affected by the hepatitis viruses but secondarily involved in the course of chronic liver diseases, such as cholangiocytes located in medium-large ducts (septal duct) or cells located in PBGs[1,2]. Therefore, when the association of HBV or HCV with IH-CCA is factored in when calculating total cases of IH-CCA irrespective of their histogenesis, the magnitude of the association is certainly attenuated.
It should be noted that the mortality rates of all types of liver cancer (including liver cancers of poorly specified morphology) has increased in recent decades and that the improved diagnostic tools are not the only possible explanation for this epidemiological observation. Taking into consideration the HCC increases in Japan, which are mostly HCV-related, it has been suggested that also US might experience a similar epidemic increase of HCV related primary tumours in the near future. Analyzing the deaths relating to liver disease occurring from 1990 through 1998 in the US population, the age-specific and age-adjusted mortality rates for hepatitis C-related diseases increased by 220% from 1993 to 1998 (0.57 to 1.67/100 000), the rate for primary biliary cirrhosis increased overall by 12.8%, while mortality rate for alcohol-related chronic liver disease declined and remained unchanged for HBV-related liver diseases. As described by Welzel et al, the incidence of IH-CCA in the USA increased 4% annually between 1992 and 2000. Thus, the increase in IH-CCA incidence overlaps geographically and temporally with the increase in the mortality rates for HCV-related liver diseases. At the same time, it is unlikely that HBV infection could play a role in the increased mortality rates for IH-CC, as HBV infection rates and mortality remained stable or slightly decreased in the U.S. population in recent decades[76,77]. As far as other risk factors concerned, liver flukes are virtually absent in western countries and PSC-IBD incidence seems to be stable. Therefore, the reported progressive and impressive increase in incidence and mortality for IH-CCA reported worldwide could be reasonably ascribed to the burden of HCV infection.
Recently, we demonstrated that PBGs are stem cell niches in human extra hepatic bile ducts and that the sites for high abundance of PGBs overlap with the sites where malignancies occur with higher frequency in extra-hepatic bile ducts (Figure 1). PBGs are strongly involved in the inflammatory diseases of the large intra-hepatic and extra-hepatic bile ducts, such as liver flukes, cholangitis, PSC, choledochal cysts, secondary biliary cirrhosis, choledocholithiasis, hepatolithiasis, cholecystitis and in CCA[78-84]. In these pathological conditions, PBG cells proliferate and acquire the expression of stem cell and neuroendocrine markers (C-met, c-erbB-2, argyrophil granules, chromogranin A)[81,82,84,85]. On the basis of these recent observations, we hypothesize that early cells within PBGs are the sites of origin of malignancies associated with chronic diseases or pathologic conditions of the biliary tree. Further studies are needed to corroborate this hypothesis which could explain the large different epidemiologic profile of IH- and EH-CCA.
Peer reviewer: Cosimo Sperti, MD, Department of Medical and Surgical Sciences, Clinica Chirurgica IV, via Giustiniani 2, Padova 35128, Italy
S- Editor Wang JL L- Editor Hughes D E- Editor Yang C
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domain: biology


text:
A conservative book publisher says the search engine giant Google rejected his ad for a book critical of Bill and Hillary Clinton while continuing to accept anti-Bush themes.
Eric Jackson, CEO of World Ahead, said his ads for “Their Lives: The Women Targeted by the Clinton Machine” were rejected, without futher explanation, due to “unacceptable content.”
Jackson says Google’s online ad guidelines make no mention of political content being disallowed.
He points out that while ads for the anti-Clinton book — which featured images of the book’s cover and pictures of the former first couple — were deemed offensive, the company continues to run ads for overtly liberal advertisers with headlines such as “Hate Bush? So Do We,” and “George W. Bush fart doll.”
As WorldNetDaily reported, 98 percent of all political donations by Google employees went to support Democrats.
CEO Eric Schmidt gave the maximum legal limit of donations to Democratic presidential nominee Sen. John Kerry and to primary candidate Howard Dean.
Schmidt also contributed the maximum amount to Sen. Clinton, whose role in helping her husband intimidate his female accusers is addressed in the new book.
Last month, Google, valued recently at $80 billion, rejected an attempt by the conservative activist group RightMarch.com to run ads critical of Rep. Nancy Pelosi, D-Calif., while continuing to run attack ads against besieged House Majority Leader Tom DeLay, R-Texas.
Also, Google has agreed to allow the communist Chinese government to have the search engine block “objectionable” search terms such as “democracy.”
The company came under fire for a recent editorial decision to rank news articles in search results by
“quality,” giving preferential placement to large and predominately liberal media outlets such as CNN and the BBC over conservative news sources, even if they are more recent or pertinent.
If you would like to sound off on this issue, participate in today’s WND Poll.
Order your copy of “Their Lives” online, or if you prefer ordering by phone, call our toll-free order line: 1-800-4-WND-COM (1-800-496-3266).

domain: politics


text:
DDT use declining toward oblivion: UNEP caption – Source: DDT Expert Group. Report of the Effectiveness Evaluation on DDT Pursuant to the Article 16 of the Stockholm Convention Animation prepared by: UN Environment Chemicals and Health Branch 2016, with the latest information available and may not reflect the current status.
More than 180 nations signed the Persistent Organic Pollutants Treaty (POPs), often called the Stockholm Convention. The treaty pledges nations to voluntarily work to rid the planet of dangerous and toxic organic chemicals.
In 2001, 43 nations said they thought DDT would be useful. But by 2015, 33 of those nations gave up DDT, due to insects developing resistance and immunity.
India, the sole remaining nation where manufacture of DDT occurs, plans to stop all DDT production by 2020. India discovered that more DDT makes the insect pests more resistant faster, instead of beating disease carriers.
As a journalist, this guy has a piece of a world-wide scoop.
India is probably the last nation on Earth producing DDT. In the last decade other two nations making the stuff got out of the business — North Korea and China. For several years now India has been the largest manufacturer of DDT, and far and away the greatest user, spraying more DDT against malaria-carrying mosquitoes, sand flies, and agricultural and household pests than the rest of the world combined.
As if an omen, India’s malaria rates did not drop, but instead rose, even as malaria rates dropped or plunged in almost every other nation on Earth.
Under the 2001 Stockholm Convention on Persistent Organic Pollutants (POPs) signed by more than 150 nations (not including the U.S.), DDT was one of a dozen chemicals targeted to be phased out due to its extremely dangerous qualities, including long-term persistence in the environment and bioaccummulation, by which doses of the stuff increase up the food chain, delivering crippling and fatal doses to top predators.
A perfect substitute for DDT in fighting some disease-carrying insects (“vectors”) has never been developed. Health officials asked, and the Stockholm negotiators agreed to leave DDT legally available to fight disease. Annex B asked nations to tell the World Health Organization if it wanted to use DDT. Since 2001, as DDT effectiveness was increasingly compromised by resistance evolved in insects, fewer and fewer nations found it useful.
The site Mr. Nazakat linked to is up and down, and my security program occasionally says the site is untrustworthy. It’s obscure at best. Shouldn’t news of this type be in some of India’s biggest newspapers?
I found an article in theDeccan Herald, confirming the report, but again with some
India-United Nations pact to end DDT use by 2020
India-United Nations pact to end DDT use by 2020
New Delhi, August 26, 2015, DHNS:
It would be better to switch to another insecticide, says expert
India has launched a $53 million project to phase out DDT by 2020 and replace them with Neem-based bio-pesticides that are equally effective.
India is the lone user of DDT, though only in the malaria control programme, while rest of the world got rid of the chemical that has a lasting adverse impact on the environment.
India on Tuesday entered into a $53 million (Rs 350 crore) partnership with the United Nations Industrial Development Organisation (UNIDO), United Nations Environment Programme and the Global Environment Facility to replace DDT with safer, more effective and green alternatives.
“As per the plan, the National Botanical Research Organisation, Lucknow, tied up with a company to produce Neem-based alternatives for the malaria programme. The production will start in six months,” Shakti Dhua, the regional coordinator of UNIDO told Deccan Herald.
Till last year, the annual DDT requirement was about 6,000 tonnes that has now been cut down to 4,000 tonnes as the government decided to stop using it in the Kala-Azar control programme.
A recent study by an Indo-British team of medical researchers found that using DDT without any surveillance is counter-productive as a vector control strategy as sand flies not only thrive but are also becoming resistant to DDT.
“It would be better to switch to another insecticide, which is more likely to give better results than DDT,” said Janet Hemingway, a scientist at the Liverpool School of Tropical Medicine. While the Health Ministry wanted to bring in synthetic pyrethroids, the United Nation agencies supports the bio-pesticides because of their efficacy and long-lasting effects.
“The new initiative would help check the spread of malaria and other vector-borne diseases. These include botanical pesticides, including Neem-based compounds, and long-lasting insecticidal safety nets that will prevent mosquito bites while sleeping,” Dhua said.
Ending the production and use of DDT is a priority for India as it is a signatory to the Stockholm Convention on Persistent Organic Pollutants (POP) of 2002 that seeks to eliminate the use of these chemicals in industrial processes, drugs and pesticides. DDT is one of the POPs.
The clock is counting down the last years of DDT. Good.
If events unroll as planned, DDT making will end by 2020, 81 years after it was discovered to kill bugs, 70 years after it was released for civilian years, 70 years after problems with its use was first reported by the U.S. Fish and Wildlife Service, 58 years after the publication of Rachel Carson’s Silent Spring, 50 years after European nations banned some uses, 48 years after the famous U.S. ban on agricultural use, 19 years after the POPs Treaty.
Logo of the Stockholm Convention on Persistent Organic Pollutants (POPs Treaty) Wikipedia image
In the stuffy talk of international relations, the Stockholm Convention in this case refers to a treaty put into effect in 2001, sometimes known as the Persistent Organic Pollutants Treaty (POPs). Now with more than 152 signatory nations and 178 entities offering some sort of ratification (not the U.S., sadly), the treaty urges control of chemicals that do not quickly break down once released into the environment, and which often end up as pollutants. In setting up the agreement, there was a list of a dozen particularly nasty chemicals branded the “Dirty Dozen” particularly targeted for control due to their perniciousness — DDT was one of that group.
DDT can still play a role in fighting some insect-carried diseases, like malaria. Since the treaty was worked out through the UN’s health arm, the World Health Organization (WHO), it holds a special reservation for DDT, keeping DDT available for use to fight disease. Six years ago WHO developed a group to monitor DDT specifically, looking at whether it is still needed or whether its special provisions should be dropped. The DDT Expert Group meets every two years.
Stockholm Convention continues to allow DDT use for disease vector control
Fourth meeting of the DDT Expert Group assesses continued need for DDT, 3–5 December 2012, Geneva
Mosqutio larvae, WHO image
The Conference of the Parties to the Stockholm Convention, under the guidance of the World Health Organization (WHO), allows the use of the insecticide DDT in disease vector control to protect public health.
The Stockholm Convention lists dichlorodiphenyltrichloroethane, better known at DDT, in its Annex B to restrict its production and use except for Parties that have notified the Secretariat of their intention to produce and /or use it for disease vector control. With the goal of reducing and ultimately eliminating the use of DDT, the Convention requires that the Conference of the Parties shall encourage each Party using DDT to develop and implement an action plan as part of the implementation plan of its obligation of the Convention.
At its fifth meeting held in April 2011, the Conference of the Parties to the Convention concluded that “countries that are relying on DDT for disease vector control may need to continue such use until locally appropriate and cost-effective alternatives are available for a sustainable transition away from DDT.” It also decided to evaluate the continued need for DDT for disease vector control at the sixth meeting of the Conference of the Parties “with the objective of accelerating the identification and development of locally appropriate cost-effective and safe alternatives.”
The DDT Expert Group was established in 2006 by the Conference of the Parties. The Group is mandated to assess, every two years, in consultation with the World Health Organization, the available scientific, technical, environmental and economic information related to production and use of DDT for consideration by the Conference of the Parties to the Stockholm Convention in its evaluation of continued need for DDT for disease vector control.
The fourth meeting of the DDT Expert Group reviewed as part of this ongoing assessment:
Insecticide resistance (DDT and alternatives)
New alternative products, including the work of the Persistent Organic Pollutants Review Committee
Transition from DDT in disease vector control
Decision support tool for vector control.
The DDT expert group recognized that there is a continued need for DDT in specific settings for disease vector control where effective or safer alternatives are still lacking. It recommended that the use of DDT in Indoor Residual Spray should be limited only to the most appropriate situations based on operational feasibility, epidemiological impact of disease transmission, entomological data and insecticide resistance management. It also recommended that countries should undertake further research and implementation of non-chemical methods and strategies for disease vector control to supplement reduced reliance on DDT.
The findings of the DDT Expert Group’s will be presented at the sixth meeting of the Conference of the Parties, being held back-to-back with the meetings of the conferences of the parties to the Rotterdam and Basel conventions, from 28 April to 11 May 2013, in Geneva.
Nothing too exciting. Environmentalists should note DDT is still available for use, where need is great. Use should be carefully controlled. Pro-DDT propagandists should note, but won’t, that there is no ban on DDT yet, and that DDT is still available to fight malaria, wherever health workers make a determination it can work. If anyone is really paying attention, this is one more complete and total refutation of the DDT Ban Hoax.
Rachel Carson’s ghost expresses concern that there is not yet a safe substitute for DDT to fight malaria, but is gratified that disease fighters and serious scientists now follow the concepts of safe chemical use she urged in 1962.
Once upon a time I easily found a chart from the World Health Organization (WHO) which provided a year-by-year tally of malaria deaths, worldwide, from the 1940s to the present.
Of course, now that I need that chart to note that malaria deaths are much lower today than they were when DDT was overused generally and sometimes misused in the fight against malaria, I can’t find it. So, we’ll take the figures where we can find them.
In 2008, worldwide there were over 880,000 deaths from malaria. This is significantly lower than the usual claim of “millions of deaths each year.” We can find this figure in a document from the Global Environmental Facility (GEF), the organization that organizes the work of 182 nations to work for solutions to environmental problems, including fighting malaria, in a report on the 2009 meeting of the Stockholm Convention focused on fighting malaria, “Countries move toward more sustainable ways to roll back malaria.”
However concern over DDT is matched by concern over the global malaria burden in which close to 250 million cases a year result in over 880 000 deaths. Thus any reduction in the use of DDT or other residual pesticides must ensure the level of transmission interruption is, at least, maintained.
Number of Annual Malaria Cases Worldwide Decreases, Disease Still Remains a Challenge, WHO’s World Malaria Report 2008 Says
Thursday, September 18, 2008
There were about 247 million malaria cases worldwide in 2006, according to the World Malaria Report 2008, which was released by the World Health Organization on Thursday, Reuters reports (MacInnis, Reuters, 9/18). According to the report, 3.3 billion people worldwide were at risk for malaria in 2006, and the disease remains a major burden among children younger than age five and in many African countries (AFP/Google.com, 9/18).
The report included reduced estimates of the global malaria burden that were calculated with new surveillance measures for non-African countries. The estimate of 247 million malaria cases is lower than the estimated 350 million to 500 million annual malaria cases reported in WHO’s World Malaria Report 2005. The new report estimated there were 881,000 malaria deaths in 2006, down from the previous estimate of one million deaths. The reduced figures are the result of new calculation methods, and it is unknown whether malaria cases and deaths actually declined from 2004 to 2006, WHO said (Reuters, 9/18). Although malaria control efforts have helped reduce the global malaria burden, most malaria-endemic countries are not meeting WHO targets for malaria control, the report said, noting that there is “no evidence yet to show that malaria elimination can be achieved and maintained in areas that currently have high transmission” (Bennett/Doherty, Bloomberg, 9/18).
WHO attributed the revised malaria estimates to new assessment measures in Asia, where data used for the 2005 report had not been updated for 40 years. According to Mac Otten — coordinator of surveillance, monitoring and evaluation at WHO’s Global Malaria Program — factors such as deforestation, urbanization and malaria control efforts have affected malaria estimates in Asia (Blue, Time, 9/17). Cambodia, Laos, the Philippines, Thailand and Vietnam all reported a decline in malaria deaths in 2006 (Bloomberg, 9/18).
WHO’s surveillance methods in Africa, which estimate malaria prevalence by using climate data and sample surveys, have remained the same since the 2005 report, the report said (Reuters, 9/18). According to the report, 45 of the 109 malaria-endemic countries worldwide are in Africa, and more than half of the continent’s malaria cases in 2006 occurred in the Democratic Republic of Congo, Ethiopia, Kenya, Nigeria and Tanzania (AFP/Google.com, 9/18). The report noted that malaria interventions have helped reduce malaria cases and deaths by more than 50% in Eritrea, Rwanda, Sao Tome and Principe, and the Tanzanian island of Zanzibar (Time, 9/17).The report found that about 40% of people at risk for malaria in Africa had access to insecticide-treated nets last year, compared with 3% in 2001 (Bloomberg, 9/18). The report also found that the number of ITNs distributed to national malaria control programs was enough to cover 26% of people in 37 African countries but that most African countries did not meet WHO’s target of 80% coverage for the four main malaria treatments: ITNs, artemisinin-based combination therapies, indoor-insecticide spraying programs and treatment for pregnant women (AFP/Google.com, 9/18).
We've been soaking in the Bathtub for several months, long enough that some of the links we've used have gone to the Great Internet in the Sky.
If you find a dead link, please leave a comment to that post, and tell us what link has expired.
Retired teacher of law, economics, history, AP government, psychology and science. Former speechwriter, press guy and legislative aide in U.S. Senate. Former Department of Education. Former airline real estate, telecom towers, Big 6 (that old!) consultant. Lab and field research in air pollution control.
My blog, Millard Fillmore's Bathtub, is a continuing experiment to test how to use blogs to improve and speed up learning processes for students, perhaps by making some of the courses actually interesting. It is a blog for teachers, to see if we can use blogs. It is for people interested in social studies and social studies education, to see if we can learn to get it right. It's a blog for science fans, to promote good science and good science policy. It's a blog for people interested in good government and how to achieve it.
BS in Mass Communication, University of Utah
Graduate study in Rhetoric and Speech Communication, University of Arizona
JD from the National Law Center, George Washington University


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Diesel mechanic schools in Germantown, WI can provide you with the required skills to start a career with a growing demand for skilled workers. Going to School to become a diesel mechanic can be the start of a rewarding career for anybody possessing a high school diploma and a little mechanical skill. Many people take for granted how important diesel engines are to the transportation world. Trucks, buses, trains, ships, and even some passenger cars are driven by diesel motors and it takes specialized training to keep them running efficiently.
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You can expect to study all aspects of diesel motors and the machinery commonly associated with them at the best diesel mechanic schools. You have to search for schools that include training in air brakes, hydraulics, fuel systems, and transport refrigeration. Learning these extra skills will make you a leading candidate for virtually any diesel mechanic job you submit an application for. In the Wisconsin job market today, flexibility is very important. One last thing to look for are statistics on the number of the school’s students have gone on to become ASE Certified Mechanics. The higher number of ASE certified mechanics a program generates, the more likely it is that you will acquire a top education.
Recommended Diesel Mechanic Schools in Germantown, WI
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median earnings per week than workers with only a high school diploma*.
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With the large amount of vehicles and machinery that use diesel engines, job opportunities for diesel mechanics should remain high. Over the 10 year period 2010-2020 Careerinfonet.org projects total job expansion for diesel mechanics to be roughly 15%. They also report that job growth for diesel mechanics in Wisconsin should be at approximately 11%. With stable job growth, a career as a diesel mechanic in Germantown, WI is not a bad option at all.
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As of May 2012 the average income for diesel mechanics in the United States was reported to be $43,660 according to data provided by the U.S. Department of Labors’ Bureau of Labor Statistics. In the State of Wisconsin diesel mechanics can expect to earn an average salary of $41,130. The average income reflects both formally taught and on the job trained technicians so it is ok to assume that people with degrees or certificates will make well in excess of that salary. For a complete list of average incomes for diesel mechanics in every State take a few minutes to check out our salary data page.
Plenty of jobs and great wages, why not take a few moments and request some info from a few of the diesel mechanic training programs near you?


Low profile single point load cell designed for direct mounting in low cost scales. Suitable for most compact retail, bench and counting scales to 100kg capacity. Two additional sense wires feed back the voltage reaching the load cell which improves performance.
Signal Output at Capacity Linearity Error Non-Repeatability Combined Error Off Centre Load Error Creep/(30 mins.) Zero Balance Temperature Effect On Span/10C Temperature Effect on Zero/10C Operating Temperature Range Compensated Temperature Range Storage Temperature Range Excitation +ve Signal +ve Sense +ve
2±0.2 mV/V < 0.017% FSO < 0.010% FSO < 0.020% FSO < 0.020% FSO < 0.020% FSO < 2.0% Capacity < 0.014% FSO < 0.017% FSO <-35 ~ +65 C <-10 ~ +40 C <-50 ~ 85 C RED GREEN BLUE
Service Load Safe Load Ultimate Load Input Resistance Output Resistance Insulation Resistance Excitation Voltage (Rec) Excitation Voltage (Max) Cable ... Material Sealing Excitation -ve Signal -ve Sense -ve
100% Capacity 150% Capacity 300% Capacity 409Ω ± 6Ω 350Ω ± 6Ω > 5000 MΩ (@50 VDC) 5 ~ 12 V AC/DC 18V AC/DC 3m long, 5.0 mm 6 core screened PVC Aluminium Alloy IP65 BLACK WHITE BROWN
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Posts Tagged ‘What styles suit my body shape’
Dress looks are just about manageable without a pair of black opaque tights which by now we are all desperate to ditch. Turn this shocking pink dress with it’s on-trend ruffle details into a stylish day look with these capsule wardrobe basics: the humble denim jacket and must-have ‘fashion’ trainers. If trainers aren’t your thing switch for an animal print ballerina or a pair of ankle tie pointed flats. Natalie x
Posted February 26, 2013on:
QUESTION: I love this blue suede biker jacket (see pic) which I wore last year with the dress pictured. I’d love to find another/some other things I could wear with it such as a dress or jeans/skirt and top/accessories? My budget is about £300. Would be so glad of your ideas. Thanks!
ANSWER: Your jacket is absolutely fantastic and a great colour on you and so versatile. If you take a look at your Dressipi Fashion Fingerprint you will see what styles suit you and why. For you it is all about making the most of your gorgeous figure. With that in mind, here are some ideas we hope you’ll love:
1. Banana Republic trousers, £69.50: – These trousers are perfect for keeping this jacket working hard, whether it be at work or out to lunch with friends. Team with flats for comfort or courts for a more formal occasion.
2. Ralph Lauren top, £65: – A neutral colour top will tie your outfit together and this top from Ralph Lauren will still be great with jeans or colored trousers/jeans.
3. Dune shoes, £65: – Tan is a great choice to replace black as it goes with so much and these shoes are a great mediator between heels and flats.
4. See by Chloe tunic, £270: – If your looking for an outfit that just comes together, this beautiful tunic will be a perfect match for your jacket and is perfect for dressing up or down. Cobalt blue and fuchsia pink are no strangers so this tunic is great for your jacket.
5.Love Moschino trousers, £197.93: – We couldn’t resist recommending these gorgeous floral trousers, they will be perfect for early spring and can be worn with the tan shoes we recommended.
PS:…Our happy Dressipi user’s reply to Sarah Akinola’s recommendations and a pic of her in her new Dressipi purchases: ”
“Thanks for your help, you’re brilliant! I feel totally updated! So far I’ve bought the Ralph Lauren ruffly top (gorgeous!) and the useful tan Dune shoes and really fancy the See by Chloe tunic if/when I can afford it! I shall definitely recommend you to friends. How can we get more of your personalised advice? “
QUESTION: I am stuck in a rut particularly regarding work wear and would like some help please. All I seem to wear is leggings, tunic tops, black
trousers & long cardigans- I am trying to lose weight and am self conscious about my tummy and bottom half. Any help would be appreciated. BudgeT is high street.
ANSWER: Look at the dress- It is the answer to many style dilemmas, easy to wear, can be worn in different ways and is more flattering than trousers or a skirt and will make you feel work ready and smart. Go for dresses that emphasise your slimmer top half and disguise the areas that you wish to
hide. If you keep the dress fairly plain or choose a small print you can then embellish with a fab statement necklace or a bright cardigan. The cardigan should be a style that finishes at the waist rather than a long cardigan.
1. Scoop neck dress by Dorothy Perkins £19: This dress is a great buy, the scoop neck draws the eye to your top half and the soft gathers at the waist skim over the tummy area, as the skirt is a fuller style so it also disguises your bottom. If you are worried about your arms it has lovely 3/4 sleeves.
2. Navy embroidered dress by Dorothy Perkins £30: This dress is the perfect style for you, its in navy, one of your investment colours, the embroidery on the bodice ensures that the attention stays on your top half. The belt will give the illusion of a defined waistline whilst the full skirt hides your lower half and tummy. Wear with a bright cardigan.
3. Red cotton cardigan by Boden £39: This is a lovely spring cardigan, the true red colour is a great investment for you and will liven up any outfit. Again it will draw the eye upwards.
4. Victorian collar necklace by Topshop £18.50: Wear this with either of the dresses for a polished look.
5. J by Jasper Conran, courts, £32: Add opaque black tights and some mid heel court shoes and you have a very stylish flattering work outfit. These patent shoes from Jasper Conran at Debenhams are a great shape and not too high. I hope this has helped you find a chic workwear outfit. Nicki x
We are seeing a gorgeous flurry of snowing swirling about the windows of Dressipi HQ this morning making it ideal weather for today’s style email. We decided to help keep you cosy and chic with our hand picked selection of jumpers. Whether or not you go for a fabulous core wardrobe basic like a standard v-neck jumper in a versatile grey, or prefer a brighter take on bundling up with a cute print, here are a number of ways of ‘doing a jumper look’. It’s worth having a look at your Must Haves which appear in your Style Guide under Inspiration to see what styles and fits are perfect for you when it comes to your key jumper shapes. On the ‘basic’ front I think that grey is such a great and flattering colour (and by grey you can go from light grey to charcoal) and it really does go with everything from metallics, to neutrals, to bold brights. It’s the perfect piece for layering under an open cardigan or a fitted jacket. Colour this season is quite “juicy”. Pastels tend to have an iridescent tinge to them thanks to fashion’s take on metallics. In this outfit the metallic trousers complement the ice-cream of the jumper and I love the contrasting mix of textures. Have a bit of fun with bold prints. This French Connection jumper has a great statement floral print which would sit just as happily with a pair of jeans and flats as it does in this sassy retro-inspired look. Cosy up in a bit of knit-chic and enjoy the snow. Natalie
It’s exciting to see a fresh fashion take on a much-loved brand with a dedicated and loyal following. Watching new product hitting the Dressipi site, you can expect exciting things from Fenn Wright Manson since it was snapped up Maxine Hargreaves-Adams (daughter of Matalan founder John Hargreaves). We love the style-language that FWM is talking this season with its first collection under her stylish helm. Think versatile investment pieces, available at any time of the season, that will always work with your wardrobe.
Having been immersed in the value retail world of Matalan, Maxine explains that “I was keen to something myself and my mum used to wear it. It’s a brand that has a loyal following so it was really an exciting challenge.” The new collection is a stylish re-working of the chic, feminine essence of the brand but with a much more updated and modern take. Look out for key pieces that will run through the collections consistently like a white silk shirt, a basic cashmere open cardi and shell tops for example. Throw in some gorgeous print slinky trousers and blouses , knitwear in hot colours, versatile dresses and s/s at FWM is shaping up to be a brand to put on your must-have hit list. Natalie
QUESTION: I need some help with the way I dress, I’m a pear shape. I love being vintage with a twist of fashion. Im 22 with a lowish budget. Any help or advice you could give thanks.
ANSWER: Take the prom style dress as your basic shape and then add to it with denim and leather jackets and cropped cardigans. This style of dress is very flattering for your shape as it draws attention to your slim shoulders and upper body and disguises the hip area with the lovely feminine full skirt. It has a great vintage feel and will give you an individual look.
1. Dorothy Perkins, red dress, £45: This dress would be fab for a night out, wear with black fishnet tights for a strong vintage feel. Red is one of your investment colours and add a cropped biker jacket or little cardigan like this black fitted piece from George at Asda. Wear a skinny belt over the cardigan done up and you have another outfit.
2. H! by Henry Holland print top £20: This acrobat print top will look great with jeans or slim trousers, the peplum shape will highlight your slim waist and the scoop neck gives a lovely shape around the collarbone.
3. New Look dove print dress £16.99: This dress is a great daytime option, wear with a cropped cardigan or a denim jacket.
4. New Look leather biker jacket £39.99: This jacket is a bit of a bargain, its on sale, it has a fitted waist and is a great length for teaming with your dresses. I hope this has given you some ideas on a figure flattering vintage style on a budget. Nicki x


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Kamal Swaroop’s cult film Om Dar-B-Dar has been restored and its finally in the theatres. Don’t miss it.
DON’T . MISS. IT.
And we are going with the mood of the film, so recycling an old post by Varun Grover which was written 3/4 years ago. Don’t worry, it still reads new just like the film and its ideas. If you have seen the film and are still wondering what the real story is, this post got all your answers.
Death and mythology in a small town
बबलू बेबीलॉन से, बबली टेलीफोन से (Bablu calling from Babylon, Babli listening on telephone)
Om Dar-B-Dar. Om here and there. Or more precisely, Om here and there, helpless. That’s the name of a film I first heard about around 10-years back. It sounded like a typical wannabe ‘Indian Parallel Cinema Movement’ film of the 80’s. Though the ‘movement’ never went beyond the occasional film festival screening in India then (and now, much later, beyond the difficult-to-find DVDs in malls with bad architecture and heavy security) – it did give the otherwise angry-for-no-reason 70’s and colored-clay-pot strewn 80’s some credibility. Shyam Benegal, Govind Nihalani, Basu Chatterjee, Mani Kaul, Kumar Shahani and with a much lighter hand, Sai Paranjape made cinema which was sometimes as local as a small stretch of highway in north India (Uski Roti (Our Daily Bread), Mani Kaul, 1970) or a residential chawl in a Bombay suburb (Katha (The story), Sai Paranjpe, 1983). In fact, they were the only people making cinema with a very strict sense of time and place – love letters which started with a date and place on top.
But then, art cinema movement too had groupies trying to pass off as the real rockstar. Films with dim lights, grim faces, and half a social issue (invariably leftist in thought) would instantly be termed as ‘parallel’, get the government of India funding, and be sent to film festivals abroad. Om Dar-B-Dar sounded like that kind of film, especially after one article I had read which described the film as some kind of existential study into the life of a teenager in a small town of Rajasthan.
Watching it recently for the first time, I realized, it is anything but me-too. Or even close to ‘art cinema’, as we know it. It exists in a league of its own. And though that may not be intended as a high praise, but that’s the only way it can be described.
मिथ्या है संसार – माया है संसार (The world is a lie – the world is an illusion)
Kamal Swaroop, a scientist with DRDO (Defense Research and Development Organization) of India, turned a filmmaker, graduating from FTII, Pune, to debut with Om Dar-B-Dar. He calls his only feature film to date a kind of spoof on ‘art films’ of the time. “If anything, I wanted to make an anti-intellectual film. I didn’t want to make a film on some social issue or sad people. I just wanted to make a film about a small town”, said Swaroop in a personal interaction after the screening a few months ago. Having stayed in Pushkar in Rajasthan, famous for its annual Hindu mela (fare), probably helped him nail the setting of the film. His love for science and mythology admittedly helped in deciding the next two important aspects – the central character of teenaged Om and the basic conflict points in the story.
But is there a story in Om Dar-B-Dar? Kamal Swaroop insists there is – though the group with which I watched the film was clueless. Swaroop calls it bad conditioning – looking for story and only story in cinema. He says cinema is not necessarily mass communication, it can be a personal expression too; a painting or a poem. Though many were not convinced, Swaroop claims that the film, when screened in small villages of Rajasthan, was completely ‘understood’ and enjoyed by the simple villagers. Reasons being – less conditioning and more connection to the vibes and idiosyncrasies of a small town.
Next question – does the film have a form, a structure? Swaroop’s crisp answer – even deform is a form. What about accessibility? Comprehension? Head and tail? Again – Swaroop’s answer – why should cinema be objective? Why a film should be only one of the two things – I got it or I didn’t get it?
That raises some very valid debate points – story, form, and accessibility in cinema. Indian cinema, traditionally has been a story-driven exercise in videography. Starting off with mythological tales in the 30’s and 40’s, and evolving into equally simplistic good vs. evil (Hero vs Villain) cinema of the 60’s and 70’s – there is a long and deeply ingrained history of accessible stories pushing ‘cinema’ more and more into the ever-expanding space of ‘mass-media’. Rumor has it, two of the greatest films of Hindi cinema (Mughal-e-Azam, Guide) had their endings tweaked to accommodate popular tastes. (Anarkali being given a safe passage by the emperor and rains arriving on Raju’s death respectively).
The third aspect – form or structure, was also rarely played with in popular cinema, with the most adventurous of the lot taking the ‘flashback’ route as the only standout narrative element. It can be noted here that most of the art cinema movement films too had a strong focus on story-accessibility couple – they differed majorly in the structure/form department. In addition to having more realistic settings and acting, they succeeded in creating a new cinematic-clock for themselves – a form where time moves slower and hence more details are visible, and vice versa.
And here lies the most distinct element of Om Dar-B-Dar – cinematic clock, here, moves as fast, if not faster than a regular commercial Hindi film while the other two aspects (story and accessibility) are given the least respect. In fact, it would be much enjoyable to watch it as 20 short films (a lot of them very funny, and an equal number completely nonsensical) about Om’s family and friends, stitched together with music, surreal dreams and a mythological back-story. So, for the math-minded – ODBD is an anti-art, anti-commercial film moving at the pace of a commercial film and having the details of an art-film.
टैडपोल से हम (We are like Tadpoles)
After the film screening is over, and after heated debates on whether it can even be called a film in the first place are done with, Kamal Swaroop smiles and asks whether anybody still wants to know the story. A few hands go up and Swaroop relents.
(SPOILERS) Om, a teenager, is blessed with a magical power and he can hold his breath for any desired duration of time. This results in him putting up a show at the holy place of Pushkar (ascribed as the only heaven on Earth in Hindu mythological texts), where he goes inside water and holds his breath. Once, to protest against Brahma, the Hindu God credited as the creator of the world, who has decided to remove the ‘heaven’ status of Pushkar, the locals decide to put up a non-cooperation movement against Brahma. The only non-cooperation they can do to Brahma is to stop breathing, as that’s the only gift he has given. But since Om’s natural tendency is to not breath, for him, the non-cooperation would be the act of breathing. At the time of protest, Om happens to be inside the pond where he puts up his show. He breathes, to support the non-cooperation, and dies. (spoilers end)
But then, one has to watch the film many times to get this story – and as I said, there are at least 20 more stories, all equally layered, and delivered at a crazy pace. At times, it looks like an MTV Production, with the kind of visual liberties, caricatures, and abrupt cutting involved. (No wonder, Swaroop later helmed the launch of Channel V in India, playing a crucial role in defining the ‘funky’ auro-visual space it’s known for now.)
कसप (How do I know)
In a crucial scene in Hindi novelist Manohar Shyam Joshi’s ‘Kasap’, the male protagonist’s naada (thread of pajamas) gets stuck in a knot in front of the girl he is wooing. In Om Dar-B-Dar, a similar thing happens when a young man is about to start making love to his girlfriend. Funny, sad, frustrating, and deeply observational at the same time – moments like these make ODBD a watch to remember.
Whether it’s a film with story, structure, accessibility, or (latest buzzword) ‘take-homes’ is a debate worth drunken nights with friends. The film released in 1988, and has been getting buzz (positive, negative, both) at regular intervals. Though that doesn’t guarantee a great, path-breaking, or cult status to any work of art (or mass-media) – it surely means there are enough cinema crazies in the world.
As for whether you will like it, the only answer is ‘कसप’.

domain: artistic