In the present study, high throughput screening we identified EGCG as a novel inhibitor of human CBR1 with an IC50 value of 0.59 μM. Its potency against CBR1 compares

favorably with the potency of the known natural flavonoid inhibitors of the same enzyme, including quercetin, kaempferol, quercitrin, and genistein with IC50 values between 1 and 10 μM, and the synthetic inhibitor hydroxy-PP with an IC50 value of 0.79 μM.20, 24 Unlike most known inhibitors of CBR1, however, EGCG is already taken by humans through tea and other beverages, and purified EGCG and its analogues have been entered into different clinical trials for cancer chemoprevention and treatment; this is paving the way for EGCG to be evaluated for HCC in light of this study. EGCG is the most abundant and active compound with anticancer activity in tea. The mechanism for the cancer-preventive effect of EGCG is still under active investigation. Several putative binding proteins, including salivary proline-rich proteins, fibronectin,

fibrinogen, and histidine-rich glycoproteins, have been identified; more recently, proteins such as the 67-kDa laminin receptor,25 B cell lymphoma 2,26 vimentin,27 insulin-like high throughput screening assay growth factor 1 receptor,28 FYn,29 glucose-regulated protein 78,30 and zeta chain associated protein kinase 70,31 among others, have been identified. None of these putative EGCG-binding proteins, however, can account for the inhibition of reduction of DNR by EGCG, except for CBR1, which is identified in this study. It has been reported that EGCG alone can inhibit the growth of human HCC cell lines in vitro and induce apoptosis in HCC cells,32 and this is consistent with our observations (Supporting Information Figs. 4 and 7). The inhibitory effect selleck of EGCG on HCC xenografts has also been shown to be associated with inhibition of the vascular endothelial growth factor/vascular endothelial growth factor receptor axis.33 The aim of our research was to test the synergic

effect of EGCG on DNR by inhibiting CBR1. We therefore avoided using toxic EGCG concentrations and deliberately selected lower doses of EGCG that showed minimal toxicity in HCC cells. Several lines of evidence suggest that inhibition of CBR1 by EGCG is responsible for its ability to block DNR resistance and its synergy with DNR for the inhibition of HCC both in vitro and in vivo. EGCG specifically enhanced DNR-induced G2/M phase cell cycle arrest and cell apoptosis in HCC cells with higher CBR1 expression such as HepG2 cells. In contrast, knockdown of CBR1 expression in HepG2 cells by RNAi recapitulated EGCG’s effect. On the other hand, Hep3B with spontaneously lower expression of CBR1 exhibited little synergistic response to EGCG and DNR. Overexpression of CBR1 in Hep3B conferred resistance to DNR, which was overcome by EGCG.

Methods: A total of 42 male wistar rats were randomly divided into three groups: the control group (n = 12), the model group (n = 15), and the Olmesartan group (n = 15). R788 cost With the exception of those in the control group, all rats were given subcutaneous injections of 40 % CCl4 once every three days, 5 mg/kg for the first dose and 3 mg/kg for each subsequent dose. Rats in the control group were given subcutaneous

injections of oil in the same dosage, and from the first day, rats in Olmesartan group were given Olmesartan (4 mg/kg/d) by intragastric administration. All rats were killed after 60 days. Histopathological study of the liver tissues was done with hematoxylin-eosin (HE) and Masson staining. Ang(1–7) levels were determined by enzyme-linked immunosorbent assay (ELISA). The expression of ACE2 and Mas receptor mRNA were evaluated by Real-time PCR. The expression of ACE2 and Mas receptor protein were evaluated by Western blotting. LY2835219 nmr Results: (1) Pathological results: compared with the control group, the degree of hepatic fibrosis was increasing in the model group and the Olmesartan group, and in the Olmesartan

group the degree of hepatic fibrosis was lower than in the model group. (2) ELISA results: the Ang(1–7) level of the model group and the Olmesartan group increased compared with the control group (P < 0.05); see more and the Ang(1–7) level of the Olmesartan group

increased compared with the model group (P < 0.05). (3) Real-time PCR results: ACE and Mas receptor mRNA expression in the model group and the Olmesartan group increased compared with the control group (P < 0.05); and in the Olmesartan group ACE2 and Mas receptor mRNA expression increased compared with the model group (P < 0.05). (4) Western blotting results: ACE2 and Mas receptor protein expression of the model group and the Olmesartan group increased compared with the control group (P < 0.05); and in the Olmesartan group ACE2 and Mas receptor protein expression increased compared with the model group (P < 0.05). Conclusion: Olmesartan attenuated the degree of hepatic fibrosis, not only by inhibiting the effect of Ang II/AT1R, but also by activating the ACE2-Ang(1–7)-Mas receptor axis. Key Word(s): 1. Hepatic fibrosis; 2. ACE2; 3. Angiotensin(1–7); 4. Receptor Mas; Presenting Author: QIANG ZHAO Additional Authors: GANGWEI CHEN, ZHENG YONG, QIANG REN, NING ZHANG, FANG LIU, HAO LIU Corresponding Author: GANGWEI CHEN Affiliations: Department of Gastroenterology, First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang Objective: Hydrogen sulfide (H2S) has been considered as the third gasotransmitter, and affects multiple physiopathological progresses. Some researches report that PI3K/Akt signal pathway is a target of H2S.

and Carpino et al.7, 8 have proposed another new classification RAD001 of cholangiocarcinomas based on cell lineage. Under their classification scheme, which is compatible with the pathological classification of ICC proposed by Nakanuma et al.,5 it is suggested that there are multiple cells of origin in cholangiocarcinoma, including hepatic stem/progenitor cells postulated to be located within the

canals of Hering (hepatic stem/progenitor cell lineage) or peribiliary glands (biliary tree stem/progenitor cell lineage), as well as immature or more mature cholangiocyte derivatives, that underlie biological, epidemiological, and clinical heterogeneity in small versus large duct ICCs and extrahepatic bile duct cancer. Hepatic stem/progenitor cell “biomarkers,” such as neural cell adhesion molecule (NCAM), have been demonstrated to be selectively expressed in combined HCC-CCA9 and in the bile ductular (cholangiolocellular) type.5, 10 Small bile duct type ICCs have also been suggested to originate from

interlobular bile ducts.11 Conversely, large duct or perihilar ICCs have been suggested to arise from biliary tree stem/progenitor cells or from more mature descendents.7, 8 A multistep carcinogenesis process indicative of a hyperplasia- selleck screening library dysplasia-carcinoma sequence is also currently recognized.12-15 In this context, malignant progression of precancerous precursor lesions, notably biliary intraepithelial neoplasia (BilIN) without12, 13 or with14 intestinal metaplasia, as well as intraductal selleck chemicals papillary neoplasm of the

bile ducts exhibiting various phenotypes (e.g., intestinal type, gastric type, and oncocytic type),5 are consistent with different and distinct cell lineage pathways in the cytohistogenesis of ICC variants (i.e., conventional ICC versus less common subtypes, such as intestinal-type ICC or biliary cystic mucinous neoplasm with ovarian stroma5, 14). Although it has been generally considered that ICCs are derived from either cholangiocytes or, possibly, hepatic and/or biliary stem/progenitor cells, Fan et al.16 and Sekiya and Suzuki17 have now independently demonstrated, with unique mouse models and eloquent hepatocyte fate tracing methods, a compelling alternative to the cellular origin of ICC, namely, through transdifferentiation and neoplastic conversion of normal hepatocytes into malignant cholangiocytes by a mechanism mediated, in part, by overexpression of activated Notch. In the model described by Fan et al., ICCs induced in liver after hydrodynamic tail vein injection of the intracellular domain of Notch1 receptor plasmid, combined with concomitant injection of an Akt-overexpressing plasmid, were of the cystadenocarcinoma type, which formed in noncirrhotic liver.

In the setting of WOPN, the collection should be concomitantly treated with percutaneous drainage or endoscopic necrosectomy to prevent infection of the complex collection. The first description of transmural drainage for DDS demonstrated successful endoscopic treatment in 12 of 13 patients with DDS.[38] However, subsequent series have shown more mixed results. Over a seven-year period, selleck chemicals Pelaez-Luna et al. treated 31 patients with DDS with five patients going straight to surgery and 26 undergoing endoscopic treatment. Of the patients undergoing endoscopic treatment, 19 had good long-term

success while seven subsequently required surgery.[2] Varadarajulu et al. also described their experience with 33 patients with DDS. In their series, eight patients underwent surgery while 22 were successfully treated with transmural drainage with prolonged stenting. No patients experienced recurrent fluid collections despite three having spontaneous passage of stents after more than 100 days of follow-up.[58] Our group has recently described a combined endoscopic AG-014699 concentration and percutaneous treatment approach for WOPN and DDS.[51, 60, 62] Our prior experience treating WOPN with percutaneous drains alone demonstrated that up to one third of the patients developed external fistulas secondary to DDS with the inability to subsequently remove the drains. Therefore, we developed a new selleck technique wherein

we place transmural stents in addition to percutaneous drains for the treatment of WOPN (Fig. 2). Transmural stents are left in place indefinitely for patients with DDS. With this new technique, we have avoided cutaneous fistulas and greatly reduced the need for surgery for DDS. We have now treated more than 100 patients with WOPN with this technique with < 1% death related to pancreatitis and < 5 % requiring surgery. Interventional radiologists can offer other minimally invasive, surgery-sparing treatments for DDS. Cyanoacrylate or other glues has been described as a treatment for DDS with an

external pancreatic fistula.[63, 64] In this technique, a guidewire is advanced into the main pancreatic duct within the isolated segment of the pancreas. Subsequently, a microcatheter is advanced over the wire and glue is then injected to completely fill the pancreatic duct and all of its side branches within this section of the pancreas. This works best with a short, 3–4-cm segment of disconnected pancreas and is associated with mild procedural pancreatitis in 50% of patients. Our group has recently described a combined IR and endoscopic treatment for DDS and external pancreatic fistulas.[52] In this technique, initially a radiologist will pass a TIPS needle into the fistula tract. Using fluoroscopic and endoscopic guidance, this needle is then passed through the gastric wall into the stomach lumen.

This epidemiologic disparity between donor size and recipient needs led to the use of reduction hepatectomies/segment liver transplantation and the development of other innovative transplant surgical techniques based on reduced size grafts, including split liver transplantation and the

use of organs from living donors.[96-99] These advances allowed more widespread application of liver transplantation for children. During 2011-2012, 64 centers performed at least one liver transplant in a patient <18 years of age; 23 programs performed 20 or more transplants in this population during that time frame.[100] Pediatric pretransplant Staurosporine concentration mortality has steadily decreased, most dramatically for candidates less than 1 year of age. The number of new pediatric candidates added to the liver transplant waiting

list was 704 in 2011.[100, 101] In 2011, there were 477 deceased donor pediatric liver transplants and 59 living donor transplants. Graft survival has continued to improve for pediatric recipients. Despite this high success rate, challenges remain, including the need for targeted preoperative management to address the problems of malnutrition, and improved methods to prevent graft loss while avoiding the consequences of immunosuppression, such as posttransplant lymphoproliferative disease (PTLD) and renal injury.[99] All elements were in place for expansion and validation of Pediatric Hepatology. In the mid-1990s centers that focused this website on Pediatric Hepatology became a component of many divisions of Pediatric click here Gastroenterology. Research flourished with the application of state-of-the-art cellular and molecular biology techniques and the emergence of molecular genetics, which enhanced our understanding and recognition of the pathophysiological and genetic basis of an increasing number of disorders of the liver

in children.[102] With clinical and research efforts converging, the field rapidly gained momentum. The next key ingredient to establishing the formal field was to create and sustain a critical mass and validate the concept of Pediatric Hepatology as an academic subspecialty. In a decision that reflected validation and maturity, “Hepatology” was added to the name of the major Pediatric Gastroenterology society—which became the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). This is symmetrical with the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). In 1993, perhaps as a measure of the growth of the field (or the verbosity of the author) the chapter on Liver Disease in Infancy and Childhood in the 7th Edition of Diseases of the Liver (Leon and Eugene Schiff; editors) was 104 pages long!103 A community of colleagues interested in Pediatric Hepatology was being built.

28(40%) were males, with a mean age of 49±10 yrs. 80% were African Americans. 32% were asymptomatic, while

40% had gastrointestinal symptoms. The prominent liver test abnormality was an elevated GSK-3 beta pathway alkaline phosphatase (AP) level (375±383 IU/L). Angiotensin-converting enzyme (ACE) levels were elevated only in 49% of tested patients (n=53). Of 55 patients who had a liver biopsy, 30(55%) had no fibrosis, 14(25%) had stage 1-2, and 9(16%) had stage 3-4. 13 patients (11 treated) had paired liver biopsies over a 59±38 mos interval; 6(46%, 1 untreated) showed no change, 6(46%, 1 untreated) showed improved fibrosis, while 2(15%) showed worse fibrosis at follow-up. 52(74%) patients were treated for sarcoidosis, 31(60%) with corticosteroids, 19(37%) with ursodeoxycholic acid, 18(35%) with other immunotherapy agents. Demographic and baseline laboratory data and the follow-up periods were similar between the treated (Tx) and the untreated (No Tx) groups, except for a higher albumin in the No Tx group (4.2±0.4 vs 3.9±0.5 g/dL, p=0.02) and a lower AP in the No Tx group (224±207 vs 428±416 IU/L, p=0.05). Comparison of baseline and follow-up laboratory data for learn more each group are shown in the table. 6% of patients in each group either died or required OLT. Conclusions: Liver chemistry tests may improve in hepatic sarcoidosis with or without therapy, although untreated patients had lower

AP at baseline in this study. Transplant-free survival is similar in treated and untreated patients. Disclosures: K. Gautham Reddy – Advisory Committees or Review Panels: AASLD Transplant Hepatology Pilot Steering Committee, ACG Training Committee, Program Director’s Caucus Steering Committee; Grant/Research Support: Intercept, Ocera, Merck, Lumena Nancy Reau – Advisory Committees or Review Panels: Kadmon, Jannsen, Vertex, Idenix, AbbVie, Jannsen; Grant/Research Support: Vertex, Gilead, Genentech, AbbVie, BMS, Jannsen, BI Donald M. Jensen – Grant/Research Support: Abbvie, Boehringer, BMS, Genen-tech/Roche, Janssen Helen S. Te – Advisory Committees

or Review Panels: Gilead Sciences, Jansenn Pharmaceuticals; Grant/Research this website Support: Abbvie, BMS The following people have nothing to disclose: Nicole M. Welch, Andrew Aronsohn Background: Recent findings from the prospective UK-PBC patient cohort have shown that non-response to ursodeoxycholic acid (UDCA) therapy is associated with increased risk of death or need for transplant in PBC. Younger age at presentation and male gender were associated with increased risk of UDCA non-response. Although the implication is that age at presentation and gender are therefore risk factors for death and transplantation in PBC, the link as yet, has only been an indirect one. Here we set out to utilise the historic Newcastle cohort to directly explore the impact of age at presentation and gender on outcomes in PBC.

Patients in Copanlisib chemical structure this cohort either did not respond to treatment or were untreated, namely representing the HCV subgroup with the poorest outcome. Were some patients not treated because they were sicker as suggested by a lower platelet count in the HCV-infected cohort? Moreover, compared to those that respond to treatment, HCV nonresponders have a higher

risk of decompensation. Both NASH and HCV are common and often occur together. Unfortunately, data on concomitant fatty liver or insulin resistance was not systematically collected. The recent approval of the direct-acting antivirals for treatment of HCV raises many questions. Although the natural history of HCV as we know it is likely to change, drug interactions and side effects may limit broad use of direct-acting antivirals. Even so, with more patients achieving viral clearance, one could speculate that this will translate into less liver-related morbidity and mortality, including incident HCC in the

years to come. Although the natural evolution of disease in the HCV cohort was fairly predictable, the NASH cohort may have been influenced by several factors. In the article by Bhala et al., the use of metformin and statins was reported, but no mention was made of thiazolidenediones or vitamin E use. This is particularly relevant, because 50% of the NASH cohort had diabetes, and thiazolidenediones are commonly used in this setting. Furthermore, there Torin 1 are no data provided on the use of new medications or changes in body weight during the follow-up period. The short-term data on the effects of sustained weight loss, vitamin E, and pioglitazone are compelling, and future studies will be needed to determine their influence on the natural history of NASH.10, 11 While we await these data, we need to, at a minimum, consider the role of such factors as potentially altering the course

of NASH for the better. Given the observational nature of the study, this website the assessment of liver decompensation was left to the discretion of the investigators. Thus, the “development of varices” as a major outcome of hepatic morbidity could have been ascertained by screening endoscopy or by the development of a variceal hemorrhage. Screening practices for the detection of HCC or varices of the individual centers were not reported. Differences in how these endpoints were reported could be relevant, because the majority of patients with HCV came from Australia and Italy, and the majority of patients with NASH came from the United States and the United Kingdom, suggesting that different screening practices or definitions between the participating centers could have influenced outcome.

001 < P < 0.01 (denoted by **) corresponds to very significant, 0.01 < P < 0.05 (denoted by *) corresponds to significant, and P > 0.05 is not significant (ns). The overall sensitivity of anti-E1E2 antibodies for the prediction of treatment response was calculated using receiver operating characteristic (ROC) curves in one-point studies Deforolimus mw and at different time points before and during treatment in follow-up studies. Optimal cutoff values were defined using the highest sum of sensitivity and specificity. For each optimal cutoff value, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Five negative controls (NHS) were initially tested at different dilutions:

1/50, 1/100, 1/250, 1/500, and 1/1000 (Fig. 1A). Standard dilutions selected were 1/250 and 1/500. The cutoff values for both dilutions were determined with 17 NHS (negative KU-60019 ic50 for HCV, HBV, and HIV; Fig. 1B). The mean OD values for E1, E2A, and E2B were 0.609 ± 0.033 for 1/250 dilution and 0.374 ± 0.036 for 1/500 dilution. The cutoff was calculated as the mean value + 3 SD, and corresponded to 0.708 for the 1/250 dilution and 0.482 for the 1/500 dilution. Each serum sample was tested in triplicate for the E1, E2A, and E2B peptides. For an easier representation of results, they were expressed as the average of OD obtained for E1, E2A,

and E2B, which are very similar (Fig. 1B). The interpretation for the presence or absence of anti-E1E2A,B antibodies took place according to these mean OD values. If the mean value was greater than or equal to the cutoff for a fixed dilution, the sample was defined as positive or the limit for this dilution.

If it was under the cutoff, the sample was considered negative. All the sera positive for anti-E1E2A,B contain antibodies that bind to the D32.10 epitope, i.e., to the three peptides, E1, E2A, and E2B. Inversely, the negative sera do not contain any of them. Therefore, these antibodies are called “D32.10 epitope-binding antibodies” throughout the text. At least five NHS were systematically included in each assay, and the selleck kinase inhibitor cutoff was recalculated for each type of experiments. The intra-assay variability was evaluated by testing a same positive sample 10 times in an intra-assay run, and showed a coefficient of variation < 4%. The inter-assay variability was evaluated by testing a same positive sample in triplicate in seven independent runs at different days by the same technician, and showed a coefficient of variation < 5%. Figure 2A shows the results obtained with samples from 52 patients cured of HCV infection (Group 1: C). Twenty-two patients who had spontaneously cleared a past infection (≥10 years) corresponded to the series 1, whereas the 30 other patients whose date of acute infection was unknown corresponded to the series 2. Among the total of 52 C patients, 46 were found positive for anti-E1E2A,B antibodies (88.5%) with a higher prevalence (21 of 22, 95.5%) in the series 1.

20-22 Wildtype mice treated with APAP for 6 hours exhibited increased p-JNK that was not found with Wy-14,643-pretreatment, whereas Ppara-null mice have increased p-JNK following Wy-14,643-pretreatment (Fig. 3C). To ensure that p-JNK was associated with increased activity, kinase assays were performed and increased p-JNK levels were indeed consistent with elevated p-c-jun levels (Fig. 3C, bottom panel). APAP treatment results in a decrease in hepatic levels of GSH at 2 hours and 6 hours, due in Selleck JAK inhibitor part to the production of the quinone NAPQI from APAP that is rapidly neutralized by GSH conjugation by glutathione S-transferase.

This decrease was partially restored by Wy-14,643-pretreatment. However, the maintenance of GSH levels was even more pronounced in isolated mitochondria (Fig. 4A). H2O2 levels are inversely correlated with GSH levels and reflect increase oxidative stress. Indeed, Wy-14,643-pretreatment decreased H2O2 levels elevated by APAP treatment, and this was most pronounced in isolated mitochondria (Fig. 4B). APAP toxicity is also associated with increased levels of long-chain acylcarnitines in serum that are likely due to mitochondrial damage.15 Metabolomics comparison of serum revealed marked differences in serum metabolites between APAP-treated and Wy-14,643-pretreatment/APAP as indicated by the scores plot

separation of the two groups (Supporting Fig. 4A). This difference was driven, among others, by differences in levels of palmitoylcarnitine that were elevated in APAP-treated mouse serum and normal in Wy-14,643-pretreatment/APAP (Supporting Fig. 4B). Pretreatment with Selleckchem Z VAD FMK Wy-14,643 prior to APAP administration blocks the increase in palmitoylcarnitines, as indicated by direct quantification of palmitoylcarnitine learn more (Fig. 4C). At 2 hours post-APAP treatment, both APAP- and Wy-14,643/APAP-treated mice exhibited

extensive GSH depletion in both the liver and mitochondria (Fig. 4D). Because APAP toxicity results in elevated mitochondrial oxidative stress and mitochondrial damage, a role for UCP2 in Wy-14,643 protection against APAP-induced hepatic damage was investigated. UCPs are located in the mitochondrial inner membrane and are associated with decreased hepatic ROS.23, 24 Wy-14,643 treatment induced UCP2 mRNA in the absence and presence of APAP (Fig. 5A, left panel); similar induction was not observed in Ppara-null mice. Protein levels of UCP2 were also measured in mitochondrial extracts from control and mice treated with Wy-14,643 for 24 hours (Supporting Fig. 5). To determine whether UCP2 has a role in Wy-14,643 protection against APAP hepatotoxicity, Ucp2-null mice were subjected to Wy-14,643 and APAP treatment. Mice lacking expression of UCP2 were not protected against APAP-induced toxicity following Wy-14,643, as revealed by serum ALT and AST enzyme levels (Fig. 5B) and liver histology (Fig. 5C).

Conclusions.— Problematic headache is highly prevalent among patients with HIV/AIDS, most of which conform to the semiology of chronic migraine, although with some atypical features such as bilateral location and pressing/tightening quality. A low frequency of identifiable secondary causes is likely attributable to reduced frequency of opportunistic infections in the current era of HAART. Disease severity is strongly predictive of headache, highlighting

the importance of physician attention to headache symptoms and of patient adherence to treatment. (Headache 2012;52:455-466) “
“(Headache 2011;51;S2:93-100) check details Chronic migraine (CM) is a complex disorder requiring a multifaceted management approach encompassing lifestyle modification, trigger avoidance, behavioral therapy, pharmacotherapy, patient education and support, management of expectations, and close follow-up. The lack of pharmacotherapies approved by the US Food and Drug Administration (FDA) hinders CM prophylaxis and management. Topiramate, gabapentin, tizanidine, fluoxetine,

amitriptyline, and onabotulinumtoxinA have been evaluated for prophylactic treatment of CM in randomized, double-blind, placebo-controlled or active comparator-controlled trials. Additional well-designed, placebo-controlled studies are needed to assess the effectiveness of new and existing treatment options for CM. Understanding current clinical trial design and management guidelines is

critical find more to designing future trials that overcome the challenge of consistent www.selleckchem.com/products/bay80-6946.html use of sensitive and clinically meaningful outcome measures. Topiramate is approved for episodic migraine management and has been studied for CM management. A growing body of evidence has shown it to be safe, effective, and well-tolerated in specific patient populations. However, intolerable adverse effects and inadequate efficacy associated with topiramate may lead to poor adherence. The efficacy, safety, and tolerability of onabotulinumtoxinA have been demonstrated in studies in various migraine patient populations, leading to recent FDA approval of onabotulinumtoxinA for the prophylactic treatment of CM in adults. These studies included patients with or without medication overuse, which may affect 30% to 80% of CM patients in the USA. In this program, we will analyze and discuss recent clinical trials investigating topiramate and onabotulinumtoxinA for CM. “
“The term New Daily Persistent Headache (NDPH) has been used for nearly 25 years and yet the entity remains enigmatic. It can be argued the simplest, indeed most appropriate, approach is to use the term to mean simply what it says- i.e. as an umbrella description, rather like chronic daily headache. NDPH should be used as a diagnostic umbrella inviting better characterization, not be an achievement in itself.