5.1. BDCA3+ DCs were able to induce ISGs in the coexisting JFH-1-positive Huh7.5.1 cells. The treatments of BDCA3+ DCs with anti-CD81 antibody, cloroquine, or bafilomycin A1 reduced HCVcc-induced IL-28B release, whereas BDCA3+ DCs comparably produced IL-28B upon replication-defective selleck kinase inhibitor HCVcc. The TRIF-specific inhibitor reduced IL-28B release from HCVcc-stimulated BDCA3+ DCs. In response to HCVcc or JFH-1-Huh7.5.1, BDCA3+ DCs in healthy subjects with IL-28B major (rs8099917, TT)

released more IL-28B than those with IL-28B minor genotype (TG). Conclusion: Human BDCA3+ DCs, having a tendency to accumulate in the liver, recognize HCV in a CD81-, endosome-, and TRIF-dependent manner and produce substantial amounts of IL-28B/IFN-λ3, the ability of which is superior in subjects with IL-28B major genotype. (HEPATOLOGY 2013) Hepatitis C virus (HCV) infection is one of the most serious health problems in the world. More than 170 million people are chronically infected with HCV and are at high risk of developing liver cirrhosis and hepatocellular carcinoma. Genome-wide association studies have successfully identified the genetic polymorphisms Sirolimus (single nucleotide

polymorphisms, SNPs) upstream of the promoter region of the interleukin (IL)-28B / interferon-lambda 3 (IFN-λ3) gene, which are strongly associated with the efficacy of pegylated interferon-α (PEG-IFN-α) and ribavirin therapy or spontaneous HCV clearance.1-4 IFN-λs, or type III IFNs, MCE公司 comprise a family of highly homologous molecules consisting of IFN-λ1 (IL-29), IFN-λ2 (IL-28A),

and IFN-λ3 (IL-28B). In clear contrast to type I IFNs, they are released from relatively restricted types of cells, such as hepatocytes, intestinal epithelial cells, or dendritic cells (DCs). Also, the cells that express heterodimeric IFN-λ receptors (IFN-λR1 and IL-10R2) are restricted to cells of epithelial origin, hepatocytes, or DCs.5 Such limited profiles of cells expressing IFN-λs and their receptors define the biological uniqueness of IFN-λs. It has been shown that IFN-λs convey anti-HCV activity by inducing various interferon-stimulated genes (ISGs),5 the profiles of which were overlapped but others were distinct from those induced by IFN-α/β. Some investigators showed that the expression of IL-28 in PBMC was higher in subjects with IL-28B major than those with minor; however, the levels of IL-28 transcripts in liver tissue were comparable regardless of IL-28B genotype.2, 6 At the primary exposure to hosts, HCV maintains high replicative levels in the infected liver, resulting in the induction of IFNs and ISGs. In a case of successful HCV eradication, it is postulated that IFN-α/β and IFN-λ cooperatively induce antiviral ISGs in HCV-infected hepatocytes. It is of particular interest that, in primary human hepatocytes or chimpanzee liver, IFN-λs, but not type I IFNs, are primarily induced after HCV inoculation, the degree of which is closely correlated with the levels of ISGs.

Italian patients with severe haemophilia aged ≥65 years born in the 1940s or earlier were compared with men without bleeding disorders matched for age and geography. HRQoL was assessed via generic and disease-specific questionnaires. Potential associations with concomitant illnesses, orthopaedic status, physical functioning, http://www.selleckchem.com/products/PD-0325901.html cognitive status and depression were evaluated. In addition, the newly adapted HRQoL questionnaire specific for elderly persons with haemophilia (Haem-A-QoLEldlery)

was psychometrically tested and validated. Thirty-nine patients, aged 65–78 years, were investigated, 33 with haemophilia A and six with haemophilia B, and compared to 43 controls, aged 65–79 years. Chronic blood borne viral infections, hypertension and arthropathy

were more www.selleckchem.com/products/PD-98059.html frequent in patients, whereas hypercholesterolemia and cardiovascular diseases were more frequent in controls. Psychometric characteristics of Haem-A-QoLElderly showed good to excellent values for reliability and validity. HRQoL was worse in patients at EQ-VAS, WHOQOL-BREF and WHOQOL-Old. The highest impairments were found in patients by means of the haemophilia-specific Haem-A-QoLElderly in such dimensions as ‘physical activity & leisure’, ‘physical health’ and ‘view’. A poor orthopaedic status was negatively associated with HRQoL. Compared to age-matched controls elderly patients with haemophilia had an impaired HRQoL in association with their health status. The newly developed Haem-A-QoLElderly proved to be a reliable and valid instrument for HRQoL assessment in elderly haemophilia patients. “
“This

chapter contains sections titled: Musculoskeletal assessment: outcome measurement Musculoskeletal outcome: the body—assessment of structure and function Musculoskeletal outcome: the person—assessment of activities and functional independence in hemophilia Musculoskeletal outcome: in society—assessment MCE公司 of participation and quality of life Conclusion Acknowledgment References “
“Summary.  Recurrent haemarthroses leading to chronic synovitis and arthropathy remain a major cause of morbidity in patients with haemophilia. Radioactive synovectomy (RS) is considered the first choice of treatment for chronic haemophilic synovitis. The aim of this study was to evaluate the effect of RS with Yttrium90 citrate (C-Y90) in the joints of patients with chronic haemophilic synovitis. From 2003 to 2007, 245 joints (118 knees, 76 elbows, 49 ankles and two shoulders) of 190 patients with haemophilia or von Willebrand disease were submitted to RS with C-Y90 at Hemocentro de Mato Grosso, Brazil. Forty joints had radiographic Pettersson scores above 8. There were 36 joints of 22 patients with inhibitors to factor VIII. The procedure was safe with low occurrence of adverse events. The main effect was the overall reduction in joint bleeding frequency, from 19.

Italian patients with severe haemophilia aged ≥65 years born in the 1940s or earlier were compared with men without bleeding disorders matched for age and geography. HRQoL was assessed via generic and disease-specific questionnaires. Potential associations with concomitant illnesses, orthopaedic status, physical functioning, CHIR-99021 supplier cognitive status and depression were evaluated. In addition, the newly adapted HRQoL questionnaire specific for elderly persons with haemophilia (Haem-A-QoLEldlery)

was psychometrically tested and validated. Thirty-nine patients, aged 65–78 years, were investigated, 33 with haemophilia A and six with haemophilia B, and compared to 43 controls, aged 65–79 years. Chronic blood borne viral infections, hypertension and arthropathy

were more 5-Fluoracil clinical trial frequent in patients, whereas hypercholesterolemia and cardiovascular diseases were more frequent in controls. Psychometric characteristics of Haem-A-QoLElderly showed good to excellent values for reliability and validity. HRQoL was worse in patients at EQ-VAS, WHOQOL-BREF and WHOQOL-Old. The highest impairments were found in patients by means of the haemophilia-specific Haem-A-QoLElderly in such dimensions as ‘physical activity & leisure’, ‘physical health’ and ‘view’. A poor orthopaedic status was negatively associated with HRQoL. Compared to age-matched controls elderly patients with haemophilia had an impaired HRQoL in association with their health status. The newly developed Haem-A-QoLElderly proved to be a reliable and valid instrument for HRQoL assessment in elderly haemophilia patients. “
“This

chapter contains sections titled: Musculoskeletal assessment: outcome measurement Musculoskeletal outcome: the body—assessment of structure and function Musculoskeletal outcome: the person—assessment of activities and functional independence in hemophilia Musculoskeletal outcome: in society—assessment medchemexpress of participation and quality of life Conclusion Acknowledgment References “
“Summary.  Recurrent haemarthroses leading to chronic synovitis and arthropathy remain a major cause of morbidity in patients with haemophilia. Radioactive synovectomy (RS) is considered the first choice of treatment for chronic haemophilic synovitis. The aim of this study was to evaluate the effect of RS with Yttrium90 citrate (C-Y90) in the joints of patients with chronic haemophilic synovitis. From 2003 to 2007, 245 joints (118 knees, 76 elbows, 49 ankles and two shoulders) of 190 patients with haemophilia or von Willebrand disease were submitted to RS with C-Y90 at Hemocentro de Mato Grosso, Brazil. Forty joints had radiographic Pettersson scores above 8. There were 36 joints of 22 patients with inhibitors to factor VIII. The procedure was safe with low occurrence of adverse events. The main effect was the overall reduction in joint bleeding frequency, from 19.

GM has received research funding, advisory board payments and speaker payments from Gilead and research funding and speaker payments from Janssen. H LORD,1 C TRELOAR,2 E CAMA,2 J NEWLAND,2 MT LEVY1 1Liverpool Hospital UNSW, Sydney Australia, 2Centre for Social Research in Health, UNSW Australia Introduction: Chronic B Hepatitis Virus is characteriZed LBH589 solubility dmso by 5 distinct phases named by underlying patho-physiological mechanism. Recommended monitoring and therapy is tailored to each phase. We have observed that

patients seem unaware of this, do not appreciate the dynamic nature of chronic HBV nor the monitoring and treatment implications. Methods: 1. We examined HBV specific patient information resources of national and international hepatitis / government organizations to determine what content was presented (significant content ≥10% of total content or own paragraph). 2. A visual resource using metaphorical Hepatitis B Bear imagery and renamed HBV phases; Silent, Damage, Control, Escape and Clear was developed. 3. Patients were surveyed to determine their opinion of the phases presented in this way. 4. A video, “Understanding Hepatitis B” using actors, Bear imagery Sirolimus concentration and scenarios was developed and launched onto

YouTube. 5. An independently conducted qualitative and quantitative survey was conducted to evaluate the efficacy of the video in conveying information. Results: 1. 18

patient HBV information resources were examined; 100% included information on prevention/vaccination, 94% on routes of transmission, 89% on complications of HBV (cancer and cirrhosis), 56% on monitoring recommendations , 78% on therapy but only 6% mentioned the phases of HBV infection in a significant way. 2 and 3. The renamed phases and bear imagery were evaluated by patients in our clinic, who strongly agreed (77%) or agreed (23%) that the illustrations assisted their understanding of HBV phases. The majority (70%) did not find the images upsetting or confusing. 23% did, largely because of the damage phase, which was subsequently modified. 4 and 5. To date, the video has been watched by over 16,000 members of the public. 127 community members were evaluated on their knowledge before and after watching the 上海皓元 video. Correct understanding of the phases increased significantly after watching the video (14% to 60%). A majority (61%) of respondents found the bear pictures useful. Qualitative responses overwhelmingly supported the usefulness of the bear. Conclusion: This work provides evidence that the current health literacy resources of HBV do not address the important information of the phases and suggests a novel Hepatitis B Bear based resource as one solution. An App (see understandinghepatititisB.com) is being developed that may also assist.

Comparable potency and efficacy of N8 and Advate® was found based on TEG® parameters. Finally, similar binding

profiles to immobilized lipoprotein receptor-related protein (LRP) of N8 and Advate® were observed. The study demonstrated that N8 is fully functional in a variety of assays measuring FVIII activity. No functional differences were found between N8 and comparator compounds. “
“Ten weeks prior to a scheduled left total knee arthroplasty, a 25-year-old man with severe haemophilia A and a high-titre inhibitor presented to the physical therapist for a preoperative assessment at the haemophilia treatment centre (HTC). Prior to the recommendation to proceed to surgery, the therapist and other members of the multidisciplinary care team had surmised that, despite two previous radiosynovectomies, Cetuximab in vivo an arthroscopic synovectomy, and most recently at the age of 18 years, an arthroscopic debridement, the patient continued to have a progression of joint disease manifested by pain, restricted selleck products range of motion and reduced strength. Based on these findings and the patient’s history of consistent adherence to and follow-through with recommended treatments, the HTC staff and orthopaedic surgeon determined that he was a

good candidate for total knee replacement. The patient’s pain and joint disease severely limited his mobility and participation in functional activities. The most recent radiographs were notable for severe tricompartmental arthropathy of the left knee with joint deformity, flexion contracture, and osteoporosis. When queried about current haemostatic therapy during the initial preoperative visit with the physical therapist, the patient explained that he was self-infusing a bypassing agent to treat active bleeds and as prophylactic treatment before participating in vigorous physical activity, as advised by his haematologist. He had previously managed his joint pain with cyclooxygenase-2 inhibitors and both short- and long-acting opioids, in addition to physical

therapy. His current personal inventory of mobility and rehabilitative aids consisted of crutches, 上海皓元 compressive wraps, and a cold-compression unit. Further assessment of relevant environmental and psychosocial factors revealed that the patient was living with his girlfriend and 3-year-old daughter, for whom he was the primary caregiver, in a two-story home with five steps to enter. He was also working part-time from home as a computer consultant. The visit concluded with a formal physical assessment and discussion of next steps, including plans for additional preoperative physical therapy sessions. The therapist also informed the patient about what to expect postoperatively in terms of rehabilitation and recovery.

In the original phase 3 studies, histological improvement was observed in the majority of patients (73%) as early as week 48, but only a minority (32%) demonstrated an improvement in fibrosis. The current analyses of the long-term histology cohort summarize the effects of continued entecavir therapy on hepatic necroinflammation and fibrosis in nucleoside-naive, HBeAg-positive and HBeAg-negative CHB patients.

After a median exposure to entecavir therapy of approximately 6 years, histological improvement and improvement of fibrosis increased to 96% and 88% of patients, respectively. Most patients (75%) in the cohort who had a baseline HAI score ≥4 achieved a score ≤3 by the time of long-term biopsy. These histological analyses click here extend previous observations NVP-BEZ235 of the clinical efficacy of entecavir at 48 weeks in patients with advanced fibrosis or cirrhosis.38 All

patients who had evidence of advanced fibrosis or liver cirrhosis at the phase 3 baseline demonstrated improvement in fibrosis at the long-term assessment. Suppression of viral replication below the level of polymerase chain reaction assay detection (serum HBV DNA level <300 copies/mL) occurred in all patients, and most patients (86%) also had a normal serum ALT level at the time of long-term biopsy. Because of the sustained suppression of HBV DNA to a level <300 copies/mL, these patients were at

minimal risk for antiviral drug resistance, and no evidence of virological rebound or genotypic resistance to entecavir was observed in this study. A majority of patients (55%) lost HBeAg, and 33% experienced HBe seroconversion at the time of long-term biopsy. 上海皓元 Patients who did not demonstrate HBe seroconversion during long-term treatment also experienced improvements in liver histology and reversal of fibrosis, and this suggests that these outcomes are more closely associated with HBV DNA suppression than the immunological response to therapy. The baseline demographics of the patients in the long-term histology cohort and the phase 3 studies suggest that the two populations are comparable; however, the current data set has some limitations. For all patients who entered the rollover study, the dose of entecavir increased from 0.5 mg in the phase 3 studies to 1.0 mg daily in the rollover study, and 51 of 57 patients (89%) in this cohort received a median of 29 weeks of concurrent lamivudine before they continued on entecavir monotherapy for the remainder of the observation period. Because amendments were made to the long-term rollover study as new data emerged, it is not possible to evaluate any potential contribution of the increased dose of entecavir or the brief period of concurrent lamivudine to the results.

In the original phase 3 studies, histological improvement was observed in the majority of patients (73%) as early as week 48, but only a minority (32%) demonstrated an improvement in fibrosis. The current analyses of the long-term histology cohort summarize the effects of continued entecavir therapy on hepatic necroinflammation and fibrosis in nucleoside-naive, HBeAg-positive and HBeAg-negative CHB patients.

After a median exposure to entecavir therapy of approximately 6 years, histological improvement and improvement of fibrosis increased to 96% and 88% of patients, respectively. Most patients (75%) in the cohort who had a baseline HAI score ≥4 achieved a score ≤3 by the time of long-term biopsy. These histological analyses see more extend previous observations Palbociclib research buy of the clinical efficacy of entecavir at 48 weeks in patients with advanced fibrosis or cirrhosis.38 All

patients who had evidence of advanced fibrosis or liver cirrhosis at the phase 3 baseline demonstrated improvement in fibrosis at the long-term assessment. Suppression of viral replication below the level of polymerase chain reaction assay detection (serum HBV DNA level <300 copies/mL) occurred in all patients, and most patients (86%) also had a normal serum ALT level at the time of long-term biopsy. Because of the sustained suppression of HBV DNA to a level <300 copies/mL, these patients were at

minimal risk for antiviral drug resistance, and no evidence of virological rebound or genotypic resistance to entecavir was observed in this study. A majority of patients (55%) lost HBeAg, and 33% experienced HBe seroconversion at the time of long-term biopsy. 上海皓元医药股份有限公司 Patients who did not demonstrate HBe seroconversion during long-term treatment also experienced improvements in liver histology and reversal of fibrosis, and this suggests that these outcomes are more closely associated with HBV DNA suppression than the immunological response to therapy. The baseline demographics of the patients in the long-term histology cohort and the phase 3 studies suggest that the two populations are comparable; however, the current data set has some limitations. For all patients who entered the rollover study, the dose of entecavir increased from 0.5 mg in the phase 3 studies to 1.0 mg daily in the rollover study, and 51 of 57 patients (89%) in this cohort received a median of 29 weeks of concurrent lamivudine before they continued on entecavir monotherapy for the remainder of the observation period. Because amendments were made to the long-term rollover study as new data emerged, it is not possible to evaluate any potential contribution of the increased dose of entecavir or the brief period of concurrent lamivudine to the results.

Yun Yen.

Hela, HepG2, Hep3B, SK-Hep-1, and PLC/PRF/5 cells were cultured in modified Eagle’s medium with 10% fetal bovine serum supplement. SNU475, SNU398, and Huh7 cells were cultured in RPMI 1640 medium with 10% fetal bovine serum. Primary hepatocytes were isolated and cultured as described.17 Kupffer cells were isolated with OptiPrep Density Gradient Medium (Sigma, St. Louis, MO) according to a published protocol.18 Stellate cells were isolated and purified by pronase and collagenase.19 Purity of stellate cells, determined by intrinsic vitamin A autofluorescence, was more than 90%. The primary cells were seeded on six-well plates with Dulbecco’s modified Eagle’s medium containing 10% fetal bovine serum. For knockdown of miR-194 in HepG2 cells, 100 nM miR-194 inhibitors (Ambion, Austin, TX) were transfected into cells with 2 μL HiPerfect (Qiagen, Valencia, CA) on a six-well plate. MDH1-PGK-eGFP-2.0 plasmid (Addgene 11375) JAK inhibitor was used to transduce a precursor sequence of miR-194 to liver mesenchymal-like cancer cell lines.20 A multiplicity of infection of 3 to 6 was used to generate stable cell lines with miR-194 overexpression. RNAs were extracted using Tri-Reagent (Molecular Research Center, Inc., Cincinnati, OH). miR-194 expression in human organs was analyzed

with FirstChoice Human Total RNA Survey Panel (Applied Biosystems, Foster City, CA). The reverse transcription was performed with Superscript III reverse transcriptase (Invitrogen, Carlsbad, CA). Real-time polymerase chain reaction (PCR) Small molecule library was performed using the Power SYBR Green PCR Master Mix protocol (Applied Biosystems).13 5S RNA was used to normalize expression levels of miRNAs. Sequences of the primers are provided in Supporting Information Table 1. For analysis of mRNAs, reverse transcription was performed with Superscript III reverse transcriptase and Oligo(dT)20 at 50°C for 1 hour. Primers for miR-194 target genes CDH2, HBEGF, RAC1, IGF1R, and DNMT3B were

provided in Supporting Information Table 2. Gene expression levels for mRNAs were standardized with β-actin (Ambion). Proteins were separated by 10% sodium dodecyl MCE公司 sulfate–polyacrylamide gel electrophoresis and transferred to nitrocellulose membranes. After blocking in 5% nonfat milk, membranes were incubated with the following primary antibodies: anti–E-cadherin and anti–N-cadherin antibodies from Cell Signaling Technology, Inc. (Danvers, MA); anti-vimentin from Santa Cruz Biotechnology (Santa Cruz, CA) and anti-β-actin from Sigma. Membranes were washed and exposed to peroxidase-conjugated secondary antibodies (Amersham Bioscience, UK). For morphology study, 0.5 × 106 SK-Hep-1 cells transduced by miR-194 virus or control were seeded on a 10-cm dish and incubated at 37°C with 5% CO2 for 36 hours. For cell proliferation study, 5 × 103 SK-Hep-1 cells were seeded in each well of a 96-well plate.

4a) and the resected specimens from all three patients. Malignant cells were not observed in any of the patients. Full spectrum of LPSP-like histology was not observed in any of the resected specimens from patients with PSC and CCC. The significant infiltration of IgG4-positive plasma cells (≥10 cells/HPF)

was observed with endobiliary biopsy in nine of 13 patients, and liver biopsy in two of three patients (Figs 3b,4b). Surgical resections of the liver were performed in three of five patients who showed few IgG4-positive plasma cells Panobinostat in vitro in their biopsy specimens. With the resected specimens, a histological diagnosis of ISC with a significant infiltration of IgG4-positive plasma cells could be finally documented in all three patients. The infiltration of IgG4-postive cells was not observed in any patient with disease controls;

none in 13 patients with PSC, and 13 patients with hilar CCC. After induction therapy with 30–40 mg prednisolone daily for 1–2 months, all 13 patients who were treated for biliary strictures showed marked improvement/resolution of MAPK Inhibitor Library biliary strictures upon follow-up cholangiogram (Fig. 5). The remaining three patients who had undergone liver resection also showed steroid responsiveness in the extrabiliary involvement of organs typical of IgG4-related autoimmune disease. Steroids were then gradually tapered over 2–3 months to a maintenance dose (5–7.5 mg) for an average of 9 months. Endobiliary stents and a percutaneous drainage catheter for biliary drainage were placed in seven patients and one patient, respectively. During the median follow-up period of 22 months

(range: 3–55 months) after complete steroid withdrawal, relapse was observed in one patient (case 1). Strictures at the hilum and masses in the renal pelvis occurred 12 months after the cessation of steroid therapy. The patient responded well to another round of steroid therapy and was stable at 27 months’ follow up. A novel concept of IgG4-related systemic disease was recently proposed by Kamisawa,7 and IgG4-positive plasma cell infiltration could be demonstrated in various organs, as well as the pancreas.8 In addition to the pancreas, the bile duct was generally the most commonly involved organ in IgG4-related systemic disease. Although clinical presentation and biliary imaging findings of ISC were not very distinct from those of PSC or hilar CCC, the treatment 上海皓元医药股份有限公司 and prognosis of ISC were much different compared to PSC or CCC. ISC shows dramatic response to steroid therapy and is a medically-treatable disease. In contrast, PSC is refractory to steroids, and ultimately leads to liver failure and the consequent necessity of liver transplantation, while surgical resection is the mainstay of treatment for CCC. Although the prognosis of ISC is generally favorable compared to PSC, the delayed diagnosis of ISC might allow it to progress to an irreversible stage, refractory to steroids and ultimately biliary cirrhosis.

Coexisting guild members with ecomorphological differences may, however, not always have clearly separated niches, but are likely to have similar preferences and exploit the same resources, at least opportunistically

or during certain parts of the year if resources are not limited (Nummi, 1993; Guillemain et al., 2002). In migratory species exploiting seasonally Ulixertinib nmr changing environments, resource limitation may occur only during some periods of the annual cycle, or even in some years only. Accordingly, on an annual basis, different species may show a high overlap in food resource use during some seasons. However, we did not find a significant effect of season. If competition does indeed increase during winter, when ducks tend to aggregate, a greater reduction in food overlap would have been expected (see Guillemain et al., Idasanutlin nmr 2002). We argue that the observed differences in average seed size in the diet of the three studied species are a result of different lamellar density. The patterns of food size separation between the three species are compatible with the idea of coexistence under interspecific competition, a process that has long created harsh debate (e.g. Roughgarden, 1983). Our study thus supports the idea that interspecific competition may indeed be a structuring force in dabbling duck communities in the Western Palearctic, even if only intermittently

so. We are thankful to M.-S. Landry for helping us retrieving European duck diet studies, and to M. Sanchez and V. Schricke for kindly providing their own unpublished data. We thank J. W. H. Ferguson and an anonymous reviewer for constructive criticism on the manuscript. A.-L. Brochet was funded

by a Doctoral grant from Office National de la Chasse et de la Faune Sauvage, with additional funding from a research agreement between ONCFS, the Tour du Valat, Laboratoire de Biométrie et de Biologie Evolutive (UMR 5558 CNRS Université Lyon 1) and the Doñana Biological Station (CSIC). L. Dessborn and J. Elmberg were funded by grants V-98-04 and V-162-05 from the Swedish Environmental Protection medchemexpress Agency. “
“Science progresses through ideas or hypotheses; novel ways of viewing the world. If those ideas survive testing, then they are considered ‘the truth’, or more crucially, truth-for-now, for the essence of science is that if a new idea provides a better explanation of the way the world is, the truth changes. Darwin’s idea of evolution by natural selection, published as the Origin in 1859, replaced the earlier truth of physico- or natural-theology introduced by John Ray in 1691. Despite resistance by the church, Darwin’s truth gained widespread acceptance, in part due to the efforts of T. H. Huxley, who on reading the Origin said ‘How extremely stupid not to have thought of that!’ Despite natural selection’s enormous explanatory power, there were certain phenomena it apparently could not explain, including female promiscuity.