5F). Previous studies have shown that long-lived Little mice see more have increased levels of genes involved in the xenobiotic detoxification and that crossing these mice with FXR KO mice corrected their expression.17 We performed western

blot analysis and found a four- to five-fold elevation of FXR in 24- to 36-month-old Little mice (Fig. 6A,B). It has been shown that the frequency of liver tumors increases with age and reaches around 30% at the age of 24 months.5 However, Little mice do not develop liver cancer with age. Therefore, we tested the hypothesis that high levels of FXR in old Little mice protect the liver from development of cancer. WT and Little mice were treated with DEN, and liver tumors were examined 35-36 weeks after DEN injection. We examined five WT mice and five Little mice and found that all WT animals developed advanced liver cancer, whereas only two Little mice Kinase Inhibitor Library screening had few tumor nodules of a very small size (Fig. 6C). Three other Little mice did not have liver cancer. Examination of liver sections via hematoxylin and eosin staining revealed that the livers of WT mice contained multiple diverse nodules of proliferating hepatocytes, including enlarged cells with moderate anisonucleosis on the left and a cluster of small, uniform, deeply

basophilic cells on the right (Fig. 6D). In contrast, livers of Little mice treated with DEN showed unremarkable architecture and cytology, with uniform hepatocytes containing minimal cytoplasmic lipid and glycogen. We found that the number of replicating hepatocytes increased significantly in WT mice (up to 25%-30%), while around 5% of hepatocytes were BrdU-positive

in the livers of Little mice (Fig. 6E,F). These data show that Little mice are resistant to the development of liver cancer after DEN treatment. We next determined the molecular mechanisms by which Little mice are protected from liver cancer. A recent report showed that gankyrin causes degradation of the liver-specific transcription factor hepatocyte nuclear factor 4α (HNF4α).22 Therefore, we included this MCE公司 protein in our studies. We found that gankyrin was elevated and that it caused reduction of C/EBPα, Rb, HNF4α, and p53 in control WT mice (Fig. 7A,B). FXR was slightly reduced in WT mice; however, in Little mice, FXR levels remained at high levels, leading to the lack of activation of the gankyrin and to no reduction of C/EBPα, Rb, HNF4α, or p53. The reduction of the tumor repressor proteins in WT mice took place on the levels of protein degradation, since levels of mRNA were not changed significantly (Fig. 7C). To determine whether gankyrin is responsible for the degradation of tumor suppressor proteins, we examined interactions of these proteins with gankyrin. In these experiments, we used up to 1 mg of nuclear extracts for the co-immunoprecipitation studies.

Reverse-transcription of RNA was performed using a SuperScript III First Strand Synthesis Supermix kit (Invitrogen, Carlsbad, CA) with random hexamers according

to the manufacturer’s instructions. Polymerase chain reaction was conducted with a Platinum PCR SuperMix kit (Invitrogen). Reaction products were purified on a Biomek FX system (Beckman Coulter, Fullerton, CA) using a magnetic bead kit (Agencourt Bioscience Corporation, Beverly, MA). DNA sequencing of purified material was conducted on a 3730xl DNA Analyzer (Applied Biosystems). To investigate a potential correlation between exposure to narlaprevir and antiviral activity, plasma samples were collected over the course of the study for pharmacokinetic profiling of narlaprevir with or without ritonavir. In period 1, serial blood narlaprevir pharmacokinetic samples were HDAC inhibitor drugs taken on days 1 and 7. Additional narlaprevir pharmacokinetic Tamoxifen in vitro sampling was performed on days 2, 5, 6, and 7 for trough level (Cmin) determination. In period 2, serial blood narlaprevir pharmacokinetic samples were collected on days 1, 7, and 14, and additional pharmacokinetic samples for Cmin determination were obtained on days 2, 8, 10, 12, and 14. Plasma

concentrations of narlaprevir were determined using a validated liquid chromatographic–tandem mass spectrometric method with a limit of quantification of 6.08 ng/mL. Patients were monitored for safety and tolerability at regular intervals from the start of dosing through a follow-up visit 24 weeks after completion of SOC. Safety assessments included physical examination, vital signs, clinical laboratory tests, electrocardiograms, and the recording of all adverse events. Forty-one patients (10 patients each in cohorts 1-3 and 11 patients in cohort 4) were enrolled in the study. One patient in cohort 4 discontinued

immediately after the first dose on day 1 because of intolerance to the drug suspension; study medication was stopped at the discretion of the investigator, and this MCE patient was replaced. A total of 40 patients completed the narlaprevir treatment phase of the study and initiated SOC immediately after period 2. Treatment-experienced patients consisted of 12 relapse patients and eight nonresponders. Demographic and other baseline characteristics of the randomized patients are shown in Table 1. The pharmacokinetic profile of narlaprevir 800 mg three times daily or 400 mg with ritonavir two times daily was characterized (Table 2). Exposure to narlaprevir with and without coadministration of PEG-IFN-α-2b for both treatment-naïve and treatment-experienced patients was comparable. Narlaprevir was eliminated more slowly when coadministered with ritonavir than when administered alone. Dose-normalized daily exposures (area under the curve) on day 14 in the presence of PEG-IFN-α-2b and ritonavir increased 7.

014) or female gender (median 18 months [12 to 42]

vs 12 [5 to 30]; P trend = .070) was also evident. Notably, 76 out of 101 patients referred to our Center received an appropriate diagnosis according to International Classification of Headache Disorders II at the time of our visit only. Of note, up to 21% of this group were previously misdiagnosed (for epilepsy 43%, sinusitis 38%, or other diseases 19%), a fact that contributed to a longer time of clinical assessment (median 39 months) before reaching a correct diagnosis. The other group of 80 patients (79%) did not receive BAY 57-1293 mw a specific diagnosis and treatment, and were not studied until their symptom became chronic

and disabling. Conclusion.— Pediatric headache is still under-diagnosed and not adequately considered as a health problem in the medical community as well as social settings. There is a need for educational programs regarding headache involving not only general practitioners, pediatricians, and neurologists, but also the general population. These are desirable in order to raise awareness of such a condition and, accordingly, treat children Erastin chemical structure accurately. “
“(Headache 2011;51:752-778) Pain research, and headache research in particular, during the 20th century, has generated an enormous volume of literature promulgating theories, questions, and temporary answers. This narrative review describes the most important events in the history of migraine research medchemexpress between 1910 and 2010. Based on the standard textbooks of headache: Wolff’s Headache (1948 and 1963) and The Headaches (1993, 2000, and 2006) topics were selected for a historical review. Most notably these included: isolation and

clinical introduction of ergotamine (1918); further establishment of vasodilation in migraine and the constrictive action of ergotamine (1938); identification of pain-sensitive structures in the head (1941); Lashley’s description of spreading scotoma (1941); cortical spreading depression (CSD) of Leão (1944); serotonin and the introduction of methysergide (1959); spreading oligemia in migraine with aura (1981); oligemia in the wake of CSD in rats (1982); neurogenic inflammation theory of migraine (1987); a new headache classification (1988); the discovery of sumatriptan (1988); migraine and calcitonin gene-related peptide (1990); the brainstem “migraine generator” and PET studies (1995); migraine as a channelopathy, including research from the genetic perspective (1996); and finally, meningeal sensitization, central sensitization, and allodynia (1996). Pathophysiological ideas have evolved within a limited number of paradigms, notably the vascular, neurogenic, neurotransmitter, and genetic/molecular biological paradigm.

63 Dr Okanoue has written a detailed review of NAFLD and NASH in Japan, highlighting the importance of HCC as a complication of type 2 diabetes as well as other aspects, which accompanies the present article in this 25th anniversary

supplement of JGH.64 Table 2 lists cross-sectional studies in the Asia-Pacific region where histologic details were provided. Overall, over half of these patients had NASH.27,59,66–72 However, it is important to note that the definition of NASH has not been uniform among studies. Histologic studies are biased towards patients seen at tertiary centres, usually presenting with abnormal liver function tests and multiple metabolic risk factors; patients http://www.selleckchem.com/products/RO4929097.html are therefore likely to have more active disease. Even so, advanced liver fibrosis or cirrhosis have been relatively uncommonly reported. For example, in a study of 246 NAFLD patients from France and Hong Kong, advanced fibrosis or cirrhosis was found in 28% of Caucasian patients but in only 17% of Chinese patients.74 The reason for the apparently lower prevalence of advanced disease in Asian NAFLD patients is not completely understood. We believe it is likely to be due to a combination of both genetic and environmental factors, as well as socio-economic history between geographic regions. Thus, it is likely that the probability of whether a patient would develop cirrhosis and its complications is linked to the duration of “metabolic

BMN 673 purchase overload”. Since the economic surge in many Asian countries

only began in the 1980s and 1990s, it is possible that current patients who exhibit only signs of mild liver injury may yet present later with more severe complications, consistent with the clinical observation in Australia that the vast majority of patients with liver complications from NAFLD are aged older than 60 years. Further, with increasing adult and also 上海皓元医药股份有限公司 childhood obesity, the number of Asian patients with developing advanced liver disease is expected to rise. A small case series of Sri Lankan children with advanced hepatic fibrosis secondary to NASH is a case in point; 4 of the 5 children were obese (BMI 26–31 kg/m2) and all were insulin-resistant.34 Finally, cases of NASH-related cirrhosis masquerading as “cryptogenic” cirrhosis should also be considered in the tally of patients developing advanced liver disease, as discussed next. By general agreement, the majority of Western cases with cryptogenic cirrhosis (CC) represent “burnt-out” NAFLD.75 Whether these considerations also apply to patients with CC in a viral hepatitis-endemic region has not been well studied. Here too, published data would suggest that many such cases are also secondary to fatty liver. In a study of liver explants from 30 Indian patients with CC, 19 (63%) showed histologic features consistent with NAFLD.76 The bigger question is the contribution of NAFLD/NASH to cirrhosis in the general population. Here too, there are some unsettling trends.

In this review, we summarize the data from two nationwide surveys undertaken in Japan as well as recent data from Japanese and international studies. PRIMARY BILIARY CIRRHOSIS (PBC) is an autoimmune liver disease. It tends to affect females Selleckchem Atezolizumab more than males. PBC selectively damages the intrahepatic small bile ducts, particularly interlobular

bile ducts. Because of progressive loss of bile ducts, PBC develops into chronic cholestasis and finally biliary cirrhosis. The clinical presentation of PBC has been changing over the years. In particular, the proportion of asymptomatic patients at diagnosis has increased. In contrast to other biliary diseases such as primary sclerosing cholangitis (PSC), the associated malignant tumor of PBC is hepatocellular carcinoma (HCC), although its incidence is low.

The detailed clinicopathological significance and carcinogenesis of HCC associated with PBC remain unknown. In this review, recent data from Japan[1] and other countries are reviewed. SEVERAL STUDIES HAVE indicated that PBC may be associated with an increased risk of extrahepatic malignancies as well as HCC, although they represent a rare complication. By surveying 212 Greek patients with PBC, 10.8% patients were diagnosed with malignancy, 3.8% patients with HCC and 7.0% with extrahepatic malignancies.[2] Moreover, a meta-analysis using PubMed and EMBASE databases revealed that PBC is closely associated with a 上海皓元医药股份有限公司 greater risk

learn more of overall cancer and HCC, but not with other cancers.[3] With respect to HCC, its incidence in patients with PBC varies from 0.76% to 5.9% depending on reports.[2, 4-9] However, one report has stated that PBC is not a risk factor for HCC.[10] These divergent results may be because of the low prevalence of the association with HCC as well as geographical and environmental differences. However, the number of PBC patients associated with HCC has been recently increased, which may be due to the improvement of therapeutic effects and prognosis.[11-13] National surveys of patients with PBC in Japan have been undertaken 15 times biennially or triennially by the Intractable Hepato-Biliary Diseases Study Group for Research on Measures for Intractable Disease, which is supported by Health Labor Sciences Research Grants in Japan. The surveys involved 8509 patients registered in the 1st–15th surveys performed between 1980 and 2012.[9, 14, 15] According to the 15th National Survey performed in 2012, the incidence of malignancy at the time of PBC diagnosis was 3.3%. Liver cancer was the most common (24%), followed by gastric cancer (16%), colon cancer (12%), breast cancer (10%), uterine cancer (5%), thyroid cancer (6%), hematopoietic cancer (5%), ovarian cancer (3%), lung cancer (3%) and others (16%).

19 In the present study, two of the 82 (2.4%) HCC samples exhibited FGF3/FGF4 gene amplification in the HCC series. If only MG-132 order 2%-3% of HCC patients harbor the FGF3/FGF4 amplification, its value as a biomarker seems to be limited in clinics because a frequency of 2%-3% is too low to stratify the patients for specific targeted therapy. However, a combination of

biomarkers—including FGF3/FGF4 amplification, lung metastasis, tumor differentiation, and other unrevealed dysregulation of FGFR signaling—may increase the response prediction. In addition, 2%-3% of FGF3/FGF4 amplification may be a promising therapeutic target for future FGFR-targeted therapies in the treatment of HCC. Tumor shrinkage might be due to the mixed effect (sorafenib + 5FU + interferon) of combination therapy in the initially described patient. However,

click here during this patient’s long clinical course, tumor regrowth was observed following withdrawal of sorafenib because of oral hemorrhage, and tumor reshrinkage was observed when sorafenib treatment recommenced. Thus, we considered that tumor shrinkage might be achieved by the effect of sorafenib on its own, rather than 5FU + interferon. Regarding determinants of drug sensitivity to sorafenib, the mechanism of hypersensitivity in the gastric cancer cell lines HSC-39, HSC-43, and KATO-III is FGFR2 gene amplification and is thought to be the addiction of these cell lines to this gene,14 since sorafenib has a relatively weak but significant inhibitory effect on FGFR1 at a concentration of 580 ± 100 nM.3 This result suggests that the blockade of FGFR signaling by sorafenib may lead to a significant treatment response, at least in FGFR2-amplified cells. In this study, we found that FGF4, but not FGF3 overexpression, was partially involved in the sensitivity to sorafenib in vivo. The limitations of the study are the small number of responder patients and the potential bias in their selection because of the retrospective study design. Further clinical study of responders to sorafenib is necessary. We are presently

undertaking a prospective molecular translational study (2010-2012) 上海皓元 in a cohort of Japanese patients with sorafenib-treated HCC. Multiple lung metastases were frequently observed among responders to sorafenib (38%) but were less common among nonresponders (5%). Based on a Japanese follow-up survey of patients with primary HCC, lung metastasis was observed in 7% (169/2355) of the patients at the time of autopsy.20 Another study demonstrated that 15% of patients were found to have extrahepatic metastases, and lung metastasis was detected in 6% of 995 consecutive HCC patients.21 When compared with these data from large-scale studies, the frequency of lung metastasis among responders to sorafenib seems quite high. In addition, a poorly differentiated histological type tended to be more common among responders, although the correlation was not significant.

Furthermore, the area under the curve (AUC) at 5 year was dramatically increased from 0.619 to 0.624 after adding the rs10505477 risk score to the traditional clinical risk score (TNM stage and lymph node metastasis). However, there was no selleck products association be found between the rs1562430 and the survival of gastric cancer. These findings suggested the SNP rs10505477 may contribute to the survival of gastric cancer and be a potential prognostic biomarker of gastric cancer. “
“Background and Aim:  In hilar cholangiocarcinoma, an accurate

assessment of preoperative resectability is important to optimize surgical resection. We investigated the accuracy of the combination of intraductal ultrasonography (IDUS) and percutaneous transhepatic cholangioscopy (PTCS) for evaluating Idelalisib molecular weight longitudinal extent in hilar cholangiocarcinoma. Methods:  Patients diagnosed with hilar cholangiocarcinoma underwent multidetector computed tomography (MDCT) and magnetic resonance cholangiography (MRC) for tumor staging and Bismuth type. Percutaneous transhepatic biliary drainage was performed at the left or right bile duct of

the liver section that was anticipated to be preserved in the surgical treatment. After tract dilation, PTCS with cholangioscope-directed biopsy and IDUS were sequentially performed to evaluate Bismuth type. Surgical treatment was executed

according to tumor staging and longitudinal tumor extent. Postoperative histological Bismuth types were compared to preoperative Bismuth types based on MDCT, MRC, PTCS medchemexpress with biopsy, and IDUS. Results:  From June 2006 to November 2008, 25 patients with hilar cholangiocarcinoma were enrolled, with 20 of these patients evaluable. The accuracy of MDCT, MRC, PTCS with biopsy, and IDUS for the evaluation of Bismuth type was 80%, 84.2%, 90%, and 85.0%, respectively, in 20 patients, and 82.4%, 82.4%, 94.1%, and 88.2%, respectively, in 18 patients with Bismuth type IIIa, IIIb, or IV cancer. The accuracy of the combination of IDUS and PTCS with biopsy was 95% in 20 patients, and 100% in 18 with Bismuth type IIIa, IIIb, or IV cancer. Conclusions:  The combination of IDUS and PTCS with biopsy was highly accurate for assessing Bismuth type and may help in the identification of an optimal surgical plan for the treatment of hilar cholangiocarcinoma, especially in Bismuth type IIIa, IIIb, or IV. “
“Evidence suggests an association between low serum 25-hydroxy-vitamin D3 [25(OH)D3] levels and the presence and prognosis of liver disease. Vitamin D receptor (VDR) has been widely detected in the liver, but its expression in the course of liver disease has never been investigated.

In the SHARP trial, 602 patients with HCC were randomized to either sorafenib 400 mg b.i.d. or placebo and both were added Selleckchem KU 57788 to best supportive care (BSC). BSC excluded local therapy such as surgery, radiation, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, cryoablation, and other systemic treatments.

Primary end-points in the study included overall survival (OS) and time to symptomatic progression, and a secondary end-point was time to progression (TTP).10 Results showed that sorafenib significantly prolonged OS and TTP compared to patients in the placebo arm (median OS 10.7 months vs 7.9 months, hazard ratio 0.69, P < 0.001, median TTP 5.5 vs 2.8 months, hazard ratio 0.58, P < 0.001).10,11 Sorafenib was also found to be a well-tolerated treatment with manageable adverse events (AE). Thus, sorafenib was the first systematic agent to show survival JNK inhibitor benefit in the advanced HCC patient population and as a result, the only systemic therapy approved by the Food and Drug Administration (FDA) for the treatment of advanced HCC. The aim of this study was to assess the cost-effectiveness of sorafenib in the treatment of advanced

HCC compared to BSC from the US third-party-payer perspective. The cost and health outcomes associated with both treatments, and the potential advantages and cost-effectiveness of using sorafenib as an active therapy over palliative care, were estimated in this target patient population. Currently, cost-effectiveness evaluations are widely used in many countries around the world and it may become an integral part of health technology assessment

in the USA,12 especially after the new health-care reform that aims for universal coverage. An economic model was developed in Microsoft Excel to evaluate the potential costs, health outcomes, and cost-effectiveness of sorafenib in the treatment of advanced HCC. Based on the SHARP study, the model considered adult patients (18 years and older) diagnosed with HCC who had: A life expectancy of at least 12 weeks; Given that there are no other agents 上海皓元 besides sorafenib that have demonstrated significant OS benefit1 or have been approved for this patient population by the FDA,13 sorafenib was compared to BSC. BSC incorporated medical staff visits, hospitalizations, and laboratory and radiology tests. The analysis was conducted from the perspective of a third-party managed-care payer in the USA. Hence, only direct medical costs were included. The time horizon for estimating cost-effectiveness, or the follow-up time for the model, should be sufficiently long to reflect all important differences in costs and outcomes between the technologies being compared. As HCC is a chronic disease, costs and outcomes accumulate over the patient’s lifetime.

Red cod contributed the most in terms of mass (37%), while ahuru and Hector’s lanternfish (Lampanyctodes hectoris) were consumed in large numbers. Prey ranged from <1 cm to >60 cm in total length, but the majority of prey items were <10 cm Kinase Inhibitor Library long, indicating that for some species, juveniles were targeted. Diets of dolphins from South Island east and west coasts were significantly

different, due largely to javelinfish (Lepidorhynchus denticulatus) being of greater importance in west coast stomachs, and a greater consumption of demersal prey species in the east. The feeding ecology of Hector’s dolphin is broadly similar to that of other Cephalorhynchus species. Hector’s dolphin is shown to feed on species from throughout the water column, and differences in diet between CP-690550 cell line populations are thought to reflect prey availability. “
“A complementary approach of stomach content and stable isotope analyses was used to characterize the foraging ecology and evaluate niche overlap between pygmy (Kogia breviceps) and dwarf (K. sima) sperm whales stranded on the U.S. mid-Atlantic coast between 1998 and 2011. Food habits analysis demonstrated both species were primarily teuthophagous, with 35 species of cephalopods, and 2 species of mesopelagic fishes represented in their overall

diets. Pianka’s Index of niche overlap suggested high overlap between whale diets (On = 0.92), with squids from the families Histioteuthidae, Cranchidae, and Ommastrephidae serving as primary prey. Pygmy sperm whales consumed slightly larger prey sizes (mean mantle length [ML] = 10.8 cm) than dwarf sperm whales (mean ML = 7.8 cm). Mean prey sizes consumed by pygmy sperm whales increased with growth, but showed no trend in dwarf sperm whales. Significant differences were not detected in δ15N and δ13C values of muscle tissues from pygmy (10.8‰ ± 0.5‰, −17.1‰ ± 0.6‰), and dwarf sperm whales

(10.7‰ ± 0.5‰, −17.0‰ ± 0.4‰), respectively. Isotopic niche widths also did not differ significantly and dietary overlap was high between the two species. Results MCE suggest the feeding ecologies of the pygmy and dwarf sperm whales are similar and both species occupy equivalent trophic niches in the region. “
“Invasive tags designed to provide information on animal movements through radio or satellite monitoring have tremendous potential for the study of whales and other cetaceans. However, to date there have been no published studies on the survival of tagged animals over periods of years or decades. Researchers from the National Marine Mammal Laboratory and the Woods Hole Oceanographic Institution tracked five humpback whales with implanted radio tags in southeastern Alaska in August 1976 and July 1977, and tracked two humpback whales in Prince William Sound, Alaska, in June 1978.

A U.S. payer perspective, 3 %discount rate, and willingness to pay (WTP) threshold of $100,000/ QALY were used. Sensitivity analyses included pre-LT therapy length, cost & efficacy, Rapamycin & scenarios with newer regimens. Results: Post-LT therapy resulted in 2.7-4.3 QALYs and costs of $275,000-$519,000 depending on MELD (Table). Pre-LT therapy extended QALYs and costs, with greater gains and costs at low MELDs. The ICERs were above the WTP threshold except for MELD=20-29 where the LT rate meant most

patients got <48 wks of SOF/RBV but enough to attain post-LT SVR. MELDs<20 had longer wait times with longer courses of pre-LT therapy while MELDs>30 either died or went to LT before SVR was achieved; both had high ICERs. Shorter durations reduced ICERs for MELDs<30; at a duration of 24 wks, any MELD<30 fell below the WTP threshold using SOF/RBV without change in ICERs for MELDs>30. Improved SVR rates for cirrhotics who complete therapy pre- LT & lower drug costs also reduced ICERs below the WTP threshold for low MELDs. Conclusion: SOF/RBV for up to 48 wks pre-LT provides good value for money with MELD=20-29 at listing. Future regimens with high SVR rates, shorter durations & lower costs may improve the economic appeal of pre-LT therapy for MELDs<30, but not those >30. Disclosures:

Alissa J. Wright – Grant/Research Support: Pfizer, Sunovion, Astellas Arthur Y. Kim – Consulting: Abbvie Pharmaceuticals, Gilead Pharmaceuticals; Grant/Research Support: Bristol-Myers Squibb, Gilead Pharmaceuticals selleck chemicals llc Raymond T. Chung – Consulting: Abbvie; Grant/Research Support: Gilead, Mass Biologics The following people have nothing to disclose: Jay A. Fishman, Benjamin P. Linas medchemexpress Purpose: The current study aims at identifying demographics and clinical characteristics associated with high HRU and costs among patients with CHC. Methods:

Health insurance claims from 60 self-insured U.S companies from 01/2001-03/2013 were analyzed. Adult patients with ≥2 CHC claims (ICD-9: 070.44 or 070.54), ≥6 months of continuous insurance coverage before the first CHC diagnosis and ≥36 months of observation post-CHC were included. Patients diagnosed with HIV were excluded. Patients were categorized in four mutually exclusive groups based on quartile distribution of cumulative healthcare costs during the 36-month follow-up [i.e. 25th ($9,600), 50th ($25,092), and the 75th ($54,100) percentiles]. Demographics and baseline comorbidities including CHC-related and non-CHC conditions were described. A multinomial logistic regression model was estimated to identify baseline demographic and clinical characteristics associated with the highest quartiles of HRU and costs. Results: A total of 4,898 CHC patients formed the study population. The mean age was 53.3, 53.2, 51.3, and 51.