Monitoring of liver lipid accumulation typically involves analysi

Monitoring of liver lipid accumulation typically involves analysis of biopsy samples, carrying an associated risk to the patient. Magnetic resonance (MR) techniques allow non-invasive, safe and repeatable measurement click here of hepatic lipid content and composition. We investigated the potential of MR spectroscopy for monitoring in LAL deficient patients and in ex vivo LAL deficient rat liver tissue. We assessed the effects of enzyme

replacement therapy with sebelipase alfa (a recombinant human LAL) on hepatic lipid content and composition in the preclinical model using MR spectroscopy. Methods: Two patient cohorts comprising LAL-deficient (n=3) and NAFLD (n=5) were studied. Preclinical studies comprised ex vivo liver samples from wild type, NAFLD, LALdeficient, and LAL-deficient rats receiving 4 weeks of sebelipase alfa treatment. Hepatic 1H MR spectroscopy was performed using 3T (human) and 7Ī (preclinical) MRI scanners to quantify hepatic cholesterol and triglyceride content. Magnitude of signal originating from CH3 and CH2 resonances in lipid species was determined from MR data, and a spectral

model fitted to the data to determine concentrations Selleckchem AZD1152HQPA and ratios of cholesterol and fatty acid chain moieties. Results: Hepatic cholesterol ester accumulation was identified GNA12 in both human and preclinical studies. LAL deficient patients had ratios of cholesterol: fatty acid moiety of 0.39 ± 0.13, compared to <0.01 in the NALFD group. In preclinical studies

a good correlation was observed between biochemical and MR assay of hepatic cholesterol content (R2 = 0.86), and marked reduction of cholesterol content was observed in LAL deficient animals treated with sebelipase alfa. Conclusions: We demonstrate an entirely non-invasive method to identify and quantify the hepatic lipid signature. The approach provides a more favorable alternative to repeated biopsy sampling for diagnosis and disease progression of patients with LAL deficiency and other disorders characterised by increased free cholesterol and/or cholesteryl esters. 1H MR Spectra from LAL Deficient & NAFLD Patients Disclosures: Mark Leavitt – Employment: Synageva Corp; Stock Shareholder: Synageva Corp Wei Hu – Employment: Synageva BioPharma Corp. Joseph V. Rutkowski – Employment: Synageva BioPharma Andrew M. Blamire – Grant/Research Support: Synageva Anthony G. Quinn – Employment: Synageva BioPharma; Management Position: Synageav BioPharma; Stock Shareholder: Synageva BioPharma The following people have nothing to disclose: Peter E. Thelwall, Fiona E. Smith, Kieren G. Hollingsworth, Christian Thoma, Michael I.

Monitoring of liver lipid accumulation typically involves analysi

Monitoring of liver lipid accumulation typically involves analysis of biopsy samples, carrying an associated risk to the patient. Magnetic resonance (MR) techniques allow non-invasive, safe and repeatable measurement check details of hepatic lipid content and composition. We investigated the potential of MR spectroscopy for monitoring in LAL deficient patients and in ex vivo LAL deficient rat liver tissue. We assessed the effects of enzyme

replacement therapy with sebelipase alfa (a recombinant human LAL) on hepatic lipid content and composition in the preclinical model using MR spectroscopy. Methods: Two patient cohorts comprising LAL-deficient (n=3) and NAFLD (n=5) were studied. Preclinical studies comprised ex vivo liver samples from wild type, NAFLD, LALdeficient, and LAL-deficient rats receiving 4 weeks of sebelipase alfa treatment. Hepatic 1H MR spectroscopy was performed using 3T (human) and 7Ī (preclinical) MRI scanners to quantify hepatic cholesterol and triglyceride content. Magnitude of signal originating from CH3 and CH2 resonances in lipid species was determined from MR data, and a spectral

model fitted to the data to determine concentrations Cisplatin and ratios of cholesterol and fatty acid chain moieties. Results: Hepatic cholesterol ester accumulation was identified Phospholipase D1 in both human and preclinical studies. LAL deficient patients had ratios of cholesterol: fatty acid moiety of 0.39 ± 0.13, compared to <0.01 in the NALFD group. In preclinical studies

a good correlation was observed between biochemical and MR assay of hepatic cholesterol content (R2 = 0.86), and marked reduction of cholesterol content was observed in LAL deficient animals treated with sebelipase alfa. Conclusions: We demonstrate an entirely non-invasive method to identify and quantify the hepatic lipid signature. The approach provides a more favorable alternative to repeated biopsy sampling for diagnosis and disease progression of patients with LAL deficiency and other disorders characterised by increased free cholesterol and/or cholesteryl esters. 1H MR Spectra from LAL Deficient & NAFLD Patients Disclosures: Mark Leavitt – Employment: Synageva Corp; Stock Shareholder: Synageva Corp Wei Hu – Employment: Synageva BioPharma Corp. Joseph V. Rutkowski – Employment: Synageva BioPharma Andrew M. Blamire – Grant/Research Support: Synageva Anthony G. Quinn – Employment: Synageva BioPharma; Management Position: Synageav BioPharma; Stock Shareholder: Synageva BioPharma The following people have nothing to disclose: Peter E. Thelwall, Fiona E. Smith, Kieren G. Hollingsworth, Christian Thoma, Michael I.

The latter hypothesis requires more investigation, which is also

The latter hypothesis requires more investigation, which is also the case for SRT1720 understanding the optimal dosing required to allow this potential benefit of prophylaxis to occur. For most

of the other debated non-genetic factors, the impact on the immunological outcome is, to date, not supported by the literature. Because the factors are often interrelated, it is also difficult to identify the relative contribution of each. This is also reflected by the results of the survey carried out among the EHTSB members, in which the impact of the majority of the factors was extremely variable; a pattern also recently reported in a survey by van den Berg and Chalmers [68]. The genetic profile of the patient will have a major impact on the immunological outcome and must be considered. This has not been done in the current literature. As haemophilia is a rare disease, and inhibitors develop in a minority of patients,

find more the statistical power of studies addressing these issues will, by definition, be limited. In light of the complexity of the aetiology of inhibitor development, future research should be directed at the identification of early immunological markers of high risk patients. In 2007, the EMEA [8] produced a report that defined many of the variables that should be considered when evaluating the literature on inhibitor formation. Unfortunately, several of these variables have not been included in a substantial G protein-coupled receptor kinase number of published studies, which will indeed influence the accuracy, validity and interpretation of the data. For example, the type of assay used to measure and to identify the inhibitor. The Nijmegen modification of the Bethesda assay was considered the ‘gold standard’ with a cut-off point of >0.6 BU. In addition, confirmatory tests on a second, separately drawn sample within a month should be performed. As seen in the tables, however,

these requirements are frequently not adhered to by studies published in the current literature. Moreover, the previous exposure to factor concentrates will be of major importance. According to the EMEA report, PUPs should be defined as those patients who have never been exposed to clotting factor products. Frequently, inhibitor studies involve patients who are considered to be MTPs. This term was considered inappropriate and these patients should instead be defined as previously treated patients (PTPs). This will have an impact on the interpretation of inhibitor incidence in each cohort described. It was also suggested that the number of EDs should be utilized as parameters to categorize risk rather than rely on the categories of PUP or MTP. In the case of factor concentrate immunogenicity, it was agreed that PTPs was the optimal group to study to limit the impact of confounding factors.

Tumor necrosis factor (TNF) alpha inhibitors, in particular, IFX,

Tumor necrosis factor (TNF) alpha inhibitors, in particular, IFX, have been evaluated in the maintenance of remission in UC. Current guidelines recommend that biologic agents are used only in patients failing conventional therapies or who are steroid dependent. Infliximab in moderate-to-severe ulcerative colitis.  IFX is a TNF-alpha inhibitor with steroid-sparing effect in UC and may be given every 8 weeks for scheduled maintenance after the initial loading buy Y-27632 dose. Two large randomized placebo-controlled trials of IFX (ACT 1 and ACT 2) enrolled moderate to severe UC patients unresponsive to standard therapy.158 The studies showed that the clinical

response rates in patients treated with IFX given at weeks 0, 2, and 6 and then every 8 weeks through week 46, was significantly higher (46%) than for placebo at week 54 (20%) (P = 0.001). Similarly, the 54-week remission rate was significantly higher for the

groups treated with IFX at 35% compared to placebo remission rate of selleck 17% (P = 0.001). Further analysis of the ACT 1 & 2 trial data indicates that there was an associated reduction in colectomy (hazard ratio 0.57, 95% CI 0.37–0.89) during the trial. However, even at 5 mg/kg IFX every 8 weeks, only 21% (at 7 months) and 26% (at 12 months) achieved steroid-free remission.30 Adverse effects to anti-TNF-alpha agents.  Adverse events reported with IFX therapy include increased susceptibility to infections that might be primary, opportunistic or reactivation, infusion-related reactions, serum sickness-like reaction, neurological, immunological and other reactions. IFX is contraindicated in people with moderate or severe heart failure, active infections, and demyelinating conditions. Anti-TNF drugs increase the risk of reactivation of latent TB and

can result in overwhelming Janus kinase (JAK) disseminated and extra-pulmonary disease by 4–20 fold.159 Other biologic agents.  Adalimumab may be an option in the maintenance of clinical remission of UC patients intolerant to, or with lost efficacy to, IFX.160 Large scale studies are currently underway in the evaluation of this and other biologic agents in UC. Methotrexate.  Data on methotrexate (MTX) in the treatment of UC remain limited and inconsistent. A randomized placebo-controlled study using MTX at the dose of 12.5 mg/week orally showed no benefit.161 Higher dosage and parenteral administration, however, may be beneficial. Open labeled studies have achieved remission rates of 42–60% including in patients who had failed AZA/6-MP.162,163 Adequately-powered prospective randomized controlled studies of MTX in UC are required. Methotrexate remains a therapeutic option in refractory UC patients who failed AZA/ 6-MP treatment given the limited availability of alternatives to thiopurines, such as biologic agents, in many parts of Asia. Calcineurin inhibitors.  Cyclosporin and tacrolimus are calcineurin inhibitors that reduce interleukin-2 production. Cyclosporin.

This group also reported that H pylori induced the anti-microbia

This group also reported that H. pylori induced the anti-microbial peptide human β-defensin 2 in epithelial AGS cells, and this appeared to be mediated by NOD1-dependent activation of NF-kB [16]. This host cell response was reported to be cagPAI-dependent but OMV-mediated triggering of NOD1, which seemed to be less efficient than the cagPAI-dependent pathway, was not tested. Because whole bacteria, H. pylori lysates and OMVs, contain multiple possible PRR ligands, Watanabe et al. [17] used a more specifically defined Opaganib in vivo NOD1 ligand, namely γ-d-glutamyl-meso-diaminopimelic acid (iE-DAP), for

determining the ability of NOD1 ligands to trigger NF-κB activation. In epithelial cells, iE-DAP-activated NOD1 was not linked to NF-κB activation but to IRF7 stimulation resulting from RICK-binding to TNF receptor-associated factor TRAF-3. IRF7-induced type I interferon-β (IFN-β). The latter triggered an autocrine/paracrine loop that led to the synthesis of chemokines such as CXCL10, IL-8, and i-TAC [17]. Interruption of this loop in a mouse model increased bacterial load early after infection, indicating that such NOD1 emanating signals trigger anti-bacterial effector functions in mice. To reconcile the divergent findings with regard to NOD1-mediated NF-κB activation in H. pylori infection, it will be necessary to refine analyses whether (and how) NOD1 activation and NF-κB signaling are linked.

This may extend to the newly reported H. pylori NOD1 association with the MAPK and AP-1 signaling cascades [18]. Obviously, H. pylori can be sensed by members of all PRR families. Furthermore, Gringhuis et al. [19] showed that certain H. pylori strains selleck chemicals llc can, dependent on carbohydrate expression on their surfaces, negatively influence IL-6 Beta adrenergic receptor kinase and IL-12 secretion, but positively influence IL-10 secretion via binding to the dendritic cell-specific C-type lectin DC-SIGN. Despite the obvious challenges of weighing the relative contribution of these recognition processes, understanding the cell biology basis, e.g. of intracytoplasmic recognition of bacterial ligands, may hold interesting surprises.

Necchi et al. mapped the intracellular distribution of NOD-1 in histologic sections of infected patients and also in cells exposed to H. pylori in vitro, revealing so-called Particle-rich Cytoplasmic Structures (PaCS) [20]. These structures may be a kind of “aggresome” structures that are known to be linked to intracellular protein degradation [21]. Indeed they found NOD1 to be co-localized with H. pylori remnants (defined antigens such as VacA and outer membrane proteins) and with ubiquinated proteins and proteasomes. Furthermore, this study highlights another level of complexity in host–H. pylori interplay, i.e. the impact of the pathogen’s subcellular distribution. Our current knowledge of the subcellular localization of H. pylori and the existence of differential localization between strains remains minimal.

8%, and 596 % respectively, which were comparable to those of CO

8%, and 59.6 % respectively, which were comparable to those of COLR (p

=0.579). Conclusions: MILR showed better perioperative outcomes with comparable oncologic outcomes for the treatment of HCC. According to the complexity of procedures, the robotic surgery may expand the indication of minimally invasive liver resection in patients with HCC. Disclosures: The following people have nothing to disclose: Dai Hoon Han, Eun Jung Park, Gi Hong Choi, Jin Sub Choi Background and Aims: Whether or not nonalcoholic steatohepatitis (NASH) on the non-tumor part plays an important role in determining the prognosis of patients with hepatocellular carcinoma (HCC) is still not fully elucidated. PI3K inhibitor This study aimed to compare the outcomes between early-stage

HCC patients with and those without NASH after resection surgery. Methods: We enrolled 188 patients who underwent resection surgery for HCC within the Milan criteria. After surgery, fibrosis, steatosis, lobular inflammation, portal inflammation and ballooning on the non-tumor part were assessed PI3K Inhibitor Library clinical trial comprehensively. The diagnosis and grading of NASH was determined by Brunt score. Factors in terms of overall survival after surgery were analyzed by multivariate analysis. Results: There were 73 (38.8%) patients had NASH with Brunt score ≥1.Patients with NASH had larger body mass index (24.97±3.17 kg/m2 vs. 23.29±3.58 FER kg/m2, p=0.002), higher fasting glucose levels (115.05±52.34 mg/dL vs. 99.05±34.68 mg/dL, p=0.014), and higher rates of ballooning (75.3% vs. 32.2%, p<0.001) than those without NASH on the non-tumor part. But the viral factors (rates of chronic hepatitis B or chronic hepatitis C), and tumor factors (tumor size, number, venous invasion, cell differentiation) were comparable between these two groups. After a median follow-up of 69.8 months, 73 patients died. The cumulative survival rates at 5

years were 75.8% and 57.3% for patients without NASH and those with Brunt score ≥1, respectively (p=0.007). Multivariate analysis disclosed that age > 65 years (hazard ratio, HR 1.996, 95% confidence interval, CI 1.89-3.349, p=0.009), serum platelet count < 105 /mm3 (HR 2.198, 95% CI 1.274-2.747, p=0.005), indocyanine green retention rate at 15 minutes > 10% (HR 2.038, 95% CI 1.108-3.749, p=0.022), multinodularity (HR 2.400, 95% CI 1.320-4.365, p=0.004), and presence of NASH with Brunt score ≥1(HR 1.774, 95% CI 1.081-2.913, p=0.023) were the independent risk factors associated with poor overall survival after resection surgery. Conclusions: The presence of NASH on the non-tumor part was associated with poor overall survival in HCC patients who were within Milan criteria and underwent resection surgery.

8%, and 596 % respectively, which were comparable to those of CO

8%, and 59.6 % respectively, which were comparable to those of COLR (p

=0.579). Conclusions: MILR showed better perioperative outcomes with comparable oncologic outcomes for the treatment of HCC. According to the complexity of procedures, the robotic surgery may expand the indication of minimally invasive liver resection in patients with HCC. Disclosures: The following people have nothing to disclose: Dai Hoon Han, Eun Jung Park, Gi Hong Choi, Jin Sub Choi Background and Aims: Whether or not nonalcoholic steatohepatitis (NASH) on the non-tumor part plays an important role in determining the prognosis of patients with hepatocellular carcinoma (HCC) is still not fully elucidated. Wnt inhibitor This study aimed to compare the outcomes between early-stage

HCC patients with and those without NASH after resection surgery. Methods: We enrolled 188 patients who underwent resection surgery for HCC within the Milan criteria. After surgery, fibrosis, steatosis, lobular inflammation, portal inflammation and ballooning on the non-tumor part were assessed selleckchem comprehensively. The diagnosis and grading of NASH was determined by Brunt score. Factors in terms of overall survival after surgery were analyzed by multivariate analysis. Results: There were 73 (38.8%) patients had NASH with Brunt score ≥1.Patients with NASH had larger body mass index (24.97±3.17 kg/m2 vs. 23.29±3.58 Cytidine deaminase kg/m2, p=0.002), higher fasting glucose levels (115.05±52.34 mg/dL vs. 99.05±34.68 mg/dL, p=0.014), and higher rates of ballooning (75.3% vs. 32.2%, p<0.001) than those without NASH on the non-tumor part. But the viral factors (rates of chronic hepatitis B or chronic hepatitis C), and tumor factors (tumor size, number, venous invasion, cell differentiation) were comparable between these two groups. After a median follow-up of 69.8 months, 73 patients died. The cumulative survival rates at 5

years were 75.8% and 57.3% for patients without NASH and those with Brunt score ≥1, respectively (p=0.007). Multivariate analysis disclosed that age > 65 years (hazard ratio, HR 1.996, 95% confidence interval, CI 1.89-3.349, p=0.009), serum platelet count < 105 /mm3 (HR 2.198, 95% CI 1.274-2.747, p=0.005), indocyanine green retention rate at 15 minutes > 10% (HR 2.038, 95% CI 1.108-3.749, p=0.022), multinodularity (HR 2.400, 95% CI 1.320-4.365, p=0.004), and presence of NASH with Brunt score ≥1(HR 1.774, 95% CI 1.081-2.913, p=0.023) were the independent risk factors associated with poor overall survival after resection surgery. Conclusions: The presence of NASH on the non-tumor part was associated with poor overall survival in HCC patients who were within Milan criteria and underwent resection surgery.

11) Multiple swallows were observed for 32% of patients and spon

11). Multiple swallows were observed for 32% of patients and spontaneous UES relaxation for 24% (no difference between the 3 subtypes). EGJ resting and relaxation pressures did not differ between the 3 subtypes and UES pressure was as well similar

in the 3 groups. Mean overall length of lower esophageal sphincter (LES) and abdominal LES length did not differ between the 3 subtypes. Conclusion: Type II is more common in untreated Chinese achalasia patients. Large-sample multicenter trials are necessary INK 128 in vivo in the future. Key Word(s): 1. Achalasia; 2. Dysphagia; 3. Esophageal manometry; Presenting Author: KUILIANG LIU Additional Authors: XIANGCHUN LIN, JING WU, HONG LIU, MINGMING MENG, HUI SU, WEIPING TAI Corresponding Author: XIANGCHUN LIN Affiliations: Beijing Shijitan Hospital Objective: Gastrointestinal duplication cysts are

rare congenital abnormalities. Malignant transformation of gastrointestinal duplications is thought to be rare. Methods: Here we report a case of gastric duplication with peritoneal metastatic adenocarcinoma. We recommend to raise the awareness of the malignant potential in adult patients with gastrointestinal duplication cysts and treat them as malignant tumor Results: Case description: A 28-year-old male presented to his routine health GW 572016 screening when abdominal sonography and subsequent computed tomography (CT) revealed a cystic lesion with no contrast-enhancement. A 10 x 10 cm cystic adherent to gastric corpus was found during the following laparoscopic surgery, howerver, attempt to remove the lesion pentoxifylline en bloc was unsuccessful, with ruptured cyst contaminating the peritonel cavity. The microscopic examination confirmed the diagnosis of gastric duplication. Seven months after

that, the patient suffered progressively increasing ascites, repeated cytologic analysis of which revealed small nests of adenocarcinoma cells, with primary unknown. A diagnostic laparoscopy showed multiple white nodules scattered over the surface of liver, greater omentum and peritoneum (Fig. 1). Biopsy of the omental nodules revealed adenocarcinoma (Fig. 2), with immunohistochemical staining of cytokeratin 20 (CK 20), CK 7 and P53 all positive, and the peritoneal carcinomatosis was diagnosed. Conclusion: Based on the clinical presentation and chronology, the malignancy is likely from gastric duplication cyst. This case highlights the importance of accurate preoperative diagnosis and optimal surgical management for gastric duplication, as well as the consideration of malignant transformation during surgical evaluation of adult patients with gastric duplication cysts. Key Word(s): 1. gastric duplication; 2. malignancy; 3.

9–36) for patients ≤18, and 11 (08–61) for adult patients Less

9–36) for patients ≤18, and 11 (0.8–61) for adult patients. Less agreement was observed concerning estimated effective dose for secondary prophylaxis in adults: median 2000 IU every other day The majority (63%) of experts expected that a single minor joint bleed could cause irreversible damage, and would accept up to three minor joint bleeds or one trauma related joint bleed annually on prophylaxis. Expert judgement elicitation allowed structured capturing of quantitative learn more expert estimates. It generated novel data to be used

in computer modelling, clinical care, and trial design. “
“Summary.  In an ongoing health-technology assessment of haemophilia treatment in Sweden, performed by the governmental agency Dental and Pharmaceutical Benefits Agency (TLV; tandva˚rds-och lākemedelsförma˚nsverket), the Swedish Council on Health Technology Assessment (SBU; statens beredning för medicinsk utvārdering) was called upon to evaluate treatment of haemophilia A and B and von KU 57788 Willebrand’s disease (VWD) with clotting factor concentrates. To evaluate the following questions: What are the short-term and long-term effects of different treatment strategies? What methods are available to treat haemophilia patients that have developed inhibitors against factor concentrates? Based on the questions addressed by the project, a systematic database search was conducted in PubMed, NHSEED, Cochrane Library, EMBASE

and other relevant databases. The literature search covered all studies in the field published from 1985 up to the spring of 2010. In most instances, the scientific evidence is insufficient for the questions raised in the review. Concentrates of coagulation factors have good haemostatic effects

on acute bleeding and surgical intervention in haemophilia A and B and VWD, but conclusions cannot be drawn about possible differences in the effects of different dosing strategies for acute bleeding and surgery. Prophylaxis initiated at a young age can prevent future joint damage in persons with Dapagliflozin haemophilia. The available treatment options for inhibitors have been insufficiently assessed. The economic consequences of various treatment regimens have been insufficiently analysed. Introduction of national and international registries is important. “
“Sweden has been a pioneer in the treatment of haemophilia, with the first concentrate available in the 1950s. Treatment has improved over the years to its current state-of-the art. The aim of the current study was to evaluate the long-term outcome of haemophilia in terms of incidence, morbidity and mortality. Patients diagnosed with haemophilia A or B registered at the national haemophilia centres and/or the Patient Registry and born before 2009 and alive in 1968 were enrolled and linked to the Cause of Death-, Migration- and Medical Birth registries. Five age- and sex-matched controls were selected for each patient. A total of 1431 patients with haemophilia A or B were compared with 7150 controls.

Perhaps related to this is the similarly counterintuitive finding

Perhaps related to this is the similarly counterintuitive finding that the good-response IL28B genotype is associated with higher HCV viral load at baseline, whereas high viral load is generally predictive of poor treatment outcomes. It has been demonstrated through simulation studies that this relationship may be explained by a kind of selection bias, in which patients with both low baseline viral load and the good-response IL28B genotype are particularly likely to spontaneously resolve HCV infection, so that patients carrying the good-response genotype that progress to chronic infection (i.e., those ascertained in chronic HCV

cohorts) are more likely to carry high viral loads, compared to poor-response IL28B genotypes.35 Whether this Apitolisib ic50 indeed occurs has yet to be determined and will require prospective study of HCV viral kinetics as well as immune and liver-specific responses in infected patients from the acute phase through establishment of chronic infection. Such studies will be crucial to our understanding of the effect of IL28B genotype on both spontaneous and treatment-induced clearance of HCV and may shed light on the relevance of hepatic ISG expression and peripheral

IFN-λ production to HCV clearance. Examination BAY 73-4506 of the relationship between IL28B genotype and early viral kinetics may shed some light on the possible mechanisms for the genetic association; however, studies to date have shown mixed results. Several reports36-39 have suggested that the mafosfamide protective IL28B genotype is associated with a steeper first-phase decline (i.e., decrease in viral titer over the first several days of treatment), with a generally weaker effect on the second-phase decline (i.e., 2-28 days after treatment initiation), suggesting, per Neumann et

al.,40 that the major mode of IL28B action may be on the clearance of free virus. Consistent with this, a study of Taiwanese chronic HCV patients employing a constrained version of the Neumann model suggested that the primary effect of IL28B genotype may be on the viral clearance rate41; however, others have suggested that the assumptions underlying this constrained model may be unrealistic and may complicate the interpretation.42 In contrast, a study employing a smaller sample size, but a denser sampling scheme in the initial phase, suggested that the primary IL28B effect may be on the death rate of infected hepatocytes (δ), though there was a trend toward an association between IL28B genotype and first-phase decline as well.43 A better understanding of the precise relationship between IL28B genotype and viral kinetics will require more detailed, well-powered prospective studies. There is some evidence in favor of an interplay between IL28B and natural killer (NK) cell activity in HCV responses.