A human monoclonal antibody targeting scavenger receptor class B type I precludes hepatitis C virus infection and viral spread in vitro and in vivo

Endstage liver disease caused by chronic hepatitis C virus (HCV) infection is the leading indication for liver transplantation in the Western world. However, immediate reinfection of the grafted donor liver by circulating virus is inevitable and liver disease progresses much faster than the original disease. Standard antiviral therapy is not well tolerated and usually ineffective in liver transplant patients, whereas anti-HCV immunotherapy is hampered by the extreme genetic diversity of the virus and its ability to spread by way of cell-cell contacts. We generated a human monoclonal antibody against scavenger receptor class B type I (SR-BI), monoclonal antibody (mAb)16-71, which can efficiently prevent infection of Huh-7.5 hepatoma cells and primary hepatocytes by cell-culture-derived HCV (HCVcc). Using an Huh7.5 coculture system we demonstrated that mAb16-71 interferes with direct cell-to-cell transmission of HCV. Finally we evaluated the in vivo efficacy of mAb16-71 in "human liver urokinase-type plasminogen activator, severe combined immune deficiency (uPA-SCID) mice" (chimeric mice). A 2-week anti-SR-BI therapy that was initiated 1 day before viral inoculation completely protected all chimeric mice from infection with serum-derived HCV of different genotypes. Moreover, a 9-day postexposure therapy that was initiated 3 days after viral inoculation (when viremia was already observed in the animals) suppressed the rapid viral spread observed in untreated control animals. After cessation of anti-SR-BI-specific antibody therapy, a rise of the viral load was observed. CONCLUSION: Using in vitro cell culture and human liver-chimeric mouse models, we show that a human mAb targeting the HCV coreceptor SR-BI completely prevents infection and intrahepatic spread of multiple HCV genotypes. This strategy may be an efficacious way to prevent infection of allografts following liver transplantation in chronic HCV patients, and may even hold promise for the prevention of virus rebound during or following antiviral therapy.     

Identification of rare copy number variants in high burden schizophrenia families

Over the last years, genome‐wide studies consistently showed an increased burden of rare copy number variants (CNVs) in schizophrenia patients, supporting the “common disease, rare variant” hypothesis in at least a subset of patients. We hypothesize that in families with a high burden of disease, and thus probably a high genetic load influencing disease susceptibility, rare CNVs might be involved in the etiology of schizophrenia. We performed a genome‐wide CNV analysis in the index patients of eight families with multiple schizophrenia affected members, and consecutively performed a detailed family analysis for the most relevant CNVs. One index patient showed a DRD5 containing duplication. A second index patient presented with an NRXN1 containing deletion and two adjacent duplications containing MYT1L and SNTG2. Detailed analysis in the subsequent families showed segregation of the identified CNVs. With this study we show the importance of screening high burden families for rare CNVs, which will not only broaden our knowledge concerning the molecular genetic mechanisms involved in schizophrenia but also allow the use of the obtained genetic data to provide better clinical care to these families in general and to non‐symptomatic causal CNV carriers in particular. © 2013 Wiley Periodicals, Inc.     

Fibrous Component of the Temporomandibular Joint Disk

This article describes the spatial arrangement of collagen fibrils in the articular disk of the normal human temporomandibular joint (TMJ). Disks obtained at necropsy were examined by light microscopy and scanning electron microscopy. Observations by light microscopy showed dense cartilaginous tissue composed of collagen fiber bundles running in all directions. Observations by scanning electron microscopy revealed a network of collagen fibrils which were predominantly organized in bundles. In the surface layers an anteroposterior orientation was detectable. The authors concluded that the fibrous component of the TMJ articular disk is composed of collagen fibrils, organized in a three-dimensional network and able to resist compression forces due to loading.     

Electromyography Before and After Treatment of TMJ Dysfunction

The patient described in this article suffered from pain in the right side of her face for five years before she saw the authors. Earlier treatment with medication and neurosurgery had not been successful. The authors used electromyography to examine the disturbed muscle function and to investigate a possible cause for the pain in the muscles of mastication. The silent periods of the patient's muscles were measured before and after treatment, since it is known from the literature that the EMG silent periods may be elongated in patients with TMJ dysfunction or occlusal irregularities. The coordination of both heads of this patient's lateral pterygoid muscles were bilaterally investigated before and after treatment. Treatment consisted of splint therapy and selective grinding. Oral rehabilitation was also undertaken, beginning three months after the disappearance of the patient's symptoms.     

Affective Decision-Making Is Predictive of Three-Month Relapse in Polysubstance-Dependent Alcoholics

Background/Aims: Common and long-lasting deficits in decision-making in polysubstance-dependent alcoholics (PSA) reflect neurobiological alterations that define the chronic nature of addiction. These deficits affect goal-directed behavior and might be critical risk factors predicting relapse in PSA. Methods: The Delay Discounting Task (DDT) and the Iowa Gambling Task (IGT) assessed the delay-discounting and decision-making skills among 37 abstinent PSA. Results: The findings indicated that IGT but not DDT performances were associated with 3-month abstinence, irrespective of the influence of personality traits and coexistent medications. Conclusion: The results show that the IGT, which assesses processes that are important in the latter stages of addiction, is ecologically more valid compared to the DDT, which assesses processes important in the early stages. They underline the importance of using neurocognitive measures to identify high relapse risk patients and emphasize the relevance of promoting new treatments.     

Predictive Value of Four Kallikrein Markers for Pathologically Insignificant Compared With Aggressive Prostate Cancer in Radical Prostatectomy Specimens: Results From the European Randomized Study of Screening for Prostate Cancer Section Rotterdam

Background

Treatment decisions can be difficult in men with low-risk prostate cancer (PCa).

Objective

To evaluate the ability of a panel of four kallikrein markers in blood—total prostate-specific antigen (PSA), free PSA, intact PSA, and kallikrein-related peptidase 2—to distinguish between pathologically insignificant and aggressive disease on pathologic examination of radical prostatectomy (RP) specimens as well as to calculate the number of avoidable surgeries.

Design, setting, and participants

The cohort comprised 392 screened men participating in rounds 1 and 2 of the Rotterdam arm of the European Randomized Study of Screening for Prostate Cancer. Patients were diagnosed with PCa because of an elevated PSA ≥3.0 ng/ml and were treated with RP between 1994 and 2004.

Outcome measurements and statistical analysis

We calculated the accuracy (area under the curve [AUC]) of statistical models to predict pathologically aggressive PCa (pT3–T4, extracapsular extension, tumor volume >0.5 cm³, or any Gleason grade ≥4) based on clinical predictors (age, stage, PSA, biopsy findings) with and without levels of four kallikrein markers in blood.

Results and limitations

A total of 261 patients (67%) had significant disease on pathologic evaluation of the RP specimen. While the clinical model had good accuracy in predicting aggressive disease, reflected in a corrected AUC of 0.81, the four kallikrein markers enhanced the base model, with an AUC of 0.84 (p < 0.0005). The model retained its ability in patients with low-risk and very-low-risk disease and in comparison with the Steyerberg nomogram, a published prediction model. Clinical application of the model incorporating the kallikrein markers would reduce rates of surgery by 135 of 1000 patients overall and 110 of 334 patients with pathologically insignificant disease. A limitation of the present study is that clinicians may be hesitant to make recommendations against active treatment on the basis of a statistical model.

Conclusions

Our study provided proof of principle that predictions based on levels of four kallikrein markers in blood distinguish between pathologically insignificant and aggressive disease after RP with good accuracy. In the future, clinical use of the model could potentially reduce rates of immediate unnecessary active treatment.     

The effect of gastric juice on interleukin-8 production by cystic fibrosis primary bronchial epithelial cells

CF patients are often treated with proton pump inhibitors (PPIs) to reduce acidic gastro-esophageal reflux (GER) and bronchial aspiration of duodeno-gastric contents is common in CF. We have previously demonstrated that gastric juice (GJ) from patients “on” PPI can induce interleukin-8 (IL-8) production by bronchial epithelial cells in culture. We hypothesized that such effect would be more pronounced in CF patients known to have high inflammatory susceptibility. We aimed to evaluate the effect of GJ on IL-8 production by primary bronchial epithelial cells (PBEC), derived from a CF patient and a healthy subject.MethodsPBEC obtained from one donor (normal PBEC) and one receptor (CF-PBEC) for lung transplantation were stimulated with GJ from patients “off” and “on” PPI. IL-8 levels were measured in the supernatant.ResultsGJ from patients “on” PPI provoked a significant higher IL-8 production compared to GJ from patients “off” PPI, both in normal PBEC [462 (200–1468) vs. 11 (4–28) pg/ml, p = 0.0001] as in CF-PBEC [1468 (841–2449) vs. 85 (26–131) pg/ml, p < 0.0001]. Exposure of the cells to GJ “off” PPI and “on” PPI provoked significantly higher IL-8 production in the CF-PBEC compared to the normal PBEC [“off” PPI 85 (26–131) vs. 11 (4–28) pg/ml, p = 0.01; “on” PPI 1468 (841–2449) vs. 462 (200–1468) pg/ml, p = 0.01]. Filtration (0.20 μm) of the GJ “on” PPI, to eliminate large particles and bacterial sub-products, resulted in a significant decrease of IL-8 production.ConclusionPatients with CF, treated with PPIs, have GJ with high pH and high endotoxin levels. These patients often have GER and bronchial aspiration. The aspirated material (GJ “on” PPI) has a significantly enhanced inflammatory effect on CF bronchial epithelial cells in culture. As chronic PPI treatment in CF may result in a paradoxically increased inflammatory effect in the airways, alternative anti-reflux therapies should be considered in CF.