Toll-like receptor 2-mediated innate immune response in human nonparenchymal liver cells toward adeno-associated viral vectors

Adeno-associated viral vectors (rAAV) are frequently used in gene therapy trials. Although rAAV vectors are of low immunogenicity, humoral as well as T cell responses may be induced. While the former limits vector reapplication, the expansion of cytotoxic T cells correlates with liver inflammation and loss of transduced hepatocytes. Because adaptive immune responses are a consequence of recognition by the innate immune system, we aimed to characterize cell autonomous immune responses elicited by rAAV in primary human hepatocytes and nonparenchymal liver cells. Surprisingly, Kupffer cells, but also liver sinusoidal endothelial cells, mounted responses to rAAV, whereas neither rAAV2 nor rAAV8 were recognized by hepatocytes. Viral capsids were sensed at the cell surface as pathogen-associated molecular patterns by Toll-like receptor 2. In contrast to the Toll-like receptor 9-mediated recognition observed in plasmacytoid dendritic cells, immune recognition of rAAV in primary human liver cells did not induce a type I interferon response, but up-regulated inflammatory cytokines through activation of nuclear factor κB. CONCLUSION: Using primary human liver cells, we identified a novel mechanism of rAAV recognition in the liver, demonstrating that alternative means of sensing rAAV particles have evolved. Minimizing this recognition will be key to improving rAAV-mediated gene transfer and reducing side effects in clinical trials due to immune responses against rAAV.     

Side of onset does not influence cognition in newly diagnosed untreated Parkinson's disease patients

BackgroundA relation between the side of motor onset and cognitive impairment in early PD has been reported, suggesting that the asymmetric degeneration affecting subcortical regions may play a pivotal role in lateralized cognitive function. However, evidences are controversial and all previous studies were performed on treated patients, though it is known that dopaminergic therapy can affect cognition in PD.MethodsSixty-nine early untreated PD patients underwent an extensive neuropsychological battery exploring memory, visuospatial and attention/executive functions. Patients were divided with respect of the side of onset (right vs. left) and further grouped according to motor phenotype (tremor vs. rigidity-bradykinesia). Multivariate analysis of variance has been carried out to compare clinical and neuropsychological data between subgroups.ResultsThere were no differences in any neuropsychological task between right-sided and left-sided onset subgroups, irrespective of tremor dominant or rigid-bradykinetic phenotype. Age at onset was significantly higher in patients with any cognitive impairment as compared with patients without (66.7 ± 3.2 vs. 56.3 ± 6.8 years, p = 0.001).ConclusionSide of motor onset is not a major determinant for developing lateralized cognitive deficits in newly diagnosed untreated PD patients.     

Randomized controlled trial of health maintenance reminders provided directly to patients through an electronic PHR

BACKGROUND

Provider and patient reminders can be effective in increasing rates of preventive screenings and vaccinations. However, the effect of patient-directed electronic reminders is understudied.

OBJECTIVE

To determine whether providing reminders directly to patients via an electronic Personal Health Record (PHR) improved adherence to care recommendations.

DESIGN

We conducted a cluster randomized trial without blinding from 2005 to 2007 at 11 primary care practices in the Partners HealthCare system.

PARTICIPANTS

A total of 21,533 patients with access to a PHR were invited to the study, and 3,979 (18.5%) consented to enroll.

INTERVENTIONS

Patients in the intervention arm received health maintenance (HM) reminders via a secure PHR “eJournal,” which allowed them to review and update HM and family history information. Patients in the active control arm received access to an eJournal that allowed them to input and review information related to medications, allergies and diabetes management.

MAIN MEASURES

The primary outcome measure was adherence to guideline-based care recommendations.

KEY RESULTS

Intention-to-treat analysis showed that patients in the intervention arm were significantly more likely to receive mammography (48.6% vs 29.5%, p = 0.006) and influenza vaccinations (22.0% vs 14.0%, p = 0.018). No significant improvement was observed in rates of other screenings. Although Pap smear completion rates were higher in the intervention arm (41.0% vs 10.4%, p < 0.001), this finding was no longer significant after excluding women’s health clinics. Additional on-treatment analysis showed significant increases in mammography (p = 0.019) and influenza vaccination (p = 0.015) for intervention arm patients who opened an eJournal compared to control arm patients, but no differences for any measure among patients who did not open an eJournal.

CONCLUSIONS

Providing patients with HM reminders via a PHR may be effective in improving some elements of preventive care.

Electronic supplementary material

The online version of this article (doi:10.1007/s11606-011-1859-6) contains supplementary material, which is available to authorized users.KEY WORDS: health maintenance reminders, personal health record, preventive care, clinical decision support, Patient Gateway     

Thrombomodulin as a regulator of the anticoagulant pathway: implication in the development of thrombosis

Thrombomodulin is a cell surface-expressed glycoprotein that serves as a cofactor for thrombin-mediated activation of protein C (PC), an event further amplified by the endothelial cell PC receptor. The PC pathway is a major anticoagulant mechanism that downregulates thrombin formation and hedges thrombus formation. The objectives of this review were to review recent findings regarding thrombomodulin structure, its involvement in the regulation of hemostasis and further discuss the implication, if any, of the genetic polymorphisms in the thrombomodulin gene in the risk of development of thrombosis. We performed a literature search by using electronic bibliographic databases. Although the direct evaluation of risk situations associated with thrombomodulin mutations/polymorphisms could be of clinical significance, it appears that mutations that affect the function of thrombomodulin are rarely associated with venous thromboembolism. However, several polymorphisms are reported to be associated with increased risk for arterial thrombosis. Additionally studies on knock out mice as well studies on humans bearing rare mutations suggest that thrombomodulin dysfunction may be implicated in the pathogenesis of myocardial infraction.     

Low achieved diastolic pressure in tightly controlled mid-older hypertensive subjects is associated with favorable arterial properties

Low diastolic blood pressure (DBP) is commonly seen in well-controlled hypertensive subjects. We evaluated arterial properties in 53 hypertensive subjects with low on-treatment DBP (<70 mm Hg; LODP), 54 subjects with normal BP and spontaneously low DBP (SLDP), and 52 treated hypertensive subjects with DBP ≥70 mm Hg (HNDP). The two measures of large artery rigidity, pulse wave velocity and augmentation index, were similar in LODP and SLDP groups. In contrast, the HNDP group had higher PWV and the lowest large and small artery compliance in comparison with all other groups. Low on-treatment DBP is associated with favorable arterial properties in mid-older hypertensive patients.     

Comparative outcomes of open versus laparoscopic sacrocolpopexy among medicare beneficiaries

Introduction and hypothesis

Since the first reported laparoscopic sacrocolpopexy in 1991, a limited number of single-center studies have attempted to assess the procedure’s effectiveness and safety. Therefore, we analyzed a national Medicare database to compare real-world short-term outcomes of open and laparoscopically assisted (including robotic) sacrocolpopexy in a United States sample of patients.

Methods

Public Use File data for a 5 % random national sample of all Medicare beneficiaries aged 65 and older were obtained from the Centers for Medicare and Medicaid Services for the years 2004–2008. Women with pelvic organ prolapse were identified using ICD-9 diagnosis codes. CPT-4 procedure codes were used to identify women who underwent open (code 57280) or laparoscopic (code 57425) sacrocolpopexy. Individual subjects were followed for 1 year post-operatively. Outcomes measured, using ICD-9 and CPT-4 codes, included medical and surgical complications and re-operation rates.

Results

Seven hundred and ninety-four women underwent open and 176 underwent laparoscopic (including robotic) sacrocolpopexy. Laparoscopic sacrocolpopexy was associated with a significantly increased rate of re-operation for anterior vaginal wall prolapse (3.4 % vs 1.0 %, p?=?0.018). However, more medical (primarily cardiopulmonary) complications occurred post-operatively in the open group (31.5 % vs 22.7 %, p?=?0.023). When sacrocolpopexy was performed with concomitant hysterectomy, mesh-related complications were significantly higher in the laparoscopic group (5.4 % vs 0 %, p?=?0.026).

Conclusion

Laparoscopic sacrocolpopexy resulted in an increased rate of reoperation for prolapse in the anterior compartment. When hysterectomy was performed at the time of sacrocolpopexy, the laparoscopic approach was associated with an increased risk of mesh-related complications.     

Imaging Metal-on-Metal Hip Replacements: the Norwich Experience

Background

Adverse reaction to metal debris is a relatively recently described and often a silent complication of metal-on-metal (MOM) total hip replacements (THR). The Norfolk & Norwich University Hospital has been performing metal artefact reduction (MARS) MRI for 8 years in a variety of different types of MOM THR.

Questions/purposes

The aims of this review are to describe the experience of using MARS MRI in Norwich and to compare our experience with that published by other groups.

Methods

A MEDLINE keyword search was performed for studies including MRI in MOM THR. Relevant publications were reviewed and compared with published data from the Norfolk & Norwich University Hospital. The similarities and differences between these data were compared and possible explanations for these discussed.

Results

MARS MRI appears to be the most useful tool for diagnosing, staging and monitoring adverse reactions to metal debris (ARMD). There appears to be no clinically useful association between clinical and serological markers of disease and the severity of MR findings. Although severe early ARMD is associated with significant morbidity, mild disease is often stable for years. If patients with normal initial MR examinations develop ARMD, this usually occurs 7 years. A 1-year interval between MRI examinations is reasonable in asymptomatic patients.

Conclusions

There is a general international consensus that ARMD is prevalent in symptomatic and asymptomatic patients with MOM THR and that while appearances vary with the type of prosthesis, there are characteristic features that make MARS MRI essential for diagnosis, staging and surveillance of the disease.     

Negative Affect Predicts Adults’ Ratings of the Current, but Not Childhood, Impact of Adverse Childhood Events

Adverse childhood events (ACE’s) have been empirically related to a wide range of negative health and mental health outcomes. However, not all individuals who experience ACE’s follow a trajectory of poor outcomes, and not all individuals perceive the impact of ACE’s as necessarily negative. The purpose of this study was to investigate positive and negative affect as predictors of adults’ ratings of both the childhood and adult impact of their childhood adversity. Self-report data on ACE experiences, including number, severity, and ‘impact’ were collected from 158 community members recruited on the basis of having adverse childhood experiences. Results indicated that, regardless of event severity and number of different types of adverse events experienced, high levels of negative affect were the strongest predictor of whether the adult impact of the adverse childhood events was rated as negative. All individuals rated the childhood impact of events the same. Implications are discussed.