Blocking of integrins inhibits HIV‐1 infection of human cervical mucosa immune cells with free and complement‐opsonized virions

The initial interaction between HIV‐1 and the host occurs at the mucosa during sexual intercourse. In cervical mucosa, HIV‐1 exists both as free and opsonized virions and this might influence initial infection. We used cervical explants to study HIV‐1 transmission, the effects of opsonization on infectivity, and how infection can be prevented. Complement opsonization enhanced HIV‐1 infection of dendritic cells (DCs) compared with that by free HIV‐1, but this increased infection was not observed with CD4⁺ T cells. Blockage of the α4‐, β7‐, and β1‐integrins significantly inhibited HIV‐1 infection of both DCs and CD4⁺ T cells. We found a greater impairment of HIV‐1 infection in DCs for complement‐opsonized virions compared with that of free virions when αM/β2‐ and α4‐integrins were blocked. Blocking the C‐type lectin receptor macrophage mannose receptor (MMR) inhibited infection of emigrating DCs but had no effect on CD4⁺ T‐cell infection. We show that blocking of integrins decreases the HIV‐1 infection of both mucosal DCs and CD4⁺ T cells emigrating from the cervical tissues. These findings may provide the basis of novel microbicidal strategies that may help limit or prevent initial infection of the cervical mucosa, thereby reducing or averting systemic HIV‐1 infection.     

A mechanical microconnector system for restoration of tissue continuity and long-term drug application into the injured spinal cord

Complete transection of the spinal cord leaves a gap of several mm which fills with fibrous scar tissue. Several approaches in rodent models have used tubes, foams, matrices or tissue implants to bridge this gap. Here, we describe a mechanical microconnector system (mMS) to re-adjust the retracted spinal cord stumps. The mMS is a multi-channel system of polymethylmethacrylate (PMMA), designed to fit into the spinal cord tissue gap after transection, with an outlet tubing system to apply negative pressure to the mMS thus sucking the spinal cord stumps into the honeycomb-structured holes. The stumps adhere to the microstructure of the mMS walls and remain in the mMS after removal of the vacuum. We show that the mMS preserves tissue integrity and allows axonal regrowth at 2, 5 and 19 weeks post lesion with no adverse tissue effects like in-bleeding or cyst formation. Preliminary assessment of locomotor function in the open field suggested beneficial effects of the mMS. Additional inner micro-channels enable local substance delivery into the lesion center via an attached osmotic minipump. We suggest that the mMS is a suitable device to adapt and stabilize the injured spinal cord after surgical resection of scar tissue (e.g., for chronic patients) or traumatic injuries with large tissue and bone damages.     

Clinical course of central nervous system demyelinating neurological adverse events associated with anti-TNF therapy

Journal of Neurology - Previous studies have reported an association between anti-tumor necrosis factor alpha (anti-TNFα) treatment and central nervous system (CNS) events. We described eight...     

Genetic parameters and allele frequencies of five new European Standard Set STR loci (D10S1248, D22S1045, D2S441, D1S1656, D12S391) in the population of Romania

Aim

To establish allele frequencies and genetic parameters for 5 new European Standard Set short tandem repeat (STR) loci in the population of Romania and to compare them with those in other populations.

Methods

DNA was isolated using QIAamp 96 DNA Swab BioRobot Kit and Chelex 100 methods. Polymerase chain reaction amplification was done using Investigator ESSplexPlus Kit (D1S1656, D2S441, D2S1338, D3S1358, D8S1179, D10S1248, D12S391, D16S539, D18S51, D19S433, D21S11, D22S1045, FGA, TH01, and vWA). For DNA typing, Applied Biosystems 3500/3500xL Genetic Analyzer was used. Statistical analysis was done using Powerstats, GDA, and Arlequin software.

Results

Power of discrimination and polymorphism information content was highest for two new ESS loci, D1S1656 and D12S391. Comparison of allele frequencies for 5 new ESS loci in Romanian population with previously published population data showed significant differences for all compared populations, with the exception of Hungary. Geographically more distant populations, such as Spain, Sweden, United Kingdom, Germany, and Portugal differed more than closer populations.

Conclusion

New ESS STR loci are very useful for the analysis of forensic samples (persons or traces) due to their characteristics (shortness and high polymorphism). In comparisons with other common STR markers, they have a higher power of discrimination and also higher polymorphism information content, and could be used in any national DNA database.The establishment of standard sets (or common sets) of short tandem repeat (STR) markers which had first been a necessity for the forensic scientific community, as a result of globalization became a necessity for the worldwide law enforcement agencies. STR markers standard sets facilitate communication and judicial transmission of the forensic DNA typing results between different forensic groups or countries (1).Although several STR sets have been proposed (2), three of them are most frequently used: Interpol Standard Set of Loci – ISS (FGA, TH01, VWA, D3S1358, D8S1179, D18S51, D21S11), US Core Loci – CODIS (CSF1PO, FGA, TH01, TPOX, VWA, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11), and European Standard Set of Loci – ESS (D3S1358, VWA, D8S1179, D21S11, D18S51, TH01, FGA, D1S1656, D2S441, D10S1248, D12S391, D22S1045).The five new European Standard Set STR loci studied in Romanian population are an upgrade of an earlier version of ESS consisiting of 7 STRs (3), adopted by the European Council in 2001. The DNA Working Group of the European Network of Forensic Science Institutes (ENFSI) reviewed the usefulness of the ESS in light of the increased exchange of DNA analysis results in 2009 and recommended the expansion with 5 new ones (4).Romania adopted the new 5 ESS loci and started to use them at the national level at the beginning of 2012 as part of the Investigator ESSplex Plus Kit, which replaced the AmpFlSTR Identifiler PCR Amplification Kit used before for Romanian National DNA Database supplying. As a consequence, and due to the lack of any study involving D10S1248, D22S1045, D2S441, D1S1656, and D12S391 loci in the Romanian population, allele distribution and genetic parameters of these loci have to be determined. The aim of this study was to establish allele frequencies and genetic parameters for 5 new ESS loci in population of Romania and to compare them with those in other populations .     

Web-based self-management support training for health professionals: A pilot study

Objective

To evaluate a web-based self-management training for health professionals. Patients spend 99% of their time outside the healthcare system. Thus self-management support from health professionals is central to optimal care. Our objective was to teach health professionals the skills to provide this support.

Methods

Primary care residents and practicing providers enrolled in six groups. Each group received four web-based interactive training sessions derived from self-efficacy theory. Retrospective-pre/post assessed changes in self-management beliefs and confidence. Wilcoxon signed-rank tests with Bonferroni correction compared responses. Focus groups solicited qualitative feedback.

Results

Fifty-seven residents and providers across the United States enrolled. Residents demonstrated positive changes on all belief questions (P 0.001–0.012). Practicing providers had a non-significant positive change on one and significant changes on the remainder (P 0.001–0.018). Both types of participants demonstrated significant increases on confidence questions regarding their ability to support self-management (P < 0.01 for all). Participants described learned techniques as being useful, reducing burnout, and increasing acceptance of patient involvement in care planning.

Conclusion

The web-based self-management support training for health professionals was feasible and changed beliefs and confidence.

Practice implications

The program may maximize patient self-management by increasing provider self-efficacy and skill for self-management support.     

Hereditary uveal melanoma: A report of a germline mutation in BAP1

Melanoma of the eye is a rare and distinct subtype of melanoma, which only rarely are familial. However, cases of uveal melanoma (UM) have been found in families with mixed cancer syndromes. Here, we describe a comprehensive search for inherited genetic variation in a family with multiple cases of UM but no aggregation of other cancer diagnoses. The proband is a woman diagnosed with UM at 16 years who within 6 months developed liver metastases. We also identified two older paternal relatives of the proband who had died from UM. We performed exome sequencing of germline DNA from members of the affected family. Exome‐wide analysis identified a novel loss‐of‐function mutation in the BAP1 gene, previously suggested as a tumor suppressor. The mutation segregated with the UM phenotype in this family, and we detected a loss of the wild‐type allele in the UM tumor of the proband, strongly supporting a causative association with UM. Screening of BAP1 germline mutations in families predisposed for UM may be used to identify individuals at increased risk of disease. Such individuals may then be enrolled in preventive programs and regular screenings to facilitate early detection and thereby improve prognosis. © 2013 Wiley Periodicals, Inc.     

An Easily Accessible Web-Based Minimization Random Allocation System for Clinical Trials

Background

Minimization as an adaptive allocation technique has been recommended in the literature for use in randomized clinical trials. However, it remains uncommonly used due in part to a lack of easily accessible implementation tools.

Objective

To provide clinical trialists with a robust, flexible, and readily accessible tool for implementing covariate-adaptive biased-coin randomization.

Methods

We developed a Web-based random allocation system, MinimRan, that applies Pocock–Simon (for trials with 2 or more arms) and 2-way (currently limited to 2-arm trials) minimization methods for trials using only categorical prognostic factors or the symmetric Kullback–Leibler divergence minimization method for trials (currently limited to 2-arm trials) using continuous prognostic factors with or without categorical factors, in covariate-adaptive biased-coin randomization.

Results

In this paper, we describe the system’s essential statistical and computer programming features and provide as an example the randomization results generated by it in a recently completed trial. The system can be used in single- and double-blind trials as well as single-center and multicenter trials.

Conclusions

We expect the system to facilitate the translation of the 3 validated random allocation methods into broad, efficient clinical research practice.