Blood-bank testing for infectious diseases: how safe is blood transfusion?

Remarkable progress has been made in transfusion safety from infection over the past three decades. Donor deferrals for at-risk behaviors, the introduction of more-sensitive viral-screening assays and the recent introduction of nucleic-acid amplification technology have nearly eliminated transmission of HIV and hepatitis C virus (HCV) by blood transfusion in North America. Nevertheless, risks of other infectious agents for which such robust screening tools have not been developed, such as bacteria and parasites, still remain. As a result of these successes, the non-infectious risks such as misidentification of patients and inadequate and inappropriate transfusion have become the primary sources of transfusion risk.     

Lignans in treatment of cancer and other diseases†

Lignans are widely distributed in nature and display an impressive range of biological activities. The extensive pharmaceutical use of lignans is linked to their antitumor, antiviral, hepatoprotective, and platelet activating factor (PAF) antagonistic activities, among many others. This review article highlights selected pharmacologically active lignans, outlines their therapeutic relevance to the treatment of cancer and other diseases, and accentuates research on plant-derived lignans, particularly preclinical lead identification and optimization studies performed in the authors' Natural Products Laboratory (NPL). Antitumor and anti-HIV lignans have been discovered and developed in the NPL by using bioactivity-directed fractionation and isolation as well as rational drug design-based structural modification and analog synthesis approaches. Notably, a significant and ongoing project on podophyllotoxin and its semisynthetic analog etoposide has led to the development of a potent derivative designated GL-331. GL-331 has received investigational new drug (IND) approval from the FDA and is currently in clinical trials against various cancers, especially drug-resistant cancers. Further design, synthesis, and evaluation of GL-331-related analogs are discussed.     

How to assess the pathogenicity of mutations in Charcot-Marie-Tooth disease and other diseases?

Knowledge whether a certain DNA variant is a pathogenic mutation or a harmless polymorphism is a critical issue in medical genetics, in which results of a molecular analysis may serve as a basis for diagnosis and genetic counseling. Due to its genetic heterogeneity expressed at the levels of loci, genes and mutations, Charcot-Marie-Tooth (CMT) disease can serve as a model group of clinically homogenous diseases for studying the pathogenicity of mutations. Close to a 17p11.2-p12 duplication occurring in 70% of patients with the demyelinating form of CMT disease, numerous mutations have been identified in poorly characterized genes coding for proteins of an unknown function. Functional analyses, segregation analyses of large pedigrees, and inclusion of large control groups are required to assess the potential pathogenicity of CMT mutations. Hence, the pathogenicity of numerous CMT mutations remains unclear. Some variants detected in the CMT genes and originally described as pathogenic mutations have been shown to have a polymorphic character. In contrast, polymorphisms initially considered harmless were later reclassified as pathogenic mutations. However, the process of assessing the pathogenicity of mutations, as presented in this study for CMT disorders, is a more general issue concerning all disorders with a genetic background. Since the number of DNA variants is still growing, in the near future geneticists will increasingly have to cope with the problem of pathogenicity of identified genetic variants.     

Is oxidative damage the fundamental pathogenic mechanism of Alzheimer's and other neurodegenerative diseases?

In less than a decade, beginning with the demonstration by Floyd, Stadtman, Markesbery et al. of increased reactive carbonyls in the brains of patients with Alzheimer's disease (AD), oxidative damage has been established as a feature of the disease. Here, we review the types of oxidative damage seen in AD, sites involved, possible origin, relationship to lesions, and compensatory changes, and we also consider other neurodegenerative diseases where oxidative stress has been implicated. Although much data remain to be collected, the broad spectrum of changes found in AD are only seen, albeit to a lesser extent, in normal aging with other neurodegenerative diseases showing distinct spectrums of change.     

Antibody gene therapy： an attractive approach for the treatment of cancers and other chronic diseases

Monoclonal antibodies(mAb)have been successfullyapplied to the treatment of chronic diseases,such as cancer,inflammation and immune diseases.With the technicaladvances in antibody engineering,development of smallrecombinant antibody fragments as high affinity therapeu-tics with reduced immunogenicity has become under thespotlight.A popular format of the engineered recombinantantibody fragments is the single-chain fixed-variable(scFv)molecules,in which the VH and VL regions of the parentalantibody are jointed together by a polypeptide linker.ThescFv fragment retains the target specificity and antigen-binding affinity of the intact antibody,and can be geneti-cally designed and produced in large quantity by ectopicallyexpressing both VH and VL regions from a single cDNAin cells.Due to its smaller size,the scFv molecule showsimproved pharmacokinetics in tumor penetration and isbetter tolerated by the host immune system.Despite thesepotential advantages of using scFv molecules for immu-notherapy,especially for chronic diseases such as cancers,the treatment efficacy,however,is often compromised bythe rapid blood clearance and insufficient concentration ofthe infused scFv fragments at the target site.To achievehigh local concentrations in the target tissues,large amountof the recombinant scFv proteins(hundreds milligrams or     

Could a blood test for PTSD and depression be on the horizon?

ABSTRACT

Introduction: Depression and posttraumatic stress disorder (PTSD) are two complex and debilitating psychiatric disorders that result in poor life and destructive behaviors against self and others. Currently, diagnosis is based on subjective rather than objective determinations leading to misdiagnose and ineffective treatments. Advances in novel neurobiological methods have allowed assessment of promising biomarkers to diagnose depression and PTSD, which offers a new means of appropriately treating patients.

Areas covered: Biomarkers discovery in blood represents a fundamental tool to predict, diagnose, and monitor treatment efficacy in depression and PTSD. The potential role of altered HPA axis, epigenetics, NPY, BDNF, neurosteroid biosynthesis, the endocannabinoid system, and their function as biomarkers for mood disorders is discussed. Insofar, we propose the identification of a biomarker axis to univocally identify and discriminate disorders with large comorbidity and symptoms overlap, so as to provide a base of support for development of targeted treatments. We also weigh in on the feasibility of a future blood test for early diagnosis.

Expert commentary: Potential biomarkers have already been assessed in patients’ blood and need to be further validated through multisite large clinical trial stratification. Another challenge is to assess the relation among several interdependent biomarkers to form an axis that identifies a specific disorder and secures the best-individualized treatment. The future of blood-based tests for PTSD and depression is not only on the horizon but, possibly, already around the corner.     

Formation and participation of nano-amyloids in pathogenesis of Alzheimer’s disease and other amyloidogenic diseases

Studies of neurodegenerative disorders attract much attention of the world scientific community due to increasing dissemination of Alzheimer’s disease. The reason for such pathologies consists in transition of a “healthy” molecule or peptide from its native conformation into a very stable “pathological” form. During this process, molecules existing in the “pathological” conformation aggregate and form amyloid fibrils that can undergo an uncontrolled increase. Novel knowledge is required on sporadic forms of Alzheimer’s disease, on the nature of triggering mechanisms of the conformational transitions of beta-amyloid fragments from normally functioning proteins into new structure, nano-beta-amyloids, that escape of neuronal and whole-body control resulted in the loss of neurons. This review summarized results of studies on the formation of amyloid fibrils and their role in pathogenesis of amyloid diseases.     

Are Girls Good and Boys Bad for Parental Longevity?

Using historical data from the Utah Population Database, this analysis finds significant, consistent, but small adverse mortality effects for mothers after age 50 who had mostly sons. Examination of age-dependent effects indicates that this association increases with mother’s age. Additionally, mothers who had mostly daughters faced mortality risks that increased with age. Offspring sex composition did not have a significant effect on paternal mortality. Interaction analyses were conducted to examine the effect of offspring sex composition with regard to historical period, residential location, socioeconomic status, and childhood survival. No other interactions were found to be statistically significant. Having mostly boys remained detrimental to maternal mortality regardless of childhood survival.

Does random blood glucose sampling outdate testing for glycosuria in the detection of diabetes during pregnancy?

A random blood glucose concentration was determined in 2403 pregnant women attending an antenatal clinic at between 28 and 32 weeks'' gestation. The calculated 99% cut off values were 6.1 mmol/l (110 mg/100 ml) within two hours after a meal and 5.6 mmol/l (101 mg/100 ml) more than two hours after a meal. Patients with a blood glucose concentration in excess of these values were referred for a 75 g oral glucose tolerance test. Of 59 referred, four were found to have previously unsuspected but unequivocal diabetes mellitus and another four to have impaired glucose tolerance on the basis of the World Health Organisation''s criteria. Screening all antenatal patients by randomly measuring blood glucose concentrations is not only cheap and efficient but also does not interfere with the routine of busy antenatal clinics.     

Lassa fever,Marburg and Ebola virus diseases and other exotic diseases: is there a risk to Canada?

There are seven exotic diseases of concern; three of these, the most unpredictable and least understood, are Lassa fever, Marburg virus disease and Ebola virus disease. In this article the epidemiologic aspects of these diseases are discussed, with particular emphasis on exportation from their indigenous areas in Africa and on the occurrence of secondary cases. Any of these conditions could be brought into Canada either by aeromedical evacuation or inadvertently. Between 1972 and 1978 there were seven occasions when Canada could have been involved with handling cases of Lassa fever. The Government of Canada has purchased several containment bed and transit isolators. These units, with filtered air under negative pressure, accommodate infectious patients being transported and cared for without contaminating medical attendants or the environment.     

Can immunological principles and cross-disciplinary science illuminate the path to vaccines for HIV and other global health challenges?

Vaccines are one of the most impactful and cost-effective public health measures of the twentieth century. However, there remain great unmet needs to develop vaccines for globally burdensome infectious diseases and to allow more timely responses to emerging infectious disease threats. Recent advances in the understanding of immunological principles operative not just in model systems but in humans in concert with the development and application of powerful new tools for profiling human immune responses, in our understanding of pathogen variation and evolution, and in the elucidation of the structural aspects of antibody–pathogen interactions, have illuminated pathways by which these unmet needs might be addressed. Using these advances as foundation, we herein present a conceptual framework by which the discovery, development and iterative improvement of effective vaccines for HIV, malaria and other globally important infectious diseases might be accelerated.