Predictive Value of Assessing Diastolic Strain Rate on Survival in Cardiac Amyloidosis Patients with Preserved Ejection Fraction

Objectives

Since diastolic abnormalities are typical findings of cardiac amyloidosis (CA), we hypothesized that speckle-tracking-imaging (STI) derived longitudinal early diastolic strain rate (LSR_dias) could predict outcome in CA patients with preserved left ventricular ejection fraction (LVEF >50%).

Background

Diastolic abnormalities including altered early filling are typical findings and are related to outcome in CA patients. Reduced longitudinal systolic strain (LS_sys) assessed by STI predicts increased mortality in CA patients. It remains unknown if LSR_dias also related to outcome in these patients.

Methods

Conventional echocardiography and STI were performed in 41 CA patients with preserved LVEF (25 male; mean age 65±9 years). Global and segmental LS_sys and LSR_dias were obtained in six LV segments from apical 4-chamber views.

Results

Nineteen (46%) out of 41 CA patients died during a median of 16 months (quartiles 5–35 months) follow-up. Baseline mitral annular plane systolic excursion (MAPSE, 6±2 vs. 8±3 mm), global LSR_dias and basal-septal LSR_dias were significantly lower in non-survivors than in survivors (all p<0.05). NYHA class, number of non-cardiac organs involved, MAPSE, mid-septal LS_sys, global LSR_dias, basal-septal LSR_dias and E/LSR_dias were the univariable predictors of all-cause death. Multivariable analysis showed that number of non-cardiac organs involved (hazard ratio [HR]  = 1.96, 95% confidence interval [CI] 1.17–3.26, P = 0.010), global LSR_dias (HR = 7.30, 95% CI 2.08–25.65, P = 0.002), and E/LSR_dias (HR = 2.98, 95% CI 1.54–5.79, P = 0.001) remained independently predictive of increased mortality risk. The prognostic performance of global LSR_dias was optimal at a cutoff value of 0.85 S⁻¹ (sensitivity 68%, specificity 67%). Global LSR_dias <0.85 S⁻¹ predicted a 4-fold increased mortality in CA patients with preserved LVEF.

Conclusions

STI-derived early diastolic strain rate is a powerful independent predictor of survival in CA patients with preserved LVEF.     

Magnetoresistive-based real-time cell phagocytosis monitoring

The uptake of large particles by cells (phagocytosis) is an important factor in cell biology and also plays a major role in biomedical applications. So far, most methods for determining the phagocytic properties rely on cell-culture incubation and end-point detection schemes. Here, we present a lab-on-a-chip system for real-time monitoring of magnetic particle uptake by human fibroblast (NHDF) cells. It is based on recording the time evolution of the average position and distribution of magnetic particles during phagocytosis by giant-magnetoresistive (GMR) type sensors. We employ particles with a mean diameter of 1.2 μm and characterize their phagocytosis-relevant properties. Our experiments at physiological conditions reveal a cellular uptake rate of 45 particles per hour and show that phagocytosis reaches saturation after an average uptake time of 27.7h. Moreover, reference phagocytosis experiments at 4°C are carried out to mimic environmental or disease related inhibition of the phagocytic behavior, and our measurements clearly show that we are able to distinguish between cell-membrane adherent and phagocytosed magnetic particles. Besides the demonstrated real-time monitoring of phagocytosis mechanisms, additional nano-biointerface studies can be realized, including on-chip cell adhesion/spreading as well as cell migration, attachment and detachment dynamics. This versatility shows the potential of our approach for providing a multifunctional platform for on-chip cell analysis.     

Turmeric: old spice,new spice

The history of chemical investigations into the yellow components of turmeric can be traced from 1815. Although the major yellow component of turmeric, curcumin, often is represented as a 1,3-diketone in the solid state and in nonaqueous solution, it exists in the enol form. The struggle to identify the chemical structure of curcumin continued for nearly a century and was complicated by the difficult purification of curcumin and by the presence of two additional yellow components. Food remains the main use for turmeric (old spice); its use as a dye has diminished since the 19th century, but it may have pharmaceutical uses (new spice).     

Development of a Mouse Monoclonal Antibody Cocktail for Post-exposure Rabies Prophylaxis in Humans

As the demand for rabies post-exposure prophylaxis (PEP) treatments has increased exponentially in recent years, the limited supply of human and equine rabies immunoglobulin (HRIG and ERIG) has failed to provide the required passive immune component in PEP in countries where canine rabies is endemic. Replacement of HRIG and ERIG with a potentially cheaper and efficacious alternative biological for treatment of rabies in humans, therefore, remains a high priority. In this study, we set out to assess a mouse monoclonal antibody (MoMAb) cocktail with the ultimate goal to develop a product at the lowest possible cost that can be used in developing countries as a replacement for RIG in PEP. Five MoMAbs, E559.9.14, 1112-1, 62-71-3, M727-5-1, and M777-16-3, were selected from available panels based on stringent criteria, such as biological activity, neutralizing potency, binding specificity, spectrum of neutralization of lyssaviruses, and history of each hybridoma. Four of these MoMAbs recognize epitopes in antigenic site II and one recognizes an epitope in antigenic site III on the rabies virus (RABV) glycoprotein, as determined by nucleotide sequence analysis of the glycoprotein gene of unique MoMAb neutralization-escape mutants. The MoMAbs were produced under Good Laboratory Practice (GLP) conditions. Unique combinations (cocktails) were prepared, using different concentrations of the MoMAbs that were capable of targeting non-overlapping epitopes of antigenic sites II and III. Blind in vitro efficacy studies showed the MoMab cocktails neutralized a broad spectrum of lyssaviruses except for lyssaviruses belonging to phylogroups II and III. In vivo, MoMAb cocktails resulted in protection as a component of PEP that was comparable to HRIG. In conclusion, all three novel combinations of MoMAbs were shown to have equal efficacy to HRIG and therefore could be considered a potentially less expensive alternative biological agent for use in PEP and prevention of rabies in humans.     

Aging impairs double‐strand break repair by homologous recombination in Drosophila germ cells

Aging is characterized by genome instability, which contributes to cancer formation and cell lethality leading to organismal decline. The high levels of DNA double‐strand breaks (DSBs) observed in old cells and premature aging syndromes are likely a primary source of genome instability, but the underlying cause of their formation is still unclear. DSBs might result from higher levels of damage or repair defects emerging with advancing age, but repair pathways in old organisms are still poorly understood. Here, we show that premeiotic germline cells of young and old flies have distinct differences in their ability to repair DSBs by the error‐free pathway homologous recombination (HR). Repair of DSBs induced by either ionizing radiation (IR) or the endonuclease I‐SceI is markedly defective in older flies. This correlates with a remarkable reduction in HR repair measured with the DR‐white DSB repair reporter assay. Strikingly, most of this repair defect is already present at 8 days of age. Finally, HR defects correlate with increased expression of early HR components and increased recruitment of Rad51 to damage in older organisms. Thus, we propose that the defect in the HR pathway for germ cells in older flies occurs following Rad51 recruitment. These data reveal that DSB repair defects arise early in the aging process and suggest that HR deficiencies are a leading cause of genome instability in germ cells of older animals.     

A Dutch guideline for the treatment of scoliosis in neuromuscular disorders

Background

Children with neuromuscular disorders with a progressive muscle weakness such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy frequently develop a progressive scoliosis. A severe scoliosis compromises respiratory function and makes sitting more difficult. Spinal surgery is considered the primary treatment option for correcting severe scoliosis in neuromuscular disorders. Surgery in this population requires a multidisciplinary approach, careful planning, dedicated surgical procedures, and specialized after care.

Methods

The guideline is based on scientific evidence and expert opinions. A multidisciplinary working group representing experts from all relevant specialties performed the research. A literature search was conducted to collect scientific evidence in answer to specific questions posed by the working group. Literature was classified according to the level of evidence.

Results

For most aspects of the treatment scientific evidence is scarce and only low level cohort studies were found. Nevertheless, a high degree of consensus was reached about the management of patients with scoliosis in neuromuscular disorders. This was translated into a set of recommendations, which are now officially accepted as a general guideline in the Netherlands.

Conclusion

In order to optimize the treatment for scoliosis in neuromuscular disorders a Dutch guideline has been composed. This evidence-based, multidisciplinary guideline addresses conservative treatment, the preoperative, perioperative, and postoperative care of scoliosis in neuromuscular disorders.     

Anni 2.0: a multipurpose text-mining tool for the life sciences

Anni 2.0 is an online tool () to aid the biomedical researcher with a broad range of information needs. Anni provides an ontology-based interface to MEDLINE and retrieves documents and associations for several classes of biomedical concepts, including genes, drugs and diseases, with established text-mining technology. In this article we illustrate Anni's usability by applying the tool to two use cases: interpretation of a set of differentially expressed genes, and literature-based knowledge discovery.     

A Serological Survey of Ruminant Livestock in Kazakhstan During Post-Soviet Transitions in Farming and Disease Control

The results of a serological survey of livestock in Kazakhstan, carried out in 1997–1998, are reported. Serum samples from 958 animals (cattle, sheep and goats) were tested for antibodies to foot and mouth disease (FMD), bluetongue (BT), epizootic haemorrhagic disease (EHD), rinderpest (RP) and peste des petits ruminants (PPR) viruses, and to Brucella spp. We also investigated the vaccination status of livestock and related this to changes in veterinary provision since independence in 1991. For the 2 diseases under official surveillance (FMD and brucellosis) our results were similar to official data, although we found significantly higher brucellosis levels in 2 districts and widespread ignorance about FMD vaccination status. The seroprevalence for BT virus was 23%, and seropositive animals were widespread suggesting endemicity, despite the disease not having being previously reported. We found a few seropositives for EHDV and PPRV, which may suggest that these diseases are also present in Kazakhstan. An hierarchical model showed that seroprevalence to FMD and BT viruses were clustered at the farm/village level, rather than at a larger spatial scale. This was unexpected for FMD, which is subject to vaccination policies which vary at the raion (county) level.