Amyloidosis: Diagnostic investigations, clinical categories, prognosis and management

BACKGROUND: Amyloidosis is a very rare disorder of protein misfolding characterised by the deposition of certain proteins in an abnormal fibrillary form within the extracellular space, which disrupts the normal structure and function of organs throughout the body. Amyloid deposition may be systemic or localised, though there have been few systematic clinical studies of the latter. Treatment depends on the respective amyloid fibril type, and comprises chemotherapy regimens derived from myeloma for the most prevalent systemic monoclonal immunoglobulin light chain (AL) type. The clinical features of systemic AL amyloidosis are protean, commonly including a variety of poorly understood coagulation abnormalities and fatigue symptoms of uncertain cause. Measurement of serum free light chains (FLC) has been a very important advance in guiding treatment of systemic AL amyloidosis. Novel treatment approaches include the serum amyloid P component (SAP) depleting drug ((R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl] pyrrolidine-2 carboxylic acid which has shown promise in a pilot study in patients with hereditary fibrinogen amyloidosis. AIMS: To compare the performance of two commercially available serum free light chain assays and study the prognostic utility of each in systemic AL amyloidosis. To investigate the underlying bleeding and coagulation abnormalities, associated prognostic implications, endothelial dysfunction and implications for the possibility of light chain toxicity. To explore the sleep disordered breathing morbidity in amyloidosis. To investigate the incidence, patient characteristics and survival outcomes in patients with localised AL amyloidosis. To explore a subgroup of localised amyloidosis: tracheobronchial and laryngeal amyloidosis from a clinical and proteomic perspective. To examine two types of treatment in systemic amyloidosis: the use of lenalidomide based chemotherapy with prior use of Thalidomide/Bortezomib treatment in systemic AL amyloidosis and CPHPC treatment. RESULTS AND CONCLUSIONS: Both FreeliteTM and N Latex assays have high sensitivity for detecting abnormal FLC in patients with systemic light chain amyloidosis, showing an excellent correlation between the assays for identifying the abnormal light chain subtype but with discordance in the absolute values. Coagulation abnormalities in systemic AL amyloidosis were frequent and included the following abnormalities: elevated concentration of fibrinogen in 42 (56.8%), elevated FVIII 67 (90.5%) and vWF Ag 67 (90.5%). Kaplan Meier estimates showed that vWF Ag (p=0.039) and FVIII (p=0.01) thresholds greater than 280IU associated with a significant survival disadvantage. A fall in the vWF Ag levels following chemotherapy in those achieving a clonal response suggests potential light chain toxicity implications. Albumin concentration lower than 25g/L correlated with coagulation factors which are prothrombotic, implying that anticoagulation may be an important consideration in newly diagnosed systemic AL. Thus these findings suggest the potential prognostic utility of vWF Ag levels and thrombotic risks associated with newly diagnosed systemic AL patients. Recurrent overnight oxygen desaturations proved to be frequent in patients with cardiac and/or soft tissue amyloidosis, although the occurrence of sleep disordered breathing (SDB) needs confirmation with formal polysomnography. Patients with poor right heart ventricular systolic function score high with SDB questionnaires, which was associated with adverse outcome in newly diagnosed cardiac AL amyloidosis. Localised AL amyloidosis is a very different disease from systemic AL amyloidosis, with a far superior prognosis. Local surgical resection is adequate in most patients with localised amyloidosis in whom treatment is needed, and radiotherapy can have a useful role in some patients whose disease cannot be controlled by local measures. Progression to systemic AL amyloidosis is extremely rare except among patients with lymph node involvement. Patients with lymph node involvement and those with isotypic specific circulating free light chains warrant closer follow up for development of systemic amyloidosis. Most patients with localised AL have excellent long term outcomes. Laryngeal and tracheobronchial amyloidosis is a subtype of localised amyloidosis, in which hoarseness and dyspnoea are the predominant symptoms, the 2 year OS 93% and 90% respectively. Proteomic analysis of amyloid dissected from biopsies showed the presence of the amyloid signature proteins, apolipoprotein A1 (in greater amounts protein) and insulin-like growth factor binding protein complex in all samples compared with patients with systemic AL or transthyretin amyloidosis. Of interest, apolipoprotein A1 has been described within the respiratory tract and insulin growth factor has been postulated to play a role in inflammation, which may be relevant with respect to the pathogenesis and effects of airways amyloidosis. Lenalidomide and dexamethasone combination treatment following prior proteasome inhibitor based therapy produced an overall haematologic response rate of 61%, including 20% complete responses. Renal responses among patients who received prolonged treatment were surprisingly frequent; twenty one out of 38 (55%) evaluable patients achieved a renal response (40% on an ITT basis) – 7 (18%) at 6 months, 7 (18%) at 12 months and an additional 7 (18%) patients at 18 months by long term follow up. This raises the possibility that immunomodulatory effects of lenalidomide therapy might enhance the otherwise slow natural regression of amyloid deposits. CPHPC depletes circulating Serum amyloid P (SAP) component as a treatment for systemic amyloidosis.1 Our study of 10 patients suggested a significant reduction in the natural progression of renal decline and renal survival along with an excellent safety profile; this was supported by our QoL assessments using SFv36 questionnaires. The work in this thesis has thus contributed to improved characterisation and clinical management of various types of amyloidosis, and has identified several avenues of therapy that merit further investigation in larger populations and randomised clinical trials

Resin-rich volumes ( RRV ) and the performance of fibre-reinforced composites: a review

This review considers the influence of Resin-Rich Volumes (RRV) on the static and dynamic mechanical and physical behaviour of fibre-reinforced composites. The formation, shape and size, and measurement of RRV in composites consequent upon different fabric architectures and manufacturing processes is discussed. The majority of studies show a negative effect of the RRV on the mechanical behaviour of composite materials. The main factors that cause the RRV are (a) the clustering of fibres as bundles in textiles, (b) the stacking sequence, (c) the consolidation characteristics of the reinforcement, (d) the resin flow characteristics as a function of tempera-ture, and (e) the composite manufacturing process and cure cycle. RRV are stress concentrations that lead to a disproportionate fall in composite strength. Anyone considering moving from autoclave consolidation to out-of-autoclave (OOA) processes should be cautious of the potential effects of the change

Data driven contagion risk management in low-income countries using machine learning applications with COVID-19 in South Asia

In the absence of real-time surveillance data, it is difficult to derive an early warning system and potential outbreak locations with the existing epidemiological models, especially in resource-constrained countries. We proposed a contagion risk index (CR-Index)—based on publicly available national statistics—founded on communicable disease spreadability vectors. Utilizing the daily COVID-19 data (positive cases and deaths) from 2020 to 2022, we developed country-specific and sub-national CR-Index for South Asia (India, Pakistan, and Bangladesh) and identified potential infection hotspots—aiding policymakers with efficient mitigation planning. Across the study period, the week-by-week and fixed-effects regression estimates demonstrate a strong correlation between the proposed CR-Index and sub-national (district-level) COVID-19 statistics. We validated the CR-Index using machine learning methods by evaluating the out-of-sample predictive performance. Machine learning driven validation showed that the CR-Index can correctly predict districts with high incidents of COVID-19 cases and deaths more than 85% of the time. This proposed CR-Index is a simple, replicable, and easily interpretable tool that can help low-income countries prioritize resource mobilization to contain the disease spread and associated crisis management with global relevance and applicability. This index can also help to contain future pandemics (and epidemics) and manage their far-reaching adverse consequences

Phase variable DNA repeats in 'Neisseria gonorrhoeae' influence transcription, translation, and protein sequence variation

There are many types of repeated DNA sequences in the genomes of the species of the genus Neisseria, from homopolymeric tracts to tandem repeats of hundreds of bases. Some of these have roles in the phase-variable expression of genes. When a repeat mediates phase variation, reversible switching between tract lengths occurs, which in the species of the genus Neisseria most often causes the gene to switch between on and off states through frame shifting of the open reading frame. Changes in repeat tract lengths may also influence the strength of transcription from a promoter. For phenotypes that can be readily observed, such as expression of the surface-expressed Opa proteins or pili, verification that repeats are mediating phase variation is relatively straightforward. For other genes, particularly those where the function has not been identified, gathering evidence of repeat tract changes can be more difficult. Here we present analysis of the repetitive sequences that could mediate phase variation in the Neisseria gonorrhoeae strain NCCP11945 genome sequence and compare these results with other gonococcal genome sequences. Evidence is presented for an updated phase-variable gene repertoire in this species, including a class of phase variation that causes amino acid changes at the C-terminus of the protein, not previously described in N. gonorrhoeae

Androgen-induced cerebral venous sinus thrombosis in a young body builder: case report

BACKGROUND: Cerebral venous sinus thrombosis is an infrequent disease with a variety of causes. Pregnancy, puerperium, contraceptive pills and intracranial infections are the most common causes. The patient may present with headache, focal neurological deficits and seizures. The clinical outcome is highly variable and treatment with heparin is advised. CASE PRESENTATION: The patient is a 22 year old male who presented with headache, repeated vomiting and papilledema. He was a bodybuilder doing exercise since 5 years ago, who had used nandrolone decaonoate 25 milligrams intramuscularly during the previous 5 months. Brain MRI and MRV showed superior sagital and transverse sinus thrombosis and extensive investigations did not reveal any known cause. CONCLUSIONS: We suggested that androgen was the predisposing factor in our patient. Androgens may increase coagulation factors or platelet activity and cause arterial or venous thrombosis. As athletes may hide using androgens it should be considered as a predisposing factor for thrombotic events in such patients

Functional ectodomain of the hemagglutinin-neuraminidase protein is expressed in transgenic tobacco cells as a candidate vaccine against Newcastle disease virus.

Recently, the use of plants for the production of recombinant proteins has been well demonstrated with promising outcomes. In this study, an efficient Nicotiana tabacum L. cv. Bright Yellow 2 (BY-2) cells system expressing the ectodomain of hemagglutinin-neuraminidase (eHN) protein from Newcastle disease virus (NDV) strain AF2240 was established. Transgenic tobacco BY-2 cell cultures expressing the immunogenic eHN protein were generated and the translation efficiency of eHN protein was enhanced using the 5′-untranslated region of Nicotiana tabacum alcohol dehydrogenase gene (NtADH 5′-UTR) under the control of strong cauliflower mosaic virus (CaMV 35S) promoter. Transgenic lines verified by real-time PCR showed high level of eHN mRNA transcripts and immunoblotting confirmed the presence of 66 kD eHN protein. The eHN protein was stably produced in an average of 0.2–0.4 % total soluble protein. Green fluorescent protein-tagged eHN protein was expressed and localized at the cytosol of BY-2 cell. All mice receiving purified eHN protein from transgenic tobacco BY-2 cells produced specific anti-NDV antibodies. We concluded that plant made eHN elicit immune response and can serve as candidate vaccine against NDV

Characterization of MHz pulse repetition rate femtosecond laser-irradiated gold-coated silicon surfaces

In this study, MHz pulse repetition rate femtosecond laser-irradiated gold-coated silicon surfaces under ambient condition were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction analysis (XRD), and X-ray photoelectron spectroscopy (XPS). The radiation fluence used was 0.5 J/cm2 at a pulse repetition rate of 25 MHz with 1 ms interaction time. SEM analysis of the irradiated surfaces showed self-assembled intermingled weblike nanofibrous structure in and around the laser-irradiated spots. Further TEM investigation on this nanostructure revealed that the nanofibrous structure is formed due to aggregation of Au-Si/Si nanoparticles. The XRD peaks at 32.2°, 39.7°, and 62.5° were identified as (200), (211), and (321) reflections, respectively, corresponding to gold silicide. In addition, the observed chemical shift of Au 4f and Si 2p lines in XPS spectrum of the irradiated surface illustrated the presence of gold silicide at the irradiated surface. The generation of Si/Au-Si alloy fibrous nanoparticles aggregate is explained by the nucleation and subsequent condensation of vapor in the plasma plume during irradiation and expulsion of molten material due to high plasma pressure

Genetic variation of male reproductive success in a laboratory population of Anopheles gambiae

<p>Abstract</p> <p>Background</p> <p>For Anopheline mosquitoes, the vectors of human malaria, genetic variation in male reproductive success can have important consequences for any control strategy based on the release of transgenic or sterile males.</p> <p>Methods</p> <p>A quantitative genetics approach was used to test whether there was a genetic component to variation in male reproductive success in a laboratory population of <it>Anopheles gambiae</it>. Swarms of full sibling brothers were mated with a fixed number of females and their reproductive success was measured as (1) proportion of ovipositing females, (2) proportion of ovipositing females that produced larvae, (3) proportion of females that produced larvae, (4) number of eggs laid per female, (5) number of larvae per ovipositing female and (6) number of larvae per female.</p> <p>Results</p> <p>The proportion of ovipositing females (trait 1) and the proportion of ovipositing females that produced larvae (trait 2) differed among full sib families, suggesting a genetic basis of mating success. In contrast, the other measures of male reproductive success showed little variation due to the full sib families, as their variation are probably mostly due to differences among females. While age at emergence and wing length of the males were also heritable, they were not associated with reproductive success. Larger females produced more eggs, but males did not prefer such partners.</p> <p>Conclusion</p> <p>The first study to quantify genetic variation for male reproductive success in <it>A. gambiae </it>found that while the initial stages of male reproduction (i.e. the proportion of ovipositing females and the proportion of ovipositing females that produced larvae) had a genetic basis, the overall reproductive success (i.e. the mean number of larvae per female) did not.</p