Therapeutic potential of abalone and status of bioactive molecules: A comprehensive review.

Marine organisms are increasingly being investigated as sources of bioactive molecules with therapeutic applications as nutraceuticals and pharmaceuticals. In particular, nutraceuticals are gaining popularity worldwide owing to their therapeutic potential and incorporation in functional foods and dietary supplements. Abalone, a marine gastropod, contains a variety of bioactive compounds with anti-oxidant, anti-thrombotic, anti-inflammatory, anti-microbial, and anti-cancer activities. For thousands of years different cultures have used abalone as a traditional functional food believing consumption provides health benefits. Abalone meat is one of the most precious commodities in Asian markets where it is considered a culinary delicacy. Recent research has revealed that abalone is composed of many vital moieties like polysaccharides, proteins, and fatty acids that provide health benefits beyond basic nutrition. A review of past and present research is presented with relevance to the therapeutic potential of bioactive molecules from abalone.

Measurement of myocardial amyloid deposition in systemic amyloidosis: insights from cardiovascular magnetic resonance imaging.

BACKGROUND: Cardiac involvement in systemic amyloidosis is caused by the extracellular deposition of misfolded proteins, mainly immunoglobulin light chains (AL) or transthyretin (ATTR), and may be detected by cardiovascular magnetic resonance (CMR). The aim of this study was to measure myocardial extracellular volume (ECV) in amyloid patients with a novel T1 mapping CMR technique and to determine the correlation between ECV and disease severity. METHODS: Thirty-six patients with biopsy-proven systemic amyloidosis (mean age 70 ± 9 years, 31 men, 30 with AL and six with ATTR amyloidosis) and seven patients with possible amyloidosis (mean age 64 ± 10 years, six men) underwent comprehensive clinical and CMR assessment, with ECV estimation from pre- and postcontrast T1 mapping. Thirty healthy subjects (mean age 39 ± 17 years, 21 men) served as the control group. RESULTS: Amyloid patients presented with left ventricular (LV) concentric hypertrophy with impaired biventricular systolic function. Cardiac ECV was higher in amyloid patients (definite amyloidosis, 0.43 ± 0.12; possible amyloidosis, 0.34 ± 0.11) than in control subjects (0.26 ± 0.04, P < 0.05); even in amyloid patients without late gadolinium enhancement (0.35 ± 0.10), ECV was significantly higher than in the control group (P < 0.01). A cut-off value of myocardial ECV >0.316, corresponding to the 95th percentile in normal subjects, showed a sensitivity of 79% and specificity of 97% for discriminating amyloid patients from control subjects (area under the curve of 0.884). Myocardial ECV was significantly correlated with LV ejection fraction (R(2)  = 0.16), LV mean wall thickness (R(2)  = 0.41), LV diastolic function (R(2)  = 0.21), right ventricular ejection fraction (R(2)  = 0.13), N-terminal fragment of the pro-brain natriuretic peptides (R(2)  = 0.23) and cardiac troponin (R(2)  = 0.33). CONCLUSION: Myocardial ECV was increased in amyloid patients and correlated with disease severity. Thus, measurement of myocardial ECV represents a potential noninvasive index of amyloid burden for use in early diagnosis and disease monitoring.

Common evolution of waprin and kunitz-like toxin families in Australian venomous snakes.

The venoms of Australian snakes contain a myriad of pharmacologically active toxin components. This study describes the identification and comparative analysis of two distinct toxin families, the kunitztype serine protease inhibitors and waprins, and demonstrates a previously unknown evolutionary link between the two. Multiple cDNA and full-length gene isoforms were cloned and shown to be composed of three exons separated by two introns. A high degree of identity was observed solely within the first exon which coded for the propeptide sequence and its cleavage site, and indicates that each toxin family has arisen from a gene duplication event followed by diversification only within the portion of the gene coding for the functional toxin. It is proposed that while the mechanism of toxin secretion is highly conserved, diversification of mature toxin sequences allows for the existence of multiple protein isoforms in the venom to adapt to variations within the prey environment.

Multimodality imaging in the diagnosis, risk stratification, and management of patients with dilated cardiomyopathies: an expert consensus document from the European Association of Cardiovascular Imaging.

Dilated cardiomyopathy (DCM) is defined by the presence of left ventricular or biventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease sufficient to explain these changes. This is a heterogeneous disease frequently having a genetic background. Imaging is important for the diagnosis, the prognostic assessment and for guiding therapy. A multimodality imaging approach provides a comprehensive evaluation of all the issues related to this disease. The present document aims to provide recommendations for the use of multimodality imaging according to the clinical question. Selection of one or another imaging technique should be based on the clinical condition and context. Techniques are presented with the aim to underscore what is 'clinically relevant' and what are the tools that 'can be used'. There remain some gaps in evidence on the impact of multimodality imaging on the management and the treatment of DCM patients where ongoing research is important.

Gene modulatory effects, pharmacokinetics, and clinical tolerance of interferon-alpha1b: a second member of the interferon-alpha family.

Interferon-alpha1 (IFN-alpha1), which may have a primary role in innate immunity, differs significantly in amino-acid sequence from IFN-alpha2, the only recombinant IFN-alpha with substantial clinical evaluation. Patients with metastatic malignancies received daily subcutaneous doses of 1.5-270 mug/m(2) of recombinant IFN-alpha1b. Gene modulation, pharmacokinetics, tolerability, and disease response were determined. Significant (P<0.01) dose and gene-dependent increases of 2-10 fold occurred in IFN-stimulated genes, including four (tumor necrosis factor-related apoptosis-inducing ligand, cig 5, p56, GEM) never previously identified as increased in patients; significant increases (P<0.01) resulted at the lowest dose (1.5 microg/m(2); 1.5 x 10(4) human antiviral units/m(2)). Increases (P<0.01) were sustainable for >4 weeks. Peak levels of IFN-alpha1b were at 3 h; an increase of approximately eightfold in both C(max) and AUC occurred between 15 microg/m(2) and 270 microg/m(2). Chronic toxicities of anorexia, weight loss, and fatigue were relatively uncommon. Eighteen patients were treated for >8 weeks; none experienced >grade 1 weight loss. Three patients at the highest dose developed grade 3 fatigue after > or =3 months, which required dose reduction or discontinuation. Patient acceptability of fatigue defined a dose for initiation of Phase II trials, 270 microg/m(2). Six patients (five with renal cell carcinoma) had progression-free survival for >1 year, including two who had partial responses. IFN-alpha1b resulted in potent stimulation of IFN-regulated genes and tumor regressions in renal cell carcinoma. Unique gene modulatory effects, when coupled with the moderate severity of side effects and a potentially central role in innate immunity, provide rationale for further clinical evaluation of IFN-alpha1 in virus infections and cancer.

Analysis of factors affecting the severity of crashes in urban road intersections.

Road crashes are events which depend on a variety of factors and which exhibit different magnitudes of outputs when evaluated with respect to the effects on road users. Despite a lot of research into the evaluation of crash likelihood and frequency, only a few works have focused exclusively on crash severity with these limited to sections of freeways and multilane highways. Hence, at present there is a large gap in knowledge on factors affecting the severity of crashes for other road categories, facilities, and scenarios. The paper deals with the identification of factors affecting crash severity level at urban road intersections. Two official crash records together with a weather database, a traffic data source with data aggregated into 5min intervals, and further information characterising the investigated urban intersections were used. Analyses were performed by using a back propagation neural network model and a generalized linear mixed model that enable the impact assessment of flow and other variables. Both methods demonstrate that flows play a role in the prediction of severity levels.

Dendritic cells in autologous hematopoietic stem cell transplantation for diffuse large B-cell lymphoma: graft content and post transplant recovery predict survival.

Allograft dendritic cell (DC) content has been identified as a predictor of relapse and event-free survival after allogeneic bone marrow transplantation. However, the prognostic importance of DCs has not been evaluated in the setting of autologous hematopoietic stem cell transplantation (HSCT). We prospectively determined pre-transplant and post transplant DC levels, including DC1 and DC2 subset levels, in 53 patients with diffuse large B-cell non-Hodgkin's lymphoma (DLBC NHL) undergoing autologous HSCT. Pre-transplant DCs were measured in the collected stem cell products and were therefore indicative of cell numbers infused directly into patients; post transplant analysis of DCs was performed on the peripheral blood of patients 6 weeks after the infusion of autologous stem cells. Higher pre-transplant levels of DC1 cells and total DCs were significantly associated with improved survival. Similarly, greater post transplant levels of total DCs and both subsets were significantly associated with survival. These findings suggest a relationship between DC reconstitution and survival following autologous HSCT for DLBC NHL. Strategies to increase autograft DC content or accelerate DC recovery after autologous HSCT might improve outcomes in this setting.

Measurement of autoantibodies against fibrinogen and fibrin degradation products by enzyme-linked immunoassay.

We have devised a simple enzyme immunoassay to detect and quantitate autoantibodies against derivatives of fibrinogen. This assay has been applied with a range of antigens including a fibrinogen lysate (containing X, Y, D and E), D dimer, D dimer-E and a preparation of high molecular weight complexes derived from crosslinked fibrin. We have found that autoantibodies interacting with these antigens can be detected in varying concentrations in most sera from both normal subjects and patients with a variety of diseases and are evidently of mixed Ig class. These autoantibodies are directed against at least several cryptic antigens which appear during fibrinogen/fibrin degradation and some appear to be directed specifically against cross-linked fibrin derivatives. No clear disease correlates have yet emerged but a relationship between elevated levels and prior infective, thrombotic, inflammatory or traumatic disorders is likely. It is suggested that these autoantibodies may contribute to the catabolism of fibrinogen derivatives, provide a marker of thrombosis, and sometimes produce pathologic effects.

Measurement of crosslinked fibrin degradation products - an immunoassay using monoclonal antibodies.

We have prepared a monoclonal antibody which recognises an antigenic determinant on D dimer, a specific fragment resulting from the degradation of crosslinked fibrin. This antibody has been used in the development of an enzyme-linked immunoassay for D dimer and related degradation products containing crosslinked gamma-gamma chains, to provide a simple assay of circulating crosslinked fibrin degradation products suitable for clinical use. Since these crosslinked fibrin degradation products are characteristic of fibrinolysis, as distinct from fibrinogenolysis, their measurement should aid in the diagnosis, evaluation and monitoring of thrombotic and thrombolytic states. In preliminary studies, low concentrations of crosslinked fibrin derivatives were detected in normal sera. High levels were found in 30/30 patients with disseminated intravascular coagulation and in the majority of patients having deep venous thrombosis or pulmonary embolism.

Measurement of crosslinked fibrin derivatives--use in the diagnosis of venous thrombosis.

The measurement of crosslinked fibrin derivatives in plasma has received evaluation as a screening test in the diagnosis of venous thrombosis. Plasma samples were taken from 104 patients undergoing venography because of clinical suspicion of lower limb venous thrombosis. The samples were assayed using a monoclonal antibody identifying an epitope on D dimer and larger crosslinked fibrin derivatives in an enzyme immunoassay. 100% of patients with positive venograms had elevated levels of these molecules. While a percentage of patients with negative venograms also had increased levels, alternative clinical explanations were apparent in most. A normal D dimer value excludes the diagnosis of venous thrombosis, while an increased value supports it. The measurement of crosslinked fibrin derivatives in plasma may play a role in the selection of patients for venography.

Rapid detection of cross-linked fibrin degradation products in plasma using monoclonal antibody-coated latex particles.

Conformational and structural changes on conversion of fibrinogen to fibrin and its cross-linking by Factor XIIIa lead to the development of new antigenic determinants that permit differentiation between their plasminolytic cleavage products. A monoclonal antibody (DD-3B6/22) that is specific for cross-linked fibrin derivatives containing the D dimer configuration has been used in developing a latex agglutination procedure that can detect fibrin degradation products in either plasma or serum. Fibrinogen or its degradation products do not cross-react with this antibody. Results were calibrated with an enzyme immunoassay, which used a purified D dimer standard. Plasmas from 40 normal subjects, all having D dimer levels below 250 ng/mL measured by enzyme immunoassay, were all negative by latex assay. In contrast, positive latex agglutination titers were obtained with 87 of 88 patients with demonstrated deep venous thrombosis, pulmonary embolism, or disseminated intravascular coagulation. Compared to enzyme immunoassay, latex agglutination assay is less sensitive, but this latex procedure provides a rapid and less elaborate test for elevated levels of cross-linked fibrin degradation products in patients with thrombosis. Plasma assays for fibrin degradation products are preferable to those using serum.

Measurement of cross linked fibrin derivatives in plasma: an immunoassay using monoclonal antibodies.

Fibrinogen degradation, fibrin polymerisation, and the insertion of cross links into fibrin by fibrin stabilising factor lead to the appearance of new antigenic determinants. Antibodies against these antigenic sites may react specifically with the derivatives but not with the parent molecules. We have utilised a monoclonal antibody, which interacts with the cross linked fragment D dimer and related high molecular weight fibrin derivatives, to develop an enzyme immunoassay which measures cross linked fibrin derivatives in plasma and serum using D dimer as standard. Mean concentration in plasma from normal subjects was 75 ng/ml with an upper limit of about 144 ng/ml. Concentrations in patients with pulmonary embolism, deep venous thrombosis, arterial thromboembolism, and disseminated intravascular coagulation were raised in all cases. Confirmation of the specific increase of cross linked fibrin derivatives in patients with disseminated intravascular coagulation was obtained by parallel monitoring of their fibrin degradation products in serum using affinity chromatography and sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis. In many patients the plasma concentrations greatly exceeded the serum values of cross linked fibrin degradation products, suggesting that the procedure can measure fibrin derivatives in plasma which are absent from serum.

Left varicocele at puberty.

A study was made of 160 cases of left varicocele treated during 1979-1980; there were 35 patients under sixteen years old. Also 74.3 per cent of patients already had mono- or bilateral testicular hypotrophy. Testicular biopsy revealed 90 per cent had histologic lesions of varying nature and degree. We believe varicocele formation is related to physiologic changes during puberty. These data suggest that early recognition of varicocele and its correction before the appearance of irreversible testicular lesions may prevent male sterility.

Fibrinolysis as a feature of disseminated intravascular coagulation (DIC) after Pseudonaja textilis textilis envenomation.

Blood was obtained from four patients envenomated by the Australian common brown snake, Pseudonaja textilis textilis. This elapid snake has one of the most toxic venoms in the world, containing extremely potent neurotoxic and coagulant components. The latter is a potent complete prothrombinase, converting prothrombin to alpha-thrombin, and comprises more than 30% of the total venom protein. The four envenomated patients developed a typical consumption coagulopathy. Serial serum and plasma samples from patients were studied by immunoaffinity adsorption, 2-alanine precipitation of fibrinogen and fibrinogen-related products and 2-dimensional immunoelectrophoresis, and assayed for crosslinked fibrin degradation products as D dimer, using the monoclonal antibody, DD-3B6/22. These procedures showed the virtually complete disappearance of fibrinogen, accompanied by the appearance of large quantities of fibrinogen and fibrin degradation products consisting of both crosslinked and noncrosslinked species. With recovery, a homogeneous high molecular weight fibrinogen was observed. The data suggest that the prothrombin activator of this venom causes the generation of thrombin which subsequently converts fibrinogen to fibrin and stimulates partial crosslinking of both alpha and gamma-chains. The resultant disseminated intravascular coagulation is accompanied by very active secondary fibrinolysis which apparently limits the extent of any microvascular thrombosis but which may contribute to a bleeding tendency.

An immunoassay for human D dimer using monoclonal antibodies.

Monoclonal antibodies (MAb) were raised against human D dimer. The hybridomas were screened with a solid phase enzyme immunoassay against D dimer and fibrinogen degradation products. Among the panel of MAb identified, two distinct patterns emerged; the majority belonging to a panspecific class reacting against epitopes present on both D dimer and fibrinogen degradation product Dcate and a monospecific class reacting with determinants apparently present only on D dimer. A number of MAb were further characterised for their ability to specifically capture antigen in a solid phase enzyme immunoassay and assays were developed which have a sensitivity of 10 ng/ml for D dimer or crosslinked fibrin derivatives and may be suitable for detection of crosslinked derivatives in serum and plasma samples in a clinical situation.

Venom of the Australian rough-scaled snake, Tropidechis carinatus: lethal potency and electrophysiological actions.

A series of experiments to define the lethal potency (LD50) and electrophysiological properties of the venom of the Australian Rough-scaled Snake (Tropidechis carinatus) are described. Crude pooled venom contains at least five fractions which were separated using liquid chromatography and high pressure liquid chromatography techniques (Fractions I-V). LD50 studies are reported using each of these fractions, with data for both adult and neonatal mice. Fraction I (mol. wt greater than 100,000) was essentially non-toxic. Fraction IV (mol. wt less than or equal to 10,000) and Fraction V (mol. wt less than 1,000) were potent toxic components with LD50'S (s.c. injection; fraction in 0.1% bovine serum albumin and 0.85% saline; neonatal mice) of 0.04 mg/kg and 0.06 mg/kg respectively. LD50'S for the whole crude venom were similar in both adult and neonatal mice. Electrophysiological studies using a Bulbring preparation (rat isolated phrenic nerve-hemidiaphragm) indicated that Fractions I, IIa and IIb were inactive. Fraction IV (mol. wt less than or equal to 10,000) caused rapid neuromuscular blockade which appeared to be irreversible. Neurophysiological experiments with a rat isolated extensor digitorum longus muscle preparation suggested that the major toxic activity of the whole venom resides in Fractions III and IV, and that both of these fractions have presynaptic and postsynaptic action.

Hemolytic uremic syndrome following taipan envenomation with response to plasmapheresis.

We report a case of hemolytic uremic syndrome (HUS) in a 33 year old male who was bitten by a taipan, with apparent massive envenomation. The microangiopathic hemolytic anemia (MAHA) and thrombocytopenic aspects of his HUS appeared to respond to plasmapheresis, but his anuric renal failure persisted. He also had prolonged severe muscular paralysis which gradually began to resolve over the course of two weeks. At this point he suffered a cardiac arrest sustaining severe and subsequently fatal hypoxic brain injury. This case raises the possibility that the taipan venom may have induced HUS by damaging the renal endothelium. His cardiac arrest was not apparently related to his HUS.

Plasma cross-linked fibrin degradation product (XLFbDP) assays in an in vivo model of fibrinolysis.

Assumptions regarding the elaboration of plasma cross-linked fibrin degradation products (XLFbDPs) in vivo were tested using an experimental model in which particulate human fibrin was infused into rabbits and the products of lysis monitored with an immunoassay utilizing DD-3B6/22, a monoclonal antibody to human cross-linked derivatives. XLFbDPs were generated following the infusion of a suspension of cross-linked fibrin, attaining a peak between 40 and 60 min, then falling at a rate approximating a plasma half-life of 2 h. The major in vivo products of lysis of cross-linked fibrin, identified by SDS-PAGE of immunoextracted plasma, were D-dimer and high-molecular-weight moieties. Peak levels of XLFbDPs achieved correlated with the amount of fibrin administered. Since XLFbDP levels were no higher when fibrin infusion was followed by infusions of streptokinase and human plasminogen, it is concluded that endogenous mechanisms of lysis were already maximally stimulated. Infusions of non-cross-linked (NXL) fibrin or of fibrinogen led to much smaller, but measurable, rises in XLFbDP. In the latter group, XLFbDP levels rose further following fibrinolytic therapy. Treatment with epsilon aminocaproic acid (EACA) caused partial (greater than 50%) inhibition of lysis while pre-treatment with nitrogen mustard, inducing leucopenia, virtually abolished the appearance of XLFbDPs in the circulation. This implies that fibrinolytic responses are substantially dependent upon cellular functions sensitive to nitrogen mustard.

Textilinins from Pseudonaja textilis textilis. Characterization of two plasmin inhibitors that reduce bleeding in an animal model.

The incidence of vein-graft occlusion associated with myocardial infarction and thrombosis following the use of the plasmin inhibitor, aprotinin, to reduce blood loss during vascular surgery has prompted the isolation of an alternative kinetically distinct inhibitor of plasmin from the venom of Pseudonaja textilis. This inhibitor has been called textilinin (Txln) and two distinct forms have been isolated from the Brown-snake venom (molecular weight, 6688 and 6692). A comparison of plasmin inhibitor constants for aprotinin and the Txlns 1 and 2 indicated that the former bound very tightly (inhibitor constant, Ki approximately 10(-11) mol/l), while both of the latter bound less tightly (Ki approximately 10(-9) mol/l). Homogeneity of Txlns 1 and 2 was confirmed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and mass spectrometry. A sequence difference of six amino acids was observed between the two forms of Txln. Txln 1 and 2 showed, respectively, 45 and 43% homology with aprotinin, while there was 58 and 55% homology, respectively, with a plasmin inhibitor from the venom of eastern Taipan, Oxyuranus scutellatus. Both Txlns have six cysteines, like other inhibitors of this group, and homology was determined by alignment of these cysteines. Both have been shown to reduce blood loss by about 60% in a murine tail vein bleeding model. It is proposed that the kinetic profiles of Txln 1 and 2 for plasmin allow the arrest of haemorrhage without the possible threat of thrombosis.

Acoustic intrameatal meningiomas.

BACKGROUND: The sporadic finding of an acoustic intrameatal meningioma stimulated the authors to the present study. An analysis of the cases previously reported in the literature aimed to outline a preliminary account about biological, radiological and surgical specific hallmarks of these tumours. METHODS: Eight previous cases of meningiomas, meeting the prerequisite of origin and situation within the internal acoustic canal, have been discovered in the known literature since 1975. A further case was recently observed in our experience. The cases in the series showed no sex prevalence and in most of them the age of incidence was comprised between the fifth and sixth decade of life. Hearing loss was the prevalent symptom, lasting 1 month to 7 years before presentation. Myelocisternography, myelo-CT or high resolution CT/MR revealed no specific radiological features to distinguish small intrameatal meningiomas from the more frequently occurring vestibular schwannomas, while CT scan with bone algorithm could point out valuable indirect details for differential diagnosis. Various surgical approaches, i.e. middle fossa, translabyrinthine and retromastoid, were utilized by the different authors. RESULTS: Basing on apparent individual surgical preference, one of three different surgical routes (translabyrinthine, middle fossa, retromastoid) was chosen for 10 procedures in 9 patients. In all, except two cases the impression at surgery was of complete tumour removal. CONCLUSIONS: The possibility for meningiomas to recur and invade the surrounding bone requires a differential diagnosis from vestibular schwannomas. In the absence of intrinsic distinctive signs, radiological evaluation of peritumoral bone alterations could help diagnosis. Although the various surgical routes have often proved effective, temporal bone invasion justifies more extensive approach even in small tumours.