The hemolysins of staphylococcus aureus

On the basis of chemical and immunologic evidence, most investigators now believe that Staphylococcus aureus may produce at least four distinct hemolytic proteins. These have been designated alpha, beta, gamma and delta hemolysins. The function of these hemolysins in the economy of the Staphylococcus has not been fully elucidated, but some detail is available with regard to their nature and in vitro mode of action. Agreement on the properties of the four hemolysins has nevertheless been difficult to obtain because of wide variation in methods of purification and choice of strains. Moreover, confusion has existed in many laboratories with regard to the identity of the hemolysin under study.Recent work has permitted a number of generalizations to be made. Amino acid analyses of the hemolysins have revealed that no unusual acids are present. All hemolysins are soluble in water although of somewhat varying stability, and when pure, no carbohydrate, lipid or other accessory materials have been detected. It is also fairly well-established that at least three, the alpha, beta and delta hemolysins, are basic proteins the isoelectric points of which are in the range of 8.5-9.6. Apart from the delta lysin, their molecular weights are less than 100,000 daltons, the majority of observations being in the range of 20,000-50,000 daltons.The mode of action of the hemolysins has generated some debate, but it is accepted that the beta lysin is an enzyme which degrades sphingomyelin, a phospho¬ lipid widely distributed in cell membranes. The view that the delta lysin is also a phospholipase which attacks phosphatidyl-inositol has frequently been challenged but it must be pointed out that until very recently, workers have not clearly distinguished between gamma and delta lysins. The precise mode of action of the latter is unknown but contemporary work indicates that although gamma lysin has no action on sphingomyelin, phosphatidylinositol or other comnon phospholipids, nitrogen and phosphorus are released from erythrocyte membranes treated with the lysin. Furthermore, it can be shown that hemolysis is inhibited by the membranes when these are added to lysin-red cell suspensions, and that phospholipids extracted from human erythrocytes competitively inhibit the lytic reaction. The mode of action of the alpha lysin has also been elusive but considerable evidence has been compiled which indicates that the lysin is produced by the Staphylococcus as an inactive protease which degrades membranes that contain an activating protease. It has been observed that hemolytic sensitivity of erythrocyte species to alpha lysin is directly correlated with the level of activator present on the membranes. Apart from this, several investigators have demonstrated that the lysin has surface activity, but it is difficult to reconcile the two points of view.No agreement has been reached on the biological properties of the beta, ganma and delta hemolysins in view of the difficulties of purification and definition. Most workers agree, however, that the alpha lysin kills mice and rabbits in doses at the microgram level (although it is thousands of times less toxic than botulinum or tetanus toxins) and that it causes tissue necrosis when injected into the skin. In vivo production of the hemolysins in animals and man has been demonstrated by the detection of circulating antibody in normal and diseased subjects, but until the present, controversy existed over whether the delta lysin was in fact capable of eliciting an antibody response, since serum lipoproteins inhibited its lytic activity. The use of homogeneous preparations of the lysin and purified antibody has conclusively demonstrated its immunogenicity

The Harmonica as a Blues Instrument

The modern harmonica,or harp, has been around since the early 19th century. It is typically used in blues, country, rock and roll and folk music. These musical genres are somewhat similar in structure and form, and often borrow ideas from each other. The harmonica is appropriate as a back up to the main vocal melody and instruments due to its rich harmonic structure and subdued intensity. The ability to apply vibrato and gradual slurs make it a perfect instrument to achieve a ``bluesy sound. Our harp research group has investigated the physical properties of harmonica structure to illustrate how different structures lead to varied sounds, each of which is appropriate to a particular style of music. We present an overview of the use of the harmonica as a blues instrument and describe the details and significance of our research project

Measurement issues associated with quantitative molecular biology analysis of complex food matrices for the detection of food fraud

A review of measurement issues associated with quantitative molecular analysis of complex food matrices for the detection of food fraud.</p

Characterizing the Neurobiological Mechanisms of Action of Exercise and Cognitive–Behavioral Interventions for Rheumatoid Arthritis Fatigue : a magnetic resonance imaging brain study

Open Access via the Wiley/JISC agreement Acknowledgements We would like to thank all the investigators from the original LIFT study, including Kathryn Martin, Lorna Aucott, Neeraj Dhaun, Emma Dures, Stuart R. Gray, Elizabeth Kidd, Vinod Kumar, Karina Lovell, Graeme MacLennan, Paul McNamee, John Norrie, Lorna Paul, Jon Packham, Stefan Siebert, Alison Wearden, and Gary Macfarlane, without whose work this research would not be possible. Furthermore, we thank all the participants who generously supported the LIFT trial. We also acknowledge the contribution of the Trial Steering Committee and Data Monitoring Committee, and Brian Taylor and Mark Forrest (Centre for Healthcare Randomised Trials [CHaRT], University of Aberdeen, Aberdeen, UK) for their technical assistance Funding This study was funded by the Chief Scientist Office (TCS/17/14) and Versus Arthritis (22092).Peer reviewe

Characterising the neurobiological mechanisms of action of exercise and cognitive behavioural interventions for rheumatoid arthritis fatigue: an MRI brain study

Objective: Chronic fatigue is a major clinical unmet need among patients with rheumatoid arthritis (RA). Current therapies are limited to nonpharmacological interventions, such as personalized exercise programs (PEPs) and cognitive–behavioral approaches (CBAs); however, most patients still continue to report severe fatigue. To inform more effective therapies, we conducted a magnetic resonance imaging (MRI) brain study of PEPs and CBAs, nested within a randomized controlled trial (RCT), to identify their neurobiological mechanisms of fatigue reduction in RA. Methods: A subgroup of patients with RA (n = 90), participating in an RCT of PEPs and CBAs for fatigue, undertook a multimodal MRI brain scan following randomization to either usual care (UC) alone or in addition to PEPs and CBAs and again after the intervention (six months). Brain regional volumetric, functional, and structural connectivity indices were curated and then computed employing a causal analysis framework. The primary outcome was fatigue improvement (Chalder fatigue scale). Results: Several structural and functional connections were identified as mediators of fatigue improvement in both PEPs and CBAs compared to UC. PEPs had a more pronounced effect on functional connectivity than CBAs; however, structural connectivity between the left isthmus cingulate cortex (L-ICC) and left paracentral lobule (L-PCL) was shared, and the size of mediation effect ranked highly for both PEPs and CBAs (ßAverage = −0.46, SD 0.61; ßAverage = −0.32, SD 0.47, respectively). Conclusion: The structural connection between the L-ICC and L-PCL appears to be a dominant mechanism for how both PEPs and CBAs reduce fatigue among patients with RA. This supports its potential as a substrate of fatigue neurobiology and a putative candidate for future targeting

Long-term complete responses after 131I-tositumomab therapy for relapsed or refractory indolent non-Hodgkin's lymphoma

We present the long-term results of 18 chemotherapy relapsed indolent (N=12) or transformed (N=6) NHL patients of a phase II anti-CD20 131I-tositumomab (Bexxar®) therapy study. The biphasic therapy included two injections of 450 mg unlabelled antibody combined with 131I-tositumomab once as dosimetric and once as therapeutic activity delivering 75 or 65 cGy whole-body radiation dose to patients with normal or reduced platelet counts, respectively. Two patients were not treated due to disease progression during dosimetry. The overall response rate was 81% in the 16 patients treated, including 50% CR/CRu and 31% PR. Median progression free survival of the 16 patients was 22.5 months. Median overall survival has not been reached after a median observation of 48 months. Median PFS of complete responders (CR/CRu) has not been reached and will be greater than 51 months. Short-term side effects were mainly haematological and transient. Among the relevant long-term side effects, one patient previously treated with CHOP chemotherapy died from secondary myelodysplasia. Four patients developed HAMA. In conclusion, 131I-tositumomab RIT demonstrated durable responses especially in those patients who achieved a complete response. Six of eight CR/CRu are ongoing after 46–70 months

Plasma biomarkers of inflammation, endothelial function and haemostasis in cerebral small vessel disease

Background: The cause of lacunar ischemic stroke, a clinical feature of cerebral small vessel disease (SVD), is largely unknown. Inflammation and endothelial dysfunction have been implicated. Plasma biomarkers could provide mechanistic insights but current data are conflicting. White matter hyperintensities (WMHs) are an important imaging biomarker of SVD. It is unknown if plasma biomarkers add predictive capacity beyond age and vascular risk factors in explaining WMH. Methods: We prospectively recruited patients presenting with non-disabling ischemic stroke, classifying them clinically and with the help of MRI as lacunar or cortical. We measured biomarkers of inflammation, endothelial dysfunction and hemostasis for >1 month after stroke and compared biomarker levels between stroke subtypes. We quantitatively calculated WMH. We used multiple linear regression analysis to model WMH as a function of age, sex, hypertension and smoking (the baseline model). We fitted exploratory models using plasma biomarkers as predictor variables to assess model improvement over baseline. Results: We recruited 125 patients. The lacunar group (n = 65) had lower tissue plasminogen activator (t-PA) levels in unadjusted (7.39 vs. 8.59 ng/ml, p = 0.029) and adjusted (p = 0.035) analyses compared with the cortical group (n = 60). There were no significant differences in the other plasma biomarkers. The results for t-PA were consistent with an updated meta-analysis, although the effect remains non-significant (standardized mean difference -0.08 (95% CI -0.25 to 0.09)). The baseline regression model explained 29% of the variance in quantitative WMH (R2 0.289). Inflammatory biomarkers showed minor improvement over baseline (R2 0.291), but the other plasma biomarkers did not improve the baseline model. Conclusion: Plasma t-PA levels appear to differ between lacunar and cortical stroke subtypes, late after stroke, independent of age, sex and vascular risk factors and may reflect endothelial dysfunction. Except for a minor additional predictive effect of inflammatory markers, plasma biomarkers do not relate to WMH severity in this small stroke population

Relationship Between Venules and Perivascular Spaces in Sporadic Small Vessel Diseases

Background and Purpose— Perivascular spaces (PVS) around venules may help drain interstitial fluid from the brain. We examined relationships between suspected venules and PVS visible on brain magnetic resonance imaging. Methods— We developed a visual venular quantification method to examine the spatial relationship between venules and PVS. We recruited patients with lacunar stroke or minor nondisabling ischemic stroke and performed brain magnetic resonance imaging and retinal imaging. We quantified venules on gradient echo or susceptibility-weighted imaging and PVS on T2-weighted magnetic resonance imaging in the centrum semiovale and then determined overlap between venules and PVS. We assessed associations between venular count and patient demographic characteristics, vascular risk factors, small vessel disease features, retinal vessels, and venous sinus pulsatility. Results— Among 67 patients (69% men, 69.0±9.8 years), only 4.6% (range, 0%–18%) of venules overlapped with PVS. Total venular count increased with total centrum semiovale PVS count in 55 patients after accounting for venule-PVS overlap (β=0.468 [95% CI, 0.187–0.750]) and transverse sinus pulsatility (β=0.547 [95% CI, 0.309–0.786]) and adjusting for age, sex, and systolic blood pressure. Conclusions— Despite increases in both visible PVS and suspected venules, we found minimal spatial overlap between them in patients with sporadic small vessel disease, suggesting that most magnetic resonance imaging-visible centrum semiovale PVS are periarteriolar rather than perivenular

Radioimmunotherapy of B-cell lymphoma with radiolabelled anti-CD20 monoclonal antibodies

CD20 has proven to be an excellent target for the treatment of B-cell lymphoma, first for the chimeric monoclonal antibody rituximab (Rituxan™), and more recently for the radiolabelled antibodies Y-90 ibritumomab tiuxetan (Zevalin™) and I-131 tositumomab (Bexxar™). Radiation therapy effects are due to beta emissions with path lengths of 1–5 mm; gamma radiation emitted by I-131 is the only radiation safety issue for either product. Dose-limiting toxicity for both radiolabelled antibodies is reversible bone marrow suppression. They produce response rates of 70%–90% in low-grade and follicular lymphoma and 40%–50% in transformed low-grade or intermediate-grade lymphomas. Both products produce higher response rates than related unlabelled antibodies, and both are highly active in patients who are relatively resistant to rituximab-based therapy. Median duration of response to a single course of treatment is about 1 year with complete remission rates that last 2 years or longer in about 25% of patients. Clinical trials suggest that anti- CD20 radioimmunotherapy is superior to total body irradiation in patients undergoing stem cell supported therapy for B-cell lymphoma, and that it is a safe and efficacious modality when used as consolidation therapy following chemotherapy. Among cytotoxic treatment options, current evidence suggests that one course of anti-CD20 radioimmunotherapy is as efficacious as six to eight cycles of combination chemotherapy. A major question that persists is how effective these agents are in the setting of rituximab- refractory lymphoma. These products have been underutilised because of the complexity of treatment coordination and concerns regarding reimbursement