Niphatoxin C, a cytotoxic tripyridine alkaloid from Callyspongia sp

As part of our studies to discover P2X 7 receptor antagonists, the sponge Callyspongia sp. was investigated. A new tripyridine alkaloid niphatoxin C ( 1) was isolated and had P2X 7 receptor antagonism; however, cytotoxicity of THP-1 cells was the predominant biological effect at higher concentrations. Its structure was determined by 1- and 2-D NMR spectroscopy.     

Urinary biomarkers of IgA nephropathy and other IgA-associated renal diseases

IgA nephropathy is the most common primary glomerulonephritis and is a frequent cause for chronic kidney disease in children and young adults. Glomerular deposition of IgA also characterizes other renal disorders, including Henoch-Schoenlein purpura nephritis and immune-complex glomerulonephritis afflicting patients with liver disease due to chronic infection with the hepatitis C virus. Several treatment options are often considered, with the goal to prevent end-stage renal failure. Unfortunately, the diagnosis currently requires an invasive procedure, a renal biopsy. Because of the inherent risks, repetitive renal biopsy is frequently foregone as a means to monitor the clinical course or response to treatment. Recent advances in the analysis of the urinary proteome suggest that the excreted polypeptides include disease-specific patterns. We review recent studies of the various techniques for the identification and validation of such urinary biomarkers of IgA-associated glomerulonephritides. Currently, capillary electrophoresis coupled with mass spectrometry (MS) offers the greatest promise. To date, it seems more likely that disease-specific urinary polypeptide biomarkers are comprised of a panel of several distinct and well-defined peptides rather than a single molecule. Even most patients in clinical remission with normal clinical testing (dipstick urinalysis and quantitative proteinuria) were correctly classified by the pattern of polypeptides identified by capillary electrophoresis coupled with MS. With confirmation and refinement, such urinary testing may provide a tool for the diagnosis and monitoring of patients with IgA-associated renal diseases that is more sensitive than current standard clinical testing and far less risky than renal biopsy.     

Inhibition of atherosclerosis by the serine palmitoyl transferase inhibitor myriocin is associated with reduced plasma glycosphingolipid concentration

Glycosphingolipids (GSL) have been implicated as potential atherogenic lipids. Inhibition of hepatic serine palmitoyl transferase (SPT) reduces plasma sphingomyelin (SM) levels in the absence of changes in cholesterol or triglyceride (TG) concentration and this leads to a reduction of atherosclerosis in apolipoprotein-E gene knockout (apoE(-/-)) mice. The possibility that the reduced atherosclerosis resulting from SPT inhibition is associated with decreases in plasma GSL concentration has not been examined and was the primary aim of this investigation. We show that intraperitoneal delivery of the SPT inhibitor myriocin for 9 weeks inhibits atherosclerosis in apoE(-/-) mice fed a high fat diet. Lesion inhibition was most pronounced at the aortic arch and distal sites of the thoracic and abdominal aorta. There was also a trend towards a reduction in lesion area at the aortic root. Myriocin treatment resulted in significant reductions in both plasma SM and GSL concentration of 42% and 25%, as assessed by enzymatic and HPLC methods, respectively. Moreover, SM and GSL concentrations were significantly correlated, indicating that SPT inhibition suppresses the synthesis of both these sphingolipids concomitantly. The inhibition of atherosclerosis induced by myriocin was not associated with changes in plasma cholesterol or TG concentrations or lipoprotein profiles as determined by FPLC. These data indicate that therapeutic reduction of plasma SM and/or GSL concentrations may offer a novel treatment for atherosclerosis.     

The accuracy of combined versus largest diameter in staging multifocal breast cancer

BACKGROUND: Evaluating the size of multifocal breast cancer for staging purposes is problematic. Historically, the largest tumor focus in isolation has been used to stage multifocal disease and determine optimum adjuvant therapy. This study compared multifocal and unifocal breast cancer to determine if multifocal breast cancer presents at a higher stage. STUDY DESIGN: We performed a retrospective review of a prospectively collected database of 328 patients who underwent sentinel lymph node biopsy over a 7-year period. Clinical presentation and histopathologic features of multifocal breast cancer were compared with those of unifocal disease. RESULTS: Fifty-three (16%) patients presented with multifocal disease. Higher tumor grade was observed in the multifocal tumors compared with unifocal tumors (34% versus 20% grade III tumor, multifocal versus unifocal disease; p=0.03). Use of combined tumor focus diameter upstaged (pT status) 18 (34%) patients with multifocal tumors. There was no difference in nodal positivity based on pT status between largest and combined diameter multifocal disease. CONCLUSIONS: Combined tumor diameter in multifocal breast cancer does not correspond with an increase in sentinel node positivity and should not be used for staging purposes.     

Use of nonsteroidal anti-inflammatory drugs in infants. A survey of members of the Association of Paediatric Anaesthetists of Great Britain and Ireland

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used as perioperative analgesics. Many are currently used off label. Diclofenac is currently licensed for use in children over 1 year of age for the treatment of juvenile rheumatoid arthritis, while ibuprofen is licensed for use in children weighing over 7 kg. The dose and interval in children is currently extrapolated from adult studies, as the pharmacokinetic (PK) and pharmacodynamic (PD) data are lacking in infants. METHODS: A postal questionnaire was sent to members of the Association of Paediatric Anaesthetist of Great Britain and Ireland seeking to clarify members' prescribing patterns of NSAIDs, especially in infants. Information regarding the choice of NSAIDS, route of administration, lower age limit, dose interval, dose and practice in two specific perioperative contexts (adenotonsillectomy and open heart surgery) was sought. RESULTS: The response rate was 80%. NSAIDs are used by 86% of responders in infants. Diclofenac is most commonly used intraoperatively (78%); while ibuprofen (73%) was used more frequently postoperatively. NSAIDs are used by 21% of respondents in ICU. Commonest routes of administration were oral (81%) and rectal (80%), rarely intravenously (9%). The commonest dose for diclofena is 1 mg x kg(-1) (59%); the dosing schedule employed being 8 hourly in 53% of cases. NSAIDs are used by 57% of responders as part of their analgesic regime for adenotonsillectomies. CONCLUSION: Members of the Association of Paediatric Anaesthetists of Great Britain and Ireland commonly prescribe NSAIDs in infants. This is despite the dearth of PK and PD data in this age group.     

Promoting Recovery and Addressing Stigma: Mental Health Awareness through Community Development in a Low - Income Area

One in four Scots will experience mental ill-health at some point in their lives, with increased prevalence in low-income communities. The associated stigma increases the negative impact on an individual's life. This paper outlines the development of a local anti-stigma programme that can be replicated in other areas, and presents key findings from the evaluation. This innovative model, which promotes recovery and addresses stigma, draws on a broad coalition of community support, and enables service users to lead its design and delivery. The paper argues that local initiatives, when complemented by a national programme, can achieve a positive additional impact on attitudes and behaviours; that multiple and flexible approaches are needed for different target groups; that the personal narrative about recovery has a particularly strong impact on participants; and that it may be desirable to tackle stigma in the context of addressing positive mental health. Refinements to the model are discussed.     

Metabolic activity diffusion imaging (MADI): II. Noninvasive,high-resolution human brain mapping of sodium pump flux and cell metrics

We introduce a new ¹H₂O magnetic resonance approach: metabolic activity diffusion imaging (MADI). Numerical diffusion-weighted imaging decay simulations characterized by the mean cellular water efflux (unidirectional) rate constant (k_io), mean cell volume (V), and cell number density ( ρ ) are produced from Monte Carlo random walks in virtual stochastically sized/shaped cell ensembles. Because of active steady-state trans-membrane water cycling (AWC), k_io reflects the cytolemmal Na⁺, K⁺ATPase (NKA) homeostatic cellular metabolic rate (^cMR_NKA). A digital 3D “library” contains thousands of simulated single diffusion-encoded (SDE) decays. Library entries match well with disparate, animal, and human experimental SDE decays. The V and ρ values are consistent with estimates from pertinent in vitro cytometric and ex vivo histopathological literature: in vivo V and ρ values were previously unavailable. The library allows noniterative pixel-by-pixel experimental SDE decay library matchings that can be used to advantage. They yield proof-of-concept MADI parametric mappings of the awake, resting human brain. These reflect the tissue morphology seen in conventional MRI. While V is larger in gray matter (GM) than in white matter (WM), the reverse is true for ρ . Many brain structures have k_io values too large for current, invasive methods. For example, the median WM k_io is 22s⁻¹; likely reflecting mostly exchange within myelin. The k_io•V product map displays brain tissue ^cMR_NKA variation. The GM activity correlates, quantitatively and qualitatively, with the analogous resting-state brain ¹⁸FDG-PET tissue glucose consumption rate (^tMR_glucose) map; but noninvasively, with higher spatial resolution, and no pharmacokinetic requirement. The cortex, thalamus, putamen, and caudate exhibit elevated metabolic activity. MADI accuracy and precision are assessed. The results are contextualized with literature overall homeostatic brain glucose consumption and ATP production/consumption measures. The MADI/PET results suggest different GM and WM metabolic pathways. Preliminary human prostate results are also presented.