Withanolide A series steroidal lactones from Eucalyptus globulus bark

A new steroidal lactone of the Withanolide A series has been isolated from the supercritical fluid extract of Eucalyptus globulus L. (bark) as a major component (I) along with a known structurally similar steroidal lactone as minor component (II). The structural identification of the new lactone was accomplished by different spectroscopic techniques viz. ¹H and ¹³C NMR, etc. The relative stereochemistry was unequivocally determined from the X-ray crystallography.     

Molecular dynamics simulation of drug uptake by polymer

Drug uptake by polymer was modeled using a molecular dynamics (MD) simulation technique. Three drugs—doxorubicin (water soluble), silymarin (sparingly water soluble) and gliclazide (water insoluble)—and six polymers with varied functional groups—alginic acid, sodium alginate, chitosan, Gantrez AN119 (methyl-vinyl–ether-co-malic acid based), Eudragit L100 and Eudragit RSPO (both acrylic acid based)—were selected for the study. The structures were modeled and minimized using molecular mechanics force field (MM+). MD simulation (Gromacs-forcefield, 300 ps, 300 K) of the drug in the vicinity of the polymer molecule in the presence of water molecules was performed, and the interaction energy (IE) between them was calculated. This energy was evaluated with respect to electric-dipole, van der Waals and hydrogen bond forces. A good linear correlation was observed between IE and our own previous data on drug uptake^* [R ² = 0.65, R_adj² = 0.65,R_pre² = 0.56, {\hbox{R}}_{\rm{adj}}^2 = 0.65,{\hbox{R}}_{\rm{pre}}^2 = 0.56, and a F ratio of 30.25, P < 0.001; Devarajan et al. (2005) J Biomed Nanotechnol 1:1–9]. Maximum drug uptake by the polymeric nanoparticles (NP) was achieved in water as the solvent environment. Hydrophilic interaction between NP and water was inversely correlated with drug uptake. The MD simulation method provides a reasonable approximation of drug uptake that will be useful in developing polymer-based drug delivery systems.     

Impact of specialist follow-up in outpatients with congestive heart failure

Background

There is uncertainty about whether physician specialty influences the outcomes of outpatients with congestive heart failure after adjustment for differences in case mix. Our objective was to determine the impact of physician specialty on outcomes in outpatients with new-onset congestive heart failure.

Methods

The study was a population-based retrospective cohort study involving patients with new-onset congestive heart failure discharged from 128 acute care hospitals in Alberta between Apr. 1, 1998, and July 1, 2000. Outcomes were resource utilization (clinic visits, emergency department visits and hospital admissions) and survival at 30 days and 1 year.

Results

A total of 3136 patients were discharged from hospital with a new diagnosis of congestive heart failure (median age 76 years, 50% men). Of these, 1062 (34%) received no follow-up visits for cardiovascular care, 738 (24%) were seen by a family physician (FP) alone, 29 (1%) by a specialist (cardiologist or general internist) alone and 1307 (42%) by both a specialist and an FP. Compared with patients who received no follow-up cardiovascular care, patients who received regular cardiovascular follow-up visits with a physician had fewer visits to the emergency department (38% v. 80%), fewer were admitted to hospital (13% v. 94%), and the adjusted 1-year mortality was lower (22% v. 37%) (all p < 0.001). Compared with patients who received combined specialist and FP care, patients cared for exclusively by FPs had fewer outpatient visits (median 9 v. 17 in the first year), fewer of these patients presented to the emergency department (24% v. 45% in the first year), and fewer were readmitted for cardiovascular care (7% v. 16%) (all p < 0.001). However, the adjusted mortality at 1 year was lower among patients treated with combined care (17% v. 28%, p < 0.001) despite a higher burden of comorbidities. In a multivariate model adjusting for comorbidities (with no cardiovascular follow-up visits as the reference category), the mortality was lower among patients followed on an outpatient basis by an FP alone (odds ratio [OR] 0.66, 95% confidence interval [CI] 0.53–0.82) or by an FP and a specialist (OR 0.34, 95% CI 0.28–0.42). In a proportional hazards model with time-dependent covariates (with adjustment for frequency of follow-up visits), the risk of all-cause mortality was reduced significantly (hazard ratio 0.98, 95% CI 0.97– 0.99) with each specialist visit compared with FP care alone.

Interpretation

Patients with congestive heart failure followed by both specialists and FPs had significantly better survival than those followed by FPs alone (or those who received no specific cardiovascular follow-up care). Methods to improve timely and appropriate access to specialists and to improve collaborative care structures are needed.Congestive heart failure (CHF) afflicts up to 2% of North American adults and, despite many advances in diagnosis and therapy, still portends a poor prognosis, with 1-year mortality of 30%–50%.^1,2,3,4,5 Although the prognosis of patients with CHF is poor even with optimal management, suboptimal diagnosis, investigation and treatment of heart failure and comorbidities (e.g., coronary artery disease) in community-dwelling patients contributes to poor survival.^6,7,8,9In previous studies hospital inpatients with CHF who were cared for by specialists received more evidence-based therapies and had better outcomes than those cared for by nonspecialists.^{8,10,11,12,13} However, none of these studies examined the care delivered after discharge from hospital. Although management in specialized multidisciplinary clinics is associated with better outcomes,¹⁴ it is unclear whether similar benefits can be expected when patients are cared for by specialist physicians operating outside the setting of a multidisciplinary clinic. Two recent studies from the United States that reported better outcomes with specialist care^7,15 were flawed, in that neither study adjusted for frequency of outpatient visits or the possibility of time-dependent bias¹⁶ (whereby some variables, including the number of visits, will change over time).To address this important public health issue, we sought to determine whether there is a relation between ambulatory care follow-up and outcomes in patients with new-onset CHF.     

Downregulation of calcineurin activity in cervical carcinoma

Background  

Calcineurin (CaN) is an important serine-threonine phosphatase (PP2B), which plays a crucial role in calcium-calmodulin mediated signal transduction events. Calcineurin has been implicated in pathogenesis of various diseases cardiac hypertrophy, diabetic neuropathy and Alzheimer's, however its role in neoplasia remains unclear.     

Berberine chloride causes a caspase-independent,apoptotic-like death in Leishmania donovani promastigotes

Berberine chloride, a quarternary isoquinoline alkaloid, is a promising anti-leishmanial compound, IC₅₀ being 7.1 µM in L. donovani promastigotes. This leishmanicidal activity was initiated by its pro-oxidant effect, evidenced by enhanced generation of reactive oxygen intermediates that was accompanied by depletion of thiols; pre-incubation in N-acetyl cysteine, attenuated its cell viability, corroborating that generation of free radicals triggered its parasiticidal activity. Externalization of phosphatidylserine and elevation of intracellular calcium preceded depolarization of the mitochondrial membrane potential, which translated into an increase in the sub G₀/G₁ population and was accompanied by DNA laddering, hallmarks of apoptosis. Berberine chloride failed to induce caspase activity and anti-leishmanial activity in the presence of a pan caspase inhibitor, Z-Val-Ala-DL-Asp (methoxy)-fluoromethylketone remained unchanged, which indicated that the apoptosis was caspase independent. Collectively, the data indicates that Berberine chloride triggers an apoptosis-like death following enhanced generation of reactive oxygen species, thus meriting further pharmacological investigations.     

Analysis of mitochondrial genome revealed a rare 50 bp deletion and substitutions in a family with hypertension

We have sequenced the complete mtDNA of a family with hypertension (HT), type 2 diabetes (T2D) and coronary artery disease (CAD). Our analysis revealed two novel mutations (C3519T, G13204A); of which G13204A replaces valine to isoleucine. In silico analysis of a rare missense mutation (T8597C) showed a deleterious effect. We also observed a 50 bp deletion (m.298_347del50) in the hypervariable region II (HVSII) of all the individuals, who had a common maternal lineage. This (50 bp) deletion was not found in 17,785 individuals from different ethnic populations of India or in a variety of different disease phenotypes. We predict that the mtDNA mutations might be responsible for the HT. Analysis of POLG (polymerase gamma) gene revealed 14 variants which might be responsible for some of the mtDNA mutations seen in this family.     

Isthmin is a novel secreted angiogenesis inhibitor that inhibits tumour growth in mice

Anti‐angiogenesis represents a promising therapeutic strategy for the treatment of various malignancies. Isthmin (ISM) is a gene highly expressed in the isthmus of the midbrain–hindbrain organizer in Xenopus with no known functions. It encodes a secreted 60 kD protein containing a thrombospondin type 1 repeat domain in the central region and an adhesion‐associated domain in MUC4 and other proteins (AMOP) domain at the C‐terminal. In this work, we demonstrate that ISM is a novel angiogenesis inhibitor. Recombinant mouse ISM inhibited endothelial cell (EC) capillary network formation on Matrigel through its C‐terminal AMOP domain. It also suppressed vascular endothelial growth factor (VEGF)‐basic fibroblast growth factor (bFGF) induced in vivo angiogenesis in mouse. It mitigated VEGF‐stimulated EC proliferation without affecting EC migration. Furthermore, ISM induced EC apoptosis in the presence of VEGF through a caspase‐dependent pathway. ISM binds to αvβ5 integrin on EC surface and supports EC adhesion. Overexpression of ISM significantly suppressed mouse B16 melanoma tumour growth through inhibition of tumour angiogenesis without affecting tumour cell proliferation. Knockdown of isthmin in zebrafish embryos using morpholino antisense oligonucleotides led to disorganized intersegmen‐tal vessels in the trunk. Our results demonstrate that ISM is a novel endogenous angiogenesis inhibitor with functions likely in physiological as well as pathological angiogenesis.