Formulation and evaluation of poly (L-lactide-co-ε-caprolactone) loaded gliclazide biodegradable nanoparticles as a control release carrier

A biodegradable nanoparticle has been used frequently as drug delivery carrier due to its better encapsulation capacity, sustained/ control release property and less toxicity. Gliclazide (GLZ) is a second generation of hypoglycemic sulfonylurea and acts selectively on pancreatic ß cell to control diabetes mellitus. The objective of this study was to produce controlled release nanoparticles of Gliclazide using poly (L-lactide-co-ε-caprolactone) (PLCL). The method was optimized using design of experiments by employing a 3-factor, 3-level Design Expert (version 8.0.7.1) Statistical Design Software and was subjected to various characterization studies including Field Emission Scanning Electron Microscopy (FE-SEM), X-ray diffraction (XRD), Encapsulation efficiency (%EE), Particle Size Distribution (PSD), etc. Formulated nanoparticles were also subjected to Fourier Transform Infrared Spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC) for studying interaction between drug and polymer and the effect of lyophilization (Freeze Drying) on developed nanoparticles.  The release profiles and encapsulation efficiencies are depended on the concentration of PLCL. These data demonstrated the efficacy of the biodegradable polymeric nanoparticles in controlling the gliclazide drug release profile as novel drug delivery system

Increased S-nitrosylation and proteasomal degradation of caspase-3 during infection contribute to the persistence of adherent invasive escherichia coli (AIEC) in immune cells

Adherent invasive Escherichia coli (AIEC) have been implicated as a causative agent of Crohn's disease (CD) due to their isolation from the intestines of CD sufferers and their ability to persist in macrophages inducing granulomas. The rapid intracellular multiplication of AIEC sets it apart from other enteric pathogens such as Salmonella Typhimurium which after limited replication induce programmed cell death (PCD). Understanding the response of infected cells to the increased AIEC bacterial load and associated metabolic stress may offer insights into AIEC pathogenesis and its association with CD. Here we show that AIEC persistence within macrophages and dendritic cells is facilitated by increased proteasomal degradation of caspase-3. In addition S-nitrosylation of pro- and active forms of caspase-3, which can inhibit the enzymes activity, is increased in AIEC infected macrophages. This S-nitrosylated caspase-3 was seen to accumulate upon inhibition of the proteasome indicating an additional role for S-nitrosylation in inducing caspase-3 degradation in a manner independent of ubiquitination. In addition to the autophagic genetic defects that are linked to CD, this delay in apoptosis mediated in AIEC infected cells through increased degradation of caspase-3, may be an essential factor in its prolonged persistence in CD patients

Cost-Effectiveness of a Chemoprophylactic Intervention with Single Dose Rifampicin in Contacts of New Leprosy Patients

In 2008, 249,007 new leprosy patients were detected in the world. It therefore remains necessary to develop new and effective interventions to interrupt the transmission of M. leprae. We assessed the economic benefits of single dose rifampicin (SDR) for contacts as chemoprophylactic intervention in the control of leprosy. The study is based on a large trial including 21,711 contacts of 1,037 patients with newly diagnosed leprosy. We gave a single dose of rifampicin or placebo to contacts and followed them up for four years. The main outcome measure was the development of clinical leprosy. The cost effectiveness was expressed in US dollars per prevented leprosy case. Chemoprophylaxis with SDR for preventing leprosy among contacts of leprosy patients is cost-effective at all contact levels and thereby a cost-effective prevention strategy. In total $6,009 was invested and 38 leprosy cases were prevented after 2 years, costing$158 per prevented leprosy case. Implementation studies are necessary to establish whether this intervention is acceptable and feasible in other leprosy endemic areas of the world

Patterns of mandibular invasion in oral squamous cell carcinoma of the mandibular region

BACKGROUND: Mandibular resections are routinely carried out for achieving a R0 resection for oral cancers. However, the need of mandibular resection to achieve this has always been questioned. The present study was carried out to define the pattern of mandibular involvement in carcinoma of the mandibular region. PATIENTS AND METHODS: A total of 25 consecutive patients who had undergone mandibular resection and were found to have mandibular invasion were studied in a prospective open fashion. After decalcification the specimens were serially sectioned at 1 cm interval to identify invasion of mandibular bone. Type of invasion, route of spread and host cell reactions were also recorded. RESULTS: The mandibular involvement was infiltrative in 14(56%) and erosive in 11(44%). It was cortical in 5(20%), marrow involvement was seen in 15(60%) while 5(20%) had spread through the inferior alveolar canal. Of the 25, 24(96%) lesions were located with in 1 cm of the mandible. CONCLUSION: The possibility of mandibular involvement is higher in patients where tumours are located with in 1 cm of the mandible. Involvement of mandible through the canal of inferior alveolar nerve in the present study was relatively high (20%). Therefore it is recommended that before a decision is taken to preserve the mandible it should be thoroughly screened for possible involvement

Inner-sphere oxidation of ternary iminodiacetatochromium(III) complexes involving DL-valine and L-arginine as secondary ligands. Isokinetic relationship for the oxidation of ternary iminodiacetato-chromium(III) complexes by periodate

<p>Abstract</p> <p>Background</p> <p>In this paper, the kinetics of oxidation of [Cr^III(HIDA)(Val)(H₂O)₂]⁺and [Cr^III(HIDA)(Arg)(H₂O)₂]⁺(HIDA = iminodiacetic acid, Val = DL-valine and Arg = L-arginine) were studied. The choice of ternary complexes was attributed to two considerations. Firstly, in order to study the effect of the secondary ligands DL-valine and L-arginine on the stability of binary complex [Cr^III(HIDA)(IDA)(H₂O)] towards oxidation. Secondly, transition metal ternary complexes have received particular focus and have been employed in mapping protein surfaces as probes for biological redox centers and in protein capture for both purification and study.</p> <p>Results</p> <p>The results have shown that the reaction is first order with respect to both [IO₄^-] and the complex concentration, and the rate increases over the pH range 2.62 – 3.68 in both cases. The experimental rate law is consistent with a mechanism in which both the deprotonated forms of the complexes [Cr^III(IDA)(Val)(H₂O)₂] and [Cr^III(IDA)(Arg)(H₂O)₂] are significantly more reactive than the conjugate acids. The value of the intramolecular electron transfer rate constant for the oxidation of [Cr^III(HIDA)(Arg)(H₂O)₂]⁺, <it>k</it>₃(1.82 × 10^-3s^-1), is greater than the value of <it>k</it>₁(1.22 × 10^-3s^-1) for the oxidation of [Cr^III(HIDA)(Val)(H₂O)₂]⁺at 45.0°C and <it>I </it>= 0.20 mol dm^-3. It is proposed that electron transfer proceeds through an inner-sphere mechanism <it>via </it>coordination of IO₄^-to chromium(III).</p> <p>Conclusion</p> <p>The oxidation of [Cr^III(HIDA)(Val)(H₂O)₂]⁺and [Cr^III(HIDA)(Arg)(H₂O)₂]⁺by periodate may proceed through an inner-sphere mechanism via two electron transfer giving chromium(VI). The value of the intramolecular electron transfer rate constant for the oxidation of [Cr^III(HIDA)(Arg)(H₂O)₂]⁺, <it>k</it>₃, is greater than the value of <it>k</it>₁for the oxidation of [Cr^III(HIDA)(Val)(H₂O)₂]⁺. A common mechanism for the oxidation of ternary iminodiacetatochromium(III) complexes by periodate is proposed, and this is supported by an excellent isokinetic relationship between ΔH* and ΔS* values for these reactions.</p

Biosynthesis of Gold Nanoparticles by Foliar Broths: Roles of Biocompounds and Other Attributes of the Extracts

Biosynthesis of nanoparticles has arisen as a promising alternative to conventional synthetic methodologies owing to its eco-friendly advantages, and the involved bioprotocol still needs further clarification. This research, for the first time from the standpoint of statistics, confirmed an electrostatic force or ionic bond-based interaction between the chloroauric ions and the involved bioconstituents and manifested that reducing sugars and flavonoids were both important reductants responsible for conversion of Au(III) to Au(0). The result also demonstrated that the proteins were not the reducing agents, yet they might be protection agents in biosynthesis of gold nanoparticles (GNPs). Besides, a significant linear relationship was found between the anti-oxidant ability of the foliar broths and their capability to reduce Au(III) into Au(0). Furthermore, the preliminary investigation based on the boxplot on the size/shape distribution of the biosynthesized GNPs revealed that gold nanospheres with higher degree of homogeneity in size tended to be promoted by foliar broths containing higher content of reducing sugars/flavonoids and proteins. Otherwise, i.e., for those broths with lower content of the above biocompounds, sphere GNPs of wider size distribution or even gold nanotriangles tended to be fabricated

Plasmodium vivax: paroxysm-associated lipids mediate leukocyte aggregation

<p>Abstract</p> <p>Background</p> <p>Paroxysms are recurrent febrile episodes, characteristic of <it>Plasmodium vivax </it>infections, which coincide with the rupture of schizont-infected erythrocytes in the patients' circulation. The present study describes the formation of prominent aggregates of leukocytes <it>in vitro </it>in the presence of parasite and host factors released during paroxysms.</p> <p>Methods</p> <p>Whole blood cells from uninfected malaria-naïve donors were incubated with plasma taken during a paroxysm or normal human plasma as a control and cell smears were observed under the microscope for the presence of leukocyte aggregates. Plasma factors involved in mediating the leukocyte aggregation were identified using immune depletion and reconstitution experiments. Furthermore, biochemical characterization was carried out to determine the chemical nature of the active moieties in plasma present during paroxysms.</p> <p>Results</p> <p>Leukocyte aggregates were seen exclusively when cells were incubated in plasma collected during a paroxysm. Immune depletion and reconstitution experiments revealed that the host cytokines TNF-alpha, GM-CSF, IL-6 and IL-10 and two lipid fractions of paroxysm plasma comprise the necessary and sufficient mediators of this phenomenon. The two lipid components of the paroxysm plasmas speculated to be of putative parasite origin, were a phospholipid-containing fraction and another containing cholesterol and triglycerides. The phospholipid fraction was dependent upon the presence of cytokines for its activity unlike the cholesterol/triglyceride-containing fraction which in the absence of added cytokines was much more active than the phospholipids fraction. The biological activity of the paroxysm plasmas from non-immune patients who presented with acute <it>P. vivax </it>infections was neutralized by immune sera raised against schizont extracts of either <it>P. vivax </it>or <it>Plasmodium falciparum</it>. However, immune sera against <it>P. vivax </it>were more effective than that against <it>P. falciparum </it>indicating that the parasite activity involved may be antigenically at least partially parasite species-specific.</p> <p>Conclusion</p> <p>Leukocyte aggregation was identified as associated with paroxysms in <it>P. vivax </it>infections. This phenomenon is mediated by plasma factors including host-derived cytokines and lipids of putative parasite origin. The characteristics of the phospholipid fraction in paroxysm plasma are congruent with those of the parasite-derived, TNF-inducing GPI moieties described by others. The more active cholesterol/triglyceride(s), however, represent a novel malarial toxin, which is a new class of biologically active lipid associated with the paroxysm of <it>P. vivax </it>malaria.</p

Conditional Transgenesis Using Dimerizable Cre (DiCre)

Cre recombinase is extensively used to engineer the genome of experimental animals. However, its usefulness is still limited by the lack of an efficient temporal control over its activity. We have recently developed a conceptually new approach to regulate Cre recombinase, that we have called Dimerizable Cre or DiCre. It is based on splitting Cre into two inactive moieties and fusing them to FKBP12 (FK506-binding protein) and FRB (binding domain of the FKBP12-rapamycin associated protein), respectively. These latter can be efficiently hetero-dimerized by rapamycin, leading to the reinstatement of Cre activity. We have been able to show, using in vitro approaches, that this ligand-induced dimerization is an efficient way to regulate Cre activity, and presents a low background activity together with a high efficiency of recombination following dimerization. To test the in vivo performance of this system, we have, in the present work, knocked-in DiCre into the Rosa26 locus of mice. To evaluate the performance of the DiCre system, mice have been mated with indicator mice (Z/EG or R26R) and Cre-induced recombination was examined following activation of DiCre by rapamycin during embryonic development or after birth of progenies. No recombination could be observed in the absence of treatment of the animals, indicating a lack of background activity of DiCre in the absence of rapamycin. Postnatal rapamycin treatment (one to five daily injection, 10 mg/kg i.p) induced recombination in a number of different tissues of progenies such as liver, heart, kidney, muscle, etc. On the other hand, recombination was at a very low level following in utero treatment of DiCre×R26R mice. In conclusion, DiCre has indeed the potentiality to be used to establish conditional Cre-deleter mice. An added advantage of this system is that, contrary to other modulatable Cre systems, it offers the possibility of obtaining regulated recombination in a combinatorial manner, i.e. induce recombination at any desired time-point specifically in cells characterized by the simultaneous expression of two different promoters

Uncharted waters: rare and unclassified cardiomyopathies characterized on cardiac magnetic resonance imaging

Cardiac magnetic resonance imaging (CMR) has undergone considerable technology advances in recent years, so that it is now entering into mainstream cardiac imaging practice. In particular, CMR is proving to be a valuable imaging tool in the detection, morphological assessment and functional assessment of cardiomyopathies. Although our understanding of this broad group of heart disorders continues to expand, it is an evolving group of entities, with the rarer cardiomyopathies remaining poorly understood or even unclassified. In this review, we describe the clinical and pathophysiological aspects of several of the rare/unclassified cardiomyopathies and their appearance on CMR

Comparison of glucosamine sulfate and a polyherbal supplement for the relief of osteoarthritis of the knee: a randomized controlled trial [ISRCTN25438351]

<p>Abstract</p> <p>Background</p> <p>The efficacy and safety of a dietary supplement derived from South American botanicals was compared to glucosamine sulfate in osteoarthritis subjects in a Mumbai-based multi-center, randomized, double-blind study.</p> <p>Methods</p> <p>Subjects (n = 95) were screened and randomized to receive glucosamine sulfate (n = 47, 1500 mg/day) or reparagen (n = 48, 1800 mg/day), a polyherbal consisting of 300 mg of vincaria (<it>Uncaria guianensis</it>) and 1500 mg of RNI 249 (<it>Lepidium meyenii</it>) administered orally, twice daily. Primary efficacy variable was response rate based on a 20% improvement in WOMAC pain scores. Additional outcomes were WOMAC scores for pain, stiffness and function, visual analog score (VAS) for pain, with assessments at 1, 2, 4, 6 and 8 weeks. Tolerability, investigator and subject global assessments and rescue medication consumption (paracetamol) were measured together with safety assessments including vital signs and laboratory based assays.</p> <p>Results</p> <p>Subject randomization was effective: age, gender and disease status distribution was similar in both groups. The response rates (20% reduction in WOMAC pain) were substantial for both glucosamine (89%) and reparagen (94%) and supported by investigator and subject assessments. Using related criteria response rates to reparagen were favorable when compared to glucosamine. Compared to baseline both treatments showed significant benefits in WOMAC and VAS outcomes within one week (P < 0.05), with a similar, progressive improvement over the course of the 8 week treatment protocol (45–62% reduction in WOMAC or VAS scores). Tolerability was excellent, no serious adverse events were noted and safety parameters were unchanged. Rescue medication use was significantly lower in the reparagen group (p < 0.01) at each assessment period. Serum IGF-1 levels were unaltered by treatments.</p> <p>Conclusion</p> <p>Both reparagen and glucosamine sulfate produced substantial improvements in pain, stiffness and function in subjects with osteoarthritis. Response rates were high and the safety profile was excellent, with significantly less rescue medication use with reparagen. Reparagen represents a new natural productive alternative in the management of joint health.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN25438351.</p