Clinical Evaluation of Perhexiline Maleate in Patients with Angina Pectoris

This paper reports a double-blind trial of a new antianginal drug, perhexiline. Fifty-five patients suffering from angina pectoris were studied for periods of 12 or 24 weeks in a cross-over comparison against a placebo in four centres in the United Kingdom and Ireland. Perhexiline was effective in most patients as judged by reducing the number of anginal attacks in 84% and the consumption of glyceryl trinitrate tablets in 64%. The major side effect, dizziness, noted in one-third of the patients, may be dose/body-weight related. Perhexiline is a valuable new agent for the treatment of patients with angina, especially those who do not respond to other antianginal agents.     

Cerebrospinal Fluid from Sporadic Amyotrophic Lateral Sclerosis Patients Induces Mitochondrial and Lysosomal Dysfunction

In our laboratory, we have developed (1) an in vitro model of sporadic Amyotrophic Lateral Sclerosis (sALS) involving exposure of motor neurons to cerebrospinal fluid (CSF) from sALS patients and (2) an in vivo model involving intrathecal injection of sALS-CSF into rat pups. In the current study, we observed that spinal cord extract from the in vivo sALS model displayed elevated reactive oxygen species (ROS) and mitochondrial dysfunction. Quantitative proteomic analysis of sub-cellular fractions from spinal cord of the in vivo sALS model revealed down-regulation of 35 mitochondrial proteins and 4 lysosomal proteins. Many of the down-regulated mitochondrial proteins contribute to alterations in respiratory chain complexes and organellar morphology. Down-regulated lysosomal proteins Hexosaminidase, Sialidase and Aryl sulfatase also displayed lowered enzyme activity, thus validating the mass spectrometry data. Proteomic analysis and validation by western blot indicated that sALS-CSF induced the over-expression of the pro-apoptotic mitochondrial protein BNIP3L. In the in vitro model, sALS-CSF induced neurotoxicity and elevated ROS, while it lowered the mitochondrial membrane potential in rat spinal cord mitochondria in the in vivo model. Ultra structural alterations were evident in mitochondria of cultured motor neurons exposed to ALS-CSF. These observations indicate the first line evidence that sALS-CSF mediated mitochondrial and lysosomal defects collectively contribute to the pathogenesis underlying sALS.     

Discovery and characterization of [(cyclopentyl)ethyl]benzoic acid inhibitors of microsomal prostaglandin E synthase-1

We describe a novel class of acidic mPGES-1 inhibitors with nanomolar enzymatic and human whole blood (HWB) potency. Rational design in conjunction with structure-based design led initially to the identification of anthranilic acid 5, an mPGES-1 inhibitor with micromolar HWB potency. Structural modifications of 5 improved HWB potency by over 1000×, reduced CYP2C9 single point inhibition, and improved rat clearance, which led to the selection of [(cyclopentyl)ethyl]benzoic acid compound 16 for clinical studies. Compound 16 showed an IC₈₀ of 24 nM for inhibition of PGE₂ formation in vitro in LPS-stimulated HWB. A single oral dose resulted in plasma concentrations of 16 that exceeded its HWB IC₈₀ in both rat (5 mg/kg) and dog (3 mg/kg) for over twelve hours.     

Use of Saccharum spontaneum (wild sugarcane) as biomaterial for cell immobilization and modulated ethanol production by thermotolerant Saccharomyces cerevisiae VS3

Saccharum spontaneum is a wasteland weed consists of 45.10 ± 0.35% cellulose and 22.75 ± 0.28% of hemicellulose on dry solid (DS) basis. Aqueous ammonia delignified S. spontaneum yielded total reducing sugars, 53.91 ± 0.44 g/L (539.10 ± 0.55 mg/g of substrate) with a hydrolytic efficiency of 77.85 ± 0.45%. The enzymes required for hydrolysis were prepared from culture supernatants of Aspergillus oryzae MTCC 1846. A maximum of 0.85 ± 0.07 IU/mL of filter paperase (FPase), 1.25 ± 0.04 IU/mL of carboxy methyl cellulase (CMCase) and 55.56 ± 0.52 IU/mL of xylanase activity was obtained after 7 days of incubation at 28 ± 0.5 °C using delignified S. spontaneum as carbon source under submerged fermentation conditions. Enzymatic hydrolysate of S. spontaneum was then tested for ethanol production under batch and repeated batch production system using “in-situ” entrapped Saccharomyces cerevisiae VS₃ cells in S. spontaneum stalks (1 cm × 1 cm) size. Immobilization was confirmed by the scanning electron microscopy (SEM). Batch fermentation of VS₃ free cells and immobilized cells showed ethanol production, 19.45 ± 0.55 g/L (yield, 0.410 ± 0.010 g/g) and 21.66 ± 0.62 g/L (yield, 0.434 ± 0.021 g/g), respectively. Immobilized VS₃ cells showed maximum ethanol production (22.85 ± 0.44 g/L, yield, 0.45 ± 0.04 g/g) up to 8th cycle during repeated batch fermentation followed by a gradual reduction in subsequent cycles of fermentation.     

Trunk, abdomen, and pressure sore reconstruction

LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Describe the principles of wound closure, torso reconstruction, and pressure sore reconstruction. 2. Outline standard options to treat defects of the chest, abdomen, and back and pressure ulcers in all anatomical areas. 3. Manage and prevent pressure ulcers. SUMMARY: Chest wall reconstruction is indicated following tumor resection, radiation wound breakdown, or intrathoracic sepsis. Principles of wound closure and chest wall stabilization, where indicated, are discussed. Principles of abdominal wall reconstruction continue to evolve with the introduction of newer bioprosthetics and the application of functional concepts for wound closure. The authors illustrate these principles using commonly encountered clinical scenarios and guidelines to achieve predictable results. Pressure ulcers continue to be devastating complications to patients' health and a functional hazard when they occur in the bedridden, in patients with spinal cord injuries, and in patients with neuromuscular disease. Management of pressure ulcers is also very expensive. The authors describe standard options to treat defects of the chest, abdomen, and back and pressure ulcers in all anatomical areas. A comprehensive understanding of principles and techniques will allow practitioners to approach difficult issues of torso reconstruction and pressure sores with a rational confidence and an expectation of generally satisfactory outcomes. With pressure ulcers, prevention remains the primary goal. Patient education and compliance coupled with a multidisciplinary team approach can reduce their occurrence significantly. Surgical management includes appropriate patient selection, adequate débridement, soft-tissue coverage, and use of flaps that will not limit future reconstructions if needed. Postoperatively, a strict protocol should be adapted to ensure the success of the flap procedure. Several myocutaneous flaps commonly used for the surgical management of pressure are discussed. Commonly used flaps in chest and abdominal wall reconstruction are discussed and these should be useful for the practicing plastic surgeon.     

Novel Binding Motif and New Flexibility Revealed by Structural Analyses of a Pyruvate Dehydrogenase-Dihydrolipoyl Acetyltransferase Subcomplex from the Escherichia coli Pyruvate Dehydrogenase Multienzyme Complex

The Escherichia coli pyruvate dehydrogenase multienzyme complex contains multiple copies of three enzymatic components, E1p, E2p, and E3, that sequentially carry out distinct steps in the overall reaction converting pyruvate to acetyl-CoA. Efficient functioning requires the enzymatic components to assemble into a large complex, the integrity of which is maintained by tethering of the displaced, peripheral E1p and E3 components to the E2p core through non-covalent binding. We here report the crystal structure of a subcomplex between E1p and an E2p didomain containing a hybrid lipoyl domain along with the peripheral subunit-binding domain responsible for tethering to the core. In the structure, a region at the N terminus of each subunit in the E1p homodimer previously unseen due to crystallographic disorder was observed, revealing a new folding motif involved in E1p-E2p didomain interactions, and an additional, unexpected, flexibility was discovered in the E1p-E2p didomain subcomplex, both of which probably have consequences in the overall multienzyme complex assembly. This represents the first structure of an E1p-E2p didomain subcomplex involving a homodimeric E1p, and the results may be applicable to a large range of complexes with homodimeric E1 components. Results of HD exchange mass spectrometric experiments using the intact, wild type 3-lipoyl E2p and E1p are consistent with the crystallographic data obtained from the E1p-E2p didomain subcomplex as well as with other biochemical and NMR data reported from our groups, confirming that our findings are applicable to the entire E1p-E2p assembly.