The 'biodrug' concept: an innovative approach to therapy

Cell engineering technology using recombinant microorganisms has created new opportunities in the development of innovative drugs. This article presents the use of living genetically engineered microorganisms, such as bacteria or yeasts, as a new delivery vehicle to the gastrointestinal tract. This 'biodrug' concept was demonstrated using recombinant Saccharomyces cerevisiae expressing the plant cytochrome P450 73A1. This enzyme provides a relevant model for potential therapeutic applications, such as 'biodetoxication' in the digestive environment. An artificial gastrointestinal tract simulating human digestion was chosen as a powerful tool to validate the biodrug concept. This approach offers a novel strategy for drug discovery and testing.     

The lateral forearm flap as a modification of the lateral arm flap: vascular anatomy and clinical implications

The forearm extension of the lateral arm flap was introduced on the basis of the vascular territory of the posterior radial collateral artery extending beyond the elbow into the forearm. However, there is controversy as to whether the posterior radial collateral artery extends as a single trunk below the elbow or if it terminates more proximally with only a rich vascular plexus extending beyond the elbow. The purpose of this study was to revisit the artery's anatomy in the region of the elbow and to study its distribution in the forearm. Using latex and barium-gelatin injections of the posterior radial collateral artery in ten cadaveric upper limbs, it was observed that terminal branching of the artery occurred 4.5 cm proximal to the lateral epicondyle of the humerus. Distal to the epicondyle, the terminal branches of the posterior radial collateral artery were seen to fan out as finely arborized branches supplying the lateral forearm skin. No single, constant vascular trunk to the forearm skin could be identified. Furthermore, in its distribution toward the periphery, the terminal branches of the posterior radial collateral artery took an increasingly superficial course. Proximal to the epicondyle, the vessels lay deep within the subcutaneous fat, whereas distal to the epicondyle, they were very close to skin. These findings suggest that lateral forearm skin cannot be islanded without risk of vascular disruption and that the distally sited flap should include skin proximal to the epicondyle for safety.     

Human pathogens,nosocomial infections,heat-sensitive textile implants,and an innovative approach to deal with them

Implantable polymers, as used for biomedical applications, inherently have to be sterile. Nonetheless, most implants, particularly those comprised of biomaterials developed in recent years for tissue engineering, are heat sensitive. Therefore, use of hazardous (radio)chemicals—due to lack of alternative methods—is still state of the art for sterilization processes. The drawbacks of these techniques, both drastic and well known, lead to the demand for an alternative sterilization method, which is equally obvious and urgent. High-pressure fluid treatment is a low-temperature technique that is already in use for pasteurization of liquid food products. This paper explores inactivation of vegetative microorganisms, spores, and endotoxins adherent to solid surfaces using compressed CO₂. Pressures ranging from 50 to 100 bar and temperatures from 25 °C to 50 °C were explored to investigate liquid, gaseous or supercritical state. Analysis of variance (ANOVA) and statistical modeling were used to identify the optimum parameter settings for inactivation of pathogenic bacteria and fungi (Candida albicans, Staphylococcus aureus). The addition of small amounts of ozone ensures inactivation of persistent spores (Bacillus stearothermophilus, B. subtilis) up to 10⁶ cfu/ml, while endotoxins remain in practically unchanged concentration on the polymer surface. We then discuss environmental issues of the process and inactivation mechanisms. The replacement of conventional chemicals with nonpersistent ones resolves organizational and safety-related issues and protects natural resources as well as handling staff. The pressurized-fluid-based method exhibits mild treatment parameters, thus protecting sensitive textures. Finally, an outlook on possible applications of this innovative technique is presented.     

The correct approach to community-acquired pneumonia in immunocompetent adults: review of current guidelines

Community-acquired pneumonia (CAP) often represents a clinical emergency requiring prompt and adequate antimicrobial treatment. The choice of antimicrobials, however, is difficult due to the variety of potential pathogens and to the spread of drug-resistance. Hence, a correct therapeutic approach should be based on the knowledge of the most frequently reported etiologies for the different clinical conditions, specific patient risk factors and the treatment setting (home, hospital, intensive or non intensive care unit) chosen accordingly. The awareness of the local drug-resistance epidemiology and individual patient characteristics, such as age, history of antibiotic treatments and related adverse events, underlying diseases, concurrent therapies and expected adherence to treatment should also be considered. Lastly, an adequate CAP management should address other issues, including therapy duration, monitoring of its efficacy and adverse effects, and supportive measures. The guidelines for CAP management aim to provide the physician with the necessary knowledge and criteria to assist him in these crucial decisions, and their adoption result in a significant reduction of mortality, frequency and length of hospitalization, and costs. Herein, the authors review and discuss some of the main current guidelines for CAP management, highlighting their differences and similarities.     

The addition of muscle to the lateral arm and radial forearm flaps for wound coverage.

There is good evidence of the benefit of transferring vascularized muscle into wounds that are contaminated or have been infected previously. This benefit particularly applies in cavities around bones and joints. We present two patients in whom the inclusion of a portion of muscle in the lateral arm and radial forearm flaps allowed the effective combination of good-quality skin cover with the properties of vascularized muscle.     

Fasciocutaneous vessels in the upper arm: application to the design of new fasciocutaneous flaps

The principles of the blood supply to the upper arm are described. Despite the large, fleshy nature of the biceps and the triceps, the blood supply to upper arm skin is not from the underlying muscles, but is by fasciocutaneous perforators emerging along the medial and lateral intermuscular septa. Fifty dissections of preserved cadavers have shown that on the lateral side the fasciocutaneous perforators consistently arise from the middle collateral artery. The available length of this vessel and its diameter have been measured and are reported. The design of a flap based on this vessel, in a manner analogous to the Chinese forearm flap on the radial artery, is described.     

Two-dimensional Monte Carlo simulations in LCA: an innovative approach to guide the choice for the environmentally preferable option

The International Journal of Life Cycle Assessment - Uncertainty and variability need to be taken into account in life cycle assessment (LCA) studies to make robust decisions. We introduce a novel...     

The universal tip: a systematic approach to aesthetic problems of the lower lateral cartilages

A systematic approach to the various common aesthetic problems of the lower lateral cartilages is presented. Since this approach and technique may be applied to a wide variety of problems, we have taken the liberty of calling this the universal tip. These concepts have emerged from study of the literature and have evolved over the past thousand rhinoplasties. A classification of lower lateral cartilage problems includes five basic variations: (1) the wide, amphorous, ill-defined tip, (2) insufficient projection of the tip, (3) overprojection of the tip, (4) dependent tip with lack of definition, and (5) asymmetrical tip. It is important to realize that any of these five categories may be found in various combinations with each other. The details and fundamental steps of this universal tip technique are presented along with illustrative case examples in each of the five basic variations. In approximately 4 percent of patients there is a postoperative asymmetry in the position of cartilaginous flaps in the region of the dome of the lower lateral cartilage. These abnormalities plus abnormal ridges or bossa can usually be corrected at the time of secondary surgery under local anesthesia.     

Monoclonal antibodies to rat renal tissue: an approach to the immunohistological analysis of the nephron-collecting duct system, and ultra-structural localization of antigens

Summary To obtain more accurate information on the nephron-collecting duct system, monoclonal antibodies against renal tissue were prepared. BALB/c mice were immunized every two weeks with rat renal tissue, either cortex or medulla. Spleen cells were collected and fused with myeloma cells sensitive to hypoxanthine-aminopterin-thymidine medium. Hybrids were selected for production of antibodies by indirect immunofluorescence and cloned by the limiting dilution method. Tissue reactivity of the antibodies obtained was defined by immunofluorescence. The intracellular localization of antigenic determinants was ascertained by immunoelectron microscopy. The antibodies were classified into four major groups: (1) antibodies against proximal tubules; (2) antibodies against distal tubules and the loop of Henle; (3) antibodies against collecting duct system; and (4) antibodies against glomeruli. Using immunoelectron microscopy, various intracellular antigenic determinants were recognized, such as brush border, apical canaliculi, vacuolar apparatus, luminal and basolateral plasma membranes. The results obtained indicated that electron microscopy is indispensable for the immunohistological study of the nephroncollecting duct system. The observations help to understand morphological and functional diversity of the nephron-collecting duct system.     

The crystal structure of an engineered monomeric triosephosphate isomerase, monoTIM: the correct modelling of an eight-residue loop

BACKGROUND: The triosephosphate isomerase (TIM) fold is found in several different classes of enzymes, most of which are oligomers; TIM itself always functions as a very tight dimer. It has recently been shown that a monomeric form of TIM ('monoTIM') can be constructed by replacing a 15-residue interface loop, loop-3, with an eight-residue fragment; modelling suggests that this should result in a short strain-free turn, resulting in the subsequent helix, helix-A3, having an additional turn at its amino terminus. RESULTS: The crystal structure of monoTIM shows that it retains the characteristic TIM-barrel (betaalpha)8-fold and that the new loop has a structure very close to that predicted. Two other interface loops, loop-1 and loop-4, which contain the active site residues Lys13 and His95, respectively, show significant changes in structure in monoTIM compared with dimeric wild-type TIM. CONCLUSION: The observed structural differences between monoTIM and wild-type TIM indicate that the dimeric appearance of TIM determines the location and conformation of two of the four catalytic residues.     

Restoring the balance of the autonomic nervous system as an innovative approach to the treatment of rheumatoid arthritis

The immunomodulatory effect of the autonomic nervous system has raised considerable interest over the last decades. Studying the influence on the immune system and the role in inflammation of the sympathetic as well as the parasympathetic nervous system not only will increase our understanding of the mechanism of disease, but also could lead to the identification of potential new therapeutic targets for chronic immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA). An imbalanced autonomic nervous system, with a reduced parasympathetic and increased sympathetic tone, has been a consistent finding in RA patients. Studies in animal models of arthritis have shown that influencing the sympathetic (via α- and β-adrenergic receptors) and the parasympathetic (via the nicotinic acetylcholine receptor α7nAChR or by electrically stimulating the vagus nerve) nervous system can have a beneficial effect on inflammation markers and arthritis. The immunosuppressive effect of the parasympathetic nervous system appears less ambiguous than the immunomodulatory effect of the sympathetic nervous system, where activation can lead to increased or decreased inflammation depending on timing, doses and kind of adrenergic agent used. In this review we will discuss the current knowledge of the role of both the sympathetic (SNS) and parasympathetic nervous system (PNS) in inflammation with a special focus on the role in RA. In addition, potential antirheumatic strategies that could be developed by targeting these autonomic pathways are discussed.     

The muscle strength and size response to upper arm, unilateral resistance training among adults who are overweight and obese

Overweight and obesity result in musculoskeletal impairments that limit exercise capacity. We examined if the muscle strength and size response to resistance training (RT) differed among 687 young (mean +/- SEM, 24.2 +/- 0.2 years) overweight and obese (OW) compared to normal weight (NW) adults as denoted by the body mass index (BMI). Subjects were 449 NW (22.0 +/- 0.1 kg.m(-2), 23.4 +/- 0.3 years) and 238 OW (29.2 +/- 0.2 kg.m(-2), 25.6 +/- 0.4 years) men (n = 285) and women (n = 402) who underwent 12 weeks (2 d.wk(-1)) of RT of the nondominant arm. Maximum voluntary contraction (MVC) and 1 repetition maximum (1RM) assessed peak elbow flexor strength. Magnetic resonance imaging measured the biceps muscle cross sectional area (CSA). Multiple dependent variable analysis of covariance tested if muscle strength and size differed among BMI groups pre-, post-, and pre-to-post-RT. Overweight and obese had greater MVC, 1RM, and CSA than NW pre- and post-RT (p < 0.001). Maximum voluntary contraction and 1RM gains were not different between BMI groups pre- to post-RT (p >or= 0.05). When adjusted for baseline values, NW had greater relative MVC (21.2 +/- 1.0 vs. 17.4 +/- 1.4%) and 1RM (54.3 +/- 1.5 vs. 49.0 +/- 2.0%) increases than OW (p < 0.05). Normal weight also had greater allometric MVC (0.48 +/- 0.02 kg.kg(-0.67) vs. 0.40 +/- 0.03 kg.kg(-0.67)) and 1RM (0.25 +/- 0.00 vs. 0.22 +/- 0.01 kg.kg(-0.67)) gains than OW (p < 0.05). CSA gains were greater among OW than NW (3.6 +/- 0.2 vs. 3.2 +/- 0.1 cm(2)) (p < 0.001); however, relative CSA increases were not different between BMI groups (19.4 +/- 0.5 vs. 18.4 +/- 0.7%) (p >or= 0.05). Despite similar relative muscle size increases, relative and allometic strength gains were less among OW than NW. These findings indicate the short-term relative and allometric muscle strength response to RT may be attenuated among adults who are overweight and obese.     

Use of an adipofascial flap based on the proximal perforators of the ulnar artery to correct contracture of elbow burn scars: an anatomic and clinical approach.

Different techniques can be used to repair contracture of burn scars on the elbow, including local or distant pedicle flaps, muscle or myocutaneous flaps, free flaps, and tissue expanders. Among these, a pedicled adipofascial flap based on the most proximal two to four perforators of the ulnar artery (located 1 to 5 cm from the origin of the artery) can be anastomosed to form a sort of axially patterned blood supply within the fascia and subcutaneous fat. Therefore, no major vessel in the forearm need ever be severed. In addition, use of this type of flap preserves muscle function. The pedicled adipofascial flap described in this article allows for early rehabilitation because the flap is thin and pliable. Additional advantages are the easy and quick dissection and completion of the procedure in one stage. A detailed anatomic dissection of the flap was performed on 16 upper extremities from fresh cadavers; an injection study was also performed to determine the location and dimensions of the pedicle flap and its area of reach around the elbow. In the past 3 years, 14 flaps were used in 13 patients to repair elbow defects after release of burn scar contractures. Flap dimensions ranged from 4 x 7 cm to 6 x 14 cm (mean flap size, 74 cm). The results were very satisfactory.