Rapid virological response as a predictor of sustained response in HCV-infected patients with persistently normal alanine aminotransferase levels: A multicenter study.

Rapid virological response (RVR) is now considered the strongest predictor of sustained virological response (SVR) in patients with HCV undergoing antiviral treatment, and thus, shorter antiviral treatment for these patients has been suggested. However, no data exist on the predictive value of RVR in HCV carriers with normal ALT values. A total of 137 patients with persistently normal ALT treated with peginterferon alfa 2a and ribavirin were studied. Fifteen patients dropped out early because of side effects, and in 10 patients with HCV-1 treatment was discontinued because of lack of early virological response (EVR). RVR was observed in 68% of the patients (42% patients with HCV-1, 90% HCV-2 and 64% HCV-3). An end-of-treatment response was observed in 86% of the patients (68% HCV-1, 100% HCV-2 and 91% HCV-3). SVR was maintained in 91 patients (46% HCV-1, 97% HCV-2 and 82% HCV-3). Overall, 92% patients with rapid response did obtain HCV eradication vs only 38% of those without rapid response. HCV-1 patients with baseline HCV RNA <400×10(3) IU/mL were more likely to achieve RVR and SVR than those with higher HCV RNA levels. We conclude that patients with genotype 1 and normal ALT who achieve HCV RNA negativity at week 4 may have a higher probability of eradicating their infection. Because of the concomitant favourable demographic and virological features often found in this particular subset of patients, the duration of therapy in these people might be shortened in the case of RVR. Persistently normal alanine aminotransferase levels patients with genotype 2 or 3 have a high chance of achieving SVR, so retesting of HCV RNA during treatment may have no additional practical value in these subjects.

Bioabsorbable scaffold for in situ bone regeneration.

A non-porous poly-DL-lactide tubular chamber filled by demineralised bone matrix (DBM) and bone marrow stromal cells (BMSC) in combination, was evaluated as a scaffold for guided bone regeneration (GBR) in an experimental model using the rabbit radius. The tubular chamber had an internal diameter of 4.7 mm, a wall thickness of 0.4 mm and a length of 18 mm. Autologous BMSC were obtained, under general anaesthesia from rabbit iliac crest and isolated by centrifugation technique. Allogenic DBM was obtained from cortico-cancellous bone of rabbits. In general anaesthesia, a 10-mm defect was bilaterally created in the radii of 10 rabbits. On the right side (experimental side) the defect was bridged with the chamber filled with both BMSC and DBM. On the left side (control side) the defect was treated by positioning DBM and BMSC between the two stumps. At an experimental time of 4 months histology and histomorphometry demonstrated that the presence of a tubular chamber significantly improved bone regrowth in the defect The mean thickness of newly-formed bone inside the chamber was about 56.7+/-3.74% of the normal radial cortex, in comparison with 46.7+/-10.7% when DBM and BMSC without the chamber were placed in the defect, P<0.05). These results confirmed the effectiveness of the chamber as a container for factors promoting bone regeneration.

Osteoporosis and biomaterial osteointegration.

Biomaterial osteointegration depends not only on the properties of the implanted material but also on the characteristics and regenerative capability of the host bone. For this reason, researchers involved in biomaterial evaluation now place great importance on the various pathologies often present in orthopaedic patients which can negatively affect the success of surgical implants. Osteoporosis is undoubtedly one of the most frequently encountered of such diseases. Models reproducing the osteoporotic condition can be useful to understand the influence of the pathology on cell behaviour, bone regeneration and osteointegration processes, thus increasing our basic knowledge and allowing the development of surgical techniques and implant biomaterials more suitable for use in the surgical treatment of fractures in osteoporotic patients. The present paper is a literature review and, after a short description of how the presence of osteoporosis could influence bone regenerative processes, the results of the main studies on biomaterial biocompatibility and osteointegration both in vitro and in vivo in the presence of osteoporotic condition are reported. Both cell cultures and animal models are able to demonstrate the different response of bone to biomaterials by comparing healthy and pathological conditions. The use of pathological bone-derived cells and pathological animals is therefore recommended to test candidate orthopaedic materials.

New polymers for drug delivery systems in orthopaedics: in vivo biocompatibility evaluation.

The use of biodegradable polymers for drug delivery systems excluded the need for a second operation to remove the carrier. However, the development of an avascular fibrous capsule, reducing drug release, has raised concern about these polymers in terms of tissue-implant reaction. Five novel polymers were evaluated in vivo after implantation in the rat dorsal subcutis and compared to the reference polycaprolactone (PCL). Poly(cyclohexyl-sebacate) (PCS), poly(L-lactide-b-1,5-dioxepan-2-one-b-L-lactide) (PLLA-PDXO-PLLA), two 3-hydroxybutyrate-co-3-hydroxyvalerate copolymers (D400G and D600G), and a poly(organo)phosphazene (POS-PheOEt:Imidazole) specimens were histologically evaluated in terms of the inflammatory tissue thickness and vascular density at 4 and 12 weeks from surgery. The highest values of inflammatory tissue thickness were observed in D600G (P < 0.01), PCS (P < 0.001) and PLLA-PDXO-PLLA (P < 0.001) at 4 weeks, while POP-PheOEt:Imidazole showed the lowest value of inflammatory tissue thickness (P < 0.05) at 12 weeks. D400G, D600G, PLLA-PDXO-PPLA and POP-PheOEt:Imidazole showed higher (P < 0.001) values of vascular density near the implants in comparison to PCL at 4 weeks. Finally, D400G and D600G increased their vessel densities while POP-PheOEt:Imidazole and the synthetic polyester PLLA-PDXO-PLLA presented similar vessel density values during experimental times. These different behaviours to improve neoangiogenesis without severe inflammatory tissue-responses could be further investigated with drugs in order to obtain time-programmable drug delivery systems for musculoskeletal therapy.

Open circuit mouthpiece ventilation: Concise clinical review.

In 2013 new "mouthpiece ventilation" modes are being introduced to commercially available portable ventilators. Despite this, there is little knowledge of how to use noninvasive intermittent positive pressure ventilation (NIV) as opposed to bi-level positive airway pressure (PAP) and both have almost exclusively been reported to have been used via nasal or oro-nasal interfaces rather than via a simple mouthpiece. Non-invasive ventilation is often reported as failing because of airway secretion encumbrance, because of hypercapnia due to inadequate bi-level PAP settings, or poor interface tolerance. The latter can be caused by factors such as excessive pressure on the face from poor fit, excessive oral air leak, anxiety, claustrophobia, and patient-ventilator dys-synchrony. Thus, the interface plays a crucial role in tolerance and effectiveness. Interfaces that cover the nose and/or nose and mouth (oro-nasal) are the most commonly used but are more likely to cause skin breakdown and claustrophobia. Most associated drawbacks can be avoided by using mouthpiece NIV. Open-circuit mouthpiece NIV is being used by large populations in some centers for daytime ventilatory support and complements nocturnal NIV via "mask" interfaces for nocturnal ventilatory support. Mouthpiece NIV is also being used for sleep with the mouthpiece fixed in place by a lip-covering flange. Small 15 and 22mm angled mouthpieces and straw-type mouthpieces are the most commonly used. NIV via mouthpiece is being used as an effective alternative to ventilatory support via tracheostomy tube (TMV) and is associated with a reduced risk of pneumonias and other respiratory complications. Its use facilitates "air-stacking" to improve cough, speech, and pulmonary compliance, all of which better maintain quality of life for patients with neuromuscular diseases (NMDs) than the invasive alternatives. Considering these benefits and the new availability of mouthpiece ventilator modes, wider knowledge of this technique is now warranted. This review highlights the indications, techniques, advantages and disadvantages of mouthpiece NIV.

Effects of phosphatidylserine on p38 mitogen activated protein kinase, cyclic AMP responding element binding protein and nuclear factor-kappaB activation in resting and activated microglial cells.

In the last few years, the interaction between phosphatidylserine (PS), a phospholipid that becomes permanently exposed on the external cell surface in the early phases of apoptosis, and its specific receptor (PtdSerR) has emerged as a crucial event for the engulfing of apoptotic cells and for preventing the acquisition of pro-inflammatory functions by peripheral macrophages. Recently, we demonstrated that PtdSerR is expressed in microglial cultures purified from neonatal rat brain, and that PS-liposomes, used to mimic apoptotic cells, strongly reduce the lipopolysaccharide (LPS)-induced release of inflammatory mediators. Here, we show that in resting microglia, PS-liposomes induce cyclic AMP responding element binding protein (CREB) phosphorylation but do not activate nuclear factor-kappaB (NF-kappaB) and p38 mitogen-activated protein kinase (p38), in line with the non-inflammatory consequences of the recognition and removal of apoptotic cells by macrophages. In LPS-activated microglia, PS-liposomes did not affect NF-kappaB activation but inhibited the phosphorylation of p38 and delayed that of CREB. To our knowledge, this is the first biochemical evidence of the molecular signaling evoked by PS/PtdSerR interaction possibly related to repression of pro-inflammatory activities in microglial cells.