JL was a recipient of a scholarship from

Fondation universitaire Armand-Frappier de l’INRS and a McGill Internal Studentship. M.C.R. is a recipient of a Career Award from FRQS. The funding sources had no involvement in study design, data collection, analysis, interpretation, writing of the report, or in the decision to submit the article for publication. Compilation based on data from the ©Gouvernement du Québec, Institut de la statistique du Québec (ISQ), 2012. ISQ is not responsible for compilations or interpretation of results. “
“Cycling confers individual and population-level health benefits, including benefits from decreased cardiovascular risk, improved mental wellbeing, decreased check details air pollution and decreased exposure to road traffic collisions (de Hartog et al., 2010, Lindsay et al., 2011, Pucher et al., 2010a, Pucher

et al., 2010b, Rojas-Rueda et al., 2011 and Woodcock et al., 2009). Yet levels of cycling in the UK remain low (Department for Transport, 2010). Promoting active travel is now high on the public health agenda (Douglas et al., 2011) and public bicycle sharing schemes have become a popular intervention, with an estimated 375 schemes in 33 countries around Selleck KU57788 the world (Midgley, 2011). In the UK, London’s public bicycle sharing scheme, the Barclays Cycle Hire (BCH) scheme, was introduced by the public body Transport for London in July 2010. At its launch, the scheme comprised 3000 bicycles located at 315 docking stations throughout central London (Transport for London, 2010b). When registering, individuals pay until £3 for a BCH ‘key’ and then choose between 1-day access (£1), 7-day access (£5) or annual access (£45). After paying the access fee trips of under 30 min are free but longer trips incur additional usage charges. Registration was compulsory prior to 3rd December 2010, but since this date non-registered individuals have been able to buy 1-day or 7-day access as pay-as-you-go ‘casual’ users.

A debit or credit card is required to pay for keys, access and usage charges (Transport for London, 2010a). The BCH scheme is one of the Mayor of London’s initiatives to increase London’s modal share of cycling from 2% to 5% by 2026 (Transport for London, 2010b and Transport for London, 2010c). There are, however, concerns that interventions to promote cycling may be inequitable, with levels of cycling uptake in the UK higher amongst affluent white men (Marmot, 2010, Parkin et al., 2008 and Steinbach et al., 2011). While the aim of the BCH scheme was not to reduce inequalities (Transport for London, 2010b and Transport for London, 2010c), it has been argued that the health and equity impacts of all public investment projects should be evaluated (Kahlmeier et al., 2010 and Ståhl et al., 2006). Despite public bicycle sharing schemes existing in many other European and North American cities, evidence reviews have identified few published evaluations (Pucher et al., 2010a, Pucher et al.

S2. The majority had dated health cards available for most of the interviews with the exception of the 2 years interview,

when many cards had been lost or were no longer readable due to wear and tear. Vaccination coverage at the end of follow-up ranged from 80% for the measles vaccine (95% confidence interval 76–83) to 100% for the BCG vaccine (95%CI SP600125 supplier 99–100), see Table 1 and Fig. 1 and Fig. 2, Fig. S3. The vaccination coverage rates for each vaccine at specific ages (3 months, 6 months, 12 months and 18 months) and median delays with inter-quartile ranges (IQR) are available in Table S1. The proportion of infants that had received all the vaccines was 75% (95%CI 71–79), see Fig. 3 which represents cumulative vaccination. The coverage for vitamin A supplementation based on health card information was 84% (95%CI 81–87). Of these, 68% received supplementation together with vaccines – in particular together with the BCG vaccine. Self-reported

information on vitamin A supplementation differed from health card information, with 94% reporting that their children had been given vitamin A. Timely vaccination ranged from 56% for the measles vaccine (95%CI 54–57) to 89% for the BCG vaccine (95%CI 86–91). Among those who were vaccinated late with the measles vaccine, the median age at vaccination was 64 weeks. This is equivalent to a median delay of 24 weeks from the recommended timing (11 Hydroxychloroquine cell line Fossariinae weeks delay from the end of the recommended range.) Only 18% received all the vaccines within the recommended time ranges (95%CI. 15–22). The Cox regression model revealed a dose–response relationship between mother’s education and timely vaccination, both in the univariable analysis and the multivariable models, see Table 2. This association was evident also when using years of schooling as a continuous variable (hazard ratio 0.94 per year of education; 95%CI 0.91–0.97; p < 0.001). Vaccination did not differ between the intervention and control clusters of the

intervention promoting exclusive breastfeeding for 6 months through peer counselling. Although the coverage for the individual EPI vaccines was reasonably high with the exception of the measles vaccine, timely and age-appropriate vaccination was lower. About a quarter of the vaccines were given outside the recommended time ranges. Around 75% of the children received all the recommended vaccines, but only 18% got all vaccines within their recommended time ranges. The coverage rates for the individual vaccines we report were slightly different from the national reported statistics from Uganda in 2008 [18] and [19]. According to these, Mbale District had a coverage rate of 85% for the third oral polio vaccine (compared to our estimate of 93%), which is higher than the national estimate of 79%. For measles, the reported number in Mbale was 105% (compared to our estimate of 80%), with a national estimate of 77%.

In our study, however, participants with stroke did not differ in their views when compared to participants with orthopaedic or other conditions. Participants with stroke were mostly happy with the amount of therapy and equally as likely to want more physiotherapy as patients with orthopaedic or other conditions. Another possible reason that results differ is that participants in our study were Anti-diabetic Compound Library research buy still receiving physiotherapy at the time the interviews were conducted and were not reflecting back after therapy had finished. Participants in our study said they were happy to let their physiotherapists decide how much therapy they received and reported that they trusted

their therapists as experts and had faith that they would do what was best for http://www.selleckchem.com/products/MLN8237.html them. This may be indicative of our sample of older adults who are of the generation who

simply believe that ‘doctor knows best’ (Hovenga and Kidd 2010) in contrast to younger patients who may be less accepting of authority. Some participants who received Monday to Friday therapy were happy with the amount of physiotherapy because they feared they would not be able to cope with any more due to fatigue. Participants who received Saturday physiotherapy were more likely to advocate for even more intensive therapy, possibly due to the fact that they knew they could manage the additional physiotherapy without negative consequences and they had different

expectations of what weekends in rehabilitation should comprise. Quantitative data from an independent group of patients in the same setting (Peiris et al 2012) found those who received extra Saturday therapy were more active over the entire weekend (including Sunday when no therapy was received) than those who did not receive Saturday therapy. This supports the notion that patients who received else Monday to Friday physiotherapy felt it was important to rest on the weekend while those who received extra Saturday therapy had the expectation to keep working on their rehabilitation goals throughout the weekend. Boredom is a common complaint in hospitalised adults (Clissett 2001) and it emerged as a sub-theme in how the participants experienced physiotherapy. Quantitative results (Peiris et al 2012) confirmed that patients were most active during therapy (where patients reported that interacting with others was enjoyable and motivational) and were sedentary outside of therapy (where patients reported boredom). Additional Saturday physiotherapy extended therapy time and helped ease boredom on the weekend. Following cardiovascular surgery patients reported higher satisfaction levels when receiving weekend physiotherapy as they felt they had more time to communicate with their therapists (van der Peijl et al 2004).

The plates were incubated at 37 °C in 5% CO2 for 3 days. The presence of cytopathic effects (CPEs) was determined under a microscope, and viral titers were calculated as log10 of TCID50/ml. When no CPE was observed using undiluted viral solution, it

was defined as an undetectable level, which was considered to be lower than 1.4 log10 of TCID50/ml. Activation of the inflammasome in peritoneal resident macrophages was examined according to the protocol previously reported [15]. Briefly, peritoneal resident macrophages were collected from C57BL/6 mice (Charles River Laboratories Japan, Inc., Kanagawa, Japan) and were prepared with complete RPMI1640 medium (Invitrogen). Macrophages were primed with 50 ng/ml LPS (Sigma-Aldrich) see more for 18 h and then stimulated with sHZ or Alum (Invivogen)

for 8 h. The concentration of IL-1β in supernatant was measured by ELISA (R&D systems, Minneapolis, MN). Viral titers and body temperature of each animal were calculated as the area under the curve (AUC) by the trapezoidal method. Statistical significance between groups was determined by Dunnett’s multiple comparison test using the statistical analysis software SAS (version 9.2) for Windows (SAS Institute, Cary, NC). To examine the adjuvant effect of sHZ on HA split vaccine, ferrets (n = 4 per group) were twice www.selleckchem.com/products/XL184.html immunized with SV with or without sHZ (800 μg) or Fluad, and then their serum HI titers were measured every week. Fluad is composed of SV adjuvanted with MF59, a licensed squalene-based emulsion, widely used in clinical settings Farnesyltransferase [16]. On day 28 after the first immunization, HI titers of SV/sHZ group against H1, H3, and B virus antigens were significantly up-regulated, of which the GMT was 135, 28, and 40, respectively, comparable to those elicited by MF59 (p < 0.05, Fig. 1A–C). After the second immunization, HI titers of the SV/sHZ group against all three antigens were significantly higher than those of the SV group on day 35 (p < 0.05) ( Fig. 1A–C). The GMTs of the

HI titers against H1, H3, and B antigens in the SV/sHZ group were 905, 190, and 381, respectively. The boosting effect of sHZ was also comparable to that of MF59. By contrast, HI titers against three HA antigens of the SV group were not enhanced at every analysis point ( Fig. 1A–C). These results demonstrated that sHZ has a potent adjuvanticity to enhance the immunogenicity of SV, and its activity was comparable to that of MF59 in ferrets. Next, the dose-dependent adjuvanticity of sHZ to enhance the immunogenicity of SV was examined. Ferrets were twice immunized with SV/sHZ (50–800 μg), and HI titers were measured at every week. The adjuvanticity to enhance HI titers against HA antigens of H1 and B was observed with at least 200 μg of sHZ after the first immunization, but no boosting effect of 200 μg of sHZ was observed after the second immunization (Fig. 2).

philoxeroides seedlings in response to Cr exposure are also shown in ( Fig. 9). Since the soluble protein content in the leaf tissues were slightly higher in Cr treated plants than in control plants in the 12 day of the experiment; it is likely that Cr induced stress over the course of the treatment and that antioxidative enzymes activities were consequently same. It is reported that heavy metal stress

has been shown to induce a variety of proteins resulting in an overall increase in protein content. 19 However the additional experiment HKI-272 cell line is necessary to confirm the tolerance of these plants to heavy metal stress. The results of the present study indicated that A. philoxeroides accumulates high amounts of Cr in roots than shoots. A. philoxeroides is a fast growing plant and has the ability to tolerate high Cr (150 mg/l Cr) concentrations. Thus it can be used for phytoremediation. All authors have none to declare. “
“Mycophenolate mofetil (MMF) is an immunosuppressant and prodrug of mycophenolic acid, used extensively in transplant medicine. It is a reversible inhibitor of inosine monophosphate dehydrogenase1 in purine biosynthesis, more specifically guanine synthesis. MMF is also

used in the treatment of autoimmune diseases, such as Behcet’s check details disease, pemphigus vulgaris and systemic lupus erythematosus. The chemical name for MMF is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. The empirical formula and molecular weight of the drug are C23H31NO7 and 433.50 g respectively. The chemical structure of MMF is presented in Fig. 1. An extensive literature surrey is carried out and found a few HPLC2, 3, 4, 5, 6 and 7 methods have been reported for the determination of MMF present in biological fluids or biological matrixes. Very few reverse phase-HPLC

methods8 and 9 are reported for the determination of the drug in dosage forms. But no LC/MS method is reported to determine the quantity of MMF in pharmaceutical formulations; of therefore the authors are interested in developing a new LC/MS method for the assay of MMF in pharmaceutical formulations. The scope of the present investigation is to apply this method to determine the amount of MMF and to study the stability of MMF under forced degradation. This manuscript gives the first report for the application of proposed LC/MS method in stability testing and assay of pharmaceutical dosage forms with less-time consuming analysis. HPLC grade methanol (sd Fine-Chem Limited, Mumbai, India), acetonitrile (Qualigens Fine Chemicals, Mumbai, India) and ammonium acetate (Qualigens Fine Chemicals, Mumbai, India); AR grade glacial acetic acid (Loba Chemie Pvt. Ltd., Mumbai, India), hydrochloric acid, sodium hydroxide, methanol and hydrogen peroxide (Qualigens Fine Chemicals, Mumbai, India) and Milli-Q water (RANKEM Laboratories, Mumbai, India) were used for the present investigation.

1H NMR (300 MHz, DMSO-d6, δ ppm): 7.3–8.2 (m, 8H, Ar), 7.78 (s, 1H, CH), 4.8 (s, 2H, CH2), 2.9 (s, 6H, CH3). Anal. calcd. for C19H17N3O4S: C 59.52, H 4.47, N 10.96. Found: C 59.46, Protein Tyrosine Kinase inhibitor H 4.23, N 10.85. 5-(4-Hydroxybenzylidene)-N-(4-nitrobenzyl)-1,3-thiazolidine-2,4-dione (4f): Pale yellow solid, IR (KBr, cm−1): 3004, 1752, 1630, 1518, 1431, 1377, 638. 1H NMR (300 MHz, DMSO-d6, δ ppm): 8.9 (s, 1H, OH), 7.3–8.0 (m, 8H, Ar), 7.9 (s, 1H, CH), 5.2 (s, 2H, CH2). Anal. calcd. for C17H12N2O5S: C 57.3, H 3.39, N 7.86. Found: C 57.12, H 3.18, N 7.67. 5-(4-Hydroxy-3-methoxybenzylidene)-N-(4-nitrobenzyl)-1,3-thiazolidine-2,4-dione (4g):

Pale yellow solid, IR (KBr, cm−1): 2943, 1728, 1660, 1278, 1508, 1456, 1356, 693. 1H NMR (300 MHz, DMSO-d6, δ ppm): 9.03 (s, 1H, OH), 7.5–8.1 (m, 8H, Ar), 7.9 (s, 1H, CH), 4.8 (s, 2H, CH2), 3.7 (s, 3H, OCH3). Anal. calcd. for C18H14N2O6S: C 55.95, H 3.65, N 7.25. Found: C 55.81, H 3.44, N 7.13. 5-(3,4-Dimethoxybenzylidene)-N-(4-nitrobenzyl)-1,3-thiazolidine-2,4-dione (4h): Pale yellow solid, IR (KBr, cm−1): 2996, 1698, 1633, 1553, 1411, 1163, 686. 1H NMR (300 MHz, DMSO-d6, δ ppm): 7.2–8.05 (m, 8H, Ar), 7.94 (s, 1H, CH), 4.9 (s, 2H, CH2), 3.83 (s, 6H, OCH3). Anal. calcd. for C19H16N2O6S: C 56.99, H 4.03, N 7. Found: C 56.89, H 4.01, N 6.94. The Lipinski (RO5) parameters, topological polar surface

area (TPSA), molar volume (MV) and rotatable bonds (RB) were calculated Selleck Epacadostat using Molinspiration web JME editor. According to RO5, the molecules show good oral absorption when the values of M. Wt. <500, calculated Log P (cLog P) <5, HBD <5 and HBA <10. The absorption percentage (% ABS) was calculated according to Zhao et al. using the formula % ABS = 109 − (0.345*TPSA). A series of 1,3-thiazolidine-2,4-dione analogues with a combination of substituents at N3- and 5-positions were synthesized by making use of knoevenagel reaction. The characteristic –NH peak was absent in the respective IR and 1H NMR spectrums of the synthesized compounds and presence of benzylidene ( CH) peak in the range of δ 7.9–8.0 in the 1H NMR spectrum confirmed the knoevenagel condensation of different aromatic aldehydes

with N-substituted-1,3-thiazolidine-2,4-diones. The structures tuclazepam of the compounds were also established by mass spectra and elemental analysis. As expected, all the synthesized compounds were obeying the RO5, which explains their possible oral absorption. The values of TPSA and the positive drug score indicate that the compounds have potential to be new drug candidates. Synthesis of few more analogues of similar kind, exploring their biological activities and prediction of their SAR is under investigation. All authors have none to declare. The author NS is thankful to Gokaraju Rangaraju Educational Society (GRES) for providing necessary laboratory facilities. “
“The current global demand for H2 was estimated to be approximately 45 million tons/annum.

, 2013)). Hence, the combinations of two active drugs are common ( Schifano et al., 2011).

However, drugs are also adulterated with more or less psychoactive active compounds: amphetamines are often mixed with e.g. caffeine ( Vanattou-Saifoudine et al., 2012) and cocaine has been found to be mixed with a wide variety of adulterants. One prominent example of these adulterants is levamisole ( Fig.1A) which has been found in most of the drug samples sold as cocaine in the past. Levamisole is used by veterinarians as an anthelmintic drug ( Martin et al., 2012); its mode of action is the stimulation of ionotropic acetylcholine receptors (AChR) resulting in calcium influx causing learn more paralysis of the worms ( Levandoski et al., 2003 and Rayes et al., 2004). Under the trade name Ergamisol, levamisole was also used to treat worm infections in humans but had to be withdrawn from the U.S market in 2000 because of its severe side-effects ( Renoux, 1980). Most recently, several drug consumers suffered from agranulocytosis after repeated intake of cocaine adulterated

(“cut”) with levamisole ( Muirhead MG 132 and Eide, 2011 and Wolford et al., 2012). Several plausible explanations exist why levamisole is used as a cocaine-adulterant: (i) levamisole was reported to improve the mood of patients and induced insomnia and hyperalertness (Mutch and Hutson, 1991). (ii) The chemical properties of levamisole are similar to cocaine; for instance, color and melting point render both drugs almost indistinguishable without further chemical analysis (Chang et al., 2010). (iii) The use oxyclozanide of levamisole as a drug in veterinary medicine makes it easily available and keeps the costs low (Waller, 2006). (iv) Levamisole

was found to be rapidly metabolized in the human body to aminorex and related metabolites (Hess et al., 2013 and Reid et al., 1998). Aminorex (Fig.1A) is an amphetamine-like agent that was detected in racehorses after levamisole administration (Barker, 2009). Moreover, aminorex was detected in human urine samples in a multitude of cocaine abusers (Bertol et al., 2011 and Karch et al., 2012). Aminorex was marketed as an appetite suppressant in the mid-1960s mainly in Switzerland, Austria, and Germany; it was found to cause pronounced vasoconstriction in the pulmonary vasculature (Byrne-Quinn and Grover, 1972, Stuhlinger et al., 1969 and Rothman et al., 1999) and was withdrawn in 1972 due to several cases of fatal and life-threatening pulmonary hypertension (Fishman, 1999a). In the present work, we examined whether levamisole exerts direct effects on neurotransmitter transporters and compared these to the action of its metabolite, aminorex. Dulbecco’s modified Eagle’s medium (DMEM) and trypsin were purchased from PAA Laboratories GmbH (Pasching, Austria). Fetal calf serum was purchased from Invitrogen.

The E. coli TOP10 strain was transformed by electroporation with the constructed plasmid (pET28b/clpP). The constructed plasmid pET28b/clpP Hydroxychloroquine was confirmed by digestion and sequenced with fluorescent terminators (Big Dye, Applied Biosystems) using the ABI PRISM® 3100 Genetic Analyzer (Applied Biosystems). Once analyzed, the plasmid was transformed into E. coli BL21 Star (DE3)™. The cell viability of the stock of recombinant E. coli BL21 Star (DE3)™/pET28b/clpP in LB (5 g/L yeast extract, 10 g/L tryptone, 5 g/L NaCl, pH 7) with 25% glycerol, stored at −70 °C, was assessed by counting the colony forming units (CFUs) for all the experimental design experiments. Serial dilutions were made

in PBS pH 7.4 and transferred to Petri plates containing LB Agar and 50 μg/mL kanamycin (concentration of stocks around 1010 CFU/mL). Recombinant E. coli BL21 Star (DE3)™/pET28b/ClpP was pre-inoculated (10 μL) in 10 mL of the LB medium enriched with 1% glucose, 0.4% glycerol and 50 μg/mL kanamycin. Proteasome structure The pre-inoculum was incubated for 16 h at 37 °C and 200 rpm in 50 mL

flasks under agitation. The inoculum was prepared in 500 mL flasks with 2 mL pre-inoculum and 100 mL of the LB medium enriched with 1% glucose, 0.4% glycerol and different kanamycin concentrations according to the experimental design (as described in the next section). The culture was incubated at 37 °C and 200 rpm until it reached the exponential growth phase (Abs600 nm between 0.65 and 0.75). At this point, expression was induced with IPTG for 4 h under different induction concentrations according to the experimental design. E. coli BL21 (DE3) Star/pET28a was used as a negative control. 1 mL samples were taken from each experiment before and after the 4 h expression period to assess cell growth, ClpP expression (by SDS-PAGE) and solubility. The cells were harvested by centrifugation at 20,817 × g for 5 min to separate the culture medium. In order to assess the solubility of the expressed

protein the cells were resuspended in a lysis buffer (20 mM Tris, 1 mM EDTA, pH 8.0) at a ratio of 25 μL buffer to each 0.1 of Abs600 nm (normalizing to Abs600 nm), to obtain the total protein extract. The total extract was put through five 10 s ultrasound cycles at 30% amplitude in an ultrasonic Bumetanide cell disruptor (Sonics & Materials, Inc.). The soluble and insoluble fractions of the total protein were separated from the cultures by centrifugation (20,817 × g for 10 min at 10 °C). The samples were added to 12% SDS-PAGE [17], stained with Coomassie Blue R-250. The influence of kanamycin and IPTG concentration on cell growth, the concentration of expressed protein and plasmid stability was assessed by using a central composite design for two variables. Eight experiments were performed, four of which were replications at the center point (CP), as described in the previous section.

The PPP agreement is with the Biovac Institute which has a research and a development function and is developing local capacity for the production of vaccines. NAGI has no formal ties with NITAGs in other countries and has informal Obeticholic Acid ties only through its representatives on the WHO AFRO Task Force on Immunization (TFI). NAGI considers economic issues when making its recommendations, specifically the cost of the vaccine and the overall program as well as the program’s overall affordability and sustainability. The introduction of PCV and rotavirus vaccine, for example, was supported by cost-effectiveness data submitted to the Minister of Health. Similarly, the transition from

OPV + diphtheria–tetanus–whole cell pertussis–Haemophilus influenzae type b conjugate vaccine (DTP–HibCV) to pentavalent vaccine (DTPa–IPV + HibCV) was decided after it was costed. Formal economic evaluations are not carried out either by the DoH or NAGI. However, NAGI frequently supported by economic data from the research units of its members. These data are then submitted to the DoH. The committee may accept economic evaluations done internationally or regionally, as well as by manufacturers, but this has not been the case in the past. The DoH would need to consider affordability and sustainability

of new vaccines in addition to other programmatic needs. Since South Africa is classified by the World Bank as a category C country, it is not eligible the for selleck GAVI funding and is therefore required to purchase all its vaccine needs. Although the country produced almost all of its bacterial and viral vaccines up until 30 years ago, it is now solely dependent on imported vaccines. The budget for vaccine purchase thus competes with other high priority health needs and economic and financial considerations necessarily play a pivotal role in deciding vaccine strategies. Nevertheless, the mandate of

NAGI from the DoH is to focus its recommendations on medical and epidemiological criteria rather than on economic considerations. Once NAGI decides upon its recommendations they are referred to the DoH for further steps. The committee itself does not have any decision-making powers since it is purely an advisory board appointed by the MoH. Its recommendations may influence the decision-making of the minister and the National Health Council representing the 9 provinces. NAGI recommendations are also considered by the EPI directorate to be elements strengthening the EPI program and to provide assistance in troubleshooting. The Government, however, is not obliged to implement NAGI suggestions, although it does so in over 75% of the cases. When it does not, this is often because of competing priorities associated in many cases with the cost of the vaccine. The Ministry of Finance provides the budget for implementing vaccine and immunization recommendations.

Although the addition of types is being tested (see nine-valent vaccines), a pan-HPV Hydroxychloroquine research buy vaccine that could be easily and cheaply produced (one antigen instead of nine or more) would limit the need for further cervical cancer screening interventions. Indeed, these have to remain in place with the current vaccine strategy as a significant fraction (approximately 30%) is caused by high-risk HPV types, which are not covered in the current formulation [64]. This double-barrel strategy becomes a heavy burden on public health spending and is difficult to implement in low-income countries. Human papillomaviruses are

small non-enveloped DNA viruses of which the capsid contains mainly the L1 protein but also smaller amounts of L2. The L1 is abundantly click here present in a multivalent format in which the epitopes are present as a dense, highly repetitive array, which strongly stimulates B cells [18]. In contrast, in the natural infection the L2 protein is barely visible for the immune system. However, the L2 protein becomes more exposed after the virus binds to the basement membrane due to conformational changes. This short and transient exposure however fails to elicit any anti-L2 neutralizing antibody response. This could partly explain the conservation of the L2 epitope. Indeed, a small proportion of the L2 protein, especially between amino acid 20 and 38, is highly

preserved between various high-risk HPV types [64]. In addition, different antibodies against

this region show neutralizing activity against a wide range of papillomaviruses. before The main problem up to now with L2-based vaccines is poor immunogenicity, as the titers of neutralizing antibodies are much lower [64]. Recently, more success has been obtained in mice by the use of bacteriophage VLPs [65] and orally administered Lactobacillus casei expressing L2 on their surface [66]. The latter induced a significant vaginal mucosal immunity with production of broadly protective IgA, which could be effective in early phases of the viral infection, suggesting that this type of oral immunisation may be a promising strategy for prophylactic vaccination of humans. In addition to the use of bacteriophages, combinations of (cocktails of) adjuvantia, multimerisation and epitope display techniques have been tested leading to antibody responses which were only slightly lower than the responses elicited by L1. Potentially due to the physiological role of L2 in the viral entry and intracellular trafficking it has been shown that L2 vaccination can be therapeutic against papillomas, even without eliciting a neutralizing antibody response [67]. In the latter case, a heavy T cell infiltrate mounted a cellular response, killing infected cells and inducing rapid clearance of virus and lesion. The L2 vaccines are therefore promising for the future but further clinical testing in human patients needs to be done before further conclusions can be drawn.