While the olfactory navigation hypothesis is by far the most extensively tested when considering pigeon homing, it has rarely been considered when discussing true navigation in migrating birds. Stable odour gradients such as would be necessary for a bi-coordinate map have not been demonstrated to exist beyond approximately 200 km (Wallraff

& Andreae, 2000). This makes it difficult to explain the majority of displacement experiments on migrants by the use of olfactory navigation. Nevertheless, two experiments on homing of migratory birds in the breeding season found a deficit in performance after olfactory deprivation (Fiaschi, Farina selleckchem & Ioalé, 1974; Wallraff et al., 1995). More selleck kinase inhibitor surprisingly, a recent experiment demonstrated that adult catbirds displaced 1000 km east from Illinois to Princeton in the US, subjected to olfactory deprivation by zinc sulphate treatment and then radio-tracked from a light aircraft were unable to correct for the displacement in the way that controls were (Holland et al., 2009). If this finding

is borne out by further experimental support and shown to be a deficit based on the removal of navigation cues, then it may require a re-analysis of the bi-coordinate map theory for true navigation. It appears to be hard to explain how stable olfactory gradients could exist over the 1000 km necessary to explain this behaviour navigationally. Homing pigeons have not been shown to use olfactory cues beyond 700 km, and then only if they had access to environmental air during the displacement (Wallraff, 1981). With regard to the use of olfactory signals by migrants, an interesting parallel finding from a neurobiological study of migratory restlessness is that both visual and olfactory areas of the brain become more active at night during the migratory period, while they are most active during the day outside this time (Rastogi et al., 2011). This suggests

that olfaction plays a significant role in migratory behaviour, but it is still an open question as to what role this is. A recent hypothesis proposes that in fact the primary role of olfaction across organisms (and thus reason for its evolution) is navigation (Jacobs, 2012). If it does indeed turn selleck products out to be the case, then theories of true navigation based on a bi-coordinate map made stable environmental gradients may need to be significantly reconsidered, because olfactory cues do not seem to fit easily into this paradigm. The intensity of the Earth’s magnetic field was proposed as a cue for bird navigation over a century ago (Viguier, 1882). The Earth’s magnetic field is stronger at the poles than at the equator and it therefore has the potential to indicate latitudinal position. However, this is only functional over a relatively coarse scale (Bingman & Cheng, 2006).

While the olfactory navigation hypothesis is by far the most extensively tested when considering pigeon homing, it has rarely been considered when discussing true navigation in migrating birds. Stable odour gradients such as would be necessary for a bi-coordinate map have not been demonstrated to exist beyond approximately 200 km (Wallraff

& Andreae, 2000). This makes it difficult to explain the majority of displacement experiments on migrants by the use of olfactory navigation. Nevertheless, two experiments on homing of migratory birds in the breeding season found a deficit in performance after olfactory deprivation (Fiaschi, Farina find more & Ioalé, 1974; Wallraff et al., 1995). More Fulvestrant surprisingly, a recent experiment demonstrated that adult catbirds displaced 1000 km east from Illinois to Princeton in the US, subjected to olfactory deprivation by zinc sulphate treatment and then radio-tracked from a light aircraft were unable to correct for the displacement in the way that controls were (Holland et al., 2009). If this finding

is borne out by further experimental support and shown to be a deficit based on the removal of navigation cues, then it may require a re-analysis of the bi-coordinate map theory for true navigation. It appears to be hard to explain how stable olfactory gradients could exist over the 1000 km necessary to explain this behaviour navigationally. Homing pigeons have not been shown to use olfactory cues beyond 700 km, and then only if they had access to environmental air during the displacement (Wallraff, 1981). With regard to the use of olfactory signals by migrants, an interesting parallel finding from a neurobiological study of migratory restlessness is that both visual and olfactory areas of the brain become more active at night during the migratory period, while they are most active during the day outside this time (Rastogi et al., 2011). This suggests

that olfaction plays a significant role in migratory behaviour, but it is still an open question as to what role this is. A recent hypothesis proposes that in fact the primary role of olfaction across organisms (and thus reason for its evolution) is navigation (Jacobs, 2012). If it does indeed turn selleck chemicals out to be the case, then theories of true navigation based on a bi-coordinate map made stable environmental gradients may need to be significantly reconsidered, because olfactory cues do not seem to fit easily into this paradigm. The intensity of the Earth’s magnetic field was proposed as a cue for bird navigation over a century ago (Viguier, 1882). The Earth’s magnetic field is stronger at the poles than at the equator and it therefore has the potential to indicate latitudinal position. However, this is only functional over a relatively coarse scale (Bingman & Cheng, 2006).

Antifibrinolytics can be used as a concomitant treatment, especially for mucosal bleeding. Patients with mild haemophilia B do not respond to desmopressin. Until the late 1990s, inhibitors in mild haemophilia A were considered very rare. However, since the publication of Hay et al. [25] in 1998 on behalf of the UK Haemophilia Centre Directors Organisation, it has been appreciated that inhibitors in mild/moderate haemophilia are more frequent than previously thought. Clinical problems associated with inhibitors in mild haemophilia are Kinase Inhibitor Library often

considerable, as in the majority of cases, adult patients are confronted with a change in phenotype from mild-to-severe and they suddenly experience spontaneous severe bleeding. Patients with mild haemophilia are at lower risk of inhibitor development than are severely affected patients. The prevalence of these inhibitors has been estimated to be between 3% and 13% [26–28]. In a prospective study of inhibitor incidence among 1306 haemophilia A patients, only 6% of the inhibitors were found in patients with factor VIII >0.03 IU mL−1 [29]. Sixteen (28%) of 57 new inhibitors reported between January 1990 and January 1997 in the UK Haemophilia Centre Doctors’ Organisation

(UKHCDO) inhibitor register arose in patients with mild or moderate haemophilia. The annual incidence of inhibitors in the UK was 3.5 per 1000 registered with severe CP-690550 in vivo haemophilia and 0.84 per 1000 patients registered with mild/moderate haemophilia [30]. Usually, the presence of an inhibitor in patients with mild haemophilia is suggested by a change to a severe bleeding pattern with spontaneous bleedings or uncontrollable postsurgery bleeding. This change in bleeding pattern is explained by cross-reactivity of the inhibitor with the mutated factor VIII

of the patient resulting in a residual factor VIII level of <0.01 IU mL−1 [31–33]. The bleedings occur often in muscles and joints as in severe congenital haemophilia, but sometimes, the bleeding pattern is more reminiscent of acquired haemophilia with the occurrence of large cutaneous bruising, gastrointestinal and urogenital bleeding [25]. Occasionally, there is no change in residual factor VIII level, but an inhibitor is detected this website in the Bethesda assay and/or there is lack of efficiency of factor VIII transfusions [33–35]. In some cases, the specificity of the immune response reverts over time from neutralization of both mutated self and transfused normal factor VIII to tolerance to self, resulting in a recovery of the original basal factor VIII level and response to desmopressin, despite the persistence of antibodies to exogenous FVIII [25,31,33,34]. Inhibitors in mild haemophilia occur more commonly later in life and an episode of intensive treatment with factor VIII concentrate (for bleeding, trauma or surgery) seems to precede detection of the inhibitor in most reported cases.

In 32 cases, transnasal gastroscope was used as a tool to accomplish the placement of

naso-enteric nutrition tube and capsule-endoscopy examination. No complications such as perforation and bleeding occurred. Conclusion: Transnasal gastroscopy has great practical value in the diagnosis and treatment of the upper digestive disorders. Key Word(s): 1. Gastroscopy; Opaganib molecular weight 2. Endoscopic diagnosis; 3. Endoscopic therapy; Presenting Author: KNYAZEV MIKHAIL Additional Authors: DOUVANSKY VLADIMIR Corresponding Author: DOUVANSKY VLADIMIR Affiliations: policlinik 2 MER RF; state center of laser medicine Objective: This study aimed to determine the relative value of the frequency and significance of the differences learn more in relative values of frequencies of purple or green Autofluorescence imaging (AFI) staining of the epithelial neoplasia in the stomach. Methods: Gastroscopy AFI performed in patients with various gastrointestinal disorders of both sexes aged 22 to 78 years. Gastroscope

Olimpus Lucera GIF-Q260Z, HD, ZOOM, NBI, AFI used. All lesions were assessed histopathologically from biopsy specimens. Epithelial neoplasia were classified based into categories on the Vienna system. Two groups were formed, one consisted of gastric neoplasia 2–5 category and the control group included neoplasia of category 1 (negative for neoplasia \ dysplasia). AFI background staining, that depends on the symptoms of atrophic gastritis in the body

and antrum of the stomach, was not included in the present item. Results: There were 123 gastric epithelial neoplasia, 102 in the main group and 21 in the control. Neoplasia of category 2 were found 60, category 3 were 30 and category 4–5 were 12. AFI purple staining selleck chemicals llc were 76 entities, the relative frequency of purple color was 23% (95% confidence interval was 7–46%, t = 1.96) for the neoplasia category 1, for the other categories in total 68% (95% confidence interval was 59–78%, t = 1.96). The relative frequency of green staining AFI was determined in 76% (CI 54–92%, t = 1.96) was for neoplasia category 1. For the other categories of neoplasia 5–2 the same parameters was 31% (CI 22–40%, t = 1.96). The significance level for comparison of the relative frequencies of groups neoplasia 5–2 category with purple and green color neoplasia was 0.004 (t < t05, t = 1.98), p > 0.05. The significance level for comparison of the relative frequencies of groups neoplasia 1 category with a purple and green staining of neoplasia was 0.032 (t < t05, t = 2.09) p > 0.05. Conclusion: The reliability of 95% can be argued that a high probability of 54–92% staining autofluorescence in green have neoplasia category 1. With 95% reliability can be argued that a high probability of 59–78% staining autofluorescence of purple have neoplasia category 2–5.

In 32 cases, transnasal gastroscope was used as a tool to accomplish the placement of

naso-enteric nutrition tube and capsule-endoscopy examination. No complications such as perforation and bleeding occurred. Conclusion: Transnasal gastroscopy has great practical value in the diagnosis and treatment of the upper digestive disorders. Key Word(s): 1. Gastroscopy; NSC 683864 2. Endoscopic diagnosis; 3. Endoscopic therapy; Presenting Author: KNYAZEV MIKHAIL Additional Authors: DOUVANSKY VLADIMIR Corresponding Author: DOUVANSKY VLADIMIR Affiliations: policlinik 2 MER RF; state center of laser medicine Objective: This study aimed to determine the relative value of the frequency and significance of the differences FK506 in relative values of frequencies of purple or green Autofluorescence imaging (AFI) staining of the epithelial neoplasia in the stomach. Methods: Gastroscopy AFI performed in patients with various gastrointestinal disorders of both sexes aged 22 to 78 years. Gastroscope

Olimpus Lucera GIF-Q260Z, HD, ZOOM, NBI, AFI used. All lesions were assessed histopathologically from biopsy specimens. Epithelial neoplasia were classified based into categories on the Vienna system. Two groups were formed, one consisted of gastric neoplasia 2–5 category and the control group included neoplasia of category 1 (negative for neoplasia \ dysplasia). AFI background staining, that depends on the symptoms of atrophic gastritis in the body

and antrum of the stomach, was not included in the present item. Results: There were 123 gastric epithelial neoplasia, 102 in the main group and 21 in the control. Neoplasia of category 2 were found 60, category 3 were 30 and category 4–5 were 12. AFI purple staining see more were 76 entities, the relative frequency of purple color was 23% (95% confidence interval was 7–46%, t = 1.96) for the neoplasia category 1, for the other categories in total 68% (95% confidence interval was 59–78%, t = 1.96). The relative frequency of green staining AFI was determined in 76% (CI 54–92%, t = 1.96) was for neoplasia category 1. For the other categories of neoplasia 5–2 the same parameters was 31% (CI 22–40%, t = 1.96). The significance level for comparison of the relative frequencies of groups neoplasia 5–2 category with purple and green color neoplasia was 0.004 (t < t05, t = 1.98), p > 0.05. The significance level for comparison of the relative frequencies of groups neoplasia 1 category with a purple and green staining of neoplasia was 0.032 (t < t05, t = 2.09) p > 0.05. Conclusion: The reliability of 95% can be argued that a high probability of 54–92% staining autofluorescence in green have neoplasia category 1. With 95% reliability can be argued that a high probability of 59–78% staining autofluorescence of purple have neoplasia category 2–5.

Also, treatment with EGCG in combination with DNR seemed at least partially to overcome the acquired resistance to DNR in Hep3B-CBR1 cells. In a complementary experiment, we decreased the expression of CBR1 in HepG2 cells by RNA interference (RNAi). The efficiency of small interfering RNA (siRNA) in knocking down the expression of CBR1 in

HepG2 cells was verified (Fig. 4D). Upon CBR1 knockdown, HepG2-CBR1 siRNA cells became more sensitive to DNR. With 0.2 μM DNR, the cells showed 49.7% viability in comparison with 70.4% for the control cells (HepG2 nonsilence RNAi; Fig. 4E). Again, no differences were observed in their sensitivity to 5-FU (P > 0.05; Fig. 4F). In control HepG2 cells, EGCG significantly enhanced the DNR-induced inhibition of proliferation, which was similar to that of wild-type HepG2 cells, whereas EGCG did not show a marked enhancing effect on DNR activity in HepG2-CBR1 RNAi cells (Fig.

selleck 4E). Taken together, these results clearly demonstrate that CBR1 specifically affects the sensitivity of cancer cells to DNR and that EGCG can reverse CBR1-mediated resistance to DNR. To obtain direct evidence that EGCG enhances the activity of DNR by inhibiting DNR reduction by CBR1, cellular concentrations of DNR and DNROL were measured with HPLC. HepG2 cell lysates contained a DNROL level of 32.0 ng/mg of protein/minute, and levels of DNROL were reduced by 17.7%, 43.8%, and 66.2% in the presence of 20, 40, and 80μM EGCG, respectively (Fig. 5A). SMMC7721 cell lysates showed a DNROL selleck chemicals level of 34.1 ng/mg of protein/minute, and the lowest find more dose of EGCG (20 μM) could significantly affect DNR carbonyl reduction (P < 0.01; Fig. 5B). The dose-dependent effect of EGCG on DNR reduction further supports the notion that EGCG specifically inhibits DNR reduction. The control Hep3B-pcDNA cell lysates showed DNR-reducing activity of 7.7 ng/mg of protein/minute, whereas Hep3B-CBR1 cells stably expressing CBR1 had higher DNR-reducing activity (42.6 ng/mg of protein/minute, i.e., an increase of 5.4-fold). The DNR-reducing activity of the Hep3B-CBR1 cell

lysate was decreased to 35.4, 28.8, and 19.4 ng/mg of protein/minute when 20, 40, and 80 μM EGCG was added, respectively (Fig. 5C). These results are consistent with Fig. 4B, which shows that CBR1 contributes to the acquired resistance toward DNR and that EGCG can reverse the resistance by inhibiting CBR1 activity. In order to evaluate the potential benefit of a combination therapy using EGCG and DNR for HCC, we determined the effects of EGCG and DNR (alone or in combination) in a xenograft model using HCC cells with high (SMMC7721) or low (Hep3B) CBR1 expression levels. For SMMC7721 xenografts, the EGCG and DNR group showed a higher level of inhibition in comparison with the EGCG-alone group or the DNR-alone group (Fig. 6A). As shown in Fig. 6B, the average tumor weight in the control group was 0.

Note the difference in units for HBV DNA levels. In the current Guidelines and in Japan in general, HBV DNA is expressed as copies/mL, but elsewhere the unit IU/mL is used (IU stands for international units). The AASLD, EASL and APASL guidelines all use IU/mL. Table 10 shows conversion rates between IU/mL and copies/mL. For example, the general treatment cutoff of 2000 IU/mL is equivalent to 4.07 log copies/mL (conversion rate 5.82) using the TaqMan method (Roche). Note that conversion rates may differ between real-time PCR methods; for example,

the same treatment standard would be 3.83 log copies/mL (conversion rate 3.41) using the AccuGene method (Abbott). Further research is required into these discrepancies. TaqMan (Roche) (×5.82) 116 9.9×108 AccuGene (Abbott) (×3.41) 34 3.4×109 Recommendation Real-time PCR is recommended for HBV DNA quantification in the clinical setting. RAD001 HBsAg is an antigen within the HBV envelope that is present within the blood as the Dane particle as well as empty particles, small spherical particles and tubular particles, all of which are generated from covalently closed CHIR-99021 manufacturer circular DNA (cccDNA) in the hepatocytes, as shown in Figure 2. Qualitative reagents have traditionally been used for measuring HBsAg and for the diagnosis of hepatitis B. But recent

years have seen the development of a number of new quantitative reagents with considerable

potential for prognosis and evaluation of therapeutic effects.[64, this website 65] Table 11 lists reagents used for measuring HBsAg. Mono (two types) Mono (two types) Mono (various) Mono (two types) Mono (two types) Mono (various) Mono (two types) 0.1∼2000 C.O.I. 0.05∼250 IU/mL (manual/auto dilution) 0.03∼2500 IU/mL (auto dilution) 0.005∼150 IU/mL (auto dilution) Observations generated by qualitative reagents are expressed in terms of a cut-off index (COI), where a value of 1.0 or higher is deemed positive and higher measurements are semiquantitative, used for reference purposes. Common quantitative reagents include Architect (Abbott) and HISCL (Sysmex). Table 11 shows the threshold criteria and measurement ranges in IU/mL. Quantification covers a wide range through dilution. A newly developed quantitative reagent for HBsAg called Lumipulse HBsAg-HQ claims ten times the sensitivity of conventional reagents, and shows considerable potential for clinical settings. HBsAg levels vary in accordance with factors such as age, HBV DNA levels and HBV genotype.[66] HBV DNA is considered unsuitable for evaluating therapeutic effects because the HBV DNA levels often falls below the limit of detection shortly after the commencement of antiviral treatment. Several reports therefore recommend monitoring the HBsAg levels over time instead.

Note the difference in units for HBV DNA levels. In the current Guidelines and in Japan in general, HBV DNA is expressed as copies/mL, but elsewhere the unit IU/mL is used (IU stands for international units). The AASLD, EASL and APASL guidelines all use IU/mL. Table 10 shows conversion rates between IU/mL and copies/mL. For example, the general treatment cutoff of 2000 IU/mL is equivalent to 4.07 log copies/mL (conversion rate 5.82) using the TaqMan method (Roche). Note that conversion rates may differ between real-time PCR methods; for example,

the same treatment standard would be 3.83 log copies/mL (conversion rate 3.41) using the AccuGene method (Abbott). Further research is required into these discrepancies. TaqMan (Roche) (×5.82) 116 9.9×108 AccuGene (Abbott) (×3.41) 34 3.4×109 Recommendation Real-time PCR is recommended for HBV DNA quantification in the clinical setting. Dasatinib HBsAg is an antigen within the HBV envelope that is present within the blood as the Dane particle as well as empty particles, small spherical particles and tubular particles, all of which are generated from covalently closed see more circular DNA (cccDNA) in the hepatocytes, as shown in Figure 2. Qualitative reagents have traditionally been used for measuring HBsAg and for the diagnosis of hepatitis B. But recent

years have seen the development of a number of new quantitative reagents with considerable

potential for prognosis and evaluation of therapeutic effects.[64, check details 65] Table 11 lists reagents used for measuring HBsAg. Mono (two types) Mono (two types) Mono (various) Mono (two types) Mono (two types) Mono (various) Mono (two types) 0.1∼2000 C.O.I. 0.05∼250 IU/mL (manual/auto dilution) 0.03∼2500 IU/mL (auto dilution) 0.005∼150 IU/mL (auto dilution) Observations generated by qualitative reagents are expressed in terms of a cut-off index (COI), where a value of 1.0 or higher is deemed positive and higher measurements are semiquantitative, used for reference purposes. Common quantitative reagents include Architect (Abbott) and HISCL (Sysmex). Table 11 shows the threshold criteria and measurement ranges in IU/mL. Quantification covers a wide range through dilution. A newly developed quantitative reagent for HBsAg called Lumipulse HBsAg-HQ claims ten times the sensitivity of conventional reagents, and shows considerable potential for clinical settings. HBsAg levels vary in accordance with factors such as age, HBV DNA levels and HBV genotype.[66] HBV DNA is considered unsuitable for evaluating therapeutic effects because the HBV DNA levels often falls below the limit of detection shortly after the commencement of antiviral treatment. Several reports therefore recommend monitoring the HBsAg levels over time instead.

More recently, a series of elegant gene transfer experiments investigating the interaction among VWF, FVIII and FVIII inhibitory antibodies in mouse and human samples provided convincing in vitro and in vivo evidence that VWF exerts a protective effect by reducing inhibitor

inactivation of FVIII [31]. Are there explanations buy CB-839 for reduced FVIII:C activity observed in patients receiving products from recombinant origin? Lin and coworkers determined VWF- binding profiles and quantified the FVIII protein content (FVIII:Ag) per unit of FVIII:C for several commercially available rFVIII and pdFVIII concentrates using gel filtration chromatography and enzyme-linked immunosorbent assay, respectively [12]. In contrast to plasma-derived products in which the binding of FVIII:Ag to VWF was at or near 100%, rFVIII concentrates invariably contained a fraction of FVIII:Ag find more molecules (approximately 20%) unable to associate with VWF (Table 4). As well as providing valuable evidence of a difference between plasma-derived

and recombinant products at the molecular level, the results of this study raised two important clinical questions: Why does rFVIII have less affinity than pdFVIII for VWF? Is there ‘free’ FVIII in the circulation after the infusion of rFVIII concentrates? Answering these questions requires taking a closer look at the molecular aspects of the union between FVIII and VWF and, in particular, the role of tyrosine sulphation sites within the FVIII molecule. FVIII contains six individual tyrosine residues which, once sulphated, modulate FVIII activity through different mechanisms

[39]. Among the six residues, posttranslational sulphation of tyrosine at amino acid position 1680 (Tyr1680) is required for the binding of FVIII to VWF (Fig. 8) selleck compound [39-41]. Supporting this molecular finding is the clinical observation that a single missense mutation resulting in a tyrosine-phenylalanine substitution at amino acid position 1680 was associated with a mild haemophilia phenotype, with the patient exhibiting 10% of normal FVIII activity and 20% of normal FVIII antigen [42, 43]. In all cells, a DNA sequence is translated into a unique amino acid sequence. Following translation, several posttranslational modifications occur, which include carboxylation, glycation, phosphorylation and sulphation among others. These posttranslational modifications are crucial for correct functioning of the protein and are specific to the cell line, including species and organ. A recent study compared the extent of Tyr1680 sulphation among FVIII products of recombinant and plasma-derived origin [44]. In plasma-derived products, Tyr1680 sulphation was 100%, whereas, in recombinant FVIII products, the percentage of sulphated Tyr1680 ranged from 83.3 to >99%.

The three talks in this session are totally,

or at least in part, directed at strategies that may be clinically effective even in the absence of correction of the missing plasma clotting factor, although the haematopoietic stem cell or blood outgrowth endothelial cell therapy could achieve plasma correction as well. Two of the approaches achieve localized coagulation factor expression without necessarily correcting the systemic defect – one is with synthesis of FVIII or FIX within the joint space and the other is with the local release of FVIII (or FIX) by platelets at the site of vascular injury. All of the three approaches have demonstrated efficacy learn more in small animal models and are now the subject of larger animal studies. None has yet to progress to human trials. Gene therapy of haemophilia has been initiated through a number of approaches including expression in muscle find more [1], liver [2] and

omental implanted fibroblasts [3], i.v. injection of an expression construct under the control of a ubiquitous promoter [4]. The follow summarizes three talks given at the World Federation of Haemophilia Meeting in Buenos Aires, Argentina on gene therapy of hemophilia that emphasize new approaches or strategies for gene therapy of hemophilia. Bleeding-induced joint destruction is the major morbidity complicating factor VIII and factor IX deficiency. Standard and appropriate therapy to maintain the health

of joints requires restoring factor activity throughout the entire circulating blood volume. Although bleeding selleck inhibitor into six joints (knees, ankles and elbows) is estimated to account for 80% of haemarthroses [5], few therapies are directed locally to the joints. Gene therapy has been pioneered for rheumatoid arthritis and osteoarthritis [6–8] diseases, which share many pathological features with bleeding-induced arthropathy [9]; the approaches have primarily sought to modulate inflammatory or angiogenic cytokine expression in the joint space. While multiple gene delivery approaches to achieve systemic correction of haemophilia A and B have been investigated, clinical success has yet to be achieved [2,10–12]. Local therapy directed to joints could potentially address the major complication of haemophilia while circumventing some barriers to systemic expression, for example if the requirement for the total therapeutic protein expression was decreased or if the immune presentation of potentially immunogenic gene delivery vectors or clotting factor differed quantitatively or qualitatively. A series of investigations now have explored the hypothesis that extravascular clotting factor in the joint tissues in haemophilia can contribute to local haemostasis and protection from joint deterioration independently of circulating plasma clotting factor [11,12].