Apical but not sub-apical hyphal compartments are self-sustaining in growth.

It was recently demonstrated that apical compartments of Aspergillus niger hyphae are self-sustaining in growth. This was shown by assessing the growth rate of individual hyphae before and after dissection of the second compartment. Using the same methodology, it is here demonstrated that single apical compartments of the septate fungi Penicillium chrysogenum and Schizophyllum commune as well as the 500-µm-apical region of the non-septate fungus Rhizopus stolonifer are also self-sustaining in growth. In contrast, single 2nd compartments (obtained by dissection of the first and third compartment) of the septate fungi or the region between 500 and 1000 µm from tips of R. stolonifer were severely impacted in their growth rate. In addition, it is shown that existing or newly formed branches originating from the 2nd compartments function as a backup system for hyphal growth when the apical part of the hypha of the three studied fungi is damaged. Together, it is concluded that the apical compartments/zones of the studied fungi are self-sustaining in growth. In contrast, the subapical region is not self-sustaining but functions as a backup once the apical zone is damaged. This back up system is relevant in nature because the apices of hyphae are the first to be exposed to (a)biotic stress conditions when entering an unexplored substrate.

Heparin incorporating liposomes as a delivery system of heparin from PET-covered metallic stents: effect on haemocompatibility.

We investigate the possibility of coating polymer-covered stents with heparin-encapsulating liposomes for improving their haemocompatibility. Thin-film hydration (for multilamellar vesicles, MLV), and the dehydration-rehydration vesicle (DRV) methods are used for preparation of low-molecular weight heparin (LMWH)-encapsulating liposomes with varying lipid compositions. Liposomes are characterized for LMWH encapsulation and retention. For measurement of LMWH, a chromogenic technique is adjusted. For evaluation of heparin release from vesicles in platelet poor plasma (PPP) coagulation time is measured in presence of liposomal samples. Results reveal that LMWH encapsulation in liposomes is higher in DRV, however compositions with high encapsulation are leaky during buffer incubation. Most liposomes release LMWH slowly during plasma incubation (retention after 24 h ranges between 74% and 95%). Concerning the haemocompatibility of polyethylene terephthlate-covered stents after coating with LMWH-encapsulating liposomes, there is a marked increase (higher for DRV-coated stents compared to MLV) in plasma recalcification time compared to the control (plain blood) and reference (non-coated stent), which increases with blood-material contact time. This is probably due to LMWH release, demonstrating that encapsulated LMWH retains its biological functionality. Interestingly, the DRV-coated stents retained a high plasma recalcification time and a large number of liposomes on the stents (as proven by SEM studies) even after extensive washing (high shear conditions), proving that this method may be functional under high flow applying in vivo conditions.

Interferon beta-1a in MS: results following development of neutralizing antibodies in PRISMS.

BACKGROUND: Debate continues concerning the relevance of neutralizing antibody (NAb) development on the efficacy of interferon (IFN) therapy in patients with multiple sclerosis (MS). The PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study of subcutaneous IFNbeta-1a showed significant benefit on all efficacy outcomes with no significant impact from NAb development on relapses at 2 years. The 2-year extension permitted longer observation following NAb development. METHODS: Exploratory post-hoc analyses of pharmacodynamic response and clinical and MRI outcomes were performed on data from 368 patients with relapsing MS treated with IFN from study start, based on NAb status. RESULTS: Persistent NAbs, above 20 NU/mL, were present in 14% of the 44-microg three times weekly (TIW) and 24% of the 22-microg TIW group over 4 years. NAb development was associated with reduced pharmacodynamic marker induction at 1 year. Over the entire 4 years of study, relapse and disability measures were similar between NAb+ and NAb- patients. However, once NAbs developed, significant differences were noted between NAb+ and NAb- groups, particularly on MRI and relapse measures. The presence of binding antibodies alone did not affect outcome. CONCLUSION: Neutralizing antibody development in interferon-treated patients is correlated with reduced efficacy and is a potential cause for renewed disease activity.

Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale.

The symptoms, severity, and course of multiple sclerosis (MS) vary among patients, leading to complex treatment issues. In recent years, research has focused on specific adhesion molecules that participate in the activation and function of lymphocytes, especially the migration of these cells to sites of inflammation. In particular, the integrin, very late activation antigen (VLA)-4, has been implicated in mediating adhesion and migration of immune cells through interaction with its ligand, vascular cell adhesion molecule (VCAM)-1. VLA-4 is comprised of alpha4/beta1 and is critical in mediating Th-1 cell migration in the animal model of MS, experimental autoimmune encephalomyelitis, and has been the target of several recent clinical trials in MS. The humanized monoclonal antibody to alpha4 integrin, natalizumab (Tysabri, Biogen Idec/Elan), was recently approved in the United States for the treatment of relapsing MS. The authors discuss the mechanisms by which alpha4 integrins alter lymphocyte function as a rationale for anti-alpha4 integrin use in MS.

Significant linkage to migraine with aura on chromosome 11q24.

Migraine with aura (MA) is a prevalent neurological condition with strong evidence for a genetic basis. Familial hemiplegic migraine, a rare Mendelian form of MA, can be caused by mutations in the calcium channel gene, CACNA1A or in the ATP1A2 gene, a Na+/K+ pump. Susceptibility genes for the more prevalent forms of migraine have yet to be identified despite several reports of linkage including loci on 4q24, 1q31, 19p13 and Xq24-28. We have undertaken a genome-wide screen of 43 Canadian families, segregating MA with families chosen for an apparent autosomal dominant pattern of transmission. Diagnosis was based upon International Headache Society Criteria. Parametric linkage analysis revealed a novel locus on 11q24 with a two-point LOD score of 4.2 and a multi-point parametric LOD score of 5.6. We did not find any support for linkage at previously reported loci. The lack of consensus amongst linkage studies, including this study, is probably an indication of the heterogeneity that is inherent for MA. Nevertheless, the finding of a highly significant locus with a LOD score of 5.6 is powerful evidence that a gene increasing susceptibility to MA resides on 11q24. Several candidate genes map to this region of the genome including a number of ion channel genes such as GRIK4, SCNB2, KCNJ5 and KCNJ1.

Interferons in relapsing remitting multiple sclerosis: a systematic review.

BACKGROUND: Recombinant interferons have been approved by many national regulatory agencies for treatment of relapsing remitting multiple sclerosis, but widespread discussion continues about their true effectiveness, benefits, side-effects, and costs. METHODS: With the Cochrane Collaboration methodology, we reviewed all published, randomised, placebo-controlled trials of recombinant interferons undertaken in patients with relapsing remitting multiple sclerosis between 1993 and 2002. Our primary aim was to find out whether recombinant interferons reduced the number of patients who had clinical exacerbations and disease progression, compared with placebo. FINDINGS: The seven trials that met our criteria included 1215 randomised patients: data from 667 (55%) were available for analysis at 1 year's and from 919 (76%) at 2 years' follow-up. Interferon seemed to reduce the number of patients who had exacerbations during the first year of treatment (relative risk 0.73, 95% CI 0.54-0.99), but results at 2 years' follow-up were not robust and were difficult to interpret because of the many dropouts. Although the number of patients who had exacerbations (0.81, 0.74-0.89) or progressed (0.70, 0.55-0.88) during the first 2 years fell significantly in the protocol analysis, results were inconclusive after sensitivity analyses for exacerbations (1.11, 0.73-1.68) and disease progression (1.31, 0.60-2.89). Data were insufficient to establish whether steroid use and admissions to hospital were reduced in the interferon group. Similarly, MRI outcome data could not be analysed quantitatively. Side-effects were common, and acute toxic effects adversely affected quality of life. INTERPRETATION: Recombinant interferons slightly reduce the number of patients who have exacerbations during first year of treatment. Their clinical effect beyond 1 year is uncertain and new trials are needed to assess their long-term effectiveness and side-effects.

A controlled trial of natalizumab for relapsing multiple sclerosis.

BACKGROUND: In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis. METHODS: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being. RESULTS: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram). CONCLUSIONS: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.

Evidence for holistic processing of faces viewed as photographic negatives.

Inversion and photographic negation both impair face recognition. Inversion seems to disrupt processing of the spatial relationship between facial features ('relational' processing) which normally occurs with upright faces and which facilitates their recognition. It remains unclear why negation affects recognition. To find out if negation impairs relational processing, we investigated whether negative faces are subject to the 'chimeric-face effect'. Recognition of the top half of a composite face (constructed from top and bottom halves of different faces) is difficult when the face is upright, but not when it is inverted. To perform this task successfully, the bottom half of the face has to be disregarded, but the relational processing which normally occurs with upright faces makes this difficult. Inversion reduces relational processing and thus facilitates performance on this particular task. In our experiments, subjects saw pairs of chimeric faces and had to decide whether or not the top halves were identical. On half the trials the two chimeras had identical tops; on the remaining trials the top halves were different. (The bottom halves were always different.) All permutations of orientation (upright or inverted) and luminance (normal or negative) were used. In experiment 1, each pair of 'identical' top halves were the same in all respects. Experiment 2 used differently oriented views of the same person, to preclude matches being based on incidental features of the images rather than the faces displayed within them. In both experiments, similar chimeric-face effects were obtained with both positive and negative faces, implying that negative faces evoke some form of relational processing. It is argued that there may be more than one kind of relational processing involved in face recognition: the 'chimeric-face effect' may reflect an initial 'holistic' processing which binds facial features into a 'Gestalt', rather than being a demonstration of the configurational processing involved in individual recognition.

The influence of feature-based information in the age processing of unfamiliar faces.

The influence of the internal features (eyes, nose, and mouth) in the age processing of unfamiliar faces was examined. Younger and older versions of the faces of six individuals (covering three different age ranges, from infancy to maturity) were used as donor stimuli. For each individual in turn, the effects on age estimates of placing older features in the younger face version (or vice versa) were investigated. Age estimates were heavily influenced by the age of the internal facial features. Experiment 2 replicated these effects with a larger number of faces within a narrower age range (after growth is complete and before major skin changes have occurred). Taken together, these two experiments show that the internal facial features may be influential in conveying age information to the perceiver. However, the mechanisms by which features exert their influence remain difficult to determine: although age estimates might be based on local information from the features themselves, an alternative possibility is that featural changes indirectly influence age estimates by altering the global three-dimensional shape of the head.

Recognising the ageing face: the role of age in face processing.

The effect of age-induced changes on face recognition were investigated as a means of exploring the role of age in the encoding of new facial memories. The ability of participants to recognise each of six previously learnt faces was tested with versions which were either identical to the learnt faces, the same age (but different in pose and expression), or younger or older in age. Participants were able to cope well with facial changes induced by ageing: their performance with older, but not younger, versions was comparable to that with faces which differed only in pose and expression. Since the large majority of different age versions were recognised successfully, it can be concluded that the process of recognition does not require an exact match in age characteristics between the stored representation of a face and the face currently in view. As the age-related changes explored here were those that occur during the period of growth, this in turn implies that the underlying structural physical properties of the face are (in addition to pose and facial expression) invariant to a certain extent.

Factors influencing the accuracy of age estimates of unfamiliar faces.

Factors affecting the accuracy with which adults could assess the age of unfamiliar male faces aged between 5 and 70 years were examined. In the first experiment twenty-five 'young' adult subjects, aged 16-25, and twenty-five 'old' adults, aged 51-60, were used. Each subject saw five versions of three different faces: these consisted of an original version of each face and four manipulated versions of it. The manipulations consisted of mirror reversal, pseudo-cardioidal strain, thresholding, and elimination of all but the internal features of the face. The second experiment was similar except that a between-subjects design was used: each subject saw three faces for each age category of target face, but was exposed to only a single type of manipulation (plus a set of 'original' faces which were identical for all groups, so that the comparability of the different groups in age estimation could be checked). Results from both experiments were similar. Age estimates for unmanipulated 'original' faces were highly accurate, although subjects were most accurate with target faces that were within their own age range. Results for the manipulated faces implied that the importance of cardioidal strain as a necessary and sufficient cue to age may have been overestimated in previous reports: subjects' age estimates were accurate when cardioidal strain was absent from the stimulus, and poor when cardioidal strain was the only cue available.

Carcinoma of the hepatic duct junction.

A series of 54 patients with carcinoma of the hepatic duct junction is reveiwed. The condition is probably less rare than previous publications would suggest as the condition is frequently missed at operation. An account of the presentation, investigation and treatment of these patients is given, as well as the results obtained. In the discussion that follows, it is pointed out that if systematic investigation is carried out, with particular regard to adequate radiological investigations, both prior to and during surgery, the correct diagnosis can be made, although histological proof may be difficult to obtain. These tumours are seldom resectable, but good and worthwhile palliation may be obtained.