Nerve conduction velocity in CMT1A: what else can we tell?

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease (CMT) type 1A is characterized by uniformly reduced nerve conduction velocity (NCV) that is fully penetrant since the first years of life, remains fairly stable through the life and does not correlate with disability whereas compound muscular action potential (CMAP) amplitude does. The aim of the present study was to analyze the large amount of electrophysiological data collected in the ascorbic acid trial in Italy and the UK (CMT-TRIAAL/CMT-TRAUK) and to use these data to gain insights into the pathophysiology of NCV in CMT1A. METHODS: Baseline electrophysiological data from 271 patients were analysed. Electrophysiological recordings were taken from the motor ulnar, median and peroneal nerves and the sensory ulnar nerve. Distal motor latency (DML), motor (MNCV) and sensory (SNCV) nerve conduction velocity, and amplitudes of CMAPs and sensory action potentials were assessed. Electrophysiological findings were correlated with age of patients at examination and the Charcot-Marie-Tooth Examination Score (CMTES). RESULTS: NCV was markedly and uniformly reduced. CMAP amplitudes were overall reduced but more severely in lower limbs. DML decreased and MNCV and SNCV increased with age of the patients, whereas CMAP amplitudes worsened with age and also correlated with CMTES. CONCLUSIONS: This is the largest sample of electrophysiological data obtained so far from CMT1A patients. Axonal degeneration as assessed by means of CMAP amplitude reflected clinical impairment and was consistent with a slowly progressive length-dependent neuropathy. All patients typically had markedly slowed NCV that did, however, slightly increase with age of the patients. The improvement of NCV might depend on myelin thickness remodelling that occurs during the adult life of CMT1A patients.

Regarding the past, what is the trial you have always been dreaming of in CIDP?

Chronic inflammatory demyelinating polyradiculoneuropathy is an orphan disease of poorly understood cause. While first line treatments with corticosteroids, intravenous immunoglobulin and plasma exchange have at least short-term efficacy, no trial has shown that immunosuppressants work. In our dream, we will take advantage of the recently improved EU regulations to launch a Europe wide trial which will investigate the cause of the disease. It will compare three parallel groups, the anti-B cell agent rituximab, the anti-T cell agent abatacept and usual care. The trial will not be blinded and the design will be very simple. The primary outcome measure will be improvement from baseline of the overall neuropathy limitations scale (ONLS) score by 1 or more grades at 12 weeks without increase in concomitant corticosteroids or IVIg or use of plasma exchange. There will be an option to substitute improvement in the Rasch-built overall disability scale depending on future experience with that scale as the primary outcome measure. The trial will require 3 groups of 60 participants to detect an increase from 20% in the usual care group to 30% with one of the other agents with a power of 90% and P-value of 5%. It will be larger than any trial of an immunosuppressant agent so far performed in CIDP. However, recruitment will be easier because inclusion criteria will be broad and allow randomisation of any patient in whom their neurologist wishes to introduce an immunosuppressant. Avoidance of blinding and use of simple monitoring with facetime will simplify running the trial and reduce expense. The trial will follow participants and measure outcomes at 12 months. Other outcomes will consist only of grip strength, time to walk 10 m and Euroqol, the last allowing us to estimate the cost per QALY of rituximab or abatacept. Even including central analysis of key biomarkers, the trial will only cost 3 million euros, a fraction of the cost of the usual phase III pharmaceutical company trial.

Responsiveness of clinical outcome measures in Charcot-Marie-Tooth disease.

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease (CMT) is a very slowly progressive neuropathy which makes it difficult to detect disease progression over time and to assess intervention efficacy. Experience from completed clinical trials with ascorbic acid and natural history studies confirm difficulties in detecting such changes. Consequently, sensitive-to-change outcome measures (OMs) are urgently needed. METHODS: The relative responsiveness of clinical scales of the Italian-UK ascorbic acid trial (placebo arm) were assessed by using the standardized response mean (SRM), which is the ratio of the paired scores mean change over time to the standard deviation of the score change (0 is worst responsiveness). RESULTS: Little worsening of OM scores was found over 2 years. In detail, the primary OM of the trial, the CMT Neuropathy Score version 1 (CMTNSv1), showed low responsiveness (SRM 0.13). Some CMTNS items showed slightly greater responsiveness (CMT Examination Score 0.17; CMTNS Signs 0.19). Myometric assessments of handgrip and foot dorsiflexion strength were the most responsive (SRM -0.31 and -0.38, respectively). Amongst the other measures, the nine-hole peg test, which assesses upper limb functioning, showed the best sensitivity to change (SRM 0.28). CONCLUSIONS: Overall these OMs showed low or negligible responsiveness, confirming the need to improve current OMs and to develop novel ones for prognostic and interventional studies. However, handgrip and foot dorsiflexion myometry are worth retaining for future trials as they were the most responsive and are likely to be clinically relevant for patients.

Is overwork weakness relevant in Charcot-Marie-Tooth disease?

BACKGROUND: In overwork weakness (OW), muscles are increasingly weakened by exercise, work or daily activities. Although it is a well-established phenomenon in several neuromuscular disorders, it is debated whether it occurs in Charcot-Marie-Tooth disease (CMT). Dominant limb muscles undergo a heavier overload than non-dominant and therefore if OW occurs we would expect them to become weaker. Four previous studies, comparing dominant and non-dominant hand strength in CMT series employing manual testing or myometry, gave contradictory results. Moreover, none of them examined the behaviour of lower limb muscles. METHODS: We tested the OW hypothesis in 271 CMT1A adult patients by comparing bilateral intrinsic hand and leg muscle strength with manual testing as well as manual dexterity. RESULTS: We found no significant difference between sides for the strength of first dorsal interosseous, abductor pollicis brevis, anterior tibialis and triceps surae. Dominant side muscles did not become weaker than non-dominant with increasing age and disease severity (assessed with the CMT Neuropathy Score); in fact, the dominant triceps surae was slightly stronger than the non-dominant with increasing age and disease severity. DISCUSSION: Our data does not support the OW hypothesis and the consequent harmful effect of exercise in patients with CMT1A. Physical activity should be encouraged, and rehabilitation remains the most effective treatment for CMT patients.

Epidemiology of chronic inflammatory neuropathies in southeast England.

BACKGROUND AND PURPOSE: There is little information about the prevalence and disease burden of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN) and paraproteinaemic demyelinating neuropathy (PDN). METHODS: Multiple sources were used to study the prevalence and clinical features of these diseases in a southeast England population of 3,557,352 people. RESULTS: The crude prevalences were as follows: CIDP, 2.84 (95% CI 2.31-3.45); MMN, 0.53 (95% CI 0.32-0.83); and PDN, 1.04 (95% CI 0.73-1.43) per 100,000 population. All three diseases were more common in men than in women. The peak decade of onset was older in those with CIDP (70-79 years) and PDN (70-79 years) than in those with MMN (50-59 years). Disability was greater in CIDP and PDN, with median (range) overall neuropathy limitations scores of 4 (0-8) and 4 (1-6), respectively, than in MMN, with a score of 2 (1-5). CONCLUSION: The common forms of chronic inflammatory neuropathy cause a considerable disease burden in the community.

Economic costs and quality of life in chronic inflammatory neuropathies in southeast England.

BACKGROUND AND PURPOSE: Cost-of-illness studies and health-related quality of life (HRQoL) measurements are needed to assess the effects of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN) and paraproteinaemic demyelinating neuropathy (PDN) on society. METHODS: This study was conducted in 2008 in a southeast England population of 3,557,352 people. Data on service use and treatment were collected with a client service receipt inventory and service costs were calculated by combining these data with national unit costs. The EuroQol was used to calculate utility scores, a measurement of HRQoL. RESULTS: The total annual cost-of-illness per patient was £22,085 for CIDP, £22,812 for MMN and £7566 for PDN. The annual total cost per patient was £49,430 for individuals on intravenous immunoglobulin (IVIg) and £9046 for those not on IVIg (P < 0.01). The mean (SD) utility scores were 0.62 (0.23) for CIDP, 0.63 (0.22) for PDN and 0.72 (0.14) for MMN (P = 0.52). The mean (SD) utility score for those on IVIg was 0.65 (0.16) and those not on IVIg 0.63 (0.23) (P = 0.77). CONCLUSION: The use of IVIg was the most important determinant of cost in all three diseases and the higher frequency of its use in CIDP and MMN accounted for the much greater average cost per patient in these diseases. There was no significant difference in HRQoL amongst the three diseases or between those receiving or not receiving IVIg.

Vigorimeter grip strength in CIDP: a responsive tool that rapidly measures the effect of IVIG--the ICE study.

BACKGROUND AND PURPOSE: In a recent trial in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), the ICE study, grip strength measurement captured significantly more improvement in patients receiving immune globulin (IGIV-C) intravenously than in those receiving placebo. METHODS: We conducted a systematic analysis to determine the sensitivity of grip strength as an indicator of meaningful clinical changes in CIDP. RESULTS: A randomized double-blind trial was undertaken in 117 CIDP patients who received IGIV-C or placebo every 3 weeks for up to 24 weeks. Grip strength and inflammatory neuropathy cause and treatment (INCAT) disability scores were assessed at each visit, and the responsiveness of each scale was compared. A minimum clinically important difference cut-off value for grip strength (>8 kPa) and INCAT score (>1 point) was applied to assess the proportion of responders to IGIV-C versus placebo. This analysis showed that grip strength demonstrated significant improvement earlier (as early as day 16) than the INCAT disability scale in patients receiving IGIV-C compared with placebo. A significantly higher proportion of improvers were seen in the IGIV-C group (37.5%-50.9%) than in the placebo group (21.1%-25.9%) for grip strength at day 16, week 3, week 6 and the end of the first period. Also, grip strength showed within the first 6 weeks in the placebo group significantly more patients with a clinically meaningful deterioration (>8 kPa), compared with the INCAT (>1-point deterioration) findings. CONCLUSIONS: Grip strength can be considered a sensitive tool for assessing clinically relevant changes in patients with CIDP. Its use in daily practice is suggested.

Altering the dewetting characteristics of ultrathin gold and silver films using a sacrificial antimony layer.

Solid state dewetting of ultrathin films is the most straightforward means of fabricating substrate-supported noble metal nanostructures. This assembly process is, however, quite inflexible, yielding either densely packed smaller structures or widely spaced larger structures. Here, we demonstrate the utility of introducing a sacrificial antimony layer between the substrate and noble metal overlayer. We observe an agglomeration process which is radically altered by the concurrent sublimation of antimony. In stark contrast with conventional dewetting, where the thickness of the deposited metal film determines the characteristic length scales of the assembly process, it is the thickness of the sacrificial antimony layer which dictates both the nanoparticle size and interparticle spacing. The result is a far more flexible self-assembly process where the nanoparticle size and areal density can be varied widely. Demonstrations show nanoparticle areal densities which are varied over four orders of magnitude assembled from the identical gold layer thickness, where the accompanying changes to nanostructure size see a systematic shift in the wavelength of the localized surface plasmon resonance. As a pliable self-assembly process, it offers the opportunity to tailor the properties of an ensemble of nanostructures to meet the needs of specific applications.

[Guillain-Barré syndrome after exposure to influenza]. / Guillain-Barré-Syndrom nach Exposition mit Influenza.

Guillain-Barré Syndrome (GBS) is an acquired, monophasic inflammatory polyradiculoneuritis of autoimmune origin, which occurs after infection and occasionally also after vaccination. Seasonal and pandemic influenza vaccines have in particular been implicated as triggers for GBS. However, a number of recent studies indicate that infection with influenza virus may also cause GBS. This review summarizes the epidemiological and experimental data of the association of GBS with exposure to influenza antigens by immunization (including vaccines against A/H1N1/2009) and infection. Vaccination against influenza is associated with a very low risk for the occurrence of GBS. In contrast infection with influenza may play a more important role as a triggering factor for GBS than previously assumed.

Long-term trends in CD4 cell counts and impact of viral failure in individuals starting antiretroviral therapy: UK Collaborative HIV Cohort (CHIC) study.

OBJECTIVE: The aim of the study was to describe trends in CD4 cell counts in HIV-infected patients after initiation of combination antiretroviral therapy (cART), according to CD4 cell count at initiation (baseline), and to quantify the implications of virological failure for these trends. METHODS: Eligible participants from the UK Collaborative HIV Cohort (CHIC) were antiretroviralnaïve and started cART after 1997. Random effects were used to model CD4 cell count trends, accounting for multiple measurements within participants. We assessed whether CD4 cell count trends varied according to baseline CD4 cell count and separately in participants with and without post-cART virological failure. Effects of post-cART virological failure (>1000 HIV-1 RNA copies/mL) on subsequent CD4 cell counts were evaluated. FINDINGS: A total of 7069 participants were included in the analysis (median follow-up in all baseline CD4 cell count groups was ≥ 35 months). Among participants without virological failure ≥ 6 months after the start of cART, CD4 cell counts continued to increase up to 8 years, with little evidence that differences between baseline CD4 cell count groups diminished over time. Virological failure ≥ 6 months after the start of cART was associated with lower subsequent CD4 cell counts, with greater CD4 cell count reduction for more recent virological failure and higher viral load. CONCLUSIONS: Post-cART CD4 cell counts are strongly related to pre-cART CD4 cell counts. CD4 cell count recovery is greatest in individuals who can avoid viral loads >1000 copies/mL while on cART.

Confirming the efficacy of intravenous immunoglobulin in CIDP through minimum clinically important differences: shifting from statistical significance to clinical relevance.

BACKGROUND: The ICE trial demonstrated the efficacy of immune globulin intravenous (IGIV-C) over placebo in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). However, improving the interpretability of the results by analysing the minimum clinically important difference (MCID) had not been considered. OBJECTIVES: To identify MCID thresholds of various outcome measures using different methods and to test treatment differences (IGIV-C vs placebo) using these thresholds. METHODS: One anchor-based (Short Form-36 question 2) and three distribution-based (½ SD, 1 SE of measurement, and effect size) techniques were employed to identify MCID cut-offs for various impairments (electromyographic parameters, Medical Research Council (MRC) sum score, grip strength, inflammatory neuropathy cause and treatment (INCAT) sensory sum score), disability (INCAT scale score, Rotterdam handicap scale (RHS) score) and quality of life (SF-36). IGIV-C or placebo was administered every 3 weeks for up to 24 weeks to 117 CIDP patients. Patients who did not improve by ≥1 point on the INCAT scale received alternate treatment. The proportion of patients with results exceeding identified MCID thresholds was compared. Results MCID cut-offs for outcomes were determined using each method. For the INCAT disability scale (primary ICE-trial outcome), all MCID methods identified significantly more responders with IGIV-C than placebo. Significant differences favouring IGIV-C were also demonstrated for various nerve conduction parameters, MRC sum score, grip strength, RHS score and SF-36 physical component summary score. CONCLUSION: In addition to being statistically significant, all MCID analyses showed that CIDP improvements with IGIV-C are clinically meaningful. Consideration of MCID is recommended in future therapeutic trials. Trial Registration Number NCT00220740 (http://ClinicalTrials.gov).

Clinical applications of intravenous immunoglobulins in neurology.

Intravenous immunoglobulin (IVIg) is used increasingly in the management of patients with neurological conditions. The efficacy and safety of IVIg treatment in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Guillain-Barré syndrome (GBS) have been established clearly in randomized controlled trials and summarized in Cochrane systematic reviews. However, questions remain regarding the dose, timing and duration of IVIg treatment in both disorders. Reports about successful IVIg treatment in other neurological conditions exist, but its use remains investigational. IVIg has been shown to be efficacious as second-line therapy in patients with dermatomyositis and suggested to be of benefit in some patients with polymyositis. In patients with inclusion body myositis, IVIg was not shown to be effective. IVIg is also a treatment option in exacerbations of myasthenia gravis. Studies with IVIg in patients with Alzheimer's disease have reported increased plasma anti-Abeta antibody titres associated with decreased Abeta peptide levels in the cerebrospinal fluid following IVIg treatment. These changes at the molecular level were accompanied by improved cognitive function, and large-scale randomized trials are under way.

Humoral and cellular immune responses to myelin protein peptides in chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVES: Evidence that chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease was sought, by studying cellular and humoral immune responses to peripheral nerve myelin proteins. METHODS: 40 CIDP, 36 healthy control subjects (HC) and subjects with non-immune mediated neuropathies (other neuropathies, ON) for antibodies were studied by ELISA and cellular responses by cytokine ELISPOT (INF gamma, IL10) and ELISA (IL17) to synthetic peptides representing P0, P2 and PMP22. RESULTS: Antibodies to P0, P2 or PMP22 peptides were detected in only a minority of CIDP, both not treated (nT-CIDP) and treated (T-CIDP). IgG antibodies to P2(80-105) were significantly more frequent in CIDP than in HC (4/30 vs 0/32; p<0.05) but the difference from ON (1/25) was not significant. In ELISPOT assays, IFN gamma was detected at a low frequency in CIDP and did not differ from HC or ON. In contrast, IL10 responses against P2(1-85) were more frequent in nT and T-CIDP (7/24 and 3/16) than HC (0/36; p<0.001 and p<0.05, respectively). The production of IL17 in cell-culture supernatants was not increased. CONCLUSIONS: Antibodies to non-conformational antigenic epitopes of myelin proteins rarely occur in CIDP. None of the myelin protein peptides elicited IFN gamma responses, but P2 elicited IL10 responses significantly more often in CIDP patients than in controls. This reactivity may be part of an antigen-specific Th2 type pathogenetic or regulatory mechanism or represent a transitory epiphenomenon due to nerve damage. In our study, P2 was the protein antigen most likely to be involved in the aberrant immune responses in CIDP.

Regional distribution, developmental changes, and cellular localization of CNTF-mRNA and protein in the rat brain.

Ciliary neurotrophic factor (CNTF) is a potent survival molecule for a variety of embryonic neurons in culture. The developmental expression of CNTF occurs clearly after the time period of the physiological cell death of CNTF-responsive neurons. This, together with the sites of expression, excludes CNTF as a target-derived neuronal survival factor, at least in rodents. However, CNTF also participates in the induction of type 2 astrocyte differentiation in vitro. Here we demonstrate that the time course of the expression of CNTF-mRNA and protein in the rat optic nerve (as evaluated by quantitative Northern blot analysis and biological activity, respectively) is compatible with such a glial differentiation function of CNTF in vivo. We also show that the type 2 astrocyte-inducing activity previously demonstrated in optic nerve extract can be precipitated by an antiserum against CNTF. Immunohistochemical analysis of astrocytes in vitro and in vivo demonstrates that the expression of CNTF is confined to a subpopulation of type 1 astrocytes. The olfactory bulb of adult rats has comparably high levels of CNTF to the optic nerve, and here again, CNTF-immunoreactivity is localized in a subpopulation of astrocytes. However, the postnatal expression of CNTF in the olfactory bulb occurs later than in the optic nerve. In other brain regions both CNTF-mRNA and protein levels are much lower.

Derivation and validation of diagnostic criteria for chronic inflammatory demyelinating polyneuropathy.

To develop diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP), a retrospective series of patients' records diagnosed by sexpert consensus as CIDP or other chronic polyneuropathies were analyzed. Classification and regression tree analysis was applied to 150 patients to derive a classification rule. According to the rule, diagnosis of CIDP required that a patient have a chronic non-genetic polyneuropathy, progressive for at least eight weeks, without a serum paraprotein and either 1) recordable compound muscle action potentials in > or =75% of motor nerves and either abnormal distal latency in >50% of nerves or abnormal motor conduction velocity in >50% of nerves or abnormal F wave latency in >50% of nerves; or 2) symmetrical onset of motor symptoms, symmetrical weakness of four limbs, and proximal weakness in > or =1 limb. When validated in 117 patients, the rule had 83% sensitivity (95% confidence interval 69%-93%) and 97% specificity (95% confidence interval 89%-99%) and performed better than published criteria.

Evidence that fibroblast growth factor 5 is a major muscle-derived survival factor for cultured spinal motoneurons.

We examined the potential role of fibroblast growth factor 5 (FGF-5) as a target-derived trophic factor for spinal motoneurons. Northern analysis of total RNA from rat skeletal muscle revealed an FGF-5 mRNA transcript both during the period of embryonic motoneuron death and in the adult. Recombinant human FGF-5 supported the survival of highly enriched cultures of embryonic chick motoneurons. Significant proportions of the motoneuron survival activity of rat skeletal muscle extracts could be immunoprecipitated using an antiserum to FGF-5. The immunoprecipitable activity was present in soluble and matrix-bound forms in embryonic muscle, but bound exclusively to the extracellular matrix in adult muscle. These results, along with the secretory nature of FGF-5, suggest that FGF-5 may act as a target-derived trophic factor for motoneurons.

A prospective study of physiotherapist prescribed community based exercise in inflammatory peripheral neuropathy.

There is insufficient evidence to support the use of exercise in the management of chronic disablement in people with inflammatory peripheral neuropathy. Therefore, our study aimed to determine the feasibility and effectiveness of a physiotherapist prescribed community based exercise programme for reducing chronic disablement in patients with stable motor neuropathy. We assessed the effects of a 12 week unsupervised, community based strengthening, aerobic and functional exercise programme on activity limitation and other measures of functioning in 16 people with stable motor neuropathy and 10 healthy control subjects. Fourteen of 16 patients and 8 out of 10 healthy control subjects completed the study and exercised safely in the community with no adverse events. Significant improvements were seen in all measures of activity limitation and in wider measures of health including anxiety, depression and fatigue in the patient group. Improvements were sustained at six months after completion of the exercise programme, except for depression. Ten patients continued to exercise regularly at six months. These findings demonstrate that individually prescribed community based exercise is feasible and acceptable for people with stable motor neuropathy and participation in exercise may be successful in reducing chronic disablement. Future randomised controlled trials are needed to examine the efficacy of this complex community based intervention.

Immunosuppressive treatment for non-systemic vasculitic neuropathy.

BACKGROUND: Non-systemic vasculitic neuropathy is a rare disabling disease that usually has a subacute onset of progressive or relapsing-remitting sensory or sensorimotor deficits. Asymmetry, pain and weakness are key features. The diagnosis can only be made by exclusion of other causes, the absence of systemic vasculitis or other rheumatic diseases, and the demonstration of vasculitis in a nerve or a combined nerve and muscle biopsy. There is a need for efficacious therapy to prevent disease progression and to improve prognosis. OBJECTIVES: To assess if immunosuppressive treatment in non-systemic vasculitic neuropathy reduces disability, and ameliorates neurological symptoms, and if such therapy can be given safely. SEARCH STRATEGY: The Cochrane Neuromuscular Disease Group Trials Register (March 2006), The Cochrane Library (Issue 1, 2006), MEDLINE, EMBASE, LILACS, and ISI were searched from January 1980 until April 2006. In addition, the reference lists of relevant articles, reviews and textbooks were handsearched. SELECTION CRITERIA: All randomised or quasi-randomised trials that examined the efficacy of immunosuppressive treatment for non-systemic vasculitic neuropathy at least one year after the onset of therapy were sought. Participants had to fulfill the following criteria: absence of systemic or neurological disease, exclusion of any recognised cause of the neuropathy by appropriate clinical or laboratory investigations, electrophysiological studies in agreement with axonal neuropathy, confirmation of vasculitis in a nerve or a combined nerve and muscle biopsy. The primary outcome measure was to be improvement in disability. Secondary outcome measures were to be change in the mean disability score, change in muscle strength measured with the Medical Research Council sum score, change in pain or other positive sensory symptoms, number of relapses, and adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed and extracted details of all potentially relevant trials. For included studies pooled relative risks and pooled weighted standardised mean differences were to be calculated to assess treatment efficacy. MAIN RESULTS: Fifty-nine studies were identified and assessed for possible inclusion in the review, but all were excluded because of insufficient quality or lack of relevance. AUTHORS' CONCLUSIONS: No adequate randomised or quasi-randomised controlled clinical trials have been performed on which to base treatment for non-systemic vasculitic neuropathy. Randomised trials of corticosteroids and other immunosuppressive agents are needed.

Current strategies for modulating lymphangiogenesis signalling pathways in human disease.

The recent discovery that members of the vascular endothelial growth factor (VEGF) family of secreted glycoproteins can mediate lymphatic vessel growth (lymphangiogenesis) via cell surface receptor tyrosine kinases expressed on endothelial cells has opened the way for therapeutic intervention for pathologies involving dysregulated lymphatic vessel function. At least two members of this family, VEGF-C and VEGF-D, have been shown to induce lymphangiogenesis in vivo. Lymphatic vessels and their specific growth factors have been directly implicated in a number of significant human pathologies. In cancer, VEGF-C and VEGF-D appear to correlate with tumor metastasis and poor patient outcome in a range of prevalent human cancers. Experimental studies have demonstrated that expression of the lymphangiogenic growth factors in tumor models induces increased lymphangiogenesis and results in spread of tumor cells via the lymphatics. In contrast, conditions such as lymphedema, where lymphatic vessels fail to clear fluid from interstitial spaces, are opportunities for which the application of growth factors to generate new lymphatic vessels may be a viable therapeutic option. The list of molecules that control lymphangiogenesis is now expanding, allowing more opportunities for the development of drugs with which to manipulate the relevant signalling pathways. Modulating these pathways and other molecules with specificity to the lymphatic endothelium could offer alternative treatments for a number of important clinical conditions.

A modified peripheral neuropathy scale: the Overall Neuropathy Limitations Scale.

A new peripheral neuropathy activities measure, the Overall Neuropathy Limitations Scale (ONLS), was derived by modifying the Overall Disability Sum Score (ODSS) slightly. Its inter-rater reliability was found to be high and its correlation with the ODSS (r = 0.97), 36-item Short Form Questionnaire Physical Component Summary Score, and participation and impairment measures was significant. Acceptable responsiveness (standardised response mean 0.76) was shown by the ONLS. The results obtained from the questionnaire agreed closely with those obtained from observation of the tasks on the ONLS, but were not equivalent. The simplicity of the ODSS is shared by the ONLS, but the ONLS has better content validity and less ceiling effect, which may make it more useful for clinical practice and research.