Although inflammation is an essential component of the protective response to fungi, its dysregulation may significantly worsen fungal diseases. We found here that the IL‐23/IL‐17 developmental pathway acted as a negative regulator of the Th1‐mediated immune resistance to fungi and played an inflammatory role previously attributed to uncontrolled Th1 cell responses. Both inflammation and infection were exacerbated by a heightened Th17 response against Candida albicans and Aspergillus fumigatus, two major human fungal pathogens. IL‐23 acted as a molecular connection between uncontrolled fungal growth and inflammation, being produced by dendritic cells in response to a high fungal burden and counter‐regulating IL‐12p70 production. Both IL‐23 and IL‐17 subverted the inflammatory program of neutrophils, which resulted in severe tissue inflammatory pathology associated with infection. Our data are the first demonstrating that the IL‐23/IL‐17 pathway promotes inflammation and susceptibility in an infectious disease model. As IL‐23‐driven inflammation promotes infection and impairs antifungal resistance, modulation of the inflammatory response represents a potential strategy to stimulate protective immune responses to fungi.See accompanying commentary: http://dx.doi.org/10.1002/eji.200737804

Our aim was to perform a comprehensive analysis of the global and segmental features of gait in patients with genetically confirmed inherited ataxias. Sixteen patients with autosomal dominant (spinocerebellar ataxia, SCA1 or 2) or recessive (Friedreich's ataxia, FRDA) ataxia were studied. We used a motion analysis system to record gait kinematic and kinetic data. We measured the mean values of global (time-distance parameters, COM displacement, support moment) and segmental gait parameters (joint displacement and inter-joint coordination), as both discrete and continuous variables, and their variability and correlations with International Cooperative Ataxia Rating Scale (ICARS) scores. We found a marked difference in all global gait parameters between the ataxic patients and the controls and close correlations between longer stride and stance duration and lower gait, posture and total ICARS scores. The only difference between the two patient groups was a shorter step length in the FRDA patients. As regards the segmental features, we found a significantly different waveform shape for all continuous kinematic and kinetic measures between the ataxic patients and the healthy controls, but only minor differences for the discrete measures. Intersegmental coordination evaluated using the continuous relative phase method revealed an irregular alternating joint behaviour without clear evidence of the synchronous pattern of alternating proximal/distal joint seen in healthy subjects. For almost all gait parameters we observed a markedly higher intra-subject variability in the ataxic patients versus the controls, which was strongly related to the clinical ICARS scores. Patients with chronic, progressive inherited ataxias lose the ability to "stabilize" a walking pattern that can be repeated over time. The most peculiar aspect of the gait of inherited ataxia patients, regardless the different genetic forms, seems to be the presence of increased variability of all global and segmental parameters rather than an invariant abnormal gait pattern.

Several studies have demonstrated how cerebellar ataxia (CA) affects gait, resulting in deficits in multijoint coordination and stability. Nevertheless, how lesions of cerebellum influence the locomotor muscle pattern generation is still unclear. To better understand the effects of CA on locomotor output, here we investigated the idiosyncratic features of the spatiotemporal structure of leg muscle activity and impairments in the biomechanics of CA gait. To this end, we recorded the electromyographic (EMG) activity of 12 unilateral lower limb muscles and analyzed kinematic and kinetic parameters of 19 ataxic patients and 20 age-matched healthy subjects during overground walking. Neuromuscular control of gait in CA was characterized by a considerable widening of EMG bursts and significant temporal shifts in the center of activity due to overall enhanced muscle activation between late swing and mid-stance. Patients also demonstrated significant changes in the intersegmental coordination, an abnormal transient in the vertical ground reaction force and instability of limb loading at heel strike. The observed abnormalities in EMG patterns and foot loading correlated with the severity of pathology [International Cooperative Ataxia Rating Scale (ICARS), a clinical ataxia scale] and the changes in the biomechanical output. The findings provide new insights into the physiological role of cerebellum in optimizing the duration of muscle activity bursts and the control of appropriate foot loading during locomotion.

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