The two-year progression of structural and functional cerebral MRI in amyotrophic lateral sclerosis.

MRI has emerged as one of several urgently needed candidate disease progression biomarkers for the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), not least due to its unique ability to non-invasively assess structural and functional cerebral pathology. We sought to identify the extent of detectable change in cerebral MRI metrics over a more prolonged period. Analysis of multi-modal MRI data was performed in a cohort of sixteen patients (13 ALS and 3 with primary lateral sclerosis) in whom it was possible to acquire six-monthly images over two years. Structural brain changes were assessed using voxel-based morphometry of grey matter and shape analysis of sub-cortical grey matter structures, tract-based spatial statistics of diffusion tensor imaging (DTI) metrics optimized for longitudinal analysis in the white matter, as well as whole brain voxel-wise statistics of DTI metrics. Changes in resting state functional MRI (rs-fMRI) were investigated via independent component and dual regression analyses of functional connectivity (FC), controlled for confounding effects of grey matter decline. Both linear changes with time and brain changes correlated with revised ALS functional rating score (ALSFRS-R) decline were studied. Widespread and progressive reductions in grey matter were observed in the precentral gyri and posterior cingulate cortex, as well as progressive local atrophy of the thalamus, caudate, and pallidum bilaterally, and right putamen, hippocampus and amygdala. The most prominent DTI tract-based changes were in the superior longitudinal fasciculi and corpus callosum. More widespread areas of DTI changes included the thalami and caudate nuclei, hippocampi and parahippocampal gyri, insular cortices, anterior and posterior cingulate gyri, frontal operculum and cerebellum. FC decreases were noted between the sensorimotor resting state network and the frontal pole, between a network comprising both thalami and an area in the visual cortex, in relation to both time from baseline and ALSFRS-R decline. FC increases between the left primary motor cortex and left fronto-parietal network were seen for both statistical approaches. A longer period of follow-up, though necessarily involving more slowly-progressive cases, demonstrated widespread changes in both grey and white matter structural MRI measures. The mixed picture of regional decreases and increases in FC is compatible with compensatory change, in what should be viewed as a brain-based disease characterised by larger-scale disintegration of motor and frontal projection cerebral networks.

Structure of an amide bond forming F(420):gamma-glutamyl ligase from Archaeoglobus fulgidus -- a member of a new family of non-ribosomal peptide synthases.

F(420) is a flavin-like redox-active coenzyme commonly used by archaea and some eubacteria in a variety of biochemical reactions in methanogenesis, the formation of secondary metabolites, the degradation of nitroaromatic compounds, activation of nitroimidazofurans, and F(420)-dependent photolysis in DNA repair. Coenzyme F(420)-2 biosynthesis from 7,8-didemethyl-8-hydroxy-5-deazariboflavin (Fo) and lactaldehyde involves six enzymatic steps and five proteins (CofA, CofB, CofC, CofD, and CofE). CofE, a F(420)-0:gamma-glutamyl ligase, is responsible for the last two enzymatic steps; it catalyses the GTP-dependent addition of two L-glutamate residues to F(420)-0 to form F(420)-2. CofE is found in archaea, the aerobic actinomycetes, and cyanobacteria. Here, we report the first crystal structure of the apo-F(420)-0:gamma-glutamyl ligase (CofE-AF) from Archaeoglobus fulgidus and its complex with GDP at 2.5 A and 1.35 A resolution, respectively. The structure of CofE-AF reveals a novel protein fold with an intertwined, butterfly-like dimer formed by two-domain monomers. GDP and Mn(2+) are bound within the putative active site in a large groove at the dimer interface. We show that the enzyme adds a glutamate residue to both F(420)-0 and F(420)-1 in two distinct steps. CofE represents the first member of a new structural family of non-ribosomal peptide synthases.

Do video sounds interfere with auditory event-related potentials?

To make the electroencephalogram (EEG) recording procedure more tolerable, listeners have been allowed in some experiments to watch an audible video while their auditory P1, N1, P2, and mismatch negativity (MMN) event-related potentials (ERPs) to experimental sounds have been measured. However, video sounds may degrade auditory ERPs to experimental sounds. This concern was tested with 19 adults who were instructed to ignore standard and deviant tones presented through headphones while they watched a video with the soundtrack audible in one condition and silent in the other. Video sound impaired the size, latency, and split-half reliability of the MMN, and it decreased the size of the P2. However, it had little effect on the P1 or N1 or on the split-half reliability of the P1-N1-P2 waveform, which was significantly more reliable than the MMN waveform regardless of whether the video sound was on or off. The impressive reliability of the P1 and N1 components allows for the use of video sound during EEG recording, and they may prove useful for assessing auditory processing in listeners who cannot tolerate long testing sessions.

The prevalence of dermatophyte infection in well-controlled diabetics and the response to Trichophyton antigen.

The prevalence of dermatophyte infection was assessed in 100 patients with well-controlled insulin-dependent diabetes, and in a control group of 100 non-diabetics matched for age, sex, occupation and sporting activity. Immediate and delayed responses to intradermal testing with Trichophyton antigen were recorded in both groups. The overall infection rate (skin and nails) was 19% in diabetics and 17% in controls. There was a higher infection rate in the skin of diabetics (17%) than in controls (8%), but this was not significant. Nail infection was seen in 12% of diabetics and in 11% of controls. Intradermal testing with Trichophyton antigen gave a higher proportion of both immediate and delayed positive results in diabetics. However, more control patients showed only an immediate positive response or only a delayed one. There was no evidence of an increased infection rate in those with immediate positive responses or of diminished infection rates in those with delayed positive responses, and no correlation with oral Candida infection. These findings applied equally to diabetics and controls.

A critique of the practice-expense values of the resource-based relative value scale.

The resource-based relative value scale (RBRVS) was implemented by the Health Care Financing Administration on January 1, 1992. The practice-expense payments from the old Medicare fee scale were moved unchanged into RBRVS. This resulted in underpayment of office-based practice expenses and overpayment of hospital-based practice expenses. For example, office visits are underpaid by $10.28, whereas coronary angiograms are overpaid by $123.00. Unpaid practice expenses reduce the after-expense physician-work fee of the average office visit by about one half, yet overpayment of practice expenses for some hospital procedures almost doubles the after-expense physician-work fee for some subspecialties. Inflation will likely increase the actual practice expense of the average office visit to the point that the after-expense physician-work fee for the family physician will be reduced to zero by the year 2001.

Offsetting toxicity of antineoplastic agents.

PCO, a yeast extract, offsets at least in part the mitotic inhibitory effect of methotrexate and fluorouracil on bone marrow cells in vitro but increases the antimitotic activity of the drugs on ascites Krebs-2 carcinoma under similar conditions. In vivo, PCO enhances the action of methotrexate against the L-1210 lymphoid leukemia and does not interfere with the effectiveness of fluorouracil against the ascites Krebs-2 tumor.