Ex vivo intestinal adhesion of Escherichia coli LF82 in Crohn's disease

Adherent-invasive Escherichia coli (AIEC) are reported to inhabit the gut mucosa in Crohn’s disease (CD), however, little is known about the importance of host factors for the interplay between AIEC and the human gut.To examine if differences in bacterial adhesion patterns are disease associated, the AIEC-prototype strain LF82 was evaluated for its ability to adhere to ileal and colonic biopsies from CD and healthy controls (HC). Moreover, the efficacy of the non-pathogenic E. coli Nissle 1917 (ECN) in averting LF82 adhesion to ileal mucosa was assessed.Similar numbers of LF82 adhered to biopsies from CD and HC. A significantly greater LF82 attachment to ileal versus colonic mucosa was found in HC (P < 0.01), however, not in CD. ECN did not reduce the adhesion of LF82 to ileal specimens in CD or HC.These results show that enhanced bacterial adhesion ability is unlikely to play any significant role in CD, thus implying that other host protective factors may be impaired in CD. Further, exclusion of LF82 attachment by ECN co-incubation does not appear to represent a relevant treatment regimen.     

Monozygotic twin pairs discordant for Hashimoto's thyroiditis share a high proportion of thyroid peroxidase autoantibodies to the immunodominant region A. Further evidence for genetic transmission of epitopic "fingerprints"

Thyroid peroxidase antibodies (TPOAbs) in patients with Hashimoto's thyroiditis (HT) predominantly react with two immunodominant regions (IDR-A, IDR-B). Theoretically, as shown for the level of TPOAbs, the autoantibody epitopic recognition of the IDRs could be under genetic control. To examine this, we compared the distribution of TPOAb epitopic fingerprints between healthy monozygotic (MZ) co-twins and siblings to patients with clinically overt HT with a control group of euthyroid subjects, matched for sex and age, but without autoimmune thyroid disease (AITD) among their first-degree relatives. Two ELISAs based on competition with rabbit antisera were used to determine the IDR specificities in 23 patients with HT, 6 MZ co-twins, 8 siblings to patients with HT, and 11 healthy euthyroid subjects without predisposition to AITD. The fraction of TPOAbs recognizing IDR-A was 19, 18, and 9% in HT patients, MZ-co-twins, and siblings, respectively, which was higher than the 0% found in the group of healthy subjects without predisposition to AITD (p = 0.007 vs. HT; p = 0.1078 vs. MZ co-twin and p = 0.069 vs. siblings). Moreover, the IDR-A fraction differed between healthy MZ-co-twins and ordinary siblings (18% vs. 9%, p = 0.0127). In conclusion, our data indicate that the propensity to produce autoantibodies directed against the IDR-A epitope of TPO is genetically determined. This finding may have implications with respect to inheritance of autoantibody specificities in other autoimmune diseases.     

Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment

Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy-1 gene (OPA1), most commonly the p.R445H mutation. We present eight probands and their families from the US, Sweden, and UK with OA and SNHL, whom we analyzed for mutations in OPA1 and WFS1. Among these families, we found three heterozygous missense mutations in WFS1 segregating with OA and SNHL: p.A684V (six families), and two novel mutations, p.G780S and p.D797Y, all involving evolutionarily conserved amino acids and absent from 298 control chromosomes. Importantly, none of these families harbored the OPA1 p.R445H mutation. No mitochondrial DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indicating that the mutation is disease-causing. Our data support OA and SNHL as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1, p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1. Our findings suggest that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome.     

Serum ghrelin levels are suppressed in hypopituitary patients following insulin-induced hypoglycaemia irrespective of GH status

OBJECTIVE: Circulating ghrelin is suppressed during insulin-induced hypoglycaemia in healthy subjects, but it is unknown whether this is determined by feedback inhibition from counter-regulatory hormones. We therefore investigated the impact of GH and cortisol on ghrelin secretion during insulin-induced hypoglycaemia. DESIGN: Serum levels of ghrelin, GH, and cortisol were measured in 41 adult patients with suspected hypopituitarism during insulin-induced hypoglycaemia. Based on their peak GH response (cut-off level: 3 microg/l), the patients were divided into a GH-sufficient group (GHS) and a GH-deficient group (GHD). RESULTS: The GHS patients (n = 16) were younger (P < 0.01), had lower baseline cortisol levels [255 +/- 37 vs. 372 +/- 38 nmol/l (P = 0.04)], and tended to have a lower body mass index (P = 0.09) as compared to GHD patients (n = 25). By definition, peak GH (microg/l) was higher in GHS patients [15.0 +/- 1.8 vs. 1.0 +/- 0.2 (P < 0.0001)].The increase in serum cortisol during the ITT (insulin-tolerance test) was higher and occurred later in GHS patients [Cmax (nmol/l): 561 +/- 41 vs. 412 +/- 50 (P = 0.04); Tmax (minutes): 65 +/- 5 vs. 49 +/- 5 (P = 0.03)]. Serum ghrelin levels changed significantly with time during ITT in both groups (P < 0.0001), characterized by a moderate decline during the initial 50-60 min and a return to baseline after 2 h. No significant differences were recorded in AUCghrelin during the ITT between the two groups. No gender differences in ghrelin levels were recorded. CONCLUSIONS: (i) Like in healthy subjects serum ghrelin levels are suppressed during an ITT in patients with suspected hypopituitarism. (ii) The suppression of ghrelin was similar in GHD and GHS subjects and was not determined by cortisol. (iii) We hypothesize that insulin rather than hypoglycaemia accounts for ghrelin suppression during an ITT.     

Low birth weight is not associated with thyroid autoimmunity: a population-based twin study

CONTEXT: Low birth weight has been proposed as a risk factor for the development of antibodies toward thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) in adult life. However, the association could also be due to genetic or environmental factors affecting both birth weight and the development of thyroid autoantibodies. The effect of these confounders can be minimized through investigation of twin pairs. OBJECTIVE AND DESIGN: To examine the impact of low birth weight on the development of thyroid autoimmunity, we studied whether within-twin-cohort and within-twin-pair differences in birth weight are associated with differences in the serum concentration of TPOAb and TgAb in adult life. PARTICIPANTS: We studied 1024 euthyroid twin individuals who were distributed in 512 same-sex twin pairs. METHODS: Original midwife protocols were traced manually through the Provincial Archives of Denmark. TPOAb and TgAb were measured using solid-phase time-resolved fluoroimmunometric assays. RESULTS: There were no statistically significant associations between birth weight and serum concentrations of TPOAb [regression coefficient (beta) = 0.003 (95% confidence interval, -0.010 to 0.015); P = 0.67] or TgAb [beta = 0.002 (-0.010 to 0.014); P = 0.77]. When restricting the analysis to twin pairs with a within-pair difference in birth weight of 500 g or greater or to twin pairs born 4 wk or more before term, the regression coefficients were almost unchanged. Controlling for potential confounders (sex, zygosity, gestational age, TSH, and smoking) did not change the findings of nonsignificant regression coefficients. CONCLUSION: Low birth weight per se has no evident role in the etiology of thyroid autoimmunity.     

Deep brain stimulation of the ventrointermediate nucleus of the thalamus to treat essential tremor improves motor sequence learning

The network of brain structures engaged in motor sequence learning comprises the same structures as those involved in tremor, including basal ganglia, cerebellum, thalamus, and motor cortex. Deep brain stimulation (DBS) of the ventrointermediate nucleus of the thalamus (VIM) reduces tremor, but the effects on motor sequence learning are unknown. We investigated whether VIM stimulation has an impact on motor sequence learning and hypothesized that stimulation effects depend on the laterality of electrode location. Twenty patients (age: 38–81 years; 12 female) with VIM electrodes implanted to treat essential tremor (ET) successfully performed a serial reaction time task, varying whether the stimuli followed a repeating pattern or were selected at random, during which VIM‐DBS was either on or off. Analyses of variance were applied to evaluate motor sequence learning performance according to reaction times (RTs) and accuracy. An interaction was observed between whether the sequence was repeated or random and whether VIM‐DBS was on or off (F[1,18] = 7.89, p = .012). Motor sequence learning, reflected by reduced RTs for repeated sequences, was greater with DBS on than off (T[19] = 2.34, p = .031). Stimulation location correlated with the degree of motor learning, with greater motor learning when stimulation targeted the lateral VIM (n = 23, ρ = 0.46; p = .027). These results demonstrate the beneficial effects of VIM‐DBS on motor sequence learning in ET patients, particularly with lateral VIM electrode location, and provide evidence for a role for the VIM in motor sequence learning.