23S rRNA base pair 2057-2611 determines ketolide susceptibility and fitness cost of the macrolide resistance mutation 2058A-->G

The 23S rRNA A2058G alteration mediates macrolide, lincosamide, and streptogramin B resistance in the bacterial domain and determines the selectivity of macrolide antibiotics for eubacterial ribosomes, as opposed to eukaryotic ribosomes. However, this mutation is associated with a disparate resistance phenotype: It confers high-level resistance to ketolides in mycobacteria but only marginally affects ketolide susceptibility in streptococci. We used site-directed mutagenesis of nucleotides within domain V of 23S rRNA to study the molecular basis for this disparity. We show that mutational alteration of the polymorphic 2057-2611 base pair from A-U to G-C in isogenic mutants of Mycobacterium smegmatis significantly affects susceptibility to ketolides but does not influence susceptibility to other macrolide antibiotics. In addition, we provide evidence that the 2057-2611 polymorphism determines the fitness cost of the 23S rRNA A2058G resistance mutation. Supported by structural analysis, our results indicate that polymorphic nucleotides mediate the disparate phenotype of genotypically identical resistance mutations and provide an explanation for the large species differences in the epidemiology of defined drug resistance mutations.     

Surgery for fulminating colitis during pregnancy

Two cases of fulminating colitis presenting during pregnancy are described. In both cases, resectional surgery was performed. In the first case, cesarean section was combined with subtotal colectomy and ileostomy during the 32nd week of gestation. In the second case, cesarean section was performed during the 33rd week of gestation and proctocolectomy in the puerperium. In both cases, histopathologic examination showed colitis more consistent with Crohn's disease. It is concluded that if fulminating colitis appears during pregnancy it should be treated in the same manner as in the nonpregnant state.     

RV Fractional Area Change and TAPSE as Predictors of Severe Right Ventricular Dysfunction in Pulmonary Hypertension: A CMR Study

Background

The right ventricular ejection fraction (RVEF) is a surrogate marker of right ventricular function in pulmonary hypertension (PH), but its measurement is complicated and time consuming. The tricuspid annular plane systolic excursion (TAPSE) measures only the longitudinal component of RV contraction while the right ventricular fractional area change (RVFAC) takes into account both the longitudinal and the transversal components. The aim of our study was to evaluate the relationship between RVEF, RVFAC, and TAPSE according to hemodynamic severity in two groups of patients with PH: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).

Methods and Results

Fifty-four patients with PAH (n?=?15) and CTEPH (n?=?39) underwent right heart catheterization and cardiac magnetic resonance (CMR). The ventricular volumes and areas, TAPSE, and eccentricity index were measured. The RVFAC was more strongly correlated with the RVEF (r?=?0.81, p?<?0.0001) than the TAPSE (r?=?0.63, p?<?0.0001). RVEF?<?35% was better predicted by the RVFAC than the TAPSE (TAPSE: AUC?=?0.77 and RVFAC: AUC?=?0.91; p?=?0.042). In the group with the worse hemodynamic status, the RVFAC correlated much better with the RVEF than the TAPSE. There were no significant differences in the CMR data analyzed between the groups of PAH and CETPH patients.

Conclusions

The RVFAC is a good index to estimate RVEF in PH patients; even better than the TAPSE in patients with more severe hemodynamic profile, possibly for including the transversal component of right ventricular function in its measurement. Furthermore, RVFAC performance was similar in the two PH groups (PAH and CTEPH).

     

Vagotomy and gallbladder function

The effect of vagotomy on gallbladder function was investigated in a clinical and experimental study. In the clinical study both the size of the gallbladder and its capacity to respond to cholecystokinin were evaluated radiologically before and after vagotomy. In studies in the rabbit, both the immediate effect of vagotomy on the gallbladder and the effect of varying doses of cholecystokinin on gallbladder pressure were studied before and after vagotomy. In studies in the cat the long-term effect of vagotomy was studied with respect to the histology of the gallbladder and the composition of bile.The clinical investigation showed that vagotomy was followed by a significant increase in the volume of the gallbladder and that the effect of the cholecystokinin on the gallbladder remained unchanged after vagotomy. In experiments in the rabbit it was found that cholecystokinin in a dose of 1 unit/kg body weight exerted a somewhat lesser effect on gallbladder pressure after vagotomy than before, while after vagotomy a dose, approximately four times greater, resulted in a stronger gallbladder response. Further, the experiments showed that the chemical composition of the bile seemed to be altered after vagotomy, while the gallbladder remained histologically essentially unchanged.     

The dystrophin gene and cognitive function in the general population

The aim of our study is to investigate whether single-nucleotide dystrophin gene (DMD) variants associate with variability in cognitive functions in healthy populations. The study included 1240 participants from the Erasmus Rucphen family (ERF) study and 1464 individuals from the Rotterdam Study (RS). The participants whose exomes were sequenced and who were assessed for various cognitive traits were included in the analysis. To determine the association between DMD variants and cognitive ability, linear (mixed) modeling with adjustment for age, sex and education was used. Moreover, Sequence Kernel Association Test (SKAT) was used to test the overall association of the rare genetic variants present in the DMD with cognitive traits. Although no DMD variant surpassed the prespecified significance threshold (P<1 × 10⁻⁴), rs147546024:A>G showed strong association (β=1.786, P-value=2.56 × 10⁻⁴) with block-design test in the ERF study, while another variant rs1800273:G>A showed suggestive association (β=−0.465, P-value=0.002) with Mini-Mental State Examination test in the RS. Both variants are highly conserved, although rs147546024:A>G is an intronic variant, whereas rs1800273:G>A is a missense variant in the DMD which has a predicted damaging effect on the protein. Further gene-based analysis of DMD revealed suggestive association (P-values=0.087 and 0.074) with general cognitive ability in both cohorts. In conclusion, both single variant and gene-based analyses suggest the existence of variants in the DMD which may affect cognitive functioning in the general populations.     

Evaluation of interleukin-6 and its soluble receptor components sIL-6R and sgp130 as markers of inflammation in inflammatory bowel diseases

Purpose

Interleukin-6 (IL-6) production and signalling are increased in the inflamed mucosa in inflammatory bowel diseases (IBD). As published serum levels of IL-6 and its soluble receptors sIL-6R and sgp130 in IBD are from small cohorts and partly contradictory, we systematically evaluated IL-6, sIL-6R and sgp130 levels as markers of disease activity in Crohn’s disease (CD) and ulcerative colitis (UC).

Methods

Consecutive adult outpatients with confirmed CD or UC were included, and their disease activity and medication were monitored. Serum from 212 CD patients (815 measurements) and 166 UC patients (514 measurements) was analysed, and 100 age-matched healthy blood donors were used as controls.

Results

IL-6 serum levels were significantly elevated in active versus inactive CD and UC, also compared with healthy controls. However, only a fraction of IBD patients showed increased serum IL-6. IL-6 levels ranged up to 32.7 ng/mL in active CD (>?5000-fold higher than in controls), but also up to 6.9 ng/mL in inactive CD. Increases in active UC (up to 195 pg/mL) and inactive UC (up to 27 pg/mL) were less pronounced. Associations between IL-6 serum levels and C-reactive protein concentrations as well as leukocyte and thrombocyte counts were observed. Median sIL-6R and sgp130 levels were only increased by up to 15%, which was considered of no diagnostic significance.

Conclusions

Only a minority of IBD patients shows elevated IL-6 serum levels. However, in these patients, IL-6 is strongly associated with disease activity. Its soluble receptors sIL-6R and sgp130 do not appear useful as biomarkers in IBD.

     

Functional and Physiologic Assessment of the Colonic Reservoir or Side-to-End Anastomosis After Low Anterior Resection for Rectal Cancer: A Two-Year Follow-Up

PURPOSE Functional disturbances are common after anterior resection for rectal cancer. This study was designed to compare functional and physiologic outcome after low anterior resection and total mesorectal excision with a colonic J-pouch or a side-to-end anastomosis.METHODS Functional and physiologic variables were analyzed in patients randomized to a J-pouch (n = 36) or side-to-end anastomosis (n = 35). Postoperative functional outcome was investigated with questionnaires. Anorectal manometry was performed preoperatively and at six months, one year, and two years postoperatively.RESULTS There was no statistical difference in functional outcome between groups at two years. Maximum neorectal volume increased in both groups but was approximately 40 percent greater at two years in pouches compared with the side-to-end anastomosis. Anal sphincter pressures volumes were halved postoperatively and did not recover during follow-up of two years. Male gender, low anastomotic level, pelvic sepsis, and the postoperative decrease of sphincter pressures were independent factors for more incontinence symptoms.CONCLUSIONS Colonic J-pouch and side-to-end anastomosis gives comparable functional results two years after low anterior resection. Neorectal volume had no detectable influence on function. There was a pronounced and sustained postoperative decrease in sphincter pressures.Supported by the Stockholm County Council, Public Health and Medical Services Committee and the Swedish Research Council, grant #09101.Reprints are not available.