Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome

BACKGROUND & AIMS: Serotonin (5-HT) is a critical signaling molecule in the gut. 5-HT released from enterochromaffin cells initiates peristaltic, secretory, vasodilatory, vagal, and nociceptive reflexes. Despite being pathophysiologically divergent, ulcerative colitis (UC) and irritable bowel syndrome (IBS) are both associated with clinical symptoms that include alterations in the normal patterns of motility, secretion, and sensation. Our aim was to test whether enteric 5-HT signaling is defective in these disorders. METHODS: Rectal biopsy specimens were obtained from healthy controls and patients with UC, IBS with diarrhea (IBS-D), and IBS with constipation (IBS-C). Key elements of 5-HT signaling, including measures of 5-HT content, release, and reuptake, were analyzed with these samples. RESULTS: Mucosal 5-HT, tryptophan hydroxylase 1 messenger RNA, serotonin transporter messenger RNA, and serotonin transporter immunoreactivity were all significantly reduced in UC, IBS-C, and IBS-D. The enterochromaffin cell population was decreased in severe UC samples but was unchanged in IBS-C and IBS-D. When 5-HT release was investigated under basal and mechanical stimulation conditions, no changes were detected in any of the groups relative to controls. CONCLUSIONS: These data show that UC and IBS are associated with similar molecular changes in serotonergic signaling mechanisms. While UC and IBS have distinct pathophysiologic properties, these data suggest that shared defects in 5-HT signaling may underlie the altered motility, secretion, and sensation. These findings represent the first demonstration of significant molecular alterations specific to the gut in patients with IBS and support the assertion that disordered gastrointestinal function in IBS involves changes intrinsic to the bowel.     

Short-term effectiveness of a community-implemented falls prevention referral service

Purpose: To evaluate the effectiveness of the 16-week evidence-based Steady Steps exercise referral scheme at improving physical function, balance confidence, and quality of life (QoL) of community-dwelling older adults at risk of falling.

Method: A non-experimental, practice-based study involving a retrospective analysis of participant outcomes. Pre–post comparisons of three performance-based measures of gait and balance and of person-reported outcomes for balance confidence and QoL were performed. Effectiveness was evaluated in terms of statistically significant changes and relative to published fall-risk thresholds and minimal detectable changes (MDCs) or minimum clinically important differences.

Results: One hundred and thirty-six participants completed the program over 19?months. Statistically significant differences were observed for all outcomes (p?40% reported clinically important improvements in QoL.

Conclusions: While the non-experimental design precludes conclusive evidence of causation, the highly significant and clinically meaningful improvements observed in individuals who completed the evidence-based Steady Steps program support its translation of evidence into effective practice. Continued implementation and evaluation of such practices and their longer-term effects are warranted.

• Implications for Rehabilitation

• Falls in older adults represent an escalating public health problem, and rehabilitation professionals are charged with developing and/or identifying feasible and effective evidence-based programs that target and reduce falls risk in this population.

• Our findings support Steady Steps as an effective third-sector referral rehabilitation service that successfully translates research evidence-based exercise interventions into effective practice, positively impacting physical function, balance confidence and quality of life (QoL) in community-dwelling older adults.

• Our study provides practice-based evidence of the effectiveness of exercise interventions that are progressively challenging, deliver a high dose of moderate to high intensity and target the main falls risk factors of muscle weakness and gait and balance impairment.

• In spite of their limitations, non-experimental, practice-based approaches provide rehabilitation professionals with feasible opportunities for evaluating existing services, such as Steady Steps, and contributing to the overall evidence-base for falls prevention and management.

     

Association of baseline levels of markers of bone and cartilage degradation with long-term progression of joint damage in patients with early rheumatoid arthritis: the COBRA study

OBJECTIVE: The known risk factors for radiologic progression in rheumatoid arthritis (RA) are not optimally discriminative in patients with early disease who do not have evidence of radiologic damage. We sought to determine whether urinary C-terminal crosslinking telopeptide of type I (CTX-I) and type II (CTX-II) collagen (markers of bone and cartilage destruction, respectively) are associated with long-term radiologic progression in patients with early RA. METHODS: This was a prospective study of 110 patients with early RA who were participating in the COBRA (Combinatietherapie Bij Reumato?de Artritis) clinical trial and followup study, a randomized controlled trial comparing the efficacy of oral pulse prednisolone, methotrexate, plus sulfasalazine with sulfasalazine alone. We investigated the relationship between baseline levels of urinary CTX-I and CTX-II and the mean annual progression of joint destruction over a median of 4 years, as measured by changes in the modified Sharp score (average of 2 independent readers). RESULTS: In multivariate logistic regression analysis, baseline urinary CTX-I and CTX-II levels in the highest tertile were the strongest predictors of radiologic progression (Sharp score increase >2 units/year; odds ratio 7.9 and 11.2, respectively), independently of treatment group, erythrocyte sedimentation rate (ESR), Disease Activity Score in 28 joints, rheumatoid factor (RF), and baseline joint damage (Sharp score). The likelihood ratios for a positive test were 3.8 and 8.0 for CTX-I and CTX-II, respectively, which compared favorably with the likelihood ratios for the ESR (3.0), baseline joint damage (1.6), and RF (1.8). When patients were grouped according to the presence (Sharp score >/=4, n = 49) and absence (Sharp score <4, n = 61) of joint damage at baseline, CTX-I and CTX-II levels were predictive only in those without baseline joint damage (odds ratio 14.9 and 25.7, respectively). CONCLUSION: High baseline levels of urinary CTX-I and CTX-II independently predict an increased risk of radiologic progression over 4 years in patients with early RA, especially those without radiologic joint damage. Urinary CTX-I and CTX-II may be useful for identifying individual RA patients at high risk of progression very early in the disease, before erosions can be detected radiographically. Such patients may be in special need of treatments that inhibit bone and cartilage degradation.     

Evidence for diploidy in metacyclic forms of African trypanosomes.

The DNA contents of bloodstream form trypanosomes (life cycle stages circulating in the blood of the vertebrate host) of four African Trypanosoma species and of metacyclic forms (the life cycle stage that is injected into the vertebrate by the tsetse fly during its bite) of the same four species were measured by cytofluorometry of individual cells or nuclei. The results showed unambiguously that the metacyclic forms cannot be considered to be products of meiosis containing only half of the DNA of bloodstream forms, in contrast to what was previously reported for Trypanosoma brucei [Zampetti-Bosseler, F., Schweizer, J., Pays, E., Jenni, L. & Steinert, M. (1986) Proc. Natl. Acad. Sci. USA 83, 6063-6064] during an attempt to localize the gametes in the life cycle after experimental evidence of sexual gene exchange in this parasite was reported.     

Patients at the outpatient rheumatology clinic: do they really need to be there?

BACKGROUND: The workload at many outpatient clinics within the Dutch health care system has been growing relentlessly, resulting in unacceptable waiting lists and reduced accessibility. Assessing streams of patients and introducing a method of accelerated referral of patients back to the general practitioner (GP) under specialist guidance could help to alleviate these problems. METHODS: Seventeen GPs collaborated with rheumatologists during a 2-year period in a 'joint consultation' model in which GPs and rheumatologists discussed patients together. All patient charts belonging to patients who had been referred to the outpatient clinic by these 17 GPs were identified. Rheumatologists assessed whether or not these patients could be referred back to the participating GPs under the guidance of the specialist in the joint consultation model. RESULTS: Of 276 eligible patients, 121 were discharged from the outpatient clinic. Eighty-seven patients required specialist follow-up, 22 patients refused to participate, and six patients were not entered into the study by the rheumatologist. Some 21 patients eventually entered the study, 18 of whom were referred back to the GP. CONCLUSION: The role of joint consultation appears to be limited. Improving the referral behavior of GPs should take precedence over transferring follow-up from the outpatient clinic to the primary care level.     

Septic arthritis of the pubic symphysis: review of 100 cases

We report a novel case of septic arthritis of the symphysis pubis due to Streptococcus pneumoniae and review 99 previously reported cases of infection of this joint. Typical features of pubic symphysis infection included fever (74%), pubic pain (68%), painful or waddling gait (59%), pain with hip motion (45%), and groin pain (41%). Risk factors included female incontinence surgery (24%); sports, especially soccer (19%); pelvic malignancy (17%); and intravenous drug use (15%). Septic arthritis of the pubic symphysis is often misdiagnosed as osteitis pubis, a sterile inflammatory condition. Causative organisms differed according to risk factors. Staphylococcus aureus was the major cause among athletes, Pseudomonas aeruginosa among intravenous drug users, and infections among patients with pelvic malignancies were usually polymicrobial, involving fecal flora. Patients with recent urinary incontinence surgery usually had monomicrobial infection, with no predominant pathogen. Since osteomyelitis is present in 97% of patients, we recommend antibiotic courses of 6 weeks' duration. Surgical debridement is required in 55% of patients.