Citations

The SCN5A-encoded voltage-gated mechanosensitive Na+channel NaV1.5 is expressed in human gastrointestinal smooth muscle cells and interstitial cells of Cajal. NaV1.5 contributes to smooth muscle electrical slow waves and mechanical sensitivity. In predominantly Caucasian irritable bowel syndrome (IBS) patient cohorts, 2–3% of patients have SCN5A missense mutations that alter NaV1.5 function and may contribute to IBS pathophysiology. In this study we examined a racially and ethnically diverse cohort of IBS patients for SCN5A missense mutations, compared them with IBS-negative controls, and determined the resulting NaV1.5 voltage-dependent and mechanosensitive properties. All SCN5A exons were sequenced from somatic DNA of 252 Rome III IBS patients with diverse ethnic and racial backgrounds. Missense mutations were introduced into wild-type SCN5A by site-directed mutagenesis and cotransfected with green fluorescent protein into HEK-293 cells. NaV1.5 voltage-dependent and mechanosensitive functions were studied by whole cell electrophysiology with and without shear force. Five of 252 (2.0%) IBS patients had six rare SCN5A mutations that were absent in 377 IBS-negative controls. Six of six (100%) IBS-associated NaV1.5 mutations had voltage-dependent gating abnormalities [current density reduction (R225W, R433C, R986Q, and F1293S) and altered voltage dependence (R225W, R433C, R986Q, G1037V, and F1293S)], and at least one kinetic parameter was altered in all mutations. Four of six (67%) IBS-associated SCN5A mutations (R225W, R433C, R986Q, and F1293S) resulted in altered NaV1.5 mechanosensitivity. In this racially and ethnically diverse cohort of IBS patients, we show that 2% of IBS patients harbor SCN5A mutations that are absent in IBS-negative controls and result in NaV1.5 channels with abnormal voltage-dependent and mechanosensitive function.NEW & NOTEWORTHY The voltage-gated Na+channel NaV1.5 contributes to smooth muscle physiology and electrical slow waves. In a racially and ethnically mixed irritable bowel syndrome cohort, 2% had mutations in the NaV1.5 gene SCN5A. These mutations were absent in irritable bowel syndrome-negative controls. Most mutant NaV1.5 channels were loss of function in voltage dependence or mechanosensitivity.

Vascularized toe joint transfer for finger proximal interphalangeal joint reconstruction can result in sub-optimal arc of motion and extension lag due to inappropriate intercalated bony segment length. We investigated the impact of intercalated segment length on passive arc of motion and extension lag of the reconstructed proximal interphalangeal joint. Cadaveric intercalated joint grafts were harvested from lesser toes and transferred to cadaveric fingers. The pre-determined finger proximal interphalangeal joint defect size was 2 cm. Three different intercalated segment lengths were inserted and resulting proximal interphalangeal joint arc of motion and extension lag were measured. The average arc of motion of finger proximal interphalangeal joints was 81° and 54° for toe proximal interphalangeal joints. Long intercalated segments had an average arc of motion of 30° with 32° extension lag. Equal-length intercalated segments had an average 49° arc of motion with 15° extension lag. Short intercalated segments had an average arc of motion of 71° with 8° extension lag. Shorter intercalated segments provide the greatest reduction in extension lag.

Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase–isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase–isomaltase ( SI ) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. Results CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case–control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). Conclusions SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.

Objective: Vascularized toe joint transfer for finger proximal interphalangeal joint (PIPJ) reconstruction is a well-described technique in the literature. However, the reconstructed PIPJ is known to have issues with suboptimal range of motion and extension lag. One of the reasons for this problem is the length of the intercalated bony segment. There is a lack of evidence and consensus regarding the optimal length of the intercalated segment. This study hence was performed to determine the impact of the intercalated segment length on the subsequent passive arc of motion (AOM) and extension lag of the reconstructed PIPJ. Materials and Methods: We harvested the intercalated joint graft (the toe PIPJ along with its associated extensor tendons) from the lesser toes and transferred it to the finger of cadavers. A predetermined constant PIPJ defect size of 2 cm was created on the finger. By insetting 3 different lengths of the intercalated segment to the finger PIPJ, we investigated the effect of shortened (1.5 cm), exact (2.0 cm), or lengthened (2.5 cm) intercalated segment lengths on the AOM and extension lag of the reconstructed PIPJ. Results: The average AOM of finger PIPJ was 81.0° ± 19.1° and that of the toe PIPJ was 53.6° ± 16.1°. In the group with longer intercalated segment, the average AOM was 29.9° ± 10.5° with an extension lag of 32° ± 11.7°. In the group with equal intercalated segment length, the average AOM was 49.1° ± 11.5° with an extension lag of 15.4° ± 10.6°. In the group with shorter intercalated segment, the average AOM was 70.9° ± 12.6° with an extension lag of 8.4° ± 8.9°. Conclusions: From our study, shortening the intercalated segment may provide the most reduction in the extension lag of the reconstructed PIPJ. Future studies could involve further refinement of the amount of length to be shortened. This would probably lie between 0 to 5 mm.

Severely comminuted fractures of the metatarsal bones with significant bone and soft-tissue loss have commonly subjected patients to proximal amputation procedures. We describe two patients who experienced high-energy traumatic injuries to their limbs that resulted in significant destruction of their first and second metatarsal bones with overlying soft-tissue trauma not amenable to local coverage. In both cases, a vascularized free fibular osteocutaneous flap was used to reconstruct the metatarsal bone defect and traumatized soft tissues so that a proximal amputation was avoided. At an average of 14 months of follow-up, both patients had recovered well and regained independent ambulation, with one patient being able to play soccer. We show that the free fibular osteoseptocutaneous flap is useful in reconstructing significant metatarsal bone defects and in avoiding amputations in this patient population. The skin component of the flap may be used to fill soft-tissue losses, and the fibula bone may be osteotomized so that more than one ray may be reconstructed. (J Am Podiatr Med Assoc 101(6): 531–536, 2011)

Summary Background The nonselective 5‐ HT 4 receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events ( AEs ). Aim To perform a systematic review of the safety profile, particularly cardiovascular, of 5‐ HT 4 agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy. Methods Articles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD ‐5108 (velusetrag) and ATI ‐7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 2006–2008 and DDW 2008–2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data. Results Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5‐ HT 4 agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically. Two nonselective 5‐ HT 4 agonists had reports of cardiovascular AEs : cisapride ( QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5‐ HT 1 receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5‐ HT 4 agonists prucalopride, velusetrag, naronapride, or for nonselective 5‐HT 4 agonists with no hERG or 5‐ HT 1 affinity (renzapride, clebopride, mosapride). Conclusions 5‐ HT 4 agonists for GI disorders differ in chemical structure and selectivity for 5‐ HT 4 receptors. Selectivity for 5‐ HT 4 over non‐5‐ HT 4 receptors may influence the agent's safety and overall risk–benefit profile. Based on available evidence, highly selective 5‐ HT 4 agonists may offer improved safety to treat patients with impaired GI motility.

Regulatory T cells (T reg cells) are characterized by the expression of the forkhead lineage-specific transcription factor Foxp3, and their main function is to suppress T cells. While evaluating T reg cells, we identified a population of Foxp3-positive cells that were CD11b+F4/80+CD68+, indicating macrophage origin. These cells were observed in spleen, lymph nodes, bone marrow, thymus, liver, and other tissues of naive animals. To characterize this subpopulation of macrophages, we devised a strategy to purify CD11b+F4/80+Foxp3+ macrophages using Foxp3-GFP mice. Analysis of CD11b+F4/80+Foxp3+ macrophage function indicated that these cells inhibited the proliferation of T cells, whereas Foxp3− macrophages did not. Suppression of T cell proliferation was mediated through soluble factors. Foxp3− macrophages acquired Foxp3 expression after activation, which conferred inhibitory properties that were indistinguishable from natural Foxp3+ macrophages. The cytokine and transcriptional profiles of Foxp3+ macrophages were distinct from those of Foxp3− macrophages, indicating that these cells have different biological functions. Functional in vivo analyses indicated that CD11b+F4/80+Foxp3+ macrophages are important in tumor promotion and the induction of T reg cell conversion. For the first time, these studies demonstrate the existence of a distinct subpopulation of naturally occurring macrophage regulatory cells in which expression of Foxp3 correlates with suppressive function.

Serotonin (5-HT) is one of the key mediators of gut motility, secretion and sensation. Most 5-HT is localized in the gastrointestinal tract. Particularly important for gut function and regulation are the 5-HT1P, 5-HT3and 5-HT4receptors. These receptors have been the focus of research evaluating the pathophysiologic mechanisms of irritable bowel syndrome (IBS) as well as targets for the development of novel agents to treat irritable bowel syndrome. Alosetron is one of three 5-HT3antagonists currently available. The other two, ondansetron and granisetron, are primarily used in the treatment of chemotherapy-induced nausea and vomiting. Alosetron, which slows gut transit, has been approved for the treatment of severe diarrhea-predominant IBS (IBS-D) in women. This review will examine the common, yet therapeutically challenging, disorder IBS, as well as the role of alosetron in the treatment of IBS-D.