Loop Ileostomy Closure After Restorative Proctocolectomy: Outcome in 1,504 Patients

PURPOSE Routine use of a temporary loop ileostomy for diversion after restorative proctocolectomy is controversial because of reported morbidity associated with its creation and closure. This study intended to review our experience with loop ileostomy closure after restorative proctocolectomy and determine the complication rates. In addition, complication rates between handsewn and stapled closures were compared.METHODS Our Department Pelvic Pouch Database was queried and charts reviewed for all patients who had ileostomy closure after restorative proctocolectomy from August 1983 to March 2002.RESULTS A total of 1,504 patients underwent ileostomy closure after restorative proctocolectomy during a 19-year period. The median length of hospitalization was three (range, 1–40) days and the overall complication rate was 11.4 percent. Complications included small-bowel obstruction (6.4 percent), wound infection (1.5 percent), abdominal septic complications (1 percent), and enterocutaneous fistulas (0.6 percent). Handsewn closure was performed in 1,278 patients (85 percent) and stapled closure in 226 (15 percent). No significant differences in complication rates and length of hospitalization were found between handsewn and stapled closure techniques.CONCLUSIONS Our results demonstrated that ileostomy closure after restorative proctocolectomy can be achieved with a low morbidity and a short hospitalization stay. In addition, we found that complication rates and length of hospitalization were similar between handsewn and stapled closures.Published online: 28 January.Read at the meeting of The American Society of Colon and Rectal Surgeons, New Orleans, Louisiana, June 21 to 26, 2003.     

Efficacy and safety of anticoagulation in non-malignant portal vein thrombosis in patients with liver cirrhosis

Background and aim

Treatment for portal vein thrombosis (PVT) is not well established. Nevertheless, anticoagulation therapy can seemingly be used as first-line therapy. However, there are limited data on the role of this treatment in patients with PVT and cirrhosis. We sought to assess the safety and efficacy of anticoagulation therapy in a series of patients with non-malignant PVT and liver cirrhosis.

Information capacity of specific interactions

Specific interactions are a hallmark feature of self-assembly and signal-processing systems in both synthetic and biological settings. Specificity between components may arise from a wide variety of physical and chemical mechanisms in diverse contexts, from DNA hybridization to shape-sensitive depletion interactions. Despite this diversity, all systems that rely on interaction specificity operate under the constraint that increasing the number of distinct components inevitably increases off-target binding. Here we introduce “capacity,” the maximal information encodable using specific interactions, to compare specificity across diverse experimental systems and to compute how specificity changes with physical parameters. Using this framework, we find that “shape” coding of interactions has higher capacity than chemical (“color”) coding because the strength of off-target binding is strongly sublinear in binding-site size for shapes while being linear for colors. We also find that different specificity mechanisms, such as shape and color, can be combined in a synergistic manner, giving a capacity greater than the sum of the parts.Specific interactions between many species of components are the bedrock of biochemical function, allowing signal transduction along complex parallel pathways and self-assembly of multicomponent molecular machines. Inspired by their role in biology, engineered specific interactions have opened up tremendous opportunities in materials synthesis, achieving new morphologies of self-assembled structures with varied and designed functionality. The two major design approaches for programming specific interactions use either chemical specificity or shape complementarity.Chemical specificity is achieved by dividing binding sites into smaller regions, each of which can be given one of A “colors” or unique chemical identities. Sites bind to each other based on the sum of the interactions between corresponding regions. For example, a recent two-color system paints the flat surfaces of three-dimensional polyhedra with hydrophobic and hydrophilic patterns (1) or with a pattern of solder dots (2), allowing polyhedra to stick to each other based on the registry between their surface patterns. Another popular approach uses DNA hybridization, where specific matching of complementary sequences has been used to self-assemble structures purely from DNA strands (3, 4) and from nanoparticles coated with carefully chosen DNA strands (5–9).Shape complementarity uses the shapes of the component surfaces to achieve specific binding, even though the adhesion is via a nonspecific, typically short-range potential. In the synthetic context, shape-based modulation of attractive forces over a large dynamic range was first proposed and experimentally demonstrated for colloidal particles (10, 11), using tunable depletion forces (12, 13). Recent experiments have explored the range of possibilities opened up by such ideas, from lithographically designed planar particles (14) with undulating profile patterns to “Pacman” particles with cavities that exactly match smaller complementary particles (15). The number of possible shapes that can be made using these types of methods depends on fabrication constraints but the possibilities can be quite rich (16, 17). Using only nonspecific surface attraction, experiments have achieved numerous and complex morphologies such as clusters, crystals, glasses, and superlattices (10, 18–21).A further class of programmable specific interactions combines both chemical specificity and shape complementarity. The canonical example is protein-binding interactions (22); the binding interactions between two cognate proteins are specified by their amino acid sequence, which programs binding pockets with complex shape and chemical specificity. Recent efforts (23, 24) aim to rationally design these protein interactions for self-assembly. Because both the shape of the binding pocket and its chemical specificity are determined by the same amino acid sequence, these two features cannot be controlled independently. Other synthetic systems offer the promise of independent control of chemical and shape binding specificity, giving a larger set of possible interactions.These diverse systems achieve specific interactions through disparate physical mechanisms, with different control parameters for tuning binding specificity. However, they must all solve a common problem (25, 26): create a family of N “lock” and “key” pairs that bind well within pairs but avoid off-target binding across pairs (“crosstalk”). Any crosstalk limits the efficacy of the locks and keys. For example, in the context of DNA-based affinities, although there are 4^L unique sequences of length L, the strong off-target binding severely restricts the number that can be productively used. Analogously, for colloidal systems driven by depletion interactions, there can be significant off-target binding due to partial contact. The performance of a system of specific interactions depends acutely on how the system constraints (e.g., number of available bases, fabrication length scale, etc.) limit its ability to avoid crosstalk.In this paper, we develop a general information theory-based framework for quantitatively analyzing specificity in both natural and synthetic systems. We use a metric based on mutual information to derive a bound on the number of different interacting particles that a system can support before crosstalk overwhelms interaction specificity. Increasing the number of nominally distinct pairs beyond this limit cannot increase the effective number of distinguishable species. We compute this information-theoretic “capacity” for different experimental systems of recent interest, including DNA-based affinities and colloidal experiments in shape complementarity. We show that shape-based coding fundamentally results in lower crosstalk and higher capacity than color-based coding. We also find that shape- and color-based coding can be combined synergistically, giving a superadditive capacity that is greater than the sum of the color and shape parts.     

How oral probiotics affect the severity of an experimental model of progressive multiple sclerosis? Bringing commensal bacteria into the neurodegenerative process

ABSTRACT

A growing number of studies support that the bidirectional interactions between the gut microbiota, the immune system and the CNS are relevant for the pathophysiology of MS. Several studies have reported alterations in the gut microbiome of MS patients. In addition, a variety of studies in animal models of MS have suggested that specific members of the gut commensal microbiota can exacerbate or ameliorate neuroinflammation. Probiotics represent oral nontoxic immunomodulatory agents that would exert benefits when using in combination with current MS therapy. Here we investigate the effect of Vivomixx on the gut microbiome and central and peripheral immune responses in a murine model of primary progressive MS. Vivomixx administration was associated with increased abundance of many taxa such as Bacteroidetes, Actinobacteria, Tenericutes and TM7. This was accompanied by a clear improvement of the motor disability of Theiler’s virus infected mice; in the CNS Vivomixx reduced microgliosis, astrogliosis and leukocyte infiltration. Notably, the presence of Breg cells (CD19⁺CD5⁺CD1d^high) in the CNS was enhanced by Vivomixx, and while spinal cord gene expression of IL-1β and IL-6 was diminished, the probiotic promoted IL-10 gene expression. One of the most significant findings was the increased plasma levels of butyrate and acetate levels in TMEV-mice that received Vivomixx. Peripheral immunological changes were subtle but interestingly, the probiotic restricted IL-17 production by Th17-polarized CD4⁺ T-cells purified from the mesenteric lymph nodes of Theiler’s virus infected mice. Our data reinforce the beneficial effects of oral probiotics that would be coadjuvant treatments to current MS therapies.     

Similar cell surface expression of beta2-microglobulin-free heavy chains by HLA-B27 subtypes differentially associated with ankylosing spondylitis

OBJECTIVE: To determine whether the cell surface features of HLA-B27 subtypes reported to be differentially associated with ankylosing spondylitis (AS) differ in a way that correlates with disease susceptibility. METHODS: Human cell transfectants expressing or lacking the transporter associated with antigen processing were used to determine the cell surface expression of B27 subtypes by flow cytometry with antibodies recognizing the B27 heterodimer or beta2-microglobulin (beta2m)-free heavy chains. RESULTS: In lymphoid cells with an intact peptide-loading complex, all B27 subtypes, irrespective of their association with disease, showed similar ratios of free heavy chain to heterodimer, suggesting similar surface stability. A substantial decrease in dissociated heavy chains, which never reached 100%, was observed upon addition of a B27 ligand, with no significant differences among subtypes. This is compatible with similar surface expression of irreversible beta2m-free heavy chain forms among subtypes differentially associated with disease. In cells lacking the transporter associated with antigen processing, both disease-associated and non-disease-associated subtypes expressed a population of heterodimers at 26 degrees C that was less stable than the population expressed at 37 degrees C. In the presence of exogenous peptide, the expression of heterodimers increased, without a concomitant decrease in beta2m-free heavy chains. This suggests that in these cells, and for all subtypes tested, most of the dissociated heavy chains at the cell surface are in irreversible forms. At 37 degrees C, the expression of beta2m-free B27 heavy chains was very low on T2 transfectant cells. CONCLUSION: HLA-B27 subtypes showing differential associations with AS are similar in their extent of beta2m dissociation and surface expression of free heavy chains.     

Clinical observations of nebulized flunisolide in infants and young children with asthma and bronchopulmonary dysplasia.

Severe bronchopulmonary dysplasia (BPD) is frequently associated with asthma. The combination is often severe enough to necessitate corticosteroid therapy. There are no commercially available nebulizer solutions of corticosteroids for use in infants and young children. Seven infants and small children with very severe BPD and asthma aged 6-24 months, were treated with flunisolide, 187-250 micrograms q.i.d. in the form of nasal spray delivered by nebulizer. After treatment for 2.5-20 months, four patients showed clinical improvement, one initially improved but later deteriorated and died of cardiac failure, and two patients showed no improvement and died within 3 months. The number of days of hospitalization was significantly reduced from 8.4/month to 2.5/month (P less than 0.05). No side-effects were detected and it was felt that the three patients who died, did so as a consequence of very severe BPD and its cardiac consequences. The suspension remained stable for 80 min when mixed with normal saline, cromolyn sodium, albuterol, or acetylcysteine. It is concluded that nebulized flunisolide is a potentially useful treatment for infants and young children with asthma and BPD.     

Low salt intake modulates insulin signaling, JNK activity and IRS-1ser307 phosphorylation in rat tissues

A severe restriction of sodium chloride intake has been associated with insulin resistance and obesity. The molecular mechanisms by which the low salt diet (LS) can induce insulin resistance have not yet been established. The c-jun N-terminal kinase (JNK) activity has been involved in the pathophysiology of obesity and induces insulin resistance by increasing inhibitory IRS-1(ser307) phosphorylation. In this study we have evaluated the regulation of insulin signaling, JNK activation and IRS-1(ser307) phophorylation in liver, muscle and adipose tissue by immunoprecipitation and immunoblotting in rats fed with LS or normal salt diet (NS) during 9 weeks. LS increased body weight, visceral adiposity, blood glucose and plasma insulin levels, induced insulin resistance and did not change blood pressure. In LS rats a decrease in PI3-K/Akt was observed in liver and muscle and an increase in this pathway was seen in adipose tissue. JNK activity and IRS-1(ser307) phosphorylation were higher in insulin-resistant tissues. In summary, the insulin resistance, induced by LS, is tissue-specific and is accompanied by activation of JNK and IRS-1(ser307) phosphorylation. The impairment of the insulin signaling in these tissues, but not in adipose tissue, may lead to increased adiposity and insulin resistance in LS rats.