A systematic review of high-fibre dietary therapy in diverticular disease

The exact pathogenesis of diverticular disease of the sigmoid colon is not well established. However, the hypothesis that a low-fibre diet may result in diverticulosis and a high-fibre diet will prevent symptoms or complications of diverticular disease is widely accepted. The aim of this review is to assess whether a high-fibre diet can improve symptoms and/or prevent complications of diverticular disease of the sigmoid colon and/or prevent recurrent diverticulitis after a primary episode. Clinical studies were eligible for inclusion if they assessed the treatment of diverticular disease or the prevention of recurrent diverticulitis with a high-fibre diet. The following exclusion criteria were used for study selection: studies without comparison of the patient group with a control group. No studies concerning prevention of recurrent diverticulitis with a high-fibre diet met our inclusion criteria. Three randomised controlled trials (RCT) and one case-control study were included in this systematic review. One RCT of moderate quality showed no difference in the primary endpoints. A second RCT of moderate quality and the case-control study found a significant difference in favour of a high-fibre diet in the treatment of symptomatic diverticular disease. The third RCT of moderate quality found a significant difference in favour of methylcellulose (fibre supplement). This study also showed a placebo effect. High-quality evidence for a high-fibre diet in the treatment of diverticular disease is lacking, and most recommendations are based on inconsistent level 2 and mostly level 3 evidence. Nevertheless, high-fibre diet is still recommended in several guideline

The structure of the PapD-PapGII pilin complex reveals an open and flexible P5 pocket

P pili are hairlike polymeric structures that mediate binding of uropathogenic Escherichia coli to the surface of the kidney via the PapG adhesin at their tips. PapG is composed of two domains: a lectin domain at the tip of the pilus followed by a pilin domain that comprises the initial polymerizing subunit of the 1,000-plus-subunit heteropolymeric pilus fiber. Prior to assembly, periplasmic pilin domains bind to a chaperone, PapD. PapD mediates donor strand complementation, in which a beta strand of PapD temporarily completes the pilin domain's fold, preventing premature, nonproductive interactions with other pilin subunits and facilitating subunit folding. Chaperone-subunit complexes are delivered to the outer membrane usher where donor strand exchange (DSE) replaces PapD's donated beta strand with an amino-terminal extension on the next incoming pilin subunit. This occurs via a zip-in-zip-out mechanism that initiates at a relatively accessible hydrophobic space termed the P5 pocket on the terminally incorporated pilus subunit. Here, we solve the structure of PapD in complex with the pilin domain of isoform II of PapG (PapGIIp). Our data revealed that PapGIIp adopts an immunoglobulin fold with a missing seventh strand, complemented in parallel by the G1 PapD strand, typical of pilin subunits. Comparisons with other chaperone-pilin complexes indicated that the interactive surfaces are highly conserved. Interestingly, the PapGIIp P5 pocket was in an open conformation, which, as molecular dynamics simulations revealed, switches between an open and a closed conformation due to the flexibility of the surrounding loops. Our study reveals the structural details of the DSE mechanism

Incidence and Risk Factors of Recurrence after Surgery for Pathology-proven Diverticular Disease

Contains fulltext : 69776.pdf (publisher's version ) (Closed access)BACKGROUND: Diverticular disease is a common problem in Western countries. Rationale for elective surgery is to prevent recurrent complicated diverticulitis and to reduce emergency procedures. Recurrent diverticulitis occurs in about 10% after resection. The pathogenesis for recurrence is not completely understood. We studied the incidence and risk factors for recurrence and the overall morbidity and mortality of surgical therapy for diverticular disease. METHODS: Medical records of 183 consecutive patients with pathology-proven diverticulitis were eligible for evaluation. Mean duration of follow-up was 7.2 years. Number of preoperative episodes, emergency or elective surgeries, type of operation, level of anastomosis, postoperative complications, persistent postoperative pain, complications associated with colostomy reversal, and recurrent diverticulitis were noted. The Kaplan-Meier method was used to calculate the cumulative probability of recurrence. Cox regression was used to identify possible risk factors for recurrence. RESULTS: The incidence of recurrence was 8.7%, with an estimated risk of recurrence over a 15-year period of 16%. Risk factors associated with recurrence were (younger) age (p < 0.02) and the persistence of postoperative pain (p < 0.005). Persistent abdominal pain after surgery was present in 22%. Eighty percent of patients who needed emergency surgery for acute diverticulitis had no manifestation of diverticular disease prior to surgery. In addition, recurrent diverticulitis was not associated with a higher percentage of emergency procedures. CONCLUSION: Estimated risk of recurrence is high and abdominal complaints after surgical therapy for diverticulitis are frequent. Younger age and persistence of postoperative symptoms predict recurrent diverticulitis after resection. The clinical implication of these findings needs further investigation. The results of this study support the careful selection of patients for surgery for diverticulitis

Association of physical function with predialysis blood pressure in patients on hemodialysis

BACKGROUND: New information from various clinical settings suggests that tight blood pressure control may not reduce mortality and may be associated with more side effects. METHODS: We performed cross-sectional multivariable ordered logistic regression to examine the association between predialysis blood pressure and the short physical performance battery (SPPB) in a cohort of 749 prevalent hemodialysis patients in the San Francisco and Atlanta areas recruited from July 2009 to August 2011 to study the relationship between systolic blood pressure and objective measures of physical function. Mean blood pressure for three hemodialysis sessions was analyzed in the following categories: <110 mmHg, 110-129 mmHg (reference), 130-159 mmHg, and ≥160 mmHg. SPPB includes three components: timed repeated chair stands, timed 15-ft walk, and balance tests. SPPB was categorized into ordinal groups (≤6, 7-9, 10-12) based on prior literature. RESULTS: Patients with blood pressure 130-159 mmHg had lower odds (OR 0.57, 95% CI 0.35-0.93) of scoring in a lower SPPB category than those whose blood pressure was between 110 and 129 mmHg, while those with blood pressure ≥160 mmHg had 0.56 times odds (95% CI 0.33-0.94) of scoring in a lower category when compared with blood pressure 110-129 mmHg. When individual components were examined, blood pressure was significantly associated with chair stand (130-159 mmHg: OR 0.59, 95% CI 0.38-0.92) and gait speed (≥160 mmHg: OR 0.59, 95% CI 0.35-0.98). Blood pressure ≥160 mmHg was not associated with substantially higher SPPB score compared with 130-159 mmHg. CONCLUSIONS: Patients with systolic blood pressure at or above 130 mmHg had better physical performance than patients with lower blood pressure in the normotensive range. The risk-benefit tradeoff of aggressive blood pressure control, particularly in low-functioning patients, should be reexamined

Cellular Radiosensitivity: How much better do we understand it?

Purpose: Ionizing radiation exposure gives rise to a variety of lesions in DNA that result in genetic instability and potentially tumorigenesis or cell death. Radiation extends its effects on DNA by direct interaction or by radiolysis of H2O that generates free radicals or aqueous electrons capable of interacting with and causing indirect damage to DNA. While the various lesions arising in DNA after radiation exposure can contribute to the mutagenising effects of this agent, the potentially most damaging lesion is the DNA double strand break (DSB) that contributes to genome instability and/or cell death. Thus in many cases failure to recognise and/or repair this lesion determines the radiosensitivity status of the cell. DNA repair mechanisms including homologous recombination (HR) and non-homologous end-joining (NHEJ) have evolved to protect cells against DNA DSB. Mutations in proteins that constitute these repair pathways are characterised by radiosensitivity and genome instability. Defects in a number of these proteins also give rise to genetic disorders that feature not only genetic instability but also immunodeficiency, cancer predisposition, neurodegeneration and other pathologies. Conclusions: In the past fifty years our understanding of the cellular response to radiation damage has advanced enormously with insight being gained from a wide range of approaches extending from more basic early studies to the sophisticated approaches used today. In this review we discuss our current understanding of the impact of radiation on the cell and the organism gained from the array of past and present studies and attempt to provide an explanation for what it is that determines the response to radiation

Controversies in the Surgical Management of Sigmoid Diverticulitis

The timing and appropriateness of surgical treatment of sigmoid diverticular disease remain a topic of controversy. We have reviewed the current literature on this topic, focusing on issues related to the indications and types of surgery. Current evidence would suggest that elective surgery for diverticulitis can be avoided in patients with uncomplicated disease, regardless of the number of recurrent episodes. Furthermore, the need for elective surgey should not be influenced by the age of the patient. Operation should be undertaken in patients with severe attacks, as determined by their clinical and radiological evaluation

Active Site Mutations Change the Cleavage Specificity of Neprilysin

Neprilysin (NEP), a member of the M13 subgroup of the zinc-dependent endopeptidase family is a membrane bound peptidase capable of cleaving a variety of physiological peptides. We have generated a series of neprilysin variants containing mutations at either one of two active site residues, Phe563 and Ser546. Among the mutants studied in detail we observed changes in their activity towards leucine5-enkephalin, insulin B chain, and amyloid β1–40. For example, NEPF563I displayed an increase in preference towards cleaving leucine5-enkephalin relative to insulin B chain, while mutant NEPS546E was less discriminating than neprilysin. Mutants NEPF563L and NEPS546E exhibit different cleavage site preferences than neprilysin with insulin B chain and amyloid ß1–40 as substrates. These data indicate that it is possible to alter the cleavage site specificity of neprilysin opening the way for the development of substrate specific or substrate exclusive forms of the enzyme with enhanced therapeutic potential

Recommendations for the design of therapeutic trials for neonatal seizures

Although seizures have a higher incidence in neonates than any other age group and are associated with significant mortality and neurodevelopmental disability, treatment is largely guided by physician preference and tradition, due to a lack of data from welldesigned clinical trials. There is increasing interest in conducting trials of novel drugs to treat neonatal seizures, but the unique characteristics of this disorder and patient population require special consideration with regard to trial design. The Critical Path Institute formed a global working group of experts and key stakeholders from academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups to develop consensus recommendations for design of clinical trials to treat neonatal seizures. The broad expertise and perspectives of this group were invaluable in developing recommendations addressing: (1) use of neonate-specific adaptive trial designs, (2) inclusion/exclusion criteria, (3) stratification and randomization, (4) statistical analysis, (5) safety monitoring, and (6) definitions of important outcomes. The guidelines are based on available literature and expert consensus, pharmacokinetic analyses, ethical considerations, and parental concerns. These recommendations will ultimately facilitate development of a Master Protocol and design of efficient and successful drug trials to improve the treatment and outcome for this highly vulnerable population

Childhood Atopic Diseases and Early Life Circumstances: An Ecological Study in Cuba

Background: Children are especially vulnerable during periods of resource shortage such as economic embargoes. They are likely to suffer most from poor nutrition, infectious diseases, and other ensuing short-term threats. Moreover, early life circumstances can have important consequences for long-term health. We examined the relationship between early childhood exposure to the Cuban economic situation in the nineties and the occurrence of atopic diseases later in childhood. Methodology/Principal Findings: A cross-sectional study of 1321 primary schoolchildren aged 4-14 was conducted in two Cuban municipalities. Asthma, allergic rhinoconjunctivitis and atopic dermatitis were diagnosed using the International Study of Asthma and Allergies in Childhood questionnaire. Children were divided into three groups of exposure to the economic situation in the nineties according to birth date: (1) unexposed; (2) exposed during infancy; (3) exposed during infancy and early childhood. Associations were assessed using multiple logistic regression models. Exposure during infancy had a significant inverse association with the occurrence of asthma (OR 0.56, 95% CI 0.33-0.94) and allergic rhinoconjunctivitis (OR 0.46, 95% CI 0.25-0.85). The associations were stronger after longer exposure, i.e. during infancy and early childhood, for asthma (OR 0.40, 95% CI 0.17-0.95) and allergic rhinoconjunctivitis (OR 0.29, 95% CI 0.11-0.77). No significant associations were found for atopic dermatitis. Conclusions/Significance: Exposure to the economic situation in the nineties during infancy and early childhood was inversely associated with asthma and allergic rhinoconjunctivitis occurrence later in childhood. We hypothesize that factors related to this period, such as infectious diseases and undernutrition, may have an attenuating effect on atopic disease development. The exact cause and underlying mechanisms need to be further elucidated

A multicenter randomized clinical trial investigating the cost-effectiveness of treatment strategies with or without antibiotics for uncomplicated acute diverticulitis (DIABOLO trial)

Background. Conservative treatment of uncomplicated or mild diverticulitis usually includes antibiotic therapy. It is, however, uncertain whether patients with acute diverticulitis indeed benefit from antibiotics. In most guidelines issued by professional organizations antibiotics are considered mandatory in the treatment of mild diverticulitis. This advice lacks evidence and is merely based on experts' opinion. Adverse effects of the use of antibiotics are well known, including allergic reactions, development of bacterial resistance to antibiotics and other side-effects. Methods. A randomized multicenter pragmatic clinical trial comparin