Long term persistence and risk factors for anorectal symptoms following low anterior resection for rectal cancer.

BACKGROUND: Rectal cancer is commonly treated by chemoradiation therapy, followed by the low anterior resection anal sphincter-preserving surgery, with a temporary protecting ileostomy. After reversal of the stoma a condition known as low anterior resection syndrome (LARS) can occur characterized by a combination of symptoms such as urgent bowel movements, lack of control over bowel movements, and difficulty fully emptying the bowels. These symptoms have a significant negative impact on the quality of life for individuals who have survived the cancer. Currently, there is limited available data regarding the presence, risk factors, and effects of treatment for these symptoms during long-term follow-up. AIMS: To evaluate long term outcomes of low anterior resection surgery and its correlation to baseline anorectal manometry (ARM) parameters and physiotherapy with anorectal biofeedback (BF) treatment. METHODS: One hundred fifteen patients (74 males, age 63 ± 11) who underwent low anterior resection surgery for rectal cancer were included in the study. Following surgery, patients were managed by surgical and oncologic team, with more symptomatic LARS patients referred for further evaluation and treatment by gastroenterologists. At follow up, patients were contacted and offered participation in a long term follow up by answering symptom severity and quality of life (QOL) questionnaires. RESULTS: 80 (70%) patients agreed to participate in the long term follow up study (median 4 years from stoma reversal, range 1-8). Mean time from surgery to stoma closure was 6 ± 4 months. At long term follow up, mean LARS score was 30 (SD 11), with 55 (69%) patients classified as major LARS (score > 30). Presence of major LARS was associated with longer time from surgery to stoma reversal (6.8 vs. 4.8 months; p = 0.03) and with adjuvant chemotherapy (38% vs. 8%; p = 0.01). Patients initially referred for ARM and BF were more likely to suffer from major LARS at long term follow up (64% vs. 16%, p < 0.001). In the subgroup of patients who underwent perioperative ARM (n = 36), higher maximal squeeze pressure, higher maximal incremental squeeze pressure and higher rectal pressure on push were all associated with better long-term outcomes of QOL parameters (p < 0.05 for all). 21(54%) of patients referred to ARM were treated with BF, but long term outcomes for these patients were not different from those who did not perform BF. CONCLUSIONS: A significant number of patients continue to experience severe symptoms and a decline in their quality of life even 4 years after undergoing low anterior resection surgery. Prolonged time until stoma reversal and adjuvant chemotherapy emerged as the primary risk factors for a negative prognosis. It is important to note that referring patients for anorectal physiology testing alone tended to predict poorer long-term outcomes, indicating the presence of selection bias. However, certain measurable manometric parameters could potentially aid in identifying patients who are at a higher risk of experiencing unfavorable functional outcomes. There is a critical need to enhance current treatment options for this patient group.

The structure of the Physcomitrium patens photosystem I reveals a unique Lhca2 paralogue replacing Lhca4.

The moss Physcomitrium patens diverged from green algae shortly after the colonization of land by ancient plants. This colonization posed new environmental challenges, which drove evolutionary processes. The photosynthetic machinery of modern flowering plants is adapted to the high light conditions on land. Red-shifted Lhca4 antennae are present in the photosystem I light-harvesting complex of many green-lineage plants but absent in P. patens. The cryo-EM structure of the P. patens photosystem I light-harvesting complex I supercomplex (PSI-LHCI) at 2.8 Å reveals that Lhca4 is replaced by a unique Lhca2 paralogue in moss. This PSI-LHCI supercomplex also retains the PsaM subunit, present in Cyanobacteria and several algal species but lost in vascular plants, and the PsaO subunit responsible for binding light-harvesting complex II. The blue-shifted Lhca2 paralogue and chlorophyll b enrichment relative to flowering plants make the P. patens PSI-LHCI spectroscopically unique among other green-lineage supercomplexes. Overall, the structure represents an evolutionary intermediate PSI with the crescent-shaped LHCI common in vascular plants, and contains a unique Lhca2 paralogue that facilitates the moss's adaptation to low-light niches.

Rest Frame Interference in Rotating Structures and Metamaterials.

Using the formulation of electrodynamics in rotating media, we put into explicit quantitative form the effect of rotation on interference and diffraction patterns as observed in the rotating medium's rest frame. As a paradigm experiment we focus the interference generated by a linear array of sources in a homogeneous medium. The interference is distorted due to rotation; the maxima now follow curved trajectories. Unlike the classical Sagnac effect in which the rotation induced phase is independent of the refraction index n, here the maxima bending increases when n decreases, suggesting that ε-near-zero metamaterials can enhance optical gyroscopes and rotation-induced nonreciprocal devices. This result is counterintuitive as one may expect that a wave that travels faster would bend less. The apparent contradiction is clarified via the Minkowski momentum picture for a quasiparticle model of the interference that introduces the action of a Coriolis force, and by the Abraham picture of the wave-only momentum. Our results may also shed light on the Abraham-Minkowski controversy as examined in noninertial electrodynamics.

Long-term outcome of anorectal biofeedback for treatment of fecal incontinence.

BACKGROUND: Long-term outcome data for anorectal biofeedback (BF) for fecal incontinence (FI) is scarce. Our aims were to describe the long-term symptom profile, quality of life, and need for surgery in FI patients following BF. METHODS: One hundred and eight consecutive female patients with FI who completed an instrumented BF course were identified for long-term follow-up. In 61 of 89 contactable patients, outcome measures were assessed at short-term (end of BF), mid-term (9 months median), and long-term (7 years median) follow-up after treatment. KEY RESULTS: Long-term response rate (50% or more reduction in FI episodes/wk compared to before BF and not requiring surgical intervention) was seen in 33/61 (54%) patients. Thirteen of these had complete continence. Improvement was seen at short, mid, and long-term follow-up for patients' satisfaction and control of bowel function. In contrast, fecal incontinence severity index and quality of life measures, which improved in short and mid-term, were no different from baseline by long-term follow-up. Patients classified as short-term responders were far more likely to display a long-term response compared to short-term non-responders (68% vs 18%, P < .001). CONCLUSIONS & INFERENCES: Long-term symptom improvement was observed in more than half of FI patients at 7 year post BF follow-up. Quality of life improvements, however, were not maintained. Patients improving during the initial BF program have a high chance of long-term improvement, while patients who do not respond to BF should be considered early for other therapies.

The importance of a high rectal pressure on strain in constipated patients: implications for biofeedback therapy.

BACKGROUND: A subset of patients with chronic constipation display a relatively high manometric rectal pressure on strain. We hypothesized that these patients represent a unique phenotype of functional defecatory disorder (FDD) and would benefit from undergoing anorectal biofeedback (BF). METHODS: Of 138 consecutive patients with chronic constipation and symptoms of FDD, 19 were defined as having a high rectal pressure on strain, using a statistically derived cut-off of 78 mm Hg. This subset was compared with remaining patients in regard to baseline clinical profile and physiology, and outcome of BF. KEY RESULTS: There was a greater representation of males in the high rectal pressure group. Their constipation score, impact of bowel dysfunction on quality of life and satisfaction with bowel habits did not differ from the remaining patients. Eighty-four percent of patients in the high group successfully expelled the rectal balloon and 95% displayed paradoxical anal contraction on strain (P<.05 compared with the remaining patients). Following BF, 89% of patients in the high group reduced their rectal pressure to normal. End of BF treatment outcomes improved significantly, and to a similar degree, in both groups. CONCLUSIONS & INFERENCES: We have identified a subgroup of patients with dyssynergic symptoms but without a formal Rome III diagnosis of FDD, who were characterized by a high straining rectal pressure. Although these patients displayed some physiological differences to the patients with lower straining rectal pressure, they suffer similarly. Importantly, we have shown that these patients can respond favorably to anorectal BF.

Anorectal biofeedback for neurogenic bowel dysfunction in incomplete spinal cord injury.

STUDY DESIGN: A case-control study of prospectively collected data was performed. OBJECTIVES: To compare anorectal biofeedback (BF) outcomes in patients with incomplete motor spinal cord injury (SCI) and neurogenic bowel dysfunction (NBD) with a group of functional anorectal disorder-matched control patients. SETTING: Neurogastroenterology Unit affiliated with a Spinal Injury Unit in a tertiary referral centre in Sydney, Australia. METHODS: All consecutive patients with SCI and NBD referred for anorectal manometry and BF were matched in a 1:2 ratio with age, gender, parity and functional anorectal disorder-matched control patients. Instrumented BF was performed in six nurse-guided weekly visits. Outcomes included changes in anorectal physiology measures, symptom scores and quality-of-life measures. RESULTS: Twenty-one patients were included. These were matched with 42 patient controls. Following BF, symptom scores improved significantly in both groups, as did effect of bowel disorder on quality of life. Improvement in these measures did not differ between the groups. Patients with SCI and NBD showed improvement in their sensory and motor anorectal function, including lowering of first sensation threshold and more effective balloon expulsion. CONCLUSIONS: Patients with incomplete motor SCI responded as well to anorectal BF as functional anorectal disorder-matched controls. Spinal cord-injured patients also showed improvement in anorectal sensorimotor dysfunction and balloon expulsion. These novel findings indicate that clinicians should not be dissuaded from considering behaviour-based therapeutic interventions such as anorectal BF in selected spinal cord-injured patients.

Induction infliximab levels among patients with acute severe ulcerative colitis compared with patients with moderately severe ulcerative colitis.

BACKGROUND: Infliximab is effective as salvage therapy for patients with steroid refractory acute severe ulcerative colitis (UC). Although current data suggest that the pharmacokinetics of infliximab are influenced by inflammatory burden in patients with acute severe UC, data comparing infliximab trough levels in patients with acute severe UC vs. moderately severe UC are scarce. AIM: To compare infliximab trough and anti-infliximab antibody levels at a standard fixed time-point during induction between patients with acute severe and moderately severe UC. METHODS: A multi-centre retrospective study comparing infliximab drug and antibody levels 14 days after the first infusion in hospitalised acute severe UC versus out-patients with moderately severe UC was performed. RESULTS: Sixteen acute severe UC patients, hospitalised between 2010-2015 and refractory to intravenous corticosteroids, were treated with infliximab 5 mg/kg salvage therapy. They were compared to 16 moderately severe UC out-patient controls. Mean infliximab trough levels at day 14 were significantly lower in patients with acute severe UC compared to moderately severe UC (7.15 ± 5.3 vs. 14.4 ± 11.2 µg/mL, P = 0.007). Seven patients (three acute severe and four moderate severe UC) were primary nonresponders to infliximab induction therapy. Infliximab level at day 14 did not differ between responders and nonresponders (9.8 ± 9 vs. 12.1 ± 10.6 µg/mL, respectively, P = N.S.). However, week 2 median antibody-to-infliximab levels were numerically higher among primary nonresponders (3.4 ± 5.7 vs. 1.2 ± 4 µg/mL-eq, respectively, P = 0.06). CONCLUSIONS: Infliximab trough levels at day 14 were lower in patients with acute severe UC compared to moderately severe UC, possibly due to a higher inflammatory burden and/or increased drug clearance. However, drug levels at day 14 were not lower among nonresponders compared with responders. Controlled trials are warranted to examine whether an a-priori-intensified infliximab induction protocol will lead to an improved outcome in acute severe UC.

Effect of Aggregatibacter actinomycetemcomitans from Aggressive Periodontitis patients on Streptococcus mutans.

OBJECTIVES: To determine in vivo association between Aggregatibacter actinomycetemcomitans (Aa) and Streptococcus mutans (Sm) in aggressive periodontitis patients (AgP) and the in vitro influence on Sm of saliva and of Aa strains isolated from individual Aa-positive patients. MATERIALS AND METHODS: Clinical indices and saliva samples were taken from 30 AgP patients. Aa and mutans streptococci levels were determined. Antibacterial effect of saliva from 12 Aa-positive patients, and their individual Aa strain, was checked turbidimetrically in vitro on Sm. RESULTS: Aa salivary level was inversely correlated with levels of mutans streptococci and directly correlated with pockets of ≥7 mm. During exponential growth phase: (i) All Aa-positive and Aa-negative saliva samples showed no significant influence on Sm growth. (ii) Each individually isolated Aa strain presented significant inhibitory effect on Sm growth. During stationary growth phase, all the above demonstrated an inhibitory effect on Sm growth, with significantly greater influence of Aa individual strains. CONCLUSION: Saliva of each AgP Aa-positive subject had an inhibitory effect on Sm growth, which is most likely derived from Aa bacterial physiology. This research raises the possibility that suppression of Aa due to periodontal treatment may increase Sm levels and hence caries incidence.

Adalimumab drug and antibody levels as predictors of clinical and laboratory response in patients with Crohn's disease.

BACKGROUND: Adalimumab is an effective treatment for Crohn's disease (CD). Anti-adalimumab antibodies (AAA) and low trough serum drug concentrations have been implicated as pre-disposing factors for treatment failure. AIMS: To assess adalimumab and AAA serum levels, and to examine their association and discriminatory ability with clinical response and serum C-reactive protein (CRP). METHODS: We performed a cross-sectional study using trough sera from adalimumab-treated CD patients. Demographical data, Montreal classification, treatment regimen and clinical status were recorded. Serum adalimumab, AAA and CRP were measured. Receiver operating characteristic analysis and a multivariate regression model were performed to find drug and antibody thresholds for predicting disease activity at time of serum sampling. RESULTS: One hundred and eighteen trough serum samples were included from 71 patients. High adalimumab trough serum concentration was associated with disease remission (Area Under Curve 0.748, P < 0.001). A cut-off drug level of 5.85 µg/mL yielded optimal sensitivity, specificity and positive likelihood ratio for remission prediction (68%, 70.6% and 2.3, respectively). AAA were inversely related with adalimumab drug levels (Spearman's r = -0.411, P < 0.001) and when subdivided into categorical values, positively related with disease activity (P < 0.001). High drug levels and stricturing vs. penetrating or inflammatory phenotype, but not AAA levels, independently predicted disease remission in a multivariate logistic regression model. CONCLUSIONS: Adalimumab drug levels were inversely related to disease activity. High levels of anti-adalimumab antibodies were positively associated with disease activity, but this association was mediated mostly by adalimumab drug levels.

Metaweaves: sector-way nonreciprocal metasurfaces.

Confluent with the single dimension of time, breach of time-reversal symmetry is usually perceived as a one-dimensional concept. In its ultimate realization-the one-way guiding device-it allows optical propagation in one direction, say +z, and forbids it in the opposite direction -z. Hence, in studies of time-reversal asymmetry the mapping t↦-t is naturally associated with z↦-z. However, strongly nonreciprocal or one-way nanoscale threads can be used to weave metasurfaces thus adding dimensions to this concept. In this new family of surfaces the aforementioned association cannot be made. An example of appropriate threads is the planar one-way particle chains based on the two-type rotation principle. The resulting surfaces-the metaweaves-possess generalized nonreciprocity such as "sector-way" propagation, and offer new possibilities for controlling light in thin surfaces. We study several metaweave designs and their asymmetries in the wave-vector space.

The decline of anti-drug antibody titres after discontinuation of anti-TNFs: implications for predicting re-induction outcome in IBD.

BACKGROUND: Anti-drug antibodies can be elicited by infliximab and adalimumab, but the rate of their decay after therapy is stopped is unknown. AIM: To investigate the decline of anti-drug antibody titre after anti-TNF cessation, and to evaluate the clinical utility of anti-drug antibody measurement before anti-TNF re-induction. METHODS: Inflammatory bowel disease (IBD) patients who stopped anti-TNF therapy and had measurable anti-drug antibodies were prospectively followed up by serial blood measurements of antibodies levels. The clinical outcome of a second cohort of patients who received re-induction by infliximab or adalimumab after a drug holiday >4 months was determined vis-à-vis their anti-drug antibodies status before re-induction. RESULTS: The first cohort included 22 patients with anti-drug antibodies who were prospectively followed up after cessation of anti-TNF. Sixteen had antibodies-to-infliximab (ATI) and six had antibodies-to-adalimumab (ATA). ATI titres declined within 12 months to below detection levels in 13/16 infliximab-treated patients, whereas ATA titres became undetectable in only 2/6 adalimumab-treated patients (P = 0.04). The second cohort comprised 27 patients who resumed anti-TNFs (24 infliximab, 3 adalimumab). Of these, 3/5 patients with measurable anti-drug antibodies before re-induction experienced severe hypersensitivity reaction and/or nonresponse mandating drug-discontinuation, compared to 11/22 patients who were re-induced without measurable anti-drug antibodies (OR = 1.5, 95% CI 0.2-11, P = 0.7). CONCLUSIONS: Antibodies to infliximab titres decline to undetectable levels within one year of cessation of infliximab in the majority of patients, whereas antibodies to adalimumab seem to persist longer after adalimumab discontinuation. Measuring antibodies to infliximab prior to infliximab re-induction is probably of little clinical utility, especially if more than a 12-month drug-holiday has elapsed.

Candida, mutans streptococci, oral hygiene and caries in children.

OBJECTIVE: to test the association between Candida and mutans streptococci (ms), oral hygiene and caries levels and in children. METHODS: 22 boys and 12 girls (age 6 to 14.5 years) participated in the study. Each participant received a toothbrush, and was asked to brush his/her teeth after proper instructions. Dental caries and oral hygiene were recorded. Candida and ms levels were determined in saliva samples. RESULTS: Candida colonies were observed in 70.5% of the children. No association was found between Candida and caries or plaque and gingival indices. C. albicans-positive children demonstrated significantly higher brushing scores. CONCLUSIONS: Our findings may suggest that there is no clear association between Candida in saliva, and levels of cariogenic bacteria and caries risk in children.

Escherichia coli maltose-binding protein as a molecular chaperone for recombinant intracellular cytoplasmic single-chain antibodies.

Recombinant single-chain antibodies (scFvs) that are expressed in the cytoplasm of cells are of considerable biotechnological and therapeutic potential. However, the reducing environment of the cytoplasm inhibits the formation of the intradomain disulfide bonds that are essential for correct folding and functionality of these antibody fragments. Thus, scFvs expressed in the cytoplasm are mostly insoluble and inactive.Here, we describe a general approach for stabilizing scFvs for efficient functional expression in the cell cytoplasm in a soluble, active form. The scFvs are expressed as C-terminal fusions with the Escherichia coli maltose-binding protein (MBP). We tested a large panel of scFvs that were derived from hybridomas and from murine and human scFv phage display and expression libraries by comparing their stability and functionality as un-fused versus MBP fused proteins. We found that MBP fused scFvs are expressed at high levels in the cytoplasm of E. coli as soluble and active proteins regardless of the redox state of the bacterial cytoplasm. In contrast, most un-fused scFvs can be produced (to much lower levels) in a functional form only when expressed in trxB(-) but not in trxB(+) E. coli cells. We show that MBP-scFv fusions are more stable than the corresponding un-fused scFvs, and that they perform more efficiently in vivo as cytoplasmic intrabodies in E. coli. Thus, MBP seems to function as a molecular chaperone that promotes the solubility and stability of scFvs that are fused to it.

Bacterial penetration and proliferation in root canal dentinal tubules after applying dentin adhesives in vitro.

Endodontic treatment is aimed at eliminating infection and preventing bacterial regrowth in the root canal and dentinal tubules. In the present study the ability of two dentin adhesives to prevent bacterial penetration and subsequent proliferation in dentinal tubules was evaluated. Cylindrical root specimens prepared from freshly extracted bovine teeth were used in an in vitro model of dentinal tubule infection. After removal of the smear layer the intracanal dentinal tubules of the specimens were acid-etched and treated with either Gluma or EBS. Untreated specimens served as controls. Specimens were infected with Enterococcus faecalis and incubated in Brain Heart Infusion for 21 days. Powder dentin samples obtained from within the canal lumina, using ISO 025 to 033 burs, were examined for the presence of vital bacteria by inoculating on agar plates and counting colony-forming units. A significant difference was found between the experimental groups and the untreated group. After application with Gluma specimens showed the least viable bacteria in dentinal tubules. Data suggested that dentin adhesives reduced bacterial invasion into dentin and therefore have a potential role in endodontic treatment.

Characterization of dentin-bonding-amalgam interfaces.

Applying a bonding agent and a resinous adhesive layer before amalgam condensation has become a common clinical procedure. However, interactions between the different interfaces formed, and the extent of sealing obtained, have not been extensively studied. This study characterized the interfaces formed in the bonded amalgam restoration. Specifically, the individual contributions of the bonding agent (One-Step) and the adhesive resin (Resinomer) were examined, along with their mode of application on the prevention of microleakage and the formation of a tight, continuous adhesion to amalgam. To this end, a dye penetration assay and scanning electron microscopy (SEM) were used, including high resolution elemental analysis, for the characterization of the sealing properties and the interface structure obtained following various procedures of applying amalgam adhesives. Results indicated that placing bonding material under the amalgam restoration is essential to preventing microleakage. When condensed against uncured or cured adhesive material, the adhesive resinous glass layer creates a thick interface with protrusions and inclusions in the amalgam, though microleakage studies indicate that condensation over the uncured adhesive results in a better seal than that of the cured adhesive. SEM combined with elemental analysis indicates that the adhesion between amalgam and adhesive material is mainly of mechanical character and is formed by interdigitations of the adhesive material protruding into the amalgam. Gaps formed at the various interfaces in the different modalities could be localized. In addition, resinous glass composite alone, without bonding, was found to provide an unacceptable degree of sealing between the tooth and amalgam. The clinical significance of these findings is further discussed.

Cell surface hydrophobicity of pigmented and nonpigmented clinical Serratia marcescens strains.

The cell surface hydrophobicity of 10 pigmented and 4 nonpigmented clinical Serratia marcescens strains was studied, based on the ability of the strains to adhere to hydrocarbons and to polystyrene. The cell surface hydrophobicity depended greatly on growth temperature; all of the strains tested were adherent following growth at 30 degrees C, whereas none was adherent following growth at 38 degrees C. In previous studies, the pigment prodigiosin has been cited as responsible for cell surface hydrophobicity in various Serratia strains. However, the observed ability of the nonpigmented strains to adhere to the test hydrocarbons and to polystyrene indicates that Serratia strains can possess hydrophobic surface properties in the absence of this pigment. Moreover, strain 1785 cells were adherent whether they were grown at 30 or 36.5 degrees C, even though pigment was not synthesized at the higher temperature. In Escherichia coli correlations have been noted between increased cell surface hydrophobicity and the presence of mannose-specific adhesins; no such relationship was found in the S. marcescens strains tested. The expression of cell surface hydrophobicity in clinical S. marcescens strains at 30 degrees C and the loss of hydrophobicity at host temperatures raise the possibility that infective cells from the environment are initially hydrophobic, but lose this property upon subsequent proliferation within a host.