Diarrhoea risk factors in enterally tube fed critically ill patients : a retrospective audit

Objective: Diarrhoea in the enterally tube fed (ETF) intensive care unit (ICU) patient is a multifactorial problem. Diarrhoeal aetiologies in this patient cohort remain debatable; however, the consequences of diarrhoea have been well established and include electrolyte imbalance, dehydration, bacterial translocation, peri anal wound contamination and sleep deprivation. This study examined the incidence of diarrhoea and explored factors contributing to the development of diarrhoea in the ETF, critically ill, adult patient. ---------- Method: After institutional ethical review and approval, a single centre medical chart audit was undertaken to examine the incidence of diarrhoea in ETF, critically ill patients. Retrospective, non-probability sequential sampling was used of all emergency admission adult ICU patients who met the inclusion/exclusion criteria. ---------- Results: Fifty patients were audited. Faecal frequency, consistency and quantity were considered important criteria in defining ETF diarrhoea. The incidence of diarrhoea was 78%. Total patient diarrhoea days (r = 0.422; p = 0.02) and total diarrhoea frequency (r = 0.313; p = 0.027) increased when the patient was ETF for longer periods of time. Increased severity of illness, peripheral oxygen saturation (Sp02), glucose control, albumin and white cell count were found to be statistically significant factors for the development of diarrhoea. ---------- Conclusion: Diarrhoea in ETF critically ill patients is multi-factorial. The early identification of diarrhoea risk factors and the development of a diarrhoea risk management algorithm is recommended.

Probiotics and diarrhoea management in enterally tube fed critically ill patients : what is the evidence?

Objective: The aim of this literature review is to identify the role of probiotics in the management of enteral tube feeding (ETF) diarrhoea in critically ill patients.---------- Background: Diarrhoea is a common gastrointestinal problem seen in ETF patients. The incidence of diarrhoea in tube fed patients varies from 2% to 68% across all patients. Despite extensive investigation, the pathogenesis surrounding ETF diarrhoea remains unclear. Evidence to support probiotics to manage ETF diarrhoea in critically ill patients remains sparse.---------- Method: Literature on ETF diarrhoea and probiotics in critically ill, adult patients was reviewed from 1980 to 2010. The Cochrane Library, Pubmed, Science Direct, Medline and the Cumulative Index of Nursing and Allied Health Literature (CINAHL) electronic databases were searched using specific inclusion/exclusion criteria. Key search terms used were: enteral nutrition, diarrhoea, critical illness, probiotics, probiotic species and randomised clinical control trial (RCT).---------- Results: Four RCT papers were identified with two reporting full studies, one reporting a pilot RCT and one conference abstract reporting an RCT pilot study. A trend towards a reduction in diarrhoea incidence was observed in the probiotic groups. However, mortality associated with probiotic use in some severely and critically ill patients must caution the clinician against its use.---------- Conclusion: Evidence to support probiotic use in the management of ETF diarrhoea in critically ill patients remains unclear. This paper argues that probiotics should not be administered to critically ill patients until further research has been conducted to examine the causal relationship between probiotics and mortality, irrespective of the patient's disease state or projected prophylactic benefit of probiotic administration.

Development of a 3-dimensional human skin equivalent wound model for investigating novel wound healing therapies

Numerous difficulties are associated with the conduct of preclinical studies related to skin and wound repair. Use of small animal models such as rodents is not optimal because of their physiological differences to human skin and mode of wound healing. Although pigs have previously been used because of their human-like mode of healing, the expense and logistics related to their use also renders them suboptimal. In view of this, alternatives are urgently required to advance the field. The experiments reported herein were aimed at developing and validating a simple, reproducible, three-dimensional ex vivo de-epidermised dermis human skin equivalent wound model for the preclinical evaluation of novel wound therapies. Having established that the human skin equivalent wound model does in fact “heal," we tested the effect of two novel wound healing therapies. We also examined the utility of the model for studies exploring the mechanisms underpinning these therapies. Taken together the data demonstrate that these new models will have wide-spread application for the generation of fundamental new information on wound healing processes and also hold potential in facilitating preclinical optimization of dosage, duration of therapies, and treatment strategies prior to clinical trials.

Double jeopardy : comorbid anxiety and depression in later life

Comorbid depression and anxiety in late life present challenges for geriatric mental health care providers. These challenges include identifying the often complex diagnostic presentations both clinically and in a research context. This potent comorbidity can be conceived as double jeopardy in older adults, further diminishing their quality of life. Geriatric health care providers need to understand psychiatric comorbidity of this type for accurate diagnosis and early referral to specialists, and to coordinate interdisciplinary care. Researchers in the field also need to recognize potential multiple impacts of comorbidities with respect to assessment and treatment domains. This article describes the prevalence of late-life depression and anxiety disorders and reviews studies on this comorbidity in older adults. Risk factors and protective factors for anxiety and depression in later life are reviewed, and information is provided about comparative symptoms, the selection of assessment tools, and challenges to the provision of interdisciplinary, evidence-based care.

Manipulating double-decker molecules at the liquid-solid interface

We have used a scanning tunneling microscope to manipulate heteroleptic phthalocyaninato, naphthalocyaninato, porphyrinato double-decker molecules at the liquid/solid interface between 1-phenyloctane solvent and graphite. We employed nano-grafting of phthalocyanines with eight octyl chains to place these molecules into a matrix of heteroleptic double-decker molecules; the overlayer structure is epitaxial on graphite. We have also used nano-grafting to place double-decker molecules in matrices of single-layer phthalocyanines with octyl chains. Rectangular scans with a scanning tunneling microscope at low bias voltage resulted in the removal of the adsorbed doubledecker molecular layer and substituted the double-decker molecules with bilayer-stacked phthalocyanines from phenyloctane solution. Single heteroleptic double-decker molecules with lutetium sandwiched between naphthalocyanine and octaethylporphyrin were decomposed with voltage pulses from the probe tip; the top octaethylporphyrin ligand was removed and the bottom naphthalocyanine ligand remained on the surface. A domain of decomposed molecules was formed within the double-decker molecular domain, and the boundary of the decomposed molecular domain self-cured to become rectangular. We demonstrated a molecular “sliding block puzzle” with cascades of double-decker molecules on the graphite surface.

Processing load and the use of concrete representations and strategies for solving linear equations

This paper is a report of students' responses to instruction which was based on the use of concrete representations to solve linear equations. The sample consisted of 21 Grade 8 students from a middle-class suburban state secondary school with a reputation for high academic standards and innovative mathematics teaching. The students were interviewed before and after instruction. Interviews and classroom interactions were observed and videotaped. A qualitative analysis of the responses revealed that students did not use the materials in solving problems. The increased processing load caused by concrete representations is hypothesised as a reason.

Long term immunity to live attenuated Japanese encephalitis chimeric virus vaccine : randomized, double-blind, 5-year phase II study in healthy adults.

In a randomized, double-blind study, 202 healthy adults were randomized to receive a live, attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) and placebo 28 days apart in a cross-over design. A subgroup of 98 volunteers received a JE-CV booster at month 6. Safety, immunogenicity, and persistence of antibodies to month 60 were evaluated. There were no unexpected adverse events (AEs) and the incidence of AEs between JE-CV and placebo were similar. There were three serious adverse events (SAE) and no deaths. A moderately severe case of acute viral illness commencing 39 days after placebo administration was the only SAE considered possibly related to immunization. 99% of vaccine recipients achieved a seroprotective antibody titer ≥ 10 to JE-CV 28 days following the single dose of JE-CV, and 97% were seroprotected at month 6. Kaplan Meier analysis showed that after a single dose of JE-CV, 87% of the participants who were seroprotected at month 6 were still protected at month 60. This rate was 96% among those who received a booster immunization at month 6. 95% of subjects developed a neutralizing titer ≥ 10 against at least three of the four strains of a panel of wild-type Japanese encephalitis virus (JEV) strains on day 28 after immunization. At month 60, that proportion was 65% for participants who received a single dose of JE-CV and 75% for the booster group. These results suggest that JE-CV is safe, well tolerated and that a single dose provides long-lasting immunity to wild-type strains

Concomitant or sequential administration of live attenuated Japanese encephalitis chimeric virus vaccine and yellow fever 17D vaccine : randomized double-blind phase II evaluation of safety and immunogenicity

A randomized, double-blind, study was conducted to evaluate the safety, tolerability and immunogenicity of a live attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) co-administered with live attenuated yellow fever (YF) vaccine (YF-17D strain; Stamaril(®), Sanofi Pasteur) or administered successively. Participants (n = 108) were randomized to receive: YF followed by JE-CV 30 days later, JE followed by YF 30 days later, or the co-administration of JE and YF followed or preceded by placebo 30 days later or earlier. Placebo was used in a double-dummy fashion to ensure masking. Neutralizing antibody titers against JE-CV, YF-17D and selected wild-type JE virus strains was determined using a 50% serum-dilution plaque reduction neutralization test. Seroconversion was defined as the appearance of a neutralizing antibody titer above the assay cut-off post-immunization when not present pre-injection at day 0, or a least a four-fold rise in neutralizing antibody titer measured before the pre-injection day 0 and later post vaccination samples. There were no serious adverse events. Most adverse events (AEs) after JE vaccination were mild to moderate in intensity, and similar to those reported following YF vaccination. Seroconversion to JE-CV was 100% and 91% in the JE/YF and YF/JE sequential vaccination groups, respectively, compared with 96% in the co-administration group. All participants seroconverted to YF vaccine and retained neutralizing titers above the assay cut-off at month six. Neutralizing antibodies against JE vaccine were detected in 82-100% of participants at month six. These results suggest that both vaccines may be successfully co-administered simultaneously or 30 days apart.

Cytochrome p450 isozyme protein verified in the skin of southern hemisphere humpback whales (megaptera novaeangliae) : implications for biochemical biomarker assessment

Large mysticete whales represent a unique challenge for chemical risk assessment. Few epidemiological investigations are possible due to the low incidence of adult stranding events. Similarly their often extreme life-history adaptations of prolonged migration and fasting challenge exposure assumptions. Molecular biomarkers offer the potential to complement information yielded through tissue chemical analysis, as well as providing evidence of a molecular response to chemical exposure. In this study we confirm the presence of cytochrome P450 reductase (CPR) and cytochrome P450 isoenzyme 1A1 (CYP1A1) in epidermal tissue of southern hemisphere humpback whales (Megaptera novaeangliae). The detection of CYP1A1 in the integument of the humpback whale affords the opportunity for further quantitative non-destructive investigations of enzyme activity as a function of chemical stress.

Channel plasmon-polariton modes in V grooves filled with dielectric

We investigated the effect of dielectric filling in a V groove on the propagation parameters of channel plasmon-polariton (CPP) modes. In particular, existence conditions and critical groove angles, mode localization, field structure, dispersion, and propagation distances of CPP modes are analyzed as functions of dielectric permittivity inside the groove. It is demonstrated that increasing dielectric permittivity in the groove results in a rapid increase of mode localization near the tip of the groove and increase of both the critical angles that determine a range of groove angles for which CPP modes can exist. Detailed analysis of the field structure has demonstrated that the maximum of the field in a CPP mode is typically reached at a small distance from the tip of the groove. The effect of rounded tip is also investigated.

Recent advances in cancer therapy targeting proteins involved in DNA double-strand break repair

Damage to genetic material represents a persistent and ubiquitous threat to genomic stability. Once DNA damage is detected, a multifaceted signaling network is activated that halts the cell cycle, initiates repair, and in some instances induces apoptotic cell death. In this article, we will review DNA damage surveillance networks, which maintain the stability of our genome, and discuss the efforts underway to identify chemotherapeutic compounds targeting the core components of DNA double-strand breaks (DSB) response pathway. The majority of tumor cells have defects in maintaining genomic stability owing to the loss of an appropriate response to DNA damage. New anticancer agents are exploiting this vulnerability of cancer cells to enhance therapeutic indexes, with limited normal tissue toxicity. Recently inhibitors of the checkpoint kinases Chk1 and Chk2 have been shown to sensitize tumor cells to DNA damaging agents. In addition, the treatment of BRCA1- or BRCA2-deficient tumor cells with poly(ADP-ribose) polymerase (PARP) inhibitors also leads to specific tumor killing. Due to the numerous roles of p53 in genomic stability and its defects in many human cancers, therapeutic agents that restore p53 activity in tumors are the subject of multiple clinical trials. In this article we highlight the proteins mentioned above and catalog several additional players in the DNA damage response pathway, including ATM, DNA-PK, and the MRN complex, which might be amenable to pharmacological interventions and lead to new approaches to sensitize cancer cells to radio- and chemotherapy. The challenge is how to identify those patients most receptive to these treatments.

hSSB1 interacts directly with the MRN complex stimulating its recruitment to DNA double-strand breaks and its endo-nuclease activity

hSSB1 is a recently discovered single-stranded DNA binding protein that is essential for efficient repair of DNA double-strand breaks (DSBs) by the homologous recombination pathway. hSSB1 is required for the efficient recruitment of the MRN complex to sites of DSBs and for the efficient initiation of ATM dependent signalling. Here we explore the interplay between hSSB1 and MRN. We demonstrate that hSSB1 binds directly to NBS1, a component of the MRN complex, in a DNA damage independent manner. Consistent with the direct interaction, we observe that hSSB1 greatly stimulates the endo-nuclease activity of the MRN complex, a process that requires the C-terminal tail of hSSB1. Interestingly, analysis of two point mutations in NBS1, associated with Nijmegen breakage syndrome, revealed weaker binding to hSSB1, suggesting a possible disease mechanism.

hSSB1 rapidly binds at the sites of DNA double-strand breaks and is required for the efficient recruitment of the MRN complex

hSSB1 is a newly discovered single-stranded DNA (ssDNA)-binding protein that is essential for efficient DNA double-strand break signalling through ATM. However, the mechanism by which hSSB1 functions to allow efficient signalling is unknown. Here, we show that hSSB1 is recruited rapidly to sites of double-strand DNA breaks (DSBs) in all interphase cells (G1, S and G2) independently of, CtIP, MDC1 and the MRN complex (Rad50, Mre11, NBS1). However expansion of hSSB1 from the DSB site requires the function of MRN. Strikingly, silencing of hSSB1 prevents foci formation as well as recruitment of MRN to sites of DSBs and leads to a subsequent defect in resection of DSBs as evident by defective RPA and ssDNA generation. Our data suggests that hSSB1 functions upstream of MRN to promote its recruitment at DSBs and is required for efficient resection of DSBs. These findings, together with previous work establish essential roles of hSSB1 in controlling ATM activation and activity, and subsequent DSB resection and homologous recombination (HR).

Phosphorylation of Exo1 modulates homologous recombination repair of DNA double-strand breaks

DNA double-strand break (DSB) repair via the homologous recombination pathway is a multi-stage process, which results in repair of the DSB without loss of genetic information or fidelity. One essential step in this process is the generation of extended single-stranded DNA (ssDNA) regions at the break site. This ssDNA serves to induce cell cycle checkpoints and is required for Rad51 mediated strand invasion of the sister chromatid. Here, we show that human Exonuclease 1 (Exo1) is required for the normal repair of DSBs by HR. Cells depleted of Exo1 show chromosomal instability and hypersensitivity to ionising radiation (IR) exposure. We find that Exo1 accumulates rapidly at DSBs and is required for the recruitment of RPA and Rad51 to sites of DSBs, suggesting a role for Exo1 in ssDNA generation. Interestingly, the phosphorylation of Exo1 by ATM appears to regulate the activity of Exo1 following resection, allowing optimal Rad51 loading and the completion of HR repair. These data establish a role for Exo1 in resection of DSBs in human cells, highlighting the critical requirement of Exo1 for DSB repair via HR and thus the maintenance of genomic stability.

Obesity screening for young Japanese males and females using skin fold measurements : the classification revisited

Anthropometric assessment is a simple, safe, and cost-efficient method to examine the health status of individu-als. The Japanese obesity classification based on the sum of two skin folds (Σ2SF) was proposed nearly 40 years ago therefore its applicability to Japanese living today is unknown. The current study aimed to determine Σ2SF cut-off values that correspond to percent body fat (%BF) and BMI values using two datasets from young Japa-nese adults (233 males and 139 females). Using regression analysis, Σ2SF and height-corrected Σ2SF (HtΣ2SF) values that correspond to %BF of 20, 25, and 30% for males and 30, 35, and 40% for females were determined. In addition, cut-off values of both Σ2SF and HtΣ2SF that correspond to BMI values of 23 kg/m2, 25 kg/m2 and 30 kg/m2 were determined. In comparison with the original Σ2SF values, the proposed values are smaller by about 10 mm at maximum. The proposed values show an improvement in sensitivity from about 25% to above 90% to identify individuals with ≥20% body fat in males and ≥30% body fat in females with high specificity of about 95% in both genders. The results indicate that the original Σ2SF cut-off values to screen obese individuals cannot be applied to young Japanese adults living today and modification is required. Application of the pro-posed values may assist screening in the clinical setting.