Optimising delivery of care in coeliac disease - comparison of the benefits of repeat biopsy and serological follow-up.

BACKGROUND: The majority of deleterious health consequences of coeliac disease (CD) are most likely to be secondary to intestinal inflammation; hence, mucosal recovery is a desirable goal of therapy. Follow-up in CD is controversial and serological response is often used as a surrogate for histological recovery. AIMS: To inform the clinical management of CD using comparative serological and histological data from a biopsy-driven pathway of care. METHODS: A retrospective analysis of the Cambridge Coeliac Clinic database of 595 patients routinely followed up by biopsy and serology. RESULTS: Paired biopsy results were available for 391 patients (15% seronegative). Persisting villous atrophy (VA) occurred in 182 patients (47%). The sensitivity of anti-tissue transglutaminase (TTG) antibody for ongoing VA was only 43.6%. Information on dietetic management and further biopsy to assess response was available for 94 initially unresponsive patients, in whom targeted dietetic intervention by removal of identified gluten sources or avoidance of trace amounts of gluten led to resolution of persistent VA in 50%. The effects of institution of a formal care pathway are analysed in 298 patients. Discharge to primary care and clinical management was facilitated by the information derived from repeat biopsy. CONCLUSIONS: Serology appears to be a poor surrogate marker for mucosal recovery on a gluten-free diet; dietary assessment fails to identify a potential gluten source in many patients with ongoing villous atrophy. The benefits of re-biopsy on diet include stratification of patients with coeliac disease suitable for early discharge from secondary care or those requiring more intensive clinical management.

An audit of level two and level three checks of anaesthesia delivery systems performed at three hospitals in South Australia.

Anaesthetists may subject patients to unnecessary risk by not checking anaesthetic equipment thoroughly before use. Numerous adverse events have been associated with failure to check equipment. The Australian and New Zealand College of Anaesthetists and anaesthetic delivery system manufactures have made recommendations on how anaesthetic equipment should be maintained and checked before use and for the training required for staff who use such equipment. These recommendations are made to minimise the risk to patients undergoing anaesthesia. This prospective audit investigated the adherence of anaesthetic practitioners to a selection of those recommendations. Covert observations of anaesthetic practitioners were made while they were checking their designated anaesthetic machine, either at the beginning of a day's list or between cases. Structured interviews with staff who check the anaesthetic machine were carried out to determine the training they had received. The results indicated poor compliance with recommendations: significantly, the backup oxygen cylinders' pressure/contents were not checked in 45% of observations; the emergency ventilation device was not checked in 67% of observations; the breathing circuit was not tested between patients in 79% of observations; no documentation of the checks performed was done in any cases; and no assessment or accreditation of the staff who performed these checks was performed. It was concluded that the poor compliance was a system failing and that patient safety might be increased with training and accrediting staff responsible for checking equipment, documenting the checks performed, and the formulation and use of a checklist.

Two unusual clinical and radiological presentations of biotinidase deficiency.

Biotinidase deficiency is due to a defect in recycling of biotin and is a treatable autosomal recessive inherited disorder. We describe two cases with unusual presenting symptoms and rarely described MRI findings. We propose that the diagnosis of biotinidase deficiency should be considered when there are symmetrical MRI changes in the medial thalamus, dorsal brainstem, medulla and spinal cord as in our two cases. As long as there isn't newborn screening for biotinidase deficiency in the UK; increased awareness of this disorder and recognition of biotinidase deficiency as a cause of bilateral symmetrical MRI patterns similar to our patients, would facilitate early diagnosis and prevent many of the devastating neurological sequelae associated with missing the condition.

Use of Hydrogenophaga pseudoflava penetration to quantitatively assess the impact of filtration parameters for 0.2-micrometer-pore-size filters.

Filters rated as having a 0.2-microm pore size (0.2-microm-rated filters) are used in laboratory and manufacturing settings for diverse applications of bacterial and particle removal from process fluids, analytical test articles, and gasses. Using Hydrogenophaga pseudoflava, a diminutive bacterium with an unusual geometry (i.e., it is very thin), we evaluated passage through 0.2-microm-rated filters and the impact of filtration process parameters and bacterial challenge density. We show that consistent H. pseudoflava passage occurs through 0.2-microm-rated filters. This is in contrast to an absence of significant passage of nutritionally challenged bacteria that are of similar size (i.e., hydrodynamic diameter) but dissimilar geometry.

Substituted titanocenes induce caspase-dependent apoptosis in human epidermoid carcinoma cells in vitro and exhibit antitumour activity in vivo.

Titanocene compounds are a novel series of agents that exhibit cytotoxic effects in a variety of human cancer cells in vitro and in vivo. In this study, the antiproliferative activity of two titanocenes (Titanocenes X and Y) was evaluated in human epidermoid cancer cells in vitro. Titanocenes X and Y induce apoptotic cell death in epidermoid cancer cells, with IC50 values that are comparable to cisplatin. Characterisation of the cell death pathway induced by titanocene compounds in A431 cells revealed that apoptosis is preceded by cell cycle arrest and the inhibition of cell proliferation. The induction of apoptosis is dependent on the activation of caspase-3 and -7 but not caspase-8. Furthermore, the antitumour activity of Titanocene Y was tested in an A431 xenograft model of epidermoid cancer. Results indicate that Titanocene Y significantly reduced the growth of A431 xenografts with an antitumour effect similar to cisplatin. These results suggest that titanocenes represent a novel series of promising antitumour agents.

Novel titanocene anti-cancer drugs and their effect on apoptosis and the apoptotic pathway in prostate cancer cells.

Advanced prostate cancer is not curable by current treatment strategies indicating a significant need for new chemotherapeutic options. Highly substituted ansa-titanocene compounds have shown promising cytotoxic activity in a range of cancers. The objectives of this study are to examine the effects of these titanocene compounds on prostate cancer cells. Prostate cell lines were treated with three novel titanocene compounds and compared to titanocene dichloride and cisplatin. Percent apoptosis, viability and cell cycle were assessed using propidium iodide DNA incorporation with flow cytometry. Cytochrome C was assessed by western blotting of mitochondrial and cytoplasmic fractions. Apoptosis Inducing Factor was assessed by confocal microscopy. These novel compounds induced more apoptosis compared to cisplatin in a dose dependent manner. Compound Y had the most significant effect on cell cycle and apoptosis. Despite the release of cytochrome C from the mitochondrial fraction there was no inhibition of apoptosis with the pan caspase inhibitor, ZVAD-FMK. AIF was shown to translocate from the cytosol to the nucleus mediating a caspase independent cell death. Bcl-2 over expressing PC-3 cells, which were resistant to cisplatin induced apoptosis, underwent apoptosis following treatment with all the titanocene compounds. This study demonstrates possible mechanisms by which these novel titanocene compounds can mediate their apoptotic effect in vitro. The fact that they can induce more apoptosis than cisplatin in advanced cancer cell lines would confer an advantage over cisplatin. They represent exciting new agents with future potential for the treatment of advanced prostate cancer.

Electron microscopic immunocytochemical detection of PSD-95, PSD-93, SAP-102, and SAP-97 at postsynaptic, presynaptic, and nonsynaptic sites of adult and neonatal rat visual cortex.

Membrane-associated guanylate kinases (MAGUKs) assemble protein complexes at sites of cell-cell contact. At excitatory synapses in brain, MAGUKs localize to the postsynaptic density (PSD) and interact with N-methyl-D-aspartate (NMDA) glutamate receptors and downstream signaling proteins. However, NMDA receptors are not restricted to the PSDs, as electron microscopic immunocytochemical (EM-ICC) results indicate that NMDA receptors also occur at nonsynaptic portions of dendrites, perhaps functioning as reserves for rapid insertion into synaptic membranes in response to appropriate synaptic activity. NMDA receptors also occur in axons, at least in part to support glutamate-dependent enhancement of transmitter release. In this study, a systematic EM-ICC survey was performed to determine whether the distributions of four neuronal MAGUKs-PSD-95, PSD-93, SAP-102, and SAP-97-resemble that of NMDA receptors. Quantitative analysis revealed that the density of PSD-95 over thick PSDs of asymmetric axo-spinous synaptic junctions is 2-3-fold the level in the immediately adjacent cytoplasm of spines and terminals, while symmetric synapses show no association with PSD-95. Similarly, all four MAGUKs occur over PSDs of spines. However, we also detected MAGUK immunoreactivity, albeit more diffusely, along presynaptic membranes and in the cytoplasm of axons and dendritic shafts. In fact, the overall distribution of PSD-95 within the neuropil is equally prevalent along plasma membranes (including synaptic portions) as in the cytoplasm, away from plasma membranes. These results suggest that MAGUKs have dual roles: to maintain receptors at synapses and to regulate shuttling of receptors between nonsynaptic and synaptic sites.

Competitive sorption of platinum and palladium on chitosan derivatives.

Glutaraldehyde-cross-linked chitosan (GCC), thiourea derivative of chitosan (TGC) and rubeanic acid derivative of chitosan (RADC) have previously been shown to be very efficient at removing platinum and palladium from single component dilute acidic solutions. This study examines the competitive sorption of these metal anions in bi-component mixtures for GCC, TGC and RADC. Palladium sorption is less sensitive to the presence of platinum than the reverse: the maximum sorption capacity decreases less for palladium than for platinum in the presence of the competitor anion (the metals being in their chloro-metal forms). Moreover, the Langmuir-shape of the sorption isotherm for palladium is unaffected (with the usual plateau reached at low residual palladium), while in the case of platinum sorption, the isotherms exhibit a significant decrease of the sorption capacity at high residual platinum concentration which increases with increasing concentrations of palladium. RADC is more selective for palladium over platinum than the other chitosan derivatives. A preliminary study of the competitive sorption kinetics in both batch and fixed bed systems is presented for RADC and confirms the higher affinity of the sorbent for palladium than for platinum.

Contrasting localizations of MALS/LIN-7 PDZ proteins in brain and molecular compensation in knockout mice.

Proteins containing PDZ (postsynaptic density-95, discs large, zonula occludens) domains play a general role in recruiting receptors and enzymes to specific synaptic sites. In Caenorhabditis elegans, a complex of three PDZ proteins, LIN-2/7/10, mediates basolateral targeting of a receptor tyrosine kinase. Homologs of these LIN proteins have also been identified in higher organisms, and here we analyze the MALS/Veli (mammalian LIN-7/vertebrate homolog of LIN-7) proteins in brain. Immunohistochemical staining and in situ hybridization show that MALS occur differentially in discrete populations of neurons throughout the brain. Most neurons express only one MALS protein, although some cells contain two or even all three MALS isoforms. At the subcellular level, MALS proteins are found in both dendritic and axonal locations, suggesting that they may regulate processes at both pre- and postsynaptic sites. Targeted disruption of MALS-1 and MALS-2 does not yield a detectable phenotype, and hippocampal synaptic function and plasticity are intact in the MALS-1/2 double knockouts. Interestingly, MALS-3 protein is dramatically induced in the MALS-1/2 double knockouts, implying that dynamic changes in protein expression may play an important regulatory role for this family of synaptic PDZ proteins.

Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms.

Stargazer, an ataxic and epileptic mutant mouse, lacks functional AMPA (alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate) receptors on cerebellar granule cells. Stargazin, the mutated protein, interacts with both AMPA receptor subunits and synaptic PDZ proteins, such as PSD-95. The interaction of stargazin with AMPA receptor subunits is essential for delivering functional receptors to the surface membrane of granule cells, whereas its binding with PSD-95 and related PDZ proteins through a carboxy-terminal PDZ-binding domain is required for targeting the AMPA receptor to synapses. Expression of a mutant stargazin lacking the PDZ-binding domain in hippocampal pyramidal cells disrupts synaptic AMPA receptors, indicating that stargazin-like mechanisms for targeting AMPA receptors may be widespread in the central nervous system.

The Escherichia coli K-12 gntP gene allows E. coli F-18 to occupy a distinct nutritional niche in the streptomycin-treated mouse large intestine.

Escherichia coli F-18 is a human fecal isolate that makes type 1 fimbriae, encoded by the fim gene cluster, and is an excellent colonizer of the streptomycin-treated mouse intestine. E. coli F-18 fimA::tet, lacking type 1 fimbriae, was constructed by bacteriophage P1 transduction of the fim region of the E. coli K-12 strain ORN151, containing the tetracycline resistance gene from Tn10 inserted in the fimA gene, into E. coli F-18. E. coli F-18 fimA::tet was found to occupy a distinct niche in the streptomycin-treated mouse intestine when fed in small numbers (10(4) CFU) to mice, along with large numbers (10(10) CFU) of E. coli F-18, as defined by the ability of the E. coli F-18 fimA::tet strain to grow and colonize only 1 order of magnitude below E. coli F-18. The same effect was observed when mice already colonized with E. coli F-18 were fed small numbers of E. coli F-18 fimA::tet. Experiments which show that the E. coli K-12 gene responsible for this effect is not fim::tet but gntP, which maps immediately downstream of the fim gene cluster, are presented. gntP encodes a high-affinity gluconate permease, suggesting that the distinct niche in the mouse large intestine is defined by the presence of gluconate. The data presented here support the idea that small numbers of an ingested microorganism can colonize the intestine as long as it can utilize an available nutrient better than any of the other resident species can.

Escherichia coli F-18 and E. coli K-12 eda mutants do not colonize the streptomycin-treated mouse large intestine.

The Escherichia coli human fecal isolates F-18 and K-12 are excellent colonizers of the streptomycin-treated mouse intestine. E. coli F-18 and E. coli K-12 eda mutants (unable to utilize glucuronate, galacturonate, and gluconate) were constructed by insertional mutagenesis. Neither the E. coli F-18 eda nor the E. coli K-12 eda mutant was able to colonize the streptomycin-treated mouse intestine, whether they were fed to mice together with their respective parental strains or alone. Complementation of the eda mutants with pTC190 (containing a functional E. coli K-12 eda gene) completely restored the colonization ability of both eda mutants. Relative to their parental strains, the E. coli F-18 eda mutant and the E. coli K-12 eda mutant grew poorly in cecal mucus isolated from mice fed either normal mouse chow or a synthetic diet containing sucrose as the sole carbon source, yet the mutants and parental strains demonstrated identical growth rates in minimal medium with glucose as the carbon source. E. coli F-18 edd eda and E. coli K-12 edd eda double mutants colonized the streptomycin-treated intestine when fed to mice alone; however, when fed simultaneously with their respective parental strains, they were poor colonizers. Since the edd gene is involved only in gluconate metabolism via the Entner-Doudoroff pathway, these results implicate the utilization of gluconate and the Entner-Doudoroff pathway as important elements in E. coli colonization of the streptomycin-treated mouse large intestine.

A concept analysis of personal knowledge: application to nursing education.

A concept analysis of personal knowledge is completed using the Walker and Avant method. The analysis is based on Polanyi's concept of personal knowledge with a working definition being extrapolated from his writings combined with Belenky and colleagues' concept of constructed knowledge. The goal is to construct a definition of personal knowledge which recognizes the multifaceted processing used by humans in the endeavour to perceive new patterns, and which is free from discrimination based on age, sex, culture, discipline, world view or learning style. Knowledge is defined as pattern recognition which may be probabilistically rather than exactly predictive. Personal knowledge is defined as recognition of a new pattern through processing by the human being. The processing may consist of any combination of human and environmental interaction, 'rational intuiting', appraisal, active comprehension and personal judgement, all in a setting of departure from the current conceptual framework. The pattern may be new to the person or to humanity. Personal knowledge is denoted by perception of the person. The antecedents, attributes and consequences are taken from the literature. The empirical referents are hypothesized from a review of the nursing, social work and education literature. After defining personal knowledge and differentiating it from other phenomena, it is integrated into nursing education. An educator accepting personal knowledge as an expectation for students approaches the teaching/learning situation by planning to create an atmosphere in which individual growth and illumination can occur. Therein personal knowledge is integrated into nursing education using the most barrier-free theoretical frameworks in the areas of learning, curriculum and instruction.

Clinical efficacy of methadone in patients refractory to other mu-opioid receptor agonist analgesics for management of terminal cancer pain. Case presentations and discussion of incomplete cross-tolerance among opioid agonist analgesics.

BACKGROUND: Development of tolerance to opioid analgesics occurs often in patients with cancer-related pain. Cross-tolerance among opioid analgesics provides the physician with a major management problem. Incomplete cross-tolerance among opioid analgesics has been demonstrated to occur in animals and humans. The current study provides clinical evidence of the incomplete cross-tolerance of methadone with a number of mu-opioid agonist analgesics in patients with advanced cancer-related pain. RESULTS: Patients presented in the current study had cancer-related pain refractory to other mu--opioid receptor agonist analgesics as evidenced by inadequate analgesia despite escalation of opioid dose. All patients were adequately managed by conversion of their opioid dose to methadone. Additionally, the dose of methadone required to establish and maintain analgesia in these patients was modest compared with previous opioid dose requirements. CONCLUSIONS: Methadone is a potent opioid analgesic that demonstrates incomplete cross-tolerance with other mu-opioid receptor agonist analgesics. Conversion of the opioid-tolerant patient with cancer-related pain to methadone may represent an important therapeutic option in the management of patients with this difficult problem.

Effect of position on the spread of buffered 2% chloroprocaine administered epidurally for the second stage of labor.

Increasing the pH of epidurally administered local anesthetics hastens their onset of action and improves the quality of neural blockade. The effect of body position on the epidural spread of alkalinized 2% chloroprocaine HCl for the second stage of labor has not been reported. We studied the epidural cephalad and caudad spread of 2% chloroprocaine buffered with sodium bicarbonate administered epidurally at the beginning of the second stage of labor. We randomly assigned 30 patients to one of two groups, each consisting of 15 patients. Group 1 received an epidural redose in the upright position, and the patients in group 2 received a redose in the supine position. There were no differences with respect to the sacral or cephalad spread. From the results of this study, we conclude that patients may receive epidurally administered 2% chloroprocaine late during the first stage of labor while in a supine position.