Fecal microbiota transplantation for fulminant Clostridium difficile infection in an allogeneic stem cell transplant patient.

We present a case of severe Clostridium difficile infection (CDI) in a non-neutropenic allogeneic hematopoietic stem cell transplant recipient who was treated successfully with fecal microbiota therapy after standard pharmacologic therapy had failed. Following naso-jejunal instillation of donor stool, the patient's symptoms resolved within 48 h. Bowel resection was averted. This is the first case in the literature, to our knowledge, to describe fecal microbiota therapy in a profoundly immunocompromised host with severe CDI. We propose that fecal microbiota therapy be considered as a therapeutic option in immunosuppressed patients with refractory severe CDI.

Effect of post-brushing mouthwash solutions on salivary fluoride retention--study 2.

OBJECTIVE: This study evaluated the effects of three post-brushing mouthwashes containing 0 ppm F, 225 ppm F, and 500 ppm F, respectively, on salivary fluoride retention after brushing with 1450 ppm fluoride (as NaF) toothpaste and rinsing with water immediately after brushing. METHODS: In this three-phase, randomized, cross-over study, an ion-specific electrode was used to measure salivary F levels in thirty trial participants before brushing (Time 0), and after brushing, rinsing with water, and then rinsing with one of the three mouthwashes. Time points evaluated after brushing were one, three, five, 10, 20, 30, 45, and 60 minutes. For saliva sample collections, subjects were asked to pool saliva in their mouths for 10 seconds before spitting out into a container for each of the time points. RESULTS: The AUC0-60 means for F in saliva were 554, 252, and 20 for the 500, 225, and 0 ppm F mouthwash groups, respectively. The 500 ppm F mouthwash resulted in a 2660% increase in total fluoride salivary retention over 60 minutes when compared with the 0 ppm F group, and a 120% increase when compared with the 225 ppm F group. A significant difference (p < 0.001) in the AUC0-60 means between the three groups was observed using analysis of variance (ANOVA). Paired t-tests also showed significant differences in the mean fluoride retention over 60 minutes for all three pair-wise group comparisons (p < 0.001). CONCLUSION: Use of a fluoride mouthwash containing 225 ppm F or 500 ppm F produced a significant increase in salivary fluoride retention following brushing with a 1450 ppm F toothpaste and rinsing with water compared to rinsing without fluoride. The use of the 500 ppm F mouthwash may be of particular benefit to those at high caries risk.

Colour match between porcelain and porcelain-repairing resin composites.

The aim of this study was to evaluate the differences in colour between dental porcelain and porcelain-repairing resin composites. Porcelain discs were fabricated using four dentine shades in 1mm and 2mm thicknesses. Another series of discs was fabricated in 1mm and 2 mm thicknesses using three different brands of composite. Four single shades were used for the 1mm thick discs, and four single and 12 combined shades for the 2mm thick discs. The colour was measured using a spectrophotometer and colour differences deltaE* were calculated between samples. Colour differences were in the range of (deltaE* = 3.5-26.9), above the accepted threshold for perceptibility (deltaE* > 1) with a number above the threshold for what is considered to be clinically acceptable (deltaE* > 5.5). Improvements in colour match were seen for certain shade combinations of repairing composites, in contrast to when a single shade of composite was used.

The health and well-being of cancer survivors in the UK: findings from a population-based survey.

BACKGROUND: To compare self-reported health and well-being in a sample of cancer survivors with individuals who have not had cancer and with individuals who have a serious chronic condition other than cancer. PATIENTS AND METHODS: A cross-sectional survey drawn from an online panel of 400,000 UK citizens supplemented with other online recruitment and telephone recruitment. The participants were 4892 individuals 30 years of age or above, including 780 individuals with a previous cancer diagnosis, 1372 individuals with one or more of 10 chronic conditions but not cancer and 2740 individuals without a previous cancer diagnosis or chronic condition. Thirteen measures of health and well-being were constructed from answers to 25 survey items covering physical, psychological and social dimensions of health and well-being. RESULTS: Cancer survivors were significantly more likely to report poor health outcomes across all 13 measures than those with no history of cancer or a chronic condition. The adjusted odds ratios for cancer survivors with no chronic conditions compared with healthy participants ranged from 1.37 (95% confidence interval (CI): 1.31-1.96) for emotional well-being to 3.34 (95% CI: 2.74-4.08) for number of health professionals consulted in the last 12 months. The health profile of cancer survivors was similar to those with a history of a serious chronic health condition. CONCLUSIONS: A substantial number of individuals who have had a diagnosis of cancer experience ongoing poor health and well-being following cancer and cancer treatment. The results of this study provide an initial basis for the development of specific help and support for cancer survivors.

Supportive care needs of patients following treatment for colorectal cancer: risk factors for unmet needs and the association between unmet needs and health-related quality of life-results from the ColoREctal Wellbeing (CREW) study.

PURPOSE: To investigate unmet needs of patients with colorectal cancer (CRC) at the end of treatment and whether unmet needs improve over time. Identify predictors of need following treatment and whether unmet need is associated with worse health-related quality of life (HRQoL). METHODS: As part of the UK ColoREctal Wellbeing (CREW) cohort study, patients treated for CRC completed the Supportive Care Needs Survey Short Form-34 (SCNS SF-34) 15 and 24 months following surgery, along with questionnaires measuring HRQoL, wellbeing, life events, social support, and confidence to manage their cancer before surgery, 3, 9, 15, and 24 months post-surgery. RESULTS: The SCNS SF-34 was completed by 526 patients at 15 months and 510 patients at 24 months. About one-quarter of patients had at least one moderate or severe unmet need at both time points. Psychological and physical unmet needs were the most common and did not improve over time. Over 60% of patients who reported 5 or more moderate or severe unmet needs at 15 months experienced the same level of unmet need at 24 months. HRQoL at the beginning of treatment predicted unmet needs at the end of treatment. Unmet needs, specifically physical, psychological, and health system and information needs, were associated with poorer health and HRQoL at the end of treatment. CONCLUSIONS: Unmet needs persist over time and are associated with HRQoL. Evaluation of HRQoL at the start of treatment would help inform the identification of vulnerable patients. Assessment and care planning in response to unmet needs should be integrated into person-centred care. IMPLICATIONS FOR CANCER SURVIVORS: Early identification of CRC patients at risk of unmet needs will help infrom personalised survivorship care plans. The implementation of personalised and tailored services are likely to confer HRQoL gains.

The influence of varying fluoride concentrations on in vitro remineralisation of artificial dentinal lesions with differing lesion morphologies.

OBJECTIVE: The influence of low-level fluoride (F) concentrations and lesion characteristics on the remineralisation of sub-surface root caries was investigated in vitro. DESIGN: Experimentally produced dentinal carious lesions were exposed to artificial saliva in the presence of 0.00ppm, 0.48ppm, 2.49ppm or 4.91ppm F (as NaF) for 5 days. Calcium, phosphate and fluoride ion uptake was quantified by chemical assay. Baseline changes in the mineral content and distribution of the lesions were assessed by transverse microradiography (TMR). RESULTS: The uptake of calcium and phosphate was significantly increased (p<0.05) by fluoride, even at low concentrations. The action of fluoride was influenced by the mineral content and distribution of the lesions at baseline, however, with the location and degree of mineral deposition being strongly related to the mineral content of the lesions surface layer. CONCLUSIONS: The process of remineralisation of root dentine is multifactorial. The morphology of lesions at baseline significantly affected the location and quantity of mineral deposition.

The efficacy of techniques for the disinfection of artificial sub-surface dentinal caries lesions and their effect on demineralization and remineralization in vitro.

OBJECTIVES: The efficacy of three techniques for the disinfection of artificial sub-surface root caries lesions and their response to subsequent episodes of de- and remineralization was investigated quantitatively in vitro. METHODS: Sub-surface dentinal lesions (n=20), cut into four experimental blocks and deliberately contaminated with Streptococcus mutans, were subject to either steam autoclaving (121 degrees C, 5min), gamma irradiation (4100Gy), immersion in 0.1% (w/v) thymol-distilled water solution (24h) or reserved as a control. Next, the lesions were incubated aerobically in sterile nutrient broth for 24h at 37 degrees C and resultant cultures plated onto blood agar and neutralisation agar. Ten blocks from each experimental group were then immersed in an acidic buffer solution or exposed to artificial saliva for 5 days. Baseline changes in the mineral content and distribution of the lesions were assessed by transverse microradiography (TMR). RESULTS: Micro-organisms were recovered from each control block and one block treated by gamma irradiation. Steam autoclaving and immersion in a thymol solution significantly decreased (p<0.05) the amount of mineral lost from the body of lesions subject to a further acid challenge. Mineral ion uptake by lesions exposed to artificial saliva was significantly increased (p<0.05) through disinfection by steam autoclaving. CONCLUSIONS: Gamma irradiation proved the most acceptable method for the disinfection of sub-surface root dentine lesions having the least adverse effect on demineralization and remineralization.

Drug design against a shifting target: a structural basis for resistance to inhibitors in a variant of influenza virus neuraminidase.

BACKGROUND: Inhibitors of the influenza virus neuraminidase have been shown to be effective antiviral agents in humans. Several studies have reported the selection of novel influenza strains when the virus is cultured with neuraminidase inhibitors in vitro. These resistant viruses have mutations either in the neuraminidase or in the viral haemagglutinin. Inhibitors in which the glycerol sidechain at position 6 of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (Neu5Ac2en) has been replaced by carboxamide-linked hydrophobic substituents have recently been reported and shown to select neuraminidase variants. This study seeks to clarify the structural and functional consequences of replacing the glycerol sidechain of the inhibitor with other chemical constituents. RESULTS: The neuraminidase variant Arg292-->Lys is modified in one of three arginine residues that encircle the carboxylate group of the substrate. The structure of this variant in complex with the carboxamide inhibitor used for its selection, and with other Neu5Ac2en analogues, is reported here at high resolution. The structural consequences of the mutation correlate with altered inhibitory activity of the compounds compared with wild-type neuraminidase. CONCLUSIONS: The Arg292-->Lys variant of influenza neuraminidase affects the binding of substrate by modification of the interaction with the substrate carboxylate. This may be one of the structural correlates of the reduced enzyme activity of the variant. Inhibitors that have replacements for the glycerol at position 6 are further affected in the Arg292-->Lys variant because of structural changes in the binding site that apparently raise the energy barrier for the conformational change in the enzyme required to accommodate such inhibitors. These results provide evidence that a general strategy for drug design when the target has a high mutation frequency is to design the inhibitor to be as closely related as possible to the natural ligands of the target.

Therapy of Mycobacterium marinum infections. Use of tetracyclines vs rifampin.

We describe four patients with Mycobacterium marinum infections who did not respond to two- to six-week courses of therapy with tetracycline, minocycline, and doxycycline. All four patients had prompt responses to therapy with either rifampin alone (two patients) or rifampin in combination with ethambutol. Results of antimicrobial sensitivity tests may be helpful in guiding therapy. Rifampin may be the drug of choice for treatment of these infections.

Development of an in situ root caries model. A. In vitro investigations.

OBJECTIVES: The paper describes preliminary in vitro investigations, the objectives of which were to examine the influence of certain experimental parameters on artificial carious lesion formation in root hard tissues, and their remineralisation. These experiments formed part of a wider study that aimed to develop an in situ model of root caries, based on the existing coronal caries model used in Liverpool. The present studies examined the effects (a) of the anatomical origin of the dentine, the presence or absence of cementum, the exposure time and the type of demineralising system, on lesion development, and (b) of baseline lesion size on the extent and location of mineral re-precipitation. METHODS: Mineral content parameters in plano-parallel sections taken from dentine lesions were determined by computer-controlled transverse microradiography. RESULTS: The importance of the anatomical origin of the dentine on lesion formation was investigated by comparing in vitro lesion formation in premolar and molar dentine, and in dentine from apical, middle and coronal thirds of the root: no difference was observed between these sites. Lesions formed more rapidly in acid buffer solutions than in acid gel systems, and were more reliably produced when cementum was removed. The effect of baseline lesion size on subsequent in vitro remineralisation demonstrated that a small baseline mineral content was associated with a larger percentage mineral gain. The location of mineral deposition throughout the lesion was also influenced by baseline mineral content parameters. CONCLUSIONS: The results form a basis for the further development of an in situ dentinal caries model, providing data to suggest that manipulation of parameters involved in the preparation of artificial carious lesions has a significant effect on the behaviour of the lesion, particularly the phenomenon of remineralisation. Further work is needed to investigate the behaviour of the model in situ.

Development of an in situ root caries model B. In situ investigations.

OBJECTIVES: The aims of this pilot study were to assess the suitability of an in situ model for root caries studies, and to investigate the effect of sub-surface lesion mineral content and ultrastructural organisation on remineralisation. METHODS: Subjects were selected by criteria generally used for coronal caries models. Plaque pH responses and salivary flow rates were determined by standard methods. The chosen substrate was human dentine with artificially induced caries-like demineralisation and sterilised by gamma-irradiation (4100 Gy). Two levels of baseline demineralisation were induced by exposure to an acid buffer for 2 or 5 days. Mineral content was measured by computer-controlled quantitative microradiography. RESULTS: Remineralisation in situ was greater in smaller lesions with lower surface mineral content than in larger lesions in which the surface mineral content was high. CONCLUSIONS: The model is suitable for further development for investigating dentinal caries. More work is needed to validate the model by means of a fluoride dose-response study.

Quantification of dental plaque in the research environment.

OBJECTIVES: To review the established and novel methods of plaque quantification employed in dental research, including a discussion of their merits and to present a new method of planimetrically measuring plaque using light induced fluorescence. METHOD: Quantitative light-fluorescence (QLF) images were acquired from the buccal surfaces of an individual who had refrained from oral hygiene both with and without traditional plaque disclosure. Digital photographs were also taken. Images were analysed using a novel method and a percentage plaque index produced. RESULTS: Traditional plaque indices are problematic due to their integral nature and their failure to detect small, but potentially clinically relevant changes in plaque area. The use of a fluorescent technique demonstrated good reliability although there was no correlation between red fluorescent plaque and total disclosed plaque suggesting that the auto-fluorescing plaque is not a good measure of total plaque volume. CONCLUSIONS: The use of planimetric techniques can increase the power of plaque studies, potentially reducing the number of subjects and time required to separate therapies or products. Fluorescent methods of quantification have potential as they enable clear separation of the plaque covered and non-covered tooth surfaces.

The use of in situ models and QLF for the study of coronal caries.

OBJECTIVES: The purpose of the paper is to review aspects of the systems available to model the caries process in enamel. METHODS: The in situ model developed in Liverpool, and the new method of quantifying mineral loss, Quantitative Light-induced Fluorescence (QLF), are described. QLF is a powerful new diagnostic tool which can be used to measure demineralisation and remineralisation in tooth surfaces in vivo; studies to optimise, validate and use QLF in different clinical situations are described. RESULTS: Examples of the use of in situ models show that they are particularly valuable for monitoring de and remineralisation of artificial lesions in relation to product testing as alternatives to clinical trials, and present significant advances over in vitro methods. Quantification of mineral loss by Transverse Microradiography (TMR) as in the traditional Liverpool model has produced much valuable information, but the destructive nature of the method limits experimental design, and removes the system from the clinical situation. As a possible alternative, QLF has been validated and optimised. Longitudinal measures can be made on the same surface, and examples of its use are for monitoring recurrent caries and demineralisation around orthodontic brackets. CONCLUSIONS: While current in situ models provide a major advance over earlier caries models, measurement of de and remineralisation by destructive methods such as transverse microradiography limits the design of experimental investigations. QLF offers significant time saving, reduces the cost of clinical studies, and because the measurements can be carried out longitudinally in vivo, can remove the need for intra-oral appliances carrying experimental tissues.

Cancer survivors' self-efficacy to self-manage in the year following primary treatment.

PURPOSE: Cancer survivors are increasingly expected to manage the consequences of cancer and its treatment for themselves. There is evidence that self-efficacy is important for successful self-management and that this can be enhanced with support. The purpose of this study was to assess self-efficacy to manage problems in the year following primary treatment. METHODS: This cross-sectional online survey included cancer survivors who had completed their treatment within the past 12 months. Self-efficacy was assessed and variables expected to be associated with self-efficacy were measured using validated scales including quality of life, well-being, illness perceptions, depression and social support. RESULTS: One hundred eighty-two respondents (mean age 50; 81% female) completed the survey. They had been treated for a range of cancers; most commonly breast (45%). Self-efficacy scores varied between individuals and according to the illness-related task to be managed. Respondents were least confident in managing fatigue and most confident in accessing information about their cancer. Individuals most likely to report low self-efficacy were women, those experiencing higher levels of pain and/or depression, lower well-being scores, lower socio-economic status, low levels of social support, or a more negative perception of cancer. CONCLUSIONS: Self-efficacy to self-manage problems faced as a consequence of cancer and its treatment can vary widely in the year following treatment. Fatigue may be particularly difficult to manage. IMPLICATIONS FOR CANCER SURVIVORS: Variations in self-efficacy highlight the importance of assessing specific problems faced and people's confidence to manage them in order to tailor appropriate self-management support.

Refining the mouse chromosomal location of Cdm, the major gene associated with susceptibility to cadmium-induced testicular necrosis.

Cadmium (Cd++) is a widespread environmental pollutant and classifed as an IARC 'Category I' human carcinogen. Cd++ can also cause severe renal toxicity and may be involved clinically in cardiovascular disease and osteoporosis. Genetic differences in sensitivity to cadmium toxicity have been noted in humans, whereas, among inbred mouse strains, unequivocal genetic data exist. Resistance to cadmium-induced testicular damage was reported in 1973 to be associated with a single major recessive gene, named Cdm, which has now been localized to mouse chromosome (Chr) 3. Using polymorphic microsatellite markers and semiquantitative histological parameters, we have corroborated the original 1973 data concerning mendelian inheritance and have further refined the region containing the Cdm gene from more than 24 cM to 0.64 cM (estimated 40-80 genes). We phenotyped 26 recombinant inbred lines generated from C57BL/6J (B6, resistant) and DBA/2J (D2, sensitive) inbred mice, and determined that the Cdm gene maps between microsatellite markers D3Mit110 and D3Mit255. Although toxicity to numerous heavy metals is well known, virtually no molecular mechanisms have yet been uncovered either in humans or laboratory animals. Identification and characterization of the mouse Cdm gene should enhance our understanding of heavy metal toxicity by identifying and characterizing, for the first time, a major mammalian gene responsible for susceptibility to diseases caused by heavy metal toxicity.

Inhibition of HIV replication by amino-sugar derivatives.

The plant alkaloids castanospermine, dihydroxymethyldihydroxypyrrolidine and deoxynojirimycin have recently been shown to have potential anti-HIV activity [(1987) Proc. Natl. Acad. Sci. USA 84, 8120-8124; (1987) Nature 330, 74-77; (1987) Lancet i, 1025-1026]. They are thought to act by inhibiting alpha-glucosidase I, an enzyme involved in the processing of N-linked oligosaccharides on glycoproteins. We report here the relative efficacy of a spectrum of amino-sugar derivatives as inhibition of HIV cytopathicity. Several alpha-glucosidase inhibitors and alpha-fucosidase inhibitors were found to be active at concentrations which were non-cytotoxic.

CNS nocardiosis: response to sulfamethoxazole-trimethoprim.

Two patients with neurologic nocardiosis are described. Sulfamethoxazole-trimethoprim therapy was successfully used in a patient with Nocardia meningitis and in a patient with multiple Nocardia brain abscesses.

Recurrent Streptococcus mutans endocarditis.

Recurrent bacterial endocarditis is associated with several risk factors including parenteral drug abuse, past valvular heart disease, and periodontitis. Recurrence rates vary from 2 to 18 percent for a single recurrence, and 1 to 5 percent for two recurrences. An unusual case study of a patient experiencing three episodes of bacterial endocarditis following dental work is described. The episodes occurred at least one year apart and were characterized by biochemically identical strains of Streptococcus mutans.

Current status of nosocomial infection control in extended care facilities.

The 1980s saw the birth and growth of the distinct field of infection control in the extended care facility (ECF). Major advances in the field during the last decade have been surveys documenting the magnitude of the problem of ECF nosocomial infections, descriptive studies of ECF nosocomial infections, descriptive studies of ECF epidemics, development of ECF infection control programs, and recognition of the unique problems of the ECF infection control program. As the field matures, areas that should receive additional attention during the upcoming decade include: analysis of the risk factors and consequences of ECF nosocomial infections; analysis of resident and institutional variables that predict nosocomial infection; and studies on the efficacy of both infection control programs and specific infection control measures. ECF infection control programs have benefited a great deal from hospital infection control, but ECF infection control problems are quite different and demand unique solutions.

Dihydropyrancarboxamides related to zanamivir: a new series of inhibitors of influenza virus sialidases. 2. Crystallographic and molecular modeling study of complexes of 4-amino-4H-pyran-6-carboxamides and sialidase from influenza virus types A and B.

The first paper in this series (see previous article) described structure-activity studies of carboxamide analogues of zanamivir binding to influenza virus sialidase types A and B and showed that inhibitory activity of these compounds was much greater against influenza A enzyme. To understand the large differences in affinities, a number of protein-ligand complexes have been investigated using crystallography and molecular dynamics. The crystallographic studies show that the binding of ligands containing tertiary amide groups is accompanied by the formation of an intramolecular planar salt bridge between two amino acid residues in the active site of the enzyme. It is proposed that the unexpected strong binding of these inhibitors is a result of the burial of hydrophobic surface area and salt-bridge formation in an environment of low dielectric. In sialidase from type A virus, binding of the carboxamide moeity and salt-bridge formation have only a minor effect on the positions of the surrounding residues, whereas in type B enzyme, significant distortion of the protein is observed. The results suggest that the decreased affinity in enzyme from influenza B is directly correlated with the small changes that occur in the amino acid residue interactions accompanying ligand binding. Molecular dynamics calculations have shown that the tendency for salt-bridge formation is greater in influenza A sialidase than influenza B sialidase and that this tendency is a useful descriptor for the prediction of inhibitor potency.