Reminova and EAER: Keeping Enamel Whole through Caries Remineralization.

This article aims to outline the early development of a King's College London dental spinout company, Reminova, formed to commercialize a novel clinical method of caries remineralization: electrically accelerated and enhanced remineralization (EAER). This method is being developed to address the unmet clinical need identified by modern caries management strategies to keep enamel "whole" through remineralization of clinical caries as a form of nonoperative caries treatment for initial-stage and moderate lesions. A progressive movement within dentistry is shifting away from the restorative-only model, which, it is suggested, has failed. The high prevalence of initial-stage caries across populations provides a significant opportunity to prevent restorations and reduce repeat restorations over a patient's lifetime. Reminova has set out to provide a method to repair lesions without drilling, filling, pain, or injections. The article outlines the rationale for and the chronological stages of the technology and company development. It then outlines corroborative evidence to show that EAER treatment can, in this preliminary in vitro investigation, remineralize clinically significant caries throughout the depth of the lesion as measured by Knoop microhardness and corroborated by scanning electron microscopy. Furthermore, the presented data show that EAER-treated enamel is harder than the healthy enamel measured nearby in each sample and is very similar in appearance to healthy enamel from the subjective interpretation made possible by scanning electron microscopy imagery. The data presented also show that this more "complete" remineralization to a high hardness level has been achieved with 2 remineralizing agents via in vitro human tooth samples. The broad clinical potential of this new treatment methodology seems to be very encouraging from these results. Reminova will strive to continue its mission, to ensure that, in the future, dental teams will not need to drill holes for the treatment of initial-stage and moderate caries lesions.

Site-selective doping of ordered charge states in magnetite.

Charge ordering creates a spontaneous array of differently charged ions and is associated with electronic phenomena such as superconductivity, colossal magnetoresistances (CMR), and multiferroicity. Charge orders are usually suppressed by chemical doping and site selective doping of a charge ordered array has not previously been demonstrated. Here we show that selective oxidation of one out of eight distinct Fe2+ sites occurs within the complex Fe2+/Fe3+ ordered structure of 2%-doped magnetite (Fe3O4), while the rest of the charge and orbitally ordered network remains intact. This 'charge order within a charge order' is attributed to the relative instability of the trimeron distortion surrounding the selected site. Our discovery suggests that similar complex charge ordered arrays could be used to provide surface sites for selective redox reactions, or for storing information by doping specific sites.

Silencing of TLR4 decreases liver tumor burden in a murine model of colorectal metastasis and hepatic steatosis.

BACKGROUND: The relationship between obesity and cancer has become of particular interest due to the rapidly growing prevalence of overweight individuals. Obesity predisposes individuals to the development of hepatic steatosis and is an independent risk factor for several neoplasms. Toll-like receptor 4 (TLR4) is the innate receptor for endotoxin, and steatotic livers are known to be sensitive to endotoxin. TLR4 signaling has been shown to have proneoplastic effects in vitro due to its effect on immune surveillance. Thus far, studies have predominantly focused on the effect of tumor-cell-derived TLR4 without regard to host TLR4 signaling. RESULTS: In the present study we show that steatotic livers have increased expression of TLR4. Obese animals developed higher metastatic tumor burden in the liver than lean controls regardless of the presence or absence of intact host TLR4. After silencing TLR4 expression using RNAi in the mouse colon cancer cell line MC38, there was a significant decrease in metastatic tumor burden within the liver of obese animals. CONCLUSIONS: These findings demonstrate that steatotic livers have increased susceptibility to metastatic tumor growth and that silencing tumor cell TLR4 reduces metastatic tumor burden in steatotic liver.

Powder crystallography on macromolecules.

Following the seminal work of Von Dreele, powder X-ray diffraction studies on proteins are being established as a valuable complementary technique to single-crystal measurements. A wide range of small proteins have been found to give synchrotron powder diffraction profiles where the peak widths are essentially limited only by the instrumental resolution. The rich information contained in these profiles, combined with developments in data analysis, has stimulated research and development to apply the powder technique to microcrystalline protein samples. In the present work, progress in using powder diffraction for macromolecular crystallography is reported.

Fabrication of versatile 3-D ternary nanostructures via gas-mediated metal evaporation.

By combining nanosphere lithography (NSL) with metal evaporation at two different chamber pressures, ternary metallic nanostructures with 3D topography were fabricated and characterized by field emission gun scanning electron microscopy (FEG-SEM) and atomic force microscopy (AFM). The nanostructures consist of 340 nm silicon patches surrounded by a chromium mesh of varying height and gold triangular pillars with a height of 40 nm and a diameter of about 200 nm. While NSL was applied due to its ease of use, evaporation at different chamber pressures can be combined with any kind of template mask comprising convex shape to yield novel kinds of ternary nanostructures analogous to the ones presented here. The method shows to be more versatile than plasma-based deposition techniques due to avoidance of substrate charging effects and a freely adjustable chamber pressure.

Multi-scale mechanics of granular solids from grain-resolved X-ray measurements.

This work discusses an experimental technique for studying the mechanics of three-dimensional (3D) granular solids. The approach combines 3D X-ray diffraction and X-ray computed tomography to measure grain-resolved strains, kinematics and contact fabric in the bulk of a granular solid, from which continuum strains, grain stresses, interparticle forces and coarse-grained elasto-plastic moduli can be determined. We demonstrate the experimental approach and analysis of selected results on a sample of 1099 stiff, frictional grains undergoing multiple uniaxial compression cycles. We investigate the inter-particle force network, elasto-plastic moduli and associated length scales, reversibility of mechanical responses during cyclic loading, the statistics of microscopic responses and microstructure-property relationships. This work serves to highlight both the fundamental insight into granular mechanics that is furnished by combined X-ray measurements and describes future directions in the field of granular materials that can be pursued with such approaches.

Characterization of unusual alkaliphilic gram-positive bacteria isolated from degraded brown alga thalluses.

Two orange-pigmented Gram-positive, aerobic bacteria were isolated from enrichment culture during degradation of brown alga Fucus evanescens thalluses. In this work, atomic force microscopy (AFM) has been used to study the cell morphology. The non-contact mode imaging revealed unusual irregular coccoid shape of cells, possessing a single flagellum. Bacteria produced carotenoid pigments, were chemo-organotrophic, alkaliphilic and halo-tolerant growing well on nutrient media containing up to 15% NaCl. Growth temperature ranged from 5 to 45 degrees C. The DNA base compositions were 48 mol% G + C and the level of DNA similarity of two strains was conspecific (98%). A comparative phylogenetic analysis of 16S rRNA gene sequences revealed that the strain KMM 3738 tightly clustered with recently described Planococcus maritimus (99.9% 16S rRNA gene sequence similarity). DNA-DNA hybridisation experiments revealed that DNA from the KMM 3738 showed 12-15% and 16-35% of genetic relatedness with the DNA of type strains of the genera Planomicrobium and Planococcus, respectively, and 87% with DNA from Planococcus maritimus, indicating that new isolates belong to the later species.

The Verwey structure of a natural magnetite.

A remarkably complex electronic order of Fe(2+)/Fe(3+) charges, Fe(2+) orbital states, and weakly metal-metal bonded Fe3 units known as trimerons, was recently discovered in stoichiometric magnetite (Fe3O4) below the 125 K Verwey transition. Here, the low temperature crystal structure of a natural magnetite from a mineral sample has been determined using the same microcrystal synchrotron X-ray diffraction method. Structure refinement demonstrates that the natural sample has the same complex electronic order as pure synthetic magnetite, with only minor reductions of orbital and trimeron distortions. Chemical analysis shows that the natural sample contains dopants such as Al, Si, Mg and Mn at comparable concentrations to extraterrestrial magnetites, for example, as reported in the Tagish Lake meteorite. Much extraterrestrial magnetite exists at temperatures below the Verwey transition and hence our study demonstrates that the low temperature phase of magnetite represents the most complex long-range electronic order known to occur naturally.

Immunoproliferative small-intestinal disease: clinical features and outcome in 30 cases.

Experience with 30 patients with immunoproliferative small intestinal disease followed prospectively between 1971 and 1986 is described. All presented with malabsorption or growth retardation and had similar clinical, biochemical, and radiological features, irrespective of the presence of lymphoma or immunological abnormality. Alpha-chain disease protein was detected in 4 of the 11 patients who had a non-lymphomatous, predominantly plasmacytic infiltration of the small bowel; and in 5 of the 19 cases with diffuse intestinal lymphoma. The importance of exploratory laparotomy to include full-thickness intestinal biopsy in patients who have a benign infiltrate on peroral biopsy is demonstrated by the finding of lymphoma in operative specimens in 9 of 15 patients with mature, lymphoplasmacytic cells, and 5 of 8 patients with atypical, lymphoplasmacytic cells. The majority of patients with fully established benign disease, even those elaborating alpha-chain disease protein, appeared to have a good prognosis. No patient with immunoproliferative small intestinal disease developed immunologically demonstrated alpha-chain disease or frank lymphoma, when this was not found initially at explorative laparotomy.

Maintenance therapy with sucralfate reduces rate of gastric ulcer recurrence.

Seventy-two patients with recently healed gastric ulcers were entered into a double-blind, placebo-controlled, six-month maintenance trial to assess whether sucralfate, 1 g in the morning and 2 g at night, reduces the propensity for recurrent ulceration. Patients were assessed clinically at 0, 6, 12, 18, and 24 weeks. Endoscopy was performed at the time of entry into the study and at 24 weeks, or earlier if clinical relapse occurred during this period. Eleven patients were excluded from the study because they defaulted or for other protocol violations. The other 61 patients were followed for six months or until evidence of ulcer relapse. Endoscopic recurrence was found in five of 31 patients (16 percent) randomly assigned to receive sucralfate and in 21 of 30 patients (70 percent) assigned to receive placebo. Most recurrences occurred during the first 12 weeks, with relapse rates of 10 percent and 53 percent, respectively for the sucralfate- and the placebo-treated groups. Three of the recurrences noted at 24 weeks were asymptomatic; two of these were in the sucralfate-treated group. The results indicate that a 3 g per day maintenance dose of sucralfate offers meaningful protection against recurrent gastric ulceration.

Nocturnal dosage regimen of sucralfate in maintenance treatment of gastric ulcer.

Sixty-six patients with recently healed gastric ulcers were entered into a double-blind, placebo-controlled, six-month maintenance trial to determine whether sucralfate 2 g at night reduces the liability to recurrent ulceration. Thirty-three patients were randomly assigned to treatment with sucralfate and 33 were assigned to placebo. Endoscopy was performed at the time of entry into the study and at 24 weeks, or earlier if clinical relapse occurred during this period. Of the patients available for analysis, endoscopic recurrences were found in eight of the 29 patients (28 percent) randomly assigned to sucralfate and in 15 of the 27 patients (56 percent) assigned to placebo. Eight of the recurrences noted at 24 weeks were asymptomatic and, of these, five were in the placebo-treated group. The cumulative relapse rate at 24 weeks was significantly lower in the sucralfate-treated group (p less than 0.05), and the Cox-Mantel text showed a significant difference between the cumulative relapse curves of the two treatment groups over the 24-week period (p less than 0.05). The results indicate that a single maintenance dose of sucralfate 2 g at night reduces the relapse rate in patients with recently healed gastric ulceration.

A randomized, double-blind, placebo-controlled trial of olsalazine for active Crohn's disease.

SUMMARY: : Olsalazine, consisting of two salicylate radicals linked by an azo-bond, is effective in the treatment of active ulcerative colitis. To test its effect in patients with mild to moderate attacks of Crohn's disease, the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) designed a multicentre, randomised, double-blind, placebo-controlled study. Ninety-one patients from four centres were randomised to receive either olsalazine, 1 g b.i.d., or matching placebo tablets. Twenty-six patients had ileal disease; 43, ileocolonic; and 22, colonic. Thirty-five of 46 patients taking olsalazine and 24 of 45 patients taking placebo were withdrawn before the end of the 4-month study. Diarrhoea was the most common reason for withdrawal from the olsalazine group, accounting for 22% of the patients, as compared with 4% in the placebo group. No other side effects were reported. There was no difference in the remission rate or withdrawal rate for active disease in the two groups. However, when an intent-to-treat analysis was performed, only eight of the 46 (17%) olsalazine-treated patients were considered to have entered remission or improved their symptoms compared with 22 of the 45 (49%) placebo-treated patients (p < 0.03). This study was unable to show that patients with mild to moderate attacks of Crohn's disease were significantly improved by treatment with olsalazine at a dose of 1 g daily. However, the potential benefit of a higher dose cannot be excluded.

Lack of efficacy of ridogrel, a thromboxane synthase inhibitor, in a placebo-controlled, double-blind, multi-centre clinical trial in active Crohn's disease.

BACKGROUND: Thromboxanes are produced in excess and platelets are activated in active Crohn's disease. Preliminary reports have suggested that ridogrel, a dual thromboxane synthase inhibitor and receptor antagonist, may have therapeutic benefit in patients with inflammatory bowel disease. AIMS: To investigate the efficacy of ridogrel in patients with active Crohn's disease. PATIENTS AND METHODS: This was an international, multicentre, randomized, double-blind, placebo-controlled trial of 5 mg/day oral ridogrel for 12 weeks in 85 patients with moderately active Crohn's disease. Sixty patients were randomized to receive ridogrel, and 25 to placebo. The Crohn's disease activity index (CDAI) was used to assess disease activity: remission was defined as a CDAI < 150. Changes in clinical condition, as assessed by the Harvey-Bradshaw index, global evaluation by the investigator and the patient, and blood measures of inflammation, were used as secondary outcomes. RESULTS: The patients' mean (s.d.) CDAI at recruitment was 277 (68) in the ridogrel treated group and 265 (70) in the placebo group. At their final assessment, 20 out of 60 (35%) patients who had been given ridogrel in an intention-to-treat analysis and seven out of 25 (28%) patients given placebo were in remission (no significant difference). No significant differences in Harvey- Bradshaw index or global evaluation were noted between patients given ridogrel and those given placebo. Adverse events were similar in both groups. CONCLUSION: A 5-mg dose of oral ridogrel was not more effective than placebo in inducing remission in patients with moderately active Crohn's disease. If thromboxane synthesis and platelet function are to be targeted for the treatment of Crohn's disease, more potent agents require development and assessment.

Mesalazine (Mesasal/Claversal) 1.5 g b.d. vs. placebo in the maintenance of remission of patients with Crohn's disease.

UNLABELLED: INVESTIGATORS: This multicentre study was conducted by 29 principal investigators in 11 countries. AIMS: To compare the safety and efficacy of oral mesalazine (Mesasal/Claversal, 5-ASA) 1.5 g b.d. in comparison with placebo in the maintenance of remission in 286 patients with Crohn's disease. MATERIALS AND METHODS: Patients had to score less than 150 in their Crohn's Disease Activity Index (CDAI), and had to have had one period of clinical activity (CDAI > 150) within 18 months of the study start. Patients were randomized to receive 5-ASA 1.5 g b.d. daily or matching placebo for 12 months. Study visits were scheduled for months 1, 3, 6, 9 and 12, or when symptoms suggested a relapse of the disease. Relapse was defined as a CDAI score greater than 150, with at least a 60-point increase from the baseline index score. None of the patients used glucocorticoids or immunosuppressants during the trial. RESULTS: In the first group, 207 patients with Crohn's colitis or ileocolitis were randomized: there were 101 females and 106 males, in age range 18-71 years. A total of 106 patients (51 in the 5-ASA group and 55 in the placebo group) were withdrawn from the study due to adverse events, insufficient therapeutic effect, or for other reasons. This left 101 patients (51 in the 5-ASA group and 50 in the placebo group) who completed the 12-month trial. In the second group, 79 patients with Crohn's ileitis were randomized to treatment. There were 53 females and 26 males, age range 18-66 years. A total of 41 patients (19 in the 5-ASA group and 22 in the placebo group) were withdrawn from the study. This left 38 patients (17 in the 5-ASA group and 21 in the placebo group) who completed the 12-month trial. The primary efficacy variable was the CDAI. A protocol-eligible analysis and an intent-to-treat analysis were performed. No statistical differences were noted between the two analyses. In patients with Crohn's colitis or ileocolitis, or in those with ileitis, no statistically significant differences were noted with respect to the relapse rates between the 5-ASA and the placebo treatment groups. Adverse events in the gastrointestinal system were the most frequently reported in both treatment groups. Many of the events such as diarrhoea or abdominal pain are symptoms of Crohn's disease. The majority of the events reported were mild or moderate in severity. In neither study was the prevalence of adverse events or the proportion of drop-outs different between patients in the treatment or in the placebo groups. The site of the Crohn's disease had no effect on the frequency of adverse events. CONCLUSION: The relapse rates of Crohn's disease were similar for up to 12 months in both the 5-ASA 1.5 g b.d. and the placebo treatment groups.

Granulomatous uveitis in Crohn's disease. A clinicopathologic case report.

Recurrent episodes of uveitis occurred in a young male patient with clinical as well as radiologic and histologic evidence of Crohn's ileocolitis. His left eye became blind and painful, and was enucleated. Histopathologic examination of the eye revealed a panuveitis with evidence of granuloma formation in the choroid. While granulomatous inflammation has previously been demonstrated in extraintestinal sites, to our knowledge, this is the first histopathologic evidence of granuloma formation within the eye in Crohn's disease.

Primary sclerosing cholangitis. Requiem for biliary drainage operations?

OBJECTIVE: To review the outcome of a consecutive number of patients with primary sclerosing cholangitis (PSC) treated at one institution to define prognostic variables and determine the influence of surgery on outcome. DESIGN: Case series of patients with PSC seen in Cape Town, South Africa, between 1981 and 1991. SETTING: Tertiary referral center. PATIENTS: Thirty-six patients with PSC were studied. Diagnosis was based on cholangiographic findings of multiple strictures of the bile ducts together with compatible clinical and biochemical features. Thirty-two patients were followed up prospectively for up to 9 years. MAIN OUTCOME MEASURES: Patient outcome was defined as good (stable or slowly progressive disease) or poor (death or liver transplantation). RESULTS: During the follow-up period, seven patients with PSC died and two underwent liver transplantation. Actuarial survival at 5 years was 52%. An increased serum bilirubin concentration was the only variable at presentation that independently predicted a poor outcome. Cholangiography was unhelpful in predicting patient outcome. Six patients who developed obstructive jaundice associated with advanced liver disease underwent biliary drainage operations for surgically correctable strictures, but this did not seem to prevent progression of the disease. Two patients who progressed to end-stage liver disease went on to have liver transplantation and were alive with functioning grafts at 7 and 14 months, respectively. CONCLUSIONS: Symptomatic PSC is a progressive disorder with a poor prognosis. Our experience suggests that patients with advanced liver disease caused by PSC should be considered directly for liver transplantation rather than biliary bypass operations.

High level excretion of Norwalk-like virus following resolution of clinical illness.

We report the case of an elderly woman excreting high levels (about 5 x 10(5) virions per gram of faeces) of Norwalk-like virus (NLV) in the absence of any clinical symptoms of gastroenteritis. Analysis by reverse transcription, polymerase chain reaction and DNA sequencing was carried out on a 342-nucleotide region of open reading frame 1. This indicated that the NLV belonged to genogroup 2 and was more closely related to the Camberwell subgroup, the most common circulating in southeast Australia at present, than to the Norwalk and Mexico viruses.

A communication from the left ventricle to the right atrium: a defect in the central fibrous body.

An isolated defect in the membranous atrioventricular septum was found in a five-year-old girl who presented with a cystic lesion in the right atrium. This type of left ventricular-right atrial communication could result from a structural abnormality of the central fibrous body in combination with arrested maturation of the membranous ventricular septum.

Pressurised metered dose inhalers versus all other hand-held inhaler devices to deliver beta-2 agonist bronchodilators for non-acute asthma.

BACKGROUND: A number of different inhaler devices are available to deliver beta2-agonist bronchodilators in asthma. These include hydrofluoroalkane (HFA) or chlorofluorocarbon (CFC)-free propelled pressurised metered dose inhalers (pMDIs) and dry powder devices. OBJECTIVES: To determine the clinical effectiveness of pMDI compared with any other available handheld inhaler device for the delivery of short-acting beta-2 agonist bronchodilators in non-acute asthma in children and adults. SEARCH STRATEGY: The Cochrane Collaboration Clinical Trials register was searched for studies as well as separate additional searches carried out on MEDLINE, EMBASE, CINAHL and also on the Current Contents Index as well as the Science Citation Index. In addition, 17 individual online respiratory journals and 12 electronically available clinical trial databases were also searched. The UK pharmaceutical companies who manufacture inhaled asthma medication were contacted in order to obtain details of any published or unpublished studies. SELECTION CRITERIA: - The full texts of all potentially relevant articles were reviewed independently by two reviewers. DATA COLLECTION AND ANALYSIS: Fixed and random effect models were used. Dichotomous outcomes were assessed using Odds Ratios or Relative Risks (RR) with 95% Confidence Intervals (95%CI). MAIN RESULTS: Eighty-four randomised controlled trials were included in this review, but few could be combined to assess a specific outcome for a given delivery device comparison. Only two studies required demonstration of adequate pMDI technique as an entry requirement. There were no difference between a standard CFC containing pMDI and any other device for most outcomes. Regular use of HFA-pMDI containing salbutamol reduced the requirement for short courses of oral corticosteroids (3 trials, 519 patients: RR 0.67; 95% CI 0.49, 0.91); however the total number of exacerbations were unchanged (3 trials, 1271 patients: RR 1.0; 95% CI 0.75, 1.33). REVIEWER'S CONCLUSIONS: In patients with stable asthma, short-acting beta-2 bronchodilators in standard CFC-pMDI's are as effective as any other devices. The effect of HFA-pMDI on requirement for oral corticosteroid courses to treat acute exacerbations should be confirmed. Effectiveness studies that use an intention-to-treat analysis are required.

Bacterial meningitis in developing countries.

PIP: Hemophilus influenza, Streptococcus pneumoniae, and Neisseria meningitidis account for over 75% of all cases of bacterial meningitis. S. pneumoniae is the commonest causative organism in many developing countries, particularly in Africa. In developing countries overall case fatality rates of 33-44% have been reported, rising to over 60% in adult groups. S. pneumoniae accounts for the highest mortality worldwide. Sequela rates of 22-26% of survivors have been found in African studies, mostly of a neurological nature. There have been few reports of AIDS-related bacterial meningitis in the USA, and a recent study from Uganda found no association between HIV infection and meningococcal meningitis. Stronger associations have been found between opportunistic infections, both viral (cytomegalovirus, herpes virus) and non-viral (TB, Toxoplasma gondii, Cryptococcus neoformans). A lumbar puncture and analysis of the cerebrospinal fluid should be performed on suspected cases unless there is suspicion of impending coning (decreasing consciousness or focal neurological signs). The intramuscular administration of chloramphenicol alone is comparable with intravenous use, and can be given as a shorter course of therapy (2 or 3 days) followed by an oral course. The use of adjunct therapy with corticosteroids in children is now commonplace in the USA and Europe. It appears reasonable to use dexamethasone, given early and in high dosage (0.15 mg/kg 6 hourly for 4 days), in those patients who are severely ill. Rifampicin is effective for chemoprophylaxis (10 mg/kg twice daily for 2 days for meningococcal contacts, 20 mg/kg once daily for 4 days for hemophilus contacts, maximum 600 mg per dose). The recent development and introduction of conjugate vaccines for H. influenza (HIB) has led to rapid reductions in the incidence of hemophilus meningitis in many European countries. An important step in improving prognosis is to increase awareness in both health workers and the public, to encourage early hospital referral, and early antibiotic therapy.^ieng