Adverse effects and duration of treatment of TB in Canterbury, New Zealand.

BACKGROUND Treatment of TB is often extended beyond the recommended duration. The aim of this study was to assess prevalence of extended treatment and to identify associated risk factors. We also aimed to determine the frequency and type of adverse drug reactions (ADR) experienced by this study population.METHODS We performed a retrospective cohort study of all patients treated for active TB at Christchurch Hospital, Christchurch, New Zealand, between 1 March 2012 and 31 December 2018. Data for 192 patients were collected on patient demographics, disease characteristics and treatment characteristics, including planned and actual duration of treatment and ADRs.RESULTS Of 192 patients, 35 (18.2%) had treatment extended, and 85 (46.5%) of 183 with fully drug-susceptible TB received ≥9 months treatment. The most common reasons for extension were persistent or extensive disease and ADR. Extended treatment duration was not associated with any patient or disease characteristics. We found 35 (18.2%) patients experienced at least one ADR. The most common ADRs were hepatitis, rash and peripheral neuropathy.CONCLUSION TB treatment extension beyond WHO guidelines is common. Further research is needed to guide management of those with slow response to treatment. Methods for early detection of ADR, systems to improve adherence and therapeutic drug monitoring are potentially useful strategies.

A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas.

Background: Soft tissue sarcomas (STSs) overexpress vascular endothelial growth factors (VEGF) and VEGF-receptors (VEGFR) activation have been associated with tumor aggressiveness. Tivozanib is a potent small molecule tyrosine kinase inhibitor against VEGFR1-3, with activity against PDGFRα/ß and cKIT. The primary endpoint of this study was progression free survival (PFS) rate at 16 weeks. Secondary end points were overall survival (OS), response rate, safety and correlative studies. Patients and methods: A Simon two-stage phase II trial was performed using tivozanib given orally at 1.5 mg daily, 3 week on 1 week off on a 28 day cycle until disease progression or intolerable toxicity. Results: Fifty-eight patients were enrolled and treated with tivozanib. Leiomyosarcoma was the most common STS histological type in our cohort (47%) and 27 patients (46%) had received at least 3 lines of therapy prior to study entry. Up to 24 patients (41%) had prior VEGF targeted therapies. Partial response and stable disease were observed in 2 (3.6%) and 30 (54.5%) patients. The 16 week PFS rate was 36.4% [95% confidence interval (CI) 23.7-49.1] and a median PFS of 3.5 months (95% CI 1.8-3). Median OS observed was 12.2 months (95% CI 8.1-16.8). The most frequent all grade toxicities were fatigue (48.3%), hypertension (43.1%), nausea (31%) and diarrhea (27.6%). The most common grade three toxicity was hypertension (22.4%). Correlative studies demonstrate no correlation between the expression of VEGFR 1, 2 or 3, PDGFRα/ß or FGF, and activity of tivozanib. Conclusion: Tivozanib was well tolerated and showed antitumor activity with a promising median PFS and PFS rate at 4 months in a heavily pretreated population of metastatic STSs. Our results support further studies to assess the clinical efficacy of tivozanib in STS. Clinical Trial Number: NCT01782313.

The complement receptor 3 (CD11b/CD18) agonist Leukadherin-1 suppresses human innate inflammatory signalling.

Complement receptor 3 (CR3, CD11b/CD18) is a multi-functional receptor expressed predominantly on myeloid and natural killer (NK) cells. The R77H variant of CD11b, encoded by the ITGAM rs1143679 polymorphism, is associated robustly with development of the autoimmune disease systemic lupus erythematosus (SLE) and impairs CR3 function, including its regulatory role on monocyte immune signalling. The role of CR3 in NK cell function is unknown. Leukadherin-1 is a specific small-molecule CR3 agonist that has shown therapeutic promise in animal models of vascular injury and inflammation. We show that Leukadherin-1 pretreatment reduces secretion of interferon (IFN)-γ, tumour necrosis factor (TNF) and macrophage inflammatory protein (MIP)-1ß by monokine-stimulated NK cells. It was associated with a reduction in phosphorylated signal transducer and activator of transcription (pSTAT)-5 following interleukin (IL)-12 + IL-15 stimulation (P < 0·02) and increased IL-10 secretion following IL-12 + IL-18 stimulation (P < 0·001). Leukadherin-1 pretreatment also reduces secretion of IL-1ß, IL-6 and TNF by Toll-like receptor (TLR)-2 and TLR-7/8-stimulated monocytes (P < 0·01 for all). The R77H variant did not affect NK cell response to Leukadherin-1 using ex-vivo cells from homozygous donors; nor did the variant influence CR3 expression by these cell types, in contrast to a recent report. These data extend our understanding of CR3 biology by demonstrating that activation potently modifies innate immune inflammatory signalling, including a previously undocumented role in NK cell function. We discuss the potential relevance of this to the pathogenesis of SLE. Leukadherin-1 appears to mediate its anti-inflammatory effect irrespective of the SLE-risk genotype of CR3, providing further evidence to support its evaluation of Leukadherin-1 as a potential therapeutic for autoimmune disease.

NON-CELIAC SPRUE: A CASE OF OLMESARTAN-INDUCED ENTEROPATHY.

Diarrhea, weight loss and villous atrophy is usually associated with the autoimmune disease celiac sprue, which is generally diagnosed by testing for tissue transglutaminase (tTG) or endomysial antibodies. In patients with negative serologies, however, other causes of villous atrophy must be investigated, including infection, irritable bowel disease, intestinal neoplasms and drug-induced enteropathy.

The heritability and genetics of complement C3 expression in UK SLE families.

As the central component of the complement system, C3 has sensory and effector functions bridging innate and adaptive immunity. It is plausible that common genetic variation at C3 determines either serum C3 level or susceptibility to systemic lupus erythematosus (SLE), but only a single, Japanese, study has currently showed genetic association. In a cohort of 1371 individuals from 393 UK white European SLE families, we quantified serum C3 and genotyped C3 tagSNPs. Using a Bayesian variance components model, we estimated 39.6% serum C3 heritability. Genotype/serum C3 association was determined by mixed linear models. Single nucleotide polymorphism (SNP) rs344555, located in a haplotype block incorporating the 3' end of C3, was associated with serum C3 (P=0.007), with weaker associations observed for other SNPs in this block. In an extended cohort of 585 SLE families the association between C3 variants and SLE was assessed by transmission disequilibrium test. SNP rs3745568 was associated with SLE (P=0.0046), but not with serum C3. Our disease associated SNP differs from that highlighted in the Japanese study; however, we replicate their finding that genetic variants at the 3' end of C3 are associated with serum C3. Larger studies and further fine mapping will be required to definitively identify functional variants.

The genetics of SLE: an update in the light of genome-wide association studies.

Understanding the pathogenesis of SLE remains a considerable challenge. Multiple abnormalities of both the innate and adaptive immune system have been described and, furthermore, immunological dysfunction precedes clinical presentation by many years. There is a strong genetic basis to SLE, which means that genetic studies can play a key role in furthering our understanding of this disease. Since susceptibility variants are present from birth and are unaffected by the course of the disease, or by its treatment, genetic analysis is, perhaps uniquely, capable of identifying fundamental, causative, disease mechanisms. Over the last 12 months, there has been a staggering increase in our understanding of SLE genetics. We have seen the identification of new and important SLE susceptibility genes through candidate gene studies, and we have seen the publication of two whole-genome association analyses. The 'hypothesis free' whole-genome studies have provided additional evidence in support of a number of existing susceptibility genes and have identified novel gene candidates. In this article, we review the current SLE genetics literature in the light of these recent advances and we discuss our current understanding of the functional role of the key susceptibility genes. By considering how these genes fall into clusters with shared function we can begin to understand how dysregulation at a number of key immunological steps may predispose to the development of SLE.

Quantification of the genetic component of basal C-reactive protein expression in SLE nuclear families.

C-reactive protein (CRP) is a heritable acute-phase plasma protein also expressed at low, basal, levels in healthy individuals. Elevated basal CRP has been associated with increased cardiovascular risk, while CRP dysregulation may be a feature of systemic lupus erythematosus (SLE). In this cohort of 496 Caucasian SLE families we estimated basal CRP heritability, h(2)= 27.7%. We typed a dense map of CRP single nucleotide polymorphisms (SNPs) and found that seven were associated with basal CRP using both a regression approach and an orthogonal family-based test (P = 0.001-0.011), as were haplotypes carrying the minor allele of these SNPs. SNPs in the interleukin-1beta and interleukin-6 genes were associated with basal CRP. No association was seen between CRP genotype and SLE. Using a variance components approach we estimated that the CRP genotype accounted for only 15% of the total genetic component of basal CRP variation, perhaps explaining the limited evidence of association between CRP and disease. Most of the genetic determinants of basal CRP variation therefore remain unknown. Multiple genes may be involved and identifying them will provide an insight into pathways regulating CRP expression, highlight potential cardiovascular disease and SLE candidates and improve the ability of basal CRP to predict cardiovascular risk.

Genetic determinants of basal C-reactive protein expression in Filipino systemic lupus erythematosus families.

Basal C-reactive protein (CRP) is a heritable trait associated with long-term cardiovascular disease risk. Existing studies leave ambiguity over the key functional polymorphisms and fail to adjust for trans-acting effects. In a novel cohort of 285 Filipino systemic lupus erythematosus probands and their first-degree relatives, we quantified serum CRP and typed a dense map of CRP single-nucleotide polymorphisms (SNPs), along with SNPs in the interleukin-1 beta, interleukin-6 and apolipoprotein E genes. Ten CRP SNPs demonstrated association with basal CRP in a regression model (P=0.011-0.002). These delineated two haplotypes associated with high and low basal CRP expression (P=0.002). Differences in allele frequency were seen compared with Caucasian populations, enabling us to argue for an independent genetic effect from a phylogenetically distinct haplotype tagged by SNP rs1800947. We demonstrated an association between Apo epsilon 2 and higher basal CRP. Interleukin-6 genotype was associated with basal CRP, highlighting a role for acute-phase cytokines even in basal expression. Identifying these trans-acting variants may improve the use of basal CRP as a predictor cardiovascular risk, and increase our power to detect associations between CRP and disease.

Association of LY9 in UK and Canadian SLE families.

Systemic lupus erythematosus (SLE) is a complex disease trait of unknown aetiology. Genome-wide linkage studies in human SLE identified several linkage regions, including one at 1q23, which contains multiple susceptibility genes, including the members of the signalling lymphocyte activation molecule (SLAM) locus. In mice there is a syntenic linkage region, Sle1. The SLAM genes are functionally related cell-surface receptors, which regulate signal transduction of cells in the immune system. Family-based association study in UK and Canadian SLE families identified variants in the promoter and coding region of SLAMF7 and LY9 contributing to SLE disease susceptibility. The strongest association was from rs509749, in exon 8 of LY9 (P=0.00209). rs509749 encodes a Val/Met nonsynonymous change in amino acid 602 in the cytoplasmic domain of LY9. In the parents and affected individuals from the Canadian SLE families, the risk allele of rs509049 skews the T-cell population by increasing the number of CD8+ memory T cells, while decreasing the proportion of CD4+ naïve T cells and activated T cells. Since rs509749 lies within the consensus binding site for SAP/SH2D1a, which influences downstream signalling events from LY9, the mechanism for increased CD8+ memory T cells may include differential binding SAP/SH2D1a to the cytoplasmic domain of LY9.

General aspects of the genetics of SLE.

The application of genetic techniques to the study of systemic lupus erythematosus (SLE) has identified candidate genes with diverse immunological function. There is a growing understanding that susceptibility to SLE is due to a complex interaction of multiple genes and environmental factors, and that many of these may be shared with other autoimmune diseases. In this first of a series of review articles we outline our current understanding of SLE genetics, in particular summarising the results of recent association studies.

The impact of a supplementary medication review and counselling service within the oncology outpatient setting.

The impact on the care of breast cancer patients, of a pharmacy technician-led medication review and counselling clinic, provided in an outpatient setting, was investigated using a controlled randomised study. Compared to the controls, clinic patients showed a significantly improved level of understanding of their chemotherapy support medication (95% CI for difference in mean knowledge rating scores=2.165-2.826, P<0.001) and a significant reduction in the median number of support items required (two compared to five in the control, P<0.001). This resulted in a significant reduction in mean medication expenditure per patient (26.70 vs 10.20 British Pound, 95% CI for the mean difference in cost 6.72 - 26.26 British Pound, P<0.001). The clinic was also associated with significant reductions in chemotherapy delays (P<0.001) and dose reductions due to side effects (P=0.003). Other benefits from the clinic were a reduction in pharmacy dispensing time and a highly significant reduction in pharmacy time spent resolving post-clinic prescription queries (P<0.001). Taking into account the initial technician training cost, the scheme represented an annual saving to the Trust of over 15,000 British Pound. The clinic serves as a model for those wishing to improve outpatient services to breast cancer patients.

The effect of double adhesive application on the shear bond strength to dentin of compomers using three one-bottle adhesive systems.

The development of one-bottle dentin adhesive systems resulted in much optimism about providing simplified predictable esthetic dentistry. However, laboratory testing of these systems continues to provide significant variations between facilities. A potential effect of the number of applications was noted in this author's laboratory. This study evaluated the effect of doubling the manufacturer's recommended number of applications on shear bond strength to dentin. Ninety human molars were divided into groups of 15. The occlusal surfaces were finished to 600 grit SiC to provide a flat dentin bonding surface. Prime & Bond NT-Dyract, Optibond Solo-Elan and One Step-Dyract were evaluated. Each material was tested using: (1) the recommended number of adhesive applications and (2) twice the number of applications recommended. All adhesive applications were accomplished before light curing the adhesive. The specimens were thermocycled after one week of storage and tested in shear after two weeks. Specimens were also fabricated after adding Rhodamine D to the adhesive to allow for visualization using confocal microscopy. These teeth were sectioned and viewed 24 hours after fabrication. A t-test was used to compare differences within product groups. The results showed a significant effect (p < 0.001) when a double application of Prime & Bond NT was used. No difference was seen with Optibond Solo or One Step. All specimens appeared to have a uniform, glossy appearance of adhesive during fabrication. Therefore, the appearance of the adhesive after application may not be a reliable predictor of acceptable bonding. Confocal microscopy showed that single application Prime & Bond NT specimens did not exhibit a uniform thickness of adhesive across the entire interface. Tubule penetration and hybridization was apparent for all specimens.

Changing patterns of sedation use for routine out-patient diagnostic gastroscopy between 1989 and 1998.

BACKGROUND: Knowledge of sedation trends for upper gastrointestinal endoscopy is important for health service planning, particularly in view of rapidly increasing demands on endoscopy services. However, no data are available on sedation trends in Britain over the past 10 years. AIM: To determine sedation use for routine gastroscopy in a single endoscopy unit between 1989 and 1998. METHODS: This was a retrospective study of 9795 consecutive adults (mean age 56 years, range 18-100 years; 4512 females) who had undergone a gastroscopy between 1989 and 1998. Clinical, pharmacological and endoscopic data were retrieved from a computerized database. RESULTS: Over the 10-year study period, the sedation rate remained constant for patients undergoing therapeutic endoscopy (P=0.99) and those undergoing in-patient diagnostic examinations (P=0.63). In contrast, the sedation rate for out-patient diagnostic endoscopy decreased by 54%, from a high of 70% in 1990 to 32% in 1998 (P < 0.0001). Logistic regression analysis showed that the decline in sedation use was greater in females (P < 0.0001) than males and in procedures performed by non-consultant compared to consultant staff (P=0.01). CONCLUSIONS: If our results form part of a national trend, they will have important implications for cardiopulmonary monitoring strategies, recovery room practices and for complication rates due to the use of sedation for upper gastrointestinal endoscopy.

Microleakage of high-strength glass ionomer: resin composite restorations in minimally invasive treatment.

Atraumatic Restorative Treatment (ART) has been investigated as an alternative caries treatment. The technique involves removal of loose tooth structure with a spoon excavator, followed by placement of an adhesive restorative material, often a high-strength glass ionomer. This study compares the microleakage of a high-strength glass ionomer/resin composite and two occlusal resin composite restoration techniques.

Effect of atrazine on implantation and early pregnancy in 4 strains of rats.

Atrazine (ATR) is an herbicide that has been shown to have adverse reproductive effects including alterations in levels of pituitary hormones such as prolactin (prl) and luteinizing hormone (LH) in female LE rats when administered at doses of 200 mg/kg/day for 1 and 3 days. Because the action of prl in promotion of progesterone secretion is essential for the initiation of pregnancy in rats, this study was designed to examine the effect of exposure to ATR during early pregnancy on implantation and short-term pregnancy maintenance. Rats were divided into two groups representing periods of dosing with ATR prior to the diurnal or nocturnal surges of prl. Within each group, four groups consisting of four strains of rats [Holtzman (HLZ); Sprague Dawley (SD); Long Evans (LE); Fischer 344 (F344)] were each further subdivided into four ATR dosages. Rats were dosed by gavage with 0, 50, 100, or 200 mg/kg/day ATR on days 1-8 of pregnancy (day 0 = sperm +). All animals were necropsied on day 8 or 9 of pregnancy. The 200 mg/kg dose of ATR reduced body weight gain in all but one group. Two groups of animals dosed at 100 and 200 mg/kg/day in the nocturnal dosing period showed an increase in percent preimplantation loss, and both of these were F344 rats. HLZ rats were the only strain to show a significant level of postimplantation loss and a decrease in serum progesterone at 200 mg/kg/day both following diurnal and nocturnal dosing. Doses of 100 mg/kg/day also produced postimplantation loss following diurnal and nocturnal dosing, but progesterone levels were decreased only after nocturnal dosing. Alterations in serum LH were seen in several groups. Serum estradiol was significantly increased only in SD rats dosed at the diurnal interval with 200 mg/kg ATR. We conclude that F344 rats are most susceptible to preimplantation effects of ATR and that HLZ rats appear most sensitive to the postimplantation effects of the chemical. LE and SD rats were least sensitive to effects of ATR during very early pregnancy.

Neutrophil-specific 99mTc-labeled anti-CD15 monoclonal antibody imaging for diagnosis of equivocal appendicitis.

UNLABELLED: We evaluated 99mTc-labeled anti-CD15 immunoglobulin M monoclonal antibody (LeuTech) for diagnosing acute appendicitis in patients with an equivocal clinical presentation. LeuTech avidly binds to circulating and sequestered human polymorphonuclear neutrophils in vivo, eliminating in vitro cell labeling and blood handling. METHODS: We studied 49 patients to evaluate the safety and efficacy of LeuTech imaging. 99mTc-labeled LeuTech was prepared on site using a lyophilized kit, 99mTc-labeled pertechnetate, and 2 different incubation techniques, 1 at room temperature and the other at 37 degrees C. The abdomen was serially imaged for up to 3 h after the intravenous administration of 370-740 MBq 99mTc-labeled LeuTech. Scans were read as positive or negative for acute appendicitis or other intraabdominal infection. The institutional diagnosis was established by surgery, other diagnostic studies, or 1-mo clinical follow-up. RESULTS: Scans were positive for appendicitis in all 26 patients with appendicitis, for a sensitivity of 100%, and negative for appendicitis in 19 of 23 patients without appendicitis, for a specificity of 83%. Accuracy, positive predictive value, and negative predictive value were 92%, 87%, and 100%, respectively. Results were not different between the LeuTech preparations. The rate of laparotomies with negative findings in patients who underwent surgery was 10%. The average time from injection to LeuTech visualization in the appendix for cases positive for appendicitis was 9 min. No serious adverse reactions occurred. CONCLUSION: LeuTech imaging is safe, rapid, and sensitive for diagnosis of appendicitis in equivocal cases. The potential advantages of LeuTech over currently available radiopharmaceuticals for infection imaging are ease of preparation, absence of blood handling, excellent image quality, no requirement for SPECT, and rapid diagnostic uptake.

Retentive strength of an amalgam bonding agent: chemical vs light vs dual curing.

Dentin bonding agents have been shown to enhance retention of amalgam restorations by mechanical means. Little research is available on which mode of curing may optimize amalgam bonding. This in vitro study compared the bond strengths exhibited by three variations of a bonding agent, each using a different curing mode, with two earlier versions of amalgam resin liners and cavity varnish. The six test groups of lining agents for amalgam restorations included [C] chemical-cured, [L] light-cured and [D] dual-cured versions of one filled adhesive resin (Clearfil Liner Bond 2V), [LF] Light-cured, Filled resin (Clearfil Liner Bond 2, Kuraray Co.); [LCF] Light- and Chemical-cured, Filled resin Clearfil Liner Bond + Protect Liner, Kuraray Co) and [V] Varnish (Copalite, Cooley & Cooley, Ltd). For each group, 20 Class V cavity preparations were cut in human molars. The preparations were 2.5 mm deep and 3 mm wide at the pulpal floor, with a slightly divergent taper. After treating the preparation with the bonding agent, a 3/4 inch, 18 gauge flat-headed wire nail was seated in the cavity with its head at the pulpal floor of the preparation, and Tytin amalgam (Kerr Corp, Romulus, MI) was condensed into the preparation around the nail. All restorations were stored for 24 hours in distilled water at 37 degrees C, then subjected to 2500 thermal cycles (8 degrees C to 58 degrees C). After one week the samples were tested to failure in tension using an Instron Universal Testing Machine (crosshead speed = 2 mm/min) and peak load (kg) was recorded. Significant differences in retention were found using ANOVA and the Games & Howell post hoc test (p = 0.05). The mean loads at failure (+/- SD) were C 13.1 (+/- 2.4), L 21.8 (+/- 6.1), D 26.8 (+/- 7.4), LCF 23.8 (+/- 7.4), LF 21.4 (+/- 3.3) and V 2.0 (+/- 1.8). All dentin-bonding agents exhibited significantly greater retention than the varnish. While the bond strengths of the dual cured (D) and the light-cured (L) liners were not significantly different from one another, both were significantly higher than the chemically-cured (C) resin liner in terms of retention.

Investigation of an adhesive system used with direct and indirect applications.

A laboratory investigation was performed that examined the adhesive properties of a new adhesive system. Contrasts were made with other commercially established systems, and indirect and direct bonding procedures were investigated. For the indirect evaluation, simulated restorations were bonded with an experimental resin cement. Sealing was assessed through microleakage analysis. Adhesive strength value was measured by shear bond strength methods. Further, the marginal quality of the restorations was assessed using scanning electron microscopy. Finally, the adhesive shear bond strengths were established using direct bonding.