Adherence to tyrosine kinase inhibitors among adult chronic myeloid leukemia patients in a Malaysia hospital.

Background Tyrosine kinase inhibitors have been demonstrated to improve the survival of patients with chronic myeloid leukaemia. However, medication adherence is vital for patients on chronic treatment. Objective The objective of the current study was to evaluate response to treatment, adherence by patients to tyrosine kinase inhibitors and factors associated with adherence and response. Setting A haematology clinic in a regional referral hospital in Malaysia. Method Patients aged ≥ 13 years who had been on imatinib or nilotinib for ≥ 12 months were included in this cross-sectional study. An optimal response was defined as the achievement of major molecular response at 12 months of treatment. Patient medication adherence was determined using the average medication possession ratio based on the dispensing records. The patients were considered adherent if the medication possession ratio was > 90%. Multiple logistic regression was performed to evaluate the factors associated with adherence. The association of adherence with molecular response was analysed by univariate logistic regression. Main outcome measure The primary outcome measures were the proportion of patients who achieved optimal response and the medication possession ratio. Results A total of 151 patients were screened, and 71 patients were included. Twenty-eight patients (39%) achieved major molecular response at 12 months of treatment. The median time to achieve this was 15.5 months (an interquartile range of 15). The mean medication possession ratio for imatinib and nilotinib was 0.94 (± 0.14) and 0.96 (± 0.10), respectively, but this difference was without statistical significance (t  =  - 0.517, p  =  0.610). Nausea and vomiting (odds ratio [OR] of 0.25, 95% confidence interval [CI]: 0.07-0.83, p  =  0.023) and disease phase at diagnosis (OR of 0.20, 95% CI 0.04-1.06, p  =  0.059) were associated with patient adherence. An association was not found between patient adherence and molecular response (OR of 1.03, 95% CI 0.35-3.09, p  =  0.956). Conclusion The patients in this study demonstrated a relatively deep molecular response and optimal adherence. Nevertheless, one fourth of them were noncompliant with imatinib. Therefore, active interventions are warranted to prevent treatment-associated adverse events and improve adherence.

Platelet indices as biomarkers for characterization and determination of severity in canine chronic enteropathy.

Human studies have shown an association between certain platelet indices and active inflammatory bowel disease when compared to healthy controls. The objectives of this retrospective study were to determine if any platelet indices differ between dogs with chronic enteropathies and healthy age- and sex-matched control dogs and are predictive of the severity of chronic enteropathy based on canine chronic enteropathy clinical activity index (CCECAI) scores. Medical records for 22 chronic enteropathy-positive dogs and 22 healthy control dogs were reviewed for historical and physical examination findings, platelet indices, and histologic diagnoses of chronic enteropathy. Platelet indices were compared between the groups, and an association between platelet indices and CCECAI scores in dogs with chronic enteropathy was investigated. Chronic diarrhea and weight loss were common clinical signs associated with chronic enteropathy. Lymphoplasmacytic enteritis was the most common histologic diagnosis. Only one platelet index, platelet component distribution width (P = 0.045), was found to be significantly different between the groups. For predicting severity of disease, determined by CCECAI score, statistically significant differences in indices associated with higher scores were platelet count (P = 0.024) and platelet dry mass distribution width (P = 0.036). Only platelet component distribution width showed potential in characterizing dogs with chronic enteropathy compared to normal dogs. Elevated platelet count and decreased platelet dry mass distribution width had a significant effect on total CCECAI scores. These findings suggest further investigation into the utility of platelet indices as predictors of disease presence and severity in dogs with chronic enteropathy is warranted.

Plasma N-terminal pro-brain natriuretic peptide concentrations before and after pericardiocentesis in dogs with cardiac tamponade secondary to spontaneous pericardial effusion.

OBJECTIVE: To determine if concentrations of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) are increased in dogs with cardiac tamponade and if there is a significant increase in plasma NT-proBNP after pericardiocentesis. ANIMALS: Ten client-owned dogs with spontaneous cardiac tamponade. METHODS: Prospective clinical study. Cardiac tamponade was suspected from physical examination and confirmed with echocardiography. Blood was collected and plasma NT-proBNP concentrations were measured before and 30-60 min following pericardiocentesis and resolution of cardiac tamponade. Within-subject changes in plasma NT-proBNP were compared by the Wilcoxon signed-rank test. RESULTS: The plasma NT-proBNP concentrations measured within the reference interval in seven of 10 dogs before pericardiocentesis and in six of 10 dogs following pericardiocentesis. Following pericardiocentesis, there was a statistically significant increase in median NT-proBNP concentration (733 pmol/L, range 250-3,297) compared with the values measured before (643 pmol/L, range 250-3,210, P = 0.004). The NT-proBNP concentration increased in 90% of the dogs following pericardiocentesis. CONCLUSIONS: An upper reference limit of 900 pmol/L for plasma NT-proBNP is insensitive for the diagnosis of pericardial effusion and cardiac tamponade in dogs. Plasma NT-proBNP concentration commonly increases following pericardiocentesis, perhaps related to improved ventricular filling and stretch.

Cardiac and Metabolic Variables in Obese Dogs.

BACKGROUND: The etiology of obesity-related cardiac dysfunction (ORCD) is linked to metabolic syndrome in people. Studies have indicated that obese dogs have components of metabolic syndrome, warranting evaluation for ORCD in obese dogs. OBJECTIVES: To evaluate cardiac structure and function and metabolic variables in obese dogs compared to ideal weight dogs. ANIMALS: Forty-six healthy, small-breed (<25 pounds), obese dogs (n = 29) compared to ideal weight dogs (n = 17). METHODS: A cross-sectional study of cardiac structure and function by standard and strain echocardiographic measurements and quantification of serum metabolic variables (insulin:glucose ratios, lipid analysis, adiponectin, inflammatory markers). RESULTS: Compared to the ideal weight controls, obese dogs had cardiac changes characterized by an increased interventricular septal width in diastole to left ventricular internal dimension in diastole ratio, decreased ratios of peak early to peak late left ventricular inflow velocities, and ratios of peak early to peak late mitral annular tissue velocities, and increased fractional shortening and ejection fraction percentages. The left ventricular posterior wall width in diastole to left ventricular internal dimension in diastole ratios were not significantly different between groups. Systolic blood pressure was not significantly different between groups. Obese dogs had metabolic derangements characterized by increased insulin:glucose ratios, dyslipidemias with increased cholesterol, triglyceride, and high-density lipoprotein concentrations, decreased adiponectin concentrations, and increased concentrations of interleukin 8 and keratinocyte-derived chemokine-like inflammatory cytokines. CONCLUSIONS AND CLINICAL IMPORTANCE: Compared to ideal weight controls, obese dogs have alterations in cardiac structure and function as well as insulin resistance, dyslipidemia, hypoadiponectinemia, and increased concentrations of inflammatory markers. These findings warrant additional studies to investigate inflammation, dyslipidemia, and possibly systemic hypertension as potential contributing factors for altered cardiac function.

Establishment of reference ranges and evaluation of in vitro concentration-dependent platelet inhibition by acetylsalicylic acid for multiple electrode impedance aggregometry in healthy dogs.

Acetylsalicylic acid (ASA, aspirin) is an antiplatelet medication used for prevention of thromboembolism. Effects of ASA appear to vary widely between dogs, but the underlying mechanisms are not understood. The Multiplate analyzer is a newer form of whole-blood impedance aggregometry recently validated for use in healthy dogs. A method utilizing this instrument to measure ASA effects on platelet function has not been established. The goals of this study were to establish reference ranges for the Multiplate in healthy dogs and secondly, to develop a technique to determine the in vitro concentration of ASA needed to cause 50% inhibition of platelet aggregation (IC50). Reference ranges established from 40 dogs at multiple test times for three agonists were consistent with previously published values. In vitro IC50 values were calculated using the sigmoid Emax model in 20 healthy dogs on two occasions to determine individual repeatability. Calculated in vitro IC50 demonstrated four ASA response groups: responder (n = 16), poor responder (n = 1), variable responder (n = 2), and nonresponder (n = 1). Multiplate within-assay variability was  <10% for area under the curve (AUC), and between-assay baseline AUC variability was  <15%. The described technique allowed for determination of an in vitro IC50 for ASA in dogs using a multiple electrode impedance aggregometer.

Reduced prostate cancer risk with green tea and epigallocatechin 3-gallate intake among Hong Kong Chinese men.

BACKGROUND: In vitro and in vivo studies suggested that polyphenol epigallocatechin 3-gallate (EGCG) in tea may have anti-carcinogenic effect on prostate cells, but this protective effect has less been examined in epidemiology studies. We aimed to investigate the association between prostate cancer (PCA) risk and habitual green tea intake among Chinese men in Hong Kong; meanwhile, the relationship with EGCG was also explored. METHODS: We consecutively recruited 404 PCA cases and 395 controls from the same hospital who had complete data on habitual tea consumption, including green, oolong, black and pu'er tea. We reconstructed the level of EGCG intake according to a standard questionnaire and the analytic values for EGCG extracted from the literature published by Lin et al. in 2003. We calculated odds ratios (ORs) for tea consumption and EGCG intake using unconditional multiple logistic regression, and examined their exposure--response relationships with PCA risk. RESULTS: A total of 32 cases and 50 controls reported habitual green tea drinking, showing an adjusted OR of 0.60 (95% confidence interval (CI): 0.37, 0.98). A moderate excess risk was observed among the habitual pu'er tea drinkers (OR=1.44, 95% CI: 1.02, 1.91). A significantly lower intake of EGCG was observed among cases (54.4 mg) than the controls (72.5 mg), which resulted in an inverse gradient of PCA risk with the increasing intake of EGCG (test for trend, P=0.015). CONCLUSION: PCA risk among Chinese men in Hong Kong was inversely associated with green tea consumption and EGCG intake, but these results need to be replicated in larger studies.

Risk factors associated with human immunodeficiency virus (HIV) infection among attendees of public sexually transmitted infection clinics in Hong Kong: implications for HIV prevention.

OBJECTIVE: To examine the risk factors for human immunodeficiency virus (HIV) transmission among attendees of public sexually transmitted infection clinics in Hong Kong. DESIGN: Retrospective matched case-control study. SETTING: All public sexually transmitted infection clinics in Hong Kong. PATIENTS: All public sexually transmitted infection clinic attendees' records from January 1995 to December 2002 were reviewed. MAIN OUTCOME MEASURES: HIV sero-positivity in corresponding clinic attendees. RESULTS: A total of 196 HIV-positive cases among 149,336 sexually transmitted infection clinic attendees were recruited into the study. Multivariate analysis using conditional logistic regression revealed that HIV infection was associated with the following factors: belonging to non-Chinese ethnic groups (mainly South-East Asian) [odds ratio=9.32; 95% confidence interval, 3.27-26.55], coexisting syphilis (other than primary) [5.67; 1.66-19.36], current non-gonococcal urethritis (2.10; 1.08-4.07), current genital warts (1.94; 1.10-3.43), history of prior sexually transmitted infection (2.19; 1.29-3.72), having casual sex with friends (2.89; 1.07-7.80), and casual sex in Mainland China (1.91; 1.04-3.49). Sexual orientation was also considered to be a potential risk factor, as only those who tested positive reported to be homosexual or bisexual. CONCLUSION: Sexually transmitted disease patients represent an identifiable group who are at high risk of HIV infection. This study found that there were certain factors which increased the risk of HIV infection among patients attending public sexually transmitted infection clinics. Targeted interventions should therefore be offered to such high-risk individuals, so as to prevent and control HIV transmission.

Universal antenatal human immunodeficiency virus (HIV) testing programme is cost-effective despite a low HIV prevalence in Hong Kong.

OBJECTIVE: To evaluate the cost-effectiveness of universal antenatal human immunodeficiency virus (HIV) testing in Hong Kong. DESIGN: Cost-effectiveness analysis from the health care provider's perspective. SETTING: Public antenatal clinics in Hong Kong. PARTICIPANTS: All pregnant women who gave birth in Hong Kong during the inclusive period 1 September 2001 and 31 December 2004. MAIN OUTCOME MEASURES: The primary endpoints were (i) the cost per HIV infection avoided and (ii) the cost per life-year gained. RESULTS: From 2001 to 2004, a total of 160,878 deliveries were recorded in Hong Kong; and 75% of the corresponding women had HIV testing before delivery. In all, 28 women tested HIV-positive and gave birth to 15 babies, one of which was HIV-positive. The mother of the infected baby presented late in labour, without her HIV status being diagnosed and thus missed the opportunity for prompt intervention. Assuming a natural transmission rate of 25%, it was estimated that six out of seven anticipated HIV infections among the newborns had been avoided. The cost for implementation of the programme for the first 3 years was HKD12 227 988. Hence, the average costs per HIV infection averted and per discounted life-year gained were HKD2 037 998 and HKD79 099, respectively. Sensitivity analysis showed that both the coverage and the loss-to-follow-up rate were the major determinants of the cost-effectiveness of the universal antenatal testing programme in Hong Kong. CONCLUSION: The universal antenatal testing programme in Hong Kong is largely efficient. In view of the low prevalence of HIV infection, high rates of HIV testing and uptake of antiretroviral prophylaxis are crucial to the success of the programme.

In vivo assessment of hydroxyapatite and silicate-substituted hydroxyapatite granules using an ovine defect model.

Phase pure hydroxyapatite (HA) and two silicate-substituted hydroxyapatites (0.8 and 1.5 wt% Si, or 2.6 and 4.9 wt% SiO4) were prepared by aqueous precipitation methods. The filter-cakes of HA and silicate-substituted hydroxyapatite (SiHA) compositions were processed into granules 1.0-2.0 mm in diameter and sintered at 1200 degrees C for 2 h. The sintered granules underwent full structural characterisation, prior to assessment in an ovine defect model by implantation for a period of 6 and 12 weeks. The results indicate that HA and SiHA implants were well accepted by the host tissue, with no evidence of inflammation. New bone formation was observed directly on the surfaces and in the spaces between the granular implants. Quantitative histomorphometry as determined by the percentage of bone ingrowth and bone coverage for both SiHA implant compositions was significantly greater than that for phase pure HA. These findings indicate that the in vivo bioactivity of hydroxyapatite was significantly improved by the incorporation of silicate ions into the HA structure, making SiHA ceramics attractive alternatives to conventional HA materials for use as bone graft substitute ceramics.

Immobilization of aminoacylase in polyethyleneimine stabilized calcium alginate beads for L-phenylalanine production.

Aminoacylase I (E.C.3.5.1.14) was immobilized by entrapment in calcium alginate beads coated with polyethyleneimine for the production of L-phenylalanine by the hydrolysis of a racemic mixture of N-acetyl-DL-phenylalanine. The operational stability in terms of batch operation and continuous reaction in packed-bed bioreactor were studied. Kinetic constants, Km and Vmax values of free and immobilized enzymes were studied. Polyethyleneimine treatment was found to enhance the operational stability of the enzyme though its activity was substantially reduced. When polyethyleneimine-coated calcium alginate beads were packed into packed bed bioreactor, it was stable for at least 25 days under continuous operation without appreciable loss of activity.

Covalent immobilization of aminoacylase to alginate for L-phenylalanine production.

Aminoacylase I (EC. 3.5.1.14) was immobilized by covalent crosslinking to alginate molecules with 1-ethyl-3-(3-dimethyl-aminopropyl)-carbodiimide HCl followed by calcium alginate bead formation for the production of L-phenylalanine from the racemic mixtures of N-acetyl-DL-phenylalanine. Different concentrations of the coupling reagent were tested and the coupling process was optimized. The immobilized and the partially purified aminoacylase were characterized in terms of the activity, operational stability, thermal stability, pH and temperature optima and kinetic constants, Km and Vmax. The activity of the enzyme covalently immobilized in calcium alginate beads was enhanced by about 75% compared to that of free enzyme. The beads showed stable activity under operational conditions, they lost about 40% of their activity after four reaction cycles. The immobilized aminoacylase was more stable over a broader pH range. Thus this simple method provides irreversible immobilization of aminoacylase to give a biocatalyst with good operational stability and enhanced activity.

Immobilization of aminoacylase by encapsulation in poly-L-lysine-stabilized calcium alginate beads.

Aminoacylase I (EC 3.5.1.14) encapsulated in calcium alginate beads stabilized with poly-L-lysine was used for the production of L-phenylalanine by the hydrolysis of a racemic mixture of N-acetyl-DL-phenylalanine. The immobilized aminoacylase was studied with respect to operational stability, thermal stability, effects of pH and temperature and kinetic constants. The leakage of enzyme from the stabilized beads was eliminated. The immobilized enzyme retained high biological activity. The Km and Vmax values for the stabilized beads were 11.11 mmol dm-3 and 0.076 mumol min-1 respectively. The optimum pH and temperature for the hydrolysis were 6.5 and 55 degrees C respectively. Scanning electron micrographs revealed crosslinked structures on the surface of the beads. The operational performances of the beads in a batch reaction and a packed-bed bioreactor for continuous reaction were investigated. With batch reaction, only about 5% of enzyme activity was lost within ten reaction cycles and there was no significant loss of activity over 600 h of continuous operation after equilibrium was reached, and a conversion yield of about 80% was obtained.

Competitive binding of gangliosides and glycophorin to wheat germ agglutinin.

Gangliosides and glycophorin are receptors for wheat germ agglutinin. The competitive binding of these molecules to wheat germ agglutinin is studied by electron spin resonance spectroscopy with spin labels attached to the oligosaccharide chains of gangliosides. Evidence shows that glycophorin is more accessible to wheat germ agglutinin binding than gangliosides. The interactions of gangliosides and glycophorin in liposomes is disrupted on low level binding of WGA.

Correlation of rotational mobility and flexibility of Sendai virus spike glycoproteins with fusion activity.

The rotational mobility of Sendai virus glycoprotein spikes was measured by flash-induced transient dichroism of eosin triplet probes. The possible importance of this molecular motion for function was investigated by parallel assays of hemagglutination and fusion with erythrocytes. For mobility measurements, the glycoproteins were labeled on amino groups with eosin-5-isothiocyanate and on the galactose residues of the oligosaccharide chains with eosin-5-thiosemicarbazide. The decay of the absorption anisotropy of both probes, which has a time constant of about 100-200 musec at 37 degrees is attributed to the rotation of the proteins about an axis normal to the plane of the membrane. This motion was inhibited by crosslinking of the spike proteins with glutaraldehyde or by the specific binding of human erythrocyte glycophorin (a virus receptor) to the HN glycoprotein. Low values of the initial anisotropy for both probes indicate the existence of a second, faster motion. This is attributed to segmental motion of the glycoproteins. Segmental motion is inhibited by crosslinking with glutaraldehyde but appears to be little affected by interaction with glycophorin. The temperature dependence of the segmental and rotational motion of the proteins revealed a pronounced increase in mobility in the range of 30-35 degrees which was not paralleled by the lipid motion of the Sendai virus envelope membrane. Since the temperature dependence of virus-induced hemolysis has a similar characteristic, the mobility of glycoproteins appears to be correlated with the fusion activity. The hemagglutination activity, however, is not dependent on the mobility of the glycoprotein spikes.

Headgroup oligosaccharide dynamics of a transmembrane glycoprotein.

Glycophorin, a major integral membrane glycoprotein of the human erythrocyte, has been spin labelled on oligosaccharide chains. Electron paramagnetic resonance studies of this glycoprotein in systems of controlled complexity have provided a degree of insight into its headgroup behaviour. (i) When glycophorin is free in solution its oligosaccharide chains exhibit uniformly high freedom of motion. This motional freedom is not attributable to the presence of N-acetyl-neuraminic acid residues. (ii) No evidence has been found of a finite tendency for headgroup sugars to associate with hydrophobic regions of phospholipid or glycoprotein. (iii) Headgroup oligosaccharide dynamics are essentially independent of the state of and interactions of the polypeptide hydrophobic portion (that portion which traverses the membrane). (iv) Nonspecific interaction with proteins and polysaccharides can readily reduce oligosaccharide chain mobility by some 25%, but does not alter their basic behaviour. (v) Binding of wheat germ agglutinin, dramatically immobilizes (terminal) N-acetylneuraminic acid residues. (vi) The above observations hold over the temperature range 0-40 degrees C. (vii) Headgroup carbohydrate mobility is at a minimum in the region of headgroup neutrality (pH 2.6-3.5) and is pH invariant over several pH units in the physiological range.

Ganglioside headgroup dynamics.

Gangliosides, spin-labelled specifically on N-acetylneuraminic acid residues or on random-headgroup sugars, have been used to extend previous studies of headgroup behaviour. Headgroup sugar mobility is seen to be homogeneous and relatively unrestricted in a range of systems including three lines of cultured cells. The effects of temperature and pH have been considered. Binding of small quantities of the lectin, wheat germ agglutinin, was found to increase average headgroup mobility for gangliosides in lipid bilayers, most likely as a result of a disordering effect on ganglioside clusters.

Response of rat lung to tobacco smoke condensate or fractions derived from it administered repeatedly by intratracheal instillation.

The repeated intratracheal instillation of cigarette smoke condensate (SWS) in rats at close to maximum tolerated dose levels failed to induce squamous neoplasms in the lungs although such treatment was associated with an increased incidence of cuboidal/columnar metaplasia (CCM) and squamous metaplasia (Sq.M) of alveolar epithelium. With one exception, various fractions of SWS had no effect on lung tumour incidence though some were more effective than SWS in increasing the incidence of CCM and Sq.M. The exceptional fraction, Fraction P, which contains most of the polycyclic aromatic hydrocarbons of smoke and is the most effective of the fractions tested in producing tumours in mouse skin, gave rise to 4 squamous tumours of doubtful malignancy and one metastasizing squanmous carcinoma among 3 groups of 18 animals exposed at 3 different dose levels. The results are discussed in relation to the possible development of a method for comparing condensates for relative lung carcinogenicity.